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

Abstract

This invention relates to a method for preparing optically active 2-aryl-substituted 6,7-dihydro-5H-cyclopentano[b]pyridine-7-ol, the method comprising asymmetric transfer hydrogenation of the corresponding ketone in the presence of a ruthenium catalyst containing a palmitic diamine or an amino alcohol ligand.

Description

Technical Field

[0001] This invention relates to a method for preparing optically active 2-aryl-substituted 6,7-dihydro-5H-cyclopentano[b]pyridine-7-ol, the method comprising asymmetric transfer hydrogenation of the corresponding ketone in the presence of a ruthenium catalyst containing a palmitic diamine or an amino alcohol ligand. Prior Technology

[0002] As known from WO 2019 / 185541, palmar aryl-substituted bicyclic pyridine-phosphonite esters are excellent (P,N)-ligands for the iridium-catalyzed enantioselective hydrogenation of 4-substituted N-acetylglucosinolates. Using these ligands, the obtained 4-substituted N-acetylglucosinolates can be obtained in high yield and with excellent enantioselectivity (up to 98% ee). Subsequent rearrangement yields the corresponding 4-aminodihydroindene derivative (EP 0 654 464), which is an important intermediate for the preparation of various N-dihydroindene heteroarylcarboxylic amines with fungicidal activity (EP 0 654 464, WO 2011 / 162397, WO 2012 / 00, WO 2015 / 197530).

[0003] Palmar aryl-substituted bicyclic pyridine-phosphonites can be prepared by palmar HPLC separation of racemic aryl-substituted 6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol, followed by deprotonation and subsequent treatment with di(cyclo)alkylphosphine to convert it to the corresponding phosphonite (S. Kaiser et al., Angew. Chem. Int. Ed. 2006, 45, 5194-5197). It is also known that racemic alcohols can be separated by lipases or by copper-catalyzed benzoylation kinetics (DH Woodmansee et al., Chem. Sci. 2010, 1, 72-78; C. Mazet et al., Org. Lett. 2006, 8, 1879-1882). However, a general drawback of racemic separation methods is that they always yield equal amounts of desired and undesired enantiomers, which requires additional steps, such as converting the undesired enantiomers into the desired enantiomers by repeated oxidation and racemic separation sequences.

[0004] In principle, methods for the asymmetric reduction of bicyclic pyridones are already available. The asymmetric transfer hydrogenation of bicyclic pyridones in the presence of a palmitic iron catalyst was known from A. Naik et al., Chem. Commun. 2010, 46, 4475-4477. However, it was found that the substituent at the 2-position is unfavorable for enantioselectivity, thus only 2-aryl-substituted bicyclic pyridinols can be obtained with moderate enantioselectivity (52-72% ee). Similarly, the enantioselective reduction of 2-phenyl-6,7-dihydro-5H-quinolin-8-one catalyzed by (S)-Me-CBS-borane has been reported to yield the corresponding ketone with an enantioselectivity of only 72% (Tetrahedron: Asymmetry, 2009, 20, 1425–1432).

[0005] Based on the prior art described above, the object of this invention is to provide a method for preparing optically active 2-aryl-substituted 6,7-dihydro-5H-cyclopentano[b]pyridine-7-ol derivatives, which has advantages over prior art methods. In particular, this method should allow the desired enantiomers to be obtained in high yield and with high enantiomeric purity. Summary of the Invention

[0006] The above objective is achieved through preparative methods. [(Ia)] or Methods for achieving [(Ib)] compounds, [(Ia) (Ib)] in R1 and R2 are independently selected from the group consisting of hydrogen and C1-C4-alkyl groups. Each R3 (if present) is independently selected from C1-C4-alkyl groups, and n is 0, 1, 2, or 3. This method includes asymmetric transfer hydrogenation in the presence of a palmitic ruthenium catalyst and a polar solvent. [II]) Ketones [(II)] [,] The substituents R1, R2, R3 and the integer n are as follows: [(Ia)] or [(Ib)] Definition of a compound, The ruthenium catalyst contains palmate amino alcohol ligands or palmate diamine ligands.

[0007] It has been surprisingly discovered that asymmetric transfer hydrogenation of corresponding 2-aryl-substituted bicyclic pyridones (formula: ) can be achieved in the presence of a palmite ruthenium catalyst containing palmite amino alcohols or diamines as ligands. [II]) Optically active 2-aryl-substituted 6,7-dihydro-5H-cyclopentano[b]pyridine-7-ol derivatives (formula) can be prepared in high yield and with excellent enantioselectivity. [Ia] and [Ib]). Simple Explanation of the Diagram

[0008] none Implementation

[0009] definition

[0010] In the above and below equations, the symbols listed are defined using a general term, and they typically represent the following substituents:

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

[0012] As used herein, the term “C1-C4-alkyl” refers to a saturated, branched, or straight-chain hydrocarbon chain having 1, 2, 3, or 4 carbon atoms. Examples of C1-C4-alkyl include methyl, ethyl, propyl (n-propyl), 1-methylethyl (isopropyl), butyl (n-butyl), 1-methylpropyl (secondary butyl), 2-methylpropyl (iso-butyl), and 1,1-dimethylethyl (tertiary butyl).

[0013] As used herein, the term "C2-C6-alkyl" refers to a saturated, branched, or straight-chain hydrocarbon chain having 2, 3, 4, 5, or 6 carbon atoms. Examples of C2-C6-alkyl include (but are not limited to) ethyl, propyl (n-propyl), 1-methylethyl (isopropyl), butyl (n-butyl), 1-methylpropyl (secondary butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tertiary 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 phenyl groups that are unsubstituted or substituted as defined herein and that are attached to the parent moiety via a -(CH2)3-, -(CH2)4- or -(CH2)2-O-CH2- linker.

[0015] As used herein, when a group is referred to as “substituted,” the group may be substituted by one or more substituents, which may be the same or different. The expression “one or more substituents” means that, provided that stability and chemical feasibility are satisfied, the number of substituents ranges from one to the maximum possible number of substituents based on the number of effective bonding sites.

[0016] As used herein, the term "enantiomer selectivity" indicates a preference for forming one of the two possible enantiomers of the hydrogenated product, i.e., formula ( [Ia])(or( [Ia']))'s enantiomer or formula ( [Ib])(or ( [Ib'])) enantiomers. "Enantiomer excess" or "ee" indicates the degree of enantiomer selectivity: %ee = %

[0017] The primary enantiomer can be selected by palmar ligand selection, for example by selective ligand selection. [(IIIa]) palmar ligands or opposite enantiomers (formula ( [IIIb]) coordination groups), or by selective ( [IVa]) palmar ligands or opposite enantiomers (formula ( [IVb]) is controlled by the ligands.

