Asymmetric transfer hydrogenation of 2-aryl-substituted bicyclic pyridine ketones in the presence of a chiral ruthenium catalyst

Abstract

The present invention relates to a method for preparing optically active 2-aryl-substituted 6,7-dihydro-5H-cyclopenta[b]pyridin-7-ols, which comprises asymmetric transfer hydrogenation of the corresponding ketones in the presence of a ruthenium catalyst containing a chiral diamine or aminoalcohol ligand.

Description

[Technical Field]

[0001] The present invention relates to a method for preparing optically active 2-aryl-substituted 6,7-dihydro-5H-cyclopenta[b]pyridine-7-ol, comprising asymmetric transfer hydrogenation of a corresponding ketone in the presence of a ruthenium catalyst containing a chiral diamine or amino alcohol ligand. [Background technology]

[0002] It is known from WO2019 / 185541 that chiral aryl-substituted bicyclic pyridine phosphinites are excellent (P,N) ligands for iridium-catalyzed enantioselective hydrogenation of 4-substituted N-acetyl-dihydroquinolines. Using these ligands, the resulting 4-substituted N-acetyl-tetrahydroquinolines can be obtained in high yield and with excellent enantioselectivity (up to 98% ee). Subsequent rearrangement yields the corresponding 4-aminoindan derivatives (EP0654464), which are important intermediates for the preparation of various N-indanyl heteroarylcarboxamides with bactericidal activity (EP0654464, WO2011 / 162397, WO2012 / 084812, WO2015 / 197530).

[0003] Chiral aryl-substituted bicyclic pyridine-phosphinites can be prepared by butyrating a racemic aryl-substituted 6,7-dihydro-5H-cyclopenta[b]pyridine-7-ol via chiral HPLC, followed by deprotonation to the corresponding phosphinite and subsequent treatment with di(cyclo)alkylchlorophosphine (S. Kaiser et al., Angew. Chem. Int. Ed. 2006, 45, 5194-5197). Kinetic resolution of racemic alcohols using lipase or copper-catalyzed benzoylation is also known (DH Woodmansee et al., Chem. Sci. 2010, 1, 72-78; C. Mazet et al., Org. Lett. 2006, 8, 1879-1882). However, a common disadvantage of racemic reconstitution is that the desired enantiomer and the undesirable enantiomer are always obtained in equal amounts, requiring additional steps, such as repeated oxidation and racemic reconstitution sequences, to convert the undesirable enantiomer to the desired one.

[0004] In principle, asymmetric reduction methods for bicyclic pyridine ketones are already available. Asymmetric transfer hydrogenation of bicyclic pyridine ketones in the presence of a chiral iron catalyst is known from "A. Naik et al., Chem.Commun. 2010, 46, 4475-4477". However, it has been found that the substituent at position 2 is detrimental to enantioselectivity, and as a result, 2-aryl-substituted bicyclic pyridine alcohols can only be obtained with moderate enantioselectivity (52-72% ee). Similarly, it has been reported that enantioselective reduction catalyzed by 2-phenyl-6,7-dihydro-5H-quinoline-8-one using (S)-Me-CBS-borane yields the corresponding ketone with an enantiomeric excess of only 72% (Tetrahedron:Asymmetry, 2009, 20, 1425-1432). [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] WO2019 / 185541 [Patent Document 2] EP0654464 [Patent Document 3] WO2011 / 162397 [Patent Document 4] WO2012 / 084812 [Patent Document 5] WO2015 / 197530 [Non-patent literature]

[0006] [Non-Patent Document 1] S.Kaiser et al.,Angew.Chem.Int.Ed.2006,45,5194-5197 [Non-Patent Document 2] DHWoodmansee et al.,Chem.Sci.2010,1,72-78 [Non-Patent Document 3] C.Mazet et al.,Org.Lett.2006,8,1879-1882 [Non-Patent Document 4] A.Naik et al.,Chem.Commun.2010,46,4475-4477 [Non-Patent Document 5] Tetrahedron:Asymmetry,2009,20,1425-1432 [Overview of the project]

[0007] In view of the above-mentioned prior art, an object of the present invention is to provide a method for preparing optically active 2-aryl-substituted 6,7-dihydro-5H-cyclopenta[b]pyridine-7-ol derivatives that has advantages over the preparation methods of the prior art. In particular, the preparation method should enable the preparation of a desired enantiomer in high yield and high enantiomer purity.

[0008] The above purpose is to use formula (Ia) or formula (Ib) [ka] [During the ceremony, R 1 and R 2 These are independently selected from the group consisting of hydrogen and C1-C4-alkyl groups; Each R 3 If present, it is independently selected from C1-C4 alkyl groups; and, n is 0, 1, 2, or 3. This is achieved by a method for preparing a compound represented by, where the method is Formula (II) [ka] [In the formula, substituent R 1 , R 2 , R 3 And the integer n is as defined for the compound represented by formula (Ia) or formula (Ib). The process involves subjecting a ketone represented by to asymmetric transfer hydrogenation in the presence of a chiral ruthenium catalyst and a polar solvent, wherein the ruthenium catalyst comprises a chiral amino alcohol ligand or a chiral diamine ligand.

[0009] Surprisingly, it was discovered that optically active 2-aryl-substituted 6,7-dihydro-5H-cyclopenta[b]pyridine-7-ol derivatives (formulas (Ia) and (Ib)) can be prepared in high yield and with excellent enantioselectivity by subjecting them to asymmetric transfer hydrogenation in the presence of a chiral ruthenium catalyst containing a chiral amino alcohol or diamine, using the corresponding 2-aryl-substituted bicyclic pyridine ketone (formula (II)) as a ligand.

[0010] definition In the definitions of the symbols given in the above and below formulas, the following collective terms were used to generally represent substituents.

[0011] As used herein, the term "halogen" refers to a fluorine, chlorine, bromine, or iodine atom.

[0012] As used herein, the term "C1-C4-alkyl" refers to a molecular chain or linear saturated hydrocarbon chain having one, two, three, or four carbon atoms. Examples of C1-C4 alkyl include methyl, ethyl, propyl (n-propyl), 1-methylethyl (isopropyl), butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), and 1,1-dimethylethyl (tert-butyl).

[0013] As used herein, the term "C2-C6-alkyl" refers to a branched or straight saturated hydrocarbon chain having two, three, four, five, or six carbon atoms. Examples of C2-C6 alkyl groups, though not limited to them, include ethyl, propyl (n-propyl), 1-methylethyl (isopropyl), butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, and 1-ethyl-2-methylpropyl.

[0014] As used herein, the terms "phenyl-(CH2)3-", "phenyl-(CH2)4-", and "phenyl-(CH2)2-O-CH2-" refer to a phenyl group that is either unsubstituted or substituted as defined herein and is attached to the parent moiety via a -(CH2)3-, -(CH2)4-, or -(CH2)2-O-CH2- linker.

[0015] Where used herein, when a group is said to be “substituted,” that group may be substituted with one or more substituents, which may be the same or different. The expression “one or more substituents” indicates a number of substituents ranging from one to the maximum number of substituents possible based on the number of available bonding sites, provided that the conditions of stability and chemical feasibility are met.

