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Title:
PROCESS FOR PREPARING 6-O-ALKENYL-SUBSTITUTED ERYTHROMYCIN DERIV ATIVES
Document Type and Number:
WIPO Patent Application WO/2000/078773
Kind Code:
A2
Abstract:
In one aspect, the invention relates to a process for preparing 6-O-substituted erythromycin derivatives comprising reacting 2'-substituted and optionally 4'-substituted 9-oxime erythromycin derivatives with an alkylating agent in the presence of a palladium catalyst and phosphine. In another aspect, the invention relates to processes for preparing 6-O-substituted erythromycin ketolides using the palladium-catalyzed alkylation reaction.

Inventors:
STONER ERIC J
PETERSON MATTHEW J
KU YI-YIN
CINK RUSSELL D
COOPER ARTHUR J
DESHPANDE MAHENDRA N
GRIEME TIM
HAIGHT ANTHONY R
HILL DAVID R
HSU MARGARET CHI-PING
KING STEVEN A
LEANNA MARVIN R
LEE ELAINE C
MCLAUGHLIN MAUREEN A
MORTON HOWARD E
NAPIER JAMES J
PLATA DANIEL J
RAJE PRASAD S
RASMUSSEN MICHAEL
RILEY DAVID
TIEN JIEN-HEH J
WITTENBERGER STEVEN J
Application Number:
PCT/US2000/016579
Publication Date:
December 28, 2000
Filing Date:
June 15, 2000
Export Citation:
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Assignee:
ABBOTT LAB (US)
International Classes:
A61P31/04; C07B61/00; C07H1/00; C07H17/08; (IPC1-7): C07H17/08; A61K31/70; A61P31/04
Domestic Patent References:
WO1999011651A21999-03-11
WO1997042206A11997-11-13
WO1999016779A11999-04-08
WO1999021864A11999-05-06
WO1998009978A11998-03-12
Attorney, Agent or Firm:
Sickert, Dugal S. (100 Abbott Park Road Abbott Park, IL, US)
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Claims:
WHAT IS CLAIMED IS:
1. A process for preparing 6Osubstituted erythromycin derivatives comprising reacting an erythromycin derivative with an alkylating agent having the formula: wherein: R is independently selected from the group consisting of : hydrogen, an alkyl group of one to ten carbon atoms, halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl at each occurrence; R'is an alkyl group of one to ten carbon atoms, and X is O or NR', wherein R'is alkyl or aryl, or R'and R'taken together form an aromatic or nonaromatic ring; in the presence of palladium catalyst and a phosphine.
2. The process according to Claim 1, wherein the alkylating agent is selected from the group consisting of allyl isopropyl carbonate, allyl tbutyl carbonate, allyl N, N diisopropyl carbamate, 3 (3quinolyl)2propen1ol tbutyl carbonate and 1 (3quinolyl) 2propene1ol tbutyl carbonate.
3. The process according to Claim 2, wherein the alkylating agent is selected from the group consisting of allyl tbutyl carbonate, 3 (3quinolyl)2propen1ol tbutyl carbonate and 1 (3quinolyl)2propen1ol tbutyl carbonate.
4. The process according to Claim 1, wherein the palladium catalyst is selected from the group consisting of palladium acetate, tetrakis (triphenylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, and (tetradibenzylideneacetone) dipalladium.
5. The process according to Claim 1, wherein the phosphine is selected from the group consisting of triphenylphosphine, bis (diphenylphosphine) methane, bis (diphenylphosphine) ethane, bis (diphenylphosphine) propane, 1,4bis (diphenyl phosphine) butane, bis (diphenylphosphine) pentane, and tri (otolyl) phosphine.
6. The process according to Claim 1, wherein the ratio of palladium catalyst to the phosphine ranges from about 2: 1 to about 1: 8.
