BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention is a novel crystal form of 17p-hydroxy-7a- (5'-methyl-2'-furyl)- pregna-4,9 (11)-dien-3-one-21-carboxylic acid, y-lactone.

The present invention includes a process for the transformation of a 3-enol ether 3'5- steroid to the corresponding A4, 6-3-ketal steroid (I-P).

The present invention includes a process for the transformation of a A46-3-keto steroid or ketal thereof (I), to the corresponding A4-3-ketosteroid-7a-carboxylic acid (VI).

The present invention also includes a novel processes and novel intermediates to produce the pharmaceutically useful compound eplerenone.

Further, the invention includes processes for transformation of 1 la-hydroxy-17- lactone (CI) or 1 la-hydroxy steroids (CIV) to the corresponding #9(11)-17-lactone(CII) or A9 (")-steroids (CV) using a N-fluoroalkylamine reagents (CVI).

2. Description of the Related Art There is no reliable method to predict the existence of a crystal form of a pharmaceutical. Further, if a material is crystalline there is no reliable method to predict its physical properties. Therefore, patents to novel crystal forms are well known. For example, US Patent 3,565, 924 discloses and claims 25-hydroxycocalciferol (25-HCC) which is a non- crysalline solid. Later a novel crystal form, 25-HCC hemihydrate was patented, see US Patent 3,833, 622. US Patent 4,521, 431 discloses crystal forms 1 and 2 of ranitidine hydrochloride.

US Patent 4,504, 657 claims"crystalline 7- [D-. alpha.- (p-hydroxyphenyl) acetamido] -3-methyl- 3-cephem-4-carboxylic acid monohydrate. US Patent 6,452, 007 Bl claims the"S"and"T" crystal forms of 1- [5-methanesulfonamidoindolyl-2-carbonyl] 4- [3- (1-methylethylamino)-2- pyridinyl] piperazine. US Patent 6,444, 813 B2 claims a novel crystal form of a known antibacterial agent, linezolid.

International Publications WO01/41535 and WO01/42272 disclose crystal forms of pharmaceutical agent eplerenone.

SUMMARY OF INVENTION Disclosed is a process for the preparation of a #4,6-ketal of formula (I-P) where R31 and R32 are (1) the same or different and are Cl-C3 alkyl, and (2) taken with the attached-O-C-O to form a cyclic ketal of 5 or 6 atoms of the formula - (CH2)- (CR33R34) nl- (CH2)- where ni is 0 or 1 ; where R33 and R34 are the same or different and are -H, Cl-C3 alkyl, which comprises (1) contacting a #3,5-3-enol ether of formula (ALkyl enol ether) (Alkyl enol ether) where R3 is Cl-C3 alkyl, <BR> <BR> <BR> <BR> CH3-CO-,<BR> <BR> <BR> <BR> <BR> #-CO- or RSi-1RSi-2RSi-3Si- where RSi-1, RSi-2 and RSi-3 are the same or different and are Cl-C4 alkyl ; with a hydride abstractor and an alcohol selected from the group consisting of alcohols of the formula: (a) R31-OH, where R31 is as defined above,

(b) R32-OH, where R32 is as defined above, (c) HO-(CH2)-(CR33R34)N1-(CH2)-OH where ni, R33 and R34 are as defined above, (d) HO-CH2-CH2-OH.

Also disclosed is a 7a-substituted steroid of formula (IT) where (1) R3 is = 0 ; R4 is R4-1 : R4-2 where one of R4-1 and R4-2 is -H and the other of R4-1 and R4-2 is taken together with Rs to form a second bond between the carbon atoms to which they are attached; R6 is-H:-H ; (II) R3 is R3-3 : R3-4 and R4 is R4-3:R4-4 where one of s and R3-4 is -O-R31 where R31 is Cl-C3 alkyl, the other of R3-3 and R3 is taken together with one ofR4-3 and R4-4 to form a second bond between the carbon atoms to which they are attached, and the other of 3 and R is-H ; R6 is R6-3 : 6-4 where one of R6-3 and R6-4 is taken together with Rs to form a second bond between the carbon atoms to which they are attached and the other of R63 and R6-4 is-H; (III) R3 is α-R3-5 : P-R3-6 where 3-5 is -O-R31 and R3-6 is -O-R32 where R31 and R32 are the same or different and are selected from the group consisting of Cl-C3 alkyl and R31 and R32 are taken with the attached -O-C-O- to form a cyclic ketal of 5 or 6 atoms of the formula -(CH2)-(CR33R34)n1-(CH2)- where nl is 0 or 1 ; where R33 and R34 are the same or different and are-H and Cl-C3 alkyl ; R4 is -H : -H; R6 is R6 s : R6-6 where one of R6-5 and R6-6 is taken together with Rs to form a second bond between the carbon atoms to which they are attached and the other of R6-5 and R6. 6 is -H ;

(IV) R3 is a-R37 : ß-R3-8 where R3-7 is -O-R31 and R3-8 is -O-R32 where R31 and R32 are as defined above; R4 is R4-7 : R4-8 where one of 7 and R4 8 is taken together with R5 to form a second bond between the carbon atoms to which they are attached and the other of R4-7 and R4-8 is-H; R6 is-H : -H; where R7-1 is a molecular fragment of the formula (-A1) or of the formula (-A2) where Xi is: -S-, -O- or -NH1-1- and where X1-1 is: -H, Cl-C4 alkyl, -CO-OX1-2 where X1-2 is C1-C4 alkyl or -CH2-#, -CO-X1-2 where X1-2 is as defined above, -CO-# where -# is substituted in the o-position with -CO-O-(C1-C4 alkyl), -S02- (CI-C3 alkyl), -SO2-# where (p is optionally substituted with 1 or 2 Cl-C4 alkyl, C1-C4 alkoxy ; where Rb is selected from the group consisting of -H, Cl-C4 alkyl or

phenyl optionally substituted with 1 or 2 C1-C4 alkyl, Ci-C4 alkoxy, where Re is selected from the group consisting of : - H, C1-C4 alkyl, Cl-C4 alkoxy, - 0-Si (R) 3 where the R's are the same or different and are-H, Cl-C4 alkyl, -#, C1-C4 alkoxy and-OH, -F, -Cl, -Br, -I, - CO-OCH3 and -CO-Rc-1 where Rc-1 is Cl-C4 alkyl or-cep ; where Rd is selected from the group consisting of <BR> <BR> <BR> <BR> - H,<BR> <BR> <BR> <BR> <BR> <BR> <BR> - C=N, Ci-Cio alkyl ; C1-C4 alkoxy ; -CH2-ORd-1 where Rd-1 is-H or Cl-C4 alkyl, -CH2-N(Rd-6) 2 where the two Rd-6 are the same or different and are: Cl-C4 alkyl, - @ -CO-Rd-6a where Rd-6a is Cl-C4 alkyl or -#, -CH2-O-CO-Rd-1 where Rd-1 is as defined above, -CH(ORd-1) 2 where Rd-1 is as defined above and where the two Rd-1 taken together are: -CH2-CH2-, -CH2-CH2-CH2-, - CH2-C (CH3-) 2-CH2-, -CH(-O-CO-Rd-1) 2 where Rd-1 is as defined above, -Si (R) 3 where R is as defined above, - 0-Si (R) 3 where R is as defined above, -Sn(Rb-1) 3 where Rb-1 is as defined above, -S-Rd-5 where Rd-5 is C1-C4 alkyl or -#, -N(Rd-6) 2 where Rd 6 is as defined above, where Re and Rd taken together with the atoms to which they are attached to form

where El are the same or different and are: <BR> <BR> <BR> <BR> - H,<BR> <BR> <BR> <BR> <BR> Cl-C4 alkyl, -F, -Cl, -Br, -I, - OEl_1 where E1-1 is: - H, C1-C4 alkyl, -# or -SiE1-2E1-3E1-4 where E1-2, E1-3 and E1-4 are the same or different and are C1-C4 alkyl or Cl-C4 alkoxy, - S-EI_s where El s is Cl-C4 alkyl or-T.

-S-(O)1-2-E1-5 where E1-5 is as defined above, -N(Rd-6)2 where the two Rd-6 are the same or different and are as defined above, -P(O)(O-E1-1) 2 where 1-1 is as defined above, -Si (R) 3 where R is as defined above; -CE1=M (-B) where El is as defined above and where M is: (1) =0, (2) =N-E2 where E2 is selected from the group consisting of -H

C1-C4 alkyl, Cl-C4 alkenyl containing 1 or 2 double bonds, Cl-C4 alkynyl containing 1 triple bond, -CO-OE2-1 where E2-1 is-H or Cl-C4 alkyl, -C(E2-1)2-OE2-2 where E2-1 are the same or different and are as defined above and where E2-2 is C1-C4 alkyl, -# or -Si (R) 3 where the three R are the same or different and are defined above, - OEZ_2 where E2-2 is as defined above, - S-Ez_3 where E2-3 is Cl-C4 alkyl or-T, -S-(O)1-2-E2-3 where E2-3 is as defined above, -N(Rd-6) 2 where the two Rd6 are the same or different and are as defined above; -Si (R) 3 where the three R are as defined above; (3) =C (E2) 2 where the E2 are the same or different and are as defined above, where Ei and E2 are taken together with the atoms to which they are attached to form a ring of 5 thru 7 members, optionally containing 3 thru 5 -O-, - S-, -N=, -NXI-1- where XI-I is as defined above, -CE2= where E2 is as defined above, - C (Rb) 2- where Rb is as defined above, and optionally containing 1 or 2 additional double bonds; -C=C-E2 (-C) where E2 is as defined above; -CH2-CH=CH2 -CH=C=CH2 (-D2) -CH2-C=C-H (-D3)

where Rg is: (1)-H, (2)-OH, (3)-O-(HYDROXY PROTECTING GROUP) where HYDROXY PROTECTING GROUP is selected from the group consisting of -Si-(CH3)3, -Si(-CH2-CH3) 3, -CO-CH3, - CO-H and -SiH (CH3) 2, (4)-F ; where Ru is: (1) =O, (2) -H:-H, (3) α-R11-1:ß-R11-2 where R11-1 is: (a)-H, (B)-O-R1-3 where RI 1-3 is: (i)-H, (ii) a HYDROXY PROTECTING GROUP) where HYDROXY PROTECTING GROUP is as defined above, and where Rl 2 is: (a)-H, (b)-O-R11-4 where R11-4 is : (i)-H, (ii) a HYDROXY PROTECTING GROUP) where HYDROXY PROTECTING GROUP is as defined above, with the proviso that one ofRn-i and RI 2 must be-H, (4) Ri 1-5 : R11-6 where one of R11-5 or Ri 1-6 and R9 are taken together with Rg to form a second bond between C-9 and C-11 and the other of Rll s or R11-6 is-H, (5) α-R11-7 : ß-R11-8 where R, 1-7 and Rg are taken together with -O- to form an epoxide between C-9 and C-11 and R11-8 is-H; where Rl7 is:

(1) =o ; (2) α-R17-1 : ß-R17-2 where R17-1 is: (a)-H, <BR> <BR> <BR> (b)-C=C-H,<BR> <BR> <BR> <BR> <BR> (c)-C=N, (d)-C#C-CH2-O-R17-1-1 where R17-1-1 is selected from the group consisting of (i)-H, (ii) -Si (R17-1-2) 3 where Ri7-1-2 are the same or different and are Cl-C4 alkyl, (iii) 1-ethoxyethyl, (iv) 2-tetrahydropyranyl, (e)-C=C-CHz-0- (HYDROXY PROTECTING GROUP), where HYDROXY PROTECTING GROUP is as defined above, (f)-CH2-CH2-CH2-OH, (g)-CH2-CH2-CH2-O-(HYDROXY PROTECTING GROUP), where HYDROXY PROTECTING GROUP is as defined above, (h)-CH2-CH2-CO-O-and where R] 7-2 is-OH ; (3) a-RI73 : ß-R17-4 where R17-5 is-OH and where Ri7-4 is: (a)-CO-CH3, (b)-CO-CH2-OH, (c)-CO-CH2-O-CO(CH2)0-3-CH3 ; (4) a-Ri7-5 : ß-17-6 where R17-5 and R17-6 are taken with the attached carbon atom to form a three member epoxide containing -O-CH2- where the attachment of the-0 is at R17-6 in the ß-orientation and the attachment of the CH2-is at R17-5 in the a-orientation; (5) α-R17-7 : ß-R17-8 where Ri7. and Rl78 are taken with the attached carbon atom to form a five member lactone containing -O-CO-CH2-CH2- where the attachment of the CH2-is at Rl77 in the oc-orientation and the attachment of the-0 is at Ri7. in the ß- orientation; (6)-O-CH (OR17-9)-CH2-Ch2..... where the bond from the oxygen (-O) is one of the four bonds at C-17 in the ß-configuration and the bond from the methylene group

(CH2.....) is another of the four bonds at C-17 in the a-configuration to form a 5 member heterocycle containing one oxygen atom, where R17-9 is-H or Cl-C3 alkyl ; (7) a-Ri7. : ß-R17-12 where R17-10 is -(CH2)1-2-CH=CH2 and Ri7-i2 is -OH.

Further disclosed is a cis enedione of the formula (in-cM) and a trans enedione of the formula (III-trans)

where (I) R3 is = O ; R4 is R4 l : R4-2 where one of R4-1 and R4-2 is-H and the other of R4-1 and R42 is taken together with R5 to form a second bond between the carbon atoms to which they are attached; R6 is-H:-H ; (in) R3 is α-R3-5 : ß-R3-6 where R3-5 is -O-R31 and R3-6 is -O-R32 where R31 and R32 are the same or different and are selected from the group consisting of Cl-C3 alkyl and R31 and R32 are taken with the attached -O-C-O- to form a cyclic ketal of 5 or 6 atoms of the formula

- (CH2)- (CR33R34) nl- (CH2)- where nl is 0 or 1 ; where R33 and R34 are the same or different and are-H and Cl-C3 alkyl ; R4 is -H : -H; R6 is R6-5 : R6-6 where one of R6-5 and R6-6 is taken together with R5 to form a second bond between the carbon atoms to which they are attached and the other of R6-5 and R6-6 is -H ; (IV) R3 is a-R3-7 : ß-R3-8 where R3-7 is-0-R31 and R3-8 is-0-R32 where R31 and R32 are as defined above; R4 is R4-7:R4-8 where one of R47 and R4-8 is taken together with R5 to form a second bond between the carbon atoms to which they are attached and the other of R4-7 and R4-8 is -H ; R6 is-H : -H; where R9, R11 R17 are as defined above; where Rb is selected from the group consisting of - H, Cl-C4 alkyl or phenyl optionally substituted with 1 or 2 Cl-C4 alkyl, Cl-C4 alkoxy, where Rc is selected from the group consisting of: -H, Cl-C4 alkyl, Cl-C4 alkoxy, - 0-Si (R) 3 where the R's are the same or different and are -H, C1-C4 alkyl, -#, Cl-C4 alkoxy and-OH, -F, -Cl, -Br, -I, -CO-OCH3 and -CO-Rc-1 where Rc-1 is C1-C4 alkyl or -# ; where Rd is selected from the group consisting of <BR> <BR> <BR> <BR> - H,<BR> <BR> <BR> <BR> <BR> <BR> <BR> - C=N, Cl-Cl0 alkyl ; Cl-C4 alkoxy ;

-CH2-ORd-1 where Rd-1 is -H or Cl-C4 alkyl, -CH2-N(d-6)2 where the two Rd 6 are the same or different and are: C1-C4 alkyl, <BR> <BR> <BR> <BR> - #,<BR> <BR> <BR> <BR> - CO-Rd-6a where Rd-6a is Cl-C4 alkyl or-cp, -CH2-O-CO-Rd-1 where Rd-1 is as defined above, -CH(ORd-1) 2 where Rd-1 is as defined above and where the two Rd-1 taken together are: -CH2-CH2-, -CH2-CH2-CH2-, - CH2-C (CH3-) 2-CH2-, -CH(-O-CO-Rd-1) 2 where Rd-1 is as defined above, -Si (R) 3 where R is as defined above, - 0-Si (R) 3 where R is as defined above, - Sn (Rb-i) 3 where Rb-1 is as defined above, -S-Rd-5 where Rd-5 is Cl-C4 alkyl or -#, - N (Rd-6) 2 where Rd-6 is as defined above, where Re and Rd taken together with the atoms to which they are attached to form where El are the same or different and are: - H, C1-C4 alkyl, -F, -Cl, -Br, -I, -OE1-1 where E11 is: - H, Cl-C4 alkyl, - (pour

-SiE1-2E1-3E104 where EI-2, EI-3 and E1-4 are the same or different and are Cl-C4 alkyl or Cl-C4 alkoxy, - S-Ei. s where Ei-5 is Cl-C4 alkyl or-y, -S-(O)1-2-E1-5 where EI-5 is as defined above, -N(Rd-6)2 where the two Rd-6 are the same or different and are as defined above, -P(O)(O-E1-1)2 where E1-1 is as defined above, -Si (R) 3 where R is as defined above.

Disclosed is 17ß-hydroxy-7a-(5'-methyl-2'-furyl)-pregna-4, 9 (11)-dien-3-one-21- carboxylic acid, y-lactone a compound of the formula in crystalline form having a powder X-ray diffraction spectrum of : Two-Theta Angle (°) with a range of From To 6.46 6.59 10.46 10.70 11.48 11.70 12.55 12.79 14.19 14.36 15.06 15.30 16.10 16.65 16.55 16.74

17.79 18.01 18.25 18.46 19.46 19.70 20.06 20.30 20.86 21.25 21.60 21.80 23.14 23.35 24.74 24.95 25. 15 25.96 25.85 26.05 27.35 27.55 28.26 28.90 28.75 28.85 29.91 30.14 30.90 31.10 31.86 32.05 32.59 32.79 33.14 33.89 33.63 34.00 34.27 34.49 35.52 35.75 36.06 36.30 37.02 37.21 37.74 37.91 38.42 38.64 39.35 39.39 to a reasonable degree of scientific certainty, where Two-Theta Angle is measured in degrees.

Also disclosed is 17p-hydroxy-7a- (5'-methyl-2'-furyl)-pregna-4, 9 (11)-dien-3-one-21- carboxylic acid, y-lactone in crystalline form having a powder X-ray diffraction spectrum of : Two-Theta Angle (°) and Relative Intensity (%) with a ranges of :

Two-Theta Angle Relative Intensity (%) From To From To 6.46 6.59 1.0 1.6 10.46 10.70 10.7 58.3 11.48 11.70 11.7 20.8 12.55 12.79 2.2 4.2 14.19 14.36 14.4 100.0 15.06 15.30 15.3 29.5 16. 10 16. 65 7.2 50.3 16.55 16.74 16.7 66.4 17.79 18.01 18.0 100.0 18.25 18.46 18.5 34.5 19.46 19.70 6.1 12.6 20.06 20.30 19.5 28.1 20.86 21.25 16.1 36.3 21.60 21.80 10.8 20.0 23.14 23.35 23.3 48.0 24.74 24.95 11.5 19.0 25.15 25.96 4.4 30.3 25.85 26.05 12.1 31.2 27.35 27.55 9.5 22.7 28.26 28.90 2.1 6.2 28.75 28.85 6.6 11.1 29.91 30.14 1.9 3.5 30.90 31.10 5.6 10.4 31.86 32.05 1.2 3.7 32.59 32.79 0.9 2.3 33.14 33.89 1.6 4.5 33.63 34.00 1.1 4.9 34.27 34.49 1.4 2.2 35.52 35.75 1.3 3.9

36.06 36.30 7.9 27.0 37.02 37.21 3.9 6.2 37.74 37.91 1.0 2.2 38.42 38.64 1.2 2.9 39.35 39.39 1.6 1.8 to a reasonable degree of scientific certainty, where Two-Theta Angle is measured in degrees and Relative Intensity is the intensity percentage of each peak relative to the strongest peak.

Further disclosed is 17p-hydroxy-7a- (5'-methyl-2'-furyl)-pregna-4, 9 (11)-dien-3-one- 21-carboxylic acid, y-lactone in crystalline form having a powder X-ray diffraction spectrum of Two-Theta Angle (°), d-spacing (A) and Relative Intensity (%) with ranges of : Two-Theta Anle (°) d-spacing (A) _ Relative Intensitv (%) From To From To From To 6.46 6.59 13.39 13.66 1.0 1.6 10.46 10.70 8.26 8.45 10.7 58.3 11.48 11.70 7.56 7.70 11.7 20.8 12.55 12.79 6.92 7.05 2.2 4.2 14.19 14.36 6.16 6.24 14.4 100.0 15.06 15.30 5.79 5.88 15.3 29.5 16.10 16.65 5.32 5.50 7.2 50.3 16.55 16.74 5.29 5.35 16.7 66.4 17.79 18.01 4.92 4.98 18.0 100.0 18.25 18.46 4.80 4.86 18.5 34.5 19.46 19.70 4.50 4.56 6.1 12.6 20.06 20.30 4.37 4.42 19.5 28.1 20.86 21.25 4.18 4.26 16.1 36.3 21.60 21.80 4.07 4.11 10.8 20.0 23.14 23.35 3.81 3.84 23.3 48.0 24.74 24.95 3.57 3.60 11.5 19.0 25.15 25.96 3.43 3.54 4.4 30.3

25.85 26.05 3.42 3.44 12.1 31.2 27.35 27.55 3.24. 3.26 9.5 22.7 28.26 28.90 3.09 3.16 2.1 6.2 28.75 28.85 3.09 3.10 6.6 11.1 29.91 30.14 2.96 2.98 1.9 3.5 30.90 31.10 2.87 2.89 5.6 10.4 31.86 32.05 2.79 2.81 1.2 3.7 32.59 32.79 2.73 2.75 0.9 2.3 33.14 33.89 2.64 2.70 1.6 4.5 33.63 34. 00 2.63 2.66 1.1 4.9 34.27 34.49 2.60 2.61 1.4 2.2 35.52 35.75 2.51 2.53 1. 3 3.9 36.06 36.30 2.47 2.49 7.9 27.0 37.02 37.21 2.41 2.43 3.9 6.2 37.74 37.91 2.37 2.38 1.0 2.2 38.42 38.64 2.33 2.34 1.2 2.9 39. 35 39. 39 2.29 2.29 1.6 1.8 to a reasonable degree of scientific certainty, where Two-Theta Angle is measured in degrees, d-Spacing is measured in angstroms, and Relative Intensity is the intensity percentage of each peak relative to the strongest peak.

DETAILED DESCRIPTION OF THE INVENTION Eplerenone is 9a, lla-epoxy-17p-hydroxypregn-4-en-3-one-7a, 21-dicarboxylic acid, y-lactone, methyl ester and as such contains a 7a-carbomethoxy substituent. It is useful as a pharmaceutical agent for the treatment of hypertension and congestive heart failure. A major difficulty in the production of eplerenone is introduction of the 7Ol-carbomethoxy substituent.

The processes and intermediates of the present invention are improved processes for the preparation of eplerenone.

CHART A discloses the general process of the invention when the adduct at the 7a- position,-R71 is (-A1). The process of the present invention begins with a protected or

unprotected #4,6-3-keto steroid (1). Since the steroid A-ring can be protected or not protected, CHART B discloses an improved process for protection of the #4,6-3-keto steroid (1) starting material as a C-3 protected #4,6-3-ketal steroid (I-P). CHART C discloses an alternative route (ozonolysis) for transformation of the 7a-substituted steroid (II) to eplerenone (IX). CHART D discloses the general process when the steroid A-ring is unprotected and R7 l is the variable substituent (-A1). CHART E discloses the preferred process for the transformation of a 4^6_ 3-keto steroid or ketal thereof (I) to eplerenone (IX). CHART F discloses the reversible nature of the conversion of the carboxylic acid (VI) with the 5,7-lactone (VII). CHART G discloses the general process of the invention when-R7-1 is (-A2). CHART H discloses the general process of the invention when -R7-1 is (-B), (-C), (-D1), (-D2) or (-D3).

