Method for synthesizing novel chiral ligand, metal chelate, a variety of non-natural amino acids, maraviroc and key intermediate thereof

Patent metadata

Field	Value
Publication number	US-2019233456-A1
Application number	US-201716337338-A
Country	US
Kind code	A1
Filing date	Sep 19, 2017
Priority date	Sep 29, 2016
Publication date	Aug 1, 2019
Grant date	—

Abstract

Disclosed is a method for synthesizing a novel chiral ligand, a metal chelate, a variety of non-natural amino acids, Maraviroc and a key intermediate thereof. In the invention, (R)-2-methyl proline is selected and used as a starting raw material, (S)-β3-amino acid is obtained by asymmetric resolution induced by using a nickel chelate, and Maraviroc is synthesized by using (S)-3-amino-3-phenylpropionic acid as a key intermediate with a high yield and the ee value reaching 98.2% or more. The method of the present invention has widely available materials, mild synthetic process conditions, is easy to control, and produces a product of a high optical purity.

First claim

1 . A synthesis method for a novel quaternary carbon chiral ligand, wherein the synthesis method comprises the step of synthesizing a compound of formula VI,

wherein n is an integer from 1 to 4;
R is selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl and unsubstituted or substituted phenyl, wherein the substituted phenyl means that the phenyl has 1-5 substituents, and each substituent is independently selected from the group consisting of amino, halogen, hydroxyl, C1-C4 alkyl and C1-C4 haloalkyl;
R 1 is selected from the group consisting of H, C1-C4 alkyl, C1-C4 haloalkyl and unsubstituted or substituted phenyl, wherein the substituted phenyl means that the phenyl has 1-5 substituents, and each substituent is independently selected from the group consisting of amino, halogen, hydroxyl, C1-C4 alkyl and C1-C4 haloalkyl;
R 2 is selected from the group consisting of H, halogen, amino, hydroxyl, C1-C4 alkyl and C1-C4 haloalkyl;
R 3 is selected from the group consisting of H, C1-C4 alkyl, C1-C4 haloalkyl, unsubstituted or substituted phenyl and —(C1-C4 alkylene)-(unsubstituted or substituted phenyl); wherein the substituted phenyl means that the phenyl has 1-5 substituents, and each substituent is independently selected from the group consisting of amino, halogen, hydroxyl, C1-C4 alkyl and C1-C4 haloalkyl.

2 . A novel resolution method for an alpha amino acid, an alpha substituted beta amino acid and a beta substituted beta amino acid comprising the step of hydrolyzing a compound of formula VI to obtain the alpha amino acid, the alpha substituted beta amino acid and the beta substituted beta amino acid of formula VII,

wherein n is an integer from 1 to 4, m is an integer from 0 to 1;
R is selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl and unsubstituted or substituted phenyl, wherein the substituted phenyl means that the phenyl has 1-5 substituents, and each substituent is independently selected from the group consisting of amino, halogen, hydroxyl, C1-C4 alkyl and C1-C4 haloalkyl;
R 1 is selected from the group consisting of H, C1-C4 alkyl, C1-C4 haloalkyl and unsubstituted or substituted phenyl, wherein the substituted phenyl means that the phenyl has 1-5 substituents, and each substituent is independently selected from the group consisting of amino, halogen, hydroxyl, C1-C4 alkyl and C1-C4 haloalkyl;
R 2 is selected from the group consisting of H, halogen, amino, hydroxyl, C1-C4 alkyl and C1-C4 haloalkyl;
R 3 is selected from the group consisting of H, C1-C4 alkyl, C1-C4 haloalkyl, unsubstituted or substituted phenyl and —(C1-C4 alkylene)-(unsubstituted or substituted phenyl); wherein the substituted phenyl means that the phenyl has 1-5 substituents, and each substituent is independently selected from the group consisting of amino, halogen, hydroxyl, C1-C4 alkyl and C1-C4 haloalkyl;
R 4 is selected from the group consisting of H, unsubstituted or substituted C6-C10 aryl, unsubstituted or substituted C3-C6 heteroaryl and unsubstituted or substituted C3-C6 cycloalkyl, wherein the “substituted” means that there are 1-5 substituents, and each substituent is independently selected from the group consisting of amino, halogen, hydroxyl, nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy and C1-C4 haloalkyl;
R 5 is selected from the group consisting of H, unsubstituted or substituted C6-C10 aryl, unsubstituted or substituted C3-C6 heteroaryl and unsubstituted or substituted C3-C6 cycloalkyl, wherein the “substituted” means that there are 1-5 substituents, and each substituent is independently selected from the group consisting of amino, halogen, hydroxyl, nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy and C1-C4 haloalkyl.

