RU2793738C2 - Method for preparation of enantiomerically and diastereomerically enriched cyclobutane amines and amides - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a process for the preparation of enantiomerically and diastereomerically enriched cyclobutane amines with formula (VII). The method involves (a) reducing the nitrile moiety of a compound with formula (I) to an aldehyde, wherein the reduction of the nitrile moiety of a compound with formula (I) is carried out by partial hydrogenation to the relevant intermediate imine using H₂ and a metal catalyst, followed by sequential hydrolysis to produce the compound with formula (II). The method then comprises (b) reacting a compound with formula (II) in the presence of a Lewis acid to obtain a compound with formula (III). The process then comprises (c) reacting a compound with formula (III) with an ammonium salt and H₂ in the presence of a chiral transition metal catalyst to produce an enantiomerically and diastereomerically enriched amine with formula (IV) and then reacting an amine with formula (IV) with a compound with formula (X) to form an enantiomerically and diastereomerically enriched amide with formula (VII). In these formulas, A is selected from aryl and heteroaryl, where aryl and heteroaryl are unsubstituted or substituted with one or more substituents independently selected from halogen, cyano, C₁ -C₆ alkyl, C₁ -C₆ haloalkyl, C₁ -C₆ alkoxy and C₁ -C₆ haloalkoxy; Y is a suitable leaving group such as OH, OR or halogen, preferably chlorine, R is C₁ -C₆ alkyl; E is selected from aryl and heteroaryl, where aryl and heteroaryl are unsubstituted or substituted with one or more substituents independently selected from halogen, cyano, C₁ -C₆ alkyl, C₁ -C₆ haloalkyl, C₁ -C₆ alkoxy and C₁ -C₆ haloalkoxy; * denotes stereocenter; aryl is a mono-, bi- or polycyclic aromatic system with 6-14 carbon atoms in the ring, heteroaryl is 5-7-membered rings with 1-3 identical or different heteroatoms selected from N, O and S. The proposed method allows to improve existing methods for the preparation of enantiomerically and diastereomerically enriched cyclobutanamides with formula (VII).

EFFECT: processes for the preparation of a compound with formula (III) and a process for the preparation of a compound with formula (V).

14 cl, 27 tbl, 213 ex

Description

The present invention relates to a process for producing enantiomerically and diastereomerically enriched cyclobutanamines and α-amides by carrying out the reaction of (a) cyclopropylcarbonitrile to obtain cyclopropylcarbaldehyde (b) followed by the reaction to obtain cyclobutanone or (d') followed by the reaction to obtain enamide; (c) followed by reaction to give enantiomerically and diastereomerically enriched cyclobutanamine, or (d) followed by reaction to give enamide, and (e) to give enantiomerically and diastereomerically enriched cyclobutanamide to give (f) enantiomerically and diastereomerically enriched cyclobutanamine, and ( g) followed by reaction to obtain enantiomerically and diastereomerically enriched cyclobutanamide.

The present invention relates to a process for the preparation of enantiomerically and diastereomerically enriched cyclobutanamines and α-amides according to the following Scheme 1.

A process for the preparation of compounds of formula (VII) according to Scheme 1 has been described in WO 2013/143811 and WO 2015/003951. The present invention relates to improved processes for the preparation of compounds of formula (VII), in particular to the process steps (a), (b), (c), (d), (d'), (e), (f) and (g ).

where 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, where 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; and where 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, where 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, and where the asterisk * denotes the stereocenter.

Preferably, A and E in Scheme 1 are selected from aryl and heteroaryl, where 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. More preferably A is phenyl and E is heteroaryl, wherein 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. Even more preferably A is phenyl substituted with one or two halogens and E is pyridyl substituted with one C ₁ -C ₆ haloalkyl, in particular A is phenyl substituted with two chlorine atoms and E is 3-pyridyl , substituted with trifluoromethyl, more specifically A is 2,4-dichlorophenyl and E is (2-trifluoromethyl)-pyrid-3-yl.

In a first aspect of the present invention, there is provided a process (a) for the preparation of a compound of formula (II) comprising the reduction of a nitrile moiety of a compound of formula (I) to an aldehyde, wherein the reduction of the nitrile moiety of a compound of formula (I) is carried out by partial hydrogenation to the corresponding imine intermediate using H ₂ and a metal or metal hydride catalyst followed by sequential hydrolysis to give a compound of formula (II) wherein A is defined in Scheme 1 above. In particular, the metal catalyst is selected from Pd/C (palladium on carbon) (a1) and nickel Raney (Ra/Ni) (a2), a metal hydride selected from DIBAL (diisobutylaluminum hydride) (a3) and REDAL (sodium bis(2-methoxyethoxy)aluminum hydride) (a4).

Typical reaction parameters for reaction (a) are as follows.

(a1) Conversion of a compound of formula (I) to a compound of formula (II) using Pd/C

The conversion of a compound of formula (I) to a compound of formula (II) is generally carried out in the presence of H ₂ , a catalyst such as palladium on a suitable support or carrier material, optionally a solvent such as an alcohol or hydrocarbon, in particular MeOH (methanol ), toluene or methylcyclohexane, an organic or inorganic acid, in particular HCl or trifluoroacetic acid, and water.

Preferred reaction parameters for method (a1) according to Scheme 1 are as follows.

The reaction (a1) is preferably carried out at a temperature of from 10°C to 150°C, more preferably from 0°C to 50°C, even more preferably at about 5°C.

The hydrogen gas pressure in the reaction vessel may be 0.1 to 100 bar, preferably 0.1 to 20 bar, more preferably 0.5 to 3 bar.

Preferably, 1 to 35 mol equivalents of water relative to the compound of formula (I) is charged to the reaction mixture, more preferably 2 to 16 mol equivalents, and even more preferably 3 to 6 mol equivalents.

Preferably, 1-50 mol equivalents of acid relative to the compound of formula (I) are charged to the reaction mixture, more preferably 2-30 mol equivalents, and even more preferably 4-20 mol equivalents.

Palladium on a suitable support or carrier material. In particular, 0.001 to 1.0 mole equivalent of Pd/C is added relative to the compound of formula (I). More specifically, 0.001 to 0.01 mole equivalent of Pd/C is added relative to the compound of formula (I).

Preferred conditions are such that the concentration of the compound of formula (I) is 1-30% by weight of the total reaction mixture.

(a2) Converting a compound of formula (I) to a compound of formula (II) using Raney nickel (Ra/Ni)

The conversion of a compound of formula (I) to a compound of formula (II) is generally achieved in the presence of H ₂ , a Raney nickel catalyst, an organic acid, in particular acetic acid or trifluoroacetic acid, optionally a catalyst deactivating agent, in particular pyridine or quinoline, and water.

Preferred reaction parameters for method (a2) according to Scheme 1 are as follows.

Reaction (a2) is preferably carried out at -10°C to 150°C, more preferably 0°C to 50°C, even more preferably at about 25°C.

The hydrogen gas pressure in the reaction vessel may be 0.1 to 100 bar, preferably 0.1 to 20 bar, more preferably 0.5 to 3 bar.

Preferably, 1 to 60 mol equivalents of water relative to the compound of formula (I) is charged to the reaction mixture, more preferably 2 to 40 mol equivalents, and even more preferably 5 to 12 mol equivalents.

Preferably, 1-66 mol equivalents of acid relative to the compound of formula (I) are charged to the reaction mixture.

The reaction mixture is optionally charged with 0.1-25 mol equivalents of a catalyst deactivating additive relative to the compound of formula (I).

Ra/Ni. In particular, 0.01 to 1.0 mol equivalent of Ra/Ni catalyst is added relative to the compound of formula (I), preferably 0.1 to 0.5 mol equivalent.

Preferred conditions are such that the concentration of the compound of formula (I) is 1-30% by weight of the reaction mixture.

(a3) Converting a compound of formula (I) to a compound of formula (II) using DIBAL

The conversion of a compound of formula (I) to a compound of formula (II) is typically achieved in the presence of DIBAL and an organic solvent, followed by acid work-up.

A suitable solvent for the reaction (a3) may be selected from the following classes of solvents: ethers or chlorinated and non-chlorinated hydrocarbons, or aromatics. Suitable solvents include, without limitation, dichloromethane, tetrahydrofuran, hexanes, heptane, xylenes, toluene, and cyclohexane. Preferred solvents are toluene and o-xylene.

Preferred reaction parameters for method (a3) according to Scheme 1 are as follows.

Reaction (a3) is preferably carried out at -20°C to 100°C, more preferably -10°C to 20°C, even more preferably at about 0°C.

Preferably 1-2 mol equivalents of DIBAL relative to the compound of formula (I) are charged to the reaction mixture.

Preferred reaction conditions are such that the concentration of the compound of formula (I) is 1-30% by weight of the reaction mixture.

(a4) Converting a compound of formula (I) to a compound of formula (II) using REDAL

The conversion of a compound of formula (I) to a compound of formula (II) is achieved in the presence of REDAL and an organic solvent, preferably followed by an acid treatment.

A suitable solvent may be selected from the following classes of solvents: ethers or other than chlorinated hydrocarbons, or aromatics. Suitable solvents include, without limitation, THF (tetrahydrofuran), xylenes and toluene. Preferred solvents are toluene and THF.

Preferred reaction parameters for method (a4) according to Scheme 1 are as follows.

Reaction (a4) is preferably carried out at a temperature of 20°C to 100°C, more preferably -10°C to 25°C, even more preferably 0 to 25°C.

Preferably, 0.5-1.2 mole equivalent of REDAL relative to the compound of formula (I) is charged to the reaction mixture.

Preferred conditions are such that the concentration of the compound of formula (I) is 1-35% by weight of the reaction mixture.

It should be understood that any of the preferred features for each of methods (a1), (a2), (a3) and (a4) may be combined with one or more other preferred features of methods (a1), (a2), (a3) and (a4) respectively.

In a second aspect of the present invention, a process (b) for preparing a compound of formula (III) is provided, comprising reacting a compound of formula (II) in the presence of a suitable Lewis acid, and wherein A is defined in Scheme 1 above. In particular, the Lewis acid is selected from AlCl ₃ and GaCl ₃ , preferably AlCl ₃ . Preferably, process (b) is carried out under inert conditions, such as under nitrogen gas, and in a suitable solvent.

One skilled in the art will appreciate that reaction (b) according to Scheme 1 is carried out in a suitable solvent. A suitable solvent may be selected from the following classes of solvents: chlorinated hydrocarbons or chlorinated aromatics. Suitable solvents include, without limitation, dichloromethane, chlorobenzene or dichlorobenzene. Preferred solvents are chlorinated aromatic solvents, in particular dichlorobenzene and chlorobenzene.

Preferred reaction parameters for method (b) according to Scheme 1 are as follows.

Reaction (b) is preferably carried out at a temperature of 0°C to 100°C, more preferably 20°C to 80°C, even more preferably 50 to 60°C.

Preferably, 1.0-1.5 mol equivalents of AlCl ₃ or GaCl ₃ relative to the compound of formula (II) are charged to the reaction mixture.

The concentration of the compound of formula (II) is preferably 1-40% by weight of the reaction mixture.

The process conditions for process (b) have been shown to be particularly effective, ie they lead to higher yields of the compounds of formula (III).

It should be understood that any of the preferred features for method (b) may be combined with one or more other preferred features for method (b).

In a third aspect of the present invention, there is provided a process (c) for preparing an enantiomerically and diastereomerically enriched cyclobutanamine, comprising reacting a compound of formula (III) with an ammonium salt and H ₂ in the presence of a chiral transition metal catalyst, and wherein A is defined in Scheme 1 above. one or more additives are optionally added to the reaction mixture.

The chiral transition metal catalyst contains a transition metal selected from Ru, Rh, Ir and Pd and a chiral ligand.

Chiral ligands are known in the art and can be used in the present invention, examples are given in "Catalytic asymmetric synthesis", Iwao Ojima, third Edition, Wiley-VCH 2010, and references cited therein; typical classes that are known to those skilled in the art include, without limitation, TADDOL (α,α,α',α'-tetraaryl-2,2-disubstituted 1,3-dioxolane-4,5-dimethanol), DUPHOS (phospholane ligand ), BOX (bis(oxazoline) ligand), BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl), BINOL (1,1'-bi-2-naphthol), DIOP (2,3 -o-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane), WALPHOS, TANIAPHOS, MANDYPHOS, CHENPHOS, JOSIPHOS, BIPHEMP, MeO-BIPHEP, SEGPHOS, CHIRAPHOS, PPHOS, TUNEPHOS and SYNPHOS.