[0018] The method according to the present invention is used for using formula ( [II]) Compounds were used as starting materials to prepare formula ( [Ia]) or ( [Ib]) compound, preferably ( [Ia]) compounds.

[0019] The better one is formula ( [Ia]), ( [Ib]) and ( [II]) compound, wherein R2 is H.

[0020] A better approach ( [Ia]), ( [Ib]) and ( [II]) The compound is of formula ( [Ia']), ( [Ib']) and ( [II']) compound [(Ia') (Ib')] ( [II']), R1, R3a and R3b are independently selected from C1-C4-alkyl groups.

[0021] Even better is the formula ( [Ia]), ( [Ib]) and ( [II]) compounds and formula ( [Ia']), ( [Ib']) and ( [II']) compound, wherein R1 is a methyl group.

[0022] The best is the style ( [Ia']), ( [Ib']) and ( [II']) compounds, in which R1 is a methyl group. R 3a is a methyl group, and R 3b is an ethyl group.

[0023] The method according to the present invention includes asymmetric transfer hydrogenation ( [II]) compound, preferably ( [II']) compounds. The substituents R1, R2, and R3, and the integer n in compounds of formula (II) are as follows: [Ia]) and ( [Ib]) Definition of a compound. Therefore, formula ( [II']) The substituents R1, R3a and R3b in the compound are as follows ( [Ia']) and ( [Ib']) Definition of a compound.

[0024] Asymmetric transfer hydrogenation ( [II]) The compound was produced in the presence of a palmate ruthenium catalyst containing a palmate amino alcohol ligand or a palmate diamine ligand.

[0025] Preferably, the palm-shaped ruthenium catalyst contains ( [IIIa]) or ( [IIIb]) palmate amino alcohol or diamine ligand or formula ( [IVa]) or ( [IVb]) palmar amino alcohol ligands, ( [IIIa]) ( [IIIb]) ( [IVa) (IVb)] in Y is NR 7 or O, R4 is a phenylsulfonyl group, wherein the phenyl group is unsubstituted or substituted with one or more independent substituents selected from C1-C4-alkyl and halogen groups, or R4 is 2-pyrrolidinylcarbonyl or 2-piperidinylcarbonyl, preferably (2S)-2-pyrrolidinylcarbonyl. R5 and R6 together form a -(CH2)3- or -(CH2)4- group, or R5 and R6 are independently selected from phenyl groups, and are either unsubstituted or substituted with one or more independently selected C1-C4-alkyl groups. R 7 is hydrogen, phenyl-(CH 2) 3-, phenyl-(CH 2) 4-, benzyloxymethyl, benzyloxyethyl, or phenyl-(CH 2) 2-O-CH 2-, wherein the phenyl and benzyl groups are, as appropriate, substituted with one or more independent substituents selected from C 1-C 4-alkyl groups. R8 is a C2-C6-alkyl group and R9 is hydrogen, or R8 and R9 are independently selected from phenyl groups, which are either unsubstituted or substituted with one or more substituents independently selected from C1-C4-alkyl groups, or R8 and R9 together form the following group , Bonds marked with "*" are attached to carbons containing hydroxyl groups, while bonds marked with "#" are attached to carbons containing amine groups. m is 0 or 1. x is 0, 1, or 2, and Each R10 (if present) is independently selected from C1-C4-alkyl groups.

[0026] Visual compounds ( [Ia]) or ( [Ib]) depends on whether it is the desired product, formula ( [IIIa]) or ( [IVb]) ligands or formula ( [IIIb]) or ( The coordination system of [IVa]) is suitable for use in the method according to the present invention. Generally, if formula ( If the compound [Ia] is the desired product, then formula ( [IIIa]) or ( The coordination group of [IVb] is preferably ( [IIIa]) The coordination system is suitable for use in the method according to the present invention, and conversely, if formula ( If the [Ib] compound is the desired product, then formula ( [IIIb]) or ( The coordination group of [IVa] is preferably ( The coordination system of [IIIb]) is suitable for use in the method according to the invention.

[0027] More preferably, palm-shaped ruthenium catalysts include ( [IIIa]), ( [IIIb]), ( [IVa]) or ( [IVb]) palmar coordination groups, among which Y is NR 7 or O, R4 is a phenylsulfonyl group, wherein the phenyl group is unsubstituted or substituted with one or more independent substituents selected from C1-C4-alkyl and halogen groups, or R4 is a 2-pyrrolidinylcarbonyl group, preferably (2S)-2-pyrrolidinylcarbonyl group. R5 and R6 together form a -(CH2)4- group, or R5 and R6 are unsubstituted phenyl groups. R 7 is a hydrogen, phenyl-(CH 2) 3-, phenyl-(CH 2) 4-, benzyloxymethyl, benzyloxyethyl, or phenyl-(CH 2) 2-O-CH 2- group, wherein the phenyl and benzyl groups are, as appropriate, substituted with one or more independent substituents selected from C 1-C 4-alkyl groups. R8 and R9 are unsubstituted phenyl groups, or R8 and R9 together form the following group , The bonds marked with "*" are attached to carbons containing hydroxyl groups, while the bonds marked with "#" are attached to carbons containing amine groups.

[0028] The best one is the formula ( [IIIa]) or ( [IIIb]) hand-like coordination groups, among which Y is NR 7 or O, R4 is a phenylsulfonyl group, wherein the phenyl group is unsubstituted or substituted with one or more independent substituents selected from C1-C4-alkyl and halogen groups, or R4 is a 2-pyrrolidinylcarbonyl group, preferably (2S)-2-pyrrolidinylcarbonyl group. R5 and R6 together form a -(CH2)4- group, or R5 and R6 are unsubstituted phenyl groups. R7 is a hydrogen, phenyl-(CH2)3-, phenyl-(CH2)4-, benzyloxymethyl, benzyloxyethyl or phenyl-(CH2)2-O-CH2- group, wherein the phenyl and benzyl groups are, as appropriate, substituted with one or more independent substituents selected from C1-C4-alkyl groups.