The first step in the process of CHART A is to prepare a 7a-substituted steroid (II) of the formula where (I) R3 is = 0 ; R4 is R4-1 : R4-2 where one of R41 and R42is-H and the other of R41 and R4-2 is taken together with Rs to form a second bond between the carbon atoms to which they are attached ; R6 is-H : -H; (II) R3is R33 : R3-4 and R4 is R4-3 : R4-4 where one of R3-3 and R34 is-0-R31 where R31 is Cl-C3 alkyl, the other of R3-3 and R3-4 is taken together with one of R4-3 and R4-4 to form a second bond between the carbon atoms to which they are attached, and the other of R4-3 and R44 is-H ; R6 is R6-3 : R6-4 where one of R6-3 and R6-4 is taken together with Rs to form a second bond between the carbon atoms to which they are attached and the other of R63 and R64 is-H ; (III) R3 is a-R3-5 : P-R3-6 where R3-5 is -O-R31 and R3-6 is -O-R32 where R31 and R32 are the same or different and are selected from the group consisting of

C1-C2 alkyl and R31 and R32 are taken with the attached -O-C-O- to form a cyclic ketal of 5 or 6 atoms of the formula - (CH2)-(CR33R34)n1-(CH2)- where ni is 0 or 1; where R33 and R34 are the same or different and are-H and Cl-C3 alkyl ; R4 is -H : -H; R6 is R6-5 : R6-6 where one of R6-5 and R6-6 is taken together with Rs to form a second bond between the carbon atoms to which they are attached and the other of R6 s and R6-6 is -H ; (IV) R3 is a-R3-7 : ß-R3-8 where R3-7 is -O-R31 and R3-8 is -O-R32 where R31 and R32 are as defined above; R4 is R4-7 : R4-8 where one of R4-7 and R4-8 is taken together with Rs to form a second bond between the carbon atoms to which they are attached and the other of R47 and R48 is-H ; R6 is -H:-H; where R7-1 is a molecular fragment of the formula (-A1) or of the formula (-A2) where Xi is: - S-, -O- or NX1-1- and where X1-1 is: -H, C1-C4 alkyl, -CO-OX1-2 where X1-2 is Cl-C4 alkyl or -CH2-#, -CO-X1-2 where X1-2 is as defined above,

-CO-# where -# is substituted in the o-position with -CO-O-(C1-C4 alkyl), -S02- (CI-C3 alkyl), -S02- (P where zp is optionally substituted with 1 or 2 Cl-C4 alkyl, Cl-C4 alkoxy; where Rb is selected from the group consisting of - H, C1-C4 alkyl or phenyl optionally substituted with 1 or 2 Cl-C4 alkyl, C1-C4 alkoxy, where Re is selected from the group consisting of : -H, C1-4 alkyl, C1-4 alkoxy, - 0-Si (R) 3 where the R's are the same or different and are-H, C1-4 alkyl, -#, C1-C4 alkoxy and-OH, -F, -Cl, -Br, -I, -CO-OCH3 and -CO-Rc-1 where Rc-1 is Cl-C4 alkyl or-ex ; where Rd is selected from the group consisting of <BR> <BR> <BR> <BR> - H,<BR> <BR> <BR> <BR> <BR> <BR> <BR> -C#N, C1-C10 alkyl ; Ci-C4 alkoxy; -CH2-ORd-1 where Rd-1 is-H or C1-C4 alkyl, -CH2-N(Rd-6) 2 where the two Rd-6 are the same or different and are: C1-C4 alkyl, - yea -CO-Rd-6a where Rd-6a is C1-C4 alkyl or -#,

-CH2-O-CO-Rd-1 where Rd-1 is as defined above, -CH(ORd-1) 2 where Rd-1 is as defined above and where the two Rd-1 taken together are: -CH2-CH2-, -CH2-CH2-CH2-, -CH2-C (CH3-) 2-CH2-, -CH(-O-CO-Rd-1) 2 where Rd-1 is as defined above, -Si (R) 3 where R is as defined above, - 0-Si (R) 3 where R is as defined above, -Sn(Rb-1) 3 where Rb-1 is as defined above, -S-Rd-5 where Rd-5 is C1-C4 alkyl or -#, -N(Rd-6) 2 where Rd-6 is as defined above, where R and Rd taken together with the atoms to which they are attached to form where Ei are the same or different and are: - H, C1-C4 alkyl, -F, -Cl, -Br, -I, -OE1-1 where E1-1 is : - H, C1-C4 alkyl, - (p or -SiE1-2E1-3E1-4 where E1-2, E1-3 and E1-4 are the same or different and are Cl-C4 alkyl or Cl-C4 alkoxy, -S-E1-5 where E1-5 is C1-C4 alkyl or-T, -S-(O)1-2-E1-5 where EI-5 is as defined above,

-N (Rd-6) 2 where the two Rd-6 are the same or different and are as defined above, -P(O)(O-E1-1) 2 where E1-1 is as defined above, -Si (R) 3 where R is as defined above; -CE1=M (-B) where El is as defined above and where M is: (1) =0, (2) =N-E2 where E2 is selected from the group consisting of - H Cl-C4 alkyl, Cl-C4 alkenyl containing 1 or 2 double bonds, Cl-C4 alkynyl containing 1 triple bond, -CO-OE2-1 where E2-1 is-H or Cl-C4 alkyl, -C(E2-1)2-OE2-2 where E2-1 are the same or different and are as defined above and where E2-2 is Cl-C4 alkyl, -# or -Si (R) 3 where the three R are the same or different and are defined above, - OEZ_2 where E2-2 is as defined above, - S-E2-3 where E2-3 is Cl-C4 alkyl or -#, -S-(O)1-2-E2-3 where E2-3 is as defined above, -N(Rd-6) 2 where the two Rd6 are the same or different and are as defined above; -Si (R) 3 where the three R are as defined above; (3) =C (E2) 2 where the E2 are the same or different and are as defined above, where EI and E2 are taken together with the atoms to which they are attached to form a ring of 5 thru 7 members, optionally containing 3 thru 5 -O-, - S-,

-N=, - where X1-1 is as defined above, -CE2= where E2 is as defined above, - C (Rb) 2-where Rb is as defined above, and optionally containing 1 or 2 additional double bonds; -C#C-E2 (-C) where E2 is as defined above; -CH2-CH=CH2 (-D1) -CH=C=CH2 (-D2) -CH2-C#-C-H (-D3) where Rg is: (1)-H, (2)-OH, (3)-0- (HYDROXY PROTECTING GROUP) where HYDROXY PROTECTING GROUP is selected from the group consisting of -Si(-CH3)3, -Si (-CH2-CH3) 3, - CO-CH3, - CO-H and -SiH (CH3) 2, (4) -F; where Rl l is : (1) =O, (2) -H:-H, (3) α-R11-1:ß-R11-2 where R11-1 is: (a)-H, (b)-O-R11-3 where Ru-3 is: (i)-H, (ii) a HYDROXY PROTECTING GROUP) where HYDROXY PROTECTING GROUP is as defined above, and where R11-2 is: (a)-H,

(b0-O-R11-4 where R -R11-4 is: (i)-H, (ii) a HYDROXY PROTECTING GROUP) where HYDROXY PROTECTING GROUP is as defined above, with the proviso that one of R11-1 and R11-2 must be-H, (4) Rn. 5 : Rl 1-6 where one of R, 1-5 or Rl 1-6 and Rg are taken together with Rg to form a second bond between C-9 and C-11 and the other of R11-5 or R11-6 is-H, (5) α-R11-7 : ß-R11-8 where R11-7 and Rg are taken together with -O- to form an epoxide between C-9 and C-11 and Rl 8 is-H; where Rl7 is : (1) =0 ; (2) α-R17-1:ß-R17-2 where R17-1 is: (a)-H, <BR> <BR> <BR> <BR> (b)-C=C-H,<BR> <BR> <BR> <BR> <BR> <BR> <BR> (c)-C#N, (d)C#C-CH2O-R17-1-1 where R17-1-1 is selected from the group consisting of (i)-H, (ii) -Si (R17-1-2) 3 where R17-1-2 are the same or different and are Cl-C4 alkyl, (iii) 1-ethoxyethyl, (iv) 2-tetrahydropyranyl, (e)-C-CH2-O-(HYDROXY PROTECTING GROUP), where HYDROXY PROTECTING GROUP is as defined above, (f)-CH2-CH2-CH2-OH, (g)-CH2-CH2-CH2-O-(HYDROXY PRTECTING GROUP) where HYDROXY PROTECTING GROUP is as defined above, (h)-CH2-CH2-CO-O and where R. 7. 2 is-OH; (3) α-R17-3 : ß-R17-4 where R17-3 is-OH and where Ri7. is : <BR> <BR> (a)-CO-CH3,<BR> <BR> <BR> <BR> <BR> <BR> (b)-CO-CH2-OH,

(c)-CO-CH2-O-CO-(CH2) 03-CH3 ; (4) αR17-5 : 0-RI7-6 where R17-5 and R17-6 are taken with the attached carbon atom to form a three member epoxide containing -O-CH2- where the attachment of the-0 is at R17-6 in the ß-orietation and the attachment of the CH2-is at RI 7-5 in the a-orientation; (5) α-R17-7 : ß-R17-8 where R17-7 and R17-8 are taken with the attached carbon atom to form a five member lactone containing-O-CO-CH2-CH2-where the attachment of the CH2-is at Ri7. in the a-orientation and the attachment of the-0 is at Ri7. in the ß- orientation; (6)-O-CH (OR17-9)-CH2-CH2 where the bond from the oxygen (-O_ is one of the four bonds at C-17 in the ß-configuration and the bond from the methylene group (CH2-) is another of the four bonds at C-17 in the a-configuration to form a 5 member heterocycle containing one oxygen atom, where R17-89 is-H or Cl-C3 alkyl ; (7) a-RI7 : ß-R17-12 where R17-10 is -(cH2)1-2-CH=CH2 and R17-12 is - OH ; which comprises: (1) contacting a #4,6-3-keto steroid or ketal thereof (I) of the formula where (1) R3 is = O ; R4 is R4-1 : R4-2 where one of R4-1 and R4-2 is-H and the other of R41 and R4-2 is taken together with Rs to form a second bond between the carbon atoms to which they are attached; (I-ketal) R3 is R3-9 : R3-10 where $-39 is -O-R31 and R3-10 is -O-R32 wehre R31 and R32 are the same or different and are selected from the group consisting of Cl-C3 alkyl and R31 and R32 are taken with the attached -O-C-O- to form a cyclic ketal of 5 or 6 atoms of the formula - (CH2)- (CR33R34) nl- (CH2)-

where nl is 0 or 1; where R33 and R34 are the same or different and are-H and Cl-C3 alkyl ; R4 is R4-9 : R4-10 where one of R4-9 and R4-10 is taken together with R5 to form a second bond between the carbon atoms to which they are attached and the other ofR4-9 and R4 10 is -H ; where R9, R11 and R17 are as defined above, with an adduct selected from compounds (a) of the formula (A) where Xi, R. b, Re and Rd are as defined above, and where Ra is selected from the group consisting of-H,-ZnL,-BL,-SiL3, -SnL3, -cu, -CuL, -AlL2, -HgL, -Ag, -MgL, -Li and-COOH, where L is-OH, Cl-C4 alkyl, - F,-Cl,-Br,-I,-CN,-O (CI-C3 alkyl), 2-thienyl, (CH3) 2C (O-)-C (O-) C (CH3) 2 and (b) of the formula (A') Rb-CO-CHRb-CHJRc-CO-Rd (A') where Rb, Re and Rd are as defined above; (c) of the formula (A")

where Re is: Cl-C4 alkyl, -CO-(C1-C4 alkyl or -#), -Si (R) 3 where R is as defined above and where X1, Rb, Rc and Rd are as defined above; (d) of the formula (B) Ra-CE1=M (B) where Ra, Et and M are as defined above; (e) of the formula (C) Ra-C=C-E2 (C) where Ra and E2 are as defined above; (f) of the formulas (D1, D2 and D3) Ra-CH2-CH=CH2 (D1) Ra-CH=C=CH2 (D2) Ra-CH2-C=C-H (D3) where Ra is as defined above, in the presence of : (1) a Lewis Acid, (2) a proton acid with a pKa of < about 5 or (3) a salt of a secondary amine of the formula where Rs-2 is-H, C1-C4 alkyl, -#, and -CH2-# ; $S-3 is-H, Cl-C4 alkyl ; RS-4 is-H, Cl-C4 alkyl, up ; Rs-s is-H, Ci-C4 alkyl,-cp ; and

where RS-2 is-H, C1-C4 alkyl, -#, and -cH2-# ; RS-4 is -H, c1-C4 alkyl, -# ; RS-5 is-H, C1-C4 alkyl, hop ; with an acid of pKa of < about 2.

For the A4-3-keto or ketal thereof (1) starting material it is preferred that R3, R4 and Rs are (I) R3 is = O ; R4 is R4-1 : R4-2 where one of R4-1 and R42 is-H and the other of R4-1 and R4-2 is taken together with R5 to form a second bond between the carbon atoms to which they are attached; R6 is-H:-H.

For the 7a-substituted steroid (II) there were four sets of steroid A-/B-rings identified above. Groups (I), (III) and (IV) are operable in the processes of the present invention.

However, group (II) where R3 is R3-3 : R3-4 and R4 is R4-3 : R4-4 where one of R33 and R34 is -Oj- R31 where R31 is Cl-C3 alkyl, the other of R33 and R3-4 is taken together with one of R4-3 and R4-4 to form a second bond between the carbon atoms to which they are attached, and the other of R4-3 and R44 is-H ; R6 is R63 : 6-4 where one of R6-3 and R6-4 is taken together with Rs to form a second bond between the carbon atoms to which they are attached and the other of R6-3 and R6-4 is-H; is a #3,4-3, 3-dialkoxy ring system which, as such, can not be transformed to the other intermediates of the present invention. It is useful because it can be transformed to the corresponding #4-3-keto steroid A-/B-ring system which is useful in the processes of the present invention.

For the 7a-substituted steroid (II) and other steroidal compounds of the invention, except the 5,7-bislactone (VII), with regard to the steroidal A-/B-rings, it is preferred that R3, R4, R5 and R6 are selected from the group consisting of : (I) R3 is = O ; R4 is R4 l : R4-2 where one of R4-1 and R4-2 is-H and the other of R4-1 and R4-2 is taken together with R5 to form a second bond between the carbon atoms to which they are attached; R6 is-H:-H ; (III) R3 is a-R3-5 : p-R3-6 Where R3-5 is-O-R31 and R3-5 si -O-R32 where R31 and R32 are taken with the attached-0-C-O-to form a cyclic ketal of 5 atoms of the formula -(CH2)-

(CR33R34) n1-9CH2)- where n1 is 0; R4 is-H : -H; R6 is R6-5 : R6-6 where one ofR6-5 and R6-6 is taken together with Rs to form a second bond between the carbon atoms to which they are attached and the other of R6 s and R6-6 is-H ; (III) R3 is α-R3-5 : P-R3-6 where ER3-5 is -O-R31 and R3 6 is-O-R32 where R31 and R32 are taken with the attached -O-C-O- to form a cyclic ketal of 6 atoms of the formula- (CH2)- (CR33R34) n1-(CH2)- where n1 is 1 and R33 and R34 are both Cl alkyl ; R4 is-H : -H; R6 is R6- 5 : ER6-5 where one of R6 s and R6-6 is taken together with R5 to form a second bond between the carbon atoms to which they are attached and the other of R6-5 and Rs4 is-H.

For the 7a-substituted steroid (II) and other steroidal compounds of the invention, except the 5,7-bislactone (VII), with regard to the steroidal A-/B-rings, it is more preferred that R3, R4, R5 and R6 are: (I) R3 is = O ; R4 is R4-1 : R4-2 where one of R4-1 and R42is-H and the other of i and R4-2 is taken together with Rs to form a second bond between the carbon atoms to which they are attached; R6 is-H:-H.

With regard to the steroidal C-ring, it is preferred that Rg and Rll are: (a) 11 is R11-5 : R11-6 where one of R11-5 or R11-6 and Rg are taken together with Rg to form a second bond between C-9 and C-11 and the other of R11-5 or R11-5 is -H, (b) α-R11-7 : ß-R11-8 where Rl 7 and Rg are taken together with-0-to form an epoxide between C-9 and C-11 and Ru-s is-H, (c) R9 si -H and R11 is α-R11-1 : ß-R11-2 where R11-1 is -O-R11-3 where R11-3 is -H, and where R11-2 is -H. It is more preferred that Rg and R11 are: (a) Rllis Rlls : R11-6 where one of R11-65 or R11-6 and R9 are taken together with Rg to form a second bond between C-9 and C-11 and other of Rlls or R11-6 is -H.

With regard to the steroidal D-ring, it is preferred that Ri ? is selected from the group consisting of : (a) α0-R17-7 : ß-R17-8 where R17-7 and R17-8 are taken with the attached carbon atom to form a five member lactone containing-0-CO-CH2-CH2-where the attachment of the CH2-is at R17-7 in the a-orientation and the attachment of the-0 is at Ri7. in the orientation, (b)=O; (c) α-R17-1;ß-R17-2 where R17-1 is -C#C-H and where R17-2 is -OH,

(d)-C-=C-CH2-ORI711.

With regard to the 7a-substituted steroid (II), it is preferred that R7-1 is substituent of formula (-A1). It is also preferred that Xi is -O-. It is preferred that Rb and Re are-H and it is preferred that Rd is C, alkyl. It is preferred that Ra is-H. It is preferred that for Ra that L is - ZnL is-Cl,-Br,-I ; - BL is catecholate, two-OH, <BR> <BR> <BR> <BR> <BR> HO-CH2-CH2-OH,<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> HO-CH2-CH2-CH2-OH, HO-CH2-C (CH3) 2-CH2-OH; -SiL3 is Cl alkyl; - SnL3 is Cl or n-C4 alkyl ; -CuL is 2-thienyl or-CN and -AlL2 is Cl-C2 alkyl.

When Ra is Cu, there can be two Ra groups for one Cu in which case the Cu is anionic.

The preferences for the variable substituents R3, R4, R5, R6, R7-l, R9, Rl l, RI,, Ra, Rb, Rd and Xi are not just for the A46-3-keto steroid or ketal thereof (I) and/or the 7a- substituted steroid (Il), but rather are for all the compounds (I) thru (XV) of the invention, except as expressly noted. Similarly, the preferences for other variable substituents such as R7-2 discussed below and/or chemical reagents used in this patent such as oxygen donating agent, halogenating agent, isomerization catalyst, hydroperoxy-deoxygenating agent, acid forming agent, acylation catalyst, oxidatively cleaving agent, deoxygenating agent, are defined the same throughout the patent as the first time they are discussed. Since many of these variable substituents and chemical reagents are referred to numerous times, it would be redundant each time they are used to repeatedly mention what is included, what is preferred and more preferred.

It is preferred that the acid reactant be a Lewis acid. The Lewis acid must be electrophilic enough to complex with the A46-3-keto steroid or ketal thereof (I), but not so electrophilic that it complexes with the nucleophilic reagent (A1), (A2), (B), (C), (Dl), (D2) or (D3) as is known to those skilled in the art. Further, it is preferred that the Lewis Acid be used in the presence of an alcohol selected from the group consisting of Cl-C3 alcohols,

ethylene glycol, 1, 2- or 1,3-propylene glycol, 2, 2-dimethyl- or 2,2-diethyl-1, 3-propylene glycol and phenol. It is more preferred that the alcohol be a Cl-C3 alcohol or mixture thereof.

Useful Lewis acids include those selected from the group consisting of BX3, Ales, SnX2, SnX4, SiX4, MgX2, ZnX2, TiX4, Rh (acac) (CH2CH2) 2 (2,2'-bis (diphenylphosphino)-1, I'-binaphthyl), Rh (CH3-C=N) 2 (cyclooctadiene) (BF4), Rh (acac) (CH2CH2) 2 (dppb), LiC104, K10 Montmorillonite clay, Yb (OTf) 3, LiCo (B9C2H11)2, PdX2, CrX3, FeX3, CoX3, NiX2, SbXs, InX3, Sc (OTf) 3, #3C+X- (R) 3SiX where R is Cl-C4 alkyl and Hp ; where X is selected from the group consisting of F-, Cl-, B4-, I-, -O-SO2CF3-, PF6-, BF4-, and C104 ; Pd (CH3-CO-O-) 2 ; BF3-diethyletherate complex; BF3-acetic acid complex; BF3-methyl-t-butyl ether complex; BF3-di-n-butyletherate complex; BF3-dimethyletherate complex; BF3-dimethylsulfide complex; BF3-phenol complex; BF3-phosphoric acid complex and

BF3-tetrahydrofuran complex. It is preferred that the Lewis acid is selected from the group consisting of BF3, BF3-diethyletherate complex, BF3-acetic acid complex, BF3-methyl- t-butyl ether complex, BF3-di-n-butyletherate complex, BF3-dimethyletherate complex, BF3- dimethylsulfide complex, BF3-phenol complex, BF3-phosphoric acid complex and BF3- tetrahydrofuran complex. It is more preferred that the Lewis acid is BF3-diethyletherate. It is even more preferred that the BF3-diethyletherate is used in the presence of C-C3 alcohol and still more preferred is the use of the BF3-diethyletherate in the presence of C2 alcohol. Useful acids with a pKa of < about 5 are selected from the group consisting of formic acid, acetic acid, propionic acid, benzoic acid, acid, hydrofluoric acid, fluoroboric acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, trifluoromethanesulfonic acid, perchloric acid, trifluoroacetic and trichloroacetic. It is preferred that the acid with a pKa of < about 5 is acetic acid. When performing the transformation of the A46-3-keto steroid or ketal thereof (I) to the corresponding 7a-substituted steroid (II), at least one equivalent of the reagent of formulas (A), (B) or (C) should be used, it is preferable to use from one to two equivalents.

Use of additional reagent is not a problem, but rather a waste of compound. The reaction can be carried out in a variety of solvents, such as in a solvent/solvent mixture selected from the group consisting of : C-C6 alcohols, a solvent mixture of Cl-C6 alcohols and a solvent selected from the group consisting of acetonitrile, nitromethane, toluene, methylene chloride and acetic acid.

One factor to be considered in selecting a Lewis acid and solvent is the acid sensitivity of the 7a-substituted steroid (II). The reaction must be performed with a Lewis acid and in a solvent where the product is stable as is known to those skilled in the art. It is preferred that the solvent be a protic solvent, one that has a pKa of less than about 19. The reaction can be performed in a temperature range of from about-78° to about 60° ; preferably in a temperature range of from about-40° to about-15°. It is more preferred to perform the reaction at about - 20°. The reaction normally will take from a few hours to a day depending on the number of equivalent used and the reaction temperature.

Useful 7a-substituted steroids (II) include those selected from the group consisting of : 17p-hydroxy-7a- (5'-methyl-2'-furyl)-pregna-4, 9-dien-3-one-21-carboxylicacid, y- lactone,

11 la, 17p-dihydroxy-7a- (5'-methyl-2'-furyl)-pregn-4-en-3-one-21-carboxylic acid, y- lactone, 9α,11α-epoxy-17ß-hyudroxy-7α-(5'-methyl-2'-furyl)-pregn- 4-en-3-one-21-carboxylic acid, y-lactone, 17p-hydroxy-7a- (5'-t-butyl-2'-furyl)-pregna-4, 9 (11)-dien-3-one-21-carboxylic acid, y-lactone, 11α,17ß-dihydroxy-7α-95'-t-butyl-2'-furyl)-pegn-4-en-3-on e-232-carboxylic acid, y- lactone, 1 la, 17p-dihydroxy-7a- (4'-bromo-2'-furyl)-pregn-4-en-3-one-21-carboxylic acid, y- lactone, l l (X, 17ß-dihydroxy-7a-(4'-methyl-2'-furyl)-pregn-4-en-3-one-21-c arboxylic acid, y- lactone and 7 (x-allyl-17p-hydroxypregna-4, 9 (11)-dien-3-one, 21-carboxylic acid, y-lactone.

Rather than carrying the 7a-substituted steroid (II) on to the next step in situ, it is preferred to isolate and purify the 7a-substituted steroid (II) before performing the next step.

The preferred method of purification of the 7a-substituted steroid (II) is by crystallization.

The process for purifying the 7a-substituted steroid of formula (II) comprises crystallizing the 7a-substituted steroid (II), which contains greater than 5% of the 7p-isomer from a solvent selected from the group consisting of ethyl acetate, n-propyl acetate and butyl acetate. It is preferred to obtain the 7a-substituted steroid (II) in greater than 99. 8% isomeric purity and it is preferred that the crystallization solvent is n-propyl acetate. Crystallization co-solvents may be used.

The above purification of the 7a-substituted steroid (II) results in crystalline 7a- substituted steroid (II). However, crystalline 7a-substituted steroid (II) can also be readily obtained from other solvents, including methylene chloride, methanol, acetonitrile, acetone, cyclohexane and iso-octane as well as solvent mixtures of these solvents or a mixture of acetonitrile with water. Crystalline 7a-substituted steroid (II) can be readily obtained by methods well known to those skilled in the art for crystallization. For example, the 7a- substituted steroid (II) desired to be obtained in crystalline form is dissolved in a minimal amount of a suitable solvent, the mixture is heated until all the 7a-substituted steroid (II) is in solution and then the mixture is cooled until crystals result. Alternatively, once the 7a-

substituted steroid (II) is in solution in a suitable solvent such as ethyl acetate, the volume of the solvent can be reduced by distillation, or by passing a stream of a dry inert gas such as nitrogen over the mixture to concentrate the 7a-substituted steroid (II). Further, anti-solvents, such as cyclohexane or iso-octane, can be added to the warm mixture to help reduce the solubility of the 7a-substituted steroid (II) in the solvent and promote its crystallization as is known to those skilled in the art. The preferred solvents for crystallization are those used for purification.

It has been determined by powder X-ray diffraction (PXRD) that the crystals of 17p- hydroxy-7a- (5'-methyl-2'-furyl)-pregna-4, 9 (11)-dien-3-one-21-carboxylic acid, y-lactone (11) regardless of which process of the invention was used to make it and regardless of what solvent (s) it is crystallized from, that only one crystal form is produced. EXAMPLEs 39-53 are PXRD analysis of different samples of crystalline 17ß-hydroxy-7a-(5'-methyl-2'-furyl)- pregna-4,9 (11)-dien-3-one-21-carboxylic acid,-lactone (u) obtained by various process and crystallized from various solvent systems. The results are substantially identical. The differences are due to the identity and amount of a particular impurity that may be present as well as residual solvent as is known to those skilled in the art. It is known to those skilled in the art that even if the same sample is subjected to PXRD on more than one occasion, that the results will not be identical. That is know as experimental error and understood by those skilled in the art. It is the overall analysis that determines whether or not two crystal forms are the same or different.

In determining the PXRD of a crystal, the particular instrument used as well as the power of the instrument will affect the results. In determining whether two samples have the same or different crystal form, a scientist will compare the location of peaks or bands and look to see if there are any new bands in either sample not present in the other. In addition, the relative intensity of the peaks is very important.

The next step in the process of CHART A, is the conversion of the 7a-substituted steroid (II) to the corresponding cis-enedione (III-cis), by an oxidative process which comprises (1) contacting the 7a-substituted steroid of formula (II) with an agent selected from the group consisting of : (a) a halogenating agent in the presence of water and a base whose conjugate acid has a pKa of > about 8,

(b) an oxygen donating agent, (c) electrochemical oxidation, (d) a quinone in the presence of water or (e) nonquinone oxidants. It is preferred that the agent be a halogenating agent. Useful halogenating agents include those selected from the group consisting of dibromodimethylhydantoin, dichlorodimethylhydantoin, diiododimethylhydantoin, N- chlorosuccinamide, N-bromosuccinamide, N-iodosuccinamide, trichloroisocyanuric acid, t- butylhypochlorite and 3-bromo-1-chloro-5, 5-dimethylhydantoin; it is preferred that the halogenating is dibromodimethylhydantoin. When using a halogenating agent, the amount used should be at least one equivalent of the halogenating agent ; preferably from about 1.0 to about 1.05 equivalents of the halogenating agent are used. It is more preferred that the amount of halogenating agent be about 1. 01 equivalents. The reason is that one equivalent is required to complete the reaction but any excess needs to be quenched. Suitable quenching agents include bisulfite, isobutylvinyl ether, 2-methylfuran and hypophosphorous acid.

Useful oxygen donating agents include those selected from the group consisting of : a peracid, singlet oxygen followed by either phosphite or thiourea, triplet oxygen, hydrogen peroxide with a ketone selected from the group consisting of Q4-CO-Q5 where Q4 and Q5 are the same or different and are: Cl-C4 aLkyl optionally substituted with 1 thru 9-Cl or-F, and where the Q4 and Q5 are taken together with the attached carbon atom to form a cyclic ketone of 5 thru 7 members and ketones of the formula: 0 Cl-Cl2 alkyl Cl-Cl2 alkyl and

hydrogen peroxide in combination with methyltrioxorhenium, trichloroacetonitrile/hydrogen peroxide, trichloroacetamide/hydrogen peroxide, DDQ/water, p-chloranil/water, (p-C (CH3) 2-0-OH or an alkylhydroperoxide in combination with a metal containing activator, where alkyl is from C4-C1o alkyl and metal containing activator is selected from the group consisting of Ti (isopropoxide) 4, peroxotungstophosphate, VO (acetylacetonate) 2 and MO hexacarbonyl. It is preferred that the oxygen donating agent is a peracid. Useful peracids include those selected from the group consisting of : (a) perbenzoic acid optionally substituted with 1 or 2-Cl or-NO2, (b) percarboxylic acids of the formula Cn2 (Q6) 2n2+mC03H where n2 is 1 thru 4 and Q6 is-H,-Cl or-F, (c) perphthalic acid and (d) magnesium peroxyphthalate. An excess oxygen donating agent present must also be quenched as was done for the halogenating agents. Base is required to neutralize the acid produced during the transformation of the 7a-substituted steroid (In to the cis-enedione (III- cis). Use bases include those selected from the group consisting of acetate, bicarbonate, carbonate, propionate, benzoate, dibasic phosphate and borate; it is more preferred that the base be acetate. For example, when the halogenating agent is dibromodimethylhydantoin, hydrobromic acid is produced. Hence, one equivalent of base per equivalent of acid produced

is required. In practice, a slight excess is used, about 1.5 equivalents. Suitable solvents for this reaction are those which are water miscible and which dissolves both the 7a-substituted steroid (II) and the halogenating agent or oxygen donating agent. Acetone and THF are preferred solvents. The reaction is performed at room temperature, about 20 to about 25°.

The reaction takes a few hours depending on the reactivity of the oxygenating donating agent or halogenating agent. When formed, the cis-enedione (m-ciS) does not have to be isolated and purified, but rather can be used in subsequent transformations"as is"or in situ. It is preferred that the cis-enedione (III-cis) is 17-hydroxy-7a-(cis-1', 4'-dioxopent-2'-en- 1'yl) pregna-4,9 (11)-dien-3-one-21-carboxylic acid,-lactone. Other oxidants useful for transformation of the 7a-substituted steroid (IT) to the cis-enedione (III-cis) include quinones (listed elsewhere). The 7a-substituted steroid (II) is contacted with a stoichiometric amount of quinone and at least a stoichiometric amount of water in a water-miscible organic solvent.