Preferably, the chiral ligand is a bidentate phosphorus containing ligand of general formula (VIII):

where Z is a linker group, and R ¹ , R ² , R ³ and R ⁴ are independently selected from aryl, heteroaryl, C ₁ -C ₆ alkyl and C ₁ -C ₆ cycloalkyl, each of which is unsubstituted or substituted. Typical substituents for R ¹ , R ² , R ³ and R ⁴ are selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl and halogen. Preferably the linker group Z is selected from (R or S)-1,1'-binaphthyl, (R or S)-4,4'-bi-1,3-benzodioxole, (R or S)-2,2',6 ,6'-tetramethoxy-3,3'-bipyridine, (R or S)-6,6'-dimethoxy-1,1'-biphenyl, (R or S)-4,4',6,6'-tetramethoxy -1,1'-biphenyl, 2,2'-bis-[(R or S)-cx-(dimethylamino)benzyl]ferrocene, ferrocenylmethyl, ferrocene, benzene and ethyl. More preferably, the bidentate ligand of formula (VIII) is selected from the ligand classes B IN AP, WALPHOS, JOSIPHOS, TANIAPHOS, MANDYPHOS, CHENPHOS, MeO-BIPHEP, PPHOS, DUPHOS, TUNEPHOS, SYNPHOS and SEPGPHOS. Suitable chiral ligands in accordance with the present invention include, without limitation

(R)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl,

(S)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl,

(R)-2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthyl,

(S)-2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthyl,

(R)-2,2'-bis[di(3,5-xylyl)phosphino]-1,1'-binaphthyl,

(S)-2,2'-bis[di(3,5-xylyl)phosphino]-1,1'-binaphthyl,

(R)-5,5'-bis(diphenylphosphino)-4,4'-bi-1,3-benzodioxole,

(S)-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,

(S)-5,5'-bis(di[3,5-xylyl]phosphino)-4,4'-bi-1,3-benzodioxole,

(R)-1,13-bis(diphenylphosphino)-7,8-dihydro-6H-dibenzo[f,h][1,5]dioxin,

(S)-1,13-bis(diphenylphosphino)-7,8-dihydro-6H-dibenzo[f,h][1,5]dioxin,

(R)-2,2',6,6'-tetramethoxy-4,4'-bis(diphenylphosphino)-3,3'-bipyridine,

(S)-2,2',6,6'-tetramethoxy-4,4'-bis(diphenylphosphino)-3,3'-bipyridine,

(R)-2,2',6,6'-tetramethoxy-4,4'-bis(di(3,5-xylyl)phosphino)-3,3'-bipyridine,

(S)-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,

(S)-2,2'-bis(diphenylphosphino)-6,6'-dimethoxy-1,1'-biphenyl,

(R)-bis(diphenylphosphino)-4,4',6,6'-tetramethoxy-1,1'-biphenyl,

(S)-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-benzodioxine,

(S)-6,6'-bis(diphenylphosphino)-2,2',3,3'-tetrahydro-5,5'-bi-1,4-benzodioxine,

(R)-5,5'-bis(diphenylphosphino)-2,2,2',2'-tetrafluoro-4,4'-bi-1,3-benzodioxole,

(S)-5,5'-bis(diphenylphosphino)-2,2,2',2'-tetrafluoro-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)-(+)-5,5'-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-4,4'-bi-1,3-benzodioxole,

(S,S)-Fc-1,1'-bis[bis(3,5-dimethylphenyl)phosphino]-2,2'-bis[(S,S)С-(N,N-dimethylamino)phenylmethyl]ferrocene ,

(R,R)-Fc-1,1'-bis[bis(3,5-dimethylphenyl)phosphino]-2,2'-bis[(R,R)C-(N,N-dimethylamino)phenylmethyl]ferrocene ,

(R)-2,2'-bis[bis(3,5-diisopropyl-4-dimethylaminophenyl)phosphino]-6,6'-dimethoxy-1,1'-biphenyl,

(S)-2,2'-bis[bis(3,5-diisopropyl-4-dimethylaminophenyl)phosphino]-6,6'-dimethoxy-1,1'-biphenyl,

(S)-2,2'-bis[bis(3,4,5-trimethoxyphenyl)phosphino]-4,4',5,5',6,6'-hexamethoxy-1,1'-biphenyl,

(R)-2,2'-bis[bis(3,4,5-trimethoxyphenyl)phosphino]-4,4',5,5',6,6'-hexamethoxy-1,1'-biphenyl,

(R)-1-diphenylphosphino-2-[(R)-(N,N-dimethylamino)-[2-(diphenylphosphino)phenyl]methyl]ferrocene,

(S)-1-diphenylphosphino-2-[(S)-(N,N-dimethylamino)-[2-(diphenylphosphino)phenyl]methyl]ferrocene,

(R)-(+)-2,2'-bis(diphenylphosphino)-5,5',6,6',7,7',8,8'-octahydro-1,1'-binaphthyl,

(S)-(-)-2,2'-bis(diphenylphosphino)-5,5',6,6',7,7',8,8'-octahydro-1,1'-binaphthyl,

(R)-1-[(R)-1-[bis[3,5-bis(trifluoromethyl)phenyl]phosphino]ethyl]-2-[2-(diphenylphosphino)phenyl]ferrocene,

(S)-1-[(S)-1-[bis[3,5-bis(trifluoromethyl)phenyl]phosphino]ethyl]-2-[2-(diphenylphosphino)phenyl]ferrocene,

(R)-2,2'-bis[bis(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-6,6'-dimethoxy-1,1'-biphenyl,

(S)-2,2'-bis[bis(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-6,6'-dimethoxy-1,1'-biphenyl,

(R)-2,2'-bis[di-3,5-xylylphosphino]-6,6'-dimethoxy-1,1'-biphenyl,

(S)-2,2'-bis[di-3,5-xylylphosphino]-6,6'-dimethoxy-1,1'-biphenyl,

(R)-1-[(R)-1-(diphenylphosphino)ethyl]-2-[2-(diphenylphosphino)phenyl]ferrocene,

(S)-1-[(S)-1-(diphenylphosphino)ethyl]-2-[2-(diphenylphosphino)phenyl]ferrocene,

(R)-2,2'-bis(di-p-dimethylaminophenylphosphino)-6,6'-dimethoxy-1,1'-biphenyl,

(S)-2,2'-bis(di-p-dimethylaminophenylphosphino)-6,6'-dimethoxy-1,1'-biphenyl,

(R)-2,2'-bis[bis(3,5-di-tert-butylphenyl)phosphino]-6,6'-dimethoxy-1,1'-biphenyl,

(S)-2,2'-bis[bis(3,5-di-tert-butylphenyl)phosphino]-6,6'-dimethoxy-1,1'-biphenyl,

(R)-1-[(R)-1-[di(3,5-xylyl)phosphino]ethyl]-2-[2-[di(3,5-xylyl)phosphino]phenyl]ferrocene,

(S)-1-[(R)-1-[di(3,5-xylyl)phosphino]ethyl]-2-[2-[di(3,5-xylyl)phosphino]phenyl]ferrocene,

(R)-2,2'-bis(di-m-dimethylaminophenylphosphino)-6,6'-dimethoxy-1,1'-biphenyl,

(S)-2,2'-bis(di-m-dimethylaminophenylphosphino)-6,6'-dimethoxy-1,1'-biphenyl,

(R)-2,2'-bis[bis(3,5-diisopropyl-4-dimethoxyphenyl)phosphino]-6,6'-dimethoxy-1,1'-biphenyl,

(S)-2,2'-bis[bis(3,5-diisopropyl-4-dimethoxyphenyl)phosphino]-6,6'-dimethoxy-1,1'-biphenyl,

(-)-1,2-bis[(2S',5S)-2,5-diisopropylphospholano]benzene,

(+)-1,2-bis[(2R,5R)-2,5-diisopropylphospholano]benzene,

(R)-2,2'-bis(di-p-tolylphosphino)-6,6'-dimethoxy-1,1'-biphenyl,

(S)-2,2'-bis(di-p-tolylphosphino)-6,6'-dimethoxy-1,1'-biphenyl,

(R)-2,2'-bis(di-6-methoxy-2-naphthalenylphosphino)-6,6'-dimethoxy-1,1'-biphenyl,

(S)-2,2'-bis(di-6-methoxy-2-naphthalenylphosphino)-6,6'-dimethoxy-1,1'-biphenyl,

(R)-2,2'-bis[bis(3,5-diisopropylphenyl)phosphino]-6,6'-dimethoxy-1,1'-biphenyl,

(S)-2,2'-bis[bis(3,5-diisopropylphenyl)phosphino]-6,6'-dimethoxy-1,1'-biphenyl,

1-dicyclohexylphosphino-1'-[(S) _P -[(S) _Fc -2-[(R) _C -1-(dimethylamino)ethyl]ferrocenyl]phenylphosphino]ferrocene,

1-dicyclohexylphosphino-1'-[(R) _P -[(R) _Fc -2-[(S) _C -1-(dimethylamino)ethyl]ferrocenyl]phenylphosphino]ferrocene.

Preferred chiral ligands are selected from

(R)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl,

(S)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl,

(R)-2,2'-bis(di-n-tolylphosphino)-1,1'-binaphthyl,

(S)-2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthyl,

(R)-2,2'-bis[di(3,5-xylyl)phosphino]-1,1'-binaphthyl,

(S)-2,2'-bis[di(3,5-xylyl)phosphino]-1,1'-binaphthyl,

(R)-5,5'-bis(diphenylphosphino)-4,4'-bi-1,3-benzodioxole,

(S)-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,

(S)-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)-5,5'-bis(di[3,5-di-tert-butyl-4-methoxyphenyl]phosphino)-4,4'-bi-1,3-benzodioxole,

(R)-1,13-bis(diphenylphosphino)-7,8-dihydro-6H-dibenzo[f,h][1,5]dioxin,

(S)-1,13-bis(diphenylphosphino)-7,8-dihydro-6H-dibenzo[f,h][1,5]dioxin,

(R)-2,2',6,6'-tetramethoxy-4,4'-bis(diphenylphosphino)-3,3'-bipyridine,

(S)-2,2',6,6'-tetramethoxy-4,4'-bis(diphenylphosphino)-3,3'-bipyridine,

(R)-2,2',6,6'-tetramethoxy-4,4'-bis(di[3,5-xylyl]phosphino)-3,3'-bipyridine,

(S)-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,

(S)-2,2'-bis(diphenylphosphino)-6,6'-dimethoxy-1,1'-biphenyl,

(R)-bis(diphenylphosphino)-4,4',6,6'-tetramethoxy-1,1'-biphenyl,

(S)-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-benzodioxine,

(S)-6,6'-bis(diphenylphosphino)-2,2',3,3'-tetrahydro-5,5'-bi-1,4-benzodioxine,

(R)-(+)-2,2'-bis(diphenylphosphino)-5,5',6,6',7,7',8,8'-octahydro-1,1'-binaphthyl,

(S)-(-)-2,2'-bis(diphenylphosphino)-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)-5,5'-bis(diphenylphosphino)-2,2,2',2'-tetrafluoro-4,4'-bi-1,3-benzodioxole,

(R)-1-[(R)-1-[di(3,5-xylyl)phosphino]ethyl]-2-[2-[di(3,5-xylyl)phosphino]phenyl]ferrocene,

(S)-1-[(S)-1-[di(3,5-xylyl)phosphino]ethyl]-2-[2-[di(3,5-xylyl)phosphino]phenyl]ferrocene,

(R)-1-[(R)-1-[bis[3,5-bis(trifluoromethyl)phenyl]phosphino]ethyl]-2-[2-(diphenylphosphino)phenyl]ferrocene and

(S)-1-[(S)-1-[bis[3,5-bis(trifluoromethyl)phenyl]phosphino]ethyl]-2-[2-(diphenylphosphino)phenyl]ferrocene.

More preferably, the chiral ligand is selected from

(R)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl,

(R)-2,2'-bis(di-and-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]dioxine,

(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-benzodioxine,

(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-[(5)-1-[bis[3,5-bis(trifluoromethyl)phenyl]phosphino]ethyl]-2-[2-(diphenylphosphino)phenyl]ferrocene.

Even more preferably, the chiral ligand is (R)-2,2'-bis[di(3,5-xylyl)phosphino]-1,1'-binaphthyl.

The transition metal catalyst may consist of a pre-formed complex. Such pre-formed complexes can typically be formed by reacting a chiral ligand with a suitable transition metal-containing precursor compound.

The complexes thus obtained can then be used as a catalyst for process (c) according to Scheme 1. The transition metal-containing precursor compounds contain at least transition metals selected from Ru, Rh, Ir and Pd and typically contain ligands that are easily displaced by a chiral ligand, or they may contain a ligand that is easily removed by hydrogenation. Preferred transition metal catalysts are Ru-based complexes.

Suitable transition metal containing precursor compounds include, without limitation, RuCl ₃ , RuCl ₃ ⋅nH ₂ O, [RuCl ₂ (η ₆ -benzene)] ₂ , [RuCl ₂ (η ₆ -cymene)] ₂ , [RuCl ₂ (η ₆ -mesitylene)] ₂ , [RuCl ₂ (η ₆ -hexamethylbenzene)] ₂ , [RuCl ₂ (η ₆ -benzene)] ₂ , [Rul ₂ (η ₆ -benzene)] ₂ , trans-RuCl ₂ (DMSO) ₄ , RuCl2(PPh ₃ ) ₃ , RuCl ₂ (COD) (in which

COB=1,5-cyclooctadiene), Ru(COD)(methylallyl) ₂ , Ru(COD)(trifluoroacetate) ₂ , [Ir(COD)Cl] ₂ ,

Rh(COD)Cl, Rh(COD) ₂ BF ₄ , Rh(COD) ₂ (OTf) ₂ , Ru(COD)(OAc) ₂ . Preferred transition metal containing precursor compounds are selected from [RuCl ₂ (η ₆ -benzene)] ₂ , [RuCl ₂ (η ₆ -cymol)] ₂ , RuCl ₂ (COD), Ru(COD)(methylallyl) ₂ and Ru( COD)(trifluoroacetate) ₂ .

Examples of preformed Ru-based catalyst complexes include, but are not limited to, [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], RuCl ₂ [(S)-xylbinap] [(S,S-dpen]. Preferred Ru-based preformed catalyst complexes are selected from RuCl(p-cymene)((R)-xylbinap)]Cl, [NH ₂ Me ₂ ][(RuCl((R)-xylbinap)) ₂ (u-Cl) ₃ ], Ru(OAc) ₂ [(R)-xylbinap], [NH ₂ Me ₂ ][(RuCl(( R)-H8-binap)) ₂ (u-Cl) ₃ ], [RuCl(p-cymene)((R)-H8-binap)]Cl, Ru(OAc) ₂ [(R)-H8-binap] , [NH ₂ Me ₂ ][(RuCl((R)-H8-xylbinap)) ₂ (u-Cl) ₃ ], [RuCl(p-cymol)((R)-H8-xylbinap)]Cl, Ru( OAc) ₂ [(R)-H8-xylbinap], [NH ₂ Me ₂ ][(RuCl((S)-1-[(S)-1-[bis[3,5-bis(trifluoromethyl)phenyl]phosphino ]ethyl]-2-[2-(diphenylphosphino)phenyl]ferrocene)) ₂ (u-Cl) ₃ ], [RuCl(p-cymol)((S)-1-[(S)-1-[bis [ 3,5-bis(trifluoromethyl)phenyl]phosphino]ethyl]-2-[2-(diphenylphosphino)phenyl]ferrocene)]Cl and (S)-1-[(S)-1-[bis[3,5- bis(trifluoromethyl)phenyl]phosphino]ethyl]-2-[2-(diphenylphosphino)phenyl]ferrocene]. More preferably, Ru-based preformed catalyst complexes are selected from [NH ₂ Me ₂ ][(RuCl((R)-xylbinap)) ₂ (u-Cl) ₃ ] and Ru(OAc) ₂ [(R)-xylbinap].