[0029] The best is the style ( [IIIa-1]) or ( [IIIb-1]) palmar diamine ligand ( [IIIa-1]) ( [IIIb-1]), in R4 is a phenylsulfonyl group, wherein the phenyl group is unsubstituted or substituted by one or more independent substituents selected from C1-C4-alkyl and fluorine groups. R5 and R6 together form a -(CH2)4- group, or R5 and R6 are unsubstituted phenyl groups, and R 7 is a hydrogen, phenyl-(CH 2) 3-, phenyl-(CH 2) 4-, benzyloxymethyl, benzyloxyethyl, or phenyl-(CH 2) 2-O-CH 2- group, wherein the phenyl and benzyl groups are, as appropriate, substituted with one or more independent substituents selected from C 1-C 4-alkyl groups. Preferably, R7 is hydrogen, phenyl-(CH2)3-, and benzyloxyethyl, wherein the phenyl and benzyl groups are substituted by one or more independently selected C1-C4-alkyl groups, preferably methyl groups; and formula ( [IIIa-2]) or ( [IIIb-2]) palmate amino alcohol ligands, in which ( [IIIa-2]) ( [IIIb-2]) R4 is a 2-pyrrolidinyl carbonyl group, preferably (2S)-2-pyrrolidinyl carbonyl group, and R5 and R6 together form a -(CH2)4- group, or R5 and R6 are unsubstituted phenyl groups. Preferably, R5 and R6 are unsubstituted phenyl groups.

[0030] Mode( [IIIa]), ( [IIIb]), ( [IVa]) and ( The ligands of [IVb]) are commercially available products 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).

[0031] Preferably, the palm-shaped ruthenium catalyst has the general formula ( [Va]), ( [Vb]), ( [VIa]) or ( [VIb]): ( [Va]) ( [Vb]) ( [VIa]) ( [VIb]) in Z is NR 13 or O, R4 is a phenylsulfonyl group, wherein the phenyl group is unsubstituted or substituted with one or more independent substituents selected from C1-C4-alkyl and halogen groups, or R4 is 2-pyrrolidinylcarbonyl or 2-piperidinylcarbonyl, preferably (2S)-2-pyrrolidinylcarbonyl. R5 and R6 together form a -(CH2)3- or -(CH2)4- group, or R5 and R6 are independently selected from phenyl groups, and are either unsubstituted or substituted with one or more independently selected C1-C4-alkyl groups. Each R11 (if present) is independently selected from C1-C4-alkyl groups. R12 is C1-C4-alkyl or hydrogen and R13 is hydrogen, or R12 and R13 together form -(CH2)3-, -(CH2)4-, -CH2-O-CH2-, *-(CH2)2-O-CH2-#, or *-(CH2)-O-(CH2)2-# groups, where the bonds indicated by "*" are bonded to nitrogen, and the bonds indicated by "#" are bonded to the benzene ring. q is 0, 1, 2, 3, 4, or 5. X 1 is chlorine or bromine, or X1 is BF4-, PF6-, or SbF6-. In this case, the Ru-X1 bond system is coordination or ionic, and Ru has a positive charge. R8 is a C2-C6-alkyl group and R9 is hydrogen, or R8 and R9 are independently selected from phenyl groups, which are either unsubstituted or substituted with one or more substituents independently selected from C1-C4-alkyl groups, or R8 and R9 together form the following group , Bonds marked with "*" are attached to carbons containing hydroxyl groups, while bonds marked with "#" are attached to carbons containing amine groups. m is 0 or 1. x is 0, 1, or 2, and Each R10 (if present) is independently selected from C1-C4-alkyl groups. Each R14 (if present) 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 is BF 4-, PF 6-, or SbF 6-. In this case, the Ru-X 2 bond is coordination or ionic, and Ru has a positive charge.

[0032] Visual compounds ( [Ia]) or ( [Ib]) depends on whether it is the desired product, formula ( [Va]) or ( [VIb]) catalyst or formula ( [Vb]) or ( The catalyst system of [VIa] is suitable for use in the method according to the invention. Generally, if formula ( If the compound [Ia] is the desired product, then formula ( [Va]) or ( [VIb]) catalyst, preferably ( [Va]) catalyst system is suitable for use in the method according to the invention, conversely if formula ( If the [Ib] compound is the desired product, then formula ( [Vb]) or ( [VIa]) catalyst, preferably ( The catalyst system of [Vb] is suitable for use in the method according to the invention.

[0033] More preferably, the palm-shaped ruthenium catalyst has the general formula ( [Va]), ( [Vb]), ( [VIa]) or ( [VIb]), among which Z is NR 13 or O, R4 is a phenylsulfonyl group, wherein the phenyl group is unsubstituted or substituted with one or more independent substituents selected from C1-C4-alkyl and halogen groups, or R4 is a 2-pyrrolidinylcarbonyl group, preferably (2S)-2-pyrrolidinylcarbonyl group. R5 and R6 together form a -(CH2)4- group, or R5 and R6 are unsubstituted phenyl groups. Each R11 (if present) is independently selected from C1-C4-alkyl groups. R12 is C1-C4-alkyl or hydrogen and R 13 is hydrogen, or R12 and R13 together form -(CH2)3-, -(CH2)4-, -CH2-O-CH2-, *-(CH2)2-O-CH2-#, or *-(CH2)-O-(CH2)2-# groups, where the bonds indicated by "*" are bonded to nitrogen, and the bonds indicated by "#" are bonded to the benzene ring. q is 0, 1, 2, 3, 4, or 5. X 1 is chlorine or bromine, or X1 is BF4-, PF6-, or SbF6-. In this case, the Ru-X1 bond system is coordination or ionic, and Ru has a positive charge. R8 and R9 are unsubstituted phenyl groups, or R8 and R9 together form the following group , Bonds identified by "*" are attached to carbons containing hydroxyl groups, while bonds identified by "#" are attached to carbons containing amine groups. Each R14 (if present) 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 is BF 4-, PF 6-, or SbF 6-. In this case, the Ru-X 2 bond is coordination or ionic, and Ru has a positive charge.

[0034] The best is the general formula ( [Va]) or ( [Vb]) palm-shaped ruthenium catalyst, in which Z is NR 13 or O, R4 is a phenylsulfonyl group, wherein the phenyl group is unsubstituted or substituted by one or more independent substituents selected from C1-C4-alkyl and fluorine groups. R5 and R6 together form a -(CH2)4- group, or R5 and R6 are unsubstituted phenyl groups, and Each R11 (if present) is a methyl group. R12 is a C1-C4 alkyl group, such as methyl or isopropyl, and R 13 is hydrogen, or R12 and R13 together form -(CH2)3-, -(CH2)4-, -CH2-O-CH2-, *-(CH2)2-O-CH2-#, or *-(CH2)-O-(CH2)2-# groups, where the bonds indicated by "*" are bonded to nitrogen, and the bonds indicated by "#" are bonded to the benzene ring. q is 0, 1, or 2. X 1 is chlorine or bromine, or X1 is BF4-, PF6-, or SbF6-. In this case, the Ru-X1 bond is coordination or ionic, and Ru has a positive charge.

[0035] Mode( [Va]), ( [Vb]), ( [VIa]) and ( [VIb]) The palmar ruthenium catalyst is a commercially available product 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).

