Process for the preparation of enantiomerically and diastereomerically enriched cyclobutane amines and amides

Patent metadata

Field	Value
Publication number	US-11053188-B2
Application number	US-201816764666-A
Country	US
Kind code	B2
Filing date	Nov 14, 2018
Priority date	Nov 16, 2017
Publication date	Jul 6, 2021
Grant date	Jul 6, 2021

Abstract

The present invention relates to a process for the preparation of enantiomerically and diastereomerically enriched cyclobutane amines and amides by reacting (a) cyclopropylcarbonitrile to a cyclopropylcarbaldehyde, (b) further reacting to a cyclobutanone, or (d′) further reacting to an enamide, (c) further reacting to enantiomerically and diastereomerically enriched cyclobutane amines, or (d) further reacting to an enamide and (e) to an enantiomerically and diastereomerically enriched cyclobutylamide to obtain (f) an enantiomerically and diastereomerically enriched cyclobutane amine, and (g) further reacting to an enantiomerically and diastereomerically enriched cyclobutane amide.

First claim

What is claimed is:

1. A process for the preparation of enantiomerically and diastereomerically enriched cyclobutane amides comprising
(a) reducing the nitrile moiety of a compound of formula (I) to an aldehyde

wherein A is selected from aryl, heteroaryl, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl and C 3 -C 7 -cycloalkyl, which aryl, heteroaryl, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl and C 3 -C 7 -cycloalkyl are unsubstituted or substituted with one or more substituents independently selected from halogen, cyano, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 -alkylsulfanyl, C 1 -C 6 -haloalkylsulfanyl, C 1 -C 6 -alkylsulfinyl, C 1 -C 6 -haloalkylsulfinyl, C 1 -C 6 -alkylsulfonyl, C 1 -C 6 -haloalkylsulfonyl, C 2 -C 6 -haloalkenyl and C 2 -C 6 -haloalkynyl;
wherein the reduction of the nitrile moiety of the compound of formula (I) is carried out via partial hydrogenation to the corresponding intermediate imine applying H 2 and a metal hydrogenation catalyst, followed by subsequent hydrolysis to the compound of formula (II)

then
(b) reacting the compound of formula (II) in the presence of a suitable Lewis acid to obtain a compound of formula (III)

wherein * indicates a stereocentre, then
(c) reacting a compound of formula (III) with an ammonium salt and H 2 in presence of a chiral transition metal catalyst to obtain an enantiomerically and diastereomerically enriched amine of formula (IV)

wherein * indicates a stereocentre, and then
further reacting the amine of formula (IV) with a compound of formula (X)

wherein Y is a suitable leaving group selected from OH, OR or halogen, R is C 1 -C 6 -alkyl, and E is selected from aryl, heteroaryl, hydrogen, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl and C 3 -C 7 -cycloalkyl which aryl, heteroaryl, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl and C 3 -C 7 -cycloalkyl are unsubstituted or substituted with one or more substituents independently selected from halogen, cyano, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 -alkylsulfanyl, C 1 -C 6 -haloalkylsulfanyl, C 1 -C 6 -alkylsulfinyl, C 1 -C 6 -haloalkylsulfinyl, C 1 -C 6 -alkylsulfonyl, C 1 -C 6 -haloalkylsulfonyl, C 2 -C 6 -haloalkenyl and C 2 -C 6 -haloalkynyl;
so as to form the enantiomerically and diastereomerically enriched amide of formula (VII)

2. The process according to claim 1 , wherein
A and E are selected from aryl and heteroaryl, which aryl and heteroaryl are unsubstituted or substituted with one or more substituents independently selected from halogen, cyano, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy and C 1 -C 6 -haloalkoxy.

3. The process according to claim 1 , wherein
A is phenyl and E is heteroaryl, which phenyl and heteroaryl are unsubstituted or substituted with one or more substituents independently selected from halogen, cyano, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy and C 1 -C 6 -haloalkoxy.

4. The process according to claim 1 , wherein the compound of formula (II) is reacted in step (b) in the presence of a Lewis acid selected from AlCl 3 and GaCl 3 .

5. The process according to claim 4 , wherein
1.0-1.5 mole equivalents of AlCl 3 or GaCl 3 relative to the compound of formula (II) are added in step (b).

6. The process according to claim 1 , wherein the chiral transition metal catalyst in step (c) comprises a transition metal selected from Ru, Rh, Ir and Pd, and a chiral ligand with a bidentate phosphor of the general formula (VIII)

wherein Z is a linking group and R 1 , R 2 , R 3 and R 4 are independently selected from aryl, heteroaryl, C1-C6-alkyl and C 3 -C 6 -cycloalkyl, each of which is unsubstituted or substituted with one or more substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl and halogen.

