BACKGROUND OF THE INVENTION

Ary loxypropanolamlnes and ary lethanol amines are widely used thera- peuttc agents, particularly those compounds possessing potent beta- adrenerglc receptor blocking activity. These beta-adrenerglc blocking agents are widely used for a number of cardiovascular therapeutic Indica¬ tions, such as hypertension, angina pectorls, cardiac arrhythmias, myocardlal Infarction and more recently In the treatment of glaucoma. In addition, certain ary loxypropanolamlnes possess potent beta-adrenerglc stimulating properties and such compounds are used as cardiac stimulants.

Among beta-blocker oxypropanol amines, the R Iscmers are less active or essentially devoid of beta-blocking activity as compared to their counter- part S Isomers. Similarly, the R-lsomer beta-agonists are more potent agents than their S-lsomer counterparts.

Conventional methods for preparing such compounds util ize the nonselectlve mesylatloπ or tosylatlon of the dlol 3 followed by the separation of monomesy I ate or monotosylate 4a frc the undesirable dlmesylate or dltosylate 4b. Subsequently, the monomesylate or tosylate Is transformed Into an epoxldβ which Is then treated with the corresponding amlne to provide the desired beta-blocker In separate stages. Such a procedure Is described by Tsuda et al . In CHEM. PHARM. BULL. 29 (12) 3593-3600 (1981). In such a procedure, to prepare monotosylate, p-tol uenesuf ony I chloride (p-TsCI ) Is used, which Is not a very selective reagent and significant quantities of undesirable dltosylate are also formed. This considerably reduces the yield of the desired monotosylate and, generally, extensive purification of the mixture Is required In order

to obtain the monotosylate. Frequently this Is not posstble In a large scale manufacturing process and this process Is uneconomical as a means to obtain isomers. An efficient and an economical process for preparing the separate Isomers Is therefore highly desirable.

4a, R=Ms or Ts, R ¹ =H 4b, R=R ¹ = Ms or Ts

SUMMARY OF THE INVENTION

In accordance with the present Invention, disclosed Is a process for preparing a racemlc or chlral aryloxypropanolamlne (1) or arylethanolamlne (2) of the formula

1 wherein Ar Is aryl, substituted aryl, heteroaryl, or aralkyl and R Is al yl, substituted alkyl, aralkyl, or WB wherein W Is a straight or branched chain alkylene of from 1 to about 6 carbon atoms and wherein B Is -NR2COR3, -NR2CONR3R4, -NR2SO2R3, -NR2 ^S0 2 ^NR 3 ^R 4» « ^* -NR2COOR5, where R2. R3, R4, and R5 may be the same or different and may be hydrogen, alkyl, alkoxy alkyl, alkoxyaryl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl, except that R3 and R5 are not hydrogen when B Is -NR2SO2R3 or -NR2COOR5, or R3 and R4 may together with N form a 5- to 7-membered hetero cycl fc group.

As an example, the method Involves the utilization of tr I substituted phosphonlum hal Ides such as R3P CCI ₄ as selective chlorinating agents to provide the monochloro derivative 5.

The chlorohydrln 5 Is then converted Into the aryloxypropanol amlne 2 In the same reaction vessel or In separate steps as desired. It Is noted that the undesirable dichloro Intermediate 6 Is not formed or formed In Insignificant amounts In this reaction. The method does not cause race- mlzatloπ of the optically active Intermediate or final product and produce high purity chlral products. No complex separation steps are required to Isolate a particular Isomer. the three consecutive steps In the process may be performed In a single reaction vessel If desired. This makes the process much more efficient. Moreover, the method allows the use of economical starting material s.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present Invention, disclosed Is a process for preparing optically active aryloxypropanol amines (1) or ary Iethanol amines (2) of the formula

wherein Ar Is aryl, substituted aryl, heteroaryl or aralkyl and R is alkyl substituted alkyl, aralkyl, or WB wherein W ts a straight or branched chai alkylene of from 1 to about 6 carbon atoms and wherein B represents -NR2COR3, -NR2CONR3R4, -NR2SO2R3, -NR2SO2NR3R4, or -NR2COOR5 wherein R ₂ , R3» R4 and R5 may be the same or different and may be hydrogen, alkyl of from 1 to about 10 carbon atoms and preferably from 1 to about 6 carbon atc s, alkoxyalkyl wherein the alkyl groups may be the same or different and contain from 1 to about 10 carbon atoms and preferably frαn 1 to about

