Synthesis of 2-carboxamide cycloamino urea derivatives

Patent metadata

Field	Value
Publication number	US-9650373-B2
Application number	US-201213985069-A
Country	US
Kind code	B2
Filing date	Mar 1, 2012
Priority date	Mar 3, 2011
Publication date	May 16, 2017
Grant date	May 16, 2017

Abstract

Provided herein are processes useful for the preparation of 2-carboxamide cycloamino urea derivatives of formula (X),

and useful intermediates therefore, at internal temperatures such as less than about −5° C. to about −15° C. and using solvents such as tetrahydrofuran, bases such as amines, and the like.

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 N-bromosuccinimide or 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 tetrahydrofuran and a base amine, 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 selected from tetrahydrofuran, water or a combination thereof, 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;
R 3 is C 6 -C 14 aryloxy,
R 4 is halogen, and
X is a halide.

2. The process of claim 1 , wherein the solvent of Step B comprises toluene and ethanol.

3. The process of claim 1 wherein the base of Step C is pyridine.

4. The process of claim 1 , wherein the oxidizing agent of Step B is N-bromosuccinimide.

5. The process of claim 1 wherein the solvent of Step A comprises tetrahydrofuran, the base of Step A is lithium diisopropylamide, the solvent of Step B comprises toluene and ethanol, the oxidizing agent of Step B is N-bromosuccinimide, the solvent of Step C comprises tetrahydrofuran, the base of Step C is pyridine and the solvent of Step D comprises tetrahydrofuran and water.

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

R 2 is methyl, R 3 is phenoxy, R 4 is chlorine, and X is bromine.

7. A process for making the compound of formula (10):

comprising the following steps:
Step A: contacting the compound of formula (1) 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 the compound of formula (2) at an internal temperature in the range of −15° C. to less than −5° C., such that the compound of formula (3) is produced:

Step B: contacting the compound of formula (3) with thiourea, in a reaction mixture comprising a solvent selected from toluene, ethanol or a combination thereof and an oxidizing agent N-bromosuccinimide, such that the compound of formula (5) is produced:

Step C: contacting the compound of formula (5) with the compound of formula (7), in a reaction mixture comprising the solvent tetrahydrofuran and a base amine, such that the compound of formula (8) is produced:

and
Step D: contacting the compound of formula (8) with the compound of formula (IX)

in a reaction mixture comprising a solvent selected from tetrahydrofuran, water or a combination thereof, such that the compound of formula (10) is produced.

8. The process of claim 1 , wherein the resulting mixture of a compound of formula (I) and the solvent tetrahydrofuran and base lithium diisopropylamide of Step A is contacted with a compound of formula (II) at an internal temperature of −15° C.

9. The process of claim 1 wherein the solvent of Step D comprises tetrahydrofuran and water.

10. The process of claim 7 , wherein the resulting mixture of a compound of formula (1) and the solvent tetrahydrofuran and base lithium diisopropylamide of Step A is contacted with a compound of formula (2) at an internal temperature of −15° C.

11. The process of claim 1 , wherein the solvent of step A is an alcohol solvent, wherein the alcohol solvent is ethanol.

Assignees

• Erb Bernhard
• Gallou Isabelle Sylvie
• Kleinbeck Florian Karl
• Novartis Ag

Inventors

• Erb Bernhard
• Gallou Isabelle Sylvie
• Kleinbeck Florian Karl

Classifications

• C07D213/26 Primary

  Radicals substituted by halogen atoms or nitro radicals · CPC title

• C07D417/14 Primary

  containing three or more hetero rings · 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