Processes for preparing pyrimidine compounds

Patent metadata

Field	Value
Publication number	US-9447052-B2
Application number	US-201113698102-A
Country	US
Kind code	B2
Filing date	May 17, 2011
Priority date	May 17, 2010
Publication date	Sep 20, 2016
Grant date	Sep 20, 2016

Abstract

This invention relates to methods of making a compound of formula (I) and intermediates for same

the compounds of formula (I) being useful for treating cardiovascular and inflammatory diseases such as atherosclerosis.

First claim

What is claimed is:

1. A process for making a compound of formula (I):

wherein:
R a and R b together with the pyrimidine ring carbon atoms to which they are attached form a cyclopentyl ring;
R 1 is phenyl, unsubstituted or substituted by 1 to 3 fluoro groups;
R 2 is C (1-3) alkyl substituted by NR 5 R 6 ; or
R 2 is Het-C (0-2) alkyl in which Het is a 5- to 7- membered heterocyclic ring containing N and in which N may be substituted by C (1-6) alkyl;
R 3 is phenyl;
R 4 is phenyl unsubstituted or substituted by C (1-6) alkyl or mono to perfluoro-C (1-4) alkyl; and
R 5 and R 6 which may be the same or different are C (1-6) alkyl;
the process comprising:
(a) treating a C (1-4) alkyl 2-oxocyclopentanecarboxylate with an alkali metal salt of glycine to form a compound of formula (A)

(b) cyclising a compound of said formula (A) to form the hexahydro-1H-cyclopenta[d]pyrimidin-1-yl)acetic acid of formula (B)

by treating a compound of said formula (A) with either:
(i) a thiocyanate salt and
a) a haloalkylsilane and a proton source, with heating, or
b) an anhydrous acid, with heating; or

(ii) trimethylsilylisothiocyanate, with heating;
(c) forming a thio-4-oxo-4,5,6,7-tetrahydro-1H-cyclopenta [d]pyrimidin-1-yl)acetic acid of formula (C)

where n is 0 to 3,
by treating a compound of said formula (B) with a thio-alkylating reagent which is a benzyl derivative of formula (D)

where n is 0 to 3 and X is a leaving group, in the presence of an alkali metal base and/or an alkali metal carbonate; and
(d) forming a compound of formula (I) by treating a compound of said formula (C) with carbonyldiimidazole and the secondary amine of formula (F)

and heating the mixture.

2. The process according to claim 1 , wherein said compound of formula (A) is treated with a thiocyanate salt, a haloalkylsilane and a proton source, with heating, to form the compound of formula (B).

3. The process according to claim 1 , wherein the thiocyanate salt is ammonium thiocyanate or alkali metal thiocyanate.

4. The process according to claim 2 , wherein the thiocyanate salt is ammonium thiocyanate or alkali metal thiocyanate.

5. The process according to claim 1 , wherein the compound of formula (I) is isolated using methanol as a solvent.

6. A methanol solvate of a compound of formula (I) as defined in claim 1 .

7. The process according to claim 1 , wherein the compound of formula (A), C 1 -C 4 alkyl is methyl.

8. A process for making N-[2-(diethylamino)ethyl]-2-(2-{[(4-fluorophenyl)methyl]thio}-4-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-1-yl)-N-{[4′-(trifluoromethyl)-4-biphenyly]methyl}acetamide:

comprising:
treating a C (1-4) alkyl 2-oxocyclopentanecarboxylate with an alkali metal salt of glycine to form a compound of formula (A)

(b) cyclising the compound of formula (A) to form (4-oxo-2-thioxo-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-1-yl)acetic acid:

by treating the compound of formula (A) with either:
(i) a thiocyanate salt and
a) a haloalkylsilane and a proton source, with heating, or
b) an anhydrous acid, with heating; or

(ii) trimethylsilylisothiocyanate, with heating;
(c) forming (2-{[(4-fluorophenyl)methyl]thio}-4-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-1-yl)acetic acid:

by treating (4-oxo-2-thioxo-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-1-yl)acetic acid with a thio-alkylating reagent which is a benzyl derivative of formula (D):

where X is a leaving group, in the presence of an alkali metal base and/or an alkali metal carbonate; and
(d) forming N-[2-(diethylamino)ethyl]-2-(2-{[(4-fluorophenyl)methyl]thio}-4-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-1-yl)-N-{[4′-(trifluoromethyl)-4-biphenylyl]methyl}acetamide by treating the (2-{[(4-fluorophenyl)methyl]thio}-4-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-1-yl)acetic acid with carbonyldiimidazole and N,N-diethyl-N′-{[4′-(trifluoromethyl)-4-biphenylyl]methyl}-1,2-ethanediamine:

and heating the mixture.

9. The process according to claim 8 , wherein said compound of formula (A) is treated with a thiocyanate salt, a haloalkylsilane and a proton source, with heating, to form (4-oxo-2-thioxo-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-1-yl)acetic acid.

10. The process according to claim 8 , wherein the thiocyanate salt is ammonium thiocyanate or alkali metal thiocyanate.

11. The process according to claim 9 , wherein the thiocyanate salt is ammonium thiocyanate or alkali metal thiocyanate.

12. The process according to claim 8 , wherein the compound of formula (A), C 1 -C 4 alkyl is methyl.

13. The process according to claim 8 , wherein the N-[2-(diethylamino)ethyl]-2-(2-{[(4-fluorophenyl)methyl]thio}-4-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-1-yl)-N-{[4′-(trifluoromethyl)-4-biphenylyl]methyl}acetamide is isolated using methanol as a solvent.

14. A methanol solvate of N-[2-(diethylamino)ethyl]-2-(2-{[(4-fluorophenyl)methyl]thio}-4-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-1-yl)-N-{[4′-(trifluoromethyl)-4-biphenylyl]methyl}acetamide.

15. The process according to claim 8 , wherein the compound of formula (D) is 4-fluorobenzyl chloride:

Assignees

• Cardwell Kevin Stuart
• Crawford Claire Frances
• Davies Suzanne Helen
• Wade Charles Edward
• Glaxo Group Ltd

Inventors

• Cardwell Kevin Stuart
• Crawford Claire Frances
• Davies Suzanne Helen
• Wade Charles Edward

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• C07C229/16

  to carbon atoms of hydrocarbon radicals substituted by amino or carboxyl groups, e.g. ethylenediamine-tetra-acetic acid, iminodiacetic acids · CPC title

• C07C227/08

  by reaction of ammonia or amines with acids containing functional groups · CPC title

• C07D239/70 Primary

  condensed with carbocyclic rings or ring systems · CPC title