6 carbon atoms; cycloalkyl of from 3 to about 8 carbon atoms, alkenyl of from 3 to about 10 carbon atoms, alkoxyaryl wherein the alkyl group contains from 1 to about 6 carbon atoms, alkynyl of from 3 to about 10 carbon atoms, aryl which Includes substituted or unsubstltuted monocycl lc or polycycl lc aromatic or heterocycl Ic ring systems of from 6 to about 10 carbon atoms such as phenyl, thlenyl, Imldazole, oxazole, Indole, and the I Ike, or aralkyl wherein the alkyl portion contains from 1 to about 5 carbon atoms and the aryl portion represents substituted or unsubstltuted monocycl Ic or polycycl Ic aromatic or heterocycl Ic ring systems of from 2 t about 10 carbon atoms such as benzyl, phenethyl, 3,4-d I methoxy phenethyl, 1,1-dImethyl-2-(3-lndolyl)ethy I and the like; except that R3 and R5 are no hydrogen when B Is - R2SO23 or -NR2COOR5, or R3 and R4 may together ith form a 5- to 7-membered heterocycl Ic group such as pyrrol ϊdlne, plperldlne, pfperazlne, morphol Iπe, or thlomorphol Ine.

As used herein, the term "aryl" represents a phenyl or naphthyl group which may be unsubstltuted or substituted with alkyl of from 1 to about 6 carbon atoms, alkenyl of from 2 to about 6 carbon atoms, alkynyl of from 2 to about 10 carbon atoms, alkoxy wherein the alkyl group contains from 1 t about 6 carbon atoms, halo, acetamldo, amino, amIdo, nitro, alkyIamIno of from 1 to about 6 carbon atoms, hydroxy, hydroxyalkyl of from 1 to about 6 carbon atoms, cyano or aryIalkoxy wherein the alkyl group contains form 1 to about 6 carbon atoms and the aryl group Is substituted or unsubstltuted phenyl.

The term "heteroary I ⁿ as used herein represents pyrldlne, pyrazlne, pyrrole, pyrazole, ptperazfπe, thfophene, benzothfophene, furan, benzofuran, Imldazole, oxazole, Indole, carbazole, thlazole, thfadtazole, benzothladlazole, trlazolβ, tetrazole, azepfne, 1, 2-dIazeptne, or 1,4-thIazeplne. Preferably, the heteroaryl Is selected from the group consisting of pyrldlne, pyrazlne, thlophene, benzothfophene, benzofuran, Indole, carbazole, thladlazole or benzothladlazole, with the most preferre being pyrazlne, Indole, 1,2, 5-th ladlazole, or benzofuran.

The term "heterocyclic" as used herein represents pyrrol Idlne, plperfdlne, orphol Ine, or thlomorphol Ine.

In the term "aralkyl" as used herein, the alkyl group contains from about 1 to about 6 carbon atoms and the aryl group represents substituted or unsubstltuted monocycl lc or polycycl lc aromatic or heterocycl lc ring systems of from 5 to about 10 carbon atoms, such as benzyl, phenethyl, 3,4- I methoxy phenethyl, 1 ,1-dlmethy l-2-(3-lndoly l)-ethy I and the l ike. Aromatic (Ar) substltuents may Include lower alkyl of from 1 to about 10 carbons atoms, alkenyl of from 2 to about 10 carbon atoms, alkynyl of from 2 to about 10 carbon atoms, alkoxy wherein the alkyl group contains from 1 to about 10 carbon atoms, halo-, acetamldo, am! no, nitro, alky I am I no of fr 1 to about 10 carbon atoms, hydroxy, hydroxyalkyl of from 1 to about 10 carbon atoms, cyano, ary I alkoxy wherein the alkyl group contains from 1 to about 6 carbon atoms and the aryl group represents substituted or unsubstl tuted phenyl and groups of the formula

