# US 10,501,468 B2 · Method for preparing intermediate of 6-arylaminopyridonecarboxamide compound as MEK inhibitor

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- Number: US 10,501,468 B2
- Document ID: US10501468B2
- Status: Granted
- Kind: B2
- Application number: 16/324,876
- Filed: 2017-08-11
- Published: 2019-06-13
- Granted: 2019-12-10
- Earliest claimed: 2016-08-12
- Assignees: Chia Tai Tianqing Pharmaceutical Group Co., Ltd.; Centaurus Biopharma Co., Ltd.
- Applicants: Chia Tai Tianqing Pharmaceutical Group Co., Ltd.; Centaurus Biopharma Co., Ltd.
- Inventors: Lulu Wang; Fei Liu; Yizhong Zhu; Hongying Zhang
- Web page: https://patentgrep.com/patent/US10501468B2

## CPC

- C07D 491/048: the oxygen-containing ring being five-membered
- C07C 335/32: having sulfur atoms of isothiourea groups bound to acyclic carbon atoms
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## 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.

## Claims

### Claim 1

A method for preparing a compound of formula III, comprising reacting a compound of formula IV with a compound of formula V,
wherein Ra and Rb are each independently selected from the group consisting of hydrogen and C1-C6 alkyl;
represents X—Y═W or X═Y—W;
X and W are independently selected from the group consisting of N, O, S, and CR2;
Y is CR1; and
R1 is selected from the group consisting of H and C1-C6 alkyl, wherein the alkyl is optionally substituted with a substituent independently selected from the group consisting of halo, hydroxyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2 and C1-C6 heterocyclic group;
R2 is selected from the group consisting of H and C1-C6 alkyl;
R4, R5, R6, R7, and R8 are independently selected from the group consisting of H, halo, SR9, and OR9; and
each R9 is independently selected from the group consisting of hydrogen and C1-C10 alkyl.

### Claim 2 (depends on 1)

The method according to claim 1, wherein
Ra and Rb 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 CR2; and
R4, R5, R6, R7, and R8 are independently selected from the group consisting of H and halo.

### Claim 3 (depends on 1)

The method according to claim 1, wherein Ra and Rb are each independently selected from the group consisting of methyl and ethyl; X is O; Y is CH; W is CH; R4 is chloro; R6 is iodo; and each of R5, R7, and R8 is hydrogen.

### Claim 4 (depends on 1)

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.

### Claim 5 (depends on 1)

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.

### Claim 6 (depends on 5)

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.

### Claim 7 (depends on 1)

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.

### Claim 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 Ra and Rb are each independently selected from the group consisting of hydrogen and C1-C6 alkyl;
represents X—Y═W or X═Y—W;
X and W are independently selected from the group consisting of N, O, S, and CR2;
Y is CR1; and
R1 is selected from the group consisting of H and C1-C6 alkyl, wherein the alkyl is optionally substituted with a substituent independently selected from the group consisting of halo, hydroxyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2 and C1-C6 heterocyclic group;
R2 is selected from the group consisting of H and C1-C6 alkyl;
R4, R5, R6, R7, and R8 are independently selected from the group consisting of H, halo, SR9, and OR9; and
each R9 is independently selected from the group consisting of hydrogen and C1-C10 alkyl.

### Claim 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 Ra and Rb are each independently selected from the group consisting of hydrogen and C1-C6 alkyl;
represents X—Y═W or X═Y—W;
X and W are independently selected from the group consisting of N, O, S, and CR2;
Y is CR1; and
R1 is selected from the group consisting of H and C1-C6 alkyl, wherein the alkyl is optionally substituted with a substituent independently selected from the group consisting of halo, hydroxyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2 and C1-C6 heterocyclic group;
R2 is selected from the group consisting of H and C1-C6 alkyl;
R4, R5, R6, R7, and R8 are independently selected from the group consisting of H, halo, SR9, and OR9; and
each R9 is independently selected from the group consisting of hydrogen and C1-C10 alkyl.

### Claim 10 (depends on 4)

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.

### Claim 11 (depends on 10)

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

### Claim 12 (depends on 5)

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.

### Claim 13 (depends on 12)

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.

### Claim 14 (depends on 13)

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

### Claim 15 (depends on 6)

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

### Claim 16 (depends on 15)

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.

### Claim 17 (depends on 7)

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.

### Claim 18 (depends on 17)

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.