[0016] As used herein, the term “enantioselective” means that one of the two possible enantiomers of the hydrogenation product, namely the enantiomer represented by formula (Ia) (or formula (Ia')) or the enantiomer represented by formula (Ib) (or formula (Ib')), is preferably formed. “Enantiomeric excess” or “ee” indicates the degree of enantioselectivity:

number

[0017] The method according to the present invention is used to prepare a compound represented by formula (Ia) or (Ib), preferably the compound represented by formula (Ia), using a compound represented by formula (II) as a starting material.

[0018] Preferred is a compound represented by formula (Ia), formula (Ib) and formula (II) wherein R 2 is H.

[0019] More preferred compounds represented by formula (Ia), formula (Ib) and formula (II) are compounds represented by formula (Ia’), formula (Ib’) and formula (II’)

Chemical formula

[0020] Even more preferred are compounds represented by formula (Ia), formula (Ib) and formula (II) wherein R 1 is methyl and compounds represented by formula (Ia’), formula (Ib’) and formula (II’).

[0021] Particularly preferred are compounds represented by formula (Ia’), (Ib’) and formula (II’) [wherein R 1 is methyl; R 3a is methyl; and R 3b is ethyl]. The method according to the invention comprises asymmetric transfer hydrogenation of a compound represented by formula (II), preferably a compound represented by formula (II’). Substituents R

[0022] in the compound represented by formula (II), R 1 , R 2 and R 3 and the integer n are as defined respectively for the compounds represented by formula (Ia) and formula (Ib). Accordingly, substituents R 1 , R 3a and R 3b in the compound represented by formula (II’) are as defined respectively for the compounds represented by formula (Ia’) and formula (Ib’).

[0023] The asymmetric transfer hydrogenation of the compound represented by formula (II) is carried out in the presence of a chiral ruthenium catalyst containing a chiral amino alcohol ligand or a chiral diamine ligand.

[0024] Preferably, the chiral ruthenium catalyst is a chiral amino alcohol or diamine ligand represented by formula (IIIa) or formula (IIIb), or a chiral amino alcohol ligand represented by formula (IVa) or formula (IVb). [ka] It includes, and in the above formula, Y is NR 7 or O; R 4 is phenylsulfonyl, where phenyl is either unsubstituted or substituted with one or more substituents independently selected from C1-C4-alkyl and halogens; or R 4 is 2-pyrrolidinylcarbonyl or 2-piperidinylcarbonyl, preferably (2S)-2-pyrrolidinylcarbonyl; R 5 and R 6 They combine to form a -(CH2)3- group or a -(CH2)4- group; or, R 5 and R 6 These are independently selected from phenyl (where the phenyl is either unsubstituted or substituted with one or more substituents independently selected from C1-C4-alkyl); R 7 is hydrogen, phenyl-(CH2)3-, phenyl-(CH2)4-, benzyloxymethyl, benzyloxyethyl, or phenyl-(CH2)2-O-CH2-, where the phenyl group and benzyl group may be substituted with one or more substituents independently selected from C1-C4-alkyl groups; R 8 is C2-C6-alkyl, and R 9is hydrogen; or, R 8 and R 9 These are independently selected from phenyl (wherein phenyl is either unsubstituted or substituted with one or more substituents independently selected from C1-C4-alkyl); or R 8 and R 9 They came together, the formula [ka] [In the formula, the bond marked with "*" is bonded to the carbon having the hydroxyl group, and the bond marked with "#" is bonded to the carbon having the amino group; and here, m is either 0 or 1; x is 0, 1, or 2; and, Each R 10 [If present, it is selected independently from C1-C4 alkyl groups.] It forms a group represented by [the formula].

[0025] Depending on whether compound (Ia) or compound (Ib) is the desired product, the ligand represented by formula (IIIa) or formula (IVb), or the ligand represented by formula (IIIb) or formula (IVa), is suitable for use in the preparation method of the present invention. Generally, if the compound represented by formula (Ia) is the desired product, the ligand represented by formula (IIIa) or formula (IVb), preferably the ligand represented by formula (IIIa), is suitable for use in the preparation method of the present invention, and if the compound represented by formula (Ib) is the desired product, the ligand represented by formula (IIIb) or formula (IVa), preferably the ligand represented by formula (IIIb), is suitable for use in the preparation method of the present invention.

[0026] More preferably, the chiral ruthenium catalyst contains a chiral ligand represented by formula (IIIa), formula (IIIb), formula (IVa), or formula (IVb), where, Y is NR 7 or O; R 4 is phenylsulfonyl, where phenyl is either unsubstituted or substituted with one or more substituents independently selected from C1-C4-alkyl and halogens; or R 4 is 2-pyrrolidinylcarbonyl, preferably (2S)-2-pyrrolidinylcarbonyl; R 5 and R 6 They combine to form a -(CH2)4- group; or, R 5 and R 6 is an unsubstituted phenyl; R 7 This group is hydrogen, phenyl-(CH2)3-, phenyl-(CH2)4-, benzyloxymethyl, benzyloxyethyl, or phenyl-(CH2)2-O-CH2-, where the phenyl and benzyl groups may be substituted with one or more substituents independently selected from C1-C4-alkyl groups; R 8 and R 9 is an unsubstituted phenyl; or, R 8 and R 9 They came together, the formula [ka] [In the formula, the bonds marked with "*" are bonded to the carbon atom having the hydroxyl group, and the bonds marked with "#" are bonded to the carbon atom having the amino group.] It forms a group represented by [the formula].

[0027] The most preferred is a chiral ligand represented by formula (IIIa) or formula (IIIb), where, Y is NR 7 or O; R 4 is phenylsulfonyl, where phenyl is either unsubstituted or substituted with one or more substituents independently selected from C1-C4-alkyl and halogens; or R 4 is 2-pyrrolidinylcarbonyl, preferably (2S)-2-pyrrolidinylcarbonyl; R 5 and R 6 They combine to form a -(CH2)4- group; or, R 5 and R 6 is an unsubstituted phenyl; R 7 This group is hydrogen, phenyl-(CH2)3-, phenyl-(CH2)4-, benzyloxymethyl, benzyloxyethyl, or phenyl-(CH2)2-O-CH2-, where the phenyl and benzyl groups may be substituted with one or more substituents independently selected from C1-C4-alkyl groups.

[0028] Of particular preference are formulas (IIIa-1) or (IIIb-1). [ka] [During the ceremony, R 4 is phenylsulfonyl, where phenyl is either unsubstituted or substituted with one or more substituents independently selected from C1-C4-alkyl and fluorine; R 5 and R 6 They combine to form a -(CH2)4- group; or, R 5 and R 6 is unsubstituted phenyl; and, R 7 This group is hydrogen, phenyl-(CH2)3-, phenyl-(CH2)4-, benzyloxymethyl, benzyloxyethyl, or phenyl-(CH2)2-O-CH2-, where the phenyl and benzyl groups may be substituted with one or more substituents independently selected from C1-C4-alkyl groups; Preferably, R 7[wherein the group is hydrogen, phenyl-(CH2)3-, or benzyloxyethyl, and the phenyl group and benzyl group may be substituted with one or more substituents (preferably methyl) independently selected from C1-C4-alkyl groups] A chiral diamine ligand represented by formula (IIIa-2) or formula (IIIb-2) [ka] [During the ceremony, R 4 is 2-pyrrolidinylcarbonyl, preferably (2S)-2-pyrrolidinylcarbonyl; and, R 5 and R 6 They combine to form a -(CH2)4- group; or, R 5 and R 6 is an unsubstituted phenyl; Preferably, R 5 and R 6 [This is an unsubstituted phenyl compound.] This is a chiral amino alcohol ligand represented by [formula].