7. The process according to Claim 1, wherein the erythromycin derivative is represented by the formula: wherein: RP is independently hydrogen or hydroxylprotecting group at each occurrence except that RP may not be simultaneously hydrogen at both positions; V is selected from the group consisting of : a) 0 b) an oxime having the formula NOR2; wherein R2 is selected from the group consisting of : hydrogen, a loweralkenyl group, an aryl (loweralkyl) group, and a substituted aryl (loweralkyl) group; c) an oxime having the formula O NOCR3;wherein R3 is selected from the group consisting of : alkyl, alkylaryl, aryl, and substituted aryl; d) an oxime having the formula R4 is selected from the group consisting of : a loweralkyl group, a cycloalkyl group, a phenyl group, and an aryl (loweralkyl) group; or R4 and R 5or R4 and R6 and the atoms to which they are attached are taken together to form a 5to 7membered ring containing one oxygen atom; and R and R6 are independently selected from the group consisting of : a hydrogen atom, a loweralkyl group, a phenyl group, and an aryl (loweralkyl) group; or any pair of substituents selected from (R4 and R5), (R4 and R6) or (Rs and R6) and the atoms to which they are attached are taken together to form a 5to 7membered ring optionally containing one oxygen atom; provided that only one pair of substituents (R4 and R5), (R4 and R6) or (R5 and R6) may be taken together with the atoms to which they are attached to form a ring as defined above; e) an oxime having the formula: wherein R7, R8, and R9 are independently selected at each occurrence from hydrogen, loweralkyl, aryl substituted alkyl, aryl, cycloalkyl, and loweralkenyl; wherein R'° and R11 are independently selected at each occurrence from a hydrogen, alkyl or a nitrogen protecting group, or Rl° and Roll take together form a 5to 7 membered cycloalkyl ring; and wherein Rl2 and Rl3 are independently selected at each occurrence from hydrogen, alkyl or a nitrogen protecting group; or Rl2 and Rl3 taken together form a 5to 7 membered cycloalkyl ring; and Z is hydroxyl or a protected hydroxyl group.
8. A process for preparing a compound represented by formula: or pharmaceutically acceptable salt, ester or prodrug thereof, wherein Ra is represented by the formula: wherein: R is independently selected from the group consisting of : hydrogen, an alkyl group of one to ten carbon atoms, halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl at each occurrence; the process comprising the steps of : (a) reacting an erythromycin derivative with an alkylating agent having the formula: wherein R is as defined above; R is an alkyl group of one to ten carbon atoms, and X is O or NR', wherein R'is alkyl or aryl, or R'and R'taken together form an aromatic or nonaromatic ring; in the presence of palladium catalyst and a phosphine; (b) optionally deprotecting and deoximating the 6O substituted erythromycin of step (a) to obtain the compound of formula: wherein Z is hydroxyl or protected hydroxyl group and Ra and RP are as defined above; (c) reacting the compound from step (b) with 1,1'carbonyldiimidazole in the presence of an amine base or an amine base catalyst followed by a reaction with ammonia or ammonium hydroxide optionally carried out in the presence of a strong base to afford a compound having the formula: (d) removing the cladinose moiety from the compound obtained in step (c) by hydrolysis with acid to give a compound having the formula (e) oxidizing the 3hydroxyl group, and optionally deprotecting and isolating the desired compound.
9. The process according to Claim 8, wherein the erythromycin derivative in step (a) is a compound of the formula: wherein RP is independently hydrogen or hydroxylprotecting group at each occurrence except that RP may not be simultaneously hydrogen at both positions; V is selected from the group consisting of : a) 0 b) an oxime having the formula NOR2; wherein R2 is selected from the group consisting of : hydrogen, a loweralkenyl group, an aryl (loweralkyl) group, and a substituted aryl (loweralkyl) group; c) an oxime having the formula <BR> <BR> o<BR> <BR> <BR> <BR> <BR> NoCR3; wherein R3 is selected from the group consisting of : alkyl, alkylaryl, aryl, and substituted aryl; d) an oxime having the formula R4 is selected from the group consisting of : a loweralkyl group, a cycloalkyl group, a phenyl group, and an aryl (loweralkyl) group; or R4 and R5 or R4 and R6 and the atoms to which they are attached are taken together form a 5to 7membered ring containing one oxygen atom; and R'and R6 are independently selected from the group consisting of : a hydrogen atom, a loweralkyl group, a phenyl group, and an aryl (loweralkyl) group; or any pair of substituents selected from (R4 and R5), (R4 and R6) or (R5 and R6) and the atoms to which they are attached are taken together form a 5to 7membered ring optionally containing one oxygen atom; provided that only one pair of substituents (R4 and R5), (R4 and R6) or (R5 and R6) may be taken together with the atoms to which they are attached to form a ring as defined above; e) an oxime having the formula: wherein R7, R8, and R9 are independently selected at each occurrence from hydrogen, loweralkyl, aryl substituted alkyl, aryl, cycloalkyl, and loweralkenyl; wherein Rl° and R11 are independently selected at each occurrence from a hydrogen, alkyl or a nitrogen protecting group, or Rl° and Rl l taken together form a 5to 7 membered cycloalkyl ring; and wherein Rl2 and R13 are independently selected at each occurrence from hydrogen, alkyl or a nitrogen protecting group; or Rl2 and R13 taken together form a 5to 7 membered cycloalkyl ring; and Z is hydroxyl or a protected hydroxyl group.