0

R4-O-C-A wherein R4 Is lower alkyl, aryl or aral yl and A Is a direct bond, alkylen of from 1 to about 10 carbon atoms or alkenylene of from 2 to about 10 carbon atoms.

The term "cycloalkyl" as used herein refers to cycl Ic saturated al Iphatlc radicals containing 3 to 6 carbon atoms In the ring, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexy I.

The method Involves the utilization of tr I substituted phosphonlum hal Ide, namely the R3P/CX4 complex as selective halogenatlng agents, an example being the use of P 3P CCl4 as selective chlorinating agents to provide the monochloro derivative, which Is then converted Into the ary loxypropanol am Ine. The complete process can be performed In one reaction vessel to avoid having to Isolate and purify Intermediates, or c be performed step lse. The method can be used In the synthesis of beta agonists or beta-b I ockers or any halohydrln Intermediate. In the

R3-phosphInes, as used herein R represents alkyl, aryl, cycloalkyi, alkylamlno, amlnoalkyl, cycloalkyi, amlno or amlno cycloakyl. X represent halo, namely chloro, bro o or Iodo.

The ary lethanolamlnes can be prepared as follows, all In a single reaction vessel. Aryl 1,2-ethanedIol can be converted to the correspondin chlorohydrln by reacting It with Pf^P and CCI4 In aceton I tr f I e. The resulting chlorohydrln then can be cycl Ized to an epoxlde by treating It with one equivalent of sodium methoxlde. The ary lethanolamlne can then be obtained by treating the epoxlde with one equivalent of amlne-.

The fol lowing reaction schemes summarize the process of the present Invention.

SCHEME 1 -

R-(-) s-(-) R-(-) or S-(+) or R-(+) or S-(+)

R-(-) or R-(+) or S-(+)

S-(+) S-(-) or R-(-) or R-(+)

SCHEME 2

Referrlng to Scheme 1, the racemlc, the (R)-(+) or S-(-) 3-(ary loxy)-1 ,2- propanedlol (1) can be made by known methods. For example, the S-enantlomer can be prepared readily by reacting an appropriate phenoxlde with R-(-)-2,2-dlmethy l-4-(hydroxymethy l)-1 ,3- dloxolane methanesul fonate or p-tol uene-sul fonate, followed by acid hydrolysis of th ketal .

The ary loxypropanol am Ine (4) can be made by mixing In the same reaction vessel, In the following named order, the 3-(ary loxy)-1,2- propanedlol (1) with a tr I substituted phosphonlum hal Ide to prepare the aryl substituted halohydrln (2) which, unless desired, need not be Isolated. A suitable base Is then added to prepare the epoxlde which, likewise, need not be Isolated. A selected amlne Is then added to prepare the desired ary loxypropanol am Ine.

A suitable base for reaction ith the halohydrln would be a metal alkoxlde, metal hydroxide, metal hydride, metal carbonate or metal bicarbonate wherein the metal Is sodium, potassium or calcium, or an ammonium hydroxide or a suitable organic base. Preferred organic bases ar pyrldlne, dlmethy lamlnopyrldlne, dlmethylanf I Ine, qulnol Ine,

1,8-DIazablcycloC5.4.03undec-7-eπe (DBU), 1 ,5-Df azablcycl oC4,3.03non- 5-en (DBN) or tertiary alky I amines. Preferred bases are sodium or potasstum methoxlde, ethoxlde or t-butoxlde or a tertiary alkyl amlne.