[0029] The ligands represented by formulas (IIIa), (IIIb), (IVa), and (IVb) are commercially available or can be prepared by methods known in the art (e.g., "R. Hodgkinson et al., Organometallics, 2014, 33, 5517-5524", "V. Parekh et al., Catal. Sci. & Technol., 2012, 2, 406-414").

[0030] Preferably, the chiral ruthenium catalyst has a general formula (Va), general formula (Vb), general formula (VIa), or general formula (VIb): [ka] It is expressed as, where in the above formula, Z is NR 13 or O; R4 is phenylsulfonyl, where the phenyl is unsubstituted or substituted with one or more substituents independently selected from C1-C4-alkyl and halogen; or, R 4 is 2-pyrrolidinylcarbonyl or 2-piperidinylcarbonyl, preferably (2S)-2-pyrrolidinylcarbonyl; R 5 and R 6 together form a -(CH2)3-group or a -(CH2)4-group; or, R 5 and R 6 are independently selected from phenyl (where the phenyl is unsubstituted or substituted with one or more substituents independently selected from C1-C4-alkyl); each R 11 is independently selected from C1-C4-alkyl when present; R 12 is C1-C4-alkyl or hydrogen, and R 13 is hydrogen; or, R 12 and R 13 together form a -(CH2)3-, -(CH2)4-, -CH2-O-CH2-, * -(CH2)2-O-CH2- # or * -(CH2)-O-(CH2)2- # group, where the bond marked with "*" is bonded to the nitrogen, and the bond marked with "#" is bonded to the phenyl ring; q is 0, 1, 2, 3, 4 or 5; X 1 is chlorine or bromine; or, X 1 is BF4 - , PF6 - or SbF6 - in which case the Ru-X 1 bond is coordinative or ionic, and Ru has a positive charge; R 8is C2-C6-alkyl and R 9 is hydrogen; or R 8 and R 9 are each independently selected from phenyl (where the phenyl is unsubstituted or substituted with one or more substituents independently selected from C1-C4-alkyl); or R 8 and R 9 together form a group of the formula

Chemical formula

[0031] Depending on whether compound (Ia) or compound (Ib) is the desired product, the catalyst represented by formula (Va) or formula (VIb), or the catalyst represented by formula (Vb) or formula (VIa), is suitable for use in the preparation method of the present invention. Generally, when the compound represented by formula (Ia) is the desired product, the catalyst represented by formula (Va) or formula (VIb), preferably the catalyst represented by formula (Va), is suitable for use in the preparation method of the present invention, and when the compound represented by formula (Ib) is the desired product, the catalyst represented by formula (Vb) or formula (VIa), preferably the catalyst represented by formula (Vb), is suitable for use in the preparation method of the present invention.

[0032] More preferably, the chiral ruthenium catalyst is represented by general formula (Va), general formula (Vb), general formula (VIa), or general formula (VIb), where, Z is NR 13 or O; R 4 is phenylsulfonyl, where phenyl is either unsubstituted or substituted with one or more substituents independently selected from C1-C4-alkyl and halogens; or R 4 is 2-pyrrolidinylcarbonyl, preferably (2S)-2-pyrrolidinylcarbonyl; R 5 and R 6 They combine to form a -(CH2)4- group; or, R 5 and R 6 is an unsubstituted phenyl; Each R 11 If present, it is independently selected from C1-C4 alkyl groups; R 12 is C1-C4-alkyl or hydrogen, and R 13 is hydrogen; or, R 12 and R 13 These combine to form -(CH2)3-, -(CH2)4-, -CH2-O-CH2-, * -(CH2)2-O-CH2-# or * -(CH2)-O-(CH2)2- # A group is formed, where the bond marked with "*" is bonded to the nitrogen, and the bond marked with "#" is bonded to the phenyl ring; q is 0, 1, 2, 3, 4, or 5; X 1 is chlorine or bromine; or, X 1 BF4 - PF6 - Or SbF6 - In this case, the Ru-X 1 The bond is coordinating or ionic, and Ru has a positive charge; R 8 and R 9 is an unsubstituted phenyl; or, R 8 and R 9 They came together, the formula [ka] [In the formula, the bonds marked with "*" are bonded to the carbon atom having the hydroxyl group, and the bonds marked with "#" are bonded to the carbon atom having the amino group.] Forms a group represented by; Each R 14 If present, it is independently selected from C1-C4 alkyl groups; p is 0, 1, 2, 3, 4, 5 or 6; and, X 2 is chlorine or bromine; or, X 2 BF4 - PF6 - Or SbF6 - In this case, the Ru-X 2 The bond is either coordinating or ionic, and Ru has a positive charge.

[0033] Particularly preferred are chiral ruthenium catalysts represented by general formula (Va) or general formula (Vb), where, Z is NR 13 or O; R 4 is phenylsulfonyl, where phenyl is either unsubstituted or substituted with one or more substituents independently selected from C1-C4-alkyl and fluorine; or R 5 and R 6 They combine to form a -(CH2)4- group; or, R 5 and R 6 is unsubstituted phenyl; and, Each R 11 If present, it is methyl; R 12 is a C1-C4 alkyl group, for example, methyl or isopropyl, and R 13 is hydrogen; or, R 12 and R 13 These combine to form -(CH2)3-, -(CH2)4-, -CH2-O-CH2-, * -(CH2)2-O-CH2- # or * -(CH2)-O-(CH2)2- # A group is formed, where the bond marked with "*" is bonded to the nitrogen, and the bond marked with "#" is bonded to the phenyl ring; q is 0, 1, or 2; X 1 is chlorine or bromine; or, X 1 BF4 - PF6 - Or SbF6 - In this case, the Ru-X 1 The bond is either coordinating or ionic, and Ru has a positive charge.

[0034] The chiral ruthenium catalysts represented by formulas (Va), (Vb), (VIa), and (VIb) are commercially available or can be prepared by methods known in the art (e.g., "R. Hodgkinson et al., Organometallics, 2014, 33, 5517-5524", "V. Parekh et al., Catal. Sci. & Technol., 2012, 2, 406-414").

[0035] Equations (Va) and (Vb) [wherein R 12 A chiral ruthenium catalyst represented by formula (VIa) and formula (VIb) is a C1-C4-alkyl group, and Z is O or NH. [ka] By mixing with a chiral ligand represented by , it can be formed in situ. Here, in the above formula, R 4 , R 5 and R 6 These are defined with respect to the complexes represented by formulas (Va) and (Vb), respectively; Z is either NH or O; R 8 and R 9 These are defined with respect to the complexes represented by formulas (VIa) and (VIb), respectively; And, Here, the aromatic ligand of the above precatalyst is selected from the group consisting of p-cymene and benzene, which may be substituted with one or more methyl groups.

