PROCESS FOR THE PREPARATION OF ENANTIOMERICALLY AND DIASTEREOMERICALLY ENRICHED CYCLOBUTANE AMINES AND AMIDES

Abstract

The present invention relates to a process for the preparation of enantiomerically and diastereomerically enriched cyclobutane amines and amides by reacting (a) cyclopropylcarbonitrile to a cyclopropylcarbaldehyde, (b) further reacting to a cyclobutanone, or (d) further reacting to an enamide, 5 (c) further reacting to enantiomerically and diastereomerically enriched cyclobutane amines, or (d) further reacting to an enamide and (e) to an enantiomerically and diastereomerically enriched cyclobutylamide to obtain (f) an enantiomerically and diastereomerically enriched cyclobutane amine, and (g) further reacting to an enantiomerically and diastereomerically enriched cyclobutane amide.

Claims

1. A process for the preparation of enantiomerically and diastereomerically enriched cyclobutane amides comprising (a) reducing the nitrile moiety of a compound of formula (I) to an aldehyde ##STR00011## wherein A is selected from aryl, heteroaryl, C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl and C.sub.3-C.sub.7-cycloalkyl, which aryl, heteroaryl, C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl and C.sub.3-C.sub.7-cycloalkyl are unsubstituted or substituted with one or more substituents independently selected from halogen, cyano, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.6-alkylsulfanyl, C.sub.1-C.sub.6-haloalkylsulfanyl, C.sub.1-C.sub.6-alkylsulfinyl, C.sub.1-C.sub.6-haloalkylsulfinyl, C.sub.1-C.sub.6-alkylsulfonyl, C.sub.1-C.sub.6-haloalkylsulfonyl, C.sub.2-C.sub.6-haloalkenyl and C.sub.2-C.sub.6-haloalkynyl; wherein the reduction of the nitrile moiety of the compound of formula (I) is carried out via partial hydrogenation to the corresponding intermediate imine applying H.sub.2 and a metal catalyst, followed by subsequent hydrolysis to the compound of formula (II) ##STR00012## then (b) reacting the compound of formula (II) in the presence of a suitable Lewis acid to obtain a compound of formula (III) ##STR00013## wherein * indicates a stereocentre, then (c) reacting a compound of formula (III) with an ammonium salt and H.sub.2 in presence of a chiral transition metal catalyst to obtain an enantiomerically and diastereomerically enriched amine of formula (IV) ##STR00014## wherein * indicates a stereocentre, and then further reacting the amine of formula (IV) with a compound of formula (X) ##STR00015## wherein Y is a suitable leaving group such as OH, OR or halogen, preferably chloro, R is C.sub.1-C.sub.6-alkyl, and E is selected from aryl, heteroaryl, hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl and C.sub.3-C.sub.7-cycloalkyl which aryl, heteroaryl, C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl and C.sub.3-C.sub.7-cycloalkyl are unsubstituted or substituted with one or more substituents independently selected from halogen, cyano, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.6-alkylsulfanyl, C.sub.1-C.sub.6-haloalkylsulfanyl, C.sub.1-C.sub.6-alkylsulfinyl, C.sub.1-C.sub.6-haloalkylsulfinyl, C.sub.1-C.sub.6-alkylsulfonyl, C.sub.1-C.sub.6-haloalkylsulfonyl, C.sub.2-C.sub.6-haloalkenyl and C.sub.2-C.sub.6-haloalkynyl; so as to form the enantiomerically and diastereomerically enriched amide of formula (VII) ##STR00016##

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

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

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

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

6. The process according to claim 1, wherein the chiral transition metal catalyst in step (c) comprises a transition metal selected from Ru, Rh, Ir and Pd, preferably Ru, and a chiral ligand with a bidentate phosphor of the general formula (VIII) ##STR00017## wherein Z is a linking group and R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are independently selected from aryl, hetereoaryl, C.sub.1-C.sub.6-alkyl and C.sub.1-C.sub.6-cycloalkyl, each of which is unsubstituted or substituted with one or more substituents independently selected from C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl and halogen.

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

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

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

10. A process for the preparation of a compound of formula (III) ##STR00018## wherein A is as defined in claim 1 and * indicates a stereocentre, comprising reacting a compound of formula (II) ##STR00019## with a suitable Lewis acid.

11. A process for the preparation of a compound of formula (III) ##STR00020## wherein A is as defined in claim 1 and * indicates a stereocentre, comprising reacting a compound of formula (II) ##STR00021## with a Lewis acid selected from AlCl.sub.3 and GaCl.sub.3, preferably AlCl.sub.3.

12. The process according to claim 11, wherein 1.0-1.5 mole equivalents of AlCl.sub.3 or GaCl.sub.3 relative to the compound of formula (II) is added.

13. The process according to claim 10, wherein the compound of formula (III) ##STR00022## wherein A is as defined in any one of claims 1 to 3 and * indicates a stereocentre, is further reacted with an ammonium salt and H.sub.2 in presence of a chiral transition metal catalyst to obtain an enantiomerically and diastereomerically enriched amine of formula (IV) ##STR00023## wherein * indicates a stereocentre, and then further reacting the amine of formula (IV) with a compound of formula (X) ##STR00024## wherein Y is a suitable leaving group such as OH, OR or halogen, preferably chloro, R is C.sub.1-C.sub.6-alkyl, and E is selected from aryl, heteroaryl, hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl and C.sub.3-C.sub.7-cycloalkyl which aryl, heteroaryl, C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl and C.sub.3-C.sub.7-cycloalkyl are unsubstituted or substituted with one or more substituents independently selected from halogen, cyano, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-haloalkoxy, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.6-alkylsulfanyl, C.sub.1-C.sub.6-haloalkylsulfanyl, C.sub.1-C.sub.6-alkylsulfinyl, C.sub.1-C.sub.6-haloalkylsulfinyl, C.sub.1-C.sub.6-alkylsulfonyl, C.sub.1-C.sub.6-haloalkylsulfonyl, C.sub.2-C.sub.6-haloalkenyl and C.sub.2-C.sub.6-haloalkynyl; so as to form the enantiomerically and diastereomerically enriched amide of formula (VII) ##STR00025##

14. The process according to claim 13, wherein the chiral transition metal catalyst is as defined in any one of claims 6 to 9.

15. A process for the preparation of a compound of formula (V) ##STR00026## wherein A is as defined in claim 1, which comprises reacting a compound of formula (II) ##STR00027## in the presence of a Lewis acid selected from AlCl.sub.3 and GaCl.sub.3, preferably AlCl.sub.3, to obtain a compound of formula (III) ##STR00028## and further reacting the compound of formula (III) with acetonitrile and a suitable additive, wherein the additive is selected from acyl chlorides, anhydrides or esters, preferably the additive is selected from acetyl chloride, isopropenyl acetate, 4-methoxybenzoyl chloride and p-anisic anhydride.

Description

EXPERIMENTAL

Examples

[0303] The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon.

Instrumentation

HPLC Methods

Method 1

[0304] HPLC apparatus: Thermo Electron Corporation; SpectraSystem P200, [0305] SpectraSystemAS1000 and SpectraSystem UV1000.

[0306] Column: CHIRALPAK IA-3, 3 m, 4.6 mm100 mm.

[0307] Temperature: room temperature (rt.)

[0308] Mobile phase: EtOH+0.1 diethylamine/MeOH+0.1% diethylamine (50/50).

[0309] Flow rate: 1.0 ml/min.

[0310] Gradient: isocratic.

[0311] Detection: 223 nm.

[0312] Size of sample: 10 L.

[0313] Rt (retention time) (1S,2S)-2-(2,4-dichlorophenyl)cyclo-butaneamine: 4.8 min.

[0314] Rt (1R,2R)-2-(2,4-dichlorophenyl)cyclo-butaneamine: 3.0 min.

Method 2

[0315] HPLC apparatus: Agilent Technologies 1260 Infinity.

[0316] Column: Agilent XDB-C18, 1.8 m, 4.650 mm.

[0317] Temperature: rt

[0318] Mobile phase: A: Acetonitrile; B: MeOH; C: H.sub.2O+0.1% H.sub.3PO.sub.4.

[0319] Flow rate: 1.5 mL/min.

[0320] Gradient:

TABLE-US-00001 Time [min] A [%] B [%] C [%] 0.00 5.0 82.5 12.5 0.50 5.0 82.5 12.5 7.00 85.0 2.5 12.5 9.00 5.0 82.5 12.5

[0321] Detection: 220 nm.

[0322] Size of sample: 1 L.

[0323] Rt of cis-isomer of 2-(2,4-dichlorophenyl)cyclobutaneamine: 2.8 min.

Method 3

[0324] HPLC apparatus: Agilent Technologies 1200 Series.

[0325] Column: Phenomenex Kinetex XB C18, 2.6 m, 4.6150 mm.

[0326] Temperature: 40 C.

[0327] Mobile phase: A: H.sub.2O+0.1% (v/v) H.sub.3PO.sub.4; B: Acetonitrile.

[0328] Flow rate: 1.0 mL/min.

[0329] Gradient:

TABLE-US-00002 Time [min] A [%] B [%] 0.0 70 30 15.0 50 50 20.0 10 90 25.0 10 90 25.1 70 30 33.0 70 30

[0330] Detection: 223 nm.

[0331] Size of sample: 5 L.

[0332] Rt of cis-isomers of N-[2-(2,4-dichlorophenyl)cyclobutyl]acetamide: 9.2 min.

Method 4

[0333] HPLC apparatus: Agilent Technologies 1200 Series.

[0334] Column: CHIRALPAK IA-3, 3 m, 4.6 mm100 mm.

[0335] Temperature: rt.

[0336] Mobile phase: n-hexane/ethanol (98/2).

[0337] Flow rate: 1.0 ml/min.

[0338] Gradient: isocratic.

[0339] Detection: 223 nm.

[0340] Size of sample: 5 L.

[0341] Rt N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]acetamide: 12.4 min.

[0342] Rt N-[(1R,2R)-2-(2,4-dichlorophenyl)cyclobutyl]acetamide: 15.6 min.