The following beta-adrenerglc blocking agents, beta-agonists and partial agonists are representative of the compounds that can be made usin the described process:

Ar R Compound

- Acebutolol

ΓOTO: Adimolol

Afurolol

Alprenolol

Ancarolol

:σ -< Atenolol

CH _j CONH,

Befunolol

Betaxolol

Ar Compound

Bevantoiol

Bisprolol

Bometolol

Bornaproiol

Bucindolol

Bucumolol

Bufetoiol

Ar Compound

©C 4- Bunitrolol

Bunalol

Bupranolol

Butocrolol

Butofilolol

Carazolol

Carteolol

Carvedilol

Ar Compound

Celipro!ol

OCH-CONHCH-

:σ Cetamolol

Chinoin-103

~< Cidoprolol

-r Cloranolol

Diacetolol

Exaprolol

-<

Ar Compound

Indenolol

Indopanolol

-r Isoxaprolol

Levobunolol

Mepindolol

Metipranolol

Ar R _. Compound

^CH 3 ^0CH 2 ^CH τ@/-- Metoprolol

-j- Moprolol

Nadolol

Nafetolol

Oxprenolol

Pafenolol

Pamatolol

Ar Compound

Pargolol

Penbutolol

Pindolol

Pirepolol

Practolol

Prenalterol

Prizidilol

Procinolol

Ar Compound

Propranolol

Spirendolol

Teoprolol

CH.

Tertatolol

Timolol

Tiprenolol

^■ CONH, Tolamolol

Xibenolol

Xamoterol

OH

Ar R Compound

Al buterol

Amosulalol

4- Bufuralol

fonterol

Ibuterol

Miscellaneous Beta-Blockers Compound

Arotinolol

Bopindolol

In order to Illustrate the manner In which the above compounds may be made, reference Is made to the following examples, which, however, are not meant to I Imtt or restrict the scope of the Invention tn any respect.

EXAMPLE 1

Preparation of (S -. Methyl 3-r4-rr2-hydro*y-3- πsopropylam?nθ)propoxy~lphenyπpro foπate Hydrochlor Ide

A mixture of (S)-(-)Methy I 3-C4-(2,3-dIhydroxypropoxy)pheny Q- proplonate (74 g, 0.29 mole), trlpheny Iphosphtne (85 g, 1.1 mole) and carbon tetrach I or I dβ (140 mL) In 400 L acetonltrlle was stirred at 22° C for 16 hours. Another 8.5 g of trfphenylphςsphlne was added and stirring was continued for another 3 hours. If- desired, the product 2 can be

Isolated at this stage. The clear solution was cooled In an Ice- Isopropanol bath and to this was added dropwfse 62.8 gms. of 25% sodium methoxlde solution In methanol over 30 minutes. The Ice bath was removed and the solution was stirred at 22° C for 20 hours. To this solution was added 50 mL of Isopropylamtne and the mixture was refluxed for 4 hours. The reaction mixture was evaporated to dryness. The sol Idlfted mixture wa liquified, treated with 1000 πt. ether, and filtered over eel Ite. The filtrate was treated with hydrogen chloride for 5 minutes (pH = 2) and Immediately the oil began to separate. This oil was Isolated by decanting the ethereal layer. This process was repeated three times using 250 mL ether and the oil was sol Idlfled. The sol Id was recrystal I Ized from methyl

ethyl ketone (MEK)/ether (200 mL/35 mL) to give white crystalline product (28.6 g, 29.7?), mp 91-94° C, α ⁵ -19.1 (C 1, MeOH).