[0036] Suitable organic solvents include dichloromethane, 1,2-dichloroethane, chlorobenzene, dichlorobenzene, toluene, acetonitrile, dimethylformamide, ethanol, isopropanol, tetrahydrofuran, and 2-methyltetrahydrofuran.

[0037] Examples of suitable aromatic ligands are p-cymene and hexamethylbenzene.

[0038] The amount of ruthenium catalyst used is preferably in the range of 0.01 mol% to 10 mol%, more preferably in the range of 0.1 mol% to 5 mol%, and most preferably in the range of 0.5 mol% to 3 mol%, based on the amount of compound represented by formula (II).

[0039] The preparation method according to the present invention involves the asymmetric transfer hydrogenation of a compound represented by formula (II).

[0040] The hydrogen source used is preferably selected from the group consisting of sodium formate, potassium formate, lithium formate, calcium formate, magnesium formate, formate / triethylamine, potassium tert-butyrate / isopropanol, sodium tert-butyrate / isopropanol, and lithium tert-butyrate / isopropanol; more preferably selected from the group consisting of sodium formate, potassium formate, lithium formate, calcium formate, magnesium formate, and formate / triethylamine; and most preferably selected from sodium formate and formate / triethylamine.

[0041] The amount of hydrogen source used is preferably at least 1.0 equivalent, more preferably at least 2.0 equivalents, and most preferably 2.0 to 3.5 equivalents, based on the amount of compound represented by formula (II).

[0042] In the case of formic acid / triethylamine, formic acid acts as a hydrogen source, and therefore the amount of hydrogen source used corresponds to the amount of formic acid used. Preferably, the amount of triethylamine used is in the range of 0.2 to 1.0 equivalents, based on the amount of the compound represented by formula (II).

[0043] In the case of potassium tert-butyrate / isopropanol, sodium tert-butyrate / isopropanol, and lithium tert-butyrate / isopropanol, the isopropanol functions as both a hydrogen source and a (co)solvent, and therefore the amount of isopropanol used is typically considerably greater than the amount of hydrogen source required for the hydrogenation reaction. The amount of tert-butyrate used is preferably 0.2 to 1.0 equivalents, based on the amount of the compound represented by formula (II).

[0044] Particularly preferred is that the hydrogen source used is selected from sodium formate and formic acid / triethylamine, and the amount of the hydrogen source used is in the range of 2.0 to 3.5 equivalents based on the amount of the compound represented by formula (II).

[0045] The mobile hydrogenation is preferably carried out at a temperature within the range of 10°C to 100°C, more preferably 20°C to 80°C, and particularly 25°C to 50°C.

[0046] Reaction time is not critical and can be selected within a relatively wide range depending on the batch size. Typical reaction times range from 30 minutes to 24 hours.

[0047] According to the present invention, the asymmetric transfer hydrogenation of the compound represented by formula (II) is carried out in the presence of a polar solvent.

[0048] Suitable polar solvents are selected from the group consisting of dichloromethane, methanol, ethanol, isopropanol, n-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, dimethylformamide, acetonitrile, methanol / water, ethanol / water, isopropanol / water, n-butanol / water, tetrahydrofuran / water, 2-methyltetrahydrofuran / water, dimethylformamide / water, acetonitrile / water, and mixtures thereof.

[0049] Preferred polar solvents are selected from the group consisting of ethanol, isopropanol, 2-methyltetrahydrofuran, dimethylformamide, acetonitrile, ethanol / water, isopropanol / water, 2-methyltetrahydrofuran / water, dimethylformamide / water, acetonitrile / water, and mixtures thereof.

[0050] Particularly preferred are ethanol, isopropanol / water, dimethylformamide / water, acetonitrile / water, 2-methyltetrahydrofuran, and 2-methyltetrahydrofuran / water.

[0051] When the mobile hydrogenation is carried out in the presence of water, the post-treatment and isolation of the compound represented by formula (Ia) or formula (Ib) can be carried out in the following steps: (i) separating the aqueous phase from the organic phase; (ii) extracting the aqueous phase once or more with a suitable organic solvent (e.g., heptane, toluene, or xylene); (iii) combining the organic phase and washing with water, brine, and / or an aqueous sodium bicarbonate solution; (iv) drying the obtained organic phase by treatment with magnesium sulfate or azeotropic distillation; and (v) removing (part of) the organic solvent by distillation. The obtained product can be purified by crystallization from heptane.

[0052] The compound represented by formula (Ia) or formula (Ib) can be prepared with high enantioselectivity using the asymmetric transfer hydrogenation method according to the present invention. The compound represented by formula (Ia) or formula (Ib) obtained by the preparation method according to the present invention can be purified by forming a crystalline addition salt with camphor sulfonic acid. This makes it possible to increase the chemical purity of the desired product to >99% w / w.

[0053] The preparation method according to the present invention involves the asymmetric transfer hydrogenation of a compound represented by formula (II).

[0054] The ketone represented by formula (II) is given by formulas (Ia) and (Ib). [ka] [In the formula, substituent R 1 , R 2 , R 3 And the integer n is defined as it is with respect to the compound represented by formula (II), respectively. It can be obtained from a racemic mixture of compounds represented by by oxidation using TEMPO, TEMPO derivatives or TEMPO analogs, hypochlorites and optionally bromide salts.

[0055] Similarly, the ketone represented by formula (II') is given by formulas (Ia') and (Ib'). [ka] [In the formula, substituent R 1 , R 3a and R 3b These are defined as they are for the compounds represented by formula (II'). It can be obtained from a racemic mixture of compounds represented by by oxidation using TEMPO, TEMPO derivatives or TEMPO analogs, hypochlorites and optionally bromide salts.

[0056] It has been found that the ketone represented by formula (II) can be obtained from a racemic mixture of the compounds represented by formulas (Ia) and (Ib) by TEMPO-mediated oxidation using a catalytic amount of TEMPO, a TEMPO derivative or TEMPO analog, or a hypochlorite as the oxidizing agent, and optionally a bromide as the co-oxidizing agent. This reaction was found to work well with the pyridine-functionalized compounds represented by formulas (Ia) and (Ib), which is surprising in light of previous results disclosed in "M. Shibuya, M. Tomizawa, I. Suzuki, Y. Iwabuchi, J. Am. Chem. Soc., 2006, 128, 8412-8413". Shibuya et al. have shown that nitrosyl radicals such as TEMPO and 1-Me-AZADO do not efficiently oxidize substrates containing basic nitrogen. Furthermore, this reaction works well even with a catalytic amount of readily available TEMPO, which is surprising since Shibuya et al. have taught us to use 1-Me-AZADO (2-aza-1-methyladamantane N-oxyl) instead of TEMPO to oxidize secondary alcohols.

[0057] Suitable examples of TEMPO derivatives and TEMPO analogs are 4-hydroxy-TEMPO, 4-methoxy-TEMPO, 4-oxo-TEMPO, 2-azaadamantane N-oxyl, and 2-aza-1-methyladamantane N-oxyl.

