Process for preparing intermediates useful in the manufacture of NEP inhibitors

Patent metadata

Field	Value
Publication number	US-9624163-B2
Application number	US-201314424307-A
Country	US
Kind code	B2
Filing date	Sep 2, 2013
Priority date	Aug 31, 2012
Publication date	Apr 18, 2017
Grant date	Apr 18, 2017

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 (2), or a salt thereof,

comprising the steps of
(a) reacting a compound of formula (3), or salt thereof

wherein X is halogen or —O—R5, wherein R5 is C 1 -C 6 -alkyl
with an imide or azide nitrogen nucleophile under Mitsunobu conditions;

(b) (i) conversion of the resulting imide intermediate compound of formula (3-1) or salt thereof,

wherein X is halogen or —O—R5, wherein R5 is C 1 -C 6 -alkyl and R3 is an imide,
by hydrolysis or by treatment with hydrazine to obtain a compound of formula (2) or salt thereof,

or
(ii) reduction of the resulting intermediate azide compound of formula (3-1) or salt thereof,

wherein X is halogen or —O—R5, wherein R5 is C 1 -C 6 -alkyl and R3 is azide,
to obtain a compound of formula (2) or salt thereof.

2. A process according to claim 1 , wherein the reaction with the imide or azide nitrogen nucleophile under Mitsunobu conditions is carried out in the presence of a phosphorous(III) compound, and a dialkyl azodicarboxylate.

3. A process according to claim 1 , wherein the imide nitrogen nucleophile is selected from the group consisting of succinimide, phthalimide, substituted succinimide, substituted phthalimide, naphthalimide, substituted naphthalimide, maleinimide and substituted maleinimide.

4. A process according to claim 1 , wherein the compound of formula (3), or salt thereof

is of formula (3-a) or salt thereof

wherein X is halogen or —O—R5, wherein R5 is C 1 -C 6 -alky;
and is prepared
by reacting a compound of formula (4-a),

wherein X is halogen or —O—R5, wherein R5 is C 1 -C 6 -alkyl;
with a biphenylic compound, to obtain a compound of formula (3-a) or salt thereof.

5. A process according to claim 1 , wherein the compound of formula (2) is of formula (2-a) or salt thereof

6. A process according to claim 1 , wherein the compound of formula (3) is of formula (3-a) or salt thereof

wherein X is halogen or —O—R5, wherein R5 is C 1 -C 6 -alkyl.

7. A process according to claim 1 , wherein the compound of formula (3-1) is of formula (3-1-a) or salt thereof,

wherein X is halogen or —O—R5, wherein R5 is C 1 -C 6 -alkyl and R3 is imide.

8. A process according to claim 7 , wherein R3 is an azide.

9. A process according to claim 2 , wherein the phosphorous (III) compound is a phosphine or ylide.

10. A process according to claim 9 , wherein the phosphorous (III) compound is more preferably triphenylphosphine or tri-n-butylphosphine, and the dialkyl azodicarboxylate is diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD).

11. A process according to claim 3 , wherein the imide nitrogen nucleophile is selected from succinimide and phthalimide.

12. A process according to claim 4 , wherein the compound of formula (3) is of formula (3-a) or salt thereof

13. A process according to claim 4 , wherein said activated biphenylic compound is selected from the group consisting of biphenylmagnesium halide, di(biphenyl)magnesium, biphenyllithium, biphenylcuprate (low and higher-order cuprates) and biphenylzinc.

14. A process according to claim 4 , wherein said activated biphenylic compound is biphenylmagnesium halide.

15. A process according to claim 4 , wherein the reaction is carried out in the presence of cuprate (I) ions.

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

wherein R1 and R2 are, independently of each other, hydrogen or a nitrogen protecting group,
wherein at least one of R1 or R2 is a nitrogen protecting group,
comprising converting a compound of formula (2), or a salt thereof,

into a compound of formula (1), or a salt thereof, by introduction of a nitrogen protecting group.

17. A process according to claim 16 , wherein the hydrochloride salt of the compound of formula (2-a)

is obtained from a compound of formula (3-1-a)

wherein X is chloro or tert-butoxy, and R3 is succinimidyl or phthalimidyl,
by hydrolysis with an inorganic acid or an inorganic base, and optionally subsequent treatment with hydrochloric acid.

18. A process according to claim 17 , wherein the compound of formula (3-1-a)

wherein X is chloro or tert-butoxy, and R3 is succinimidyl or phthalimidyl,
is obtained from a compound of formula (3-a)

wherein X is chloro or tert-butoxy;
by reaction under Mitsunobu conditions with an imide selected from succinimide and phthalimide in the presence of triphenyl phosphine and a dialkyl azodicarboxylate compound in an organic solvent.

19. A process according to claim 18 , wherein the dialkyl azodicarboxylate compound is diethyl azodicarboxylate (DEAD), and the organic solvent is selected from toluene, ethyl acetate, tetrahydrofurane, and dichloromethane.

20. A process according to claim 18 , wherein said compound of formula (3-a)

wherein X is chloro or tert-butoxy;
is obtained by a Grignard reaction comprising reacting 4-bromobiphenyl and metallic magnesium in tetrahydrofuran and then reacting the obtained 4-biphenylmagnesium bromide with a compound of formula (4-a)

wherein X is chloro or tert-butoxy,
in the presence of a cuprous (I) halide, preferably cuprous iodide.

21. A process according to claim 16 , wherein the nitrogen protecting group is ter

Assignees

• Novartis Ag
• Zhejiang Jiuzhou Pharm Co Ltd

Inventors

• Zhu Guoliang
• Ye Wenfa
• Zheng Hui
• Qian Lingfeng
• Wei Junhui
• Yang Lijun
• Li Yunguang
• Luo Lijun

Classifications

• C07C269/06

  by reactions not involving the formation of carbamate groups · CPC title

• C07C213/02

  by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups · CPC title

• C07C29/36

  increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal · CPC title

• C07C269/04 Primary

  from amines with formation of carbamate groups · CPC title

• C07C215/28

  and containing six-membered aromatic rings · CPC title