Process and intermediates

Patent metadata

Field	Value
Publication number	US-10377697-B2
Application number	US-201615780957-A
Country	US
Kind code	B2
Filing date	Dec 8, 2016
Priority date	Dec 10, 2015
Publication date	Aug 13, 2019
Grant date	Aug 13, 2019

Abstract

The present invention relates to a new chemical synthesis, intermediates and catalysts useful for the preparation of the neprilysin (NEP) inhibitor sacubitril. It further relates to new intermediate compounds and their use for said new chemical synthesis route.

First claim

The invention claimed is:

1. A compound of formula (XV), or a salt thereof

wherein:
R5 is selected from the group consisting of hydrogen and a group CO—OR*, and
Ra and R* are, independently of each other, selected from the group consisting of hydrogen, a carboxyl protecting group, and C 1 -C 6 -alkyl.

2. The compound of formula (XV) according to claim 1 , wherein
a) the compound is of formula (I), or a salt thereof;

wherein:
Ra is selected from the group consisting of hydrogen, a carboxyl protecting group, and C 1 -C 6 -alkyl, or
b) the compound is of formula (II), or a salt thereof;

wherein:
Ra and R* are, independently of each other, selected from the group consisting of hydrogen, a carboxyl protecting group, and C 1 -C 6 -alkyl.

3. A process for the manufacture of a compound of formula (I), or a salt thereof;

wherein:
Ra is selected from the group consisting of hydrogen, a carboxyl protecting group and C 1 -C 6 -alkyl, comprising reacting a compound of formula (II), or a salt thereof,

wherein:
Ra and R* are, independently of each other, selected from the group consisting of hydrogen, a carboxyl protecting group, and C 1 -C 6 -alkyl, under—if required—deprotection reaction conditions, followed by decarboxylation reaction conditions, and optionally by introduction of a moiety Ra selected from the group consisting of a carboxyl protecting group and C 1 -C 6 -alkyl, to provide the compound of formula (I).

4. The process according to claim 3 , wherein the compound of the formula (II), or a salt thereof

wherein:
Ra and R* are, independently of each other, selected from the group consisting of hydrogen, a carboxyl protecting group, and C 1 -C 6 -alkyl, is prepared by a process comprising reacting a compound of formula (III),

wherein:
R* is selected from the group consisting of a carboxyl protecting group and C 1 -C 6 -alkyl, with a propionate derivative of formula (IV),

wherein:
X is a leaving group and Ra is selected from the group consisting of a carboxyl protecting group and C 1 -C 6 -alkyl, and, if required, replacing the carboxyl protecting groups R* and Ra with a group selected from the group consisting of hydrogen and C 1 -C 6 -alkyl, to provide the compound of formula (II).

5. The process according to claim 4 , wherein the compound of the formula (III),

wherein R* is selected from the group consisting of a carboxyl protecting group, and C 1 -C 6 -alkyl, is prepared by a process comprising reacting a compound of formula (V),

or a reactive derivative thereof, with a salt of a malonic acid half ester of formula (VI),

wherein R* is selected from the group consisting of a carboxyl protecting group and C 1 -C 6 -alkyl.

6. A process for the manufacture of a compound of formula (I), or a salt thereof;

wherein:
Ra is selected from the group consisting of hydrogen, a carboxyl protecting group, and C 1 -C 6 -alkyl, comprising reacting an activated dianionic derivate of the compound of formula (V), or a salt thereof,

with a compound of formula (XIV), or a salt thereof

wherein:
Rf is selected from the group consisting of
—O—R* wherein R* is selected from the group consisting of a carboxyl protecting group and C 1 -C 6 -alkyl,
—N(CH 3 )—O(CH 3 ),
morpholinyl, and
imidazolinyl,
in the presence of a base, and followed by a decarboxylation reaction, to obtain compound of formula (I), or a salt thereof wherein Ra is hydrogen, optionally followed by reacting the obtained compound of formula (I), or a salt thereof, wherein Ra is hydrogen, with an agent introducing a carboxyl protecting group, to provide the compound of formula (I), wherein Ra is a carboxyl protecting group, and/or
optionally followed by reacting the compound of the formula (I), or a salt thereof, wherein Ra is hydrogen, with a coupling reagent in the presence of an C 1 -C 6 -alkanol, to provide the compound of formula (I), wherein Ra is C 1 -C 6 -alkyl.

7. The process according to claim 5 , wherein the compound of formula (V),

is prepared by a process comprising hydrolysing a cyanide of the formula (VII)

Assignees

• Novartis Ag

Inventors

• Kleinbeck-Riniker Florian Karl
• Martin Benjamin
• Penn Gerhard
• Venturoni Francesco
• Schlama Thierry
• Ruch Thomas
• Allmendinger Thomas
• Wietfeld Bernhard
• Filipponi Paolo

Classifications

• C07C69/738 Primary

  Esters of keto-carboxylic acids {or aldehydo-carboxylic acids} · CPC title

• C07C67/035

  by reacting carboxylic acids or symmetrical anhydrides with saturated hydrocarbons · CPC title

• C07C251/40

  to carbon atoms of an unsaturated carbon skeleton · CPC title

• C07C59/84

  containing six membered aromatic rings · CPC title

• C07D265/02

  1,2-Oxazines; Hydrogenated 1,2-oxazines · CPC title