[0036] Mode( [Va]) and ( [Vb]) of palm-shaped ruthenium catalysts (where R12 is C1-C4-alkyl and Z is O or NH) and formula ( [VIa]) and ( [VIb]) ruthenium catalysts can be used in organic solvents (e.g., dichloroethane) via pre-catalysts of dichloro(aromatic)ruthenium(II) dimers, such as [RuCl₂(p-isopropyltoluene)]₂ or [RuCl₂(hexamethylbenzene)]₂, or dibromo(aromatic)ruthenium(II) dimers with formula ( [IIIa']), ( [IIIb']), ( [IVa]) or ( [IVb]) forms in situ by mixing with palmate ligands. ( [IIIa']) ( [IIIb']) ( [IVa) (IVb)] [,] in R4, R5, and R6 are each as shown in the formula. [(Va)] and Definition of [(Vb)] complexes, Z is either NH or O. R8 and R9 are as follows: [(VIa)] and The definition of [(VIb)] complexes, Furthermore, the aromatic ligand system of the pre-catalyst is selected from the group consisting of p-isopropyltoluene and benzene, and is substituted with one or more methyl groups as appropriate.

[0037] Examples of suitable organic solvents include dichloromethane, 1,2-dichloroethane, chlorobenzene, dichlorobenzene, toluene, acetonitrile, dimethylformamide, ethanol, isopropanol, tetrahydrofuran, and 2-methyltetrahydrofuran.

[0038] Examples of suitable aromatic ligands are p-isopropyltoluene and hexamethylbenzene.

[0039] According to the formula [(II)] The amount of ruthenium catalyst used is preferably in the range of 0.01 mol% to 10 mol%, more preferably 0.1 mol% to 5 mol%, and most preferably 0.5 mol% to 3 mol%.

[0040] The method according to the present invention includes asymmetric transfer hydrogenation ( [II]) compound.

[0041] The preferred hydrogen source is selected from the group consisting of sodium formate, potassium formate, lithium formate, calcium formate, magnesium formate, formic acid / triethylamine, potassium tributate / isopropanol, sodium tributate / isopropanol, and lithium tributate / isopropanol. More preferably, it is selected from the group consisting of sodium formate, potassium formate, lithium formate, calcium formate, magnesium formate, and formic acid / triethylamine. The most suitable source is sodium formate and formic acid / triethylamine.

[0042] According to the formula ( [II]) The amount of hydrogen source used is preferably at least 1.0 equivalent, more preferably at least 2.0 equivalent, and most preferably 2.0 to 3.5 equivalent, based on the amount of the compound.

[0043] In the case of formic acid / triethylamine, formic acid serves as the hydrogen source, therefore the amount of hydrogen source used corresponds to the amount of formic acid used. Preferably, according to formula... [(II)] The amount of triethylamine used is in the range of 0.2 to 1.0 equivalents based on the amount of the compound.

[0044] In the cases of potassium butyrate / isopropanol, sodium butyrate / isopropanol, and lithium butyrate / isopropanol, isopropanol is used as both the hydrogen source and the (co)solvent; therefore, the amount of isopropanol used typically exceeds the amount of hydrogen source required for the hydrogenation reaction. According to formula... [(II)] The preferred amount of tertiary butyrate is between 0.2 and 1.0 equivalents, based on the amount of the compound.

[0045] Preferably, the hydrogen source used is selected from sodium formate and formic acid / triethylamine, and is formulated according to formula ( [II]) The amount of hydrogen source used, in terms of the amount of compound, is in the range of 2.0 to 3.5 equivalents.

[0046] Transfer hydrogenation is preferably carried out at a temperature in the range of 10°C to 100°C, more preferably in the range of 20°C to 80°C, and especially in the range of 25°C to 50°C.

[0047] Reaction time is not critical and can be selected within a fairly wide range depending on batch production capacity. Typical reaction times are between 30 min and 24 h.

[0048] According to the present invention, asymmetric transfer hydrogenation ( [II]) The compound system was tested in the presence of a polar solvent.

[0049] Suitable polar solvent systems 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.

[0050] The 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.

[0051] The best choices are ethanol, isopropanol / water, dimethylformamide / water, acetonitrile / water, 2-methyltetrahydrofuran, and 2-methyltetrahydrofuran / water.

[0052] If the transfer of hydrogenation is carried out in the presence of water, then equation ( [Ia]) or ( [Ib]) The subsequent processing and isolation of the compound can be achieved by the following steps: (i) separating the aqueous phase from the organic phase, (ii) extracting the aqueous phase once or multiple times with a suitable organic solvent (e.g., heptane, toluene, or xylene), (iii) washing the combined organic phases with water, brine, and / or an aqueous sodium bicarbonate solution, (iv) treating the obtained organic phase with magnesium sulfate or drying it by azeotropic distillation, and (v) removing (partially) the organic solvent by distillation. The resulting product can be purified by crystallization from heptane.

[0053] Mode( [Ia]) or ( [Ib]) compounds can be prepared with high enantioselectivity by the asymmetric transfer hydrogenation method according to the present invention. The compounds of formula () obtained by the method according to the present invention [Ia]) or ( [Ib]) The compound can be purified by forming a crystalline addition salt with camphor sulfonic acid. This can increase the chemical purity of the desired product to >99% w / w.

[0054] The method according to the present invention includes asymmetric transfer hydrogenation ( [II]) compound.

[0055] The ketone of formula (II) can be derived from formula ( [Ia]) and ( [Ib]) racemic mixtures other than compounds [(Ia) (Ib)] (where the substituents R1, R2, R3 and the integer n are as shown in the formula) [II]) Definition of a compound It is obtained by oxidation using TEMPO, TEMPO derivatives or TEMPO analogs, hypochlorite and bromide salts as appropriate.

[0056] Similarly, formula ( [II']) ketones can be derived from formula ( [Ia']) and ( racemic mixtures other than [Ib']) compounds [(Ia') (Ib')] (where the substituents R1, R3a, and R3b are as shown in formula () [II']) Definition of a compound) It is obtained by oxidation using TEMPO, TEMPO derivatives or TEMPO analogs, hypochlorite and bromide salts as appropriate.

[0057] Discovered formula ( [II]) ketones can be derived from formula ( [Ia]) and ( [Ib]) racemic mixtures other than the compound are obtained by TEMPO-controlled oxidation using a catalytic amount of TEMPO, a TEMPO derivative or TEMPO analogue, hypochlorite as the oxidant and bromide, selected as the co-oxidant, as appropriate. This reaction has been found to be applicable to compounds with pyridine functionality of formula ( [Ia]) and ( [Ib]) compound, according to M. Shibuya, M. Tomizawa, I. Suzuki, Y. Iwabuchi, J. Am. Chem. Soc.,

[2006] The previous results disclosed in 128, 8412-8413 are surprising. Shibuya et al. taught that nitrosyl radicals, such as TEMPO and 1-Me-AZADO, cannot efficiently oxidize matrices containing basic nitrogen. Furthermore, the reaction is also suitable for the use of readily available TEMPO in catalytic amounts, as Shibuya et al. surprisingly taught the use of 1-Me-AZADO (2-aza-1-methyladamantane N-oxy) instead of TEMPO for the oxidation of secondary alcohols.