Anal. Cal. for C ₁₆ H ₂ 6CIN0 ₄ Cal : C, 57.91; H, 7.90; N, 4.22

Found: C, 57.98; H, 7.91; N. 4.13

EXAMPLE 2

Preparation of S-(+)-Methyt 3-r4-(2.3-epoxypropoγy)phenvl~lpropIonata

A mixture of S-(-)-Methyl 3-C4-2,3-dIhydroxypropoxy)pheny proplonate (50.8 g, 0.2 mole), trlpheny Iphosphlne (58 g, 0.22 mole), and carbon tetrachlorlde (100 g, 0.65 mole) In 500 mL acetonltrlle was stirred at 22° C for 24 hours. To the solution was added anhydrous potassium carbonate (40 g, 0.3 mole) and the mixture was ref luxed with stirring for 48 hours. The mixture was evaporated to dryness to give an oil, which was sol Idlf led Immediately. To this was added 600 L hexane and the mixture was ref luxed with vigorous stirring for 10 minutes and decanted while It was hot. This procedure was repeated four times. The decanted solution was cooled to 22 C and trlpheny Iphosphlne oxide was filtered off. The hexane solution was evaporated to give an oil (29 g) which was distilled under reduced pressur to give 22.5 g (47.3%) of the titled compound as a clear oil, b.p. 150° (0.1 mm Hg), _α ? ⁵ +7.9 (C 0.66, MeOH).

EXAMPLE 3

Preparation of (S -)-Methy1 -r4-2-hydro*y-3- fgopropylaιtιIne)propoxy1phenyπpropIonate Hydrochlorfda

A solution of (S)-(+)-Methy I 3-C4-(2,3-epoxypropoxy)pheny Gproplonate (22 g, 92.7 mrnolβ) and Isopropylamlne (50 mL) In 50 mL methanol was ref luxed for 2 hours and evaporated to dryness. The oily residue was redlssolved In 100 L methanol and the solution was evaporated. This procedure was repeated twice to el Imlnate traces of Isopropylamlne. The clear oil was dissolved In 200 mL methyl ethyl ketone, aclfled with hydrogen chloride, treated with 100 mL ether, seeded and allowed to stand at 22° C for 16 hours. The white crystal I Ine sol Id was filtered, washed with ether fol lowed by hexane and air dried to yield 21.6 g (70%) of the titled product, mp 91-95° C, α 25 -19.3 (C 1, MeOH).

Anal, for C ₁₆ H ₂ 6CIN0 Cal: C, 57.91; H, 7.90; N, 4.22

Found: C, 57.99; H, 7.79; N, 4.14

EXAMPLE 4

Preparation of levo-Propranolol HCI or (S -)f(3-Isopropylamtno-2- chIoro) ropoxylnapthaIene Hydroc IorIde

(4) HCI

A solution of (S)-(-)-1-(2,3-dlhydroxypropoxy)-napthalene (10.9 g, 0.05 mole), trlpheny Iphosphlne (14.4 g, 0.055 mole) and carbon tetrachlorlde (10.5 mL, 2.2 equlv.) tn dry acetonltrlle (dried over 3A Mol-sleve) was stirred at 22° C. Within 5 minutes this mixture became a clear, homogenous solution. Stirring was continued for 20 hours at 22° C and the mixture was then placed tn an Ice bath. To this was added 11.4 mL of 25% solution of sodium methoxlde In methanol and the Ice bath was removed and stirring continued for 16 hours at 22° C. The resulting mixture was diluted with 100 mL ethanol and treated with Isopropylamlne (1 mL, 2.4 equlv.) and ref luxed for 2 hours. The reaction mixture was evaporated to dryness. The oily residue was taken up with ether (200 L) and washed with water (2 x 200 L) and then extracted with 1N hydrochloric acid (1 x 500 mL). The aqueous layer was washed with ether (1 x 200 L), baslfled with 2N sodium hydroxide (pH ^■ 10) and extracted ith ether (2 x 200 L). The ethereal layers were combined and acidified with hydrogen chloride until a pH of 2 was obtained. The precipitated crystalline mass was filtered, washed with ether and air dried to give 14.1 g (95.6%) of crude levo-propranolol . The crude product was recrystal I Ized from

Isopropanol (200 L) to give 6.62 g (44.9%) of crystalline product, mp

190-191° C (Lit. 189-190° C), a. ²⁵ -26.5 (Cl, EtOH) (Lit: a ²⁵ -25.5

D D

(Cl, EtOH)).

