USRE49860EActiveUtilityPatentIndex 61
Process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide and purification thereof for use as pharmaceutical active ingredient
Est. expiryAug 1, 2034(~8.1 yrs left)· nominal 20-yr term from priority
A61K 31/4375C07D 471/04C07B 2200/13A61P 13/00A61P 13/12A61P 25/00A61P 25/04A61P 25/06A61P 25/16A61P 25/22A61P 25/24A61P 25/28A61P 29/00A61P 3/00A61P 3/04A61P 3/12A61P 3/14A61P 35/00A61P 43/00A61P 7/10A61P 9/00A61P 9/04A61P 9/06A61P 9/10A61P 9/12A61P 9/14A61P 3/10
61
PatentIndex Score
0
Cited by
57
References
28
Claims
Abstract
The present invention relates 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) and also the preparation and use of the crystalline polymorph I of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula (I).
Claims
exact text as granted — not AI-modifiedThe invention claimed is:
1. A process for preparing a compound of formula (VI)
comprising reacting a compound of formula (XIV) or formula (XIVa)
with dimethyl sulphate to give a compound of formula (XV) or (XVa)
reducing the non-isolated methyl esters of the formula (XV) or (XVa) with 1.21 equivalents of REDAL (sodium bis(2-methoxyethoxy)aluminium dihydride) and 1.28 equivalents of N-methylpiperazine to give an aldehyde of formula (XVI) or (XVIa)
reacting the aldehyde of formula (XVI) or (XVIa) without isolation to give the compound of formula (VI)
and isolating the compound of formula (VI).
2. A process for preparing compounds of formulae (VIIIa+b)
comprising dissolving a compound of formula (VI)
in isopropanol (3-7 fold), 3-7 fold, 5-10 mol % of piperidine and 5-10 mol % of glacial acetic acid at 30° C., reacting the dissolved compound of formula (VI) with a compound of formula (VII)
to give the compounds of formulae (VIII a+b)
and isolating the compounds of formulae (VIII a+b).
3. A process for preparing a compound of formula (XI)
comprising stirring a compound of formula (X)
with 2.5-5 equivalents of triethyl orthoacetate in dimethylacetamide at 100 to 120° C. for 1.5 to 3 hours and then cooling to give the compound of formula (XI)
4. A process for preparing a compound of formula (XII)
comprising saponifying a compound of formula (XI)
in a THF/water mixture (2:1, 9-fold) 2:1, 9-fold, with aqueous sodium hydroxide solution to give the compound of formula (XII)
and isolating the compound of formula (XII).
5. A process for preparing a compound of formula (XIII)
comprising reacting a compound of formula (XII)
in a one-pot reaction in THF by first admixing with carbodiimidazole and catalytic amounts of 4-(dimethylamino)pyridine to form an admixture, heating the admixture under reflux together with hexamethyldisilazane for 16 to 24 hours, hydrolysing in water with THF or water to give the compound of formula (XIII)
and isolating the compound of formula (XIII).
6. A process for preparing compounds of formulae (VIII a+b):
comprising preparing the compound of formula (VI)
according to the process of claim 1 ,
dissolving the compound of formula (VI) in isopropanol (3-7 fold), 3-7 fold, 5-10 mol % of piperidine and 5-10 mol % of glacial acetic acid at 30° C. and reacting the dissolved compound of formula (VI) with a compound of formula (VII)
to give the compounds of formulae (VIII a+b):
7. A process for preparing a compound of formula (XI)
comprising preparing the compounds of formulae (VIII a+b) according to claim 2 , reacting the compounds of formulae (VIII a+b) with a compound of formula (IX)
to give a compound of formula (X)
stirring the compound of formula (X) with 2.5-5 eq of triethyl orthoacetate in dimethylacetamide at 100 to 120° C. for 1.5 to 3 hours to give the compound of the formula (XI)
8. A process for preparing a compound of formula (XII)
comprising preparing the compound of formula (XI) according to claim 3 , saponifying the compound of formula (XI) in a THF/water mixture (2:1, 9-fold), 2:1, 9-fold, with aqueous sodium hydroxide solution to give the compound of formula (XII)
9. A process for preparing a compound of formula (XIII)
comprising preparing the compound of formula (XII)
according to the process of claim 4 ,
reacting the compound of formula (XII) in a one-pot reaction in THF by first admixing with carbodiimidazole and catalytic amounts of 4-(dimethylamino)pyridine to form an admixture, heating the admixture under reflux together with hexamethyldisilazane for 16 to 24 hours and then in a third step hydrolysing in water with THF or water to give the compound of formula (XIII)
10. A process for preparing a compound of formula (XI)
comprising preparing compounds of formulae (VIII a+b)
according to the process of claim 6
reacting the compounds of formulae (VIII a+b) with a compound of formula (IX)
to give a compound of formula (X)
stirring the compound of formula (X) with 2.5-5 eq of triethyl orthoacetate in dimethylacetamide at 100 to 120° C. for 1.5 to 3 hours to give a compound of formula (XI)
11. A process for preparing the compound of formula (XII)
comprising preparing the compound of formula (XI) according to claim 7 , and saponifying the compound of formula (XI) in a THF/water mixture (2:1, 9-fold), 2:1, 9-fold, with aqueous sodium hydroxide solution to give the compound of formula (XII)
12. A process for preparing a compound of formula (XIII)