[0058] Examples of suitable TEMPO derivatives and TEMPO analogs include 4-hydroxy-TEMPO, 4-methoxy-TEMPO, 4-sideoxy-TEMPO, 2-aza-adamantane N-oxy, and 2-aza-1-methyladamantane N-oxy.

[0059] TEMPO, TEMPO derivatives, or TEMPO analogs can be used as is or immobilized. Suitable examples of immobilized TEMPO are silicon dioxide-supported TEMPO and polystyrene-supported TEMPO.

[0060] According to the formula ( [Ia]) and ( [Ib]) compound, preferably ( [Ia']) and ( The total amount of TEMPO, TEMPO derivatives or TEMPO analogs used is preferably in the range of 0.5 mol% to 20 mol%, more preferably 1 mol% to 10 mol%, and most preferably 3 mol% to 7.5 mol%.

[0061] Suitable hypochlorites are sodium hypochlorite, potassium hypochlorite, and magnesium hypochlorite. Preferably, the hypochlorite used for TEMPO-controlled oxidation is selected from sodium hypochlorite and potassium hypochlorite. Sodium hypochlorite is particularly preferred.

[0062] According to the formula ( [Ia]) and ( [Ib]) compound, preferably ( [Ia']) and ( The amount of hypochlorite used, in terms of the total amount of [Ib']) compound, is preferably in the range of 1 to 5 equivalents, more preferably 1.1 to 2.0 equivalents, and most preferably 1.2 to 1.5 equivalents.

[0063] Suitable bromide salts are potassium bromide, sodium bromide, and tetrabutylammonium bromide and mixtures thereof.

[0064] According to the formula ( [Ia]) and ( [Ib]) compound, preferably ( [Ia']) and ( The amount of bromide salt used, in terms of the total amount of [Ib']) compound, is preferably in the range of 0.5 mol% to 20 mol%, more preferably 5 mol% to 15 mol%.

[0065] The optimal TEMPO-controlled oxidation is carried out under alkaline two-phase conditions in the presence of water, organic solvents, and phase transfer catalysts, such as tetrabutylammonium bromide (TBAB).

[0066] 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 by hypochlorite reagents.

[0067] For example, TEMPO-regulated oxidation can be carried out under alkaline two-phase conditions using a mixture of sodium hypochlorite aqueous solution and sodium bicarbonate saturated aqueous solution as the aqueous phase, dichloromethane as the organic solvent and tetrabutylammonium bromide (TBAB) as the phase-transfer catalyst.

[0068] The TEMPO-controlled oxidation is preferably carried out in a temperature range of -20°C to +25°C, and more preferably in a temperature range of -5°C to +5°C.

[0069] Reaction time is not critical and can be selected within a fairly wide range depending on batch capacity. Typical reaction times are between 5 min and 3 h.

[0070] Mode( [II]) or ( The post-treatment and isolation of the ketone [II'] can be achieved by the following steps: (i) separating the aqueous phase from the organic phase, (ii) extracting the aqueous phase once or multiple times with a suitable organic solvent (e.g., heptane), (iii) washing the combined organic phases with water or brine, (iv) drying the obtained organic phase by treating with magnesium sulfate, and (v) removing the organic solvent by distillation. The obtained formula ( [II]) or ( [II']) The product can be purified by crystallization in heptane.

[0071] Abbreviations and abbreviations: % a / a Area percentage DCE 1,2-Dichloroethane DMF dimethylformamide ee Enantiomer transcendence Et Ethyl EtOH ethanol HPLC High performance liquid chromatography Ph Phenyl i PrOH Isopropanol qNMR Quantitative NMR Me methyl MeCN Acetonitrile MeTHF 2-Methyltetrahydrofuran NEt 3 Triethylamine NMR Nuclear magnetic resonance TEMPO 2,2,6,6-Tetramethylpiperidinoxy TMB Trimethoxybenzene Ts Toluenesulfonyl (p-toluenesulfonyl) [Example]

[0072] [By means] [TEMPO] [Regulated oxidation] [(Ia'-1) / (Ib'-1)] [Preparation of starting materials] [(II'-1)] [:] Example 1:

[0073] Compound ( [Ia'-1]) and ( A mixture of racemic components other than [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 a saturated sodium bicarbonate solution (prepared with 4.5 L of water) was placed in a reactor. The beige mixture was cooled to 0°C and, under temperature control at 0°C (± 4°C), a mixture of sodium hypochlorite solution (13.4% w / w, total required: 3530 g, 5454 mmol, 1.215 equiv) and saturated sodium bicarbonate solution (total required: 3.81 kg) was added until complete conversion of the starting material was observed on process control (HPLC@220 nm). The reaction mixture was transferred to a stirred tank and diluted with water (2.8 L). The aqueous phase was separated and extracted again with dichloromethane (5.6 L). The combined organic layers were washed with water (5.6 L) and filtered through a sodium sulfate column (1 kg), followed by rinsing with dichloromethane (2.8 L). 10 L of solvent was evaporated (40°C) and 6 L of heptane was added. Another 4.5 L of solvent was evaporated and replaced with heptane. 1 L of heptane was evaporated and 2 g of the compound was added. [II'-1]) Crystallization was initiated by implanting crystals in the solution. The suspension was concentrated to a total mass of 8 kg at 45°C, 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 vacuum at 40-45°C.

[0074] Mass: 1273 g (97% of theoretical value); Appearance: Beige solid; HPLC (220 nm): ≥99% area; Detection (1H-NMR, DMSO-d6, TMB as standards): 96%; Yield (mass yield x detection): 93% of the compound. [II'-1]). Example 2

[0075] Under an inert atmosphere (N2), the compound ( [Ia'-1]) and ( A mixture of racemic components other than [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) was placed in a vial. 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 over 5 min at 0°C (± 4°C). After stirring at this temperature for 20 min, process control (HPLC@220 nm) showed complete conversion of the starting material and 82.9% a / a of the compound ( [II'-1]). Example 3

[0076] Under an inert atmosphere (N2), the compound ( [Ia'-1]) and ( A mixture of racemic components other than [Ib'-1] (0.13 g, 0.44 mmol), silicon dioxide-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. 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 over 5 min at 0°C (± 4°C). After stirring at this temperature for 20 min, process control (HPLC@220 nm) showed complete conversion of the starting material and 96.6% a / a of the compound ( [II'-1]). Example 4

[0077] Under an inert atmosphere (N2), the compound ( [Ia'-1]) and ( A mixture of racemic components other than [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. 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 over 5 min at 0°C (± 4°C). After stirring at this temperature for 20 min, process control (HPLC@220 nm) showed complete conversion of the starting material and 90.4% a / a of the compound ( [II'-1]). [Asymmetric Transfer Hydrogenation]

[0078] The reaction was carried out in appropriately sized glass containers. Unless otherwise stated, the reaction mixture was analyzed without post-treatment by HPLC (Chiralpak IC column, heptane / ethanol gradient (with 0.02% diethylamine as a stabilizing additive), 1 mL / min).