First Aspect:

Reaction (a1) of Scheme 1:

Example 1.1

[0343] 1-(2,4-dichlorophenyl)cyclopropanecarbonitrile (1.0 g, 4.61 mmol) and trifluroroacetic acid (6 mL) were added to a 50-mL flame-dried two-necked flask which was equipped with a vacuum connection, a twin pressure balloon and a magnetic stirring bar. The reaction flask was evacuated and the vacuum was released with nitrogen twice. Then palladium, 5% on peat carbon, 50% water (50 mg, 0.013 mmol) was added to the reaction flask and the flask was purged with nitrogen before the hydrogen balloon was attached. The reaction mixture was stirred at rt (room temperature) for 2 to 4 h. Hydrogen was released and the reaction flask was purged with nitrogen once the conversion was >98%. The reaction mass was filtered under an atmosphere of nitrogen. 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 obtain 1-(2,4-dichlorophenyl)cyclopropanecarbaldehyde (1.1 g) as an oil.

[0344] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.75 (s, 1H), 7.60 (d, J=1.90 Hz, 1H), 7.46-7.27 (m, 2H), 1.80-1.61 (m, 2H), 1.47-1.36 (m, 2H).

Example 1.2

[0345] 1-(2,4-dichlorophenyl)cyclopropanecarbonitrile (9.49 g, 44.0 mmol), trilfuoroacetic acid (70 g), water (4.7 g) and palladium, 5% on carbon, 50% water (300 mg, 0.15 mol %) were added to a 100 mL reactor which was equipped with a vacuum connection, a nitrogen inlet and a valve connected to a hydrogen inlet. The reactor was evacuated and the vacuum was replaced with nitrogen thrice. The same procedure was repeated with H.sub.2 and the reaction mixture was then stirred for 2 hours at 5 C. under 1.5 bar H.sub.2 pressure. 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 in toluene and washed with water twice. The resulting organic layer was concentrated under reduced pressure to afford 1-(2,4-dichlorophenyl)cyclopropanecarbaldehyde (4.2 g) as a clear brown oil.

[0346] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.75 (s, 1H), 7.60 (d, J=1.90 Hz, 1H), 7.46-7.27 (m, 2H), 1.80-1.61 (m, 2H), 1.47-1.36 (m, 2H).

Reaction (a2) of Scheme 1:

Example 2.1

[0347] 1-(2,4-dichlorophenyl)cyclopropanecarbonitrile (1.0 g, 4.64 mmol), acetic acid (17.5 mL) and water (5 ml) were added to a 50 mL flame-dried two-necked flask which was equipped with a vacuum connection, a twin pressure balloon and a magnetic stirring bar. The reaction flask was evacuated and the vacuum was released with nitrogen twice. Then, Raney Nickel (50% strength w/w) with 50% water (201 mg, 0.71 mmol) was added to the reaction flask and the flask was purged with nitrogen before the hydrogen balloon was attached. The reaction mixture was stirred at rt for 6 to 10 h. Hydrogen was released and the reaction flask was purged with nitrogen once the conversion was >98%. The reaction mass was filtered through a bed of celite under an atmosphere of nitrogen. The filtrate was acidified with concentrate aqueous HCl to pH 1.0 and diluted with water and ethyl acetate. The organic layer was extracted with a 15% aqueous sodium carbonate solution and subsequently water. The solvent was removed under reduced pressure to obtain 1-(2,4-dichlorophenyl)cyclopropanecarbaldehyde (0.81 g) as an oil.

[0348] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.75 (s, 1H), 7.60 (d, J=1.90 Hz, 1H), 7.46-7.27 (m, 2H), 1.80-1.61 (m, 2H), 1.47-1.36 (m, 2H).

Example 2.2

[0349] DCP-nitrile (9.50 g, 44.0 mmol), trilfuoroacetic 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 a vacuum connection, a nitrogen inlet and a valve connected to a H.sub.2 inlet. The reactor was evacuated and the vacuum was replaced with nitrogen thrice. A H.sub.2 partial pressure of 0.5 bar was then applied and the reaction mixture was stirred at 20 C. After the conversion was complete, H.sub.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 in toluene and washed with water. The resulting organic layer was concentrated under reduced pressure to afford DCP-aldehyde (7.4 g) as a slightly yellow oil.

[0350] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.75 (s, 1H), 7.60 (d, J=1.90 Hz, 1H), 7.46-7.27 (m, 2H), 1.80-1.61 (m, 2H), 1.47-1.36 (m, 2H).

Reaction (a3) of Scheme 1:

Example 3

[0351] 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) in a way that the temperature was kept between 5 C. and 0 C. After a post addition stirring period of 30 minutes, a 2 M aqueous HCl-solution was added to the reaction mixture at 20 C. Subsequently, the reaction mixture was 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.sub.2SO.sub.4, filtered and the solvents were removed under reduced pressure. 1-(2,4-dichlorophenyl)cyclopropanecarbaldehyde (20.1 g) was isolated as a yellow oil.

[0352] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.05 (s, 1H), 7.45 (m, 1H), 7.20 (m, 2H), 1.70 (m, 2H), 1.40 (m, 2H).

Reaction (a4) of Scheme 1:

Example 4.1

[0353] A 60% solution of REDAL in toluene (87.6 g, 260 mmol) was dosed over 4 h to a solution of 1-(2,4-dichlorophenyl)cyclopropanecarbonitrile (84.8 g, 400 mmol) in toluene (212 g) at a temperature of 0 C. After a post addition stirring period of 2 hours at 0 C., the reaction mixture was dosed onto a 50% aqueous acetic acid solution (384 g, 3.2 mol) in a way to keep temperature of the reaction mixture below <25 C. Subsequently, a 32% aqueous HCl solution (137 g, 1.2 mol) was dosed to the mixture. The phases were separated and the organic phase was extracted twice with water (75 g) before the solvent of the organic phase was removed under reduced pressure. 1-(2,4-dichlorophenyl)cyclopropanecarbaldehyde (81.0 g) was isolated as an orange oil.

[0354] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.75 (s, 1H), 7.60 (d, J=1.90 Hz, 1H), 7.46-7.27 (m, 2H), 1.80-1.61 (m, 2H), 1.47-1.36 (m, 2H).

Example 4.2

[0355] A 70% solution of REDAL in toluene (97.3 g, 0.34 mol) was dosed over 80 minutes to 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 post addition stirring period of 1 h at 20-25 C., the reaction mixture was dosed onto a mixture consisting of a 50% aqueous acetic acid solution (266.0 g, 2.19 mol) and a 35% aqueous HCl solution (160.0 g, 1.54 mol) keeping the temperature of the reaction mixture below 25 C. The phases were separated and the organic phase was extracted twice with water (60 g) before the solvent of the organic phase was removed under reduced pressure. 1-(2,4-dichlorophenyl)cyclopropanecarbaldehyde (118.4 g) was isolated as a dark orange oil.

[0356] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.75 (s, 1H), 7.60 (d, J=1.90 Hz, 1H), 7.46-7.27 (m, 2H), 1.80-1.61 (m, 2H), 1.47-1.36 (m, 2H).

Second Aspect:

Reaction (b) of Scheme 1:

Example 5.1

[0357] To a 10-mL flame-dried two-necked flask, equipped with a thermometer and a bubbler, under argon, containing 1-(2,4-dichlorophenyl)cyclopropanecarbaldehyde (1.4 g, 6.0 mmol), was added chlorobenzene (6 mL), followed by anhydrous AlCl.sub.3 (1.2 g, 9.0 mmol). The resulting suspension was heated 1 h at 45 C.

[0358] After cooling down to rt, the mixture was poured on cold 1N HCl and diluted with ethyl acetate. The aqueous phase was extracted twice with dichloromethane. The combined organic phase was washed once with 1N HCl and once with brine then dried with solid Na.sub.2SO.sub.4, filtered and concentrated under vacuum. 2-(2,4-dichlorophenyl)cyclobutanone (1.35 g) was isolated as a brown oil.

[0359] .sup.1H NMR (400 MHz, CDCl.sub.3) 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

[0360] 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.sub.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 the dosing and the post addition stirring period. Essentially complete conversion was achieved after a post addition stirring period of 1 h at Ti=50-55 C. The reaction mixture was cooled to rt and then dosed onto a 14% aqueous HCl-solution (352.7 g, 1.34 mol) in a way that Ti was kept below 40 C. The mixture was stirred for 45 minutes before the phases were separated. The organic phase was subsequently extracted twice with water (83.3 g, 4.6 mol and 80.0 g, 4.4 mol) before the organic phase was concentrated under reduced pressure. 2-(2,4-dichlorophenyl)cyclobutanone (110.6 g) was isolated as a brown oil.

[0361] .sup.1H NMR (400 MHz, CDCl.sub.3) 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

[0362] The following compounds were prepared in an analogous manner to example 5:

##STR00007##

TABLE-US-00003 TABLE 1 Example R R .sup.1H NMR (400 MHz, CDCl.sub.3) 6 H Cl 7.31-7.10 (m, 4H), 4.50 (m, 1H), 3.22 (m, 1H), 3.02 (m, 1H), 2.55 (m, 1H), 2.18 (m, 1H). 7 F F 7.22 (m, 1H), 6.80 (m, 2H), 4.55 (m, 1H), 3.25 (m, 1H), 3.09 (m, 1H), 2.53 (m, 1H), 2.13 (m, 1H). 8 Br Cl 7.35 (m, 2H), 6.95 (m, 1H), 4.75 (m, 1H), 3.25 (m, 1H), 3.06 (m, 1H), 2.63 (m, 1H), 2.06 (m, 1H). 9 Cl F 7.30 (m, 1H), 7.10 (m, 1H), 6.90 (m, 1H), 4.69 (m, 1H), 3.19 (m, 1H), 2.98 (m, 1H), 2.53 (m, 1H), 2.06 (m, 1H).

Third Aspect:

Reaction (c) of Scheme 1:

Examples 10-18

[0363] A pressure autoclave was charged with 2-(2,4-dichlorophenyl)cyclobutanone (0.5 mmol), [RuCl(p-cymene)((S)-DM-SEGPHOS)]Cl (0.005 mmol), the corresponding ammonium salt (0.5 mmol, see Table 2) and MeOH (5 mL). A hydrogen pressure of 30 bar was applied and the reaction mixture was heated to 80 C. After a stirring period of 22 h the reaction mixture was cooled to rt and analyzed via chiral HPLC (method 1) and .sup.1H NMR.

