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Claims for Patent: 6,166,213

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Claims for Patent: 6,166,213

Title: Omeprazole process and compositions thereof
Abstract:The present invention describes an improved process for the preparation, isolation, and purification of the anti-ulcer agent omeprazole whereby the sulfide precursor pyrmetazole is reacted subsurfacely with exactly one molar equivalent of meta-chloroperoxybenzoic acid in methylene chloride or toluene solution; residual organic solvent is removed from the aqueous layer by vacuum distillation; crude product is obtained by reactive crystallization with an alkyl formate and seeding; and pure product is isolated by recrystallization in methanol-water containing aqueous NaOH by subsurface addition of aqueous acetic acid to pH 9.0, seeding, filtration, washing, and drying. Compositions of omeprazole containing no chromatographically detectable levels of residual non-alcoholic organic reaction solvent are also described.
Inventor(s): Anousis; Nick (Albany, GA), McManus; James W. (Albany, GA), Banks; Benjamin Newton (Albany, GA), Zhou; Lingwen (North Brunswick, NJ), Liu; Hui (Greenbrook, NJ)
Assignee: Merck & Co., Inc. (Rahway, NJ)
Application Number:09/169,231
Patent Claims: 1. A process for the preparation of omeprazole, having the formula I, ##STR4## which comprises: (a) treating, at about -5 to +5.degree. C., a buffered solution of pyrmetazole, having the formula II, in a non-alcoholic organic ##STR5## reaction solvent, with one equivalent, relative to the number of moles of said pyrmetazole, of meta-chloroperoxybenzoic dissolved in the non-alcoholic organic reaction solvent in admixture with an alcoholic solvent at about 0-5.degree. C. followed by aging in the presence of an aqueous base;

(b) separating the aqueous phase of the aged reaction mixture from the organic phase; and

(c) removing residual non-alcoholic organic reaction solvent from said aqueous phase followed by re-adjusting the alcoholic solvent concentration to about 15% v/v.

2. The process according to claim 1 wherein the alcoholic solvent is selected from methanol, ethanol, isopropanol, and 1-butanol.

3. The process according to claim 2 wherein the alcoholic solvent is ethanol.

4. The process according to claim 1 which further comprises:

(a) crystallizing crude product from said aqueous phase by subsurface addition of a C.sub.1-3 alkyl formate to adjust the pH from about 13.5 to about 10.6-10.8, aging for about 10-20 minutes, allowing the temperature to reach about 20.degree. C., seeding, and adding remainder of said alkyl formate over 6-8 hours to adjust the pH to about 9.0-9.3; and

(b) isolating crude product by filtration and washing with ammonia-water and methanol.

5. The process according to claim 4 which further comprises:

(a) recrystallizing crude product in methanol-water containing aqueous sodium hydroxide by cooling to about 0-5.degree. C., adjusting the pH to about 10.5 by subsurface addition of 25% aqueous acetic acid, seeding, adding 25% aqueous acetic acid to a pH of about 9.0, and aging for about 0.5 hours; and

(b) isolating pure product by filtration, washing with methanol-water and cold methanol, and vacuum drying.

6. The process according to claim 1 wherein residual non-alcoholic organic reaction solvent is removed from the aqueous phase by vacuum distillation at about 25-70 mm Hg and about 15-35.degree. C. for about 1-4 hours.

7. The process according to claim 1 wherein the non-alcoholic organic reaction solvent is selected from an aromatic hydrocarbon solvent and a chlorinated aliphatic hydrocarbon solvent.

8. The process according to claim 7 wherein the aromatic hydrocarbon solvent is toluene.

9. The process according to claim 7 wherein the chlorinated aliphatic hydrocarbon solvent is selected from methylene chloride, 1,2-dichloroethane, and chloroform.

10. The process according to claim 9 wherein the chlorinated aliphatic hydrocarbon solvent is methylene chloride.

11. The process according to claim 1 wherein the aging is allowed to proceed at about 0-5.degree. C. for about 0.5-1.0 hours.

12. The process according to claim 1 wherein the buffer comprises aqueous sodium bicarbonate or aqueous potassium bicarbonate.

13. The process according to claim 1 wherein the aqueous base comprises aqueous sodium hydroxide or aqueous potasium hydroxide.

14. The process according to claim 4 wherein the C.sub.1-3 alkyl formate in Step (a) is methyl formate.

15. The process according to claim 5 wherein the volume ratio of methanol to water in Steps (a) and (b) is 2:1 to 0.5-1.

16. The process according to claim 15 wherein the volume ratio of methanol to water is 1:1.

17. The process according to claim 6 wherein the vacuum distillation is performed at a pressure of about 50 mm Hg and a temperature of about 15-25.degree. C.

18. The process according to claim 4 wherein the concentration of ammonia-water in Step (b) is 0.01-1.0%(v/v).

19. The process according to claim 18 wherein the concentration of ammonia-water is 0.1%(v/v).

20. The process according to claim 1 wherein the molar amount of oxidizing agent to be added to said pyrmetazole solution is calculated by means of a high-performance liquid chromatographic assay which quantifies the extent of oxidation of an excess of 3-methylisoquinoline to 3-methylisoquinoline-N-oxide.

21. The process according to claim 1 wherein the oxidizing agent is added subsurfacely such that the solution enters the reaction mixture at the tip of the agitator blades.

22. 5-Methoxy-2-[[4-meth oxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole (omeprazole) obtained by the process of claim 5 containing less than 100 parts per million of residual aromatic hydrocarbon solvent.

23. 5-Methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridin yl)methyl]sulfinyl]-1H-benzimidazole (omeprazole) obtained by the process of claim 5 containing less than 100 parts per million of residual chlorinated aliphatic hydrocarbon solvent.

24. 5-Methoxy-2-[[4-methoxy-3,5-dimethyl-2- pyridinyl)methyl]sulfinyl]-1H-benzimidazole (omeprazole) according to claim 22 wherein the aromatic hydrocarbon solvent is toluene.

25. 5-Methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)met hyl]sulfinyl]-1H-benzimidazole (omeprazole) according to claim 23 wherein the chlorinated aliphatic hydrocarbon solvent is methylene chloride.

26. 5-Methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl] -1H-benzimidazole (omeprazole) containing less than three parts per million of residual aromatic hydrocarbon solvent and 10-20 p.p.m. of residual methanol.

27. 5-Meth oxy-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazol e (omeprazole) containing less than three parts per million of residual chlorinated aliphatic hydrocarbon solvent and 10-20 p.p.m. of residual methanol.

28. 5-Meth oxy-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazol e (omeprazole) according to claim 26 wherein the aromatic hydrocarbon solvent is toluene.

29. 5-Methoxy-2-[[4- methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole (omeprazole) according to claim 27 wherein the chlorinated aliphatic hydrocarbon solvent is methylene chloride.
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