Method for the preparation of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro- 1-6-naphthyridine-3-carbox-amide and the purification thereof for use as an active pharmaceutical ingredient

Patent metadata

Field	Value
Publication number	US-10059707-B2
Application number	US-201515329043-A
Country	US
Kind code	B2
Filing date	Jul 29, 2015
Priority date	Aug 1, 2014
Publication date	Aug 28, 2018
Grant date	Aug 28, 2018

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).

First claim

The invention claimed is:

1. A process for preparing a compound of formula (VI)

comprising reacting a compound of formula (XIV) or formula (XlVa)

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)

and reacting the aldehyde of formula (XVI) or (XVIa) without isolation to give the compound of formula (VI)

2. A process for preparing compounds of formulae (Villa+b)

comprising dissolving a compound of formula (VI)

in isopropanol (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)

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 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) with aqueous sodium hydroxide solution to give 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 and then in a third step hydrolysing in water with THF or water to give 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), 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) 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)

Assignees

• Bayer Pharma AG
• Bayer Pharma AG

Inventors

• Platzek Johannes
• Garke Gunnar
• Grunenberg Alfons

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P7/10

  Antioedematous agents; Diuretics · CPC title

• A61P9/14

  Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P9/12

  Antihypertensives · CPC title