[0079] Preparation of palm-shaped ruthenium catalyst

[0080] The catalysts used in Examples 5-14 were prepared by dissolving ruthenium(II) catalyst precursors ([RuCl2(p-isopropyltoluene)]2 or [RuCl2(hexamethylbenzene)2, 1.0 equiv) in DCE at 60°C before the reaction, adding the ligands listed in Table 1 (1.2 equiv), stirring the solution at 60°C for 1 h, and then evaporating the DCE.

[0081] The following catalysts are commercially available products and were used in Examples 15-34 in the form of purchase: ( [Va-1]) ( [Vb-2]) ( [Va-3]) ( [Vb-4]) ( [Va-5])

[0082] Transfer hydrogenation reaction

[0083] Under an inert gas atmosphere, 9.7 mg of ketone starting material dissolved in individual solvent mixtures (see Table 1, starting material concentration 0.13 M) was used. [II'-1])(33 μmol, 1 equiv), reducing agent (see Table 1; NaCO₂₂H: 2.5 equiv; HCO₂₂H / NEt₃: 2.7 equiv / 0.6 equiv respectively), and 0.66 μmol catalyst (2 mol%, see Table 1) were packed into one well of a 96-well autoclave. The autoclave was shut off and heated to 35°C, at which temperature the reaction mixture was shaken for 17 h. Chromatographic analysis of the cooled and depressurized reaction mixture showed that the starting material ( [II'-1]) to the reduced alcohol product ( [Ia'-1]) or ( The %a / a HPLC conversion of [Ib'-1]) is shown in Table 1 below. The %a / a HPLC conversion and enantioselectivity are described in Table 1 below.

[0084] Table 1: [Example] [Catalyst precursors] [, 1) , ] [ / ] [catalyst] [, 2) , ] [Coordination Group] [, , ] [solvent] [reducing agent] [product] [(] [Main enantiomer] [)] [Conversion Rate] [, , (%a / a HPLC) ] [% , ee , ] 5 [RuCl2(p-isopropyltoluene)]2 i PrOH; H 2O HCO₂Na ( [Ib'-1]) 79.9 56.4 6 [RuCl2(p-isopropyltoluene)]2 DMF; H2O HCO₂Na ( [Ib'-1]) 43.9 80.3 7 [RuCl2(p-isopropyltoluene)]2 i PrOH; H 2O HCO₂Na ( [Ia'-1]) 100 92.3 8 [RuCl₂(hexamethylbenzene)]₂ MeTHF; H 2O HCO₂Na ( [Ib'-1]) 100 97.9 9 [RuCl2(p-isopropyltoluene)]2 MeCN; H 2O HCO₂Na ( [Ib'-1]) 100 96.1 10 [RuCl2(p-isopropyltoluene)]2 DMF HCO₃⁻ + 2H⁺; NEt₃ ( [Ib'-1]) 86.9 89.1 11 [RuCl2(p-isopropyltoluene)]2 DMF; H2O HCO₂Na ( [Ib'-1]) 100 96.8 12 [RuCl2(p-isopropyltoluene)]2 MeTHF; H 2O HCO₂Na ( [Ia'-1]) 97.2 84 13 [RuCl₂(hexamethylbenzene)]₂ MeCN; H 2O HCO₂Na ( [Ib'-1]) 98.4 30.4 14 [RuCl2(p-isopropyltoluene)]2 EtOH; H 2O HCO₂Na ( [Ib'-1]) 21.8 16.7 15 [(Va-1)] - EtOH HCO₃⁻ + 2H⁺; NEt₃ ( [Ia'-1]) 100 97.5 16 [(Va-1)] - DMF; H2O HCO₂Na ( [Ia'-1]) 98.9 95.9 17 [(Va-1)] - MeTHF HCO₃⁻ + 2H⁺; NEt₃ ( [Ia'-1]) 83.0 93.6 18 [(Va-1)] - MeCN; H 2O HCO2Na ( [Ia'-1]) 99.1 97.3 19 [(Vb-2)] - EtOH HCO₂H; NEt₃ ( [Ib'-1]) 100 97.1 20 [(Vb-2)] - DMF; H2O HCO2Na ( [Ib'-1]) 100 94.5 21 [(Vb-2)] - MeTHF HCO₂H; NEt₃ ( [Ib'-1]) 100 95.5 22 [(Vb-2)] - MeCN; H2O HCO2Na ( [Ib'-1]) 100 96.9 23 [(Va-3)] - EtOH HCO₂H; NEt₃ ( [Ia’-1]) 100 92.1 24 [(Va-3)] - DMF; H 2O HCO 2Na ( [Ia’-1]) 98.5 98.5 25 [(Va-3)] - MeTHF HCO 2H; NEt 3 ( [Ia’-1]) 96.6 91.6 26 [(Va-3)] - MeCN; H 2O HCO 2Na ( [Ia’-1]) 100 98.7 27 [(Vb-4)] - EtOH HCO 2H; NEt 3 ( [Ib’-1]) 100 96.2 28 [(Vb-4)] - MeTHF HCO 2H; NEt 3 ( [Ib’-1]) 100 96.6 29 [(Vb-4)] - DMF; H2O HCO₂Na ( [Ib'-1]) 98.2 96.3 30 [(Va-5)] - EtOH HCO₃⁻ + 2H⁺; NEt₃ ( [Ia'-1]) 100 94.1 31 [(Va-5)] - MeTHF HCO₃⁻ + 2H⁺; NEt₃ ( [Ia'-1]) 100 91.9 32 [(Va-5)] - DMF; H2O HCO₂Na ( [Ia'-1]) 98.9 96.7 1): The catalyst used in Embodiments 5-12 is of formula ( [Va]), ( [Vb]) or ( [VIa]) complexes. These catalysts are prepared prior to the reaction from the catalyst precursors and ligands listed in the table according to the method described above. Thus, the catalysts used in Examples 13 and 14 are obtained. 2): The catalysts used in Examples 15-32 are commercially available products and are used in the form of purchase. Example 33:

[0085] All solvents and solutions used in the reaction and post-processing procedures are degassed with argon gas before use. The 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. The catalyst ( Before adding [Va-3] (2 mol%, 379 mg, 0.64 mmol), allow argon gas to bubble through the suspension for 15 min. Add a solution of sodium formate (24 g, 352 mmol) in water (94 ml). Stir the reaction overnight (16 h) at 35°C (bath temperature). Separate the oil-containing upper layer in a separatory funnel and extract the aqueous phase with heptane (50 ml). Dilute the combined upper layers with heptane (25 ml) and wash with water (50 ml). Extract the separated aqueous phase again with heptane (40 ml). Wash the combined organic phases with water (50 ml) and brine (aqueous, 30%, 30 ml). [, Purification by silica column filtration , ] [, , ]

[0086] A column was packed with silicone 60 (Fluka 89943, 50 g) in heptane slurry form. An organic layer derived from the extraction was applied directly to the column and extracted with a gradient from heptane (100%) to heptane / MeTHF 3 / 1 (v / v). The product fraction was evaporated under vacuum to produce 9.3 g of beige / brown solids (verifications: 96% w / w, 94% yield, 97% ee). Example 34

[0087] The reaction is carried out under an inert gas atmosphere. All solvents and solutions used in the reaction and post-processing procedures are degassed with argon before use. Under an inert gas atmosphere (argon), the compound ( [II'-1])(1230g, 4025 mmol) and catalyst ( [Va-3] (54 g, 80 mmol) was placed in a 20-L round-bottom flask. Acetonitrile (4 L) was added and the mixture was mixed (30°C) to obtain a brown to red solution. [Solution] [1] Sodium formate (1369 g, 20.1 mol) was dissolved in degassed water (7 L). The solution was evacuated three times and rinsed with argon gas. [Solution] [2]). Will [Solution] [1] Place it in a reactor (rinse the flask with 0.5 L acetonitrile), and then put it into [Solution] [2] (rinse the flask with 1L of water).

[0088] The mixture is heated to 35°C over approximately 45 minutes and stirred at this temperature for 1 hour. The process control displays the starting material (…). [II'-1]) Complete conversion. The reaction mixture was cooled to 25°C and transferred to a separation vessel to separate the phases. The aqueous layer was re-extracted with heptane (3.7 L). The mixed organic phases (two-phase mixture) were washed with 2 x 1.85 L of semi-saturated sodium bicarbonate aqueous solution, followed by 1.85 L of saturated sodium bicarbonate aqueous solution. The organic layer was filtered through a sodium sulfate column (800 g) and rinsed with heptane (2 x 1 L). The solvent was evaporated under vacuum (45°C) to obtain 1260 g of brown to purple resin.

[0089] Analysis: HPLC non-permeable (220 nm): 97.6% area; HPLC permeable (220 nm): ee 99.7%. Chemical yield was determined after purification via salt formation and free alkalization (see Example 35). [, Formation of camphor sulfonate , ] [, , ] Example 35:

[0090] At 50°C, the crude product ( [Ia'-1] (derived from Example 34, 1321 g) was dissolved in MeTHF (7 L). A MeTHF (4 L) solution of (1 S)-(+)-10-camphorsulfonic acid (981 g, 4221 mmol) was continuously added over 20 minutes at 50°C; crystals were implanted in the solution during addition. After the addition was complete, the resulting suspension was stirred at 50°C for another 30 minutes, and then cooled to 20°C over 1 hour. The solid was filtered off, washed with MeTHF (2 x 1 L), and dried under vacuum at 45°C.

[0091] Yield: 1947 g (87% of theoretical value), white solid, HPLC (220 nm): ≥ 99% (area)

[0092] Dissolve 1945 g of this material in MeTHF (13 L) and water (5 L). Add 1.65 L of saturated Na₂CO₃ aqueous solution to raise the pH to 10. Separate the phases and wash the organic layer with water (3.3 L) and brine (30%, 1.6 L). Filter the organic layer through a sodium sulfate column (1 kg) and rinse with MeTHF (1.5 L). Evaporate the solvent under vacuum (45 °C). Co-evaporate the residue with heptane (3 x 1.3 L).

[0093] Yield: 1087 g (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 after three steps (transfer hydrogenation (Example 34), salt formation, free alkalization): 87%. Example 36

[0094] The reaction was carried out under an inert gas atmosphere. All solvents and solutions used in the reaction and post-processing procedures were degassed with nitrogen before use. The compound ( ) was reacted under an inert gas atmosphere (argon). [II'-1] (177 g, 589 mmol) and catalyst ( [Va-3] (1.92 g, 2.95 mmol) was placed in a round-bottom flask. Acetonitrile (646 mL) was added and the mixture was mixed to obtain a brown to red solution. [Solution] [1] Sodium formate (200.4 g, 2947 mmol) was dissolved in degassed water (1.15 L). The solution was further degassed by bubbling with nitrogen for 1 h. [Solution] [2]). [Solution] [2] Place it in the reactor, and then put it in [Solution] [1].

[0095] The mixture is heated to 35°C over approximately 35 minutes and stirred overnight at this temperature. The starting material is monitored during the process. [II'-1]) Complete conversion. The reaction mixture was cooled to 25°C and transferred to a separation vessel to separate the phases. Most of the acetonitrile was removed from the organic layer under reduced pressure (150-100 mbar) and a jacket temperature of 40°C. The aqueous layer was re-extracted with xylene (233 g). The xylene layer was added to the distillation cell containing the acetonitrile layer. Again, a vacuum (100 mbar, 50°C jacket temperature) was applied to remove the acetonitrile residue, water, and some xylene (distillate: 233 g). A solution of (1 S)-(+)-10-camphorsulfonic acid (136 g, 585 mmol) in MeTHF (420 g) was added continuously over 30 minutes at 50°C. The mixture was maintained at this temperature for 50 min, cooled to 10°C over 2 h, and then maintained at 10°C for another 2 h. The mixture was filtered and washed twice with 226 g of MeTHF each time. The filter cake was vacuum dried at 30°C to produce 288g of camphor sulfonate with a purity ≥99% a / a (yield (uncorrected) of 92% after two steps) and ee of 99.4%. Example 37 (Free Alkalization):

[0096] Dissolve 124 g of camphor sulfonate and 2 g of sodium bicarbonate together in toluene (428 g), MeTHF (48 g), and water (425 g). Add 49.3 g of 20% w / w sodium hydroxide aqueous solution dropwise to raise the pH to 10. Heat the mixture to 40–50°C, filter clean, and separate the phases. Wash the organic layer with 5% w / w sodium bicarbonate aqueous solution (210 mL) at 40–50°C, then evaporate to dryness to produce 70.5 g of camphor sulfonate. [Ia'-1] Beige solids (99% yield, 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 can be stopped before completion to obtain... [Ia'-1] 50% w / w toluene solution. Example 38

[0097] The reaction is carried out under an inert gas atmosphere. All solvents and solutions used in the reaction and post-processing procedures are degassed with nitrogen before use. Under an inert gas atmosphere (nitrogen), the compound ( [II'-1] (93.9% purity, 78.5 g, 251 mmol) and catalyst ( [Va-3] (0.817 g, 1.25 mmol, 0.5 mol%) was placed in a round-bottom flask. Acetonitrile (302 mL) was added, and the mixture was stirred under a constant nitrogen flow for 3 h to obtain a brown to red solution. [Solution] [1] Sodium formate (85.4 g, 1256 mmol) was dissolved in degassed water (537 mL). The solution was further degassed by bubbling nitrogen gas. [Solution] [2]). [Solution] [2] Place it in the reactor, and then put it in [Solution] [1].