TABLE-US-00004 TABLE 2 Example Ammonium salt Yield [%] ee [%] (S,S) 10 Ammonium acetate 79 83 11 Ammonium benzoate 94 74 12 Ammonium salicylate 85 76 13 Ammonium o-chlorobenzoate 79 78 14 Ammonium m-chlorobenzoate >99 72 15 Ammonium p-methoxybenzoate 84 73 16 Ammonium chloroacetate n.d. 83 17 Ammonium dichloroacetate 19 n.d. 18 Ammonium trichloroacetate 13 n.d. n.d. = not determined

Examples 19-24

[0364] A pressure autoclave was charged with 2-(2,4-dichlorophenyl)cyclobutanone (0.5 mmol), [RuCl(p-cymene)((S)-DM-SEGPHOS)]Cl (0.005 mmol), the corresponding ammonium salt (0.6 mmol, see Table 3) and MeOH (2.5 mL). A hydrogen pressure 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 h and H.sub.2O (20 mL) and HCl (1M, 2 mL) were added. The mixture was extracted with MTBE (20 mL) and the organic layer was extracted with an aqueous HCl-solution (2 ml HCl 1M and 20 mL H.sub.2O). The aqueous phase was basified using an aqueous NaOH-solution (5 M, 2 mL) and it was extracted with MTBE (320 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and the solvent was removed under reduced pressure. The residue was analyzed via chiral HPLC (method 1) and .sup.1H NMR.

TABLE-US-00005 TABLE 3 Example Ammonium salt Yield [%] ee [%] (S,S) 19 Ammonium p-chlorobenzoate 58 70 20 Ammonium hydroxyacetate 58 86 21 Ammonium lactate 57 80 22 Ammonium (S)-lactate 40 80 23 Ammonium methoxyacetate 72 82 24 Ammonium 2-acetoxyacetate 60 84

Example 25-26

[0365] A 7N ammonia solution in MeOH (108 mmol) was added to a mixture of the corresponding acid (110 mmol) in MeOH (as much to get a 10% solution of the ammonium salt) at rt. The mixture was stirred for about 10 minutes and was ready to be used in the direct asymmetric reductive amination step.

Direct Asymmetric Reductive Amination

[0366] A pressure autoclave was charged with [NH.sub.2Me.sub.2][(RuCl((R)-xylbinap)).sub.2(u-Cl).sub.3] (0.135 mmol), the previously prepared 10% solution of the corresponding ammonium salt in MeOH (108 mmol, see Table 4) and MeOH (44 g). The reaction mixture was heated to 80 C. and a hydrogen pressure of 30 bar was applied. Subsequently, a solution of 2-(2,4-dichlorophenyl)cyclobutanone (624 mmol) in MeOH (20 g) was added over 4 h to the autoclave. The reaction mixture was cooled to rt after the post addition stirring period of 2 h. Subsequently, the reaction mixture was basified and analyzed via chiral (method 1) and achiral (method 2) HPLC.

TABLE-US-00006 TABLE 4 Example Ammonium salt Yield [%] ee [%] (S,S) 25 Ammonium phenoxyacetate 73 84 26 Ammonium furan-2-carboxylate 73 77

Examples 27-46

[0367] Different additives were tested in a screening platform. The reaction vessel was charged with 2-(2,4-dichlorophenyl)cyclobutanone (2.0 mmol), [NH.sub.2Me.sub.2][(RuCl((R)-xylbinap)).sub.2(u-Cl).sub.3] (0.25 mol %), ammonium acetate (2.4 mmol), the corresponding additive (see Table 5) and MeOH (2.5 mL). A hydrogen pressure of 30 bar was applied and the reaction mixture was heated to 80 C. After a stirring period of 16 h the reaction mixture was cooled to rt and analyzed via via chiral (method 1) and achiral (method 2) HPLC.

TABLE-US-00007 TABLE 5.1 Additive ee [%] Example Additive [Eq] Yield [%] (S,S) 27 None n.a. 68 73 28 Chloroacetic acid 1.0 67 70 29 Chloroacetic acid 0.1 77 74 30 Trifluoroacetic acid 1.0 36 74 31 Trifluoroacetic acid 0.1 76 71 32 Methoxyacetic acid 1.0 81 71 33 Methoxyacetic acid 0.1 77 74 34 Salicylic acid 1.0 55 61 35 Salicylic acid 0.1 74 75 36 2-methoxybenzoic acid 1.0 46 67 37 2-methoxybenzoic acid 0.1 71 74 38 N-methylglycine 1.0 33 80 39 N-methylglycine 0.1 67 76 40 HOAc 1.0 80 70 41 NH.sub.4Br 0.1 75 77 42 Iodine 0.1 75 80 43 2,2,2-Trifluoroethanol 1.0 77 75 44 2,2,2-Trifluoroethanol 0.1 75 75 45 MgSO.sub.4 61 71 46 Molecular sieve 73 75

Examples 46.1, 46.2

[0368] A pressure autoclave was charged with 2-(2,4-dichlorophenyl)cyclobutanone (93.0 mmol), [NH.sub.2Me.sub.2][(RuCl((R)-xylbinap)).sub.2(u-Cl).sub.3] (0.1 mol %), ammonium phenoxyacetate (158.4 mmol), the corresponding additive (see Table 5.2) and MeOH (4.1 mol). A hydrogen pressure of 30 bar was applied and the reaction mixture was heated to 80 C. After a stirring period of 17 h the reaction mixture was cooled to rt and analyzed via chiral (method 1) and achiral (method 2) HPLC.

TABLE-US-00008 TABLE 5.2 Additive ee [%] Example Additive [Eq] Yield [%] (S,S) 46.1 NH.sub.4Cl 0.1 69 82 46.2 Phenoxyacetic acid 0.25 71 83

Examples 47-51

[0369] A pressure autoclave was charged with 2-(2,4-dichlorophenyl)cyclobutanone (0.5 mmol), [RuCl(p-cymene)((S)-DM-SEGPHOS)]Cl (0.005 mmol), ammonium acetate (0.6 mmol) and the corresponding solvent (5.0 mL). A hydrogen pressure 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 h and H.sub.2O (20 mL) and a 1M aqueous HCl-solution (2 mL) were added. The mixture was extracted with MTBE (20 mL) and the organic layer was extracted with an aqueous HCl-solution (2 ml HCl 1M and 20 mL H.sub.2O). The aqueous phase was basified using an aqueous 5M NaOH-solution (2 mL) and it was extracted with MTBE (320 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and the solvent was removed under reduced pressure. The residue was analyzed via chiral HPLC (method 1) and .sup.1H NMR.

TABLE-US-00009 TABLE 6 Example Solvent Yield [%] ee [%] (S,S) 47 MeOH 67 81 48 CF.sub.3CH.sub.2OH 38 55 49 EtOH 61 74 50 CH.sub.2Cl.sub.2 60 57 51 Toluene 17 63

Examples 52

[0370] A pressure autoclave was charged with 2-(2,4-dichlorophenyl)cyclobutanone (1.4 mmol), [RuCl(p-cymene)((S)-DM-SEGPHOS)]Cl (0.014 mmol), ammonium metachlorbenzoate (1.4 mmol) and MeOH (13.8 mL). A hydrogen pressure of 5 bar was applied and the reaction mixture was heated to 80 C. The reaction mixture was cooled to rt after a stirring period of 16 h. H.sub.2O (50 mL) and a 1M aqueous HCl-solution (5 mL) were added. The mixture was extracted with MTBE (50 mL) and the organic layer was extracted with an aqueous HCl-solution (5 ml HCl 1M and 20 mL H.sub.2O). The aqueous phase was basified using a 5M aqueous NaOH-solution (5 mL) and it was extracted with MTBE (350 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and the solvent was removed under reduced pressure. The residue was analyzed via chiral HPLC (method 1) and .sup.1H NMR.

Examples 53

[0371] A pressure autoclave was charged with 2-(2,4-dichlorophenyl)cyclobutanone (0.5 mmol), [RuCl(p-cymene)((S)-DM-SEGPHOS)]Cl (0.005 mmol), ammonium metachlorbenzoate (0.5 mmol) and MeOH (5 mL). A hydrogen pressure 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 h and analyzed via chiral HPLC (method 1) and .sup.1H NMR.

Examples 54

[0372] A pressure autoclave was charged with 2-(2,4-dichlorophenyl)cyclobutanone (0.46 mmol), [RuCl(p-cymene)((S)-DM-SEGPHOS)]Cl (0.0046 mmol), ammonium metachlorbenzoate (0.55 mmol) and MeOH (2.3 mL). A hydrogen pressure 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 h. H.sub.2O (20 mL) and a 1M aqueous HCl-solution (2 mL) were added. The mixture was extracted with MTBE (20 mL) and the organic layer was extracted with an aqueous HCl-solution (2 ml HCl 1M and 20 mL H.sub.2O). The aqueous phase was basified using a 5M aqueous NaOH-solution (2 mL) and it was extracted with MTBE (320 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and the solvent was removed under reduced pressure. The residue was analyzed via chiral HPLC (method 1) and .sup.1H NMR.

[0373] The results of examples 52-54 are summarized in table 7.

TABLE-US-00010 TABLE 7 Reaction time Example H.sub.2 Pressure [Bar] [h] Yield [%] ee [%] (S,S) 52 5 16 70 70 53 10 17 73 71 54 30 19 69 69

Examples 55-56

[0374] A pressure autoclave was charged with 2-(2,4-dichlorophenyl)cyclobutanone (4.0 mmol), Ru(OAc).sub.2[(R)-xylbinap] (0.02 mmol), ammonium acetate (4.8 mmol), acetic acid (6.4 mmol) and MeOH (10 mL). A hydrogen pressure of 30 bar was applied and the reaction mixture was heated to 80 C. After the corresponding stirring period the reaction mixture was cooled to rt. The mixture was diluted with MTBE and water and a 1M HCl-solution was added. The organic phase was extracted twice with a 1M HCl solution. The combined aqueous phases were basified using an aqueous 5M NaOH-solution and it was extracted three time with MTBE. The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and the solvent was removed under reduced pressure. The residue was analyzed via chiral HPLC (method 1) and .sup.1H NMR.