[0058] TEMPO, TEMPO derivatives, or TEMPO analogs can be used as is or in an immobilized form. Suitable examples of immobilized TEMPO are silica-supported TEMPO and polystyrene-supported TEMPO.

[0059] The amount of TEMPO, TEMPO derivatives, or TEMPO analogs used is preferably in the range of 0.5 mol% to 20 mol%, more preferably in the range of 1 mol% to 10 mol%, and most preferably in the range of 3 mol% to 7.5 mol%, based on the total amount of the compounds represented by formula (Ia) and formula (Ib) [preferably formula (Ia') and formula (Ib')].

[0060] Suitable hypochlorites are sodium hypochlorite, potassium hypochlorite, and magnesium hypochlorite. Preferably, the hypochlorite used in TEMPO-mediated oxidation is selected from sodium hypochlorite and potassium hypochlorite. Sodium hypochlorite is particularly preferred.

[0061] The amount of hypochlorite used is preferably in the range of 1 to 5 equivalents, more preferably in the range of 1.1 to 2.0 equivalents, and most preferably in the range of 1.2 to 1.5 equivalents, based on the total amount of the compounds represented by formula (Ia) and formula (Ib) [preferably formula (Ia') and formula (Ib')].

[0062] Suitable bromide salts are potassium bromide, sodium bromide, and tetrabutylammonium bromide, as well as mixtures thereof.

[0063] The amount of bromide salt used is preferably in the range of 0.5 mol% to 20 mol%, and more preferably in the range of 5 mol% to 15 mol%, based on the total amount of the compounds represented by formula (Ia) and formula (Ib) [preferably formula (Ia') and formula (Ib')].

[0064] Oxidation mediated by TEMPO is preferably carried out under basic two-phase conditions in the presence of water, an organic solvent, and a phase transfer catalyst (e.g., tetrabutylammonium bromide (TBAB)).

[0065] Suitable organic solvents are selected from the group consisting of dichloromethane, 1,2-dichloroethane, chlorobenzene, dichlorobenzene, toluene, acetonitrile, ethyl acetate, n-propyl acetate, n-butyl acetate, and similar solvents that are inert to oxidation with hypochlorite reagents.

[0066] For example, oxidation mediated by TEMPO can be carried out under basic two-phase conditions using a mixture of aqueous sodium hypochlorite solution and saturated aqueous sodium bicarbonate solution as the aqueous phase, dichloromethane as the organic solvent, and tetrabutylammonium bromide (TBAB) as the phase transfer catalyst.

[0067] Oxidation mediated by TEMPO is preferably carried out at a temperature in the range of -20°C to +25°C, and more preferably in the range of -5°C to +5°C.

[0068] Reaction time is not critical and can be selected within a relatively wide range depending on the batch size. Typical reaction times range from 5 minutes to 3 hours.

[0069] The post-treatment and isolation of the ketone represented by formula (II) or formula (II') can be carried out in the following steps: (i) separating the aqueous phase from the organic phase; (ii) extracting the aqueous phase once or more with a suitable organic solvent (e.g., heptane); (iii) combining the organic phases and washing with water or brine; (iv) drying the resulting organic phase by treatment with magnesium sulfate; and (v) removing the organic solvent by distillation. The resulting product represented by formula (II) or formula (II') can be purified by crystallization from heptane.

[0070] [Table 1] [Examples]

[0071] Examples Preparation of the starting material (II'-1) by TEMPO-mediated oxidation of (Ia'-1) / (Ib'-1): [ka] Example 1: A racemic mixture of compound (Ia'-1) and compound (Ib'-1) (93.3% w / w, 1421.5 g, 4489 mmol), TEMPO (35 g, 224 mmol), potassium bromide (53 g, 449 mmol), tetrabutylammonium bromide (72 g, 224 mmol), dichloromethane (6.8 L), and saturated sodium bicarbonate solution (prepared using 4.5 L of water) were placed in the reactor. The beige mixture was cooled to 0°C, and a mixture of sodium hypochlorite solution (13.4% w / w, total amount required: 3530 g, 5454 mmol, 1.215 equivalents) and saturated sodium bicarbonate solution (total amount required: 3.81 kg) was added under temperature control at 0°C (±4°C) until in-process control (HPLC@220 nm) showed complete conversion of the starting materials. The reaction mixture was transferred to a stirring vessel and diluted with water (2.8 L). The aqueous phase was separated and re-extracted with dichloromethane (5.6 L). The organic layers were combined and washed with water (5.6 L), filtered through a sodium sulfate plug (1 kg), and rinsed with dichloromethane (2.8 L). 10 L of solvent was removed by distillation (40°C), and 6 L of heptane was added. Again, 4.5 L of solvent was removed by distillation and replaced with heptane. 1 L of heptane was removed by distillation, and crystalline species were introduced into the solution by adding 2 g of compound (II'-1) to initiate crystallization. The suspension was concentrated at 45°C to a total mass of 8 kg, cooled, and rotated at 0-5°C for 3 hours. The solid was filtered off and washed with cold heptane (5 L, 0-5°C). The solid was dried under reduced pressure at 40-45°C.

[0072] Mass: 1273g (97% of theoretical value); Appearance: Beige solid; HPLC (220nm): ≥99% area; Assay (1H-NMR, DMSO-d6, TMB as standard): 96%; Yield (mass yield × assay): 93% of compound (II'-1).

[0073] Example 2 A racemic mixture of compound (Ia'-1) and compound (Ib'-1) (0.13 g, 0.44 mmol), 4-hydroxy-TEMPO (3.8 mg, 0.022 mmol), potassium bromide (15 mg, 0.044 mol), tetrabutylammonium bromide (7.1 mg, 0.022 mmol), dichloromethane (2.6 mL), and saturated sodium bicarbonate solution (1.3 mL) were placed in a vial under an inert atmosphere (N2). The beige mixture was cooled to 0°C, and a mixture of sodium hypochlorite solution (10-14% w / w, 0.7 mL) and saturated sodium bicarbonate solution (0.9 mL) was added dropwise at 0°C (±4°C) for 5 minutes. After stirring at this temperature for 20 minutes, in-process control (HPLC@220 nm) showed complete conversion of the starting materials and 82.9% a / a of compound (II'-1).

[0074] Example 3 A racemic mixture of compound (Ia'-1) and compound (Ib'-1) (0.13 g, 0.44 mmol), silica-supported TEMPO (0.35 mmol TEMPO per gram of material, 63 mg, 0.022 mmol), potassium bromide (15 mg, 0.044 mol), tetrabutylammonium bromide (7.1 mg, 0.022 mmol), dichloromethane (2.6 mL), and saturated sodium bicarbonate solution (1.3 mL) were placed in a vial under an inert atmosphere (N2). The beige mixture was cooled to 0°C, and a mixture of sodium hypochlorite solution (10-14% w / w, 0.7 mL) and saturated sodium bicarbonate solution (0.9 mL) was added dropwise at 0°C (±4°C) for 5 minutes. After stirring at this temperature for 20 minutes, in-process control (HPLC@220nm) showed complete conversion of the starting material and 96.6% a / a of compound (II'-1).