As stated above, method (c) in Scheme 1 also requires the presence of an ammonium salt. Ammonium salts can be formed in situ by adding ammonia and a suitable acid. In particular, the acids are selected from compounds of the formula

where R ^5a is selected from C ₁ -C ₆ alkyl, -(C ₀ -C ₃ alkyl) -C ₃ -C ₆ cycloalkyl, -(C ₀ -C ₃ alkyl) -C ₃ -C ₆ heterocycloalkyl, -(C ₀ -C ₃ alkyl)-NR ^5a1 R ^5a2 , -(C ₀ -C ₃ alkyl)aryl and -(C ₀ -C ₃ alkyl)heteroaryl, where C ₁ -C ₆ alkyl, -(C ₀ -C ₃ alkyl) -C ₃ -C ₆ cycloalkyl, -(C ₀ -C ₃ alkyl) -C ₃ -C ₆ heterocycloalkyl, -(C ₀ -C ₃ alkyl) aryl and - (C ₀ -C ₃ alkyl) heteroaryl are unsubstituted or substituted one or more substituents independently selected from halogen, OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, and C ₁ -C ₆ haloalkoxy; R ^5a1 and R ^5a2 are independently selected from hydrogen and C ₁ -C ₆ alkyl;

R ^5b and R ^5c' are selected from hydrogen, C ₁ -C ₆ alkyl, -(C ₀ -C ₃ alkyl) -C ₃ -C ₆ cycloalkyl, -(C ₀ -C ₃ alkyl) -C (=O) OH , -(C ₀ -C ₃ alkyl)aryl and -(C ₁ -C ₃ alkyl)heteroaryl, where C ₁ -C ₆ alkyl, -(C ₀ -C ₃ alkyl) -C ₃ -C ₆ cycloalkyl, -( C ₀ -C ₃ alkyl)aryl and -(C ₀ -C ₃ alkyl)heteroaryl are unsubstituted or substituted with one or more substituents independently selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ - C ₆ alkoxy and C ₁ -C ₆ haloalkoxy;

R ^5c , R ^6b and R ^6c are selected from hydrogen, halogen, C ₁ -C ₆ alkyl, -(C ₀ -C ₃ alkyl) -C ₃ -C ₆ cycloalkyl, -(C ₀ -C ₃ alkyl)aryl and - (C ₃ -C ₃ alkyl)heteroaryl, where C ₁ -C ₆ alkyl, -(C ₀ -C ₃ alkyl) -C ₃ -C ₆ cycloalkyl, -(C ₀ -C ₃ alkyl) aryl and -(C ₀ -C ₃ alkyl)heteroaryl are unsubstituted or substituted with one or two substituents independently selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy and C ₁ -C ₆ haloalkoxy.

In particular, the acids are selected from compounds of the formula

where R ^5a is selected from C ₁ -C ₆ alkyl, -(C ₀ -C ₃ alkyl) -C ₃ -C ₆ cycloalkyl, -(C ₀ -C ₃ alkyl) -C ₃ -C ₆ heterocycloalkyl, -(C ₀ -C ₃ alkyl) aryl and - (C ₀ -C ₃ alkyl) heteroaryl, where C ₁ -C ₆ alkyl, - (C ₀ -C ₃ alkyl) -C ₃ -C ₆ cycloalkyl, - (C ₀ -C ₃ alkyl)-C ₃ -C ₆ heterocycloalkyl, -(C ₀ -C ₃ alkyl)aryl and -(C ₀ -C ₃ alkyl)heteroaryl are unsubstituted or substituted with one or more substituents independently selected from halogen, OH, C ₁ - C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy and C ₁ -C ₆ haloalkoxy;

R ^5b is selected from C ₁ -C ₆ alkyl, -(C ₀ -C ₃ alkyl) -C ₃ -C ₆ cycloalkyl, -(C ₀ -C ₃ alkyl)aryl and -(C ₀ -C ₃ alkyl)heteroaryl, where C ₁ -C ₆ alkyl, -(C ₀ -C ₃ alkyl) -C ₃ -C ₆ cycloalkyl, -(C ₀ -C ₃ alkyl) aryl and -(C ₀ -C ₃ alkyl) heteroaryl are unsubstituted or substituted one or more substituents independently selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy and C ₁ -C ₆ haloalkoxy;

R ^6b is selected from hydrogen, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, aryl and heteroaryl, where C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, aryl and heteroaryl are unsubstituted or substituted with one or two substituents independently selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy and C ₁ -C ₆ haloalkoxy.

More specifically, the acids are selected from acetic acid, methoxyacetic acid, 2-methoxypropionic acid, tetrahydrofuran-2-carboxylic acid, o-methoxybenzoic acid, p-methoxybenzoic acid, phenoxyacetic acid, 2-furancarboxylic acid, p-chlorophenoxyacetic acid, salicylic acid, 4-tert-butylphenoxyacetic acid, acetic acid and chloroacetic acid, even more specifically phenoxyacetic acid.

It is also possible to add ammonium salts in the preformed state to the reaction mixture. In particular, the ammonium salts are selected from ammonium acetate, ammonium 2-methoxypropionate, ammonium tetrahydrofuran-2-carboxylag, ammonium o-methoxybenzoate, ammonium p-methoxybenzoate, ammonium chloroacetate, ammonium methoxyacetate, ammonium phenoxyacetate, ammonium p-chlorophenoxyacetate, 4-tert- b utilfe no x and ammonium acetate a, ammonium furan-2-carboxylate and ammonium salicylate, more particularly ammonium phenoxyacetate.

The person skilled in the art will understand that the method (c) in accordance with scheme 1 is carried out in a suitable solvent. A suitable solvent may be selected from the following classes of solvents: alcohols, ethers, esters, chlorinated or non-chlorinated hydrocarbons, and aromatics. Suitable solvents include, without limitation, methanol, ethanol, 2,2,2-trifluoroethan-1-ol, dichloromethane, and toluene. Preferred solvents are alcohols, in particular methanol.

Method (c) according to Scheme 1 is carried out in the presence of hydrogen gas (H ₂ ). The pressure of the hydrogen gas in the reaction vessel may be 1 to 500 bar, in particular 1 to 250 bar, more in particular 1 to 50 bar, even more in particular 5 to 30 bar.

Generally, the reaction temperature (c) according to Scheme 1 is 0 to 150°C, preferably 30 to 120°C, more preferably 50 to 100°C, even more preferably 70 to 90°C.

Additives may also be added to process (c) according to Scheme 1. Suitable additives may be selected from ammonium salts, ammonia, acids, drying agents such as molecular sieves and magnesium sulfate, iodine and alcohols. Examples of additives that can be added include, without limitation, chloroacetic acid, trifluoroacetic acid, methoxyacetic acid, salicylic acid, phenoxyacetic acid, furan-2-carboxylic acid, 2-methoxybenzoic acid, N-methylglycine, acetic acid, ammonium bromide, ammonium chloride, iodine, 2,2,2-trifluoroethanol, magnesium sulfate, molecular sieve materials. Preferred additives are ammonium salts or acids, for example ammonium halides such as NH ₄ Cl, or carboxylic acids such as phenoxyacetic acid.

One skilled in the art will appreciate that the pH of the reaction mixture can affect the outcome of the reaction. Typically, the pH of the reaction mixture is 2 to 7, preferably 4 to 7, and even more preferably 6 to 7.

Preferred process parameters for reaction (c) according to Scheme 1 are as follows.

The transition metal catalyst is added to the reaction mixture in an amount of 0.0001 to 0.1 mol equivalent relative to the compound of formula (III). In particular, 0.0005 to 0.01 mol equivalents are added relative to the compound of formula (III).

Transition metal catalysts may be preformed or may be formed in situ by adding chiral ligands and transition metal containing precursors to the reaction mixture. The person skilled in the art is well aware of the in situ formation of transition metal catalysts, such as those disclosed in EP 1 153 908 A2.

The reaction mixture is preferably charged with (i) 1-10 mole equivalents of the preformed ammonium salt relative to the compound of formula (III) or (ii) 1-10 mole equivalents of ammonia with respect to the compound of formula (III) and the corresponding acid are charged to form the ammonium salt in situ.

The concentration of the compound of formula (III) is preferably 1-30% by weight of the reaction mixture.

Optionally, 0.01-2 mol equivalents of one or more additives relative to the compound of formula (III) are added to the reaction mixture.

Preferably, in process (c), cis stereoisomers of the compound of formula (IV) are provided with e. And. 50% or more, preferably 75% or more, more preferably 80% or more. More preferably, the cis stereoisomers of the compounds of formula (IV) are provided in process (c) with e. And. (S,S) 50% or more, preferably 75% or more, more preferably 80% or more.

It should be understood that any of the preferred features for method (c) may be combined with one or more other preferred features of method (c).

In a fourth aspect of the present invention, there is provided a process (d) for preparing a compound of formula (V), which comprises reacting a compound of formula (III) with acetonitrile in the presence of a Lewis acid or Bronsted acid and a suitable additive, and wherein A is defined above for Scheme 1.

Method (d) according to Scheme 1 is carried out either in acetonitrile or in a suitable solvent. A suitable solvent may be selected from the following classes of solvents: chlorinated hydrocarbons or aromatics. Suitable solvents include, without limitation, dichloromethane, chlorobenzene or dichlorobenzene. Preferred solvents are chlorinated aromatics, in particular 1,2-dichlorobenzene.

Suitable Lewis or Bronsted acids include, but are not limited to, AlCl ₃ , GaCl ₃ , FeCl ₃ , BF ₃ ⋅Et ₂ O, HBF ₃ ⋅Et ₂ O, triflatic acid, nonaflatic acid (perfluorobutanesulfonic acid), MeSO ₃ H, and Eaton's reagent (7 .7 wt% phosphorus pentoxide in methanesulfonic acid).

Suitable additives may be acid chlorides, anhydrides or esters. Examples of additives that can be added include, without limitation, acetyl chloride, isopropenyl acetate, 4-methoxybenzoyl chloride, and p-anisic anhydride.

Preferred reaction parameters for method (d) according to Scheme 1 are as follows.

For reaction (d), the preferred temperature is from 0°C to 100°C, more preferably from 20°C to 80°C, even more preferably about 50°C.

Preferably, 1.0 to 2.5 mol equivalents of a Lewis acid or a Bronsted acid, relative to the compound of formula (III), are charged to the reaction mixture.

Preferably, 1-10 mole equivalents of acetonitrile relative to the compound of formula (III) are charged to the reaction mixture.

Preferably, 0.25-2.0 mol equivalents of the additive relative to the compound of formula (III) are charged to the reaction mixture.

The concentration of the compound of formula (III) is preferably 1-30% by weight of the reaction mixture.

It should be understood that any of the preferred features for method (d) may be combined with one or more other preferred features of method (d).

In the fifth aspect of the present invention, the compound of formula (V) can be obtained using method (d'), which is a combination of methods (b) and (d), with the difference that the compound (III) is not isolated, but directly converted to the compound ( V). The conversion of compound (II) to compound (III) is achieved in the presence of a Lewis acid, as described in the second aspect of the present invention. Sequential conversion of compound (III) to compound (V) is achieved by adding acetonitrile and the additive described in the fourth aspect of the present invention. Preferably, process (d') is carried out under inert conditions, such as under nitrogen gas, and in a suitable solvent.

A person skilled in the art will understand that methods (d) and (d') according to Scheme 1 are carried out in a suitable solvent. A suitable solvent may be selected from the following classes of solvents: chlorinated hydrocarbons or aromatics. Suitable solvents include, without limitation, dichloroethane, chlorobenzene or dichlorobenzene. Preferred solvents are chlorinated aromatics, in particular 1,2-dichlorobenzene.

Suitable catalyst/Lewis acid includes, without limitation, AlCl ₃ and GaCl ₃ , preferably AlCl ₃ .

Suitable additives may be acid chlorides, anhydrides or esters. Examples of additives that can be added include, without limitation, acetyl chloride, isopropenyl acetate, 4-methoxybenzoyl chloride, or p-anisic anhydride.

The preferred reaction parameters for the method (d') according to Scheme 1 correspond to the preferred reaction conditions already described for the conversion of compound (II) to compound (III) (step b) and the conversion of compound (III) to compound (V) (step d ) (second and fourth aspect of the present invention).

It should be understood that any of the preferred features for method (d') may be combined with one or more other preferred features of methods (d') and (d).

In a sixth aspect of the present invention, there is provided a process (e) for the preparation of a compound of formula (VI), which involves reacting a compound of formula (V) with H ₂ in the presence of a chiral or enantio-enriched catalyst in analogy to that disclosed in WO 2015/003951.

The chiral transition metal catalyst contains a transition metal selected from Ru and Rh and a chiral ligand.

Chiral ligands are known in the art and can be used in the present invention, examples are given in "Catalytic asymmetric synthesis", Iwao Ojima, third Edition, Wiley-VCH 2010, and references cited therein; typical classes that are known to those skilled in the art include, without limitation, TADDOL (α,α,α',α'-tetraaryl-2,2-disubstituted 1,3-dioxolane-4,5-dimethanol), DUPHOS (phospholane ligand ), BOX (bis(oxazoline) ligand), BIN AP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl), BINOL (1,1'-bi-2-naphthol), DIOP (2, 3-o-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane), WALPHOS, TANIAPHOS, MANDYPHOS, CHENPHOS, JOSIPHOS, BIPHEMP, MeO-BIPHEP, SEGPHOS, CHIRAPHOS, PPHOS, QUINOX-P, NORPHOS , TUNEPHOS and SYNPHOS.

Preferably, the chiral ligand is a bidentate phosphorus containing ligand of general formula (IX):

where X is a linker group, and R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are independently selected from aryl, heteroaryl, C ₁ -C ₆ alkt and C ₁ -C ₆ cycloalkyl, each of which is unsubstituted or substituted. Preferably the linker group X is selected from (R or S)-1,1'-binaphthyl, (R or S)-4,4'-bi-1,3-benzodioxole, (R or S)-2,2',6 ,6'-tetramethoxy-3,3'-bipyridine, (R or S)-6,6'-dimethoxy-1,1'-biphenyl, (R or S)-4,4',6,6' tetramethoxy- 1,1'-biphenyl, 2,2'-bis-[(R or S)-cx-(dimethylamino)benzyl]ferrocene, ferrocenylmethyl, ferrocene, benzene and ethyl. More preferably, the bidentate ligand of formula (IX) is selected from the ligand classes B IN AP, MANDYPHOS, JOSIPHOS, MeO-BIPHEP, TANIAPHOS, CHENPHOS, QUINOX-P and DUPHOS.

