Process for preparing pan-CDK inhibitors of the formula (I), and intermediates in the preparation

Patent metadata

Field	Value
Publication number	US-9359306-B2
Application number	US-201113824160-A
Country	US
Kind code	B2
Filing date	Sep 20, 2011
Priority date	Sep 23, 2010
Publication date	Jun 7, 2016
Grant date	Jun 7, 2016

Abstract

The invention relates to a novel process for the preparation of pan-CDK inhibitors of the formula (I), and intermediates of the preparation.

First claim

The invention claimed is:

1. A process for the preparation of a compound of the general formula (I)

in which
R 4 is a C 1 -C 6 -alkyl group or a C 3 -C 7 -cycloalkyl ring,

comprising:
cleaving of the protective groups of a benzenesulphonic acid salt of a doubly protected anilinopyrimidine of the formula (I-8-R-BSA)

by hydrogenation with palladium on activated carbon and hydrogen in methanol, and also by treatment with potassium carbonate in methanol to give a compound of formula (I).

2. The process according to claim 1 , comprising benzenesulphonic acid-catalysed coupling of a compound of formula (I-7-A)

and a compound of formula (I-4-R)

to prepare the benzenesulphonic acid salt of a doubly protected anilino-pyrimidines of formula (I-8-R-BSA).

3. The process according to claim 2 , comprising coupling a compound of formula (I-5-A)

with 2,4-dichloro-5-trifluoromethylpyrimidine in a lithium base and ethereal solvent to prepare the compound of formula (I-7-A).

4. The process according to claim 3 , comprising reacting benzaldehyde dimethyl acetal with (2R,3R)-butane-2,3-diol in the presence of pyridinium p-toluenesulphonate in toluene to provide (4R,5R)-4,5-dimethyl-2-phenyl-1,3-dioxolane, and reducing the (4R,5R)-4,5-dimethyl-2-phenyl-1,3-dioxolane with diisobutylaluminium hydride in toluene to provide the compound of formula (I-5-A).

5. The process according to claim 2 , comprising hydrogenating a compound of formula (I-3-R)

with an iron-doped palladium catalyst to provide a compound of formula (I-4-R).

6. The process according to claim 5 , wherein the hydrogenation is performed in a solvent selected from methanol, ethanol, isopropanol, tetrahydrofuran, and acetic acid.

7. The process according to claim 5 , comprising racemate cleavage of a compound of formula (I-11)

using (+)-di-O-p-toluoyl-D-tartaric acid to give an intermediate salt of formula (I-11-R-D-Tol-Tart)

and the release of a compound of formula (I-11-R)

from the salt and the insertion of a trifluoroacetate protective group to form the compound of formula (I-3-R).

8. The process according of claim 7 , wherein the cleavage is performed in acetonitrile or propionitrile.

9. The process according of claim 7 , comprising oxidation of a compound of formula (I-10)

to give a compound of formula (I-3)

and subsequent deprotection to give the compound of formula (I-11).

10. The process according to claim 9 , wherein the oxidation step takes place with potassium peroxomonosulphate.

11. The process according to claim 9 , comprising oxidative amination of a compound of formula (I-1)

by an oxidizing agent in a base to give the compound of the formula (I-10).

12. The process according to claim 11 , wherein the oxidizing agent is selected from N-bromosuccinimide, iodine, sodium hypobromide, 1,3-dibromo-5,5-dimethylhydantoin, N-chlorosuccinimide and trichlorocyanuric acid; and the base is selected from potassium tert-butylate, aqueous sodium hydroxide solution, sodium methanolate, sodium ethanolate, and sodium hydride.

13. The process according to claim 11 , comprising alkylating 4-nitrothiophenol using the compound

where X is Br, Cl, I, O—SO 2 —CH 3 or O—SO 2 -(4-methylphenyl), in the presence of potassium carbonate in N-methylpyrrolidinone to give the compound of formula (I-1).

14. The process according to claim 11 ,
wherein the oxidizing agent is 1,3-dibromo-5,5-dimethylhydantoin in trifluoroacetamide.

15. The process according to claim 3 ,
wherein the lithium base is selected from lithium hexamethyldisilazide, n-butyllithium, lithium diisopropylamide, and lithium-2,2,6,6-tetramethylpiperidine; and the ethereal solvent is selected from tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, methyl tert-butyl ether, diisopropyl ether, n-dibutyl ether, 2-methyltetrahydrofuran, and cyclopentyl methyl ether.

16. A salt of the formula (I-11-R-D-Tol-Tart)

where R 4 is a C 1 -C 6 -alkyl group or a C 3 -C 7 -cycloalkyl ring.

17. A salt of the formula (I-8-R-BSA)

where R 4 is a C 1 -C 6 -alkyl group or a C 3 -C 7 -cycloalkyl ring.

18. The salt according to claim 16 , which is

19. The salt according to claim 17 , which is

Assignees

• Krüger Joachim
• Gries Jörg
• Lovis Kai
• Haβfeld Jorma
• Bayer Ip Gmbh

Inventors

• Krüger Joachim
• Gries Jörg
• Lovis Kai
• Haβfeld Jorma

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D239/47 Primary

  One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine · CPC title

• C07C2601/00

  Systems containing only non-condensed rings · CPC title

• C07B2200/07

  Optical isomers · CPC title