Process for preparing 7H-pyrrolo[2,3-D]pyrimidine compounds

Patent metadata

Field	Value
Publication number	US-9926327-B2
Application number	US-201715426292-A
Country	US
Kind code	B2
Filing date	Feb 7, 2017
Priority date	Feb 16, 2016
Publication date	Mar 27, 2018
Grant date	Mar 27, 2018

Abstract

Described herein are improved processes for the preparation of the 7H-pyrrolo[2,3-d]pyrimidine compound, N-methyl-1-{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}-methanesulfonamide, intermediates thereof, and veterinary acceptable salts thereof.

First claim

What is claimed is:

1. A process for preparing a compound of Formula 1

or a veterinary acceptable salt thereof, comprising
(a) reacting the compound, trans-4-((methylamino)cyclohexyl)methanesulfonic acid with the 7H-pyrrolo[2,3-d]pyrimidine D1 analog in water or an aqueous organic solvent with a base at a reaction temperature of about 60° C. to about 105° C. to prepare the sulfonate salt, wherein W is Cl, F, Br, I, O-triflate, O-mesyl, or O-tosyl,

(b) conversion of the sulfonate salt, trans-4-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methane sulfonic acid, potassium salt, to the sulfonyl chloride intermediate,((trans)-4-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-methanesulfonyl chloride, in an organic solvent; and
(c) conversion of the sulfonyl chloride intermediate to the Formula 1 compound by reacting the sulfonyl chloride intermediate with a cold aqueous solution of methylamine.

2. The process of claim 1 , Step (a), wherein the 7H-pyrrolo[2,3-d]pyrimidine D1 analog is 4-chloro-7H-pyrrolo[2,3-d]pyrimidine and the reaction occurs in water or in an aqueous organic solvent that is 5% N-methylpyrrolidone or sulfolane, and the base is potassium carbonate and the reaction temperature is about 98° C. for about 12 hours.

3. The process of claim 1 , Step (b), wherein the conversion of the sulfonate salt to the sulfonyl chloride intermediate is prepared by reacting the sulfonate salt with oxalyl chloride, thionyl chloride, or phosphoryl chloride in an organic solvent.

4. The process of claim 3 wherein the organic solvent comprises acetonitrile or tetrahydrofuran, and wherein the reaction temperature is in the range of about 0° C. to about 20° C.

5. The process of claim 4 wherein the organic solvent further comprises dimethylacetamide, diisopropylformamide or dimethylformamide.

6. The process of claim 5 wherein the organic solvent comprises tetrahydrofuran and diisopropylformamide.

7. The process of claim 1 wherein the aqueous methylamine is about 40% and is at about −10° C.

8. The process of claim 7 further comprising the addition of water to the reactants after addition of the sulfonyl chloride intermediate to the cold methylamine solution.

9. The process of claim 8 wherein the reactants are slowly heated to reflux, and then the solvents are distilled off at a temperature of about 65° C. to about 75° C., the resultant solids are cooled to about 35° C., then the solids are filtered, washed with water, filtered and dried.

10. The process of claim 1 wherein trans-4-((methylamino)cyclohexyl)methane sulfonic acid is reacted with the 7H-pyrrolo[2,3-d]pyrimidine D1 analog, 4-chloro-7H-pyrrolo[2,3-d]pyrimidine with a base which is potassium carbonate in water at a reaction temperature of about 98° C. to prepare the sulfonate salt; conversion of the sulfonate salt to the sulfonyl chloride intermediate in an organic solvent which is THF; and conversion of the sulfonyl chloride intermediate to the Formula 1 compound by reacting the sulfonyl chloride intermediate with a cold aqueous solution of methylamine.

11. The process of claim 10 wherein the about 98° C. reaction proceeds for about 12 hours and wherein the organic solvent further comprises DIPF.

12. The process of claim 11 wherein oxalyl chloride, thionyl chloride, or phosphoryl chloride is added to the sulfonate salt to convert the sulfonate salt to the sulfonyl chloride intermediate and the reaction temperature is about 10° C.

13. The process of claim 12 wherein the methylamine is about 40% methylamine at about −10° C.

14. The process of claim 13 , further comprising the addition of water to the reactants after addition of the methylamine and slowly heating the reactants to reflux.

15. The process of claim 14 , further comprising the distilling off of solvents at a temperature of about 65° C. to about 75° C., cooling the resultant solids to about 35° C., isolating the solids by filtration, washing the solids with water, filtering and drying the solids.

16. A process for preparing the compound, Intermediate C,

comprising the steps of:
a) reacting 4-bromobenzylbromide with a sodium sulfite salt in water or an aqueous solvent comprising about 10-30% acetonitrile at about 80° C., and isolating the solids, Intermediate A, by filtration, wherein Intermediate A is sodium (4-bromophenyl)methanesulfonate;
b) reacting the solids, Intermediate A, in aqueous 10% to 25% methylamine and a CuBr catalyst at a temperature of at least about 50° C. for about 16 hours, then cooling the reactants to about 65° C., removal of residual copper, adding water and adjusting the pH to 3.2 with concentrated HCl, cooling the reaction to about 15° C., and isolating the solids, Intermediate B, by filtration, wherein Intermediate B is (4-(methylamino)phenyl)methanesulfonic acid;
c) reacting the solids, Intermediate B, in an aqueous organic solvent containing about 25% methanol with a palladium catalyst and hydrogen at about 50° C. to about 80° C. for about 14 hours to about 18 hours; and
d) concentrating the volume from the previous reaction, adding an alcohol and heating to about 45° C., then cooling the reaction to about 0° C. over about 4 hours, and isolating the solids, Intermediate C, by filtration, and washing with an alcohol.

17. The process of claim 16 , Step (a) wherein the acetonitrile is about 15%; and Step (b), wherein the aqueous methylamine is about 17% and the CuBr catalyst is about 2 mol % and temperature of at least about 50° C. is about 90° C., and wherein the residual copper is removed by addition of a citric acid solution.

18. The process of claim 16 , Step (c), wherein the palladium catalyst is a Pd(0) catalyst and the hydrogen is hydrogen gas at about 70° C. for about 16 hours.

19. The process of claim 16 , Step (d) wherein the alcohol is ethanol.

20. A compound selected from the group consisting of:
(4-(methylamino)phenyl)methanesulfonic acid;
trans-4-((methylamino)cyclohexyl)methanesulfonic acid;
trans-4-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methane sulfonic acid, potassium salt;
trans-4-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methane sulfonic acid, sodium salt; and
((trans)-4-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-methanesulfonyl chloride.

Assignees

• Zoetis Services Llc

Inventors

• Stuk Timothy Lee
• Billen Denis
• Westrick Valerie Sue
• Gunawardana Vageesha Warnajith Liyana

Classifications

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P43/00

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

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title