Synthesis of 2-carboxamide cycloamino urea derivatives

Patent metadata

Field	Value
Publication number	US-10059670-B2
Application number	US-201715684419-A
Country	US
Kind code	B2
Filing date	Aug 23, 2017
Priority date	Mar 3, 2011
Publication date	Aug 28, 2018
Grant date	Aug 28, 2018

Abstract

Provided herein are processes and intermediate compounds useful for the preparation of 2-carboxamide cycloamino urea derivatives, and useful intermediates therefore.

First claim

The invention claimed is:

1. A process for making a compound of formula (X):

comprising the following steps:
Step A: contacting a compound of formula (I) with the solvent tetrahydrofuran and a base lithium diisopropylamide at an internal temperature in the range of −15° C. to less than −5° C., and contacting the resulting mixture with a compound of formula (II) at an internal temperature in the range of −15° C. to less than −5° C., such that a compound of formula (III) is produced:

Step B: contacting a compound of formula (III) with thiourea, in a reaction mixture comprising a solvent selected from toluene, an alcohol solvent, or a combination thereof and an oxidizing agent 1,3-dibromo-5,5-dimethylhydantoin, such that a compound of formula (V) is produced:

Step C: contacting a compound of formula (V) with a compound of formula (VII), in a reaction mixture comprising the solvent selected from aromatic solvents, aliphatic solvents, halogenated solvents, ethereal solvents, polar aprotic solvents, water and alcohol solvents and a base, such that a compound of formula (VIII) is produced:

Step D: contacting a compound of formula (VIII) with the compound of formula (IX)

in a reaction mixture comprising a solvent, such that a compound of formula (X) is produced,
wherein:
R 1 is a branched or linear C 1 -C 7 alkyl, which may be optionally substituted one or more times with deuterium, halogen, or C 3 -C 5 cycloalkyl;
R 2 is methyl;
wherein R 3 and R 4 are independently selected from the group consisting of halogen, heteroaryl, alkoxy and aryloxy; and
X is a halide.

2. The process of claim 1 wherein the solvent of Step B comprises an alcohol solvent.

3. The process of claim 1 , wherein the solvent of step C comprises an ethereal solvent, wherein the ethereal solvent is tetrahydrofuran.

4. The process of claim 1 , wherein the solvent of step C comprises an aromatic solvent, wherein the aromatic solvent is toluene.

5. The process of claim 1 wherein the base of Step C is an amine.

6. The process of claim 1 , wherein the solvent of Step D is selected from tetrahydrofuran, toluene, water or a combination thereof.

7. The process of claim 1 , wherein the solvent of Step B comprises an alcohol solvent; the solvent of step C comprises an ethereal solvent, wherein the ethereal solvent is tetrahydrofuran; the base of Step C is an amine; and the solvent of Step D comprises tetrahydrofuran and water.

8. The process of claim 1 , wherein the solvent of Step B comprises an alcohol solvent; the solvent of step C comprises an aromatic solvent, wherein the aromatic solvent is toluene; and the solvent of Step D comprises toluene.

9. The process of claim 1 , wherein R 1 is

R 2 is methyl, R 3 is heteroaryl, R 4 is heteroaryl, and X is bromine.

Assignees

• Novartis Ag

Inventors

• Erb Bernhard
• Gallou Isabelle Sylvie
• Kleinbeck-Riniker Florian Karl

Classifications

• C07D417/14 Primary

  containing three or more hetero rings · CPC title

• C07D213/26 Primary

  Radicals substituted by halogen atoms or nitro radicals · CPC title

• C07D417/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D213/16

  containing only one pyridine ring · CPC title