Suitable chiral ligands in accordance with the present invention include, without limitation

(R)-1-[(S)-2-(di-tert-butylphosphino)ferrocenyl]ethyl-di-o-tolylphosphine,

(R,R)Fc-1,1'-bis[bis(4-methoxy-3,5-dimethylphenyl)phosphino]-2,2'-bis[(S,S) _C -(N,N-dimethylamino) phenylmethyl]ferrocene,

(R)-1-[(S)-2-cyclohexylphosphino)ferrocenyl]ethyl-bis(2-methylphenyl)-phosphine,

(S)-1-diphenylphosphino-2-[(S)-(N,N-dimethylamino)-[2-(diphenylphosphino)phenyl]methyl]ferrocene,

(R,R)-(-)-2,3-bis(tert-butylmethylphosphino)quinoxaline,

(2S,3S)-(-)-2,3-bis(diphenylphosphino)bicyclo[2.2.1]hept-5-ene,

(S)-2,2'-bis(diisopropylphosphino)-6,6'-dimethoxy-1,1'-biphenyl,

(2S,4S)-(-)-2,4-bis(diphenylphosphino)pentane,

1,1'-bis[(R) _P -[(R) _Fc -2-[(,S0c-l-(dimethylamino)ethyl]ferrocenyl]phenylphosphino]ferrocene,

1-dicyclohexylphosphino-1'-(S)P-[(S)Fc-2-[(R)C-1-(dimethylamino)ethyl]ferrocenyl]phenylphosphino]ferrocene,

(R)-1-[(S)-2-(diphenylphosphino)ferrocenyl]ethyl-di(3,5-xylyl)phosphine,

(R)Fc-1-[(S)P-tert-butylphosphinoyl]-2-[(S)-1-(diphenylphosphino)ethyl]ferrocene,

(S)-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethyl-di-tert-butylphosphine,

adduct of ethanol and (S)-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethyl-dicyclohexylphosphine,

(R)-2,2'-bis(diphenylphosphino)-6,6'-dimethoxy-1,1'-biphenyl,

(R)-(+)-1,2-bis(diphenylphosphino)propane,

(R)-1-[(S)-2-[di(1-naphthyl)phosphino]ferrocenyl]ethyl-di-tert-butylphosphine,

(S)-1-[(R)-2-[di(2-furyl)phosphino]ferrocenyl]ethyl-di-tert-butylphosphine,

(R)-1-[(S)-2-(di-tert-butylphosphino)ferrocenyl]ethyldiphenylphosphine,

(S)-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethyl-di-tert-butylphosphine,

(R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyl-dicyclohexylphosphine,

(S)-1-[(R)-2-[bis(4-methoxy-3,5-dimethylphenyl)phosphino]ferrocenyl]ethyl-dicyclohexylphosphine,

(S)-1-[(R)-2-[bis(4-methoxy-3,5-dimethylphenyl)phosphino]ferrocenyl]ethyl-di-tert-butylphosphine,

(S)-(+)-2,2'-bis[di(3,5-xylyl)phosphino]-1,1'-binaphthyl,

(S)-2,2'-bis[di-3,5-xylylphosphino]-6,6'-dimethoxy-1,1'-biphenyl,

(-)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene,

(S,S)Fc-1,1'-bis[bis(4-methoxy-3,5-dimethylphenyl)phosphino]-2,2'-bis[(R,R)C-(N,N-dimethylamino) phenylmethyl]ferrocene,

(R)-1-diphenylphosphino-2-[(R)-(N,N-dimethylamino)-[2-(diphenylphosphino)phenyl]methyl]ferrocene,

(R)-2,2'-bis[bis(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-6,6'-dimethoxy-1,1'-biphenyl,

(S)-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethyl-di(3,5-xylyl)phosphine,

(S,S)-(-)-2,3-bis(tert-butylmethylphosphino)quinoxaline,

(2S,3S)-(+)-2,3-bis(diphenylphosphino)butane,

(S)-2,2'-bis(diphenylphosphino)-6,6'-dimethoxy-1,1'-biphenyl,

(S)-(+)-1,2-bis(diphenylphosphino)propane,

(S,S)-(+)-1,2-bis(tert-butylmethylphosphino)benzene,

(-)-1,2-bis[(2S,5S)-2,5-dimethylphospholano]benzene,

(+)-1,2-bis[(2S,5S)-2,5-diethylphospholano]benzene,

(-)-1,2-bis((2R,5R)-2,5-diethylphospholano)ethane.

Preferred chiral ligands in combination with Rh are selected from

(R)-1-[(S)-2-(di-tert-butylphosphino)ferrocenyl]ethyl-di-o-tolylphosphine,

(R)-1-[(S)-2-cyclohexylphosphino)ferrocenyl]ethyl-bis(2-methylphenyl)phosphine

And

(R)-1-[(S)-2-(di-tert-butylphosphino)ferrocenyl]ethyldiphenylphosphine.

Preferred chiral ligands in combination with Ru are selected from

(S)-(+)-2,2'-bis[di(3,5-xylyl)phosphino]-1,1'-binaphthyl,

(-)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene,

(S,S)-(-)-2,3-bis(tert-butylmethylphosphino)quinoxaline,

(S,S)-(+)-1,2-bis(tert-butylmethylphosphino)benzene,

(-)-1,2-bis[(2S,5S)-2,5-dimethylphospholano]benzene,

(+)-1,2-bis [(2S,5S)-2,5-diethylphospholano] benzene,

(S)-1-[(R)-2-[bis(4-methoxy-3,5-dimethylphenyl)phosphino]ferrocenyl]ethyl-di-tert-butylphosphine and

(S)-1-[(R)-2-[bis(4-methoxy-3,5-dimethylphenyl)phosphino]ferrocenyl]ethyl-dicyclohexylphosphine.

The transition metal catalyst may consist of a pre-formed complex. Such pre-formed complexes can typically be formed by reacting a chiral ligand with a suitable transition metal-containing precursor compound. The complexes thus obtained can then be used as a catalyst for method (e) according to Scheme 1. The transition metal-containing precursor compounds contain at least the transition metals Ru and Rh and generally contain ligands which are easily displaced by a chiral ligand, or they may contain a ligand that is easily removed by hydrogenation.

Suitable transition metal containing precursor compounds include, without limitation, [Rh(COD) ₂ ]O ₃ SCF ₃ , [Rh(COD) ₂ ]BF ₄ , [Rh(COD) ₂ ]BARF (in which BARF = tetrakis[3.5 -bis(trifluoromethyl)phenyl]borate), [Rh(nbd) ₂ ]BF ₄ (in which nbd = norbornadiene), bis(2-metallyl)(COD)ruthenium, bis(COB)tetra[μ-trifluoroacetate]diruthenium( II) hydrate and [Ru(COD)(2-metallyl) ₂ ].

Examples of preformed Rh-based catalyst complexes include, but are not limited to

[Rh(COD)((R)-1-[(S)-2-(di-tert-butylphosphino)ferrocenyl]ethyl-di-o-tolylphosphine)]BF ₄ ,

[Rh(COD)((R)-1-[(S)-2-cyclohexylphosphino)ferrocenyl]ethyl-bis(2-methylphenyl)phosphine]BF ₄ ,

[Rh(COD)((R)-1-[(S)-2-(di-tert-butylphosphino)ferrocenyl]ethyldiphenylphosphine)]BF ₄ ,

[Rh(COD)((R)-1-[(5)-2-(di-tert-butylphosphino)ferrocenyl]ethyl-di-o-tolylphosphine)]O ₃ SCF ₃ ,

[Rh(COD)((R)-1-[(S)-2-cyclohexylphosphino)ferrocenyl]ethyl-bis(2-methylphenyl)phosphine)]O ₃ SCF ₃ and

[Rh(COD)((R)-1-[(S)-2-(di-tert-butylphosphino)ferrocenyl]ethyldiphenylphosphine)]O ₃ SCF ₃ .

Preferred reaction parameters for method (e) according to Scheme 1 are as follows.

A person skilled in the art will understand that the method (e) in accordance with scheme 1 is carried out in a suitable solvent. A suitable solvent may be selected from the following classes of solvents: alcohols, ethers, esters, chlorinated or non-chlorinated hydrocarbons, or aromatics. Preferred solvents are selected from methanol, isopropanol and 2,2,2-trifluoroethan-1-ol when a Rh-based catalyst is used. Preferred solvents are alcohols, in particular trifluoroethanol and isopropanol. Preferred solvents are selected from alcohols, in particular isopropanol, if a Ru-based catalyst is used.

The method (e) in accordance with scheme 1 is carried out in the presence of gaseous hydrogen (H ₂ ). The pressure of the hydrogen gas in the reaction vessel may be from 1 to 500 bar, in particular from 1 to 250 bar, more in particular from 1 to 50 bar, even more in particular from 10 to 50 bar.

Typically, the temperature in the method (e) according to scheme 1 is from 0 to 150°C, preferably from 30 to 120°C, more preferably from 20 to 100°C, even more preferably from 25 to 60°C.

The amount of catalyst that is added is from 0.0001 to 0.1 mol equivalent of the transition metal catalyst relative to the compound of formula (V). In particular, 0.0001 to 0.005 mol equivalent of transition metal catalyst is added relative to the compound of formula (V). Transition metal catalysts may be preformed or may be formed in situ by adding chiral ligands and transition metal containing precursors to the reaction mixture.

The concentration of the compound of formula (V) is preferably 1-30% by weight of the reaction mixture.

This method (e) provides enantiomerically and diastereomerically enriched amides of formula (VI) with e. And. (enantiomeric excess) 75% or more, preferably 80% or more. Preferably, in process (e), the cis enantiomers of the compounds of formula (IV) are provided with e. And. 75% or more, more preferably 80% or more.

It should be understood that any of the preferred features for method (e) may be combined with one or more other preferred features of method (e).

In a seventh aspect of the present invention, a process (f) for preparing a compound of formula (IV) is provided, which comprises reacting a compound of formula (VI) under acidic or basic conditions, preferably under acidic conditions.

Suitable acids include, without limitation, HCl, H ₂ SO ₄ , H ₃ PO ₄ , methanesulfonic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid.

The person skilled in the art will understand that the method (f) in accordance with scheme 1 is carried out in a suitable solvent. A suitable solvent may be selected from the following classes of solvents: water, alcohols, ethers, esters, chlorinated or non-chlorinated hydrocarbons, or aromatics. Suitable solvents include, without limitation, water and toluene. The preferred solvent is water.

Typical reaction parameters for method (f) according to Scheme 1 are as follows.

Preferred conditions for deacetylation are from 0° C. to 200° C., more specifically from 100° C. to 180° C., in particular at the reflux temperature for the respective system.

Acid. It was confirmed that the use of 1.0-7.0 mol equivalents relative to the compound of formula (VI) is favorable.

reaction volume. Typical conditions are such that the concentration of the compound of formula (VI) is 1-30% by weight of the reaction mixture.

It should be understood that any of the preferred features for method (f) may be combined with one or more other preferred features of method (f).

In an eighth aspect of the present invention, a process (g) for preparing a compound of formula (VII) is provided, comprising reacting a compound of formula (IV) with a compound of formula (X),

where Y is a suitable leaving group such as OH, OR or halogen, preferably chlorine, R is C ₁ -C ₆ alkyl, and A and E are as previously defined for Scheme 1.

The reaction of a compound of formula (IV) with a compound of formula (X) is carried out under typical conditions for the formation of an amide bond, which are known to the person skilled in the art. For example, reaction (g) involves the addition of a suitable base. Suitable bases include, without limitation, Et ₃ N, NaHCO ₃ and NaOH.

One skilled in the art will appreciate that reaction (g) according to Scheme 1 is carried out in a suitable solvent. A suitable solvent may be selected from the following classes of solvents: ethers, esters, chlorinated or non-chlorinated hydrocarbons, or aromatics. Suitable solvents include, without limitation, toluene, xylene, THF, MeTHF (methyltetrahydrofuran) and acetonitrile.

Preferred reaction parameters for method (g) according to Scheme 1 are as follows.

Reaction (g) is preferably carried out at a temperature of 0°C to 200°C, more preferably 100°C to 180°C, even more preferably 40 to 60°C.

Preferably, 1.0 to 3.0 mole equivalents of a base are added relative to the compound of formula (IV).

Preferably, 0-20 mol equivalents of water relative to the compound of formula (IV) are added to the reaction mixture.

The concentration of the compound of formula (IV) is preferably 1-30% by weight of the reaction mixture.

It should be understood that any of the preferred features for method (g) may be combined with one or more other preferred features for method (g).

Definitions

The term "alkyl" as used herein alone or as part of a chemical group is straight or branched chain hydrocarbons, preferably with 1-6 carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , sec-butyl, tert-butyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl , 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,2-dimethylpropyl, 1,3-dimethylbutyl, 1,4-dimethylbutyl, 2,3-dimethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3 ,3-dimethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethylbutyl and 2-ethylbutyl. Preferred are alkyl groups with 1-4 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl. The term "alkenyl", alone or as part of a chemical group, is straight or branched chain hydrocarbons, preferably with 2-6 carbon atoms and at least one double bond, e.g. vinyl, 2-propenyl, 2-butenyl, 3- butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl- 2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl, 1- ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl- 2-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4- pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-2- butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2- ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl and 1-ethyl-2-methyl-2-propenyl. Alkenyl groups with 2-4 carbon atoms are preferred, for example 2-propenyl, 2-butenyl or 1-methyl-2-propenyl.

The term "alkynyl", alone or as part of a chemical group, is straight or branched chain hydrocarbons, preferably with 2-6 carbon atoms and at least one triple bond, e.g. 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-methyl-2-butynyl, 1,1-dimethyl- 2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4- pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 4-methyl-2-pentynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl- 3-butynyl, 2,2-dimethyl-3-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl, 1-ethyl-1-methyl-2-propynyl and 2,5-hexadiynyl. C 2 -C 4 alkynyls are preferred, for example ethynyl, 2-propynyl or 2-butynyl-2-propenyl.