TABLE-US-00011 TABLE 8 Reaction time Example T [ C.] [h] Yield [%] ee [%] (S,S) 55 50 16 18 n.d. 56 80 4 76 75

Examples 57-66

[0375] Different preformed Ru-catalysts were tested in a screening platform. The reaction vessel was charged with 2-(2,4-dichlorophenyl)cyclobutanone (2.0 mmol), the corresponding catalyst (see Table 9), ammonium acetate (2.4 mmol) and MeOH (2.5 mL). A hydrogen pressure of 30 bar was applied and the reaction mixture was heated to 80 C. After a stirring period of 16 h the reaction mixture was cooled to rt and analyzed via chiral (method 1) and achiral (method 2) HPLC.

TABLE-US-00012 TABLE 9 Catalyst loading Yield ee [%] Example Catalyst [mol %] [%] (S,S) 57 [NH.sub.2Me.sub.2][(RuCl((R)- 0.25 68 73 xylbinap)).sub.2(-Cl).sub.3] 58 [NH.sub.2Me.sub.2][(RuCl((R)- 0.125 57 74 xylbinap)).sub.2(-Cl).sub.3] 59 Ru(OAc).sub.2[(R)-xylbinap] 0.25 58 73 60 Ru(OAc).sub.2[(R)-xylbinap] 0.125 20 72 61 [RuCl(p-cymene)((R)- 0.25 70 75 xylbinap)]Cl 62 [RuCl(p-cymene)((R)- 0.125 53 74 xylbinap)]Cl 63 RuCl.sub.2[(R)-xylbinap][(R)- 0.25 60 75 daipen] 64 RuCl.sub.2[(R)-xylbinap][(R)- 0.125 20 73 daipen] 65 RuCl.sub.2[(R)-xylbinap][(R,R)- 0.25 74 75 dpen] 66 RuCl.sub.2[(R)-xylbinap][(R,R)- 0.125 58 74 dpen]

Examples 67-93

[0376] Different chiral ligands in combination with ruthenium were tested in a screening platform. [Ru(Me-allyl).sub.2(cod)] and the corresponding ligand (see Table 10) were dissolved in acetone (2.5 ml) and subsequently 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 the autoclave together with 2-(2,4-dichlorophenyl)cyclobutanone (2.0 mmol), ammonium acetate (2.4 mmol) and MeOH (2.5 mL). A hydrogen pressure of 30 bar was applied and the reaction mixture was heated to 80 C. After a stirring period of 16 h the reaction mixture was cooled to rt and analyzed via chiral (method 1) and achiral (method 2) HPLC.

TABLE-US-00013 TABLE 10 Example Ligand Yield [%] ee [%] 67 (R)-()-5,5-Bis[di(3,5-di-tert-butyl-4- 27.0 66.5 methoxyphenyl)phosphino]-4,4-bi-1,3-benzodioxole (S,S) 68 (S)-1,13-Bis(diphenylphosphino)-7,8-dihydro-6H- 20.4 64.2 dibenzo[f,h][1,5]dioxonin (S,S) 69 (S,S)Fc-1,1-Bis[bis(3,5-dimethylphenyl)phosphino]-2,2- 20.7 67.7 bis[(R,R)C-(N,N-dimethylamino)phenylmethyl]ferrocene (S,S) 70 (R)-2,2-Bis[bis(3,5-diisopropyl-4- 35.3 63.1 dimethylaminophenyl)phosphino]-6,6-dimethoxy-1,1- (S,S) biphenyl 71 (S)-2,2-Bis[bis(3,4,5-trimethoxyphenyl)phosphino]- 14.0 78.2 4,4,5,5,6,6-hexamethoxy-1,1-biphenyl (R,R) 72 (R)-(+)-2,2-Bis[di(3,5-xylyl) phosphino]-1,1-binaphthyl 50.9 74.1 (S,S) 73 (R)-1-Diphenylphosphino-2-[(R)-(N,N-dimethylamino)[2- 32.9 16.6 (diphenylphosphino)phenyl]methyl]ferrocene (S,S) 74 (R)-(+)-2,2-Bis(diphenylphosphino)-5,5,6,6,7,7,8,8- 65.8 73.5 octahydro-1,1-binaphthyl (S,S) 75 (R)-1-[(R)-1-[Bis[3,5-bis(trifluoromethyl)phenyl]phosphino] 49.5 88.8 ethyl]-2-[2-(diphenylphosphino)phenyl]ferrocene (R,R) 76 (R)-2,2-Bis[bis(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]- 16.4 71.5 6,6-dimethoxy-1,1-biphenyl (S,S) 77 (S)-2,2-Bis[di-3,5-xylylphosphino]-6,6-dimethoxy-1,1- 43.9 73.7 biphenyl (R,R) 78 (R)-(+)-2,2,6,6-Tetramethoxy-4,4-bis(di(3,5- 47.3 76.7 xylyl)phosphino)-3,3-bipyridine (S,S) 79 (R)-1-[(R)-1-(Diphenylphosphino)ethyl]-2-[2- 69.4 34.6 (diphenylphosphino)phenyl]ferrocene (R,R) 80 (S)-2,2-Bis(di-p-dimethylaminophenylphosphino)-6,6- 17.3 46.5 dimethoxy-1,1-biphenyl (R,R) 81 (R)-2,2-Bis[bis(3,5-di-tert-butylphenyl)phosphino]-6,6- 26.2 70.8 dimethoxy-1,1-biphenyl (S,S) 82 (S)-(-)-6,6-Bis(diphenylphosphino)-2,2,3,3-tetrahydro-5,5- 24.4 69.0 bi-1,4-benzodioxin (R,R) 83 (R)-1-[(R)-1-[Di(3,5-xylyl)phosphino]ethyl]-2-[2-[di(3,5- 63.6 50.5 xylyl)phosphino]phenyl]ferrocene (R,R) 84 (R)-2,2-Bis(diphenylphosphino)-6,6-dimethoxy-1,1-biphenyl 24.4 69.6 (S,S) 85 (S)-2,2-Bis(di-m-dimethylaminophenylphosphino)-6,6- 39.2 63.8 dimethoxy-1,1-biphenyl (S,S) 86 (R)-2,2-Bis[bis(3,5-diisopropyl-4- 19.4 68.2 dimethoxyphenyl)phosphino]-6,6-dimethoxy-1,1-biphenyl (S,S) 87 (R)-(+)-5,5-Bis[di(3,5-xylyl)phosphino]-4,4-bi-1,3- 43.7 72.9 benzodioxole (S,S) 88 (+)-1,2-Bis[(2R,5R)-2,5-diisopropylphospholano]benzene 71.9 11.2 (R,R) 89 (S)-2,2-Bis(di-p-tolylphosphino)-6,6-dimethoxy-1,1-biphenyl 18.9 65.9 (R,R) 90 (S)-2,2-Bis(di-6-methoxy-2-naphthalenylphosphino)-6,6- 14.7 75.8 dimethoxy-1,1-biphenyl (R,R) 91 (R)-2,2-Bis[bis(3,5-diisopropylphenyl)phosphino]-6,6- 15.4 67.0 dimethoxy-1,1-biphenyl (S,S) 92 1-Dicyclohexylphosphino-1-[(S).sub.P-[(S).sub.Fc-2-[(R).sub.C-1- 17.6 44.7 (dimethylamino)ethyl]ferrocenyl]phenylphosphino]ferrocene (S,S) 93 (S)-()-5,5-Bis(diphenylphosphino)-2,2,2,2-tetrafluoro-4,4-bi- 15.6 75.2 1,3-benzodioxole (R,R)

Example 94

[0377] A solution of ammonium methoxyacetate in MeOH (323 g, 301 mmol), methanol (123 g), diacetato((R)-(+)-2,2-bis[di(3,5-xylyl)phosphino]-1,1-binaphthyl) ruthenium (0.72 g, 0.75 mmol) were charged to a pressure reactor. The reactor was sealed and 3 pressure swings to N.sub.2 (6 bar) without stirring followed by 3 pressure swings to H.sub.2 (6 bar) with stirring were carried out and the mixture was heated to 55 C. The pressure was increased to 10 bar using hydrogen and the reactor heated to 80 C. At 80 C., the pressure was 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 h. The reaction mixture was stirred for 8 h, until the hydrogen uptake had stopped. The pressure was released and 3 pressure swings to N.sub.2 (6 bar) were carried out. The reaction mass was then concentrated in vacuo (60 C., 90 mbar) to give a brown oil.

[0378] 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 the phases were left to separate. The lower aqueous phase was removed and the upper organic phase was washed with a 1M aqueous HCl solution (50 mL) and the phases were left to separate. 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 bi-phasic system was cooled to 10 C. A 30% aqueous NaOH solution (80 g) was added to reach pH 10, keeping the temperature below 20 C. The phases were left to separate. The lower aqueous phase was removed and washed twice with toluene (2100 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.

[0379] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 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, 1H), 1.15 (br s, 2H).

Examples 95-98

[0380] The following compounds in Table 11 were prepared in an analogous manner to examples 10-94.

##STR00008##

TABLE-US-00014 TABLE 11 Entry R R R .sup.1H NMR 95 F F H .sup.1H NMR (400 MHz, CDCl.sub.3) 7.30-7.20 (m, 1H), 6.93-6.86 (m, 1H), 6.84-6.76 (m, 1H), 3.88-3.80 (m, 2H), 2.46-2.35 (m, 1H), 2.29-2.11 (m, 2H), 1.77-1.66 (m, 1H). 96 CF.sub.3 H H .sup.1H NMR (400 MHz, CDCl.sub.3) 7.69 (d, J = 7.7 Hz, 1H), 7.63-7.56 (m, 2H), 7.38-7.32 (m, 1H), 4.13-4.05 (m, 1H), 3.92-3-85 (m, 1H), 2.52- 2.34 (m, 2H), 2.29-2.19 (m, 1H), 1.85-1.74 (m, 1H). 97 F CF.sub.2H H .sup.19F NMR (400 MHz, DMSO-d.sub.6) 109.7, 114.1. 98 F F F .sup.19F NMR (400 MHz, DMSO-d.sub.6) 135.6 (d, J = 21Hz, 2F), 164.3 (t, J = 21 Hz, 1F).