7. The process according to claim 6 , wherein
the linking group Z is selected from (R and S)-1,1′-binaphthyl, (R and S)-4,4′-bi-1, 3-benzodioxole, (R and S)-2, 2′, 6,6′-tetramethoxy-3, 3′-bipyridine, (R and S)-6,6′-dimethoxy-1, 1′-biphenyl, (R and S)-4,4′, 6,6′ tetramethoxy-1, 1′-biphenyl, 2, 2′-bis-[(R)-cx-(dimethylamino)benzyl]ferrocene, ferrocenyl methyl, ferrocene, benzene and ethyl.

8. The process according to claim 6 , wherein the chiral ligand is selected from
(R)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,
(R)-2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl,
(R)-2,2′-bis[di(3,5-xylyl)phosphino]-1,1′-binaphthyl,
(R)-5,5′-bis(diphenylphosphino)-4,4′-bi-1,3-benzodioxole,
(R)-5,5′-bis(di[3,5-xylyl]phosphino)-4,4′-bi-1,3-benzodioxole,
(R)-5,5′-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-4,4′-bi-1,3-benzodioxole,
(S)-1,13-bis(diphenylphosphino)-7,8-dihydro-6H-dibenzo[f,h][1,5]dioxin,
(R)-2,2′,6,6′-tetramethoxy-4,4′-bis(di(3,5-xylyl)phosphino)-3,3′-bipyridine,
(R)-2,2′-bis(diphenylphosphino)-6,6′-dimethoxy-1,1′-biphenyl,
(R)-2,2′-bis(diphenylphosphino)-4,4′,6,6′-tetramethoxy-1,1′-biphenyl,
(R)-6,6′-bis(diphenylphosphino)-2,2′,3,3′-tetrahydro-5,5′-bi-1,4-benzodioxin,
(R)-(+)-2,2′-bis(diphenylphosphino)-5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-binaphthyl,
(R)-(+)-2,2′-bis(di-3,5-xylylphosphino)-5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-binaphthyl,
(R)-5,5′-bis(diphenylphosphino)-2,2,2′,2′-tetrafluoro-4,4′-bi-1,3-benzodioxole,
(S)-1-[(S)-1-[di(3,5-xylyl)phosphino]ethyl]-2-[2-[di(3,5-xylyl)phosphino]phenyl]ferrocene, and
(S)-1-[(S)-1-[bis[3,5-bis(trifluoromethyl)phenyl]phosphino]ethyl]-2-[2-(diphenylphosphino)phenyl]ferrocene.

9. The process according to claim 6 , wherein
the chiral transition metal catalyst is selected from [RuCl(p-cymene)((S)-DM-SEGPHOS)]Cl, [RuCl(p-cymene)((R)-DM-SEGPHOS)]Cl, [NH 2 Me 2 ][(RuCl((R)-xylbinap)) 2 (u-Cl) 3 ], [NH 2 Me 2 ][(RuCl((S)-xylbinap)) 2 (u-Cl) 3 ], Ru(OAc) 2 [(R)-binap], Ru(OAc) 2 [(S)-binap], Ru(OAc) 2 [(R)-xylbinap], Ru(OAc) 2 [(S)-xylbinap], RuCl 2 [(R)-xylbinap][(R)-daipen], RuCl 2 [(S)-xylbinap][(S)-daipen], RuCl 2 [(R)-xylbinap][(R,R)-dpen] and RuCl 2 [(S)-xylbinap][(S,S)-dpen].

10. A process for the preparation of a compound of formula (III)

wherein A is as defined in claim 1 and * indicates a stereocentre, comprising reacting a compound of formula (II)

with a suitable Lewis acid.

11. A process for the preparation of a compound of formula (III)

wherein A is as defined in claim 1 and * indicates a stereocentre, comprising reacting a compound of formula (II)

Assignees

• Syngenta Participations Ag

Inventors

• Dumeunier Raphael
• Smejkal Tomas
• Mishra Brijnandan Premnath
• Gopalsamuthiram Vijayagopal Raman
• Godineau Edouard
• O'Sullivan Anthony Cornelius

Classifications

• C07C2601/04

  with a four-membered ring · CPC title

• B01J21/02

  Boron or aluminium; Oxides or hydroxides thereof · CPC title

• C07D213/803

  Processes of preparation · CPC title

• C07C49/593

  of a three- or four-membered ring · CPC title

• C07C47/457

  containing halogen · CPC title