The term "cycloalkyl", alone or as part of a chemical group, is saturated or partially unsaturated mono-, bi- or tricyclic hydrocarbons, preferably with 3-10 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1]heptyl, bicyclo[2.2.2]octyl or adamantyl.

The term "heterocyclyl", alone or as part of a chemical group, is a saturated or partially unsaturated mono-, bi- or tricyclic hydrocarbon, preferably with 3-10 carbon atoms, in which at least one carbon atom is replaced by a heteroatom selected from O , N and S, for example, tetrahydrofuran, pyrrolidine, tetrahydrothiophene.

The term "aryl" is a mono-, bi- or polycyclic aromatic system with preferably 6-14, more preferably 6-10 ring carbon atoms, eg phenyl, naphthyl, anthryl, phenanthrenyl, preferably phenyl. "Aryl" also represents polycyclic systems, eg tetrahydronaphthyl, indenyl, indanyl, fluorenyl, biphenyl. Arylalkyls are examples of substituted aryls which may be further substituted with the same or different substituents on both the aryl and alkyl portions. Benzyl and 1-phenylethyl are examples of such arylalkyls.

The term "heteroaryl" represents heteroaromatic groups, namely fully unsaturated aromatic heterocyclic groups, which fall under the above definition of heterocycles. "Heteroaryls" with 5-7 membered rings with 1-3, preferably 1-2 identical or different hetero atoms selected from N, O and S. Examples of "heteroaryls" are furyl, thienyl, pyrazolyl, imidazolyl, 1,2 ,3- and 1,2,4-triazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-, 1,3,4-, 1,2,4- and 1,2,5-oxadiazolyl, azepinyl, pyrrolyl , pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-, 1,2,4- and 1,2,3-triazinyl, 1,2,4-, 1,3,2-, 1,3,6 - and 1,2,6-oxazinyl, oxepinyl, thiepinyl, 1,2,4-triazolonyl and 1,2,4-diazepinyl.

The term "halogen" or "halo" represents fluorine, chlorine, bromine or iodine, in particular fluorine, chlorine or bromine. Chemical groups which are substituted with halogen, for example haloalkyl, halocycloalkyl, haloalkyloxy, haloalkylsulfanyl, haloalkylsulfinyl or haloalkylsulfonyl, are substituted with halogen from one to the maximum number of substituents. When "alkyl", "alkenyl", or "alkynyl" are substituted with halogen, the halogen atoms may be the same or different and may be attached to the same carbon atom or different carbon atoms.

The term "enantiomerically enriched" means that one of the enantiomers of a compound is present in excess of the other enantiomer. This excess will be referred to hereinafter as the enantiomeric excess or e. And. E. i. can be determined using chiral GC or HPLC analysis. E. i. equals the difference between the number of enantiomers divided by the sum of the numbers of enantiomers, the coefficient of which can be expressed as a percentage after multiplying by 100.

experimental part

Examples

The following examples are intended to illustrate the present invention and should not be construed as limiting it.

Equipment

HPLC methods

Method 1

Device for HPLC: Thermo Electron Corporation; SpectraSystem P200, SpectraSystem ASlOOO and SpectraSystem UV1000.

Column: CHIRALPAK IA-3, 3 µm, 4.6 mm × 100 mm.

Temperature: room temperature (r.t.)

Mobile phase: EtOH+0.1% diethylamine/MeOH+0.1% diethylamine (50/50).

Flow rate: 1.0 ml/min.

Gradient: isocratic.

Detection: 223 nm.

Sample size: 10 µl.

Rt (retention time) (1S,2S)-2-(2,4-dichlorophenyl)cyclobutanamine: 4.8 min.

Rt of (1R,2R)-2-(2,4-dichlorophenyl)cyclobutanamine: 3.0 min.

Method 2

Device for HPLC: Agilent Technologies 1260 Infinity.

Column: Agilent XDB-C18, 1.8 µm, 4.6 x 50 mm.

Temperature: k.t.

Mobile phase: A: Acetonitrile; B: MeOH; C: H ₂ O+0.1% H ₃ PO ₄ .

Flow rate: 1.5 ml/min.

Gradient:

Detection: 220 nm.

Sample size: 1 µl.

Rt of the cis isomer of 2-(2,4-dichlorophenyl)cyclobutanamine: 2.8 min.

Method 3

HPLC device: Agilent Technologies 1200 Series.

Column: Phenomenex Kinetex XB C18, 2.6 µm, 4.6 × 150 mm

Temperature: 40°C.

Mobile phase: A: H ₂ O+0.1% (v/v) H ₃ PO ₄ ; B: Acetonitrile.

Flow rate: 1.0 ml/min.

Gradient:

Detection: 223 nm.

Sample size: 5 µl.

Rt cis isomers of N-[2-(2,4-dichlorophenyl)cyclobutyl]acetamide: 9.2 min.

Method 4

HPLC device: Agilent Technologies 1200 Series.

Column: CHIRALPAK IA-3, 3 µm, 4.6 mm × 100 mm.

Temperature: k.t.

Mobile phase: n-hexane/ethanol (98/2).

Flow rate: 1.0 ml/min.

Gradient: isocratic.

Detection: 223 nm.

Sample size: 5 µl.

Rt of N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]acetamide: 12.4

min. Rt of N-[(1R,2R)-2-(2,4-dichlorophenyl)cyclobutyl]acetamide: 15.6 min.

First aspect

Reaction (a1) according to Scheme 1

Example 1.1

1-(2,4-Dichlorophenyl)cyclopropanecarbonitrile (1.0 g, 4.61 mmol) and trifluoroacetic acid (6 mL) were added to a flame-dried 50 mL two-necked flask that was equipped with a vacuum pump, double pressure balloon and magnetic stirrer. . The reaction flask was evacuated and nitrogen was introduced into the vacuum twice. Then, 5% palladium on peat charcoal with 50% water (50 mg, 0.013 mmol) was added to the reaction flask and the flask was purged with nitrogen, after which a hydrogen balloon was attached. The reaction mixture was stirred at RT (room temperature) for 2-4 hours. Hydrogen was released and the reaction flask was purged with nitrogen when the conversion was >98%. The reaction mass was filtered under nitrogen atmosphere. The trifluoroacetic acid was distilled off under reduced pressure and the residue was diluted with MTBE and washed with water. The phases were separated and the lower aqueous phase was extracted twice with MTBE. The combined organic layers were washed with water and concentrated under reduced pressure to give 1-(2,4-dichlorophenyl)cyclopropanecarbaldehyde (1.1 g) as an oil.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.75 (s, 1 H), 7.60 (d, J=1.90 Hz, 1 H), 7.46-7.27 (m, 2 H), 1.80-1.61 (m, 2 H), 1.47-1.36 (m, 2 H).

Example 1.2

1-(2,4-Dichlorophenyl)cyclopropanecarbonitrile (9.49 g, 44.0 mmol), trifluoroacetic acid (70 g), water (4.7 g) and 5% palladium on carbon with 50% water (300 mg) were added. , 0.15 mol %) into a 100 ml reactor which was equipped with a vacuum pump, a nitrogen inlet and a valve connected to the hydrogen inlet. The reactor was evacuated and the vacuum was replaced with nitrogen three times. The same procedure was repeated with H ₂ and then the reaction mixture was stirred for 2 hours at 5° C. and an H ₂ pressure of 1.5 bar. After the conversion was complete, hydrogen was released and the flask was purged with nitrogen. The reaction mixture was filtered through a pad of celite (washed with TFA) and the filtrate was concentrated under reduced pressure, diluted with toluene and washed twice with water. The resulting organic layer was concentrated under reduced pressure to give 1-(2,4-dichlorophenyl)cyclopropanecarbaldehyde (4.2 g) as a clear brown oil.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.75 (s, 1 H), 7.60 (d, J=1.90 Hz, 1 H), 7.46-7.27 (m, 2 H), 1.80-1.61 (m, 2 H), 1.47-1.36 (m, 2 H).

Reaction (а2) in accordance with scheme 1

Example 2.1

1-(2,4-Dichlorophenyl)cyclopropanecarbonitrile (1.0 g, 4.64 mmol), acetic acid (17.5 ml) and water (5 ml) were added to a flame-dried 50 ml two-necked flask which was equipped with a vacuum pump, double pressure bottle and magnetic stirrer. The reaction flask was evacuated and nitrogen was introduced into the vacuum twice. Raney nickel (50% w/w concentration) was then added with 50% water (201 mg, 0.71 mmol) and the flask was purged with nitrogen, after which a hydrogen balloon was attached. The reaction mixture was stirred at RT for 6-10 hours. Hydrogen was released and the reaction flask was purged with nitrogen when the conversion was >98%. The reaction mass was filtered through a layer of celite in a nitrogen atmosphere. The filtrate was acidified with concentrated aqueous HCl to pH 1.0 and diluted with water and ethyl acetate. The organic layer was extracted with 15% sodium carbonate aqueous solution and then with water. The solvent was removed under reduced pressure to give 1-(2,4-dichlorophenyl)cyclopropanecarbaldehyde (0.81 g) as an oil.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.75 (s, 1 H), 7.60 (d, J=1.90 Hz, 1 H), 7.46-7.27 (m, 2 H), 1.80-1.61 (m, 2 H), 1.47-1.36 (m, 2 H).

Example 2.2

DCP-nitrile (9.50 g, 44.0 mmol), trifluoroacetic acid (70 g), water (7.0 g) and Raney nickel (520 mg, 20 mol %) were added to a 100 ml reactor which was equipped with connection to vacuum pump, nitrogen inlet and valve connected to H ₂ inlet. The reactor was evacuated and the vacuum was replaced with nitrogen three times. Then an H ₂ atmosphere with a partial pressure of 0.5 bar was applied and the reaction mixture was stirred at 20°C. After the conversion was complete, H ₂ was released and the flask was purged with nitrogen. The reaction mixture was filtered through a pad of celite (washed with TFA) and the filtrate was concentrated under reduced pressure, diluted with toluene and washed with water. The resulting organic layer was concentrated under reduced pressure to give DCP-aldehyde (7.4 g) as a yellowish oil.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.75 (s, 1 H), 7.60 (d, J=1.90 Hz, 1 H), 7.46-7.27 (m, 2 H), 1.80-1.61 (m, 2 H), 1.47-1.36 (m, 2 H).

Reaction (a3) according to Scheme 1

Example 3

A 1.2 M solution of DIBAL in toluene (75.2 g, 105 mmol) was added to a solution of 1-(2,4-dichlorophenyl)cyclopropanecarbonitrile (20 g, 91.5 mmol) in toluene (40 g) so that the temperature maintained in the range from -5°C to 0°C. After a stirring period of 30 minutes after the addition, 2 M HCl aqueous solution was added to the reaction mixture at -20°C. The reaction mixture was then allowed to reach rt. The reaction mixture was diluted with ethyl acetate and extracted with water. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were extracted with water and brine, dried over Na ₂ SO ₄ , filtered and the solvents were removed under reduced pressure. 1-(2,4-dichlorophenyl)cyclopropanecarbaldehyde (20.1 g) was isolated as a yellow oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.05 (s, 1H), 7.45 (m, 1H), 7.20 (m, 2H), 1.70 (m, 2H), 1.40 ( m, 2H).

Reaction (а4) in accordance with scheme 1

Example 4.1

A 60% solution of REDAL in toluene (87.6 g, 260 mmol) was dosed over 4 hours into a solution of 1-(2,4-dichlorophenyl)cyclopropanecarbonitrile (84.8 g, 400 mmol) in toluene (212 g) at a temperature 0°C. After a stirring period of 2 hours after addition at 0°C, the reaction mixture was dosed into a 50% aqueous solution of acetic acid (384 g, 3.2 mol) so as to keep the temperature of the reaction mixture below <25°C. A 32% aqueous HCl solution (137 g, 1.2 mol) was then dosed into the mixture. The phases were separated and the organic phase was extracted twice with water (75 g), after which the organic phase solvent was removed under reduced pressure. 1-(2,4-Dichlorophenyl)cyclopropanecarbaldehyde (81.0 g) was isolated as an orange oil.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.75 (s, 1 H), 7.60 (d, J=1.90 Hz, 1 H), 7.46-7.27 (m, 2 H), 1.80-1.61 (m, 2 H), 1.47-1.36 (m, 2 H).

Example 4.2

A 70% solution of REDAL in toluene (97.3 g, 0.34 mol) was dosed over 80 minutes into a solution of 1-(2,4-dichlorophenyl)cyclopropanecarbonitrile (120.0 g, 0.54 mmol) in toluene (182 g ) at a temperature of 20-25°C. After a stirring period of 1 hour after addition at 20-25°C, the reaction mixture was metered into a mixture consisting of 50% aqueous acetic acid (266.0 g, 2.19 mol) and 35% aqueous HCl (160.0 g, 1.54 mol), maintaining the temperature of the reaction mixture below 25°C. The phases were separated and the organic phase was extracted twice with water (60 g), after which the solvent was removed from the organic phase under reduced pressure. 1-(2,4-Dichlorophenyl)cyclopropanecarbaldehyde (118.4 g) was isolated as a dark orange oil.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.75 (s, 1 H), 7.60 (d, J=1.90 Hz, 1 H), 7.46-7.27 (m, 2 H), 1.80-1.61 (m, 2 H), 1.47-1.36 (m, 2 H).

Second aspect

Reaction (b) according to Scheme 1

Example 5.1

To a flame-dried 10 ml two-necked flask equipped with a thermometer and sparger containing 1-(2,4-dichlorophenyl)cyclopropanecarbaldehyde (1.4 g, 6.0 mmol) under argon was added chlorobenzene (6 ml) followed by the addition of anhydrous AlCl ₃ (1.2 g, 9.0 mmol). The resulting suspension was heated for 1 hour at 45°C.

After cooling to rt, the mixture was poured into cold 1N. HCl and diluted with ethyl acetate. The aqueous phase was extracted twice with dichloromethane. The combined organic phase was washed once with 1 u. HCl and once with brine, then dried with solid Na ₂ SO ₄ , filtered and concentrated in vacuo. 2-(2,4-dichlorophenyl)cyclobutanone (1.35 g) was isolated as a brown oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.40 (d, J=2.2 Hz, 1H), 7.30 (d, J=8.1 Hz, 1H), 7.21 (dd, J= 2.2 and 8.4 Hz, 1H), 4.76 (m, 1H), 3.25 (m, 1H), 3.10 (m, 1H), 2.63 (m, 1H), 2, 12(m, 1H).