Fourth Aspect:

Reaction (d) of Scheme 1:

Example 99

[0381] To a solution of 2-(2,4-dichlorophenyl)cyclobutanone (5.00 g, 23.2 mmol) in chlorobenzene (23.2 mL) were added at rt AlCl.sub.3 (4.65 g, 34.9 mmol), CH.sub.3CN (6.08 mL, 116 mmol) and AcCl (2.48 mL, 34.9 mmol). A slight exotherm was observed upon addition of AcCl. The resulting yellowish suspension was heated at 50 C. for 1 h. After cooling down to rt, the reaction mixture was added dropwise to a 0 C. cold aqueous solution of 4N NaOH (116 mL) and 50 mL of toluene. A pale yellow precipitate formed during addition. After filtration, N-[2-(2,4-dichlorophenyl)cyclobuten-1-yl]acetamide (3.56 g) was obtained as a white solid.

[0382] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 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

[0383] The following compounds in Table 12 were prepared in an analogous manner to example 99:

##STR00009##

TABLE-US-00015 TABLE 12 Example R R .sup.1H NMR 100 H OCF.sub.3 .sup.1H NMR (400 MHz, CDCl.sub.3) 7.30-7.13 (m, 5H), 3.05 (m, 2H), 2.57 (m, 2H), 2.1 (s, 3H). 101 H OCHF.sub.2 .sup.1H NMR (400 MHz, Acetone-d.sub.6) 9.05 (bs, 1H), 7.38 (d, J = 8.8 Hz, 2H), 7.13 (d, J = 8.8 Hz, 2H), 6.97 (t, J = 74.5 Hz, 1H), 3.01 (t, J = 3.5 Hz, 2H), 2.55 (t, J = 3.5 Hz, 2H), 2.06 (s, 3H). 102 CF.sub.3 H .sup.1H NMR (400 MHz, CDCl.sub.3) 7.66 (d, J = 7.7 Hz, 1H), 7.51 (t, J = 7.3 Hz, 1H), 7.38-7.30 (m, 2H), 3.05 (t, J = 2.9 Hz, 2H), 2.72 (t, J = 2.9 Hz, 2H), 2.01 (s, 3H). 103 CF.sub.3 F .sup.1H NMR (400 MHz, CDCl.sub.3) 7.40-7.30 (m, 2H), 7.22-7.09 (m, 2H), 3.05 (t, J = 3 Hz, 2H), 2.69 (bs, 2H), 2.02 (s, 3H). 104 Br F .sup.1H NMR (400 MHz, CDCl.sub.3) 7.47 (bs, 1H), 7.30 (dd, J = 8.4 and 2.6 Hz, 1H), 7.19 (dd, J = 8.6 and 6.1 Hz, 1H), 7.02 (dt, J = 2.6 and 8.3 Hz, 1H), 3.03 (t, J = 3.3 Hz, 2H), 2.70 (t, J = 3.3 Hz, 2H), 2.06 (s, 3H). 105 Cl Br .sup.1H NMR (400 MHz, CDCl.sub.3) 7.61 (bs, 1H), 7.50 (d, J = 1.8 Hz, 1H), 7.35 (dd, J = 8.44 and 1.83 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 3.04 (bs, 2H), 2.67 (bs, 2H), 2.07 (s, 3H). 106 Cl F .sup.1H NMR (400 MHz, Acetone-d.sub.6) 8.94 (bs, 1H), 7.41 (dd, J = 8.6 and 6.4 Hz, 1H), 7.22 (dd, J = 8.8 and 2.5 Hz, 1H), 7.09 (dt, J = 2.5 and 8.4 Hz, 1H), 2.99 (t, J = 3.4 Hz, 2H), 2.74 (t, J = 3.3 Hz, 2H), 2.02 (s, 3H). 107 F F .sup.1H NMR (400 MHz, CDCl.sub.3) 7.73 (bs, 1H), 7.09 (dt, J = 6.6 and 8.4 Hz, 1H), 6.92-6.77 (m, 2H), 3.09 (t, J = 3.3 Hz, 2H), 2.56 (t, J = 3.5 Hz, 2H), 2.08 (s, 3H).

Examples 108-119

[0384] N-[2-(2,4-dichlorophenyl)cyclobuten-1-yl]acetamide (a compound of formula (VI)) may be prepared in analogy to example 99 applying the reaction parameters mentioned under examples 108-119:

TABLE-US-00016 TABLE 13 Lewis/ Chemical Brnsted CH.sub.3CN Additive T t CC.sup.a yield Example Acid (eq) (eq) (eq) [ C.] [h] Solvent [mol/L] [%] 108 AlCl.sub.3 (1.5) 5 p- 50 3 C.sub.6H.sub.5Cl 1 80% MeOC.sub.6H.sub.4COCl (0.25) 109 FeCl.sub.3 (1) 5 AcCl (2) 25 1.25 DCE 0.33 42% 110 BF.sub.3Et.sub.2O (1.5) 5 AcCl (2) 40 18 DCE 0.33 56% 111 HBF.sub.4Et.sub.2O (1.5) 5 AcCl (2) 25 3.5 DCE 0.33 57% 112 HBF.sub.4Et.sub.2O (1.5) 5 p-Anisic 50 18 C.sub.6H.sub.5Cl 0.5 46% anhydride (0.5) 113 HBF.sub.4Et.sub.2O (1.5) 5 Isopropenyl 25 16 C.sub.6H.sub.5Cl 0.5 53% acetate (0.5) 114 Triflic Acid (1.5) 5 AcCl (2) 25 0.5 DCE 0.33 62% 115 nonaflic acid 5 AcCl (1.5) 50 6 DCE 0.33 52% (1.5) 116 MeSO.sub.3H (5) 5 AcCl (2) 30 16 DCE 0.11 28% 117 MeSO.sub.3H (2.5) 10 p-Anisic 25 1 none 31% anhydride (0.5) 118 Eaton's reagent 5 AcCl (2) 25 23 C.sub.6H.sub.5Cl 0.5 33% (2.5) 119 Eaton's reagent 10 Isopropenyl 25 1.5 none 44% (2.5) acetate (1) .sup.aConcentration relative to compound of formula (III).

Fifth Aspect:

[0385] Reaction (d) of Scheme 1:

Example 120

[0386] To a solution of 1-(2,4-dichlorophenyl)cyclopropanecarbaldehyde (2.1 g, 9.3 mmol) in chlorobenzene (9 mL) was added at rt AlCl.sub.3 (1.9 g, 14 mmol). The resulting yellowish suspension was heated at 60 C. for 30 min. After cooling down to 35 C., CH.sub.3CN (4.38 mL, 83.7 mmol) and AcCl (1.70 mL, 23.3 mmol) were added. A slight exotherm was observed upon addition of AcCl. The reaction was heated up to 50 C. for 30 min, then, after cooling down to 5 C., the reaction mixture was added drop wise to a 0 C. cold aqueous solution of 4N NaOH (46 mL) and 50 mL of toluene. A pale yellow precipitate formed during addition. The internal temperature was maintained between 0 C. and 5 C. The bi-phasic suspension was transferred into a 250 mL separation 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 a 1N aqueous NaOH solution (50 mL) and with water (250 mL; until pH of aqueous phase was neutral). Combined organics were then dried over solid Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. N-[2-(2,4-dichlorophenyl)cyclobuten-1-yl]acetamide (2.3 g) was obtained as a yellow solid.

[0387] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 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

[0388] The following compounds of Table 14 were prepared in an analogous manner to example 120:

##STR00010##

TABLE-US-00017 TABLE 14 Example R R R .sup.1H NMR 121 F F F .sup.1H NMR (400 MHz, CDCl.sub.3) 7.51 (bs, 1H), 6.65 (m, 2H), 3.1 (bs, 2H), 2.76 (bs, 2H), 2.08 (s, 3H). 122 H Cl H .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.58 (bs, 1H), 7.36 (s, 4H), 2.88 (m, 2H), 2.46 (m, 2H), 2.02 (s, 3H). 123 Cl H H .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.76 (bs, 1H), 7.38 (m, 2H), 7.29 (t, J = 8 Hz, 1H), 7.21 (t, J = 8 Hz, 1H), 2.87 (t, J = 3.5 Hz, 2H), 2.69 (t, J = 3.5 Hz, 2H), 1.94 (s, 3H). 124 Cl F H .sup.1H NMR (400 MHz, Acetone-d.sub.6) 8.94 (bs, 1H), 7.41 (dd, J = 8.62 and 6.4 Hz, 1H), 7.22 (dd, J = 8.8 and 2.6 Hz, 1H), 7.09 (dt, J = 2.6 and 8.4 Hz, 1H), 2.99 (t, J = 3.5 Hz, 2H), 2.74 (t, J = 3.3 Hz, 2H), 2.02 (s, 3H). 125 F F H .sup.1H NMR (400 MHz, CDCl.sub.3) 7.73 (bs, 1H), 7.09 (dt, J = 6.6 and 8.4 Hz, 1H), 6.92-6.77 (m, 2H), 3.09 (t, J = 3.3 Hz, 2H), 2.56 (t, J = 3.5 Hz, 2H), 2.08 (s, 3H).

Sixth Aspect:

Reaction (e) of Scheme 1:

Examples 126-131

Pre-Formation of Catalyst

[0389] A vial was charged with bis(COD)rhodium(I)trifluoromethanesulfonate precatalyst (0.01 mmol) and (R)-1-[(S)-2-(Di-tert-butylphosphino)ferrocenyl]ethyldi-o-tolylphosphine (0.011 mmol) in a glove box. Subsequently, the corresponding solvent (10.0 mL) was added and the solution was stirred for 90 minutes at rt.

Asymmetric Hydrogenation:

[0390] A pressure autoclave was charged with N-[2-(2,4-dichlorophenyl)cyclobuten-1-yl]acetamide (0.97 mmol), the corresponding solvent (1.50 mL) and the previously prepared catalyst solution (1.00 mL). A hydrogen pressure of 10 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 h at 50 C.

[0391] The reaction mixture was concentrated under reduced pressure and analyzed by quantitative .sup.1HNMR and chiral HPLC (method 4).

TABLE-US-00018 TABLE 15 Example Solvent Conversion [%] Selectivity [%] ee [%] (S, S) 126 TFE >99 >99 86 127 THF 67 >99 92 128 DCE 38 >99 90 129 EtOAc 50 >99 90 130 MeTHF 45 >99 88 131 Acetone 50 >99 86 TFE: 2,2,2-tetrafluroroethanol; DCE: 1 2-dichloroethane. The term selectivity as used in the above table refers to the selectivity of the reaction to compounds of formula (VI).

