Sacubitril intermediate and preparation method thereof

Patent metadata

Field	Value
Publication number	US-10479753-B2
Application number	US-201816112761-A
Country	US
Kind code	B2
Filing date	Aug 26, 2018
Priority date	Feb 29, 2016
Publication date	Nov 19, 2019
Grant date	Nov 19, 2019

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. The method disclosed herein has advantages of easily obtained raw materials, simple preparation process, low cost, environment friendly, and etc., which is very suitable for industrial production.

First claim

What is claimed is:

1. A method of preparing sacubitril,

comprising the following steps:
a) preparing a compound of Formula (VI) by an enzymic catalytic reaction of a compound of Formula (V) in the presence of ω-transaminase and phosphopyridoxal,

b) optionally, preparing a compound of Formula (VII) from the compound of Formula (VI):

c) preparing sacubitril from the compound of Formula (VII),

wherein:
R 1 is phenyl, methoxy, hydroxy, chloro, bromo, iodo, mesylate, triflate or 4-methylbenzenesulfonate;
R 2 is

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 method of claim 1 ,
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

 and 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.

3. The method of claim 2 , 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;

4. The method of claim 3 , 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.

5. The method according to claim 2 , 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,

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

6. The method of claim 5 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.

7. The method of claim 5 , 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.

8. The method of claim 1 , wherein R 1 is phenyl; R 2 is

and R 3 is methyl, ethyl, propyl, i-propyl, n-butyl, t-butyl, benzyl or optionally substituted benzyl.

9. The method of claim 1 , comprising the following steps:
a) preparing a compound of Formula (VII) by an enzymic catalytic reaction of a compound of Formula (V):

in the presence of ω-transaminase and phosphopyridoxal; and
b) preparing sacubitril by an amide condensation reaction of the compound of Formula (VII) with succinic anhydride,

wherein R 1 is phenyl, and R 2 is

and R 3 is ethyl.

10. The method of preparing sacubitril of claim 1 , wherein the compound of Formula (VII) is prepared by a hydrolysis reaction of the compound of Formula (VI) and then an esterification reaction of the hydrolysis product with ethanol.

11. The method of claim 1 , wherein the compound of the Formula (VII) is prepared by a process comprising the following steps:
a) preparing a compound of Formula (X) by a reaction of a compound of Formula (V) with a compound of Formula (IX),

b) preparing a compound of Formula (XI) from the compound of Formula (X),

c) preparing a compound of Formula (XII) from the compound of Formula (XI),

d) preparing a compound of Formula (VII) from the compound of Formula (XII),

wherein:
R 1 is phenyl, methoxy, hydroxy, chloro, bromo, iodo, mesylate, triflate or 4-methylbenzenesulfonate;
R 2 is

R 3 is H, —(C 1 -C 4 )alkyl or —(C 1 -C 4 )alkyl-aryl; and
R 7 is phenyl, —(C 1 -C 4 )alkyl or —(C 1 -C 4 )alkyl-aryl.

12. The method of claim 11 , wherein the compound of Formula (IX) in step a) is D-phenylglycinol.

13. The method of claim 11 , wherein the compound of Formula (XI) is prepared from the compound of Formula (X) in the presence of titanium tetrachloride and triethyl silicane in step b).

14. The method of claim 11 , wherein the compound of Formula (XII) is prepared from the compound of Formula (XI) in the presence of palladium-carbon in step c).

Assignees

• Sunshine Lake Pharma Co Ltd

Inventors

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

Classifications

• C07C235/78

  the carbon skeleton containing rings · CPC title

• C07C59/84

  containing six membered aromatic rings · CPC title

• C07C49/255

  containing ether groups, [IMAGE cpc-sch-C07C-0958.gif] groups,[IMAGE cpc-sch-C07C-0959.gif] groups, or[IMAGE cpc-sch-C07C-0960.gif] groups · CPC title

• C07C49/245

  containing six-membered aromatic rings · CPC title

• C12P13/00

  Preparation of nitrogen-containing organic compounds · CPC title