Process for preparing sulfonamide compounds

Patent metadata

Field	Value
Publication number	US-11370807-B2
Application number	US-202016763350-A
Country	US
Kind code	B2
Filing date	Jan 3, 2020
Priority date	Jan 4, 2019
Publication date	Jun 28, 2022
Grant date	Jun 28, 2022

Abstract

The present invention relates to a process for preparing a sulfonamide compound which is an inhibitor of Bcl-2/Bcl-xL, including the compound (3R)-1-(3-(4-(4-(4-(3-(2-(4-chlorophenyl)-1-isopropyl-4-methylsulfonyl-5-methyl-1H-pyrrol-3-yl)-5-fluorophenyl)piperazine-1-yl)-phenylaminosulfonyl)-2-trifluoromethanesulfonyl-anilino)-4-phenylthio-butyl)-piperidine-4-carboxylic acid 3-phosphonopropyl ester. The present invention also relates to an intermediate for preparing the sulfonamide compound and a preparation process thereof.

First claim

What is claimed is:

1. A process for preparing a compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein R 1 is —SO 2 R′; R′ is alkyl; R 2 is alkyl;
R 3 is alkyl; R 4 is halogen; R 5 is halogen; R 6 is H, halogen, or alkyl; Y is

Q is —C(═O)O(C 1-5 alkylene); R b is hydrogen or alkyl; and n, r and s each independently are 1, 2, 3, 4, 5, or 6;
wherein the process comprises
1) converting a compound of formula 1:

to form a compound of formula 2:

and wherein the process further comprises one or more of the following steps:
2) reacting the compound of formula 2 with a compound of formula 3:

wherein R 7 is alkyl, and m is 1, 2, 3, 4, or 5;
to form a compound of formula 4:

3) converting the compound of formula 4 to form a compound of formula 5:

and
4) converting the compound of formula 5 to form the compound of formula (I); and wherein the compound of formula 1 is prepared by a method comprising one or more of the following steps:
1′) reacting a compound of formula 1′:

with a compound of formula 2′:

to form a compound of formula 3′:

2′) reacting the compound of formula 3′ with a compound of formula 4′:

to form a compound of formula 5′:

3′) reacting the compound of formula 5′ with a compound of formula 6′:

to form a compound of formula 7′,

4′) converting the compound of formula 7′ to form a compound of formula 8′:

5′) converting the compound of formula 8′ to form a compound of formula 9′:

6′) converting the compound of formula 9′ to form a compound of formula 10′:

7′) converting the compound of formula 10′ to form a compound of formula 11′:

8 ′) reacting the compound of formula 11′ with a compound of formula 12′:

to form a compound of formula 13′:

9′) converting the compound of formula 13′ to form a compound of formula 14′,

10′) reacting the compound of formula 14′ with a compound of formula 15′:

to form a compound of formula 16′:

and (formula 16′)
11′) reacting the compound of formula 16′ with a compound of formula 17′:

to form a compound of formula 1.

2. The process of claim 1 , having one or more of the following characteristics:
step 1) is carried out in a solvent in the presence of a base;
step 2) is carried out in the presence of a condensing agent and a catalyst in a polar organic solvent;
step 3) is carried out in the presence of a trialkylbromosilane;
step 4) is carried out in a polar solvent;
step 4) is carried out in the presence of bicarbonate salt and an acid; and
step 4) comprises purification by a preparative high-performance liquid chromatograph and removal of the solvent by freeze-drying.

3. The process of claim 1 , wherein the method of preparing the compound of formula 1 has one or more of the following characteristics:
step 1′) is carried out in an organic solvent
step 2′) is carried out in the presence of a catalyst and a base;
step 3′) is carried out in the presence of an organic acid and an organic base, in an organic solvent;
step 4′) is carried out in the presence of a base, in a polar solvent;
step 5′) is carried out in the presence of an organic acid, in a polar organic solvent;
step 6′) is carried out in the presence of

step 6′) is carried out at a temperature of 120±5° C.;
step 7′) is carried out in the presence of N-iodosuccinimide in an organic solvent;
step 8′) is carried out in the presence of a metal iodide in an organic solvent;
step 8′) is carried out at a temperature of 100±5° C.;
step 9′) is carried out in the presence of hydrogen and a catalyst in an organic solvent,
step 10′) is carried out in an organic solvent in the presence of a base; and
step 11′) is carried out in a polar organic solvent in the presence of a base.

4. The process of claim 1 , wherein the compound of formula 17′ is prepared by a method comprising one or more of the following steps:
1″) converting a compound of formula 1″:

wherein v is n-1;
to form a compound of formula 2″:

2″) converting the compound of formula 2″ to form a compound of formula 3″:

3″) converting the compound of formu

Assignees

• Ascentage Pharma Suzhou Co Ltd
• Ascentage Pharma Group Corp Ltd

Inventors

• Guo Ming
• Wen Jianfeng
• Lu Huirong
• Feng Jianpeng
• Zhang Jing
• Jin Ming
• Cao Qianlei

Classifications

• C07D207/36

  Oxygen or sulfur atoms · CPC title

• C07F9/65583 Primary

  each of the hetero rings containing nitrogen as ring hetero atom · CPC title

• C07B2200/07

  Optical isomers · CPC title

• C07F9/4006

  Esters of acyclic acids which can have further substituents on alkyl · CPC title

• C07F9/59

  Hydrogenated pyridine rings · CPC title