USRE49826EActiveUtility
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
Est. expiryAug 21, 2035(~9.1 yrs left)· nominal 20-yr term from priority
Inventors:Johannes Platzek
C07D 471/04C07B 2200/07A61P 11/00A61P 13/02A61P 13/12A61P 17/00A61P 19/02A61P 25/00A61P 25/04A61P 25/06A61P 25/16A61P 25/22A61P 25/24A61P 25/28A61P 27/02A61P 27/16A61P 29/00A61P 3/00A61P 3/04A61P 3/12A61P 3/14A61P 35/00A61P 37/02A61P 5/42A61P 7/10A61P 9/00A61P 9/04A61P 9/08A61P 9/10A61P 9/14A61P 3/10A61K 31/4375
75
PatentIndex Score
1
Cited by
42
References
30
Claims
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)
Claims
exact text as granted — not AI-modifiedThe invention claimed is:
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.Join the waitlist — get patent alerts
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