Granted Patent B2

US 7,528,264 · App. 11/728,341 · Granted May 5, 2009

Abstract

Claims (29)

1. A process for preparing a quinolone intermediate having the formula:

wherein:

n is 1 or 2;

X is selected from the group consisting of C 1 -C 4 alkyl, C 6 -C 10 aryl or alkylaryl, and C 3 -C 6 cycloalkyl; and

Z is selected from the group consisting of CO 2 X and COX, wherein X is as defined above;

said process comprising the steps of:

(a) reacting the compound of Formula (II):

 wherein Y is selected from the group consisting of C 1 -C 4 alkyl, C 6 -C 10 aryl or alkylaryl, and C 3 -C 6 cycloalkyl; and X, and Z are as defined for Formula (I); with about 2 to about 4 equivalents of sodium borohydride in alkanol or an admixture of alkanol/ether in a v/v ratio of from about 100/0 to about 20/80, at about −20° C. to about 10° C.;

(b) setting the temperature of the reaction mixture to a temperature in the range from about 5° C. to about 15° C.; and

(c) adding about 1.5 to about 3.0 equivalents of a calcium salt.

2. A process according to claim 1 , wherein the alkanol is a C 1 to C 4 alkanol.

3. A process according to claim 1 , wherein the ether is a C 2 to C 6 ether.

4. A process according to claim 2 , wherein the ether is a C 2 to C 6 ether.

5. A process according to claim 1 , wherein X is C 1 -C 4 alkyl.

6. A process according to claim 5 , wherein X is methyl.

7. A process according to claim 1 , wherein Z is tert-butoxycarbonyl.

8. A process according to claim 5 , wherein Y is methyl.

9. A process according to claim 1 , wherein the calcium salt is selected from the group consisting of calcium chloride and calcium bromide.

10. A process according to claim 9 , wherein the calcium salt is calcium chloride.

11. A process according to claim 1 , wherein the compound of Formula (II) is (2S,4S)-1-(1,1-dimethylethyl)-4-methyl-5-oxo-1,2-pyrrolidinedicarboxylic acid-2-methyl ester.

12. A process according to claim 1 , wherein the compound of Formula (II) is (2S,4R)-1-(1,1-dimethylethyl)-4-methyl-5-oxo-1,2-pyrrolidinedicarboxylic acid-2-methyl ester.

13. A process according to claim 1 , wherein the compound of Formula (I) is (1S,3S)-(4-Hydroxyl-1-hydroxymethyl-3-methyl-butyl)-carbamic acid tert-butyl ester:

14. A process according to claim 1 , wherein the compound of Formula (I) is (1S,3R)-(4-Hydroxyl-1-hydroxymethyl-3-methyl-butyl)-carbamic acid tert-butyl ester:

15. A process according to claim 1 , wherein the alkanol solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, and butanol.

16. A process according to claim 15 , wherein the alkanol solvent is ethanol.

17. A process according to claim 1 , wherein the ether solvent is selected from the group consisting of methyl tert-butyl ether (MTBE), ethylene glycol dimethyl ether, diethyl ether, tetrahydrofuran, diisopropyl ether, and dioxane.

18. A process according to claim 17 , wherein the ether solvent is methyl tert-butyl ether.

19. A process according to claim 16 , wherein the ether solvent is methyl tert-butyl ether.

20. A process according to claim 19 , wherein the solvent ratio (v/v) of ethanol to methyl tert-butyl ether is about 1:2.

Assignments (8)