Example 5.2

A solution of 1-(2,4-dichlorophenyl)cyclopropanecarbaldehyde (109.9 g, 0.5 mol) in 1,2-dichlorobenzene (64.8 g, 0.44 mol) was added over 90 minutes to a suspension of AlCl ₃ (87 .6 g, 0.65 mol) in 1,2-dichlorobenzene (100.0 g, 0.68 mol) at Ti=50-55°C; the suspension was purged with a light stream of nitrogen during dosing and agitation period after addition. Substantially complete conversion was achieved after a 1 hour stirring period after the addition at Ti=50-55°C. The reaction mixture was cooled to RT and then dosed into a 14% aqueous solution of HCl (352.7 g, 1.34 mol) so that Ti was maintained below 40°C. The mixture was stirred for 45 minutes, after which the phases were separated. The organic phase was then extracted twice with water (83.3 g, 4.6 mol and 80.0 g, 4.4 mol), after which the organic phase was concentrated under reduced pressure. 2-(2,4-Dichlorophenyl)cyclobutanone (110.6 g) was isolated as a brown oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.40 (d, J=2.2 Hz, 1H), 7.30 (d, J=8.1 Hz, 1H), 7.21 (dd, J= 2.2 and 8.4 Hz, 1H), 4.76 (m, 1H), 3.25 (m, 1H), 3.10 (m, 1H), 2.63 (m, 1H), 2, 12(m, 1H).

Examples 6-9

The following compounds were prepared in a manner analogous to Example 5.

Third aspect

Reaction (c) according to Scheme 1

Examples 10-18

The autoclave was loaded under pressure with 2-(2,4-dichlorophenyl)cyclobutanone (0.5 mmol), [RuCl(p-cymol)((S)-DM-SEGPHOS)]Cl (0.005 mmol), the corresponding ammonium salt (0 .5 mmol, see table 2) and MeOH (5 ml). A hydrogen atmosphere of 30 bar was applied and the reaction mixture was heated to 80°C. After a stirring period of 22 hours, the reaction mixture was cooled to rt and analyzed by chiral HPLC (method 1) and ¹ H NMR.

Examples 19-24

The autoclave was loaded under pressure with 2-(2,4-dichlorophenyl)cyclobutanone (0.5 mmol), [RuCl(p-cymol)((S)-DM-SEGPHOS)]Cl (0.005 mmol), the corresponding ammonium salt (0 .6 mmol, see table 3) and MeOH (2.5 ml). A hydrogen atmosphere of 30 bar was applied and the reaction mixture was heated to 80°C. The reaction mixture was cooled to RT after a stirring period of 18.5 hours and added H ₂ O (20 ml) and HCl (1 M, 2 ml). The mixture was extracted with MTBE (20 ml) and the organic layer was extracted with aqueous HCl (2 ml 1 M HCl and 20 ml H ₂ O). The aqueous phase was made basic with aqueous NaOH (5 M, 2 ml) and extracted with MTBE (3 x 20 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the solvent was removed under reduced pressure. The residue was analyzed by chiral HPLC (method 1) and ¹ H NMR.

Examples 25-26

Added 7 n. a solution of ammonia in MeOH (108 mmol) to a mixture of the corresponding acid (110 mmol) in MeOH (the same amount to give a 10% ammonium salt solution) at r.t. The mixture was stirred for approximately 10 minutes and was ready for use on direct asymmetric reductive amination steps.

Direct asymmetric reductive amination

[NH ₂ Me ₂ ][(RuCl((R)-xylbinap)) ₂ (μ-Cl) ₃ ] (0.135 mmol), the previously obtained 10% solution of the corresponding ammonium salt in MeOH (108 mmol, cm .table 4) and MeOH (44 g). The reaction mixture was heated to 80° C. and a 30 bar hydrogen atmosphere was applied. A solution of 2-(2,4-dichlorophenyl)cyclobutanone (624 mmol) in MeOH (20 g) was then added to the autoclave over 4 hours. The reaction mixture was cooled to RT after a 2 hour stirring period after the addition. The reaction mixture was then made basic and analyzed by chiral (method 1) and achiral (method 2) HPLC.

Examples 27-46

Various supplements were tested on the screening platform. The reaction vessel was charged with 2-(2,4-dichlorophenyl)cyclobutanone (2.0 mmol), [NH ₂ Me ₂ ] [(RuCl((R)-xylbinap)) ₂ (u-Cl) ₃ ] (0.25 mol.%), ammonium acetate (2.4 mmol), the appropriate additive (see table 5) and MeOH (2.5 ml). A hydrogen atmosphere of 30 bar was applied and the reaction mixture was heated to 80°C. After a stirring period of 16 hours, the reaction mixture was cooled to rt and analyzed by chiral (method 1) and achiral (method 2) HPLC.

Examples 46.1, 46.2

2-(2,4-Dichlorophenyl)cyclobutanone (93.0 mmol), [NH ₂ Me ₂ ][(RuCl((R)-xylbinap)) ₂ (u-Cl) ₃ ] (0, 1 mol %), ammonium phenoxyacetate (158.4 mmol), appropriate additive (see table 5.2) and MeOH (4.1 mol). A hydrogen atmosphere of 30 bar was applied and the reaction mixture was heated to 80°C. After a stirring period of 17 hours, the reaction mixture was cooled to rt and analyzed by chiral (method 1) and achiral (method 2) HPLC.

Examples 47-51

2-(2,4-Dichlorophenyl)cyclobutanone (0.5 mmol), [RuCl(p-cymol)((S)-DM-SEGPHOS)]Cl (0.005 mmol), ammonium acetate (0.5 mmol), 6 mmol) and the appropriate solvent (5.0 ml). A hydrogen atmosphere of 30 bar was applied and the reaction mixture was heated to 80°C. The reaction mixture was cooled to RT after a stirring period of 19 hours and was added H ₂ O (20 ml) and 1 M aqueous HCl solution (2 ml). The mixture was extracted with MTBE (20 ml) and the organic layer was extracted with aqueous HCl (2 ml 1 M HCl and 20 ml H ₂ O). The aqueous phase was made basic with 5 M NaOH aqueous solution (2 ml) and extracted with MTBE (3 x 20 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the solvent was removed under reduced pressure. The residue was analyzed by chiral HPLC (method 1) and ¹ H NMR.

Example 52

2-(2,4-dichlorophenyl)cyclobutanone (1.4 mmol), [RuCl(p-cymol)((S)-DM-SEGPHOS)]Cl (0.014 mmol), ammonium metachlorobenzoate (1.4 mmol), 4 mmol) and MeOH (13.8 ml). A 5 bar hydrogen atmosphere was applied and the reaction mixture was heated to 80°C. The reaction mixture was cooled to RT after a stirring period of 16 hours was Added H ₂ O (50 ml) and 1 M aqueous HCl solution (5 ml). The mixture was extracted with MTBE (50 ml) and the organic layer was extracted with aqueous HCl (5 ml 1 M HCl and 20 ml H ₂ O). The aqueous phase was made basic with 5 M NaOH aqueous solution (5 ml) and extracted with MTBE (3 x 50 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the solvent was removed under reduced pressure. The residue was analyzed by chiral HPLC (method 1) and ¹ H NMR.

Example 53

2-(2,4-dichlorophenyl)cyclobutanone (0.5 mmol), [RuCl(p-cymol)((S)-DM-SEGPHOS)]Cl (0.005 mmol), ammonium metachlorobenzoate (0.5 mmol), 5 mmol) and MeOH (5 ml). A hydrogen atmosphere of 10 bar was applied and the reaction mixture was heated to 80°C. The reaction mixture was cooled to rt after a stirring period of 17 hours and analyzed by chiral HPLC (method 1) and ¹ H NMR.

Example 54

2-(2,4-Dichlorophenyl)cyclobutanone (0.46 mmol), [RuCl(p-cymol)((S)-DM-SEGPHOS)]Cl (0.0046 mmol), ammonium metachlorobenzoate ( 0.55 mmol) and MeOH (2.3 ml). A hydrogen atmosphere of 10 bar was applied and the reaction mixture was heated to 80°C. The reaction mixture was cooled to RT after a stirring period of 19 hours was Added H ₂ O (20 ml) and 1 M aqueous HCl solution (2 ml). The mixture was extracted with MTBE (20 ml) and the organic layer was extracted with aqueous HCl (2 ml 1 M HCl and 20 ml H ₂ O). The aqueous phase was made basic with 5 M NaOH aqueous solution (2 ml) and extracted with MTBE (3 x 20 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the solvent was removed under reduced pressure. The residue was analyzed by chiral HPLC (method 1) and ¹ H NMR.

The results of Examples 52-54 are summarized in Table 7.

Examples 55-56

2-(2,4-Dichlorophenyl)cyclobutanone (4.0 mmol), Ru(OAc) ₂ [(R)-xylbinap] (0.02 mmol), ammonium acetate (4.8 mmol), acetic acid (6.4 mmol) and MeOH (10 ml). A hydrogen atmosphere of 30 bar was applied and the reaction mixture was heated to 80°C. After an appropriate stirring period, the reaction mixture was cooled to rt. The mixture was diluted with MTBE and water and 1 M HCl was added. The organic phase was extracted twice with 1 M HCl solution. The combined aqueous phases were basified with aqueous 5M NaOH and extracted three times with MTBE. The combined organic layers were dried over Na ₂ SO ₄ , filtered and the solvent was removed under reduced pressure. The residue was analyzed by chiral HPLC (method 1) and ¹ H NMR.

Examples 57-66

Various preformed Rh-based catalysts were tested on the screening platform. The reaction vessel was charged with 2-(2,4-dichlorophenyl)cyclobutanone (2.0 mmol), the appropriate catalyst (see Table 9), ammonium acetate (2.4 mmol) and MeOH (2.5 ml). A hydrogen atmosphere of 30 bar was applied and the reaction mixture was heated to 80°C. After a stirring period of 16 hours, the reaction mixture was cooled to rt and analyzed by chiral (method 1) and achiral (method 2) HPLC.

Examples 67-93

Various chiral ligands in combination with ruthenium were tested on the screening platform. Dissolved [Ru(Me-allyl) ₂ (cod)] and the corresponding ligand (see table 10) in acetone (2.5 ml) and then stirred for 1 h at 25°C. The mixture was evaporated to dryness, MeOH was added and the catalyst solution (0.25 mol.%) was transferred into an autoclave along with 2-(2,4-dichlorophenyl)cyclobutanone (2.0 mmol), ammonium acetate (2.4 mmol) and MeOH (2.5 ml). A hydrogen atmosphere of 30 bar was applied and the reaction mixture was heated to 80°C. After a stirring period of 16 hours, the reaction mixture was cooled to rt and analyzed by chiral (method 1) and achiral (method 2) HPLC.

Example 94

A high pressure reactor was charged with a solution of ammonium methoxyacetate in MeOH (323 g, 301 mmol), methanol (123 g), diacetate-((R)-(+)-2,2'-bis[di(3,5-xylyl) phosphino]-1,1'-binaphthyl)ruthenium (0.72 g, 0.75 mmol). The reactor was sealed and created 3 pressure drops to N ₂ (6 bar) without stirring, then 3 pressure drops to H ₂ (6 bar) with stirring and the mixture was heated to 55°C. The pressure was raised to 10 bar using hydrogen and the reactor was heated to 80°C. At 80°C, the pressure increased to 30 bar. A solution of 2-(2,4-dichlorophenyl)cyclobutanone in MeOH (110 g, 249 mmol) was added to the reactor over 4 hours. The reaction mixture was stirred for 8 hours until hydrogen uptake ceased. The pressure was lowered and created 3 pressure drops to N ₂ (6 bar). Then the reaction mass was concentrated in vacuo (60°C, 90 mbar) to obtain a brown oil. Water (450 ml) and ethyl acetate (300 ml) were added to the crude product. A 32% aqueous HCl solution (37.5 g) was added to reach pH 1 and phase separation was achieved. The lower aqueous phase was removed and the upper organic phase was washed with 1 M aqueous HCl (50 ml) and ensured phase separation. The lower aqueous phase was combined with the previous aqueous phase and the upper organic phase was discarded. Toluene (100 ml) was added to the combined aqueous phases and the two-phase system was cooled to 10°C. Added 30% aqueous solution of NaOH (80 g) to achieve pH 10, while maintaining the temperature below 20°C. Provided phase separation. The lower aqueous phase was removed and washed twice with toluene (2×100 ml). The combined organic and toluene layers were washed with water (100 ml) and concentrated under reduced pressure to give (1S,2S)-2-(2,4-dichlorophenyl)cyclobutanamine (45.5 g) as an oil.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.54 (m, 1H), 7.41 (d, J=1 Hz, 2H); 3.85-3.75 (m, 2H), 2.40-2.24 (m, 2H), 2.11-2.02 (m, 1H), 1.61-1.53 (m, 1 H), 1.15 (br s, 2H).

Examples 95-98

The following compounds in Table 11 were prepared in a manner analogous to Examples 10-94.

Fourth aspect

Reaction (d) according to Scheme 1

Example 99

To a solution of 2-(2,4-dichlorophenyl)cyclobutanone (5.00 g, 23.2 mmol) in chlorobenzene (23.2 ml) was added at RT AlCl ₃ (4.65 g, 34.9 mmol) , CH ₃ CN (6.08 ml, 116 mmol) and AcCl (2.48 ml, 34.9 mmol). A weak exothermic effect was observed with the addition of AcCl. The resulting yellowish suspension was heated at 50°C for 1 h. aqueous solution of NaOH (116 ml) and 50 ml of toluene. During the addition, a pale yellow precipitate formed. Filtration gave N-[2-(2,4-dichlorophenyl)cyclobuten-1-yl]acetamide (3.56 g) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.30 (bs, 1H); 7.51 (s, 1H), 7.47 (m, 2H), 2.85 (m, 2H), 2.68 (m, 2H), 1.92 (s, 3H).