[0075] Example 4 A racemic mixture of compound (Ia'-1) and compound (Ib'-1) (0.13 g, 0.44 mmol), polystyrene-supported TEMPO (1 mmol TEMPO per gram of material, 22 mg, 0.022 mmol), potassium bromide (15 mg, 0.044 mol), tetrabutylammonium bromide (7.1 mg, 0.022 mmol), dichloromethane (2.6 mL), and saturated sodium bicarbonate solution (1.3 mL) were placed in a vial under an inert atmosphere (N2). The beige mixture was cooled to 0°C, and a mixture of sodium hypochlorite solution (10-14% w / w, 0.7 mL) and saturated sodium bicarbonate solution (0.9 mL) was added dropwise at 0°C (±4°C) for 5 minutes. After stirring at this temperature for 20 minutes, in-process control (HPLC@220nm) showed complete conversion of the starting material and 90.4% a / a of compound (II'-1).

[0076] Asymmetric Mobile Hydrogenation The reaction was carried out in a glass container of appropriate dimensions. Unless otherwise indicated, the reaction mixture was analyzed by HPLC (Chiralpak IC column, heptane / ethanol gradient (containing 0.02% diethylamine as a stabilizing additive), 1 mL / min) without workup.

[0077] Preparation of chiral ruthenium catalysts [ka] The catalysts used in Examples 5-14 were pre-formed by dissolving a ruthenium(II) catalyst precursor ([RuCl2(p-cymene)]2 or [RuCl2(hexamethylbenzene)]2, 1.0 equivalent) in DCE at 60°C prior to the reaction, adding the ligands listed in Table 1 (1.2 equivalents), stirring the solution at 60°C for 1 hour, and then evaporating the DCE.

[0078] The following catalysts are commercially available, and in Examples 15-34, they were used as purchased: [ka]

[0079] Mobile hydrogenation reaction [ka] Under an inert gas atmosphere, one well of a 96-well plate autoclave was packed with 9.7 mg of ketone starting material (II'-1) (33 μmol, 1 equivalent), a reducing agent (see Table 1; NaCO2H: 2.5 equivalents; HCO2H / NEt3: 2.7 equivalents / 0.6 equivalents, respectively), and 0.66 μmol of catalyst (2 mol%, see Table 1) in each solvent mixture (see Table 1, starting material concentration 0.13 M). The autoclave was closed and heated to 35°C, and the reaction mixture was shaken at that temperature for 17 hours. Chromatographic analysis of the cooled and reduced-pressure reaction mixture revealed the %a / aHPLC conversion rate from starting material (II'-1) to the reduced alcohol product (Ia'-1) or (Ib'-1). The %a / aHPLC conversion rate and enantioselectivity are shown in Table 1 below.

[0080] [Table 2] TIFF0007836809000022.tif225165TIFF0007836809000023.tif77165

[0081] Example 33: All solvents and solutions for the reaction and workup procedures were degassed with argon before use. Ketone starting material (II'-1) (9.4 g, 32 mmol) and ethanol (70 mL) were placed in a 50 mL three-necked round-bottom flask under an argon atmosphere. Argon was passed through the suspension for 15 minutes, after which catalyst (Va-3) (2 mol%, 379 mg, 0.64 mmol) was added. A solution of sodium formate (24 g, 352 mmol) dissolved in water (94 mL) was added. The reaction mixture was stirred overnight (16 hours) at 35°C (bath temperature). The oily upper layer was separated using a separatory funnel, and the aqueous phase was extracted with heptane (50 mL). The upper layers were combined and diluted with heptane (25 mL), and washed with water (50 mL). The separated aqueous phase was extracted again with heptane (40 mL). The organic phases were combined and washed with water (50 mL) and brine (aqueous, 30%, 30 mL).

[0082] Purification by silica plug filtration Silica gel 60 (Fluka 89943, 50 g) was packed into the column as a slurry in heptane. The organic layer from the above extraction was applied directly to the column and eluted with a gradient from heptane (100%) to heptane / MeTHF 3 / 1 (v / v). The fraction of the product was evaporated under reduced pressure to obtain 9.3 g of a beige / brown solid (assay: 96% w / w, 94% yield, 97% ee).

[0083] Example 34 The reaction was carried out under an inert gas atmosphere. All solvents and solutions for the reaction and workup procedures were degassed with argon before use. Compound (II'-1) (1230 g, 4025 mmol) and catalyst (Va-3) (54 g, 80 mmol) were placed in a 20 L round-bottom flask under an inert gas atmosphere (argon). Acetonitrile (4 L) was added, and the mixture was mixed (30°C) to obtain a brownish-red solution (Solution 1). Sodium formate (1369 g, 20.1 mol) was dissolved in degassed water (7 L). The solution was evacuated and argon was passed through it three times (Solution 2). Solution 1 was placed in the reactor (the flask was rinsed with 0.5 L of acetonitrile), followed by Solution 2 (the flask was rinsed with 1 L of water).

[0084] The mixture was heated to 35°C within approximately 45 minutes and stirred at this temperature for 1 hour. Process control demonstrated the complete conversion of the starting material (II'-1). The reaction mixture was cooled to 25°C, transferred to a separation vessel, and the phases were separated. The aqueous layer was extracted again with heptane (3.7 L). The organic phase (two-phase mixture) was mixed and washed with 2 × 1.85 L of semi-saturated aqueous sodium bicarbonate, followed by washing with 1.85 L of saturated aqueous sodium bicarbonate solution. The organic layer was filtered through a sodium sulfate plug (800 g) and rinsed with heptane (2 × 1 L). The solvent was evaporated under reduced pressure (45°C) to obtain 1260 g of a brownish-purple resin.

[0085] Analysis: HPLC achiral (220nm): 97.6% area, HPLC chiral (220nm): ee 99.7%. Chemical yield was confirmed after purification by salt formation and free basement (cf. Example 35).

[0086] Camphor sulfonate formation Example 35: Crude (Ia'-1) (1321 g from Example 34) was dissolved in MeTHF (7 L) at 50°C. A solution of (1S)-(+)-10-camphorsulfonic acid (981 g, 4221 mmol) dissolved in MeTHF (4 L) was continuously added at 50°C within 20 minutes; crystal species were added to the solution during the addition. After the addition was complete, the resulting suspension was stirred at 50°C for a further 30 minutes, and then cooled to 20°C within 1 hour. The solid was filtered off, washed with MeTHF (2 × 1 L), and dried under reduced pressure at 45°C.

[0087] Yield: 1947g (87% of theoretical value), white solid; HPLC (220nm): ≥99% area.

[0088] 1945 g of this substance was dissolved in MeTHF (13 L) and water (5 L). 1.65 L of saturated Na2CO3 aqueous solution was added to raise the pH to 10. The phases were separated, and the organic layer was washed with water (3.3 L) and brine (30%, 1.6 L). The organic layer was filtered through a sodium sulfate plug (1 kg) and rinsed with MeTHF (1.5 L). The solvent was evaporated under reduced pressure (45°C). The residue was co-evaporated with heptane (3 × 1.3 L).