Examples 132-133

Pre-Formation of Catalyst

[0392] A vial was charged with bis(COD)rhodium(I)trifluoromethanesulfonate precatalyst (0.01 mmol) and (R)-1-[(S)-2-(Di-tert-butylphosphino)ferrocenyl]ethyldi-o-tolylphosphine (0.011 mmol) in a glove box. Subsequently, MeOH (5.00 mL) was added and the solution was stirred for 30 minutes at rt.

Asymmetric Hydrogenation:

[0393] A pressure autoclave was charged with N-[2-(2,4-dichlorophenyl)cyclobuten-1-yl]acetamide (0.98 mmol), MeOH (4.00 mL) and the previously prepared catalyst solution (1.00 mL). The corresponding hydrogen pressure was applied and the reaction mixture was heated to 50 C. The reaction mixture was cooled to rt after a stirring period of 2 h at 50 C.

[0394] The reaction mixture was concentrated under reduced pressure and analyzed by quantitative .sup.1HNMR and chiral HPLC (method 4).

TABLE-US-00019 TABLE 16 ee [%] Example H.sub.2 Pressure [Bar] Conv. [%] Selectivity [%] (S, S) 132 10 >99 >90 85 133 50 >99 >90 88 The term selectivity as used in the above table refers to the selectivity of the reaction to compounds of formula (VI).

Examples 134-135

Pre-Formation of Catalyst

[0395] A vial was charged with bis(COD)rhodium(I)trifluoromethanesulfonate precatalyst (0.01 mmol) and (R)-1-[(S)-2-(Di-tert-butylphosphino)ferrocenyl]ethyldi-o-tolylphosphine (0.011 mmol) in a glove box. Subsequently, MeOH (5.00 mL) was added and the solution was stirred for 30 minutes at rt.

Asymmetric Hydrogenation:

[0396] A pressure autoclave was charged with N-[2-(2,4-dichlorophenyl)cyclobuten-1-yl]acetamide (0.98 mmol), MeOH (4.00 mL) and the previously prepared catalyst solution (1.00 mL). A hydrogen pressure of 50 bar was applied and the reaction mixture was heated to the temperature specified in the table. The reaction mixture was cooled to rt after a stirring period of 2 h at the temperature specified in the table. The reaction mixture was concentrated under reduced pressure and analyzed by quantitative .sup.1HNMR and chiral HPLC (method 4).

TABLE-US-00020 TABLE 17 ee [%] Example T [ C.] Conversion [%] Selectivity [%] (S, S) 134 rt 98 >90 88 135 50 100 >90 89 The term selectivity as used in the above table refers to the selectivity of the reaction to compounds of formula (VI).

Examples 136-139

Pre-Formation of Catalyst

[0397] A vial was charged with corresponding precatalyst (0.01 mmol) and (R)-1-[(S)-2-(Di-tert-butylphosphino)ferrocenyl]ethyldi-o-tolylphosphine (0.011 mmol) in a glove box. Subsequently, the corresponding solvent (10.0 mL) was added and the solution was stirred for 90 minutes at rt.

Asymmetric Hydrogenation:

[0398] A pressure autoclave was charged with N-[2-(2,4-dichlorophenyl)cyclobuten-1-yl]acetamide (0.97 mmol), the corresponding solvent (1.50 mL) and the previously prepared catalyst solution (1.00 mL). A hydrogen pressure of 10 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 h at 50 C.

[0399] The reaction mixture was concentrated under reduced pressure and analyzed by quantitative .sup.1HNMR and chiral HPLC (method 4).

TABLE-US-00021 TABLE 18 Example Rh precatalyst Solvent Conversion [%] Selectivity [%] ee [%] (S, S) 136 [Rh(COD).sub.2]O.sub.3SCF.sub.3 THF 67 >99 88 137 [Rh(COD).sub.2]BF.sub.4 THF 21 >99 88 138 [Rh(COD).sub.2]BARF THF 77 >99 90 139 [Rh(nbd).sub.2]BF.sub.4 THF 63 >99 92 The term selectivity as used in the above table refers to the selectivity of the reaction to compounds of formula (VI).

Examples 140-149

[0400] Different preformed Rh-catalysts were tested in a screening platform. The reaction vessel was charged with N-[2-(2,4-dichlorophenyl)cyclobuten-1-yl]acetamide (31.7 mol), the corresponding catalyst (0.158 mol) and the corresponding solvent (500 L). A hydrogen pressure of 50 bar was applied and the reaction mixture was heated to 50 C. After a stirring period of 16 h the reaction mixture was cooled to rt and analyzed via achiral (method 3) and chiral HPLC (method 4).

TABLE-US-00022 TABLE 19 ee Selectivity (S, S) Example Catalyst Solvent Conversion[%] [%] [%] 140 [Rh(COD)((1S,1S,2R,2R)-2,2-Di-tert-butyl- MeOH 47.6 55.8 6.1 2,3,2,3-tetrahydro- 1H,1H(1,1)biisophosphindolyl)]BF.sub.4 141 [Rh(COD)((1S,1S,2R,2R)-2,2-Di-tert-butyl- THF 52.6 41.3 5.5 2,3,2,3-tetrahydro- 1H,1H(1,1)biisophosphindolyl]BF.sub.4 142 [Rh(COD)((R,R)-1,2-Bis[(2- MeOH 93.2 82.1 0.9 methoxyphenyl)(phenylphosphino)]ethane)]BF.sub.4 143 [Rh(COD)((R,R)-1,2-Bis[(2- THF 99.8 81.9 14.7 methoxyphenyl)(phenylphosphino)]ethane)]BF.sub.4 144 [Rh(COD)((S)-tert-butylmethylphosphino-di-tert- MeOH 100.0 90.3 32.7 butylphosphinomethane)]BF.sub.4 145 [Rh(COD)((S)-tert-butylmethylphosphino-di-tert- THF 100.0 90.2 28.4 butylphosphinomethane)]BF.sub.4 146 [Rh(COD)(()-1,2-Bis[(2R,5R)-2,5- MeOH 69.7 49.3 1.3 diethylphospholano]benzene)]O.sub.3SCF.sub.3 147 [Rh(COD)(()-1,2-Bis[(2R,5R)-2,5- THF 60.9 47.0 7.2 diethylphospholano]benzene)]O.sub.3SCF.sub.3 148 [Rh(COD)(3,4-bis[(2R,5R)-2,5- MeOH 70.7 55.2 0.5 dimethylphospholan-1-yl]furan-2,5- dione)]O.sub.3SCF.sub.3 149 [Rh(COD)(3,4-bis[(2R,5R)-2,5- THF 72.2 57.2 7.0 dimethylphospholan-1-yl]furan-2,5-dione]]O.sub.3SCF.sub.3 The term selectivity as used in the above table refers to the selectivity of the reaction to compounds of formula (VI).

Examples 150-166

Pre-Formation of Catalyst

[0401] A vial was charged with [Rh(COD).sub.2]O.sub.3SCF.sub.3 (0.158 mol) and the corresponding chiral ligand (0.190 mol) in a glove box. Subsequently, dichloroethane was added and the solution was stirred for 30 minutes at rt before the solvent was evaporated under reduced pressure.

Asymmetric Hydrogenation:

[0402] N-[2-(2,4-dichlorophenyl)cyclobuten-1-yl]acetamide (31.7 mol) and MeOH (500 L) were added to the previously prepared catalyst. A hydrogen pressure 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 h at 50 C. The reaction mixture was concentrated under reduced pressure and analyzed via achiral (method 3) and chiral HPLC (method 4).

TABLE-US-00023 TABLE 20 Yield Selectivity ee Example Ligand [%] [%] [%] 150 (R)-1-[(S)-2-(Di-tert-butylphosphino)ferrocenyl]ethyldi-o- 100.0 89.9 93.7 tolylphosphine (S, S) 151 (S,S).sub.Fc-1,1-Bis[bis(4-methoxy-3,5- 100.0 90.2 22.4 dimethylphenyl)phosphino]-2,2-bis[(R,R).sub.C-(N,N- (R, R) dimethylamino)phenylmethyl]ferrocene 152 (R)-1-[(S)-2-cyclohexylphosphino)ferrocenyl]ethyl bis(2- 100.0 89.5 85.6 methylphenyl)-phosphine (S, S) 153 (R)-1-Diphenylphosphino-2-[(R)-(N,N-dimethylamino)[2- 100.0 91.8 5.9 (diphenylphosphino)phenyl]methyl]ferrocene (R, R) 154 (R,R)-()-2,3-Bis(tert-butylmethylphosphino)quinoxaline 94.5 73.4 24.1 (S, S) 155 (2R,3R)-()-2,3-Bis(diphenylphosphino)bicyclo[2.2.1]hept- 99.2 86.2 9.3 5-ene (R, R) 156 (S)-2,2-Bis(diisopropylphosphino)-6,6-dimethoxy-1,1- 100.0 89.3 26.5 biphenyl (S, S) 157 (2S,4S)-()-2,4-Bis(diphenylphosphino)pentane 100.0 91.4 3.0 (S, S) 158 1,1-Bis[(S).sub.P-[(S).sub.Fc-2-[(R).sub.C-1- 11.3 19.3 73.0 (dimethylamino)ethyl]ferrocenyl]phenylphosphino]ferrocene (R, R) 159 1-Dicyclohexylphosphino-1-[(S).sub.P-[(S).sub.Fc-2-[(R).sub.C-1- 97.1 87.6 68.8 (dimethylamino)ethyl]ferrocenyl]phenylphosphino]ferrocene (S, S) 160 (R)-1-[(S)-2-(Diphenylphosphino)ferrocenyl]ethyldi(3,5- 99.9 91.3 20.0 xylyl)phosphine (S, S) 161 (S).sub.Fc-1-[(R).sub.P-tert-Butylphosphinoyl]-2-[(R)-1- 100.0 90.0 72.1 (diphenylphosphino)ethyl]ferrocene (R, R) 162 (R)-1-[(S)-2-(Diphenylphosphino)ferrocenyl]ethyldi-tert- 100.0 91.3 73.9 butylphosphine (R, R) 163 (R)-1-[(S)-2- 100.0 89.6 70.3 (Diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine (R, R) ethanol adduct 164 (R)-2,2-Bis(diphenylphosphino)-6,6-dimethoxy-1,1- 98.1 84.5 7.2 biphenyl (S, S) 165 (R)-(+)-1,2-Bis(diphenylphosphino)propane 78.3 38.5 10.9 (S, S) 166 (R)-1-[(S)-2-[Di(1-naphthyl)phosphino]ferrocenyl]ethyldi- 100.0 85.5 22.3 tert-butylphosphine (S, S) The term selectivity as used in the above table refers to the selectivity of the reaction to compounds of formula (VI).