The contacting is preferably done at around room temperature. In addition, the oxidation can be accomplished by electrochemistry. The electrochemical oxidation is accomplished by contacting the 7a-substituted steroid (II) with a sub-stoichiometric amount of a quinone (preferably DDQ) and at least a stoichiometric amount of water in an electrochemical cell using standard electrochemical techniques such as are described in US 4,270, 994. Finally, the oxidation can be accomplished with non-quinone agents which include, manganic acetate, potassium permanganate, ceric ammonium nitrate, iodosobenzene, iodobenzenediacetate, iodobenzenebistrifluoroacetate, chromic acid ("Jones reagent"), and lead tetraacetate. These reactions are typically run in aqueous acetone as solvent at around room temperature (20- 25°), although many water-miscible organic co-solvents can be used in place of acetone.

Other oxidizing agents that effect this transformation include hydrogen peroxide or an organic hydroperoxide (listed elsewhere) in combination with a metal catalyst such as methyltrioxorhenium, palladium acetate, ruthenium trichloride, or ruthenium tetroxide.

These reactions can be run in any solvent in which the 7a-substituted steroid (In is soluble such as methylene chloride, acetone, etc. The reactions involving ruthenium catalysts are preferably run in aqueous acetonitrile.

In the process of CHART A, the cis-enedione (m-cM) can be transformed to the corresponding trails-enedione (M-trans) or it can be converted to the peroxy compound (IV- OOH), the hydroxy compound (IV-OH), the biscarbonyl compound (V) or the carboxylic acid

(VI) or mixture thereof. When the term carboxylic acid (VI) is used, it refers to and includes the pharmaceutically acceptable salts thereof. These will include the sodium, potassium, lithium, magnesium, tetrabutylammonium and the carboxylic acid salts with DBU, tetramethylquanidine, triethylamine and others. The identity of the particular cation is not important since eventually it is lost when forming an acid which ultimately is converted to the methyl ester (VIII) and eplerenone (IX) which requires a methyl ester at the 7a-position. It is preferable to convert the cis-enedione (m-cis) to the corresponding trans-enedione (III-trans) rather than convert the cis-enedione (m-CM) to a mixture of peroxy (IV-OOH), hydroxy (IV- OH) and biscarbonyl (V) compounds.

When the cis-enedione (m-ciS) is transformed to the corresponding trans-enedione (E-trans), the cis-enedione (m-ciS) is contacted with an isomerization catalyst which can be either a chemical agent including: (a) a strong acid of pKa of < about 2 ; (b) a tertiary amine whose conjugate acid has a pKa > about 8 and (c) salt of a tertiary amine whose conjugate acid has a pKa > about 8, (d) l2, (e) (Cs-C4) 3P, (f) (p3P, or a physical agent such as (g) heating to about 80°.

It is preferred that the isomerization catalyst be a strong acid of pKa of < about 2.

When the isomerization catalyst is a strong acid of pKa of < about 2, useful strong acids of pKa of < about 2 include those selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodoic acid, hydrofluoroic acid, sulfuric acid, phosphoric acid, nitric acid, trichloroacetic acid and trifluoroacetic acid, it is preferred that the strong acid of pKa of < about 2 be hydrochloric acid. When the isomerization catalyst is a strong acid of pKa of < about 2, it is preferred that it be used in anhydrous form or if used in as an aqueous mixture that the reaction be performed as a two phase system with the aqueous phase being separate. When the isomerization catalyst is a tertiary amine whose conjugate acid has a pKa > about 8, useful tertiary amines whose conjugate acid has a pKa > about 8 include those selected from the group consisting of (Q3) 3N were Q3 is Cl-C3 alkyl, DBU, DBN, DABCO, pyridine, p-dimethylaminopyridine and pyrrolidinylpyridine. When the

isomerization catalyst is salt of a tertiary amine whose conjugate acid has a pKa > about 8, it is preferred that the salt of a tertiary amine whose conjugate acid has a pKa > about 8 be pyridine hydrochloride. Regardless of which chemical agent is used, only a catalytic amount is required. For example, after formation of the cis-enedione (m-ciS) just adding commercial chloroform containing the usual impurity of hydrochloric acid is sufficient to effect the transformation to the corresponding trans-enedione (E-trans), see EXAMPLE 4, Part 2. The isomerization of cis-enedione (m-ciS) to the corresponding trans-enedione (m-trans) can be performed at 20-25° (room temperature). At room temperature, the reaction usually takes a few hours. It is necessary to monitor the course of the reaction by standard methods such as LC or TLC to ensure that it does not go too long. If the reaction goes too long, the reaction reforms the 7a-substituted steroid (II) with a A6-double bond. Once the reaction has proceeded to completeness where it is desirous to terminate the reaction, the reaction can be terminated as follows. When the isomerization catalyst is an acid or salt of a tertiary amine whose conjugate acid has a pKa of > 8, one can terminate the reaction by washing with water.

If aqueous acid is used as the isomerization catalyst, it is best to separate the phases and then wash the non-aqueous phase with water. If the isomerization catalyst is a tertiary amine whose conjugate acid has a pKa of > 8, then the reaction mixture is washed with aqueous acid followed by water. The trans-enedione (III-trans) can be isolated and purified, however it is preferred not to isolate and purify it but rather carry it on in situ.

In the process of CHART A, the next step is the conversion of either the cis-enedione m-ciS) or trans-enedione (III-tras), or mixture thereof, to the corresponding hydroperoxy (IV-OOH) compound, hydroxy (IV-OH) compound, biscarbonyl (V) compound and/or the carboxylic acid (VI) or mixtures thereof. The cis-enedione (III-cis) or trans-enedione (E- trans), or mixture there of, is transformed to the corresponding hydroxy compound, peroxy compound (IV-OOH), or biscarbonyl compound (V) or carboxylic (VI) by contacting the cis- enedione (III-cis) or trans-enedione (E-trans) or a mixture thereof, with ozone in the presence of an alcohol of the formula R7-2-OH where R7-2 is-H or Cl-C4 alkyl optionally substituted with one or two-OH. This includes water, methanol, ethanol, propyl alcohol, isopropyl alcohol, ethylene glycol, glycerol, etc. It is preferred that R7-2 is-H, Cl or is iso- C3 ; it is more preferred that R7-2 is a mixture of-H, Cl and iso-C3. This means a mixture of water, methanol and isopropanol is the preferred R7-2-OH. The steroidal starting materials

must be in solution using a solvent that will dissolve them at the cold temperatures at which it is preferred to perform this reaction. Methylene chloride is the preferred solvent. The reaction temperatures can be as low as about-100° up to about 40°. It is preferred that the temperature be from about-78° to about-20° ; it is more preferred that the temperature be about-50°. The lower the temperature, the more selectivity; the higher the temperature the less selectivity. Hence, the actual temperature used will depend on the particular reactants used and the degree of selectivity desired. The reaction is permitted to run until the starting material is reduced to a small amount. The ozone must be stopped when the starting material is consumed or the ozone will destroy the product by reacting with the 4-and/or A9 (l l) double bonds if present. The alcohol, R72-OH, is used in a large excess to efficiently trap the carbonyl oxide intermediate produced. Further, the reaction temperature, the time the reaction is permitted to run and the nature of the particular alcohol, R7-2-OH, determines the identity of the product or if more than one product is produced, the ratio of products. If the alcohol, R72-OH, has a hindered R72 group, then the product is more likely to be the biscarbonyl compound (V), all other things being equal. Similarly, if the alcohol, R72-OH, does not have a hindered R72 group, such as methyl, then the product is more likely to be the hydroxy compound (IV-OH), all other things being equal. The preferred product produced by the oxidation process is the carboxylic acid (VI).

The hydroperoxy compound (IV-OOH) can be converted to the corresponding hydroxy compound (IV-OH) by contacting the hydroperoxy compound (IV-OOH) with a hydroperoxy-deoxygenating agent. It is preferred to use a mild hydroperoxy-deoxygenating agent, one which both deoxygenates, and second does not add to the steroid molecule. Useful hydroperoxy-deoxygenating agents include those selected from the group consisting of : QlQ2S where Q1 and Q2 are the same or different and are Cl-C4 aLkyl or phenyl, bisulfite, sulfite, thiosulfate, tetrahydrothiophene, hydrosulfite, thiourea, butyl vinyl ether,

(Cl-C4 alkyl) 3 phosphine, triphenylphosphine, and tetramethylethylene. It is preferred that the hydroperoxy-deoxygenating agent is dimethylsulfide. When the hydroperoxy-deoxygenating agent is bisulfite and sulfite, sodium and potassium are the preferred cations. One equivalent of the hydroperoxy-deoxygenating agent is required, but more then one equivalent, such as about two equivalents, are normally used to ensure that all of the hydroperoxy compound (IV-OOH) is reduced. The reaction is performed at 20-25° and is usually complete in about 1 hour. The hydroxy compound (IV- OH) can be isolated and purified if desired, however, it is preferable to carry it on in situ without isolating or purifying it. It is preferred that the hydroxy compound (IV) is 17p- hydroxy-7a- (1'-oxo-2'-isopropoxy-2'-hydroxy-ethyl) pregna-4,9 (11)-dien-3-one-21- carboxylic acid, y-lactone.

The hydroperoxy compound (IV-OOH) can be transformed to the corresponding carboxylic acid (VI) by contacting the hydroperoxy compound (IV-OOH) with a carboxylic acid forming agent selected from the group consisting of : (a) heat, (b) a base whose conjugate acid has a pKa of about 5 or above, (c) an acid which has a pKa of less than about 3, (d) an acylating agent. When the carboxylic acid forming agent is (a) heat, the reaction mixture should be heated to the range of from about 30° to about 120° ; preferably from about 80° to about 90°. When the carboxylic acid forming agent is, (b) a base whose conjugate acid has a pKa of about 5 or above, useful bases include inorganic bases selected from the group consisting of hydroxide, bicarbonate, and carbonate and organic bases selected from the group consisting of (Q3) 3N were Q3 is Cl-C3 alkyl, DBU, DBN, DABCO, pyridine and p-dimethylaminopyridine. It is preferred that the base is bicarbonate. Sufficient base is necessary to neutralize the steroid acid produced and any additional acid by-products.

When the carboxylic acid forming agent is, (c) an acid which has a pKa of less than about 3, useful acids include those selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid and organic acids of the formula of RaCjd l-COOH where RaCjd l is-H and Cl-C3 alkyl optionally substituted with 1 thru 3-Cl and-F; preferred are formic acid and trifluoroacetic acid. While catalytic amounts of acid are sufficient, several

equivalent are preferred. When the carboxylic acid forming agent is, (d) an acylating agent, useful acylating agents are selected from the group consisting ofRacid-2-CO-0-CO-Racid-2 where Raced 2 is -H, Cl-C3 alkyl optionally substituted with 1 thru 3-Cl and-F and -p. It is preferred that acylating agent is acetic anhydride or trifluoracetic anhydride.

One equivalent of the acylating agent is required. When using an acylating agent, it is preferred to use it with an acylation catalyst. Preferred acylation catalysts are pyridine andp- dimethylaminopyridine (DMAP). With regard to solvents, it is important to perform the process under homogenous reaction conditions to avoid decomposition of the hydroperoxy compound (IV-OOH). This means using one phase conditions. Therefore, the solvent of choice will depend on the carboxylic acid forming agent used. If the carboxylic acid forming agent requires water to dissolve the reagent such as when the carboxylic acid forming agent is bicarbonate, then a water miscible organic solvent such as acetone, methanol, DMF or isopropanol is required. If the carboxylic acid forming agent is pyridine then the organic solvent can be a water immiscible organic solvent such as acetonitrile, methylene chloride or ethyl acetate. Hence, the selection of the solvent depends on the nature of the carboxylic acid forming agent used as is know to those skilled in the art. With the exception of the carboxylic acid forming agent (a) heat, the other acid forming agents (b), (c) and (d) can all be reacted at 20-25°. The reaction is quite fast and is usually over in less than one hour.

Both the hydroxy compound (IV-OH) and the biscarbonyl compound (V) are converted to the corresponding carboxylic acid (VI) in the same manner. The process involves contacting the hydroxy compound (IV-OH) or the biscarbonyl compound (V), or mixture thereof, with an oxidatively cleaving agent. Useful oxidatively cleaving agents are selected from the group consisting of : (1) hydrogen peroxide with a carboxylic acid forming agent selected from the group consisting of : (a) heat, (b) a base whose conjugate acid has a pKa of about 5 or above, (c) an acid which has a pKa of less than about 3, (d) an acylating agent and an acylation catalyst;

(2) KHSO5 ; (3) hydrogen peroxide with a ketone selected from the group consisting ofQ4-CO-Q5 where Q4 and Q5 are the same or different and are: Cl-C4 alkyl optionally substituted with 1 thru 9-Cl or-F, where the Q4 and Q5 are taken together with the attached carbon atom to form a cyclic ketone of 5 thru 7 members, and ketones of the formula: and 0 0 /d Cl-C12 alkyl Cl-C12 alkyl (4) hydrogen peroxide in combination with methyltrioxorhenium, (5) (p-C (CH3) 2-0-OH or an alkylhydroperoxide in combination with a metal containing activator, where alkyl is from C4-C1o alkyl and metal containing activator is selected from the group consisting of Ti (isopropoxide) 4, peroxotungstophosphate, VO (acetylacetonate) 2 and Mo hexacarbonyl; (6) peracids selected from the group consisting of (a) perbenzoic acid optionally substituted with 1 or 2-Cl or -NO2, (b) percarboxylic acids of the formula Cn2 (Q6) 2n2+l-CO3H where n2 is 1 thru 4 and Q6 is-H,-Cl or-F, (c) perphthalic acid,

(d) magnesium peroxyphthalate. It is preferred that the oxidatively cleaving agent is hydrogen peroxide with a carboxylic acid forming agent. When the carboxylic acid forming agents are (a) heat, (b) a base whose conjugate acid has a pKa of about 5 or above, (c) an acid which has a pKa of less than about 3 or (d) an acylating agent and an acylation catalyst, they should be used in the same manner as discussed above for the transformation of the hydroperoxy compound (IV-OOH) to the corresponding carboxylic acid (VI). As stated above, one equivalent of the oxidatively cleaving agent is required. Two equivalents are normally used and the reaction is monitored so that when the reaction nears completion it is stopped, or quenched, and worked up before the oxidatively cleaving agent attacks the A4- and/or A (")-steroid double bonds. Hydrogen peroxide and bicarbonate are preferred as the oxidatively cleaving agent. With regard to solvents it is important to perform the process under homogenous reaction conditions, meaning one phase conditions. Therefore, the solvent of choice will depend on the oxidatively cleaving agent used. If the carboxylic acid forming agent requires water to dissolve the reagent such as when the carboxylic acid forming agent is bicarbonate, then a water miscible organic solvent such as acetone, DMF, methanol or isopropanol is required. If the carboxylic acid forming agent is pyridine then the organic solvent can be a water immiscible organic solvent such as acetonitrile, methylene chloride or ethyl acetate. Hence, the selection of the solvent depends on the nature of the carboxylic acid forming agent used as is known to those skilled in the art. With the exception of the carboxylic acid forming agent (a) heat, the other acid forming agents (b), (c) and (d) can all be reacted at 20-25°. The reaction is quite fast and is usually over in less than one hour. If the reaction mixture contains some hydroperoxy compound (IV-OOH), then it is useful to first treat the reaction mixture with a hydroperoxy-deoxygenating agent. It is preferred that the hydroperoxy-deoxygenating agent is dimethylsulfide.

There are a number of processes to transform a carboxylic acid (VI) to the corresponding 5,7-lactone (VII), where the C-and D-rings of the starting carboxylic acid (VI) and product 5,7-lactone are the same. The processes differ depending on the nature of the steroid A-/B-rings of the starting carboxylic acid (VI). They use different reactants and produce 5,7-lactones (VII) with different steroid A-/B-rings. One of these processes produces a 5,7-lactone of formula (VII) (VII)

where (Va) R2 is-H:-H ; R3 is = O ; R4 is-H : -H; (Vb) R2 is-H:-H ; R3 is R3a : R3b where both R3a and R3b are-OH and R4 is -H : -H; where R9, Rll and R11 are as defined above, which comprises: (1) contacting a carboxylic acid of formula (VI) (VI) where (I) R3 is = O ; R4 is R4-1 : R4-2 where one of R4-1 and R42 is-H and the other of R41 and R4-2 is taken together with R5 to form a second bond between the carbon atoms to which they are attached; R6 is-H:-H ; (III) R3 is α-R3-5 : ß-R3-6 where R3-5 is -O-R31 and R3-6 is -O-R32 where R31 and R32 are the same or different and are selected from the group consisting of Cl-C3 alkyl and R3, and R32 are taken with the attached -O-C-O- to form a cyclic ketal of 5 or 6 atoms of the formula - (CH2)-(CR33R34)n1-(CH2)- where ni is 0 or 1; where R33 and R34 are the same or different and are-H and Cl-C3 alkyl ; R4 is

- H : -H; R6 is R6-5 : R6-6 where one of R6-5 and R6-6 is taken together with Rs to form a second bond between the carbon atoms to which they are attached and the other of R6-5 and R6 6 is - H ; (IV) R3 is α-R3-7 : p-R3 8 where R3 is-O-R31 and R3 8 is-O-R32 where R31 and R32 are as defined above; R4 is R4-7 : R4-8 where one of R4-7 and R4-8 is taken together with Rs to form a second bond between the carbon atoms to which they are attached and the other of R4-7 and R4 8 is-H; R6 is-H:-H ; where Rg, Rll and Rl7 are as defined above; with a reaction medium which has a pH of less than about 5. The conversion of the carboxylic acid (VI) to the corresponding 5,7- lactone (VII) is an equilibrium reaction. The lower the pH used for the reaction medium the more the equilibrium shifts toward the 5,7-lactone (VII), hence the desire to keep the pH less than 5 and preferably in the range of 1 thru 5. It is preferred to perform the reaction under anhydrous conditions; under anhydrous conditions it is preferred that the acid be a strong acid of pKa less than about 2. Useful strong acids include those selected from the group consisting of fluorosulfonic, chlorosulfonic, benzenesulfonic, p-toluenesulfonic, methanesulfonic, trifluoromethanesulfonic, trifluoroacetic, trichloroacetic, hydrochloric, sulfuric, phosphoric and nitric; it is preferred that the acid is benzenesulfonic, p- toluenesulfonic or methanesulfonic acid. Alternatively, the process can be performed using aqueous acid as the catalyst. Under these conditions it is preferred to perform the process in a two-phase system. The amount of acid used in not very important and can be present in an amount from catalytic to excess. Bases are also operable to catalyze the reaction of the carboxylic acid (VI) to the corresponding 5,7-lactone (VII) as long as they are used in a catalytic amount. Useful bases include those selected from the group consisting of hydroxide, bicarbonate, carbonate, DBU, DBN, DABCO, pyridine, p-dimethylaminopyridine, Q7-COO- where Q7is-H, Cl-C3 alkyl orqp, (Q3) 3N where Q3 is Cl-C3 alkyl ; preferred are hydroxide, bicarbonate, carbonate, triethylamine or pyridine. The solvents for the transformation of the carboxylic acid (VI) to the corresponding 5,7-lactone (VII) are helpful in effecting the equilibrium of the reaction. It is preferred to use a solvent in which the starting carboxylic acid (VI) is soluble and in which the 5, 7-lactone (VII) is not soluble. That way the 5,7- lactone (VII) precipitates out as it is formed pushing the equilibrium towards the desired 5,7- lactone (VII). A preferred solvent is acetone. This reaction is performed from about 0° to

about 25° and is complete in a few hours. Depending on the pH of the reaction medium and solvent used, ratios of < 95/5 of carboxylic acid (VI)/5, 7-lactone (VIT) are obtained. Since this process step is an equilibrium reaction, the pH of the reaction medium helps control the final position of the equilibrium as is known to those skilled in the art.

A second process for producing a 5, 7-lactone of formula (VII) (VII)

where (Va) R2 is-H : -H, R3 is =O and R4 is-H:-H ; where Rg, Rl and and R17 as defined above, comprises: (1) contacting a carboxylic acid of formula (VI) (VI)

where (I) R3 is = O ; R4 is R41 : R4-2 where one of R41 and R4-2 is-H and the other of R4 1 and R4-2 is taken together with R5 to form a second bond between the carbon atoms to which they are attached; R6 is-H:-H ; where R, Ru and Rl7 are as defined above; under anhydrous conditions with an anhydrous reaction medium of pH less than about 5. It is preferred that the reaction medium contains an acid which has a pKa of < about 4. Useful acids which have a pKa of < about 4 include those selected from the group consisting of fluorosulfonic, chlorosulfonic, benzenesulfonic, p-toluenesulfonic, methanesulfonic, trifluoromethanesulfonic,

trifluoroacetic, trichloroacetic, hydrochloric, sulfuric, phosphoric and nitric. It is preferred that the acid is benzenesulfonic, p-toluenesulfonic or methanesulfonic. It is also preferred that the carboxylic acid (VI) is reacted with the acid in a two-phase system. The process also includes reacting the carboxylic acid (VI) with a catalytic amount of base. Useful bases include those selected from the group consisting of hydroxide, bicarbonate, carbonate, DBU, DBN, DABCO, pyridine, p-dimethylaminopyridine, Q7-COO- where Q7 is-H, C1-C3 alkyl or qp, (Q3) 3N where Q3 is Cl-C3 alkyl.

A third process for producing a 5, 7-lactone of formula (VII) (VII) where (Vc) R2 is-H:-H, R3 is -O-R3a;-O-R3b where R3a and R3b the same and are Cl- C3 alkyl or where R3a and R3b are taken together with the attached-O-C-O-to form a cyclic ketal of 5 or 6 atoms of the formula - (CH2)- (CR33R34) nl- (CH2)- where ni is 0 or 1; where R33 and R34 are the same or different and are-H and Cl-C3 alkyl, and R4 is-H: - H ; (VI) R2 is-H:-H ; R3 is R3c : R3d and r4 is R4c;R4d where one of R3c and R3d is taken with one of R4c or R4d to form a second bond between the carbon atoms to which they are attached and the other of R3C and R3d is CH3-O-or C2H5-0- ; and the other of R4C and R4d is-H; or (VII) R2 is R2e : R2f and R3 is R3e : R3f where one of R2e and R2f is taken with one of R3e or R3f to form a second bond between the carbon atoms to which they are attached and the other of R2e and R2f is-H, and the other of R3e and R3f CH3-O- or C2H5-O-; or mixtures thereof; where R9, RI1 and RI are as defined above, comprises: (1) contacting a carboxylic acid of formula (VI) (VI)

where (III) R3 is α-R3-5 : P-R3-6 where R3-54 is -O-R31 and R3-5 is -O-R32 where R31 and R32 are the same or different and are selected from the group consisting of CI-C3 alkyl and Rsi and R32 are taken with the attached -O-C-O- to form a cyclic ketal of 5 or 6 atoms of the formula - (CH2)- (CR33R34) nl- (CH2)- where n, is 0 or 1; where R33 and R34 are the same or different and are-H and Cl-C3 alkyl ; R4 is <BR> <BR> <BR> <BR> -H : -H; R6 is R60-5 : R6-6 where one of R6-5 and R6-6 is taken together with Rs to form a second bond between the carbon atoms to which they are attached and the other of R6-5 and R6 6 is -H ; (IV) R3 is a-R3-7 : ß-R3-8 where R3 is-O-R31 and R3 8 is-O-R32 where R31 and R32 are as defined above; R4 is R4-7;R4-8 where one of R47 and R4-8 is taken together with R5 to form a second bond between the carbon atoms to which they are attached and the other of R4-7 and R48 is-H; R6 is-H : -H; where R9, R11 and R17 are as defined above; with at least a catalytic amount of acid. It is preferred that the acid have a pKa of < about 4 and are as discussed above.

The present invention includes a process for the preparation of a methyl ester of formula (VIII)

where (1) R3 is = O ; R4 is R41 : R4-2 where one of R4-1 and R42 is-H and the other of R4-1 and R4-2 is taken together with R5 to form a second bond between the carbon atoms to which they are attached; R6 is-H:-H ; where Rg, Rll and RI are as defined above, which comprises: (1) contacting a 5,7-lactone of the formula (VII) where R4 is-H:-H and where R3, Rg, Rl l and Rl7 are defined above, with base, and (2) contacting the reaction mixture of step (1) with a methylating agent.

The base needs to be strong enough to open the 5,7-lactone (VII) but of the type that will not react with the methylating agent, a weak nucleophile. Useful bases include those selected from the group consisting of bicarbonate, carbonate, hydroxide and RbaseO where Rbase is Cl- C4 alkyl. It is preferred that the base is bicarbonate. The amount of base required is from about 1 to about 1.5 equivalents. Useful methylating agents include those selected from the group consisting of dimethylsulfate, methyl iodide, methyl bromide, trimethylphosphate, dimethylcarbonate and methyl chloroformate ; preferred is dimethylsulfate. The amount of methylating agent used should be the same as the number of equivalents of base used or a very slight excess over that. The preferred method of the process is to react it in a sequential manner in a two-step reaction with base first and then the methylating agent. If the reaction is performed all in one step, the base reacts with the methylating reagent necessitating the need for more base and more methylating agent. The more efficient way is to first react the 5,7-

lactone (VII) with at least one equivalent of base, preferably from about 1 to about 1.5 equivalents and then to react the salt of the carboxylate acid (VI) which is formed with the methylating agent. The solvent used will depend on the nature of the base used. If it is water soluble, such as bicarbonate or hydroxide, then a mixture of water and a water miscible organic solvent is preferred. These water miscible organic solvents include, methanol, ethanol, isopropanol, acetone, THF and DMF. If the base is water soluble and the solvent is a mixture of water and a water immiscible solvent, then a phase transfer catalyst, such as tetrabutylammonium bisulfate or tributylmethylammonium chloride is used. If the base is soluble in a water immiscible organic solvent, one that will also dissolve the 5,7-lactone (VII), then a water-immiscible organic solvent is suitable. The reaction temperature is dependent on the reactivity of the methylating agent. If an agent such as dimethylcarbonate is used the reaction will go slow and heat up to about 150° may be necessary. On the other hand, if a more reactive agent such as dimethylsulfate is used the reaction goes in about 1 hour at 40°. While in theory one equivalent of base and one equivalent of methylating agent should be sufficient, in practice more than one equivalent is needed for the optimum reaction conditions.

The 5,7-lactone (VII) can be transformed to the (salt of the) corresponding carboxylic acid (VI) by contacting the 5,7-lactone of formula (VII), with a reaction medium which as a pH > 7. The reaction is similar to the transformation of the 5,7-lactone (VII) to the methyl ester (Vin) except that no methylating agent is used. Since only base is used, the product produced is the salt of the carboxylic acid (VI). Further, since no methylating agent is present, the amount of base used is not critical. If the acid form of the carboxylic acid (VI), is desired the salt form can be acidified to produced the corresponding acid form of the carboxylic acid (VI) as is known to those skilled in the art.

There are numerous alternative routes using the present invention as set forth in CHART A as will be explained below and is known to those skilled in the art. For example, the steroid A-ring can be protected, as compound (I-P), see CHART B and the explanation below, during the transformation of (1) to (IT) or used in the unprotected form (I). Further, the C-and D-rings can have a variety of functionality during the various steps of the process.