[0098] The mixture was heated to 35°C and stirred for 6 hours over approximately 35 minutes. The starting material was monitored and displayed during the process. [II'-1]) Complete conversion. The reaction mixture was cooled to 25°C and transferred to a separation vessel to separate the phases. Most of the acetonitrile was removed from the organic layer 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 cell containing the acetonitrile layer. Again, a vacuum (100-40 mbar, 50°C jacket temperature) was applied to remove the acetonitrile residue, water, and some xylene (distillate: 139 g). 1 g of seed crystals was added at 50°C. Then, over 30 minutes, a solution of (1 S)-(+)-10-camphorsulfonic acid (58.3 g, 251 mmol) in MeTHF (241 g) was continuously added at 50°C with rapid stirring. The mixture was maintained at this temperature for 30 minutes, cooled to 10°C over 2 hours, and then maintained at 10°C overnight. The mixture was filtered and washed twice with 100 g MTBE each time. The filter cake was vacuum dried at 30°C to produce 122 g of camphor sulfonate with a test purity of 97.1% w / w and ee of 99.4% (yield after two steps, 89%).

[0099] none

[0100] none

Claims

1. A method for preparing compounds of formula (Ia) or (Ib) in the presence of a ruthenium catalyst and a polar solvent, wherein R1 and R2 are independently selected from the group consisting of hydrogen and C1-C4-alkyl, each R3 (if present) is independently selected from C1-C4-alkyl, and n is 0, 1, 2, or 3, the method comprising asymmetric transfer hydrogenation of a ketone (II) of formula (II) (wherein the substituents R1, R2, R3 and the integer n are as defined in compounds of formula (Ia) or (Ib), wherein the ruthenium catalyst has the general formula (Va), (Vb), (VIa), or (VIb): (Va) (Vb) (VIa) (VIb) wherein Z is NR13 or O, R4 is phenylsulfonyl,The phenyl group is either unsubstituted or substituted with one or more substituents independently selected from C1-C4-alkyl and halogen groups, or R4 is a 2-pyrrolidinylcarbonyl group, R5 and R6 together form a -(CH2)4- group, or R5 and R6 are unsubstituted phenyl groups, each R11 (if present) is independently selected from C1-C4-alkyl, R12 is a C1-C4-alkyl or hydrogen and R13 is hydrogen, or R12 and R13 together form a -(CH2)3-, -(CH2)4-, -CH2-O-CH2-, *-(CH2)2-O-CH2-# or *-(CH2)-O-(CH2)2-# group, wherein the bond indicated by "*" is bonded to nitrogen, and the bond indicated by "#" is bonded to the benzene ring, q is 0, 1, 2, 3, 4 or 5, X1 is chlorine or bromine, or X1 The Ru-X1 bond is BF4-, PF6-, or SbF6-, in which case the Ru-X1 bond is coordinated or ionic, and Ru has a positive charge. R8 and R9 are unsubstituted phenyl groups, or R8 and R9 together form a group of the following formula: The bond identified by "*" is attached to the carbon containing the hydroxyl group, and the bond identified by "#" is attached to the carbon containing the amino group. Each R14 (if present) is independently selected from C1-C4-alkyl groups, p is 0, 1, 2, 3, 4, 5, or 6, and X2 is chlorine or bromine, or X2 is BF4-, PF6-, or SbF6-, in which case the Ru-X2 bond is coordinated or ionic, and Ru has a positive charge.

2. The method according to claim 1, wherein the compounds of formula (Ia), (Ib) and (II) are compounds of formula (Ia'), (Ib') and (II'), wherein R1, R3a and R3b are independently selected from C1-C4-alkyl groups.

3. The method according to claim 2, wherein R1 is methyl, R3a is methyl, and R3b is ethyl.

4. The method according to any one of claims 1 to 3, wherein the hydrogen source for asymmetric transfer of the ketone of hydrogenation formula (II) 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.

5. The method according to any one of claims 1 to 3, wherein the hydrogen source for the asymmetric transfer of the ketone of hydrogenation formula (II) is sodium formate or formic acid / triethylamine.

6. The method according to any one of claims 1 to 3, wherein the amount of ruthenium catalyst used is in the range of 0.1 mol% to 5 mol% based on the amount of compound of formula (II).

7. The method according to any one of claims 1 to 3, wherein the transfer hydrogenation is carried out at a temperature in the range of 20°C to 80°C.

8. The method according to any one of claims 1 to 3, 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.

9. The method according to claim 1, wherein R12 is C1-C4-alkyl and Z is O or NH, wherein the palmar ruthenium catalyst is formed in situ in an organic solvent by mixing a dichloro(aromatic)ruthenium(II) dimer pre-catalyst or a dibromo(aromatic)ruthenium(II) dimer pre-catalyst with a palmar ligand of formula (IIIa'), (IIIb'), (IVa) or (IVb), wherein R4, R5 and R6 are each as defined in the complexes of formula (Va) and (Vb), Z is NH or O, R8 and R9 are each as defined in the complexes of formula (VIa) and (VIb), and wherein the aromatic ligand of the pre-catalyst is selected from the group consisting of p-isopropyltoluene and benzene, which may be substituted with one or more methyl groups.

10. The method according to any one of claims 1 to 3 and 9, wherein the product or mixture thereof of formula (Ia) or (Ib) is purified by forming a crystalline addition salt with camphor sulfonic acid.

11. The method according to any one of claims 1 to 3 and 9, wherein the ketone of formula (II) is obtained from a racemic mixture other than compounds of formula (Ia) and (Ib) by oxidation using TEMPO, a TEMPO derivative or TEMPO analog, a hypochlorite and, where appropriate, a bromide salt, wherein the substituents R1, R2, R3 and the integer n are as defined in compounds of formula (II).

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