[0089] Yield: 1087g (beige solid). Analysis: 99.7% qNMR (DMSO-d6, internal standard: trimethoxybenzene); 99.7% ee (Chiralpak IC column, heptane / ethanol gradient (containing 0.02% diethylamine as a stabilizing additive), 1 mL / min, 220 nm). Purity-corrected yield: 87% in 3 steps (mobile hydrogenation (Example 34), salt formation, free basement).

[0090] Example 36 The reaction was carried out under an inert gas atmosphere. All solvents and solutions for the reaction and workup procedures were degassed with nitrogen before use. Compound (II'-1) (177 g, 589 mmol) and catalyst (Va-3) (1.92 g, 2.95 mmol, 0.5 mol%) were placed in a round-bottom flask under an inert gas atmosphere (argon). Acetonitrile (646 mL) was added, and the mixture was mixed to obtain a brownish-red solution (Solution 1). Sodium formate (200.4 g, 2947 mmol) was dissolved in degassed water (1.15 L). This solution was further degassed by passing nitrogen through it for 1 hour (Solution 2). Solution 2 was placed in the reactor, followed by Solution 1.

[0091] The mixture was heated to 35°C within approximately 35 minutes and stirred at this temperature overnight. Process control demonstrated the complete conversion of the starting material (II'-1). The reaction mixture was cooled to 25°C and transferred to a separation vessel to separate the phases. From the organic layer, most of the acetonitrile was removed under reduced pressure (150-100 mbar) and a jacket temperature of 40°C. The aqueous layer was extracted again with xylene (233 g). The xylene layer was added to the distillation sump of the acetonitrile layer. Reduced pressure was again applied (100 mbar, jacket temperature 50°C) to remove the acetonitrile residue, water, and some xylene (distillate volume: 233 g). A solution of (1S)-(+)-10-camphorsulfonic acid (136 g, 585 mmol) dissolved in MeTHF (420 g) was continuously added at 50°C within 30 minutes. The mixture is maintained at that temperature for 50 minutes, cooled to 10°C within 2 hours, and then maintained at 10°C for another 2 hours. The mixture is filtered and washed twice with 226 g of MeTHF. The filtered cake is dried under reduced pressure at 30°C to obtain 288 g of camphor sulfonate with a purity of ≥99% a / a (92% yield in two steps (uncorrected)) and 99.4% ee.

[0092] Example 37 (Free basement): 124 g of camphor sulfonate was dissolved in toluene (428 g), MeTHF (48 g), and water (425 g) along with 2 g of sodium bicarbonate. 49.3 g of 20% w / w sodium hydroxide aqueous solution was added dropwise to raise the pH to 10. The mixture was heated to 40-50°C, filtered to obtain clarity, and the phases were separated. The organic layer was washed with 210 mL of 5% w / w aqueous sodium bicarbonate solution at 40-50°C, and then evaporated to dryness to obtain 70.5 g of (Ia'-1) as a beige solid (yield 99%; purity: 98% w / w; 99.4% ee (Chiralpak IC column, heptane / ethanol gradient (containing 0.02% diethylamine as a stabilizing additive), 1 mL / min, 220 nm)). Alternatively, distillation could be stopped before completion to obtain (Ia'-1) as a 50% w / w solution in toluene.

[0093] Example 38 The reaction was carried out under an inert gas atmosphere. All solvents and solutions for the reaction and workup procedures were degassed with nitrogen before use. Compound (II'-1) (purity 93.9%, 78.5 g, 251 mmol) and catalyst (Va-3) (0.817 g, 1.25 mmol, 0.5 mol%) were placed in a round-bottom flask under an inert gas atmosphere (nitrogen). Acetonitrile (302 mL) was added, and the mixture was mixed under a constant nitrogen stream for 3 hours to obtain a brownish-red solution (Solution 1). Sodium formate (85.4 g, 1256 mmol) was dissolved in degassed water (537 mL). This solution was further degassed by passing nitrogen through it (Solution 2). Solution 2 was placed in the reactor, followed by Solution 1.

[0094] The mixture was heated to 35°C within approximately 35 minutes and stirred for 6 hours. Process control demonstrated the complete conversion of the starting material (II'-1). The reaction mixture was cooled to 25°C and transferred to a separation vessel to separate the phases. From the organic layer, most of the acetonitrile was removed under reduced pressure (150-100 mbar) and a jacket temperature of 40°C. The aqueous layer was re-extracted with xylene (162 g). The xylene layer was added to the distillation sump of the acetonitrile layer. Reduced pressure was again applied (100-40 mbar, jacket temperature 50°C) to remove the acetonitrile residue, water, and some xylene (distillate volume: 139 g). At 50°C, 1 g of seed crystal was added. Then, a solution of (1S)-(+)-10-camphorsulfonic acid (58.3 g, 251 mmol) dissolved in MeTHF (241 g) was continuously added within 30 minutes with high-speed stirring at 50°C. The mixture is maintained at that temperature for 30 minutes, cooled to 10°C within 2 hours, and then maintained at 10°C overnight. The mixture is filtered and washed twice with 100 g of MTBE. The filtered cake is dried under reduced pressure at 30°C to obtain 122 g of camphor sulfonate (89% yield in two steps) with an assay purity of 97.1% w / w and an ee of 99.4%.

Claims

1. Formula (Ia) or Formula (Ib) 【Chemistry 1】 [During the ceremony, R １ and R ２ These are, independently of each other, hydrogen and C １ -C ４ - Selected from the group consisting of alkyl groups, Each R ３ If it exists, C １ -C ４ - Selected independently of alkyl, and, n is 0, 1, 2, or 3. A method for preparing a compound represented by, In the presence of a chiral ruthenium catalyst and a polar solvent, formula (II) 【Chemistry 2】 [wherein, the substituent R １ , R ２ , R ３ and the integer n are as defined for the compound represented by formula (Ia) or formula (Ib)] The process involves performing asymmetric transfer hydrogenation of a ketone represented by formula (IIIa), formula (IIIb), formula (IVa), or formula (IVb) 【Transformation 3】 [During the ceremony, Y is NR 7 or O, R4 is phenylsulfonyl, where phenyl is unsubstituted, or substituted with one or more substituents independently selected from C1-C4-alkyl and halogens, or R4 is 2-pyrrolidinylcarbonyl or 2-piperidinylcarbonyl. R5 and R6 together form a -(CH2)3- or -(CH2)4- group. Or, R5 and R6 are independently selected from phenyl (wherein the phenyl is either unsubstituted or substituted with one or more substituents independently selected from C1-C4-alkyl groups), R7 is hydrogen, phenyl-(CH2)3-, phenyl-(CH2)4-, benzyloxymethyl, benzyloxyethyl, or phenyl-(CH2)2-O-CH2-, where the phenyl group and benzyl group may be substituted with one or more substituents independently selected from C1-C4-alkyl groups. R8 is a C2-C6-alkyl group, and R9 is hydrogen, or R8 and R9 are independently selected from phenyl (wherein phenyl is either unsubstituted or substituted with one or more substituents independently selected from C1-C4-alkyl groups), or R8 and R9 together form the equation 【Chemistry 4】 [In the formula, the bonds marked with "*" are bonded to a carbon atom having a hydroxyl group, and the bonds marked with "#" are bonded to a carbon atom having an amino group, and here, m is either 0 or 1. x is 0, 1, or 2, and, Each R10, if present, is independently selected from C1-C4-alkyl groups. [Forms a group represented by] The method comprising a chiral ligand represented by .

