Process for early sacubitril intermediates

Patent metadata

Field	Value
Publication number	US-10774036-B2
Application number	US-201716472386-A
Country	US
Kind code	B2
Filing date	Dec 20, 2017
Priority date	Dec 23, 2016
Publication date	Sep 15, 2020
Grant date	Sep 15, 2020

Abstract

The invention relates to a new enantioselective process for producing useful intermediates for the manufacture of NEP inhibitors or prodrugs thereof, in particular NEP inhibitors comprising a γ-amino-δ-biphenyl-α-methylalkanoic acid, or acid ester, backbone.

First claim

The invention claimed is:

1. A process for preparing a compound of formula (III), or a salt thereof,

wherein R is hydrogen or a carboxyl protecting group,

comprising, converting a compound of formula (IV), or a salt thereof,

wherein R is hydrogen or a carboxyl protecting group,

into the compound of formula (III) by bringing it in contact with an (R)-selective ω-transaminase in the presence of an amine donor, wherein the conversion rate from the compound of formula (IV) to the compound of formula (III) is more than 50%.

2. The process according to claim 1 , wherein the amine donor is an achiral amine donor selected from the group consisting of achiral C 1 -C 7 -alkylamine, achiral C 3 -C 8 -cycloalkylamine, achiral C 6 -C 10 -aryl-C 1 -C 7 -alkylamine, achiral C 1 -C 7 -alkyldiamine, achiral amino-C 1 -C 7 -alkanoic acid, and achiral C 6 -C 10 -aryl-di(C 1 -C 7 -alkylamine).

3. The process according to claim 1 , wherein the compound of formula (IV), or a salt thereof,

wherein R is hydrogen or a carboxyl protecting group,

is obtained by a process comprising hydrolysis of a compound of formula (V),

wherein R1 is C 1 -C 7 -alkyl, C 6 -C 10 -aryl, or C 6 -C 10 -aryl-C 1 -C 7 -alkyl,

under acidic or basic conditions to obtain a compound of formula (IV).

4. The process according to claim 1 , wherein the obtained compound of formula (III), or a salt thereof,

wherein R is hydrogen or a carboxyl protecting group,

is converted into a compound of formula (II), or a salt thereof,

wherein R is hydrogen or a carboxyl protecting group, and Ra is a nitrogen protecting group,

by a process comprising introduction of a nitrogen protecting group Ra.

5. The process according to claim 1 , wherein the obtained compound of formula (III), or a salt thereof,

wherein R is hydrogen,

is first converted into a compound of formula (III), or a salt thereof,

wherein R is C 1 -C 7 -alkyl, C 6 -C 10 -aryl, or C 6 -C 10 -aryl-C 1 -C 7 -alkyl,

by a process comprising reaction with an alcohol having a formula R—OH, wherein R is C 1 -C 7 -alkyl, C 6 -C 10 -aryl, or C 6 -C 10 -aryl-C 1 -C 7 -alkyl,
which is then subsequently converted into a compound of formula (II), or a salt thereof,

wherein R is C 1 -C 7 -alkyl, C 6 -C 10 -aryl, or C 6 -C 10 -aryl-C 1 -C 7 -alkyl, and Ra is a nitrogen protecting group,

by a process comprising introduction of a nitrogen protecting group Ra.

6. The process according to claim 1 , wherein the obtained compound of formula (III), or a salt thereof,

wherein R is hydrogen or a carboxyl protecting group,

is converted into a compound of formula (I*), or a salt thereof,

by a process comprising reduction of the compound of formula (III) in the presence of a reducing agent.

7. The process according to claim 1 , wherein the compound of formula (III) has a formula (IIIa), or a salt thereof:

8. The process according to claim 2 , wherein the achiral amine donor is isopropylamine (2-aminopropane).

9. The process according to claim 3 , wherein the compound of formula (V)

wherein R1 is C 1 -C 7 -alkyl, C 6 -C 10 -aryl, or C 6 -C 10 -aryl-C 1 -C 7 -alkyl,

is obtained by a process comprising reaction of a compound of formula (VI)

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

wherein R1 is C 1 -C 7 -alkyl, C 6 -C 10 -aryl, or C 6 -C 10 -aryl-C 1 -C 7 -alkyl.

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

wherein R is hydrogen or a carboxyl protecting group, and Ra is a nitrogen protecting group,

is converted into a compound of formula (I), or a salt thereof,

wherein Ra is a nitrogen protecting group,

by a process comprising reduction of the compound of formula (II) in the presence of a reducing agent.

11. The process according to claim 4 , wherein Ra is a nitrogen protecting group selected from the group consisting of C 1 -C 6 -alkyl, which is unsubstituted or mono-, di- or tri-substituted by tri-C 1 -C 6 -alkylsilylC 1 -C 7 -alkoxy, C 6 -C 10 -aryl, or a heterocyclic group being a mono-, bi- or tricyclic ring system with 5 to 14 ring atoms and 1 to 4 heteroatoms independently selected from N, O, S, S(O), and S(O) 2 , wherein the aryl ring or the heterocyclic group is unsubstituted or substituted by one, two or three residues, selected from the group consisting of C 1 -C 7 -alkyl, hydroxyl, C 1 -C 7 -alkoxy, C 2 -C 8 -alkanoyl-oxy, halogen, nitro, cyano, and CF 3 ; C 6 -C 10 -aryl-C 1 -C 2 -alkoxycarbonyl; C 1 -C 10 -alkenyloxycarbonyl; C 1 -C 6 -alkylcarbonyl; C 6 -C 10 -arylcarbonyl; C 1 -C 6 -alkoxycarbonyl; C 6 -C 10 -aryl-C 1 -C 6 -alkoxycarbonyl; allyl; cinnamyl; sulfonyl; sulfenyl; succinimidyl; and silyl, wherein each silyl group is a SiR11R12R13 group, wherein R11, R12 and R13 are, independently of each other, C 1 -C 7 -alkyl, C 6 -C 10 -aryl, or phenyl-C 1 -C 4 -alkyl.

12. The process according to claim 10 , wherein the obtained compound of formula (I), or a salt thereof,

wherein Ra is a nitrogen protecting group,

is reacted by a process comprising a TEMPO mediated oxidation reaction or an oxidation with Dess-Martin periodinane to obtain a compound of formula (VIII), or a salt thereof,

wherein Ra a nitrogen protecting group.

13. The process according to claim 10 , wherein Ra is a nitrogen protecting group selected from the group consisting of C 1 -C 6 -alkyl, which is unsubstituted or mono-, di- or tri-substituted by tri-C 1 -C 6 -alkylsilylC 1 -C 7 -alkoxy, C 6 -C 10 -aryl, or a heterocyclic group being a mono-,

Assignees

• Novartis Ag

Inventors

• Kleinbeck-Riniker Florian Karl
• Kapferer Tobias
• Kim Hongyong
• Ku Jie
• Laumen Kurt
• Li Yunzhong
• Peng Wei
• Ruch Thomas
• Schlama Thierry
• Yang Yao

Classifications

• C07C227/06 Primary

  by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid · CPC title

• C12P13/04

  Alpha- or beta- amino acids {(other amino acids C12P13/005)} · CPC title

• C12P41/006

  by reactions involving C-N bonds, e.g. nitriles, amides, hydantoins, carbamates, lactames, transamination reactions, or keto group formation from racemic mixtures · CPC title

• C07C229/36

  with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton · CPC title