3 . The resolution method of claim 2 , wherein the compound of VI is synthesized by the following step:
reacting a compound of formula IV with an unnatural amino acid of formula V under the action of a nickel salt to form the compound of formula VI,

wherein n, m, R, R 1 , R 2 , R 3 , R 4 and R 5 are as defined in claim 2 .

4 . A Maravino intermediate having a structure of formula VI:

wherein n, m, R 1 , R 2 , R 3 , R 4 and R 5 are as defined in claim 2 .

5 . A novel chiral ligand having a structure of formula Y:

wherein n, R, R 1 , R 2 and R 3 are as defined in claim 2 .

6 . A method for synthesizing Maraviro comprising the step of synthesizing a Maraviro intermediate, wherein the Maraviro intermediate is:

the step of synthesizing the Maraviro intermediate is as defined in claim 2 ,
wherein n, R 1 , R 2 and R 3 are as defined in claim 2 and R 4 is phenyl.

7 . A method for synthesizing an unnatural amino acid comprising the following steps:

(i) reacting (R)-2-substituted proline with di-tert-butyl dicarbonate to form (R)-1-(tert-butoxycarbonyl)-2-methylproline;
(ii) subjecting (R)-1-(tert-butoxycarbonyl)-2-substituted proline to a condensation reaction with a compound of formula I to obtain a compound of formula II;
(iii) removing tert-butoxycarbonyl from the compound of formula II to obtain a compound of formula III;
(iv) subjecting the compound of formula III to a reductive amination reaction with R 3 CHO or R 3 CH 2 Cl to obtain a compound of formula IV;
(v) reacting the compound of formula IV with various unnatural amino acids of formula V under the action of a nickel salt to form a compound of VI;
(vi) hydrolyzing the compound of VI to form a compound of VII,
wherein n, m, R, R 1 , R 2 , R 3 , R 4 and R 5 are as defined in claim 2 .

8 . A method for synthesizing a key intermediate of Maraviro, wherein the key intermediate of Maraviro is:

the synthesis method includes the following steps:

(i) reacting the compound IV with 3-amino-3-phenylpropionic acid under the action of a nickel salt to obtain a compound of formula VI′;
(ii) hydrolyzing the compound of formula VI′ to obtain a compound of formula VII, wherein n, R, R 1 , R 2 and R 3 are as defined in claim 1 .

9 . A method for synthesizing Maraviro comprising the step of synthesizing a key intermediate of Maraviro, wherein the key intermediate of Maraviro is:

the step of synthesizing the key intermediate of Maraviro is as defined in claim 8 .

10 . A method for synthesizing Maraviro, wherein the method further comprises the following steps:

(i) reacting (S)-β 3 -phenylalanine with di-tert-butyl dicarbonate to obtain a compound of formula VIII;

Assignees

• Shanghai Inst Materia Medica Cas

Inventors

• Liu Hong
• Wang Jiang
• Zhou Shengbin
• Peng Panfeng
• Nian Yong
• Wang Shuni
• Shu Shuangjie
• Shen Hao
• Jiang Hualiang
• Chen Kaixian

Classifications

• C07D207/16 Primary

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• C07C227/34

  by separation of optical isomers · CPC title

• C07C229/34

  the carbon skeleton containing six-membered aromatic rings · CPC title

• C07D409/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D451/04

  with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system · CPC title