Method for preparing intermediate of 6-arylaminopyridonecarboxamide compound as MEK inhibitor

Patent metadata

Field	Value
Publication number	US-10501468-B2
Application number	US-201716324876-A
Country	US
Kind code	B2
Filing date	Aug 11, 2017
Priority date	Aug 12, 2016
Publication date	Dec 10, 2019
Grant date	Dec 10, 2019

Abstract

Provided is a method for preparing an intermediate of 6-arylaminopyridonecarboxamide compound as an MEK inhibitor, comprising preparing a compound of formula (III) as an intermediate of 6-arylaminopyridonecarboxamide compound using a compound of formula V as a raw material.

First claim

What is claimed is:

1. A method for preparing a compound of formula III, comprising reacting a compound of formula IV with a compound of formula V,

wherein R a and R b are each independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl;

represents X—Y═W or X═Y—W;
X and W are independently selected from the group consisting of N, O, S, and CR 2 ;
Y is CR 1 ; and
R 1 is selected from the group consisting of H and C 1 -C 6 alkyl, wherein the alkyl is optionally substituted with a substituent independently selected from the group consisting of halo, hydroxyl, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 and C 1 -C 6 heterocyclic group;
R 2 is selected from the group consisting of H and C 1 -C 6 alkyl;
R 4 , R 5 , R 6 , R 7 , and R 8 are independently selected from the group consisting of H, halo, SR 9 , and OR 9 ; and
each R 9 is independently selected from the group consisting of hydrogen and C 1 -C 10 alkyl.

2. The method according to claim 1 , wherein
R a and R b are each independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl;
Y is O or S;
W is CR 2 ; and
R 4 , R 5 , R 6 , R 7 , and R 8 are independently selected from the group consisting of H and halo.

3. The method according to claim 1 , wherein R a and R b are each independently selected from the group consisting of methyl and ethyl; X is O; Y is CH; W is CH; R 4 is chloro; R 6 is iodo; and each of R 5 , R 7 , and R 8 is hydrogen.

4. The method according to claim 1 , wherein the compound of formula IV reacts with the compound of formula V in a first solvent selected from the group consisting of tetrahydrofuran, dichloromethane, ethyl acetate, N,N-dimethylformamide, acetone, N,N-dimethylacetamide, N-methyl pyrrolidone, dimethyl sulfoxide, and a mixture thereof.

5. The method according to claim 1 , wherein the compound of formula IV reacts with the compound of formula V in the presence of a first base.

6. The method according to claim 5 , comprising using a molar ratio of the compound of formula IV to the first base that is 1:1˜5.

7. The method according to claim 1 , comprising using a molar ratio of the compound of formula IV to the compound of formula V that is 1˜5:1.

8. A method for preparing a compound of formula I-1, comprising:
1) reacting a compound of formula IV with a compound of formula V to obtain a compound of formula III:

2) hydrolyzing the compound of formula III to obtain a compound of formula II

and
3) reacting the compound of formula II with O-(2-(vinyloxy)ethyl)hydroxylamine, followed by hydrolysis to obtain the compound of formula I-1,

wherein R a and R b are each independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl;

represents X—Y═W or X═Y—W;
X and W are independently selected from the group consisting of N, O, S, and CR 2 ;
Y is CR 1 ; and
R 1 is selected from the group consisting of H and C 1 -C 6 alkyl, wherein the alkyl is optionally substituted with a substituent independently selected from the group consisting of halo, hydroxyl, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 and C 1 -C 6 heterocyclic group;
R 2 is selected from the group consisting of H and C 1 -C 6 alkyl;
R 4 , R 5 , R 6 , R 7 , and R 8 are independently selected from the group consisting of H, halo, SR 9 , and OR 9 ; and
each R 9 is independently selected from the group consisting of hydrogen and C 1 -C 10 alkyl.

9. A method for preparing a compound of formula I-1, comprising:
a) reacting a compound of formula IV with a compound of formula V to obtain a compound of formula III:

and
b) reacting the compound of formula III with O-(2-(vinyloxy)ethyl)hydroxylamine, followed by hydrolysis to obtain the compound of formula I-1,

wherein R a and R b are each independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl;

represents X—Y═W or X═Y—W;
X and W are independently selected from the group consisting of N, O, S, and CR 2 ;
Y is CR 1 ; and
R 1 is selected from the group consisting of H and C 1 -C 6 alkyl, wherein the alkyl is optionally substituted with a substituent independently selected from the group consisting of halo, hydroxyl, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 and C 1 -C 6 heterocyclic group;
R 2 is selected from the group consisting of H and C 1 -C 6 alkyl;
R 4 , R 5 , R 6 , R 7 , and R 8 are independently selected from the group consisting of H, halo, SR 9 , and OR 9 ; and
each R 9 is independently selected from the group consisting of hydrogen and C 1 -C 10 alkyl.

10. The method according to claim 4 , wherein the first solvent is selected from the group consisting of tetrahydrofuran, N,N-dimethylformamide, acetone, N-methyl pyrrolidone, and a mixture thereof.

11. The method according to claim 10 , wherein the first solvent is tetrahydrofuran or acetone, or a mixture thereof.

12. The method according to claim 5 , wherein the first base is selected from the group consisting of NaHMDS, LiHMDS, KHMDS, lithium diisopropylamide, tert-butyl lithium, n-butyl lithium, potassium tert-butoxide, sodium methoxide, and a mixture thereof.

13. The method according to claim 12 , wherein the first base is selected from the group consisting of NaHMDS, LiHMDS, tert-butyl lithium, and a mixture thereof.

14. The method according to claim 13 , wherein the first base is NaHMDS or LiHMDS.

15. The method according to claim 6 , wherein the molar ratio of the compound of formula IV to the first base is 1:1˜3.

16. The method according to claim 15 , wherein the molar ratio of the compound of formula IV to the first base is 1:1˜1.5.

17. The method according to claim 7 , wherein the molar ratio of the compound of formula IV to the compound of formula V is 1˜3:1.

18. The method according to claim 17 , wherein the molar ratio of the compound of formula IV to the compound of formula V is 1.5˜2:1.

Assignees

• Chia Tai Tianqing Pharmaceutical Group Co Ltd
• Centaurus Biopharma Co Ltd

Inventors

• Wang Lulu
• Liu Fei
• Zhu Yizhong
• Zhang Hongying

Classifications

• C07C335/32 Primary

  having sulfur atoms of isothiourea groups bound to acyclic carbon atoms · CPC title

• C07D491/048 Primary

  the oxygen-containing ring being five-membered · CPC title

• C07C335/16

  having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton · CPC title