Th e mother I Iquor was treated with 200 mL ether to give 1.62 g (10%, mp 189-190° C) of more crystalline I evo-propraπol ol . The above products were combined to give 55.9% yield from the dlol.

Nrø data:

Anal, for C ₁₆ H2oN02*HCI Cal: C, 65.17; H, 7.18; N, 4.75

Found: C, 64.87; H, 7.21; N, 4.81

EXAMPLE 5

Preparation of (R)-r(3-C loro-2-hy roxy) ropoxylnapth lene

CC1 ₄ /CH ₃ CN

A solution of (S)-(-)-1-(2,3-dIhydroxypropoxy)-naphthalene (5.45 g. ,

0.025 mole), 4-(dt Isopropy lamtπomethy Dtrlpheny Iphosphlne (10 g, 0.0226 mole), carbon tetrachlorlde (5 mL) tn acetonttrtle (100 L) was stirred at 22° C for 18 hours. This clear yellow solution was passed through a dry silica gel pad (1.5 cm x 2 cm, 30 g) and eluted with acetonltrlle (50 L). The el uent was evaporated to give a yellow oil. This was treated with Ispropyl ether (50 mL) and stirred for 15 minutes. The top layer was decanted and evaporated under reduced pressure to give the titled chlorohydrln as a clear oil (4.66 g, 78.8%).

EXAMPLE 6

Preparation of (R)-Ethyl 3-rr(3-Chloro-2-hydroxy) propoxyl 1.2.5- th lad Iazo -yllproplonata

A solution of S-(-) ethyl 3-[3-(2,3-dϊhydroxy-propoxy) 1, 2,5- th tad I azol-4-y I 3prop fonate (6.51 g, 0.025 mole), 4-(dI Isopropy I a- mtnomethy Dtrlpheny Iphosphlne (10g, 0.0266 mole), carbon tetrachlorlde (5 L) and acetonltrlle (100 mL) was stirred at 22° C for 18 hours. This clear solution was passed through a dry sll tea-gel pad (1.5 cm x 2 cm, 30 g) and eluted with acetonltrlle (50 mL). The el uent was evaporated to give a yellow oil. Thts was then treated with Isopropyl ether (50 L) an the top layer was separated and evaporated under reduced pressure to give the titled product as a clear oil (5.56 g., 79.7%), Rf 0.38 (SJO2, EtOAC: Hexane, 3:7), a single homogeneous spot.

EXAMPLE 7

Preparation of (S)-(+)-EthyI 3-r3-(2.3-epoxypropoxy)-1.2.5-thladlazol- 4-yl1 rop?onate

(2) K ₂ C0 ₃ /MEK

A mixture of (S)-(-)-Ethy I 3-C(2,3- thydroxypropoxy)-1 , 2,5- th tad tazo I -4-y proptonate (6.7g, 24,2 m ole), trlpheny Iphosphlne (8.26 g, 1.3 equv.) and carbon tetrachlorlde (60 mL) was heated under reflux for 16 hours, and evaporated to dryness. The residue was mixed with methyl ethyl ketone (60 mL) and anhydrous potassium carbonate (7.0 g). This mixture wa heated under reflux with vigorous stirring for 36 hours, cooled to 22° C and filtered. The filtrate was evaporated under reduced pressure and the residue was stirred vigorously In hexane (200 mL) for 15 minutes and the hexane layer was then decanted. This process was repeated twice; the organic layers were combined and evaporated under reduced pressure. The crude oil was distilled In vacuo to yield 1.9 g (30.8%) of the titled ester epoxtde, b.p. 118-122° C (0.2 mm Hg), _a ²⁵ +25.3 (C 1.5, EtOH), Rf 0.45

(SI0 ₂ , 1% MeOH tn CH CI ₂ ).