Examples 100-107

The following compounds in Table 12 were prepared in a manner analogous to Example 99.

Examples 108-119

N-[2-(2,4-Dichlorophenyl)cyclobuten-1-yl]acetamide (compound of formula (VI)) can be obtained analogously to example 99 using the reaction parameters 5 indicated in examples 108-119.

Fifth aspect

Reaction (d') according to scheme 1

Example 120

To a solution of 1-(2,4-dichlorophenyl)cyclopropanecarbaldehyde (2.1 g, 9.3 mmol) in chlorobenzene (9 ml) was added AlCl ₃ (1.9 g, 14 mmol) at rt. The resulting yellowish suspension was heated at 60° C. for 30 minutes. After cooling to 35°C, CH ₃ CN (4.38 ml, 83.7 mmol) and AcCl (1.70 ml, 23.3 mmol) were added. A weak exothermic effect was observed with the addition of AcCl. The reaction mixture was heated to 50°C for 30 min, then after cooling to 5°C, the reaction mixture was added dropwise to cold (0°C) 4N. aqueous solution of NaOH (46 ml) and 50 ml of toluene. During the addition, a pale yellow precipitate formed. The internal temperature was maintained between 0°C and 5°C. The biphasic suspension was transferred to a 250 ml separatory funnel containing 200 ml of toluene. The aqueous phase was extracted twice with toluene (250 and 50 ml), the combined organic phases were washed once with 1 N. aqueous NaOH solution (50 ml) and water (2×50 ml; until the pH of the aqueous phase became neutral). Then the combined organic layers were dried over solid Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Received N-[2-(2,4-dichlorophenyl)cyclobuten-1-yl]acetamide (2.3 g) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.30 (bs, 1H), 7.51 (s, 1H), 7.47 (m, 2H), 2.85 (m, 2H), 2, 68 (m, 2H), 1.92 (s, 3H).

Examples 121-125

The following compounds in Table 14 were prepared in a manner analogous to Example 120.

Sixth aspect

Reaction (e) according to Scheme 1

Examples 126-131

Catalyst preformation

Bis(COD)rhodium(I) trifluoromethanesulfonate precatalyst (0.01 mmol) and (R)-1-[(S)-2-(di-tert-butylphosphino)ferrocenyl]ethyl-di -o-tolylphosphine (0.011 mmol). The appropriate solvent (10.0 ml) was then added and the solution was stirred for 90 minutes at rt.

Asymmetric hydrogenation

The pressure autoclave was charged with N-[2-(2,4-dichlorophenyl)cyclobuten-1-yl]acetamide (0.97 mmol), the appropriate solvent (1.50 ml) and the previously obtained catalyst solution (1.00 ml) . A 10 bar hydrogen atmosphere was applied and the reaction mixture was heated to 50°C. The reaction mixture was cooled to rt after a stirring period of 2 hours at 50°C.

The reaction mixture was concentrated under reduced pressure and analyzed by quantitative ¹ H-NMR and chiral HPLC (method 4).

TFE: 2,2,2-tetrafluoroethanol; DCE: 1,2-dichloroethane. The term "selectivity", as used in the table above, means the selectivity of the reaction in relation to compounds of formula (VI).

Examples 132-133

Catalyst preformation

Bis(COD)rhodium(1) trifluoromethanesulfonate precatalyst (0.01 mmol) and (R)-1-[(S)-2-(di-tert-butylphosphino)ferrocenyl]ethyl-di -o-tolylphosphine (0.011 mmol). MeOH (5.00 ml) was then added and the solution was stirred for 30 minutes at rt.

Asymmetric hydrogenation

The pressure autoclave was charged with N-[2-(2,4-dichlorophenyl)cyclobuten-1-yl]acetamide (0.98 mmol), MeOH (4.00 ml) and the previously obtained catalyst solution (1.00 ml). A hydrogen atmosphere was applied at an appropriate pressure and the reaction mixture was heated to 50°C. The reaction mixture was cooled to rt after a stirring period of 2 hours at 50°C.

The reaction mixture was concentrated under reduced pressure and analyzed by quantitative ¹ H-NMR and chiral HPLC (method 4).

The term "selectivity", as used in the table above, means the selectivity of the reaction in relation to compounds of formula (VI).

Examples 134-135

Catalyst preformation

Bis(COD)rhodium(1) trifluoromethanesulfonate precatalyst (0.01 mmol) and (R)-1-[(S)-2-(di-tert-butylphosphino)ferrocenyl]ethyl-di -o-tolylphosphine (0.011 mmol). MeOH (5.00 ml) was then added and the solution was stirred for 30 minutes at rt.

Asymmetric hydrogenation

The pressure autoclave was charged with N-[2-(2,4-dichlorophenyl)cyclobuten-1-yl]acetamide (0.98 mmol), MeOH (4.00 ml) and the previously obtained catalyst solution (1.00 ml). A hydrogen atmosphere of 50 bar was applied and the reaction mixture was heated to the temperature indicated in the table. The reaction mixture was cooled to RT after a stirring period of 2 hours at the temperature indicated in the table.

The reaction mixture was concentrated under reduced pressure and analyzed by quantitative ¹ H-NMR and chiral HPLC (method 4).

The term "selectivity", as used in the table above, means the selectivity of the reaction in relation to compounds of formula (VI).

Examples 136-139

Catalyst preformation

In a sterile glove box, the appropriate precatalyst (0.01 mmol) and (R)-1-[(S)-2-(di-tert-butylphosphino)ferrocenyl]ethyl-di-otolylphosphine (0.011 mmol) were loaded into a vessel. The appropriate solvent (10.0 ml) was then added and the solution was stirred for 90 minutes at rt.

Asymmetric hydrogenation

The pressure autoclave was charged with N-[2-(2,4-dichlorophenyl)cyclobuten-1-yl]acetamide (0.97 mmol), the appropriate solvent (1.50 ml) and the previously obtained catalyst solution (1.00 ml) . A 10 bar hydrogen atmosphere was applied and the reaction mixture was heated to 50°C. The reaction mixture was cooled to rt after a stirring period of 2 hours at 50°C.

The reaction mixture was concentrated under reduced pressure and analyzed by quantitative ¹ H-NMR and chiral HPLC (method 4).

The term "selectivity", as used in the table above, means the selectivity of the reaction in relation to compounds of formula (VI).

Examples 140-149

Various preformed Rh-based catalysts were tested on the screening platform. The reaction vessel was charged with N-[2-(2,4-dichlorophenyl)cyclobutet-1-yl]acetamide (31.7 µmol), the appropriate catalyst (0.158 µmol) and the appropriate solvent (500 µl). A hydrogen atmosphere of 50 bar was applied and the reaction mixture was heated to 50°C. After a stirring period of 16 hours, the reaction mixture was cooled to rt and analyzed by achiral (method 3) and chiral HPLC (method 4).

The term "selectivity", as used in the table above, means the selectivity of the reaction in relation to compounds of formula (VI).

Examples 150-166

Catalyst preformation

[Rh(COD) ₂ ]O ₃ SCF ₃ (0.158 µmol) and the corresponding chiral ligand (0.190 µmol) were loaded into a vial in a sterile glove box. Dichloroethane was then added and the solution was stirred for 30 minutes at room temperature, after which the solvent was evaporated under reduced pressure.

Asymmetric hydrogenation

N-[2-(2,4-dichlorophenyl)cyclobuten-1-yl]acetamide (31.7 µmol) and MeOH (500 µl) were added to the previously prepared catalyst. A hydrogen atmosphere of 50 bar was applied and the reaction mixture was heated to 50°C. The reaction mixture was cooled to rt after a stirring period of 16 hours at 50°C.

The reaction mixture was concentrated under reduced pressure and analyzed by achiral (method 3) and chiral HPLC (method 4).

The term "selectivity", as used in the table above, means the selectivity of the reaction in relation to compounds of formula (VI).

Examples 167-172

Catalyst preformation

[Rh(COD) ₂ ]O ₃ SCF ₃ (4.52 mg, 0.0096 mmol) and the corresponding chiral ligand (0.01208 mmol) were loaded into a vial in a sterile glove box. Trifluoroethanol degassed with argon (10.0 ml) was then added and the solution was stirred for 60 minutes at rt.

Asymmetric hydrogenation

The pressure autoclave was charged with N-[2-(2,4-dichlorophenyl)cyclobuten-1-yl]acetamide (250 mg, 0.966 mmol), trifluoroethanol (0.50 ml) and the previously obtained catalyst solution (2.00 ml) . A 10 bar hydrogen atmosphere was applied and the reaction mixture was heated to 50°C. The reaction mixture was cooled to rt after a stirring period of 2 hours at 50°C.

The reaction mixture was concentrated under reduced pressure and analyzed by achiral (method 3) and chiral HPLC (method 4).

The term "selectivity", as used in the table above, means the selectivity of the reaction in relation to compounds of formula (VI).

Example 173

A mixture of Rh(COD) ₂ OTf (1.3 kg, 0.5 mol.%) and (R)-1-[(S)-2-(di-tert-butylphosphino)ferrocenyl]ethyl-di-o- tolylphosphine (2.1 kg, 0.7 mol.%) in TFE (174 kg, 1.74 kmol) for 90 minutes at 50°C, after which it was added to the N-[2-(2,4- dichlorophenyl)cyclobuten-1-yl]acetamide (142 kg, 0.55 kmol) in IPA (isopropyl alcohol, 866 kg, 14.4 kmol). The hydrogenation was carried out at 50° C. and a hydrogen pressure of 10 bar until complete conversion was achieved. Then the reaction solution (1176 kg; ee (S,S) 91%) was transferred to the next stage.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.1 (bs, 1H), 7.6 (d, J=4 Hz, 1H), 7.5 (m, 2H), 4.1 (m, 1H), 4.0 (m, 1H), 3.3 (s, 3H), 2.9 (quintet, J=8 Hz, 1H), 2.5 (m, 1H), 2.2 (m, 1H), 1.8 (m, 1H).

Reaction (e) according to Scheme 1 using Ru-based catalysts

Examples 174-180

Catalyst pre-formation:

Bis(2-metallyl)(COD)ruthenium precatalyst (3.72 mg) and (S,S)-(-)-2,3-bis(tert-butylmethylphosphino)quinoxaline (4, 26 mg). Dichloromethane degassed with argon (3.0 ml) was then added, followed by methanesulfonic acid (1.2 mg). The solution was stirred for 30 minutes at room temperature.

Asymmetric hydrogenation

An autoclave was charged under pressure with N-[2-(2,4-dichlorophenyl)cyclobuten-1-yl]acetamide (0.25 g, 0.97 mmol), the appropriate solvent, degassed with argon (2.0 ml), and a portion of the previously obtained catalyst solution (0.5 ml). A hydrogen atmosphere of 50 bar was applied and the reaction mixture was heated to 50°C. The reaction mixture was cooled to rt after a stirring period of 2 hours at 50°C.

The reaction mixture was concentrated under reduced pressure and analyzed by quantitative ¹ H-NMR and chiral HPLC (method 4).

The term "selectivity", as used in the table above, means the selectivity of the reaction in relation to compounds of formula (VI).

Examples 181-182

Catalyst pre-formation:

Bis(2-metallyl)(COD)ruthenium (6.2 mg) and (S,S)-(-)-2,3-bis(tert-butylmethylphosphino)quinoxaline (7.1 mg). Dichloromethane degassed with argon (4.0 ml) was then added, followed by the addition of a diethyl ether complex of fluoroboric acid (0.24 ml, 0.081 mmol/ml). The solution was stirred for 30 minutes at RT. The volume in the vessel was reduced by bubbling argon through the solution (final volume: 1 ml), after which degassed MeOH (9 ml) was added.

Asymmetric hydrogenation

The pressure autoclave was charged with N-[2-(2,4-dichlorophenyl)cyclobuten-1-yl]acetamide (0.5 g, 1.933 mmol), MeOH degassed with argon (4.0 ml), and part of the previously the resulting catalyst solution (1.0 ml). A hydrogen atmosphere was applied at an appropriate pressure and the reaction mixture was heated to 50°C. The reaction mixture was cooled to rt after a stirring period of 2 hours at 50°C.

The reaction mixture was concentrated under reduced pressure and analyzed by quantitative ¹ H-NMR and chiral HPLC (method 4).

The term "selectivity", as used in the table above, means the selectivity of the reaction in relation to compounds of formula (VI).

n. O. = not defined.

Example 183

Catalyst pre-formation:

The vessel was loaded with bis(COD)tetra[μ-trifluoroacetate]diruthenium(II) hydrate (1.40 mg, 0.0015 mmol), (S,S)-(-)-2,3-bis(tert-butylmethylphosphino) quinoxaline (1.10 mg, 0.0032 mmol) and N-[2-(2,4-dichlorophenyl)cyclobuten-1-yl]acetamide (0.40 g, 1.53 mmol). The flasks were then placed under an inert atmosphere with argon and MeOH degassed with argon (5.0 ml) was added. A hydrogen atmosphere of 50 bar was applied and the reaction mixture was heated to 50°C. The reaction mixture was cooled to rt after a stirring period of 2.5 hours at 50°C.

The reaction mixture was concentrated under reduced pressure and analyzed by quantitative ¹ H-NMR and chiral HPLC (method 4).

The term "selectivity", as used in the table above, means the selectivity of the reaction in relation to compounds of formula (VI).

Examples 184-199

Catalyst preformation

In a sterile glove box, the appropriate catalyst precursor (0.158 µmol) was loaded into the vial; when [Ru(COD)(2-metallyl) ₂ ] was used as the catalyst precursor, HBF ₄ , (0.316 µmol)) and the appropriate chiral ligand were also loaded into the vial. (0.19 µmol). Dichloroethane was then added and the solution was stirred for 30 minutes at room temperature, after which the solvent was evaporated under reduced pressure.

Asymmetric hydrogenation

N-[2-(2,4-dichlorophenyl)cyclobuten-1-yl]acetamide (31.7 µmol) and MeOH (500 µl) were added to the previously prepared catalyst. A hydrogen atmosphere of 50 bar was applied and the reaction mixture was heated to 50°C. The reaction mixture was cooled to rt after a stirring period of 16 hours at 50°C.

The reaction mixture was concentrated under reduced pressure and analyzed by achiral (method 3) and chiral HPLC (method 4).

