Process for the preparation of intermediates useful for the manufacture NEP inhibitors

Patent metadata

Field	Value
Publication number	US-9085529-B2
Application number	US-201113818576-A
Country	US
Kind code	B2
Filing date	Aug 22, 2011
Priority date	Aug 23, 2010
Publication date	Jul 21, 2015
Grant date	Jul 21, 2015

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 -amino- -biphenyl- -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 a compound of formula (2), or salt thereof,

wherein R1 and R2 are, independently of each other, hydrogen or a nitrogen protecting group, and R3 is a carboxyl group or an ester group —COOR, wherein R is C 1 -C 6 -alkyl residue, comprising the steps of
A) a) reacting a compound of formula (1), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group;
with a transition metal catalyst, optionally in the presence of a base,
to obtain the compound of formula (4), or salt thereof

wherein
R1 is hydrogen or a nitrogen protecting group; or
A) b) i) reacting a compound of formula (3), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group;
with a selenide in the presence of a base,
to obtain a compound of formula (6), or salt thereof,

wherein R1 is hydrogen or a nitrogen protecting group; and
R is aryl; and
A) b) ii) treating the compound of formula (6) with an oxidizing agent;
to obtain the compound of formula (4) or a salt thereof,

and
B) reacting the obtained compound of formula (4) or a salt thereof with a lactam ring opening agent to obtain a compound of formula (5) with (Z) configuration or salt thereof,

wherein R1 and R2 are, independently of each other, hydrogen or a nitrogen protecting group, and R is hydrogen or a C 1 -C 6 -alkyl residue, and
C) reducing the obtained compound of formula (5), or a salt thereof, to obtain the compound of formula (2).

2. A process according to claim 1 wherein the transition metal catalyst in step A) a) comprises Palladium (Pd).

3. A process according to claim 1 , wherein the reduction reaction in step C) is carried out with hydrogen in the presence of a transition metal catalyst that comprises an organometallic complex and a chiral ligand or which is an organometallic catalyst.

4. A process according to claim 3 , wherein the transition metal catalyst comprises
(i) an organometallic complex and a chiral ligand, wherein
a) the organometallic complex is the rhodium organometallic complex [Rh(cod) 2 ]O 3 SCF 3 or [Rh(nbd) 2 ]BF 4 and the chiral ligand is SL-A101-2, SL-A109-2, SL-A241-1, (R,R)-MOD-DIOP, (R)-PhanePhos, SL-F356-1, SL-J003-1, SL-J005-2, SL-J216-1, SL-J302-1, SL-M001-1, SL-M002-2, SL-M003-1, SL-T001-1, SL-T002-1 or SL-W008-1;
b) the organometallic complex is the ruthenium organometallic complex [Ru(cod)(OOCCF 3 ) 2 ] and the chiral ligand is (R)-PhanePhos or SL-M002-2;
c) the organometallic complex is a rhodium organometallic complex and the chiral ligand is SL-A242-1; or
d) the organometallic complex is a ruthenium organometallic complex, and the chiral ligand is SL-A242-1 or (R,R)-BDPP;
or
(ii) an organometallic catalyst selected from the group consisting of [Rh(cod)(SL-P005-1)]BF 4 , [Rh(cod)(SL-P114-1)]BF 4 , and [Rh(cod)(SL-P102-1)]O 3 SCF 3 .

5. A process according to claim 1 , further comprising the step of reacting the obtained compound of formula (2), or salt thereof,

wherein R1 and R2 are, independently of each other, hydrogen or a nitrogen protecting group, and R3 is a carboxyl group or an ester group —COOR, wherein R is C 1 -C 6 -alkyl residue, preferably a carboxyl group,
to obtain N-(3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methyl butanoic acid ethyl ester or a salt thereof, or N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid or a salt thereof.

Assignees

• Hook David
• Riss Bernhard
• Zhou Jianguang
• Li Yunzhong
• Bappert Erhard
• Novartis Ag

Inventors

• Hook David
• Riss Bernhard
• Zhou Jianguang
• Li Yunzhong
• Bappert Erhard

Classifications

• C07C229/34

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

• C07C271/22 Primary

  to carbon atoms of hydrocarbon radicals substituted by carboxyl groups · CPC title

• C07D207/24 Primary

  Oxygen or sulfur atoms · CPC title

• C07C227/22

  from lactams, cyclic ketones or cyclic oximes, e.g. by reactions involving Beckmann rearrangement · CPC title

• C07C227/18

  by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters · CPC title