Examples 167-172

Pre-Formation of Catalyst

[0403] A vial was charged with [Rh(COD).sub.2]O.sub.3SCF.sub.3 (4.52 mg, 0.0096 mmol) and the corresponding chiral ligand (0.01208 mmol) in a glove box. Subsequently, argon degassed trifluoroethanol (10.0 mL) was added and the solution was stirred for 60 minutes at rt.

Asymmetric Hydrogenation:

[0404] A 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 prepared catalyst solution (2.00 mL). A hydrogen pressure of 10 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 h at 50 C.

[0405] The reaction mixture was concentrated under reduced pressure and analyzed via achiral (method 3) and chiral HPLC (method 4).

TABLE-US-00024 TABLE 21 Conversion Selectivity ee Ex. Ligand [%] [%] [%] 167 (R)-1-[(S)-2-[Di(2-furyl)phosphino]ferrocenyl] >99 >99 64 ethyldi-tert-butylphosphine (R, R) 168 (R)-1-[(S)-2-(Di-tert- >99 >99 86 butylphosphino)ferrocenyl]ethyldiphenylphosphine (S, S) 169 (R)-1-[(S)-2-(Diphenylphosphino)ferrocenyl]ethyldi- >99 >99 68 tert-butylphosphine (R, R) 170 (R)-1-[(S)-2- >99 >99 0 (Dicyclohexylphosphino)ferrocenyl]ethyldicyclohexyl phosphine 171 (R)-1-[(S)-2-[Bis(4-methoxy-3,5- >99 >99 44 dimethylphenyl)phosphino]ferrocenyl]ethyldicyclo- (R, R) hexylphosphine 172 (R)-1-[(S)-2-[Bis(4-methoxy-3,5- >99 >99 58 dimethylphenyl)phosphino]ferrocenyl]ethyldi-tert- (R, R) butyl-phosphine The term selectivity as used in the above table refers to the selectivity of the reaction to compounds of formula (VI).

Example 173

[0406] A mixture of Rh(COD).sub.2OTf (1.3 kg, 0.5 mol %) and (R)-1-[(S)-2-(di-tert-butylphosphino)ferrocenyl]ethyldi-o-tolylphosphine (2.1 kg, 0.7 mol %) in TFE (174 kg, 1.74 kmol) is stirred for 90 minutes at 50 C. before it is added to a suspension of 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 is performed at 50 C. and 10 bar hydrogen till complete conversion is achieved. The reaction solution (1176 kg; ee (S,S) 91%) is then transferred to the next step.

[0407] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 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) of Scheme 1 Using Ru-Catalysts:

Examples 174-180

Pre-Formation of Catalyst:

[0408] A vial was charged with bis(2-methallyl)(COD)ruthenium precatalyst (3.72 mg) and (S,S)-()-2,3-bis(tert-butylmethylphosphino)quinoxaline (4.26 mg) in a glove box. Subsequently, argon degassed dichloromethane (3.0 mL) was added followed by methanesulfonic acid (1.2 mg). The solution was stirred for 30 minutes at rt.

Asymmetric Hydrogenation:

[0409] A pressure autoclave was charged with N-[2-(2,4-dichlorophenyl)cyclobuten-1-yl]acetamide (0.25 g, 0.97 mmol), the corresponding argon degassed solvent (2.0 mL) and a part of the previously prepared catalyst solution (0.5 mL). A hydrogen pressure 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 h at 50 C.

[0410] The reaction mixture was concentrated under reduced pressure and analyzed by quantitative .sup.1HNMR and chiral HPLC (method 4).

TABLE-US-00025 TABLE 22 Example Solvent Conversion [%] Selectivity [%] ee [%] (S, S) 174 TFE 0 0 0 175 Acetone 94 98 95 176 iPrOH 100 100 94 177 DCE 91 97 94 178 THF 50 98 96 179 MeTHF 75 95 96 180 MeOH 100 100 97 The term selectivity as used in the above table refers to the selectivity of the reaction to compounds of formula (VI).

Examples 181-182

Pre-Formation of Catalyst:

[0411] A vial was charged with bis(2-methallyl)(COD)ruthenium (6.2 mg) and (S,S)-()-2,3-bis(tert-butylmethylphosphino)quinoxaline (7.1 mg) in a glove box. Subsequently, argon degassed dichloromethane (4.0 mL) was added followed by fluoroboric acid-diethyl ether complex (0.24 ml, 0.081 mmol/mL). The solution was stirred for 30 minutes at rt. The volume in the vial was reduced by bubbling argon through the solution (final volume: 1 mL) before degassed MeOH (9 mL) was added.

Asymmetric Hydrogenation:

[0412] A pressure autoclave was charged with N-[2-(2,4-dichlorophenyl)cyclobuten-1-yl]acetamide (0.5 g, 1.933 mmol), argon degassed MeOH (4.0 mL) and a part of the previously prepared catalyst solution (1.0 mL). The corresponding hydrogen pressure was applied and the reaction mixture was heated to 50 C. The reaction mixture was cooled to rt after a stirring period of 2 h at 50 C.

[0413] The reaction mixture was concentrated under reduced pressure and analyzed by quantitative .sup.1HNMR and chiral HPLC (method 4).

TABLE-US-00026 TABLE 23 Conversion ee [%] Example H.sub.2 Pressure [bar] [%] Selectivity [%] (S, S) 181 10 67 >99 n.d. 182 50 >99 >99 96 The term selectivity as used in the above table refers to the selectivity of the reaction to compounds of formula (VI). n.d. = not determined.

Examples 183

Pre-Formation of Catalyst:

[0414] A vial was charged with bis(COD)tetra[u-trifluoroacetato]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). Subsequently, the vials were inertised with argon and argon degassed MeOH (5.0 mL) was added. A hydrogen pressure 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 h at 50 C.

[0415] The reaction mixture was concentrated under reduced pressure and analyzed by quantitative .sup.1HNMR and chiral HPLC (method 4).

TABLE-US-00027 TABLE 24 Conversion Selectivity ee [%] Example Rh precatalyst [%] [%] (S, S) 183 [Ru(cod)(CF.sub.3CO.sub.2).sub.2].sub.2 84 95 94 n H.sub.2O The term selectivity as used in the above table refers to the selectivity of the reaction to compounds of formula (VI).

Examples 184-199

Pre-Formation of Catalyst

[0416] A vial was charged with the corresponding catalyst precursor (0.158 mol; when [Ru(COD)(2-metallyl).sub.2] was applied as the catalyst precursor HBF.sub.4 (0.316 mol) was as well charged to the vial)) and the corresponding chiral ligand (0.19 mol) in a glove box. Subsequently, dichloroethane was added and the solution was stirred for 30 minutes at rt before the solvent was evaporated under reduced pressure.

Asymmetric Hydrogenation:

[0417] N-[2-(2,4-dichlorophenyl)cyclobuten-1-yl]acetamide (31.7 mol) and MeOH (500 L) were added to the previously prepared catalyst. A hydrogen pressure 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 h at 50 C. The reaction mixture was concentrated under reduced pressure and analyzed via achiral (method 3) and chiral HPLC (method 4).

TABLE-US-00028 TABLE 25 Conv. Select. ee Ex. Catalyst Precursor Ligand Remark [%] [%] [%] 184 [RuCl.sub.2(p- (R)-(+)-2,2-Bis[di(3,5-xylyl) 100.0 48.6 80.2 cymene)].sub.2 phosphino]-1,1-binaphthyl (R, R) 185 [Ru(COD)(2- (R)-(+)-2,2-Bis[di(3,5-xylyl) HBF.sub.4 100.0 54.8 85.2 metallyl).sub.2] phosphino]-1,1-binaphthyl komplex (R, R) 186 [RuCl.sub.2(p- (S)-2,2-Bis[di-3,5- 98.8 86.4 60.8 cymene)].sub.2 xylylphosphino]-6,6-dimethoxy- (S, S) 1,1-biphenyl 187 [Ru(COD)(OOCCF.sub.3).sub.2] (S)-2,2-Bis[di-3,5- 99.2 81.0 59.0 xylylphosphino]-6,6-dimethoxy- (S, S) 1,1-biphenyl 188 [Ru(COD)(2- ()-1,2-Bis((2R,5R)-2,5- HBF.sub.4 100.0 91.4 81.8 metallyl).sub.2] diethylphospholano)benzene komplex (R, R) 189 [Ru(COD)(OOCCF.sub.3).sub.2] (S,S).sub.Fc-1,1-Bis[bis(4-methoxy- 100.0 75.6 34.1 3,5-dimethylphenyl)phosphino]- (S, S) 2,2-bis[(R,R).sub.C-(N,N- dimethylamino)phenylmethyl] ferrocene 190 [Ru(COD)(2- (R)-1-Diphenylphosphino-2- HBF.sub.4 75.1 72.1 20.1 metallyl).sub.2] [(R)-(N,N-dimethylamino)[2- komplex (S, S) (diphenylphosphino)phenyl] methyl]ferrocene 191 [RuCl.sub.2(p- (S)-2,2-Bis[bis(3,5-di-tert-butyl- 95.7 60.7 28.8 cymene)].sub.2 4-methoxyphenyl)phosphino]- (R, R) 6,6-dimethoxy-1,1-biphenyl 192 [Ru(COD)(OOCCF.sub.3).sub.2] (S)-2,2-Bis[bis(3,5-di-tert-butyl- 100.0 70.8 25.8 4-methoxyphenyl)phosphino]- (R, R) 6,6-dimethoxy-1,1-biphenyl 193 [Ru(COD)(2- 1-Dicyclohexylphosphino-1- HBF.sub.4 99.9 61.4 26.1 metallyl).sub.2] [(S).sub.P-[(S).sub.Fc-2-[(R).sub.C-1- komplex (S, S) (dimethylamino)ethyl]ferrocenyl] phenylphosphino]ferrocene 194 [Ru(COD)(OOCCF.sub.3).sub.2] (R)-1-[(S)-2- 100.0 90.1 54.9 (Diphenylphosphino)ferrocenyl] (R, R) ethyldi(3,5-xylyl)phosphine 195 [Ru(COD)(2- (R,R)-()-2,3-Bis(tert- HBF.sub.4 99.9 90.4 96.2 metallyl).sub.2] butylmethylphosphino)quinoxaline komplex (R, R) 196 [Ru(COD)(OOCCF.sub.3).sub.2] (R)-1-[(S)-2- 100.0 83.2 69.7 (Diphenylphosphino)ferrocenyl] (R, R) ethyldi-tert-butylphosphine 197 [Ru(COD)(2- (2R,3R)-(+)-2,3- HBF.sub.4 100.0 85.3 24.8 metallyl).sub.2] Bis(diphenylphosphino)butane komplex (R, R) 198 [Ru(COD)(OOCCF.sub.3).sub.2] (R)-2,2- 99.2 82.6 65.7 Bis(diphenylphosphino)-6,6- (R, R) dimethoxy-1,1-biphenyl 199 [Ru(COD)(2- (R)-(+)-1,2- HBF.sub.4 100.0 88.8 3.3 metallyl).sub.2] Bis(diphenylphosphino)propane komplex (R, R) The term selectivity as used in the above table refers to the selectivity of the reaction to compounds of formula (VI).