The C-ring functionality includes, for example, 9a-hydroxy, 9a-O- (HYDROXY PROTECTING GROUP), 9a-F, 11-keto, 11-saturated, 1la-hydroxy, l la-O- (HYDROXY

PROTECTING GROUP), 11ß-hydroxy, 11ß-O-(HYDROXY PROTECTING GROUP), #9(11)-and 9a, 1 la-epoxy. The D-ring functionality includes, for example, 17-keto, 17ß- hydroxy, 17α-ethyl-17ß-hydroxy, 17α-cyano-17ß-hydroxy, 17α-C#C-CH2-O-(-H or substitutedsilyl)-17ß-Oh, 17α-C#C-CH2-O-(HYDROXY PROTECTING GROUP)-17ß- OH, 17a-CH2-CH2-CH2-OH-17ß-OH, 17a-CH2-CH2-CH2-O-(HYDROXY PROTECT1NG GROUP)-17ß-OH, 17α-17ß-CO-CH3, 17ß-CO-CH2-OH, 17ß-CO-CH2-O-CO- (CH2) 0-3-CH3 ; 17ß-O-CH2-17a resulting in a three member epoxide, y-lactone and-0- CH (ORl79)-CH2-CH2 where the bond from the oxygen (-O) is one of the four bonds at C- 17 in the P-configuration and the bond from the methylene group (CH2-) is another of the four bonds at C-17 in the a-configuration to form a 5 member heterocycle containing one oxygen atom, where R17-9 is-H or Cl-C3 alkyl. However, the D-ring functionality for the compounds of the processes of claims 539,548 and 556 does not include R17-2 being hydroxyl. HYDROXY PROTECTING GROUPs are well known to those skilled in the art.

The same HYDROXY PROTECTING GROUPs are operable at C-9, C-11 and C-17 and are selected from the group consisting of-Si (-CH3) 3,-Si (-CH2-CH3) 3, -CO-CH3,-CO-H and- SiH (CH3) 2.

At some point the A-ring, if it is not already the required #43-3-keto functionality, must be transformed to the #4-3-keto functionality. Likewise, with the C-ring, if it is not already the required 9a, 1 la-epoxide functionality, it must be transformed to the 9a, l la-epoxide.

Similarly, if the D-ring is not already the required y-lactone, it must be transformed to the y- lactone. However, those transformations can take place either before, during or after various other processes and/or steps of CHART A. It is preferred to start with the A-ring with A4-3- keto functionality, the C-ring with A9 (ll)-functionality and the D-ring as the y-lactone. With regard to the C-ring, it is preferred to maintain the #9(11)-functionality throughout the process of the invention until the-CO-O-CH3 group is fully synthesized at the 7a-position and then transform the #9(11)-functionality to the corresponding 9a, 11 a-epoxide. With regard to the C- ring one could start with a 11-keto functionality and at some point in the process reduce it to the 11 a-hydroxy functionality and then at some later point dehydrate the 11 la-hydroxy functionality to the corresponding #9(11)-oleifn functionality by either the processes of EXAMPLEs 18-20 using PCIs or by the process of EXAMPLE 31 using N- (1, 1,2, 2,3, 3,3) hexafluoropropyldiethyl-amine which is known as Ishikawa reagent. There is a thorough

discussion below as to how the dehydration of an 11 a-hydroxy steroid should be performed using the Ishakawa reagent to produce the corresponding A' (")-olefin. If the dehydration of the 11 a-hydroxy to the corresponding A-olefin takes place with a 5'-methyl-2'-furyl substituent at C-7a, with a formula (II) compound, it appears PC15 is preferred, but if the dehydration takes place on the methyl ester (VII), then the Ishikawa reagent is preferred. The #9(11)-olefin is then converted to the desired 9a, 1 a-epoxide functionality by means well known to those skilled in the art. Likewise, with regard to the D-ring, one need not start with the y-lactone in the A4s6-3-keto steroid or ketal thereof (I) starting material. One could start with 17-keto or 17p-hydroxy, etc and then at a desired point covert the starting D-ring 17- functionality to the desired y-lactone. The preferred process including what functionality is desired to start with, and where the conversions are made, is set forth in CHART E. In short, it is desired to start with the same functionality as is desired in the end product for the A-ring and D-rings. It is preferred to start with the C-ring having the #9(11)-olefin functionality which is transformed to the desired 9a, 1 la-epoxide functionality after the 7a-substitutent is finalized as-CO-O-CH3. However, as explained above and is known to those skilled in the art, there are numerous alternative ways of preparing eplerenone by the process of CHART A starting with different functionality in the A-, C-and D-rings.

CHART B discloses a process to produce the protected #4.56-ketal steroid (I-P), from the corresponding 03'5-3-alkyl enol ethers which are readily available from the corresponding #4-3-keto steroids by processes known to those skilled in the art. It is preferred use the unprotected A4s6-3-keto steroid (I) as the starting material in the process of CHART A.

However, steroidal A4'6-3-ketals (I-P) can also be used as the starting material of the process of CHART A. In the process of CHART B, the #4,6-3-ketal steroid (I-P) where R3, and R32 (1) the same or different and are Cl-C3 aLkyl, and

(2) taken with the attached-O-C-O-to form a cyclic ketal of 5 or 6 atoms of the formula - (CH2)- (CR33R34) nl- (CH2)- where n, is 0 or 1; where R33 and R34 are the same ofr fifferent and are -H, C1-C3 alkyl, is produced from the corresponding A3, 5-3-alkyl enol ether (Alkyl enol ether) where R3 is Cl-C3 alkyl, CH3-CO-, #-CO- or RSi-1RSi-2RSi-3Si- where RSi-1,RSi-2 and RSi-3 are the same or different and are Cl-C4 alkyl ; by contacting the #3,5-3-alkyl enol ether (Alkyl enol ether) with a hydride abstractor and an alcohol selected from the group consisting of alcohols of the formula : (a) R31-OH, where R31 is as defined above, (b) R32-OH, where R32 is as defined above, (c) HO- (CH2)- (CR33R34) m- (CH2)-OH where ni, R33 and R34 are as defined above, (d) HO-CH2-CH2-OH, by (1) contacting the #3,5-3-enol ether (3-alkyl enol ether).

Useful hydride abstractors include those selected from the group consisting of DDQ, p-chloranil, o-chloranil, Mn+3, Mn+7, Pb+4,Pd+2,Ru+8,Cr+6, o-iodoxybenzoic acid, o-iodoxybenzoic acid complex with DMSO, o-iodoxybenzoic acid complex with 4-methoxypyridine-N-oxide,

N-methylmorpholine-N-oxide, trimethylamine-N-oxide, iodic acid (HIO3), iodine pentoxide (kOs), ceric ammonium nitrate, iodosobenzene, iodobenzenebistrifluoroacetate, iodobenzenediacetate, tritylfluoroborate, and by electrochemical oxidation with a catalytic amount of a hydride abstractor. It is preferred that the hydride abstractor isp-chloranil or DDQ, more preferably DDQ. One equivalent of the hydride abstractor is required; more is not harmful, just wasteful. It is preferred that the alcohol is neopentylglycol also known as dimethylpropyleneglycol or 2, 2-dimethyl-1, 3-propanediol. The solvent needs to dissolve the 3-alkyl enol ether (3-alkyl enol ether) starting material. Suitable solvents include methylene chloride, acetonitrile, THF, and the alike. The reaction is operable in the temperature range of about-78° to about 40°, preferred is about-15°. The reaction is very rapid and is complete in a few minutes at-15°. The entire process is preferably performed under essentially anhydrous conditions. The term"hydride abstractor"as used herein means the reagent effects the net removal of one of the hydrogen atoms at C-7 of the 3-dienol ether, and does not imply any mechanism by which this removal occurs. It is preferred that the a 4s6_ ketal (I-P) is selected from the group consisting of 17p-hydroxypregna-4, 6,9 (11)-trien-3-one-21-carboxylic acid, y-lactone, cyclic 3- (2', 2'-dimethyl-1', 3'-propanediyl ketal), 17p-hydroxypregna-4, 6,9 (11)-trien-3-one-21-carboxylic acid, y-lactone, cyclic 3- ethanediyl ketal.

CHART C discloses that the 7a-substituted steroid (IT) can also be transformed to the corresponding cis-oxyenedione (X-cis) by (1) contacting the 7a-substituted steroid (II) with ozone in the presence of a Cl-C4 alcohol and (2) contacting the mixture of step (1) with a hydroperoxy-deoxygenating agent. The preferences for R7, Xl Rb, Rc, Rd and the other variable substituents are as set forth above as previously stated. The 7a-substituted steroid (II) is dissolved in a suitable Cl-C4 alcohol, or mixture thereof. It is preferred that the Cl-C4

alcohol is a Cl and C3 alcohols; it is more preferred the alcohol is a Cl alcohol. Cosolvents such as methylene chloride can also be used if necessary. The nature of the solvent/co- solvent is not critical as long as it will dissolve the reactants at the cold temperature at which the process is performed. The nature of the alcohol is not critical as it is eventually lost from the steroid molecule. The reaction temperatures can be as low as about-100° up to about 40°. It is preferred that the temperature be from about-78° to about-20° ; it is more preferred that the temperature be about-50°. Ozone is passed thru the reaction mixture as is known to those skilled in the art until the process of step (1) is complete. The course of the reaction is monitored as is known those skilled in the art. When the reaction of step (1) is complete, the reaction mixture of step (1) is contacted with a hydroperoxy-deoxygenating agent. It is preferred that the hydroperoxy-deoxygenating agent is trimethylphosphite. It is realized that for other processes of this invention the preferred hydroperoxy-deoxygenating agent was dimethylsulfide, but here the preferred agent is trimethylphosphite. The reaction mixture is then slowly permitted to warm to 20-25°. The reaction will proceed rapidly when it reaches the correct temperature for the particular 7a-substituted steroid (II). The cis- oxyenedione (X-cis) product can be carried along without isolation and purification if desired.

CHART C further discloses that the cis-oxyenedione (X-cis) can be transformed to the corresponding trans-oxyenedione (X-trans). The process is performed in the same manner and same way that the cis-enedione (m-CM), of CHART A, was transformed to the corresponding trans-enedione (I-trans).

The cis-oxyenedione (X-cis) or the trans-oxyenedione (X-trans), or a mixture thereof, can be transformed to the corresponding hydroperoxy compound (IV-OOH), and/or hydroxy compound (IV-OH), and/or biscarbonyl compound (V) and/or carboxylic acid (VI) or mixture thereof in the same manner and same way as the cis-enedione (IH-CM) or the trans-enedione (E-trans), or a mixture thereof, was transformed to the corresponding hydroperoxy compound (IV-OOH), and/or hydroxy compound (IV-OH), and/or biscarbonyl compound (V) and/or carboxylic acid (X) or mixture thereof. The hydroperoxy compound (IV-OOH), and/or hydroxy compound (IV-OH), and/or biscarbonyl compound (V) and/or carboxylic acid (X) or mixture thereof are then transformed to eplerenone (IX) in the same manner and same was as previously discussed for the process of CHART A.

The cis-oxyenedione (X-cis) or the trans-oxyenedione (X-trans), or a mixture thereof, can be transformed to the corresponding carboxylic acid (VI) by reaction with an oxidatively cleaving agent in the same manner and same way as the hydroxy compound (IV-OH), and/or biscarbonyl compound (V) are transformed to the corresponding carboxylic acid (VI).

CHART D sets forth the preferred process of the invention (when R71 is-Al) with regard to the steroid A-/B-ring, that the steroid A-ring is not protected. However, given the different variable substituents of the steroid C-and D-rings and combinations of variable substituents possible, in some cases it may be preferred to protect the steroid A-ring as would be apparent to one skilled in the art. But in general, it is preferred that the steroid A-ring not be protected and the preferred process be that of CHART D.

CHART E sets forth the preferred process of the invention with the preferred variable substituents for each intermediate for the conversion of the #4,5-3-keto steroid (I) to eplerenone (IX).

CHART F discloses the reversible nature of the conversion of the carboxylic acid (VI) with the 5,7-lactone (VII).

CHART G discloses the general process of the invention when the adduct -R7-1 is the cyclic adduct (-A2). The 7a-substituted steroid (II) is formed in the same manner as discussed above for CHART A when the adduct is (-A1). Then the 7a-substituted steroid (IT) where R7-1 is (-A2) is reacted in the same way, with the same reagents as used in CHART A for (-A1) to give intermediates of the same type as the intermediates of CHART A for adduct (-A1). The processes of CHARTs A and G are analogous, the reactants are the same and used in the same order. The intermediates produced are either isomers or homologs of each other.

CHART H discloses the general process of the invention when the adduct Ry. i is (-B), (-C), (-D1), (-D2) and (-D3). The process of CHART H is a two step process. The first step of the process is to transform the A4, 6-3-keto steroid or ketal thereof (11 starting material to the corresponding 7a-substituted steroid (II) where R7 s is a substituent selected from the group consisting of - CRb2=M (-B) <BR> <BR> -C-=CRc2 (-C)<BR> <BR> <BR> <BR> <BR> <BR> -CH2-CH=CH2 (-D1)

- CH=C=CH2 (-D2) - CH2-C=C-H (-D3) The second step is oxidative cleavage of the 7a-substitutent to give a carboxylic acid functionality, -CO-OH of the carboxylic acid (VI). In the olefmic substituent (-B),"M"is a group which forms a double bond with carbon and is restricted to carbon, nitrogen and oxygen. The substituent Rb2 is a group that can be transformed into a hydroxyl group by either oxidation or hydrolysis. With the acetylenic substituent (-C), the group Rc2 can be virtually any group since it is ultimately lost when the triple bond is cleaved to a carboxylic acid (VI). Likewise with the three-carbon unsaturated substituents (- D1), (-D2) and (-D3), two of the three carbon atoms are cleaved oxidatively, leaving a carboxylic acid group. In transforming the A4°6-3-keto steroid or ketal thereof (I) starting material to the corresponding 7a-substituted steroid (II), the A46-3-keto steroid or ketal thereof (I) starting material is reacted with the nucleophile selected from the group consisting of (d) of the formula (B) Ra-CEi=M (B) (e) of the formula (C) R,-C=C-E2 (C) (f) of the formulas (D1, D2 and D3) Ra-CH2-CH=CH2 (D1) Ra-CH=C=CH2 (D2) Ra-CH2-C=C-H (D3) where Ra, El, E2, M are as defined above, in the presence of : (1) a Lewis Acid, (2) a proton acid with a pKa of < about 5 or (3) a salt of a secondary amine of the formula and

with an acid of pKa of < about 2. The Lewis acid both accelerates the conjugate addition and favors formation of the 7a-stereochemistry.

Adducts (-B) and (-C) are transformed into-CO-OH of carboxylic acid (VI) by treatment with one or more oxidizing agents. The oxidizing agent (s) must be capable of cleaving the C=M double bond to a carbon-oxygen double bond, cleaving the C-Rb2 single bond to a carbon-oxygen single bond, and cleaving the carbon-carbon triple bond to carboxylic acid. The choice of oxidizing agent (s) depends on the inherent difficulty of oxidation of the substituent-CRb2=M or-C-C-RC2. The greater the difficulty of oxidation, the stronger the oxidizing agent that will be required. Suitable oxidizing agents include ozone, singlet oxygen, triplet oxygen, hydrogen peroxide, hydroperoxides, percarboxylic acids, hypohalites, and the like. In the case of 2-methylfuran adduct (IT), transformation into carboxylic acid (VI) is preferably accomplished by treatment with potassium hypobromite followed by ozone followed by dimethylsulfide followed by hydrogen peroxide.

The allyl adduct (-D1) is transformed into-CO-OH of the carboxylic acid (VI) by double bond isomerization to-CH=CH-CH3 followed by ozonization with an oxidative work-up (such as sodium chlorite). The double bond isomerization can be accomplished by any of the following reagents, rhodium trichloride in ethanol at reflux, HRuCl [P (-cep) 3] 3 at about 90°, LiNH (CH2) 3NH2 (lithium 1,3-diaminopropane) at 20-25°, PdCl2 ((p-CN) 2 in toluene at about 80°, HRh (CO) [P (-cp) 3] 3 at 20-25°, ClRh [P (-(p) 3] 3 in toluene at reflux, Cl2Ru [P (-(p) 3] 3 at 100° and cobalt chloride/sodium borohydride/P (-cep) 3 at about-18°.

The propargyl adduct (-D2) is transformed into the-CO-OH functionality of the carboxylic acid (VI) by base or transition metal-catalyzed isomerization to adduct (-C) when RC2 is Cl alkyl, which is cleaved by the method discussed above. Suitable bases for isomerization of (-D2) to (-C) include sodium amide in ammonia or THF, potassium 3- aminopropylaminde (known as"KAPA") in THF, potassium hydroxide in ethylene glycol at

about 150°, potassium t-butoxid in DMSO or t-butanol, or sodium or potassium hydride in DMF or THF. Suitable transition metal catalysts include Yb [ (p2C =N- (p] (HMPA) 4 and HCo (N2) [P (-T) 313.

The allenyl adduct (-D3) is transformed into the-CO-OH functionality of the carboxylic acid (VI) by ozonization with an oxidative work-up (such as sodium chlorite).

The present invention includes a four-step process for the transformation of a 7a- substituted steroid (I1) to the corresponding carboxylic acid (VI) product. The four steps are (1) ring opening, (2) ozonolysis, (3) reaction with a hydroperoxy deoxygenating agent and (4) reaction with an oxidatively cleaving agent. The four-step process of the invention produces better yields of the carboxylic acid (VI) than expected based on prior art process steps. The carboxylic acid (VI) is obtained by: (1) contacting the 7a-substituted steroid of formula (II) with an agent selected from the group consisting of : (a) a halogenating agent in the presence of water and a base whose conjugate acid has a pKa of > about 8, (b) an oxygen donating agent, (c) electrochemical oxidation, (d) a quinone in the presence of water or (e) nonquinone oxidants; and (2) contacting the reaction mixture of step (1) with ozone in the presence of an alcohol of the formula R7-2-OH ; (3) contacting the reaction mixture of step (2) with a hydroperoxy deoxygenating agent and (4) contacting the reaction mixture of step (3) with an oxidatively cleaving agent.

Each of these steps was thoroughly discussed above when the steps of the process were discussed individually. This process combines those same steps and they are practiced in the same manner and same way as discussed above.

The present invention includes a three-step process for the transformation of a 7a- substituted steroid (II) to the corresponding carboxylic acid (VI) product, see EXAMPLE 34, Step (1). The three steps are (1) ozonolysis, (2) reaction with a hydroperoxy deoxygenating

agent and (3) reaction with an oxidatively cleaving agent. The three-step process of the invention is a process to prepare the carboxylic acid (VI) which comprises: (1) contacting a 7a-substituted steroid (II) with ozone in the presence of an alcohol of the formula R72--OH ; (2) contacting the reaction mixture of step (1) with a hydroperoxy deoxygenating agent and (3) contacting the reaction mixture of step (2) with an oxidatively cleaving agent.

Each of these steps was thoroughly discussed above when the steps of the process were discussed individually. This process combines those same steps and they are practiced in the same manner and same way as discussed above. The carboxylic acid (VI) can be readily transformed to its tautomer-like the bislactone (VII) by contacting with an acid, see EXAMPLE 34, Step (2). In the process of the invention it is the carboxylic acid (VI) which is transformed to the methyl ester (VHI) and ultimately to eplerenone (1X). It is possible to isolate and purify this carboxylic acid (VI) by crystallization. However, one runs the risk that it will isomerize to the bislactone (VII) which is more thermodynamically stable. Therefore, as a practical matter it is preferable not to stop at the end of EXAMPLE 34, Step (1) but carry on thru the reaction mixture and isolate and crystallize the bislactone (VII). Hence, it is easier and preferable to carry the process exemplified in EXAMPLE 34 on thru Step (2), purify the bislactone (VII) obtained and then convert the bislactone (VII) back to the carboxylic acid (VI) for transformation to the methyl ester (VIII).

Eplerenone (IX) is a pharmaceutical agent useful for the treatment of hyperaldosteronism, edema, hypertension and congestive heart failure, see US Patent 4,559, 332.

The present invention also includes a novel process to transform 1 la-hydroxy steroids to the corresponding A9 (")-steroids. The #9(11)-functionality is very useful in producing eplerenone (IX) because it is readily transformed to the corresponding 9a, 1 la-epoxide functionality of eplerenone (IX).

The 11 a-hydroxy steroid (CIV) starting materials are known to those skilled in the art.

More particularly, the 1 la-hydroxy-17-lactone (CI), 1 la, l7ß-dihydroxypregn-4-en-3-one- 7Of, 21-dicarboxylic acid, y-lactone, methyl ester, is known, see, Drugs of the Future, 24 (5), 488-501 (1999), compound (VI).

For the 11 la-hydroxy steroids (CIV) it is preferred that the steroid A-ring is: (A-ring)

(1) Wl is-H : -H and Wz is-H:-H or Wl is W1-1 : W1-2 and W2 is W2-1 : W22 where one of W1-1 or Wl 2 is taken together with one of W2-1 or W2-2 to form a second bond between the carbon atoms to which they are attached and the other or W1-1 or W1-2 and W2-1 or W2-2 is-H; W3 is =0, W4 is W4-i : W4-2 where one of W4-1 and W4-2 is taken together with Ws to form a second bond between the carbon atoms to which they are attached and the other of W4-1 and W4-2 is-H; (2) W3 is =O, W4 is-H:-H and W5 is in the a-orientation and is O-CO- (attached at C7 to form a 5,7-lactone) and where Wl and W2 are as defined above; (3) W3 is -O-W3-3:-O-W3-4; W4 is W43 : W4-4, where one of W4-3 and W44 is taken together with W5 to form a second bond between the atoms to which they are attached and the other of W43 and W4-4 is-H ; W3-3 and W3-4 are: (a) the same or different and are C1-C5 alkyl, (b) taken together to form a cyclic moiety selected from the group consisting of : <BR> <BR> <BR> <BR> (i)-CH2-CH2-,<BR> <BR> <BR> <BR> <BR> <BR> <BR> (ii)-CH2-CH2-CH2-, (iii)-CH2-C (CH3) 2-CH2-; and where Wl and W2 are as defined above; (4) W3 is-0-W3-3 :-O-W3-4; W4 is-H:-H ; Ws forms a second bond between Cs and C6 ; W3-3 and W34 are as defined above: (5) W3 is W3-5 : W3-6 ; where (a) one of W3-5 and W3-6 is-H and the other of W3-5 and W3-6 is: (i)-0-W3-5A Where W3-5A is Cl-C3 alkyl, (ii)-0-CO-W3-5A where W3-5A is as defined above, (iii)-N(W3-5A)2 where W3-5A is as defined above,

(iv) piperazinyl, (v) morpholinyl, (vi) piperidinyl, (b) W3-5 and W3-6 are taken together with the carbon atom to which they are attached to form a cyclic moiety including: (i)-O-CH2-CH2-O-, (ii)-O-CH2-CH2-CH2-O-, (iii)-O-CH2-C (CH3) 2-CH2-0- and where W4 is-H:-H ; W5 forms a second bond between C5 and C6 ; (6) W3 is W3-7 : W3-8 and where W4 is W4-7 : W4-8 where (a) one of y and W3-8 is: (i)-O- W3-7A where W3-7A is C1-C3 alkyl, (i)-O-CO-W3-7A where W3-7A is as defined above, (iii)-N(W3-7A)2 where W3-7A is as defined above, (iv) piperazinyl, (v) morpholinyl, (vi) piperidinyl, and where the other ofW3-7 and W3-8 is taken together with one ofW4-7 and W4-8 to form a second bond between the carbon atoms to which they are attached and the other ofW4-7 and W4-8 is-H; W5 forms a second bond between C5 and C6 ; (7) W3 is α-W3-9 : ß-W3-10; where W3-9 si -H and W3-10 is: (a) -O-CO-W3-10A where W3-10A is Cl-C3 alkyl, (b) -O-CO-O-W3-10B where W3-10B is (i) Cl-C4 alkyl, (ii) qp optionally substituted with one thru three Cl-C3 alkyl, g-F,-Cl,-Br,-I, Cl-C3 alkoxy, (iii)-CH2-# where # is optionally substituted with one thru three C1-C3 alkyl, -F, -C, -Br, -I, C1-C3 alkoxy ; where WR4 is-H:-H ; and W5 forms a second bond between the carbon atoms at C5 and C6 ; and where Wi and W2 are as defined above;

(8) W3 is α-W3-9 : ß-W3-10 ; where W4 is W4-9 : W4-10 where W3-9 and W3-10 are as defined above; where one of W4-9 and W4-10 taken together with W5 forms a second bond between the atoms to which they are attached and the other of W4-9 and W4 s0 is-H; and where Wl and W2 are as defined above.

It is more preferred that the steroid A-ring functionality be: (1) Ws is-H:-H and W2 is-H:-H or Wl is Wl-, : W1-2 and W2 is Wiz_1 : W2-2 where one of W1-1 or W1-2 is taken together with one of W21- or W2-2 to form a second bond between the carbon atoms to which they are attached and the other or W1-1 or W1-2 and W2-1 or W2-2 is -H ; W3 is =O, W4 is W4-1 : W4-2 where one of i and W4-2 is taken together with W5 to form a second bond between the carbon atoms to which they are attached and the other of W4-1 and W4-2 is-H ; (7) W3 is α-W3-9 : ß-W3-10; where W3-9 is -H and W3-10 is: (b)-CO-W3-10A where W3-10A is Cl-C3 alkyl, (c)-CO-O-W3-10B where W3-10B is (i) C1-C4 alkyl, (ii) qp optionally substituted with one thru three Cl-C3 alkyl, -F, -Cl, -Br, -I, C1-C3 alkoxy, (iii)-CH2-# where (p is optionally substituted with one thru three Cl- C3 alkyl, -F, -Cl, -Br, -I, Cl-C3 alkoxy; where WR4 is-H:-H ; and W5 forms a second bond between the carbon atoms at C5 and C6 ; and where Wl and W2 are as defined above.

It is even more preferred that the steroid A-ring functionality be: (1) Wl is-H:-H and W2 is-H:-H or Wl is Wl-l : W1-2 and W2 is Wiz_1 : W2-2 where one of W1-1 or W1-2 is taken together with one of W2-1 or W2-2 to form a second bond between the carbon atoms to which they are attached and the other or W1-1 or Wl 2 and W2-1 or W22 is-H; W3 is =O, W4 is W4-1 : W4-2 where one of W4-1 and W4-2 is taken together with W5 to form a second bond between the carbon atoms to which they are attached and the other of i and W4-2 is-H; For the 1 la-hydroxy steroids (CIV), it is preferred that the steroid D-ring is: (D-ring)

where W17 is: (1) =0, (2) α-W17-1 : ß-W17-2 where: (a) W17-1 and W17-2 are taken together with the attached carbon atom to form an epoxide of the formula CH2-O-, (b) W17-1 and W17-2 are taken together with the attached carbon atom to form a lactone of the formula CH2-CH2-CO-O-; (3) a-Wi7-3 : ß-W17-4 where (a) W17-3 is: (i)-H, (ii)-O-CO-W17-3A where W17-3A is -H or -CO-W17-3B where W@17-3B is Cl-C4 alkyl or-cep and (b) W17-4 is -CO-CH3 ; (4) α-W17-5 : ß-W17-6 where (a) W, 7-5 is: (i)-0-CO-WI7-5A where W17-5A is Cl-C4 alkyl or-T, (b) W17-6 is : (i)-CO-CH2-0-WI7-6A where W17-6A is Cl-C4 alkyl or (p For the eplerenone-type compounds, it is preferred that W17 is: (1) =0, (2) α-W17-1:ß-W17-2 where: (a) W17-1 and W17-2 are taken together with the attached carbon atom to form an epoxide of the formula CH2-0-, (b) W17-1 and W17-2 are taken together with the attached carbon atom to form a lactone of the formula -CH2-CH2-CO-O-.

