P
USRE43844EExpiredUtilityPatentIndex 44

Process for preparing isomers of salbutamol

Assignee: HAMIED YUSUF KHWAJAPriority: Dec 11, 2000Filed: Dec 10, 2001Granted: Dec 4, 2012
Est. expiryDec 11, 2020(expired)· nominal 20-yr term from priority
Inventors:HAMIED YUSUF KHWAJAKANKAN RAJENDRA NARAYANRAORAO DHARMARAJ RAMACHANDRA
C07B 2200/07C07C 213/10C07C 227/34
44
PatentIndex Score
0
Cited by
12
References
55
Claims

Abstract

A process for making optically pure (R) and (S) salbutamol comprises obtaining the (R) or (S) isomer of either salbutamol or a salbutamol precursor in substantially optically pure form by resolving a racemic or optically impure mixture of enantiomers of salbutamol or of said precursor with either (L) or (D) tartaric acid, and where necessary converting said isomer of said precursor into either (R or (S) salbutamol respectively; then optionally converting said optically pure (R) and/or (S) salbutamol into a pharmaceutically acceptable salt.

Claims

exact text as granted — not AI-modified
1. A process for making optically pure (R) salbutamol or pharmaceutically acceptable salts thereof having a value of 95% enantiomeric excess or more, which process comprises obtaining the (R) isomer of either salbutamol or a salbutamol precursor, wherein the salbutamol precursor is 4-benzyl albuterol or methyl-5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)-benzoate in optically pure form by:
 a) dissolving a mixture of salbutamol, 4-benzyl albuterol or methyl-5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)-benzoate enantiomers and a molar excess (with respect to said salbutamol or said precursors) of (L) tartaric acid in a solvent;   b) allowing the solution to cool to crystalize a salt of one enantiomer;   c) separating the salt from the solution;   d) liberating the enantiomer from the salt;   e) when the enantiomer is 4-benzyl albuterol or methyl-5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)-benzoate, reducing the enantiomer; and   f) except when salbutamol is used in step a), debenzylating the enantiomer and recoVering the (R) enantiomer of salbuamol; then optionally converting said optically pure (R) salbutamol into a pharmeucedically acceptable salt.   
     
     
       2. A process according to  claim 1 , wherein the mole equivalent amount of tartaric acid is greater than or equal to 1.07. 
     
     
       3. A process according to  claim 1 , wherein the mole equivalent amount of tartaric acid is greater than or equal to 1.1. 
     
     
       4. A process according to  claim 1 , wherein the mole equivalent amount of tartaric acid is at least 1.18. 
     
     
       5. A process according to  claim 1 , wherein the salbutamol precursor is 4-benzyl albuterol. 
     
     
       6. A process according to  claim 1 , wherein the resolution is carried out on racemic salbutamol or on an optically impure mixture of enantiomers of salbutamol. 
     
     
       7. A process according to  claim 1 , wherein the optical purity has a value of 99% enantiomeric excess or more. 
     
     
       8. A process according to  claim 1 , further comprising converting said isomer of said precursor into either (R) salbutamol respectively; then optionally converting said optically pure (R) salbutamol into a pharmaceutically acceptable salt. 
     
     
       9. A process for making optically pure (R)-salbutamol, comprising:
 a) forming a solution comprising an optically-impure salbutamol precursor or a racemic salbutamol precursor and a molar excess of optically-pure (L)-tartaric acid in an organic solvent, the salbutamol precursor being 4-benzyl albuterol or a substituted 4-benzyl albuterol wherein the benzyl group is substituted with one or more halogen or one or more alkoxy group;   b) allowing the solution to cool to crystallize a salt of one enantiomer;   c) separating the salt from the solution;   d) liberating an optically-pure (R)-salbutamol precursor from the optically pure (R)-salbutamol precursor-(L)-tartrate salt; and   e) debenzylating the optically-pure (R)-salbutamol precursor to obtain optically-pure (R)-salbutamol.   
     
     
       10. The process of claim 9, further comprising converting the optically-pure (R)-salbutamol into a pharmaceutically-acceptable salt. 
     
     
       11. The process of claim 9, where the molar ratio of optically-pure (L)-tartaric acid to the optically impure or racemic salbutamol precursor is greater than or equal to 1.07. 
     
     
       12. The process of claim 9, where the molar ratio of optically-pure (L)-tartaric acid to the optically impure or racemic salbutamol precursor is greater than or equal to 1.1. 
     
     
       13. The process of claim 9, where the molar ratio of optically-pure (L)-tartaric acid to the optically impure or racemic salbutamol precursor is at least 1.18. 
     
     
       14. The process of claim 9, where the optically-pure (R)-salbutamol is present in an enantiomeric excess of at least 99%. 
     