10. The process according to Claim 9, wherein RP is acetyl or benzoyl.
11. The process according to Claim 8, wherein the erythromycin derivative of step (a) is an erythromycin 9oxime derivative, said erythromycin 9oxime derivative is treated with a benzoylating agent.
12. The process according to Claim 11, wherein the benzoylating agent is benzoyl chloride or benzoic anhydride.
13. The process according to Claim 11, wherein the benzoylating agent is a combination of benzoyl chloride and sodium benzoate.
14. The process according to Claim 8, wherein the alkylating agent is selected from the group consisting of allyl isopropyl carbonate, allyl tbutyl carbonate, allyl N, N diisopropyl carbamate, 3 (3quinolyl)2propen1ol tbutyl carbonate and 1 (3quinolyl) 2propene1ol tbutyl carbonate.
15. The process according to Claim 8, wherein the palladium catalyst is selected from the group consisting of palladium acetate, tetrakis (triphenylphosphine) palladium, and tris (dibenzylideneacetone) dipalladium, and (tetradibenzylideneacetone) dipalladium.
16. The process according to Claim 8, wherein the phosphine is selected from the group consisting of triphenylphosphine, bis (diphenylphosphine) methane, bis (diphenylphosphine) ethane, bis (diphenylphosphine) propane, 1,4 bis (diphenylphosphine) butane, bis (diphenylphosphine) pentane, and tri (otolyl) phosphine.
17. The process according to Claim 8, wherein the ratio of palladium catalyst to the phosphine ranges from about 2: 1 to about 1: 8.
18. The process according to Claim 8, wherein the 6Osubstituted erythromycin derivative prepared in step (a) is reacted with a sulfur oxide a sodium nitrite compound.
19. The process according to Claim 18, wherein the sulfur oxide compound is sodium hydrogen sulfite, sodium metabisilfite or sodium bisulfite.
20. The process according to Claim 19, wherein sodium hydrogen sulfite is reacted with the 6Osubstituted erythromycin derivative in the presence of an organic acid.
21. The process according to Claim 20, wherein the reaction is carried out in an aprotic solvent.
22. The process according to Claim 20, wherein the acid is tartaric acid.
23. The process according to Claim 21, wherein the aprotic solvent is tetrahydrofuran.
24. The process according to Claim 8, wherein the amine base or an amine base catalyst in step (c) is sodium hexamethyldisilazide; 1,8diazabicyclo [5.4.0]undec7ene; or a mixture thereof.
25. A process for preparing a compound of formula: or pharmaceutically acceptable salt, ester or prodrug thereof, wherein Ra is represented by the formula: wherein R is independently selected from the group consisting of : hydrogen, an alkyl group of one to ten carbon atoms, halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl at each occurrence; the process comprising the steps of: (a) removing the cladinose moiety from an erythromycin derivative by hydrolysis with an acid to give a compound having the formula (b) protecting the hydroxyl groups to obtain a compound of the formula wherein Z is hydroxyl or protected hydroxyl group; (c) treating the compound from step (b) with an alkylating agent having the formula: wherein R is as defined above; R'is an alkyl group of one to ten carbon atoms, and X is O or NR', wherein R'is an alkyl or an aryl; or R'and R'taken together form an aromatic or nonaromatic ring; in the presence of palladium catalyst and a phosphine to obtain a compound of the formula: (d) deprotecting and deoximating the compound from step (c) to obtain a compound of formula: (e) optionally protecting the 2'and 3hydroxyl groups and reacting the compound from step (d) with 1,1'carbonyldiimidazole, in the presence of an amine base or an amine base catalyst followed by reaction with ammonium hydroxide optionally carried out in the presence of a strong base to obtain a compound having the formula: (f) optionally deprotecting the 3hydroxyl group and oxidizing the 3hydroxyl group; and (g) optionally deprotecting the hydroxylprotecting groups.
