Photochemical process for producing (4R,4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridin-3-carboxamide

Patent metadata

Field	Value
Publication number	US-12398144-B2
Application number	US-202017769402-A
Country	US
Kind code	B2
Filing date	Oct 12, 2020
Priority date	Oct 17, 2019
Publication date	Aug 26, 2025
Grant date	Aug 26, 2025

Abstract

The invention relates to a method for preparing racemic (4R,4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula (I) from the enantiomers (Ia) or (Ib); a method for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula (Ia); a method for preparing racemic (4R,4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula (I) from the pyridine of the formula (II). The objects of the invention have in common the irradiation of the compound of the formulae (Ia), (Ib) and/or (II) with light in a suitable solvent, or solvent mixture, in the presence of a base. The compounds of the formulae (Ia), (Ib) and/or (II) are intermediates, by-products or target compounds in the synthesis of finerenone (compound according to formula (Ia)).

First claim

The invention claimed is:

1. A method for preparing racemic (4R,4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula (I)

from the enantiomers of the formulae (Ia) and/or (Ib)

comprising the step of (i):
(i) irradiating the enantiomers of the formulae (Ia) and/or (Ib) with light in a suitable solvent or solvent mixture in the presence of a base,
wherein the irradiation in step (i) is effected optionally at a temperature of 0° C. to 100° C.

2. The method according to claim 1 , wherein the irradiation with light in step (i) is effected at a temperature of 30° C. to 70° C.

3. The method according to claim 1 , wherein the solvent or solvent mixture in step (i) is selected from the group consisting of dichloromethane, acetone, toluene, tetrahydrofuran, methanol, 4-methyl-2-pentanone, methyl ethyl ketone, cyclohexanone, acetonitrile, dimethylformamide, dimethylsulfoxide and mixtures thereof.

4. The method according to claim 1 , wherein the concentration range of the enantiomer used in step (i) in the solvent or solvent mixture is 0.05% to 10% (m/v), based on the volume of the solvent or solvent mixture.

5. The method according to claim 1 , wherein the base in step (i) is selected from the group consisting of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), triethylamine, diisopropylethylamine, trimethylamine, tripropylamine, tributylamine, 1,4-diazabicyclo(2.2.2)octane (DABCO), 4-(dimethylamino)pyridine (DMAP), 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), tetramethylguanidine, N,N,N,N-tetramethyl-1,8-naphthalenediamine, lutidine, pyridine, imidazole, N-methylimidazole, phosphazene and mixtures thereof.

6. The method according to claim 1 , wherein the irradiation in step (i) is effected for a period from 1 hour to 40 hours.

7. A method for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula (Ia)

comprising the steps (ii), (iii) and (iv):
(ii) irradiating the compound of the formula (Ib)

with light in a suitable solvent or solvent mixture in the presence of a base, wherein the compound of the formula (Ib) is converted to a racemic compound of the formula (I)

(iii) optical resolution of this racemic compound (I) from step (ii) using a chiral tartaric acid ester of the formula (III)

in a spirits/water mixture, wherein the diastereomeric salt (Iva)

is formed, and

(iv) treating the diastereomeric salt (Iva) from step (iii) with a base, wherein the compound of the formula (Ia) is formed.

8. The method according to claim 7 , wherein the irradiation in step (ii) is effected at a temperature of 0° C. to 100° C.

9. The method according to claim 7 , wherein the solvent or solvent mixture in step (ii) is selected from the group consisting of dichloromethane, acetone, toluene, tetrahydrofuran, methanol, 4-methyl-2-pentanone, methyl ethyl ketone, cyclohexanone, acetonitrile, dimethylformamide, dimethylsulfoxide and mixtures thereof.

10. The method according to claim 7 , wherein the concentration range of the enantiomer used in step (ii) in the solvent or solvent mixture is 0.05% to 10% (m/v), based on the volume of the solvent or solvent mixture.

11. The method according to claim 7 , wherein the base in step (i) is selected from the group consisting of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), triethylamine, diisopropylethylamine, trimethylamine, tripropylamine, tributylamine, 1,4-diazabicyclo(2.2.2)octane (DABCO), 4-(dimethylamino)pyridine (DMAP), 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), tetramethylguanidine, N,N,N,N-tetramethyl-1,8-naphthalenediamine, lutidine, pyridine, imidazole, N-methylimidazole, phosphazene and mixtures thereof.

12. The method according to claim 7 , wherein the irradiation in step (ii) is effected for a period from 1 hour to 40 hours.

13. A method for preparing racemic (4R,4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula (I)

from the pyridine of the formula (II)

comprising the step (vi):
(vi) irradiating the compound of the formula (II) with light in a suitable solvent, or solvent mixture, in the presence of a base, wherein the compound according to formula (I) is formed.

14. The method according to claim 13 , wherein the irradiation in step (vi) is effected at a temperature of 0° C. to 100° C. and/or wherein the irradiation in step (vi) is carried out for a period from 1 hour to 40 hours.

15. The method according to claim 13 , wherein the solvent or solvent mixture in step (vi) is selected from the group consisting of dichloromethane, acetone, toluene, tetrahydrofuran, methanol, 4-methyl-2-pentanone, methyl ethyl ketone, cyclohexanone, acetonitrile, dimethylformamide, dimethylsulfoxide and mixtures thereof and/or wherein the base in step (iv) is selected from the group consisting of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), triethylamine, diisopropylethylamine, trimethylamine, tripropylamine, tributylamine, 1,4-diazabicyclo(2.2.2)octane (DABCO), 4-(dimethylamino)pyridine (DMAP), 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), tetramethylguanidine, N,N,N,N-tetramethyl-1,8-naphthalenediamine, lutidine, pyridine, imidazole, N-methylimidazole, phosphazene and mixtures thereof.

Assignees

• Bayer Ag

Inventors

• Platzek Johannes
• Lovis Kai

Classifications

• A61K31/4375

  the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine · CPC title

• C07B55/00

  Racemisation; Complete or partial inversion · CPC title

• C07B2200/07

  Optical isomers · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title