It is more preferred that for the eplerenone-type compounds that W17 is:

(1) =0, (2) α-W17-1#-W17-2 where: (b) Wl7 l and W17-2 are taken together with the attached carbon atom to form a lactone of the formula -CH2-CH2-CO-O-.

For the progesterones and hydroxyprotesterones it is preferred that that Wl7 is: (3) α-W17-3 : ß-W17-4 where (a) Wu-3 is: (i)-H, (ii)-O-CO-W17-3A where Wi7-3A is -H or -CO-W17-3B where W17-3B is Cl-C4 alkyl or-cep and (b) W17-4 is-CO-CH3.

For the corticoids it is preferred that Wl7 is: (4) a-Wu-s : ß-W17-6 where (a) W17-5 is: (i)-O-CO-W17-5A where Wu-sua is Cl-C4 alkyl or-T, (b) 17-5 si : (i)-CO-CH2-O-Wl76A where Wn-6A is Cl-C4 alkyl or .

The preferred combinations of steroid A-, B-and D-rings, especially for the eplerenone-type compounds, includes the ring systems set forth in CHART C. The 11 a- hydroxy steroids (CIV) of CHART C are known to those skilled in the art or can be readily prepared by known methods from known compounds.

In the process of the present invention the 11 la-hydroxy-17-lactones (CI) or 11 la- hydroxy steroids (CIV) starting material is contacted with a N-fluoroalkylamine reagent of the formula (CVI) where:

Zl is C1-C4 alkyl ; Z2 is Cl-C4 alkyl and where Zi and Z2 together with the attached nitrogen atom form a 5-or 6-member heterocycle selected from the group consisting of pyrrolidinyl, piperazinyl, piperidinyl and morpholinyl; Z3 is-F or-CF3. It is preferred that Zl and Z2 are Cl-C3 alkyl. It is more preferred that Zl and Z2 are Cl alkyl or C2 alkyl. It is preferred that the N-fluoroalkylamine (CVI) is N- (1,1, 2,3, 3,3-hexafluoropropyl) diethylamine, which is known as Ishikawa reagent, or 1,1, 2,2- tetrafluoroethyl-N, N-dimethylamine.

The process of the invention is preferably performed by use of about 1 equivalent of 11 a-hydroxy-17-lactone (CI) or 11 a-hydroxy steroid (CIV) and from about 1 to about 1.5 equivalents of Ishikawa reagent; more preferred is about 1.2 equivalents of Ishikawa reagent.

It is preferable to perform the process of the invention in a temperature range of from about 20 to about 82° ; more preferably from about 40 to about 70°. The reaction usually takes from about 1 hr to about 24 to complete depending on reaction conditions especially temperature and concentration. For example at about 60° and 0.8 molar, the reaction takes about 3 hours.

The 1 a-hydroxy-17-lactone (CI) orl la-hydroxy steroid (CIV) can be added to the N- fluoroalkylamine reagent (CVI) or the N-fluoroalkylamine reagent (CVI) can be added to the 1 la-hydroxy-17-lactone (CI) orl la-hydroxy steroid (CIV); it is more practical to add the N- fluoroalkylamine reagent (CVI) to the 1 a-hydroxy-1 7-lactone (CI) orl la-hydroxy steroid (CIV).

It is preferred to perform the process of the present invention in a solvent that is dry (KF is < 0.5%), such as acetonitrile.

The A9 (ll)-17-lactone of formula (CD), 17ß-hydroxypregna-4, 9 (11)-dien-3-one-7a, 21- dicarboxylic acid, y-lactone, methyl ester, is known, see US Patent 4,559, 332, Example l (d) and International Publication W098/25948, page 284. It is useful in the preparation of a pharmaceutical agent, 9a, 11α-epoxy-17ß-bydroxypregn-4-en-3-one-7α-21-dicarboxylic acid, -lactone, methyl ester, known as eplerenone (CIII),.

The steroid C-ring functionality #9(11)-of compounds (CII) and (CV) is a very useful functionality to chemists skilled in the art of steroids. It can be readily transformed to the corresponding 9a, 1 la-epoxy functionality and the 9a-fluoro-11 8-hydroxy functionality as well as 11-keto and others as is well known to those skilled in the art. These compounds are

useful pharmaceutical agents. Hence, the process of the invention as it pertains to the transformation of the 1 la-hydroxy steroid (CIV) to the corresponding A' (")- steroid (CV) is a very useful process and is operable with a wide variety of 11 a-hydroxy steroids (CIV) as is apparent to those skilled in the art. This includes progesterones, 17a-hydroxyprogesterones, corticoids as well as the usual common derivatives and analogs thereof such as esters, etc.

Therefore, the process produces A9 (")-steroids (CV) which are useful intermediates in the preparation of pharmaceutically useful steroids. One skilled in the art with a given A9 (1) steroid (CV) would know how to transform it to a pharmaceutically useful product.

The present invention also includes a number of processes for transforming 11 a- hydroxy compounds to the corresponding #9(11)-compounds by one or more processes described above. For example, described are processes for the transformation of (1) a 1 la- hydroxy-7a-substituted steroid (II) to the corresponding #9(11)-7α-substituted steroid (II), (2) a process for transforming a 11 a-hydroxy cis enedione (m-cis) or 1 la-hydroxy trans enedione (111-trans) to the corresponding A9 (")-trans enedione (III-trans) and (3) for transforming a 1 la-hydroxy-hydroxy compound (IV-OH) or a 1 la-hydroxy-hydroperoxy compound (IV-OOH) or a 11 a-hydroxy biscarbonyl compound (V) or mixture thereof to the corresponding A'-carboxylic acid (VI).

DEFINITIONS AND CONVENTIONS The definitions and explanations below are for the terms as used throughout this entire document including both the specification and the claims.

I. CONVENTIONS FOR FORMULAS AND DEFINITIONS OF VARIABLES The chemical formulas representing various compounds or molecular fragments in the specification and claims may contain variable substituents in addition to expressly defined structural features. These variable substituents are identified by a letter or a letter followed by a numerical subscript, for example,"Zl"or"R ;" where"i"is an integer. These variable substituents are either monovalent or bivalent, that is, they represent a group attached to the formula by one or two chemical bonds. For example, a group Zl would represent a bivalent variable if attached to the formula CH3-C (=Zl) H. Groups R ; and Rj would represent monovalent variable substituents if attached to the formula CH3-CH2-C (Ri) (Rj) H2. When chemical formulas are drawn in a linear fashion, such as those above, variable substituents contained in parentheses are bonded to the atom immediately to the left of the variable

substituent enclosed in parenthesis. When two or more consecutive variable substituents are enclosed in parentheses, each of the consecutive variable substituents is bonded to the immediately preceding atom to the left which is not enclosed in parentheses. Thus, in the formula above, both Ri and Rj are bonded to the preceding carbon atom. Also, for any molecule with an established system of carbon atom numbering, such as steroids, these carbon atoms are designated as Ci, where"i"is the integer corresponding to the carbon atom number. For example, C6 represents the 6 position or carbon atom number in the steroid nucleus as traditionally designated by those skilled in the art of steroid chemistry. Likewise the term"R6"represents a variable substituent (either monovalent or bivalent) at the C6 position.

Chemical formulas or portions thereof drawn in a linear fashion represent atoms in a linear chain. The symbol"-"in general represents a bond between two atoms in the chain.

Thus CH3-0-CH2-CH (Ri)-CH3 represents a 2-substituted-1-methoxypropane compound. In a similar fashion, the symbol"="represents a double bond, e. g., CH2=C (Ri)-O-CH3, and the symbol"="represents a triple bond, e. g., HC=C-CH (Ri)-CH2-CH3. Carbonyl groups are represented in either one of two ways:-CO-or-C (=O)-, with the former being preferred for simplicity.

Chemical formulas of cyclic (ring) compounds or molecular fragments can be represented in a linear fashion. Thus, the compound 4-chloro-2-methylpyridine can be represented in linear fashion by N*=C (CH3)-CH=CCI-CH=C*H with the convention that the atoms marked with an asterisk (*) are bonded to each other resulting in the formation of a ring. Likewise, the cyclic molecular fragment, 4-(ethyl)-1-piperazinyl can be represented by -N*- (CH2) 2-N (C2H5)-CH2-C H2- A rigid cyclic (ring) structure for any compounds herein defines an orientation with respect to the plane of the ring for substituents attached to each carbon atom of the rigid cyclic compound. For saturated compounds which have two substituents attached to a carbon atom which is part of a cyclic system,-C (Xi) (X2)- the two substituents may be in either an axial or equatorial position relative to the ring and may change between axial/equatorial.

However, the position of the two substituents relative to the ring and each other remains fixed. While either substituent at times may lie in the plane of the ring (equatorial) rather than above or below the plane (axial), one substituent is always above the other. In chemical

structural formulas depicting such compounds, a substituent (Xl) which is"below"another substituent (X2) will be identified as being in the alpha (a) configuration and is identified by a broken, dashed or dotted line attachment to the carbon atom, i. e. , by the symbol"---"or"...".

The corresponding substituent attached"above" (X2) the other (XI) is identified as being in the beta (B) configuration and is indicated by an unbroken line attachment to the carbon atom.

When a variable substituent is bivalent, the valences may be taken together or separately or both in the definition of the variable. For example, a variable R ; attached to a carbon atom as-C (=R ;)- might be bivalent and be defined as oxo or keto (thus forming a carbonyl group (-CO-) or as two separately attached monovalent variable substituents a-Ri-j and B-Rj-k. When a bivalent variable, Ri, is defined to consist of two monovalent variable substituents, the convention used to define the bivalent variable is of the form"a-Ri. j : B-Ri-k" or some variant thereof. In such a case both a-Ri-j and ßRi k are attached to the carbon atom to give-C (a-R (B-Ri-k)-. For example, when the bivalent variable R6,-C (=R6)- is defmed to consist of two monovalent variable substituents, the two monovalent variable substituents are α-R6-1:ß-R6-2, .... α-R6-9 : ß-R6 l0 etc, giving-C (α-R6-1)(ß-R6-2)-, .... -C(α-R6-9)(ß-R6-10)-, etc.

Likewise, for the bivalent variable R11 -C(=R11)-, two monovalent variable substituents are a-Rl l-i : ß-R1 1-2. For a ring substituent for which separate a and B orientations do not exist (e. g. due to the presence of a carbon carbon double bond in the ring), and for a substituent bonded to a carbon atom which is not part of a ring the above convention is still used, but the a and B designations are omitted.

Just as a bivalent variable may be defined as two separate monovalent variable substituents, two separate monovalent variable substituents may be defined to be taken together to form a bivalent variable. For example, in the formula-Cl (Ri) H-C2 (Rj) H- (Cl and C2 define arbitrarily a first and second carbon atom, respectively) R ; and Rj may be defined to be taken together to form (1) a second bond between Cl and C2 or (2) a bivalent group such as oxa (-O-) and the formula thereby describes an epoxide. When Ri and Rj are taken together to form a more complex entity, such as the group-X-Y-, then the orientation of the entity is such that Cl in the above formula is bonded to X and C2 is bonded to Y. Thus, by convention the designation"... Ri and Rj are taken together to form-CH2-CH2-O-CO-..."means a lactone in which the carbonyl is bonded to C2. However, when designated"... Rj and Ri are taken

together to form-CO-O-CH2-CH2-the convention means a lactone in which the carbonyl is bonded to Ci.

The carbon atom content of variable substituents is indicated in one of two ways. The first method uses a prefix to the entire name of the variable such as"Cl-C4", where both"1" and"4"are integers representing the minimum and maximum number of carbon atoms in the variable. The prefix is separated from the variable by a space. For example,"Cl-C4 alkyl" represents alkyl of 1 through 4 carbon atoms, (including isomeric forms thereof unless an express indication to the contrary is given). Whenever this single prefix is given, the prefix indicates the entire carbon atom content of the variable being defined. Thus C2-C4 alkoxy- carbonyl describes a group CH3- (CH2) n-0-CO-where n is zero, one or two. By the second method the carbon atom content of only each portion of the definition is indicated separately by enclosing the"Ci-Cj"designation in parentheses and placing it immediately (no intervening space) before the portion of the definition being defined. By this optional convention (Ci-C3) alkoxycarbonyl has the same meaning as C2-C4 alkoxycarbonyl because the"Cl-C3"refers only to the carbon atom content of the alkoxy group. Similarly while both C2-C6 alkoxyalkyl and (CI-C3) alkoxy (Ci-C3) alkyl define alkoxyalkyl groups containing from 2 to 6 carbon atoms, the two definitions differ since the former definition allows either the alkoxy or alkyl portion alone to contain 4 or 5 carbon atoms while the latter definition limits either of these groups to 3 carbon atoms.

When the claims contain a fairly complex (cyclic) substituent, at the end of the phrase naming/designating that particular substituent will be a notation in (parentheses) which will correspond to the same name/designation in one of the CHARTS which will also set forth the chemical structural formula of that particular substituent.

II. DEFINITIONS All temperatures are in degrees Celsius.

TLC refers to thin-layer chromatography.

LC refers to liquid chromatography.

ESTDLC refers to external standard liquid chromatography.

THF refers to tetrahydrofuran.

DMAP refers to p-dimethylaminopyridine.

DDQ refers to 2,3-dichloro-5, 6-dicyano-1, 4-benzoquinone.

DBU refers to 1, 8-diazabicyclo [5.4. 0] undec-7-ene.

DBN refers to 1, 5-diazabicyclo [4.3. 0] non-5-ene.

DABCO refers 1, 4-diazabicyclo [2.2. 2] octane.

Chromatography (column and flash chromatography) refers to purification/separation of compounds expressed as (support, eluent). It is understood that the appropriate fractions are pooled and concentrated to give the desired compound (s).

Carboxylic acid (VI) refers to and includes the pharmaceutically acceptable salts thereof.

CMR refers to C-13 magnetic resonance spectroscopy, chemical shifts are reported in ppm (8) downfield from TMS.

NMR refers to nuclear (proton) magnetic resonance spectroscopy, chemical shifts are reported in ppm (d) downfield from TMS.

In the present invention the terms conversion/transformation or convert/transform are used interchangeable and mean the same thing, the reaction of one compound to form a different compound by the process described.

TMS refers to trimethylsilyl.

Oxone refers to KHSO5.

-¢ refers to phenyl (C6H5).

MS refers to mass spectrometry expressed as m/e, m/z or mass/charge unit. [M + H] + refers to the positive ion of a parent plus a hydrogen atom. EI refers to electron impact. CI refers to chemical ionization. FAB refers to fast atom bombardment.

Pharmaceutically acceptable refers to those properties and/or substances which are acceptable to the patient from a pharmacological/toxicological point of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability.

When solvent pairs are used, the ratios of solvents used are volume/volume (v/v).

When the solubility of a solid in a solvent is used the ratio of the solid to the solvent is weight/volume (wtlv).

A9-Canrenone refers to 17ß-hydroxypregna-4, 6,9-trien-3-one-21-carboxylic acid,- lactone.

Eplerenone refers to 9a, l la-epoxy-17p-hydroxypregn-4-en-3-one-7a, 21-dicarboxylic acid, y-lactone, methyl ester.

Neopentylglycol refers to HO-CH2-C (CH3) 2-CH2-OH.

Iodosobenzene refers to (pu=0.

Iodobenzenebistrifluoroacetate refers to (pI (O-CO-CF3) 2.

Iodobenzenediacetate refers to (pI (O-CO-CH3) 2.

Tritylfluoroborate is also known as triphenylcarbenium fluoroborate and refers to 93C+BF4-. acac refers to acetylacetonate. dppb refers to diphenylphosphino butane.

Tf refers to trifluoromethanesulfonate.

Dimethylsulfide refers to CH3SCH3.

Ishikawa reagent refers to N- (1, 1, 2,2, 3,3, 3) hexafluoropropyldiethylamine.

An"oxidatively cleaving agent"is a reagent that oxidizes the biscarbonyl compound (V) or hydroxy compound (IV-OH) to the carboxylic acid (VI).

A"hydroperoxy-deoxygenating agent"is a reagent that removes an oxygen atom from a hydroperoxide compound (IV-OOH) to give the corresponding hydroxy compound (IV- OH).

A"deoxygenating agent"is a reagent that removes one oxygen atom from a molecule.

The"hydroperoxy-deoxygenating agent"is thus a particular type of deoxygenating agent.

A"carboxylic acid forming agent"is a reagent that induces a hydroperoxide compound (IV-OOH) to rearrange to a carboxylic acid (VI).

An"oxygen donating agent"is a reagent that provides an oxygen atom to a 7a- substituted steroid (II) to transform it into a cis enedione (MI-cM).

PXRD refers to powder X-ray diffraction.

EXAMPLES Without further elaboration, it is believed that one skilled in the art can, using the preceding description, practice the present invention to its fullest extent. The following detailed examples describe how to prepare the various compounds and/or perform the various processes of the invention and are to be construed as merely illustrative, and not limitations of the preceding disclosure in any way whatsoever. Those skilled in the art will promptly recognize appropriate variations from the procedures both as to reactants and as to reaction conditions and techniques.

EXAMPLE 1 17p-Hydroxypregna-4, 6,9 (11)-trien-3-one-21-carboxylic acid, y- lactone, cyclic 3- (2', 2'-dimethyl-l', 3'-propanediyl ketal) (I-P)

17p-hydroxypregna-4, 6,9 (11)-trien-3-one-21-carboxylic acid, y-lactone 3-methyl enol ether (1, 3.00 g, 8.4629 mmoles) and lithium perchlorate (199.6 mg, 1.8761 mmoles, 0.22 equivalents) are slurried in acetonitrile (20 ml) and methylene chloride (10) are cooled to - 15°, treated with 2, 2-dimethyl-1, 3-propyleneglycol (2.19 g, 21.027 mmoles, 2.48 equivalents), then treated drop wise over 73 min. with a solution of DDQ (2.29 g, 10.088 mmoles, 1. 19 equivalents) in ethyl acetate. After stirring for 40 min, the reaction mixture is quenched with ammonium hydroxide (28%, 5 ml), diluted with ethyl acetate, concentrated, diluted with methylene chloride, and filtered. The filtrate is diluted with ethyl acetate, washed with aqueous sodium bicarbonate/sodium chloride followed by water, then filtered through magnesol, eluting with methylene chloride. The eluate is concentrated to give solids which are triturated with toluene, dried by a stream of nitrogen to give the title compound, CMR (CDC13) 14.44, 22.53, 22.78, 23.02, 24.89, 28.85, 29.22, 30.07, 30.18, 31.31, 32.92, 35.37, 38.56, 39.03, 44.35, 44.43, 70.54, 70.65, 95.17, 95.43, 116.80, 120.23, 127.82, 130.27, 141.83, 145.08 and 176. 616 ; NMR (CDC13) 0.95, 0.97, 1.03, 1.18, 1.3-2. 8,3. 5-3.7, 5.44, 5.71, 5. 80and6. 028. EXAMPLE 2 17, 6-Hydroxypregna-4, 6,9 (11)-trien-3-one-21-carboxylic acid, y- lactone, cyclic 3-ethanediyl ketal (I-P)

17p-hydroxypregna-4, 6,9 (11)-trien-3-one-21-carboxylic acid,-lactone 3-methyl enol ether (I, 300 mg, 0.8463 mmoles) in methylene chloride (5 ml) is cooled to -15° then treated with ethylene glycol (220 mg, 3.544 mmoles, 4.19 equivalents). To this mixture is added drop wise over 30 min. a solution of DDQ (230 mg, 1.0132 mmoles, 1.20 equivalents). After the addition is complete, the reaction is stirred at-15° for 5 min. , at which time TLC analysis (ethyl acetate/cyclohexane, 66/34) shows conversion of the starting methyl enol ether (Rf= 0.69) into the corresponding ethylene ketal (Rf = 0.54) was nearly complete. The reaction is then quenched with concentrated ammonium hydroxide (0.5 ml), and filtered. The filtrate is then filtered through 1.0 g cartridge grade magnesol and concentrated to give the title compound, by comparison with an authentic sample, CMR (CDC13) 14.37, 22.95, 24.54, 29.15, 30.28, 31.23, 32.87, 35.30, 38.17, 38.45, 44. 27,44. 37,64. 15,64. 70,95. 07,105. 94, 116.85, 122.39, 127.41, 130.24, 141.71, 145.76 and 176. 51 ô ; NMR (CDC13) 0.97, 1.18, 1.3- 2.9, 3.8-4. 1,5. 29,5. 45,5. 70 and 5.99 S.

EXAMPLE 3 17ß-Hydroxy-7a-(5'-methyl-2'-furyl)-pregna-4, 9 (11)-dien-3-one-21- carboxylic acid, y-lactone (IT)

A9-canrenone (I, 90.0 g, 0.2659 moles) is mixed with nitromethane (730-735 ml).

Then 2-methylfuran (49.5 ml, 45.04 g, 0.5487 moles, 2.06 equivalents) is added. The resulting mixture is cooled to-20° then treated with absolute ethanol (15.8 ml, 12.55 g, 0.2723 moles, 1.02 equivalents) followed by boron trifluoride etherate, (d = 1.120 ; 37.2 ml, 41.66 g, 0.2936 moles, 1. 10 equivalents). The mixture is recooled to-18. 4° and stirred for 17 hrs. , at which time the reaction was complete by LC. The reaction mixture is quenched with ammonia (15% aqueous, 225 ml). The mixture is warmed to above 0°, water (200 ml) is added, the organic phase is separated, and the aqueous phase is extracted with methylene chloride (2 x 200 ml). The organic extracts are dried over magnesium sulfate (100 g) then filtered through magnesol (100 g cartridge grade), washing the cake with methylene chloride (5 x 200 ml). The eluate is then concentrated under reduced pressure to a foam, slurried with ethyl acetate (200 ml) and reconcentrated, then dissolved in ethyl acetate (950 ml) at 50° to 60°. The mixture is concentrated to about 500 ml volume, then diluted with cyclohexane (250 ml). The product begins to crystallize slowly. The slurry is reconcentrated to about 500 ml volume, cooled to 20-25°, further concentrated to about 400 ml volume, then cooled to 0°.

After overnight at 0°, the slurry is filtered and the cake washed with cyclohexane followed by heptane and dried in a vacuum oven at 50° to give the title compound, TLC = 0.37 (ethyl acetate/cyclohexane, 66/34), CMR (CDC13) 13. 38, 14.12, 23.18, 26.83, 29.14, 31.26, 32.93, 33.93, 34.18, 35.39, 37.57, 38.52, 40.78, 41.90, 42.39, 44.08, 95.19, 105.89, 107.12, 119.73, 126.24, 149.99, 152.74, 167.45, 76.53 and 198.56 ; NMR (CDC13) 0.95, 1.43, 1.4-2. 6,2. 16, 2.93, 3.30, 5.68 and 5.74 8.

The filtrate is concentrated to a foam which is dissolved in ethyl acetate (40 ml), concentrated to about 20 ml, seeded, diluted with cyclohexane (20 ml), concentrated to about 30 ml, cooled to 0° over the weekend, then filtered, washed with ethyl acetate/cyclohexane (1/2) and dried to give additional title compound. EXAMPLE 4 17ß-Hydroxy-7oc-(trans-1', 4'-dioxopent-2'-en-1'yl) pregna-4,9 (11)- dien-3-one-21-carboxylic acid,-lactone (E-trans)

Step A: 17ß-Hydroxy-7α-(cis-1',4'-dioxopent-2'-en-1'yl) pregna-4,9 (11)-dien-3-one- 21-carboxylic acid, γ-lactone (III-cis) A mixture of 17p-hydroxy-7 (x- (5'-methyl-2'-furyl)-pregna-4, 9 (11)-dien-3-one-21- carboxylic acid, y-lactone (II, EXAMPLE 3,5. 04 g, 11.9843 mmoles) and potassium acetate (1.7 g, 17.32 mmoles, 1.45 equivalents) in THF (40 ml) and water (12.5 ml) at 23. 8° is treated with dibromantin (2.0 g, 6.995 mmoles, 0.58 equivalents) followed by isobutyl vinyl ether (500 gel, 384 mg, 3.834 mmoles, 0.32 equivalents). The reaction mixture is stirred at 20-25° for 1 hr. , at which time conversion of the starting material (II, Rf= 0.50) into cis-and trans- enedione (Rf= 0.11) is complete by TLC (ethyl acetate/cyclohexane, 66/34). The reaction mixture is diluted with water (200 ml) and extracted with methylene chloride (2 x 100 ml).

The extracts are combined, washed with water (50 ml), dried over magnesium sulfate, filtered and concentrated to give the cis-enedione (m-csS).

Step B: 17ß-Hydroxy-7a-(trans-1', 4'-dioxopent-2'-en-1'yl) pregna-4,9 (11)-dien-3- one-21-carboxylic acid, y-lactone (III-trans) The concentrate (Step A) is taken up in chloroform (100 ml) and the mixture is stirred at 20-25° for 20 hrs. , at which time conversion of cis-enedione into trans-enedione is judged to be complete as measured by TLC and LC (cisltrans = 1.1/98. 9). The mixture is then concentrated and the concentrate is taken up in ethyl acetate (20 ml) at 20-25° and diluted with cyclohexane (80 ml), which induces crystallization. The slurry is cooled, filtered, and the cake washed with cyclohexane and dried under reduced pressure at 50'to give the title

compound, CMR (CDC13) 13.98, 23.28, 27.08, 28.66, 29. 01, 31.26, 32.77, 33.61, 34.01, 35.22, 35.28, 40.48, 40.51, 42.41, 44.43, 48.13, 94.77, 118.81, 126.03, 135.89, 137.04, 142.16, 165.21, 176.32, 197.81, 198.26 and 200.18 ; NMR (CDCl3) 1.04, 1.30, 1.51, 1.5-3. 6, 2.45, 5.71, 5.78 and 6.89 o ; MS (electrospray) m/e = 435 (p+-l) negative ion mode; EXAMPLE 5 17p-Hydroxypregna-4, 9 (11)-dien-3-one-7a, 21-dicarboxylic acid, y- lactone (VI) Step A: 17ß-hydroxy-7α-(1'-oxo-2'-isopropoxy-2'-hydroxy-ethyl) pregna-4,9 (11)- dien-3-one-21-carboxylic acid, 7-lactone (IV-OH); 17ß-hydroxy-7α-(1'-oxo- 2'-isopropoxy-2'-hydrohydroperoxyethyl) pregna-4,9 (11)-dien-3-one-21- carboxylic acid, 7-lactone (IV-OOH) and 17p-hydroxy-7a- (2'-oxo-acetyl)- pregna-4,9 (11)-dien-3-one-21-carboxylic acid, γ-lactone (V) A mixture of 17ß-hydroxy-7a-(trans-1', 4'-dioxo-pent-2'-en-1'yl) pregna-4,9 (11)- dien-3-one-21-carboxylic acid, γ-lactone (III-trans, EXAMPLE 4,551. 8 mg, 1.2640 mmoles) in isopropanol (11 ml) and methylene chloride (5 ml) is cooled to-55°. Ozone in oxygen is bubbled through this mixture until 0.4 area% (by LC) trans-enedione (III) remained. The mixture is purged of ozone by sparging with nitrogen for 7 minutes to give a mixture of the title compounds.