Examples 200-206

Pre-Formation of Catalyst

[0418] A vial was charged with bis(2-methallyl)(COD)ruthenium (3.10 mg, 0.0097 mmol), the corresponding chiral ligand (0.0107 mmol) and fluoroboric acid diethylether complex (1.72 mg, 0.0106 mmol) in a glove box. Subsequently, argon degassed dichloromethane (2.5 mL) was added and the solution was stirred for 30 minutes at rt.

Asymmetric Hydrogenation:

[0419] A pressure autoclave was charged with N-[2-(2,4-dichlorophenyl)cyclobuten-1-yl]acetamide (250 mg, 0.97 mmol), argon degassed MeOH (2.0 mL) and the previously prepared catalyst solution (0.5 mL). A hydrogen pressure 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 h at 50 C.

[0420] The reaction mixture was concentrated under reduced pressure and analyzed analyzed via achiral (method 3) and chiral HPLC (method 4).

TABLE-US-00029 TABLE 26 Conv. Select. ee Example Ligand [%] [%] [%] 200 (S)-1-[(R)-2-(Diphenylphosphino)ferrocenyl]ethyldi-tert- 90 95 72 butylphosphine (S, S) 201 (S)-1-[(R)-2-[Di(2-furyl)phosphino]ferrocenyl]ethyldi-tert- >99 >99 56 butylphosphine (S, S) 202 (R,R)-(+)-1,2-Bis(t-butylMethylphosphino)benzene 98 >99 94 (R, R) 203 ()-1,2-Bis[(2R,5R)-2,5-dimethylphospholano]benzene 91 95 80 (R, R) 204 (+)-1,2-Bis[(2S,5S)-2,5-diethylphospholano]benzene >99 98 79 (S, S) 205 ()-1,2-Bis((2S,5S)-2,5-diethylphospholano)ethane 83 87 76 (R, R) 206 (1S,1S,2R,2R)-1,1-Di-tert-butyl-(2,2)-diphospholane 56 92 79 (R, R) The term selectivity as used in the above table refers to the selectivity of the reaction to compounds of formula (VI).

Examples 207-208

Pre-Formation of Catalyst

[0421] A vial was charged with bis(2-methallyl)(COD)ruthenium (3.72 mg, 0.0116 mmol) and the corresponding chiral ligand (0.0127 mmol) in a glove box. Subsequently, argon degassed dichloromethane (3.00 mL) and a 0.081M solution of methane sulfonic acid in dichloromethane (0.16 mL, 0.0130 mmol) was added and the solution was stirred for 30 minutes at rt.

Asymmetric Hydrogenation:

[0422] A pressure autoclave was charged with N-[2-(2,4-dichlorophenyl)cyclobuten-1-yl]acetamide (250 mg, 0.97 mmol), argon degassed MeOH (2.0 mL) and the previously prepared catalyst solution (0.5 mL). A hydrogen pressure 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 h at 50 C.

[0423] The reaction mixture was concentrated under reduced pressure and analyzed via achiral and chiral HPLC.

TABLE-US-00030 TABLE 27 Conv. Select. ee Example Ligand [%] [%] [%] 207 (S)-1-[(R)-2-[Bis(4-methoxy-3,5- >99 95 85 dimethylphenyl)phosphino]ferrocenyl]ethyldi-tert-butyl-phosphine (S, S) 208 (S)-1-[(R)-2-[Bis(4-methoxy-3,5- 95 98 86 dimethylphenyl)phosphino]ferrocenyl]ethyldicyclohexylphosphine (S, S) The term selectivity as used in the above table refers to the selectivity of the reaction to compounds of formula (VI).

Seventh Aspect:

Reaction (f) of Scheme 1:

Example 209

[0424] 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) was heated to Ta=130 C. A part of the isopropanol and the trifluoroethanol (ca. 220 g) was removed at a temperature of 82 C. measured at the head of the distillation equipment before a 50% aqueous H.sub.3PO.sub.4 solution (150 g, 765 mmol) was added. More isopropanol and trifluoroethanol was removed till the temperature at the top of the distillation column reached 100 C. Subsequently, the reaction mass was stirred under reflux conditions till a conversion >95% was achieved (reaction time: about 20 h).

[0425] Water (145 g, 8.1 mol) was added to the reaction mixture once 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) before the pH of the aqueous solution was adjusted to 8.0-8.5 using a 25% aqueous ammonia solution (117.5 g, 1.7 mol). The basic aqueous phase was extracted with toluene (169 g, 1.8 mol). Subsequently, 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).

[0426] .sup.1H NMR (400 MHz, CDCl.sub.3) 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, 1H).

Example 210

[0427] A reaction mixture consisting of N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]acetamide (10 g, 35.8 mmol), methane sulfonic acid (6.9 g, 71.5 mmol) and water (6.4 g, 358 mmol) was heated to 110 C. to achieve reflux conditions. The reaction mass was stirred under reflux conditions for 21 h before it was cooled to rt. Water (40 mL) was added to the reaction mixture and subsequently extracted twice with toluene (first: 50 mL; second: 30 mL). The pH of the aqueous solution was adjusted to 8.9 using a 25% aqueous ammonia solution (9.6 g, 141 mmol). The basic aqueous phase was extracted with toluene (50 mL) to obtain a 11.9% solution of (1S,2S)-2-(2,4-dichlorophenyl)cyclobutanamine in toluene (59.8 g).

Example 211

[0428] N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]acetamide (5.0 g, 17.9 mmol) was added to a 60% aqueous H.sub.2SO.sub.4 solution (17.5 g, 107 mmol). The reaction mixture was heated to 128 C. to achieve reflux conditions. The reaction mass was cooled to 60 C. after a stirring period of 21 h at reflux conditions. Water (75 mL) was added to the reaction mixture and subsequently extracted twice with toluene (first: 25 mL; second: 25 mL). The pH of the aqueous solution was adjusted to 8.8 using a 25% aqueous ammonia solution (5.8 g, 85.1 mmol). The basic aqueous phase was extracted with toluene (100 mL). Subsequently, 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) of Scheme 1:

Example 212

[0429] A solution of (1S,2S)-2-(2,4-dichlorophenyl)cyclobutanamine in toluene (339 g, 0.40 mol) is added to solid NaHCO.sub.3(47 g, 0.56 mol). Water (140 g, 7.79 mol) is then added to the reaction mixture and the mixture is heated to Ti=50 C. Subsequently, a solution of 2-(trifluoromethyl)pyridine-3-carbonyl chloride in toluene (247 g, 0.42 mol) is added over 53 minutes at Ti=50 C. to the reaction mixture. Once complete conversion is achieved the reaction mixture is heated to Ti=70 C. and stirred for 20 minutes at this temperature. After phase separation the organic phase is extracted with water (201 g, 11.1 mol) at Ti=80 C. Subsequent to the phase separation the organic phase is concentrated to a ca. 35% solution MCH (140 g, 1.4 mol) is then added over 20 minutes to the concentrated organic phase at Ti=80 C. The reaction mixture is then cooled down to Ti=5 C. over 2.5 h whereas seeds are added at Ti=72 C. (crystallization works also without seeding). The reaction mixture is stirred for 30 minutes once the reaction mixture reached a Ti of 5 C. before the suspension is 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 an anhydrate. FT-1R 3282, 3077, 2981, 2952, 1650, 1593, 1543, 1473, 1353, 1187, 1138, 1074, 1066, 1054 cm The anhydrate of N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-2-(trifluoromethyl) pyridine-3-carboxamide (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 over 60 minutes to the reaction mixture once the reaction mixture reached a temperature of 8 C. The reaction mixture was stirred for 30 minutes after adding another aliquot of water (174 g, 9.7 mol) over 1 h. Subsequently, the final aliquot of water (340 g, 18.9 mol) was added and the suspension was stirred for 80 minutes. The suspension was filtered and the filter cake was washed with water (280 g, 4.) before it was dried under reduced pressure at 35 C. to yield the monohydrate of N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-2-(trifluoromethyl) pyridine-3-carboxamide (94.6 g).

[0430] .sup.1H NMR (400 MHz, CDCl.sub.3) 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).

[0431] FT-1R 3403, 3232, 3079, 2948, 1660, 1645, 1593, 1575, 1471, 1326, 1186, 1126, 1076, 1054 cm.

Example 213

[0432] 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) was cooled to 0 C. and seed crystals of the product in hydrate form (1.53 g) were added. A solution of 2-(trifluoromethyl)pyridine-3-carbonyl chloride (19.7 g, 91.6 mmol) in toluene (60 g) is dosed in parallel to 30% aq NaOH (14.0 g, 105 mmol) over 2 h in such a way that pH is kept between 7-9. After the end of dosing the reaction was stirred for further 3 h. The resulting thick suspension was filtered, the filter cake was washed with water (225 g) and dried at 150 mbar pressure for 16 h to yield N-[(1S,2S)-2-(2,4-dichlorophenyl)cyclobutyl]-2-(trifluoromethyl) pyridine-3-carboxamide (36.4 g, containing 7% water) as a monohydrate.

[0433] FT-IR 3403, 3232, 3079, 2948, 1660, 1645, 1593, 1575, 1471, 1326, 1186, 1126, 1076, 1054 cm.