Process and intermediates

Patent metadata

Field	Value
Publication number	US-11434192-B2
Application number	US-201916452452-A
Country	US
Kind code	B2
Filing date	Jun 25, 2019
Priority date	Dec 10, 2015
Publication date	Sep 6, 2022
Grant date	Sep 6, 2022

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 process for the manufacture of the compound N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid or a salt thereof, or the compound N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester of formula

or a salt thereof, by:
A) converting a compound of formula (I),

wherein:
Ra is selected from the group consisting of hydrogen, a carboxyl protecting group, and C 1 -C 6 -alkyl, into a compound of formula (VIII),

wherein:
Ra is selected from the group consisting of hydrogen and C 1 -C 6 -alkyl; and Re is selected from the group consisting of hydrogen and a nitrogen protecting group, by a process comprising any one of steps (i) to (vi):
(i) reacting a compound of formula (I), or a salt thereof;

wherein: Ra is hydrogen,
with ammonia, a primary or secondary amine, or salts thereof, to provide a compound of formula (VIII), wherein Ra and Re are hydrogen, or a salt thereof; or
(ii) converting a compound of formula (I), or a salt thereof;

wherein:
Ra is selected from the group consisting of hydrogen and C 1 -C 6 -alkyl, into the compound of formula (VIII), wherein Ra is selected from hydrogen and C 1 -C 6 -alkyl; and Re is hydrogen, or a salt thereof, by bringing it in contact with an (S)-selective ω-transaminase in the presence of an amine donor and a coenzyme, wherein the conversion rate from the compound of formula (I) to the compound of formula (VIII), is more than 50%; or
(iii)
a) reacting a compound of formula (I), or a salt thereof;

wherein:
Ra is selected from the group consisting of a carboxyl protecting group and C 1 -C 6 -alkyl, with an aminosulfinyl compound of formula (IX), or a salt thereof,

wherein Rb is selected from the group consisting of C 1 -C 6 -alkyl, C 6 -C 10 -aryl, C 6 -C 10 -aryl-C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkyl-C 1 -C 6 -alkyl, heterocyclyl, and heterocyclyl-C 1 -C 6 -alkyl, wherein said heterocyclyl is a mono- or polycyclic, unsaturated, partially saturated, saturated or aromatic ring system with 5 to 14 ring atoms and with one or more heteroatoms independently selected from nitrogen, oxygen, sulfur, S(═O)—, and S—(═O) 2 , and wherein each aryl or heterocyclyl group can be optionally substituted by one, two or three substituents independently selected from the group consisting of halo, C 1 -C 7 -alkyl, halo-C 1 -C 7 -alkyl, C 1 -C 7 -alkoxy, halo-C 1 -C 7 -alkoxy, and C 1 -C 7 -alkoxy-C 1 -C 7 -alkyl;
to give a sulfinimide compound of the formula (X), or a salt thereof

wherein:
Rb is selected from the group consisting of C 1 -C 6 -alkyl, C 6 -C 10 -aryl, C 6 -C 10 -aryl-C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkyl-C 1 -C 6 -alkyl, heterocyclyl, and heterocyclyl-C 1 -C 6 -alkyl, wherein said heterocyclyl is a mono- or polycyclic, unsaturated, partially saturated, saturated or aromatic ring system with 5 to 14 ring atoms and with one or more heteroatoms independently selected from nitrogen, oxygen, sulfur, S(═O)—, and S—(═O) 2 , and wherein each aryl or heterocyclyl group can be optionally substituted by one, two or three substituents independently selected from the group consisting halo, C 1 -C 7 -alkyl, halo-C 1 -C 7 -alkyl, and C 1 -C 7 -alkoxy, halo-C 1 -C 7 -alkoxy, and C 1 -C 7 -alkoxy-C 1 -C 7 -alkyl; and
Ra is selected from a carboxyl protecting group and C 1 -C 6 -alkyl;
b) reducing the obtained compound of formula (X), or a salt thereof, in the presence of a reducing agent to give a sulfinamide compound of the formula (XI), or a salt thereof

wherein:
Rb is selected from the group consisting of C 1 -C 6 -alkyl, C 6 -C 10 -aryl, C 6 -C 10 -aryl-C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkyl-C 1 -C 6 -alkyl, heterocyclyl or heterocyclyl-C 1 -C 6 -alkyl, wherein said heterocyclyl is a mono- or polycyclic, unsaturated, partially saturated, saturated or aromatic ring system with 5 to 14 ring atoms and with one or more heteroatoms independently selected from nitrogen, oxygen, sulfur, S(═O)— or S—(═O) 2 , and wherein each aryl or heterocyclyl group can be optionally substituted by one, two or three substituents independently selected from the group consisting of halo, C 1 -C 7 -alkyl, halo-C 1 -C 7 -alkyl, C 1 -C 7 -alkoxy, halo-C 1 -C 7 -alkoxy, and C 1 -C 7 -alkoxy-C 1 -C 7 -alkyl; and
Ra is selected from a carboxyl protecting group and C 1 -C 6 -alkyl;
c) reacting the obtained sulfinamide compound of formula (XI), or a salt thereof, by hydrolyzing the sulfonamide group in the presence of an acid to provide a compound of formula (VIII), or a salt thereof, wherein Ra is selected from the group consisting of a carboxyl protecting group and C 1 -C 6 -alkyl, and Re is hydrogen; and
d) removing—if present—any carboxyl protecting group from the obtained compound of formula (VIII), or a salt thereof, to provide a compound of formula (VIII), or a salt thereof, wherein Ra is selected from the group consisting of hydrogen and C 1 -C 6 -alkyl; and Re is hydrogen; or

(iv)
a) reacting a compound of formula (I), or a salt thereof;

wherein Ra is hydrogen,
with hydroxylamine or a salt thereof to provide a compound of formula (XVII), or a salt thereof

wherein Ra is hydrogen;
b) subsequently cyclizing the obtained compound of formula (XVII) to give the corresponding compound of the formula (XVIII)

c) reducing the obtained compound of formula (XVIII) in the presence of a reducing agent, to obtain the compound of formula (VIII), wherein Ra and Re are both hydrogen, or
(v)
a) reacting a compound of formula (I), or a salt thereof;

wherein Ra is hydrogen,
with ammonia or an ammonium salt, yielding a compound of the formula (XIX)

b) reducing the obtained compound of formula (XIX), with a reducing agent, to give a lactam compound of formula (XX),

c) reacting the obtained compound of formula (XX) under ring opening conditions, optionally in the presence of an C 1 -C 7 -alcohol, to provide the compound of formula (VIII), wherein Ra is selected from the group consisting of hydrogen and C 1 -C 6 -alkyl; and Re is hydrogen; or

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

• C07B2200/07

  Optical isomers · CPC title

• C07C51/373

  by introduction of functional groups containing oxygen only in doubly bound form · CPC title

• C07C59/84

  containing six membered aromatic rings · CPC title

• C07C251/40

  to carbon atoms of an unsaturated carbon skeleton · CPC title

• C07C69/738 Primary

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