Step B: 17ß-hydroxy-7α-(1'-oxo-2'-ixopropoxy-2'-hydroxy-ethyl) pregna-4,9 (11)- dien-3-one-21-carboxylic acid, γ-lactone (IV-OH), 170-hydroxy-70c- (l', 2'- dioxo-ethyl) pregna-4,9 (11)-dien-3-one-21-carboxylic acid,-lactone (V) and

17ß-Hydroxy-7a-(2'-oxo-acetyl)-pregna-4, 9 (11)-dien-3-one-21-carboxylic acid, y-lactone (V) The mixture of Step A is then quenched with dimethylsulfide (340 gel, 288 mg, 4.630 mmoles, 3.66 equivalents), warmed to 20-25°, stirred at 20-25° for 50 min. to give a mixture of the title compounds.

Step C: 17ß-Hydroxypregna-4,9(11)-dien-3-one-7α,21-dicarboxylic acid, γ-lactone (VI) The mixture of Step B is then treated with hydrogen peroxide (70% aqueous, 430 µl, 560 mg, containing 392 mg (11.52 mmoles, 9.12 equivalents) of hydrogen peroxide) and a solution of potassium bicarbonate (637.7 mg, 6.369 mmoles, 5.04 equivalents) in water (8 ml). The resulting two-phase mixture is diluted with enough methanol to produce a one- phase mixture (5 ml), which is then stirred at 20-25° for 16 hrs. , then diluted to a volume of 500 ml with methanol for purpose of LC analysis. LC analysis indicates the title compound is obtained by comparison with a known compound.

A 20.0 ml portion of the 500 ml solution was withdrawn and further diluted with methanol to a volume of 50 ml. This solution (containing 17.3 mg [0.0450 mmoles] carboxylic acid by LC) is concentrated to a low volume, diluted with water, acidified with hydrochloric acid (1N), and extracted with methylene chloride (2 x). The two extracts are each washed in sequence with water, then combined and concentrated. The concentrate is taken up in methanol/toluene (1/1 ; 2 ml) and treated with a mixture of trimethylsilyldiazomethane, (CH3) 3SiCHN2, in hexane (2.0 M, 0.25 ml, 0.50 mmoles, 11.1 equivalents). TLC analysis (ethyl acetate/cyclohexane; 66/34) indicates the title compound is obtained, Rf= 0.23 ; LC analysis (210 nm detection) indicates the same retention time as a known standard and that the title compound is obtained.

EXAMPLE 6 17ß-Hydroxypregna-4, 9 (11)-dien-3-one-7a, 21-dicarboxylic acid, y- lactone, methyl ester (VE)

The remainder of the 500 ml mixture of Step C of EXAMPLE 5 (479 ml, containing 414.4 mg [1.0777 mmoles] 17ß-hydroxypregna-4, 9 (11)-dien-3-one 7a, 21-dicarboxylic acid, y-lactone (VI, EXAMPLE 5C) is concentrated partially, diluted with water (20 ml), concentrated to a volume of about 20 ml, treated with hydrochloric acid (18 ml) and extracted with methylene chloride (25 ml, then 2 x 15 ml). The extracts are washed with water (30 ml), combined, and concentrated to a volume of 50.0 ml. Half of this mixture is concentrated to a low volume, diluted with ethyl acetate, and extracted with potassium bicarbonate (25% aqueous, 20 ml, then 10 ml). The extracts are combined, acidified to pH 3 with hydrochloric acid (IN) and extracted with methylene chloride (40 ml, then 2 x 15 ml). The extracts are then combined, washed with water, concentrated to a volume of <1 ml, and treated with a solution of sodium carbonate (349.6 mg, 3.298 mmoles, 6.12 equivalents based on carboxylic acid) in water (1.0 ml) followed by tetra-n-butylammonium bisulfate, (n-butyl) 4NHS04, (20.4 mg, 0.0601 mmoles, 0.11 equivalents) followed by dimethylsulfate (108 gel, 144.0 mg, 1.14 mmoles, 2.11 equivalents). The mixture is diluted with methylene chloride (0.1 ml), stirred at 20-25° for 11.5 hrs. , treated with hydrochloric acid (1 N, 10 ml) and extracted with methylene chloride (10 ml, then 2 x 5 ml). The extracts are combined, washed with water, and concentrated to give the title compound, consistent with a known standard.

EXAMPLE 7 17ß-Hydroxy-7a-(cis-3'-acetoxyacryloyl)-pregna-4, 9 (11)-dien-3-one- 21-carboxylic acid, y-lactone (X-cis)

A stream of 03/02 (ozone/oxygen) is passed through a cold (-78°) mixture of 17p- hydroxy-7a- (5'-methyl-2'-furyl)-pregna-4, 9 (11)-dien-3-one-21-carboxylic acid,-lactone (II, EXAMPLE 3,3. 0138 g, 7.1663 mmoles) in methylene chloride (40 ml) and methanol (10 ml) until the starting material had been consumed (LC, 25 min), then the mixture is purged with 02 followed by nitrogen, quenched with trimethylphosphite (3.0 ml, 3.16 g, 25.435 mmoles, 3.55 equivalents), and warmed to 20-25°. After stirring for 1 hr. , LC analysis indicates the title compound is obtained, CMR (100 MHz, CDCl3) 198.49, 198.23, 176.43, 166.63, 166.10, 142.74, 142.44, 125.87, 118.12, 110.39, 94.99, 49.30, 44.47, 42.30, 40. 59,-40, 35.46, 35.33, 34.11, 33.63, 32.83, 31.37, 29.11, 27.26, 23.31, 20.67 and 14.06 8 ; NMR (400 MHz,. CDC13) 0.94, 1.40, 1.5-2. 9,2. 29,5. 38, 5.63 and 7.48 8.

EXAMPLE 8 17ß-Hydroxy-7a-(bSans-3'-acetoxyacryloyl)-pregna-4, 9 (11)-dien-3- one-21-carboxylic acid, γ-lactone (X-trans) 0 H3CO ? H, C I H ''r H ii 1 ! T H 0 H"' O H Cis-Enolacetate Trans-Enolacetate" ouzo After stirring the reaction mixture of EXAMPLE 7, 17 (3-hydroxy-7a- (cis-3'- <BR> <BR> acetoxyacryloyl) -pregna-4,9 (11)-dien-3-one-21-carboxylic acid, γ-lactone (X-cis, EXAMPLE 7) for 1 hr. , the reaction mixture is quenched with hydrochloric acid (5% aqueous, 25 ml) and stirred at 20-25° for 20 min. , at which time isomerization to trans is complete. The organic phase is then separated, concentrated, and flash chromatographed (silica gel, 150 g ; gradient elution, 40% # 70% ethyl acetate/cyclohexane) to give the title compound. This material is then crystallized from ethyl acetate/heptane (70/30) to give the title compound in pure form, CMR (100 MHz, CDC13) 199.25, 198.39, 176.41, 166.79, 166.39, 149.00, 142.57, 125.67, 118.20, 113.11, 94.90, 47.75, 44.40, 42.40, 40. 45,-40, 35.63, 35.25, 34.01, 33.56, 32.73, 31.29, 29.04, 27.14, 23.32, 20.47 and 13.98 o, NMRi (400 MHz, CDC13) 1.14, 1.4-4. 1,1. 61, 2.44, 5.75, 6.14 and 8.41 8. EXAMPLE 9 17ß-Hydroxy-7α- (2'-hydroperoxy-2'-methoxyacetyl) pregna-4, 9 (11)- dien-3-one-21-carboxylic acid, y-lactone (IV-OOH) 0 H3C 0 zum A,, H3C H _ H O OCH3 O'' OH H (X-trans) (IV-OOH) 0To

A stream of ozone/oxygen is passed through a cooled (-78°) mixture of 17 (3-hydroxy- 7a- (trans-3'-acetoxyacryloyl)-pregna-4, 9 (11)-dien-3-one-21-carboxylic acid, y-lactone (X- trans, EXAMPLE 8,311. 0 mg, 0.6872 mmoles) in methylene/methanol (2/1, 6 ml) until a blue color persisted (3 min. ). The excess ozone is purged with oxygen followed by nitrogen, then the reaction mixture is warmed to 20-25° and diluted with methylene chloride to 10 ml.

A portion of this mixture (3.5 ml, from 0.2405 mmoles trans-enolacetate) is concentrated to dryness to give the title compound.

EXAMPLE 10 5a, 17ß-Dihydroxypregn-9 (11)-ene-3-one 7a, 21-dicarboxylic acid, bis-y-lactone (VIn 17ß-Hydroxy-7a-(2'-hydroperoxy-2'-methoxyacetyl) pregna-4,9 (11)-dien-3-one- 21 carboxylic acid, y-lactone (IV-OOH, EXAMPLE 9,3. 5 ml, from 0.2405 mmoles trans- enolacetate) is concentrated to dryness and the residue dissolved in trifluoroacetic acid (1.0 ml), stirred at 20-25° for 20 min. , then diluted with ethyl acetate (1.0 ml), washed with aqueous sodium bicarbonate, diluted with methylene chloride (2.0 ml), washed with diluted aqueous hydrochloric acid and concentrated. The concentrate is taken up in methylene

chloride (1.0 ml), stirred with aqueous hydrochloric acid (6N) for 30 min, then concentrated to give the title compound, CMR (100 MHz, CDC13) 206.39, 176.80, 175.59, 139.66, 124.11, 95.12, 91.11, 47.14, 43.99, 42.45, 41.66, 41.63, 41.15, 39.01, 37.04, 35.23, 33.08, 32.50, 31.42, 29.21, 23.16, 23.06 and 14. 30 # ; NMR (400 MHz, CDC13) 0.94, 1.40, 1.5-2. 6,2. 80, 5.70 8 ; MS (CI, NH3) m/e = 402 (100%, P + NH4).

EXAMPLE 11 17ß-Hydroxy-7α-(2'-oxo-acetyl)-pregna-4, 9 (11)-dien-3-one-21- carboxylic acid, y-lactone (V) 0 0 0 X X < (v A/HC 7 _v Hv (V) HRSo (III-trans) H C H'\ O,,, . i/ , Z, ^ O o 0 0 A stream of ozone/oxygen is passed through a cooled (-79°) mixture of 17p-hydroxy- 7a-(trans-1', 4'-dioxopent-2'-en-1'yl) pregna-4,9-dien-3-one-21-carboxylic acid, y-lactone (III-trans, EXAMPLE 4B, 503.4 mg, 1.1531 mmoles) in methylene chloride/methanol (1/1, 4.0 ml) until TLC analysis (acetone/methylene chloride, 3/7) indicates that conversion of starting material (Rf= 0.70) to a more polar product (Rf= 0.45) is complete (10 min. ). The reaction mixture is then quenched with dimethylsulfide (0.20 ml, 169 mg, 2.72 mmoles, 2.34 equivalents), stirred at 20-25° for 1 hr. , and then concentrated. The concentrate is flash chromatographed (silica gel, 60 g; gradient elution, acetone/methylene chloride 5%- 25%) to give the title compound, CMR (100 MHz, CD3CN) 198.68, 197.54, 187.93, 176.09, 166.40, 142.33, 125.02, 118.56, 94. 44,-44, 42.49, 40. 34,-40, 39.87, 34.60, 33.83, 33.56, 33.32, 32.39, 30.53, 28.39, 26.16, 22.43 and 13.22 5 ; NMR (400 MHz, CD3CN) 0.87, 1.37, 1.2-2. 9,5. 49,5. 63 and 8.93 8 ; MS (CI, NH3) m/e = 397 (P + H, 100%).

EXAMPLE 12 lla, 17p-Dihydroxy-7a- (5'-methyl-2'-iuiyl)-pregn-4-en-3-one-21- carboxylic acid, y-lactone (IT)

A mixture of 1 la-hydroxycanrenone (I, 30.00 g, 84.1586 mmoles) in nitromethane (240 ml) and methylene chloride (60 ml) is cooled to-20° then treated with 2-methylfuran (15.6 ml, 14.20 g, 0.1729 moles, 2.05 equivalents) followed by ethanol (5.1 ml, 4.03 g, 87.454 mmoles, 1.04 equivalents) followed by boron trifluoride diethyl etherate (BF3 OEt2, 12.0 ml, 13.44 g, 94.695 mmoles, 1.13 equivalents). The reaction mixture is stirred at-17° for 20 hrs. , then quenched with ammonia (15% aqueous, 60 ml), extracted with methylene chloride (120 ml), dried over sodium sulfate (40 g) and concentrated. The concentrate is dissolved in methylene chloride/ethyl acetate (1/1,300 ml) concentrated to a volume of 75 ml, diluted with 150 ml cyclohexane, concentrated to a volume of 200 ml, and filtered to give the title compound, CMR (75 MHz, CDC13) 199.59, 176.67, 170. 11, 152.92, 150.28, 126.20, 108.67, 105.90, 95.18, 68.55, 52.05, 45.84, 45.58, 43.08, 39.73, 38.62, 38.42, 37.47, 36.54, 35.26, 34.17, 30.91, 29.05, 22.62, 18.40, 15.58 and 13. 44 8 ; NMR (300 MHz, CDC13) 1. 01, 1.1-3. 2,1. 41, 2.20, 4.12, 5.73, 5.83 and 5.93 8.

The filtrate is concentrated. The concentrate is taken up in ethyl acetate (30 ml warm), cooled to 10°, and filtered to give a second crop of crystal of the title compound.

EXAMPLE 13 17ß-Hydroxy-7a-(5'-methyl-2'-furyl)-pregna-4, 9 (11)-dien-3-one-21- carboxylic acid, y-lactone (111)

A mixture of l lct, l7ß-dihydroxy-7a-(5'-methyl-2'-furyl)-pregn-4-en-3-one-21- carboxylic acid,-lactone (II, EXAMPLE 12,438. 3 mg, 0.9994 mmoles) in THF (7.3 ml) is cooled to-50°, then treated all at once with solid phosphorous pentachloride, (PCIs, 287.5 mg, 1. 381 mmoles, 1. 38 equivalents). After stirring for 42 min. , analysis by LC indicates that conversion to the title compound is complete. After another 21 min. , the mixture is quenched with water (22 ml) and warmed to 20-25°. After 20 min. , the mixture is extracted with methylene chloride (2 x 15 ml), dried over magnesium sulfate, and concentrated to give the title compound, identified by LC retention time comparison with a sample from EXAMPLE 3.

EXAMPLE 14 9a, 11la-Epoxy-17p-hydroxy-7a- (5'-methyl-2'-furyl)-pregn-4-en-3- one-21-carboxylic acid, y-lactone (In

A mixture of 9α,11α-epoxycanrenone (I, J. Med. Chem., 6,732 (1963) and Helv.

Chim. Acta 80,566 (1997), 10.0135 g, 28.2508 mmoles) in nitromethane (80 ml) and methylene chloride (20 ml) is cooled to-20° then treated with 2-methylfuran (5.10 ml, 4.64 g, 56.529 mmoles, 2.00 equivalents) followed by ethanol (1.7 ml, 1.343 g, 29.151 mmoles, 1.03

equivalents) followed by boron trifluoride diethyl etherate (BF3'OEt2, 3.6 ml, 4.03 g, 28.408 mmoles, 1. 01 equivalents). The reaction mixture is stirred at-20° for 24 hrs. , at which time conversion to the product is complete as determined by LC, so the reaction is quenched with aqueous ammonia (15%, 10 ml), extracted with methylene chloride (2 x 100 ml), and concentrated to a residue which is flash chromatographed (560 g silica gel; gradient elution, 50% # 90% ethyl acetate/cyclohexane). The material obtained by chromatography is triturated with cyclohexane (100 ml) at reflux for two hrs. , then cooled to 0° and filtered to give the title compound, CMR (75 MHz, CDC13) 198.10, 176.26, 165.67, 153.19, 149.96, 127.56, 107.92, 106.14, 94.66, 65.45, 49.92, 43.82, 40.00, 39.18, 37.43, 37.37, 35.54, 35.00, 33.24, 31.00, 30.81, 28.91, 26.98, 22.26, 22.00, 16.61 and 13.47 8 ; NMR (300 MHz, CDC13) 1.02, 1.3-3. 0,1. 52,2. 20,3. 28,5. 85,5. 92 and 6.01 8. The assigned structure is confirmed by X-ray crystallography.

EXAMPLE 15 17ß-Hydroxypregna-4, 9 (11)-dien-3-one-7a, 21-dicarboxylic acid, y- lactone (VI) via direct ozonization of 17ß-hydroxy-7a-(cis-4'-oxo- pent-2'-enoyl) -3-oxo-pregna-4,9 (11)-diene-21-carboxylic acid, y- lactone (m-css) A stream of ozone/oxygen is passed through a cooled (-55°) mixture of 17p-hydroxy- 7a-(cis-4'-oxo-pent-2'-enoyl)-pregna-4, 9 (11)-dien-3-one-21-carboxylic acid, y-lactone (E- cis, EXAMPLE 4 Step A, 52.4 mg, 0.1200 mmoles) in methylene chloride/isopropyl alcohol (1/1, 3.0 ml) containing water (50 mg, 2.77 mmoles, 23.1 equivalents) until disappearance of starting material is complete by LC (126 secs.). The reaction mixture is then quenched with dimethylsulfide (0.033 ml, 27.9 mg, 0.449 mmoles, 3.74 equivalents), stirred at 20-25'four 45 min. , then diluted with methanol (5 ml), treated with aqueous hydrogen peroxide (70%, 50 jell,

containing 45.6 mg [1.34 mmoles, 11.2 equivalents] of hydrogen peroxide, treated with a mixture of potassium bicarbonate (62.4 mg, 0.623 mmoles, 5.19 equivalents) in water (2 ml) and the resulting mixture stirred at 20-25°. After 15 hrs, analysis by LC indicates formation of the title compound.

EXAMPLE 16 17ß-Hydroxypregna-4, 9 (11)-dien-3-one-7a, 21-dicarboxylic acid, 7- lactone (VI) via direct ozonization of 17p-hydroxy-7a- (trans-4'-oxo- pent-2'-enoyl) -pregna-4,9 (11)-dien-3-one-21-carboxylic acid, y-lactone<BR> <BR> (E-trans) 0 0 H H3 . n H3C O H3C I H H3C S < "",'o OH OH O A stream of ozone/oxygen is passed through a cooled (-55°) mixture of 17p-hydroxy- 7a-(trans-4'-oxo-pent-2'-enoyl)-pregna-4, 9 (11)-dien-3-one-21-carboxylic acid, y-lactone (m- trans, EXAMPLE 4 Step B, 103.5 mg, 0.2371 mmoles) in methylene chloride/isopropyl alcohol (1/1,3 ml) containing water (50 mg, 2.77 mmoles, 11.7 equivalents) until disappearance of starting material is complete by LC (100 secs.). The reaction mixture is then quenched with dimethylsulfide (CH3SCH3, 65 ul, 55.0 mg, 0.885 mmoles, 3.73 equivalents), stirred at 20-25° for 45 min. , then diluted to a volume of 10.0 ml with methanol.

A 5.0 ml portion of this mixture is treated with aqueous hydrogen peroxide (70%, 50 RI, containing 45.6 mg [1.34 mmoles, 11.3 equivalents] of hydrogen peroxide, treated with a mixture of potassium bicarbonate (59 mg, 0.589 mmoles, 4.97 equivalents) in water (2.1 ml), and the resulting mixture stirred at 20-25°. After 15 hrs. , analysis by LC (ESTD) indicates formation of the title compound, CMR (100 MHz, CDC13) 199.96, 177.42, 174.28, 169.06, 142.10, 124.86, 118.60, 95.60, 44.23, 43.48, 42.61, 40.38, 39.79, 35.59, 35.08, 33.73, 33.30, 32.57, 31.05, 28.98, 26.80, 22.92 and 13.68 8 ; NMR (400 MHz, CDC13) 0.96, 1.42, 1.5-3. 0, 4.28, 5.64 and 5.74 6 ; MS (CI, NH3 ; m/e) = 402 (P +NH4+).

EXAMPLE 17 5a, 17ß-Dihydroxypregn-9(11)-ene-3-one 7α, 21-dicarboxylic acid, bis-γ-lactone, 3-dimethyl ketal (VII-ketal) Sa, 17ß-Dihydroxypregn-9 (11)-ene-3-one 7a, 21-dicarboxylic acid, bis-y-lactone (VII, EXAMPLE 10) is treated with at least one equivalent of trimethyl ortho formate in the presence of a catalytic amount ofp-toluenesulfonic acid by the procedure of International Publication W098/25948, to give the title compound.

EXAMPLE 18 17ß-hydroxypregna-4, 9 (11)-dien-3-one-7a, 21-dicarboxylic acid, γ- lactone, methyl ester (VIII) (Vill) l la, 17p-dihydroxypregn-4-en-3-one-7a, 21-dicarboxylic acid, y-lactone, methyl ester (VIII, Drugs of the Future, 24 (5), 488-501 (1999), compound (VI)), 5. 00g, 12.0 mmol) is mixed with acetonitrile (15ml). N- (1, 1, 2,3, 3,3) hexafluoropropyl)- diethylamine (V, 2.55 ml, 14.4 mmol) is added to this the steroid mixture and heated to 60° for 2.5 hours. The resulting mixture is cooled to 20-25° and the reaction is quenched with methanol (100 µL). A saturated aqueous solution of potassium bicarbonate (15 ml) is added. The acetonitrile is then removed under reduced pressure. The resulting mixture is extracted with methylene chloride (3 x 10 ml). The combined organic phases are washed with a aqueous solution of sodium chloride (10%, 20 ml). The solvent is dried with magnesium sulfate. The solvent is exchanged from methylene chloride to methyl t-butyl ether (MTBE). The mixture is concentrated to a final volume of 25 ml. The resulting slurry is stirred overnight and the final product, the title compound, is collected by filtration.

EXAMPLE 19 17ß-hydroxypregna-4, 9 (11)-dien-3-one-7a, 21-dicarboxylic acid,- lactone, methyl ester (VIII) 11α,17ß-dihydroxypregn-4-en-3-one-7α,21-dicarboxylic acid, y-lactone, methyl ester (VIII, 5.00 g, 12.0 mmol) is placed in a flask with acetonitrile (15ml). To this mixture N-

(1, 1, 2,3, 3,3) hexafluoropropyl)- diethylamine (2.55 ml, 14.4 mmol) is added and heated to 60° for 2 hrs. The mixture is cooled to 20-25° and the reaction is quenched with aqueous potassium bicarbonate (20% solution, 18 ml). The acetonitrile is removed under reduced pressure, the aqueous layer is extracted with methylene chloride (3 x 5 ml). The combined organic phases are washed with sodium chloride solution (10%, 10ml). The solvent is exchanged from methylene chloride to methyl isobutyl ketone/heptane to crystallize the title compound, mp = 198. 6-199. 5° ; MS (m/z) calculated for C24H3005 = 398.5 (M+), found 398.9 (M+); NMR (CDC13) 5.69, 5.64, 3.62, 2.97, 2.84-1. 47,1. 38 and 0.93 8 ; CMR (CDC13) 98.5, 176.4, 172.5, 166.5, 142.3, 125.6, 118.9, 95.0, 51.3, 43.0, 40.3, 35.6, 35.2, 34.1, 33.7, 32.8, 31.2, 29.0, 27.1, 23.2 and 14.0 8.

EXAMPLE 20 17ß-hydroxypregna-4, 9 (1 )-dien-3-one-7a, 21-dicarboxylic acid, y lactone, methyl ester (VEI) l la, 17 (3-dihydroxypregn-4-en-3-one-7a, 21-dicarboxylic acid, y-lactone, methyl ester (VIII, 80.00 g, 192. 1mmol) is placed in a flask with acetonitrile (80ml). To this mixture N- (1, 1, 2,3, 3,3) hexafluoropropyl)- diethylamine (40.8 ml, 224.8 mmol) is added and heated slowly to 45 to 50°, then held for 1-2 hours. The mixture is cooled to 20-25° and the reaction is quenched with aqueous potassium bicarbonate (72 g in 288 ml). Methylene chloride (240 ml) is added and after mixing the layers are separated. The aqueous phase is extracted with methylene chloride (100ml). The combined organic phases are washed with water (240 ml).

The solvent is exchanged from methylene chloride to methyl tert-butyl ether, and branched octane is added drop wise to crystallize the product which is the title compound.

EXAMPLE 21 1 7ß-Hydroxy-7a-(5'-methyl-2'-furyl)-pregna-4, 9-dien-3-one-2 1- carboxylic acid, y-lactone (IT) Following the general procedure of EXAMPLE 3, using the same reactants and making non-critical variations, the title compound is obtained, CMR (100 MHz, CDC13) 198.56, 176.53, 167.45, 152.74, 149.99, 142.84, 126.24, 119.73, 107.12, 105.89, 95.19, 44.08, 42.39, 41.90, 40.78, 38.52, 37.57, 35.39, 34.18, 33.93, 32.93, 31.26, 29.14, 26.83, 23.18, 14.12 and 13. 38 8 ; NMR (400 MHz, CDC13) 0.95, 1.43, 1.4-2. 6,2. 16,2. 93 and 5.7 8.

EXAMPLE 22 1 7ß-Hydroxy-7a-(cis-1', 4'-dioxopent-2'-en-1'yl) pregna-4,9-dien-3- one-21-carboxylic acid, y-lactone (m-ciS)

Following the general procedure of EXAMPLE 4, Step A, using the same reactants and making non-critical variations, the title compound is obtained, CMR (100 MHz, CDC13) 202. 28,-200, 199.05, 177.19, 166.56, 142.34, 138.49, 134.39, 126.37, 119.90, 95.57, 49.63, 44.90, 42.39, 41.08, 41.04, 35.82, 35.75, 34.49, 34.07, 33.25, 31.71, 30.12, 29.64, 27.49, 23.76 and 14.34 8 ; NMR (400 MHz, CDC13) 0.93, 1.40, 1.4-2. 9, 2.24, 5.66, 5.72, 6.15 and 6.28 8.

EXAMPLE 23 17, 8-Hydroxy-7a-(2'-hydroperoxy-2'-methoxyacetyl) pregna-4,9 (11)- dien-3-one-21-carboxylic acid, y-lactone (IV-OOH) Following the general procedure of EXAMPLE 9, using the same reactants and making non-critical variations, the title compound is obtained, CMR (100 MHz, CDC13) 203.54, 199.91, 177.51, 168.98, 142.42, 125.05, 117.89, 105.90, 95. 58, 55.82, 44.21, 44. 21, 42.17, 41.21, 40.37, 35.33, 34.84, 33.62, 33.16, 32.38, 30.79, 28.84, 26.72, 23.02 and 13.55 8 ; NMR (400 MHz, CDC13) 0.94, 1.42, 1.4-2. 8,3. 57,4. 34,4. 75 and 5.63 8.