     
       15. The process of claim 10, where the pharmaceutically-acceptable salt of optically-pure (R)-salbutamol is optically pure (R)-salbutamol sulphate. 
     
     
       16. The process of claim 9, where the salbutamol precursor is 4-benzyl albuterol. 
     
     
       17. A process for making optically pure (S)-salbutamol, comprising:
 a) forming a solution comprising an optically impure salbutamol precursor or a racemic salbutamol precursor and a molar excess of optically-pure (D)-tartaric acid in an organic solvent, the salbutamol precursor being 4-benzyl albuterol or a substituted 4-benzyl albuterol wherein the benzyl group is substituted with one or more halogen or one or more alkoxy group;   b) allowing the solution to cool to crystallize a salt of one enantiomer;   c) separating the salt from the solution;   d) liberating an optically-pure (S)-salbutamol precursor from the optically pure (S)-salbutamol precursor-(D)-tartrate salt; and   e) debenzylating the optically-pure (S)-salbutamol precursor to obtain optically-pure (S)-salbutamol.   
     
     
       18. The process of claim 17, further comprising converting the optically-pure (S)-salbutamol into a pharmaceutically-acceptable salt. 
     
     
       19. The process of claim 17, where the molar ratio of optically-pure (D)-tartaric acid to the optically impure or racemic salbutamol precursor is greater than or equal to 1.07. 
     
     
       20. The process of claim 17, where the molar ratio of optically-pure (D)-tartaric acid to the optically impure or racemic salbutamol precursor is greater than or equal to 1.1. 
     
     
       21. The process of claim 17, where the molar ratio of optically-pure (D)-tartaric acid to the optically impure or racemic salbutamol precursor is at least 1.18. 
     
     
       22. The process of claim 17, where the optically-pure (S)-salbutamol is present in an enantiomeric excess of at least 99%. 
     
     
       23. The process of claim 18, where the pharmaceutically-acceptable salt of optically-pure (S)-salbutamol is optically pure (S)-salbutamol sulphate. 
     
     
       24. The process of claim 17, where the salbutamol precursor is 4-benzyl albuterol. 
     
     
       25. A process for making optically pure (R)-salbutamol, comprising:
 a) forming a solution comprising optically-impure or racemic methyl-5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)-benzoate and a molar excess of optically-pure (L)-tartaric acid in an organic solvent;   b) allowing the solution to cool to crystallize an optically pure (R)-methyl-5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)-benzoate-(L)-tartrate salt;   c) separating the (R)-methyl-5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)-benzoate-(L)-tartrate salt from the solution;   d) liberating optically-pure (R)-methyl-5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)-benzoate from the optically pure (R)-methyl-5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)-benzoate-(L)-tartrate salt;   e) reducing optically-pure (R)-methyl-5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)-benzoate to produce an optically-pure (R)-salbutamol precursor, the optically-pure (R)-salbutamol precursor being 4-benzyl albuterol or a substituted 4-benzyl albuterol wherein the benzyl group is substituted with one or more halogen or one or more alkoxy group; and   f) debenzylating the optically-pure (R)-salbutamol precursor to obtain optically-pure (R)-salbutamol.   
     
     
       26. The process of claim 25, further comprising converting the optically-pure (R)-salbutamol into a pharmaceutically-acceptable salt. 
     
     
       27. The process of claim 25, where the molar ratio of optically-pure (L)-tartaric acid to the optically impure or racemic methyl-5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)-benzoate is greater than or equal to 1.07. 
     
     
       28. The process of claim 25, where the molar ratio of optically-pure (L)-tartaric acid to the optically impure or racemic methyl-5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)-benzoate is greater than or equal to 1.1. 
     
     
       29. The process of claim 25, where the molar ratio of optically-pure (L)-tartaric acid to the optically impure or racemic methyl-5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)-benzoate  is at least 1.18. 
     
     
       30. The process of claim 25, where the optically-pure (R)-salbutamol is present in an enantiomeric excess of at least 99%. 
     
     
       31. The process of claim 26, where the pharmaceutically-acceptable salt of optically-pure (R) salbutamol is optically pure (R)-salbutamol sulphate. 
     
     
       32. The process of claim 25, where the optically-pure (R)-salbutamol precursor is 4-benzyl albuterol. 
     
     
       33. A process for making optically pure (S)-salbutamol, comprising:
 a) forming a solution comprising optically-impure or racemic methyl-5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)-benzoate and a molar excess of optically-pure (D)-tartaric acid in an organic solvent;   b) allowing the solution to cool to crystallize an optically pure (S)-methyl-5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)-benzoate-(D)-tartrate salt from the solution;   c) separating the (S)-methyl-5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)-benzoate-(D)-tartrate salt from the solution;   d) liberating optically-pure (S)-methyl-5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)-benzoate from the optically pure (D)-methyl-5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)-benzoate-(D)-tartrate salt;   e) reducing optically-pure (S)-methyl-5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)-benzoate to produce an optically-pure (S)-salbutamol precursor, the optically-pure (S)-salbutamol precursor being 4-benzyl albuterol or a substituted 4-benzyl albuterol wherein the benzyl group is substituted with one or more halogen or one or more alkoxy group; and   f) debenzylating the optically-pure (S)-salbutamol precursor to obtain optically-pure (S)-salbutamol.   
     
