Claims for Patent: RE49826

Summary for Patent: RE49826

Title:	Method for the preparation of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1-6-naphthyridine-3-carboxamide and the purification thereof for use as an active pharmaceutical ingredient
Abstract:	The present invention related to a novel and improved process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula (I)
Inventor(s):	Johannes Platzek
Assignee:	Bayer Pharma AG
Application Number:	US17/367,066
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent RE49826
Patent Claims:	1. A process for preparing a compound of the formula (I) comprising separating a racemic compound of the formula (XIII) into its enantiomers, wherein the compound of the formula (XIII) is prepared by reacting a compound of the formula (XVIII) with an orthoester (XX) where R may be H or methyl, wherein the compound of the formula (XVIII) is prepared by reacting compounds of the formula (XVI a,b) with a compound of the formula (IX) and wherein the compound of the formula (XVI a,b) is prepared by reacting a compound of the formula (VI) with a compound of the formula (XVII) 2. A process for preparing a compound of the formula (I) comprising separating a racemic compound of the formula (XIII) into its enantiomers, where the compound of the formula (XIII) is prepared by reacting a compound of the formula (XVIII) with an orthoester (XX) where R may be H or methyl, and wherein the compound of the formula (XVIII) is prepared by reacting compounds of the formula (XVI a,b) with a compound of the formula (IX) 3. A process for preparing a compound of the formula (I) comprising separating a racemic compound of the formula (XIII) into its enantiomers, where the compound of the formula (XIII) is prepared by reacting a compound of the formula (XVIII) with an orthoester (XX) where R may be H or methyl. 4. A process for preparing a compound of the formula (I) comprising using the compound of the formula (XVIII) 5. A process for preparing a compound of the formula (I) comprising using the compounds of the formula (XVI a,b) 6. A process for preparing a compound of the formula (I) comprising using a compound of the formula (XVIII) and compounds of the formula (XVI a,b) 7. A compound of the formula (XVIII) and the salts, solvates and solvates of the salts thereof. 8. A compound of the formula (XVI a,b) as an E/Z mixture and the salts, solvates and solvates of the salts thereof. 9. A process for preparing a compound of the formula (XVIII) comprising reacting compounds of the formula (XVI a,b) with a compound of the formula (IX) 10. A process for preparing compounds of the formula (XVI a,b) comprising reacting a compound of the formula (VI) with a compound of the formula (XVII) 11. A process for preparing a compound of the formula (XIII) comprising reacting a compound of the formula (XVIII) with an orthoester (XX) where R may be H or methyl. 12. A process for preparing a compound of the formula (XIII) comprising reacting a compound of the formula (XVIII) with an orthoester (XX) where R may be H or methyl, and wherein the compound of the formula (XVIII) is prepared by reacting compounds of the formula (XVI a,b) with a compound of the formula (IX) 13. A process for preparing a compound of the formula (I) in crystalline polymorph I comprising preparing a compound of the formula (I) according to claim 1 and then stirring the compound of the formula (I), present in one or more polymorphs or as a solvate in an inert solvent, at a temperature of 20° C.-120° C. and isolating the compound of the formula (I) in crystalline polymorph I. 14. A compound of the formula (I) in crystalline form of polymorph I wherein the x-ray diffractogram of the compound exhibits peak maxima of the 2 theta angle at 8.5, 14.1, and 19.0. 15. The compound of formula (I) in crystalline form of polymorph I according to claim 14, wherein the x-ray diffractogram of the compound further exhibits peak maxima of the 2 theta angle at 17.2, 20.5, 25.6, and 26.5. 16. The compound of the formula (I) in crystalline form of polymorph I according to claim 14, wherein the IR spectrum of the compound exhibits band maxima at 3475, 2230, 1681, 1658, 1606, 1572, 1485, 1255, 1136 and 1031 cm−1. 17. The compound of the formula (I) in crystalline form of polymorph I according to claim 14, wherein the Raman spectrum of the compound exhibits band maxima at 3074, 2920, 2231, 1601, 1577, 1443, 1327, 1267, 827 and 155 cm−1. 18. The compound of the formula (I) in crystalline form of polymorph I according to claim 14, wherein the compound has a melting point of 252° C. 19. A compound of the formula (I) in crystalline form of polymorph I wherein the IR spectrum of the compound exhibits band maxima at 3475, 2230, 1681, 1658, 1606, 1572, 1485, 1255, 1136 and 1031 cm−1. 20. The compound of the formula (I) in crystalline form of polymorph I according to claim 19, wherein the x-ray diffractogram of the compound exhibits peak maxima of the 2 theta angle at 8.5, 14.1, 17.2, 19.0, 20.5, 25.6, and 26.5. 21. The compound of the formula (I) in crystalline form of polymorph I according to claim 19, wherein the Raman spectrum of the compound exhibits band maxima at 3074, 2920, 2231, 1601, 1577, 1443, 1327, 1267, 827 and 155 cm−1. 22. The compound of the formula (I) in crystalline form of polymorph I according to claim 19, wherein the compound has a melting point of 252° C. 23. A compound of the formula (I) in crystalline form of polymorph I wherein the Raman spectrum of the compound exhibits band maxima at 3074, 2920, 2231, 1601, 1577, 1443, 1327, 1267, 827 and 155 cm−1. 24. The compound of the formula (I) in crystalline form of polymorph I according to claim 23, wherein the x-ray diffractogram of the compound exhibits peak maxima of the 2 theta angle at 8.5, 14.1, 17.2, 19.0, 20.5, 25.6, and 26.5. 25. The compound of the formula (I) in crystalline form of polymorph I according to claim 23, wherein the IR spectrum of the compound exhibits band maxima at 3475, 2230, 1681, 1658, 1606, 1572, 1485, 1255, 1136 and 1031 cm−1. 26. The compound of the formula (I) in crystalline form of polymorph I according to claim 23, wherein the compound has a melting point of 252° C. 27. A compound of the formula (I) in crystalline form of polymorph I prepared by a process comprising obtaining the compound of formula XIII separating the compound of formula XIII by chiral separation to obtain the compound of formula I, dissolving the compound of formula I in an inert solvent, stirring at a temperature of 20° C.-120° C. and isolating the compound of the formula (I) in crystalline form of polymorph I. 28. The compound of the formula (I) in crystalline form of polymorph I according to claim 27, where the compound of the formula (XIII) is prepared by reacting a compound of the formula (XVIII) with an orthoester (XX) where R may be H or methyl. 29. A compound of the formula (I) in crystalline form of polymorph I wherein the compound is isolated in crystalline form by a process comprising: filtering a solution of the compound of the formula (XIII) in a mixture of acetonitrile and methanol or a mixture of acetonitrile and ethanol; performing a solvent exchange with ethanol; concentrating the solution until the compound crystallizes; cooling the solution to 0° C.; and isolating the compound in crystalline form. 30. A compound of the formula (I) in crystalline form of polymorph I wherein the compound is crystallized from a solvent selected from the group consisting of methanol, ethanol, tetrahydrofuran, acetonitrile, and mixtures thereof with water.