EXAMPLE 24 17ß-Hydroxy-7a-(5'-methyl-2'-furyl)-pregna-4, 9 (11)-dien-3-one-21- carboxylic acid, y-lactone (II) A mixture of A9-canrenone (1, 105 g, 0.31024 moles) in acetonitrile (450 ml) is treated with ethanol (21. 0 g, 0.4558 moles, 1.47 equivalents), isopropanol (1.5 ml, 1.177 g, 19.592 mmoles, 0.063 equivalents), and 2-methylfuran (48.5 g, 0.5907 moles, 1.90 equivalents), then cooled to-18° and treated with boron trifluoride diethyl etherate (63.0 g, 0.4439 moles, 1.43 equivalents) over 4 hours. After stirring at-18° for 24 hrs. , the mixture is quenched with triethylamine (38.0 g, 0.3755 moles, 1.21 equivalents) and concentrated to a thick slurry, which is diluted with water (350 ml), extracted with methylene chloride (400 ml), washed with water (350 ml), then concentrated, n-propyl acetate added, and further concentrated to give a slurry, which is cooled to 0°, filtered, and the cake washed with n-propyl acetate/methyl-t-butyl ether (1/1) followed by methyl-t-butyl ether to give the title compound, identified by LC retention time comparison with a sample from EXAMPLE 3.

EXAMPLE 25 5a, 17ß-Dihydroxypregn-9 (11)-ene-3-one, 7a, 21-dicarboxylic acid, bis-y lactone (VII)

A mixture of 17ß-hydroxy-7a-(5'-methyl-2'-furyl)-pregna-4, 9 (11)-dien-3-one-21- carboxylic acid, y-lactone (II, EXAMPLE 24,100 g, 0.23778 moles) and potassium acetate (50.0 g, 0.5094 moles, 2.14 equivalents) in acetone (500 ml) and water (150 ml) is cooled to - 10° and treated with a slurry of dibromantin (34.0 g, 0.1189 moles, 0.50 molar equivalents) in water (100 ml) until a rise in the redox potential occurred. At this point, LC analysis indicated complete conversion into enedione (m-ciS). The reaction mixture containing the enedione (M-cis) is then quenched with isobutyl vinyl ether (1.0 ml, 0.768 g, 7.668 mmoles, 0.032 equivalents), concentrated to a thick slurry, diluted with methylene chloride (200 ml), and treated with 20° concentrated hydrochloric acid (50.0 ml, 0.50 moles, 2.10 equivalents).

The mixture is stirred at 20-25° for 2 hrs. , at which time LC analysis indicated complete conversion to enedione (m-trans). The organic phase containing the enedione (III-trans) is separated, diluted with methylene chloride (80 ml) and methanol (300 ml), and cooled to - 48°. A stream Of 03/02 is bubbled through this mixture until LC analysis indicated complete disappearance of the enedione (III-trans), then the mixture is quenched with dimethylsulfide (30.0 ml, 25.38 g, 0.4085 moles, 1.72 equivalents), stirred at-20° for 16 hrs. , concentrated to a volume of about 300 ml, diluted with methanol (350 ml), concentrated to a volume of about 300 ml, diluted with isopropanol (40 ml) and methanol (80 ml), then treated with a warm (55- 60°) solution of potassium bicarbonate (120 g, 1.1986 moles, 5.04 equivalents) in water (240 ml). This slurry is cooled to 5-10°, then hydrogen peroxide (50%, 66.0 g, containing 33.0 g

(0.9703 moles, 4.08 equivalents) hydrogen peroxide) is added over 3 hrs. The mixture is stirred for four hrs. and quenched with dimethylsulfide (40 ml, 33.84 g, 0.5447 moles, 2.29 equivalents). After stirring at 20-25° for 23 hrs. , the mixture is diluted with methylene chloride (100 ml) and water (80 ml), and acidified to pH = 3.0 with concentrated hydrochloric acid. The two-phase mixture is heated to 36°, then the phases are separated and the aqueous phase extracted with methylene chloride (100 ml). The organic phases are combined, washed with water (75 ml), and the aqueous phase is back-extracted with methylene chloride (25 ml). The organic phases are combined, concentrated to a volume of 150 ml, then treated with benzenesulfonic acid (1.0 g of 90% pure material, containing 0.90 g (5.690 mmoles, 0.0239 equivalents) benzenesulfonic acid) and acetone (50 ml). The mixture is then concentrated atmospherically to a volume of 160 ml, then diluted with acetone (250 ml), concentrated to a volume of 200 ml, cooled to 12°, and filtered. The filter cake is washed with cold acetone (2 x 25 ml) and dried by nitrogen stream to give the title compound, CMR (100 MHz, CDC13) 206.08, 176.47, 175.41, 139.63, 124.00, 94.89, 90.97, 47.08, 43.90, 42.36, 41.58, 41.07, 38.93, 36.97, 35.16, 33.01, 32.42, 32.42, 31.35, 29.10, 23.08, 22.98 and 14.23 8 ; NMR (400 MHz, CDC13) 0.94, 1.40, 1.4-2. 8 and 5.70 ; MS (CI, NH3) m/e = 385 (P + H, 100%).

EXAMPLE 26 17ß-Hydroxy-7a-carbomethoxypregna-4, 9 (11)-dien-3-one-21- carboxylic acid, y-lactone (VIM) A mixture of 5a, 17p-dihydroxypregn-9 (11)-ene-3-one, 7a, 21-dicarboxylic acid, bis-y- lactone (VII, EXAMPLE 25,50. 0 g, 0.13005 moles) and potassium bicarbonate (16.92 g, 0.1690 moles, 1.30 equivalents) in acetone (200 ml) and water (100 ml) is stirred at 45° for 2 hrs. , at which time conversion of the 5,7-lactone (VII) into the carboxylic acid (VI) is

complete by LC. The resulting mixture is then treated with dimethylsulfate (22.92 g, 0.1817 moles, 1.40 equivalents), stirred at 45° for 3 hrs. , then treated with a solution of potassium bicarbonate (1.3 g, 0. 0130 moles, 0.100 equivalents) in water (10 ml) followed by neat triethylamine (1.81 ml, 1.314 g, 0.0130 moles, 0.100 equivalents). The mixture is stirred at 45° for 1 hr. , quenched with concentrated hydrochloric acid (1.92 ml, 2.304 g, containing 0.852 g (0.0234 moles, 0.180 equivalents) hydrochloric acid), cooled to 0°, concentrated under reduced pressure to a volume of 150 ml (pot temperature 13°), then filtered and the filter cake is washed with water (2 x 25 ml) and dried to give the title compound, by comparison with an authentic sample by LC.

EXAMPLE 27 17ß-Hydroxy-7a-(5'-t-butyl-2'-furyl)-pregna-4, 9 (11)-dien-3-one-21- carboxylic acid, y-lactone (II) A mixture of A9-canrenone (I, 3.0002 g, 8.8645 mmoles) and 2-t-butylfuran (2.53 ml, 2.204 g, 17.745 mmoles, 2.00 equivalents) in nitromethane (12.0 ml) is treated with ethanol (0.52 ml, 413 mg, 8.96 mmoles, 1.01 equivalents), cooled to-20°, and treated with boron trifluoride diethyl etherate (1.24 ml, 1.389 g, 9.785 mmoles, 1.10 equivalents). The resulting mixture is stirred at-20° for 24 hrs. , then at-5° for 12 hrs. , then at 0° for 4 hrs. , at which time the reaction appeared about 90% complete by TLC. The reaction is quenched with ammonium hydroxide (7%, 30 ml) extracted with methylene chloride (3 x 50 ml), dried over magnesium sulfate, and concentrated. The concentrate is flash chromatographed on (silica gel, 150 g; gradient elution, 10%-> 50% ethyl acetate/cyclohexane). The fractions containing pure product are combined and concentrated to give the title compound, CMR (100 MHz, CDC13) 198.56, 176.53, 167.87, 162.48, 153.02, 142.91, 125.84, 119.42, 106.70, 101. 88,95. 21,44. 05,42. 87,41. 90,40. 84, 38. 17,37. 80,35. 52,34. 20,34. 02,32. 97,32. 40,.

31.33, 29.18, 28.71, 26.79, 23.17 and 14.14 o ; NMR (400 MHz, CDC13) 0.95, 1.16, 1.45, 1.5 - 2. 6,2. 94,3. 30,5. 64,5. 72 and 5.76 8.

EXAMPLE 28 1 1α,17ß-Dihydroxy-7α-(5'-t-butyl-2'-furyl)-pregn-4-en-3-on e-21- carboxylic acid, y-lactone (n)

A mixture of 1 la-hydroxycanrenone (I, 2.03 g, 5.6947 mmoles) and 2-t-butylfuran (1.70 ml, 1.481 g, 11.924 mmoles, 2.09 equivalents) in nitromethane (16 ml) is cooled to -20°, treated with ethanol (0.35 ml, 0.276 g, 5.99 mmoles, 1. 05 equivalents) and boron trifluoride diethyl etherate (0.83 ml, 0.930 g, 6.550 mmoles, 1.15 equivalents), and stirred at -20° for 21 hrs. , at which time LC analysis indicates that the reaction is complete. The reaction mixture is then quenched with ammonium hydroxide (15%, 5.5 ml), diluted with water, extracted with methylene chloride (2 x 25 ml), dried over magnesium sulfate, filtered through 5.0 g magnesol, and concentrated to a foam, which is flash chromatographed (silica gel, 200 g; gradient elution 20%- 70% ethyl acetate/cyclohexane). The fractions containing the product are combined and concentrated to give the title compound, UV , ax = 238 mtt.

EXAMPLE 29 11 1α, 17(3-Dihydroxy-7a- (4'-bromo-2'-firyl)-pregn-4-en-3-one-21- carboxylic acid, y-lactone (D)

A mixture of 1 la-hydroxycanrenone (1, 2.0 g, 5.6425 mmoles), ethylene glycol (0.84 ml, 0.935 g, 15.06 mmoles, 2.67 equivalents), and 3-bromofuran (3.0 ml, 4.905 g, 33.372 mmoles, 5.91 equivalents) in nitromethane (32 ml) at 20-25° is treated with boron trifluoride diethyl etherate (1.4 ml, 1.568 g, 11.048 mmoles, 1.96 equivalents) and stirred at 20-25° for 20 hrs. , at which time the reaction is > 80% complete by LC. The reaction is then quenched with water, extracted with ethyl acetate, and concentrated to give a foam, which is dissolved in methylene chloride (10 ml) and flash chromatographed (silica gel, 150 g; gradient elution 0 X 6% isopropanol/methylene chloride). The product-containing fractions are then combined and rechromatographed (silica gel, 100 g silica gel; gradient elution 0 5% isopropanol/methylene chloride). The product-containing fractions are combined and crystallized from ethyl acetate/cyclohexane (1/2) to give the title compound, CMR (100 MHz, CDC13) 199.77, 176.54, 168.67, 152.83, 142.43, 126.05, 113.41, 98.03, 95.02, 69.19, 53. 51, 46.26, 46.19, 43.40, 39.57, 38.72, 38.05, 37.48, 35.39, 34.77, 34.24, 31.09, 29.11, 22.68, 18.46 andl5. 84 8 ; NMR (400 MHz, CDC13) 0.9-2. 9,1. 03,1. 42,3. 35,4. 11,6. 36 and 7.26 8 ; MS (CI, NH3) m/e = 503,505 (100%, P + H).

EXAMPLE 30 11 la, 17 (3-Dihydroxy-7a- (4'-methyl-2'-furyl)-pregn-4-en-3-one-21- carboxylic acid, y-lactone (II) A mixture of 1 la-hydroxycanrenone (I, 816 mg, 2.2891 mmoles) and 3-methylfuran (4.0 ml of 1.218 M solution in nitromethane, 4.87 mmoles, 2.13 equivalents) in nitromethane (4.0 ml) is cooled to-20° and treated with ethylene glycol (0.168 ml, 187 mg, 3.01 mmoles, 1.32 equivalents) followed by boron trifluoride diethyl etherate (0.284 ml, 318 mg, 2.241 mmoles, 0.98 equivalents). The resulting mixture is stirred at-20° for 20 hrs. , at which time the reaction is 86% complete by LC. The reaction mixture is quenched with aqueous ammonium hydroxide (15%, 4 ml) diluted with water (10 ml), extracted with methylene chloride (2 x 20 ml), dried over magnesium sulfate, and concentrated. The concentrate is

flash chromatographed (silica gel, 60 g; gradient elution 50%- 100% ethyl acetate/cyclohexane). The product-containing fractions are combined and concentrated. The concentrate is crystallized from cyclohexane/ethyl acetate (4/1) to give the title compound, CMR (100 MHz, CDCl3) 199.91, 176. 62,170. 02,150. 94,140. 81, 125.57, 115. 27, 112. 29, 95.07, 69.16, 53.50, 46.13, 45.99, 43.24, 39.52, 39.46, 38.14, 37.35, 35.32, 34.18, 31.05, 29.07, 22.28, 18.46, 15.79 and 10. 21 # ; NMR (400 MHz, CDC13) 1.04, 1.0-2. 9,1. 42,1. 96, 3. 14, 4.12, 5.34, 6.12 and 7.15 8 ; MS (CI, NH3) m/e = 439 (100%, P + H).

EXAMPLE 31 1 7ß-Hydroxy-7a-(5'-methyl-2'-furyl)-pregna-4, 9 (l l)-dien-3-one-21- carboxylic acid, y-lactone (n) Ishikawa reagent (2.4 mK, 13.7 mmol) is added to a mixture of 11 a, a, 7ß-dihydroxy- 7a- (5'-methyl-2'-furyl)-pregn-4-en-3-one-21-carboxylic acid, y-lactone (II, EXAMPLE 12,5 g, 11.4 mmol) in acetonitrile (25 mL). The mixture is heated to 60° and is determined complete in 1 hr by HPLC. The resulting mixture is cooled to 22° and quenched with saturated aqueous sodium bicarbonate (15 mL). The organic solvent is removed under reduced pressure and replaced with methylene chloride (50 mL). The organic phase is separated, washed with water (30 mL) and concentrated to a volume of 20 mL. Water (30 mL) is added and the mixture is concentrated to a volume of 20 mL. This water distillation is repeated twice to remove the N, N-diethyl-2,3, 3,3-tetrafluoropriopionamide by-product.

Then, methylene chloride (30 mL) is added to the resulting slurry to dissolve all solids. The organic layer is separated and the solvent is exchanged to n-propyl acetate to a final volume of 17-18 mL. The resulting slurry is cooled to-20° for 12 hours. The product was collected by filtration and dried under ambient nitrogen to give the title compound, mp = 198-203° ; NMR (400 MHz, CDC13) 5.737, 5.690, 3.300, 2.904, 2.164, 1.431, 0.952 and 2.569-1. 358 6 ; CMR (100 MHz, CDC13) 198.5, 176.5, 167.4, 152.7, 150.0, 142.8, 126.2, 119.7, 107.1, 105.9, 95.2, 44.1, 42.4, 41.9, 38.5, 37.6, 35.4, 33.9, 32.9, 31.3, 29.1, 26.8, 23.2, 14.1 and 13.4 8 ; MS calculated for C27H3304 = 421.238 (M + H+), found = 421.2 m/z.

EXAMPLE 32 9a, l la-Epoxy-17p-hydroxypregn-4-en-3-one-7a, 21-dicarboxylic acid, y-lactone (VI)

A mixture of 17p-hydroxy-7a- (2'-oxoacetyl)-pregna-4, 9 (11)-dien-3-one-21- carboxylic acid, y-lactone (V, EXAMPLE 11, 6.7 mg, 0.0169 mmoles) in methylene chloride (0.5 ml) is treated with peracetic acid (35%, 4 ul, containing 1.58 mg, 0.0208 mmoles, 1.23 equivalents of peracetic acid), stirred at 20-25° for 25 hours, then treated with more peracetic acid (35%, 2 p. l, containing 79 mg, 0. 0104 mmoles, 0.62 equivalents of peracetic acid), then stirred at 20-25° for 49 hrs. , at which time LC analysis indicated conversion to the title compound, LC-UV ( ? La,, = 244 nm); LC-MS (m/e 400).

EXAMPLE 33 7a-Allyl-17ß-hydroxypregna-4, 9 (11)-dien-3-one, 21-carboxylic acid, y-lactone (IT) A mixture of 17ß-hydroxypregna-4, 6,9 (11)-trien-3-one-21-carboxylic acid, y-lactone (I, 1. 0171 g, 3.0052 mmoles) in methylene chloride (62 ml) is cooled to-30° and treated with titanium tetrachloride in methylene chloride (1.0 M, 15.0 ml, 15.0 mmoles, 4.99 equivalents).

The resulting mixture is treated with allyltrimethylsilane (3.0 ml, 2.16 g, 18.876 mmoles, 6.28 equivalents) and stirred at-30° for 4 hrs. , at which time conversion of the starting material into the product (Rf= 0.27) is nearly complete by TLC (ethyl acetate/cyclohexane, 35/65).

The reaction mixture is quenched with water (25 ml), extracted with methylene chloride (3 x 25 ml), and concentrated. The concentrate (weight = 1. 6262 g) is flash chromatographed (silica silica gel, 150 g; gradient elution with ethyl acetate/cyclohexane, 15% # 55%). The fractions containing the more polar product (Rf= 0.27) are combined and concentrated to give

the title compound, W 4lax = 241 nm ; CMR (100 MHz, CDC) 198.65, 176.46, 167. 31, 143.22, 136.36, 126.51, 119.84, 116.80, 95.22, 44.15, 42.50, 41.13, 40.73, 37.33, 35.56, 35.43, 34.13, 33.78, 33.05, 31.65, 31.37, 29.14, 26.86, 23.04, and 13.78 8 ; NMR (400 MHz, CDC13) 0.94, 1.37, 1.4-2. 6,4. 95,5. 01,5. 65 and 5.74 8 ; MS (CI, NH3), m/e = 381 (P + H, 100%); The product is rechromatographed (silica gel, 60 g; gradient elution with ethyl acetate/cyclohexane, 15%--> 45%) to remove a more polar impurity (Rf = 0.06). The product-containing fractions are combined and concentrated. A portion of the residue (96.8 mg) is taken up in methylene chloride (1 ml), diluted with ethyl acetate (2 ml), concentrated to a volume of less than 1 ml, and cooled to 0°. The supernatant is decanted and the crystals recrystallized from ethyl acetate at 0°. An X-ray crystallographic study confirmed the assignment as 7a-allyl-17ß-hydroxypregna-4, 9 (11)-dien-3-one, 21-carboxylic acid, y-lactone.

EXAMPLE 34 Sa, 17ß-Dihydroxypregn-9 (11)-ene-3-one, 7a, 21-dicarboxylic acid, bis- -lactone (VII) Step (1)-17ß-Hydroxypregna-4, 9 (11)-dien-3-one-7a, 21-dicarboxylic acid,- lactone (VI) A mixture of 17ß-hydroxy-7a-(5'-methyl-2'-furyl)-pregna-4, 9 (11)-dien-3-one-21- carboxylic acid, y-lactone (II, EXAMPLE 3,20 g, 47.5568 mmoles) in methanol (60 ml) and methylene chloride (60 ml) is cooled to-55°. Ozone in oxygen is bubbled through this mixture until 0.8 area % (by LC) of starting material (II) remains. The mixture is purged of ozone by sparging with nitrogen and then quenched with dimethylsulfide (16 ml, 13.5 g, 217.9 mmoles, 4.58 equivalents), warmed to 20-25°, stirred at 20-25° for 50 min. The resulting mixture is concentrated to 80 ml, methanol (25 ml) is added, and concentrated to 80 ml again. The mixture is then treated, at 5°, with a solution of potassium bicarbonate (21. 6g ; 215.7 mmoles; 4.54 equivalents) in water (44 ml) followed by hydrogen peroxide (50% aqueous, 23.5 g, containing 11.75 g (345.5 mmoles, 7.27 equivalents) of hydrogen peroxide).

After warming to 20-30° for one hour the mixture is quenched with dimethylsulfide (8 ml, 6.75 g, 108.95 mmoles, 2.29 equivalents). Methylene chloride (20 ml) is added, and the pH adjusted to 3 with hydrogen chloride (31.5% aqueous, 26. 0g containing 8.19g (224.4 mmoles; 4.72 equivalents) of hydrogen chloride. The mixture is warmed to dissolve and the phases separated. The upper aqueous phase is extracted with methylene chloride (10 ml) and the

combined organic phases are extracted with water (10 ml. ). LC was performed on the methylene chloride mixture (after aqueous workup) under the following conditions: Column: Supelco Discovery RP Amide C16 ; 5 u ; 250 mm x 4 mm Flow: 1 ml/min Detection: UV ; 240 nm Mobile Phase: A: 950 g Water; 39 g Acetonitrile; l. Og Trifluoroacetic acid B: 754 g Acetonitrile; 39 g Water; l. Og Trifluoroacetic acid Gradient: To : 80% A/20% B Tl5 : 20% A/80% B Tls. l : 80% A/20% B T20 : 80% A/20% B Run Time: 20 minutes Flow: 1 ml/min Injection Volume: 5 X Sample Prep: 5 X or reaction mixture into lml of 1/1 Acetonitrile: phosphate buffer (1 ml phosphoric acid in 11 water; pH to 2.4 with sodium hydroxide) The reaction LC major peak (72 area %) was at 10.52 minutes; retention time of a known standard of the carboxylic acid (VI) is 10.52 minutes.

Step (2)-5a, 17ß-Dihydroxypregn-9 (11)-ene-3-one, 7oc, 21-dicarboxylic acid, bis-y-lactone (VII) The resulting organic phase containing 17ß-hydroxypregna-4, 9 (11)-dien-3-one-7a, 21- dicarboxylic acid, y-lactone (VI) is concentrated to 40 ml and para-toluene sulfonic acid monohydrate (10 mg; 0.042 mmoles; 0.001 equivalents) dissolved in acetone (15 ml) is added. Crystallization is observed after 30 minutes at reflux. The resulting slurry is concentrated to 50 ml and concentration continued while maintaining a constant volume by the addition of fresh acetone. After 80 ml of acetone has been added the slurry is cooled to 0° and the solids collected by filtration to give the title compound, CMR (100 MHz, CDC13) 206.07, 176.44, 175.41, 139.66, 123.98, 94.88, 90.99, 47.09, 43.91, 42.36, 41.57, 41.08, 38.93, 36.98, 35.17, 33.01, 32.44, 31.36, 29.10, 23.08, 22.99 and 14.24 8 ; NMR (400 MHz, CDC13) 0.94, 1.41, 1.5-2. 6,2. 80 and 5.70 8. EXAMPLE 35 17ß-hydroxypregna-4, 9 (11)-dien-3-one-7a, 21-dicarboxylic acid, y- lactone, methyl ester (CII)

(Cl) (Cil) 11a, 17ß-dihydroxypregn-4-en-3-one-7oc, 21-dicarboxylic acid,-lactone, methyl ester (CI, Drugs of the Future, 24 (5), 488-501 (1999), compound (VI) and International Publication W098/25948, pages 76 and 280; 5.00 g, 12.0 mmol) is mixed with acetonitrile (15 ml). N- (1, 1, 2,3, 3,3) hexafluoropropyl) -diethylamine (CVI, 2.55 ml, 14.4 mmol) is added to this the steroid mixture and heated to 60° for 2.5 hours. The resulting mixture is cooled to 20-25° and the reaction is quenched with methanol (100 1L). A saturated aqueous solution of potassium bicarbonate (15 ml) is added. The acetonitrile is then removed under reduced pressure. The resulting mixture is extracted with methylene chloride (3 x 10 ml). The combined organic phases are washed with a aqueous solution of sodium chloride (10%, 20 ml). The solvent is dried with magnesium sulfate. The solvent is exchanged from methylene chloride to methyl t-butyl ether (MTBE). The mixture is concentrated to a final volume of 25 ml. The resulting slurry is stirred overnight and the final product, the title compound, is collected by filtration.

EXAMPLE 36 17ß-hydroxypregna-4, 9 (11)-dien-3-one-7a, 21-dicarboxylic acid, y lactone, methyl ester (CII) l1a, 17p-dihydroxypregn-4-en-3-one-7a, 21-dicarboxylic acid, y-lactone, methyl ester (CI, 5.00 g, 12.0 mmol) is placed in a flask with acetonitrile (lSml). To this mixture the Ishikawa reagent (2.55 ml, 14.4 mmol) is added and heated to 60° for 2 hrs. The mixture is cooled to 20-25° and the reaction is quenched with aqueous potassium bicarbonate (20% solution, 18 ml). The acetonitrile is removed under reduced pressure, the aqueous layer is extracted with methylene chloride (3 x 5 ml). The combined organic phases are washed with sodium chloride solution (10%, 10ml). The solvent is exchanged from methylene chloride to

methyl isobutyl ketone/heptane to crystallize the title compound, mp = 198. 6-199. 5° ; MS (m/z) calculated for C24H305 = 398.5 (M+), found 398.9 (M+); NMR (CDC13) 5.69, 5.64, 3.62, 2.97, 2.84-1. 47,1. 38 and 0.93 8 ; CMR (CDCl3) 98.5, 176.4, 172.5, 166.5, 142.3, 125.6, 118.9, 95.0, 51. 3,43. 0,40. 3,35. 6, 35. 2,34. 1, 33. 7,32. 8,31. 2,29. 0,27. 1,23. 2 and 14.0 8.

EXAMPLE 37 17ß-hydroxypregna-4, 9 (11)-dien-3-one-7a, 21-dicarboxylic acid, y- lactone, methyl ester (CII) 1 laSl7ß-dihydroxypregn-4-en-3-one-7a, 21-dicarboxylic acid, y-lactone, methyl ester (CI, 80.00 g, 192. 1mmol) is placed in a flask with acetonitrile (80 ml). To this mixture the Ishikawa reagent (40.8 ml, 224.8 mmol) is added and heated slowly to 45 to 50°, then held for 1-2 hours. The mixture is cooled to 20-25° and the reaction is quenched with aqueous potassium bicarbonate (72 g in 288 ml). Methylene chloride (240 ml) is added and after mixing the layers are separated. The aqueous phase is extracted with methylene chloride (100 ml). The combined organic phases are washed with water (240 ml). The solvent is exchanged from methylene chloride to methyl tert-butyl ether, and branched octane is added drop wise to crystallize the product which is the title compound.

EXAMPLE 38 17p-hydroxypregna-4, 9 (11)-dien-3-one-7a, 21-dicarboxylic acid,- lactone, methyl ester (CII) 1 la, 17ß-dihydroxypregn-4-en-3-one-7a, 21-dicarboxylic acid,-lactone, methyl ester (CI, 80.00 g, 192.1 mmol) is placed in a flask with acetonitrile (80 ml). To this mixture the Ishikawa reagent (40.8 ml, 224.8 mmol) is added and heated slowly to 55 to 50°, then held for 1-2 hours. The mixture is cooled to 20-25° and the reaction is quenched with aqueous potassium bicarbonate (37.3 g in 288 ml). Methylene chloride (240 ml) is added and after mixing the layers are separated. The aqueous phase is extracted with methylene chloride (100 ml). The combined organic phases are washed with water (80 ml). The solvent is exchanged from methylene chloride to methyl iso-butyl ketone, and branched octane is added drop wise to crystallize the product which is the title compound.

EXAMPLE 39 Crystalline 17p-hydroxy-7a- (5'-methyl-2'-furyl)-pregna-4, 9 (11)-dien- 3-one-21-carboxylic acid, γ-lactone (II) A sample of 17ß-hydroxy-7α-(5'-methyl-2'-furyl)-pregna-4, 9 (11)-dien-3-one-21- carboxylic acid, y-lactone (II) produced by the process of one of EXAMPLEs 3,13, 21,24, 31

or 34, or following the general procedure of these EXAMPLEs and making non-critical variations, is obtained in crystalline form and tested by powder X-ray diffraction (PXRD) as follows. 17ß-Hydroxy-7a-(5'-methyl-2'-furyl)-pregna-4, 9 (11)-dien-3-one-21-carboxylic acid, y-lactone (n) is ground for 30 seconds using a mortar and pestle. The ground sample is placed on zero-background sample holders containing a thin layer of VaselineTM. The sample is examined by PXRD using the Rigaku Miniflex X-ray diffractometer. The diffraction pattern is collected with the sample spinning.