comprising preparing the compound of formula (XII)
according to the process of claim 8 ,
reacting the compound of formula (XII) in a one-pot reaction in THF by first admixing with carbodiimidazole and catalytic amounts of 4-(dimethylamino)pyridine to form an admixture, heating the admixture under reflux together with hexamethyldisilazane for 16 to 24 hours and then in a third step hydrolysing in water with THF or water to give the compound of formula (XIII)
13. A process for preparing a compound of formula (XII)
comprising preparing the compound of formula (XI)
according to the process of claim 10 , saponifying the compound of formula (XI) in a THF/water mixture (2:1, 9-fold), 2:1, 9-fold, with aqueous sodium hydroxide solution to give a compound of formula (XII)
14. A process for preparing a compound of formula (XIII)
comprising preparing the compound of formula (XII)
according to the process of claim 11 , reacting the compound of formula (XII) in a one-pot reaction in THF by first admixing with carbodiimidazole and catalytic amounts of 4-(dimethylamino)pyridine to form an admixture, heating the admixture under reflux together with hexamethyldisilazane for 16 to 24 hours and then in a third step hydrolysing in water with THF or water to give the compound of formula (XIII)
15. A process for preparing a compound of formula (XIII)
comprising preparing the compound of formula (XII)
according to the process of claim 13 , reacting the compound of formula (XII) in a one-pot reaction in THF by first admixing with carbodiimidazole and catalytic amounts of 4-(dimethylamino)pyridine to form an admixture, heating the admixture under reflux together with hexamethyldisilazane for 16 to 24 hours and then in a third step hydrolysing in water with THF or water to give the compound of formula (XIII)
16. A process for preparing a compound of formula (I)
comprising preparing the compound of formula (XIII) in a mixture of enantiomers according to the process of claim 5and isolating the compound of formula (I) from the mixture.
17. A process for preparing a compound of formula (I)
comprising preparing the compound of formula (XIII) in a mixture of enantiomers according to the process of claim 9 and isolating the compound of formula (I) from the mixture.
18. A process for preparing a compound of formula (I)
comprising preparing the compound of formula (XIII) in a mixture of enantiomers according to the process of claim 12 and isolating the compound of formula (I) from the mixture.
19. A process for preparing a compound of formula (I)
comprising preparing the compound of formula (XIII) in a mixture of enantiomers according to the process of claim 14 and isolating the compound of formula (I) from the mixture.
20. A process for preparing a compound of formula (I)
comprising preparing the compound of formula (XIII) in a mixture of enantiomers according to the process of claim 15 and isolating the compound of formula (I) from the mixture.
21. The process of claim 17 , wherein the isolated compound of the formula (I) is present in one or more polymorphs or as a solvate in an inert solvent, further comprising stirring the inert solvent containing the isolated compound of formula (I) at a temperature of 20° C.-120° C. and isolating the compound of the formula (I) as crystalline polymorph I.
22. The process of claim 18 , wherein the isolated compound of the formula (I) is present in one or more polymorphs or as a solvate in an inert solvent, further comprising stirring the inert solvent containing the isolated compound of formula (I) at a temperature of 20° C.-120° C. and isolating the compound of the formula (I) as crystalline polymorph I.
23. The process of claim 19 , wherein the isolated compound of the formula (I) is present in one or more polymorphs or as a solvate in an inert solvent, further comprising stirring the inert solvent containing the isolated compound of formula (I) at a temperature of 20° C.-120° C. and isolating the compound of the formula (I) as crystalline polymorph I.
24. The process of claim 20 , wherein the isolated compound of the formula (I) is present in one or more polymorphs or as a solvate in an inert solvent, further comprising stirring the inert solvent containing the isolated compound of formula (I) at a temperature of 20° C.-120° C. and isolating the compound of the formula (I) as crystalline polymorph I.
25. A process for preparing the compound of the formula (I) in crystalline form of polymorph I,
wherein the compound of the formula (I), present in one or more polymorphs or as a solvate in an inert solvent, is stirred at a temperature of 20° C.-120° C. and the compound of the formula (I) is isolated in crystalline polymorph I.
26. The process of claim 25, wherein the compound exhibits an x-ray diffractogram peak maxima of the 2 theta angle at 8.5, 14.1, 17.2, 19.0, 20.5, 25.6, 26.5.
27. The process of claim 25, wherein the compound exhibits an IR spectrum band maxima at 3475, 2230, 1681, 1658, 1606, 1572, 1485, 1255, 1136, 1031 cm −1 .
28. The process of claim 25, wherein the compound exhibits a Raman spectrum band maxima at 3074, 2920, 2231, 1601, 1577, 1443, 1327, 1267, 827, 155 cm −1 .Cited by (0)
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