Disclosed is a process for preparing 3 -substituted pyrrolidine compounds of formula (VII) or salts thereof, wherein R1 is described herein, which are intermediate compounds useful for the synthesis of darifenacin which is indicated for the treatment of overactive bladder with symptoms of urge, urinary incontinence, and the like, and pharmaceutically acceptable salts thereof. Also disclosed is a process for preparing darifenacin and pharmaceutically acceptable salts thereof.
CLAIM(S): 1. A process for preparing a compound of formula (S)-(VII): <img class="EMIRef" id="5000123-imgf000015-0001" /> wherein R<1> is selected from the group consisting of -CN and -CONH<2>, said process comprising: i) reacting (5)-malic acid of formula (iS)-(VIH): <img class="EMIRef" id="5000123-imgf000015-0002" /> with a compound of formula (XIV): H<2>N-Q (<XIV>)<5> wherein Q is a nitrogen protecting group, in a first organic solvent, to obtain a compound of formula (IX), <img class="EMIRef" id="5000123-imgf000015-0003" /> ii) optionally, isolating a compound of formula (IX); iii) reacting compound of a formula (IX) with a carbonyl reducing agent, in a second organic solvent, to obtain a compound of formula (X): HO, ^<Q> (X); iv) optionally, isolating a compound of formula (X); v) converting the hydroxyl group of compound of formula (X) into a leaving group by reacting a compound of formula (X) with an oxygen activating agent, in a third organic solvent and a base, to obtain a compound of formula (XI): YO (^NQ (XI), wherein -OY is a leaving group; vi) optionally, isolating a compound of formula (XI); vii) reacting a compound of formula (XI) with a compound of formula (XV): Ph CH-R<1> Ph (XV), wherein R<1> is selected from the group consisting of -CN and -CONH<2>, with a base, and in a fourth organic solvent, to obtain a compound of formula (XII): <img class="EMIRef" id="5000123-imgf000016-0001" /> viii) optionally, isolating a compound of formula (XII); ix) removing the nitrogen protecting group Q of compound of formula (XII), to obtain a compound of formula (S)-(VII); x) optionally, if R<1> is -CN, converting the -CN to -CONH<2>, by reacting compound of formula (S)-(VII) with a hydrolyzing agent; and xi) optionally, isolating a compound of formula (S)-(VII). 2. The process of claim 1, wherein Q is selected from the group consisting of benzyl, tosyl, and nosyl. 3. The process of claim 1 , wherein the reaction of step i) further comprises a non-oxidizing acid in catalytic amounts. 4. The process of claim 3, wherein the non-oxidizing acid is p-toluenesulfonic acid. 5. The process of claim 1, wherein the first organic solvent comprises a xylene. 6. The process of claim 1, wherein the carbonyl reducing agent is a hydride agent. 7. The process of claim 6, wherein the hydride agent is lithium aluminium hydride. 8. The process of claim 1, wherein the second organic solvent comprises tetrahydrofuran. 9. The process of claim 1, wherein the oxygen activating agent is a sulfonyl compound. 10. The process of claim 9, wherein the sulfonyl compound is /7-toluenesulfonyl chloride. 11. The process of claim 1 , wherein the third organic solvent and the base of step v) are the same and comprise pyridine. 12. The process of claim 1, wherein the base of step vii) is selected from the group consisting of an alkali metal hydride, an alkali metal hydroxide, and an alkaline-earth metal hydroxide. 13. The process of claim 1, wherein the fourth organic solvent comprises toluene. 14. The process of claim 2, wherein removing the nitrogen protecting group Q of a compound of formula (XII) comprises: (a) if the nitrogen protecting group Q is benzyl, hydrogenating a compound of formula (XII) with a hydrogen donor compound, in the presence of palladium on carbon catalyst, and in an alcohol solvent; or (b) if the nitrogen protecting group Q is tosyl, reacting a compound of formula (XII) with a concentrated acid and a reducing agent; or (c) if the nitrogen protecting group Q is nosyl, reacting a compound of formula (XII) with samarium iodide or tributyltin hydride. 15. The process of claim 14, wherein the hydrogen donor compound is ammonium formate. 16. The process of claim 1, wherein the hydrolyzing agent is aqueous sulphuric acid. 17. The process of any one of claims 1 to 16, said process further comprising preparing a salt of compound of formula (S)-(VII). 18. The process of claim 17, wherein the salt of compound of formula (S)-(VII) is the L-tartrate salt. 19. The process of claim 18, wherein the process comprises reacting a compound of formula (S)-(VII) with L -tartaric acid in an alcohol solvent. 20. The process of any one of claims 1 to 19, said process further comprising: a) reacting the compound of formula (S)-(VII), or a salt thereof, with a compound of formula (XIII): <img class="EMIRef" id="5000123-imgf000018-0001" /> wherein Z is a leaving group, in the presence of an organic solvent and a base, to obtain a compound of formula (XVI): <img class="EMIRef" id="5000123-imgf000018-0002" /> wherein, if R<1> is -CONH<2>, the compound of formula (XVI) is darifenacin base; b) if R<1> is -CN, reacting the compound of formula (XVI) with a hydrolyzing agent, to obtain darifenacin base; and c) optionally, reacting the darifenacin base with hydrogen bromide to obtain darifenacin hydrobromide salt of formula (I): <img class="EMIRef" id="5000123-imgf000018-0003" /> (i). 21. The process of claim 20, wherein the compound of formula (S)-(WU), or a salt thereof, of step i) is the L-tartrate salt compound of formula (.S)-(VII) wherein R<1> is -CONH<2>. 22. The process of claim 20, wherein Z is selected from the group consisting of halogens and sulfonate esters. 23. The process of claim 22, wherein Z is bromide. 24. The process of claim 20, wherein the hydrolyzing agent of step b) is aqueous sulphuric acid.