Experimental Conditions for Powder X-Ray Diffraction (XRD): A Rigaku Miniflex+ X-ray diffractometer was used for the acquisition of the powder XRD patterns. The instrument operates using the Cu Kot, emission with a nickel filter at 1. 50451.

The major instrumental parameters are set or fixed at: X-ray: Cu/30 kV (fixed) /15 mA (fixed) Divergence Slit: Variable Scattering Slit: 4. 2° (fixed) Receiving Slit: 0.3 mm (fixed) Scan Mode: FT Preset Time: 2.0 sec.

Scan Width: 0. 050° Scan Axis: 2ThetalTheta Scan Range: 3. 000° to 40. 000° The results of the PXRD are as follows: Two-Theta Angle d-spacing Relative Intensity (%) 6.503 13.5812 1.1 10.589 8.3479 58.3 11.557 7.6505 18.2 12.686 6.9721 4.0 14.248 6.2111 100.0 15.144 5.8455 28.3 16.608 5.3334 50.6 17.851 4.9647 84.5 18.353 4.8300 28.2

19.537 4.5399 8.3 20.148 4.4037 22.6 21.147 4.1977 28.0 21.695 4.0930 18.6 23.199 3.8309 35.1 24.757 3.5933 13.5 25.241 3.5255 6.0 25.905 3.4365 25.7 27.400 3.2523 18.1 28.262 3.1551 2.5 28.750 3.1026 8.4 29.955 2.9805 2.9 30.959 2.8861 8.2 31.950 2.7988 3.6 32.685 2.7375 2.3 33.207 2.6957 3.2 33.888 2.6431 4.0 34.356 2.6081 1.7 35.607 2.5193 2.7 36.144 2.4831 25.6 37.061 2.4237 4.5 37.797 2.3782 1.4 38.496 2.3366 2.4 where Two-Theta Angle is measured in degrees; d-Spacing is measured in angstroms ; and Relative Intensity is the intensity percentage of each peak relative to the strongest peak at 14.248 degrees.

EXAMPLE 40 Crystalline 17ß-hydroxy-7a-(5'-methyl-2'-furyl)-pregna-4, 9 (11)-dien- 3-one-21-carboxylic acid, y-lactone (

Following the general procedure of EXAMPLE 39 and making non-critical variations another sample of crystalline 17p-hydroxy-7a- (5'-methyl-2'-furyl)-pregna-4, 9 (11)-dien-3- one-21-carboxylic acid, y-lactone (II) is subjected to PXRD with with spin with the following results: Two-Theta Angle (°) d-spacing (A) Relative Intensity (%) 6.506 13.5742 1.1 10.603 8.3366 49 11.600 7.6220 17.7 12.699 6.9648 2.4 14.297 6.1900 100 15.159 5.8398 18.8 16.206 5.4648 7.2 16.650 5.3202 39.6 17.900 4.9512 59.4 18.397 4.8186 27 19.593 4.5270 8.5 20.155 4.4022 27.5 21.194 4.1886 22.4 21.702 4.0916 15.7 23.247 3.8231 24.5 24.805 3.5865 13.1 25.256 3.5234 6.2 25.948 3.4310 29.2 27.452 3.2464 14.8 28.353 3.1452 3 28.800 3.0974 7.3 29.952 2.9808 2.2 31.003 2.8821 7.2 31.988 2.7956 3.3 32.666 2.7391 1.3 33.245 2.6926 3.4

33.902 2.6420 2 34.392 2.6055 1.4 35.651 2.5163 1.9 36.192 2.4799 14.9 37.105 2.4209 4.4 37.817 2.3770 1.6 38.547 2.3336 2.4 39.394 2.2854 1.6 EXAMPLE 41 Crystalline 17ß-hydroxy-7a-(5'-methyl-2'-furyl)-pregna-4, 9 (11)-dien- 3-one-21-carboxylic acid, y-lactone (II) Following the general procedure of EXAMPLE 39 and making non-critical variations another sample of crystalline 17ß-hydroxy-7a-(5'-methyl-2'-furyl)-pregna-4, 9 (11)-dien-3- one-21-carboxylic acid, y-lactone (II) is subjected to PXRD with spin with the following results: Two-Theta Angle (°) d-spacing (A) Relative Intensity (%) 6.536 13.5120 1.2 10.505 8.4141 43.6 11.548 7.6564 15.7 12.613 7.0121 3.6 14.251 6.2099 100 15.142 5.8463 29.2 16.598 5.3368 31.6 17.848 4.9655 59.3 18.349 4.8310 34.5 19.543 4.5386 11.7 20.140 4.4054 24.3 21.002 4.2264 29.1 21.653 4.1008 15 23.197 3.8312 48 24.754 3.5936 14 25.945 3.4314 25

27.403 3.2520 21.4 28.749 3.1027 11.1 29.991 2.9770 2.2 30.953 2.8867 8.1 31.857 2.8067 3 32.683 2.7376 1.4 33.667 2.6599 3.3 36.106 2.4856 13.5 37.054 2.4242 5.5 37.795 2.3783 2.2 38.460 2.3387 2.7 EXAMPLE 42 Crystalline 17ß-hydroxy-7a-(5'-methyl-2'-furyl)-pregna-4, 9 (11)-dien- 3-one-21-carboxylic acid, y-lactone (II) Following the general procedure of EXAMPLE 39 and making non-critical variations another sample of crystalline 17p-hydroxy-7a- (5'-methyl-2'-furyl)-pregna-4, 9 (11)-dien-3- one-21-carboxylic acid, y-lactone (n) is subjected to PXRD with spin with the following results: Two-Theta Angle (°) d-spacing (A) Relative Intensity (%) 6.508 13.5698 1.4 10.590 8.3470 51.6 11.549 7.6557 16.7 12.614 7.0118 2.5 14.247 6.2116 100 15.147 5.8443 25.2 16.156 5.4815 8.5 16.637 5.3241 42.4 17.854 4.9638 66.6 18.345 4.8320 27.2 19.547 4.5376 9.5 20.143 4.4048 26.2 21.051 4.2167 28.1

21.691 4.0937 17.4 23.240 3.8243 34.5 24.797 3.5875 13.2 25.207 3.5301 7.1 25.903 3.4368 25.8 27.404 3.2519 16.1 28.261 3.1552 2.1 28.752 3.1024 7.4 29.994 2.9767 2.3 30.955 2.8865 9.7 31.938 2.7999 2.9 32.586 2.7456 2 33.196 2.6965 3.2 33.711 2.6565 2.3 34.315 2.6111 1.4 35.642 2.5169 3.2 36.147 2.4829 16.2 37.092 2.4218 4.1 37.798 2.3781 2.1 38.469 2.3382 2.1 EXAMPLE 43 Crystalline 17p-hydroxy-7a- (5'-methyl-2'-furyl)-pregna-4, 9 (11)-dien- 3-one-21-carboxylic acid, y-lactone (II) Following the general procedure of EXAMPLE 39 and making non-critical variations another sample of crystalline 17p-hydroxy-7a- (5'-methyl-2'-furyl)-pregna-4, 9 (11)-dien-3- one-21-carboxylic acid, y-lactone (n) is subjected to PXRD with spin with the following results: Two-Theta Angle (°) d-spacing (A) Relative Intensity (%) 10.596 8.3424 29.9 11.597 7.6245 16.6 12.658 6.9877 2.6 14.296 6.1904 100 15.192 5.8272 23.4 16.652 5.3193 30.3 17.899 4.9514 46.1 18.401 4.8176 29.1 19.557 4.5352 8.5 20.158 4.4015 24.5 21.000 4.2269 21.8 21.706 4.0909 14.4 23.246 3.8232 32 24.846 3.5805 13.6 25.953 3.4303 17.7 27.447 3.2469 15 28.798 3.0976 7.5 30.002 2.9760 2.7 31.003 2.8821 7.5 31.955 2.7984 1.2 32.697 2.7366 1. 5 33.247 2.6925 4.2 33.708 2.6567 1.7 34.372 2.6069 1.6 35.645 2.5167 1.9 36.154 2.4824 11. 1 37.145 2.4184 4.4 37.843 2.3754 1.3 38.537 2.3342 2.5 EXAMPLE 44 Crystalline 17p-hydroxy-7a- (5'-methyl-2'-furyl)-pregna-4, 9 (11)-dien- 3-one-21-carboxylic acid, y-lactone (D) Following the general procedure of EXAMPLE 39 and making non-critical variations another sample of crystalline 17ß-hydroxy-7a-(5'-methyl-2'-furyl)-pregna-4, 9 (11)-dien-3- one-21-carboxylic acid, y-lactone (II) is subjected to PXRD with spin with the following results: Two-Theta Angle (°) d-spacing (A) Relative Intensity (%) 10.647 8.3025 40. 1 11.602 7.6207 16.1 12.747 6.9388 3.3 14.300 6.1887 100 15.194 5.8263 25.7 16.692 5.3068 40.3 17.945 4.9389 68.4 18.401 4.8176 31.3 19.591 4.5275 8.5 20.154 4.4023 28.1 21.003 4.2262 26.5 21.707 4.0908 15.6 23.247 3.8231 34.4 24.847 3.5804 19 25.956 3.4300 30. 3 27.451 3.2464 18.5 28.845 3.0926 9.8 29.958 2.9802 3.5 31.044 2.8784 9.7 32.039 2.7912 1 1.6 32.716 2.7350 2 33.256 2.6918 4.5 33.713 2.6564 2.8 34.330 2.6100 2.2 35.652 2.5162 3.2 36.196 2.4796 17 37.146 2.4184 5.9 37.804 2.3778 2.2

38.544 2.3338 2.7 EXAMPLE 45 Crystalline 17p-hydroxy-7a- (5'-methyl-2'-furyl)-pregna-4, 9 (11)-dien- 3-one-21-carboxylic acid, y-lactone (11) Following the general procedure of EXAMPLE 39 and making non-critical variations another sample of crystalline 17p-hydroxy-7a- (5'-methyl-2'-furyl)-pregna-4, 9 (11)-dien-3- one-21-carboxylic acid, y-lactone (n) is subjected to PXRD with the following results: Two-Theta Angle (°) d-spacing (A) Relative Intensity (%) 6.594 13. 3929 1 10.604 8.3359 42.2 11.602 7.6212 16.6 12.699 6.9652 2.8 14.305 6.1866 100 15.200 5.8242 29.4 16.654 5.3188 50.3 17.943 4.9395 74.3 18.442 4.8069 27 19.607 4.5239 10 20.200 4.3925 23.9 21.051 4.2166 28.2 21.746 4.0834 16.8 23.291 3.8161 32.9 24.851 3.5798 13.5 25.299 3.5175 8.1 25.994 3.4250 27.2 27.456 3.2458 18.3 28.352 3.1453 3.1 28.845 3.0926 8 30.053 2.9710 2.9 31.005 2.8819 7.5 31.949 2.7989 2.3

33.254 2.6920 3.5 33. 949 2.6384 2.6 34.400 2.6049 1.9 35.653 2.5162 3.2 36.196 2.4796 16.2 37.190 2.4156 5.1 37.840 2.3756 1.9 38.554 2.3332 2.9 EXAMPLE 46 Crystalline 17ß-hydroxy-7a-(5'-methyl-2'-furyl)-pregna-4, 9 (11)-dien- 3-one-21-carboxylic acid, 7-lactone (II) Following the general procedure of EXAMPLE 39 and making non-critical variations another sample of crystalline 17p-hydroxy-7a- (5'-methyl-2'-furyl)-pregna-4, 9 (11)-dien-3- one-21-carboxylic acid, y-lactone (n) is subjected to PXRD with spin with the following results: Two-Theta Angle (°) d-spacing Relative Intensity (%) 10.699 8.2622 53.4 11.702 7.5562 11.8 12.790 6.9156 2.2 14.356 6.1644 73.4 15.298 5.7872 21.2 16.743 5.2908 66.4 18.005 4.9225 100 18.456 4.8034 23.1 19.698 4.5031 6.6 20.297 4.3716 23 21.252 4.1772 29 21.800 4.0735 10.8 23.348 3.8068 29.8 24.949 3.5661 12 25.346 3.5111 4.4

26. 003 3.4238 28. 7 27.547 3.2353 17.1 28.494 3.1300 4.4 28.854 3.0917 6.6 30.140 2.9626 1.9 31.103 2. 8731 7.1 32.054 2. 7900 3.7 33.316 2.6871 1.6 33.999 2.6347 4.9 35.751 2.5095 2. 5 36.297 2.4730 27 37.206 2.4146 3. 9 37.908 2.3715 1.5 38.643 2.3281 2. 3 EXAMPLE 47 Crystalline 17ß-hydroxy-7a-(5'-methyl-2'-furyl)-pregna-4, 9 (11)-dien- 3-one-21-carboxylic acid, y-lactone (Il) Following the general procedure of EXAMPLE 39 and making non-critical variations another sample of crystalline 17ß-hydroxy-7a-(5'-methyl-2'-furyl)-pregna-4, 9 (11)-dien-3- one-21-carboxylic acid, γ-lactone (II) is subjected to PXRD with spin with the following results: Two-Theta Angle (°) d-spacing Relative Intensity (%) 6.557 13.4698 1. 2 10.641 8.3067 49.6 11.608 7.6171 12.6 12.708 6.9603 2.5 14.340 6.1713 100 15.205 5.8221 27. 9 16.698 5.3048 54.7 17.947 4.9383 84 18.446 4.8060 29.1

19.606 4.5242 12.6 20.202 4.3921 25.9 21.053 4.2162 32.2 21.752 4.0824 19.1 23.295 3.8153 43.7 24.855 3.5793 14.8 25.300 3.5173 7 25.998 3.4245 31.2 27.498 3.2410 21.1 28.358 3.1447 3.3 28.846 3.0925 9.9 30.084 2.9680 2.6 31.053 2.8776 9.9 31.962 2.7978 2.7 32.779 2.7299 1.5 33.288 2.6893 3.3 33.762 2.6527 3.5 34.384 2.6060 1.8 35.701 2.5129 3.9 36.200 2.4794 18.6 37.155 2. 4178 5 37.896 2.3722 1.8 38.557 2.3330 2.8 EXAMPLE 48 Crystalline 17ß-hydroxy-7α-(5'-methyl-2'-furyl)-pregna-4, 9 (11)-dien- 3-one-21-carboxylic acid, 7-lactone (111) Following the general procedure of EXAMPLE 39 and making non-critical variations another sample of crystalline 17ß-hydroxy-7a-(5'-methyl-2'-furyl)-pregna-4, 9 (11)-dien-3- one-21-carboxylic acid, y-lactone (n) is subjected to PXRD with spin with the following results: Two-Theta Angle (°) d-spacing (A) Relative Intensity (%) 6.534 13.5158 1.4 10.545 8.3820 53 11.547 7.6569 13 12.644 6.9952 2. 6 14.248 6.2112 100 15.146 5.8447 27.4 16.597 5.3369 55.8 17.851 4.9648 84.3 18.349 4.8312 28.9 19.542 4.5388 12.4 20.144 4.4045 23.5 21.001 4.2267 36.3 21.692 4.0936 20 23.200 3.8308 45.9 24.797 3.5876 12.9 25.239 3.5256 6.1 25.902 3.4369 31.2 27.403 3.2520 22.7 28.259 3.1554 3.8 28.751 3.1025 9.9 29.990 2.9771 2.4 30.995 2.8828 10.4 31.863 2.8063 3.2 32.683 2.7377 1.7 33.889 2.6430 3. 7 35.642 2.5169 3 36.143 2.4831 19.1 37.098 2. 4214 5 37.801 2.3780 1.9 38.503 2.3362 2.4

EXAMPLE 49 Crystalline 17p-hydroxy-7a- (5'-methyl-2'-furyl)-pregna-4, 9 (11)-dien- 3-one-21-carboxylic acid, y-lactone (IT) Following the general procedure of EXAMPLE 39 and making non-critical variations another sample of crystalline 17ß-hydroxy-7a-(5'-methyl-2'-furyl)-pregna-4, 9 (11)-dien-3- one-21-carboxylic acid, y-lactone (II) is subjected to PXRD with the following results: Two-Theta Angle (°) d-spacing (A) Relative Intensity (%) 6.464 13.6629 1. 1 10.457 8.4529 28. 8 11.482 7.7003 20.8 12.546 7.0495 4.2 14.185 6.2387 100.0 15.056 5.8797 27.6 16.099 5.5007 7.2 16.545 5.3536 25.9 17.792 4.9810 37.9 18.253 4.8563 26.8 19.455 4.5590 8. 7 20.056 4.4237 22.6 20.858 4.2552 17.2 21.604 4.1100 12.8 23.139 3.8407 36.5 24.741 3.5955 11.5 25.152 3.5377 7.4 25.848 3.4440 12.7 27.347 3.2585 13.6 28.700 3.1079 6.2 29.910 2.9849 2.3 30.898 2.8917 5.6 32.599 2.7445 1.5 33.142 2.7008 3.5 33.633 2.6625 1.4

34.265 2.6148 1.5 35.520 2.5252 1.3 36.055 2.4890 8.1 37.016 2.4266 4.4 37.735 2.3820 1.0 38.415 2.3413 2.4 39.349 2.2879 1.8 EXAMPLE 50 Crystalline 17 (3-hydroxy-7a- (5'-methyl-2'-furyl)-pregna-4, 9 (11)-dien- 3-one-21-carboxylic acid, y-lactone (IT) Following the general procedure of EXAMPLE 39 and making non-critical variations another sample of crystalline 17 (3-hydroxy-7a- (5'-methyl-2'-furyl)-pregna-4, 9 (11)-dien-3- one-21-carboxylic acid,-lactone (II) is subjected to PXRD with spin with the following results: Two-Theta Angle d-spacing Relative Intensity (%) 10.652 8.2987 21.1 11.647 7.5915 18.4 12.751 6.9370 2.4 14.350 6.1673 100.0 15.252 5.8044 22.5 16.303 5.4325 8. 5 16.707 5.3020 19.7 17.996 4.9252 29.0 18.455 4.8037 24.7 19.679 4.5076 6.1 20.247 4.3823 21.0 21.058 4.2154 16.1 21.759 4.0812 12.6 23.343 3.8076 27. 8 24.899 3.5731 12.2 25.346 3.5111 6.1

26.050 3.4177 12.1 27.542 3.2358 9.5 28.899 3.0870 5.7 30.099 2.9666 2.3 31.100 2.8733 5.6 32.042 2.7909 1.3 32.790 2.7290 2.2 33.346 2.6848 4.5 33.801 2.6496 1.1 34.489 2.5983 1.4 35.708 2.5124 1.8 36.244 2.4765 7.9 37.208 2. 4145-5. 0 37.912 2.3712 1.5 38.599 2.3306 1.2 EXAMPLE 51 Crystalline 17ß-hydroxy-7a-(5'-methyl-2'-furyl)-pregna-4, 9 (11)-dien- 3-one-21-carboxylic acid, γ-lactone (II) Following the general procedure of EXAMPLE 39 and making non-critical variations another sample of crystalline 17ß-hydroxy-7a-(5'-methyl-2'-furyl)-pregna-4, 9 (11)-dien-3- one-21-carboxylic acid, y-lactone is subjected to PXRD with the following results: Two-Theta Angle (°) d-spacing (A) Relative Intensity (%) 6.575 13.4329 1. 1 10.552 8.3766 29.8 11.551 7.6546 15.3 12.608 7.0148 3.0 14.256 6.2077 100.0 15. 150 5.8432 28.5 16.606 5.3342 29.7 17.856 4.9633 49.9 18.353 4.8301 20.9

19.587 4.5284 7.8 20.187 4.3952 19.5 20.955 4.2357 17.2 21.696 4.0928 15.4 23.242 3.8239 41.8 24.800 3.5871 13.5 25.237 3.5260 5.2 25.948 3.4310 17.2 27.449 3.2467 16.2 28.794 3.0979 8.1 29.956 2.9804 2.5 30.997 2.8826 5.9 32.661 2.7395 0.9 33.210 2.6955 3.2 33.801 2.6497 2.6 34.398 2.6050 1.6 35.600 2.5197 1.7 36.145 2.4830 11.9 37.107 2.4208 4.0 37.801 2.3780 1.4 38.531 2.3346 2.1 EXAMPLE 52 Crystalline 17 (3-hydroxy-7a- (5'-methyl-2'-furyl)-pregna-4, 9 (11)-dien- 3-one-21-carboxylic acid, y-lactone (IT) Following the general procedure of EXAMPLE 39 and making non-critical variations another sample of crystalline 17ß-hydroxy-7a-(5'-methyl-2'-furyl)-pregna-4, 9 (11)-dien-3- one-21-carboxylic acid, y-lactone (IT) is subjected to PXRD with the following results: Two-Theta Angle (°) d-spacing Relative Intensity (%) 6.575 13.4329 1.1 10.552 8.3766 29.8 11.551 7.6546 15.3 12.608 7.0148 3.0 14.256 6.2077 100.0 15.150 5.8432 28. 5 16.606 5.3342 29.7 17.856 4.9633 49. 9 18.353 4.8301 20.9 19.587 4.5284 7. 8 20.187 4.3952 19.5 20.955 4.2357 17.2 21.696 4.0928 15.4 23.242 3.8239 41.8 24.800 3.5871 13.5 25.237 3.5260 5.2 25.948 3.4310 17.2 27.449 3.2467 16.2 28.794 3.0979 8.1 29.956 2.9804 2.5 30.997 2.8826 5. 9 32.661 2.7395 0.9 33.210 2.6955 3.2 33.801 2.6497 2. 6 34.398 2.6050 1.6 35.600 2.5197 1. 7 36.145 2.4830 11.9 37.107 2.4208 4.0 37.801 2.3780 1.4 38.531 2.3346 2.1 EXAMPLE 53 Crystalline 17ß-hydroxy-7a-(5'-methyl-2'-furyl)-pregna-4, 9 (11)-dien- 3-one-21-carboxylic acid, γ-lactone (II) Following the general procedure of EXAMPLE 39 and making non-critical variations another sample of crystalline 17ß-hydroxy-7a-(5'-methyl-2'-furyl)-pregna-4, 9 (11)-dien-3- one-21-carboxylic acid, y-lactone (n) is subjected to PXRD with the following results: Two-Theta Angle (°) d-spacing (A) Relative Intensity (%) 6.545 13.4926 1.6 10.598 8.3404 27.3 11.595 7.6258 15.6 12.735 6.9456 2.9 14.296 6.1902 100 15.193 5.8268 29.5 16.649 5.3203 28.8 17.902 4.9506 41.1 18.399 4.8181 31.6 19.561 4.5344 10.4 20.153 4.4025 24 21.049 4.2171 21.4 21.708 4.0906 14.8 23.253 3.8222 38.7 24.804 3.5865 13.4 25.289 3.5189 6.8 26.006 3.4235 18.2 27.492 3.2416 15.7 28.802 3.0972 9 29.998 2.9764 2.6 30.961 2.8859 8.2 32.719 2.7348 1.5 33.293 2.6889 3.8 33.756 2.6531 2.8 36.156 2.4823 11 37.113 2.4204 6.2 37.863 2. 3742 1 38. 550 2.3335 2.1

CHART A When R7-1 is (-A1)

R R17 R (I) zu Ruz 3 Rg R7-1 R 5 4 R R17 1 R9 (II) R3 (II) RUZ Ra 5 rus R1 R1 R17 R11 (I II-cis) (I I I-trans) R9 R3....... Co Re"co Rb Rb c ! ! co CO-RD R C Rc CO-Rd

CHART A-Continued CHART A-Continued

CHART B

(Alkyl enol ether) (I-P) (3-methyl enol ether) (I-P')

CHART C R, R17 1 rire R9. R3 .'',. R R4 5 R6 03 R R17 R R17 1 1 "-f o-'W e O \ R3 IRI 15'C O C R4R5R6 CiRb a Rd Rb C (X-cis) Ru rio Rye j CO Rd (IV-OOH) + (IV-OH) + (V) + (VI) l Following the general procedure of CHART A and D I (IX) CHART D When R7-1 is (-A1)

()-unprotected A-ring) (II-unprotected A-ring) (III-cis-unprotected A-ring) CHART D-Continued (III-trans-unprotected A-ring) CHART D-Continued (JE-cis) or (III-trans) or mixture of (m-cis) and (III-trans)

t Ru7 (IV-OOH-+ (V-unprotected A-ring) unprotected A-ring) A-ring) /Rs O/R9. Rg 0 Rg CO-CO-Rb f O I Rb Pub Rb R, R17 R, R17 1 R/0 (IV-OH- O/R9.,, e O (IV-OH-F2g O unprotected A-ring) O/I''C D OH vo Y (Vl-unprotected A-ring) Rb (IV-OH unprotected A-ring) + (V-unprotected A-ring) + (VI-unprotected A-ring) CHART D-Continued (IV-OH unprotected A-ring) + (V unprotected A-ring) R17 R1 R1 R11 < * < (Vll-unproteoted 0 0 H 0 A-ring) (3--C (VI-unprotected A-ring) 0 Ri R17 1 (VIII-unprotected A-ring) zu 0'C. O-CH3 f R17 I (IX-unprotected A-ring) /,, O O'CO-CH3 '-O-CHg

CHARTE (I) (II)

(III-cis)

CHART E-Continued (III-trans) CHART E-Continued (III-cis) or (III-trans) or mixture of (III-cis) or (III-trans)

CHART E-Continued CHART F (VI) <BR> <BR> <BR> (Vil)<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> (Vil) (VI)

CHART G When R7-1 is (-A2) CHART G-Continued

(XV) (VI) CHART H When R7-1 is (-B), (-C) or (-D1,-D2,-D3)

CHART I

CHARTJ

(CIV) (CV) CHART K

CHART K-Continued

CHART K-Continued

CHART L

HO, R17 ho, (ici) 3 ré R Ra 5 R6 Ishikawa Reagent or (CH3) 2N-CF2-cF2-H Ruz 1 (11) R, e 1, R4 5 R6 CHART M

RUZ Ho,, O O-Rd Rt \/ (III-cis) R4 Re/C=C Rb Rc or H R17 n S (111-trans) """cl Il OC /C Rc CO-Rd Ishikawa Reagent or (CH3) 2N-CF2-CF2-H Ruz (111-trans) R /IR R \ Rb II Rc CO Rd CHART N

HO, R (IV-OH) Rio Ra R5 Rs I C OH O Rob or HO Rb or R. e R3- 3 R5 co I-O-OH Rio Rb Rb or HO, (V) R-3) 4 R w COCORb Ra 5 ru Ishikawa Reagent or (CH3) 2N-CF2-CF2-H CHART N-Continued (VI) CHART O

0 o 0 2-methylfuran absolute ethanol boron trifluoride etherate 0 o Fui X (II) O'0t"R I I dibromatin acetate aqueous hydrochloric acid 1

CHART O - Continued 0 o H 0 (111-trans) 09 w""k° COACH3 f O CH3 ozone dimethylsulfide hydrogen peroxide bicarbonate o O.."" ! in (VI) o""rOH 0 OU O "-OH HO H 0 t p-toluenesulfonic acid 1

CHART 0-Continued o H (Vll) 0 0 0 H (Vil) O o f bicarbonate, dimethylsulfate po 0 - (mu) O #"fO Ou CH3 trichloroacetamide/hydrogen peroxide ethanol methyl ethyl ketone i CHART 0-Continued (IX)