2. The chiral ruthenium catalyst is defined by general formula (Va), general formula (Vb), general formula (VIa), or general formula (VIb): 【Transformation 5】 [During the ceremony, Z is NR １３ or O, R ４ is phenylsulfonyl, where the phenyl is either unsubstituted or C １ -C ４ - Substituted with one or more substituents independently selected from alkyl and halogens, or R ４ It is 2-pyrrolidinylcarbonyl, R ５ and R ６ Together, - (CH ２ ) ４ - Forms a group, or, R ５ and R ６ is unsubstituted phenyl, Each R １１ If it exists, C １ -C ４ - Selected independently of alkyl groups, R １２ C １ -C ４ - Alkyl or hydrogen, and, R １３ is hydrogen, or, R １２ and R １３ Together, - (CH ２ ) ３ -, - (CH ２ ) ４ -ien-CH ２ -O-CH ２ - ＊ - (CH ２ ) ２ -O-CH ２ - ＃ or ＊ - (CH ２ )-O-(CH ２ ) ２ - ＃ The group is formed, where the bonds marked with "*" are bonded to nitrogen, and the bonds marked with "#" are bonded to the phenyl ring. q is 0, 1, 2, 3, 4, or 5. X １ is chlorine or bromine, or X １ BF ４ － , PF ６ － or SbF ６ － In this case, Ru-X １ The bond is coordinating or ionic, and Ru has a positive charge. R ８ and R ９ is an unsubstituted phenyl, or R ８ and R ９ They came together, the formula 【Transformation 6】 [In the formula, the bond marked with "*" is bonded to a carbon having a hydroxyl group, and the bond marked with "#" is bonded to a carbon having an amino group] forms a group represented by Each R １４ If it exists, C １ -C ４ - Selected independently of alkyl groups, p is 0, 1, 2, 3, 4, 5 or 6, and, X ２ is chlorine or bromine, or X ２ BF ４ － , PF ６ － or SbF ６ － In this case, Ru-X ２ The bond is coordinating or ionic, and Ru has a positive charge. The method according to claim 1, comprising:

3. The chiral ruthenium catalyst is of formula (IIIa), formula (IIIb), formula (IVa) or formula (IVb) [wherein, Y is NR ７ or O, R ４ is phenylsulfonyl, where the phenyl is either unsubstituted or C １ -C ４ - Substituted with one or more substituents independently selected from alkyl and halogens, or R ４ This is (2S)-2-pyrrolidinylcarbonyl, R ５ and R ６ Together, - (CH ２ ) ４ - Forms a group, or, R ５ and R ６ is unsubstituted phenyl, R ７ is hydrogen, phenyl-(CH ２ ), phenyl-(CH ３ ), benzyloxymethyl, benzyloxyethyl or phenyl-(CH ２ ), where the phenyl and benzyl groups may be substituted with one or more substituents independently selected from C ４ -C ２ ), phenyl-(CH ２ )-O-CH ２ ), and where the phenyl group and the benzyl group may be substituted with one or more substituents independently selected from C １ -C ４ -alkyl, R ８ and R ９ is an unsubstituted phenyl, or R ８ and R ９ They came together, the formula 【Transformation 7】 [In the formula, bonds marked with "*" are bonded to a carbon atom containing a hydroxyl group, and bonds marked with "#" are bonded to a carbon atom containing an amino group.] [Forms a group represented by] The method according to claim 1, comprising a chiral ligand represented by [the specified symbol].

4. The method according to claim 1 or 3, wherein the chiral ruthenium catalyst comprises a chiral ligand represented by formula (IIIa) or formula (IIIb).

5. Compounds represented by formulas (Ia), (Ib), and (II) are given by formulas (Ia'), (Ib'), and (II'). 【Transformation 8】 【change】 [wherein, R １ , R ３ａ and R ３ｂ are each independently selected from C １ -C ４ -alkyl)] The method according to any one of claims 1 to 4, wherein the compound is represented by the compound.

6. R １ However, it is methyl, R ３ａ However, it is methyl, and, R ３ｂ However, it is ethyl. The method according to claim 5.

7. The method according to any one of claims 1 to 6, wherein the hydrogen source is selected from the group consisting of sodium formate, potassium formate, lithium formate, calcium formate, magnesium formate, formic acid / triethylamine, potassium tert-butyrate / isopropanol, sodium tert-butyrate / isopropanol, and lithium tert-butyrate / isopropanol.

8. The method according to any one of claims 1 to 7, wherein the hydrogen source is sodium formate or formic acid / triethylamine.

9. The method according to any one of claims 1 to 8, wherein the amount of ruthenium catalyst used is in the range of 0.1 mol% to 5 mol% based on the amount of the compound represented by formula (II).

10. The method according to any one of claims 1 to 9, wherein the mobile hydrogenation is carried out at a temperature in the range of 20°C to 80°C.

11. The method according to any one of claims 1 to 10, wherein the polar solvent is selected from the group consisting of dichloromethane, methanol, ethanol, isopropanol, n-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, dimethylformamide, acetonitrile, methanol / water, ethanol / water, isopropanol / water, n-butanol / water, tetrahydrofuran / water, 2-methyltetrahydrofuran / water, dimethylformamide / water, acetonitrile / water, and mixtures thereof.

12. R １２ However, C １ -C ４ - is alkyl, and Z is O or NH, and the chiral ruthenium catalyst is a dichloro(aromatic ligand)ruthenium(II) dimer precatalyst or a dibromo(aromatic ligand)ruthenium(II) dimer precatalyst in an organic solvent of formula (IIIa'), formula (IIIb'), formula (IVa) or formula (IVb) 【Chemistry 9】 By mixing with a chiral ligand represented by , it is formed in situ. Here, R ４ , R ５ and R ６ These are defined with respect to the complexes represented by formula (Va) and formula (Vb), respectively. Z is either NH or O, R ８ and R ９ These are defined with respect to the complexes represented by formulas (VIa) and (VIb), respectively. And, The method according to claim 2, wherein the aromatic ligand of the dichloro(aromatic ligand)ruthenium(II) dimer precatalyst or dibromo(aromatic ligand)ruthenium(II) dimer precatalyst is selected from the group consisting of p-cymene and benzene, which may be substituted with one or more methyl groups.

13. The method according to any one of claims 1 to 12, wherein a product represented by formula (Ia) or formula (Ib) or a mixture thereof is purified by forming a crystalline addition salt with camphor sulfonic acid.

14. The ketone represented by formula (II) is given by formulas (Ia) and (Ib). 【Chemistry 10】 [In the formula, the substituent R １ , R ２ , R ３ And the integer n is defined as it is with respect to the compound represented by formula (II). The method according to any one of claims 1 to 13, obtained by oxidation of a racemic mixture of compounds represented by using TEMPO, a TEMPO derivative or TEMPO analog, a hypochlorite, and optionally a bromide salt.

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