Process for preparing isomers of salbutamol

Abstract

A process for making opticallyOptically pure (R) and (S) salbutamol comprises obtaining the (R) or (S) isomer of either salbutamol or a salbutamol precursor in substantially optically pure formis obtained by resolving a racemic or optically impure mixture of enantiomers of salbutamol or of saida salbutamol 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.

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. Pure and isolated Levalbuterol L-tartrate having an enantiomeric excess of at least 95%. 
     
     
       10. Levalbuterol L-tartrate as claimed in claim 9, which is in crystalline form. 
     
     
       11. An optically-pure 4-benzyl albuterol salt of tartaric acid, selected from the group consisting of optically pure (R)-4-benzyl albuterol-(L)-tartrate salt and optically pure (S)-4-benzyl-albuterol-(D)-tartrate salt. 
     
     
       12. The optically-pure 4-benzyl albuterol salt of tartaric acid of claim 11, where the optically pure (R)-4-benzyl albuterol-(L)-tartrate salt is present in an enantiomeric excess of greater than about 99%. 
     
     
       13. The optically-pure 4-benzyl albuterol salt of tartaric acid of claim 11, where the optically pure (S)-4-benzyl albuterol-(D)-tartrate salt is present in an enantiomeric excess of greater than about 99%. 
     
     
       14. An optically-pure methyl-5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)-benzoate salt of tartaric acid, selected from the group consisting of optically pure (R)-methyl-5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)-benzoate(L)-tartrate salt and optically pure (S)-methyl-5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)-benzoate-(D)-tartrate salt. 
     
     
       15. The optically-pure methyl-5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)-benzoate salt of tartaric acid of claim 14, where the optically pure (R)-methyl-5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)-benzoate-(L)-tartrate salt is present in an enantiomeric excess of greater than about 99%. 
     
     
       16. The optically-pure methyl-5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)-benzoate salt of tartaric acid of claim 14, where the optically pure (S)-methyl-5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-(phenylmethoxy)-benzoate-(D)-tartrate salt is present in an enantiomeric excess of greater than about 99%. 
     
     
       17. A pure and isolated salbutamol salt of tartaric acid having an enantiomeric excess of at least 95% selected from the group consisting of (R)-salbutamol-(L)-tartrate salt and (S)-salbutamol-(D)-tartrate salt. 
     
     
       18. The pure and isolated salbutamol salt of tartaric acid of claim 17, where the (R)-salbutamol-(L)-tartrate salt is present in an enantiomeric excess of greater than about 99%. 
     
     
       19. The pure and isolated salbutamol salt of tartaric acid of claim 17, where the (S)-salbutamol-(D)-tartrate salt is present in an enantiomeric excess of greater than about 99%.