     
       34. The process of claim 33, further comprising converting the optically-pure (S)-salbutamol into a pharmaceutically-acceptable salt. 
     
     
       35. The process of claim 33, where the molar ratio of optically-pure (D)-tartaric acid to the optically impure or racemic methyl-5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)-benzoate is greater than or equal to 1.07. 
     
     
       36. The process of claim 33, where the molar ratio of optically-pure (D)-tartaric acid to the optically impure or racemic methyl-5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)-benzoate is greater than or equal to 1.1. 
     
     
       37. The process of claim 33, where the molar ratio of optically-pure (D)-tartaric acid to the optically impure or racemic methyl-5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)-benzoate is at least 1.18. 
     
     
       38. The process of claim 33, where the optically-pure (S)-salbutamol is present in an enantiomeric excess of at least 99%. 
     
     
       39. The process of claim 34, where the pharmaceutically-acceptable salt of optically-pure (S) salbutamol is optically pure (S)-salbutamol sulphate. 
     
     
       40. The process of claim 33, where the optically-pure (S)-salbutamol precursor is 4-benzyl albuterol. 
     
     
       41. A process for making optically pure (R)-salbutamol, comprising:
 a) forming a solution comprising optically impure salbutamol or racemic salbutamol and a molar excess of optically-pure (L)-tartaric acid in an organic solvent;   b) isolating a crystalline (R)-salbutamol-(L)-tartrate salt from the solution wherein the salt has an enantiomeric excess of at least 95%; and   c) liberating (R)-salbutamol having an enantiomeric excess of at least 95% from the (R)-salbutamol-(L)-tartrate salt.   
     
     
       42. The process of claim 41, further comprising converting the (R) salbutamol into a pharmaceutically-acceptable salt. 
     
     
       43. The process of claim 41, where the molar ratio of optically-pure (L)-tartaric acid to the optically impure or racemic salbutamol is greater than or equal to 1.07. 
     
     
       44. The process of claim 41, where the molar ratio of optically-pure (L)-tartaric acid to the optically impure or racemic salbutamol is greater than or equal to 1.1. 
     
     
       45. The process of claim 41, where the molar ratio of optically-pure (L)-tartaric acid to the optically impure or racemic salbutamol is at least 1.18. 
     
     
       46. The process of claim 41, where the (R)-salbutamol is present in an enantiomeric excess of at least 99%. 
     
     
       47. The process of claim 42, where the pharmaceutically-acceptable salt of (R)-salbutamol is (R)-salbutamol sulphate. 
     
     
       48. A process for making optically pure (S)-salbutamol; comprising:
 a) forming a solution comprising optically impure salbutamol or racemic salbutamol and a molar excess of optically-pure (D)-tartaric acid in an organic solvent;   b) isolating an (S)-salbutamol-(D)-tartrate salt from the solution wherein the salt has an enantiomeric excess of at least 95%; and   c) liberating (S)-salbutamol having an enantiomeric excess of at least 95% from the (S)-salbutamol-(D)-tartrate salt.   
     
     
       49. The process of claim 48, further comprising converting the (S)-salbutamol into a pharmaceutically-acceptable salt. 
     
     
       50. The process of claim 48, where the molar ratio of optically-pure (D)-tartaric acid to the optically impure or racemic salbutamol is greater than or equal to 1.07. 
     
     
       51. The process of claim 48, where the molar ratio of optically-pure (D)-tartaric acid to the optically impure or racemic salbutamol is greater than or equal to 1.1. 
     
     
       52. The process of claim 48, where the molar ratio of optically-pure (D)-tartaric acid to the optically impure or racemic salbutamol is at least 1.18. 
     
     
       53. The process of claim 48, where the (S)-salbutamol is present in an enantiomeric excess of at least 99%. 
     
     
       54. The process of claim 49, where the pharmaceutically-acceptable salt of (S)-salbutamol is (S)-salbutamol sulphate. 
     
     
       55. A process for making optically pure (R)-salbutamol-(L)-tartrate salt, comprising:
 a) forming a solution comprising optically impure salbutamol or racemic salbutamol and a molar excess of optically-pure (L)-tartaric acid in an organic solvent; and   b) isolating the optically pure (R)-salbutamol-(L)-tartrate salt from the solution wherein the salt has an enantiomeric excess of at least 95%.

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