26. The process according to Claim 25, wherein RP is independently selected at each occurrence from the group consisting of acetyl, benzoyl, and trimethylsilyl.
27. The process according to Claim 25, wherein V is and R'is phenyl, and wherein RI is benzoyl.
28. The process according to Claim 25, wherein V is NOR2, wherein R and RP at each occurrence are trimethylsilyl.
29. The process according to Claim 25, wherein RP is acetyl at the 2'and trimethylsilyl at the 4"position.
30. The process according to Claim 25, wherein V in the erythromycin derivative of step (a) has the formula: wherein R5 and R6 taken together with the carbon to which they are attached form a cyclohexyl ring and R4 is isopropyl.
31. An intermediate represented by the formula: wherein V'is oxygen or NORí4; wherein R is selected from the group consisting of acetyl, benzoyl or trimethylsilyl; RP is independently selected at each occurrence from acetyl, benzoyl or trimethylsilyl; L and T are each hydroxyl; or L taken together with T forms an 11,12carbamate; and Rais represented by the formula: wherein R is independently selected from the group consisting of : hydrogen, an alkyl group of one to ten carbon atoms, halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl at each occurrence.
32. The intermediate according to Claim 31, wherein RP is independently selected at each occurrence from the group consisting of acetyl or benzoyl.
33. The intermediate according to Claim 32, wherein Ra is 3 (3quinolyl)2 propenyl or 2allyl, RP is benzoyl, L is hydroxyl and T is hydroxyl.
Description:
INTERNATIONAL SEARCH REPORT Intern, ial Application No PCT/US 00/16579 C.(Continuation) DOCUMENTS CONSIDERED TO BE RELEVANT Category ! tat ! on of document, with indication, where appropriate, of the relevant passages Relevant to claim No. X WO 99 21864 A (ABBOTT LAB) 1,4-7, 6 May 1999 (1999-05-06) 31,32 page 40, step ld, compound 7 Rp = acetyl; page 41, step lh X WO 98 09978 A (ABBOTT LAB) 1,4-7, 12 March 1998 (1998-03-12) 31,32 Y page 95, lines 27-36; page 107, example 1-33 14; page 108, example 18 1 INTERNATIONAL SEARCH ptem nal Application No Information on patent family members PCT/US 00/16579 PCT/US 00/16579 Patent document Publication Patent family Publication cited in search report date member (s) date WO 9911651 A 11-03-1999 AU 8925398 A 22-03-1999 EP 1027360 A 16-08-2000 ZA 9807689 A 24-02-1999 WO 9742206 A 13-11-1997 US 6075011 A 13-06-2000 AU 2340797 A 26-11-1997 AU 726075 B 26-10-2000 AU 2998797 A 26-11-1997 BR 9708929 A 03-08-1999 CZ 9803518 A 14-04-1999 EP 0918783 A 02-06-1999 EP 1007530 A 14-06-2000 JP 2000509712 T 02-08-2000 WO 9742204 A 13-11-1997 WO 9916779 A 08-04-1999 AU 9317698 A 23-04-1999 BR 9812577 A 17-10-2000 CN 1271363 T 25-10-2000 EP 1025114 A 09-08-2000 NO 20001439 A 29-05-2000 ZA 9808808 A 29-03-1999 WO 9921864 A 06-05-1999 AU 1286799 A 17-05-1999 BR 9813317 A 22-08-2000 EP 1027361 A 16-08-2000 NO 20002099 A 29-06-2000 ZA 9809848 A 29-04-1999 WO 9809978 A 12-03-1998 US 5866549 A 02-02-1999 AU 4178097 A 26-03-1998 BG 103292 A 30-12-1999 BR 9711661 A 24-08-1999 CN 1237183 A 01-12-1999 CZ 9900685 A 11-08-1999 EP 0929563 A 21-07-1999 HR 970473 A 31-08-1998 NO 991022 A 03-05-1999 PL 332009 A 16-08-1999 SI 20023 A 29-02-2000 SK 28699 A 13-03-2000 US 6075133 A 13-06-2000 US 6147197 A 14-11-2000 US 6028181 A 22-02-2000



 
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