The term "selectivity", as used in the table above, means the selectivity of the reaction in relation to compounds of formula (VI).

Examples 200-206

Catalyst preformation

In a sterile glove box, bis(2-metallyl)(COD)ruthenium (3.10 mg, 0.0097 mmol), the corresponding chiral ligand (0.0107 mmol), and a fluoroboric acid diethyl ether complex (1.72 mg, 0.0106 mmol). Dichloromethane degassed with argon (2.5 ml) was then added and the solution was stirred for 30 minutes at rt.

Asymmetric hydrogenation

The pressure autoclave was charged with N-[2-(2,4-dichlorophenyl)cyclobuten-1-yl]acetamide (250 mg, 0.97 mmol), MeOH degassed with argon (2.0 ml), and the previously obtained catalyst solution (0.5 ml). A hydrogen atmosphere of 50 bar was applied and the reaction mixture was heated to 50°C. The reaction mixture was cooled to rt after a stirring period of 2 hours at 50°C.

The reaction mixture was concentrated under reduced pressure and analyzed by achiral (method 3) and chiral HPLC (method 4).

The term "selectivity", as used in the table above, means the selectivity of the reaction in relation to compounds of formula (VI).

Examples 207-208

Catalyst preformation

In a sterile glove box, bis(2-metallyl)(COD)ruthenium (3.72 mg, 0.0116 mmol) and the corresponding chiral ligand (0.0127 mmol) were loaded into the vessel. Then dichloromethane degassed with argon (3.00 ml) and a 0.081 M solution of methanesulfonic acid in dichloromethane (0.16 ml, 0.0130 mmol) were added and the solution was stirred for 30 minutes at rt.

Asymmetric hydrogenation

The pressure autoclave was charged with N-[2-(2,4-dichlorophenyl)cyclobuten-1-yl]acetamide (250 mg, 0.97 mmol), MeOH degassed with argon (2.0 ml), and the previously obtained catalyst solution (0.5 ml). A hydrogen atmosphere of 50 bar was applied and the reaction mixture was heated to 50°C. The reaction mixture was cooled to rt after a stirring period of 2 hours at 50°C.

The reaction mixture was concentrated under reduced pressure and analyzed by achiral and chiral HPLC.

The term "selectivity", as used in the table above, means the selectivity of the reaction in relation to compounds of formula (VI).

Seventh aspect

Reaction (f) according to scheme 1

Example 209

A reaction mixture consisting of N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]acetamide in isopropanol/trifluoroethanol (428 g, 153 mmol) and a suspension of Aerosil-200 (23 mg) in isopropanol (0 .5 g), heated to Ta=130°C. A portion of isopropanol and trifluoroethanol (about 220 g) was removed at a temperature of 82° C. measured at the top of the distillation equipment, after which a 50% aqueous solution of H ₃ PO ₄ (150 g, 765 mmol) was added. More isopropanol and trifluoroethanol were removed until the temperature at the top of the distillation column reached 100°C. The reaction mass was then stirred at reflux temperature until >95% conversion was achieved (reaction time: approximately 20 hours).

Water (145 g, 8.1 mol) was added to the reaction mixture after it was cooled to Ti=60°C. The reaction mixture was extracted twice with toluene (first: 169 g, 1.8 mol; second: 86 g, 0.9 mol), after which the pH of the aqueous solution was adjusted to 8.0-8.5 using 25% aqueous ammonia (117 .5 g, 1.7 mol). The main aqueous phase was extracted with toluene (169 g, 1.8 mol). Then the organic layer was concentrated under reduced pressure and filtered to obtain a 25.3% solution of (1S,2S)-2-(2,4-dichlorophenyl)cyclobutanamine in toluene (136 g).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.54 (t, J=4 Hz, 1H), 7.41 (d, J=4 Hz, 2H); 3.86-3.75 (m, 2H), 2.41-2.24 (m, 2H), 2.13-2.00 (m, 1H), 1.60-1.53 (m, 1 N).

Example 210

A reaction mixture consisting of N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]acetamide (10 g, 35.8 mmol), methanesulfonic acid (6.9 g, 71.5 mmol) and water (6.4 g, 358 mmol) was heated to 110° C. until the reflux temperature was reached. The reaction mixture was stirred at reflux temperature for 21 hours, after which it was cooled to rt. Water (40 ml) was added to the reaction mixture and then it was extracted twice with toluene (first: 50 ml; second: 30 ml). The pH of the aqueous solution was adjusted to 8.9 using 25% aqueous ammonia (9.6 g, 141 mol). The main aqueous phase was extracted with toluene (50 ml) to give a 11.9% solution of (1S,2S)-2-(2,4-dichlorophenyl)cyclobutanamine in toluene (59.8 g).

Example 211

N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]acetamide (5.0 g, 17.9 mmol) was added to 60% H ₂ SO ₄ aqueous solution (17.5 g, 107 mmol ). The reaction mixture was heated to 128° C. until the reflux temperature was reached. The reaction mass was cooled to 60° C. after a stirring period of 21 hours at reflux temperature. Water (75 ml) was added to the reaction mixture, which was then extracted twice with toluene (first: 25 ml; second: 25 ml). The pH of the aqueous solution was adjusted to 8.8 using 25% aqueous ammonia (5.8 g, 85.1 mol). The main aqueous phase was extracted with toluene (100 ml). Then the organic layer was concentrated under reduced pressure to obtain a 15.4% solution of (1S,2S)-2-(2,4-dichlorophenyl)cyclobutanamine in toluene (17.3 g).

Eighth aspect

Reaction (g) according to Scheme 1

Example 212

A solution of (1S,2S)-2-(2,4-dichlorophenyl)cyclobutanamine in toluene (339 g, 0.40 mol) was added to solid NaHCO ₃ (47 g, 0.56 mol). Then water (140 g, 7.79 mol) was added to the reaction mixture and the mixture was heated to Ti=50°C. Then a solution of 2-(trifluoromethyl)pyridine-3-carbonyl chloride in toluene (247 g, 0.42 mol) was added to the reaction mixture over 53 minutes at Ti=50°C. After reaching complete conversion, the reaction mixture was heated to Ti=70°C and stirred for 20 minutes at the same temperature. After phase separation, the organic phase was extracted with water (201 g, 11.1 mol) at Ti=80°C. After phase separation, the organic phase was concentrated to about 35% MCH solution (140 g, 1.4 mol) and then it was added over 20 minutes to the concentrated organic phase at Ti=80°C. Then the reaction mixture was cooled to Ti=5°C for 2.5 hours, while the seed was added at Ti=72°C (crystallization was also carried out without seeding). The reaction mixture was stirred for 30 minutes until the reaction mixture reached Ti=5°C, after which the suspension was filtered, washed with MCH (200 g, 2.0 mol) and dried at elevated temperature under reduced pressure to isolate N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-2-(trifluoromethyl)pyridine-3-carboxamide (141.6 g) as anhydride.

FT-IR 3282, 3077, 2981, 2952, 1650, 1593, 1543, 1473, 1353, 1187, 1138, 1074, 1066, 1054 cm ^-1

N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-2-(trifluoromethyl)pyridine-3-carboxamide anhydride (80 g) was dissolved in a mixture of acetone (240 g, 4.1 mol) and water (80 g, 4.4 mol) at Ti=55°C. The mixture was then cooled to Ti=8°C and seed crystals were added at Ti=29°C. Water (86 g, 4.8 mol) was added to the reaction mixture over 60 minutes after the reaction mixture had reached a temperature of 8°C. The reaction mixture was stirred for 30 minutes after another aliquot of water (174 g, 9.7 mol) was added over 1 hour. A final aliquot of water (340 g, 18.9 mol) was then added and the suspension stirred for 80 minutes. The suspension was filtered and the filter cake was washed with water (2×80 g, 4 times), after which it was dried under reduced pressure at a temperature of 35°C to obtain N-[(1S,2S)-2-(2,4-dichlorophenyl )cyclobutyl]-2-(trifluoromethyl)pyridine-3-carboxamide (94.6 g).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.65 (dd, J=4.6 Hz, J=1.2 Hz, 1H), 7.60-7.58 (m, 1H), 7.47- 7.44 (m, 1H), 7.41-7.40 (m, 1H), 7.33-7.25 (m, 2H), 5.54 (br d, J=7.8 Hz, 1H ), 5.03 (quin, J=7.3 Hz, 1H), 4.24 (q, J=7.8 Hz, 1H), 2.65-2.56 (m, 1H), 2.44 -2.28 (m, 2H), 2.10-2.01 (m, 1H).

FT-IR 3403, 3232, 3079, 2948, 1660, 1645, 1593, 1575, 1471, 1326, 1186, 1126, 1076, 1054 cm ^-1 .

Example 213

Cooled a biphasic mixture of (1S,2S)-2-(2,4-dichlorophenyl)cyclobutanamine (20.0 g, 87.3 mmol) in toluene (20 g) and water (40 g) to 0° C. and seed crystals were added product in the form of a hydrate (1.53 g). A solution of 2-(trifluoromethyl)pyridine-3-carbonyl chloride (19.7 g, 91.6 mmol) in toluene (60 g) was dosed in parallel in 30% aq. NaOH (14.0 g, 105 mmol) for 2 hours so as to maintain the pH in the range of 7-9. After completion of the dosing, the reaction mixture was stirred for an additional 3 hours. The resulting thick suspension was filtered, the filter cake was washed with water (2 × 25 g) and dried at a pressure of 150 mbar for 16 hours to obtain N-[(1S,2S)- 2-(2,4-dichlorophenyl)cyclobutyl]-2-(trifluoromethyl)pyridine-3-carboxamide (36.4 g containing 7% water) as monohydrate.

FT-IR 3403, 3232, 3079, 2948, 1660, 1645, 1593, 1575, 1471, 1326, 1186, 1126, 1076, 1054 cm ^-1 .

Claims (77)

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

, where A is selected from aryl and heteroaryl, where 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; where the reduction of the nitrile fragment of the compound of formula (I) is carried out by partial hydrogenation to the corresponding intermediate imine using H ₂ and a metal-based catalyst, followed by sequential hydrolysis to obtain a compound of formula (II)

then (b) carrying out the reaction of a compound of formula (II) in the presence of a Lewis acid to obtain a compound of formula (III)

where * denotes the stereocenter, then (c) reacting a compound of formula (III) with an ammonium salt and H ₂ in the presence of a chiral transition metal catalyst to produce an enantiomerically and diastereomerically enriched amine of formula (IV)

, where * denotes the stereocenter, and then subsequent reaction of an amine of formula (IV) with a compound of formula (X)

, where Y is a suitable leaving group such as OH, OR or halogen, preferably chlorine, R is C ₁ -C ₆ alkyl and E is selected from aryl and heteroaryl, where 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; to form an enantiomerically and diastereomerically enriched amide of formula (VII)

, where aryl is a mono-, bi- or polycyclic aromatic system with 6-14 carbon atoms in the ring, heteroaryl are 5-7 membered rings with 1-3 identical or different heteroatoms selected from N, O and S. 2. The method according to claim 1, where A is phenyl and E is heteroaryl, where 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. 3. The method according to any one of paragraphs. 1, 2, where the compound of formula (II) is reacted in step (b) in the presence of a Lewis acid selected from AlCl ₃ and GaCl ₃ , preferably AlCl ₃ . 4. The method according to p. 3, where in stage (b) add 1.0-1.5 mol equivalent of AlCl ₃ or GaCl ₃ relative to the compound of formula (II). 5. The method according to any one of paragraphs. 1-4, wherein the chiral transition metal catalyst in step (c) comprises a transition metal selected from Ru, Rh, Ir and Pd, preferably Ru, and a bidentate phosphorus chiral ligand of general formula (VIII)

, where Z is a linker group and R ¹ , R ² , R ³ and R ⁴ are independently selected from aryl, heteroaryl, C ₁ -C ₆ alkyl and C ₁ -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. 6. The method of claim 5 wherein the linker group Z is selected from (R and S)-1,1'-binaphthyl, (R and S)-4,4'-bis-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, ferrocenylmethyl, ferrocene, benzene and ethyl, preferably (R and S )-1,1'-binaphthyl. 7. The method according to p. 5 or 6, where the chiral ligand is selected from (R)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, (R)-2,2'-bis(di-n-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]dioxine, (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-benzodioxine, (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. 8. The method of claim 5 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]. 9. Process for the preparation of a compound of formula (III)

, where A is defined in any of paragraphs. 1, 2 and * denotes the stereocenter, involving the reaction of a compound of formula (II)

with Lewis acid. 10. Process for the preparation of a compound of formula (III)

, where A is defined in any of paragraphs. 1, 2 and * denotes the stereocenter, involving the reaction of a compound of formula (II)

with a Lewis acid selected from AlCl ₃ and GaCl ₃ , preferably AlCl ₃ . 11. The method according to p. 10, where add 1.0-1.5 mol equivalent of AlCl ₃ or GaCl ₃ relative to the compound of formula (II). 12. The method according to any one of paragraphs. 9-11, where the compound of formula (III)

where A is defined in any of paragraphs. 1, 2 and * denotes the stereocenter, additionally reacted with an ammonium salt and H ₂ in the presence of a chiral transition metal catalyst to obtain an enantiomerically and diastereomerically enriched amine of formula (IV)

, where * denotes the stereocenter, and then additionally, an amine of formula (IV) is reacted with a compound of formula (X)

, where Y is a suitable leaving group such as OH, OR or halogen, preferably chlorine, R is C ₁ -C ₆ alkyl and E is selected from aryl and heteroaryl, where 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; to form an enantiomerically and diastereomerically enriched amide of formula (VII)

13. The method according to p. 12, where the chiral transition metal catalyst is defined in any of paragraphs. 5-8. 14. Process for the preparation of a compound of formula (V)

, where A is defined in any of paragraphs. 1, 2, which involves the implementation of the reaction of the compounds of formula (II)

in the presence of a Lewis acid selected from AlCl ₃ and GaCl ₃ , preferably AlCl ₃ , to give a compound of formula (III)

and then reacting a compound of formula (III) with acetonitrile and a suitable additive, wherein the additive is selected from acid chlorides, anhydrides or esters, preferably the additive is selected from acetyl chloride, isopropenyl acetate, 4-methoxybenzoyl chloride and p-anisic anhydride.