Sacubitril intermediate and preparation method thereof

Patent metadata

Field	Value
Publication number	US-11370739-B2
Application number	US-201916679154-A
Country	US
Kind code	B2
Filing date	Nov 9, 2019
Priority date	Feb 29, 2016
Publication date	Jun 28, 2022
Grant date	Jun 28, 2022

Abstract

The present invention relates to a sacubitril intermediate and a preparation method thereof. The sacubitril intermediate disclosed herein can be prepared by a deprotection reaction of a compound. In addition, the intermediate can be used as a raw material to synthesize sacubitril.

First claim

What is claimed is:

1. A compound of Formula (V),

wherein:
R 1 is phenyl, methoxy, hydroxy, chloro, bromo, iodo, mesylate, triflate or 4-methylbenzenesulfonate;
R2 is

with the proviso that when R 1 is phenyl, R2 is not

R 3 is H, —(C 1 -C 4 )alkyl or —(C 1 -C 4 )alkyl-aryl; and
R 4 is H, —(C 1 -C 4 )alkyl, —(C 3 -C 6 )heterocyclyl, —(C 1 -C 4 )alkyl-aryl, trimethylsilyl, triethylsilyl or t-butyldimethylsilyl.

2. The compound of claim 1 , wherein R 1 is phenyl.

3. The compound of claim 1 , wherein R 3 is H, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, benzyl or substituted benzyl.

4. The compound of claim 1 , wherein R 4 is H, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, triphenylmethyl, tetrahydrofuryl, benzyl or substituted benzyl.

5. The compound of claim 1 , wherein R 2 is —COOH, —COOCH 3 , —COOCH 2 CH 3 , —COOCH(CH 3 ) 2 , —COOC(CH 3 ) 3 , —COOCH 2 Ph, —CH 2 OH, —CH 2 OCH 3 , —CH 2 OCH 2 CH 3 , —CH 2 OCH(CH 3 ) 2 , —CH 2 OC(CH 3 ) 3 , —CH 2 OCH 2 Ph, —CH 2 OC(Ph) 3 , —CH 2 OSi(CH 3 ) 3 , —CH 2 OSi(CH 2 CH 3 ) 3 , —CH 2 OSi(CH 3 ) 2 C(CH 3 ) 3 , —CONH 2 , —CONHCH 3 , —CONHCH 2 CH 3 , —CONHCH (CH 3 ) 2 , —CONHC (CH 3 ) 3 , —CONHCH 2 Ph or

with the proviso that when R 1 is phenyl, R 2 is —CH 2 OH, —CH 2 OCH 3 , —CH 2 OCH 2 CH 3 , —CH 2 OCH(CH 3 ) 2 , —CH 2 OC(CH 3 ) 3 , —CH 2 OCH 2 Ph, —CH 2 OC(Ph) 3 , —CH 2 OSi(CH 3 ) 3 , —CH 2 OSi(CH 2 CH 3 ) 3 , —CH 2 OSi(CH 3 ) 2 C(CH 3 ) 3 , —CONH 2 , —CONHCH 3 , —CONHCH 2 CH 3 , —CONHCH (CH 3 ) 2 , —CONHC (CH 3 ) 3 , —CONHCH 2 Ph or

and
wherein each Ph is phenyl.

6. The compound of claim 1 having one of the following structures:

where each Ph is phenyl.

7. The compound of claim 1 , wherein R 2 is

8. The compound of claim 7 , wherein R 1 is phenyl.

9. The compound of claim 7 , wherein R 4 is H.

10. The compound of claim 9 , wherein R 1 is phenyl.

11. A method of preparing a compound of Formula (V):

wherein the compound of Formula (V) is prepared by a deprotection reaction of a compound of Formula (IV):

in the presence of a base or an acid, wherein:
R 1 is phenyl, methoxy, hydroxy, chloro, bromo, iodo, mesylate, triflate or 4-methylbenzenesulfonate;
R 2 is

with the proviso that when R 1 is phenyl, R 2 is not

R 3 is H, —(C 1 -C 4 )alkyl or —(C 1 -C 4 )alkyl-aryl;
R 4 is H, —(C 1 -C 4 )alkyl, —(C 3 -C 6 )heterocyclyl, —(C 1 -C 4 )alkyl-aryl, trimethylsilyl, triethylsilyl or t-butyldimethylsilyl; and
R 5 is H, —(C 1 -C 4 )alkyl or —(C 1 -C 4 )alkyl-aryl.

12. The method of claim 11 , the compound of Formula (IV) is prepared by a substitution reaction of a compound of Formula (II) with a compound of Formula (III) in the presence of a base;

13. The method of claim 12 , the compound of Formula (II) is prepared by a condensation reaction of a compound of Formula (I);

wherein R 1 is as defined above; and
R 5 is H, —(C 1 -C 4 )alkyl or —(C 1 -C 4 )alkyl-aryl.

14. The method according to claim 11 , wherein the compound of the Formula (IV) is prepared by a process comprising the following steps:
a) preparing a compound of Formula (II) by a condensation reaction of a compound of Formula (I) in the presence of a base,

and
b) preparing a compound of Formula (IV) by a substitution reaction of the compound of Formula (II) with a compound of Formula (III) in the presence of a strong base;

wherein R 1 is phenyl;
R 2 is

R 3 is H, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl or benzyl;

R 4 is H, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, benzyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, triphenylmethyl, or tetrahydrofuryl;
R 5 is H, methyl, ethyl, n-propyl, i-propyl, n-butyl or benzyl; and
R 6 is triflate, mesylate or 4-methylbenzenesulfonate.

15. The method of claim 14 wherein the compound of Formula (II) is prepared by a condensation reaction of the compound of Formula (I) with N,N′-carbonyldiimidazole and a compound of Formula (VIII):

in the presence of magnesium chloride and triethylamine, wherein R 5 is H, —(C 1 -C 4 )alkyl or —(C 1 -C 4 )alkyl-aryl.

16. The method of claim 14 , wherein the compound of Formula (II) is prepared by a condensation reaction of the compound of Formula (I) with Meldrum's acid, 4-dimethylaminopyridine, R 5 OH and pivaloyl chloride in the presence of N,N-diisopropylethylamine, R 5 is H, —(C 1 -C 4 )alkyl or —(C 1 -C 4 )alkyl-aryl.

Assignees

• North & South Brother Pharmacy Investment Co Ltd
• Sunshine Lake Pharma Co Ltd

Inventors

• Chen Lei
• Sun Guodong
• Han Xiaodong
• Li Shun
• Zeng Jiebin
• Wang Zhongqing
• Luo Zhonghua

Classifications

• C12P13/005

  Amino acids other than alpha- or beta amino acids, e.g. gamma amino acids · CPC title

• C12P13/001

  Amines; Imines · CPC title

• C07F7/1892

  by reactions not provided for in C07F7/1876 - C07F7/1888 · CPC title

• C07F7/1804 Primary

  Compounds having Si-O-C linkages (Si-O-acyl linkages C07F7/1896) · CPC title

• C07D309/12

  only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers · CPC title