Processes and intermediates for NEP inhibitor synthesis

Patent metadata

Field	Value
Publication number	US-10851059-B2
Application number	US-201716325880-A
Country	US
Kind code	B2
Filing date	Aug 16, 2017
Priority date	Aug 17, 2016
Publication date	Dec 1, 2020
Grant date	Dec 1, 2020

Abstract

The present invention relates to a new chemical synthesis, intermediates and catalysts useful for the preparation of the neprilysin (NEP) inhibitor sacubitril, inter alia via nitro 5 compounds. It further relates to new intermediate compounds and their use for said new chemical synthesis route, as well as a new catalyst ligand.

First claim

The invention claimed is:

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

wherein:
R1 is hydrogen or C 1 -C 6 -alkyl;
R3 is —NO 2 or —NR′R″, wherein R′ and R″ are independently of each other hydrogen or a nitrogen protecting group; and
R4 is selected from hydrogen, C 1 -C 6 -carbonyl, C 1 -C 6 -alkoxycarbonyl, and a sulphonyl group.

2. The compound according to claim 1 , or a salt thereof, wherein the compound has a configuration according to formula (1-R):

3. A process for producing a compound of claim 1 having a formula (1-a),

comprising reacting a compound of formula (2-a)

wherein R1 is hydrogen or C 1 -C 6 -alkyl,
with a compound of formula (3)

wherein the reaction of compound of formula (2-a) with the compound of formula (3) is performed in the presence of a metal complex catalyst comprising a metal and a chiral ligand.

4. The process according to claim 3 , wherein the metal is Cu and the chiral ligand is selected from the group consisting of camphor-pyridine ligands, DAC ligands, and DPEN ligands.

5. The process according to claim 3 , wherein the compound of formula (2-a),

is prepared by oxidation of a compound of formula (2-b)

said oxidation comprising the use of an oxidant and optionally a catalyst, and
wherein in the above formulae R1 is hydrogen or C 1 -C 6 -alkyl.

6. The process according to claim 5 , wherein the compound of formula (2-b),

is prepared by oxime formation of a compound of formula (2-c),

said oxime formation comprising the use of hydroxylamine or a salt thereof, and
wherein in the above formulae R1 is hydrogen or C 1 -C 6 -alkyl.

7. The process according to claim 6 , wherein the compound of formula (2-c),

is prepared by hydroformylation, of a methacrylate of formula (2-d)

said hydroformylation comprising the use of carbon monoxide, hydrogen and optionally a metal complex catalyst, and wherein in the above formulae R1 is hydrogen or C 1 -C 6 -alkyl.

8. The process according to claim 3 , wherein the compound of formula (2-a),

is prepared by treating a compound of formula (2-d)

with nitromethane, optionally followed by a chiral separation of the compound of formula (2-a) to obtain the compound of formula (2-a-R),

wherein the chiral separation is carried out by chiral simulated moving bed (SMB) chromatography, and wherein in the above formulae R1 is hydrogen or C 1 -C 6 -alkyl.

9. A process for producing a compound of claim 1 having a formula (1-b),

comprising hydrogenation of a compound of formula (1-a)

optionally in the presence of a nitrogen protecting agent.

10. The process according to claim 9 , wherein the compound of formula (1-a) is produced by the process according to claim 3 .

11. A process for producing a compound of formula (6)

wherein R′ and R″ are independently of each other hydrogen or a nitrogen protecting group, and R1 is hydrogen or C 1 -C 6 -alkyl,
said process comprising taking a compound of formula (1-b)

wherein R′ and R″ are independently of each other hydrogen or a nitrogen protecting group, and R1 is hydrogen or C 1 -C 6 -alkyl,
optionally treating the compound of formula (1-b) with an OH-activating agent to obtain a compound of formula (1-d)

wherein R′ and R″ are independently of each other hydrogen or a nitrogen protecting group,
R1 is hydrogen or C 1 -C 6 -alkyl, and
R4 is an OH-activating group, and
subjecting the compound of formula (1-b) or (1-d) to a hydrogenation reaction to obtain the compound of formula (6).

12. The process according to claim 11 , wherein the compound of formula (1-b) or the compound of formula (1-d) wherein R4 is hydrogen, is produced by the process according to claim 9 .

13. The process according to claim 11 , wherein the hydrogenation reaction to obtain a compound of formula (6) is carried out via the intermediate compound of formula (7)

wherein R′ is hydrogen or a nitrogen protecting group,

which is reacted with a ring opening agent, wherein the ring opening agent comprises water or a C 1 -C 6 -alkanol, to obtain a compound of formula (6); and
wherein the obtained compound of formula (6) is optionally further reacted to obtain a compound of formula (8),

wherein R1 is hydrogen or C 1 -C 6 -alkyl.

14. The process according to claim 4 , wherein the chiral ligand is a compound of formula (4a),

or a compound of formula (4b),

Assignees

• Novartis Ag

Inventors

• Kleinbeck-Riniker Florian Karl
• Mafli Ives
• Martin Benjamin
• Penn Gerhard
• Sedelmeier Gottfried
• Sedelmeier Joerg
• Venturoni Francesco

Classifications

• C07D213/36

  Radicals substituted by singly-bound nitrogen atoms (nitro radicals C07D213/26) · CPC title

• C07D207/12

  Oxygen or sulfur atoms · CPC title

• C07C205/53

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

• C07C201/06

  Preparation of nitro compounds · CPC title

• C07C201/16

  Separation; Purification; Stabilisation; Use of additives · CPC title