Intermediates of neutral endopeptidase inhibitors and preparation method thereof

Patent metadata

Field	Value
Publication number	US-9278908-B2
Application number	US-201514739172-A
Country	US
Kind code	B2
Filing date	Jun 15, 2015
Priority date	Jan 22, 2010
Publication date	Mar 8, 2016
Grant date	Mar 8, 2016

Abstract

The invention relates to a new process for producing useful intermediates for the manufacture of NEP inhibitors or prodrugs thereof, in particular NEP inhibitors comprising a g-amino-d-biphenyl-a-methylalkanoic acid, or acid ester, backbone, such as N-(3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methyl butanoic acid ethyl ester or salt thereof.

First claim

The invention claimed is:

1. A process for preparing N-(3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methyl butanoic acid ethyl ester, or a salt thereof, or the compound N-(3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methyl butanoic acid comprising
i) reacting a compound of formula (3), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group;
first with a base and then with a compound of the formula CO 2 or R4COY, wherein Y is halogen or —OR′ and wherein R4 and R′ are independently selected from alkyl, aryl and arylalkyl, to obtain a compound of formula (4), or salt thereof,

wherein
R1 is hydrogen or a nitrogen protecting group; and
R4 is selected from hydroxyl, alkyl, aryl and arylalkyl; and
ii) reacting the obtained compound of formula (4), or salt thereof, with a base and formaldehyde, optionally in the presence of a phase transfer catalyst,
to obtain a compound of formula (1), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group; and
iii) subsequently converting the obtained compound of formula (1) to the compound N-(3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methyl butanoic acid ethyl ester, or a salt thereof, or the compound N-(3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methyl butanoic acid or a salt thereof.

2. The process according to claim 1 , wherein R4 is hydroxyl and wherein the compound of formula (3) is reacted first with a base and then with a compound of the formula CO 2 .

3. The process according to claim 1 , wherein R4 is selected from alkyl, aryl and arylalkyl and wherein the compound of formula (3) is reacted first with a base and then with a compound of the formula R4COY, wherein Y is halogen or —OR′ and wherein R4 and R′ are independently selected from alkyl, aryl and arylalkyl.

4. The process according to claim 1 , wherein the base in step i) is selected from
a metal hydride;
an alkali metal alkoxide;
an amine, optionally in the presence of an additive selected from an alkaline earth metal halide;
a base of the formula MRa, wherein M is an alkali metal and Ra is alkyl or aryl;
a base of the formula RcRdNM, wherein Rc and Rd are independently selected from alkyl, cycloalkyl, heterocyclyl and silyl and M is an alkali metal; and
mixtures thereof.

5. The process according to claim 1 , wherein the base in step ii) is selected from
a metal hydride;
an amine;
an inorganic base;
a base of the formula MRa, wherein M is an alkali metal and Ra is alkyl or aryl;
a base of the formula RcRdNM, wherein Rc and Rd are independently selected from alkyl, cycloalkyl, heterocyclyl and silyl and M is an alkali metal; and
mixtures thereof.

6. The process according to claim 5 , wherein the reaction further comprises adding an alkali metal salt and optionally a drying agent.

7. The process according to claim 1 , wherein steps i) and ii) take place via one-pot.

8. The process according to claim 1 , wherein
R1 is selected from t-butoxycarbonyl, benzoyl, styryl, 1-butenyl, benzyl, p-methoxybenzyl and pyrrolidinylmethyl; and
R4 is selected from t-butyl, methyl, isopropyl, phenyl and hydroxyl.

9. A process according to claim 1 , wherein the compound of formula (4) is of the formula (4a)

(4a)
wherein R1 and R4 are as defined for the compound of formula (4).

10. A process according to claim 1 , wherein the compound of formula (3) is of the formula (3a)

wherein R1 is as defined for the compound of formula (3).

11. A process according to claim 1 , wherein the compound of formula (1) is of the formula (1a)

wherein R1 is as defined for the compound of formula (1).

Assignees

• Hook David
• Zhou Jianguang
• Li Yunzhong
• Ku Jie
• Novartis Ag

Inventors

• Hook David
• Zhou Jianguang
• Li Yunzhong
• Ku Jie

Classifications

• C07D207/267

  with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atom · CPC title

• C07D207/26

  2-Pyrrolidones · CPC title

• C07D207/277

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

• C07C231/10 Primary

  from compounds not provided for in groups C07C231/02 - C07C231/08 · CPC title

• C07D207/38

  2-Pyrrolones · CPC title