Methods involving the use of novel iridium catalysts for the enantioselective hydrogenation of 4-substituted 1,2-dihydroquinolines

Abstract

New iridium catalyst for the enantioselective hydrogenation of 4-substituted 1,2-dihydroquinolines. The present invention relates to a process for the preparation of optically active 4-substituted 1,2,3,4-tetrahydroquinolines (1a, 1b) which comprises the enantioselective hydrogenation of the corresponding 4-substituted 1,2-dihydroquinolines in the presence of a chiral iridium (P,N)-ligand catalyst. [Formula 1] TIFF2022549636000037.tif29145

Description

[Technical field]

[0001] The present invention relates to a process for the preparation of optically active 4-substituted 1,2,3,4-tetrahydroquinolines which comprises the enantioselective hydrogenation of the corresponding 4-substituted 1,2-dihydroquinolines in the presence of a chiral iridium (P,N)-ligand catalyst. [Background technology]

[0002] It is known from EP 0 654 464 that N-acetyl-tetrahydroquinolines can be converted into the corresponding 4-aminoindan derivatives via a rearrangement reaction.

[0003] 4-Aminoindan derivatives are important intermediates for the preparation of various N-indanylheteroarylcarboxamides with fungicidal activity (EP0654464, WO2011 / 162397, WO2012 / 084812, WO2015 / 197530).

[0004] EP 3103789 discloses a method for the optical resolution of 1,1,3-trimethyl-4-aminoindan by converting the enantiomeric mixture into the diastereomeric salts of D-tartaric acid. (R)- and (S)-1,1,3-trimethyl-4-aminoindan are obtained after separation and basification of the diastereomeric salts. This reference also discloses a method for racemizing the undesired enantiomer, so that the overall method allows the undesired enantiomer to be converted into the desired enantiomer through several process steps. (R)-1,1,3-trimethyl-4-aminoindan is a key intermediate for the preparation of the pyrazole carboxamide fungicide impirfluxam.

[0005] Methods for preparing chiral intermediates of N-indanylheteroarylcarboxamides by asymmetric synthesis are also known. WO2015 / 141564 describes a process for preparing optically active 4-substituted 1,2,3,4-tetraquinolines, which comprises hydrogenating the corresponding 4-substituted 1,2-dihydroquinolines in the presence of a transition metal catalyst bearing an optically active ligand. Asymmetric hydrogenation of 4-substituted NH-dihydroquinolines proceeded with moderate conversions (up to 62.6%) and enantioselectivities (up to 71.3% ee), while N-acetyl-dihydroquinolines gave poorer conversions (up to 14%) and enantioselectivities (up to 31% ee). Summary of the Invention [Means for solving the problem]

[0006] In view of the above prior art, it is an object of the present invention to provide a process for the preparation of optically active 4-substituted 1,2,3,4-tetrahydroquinolines having advantages over the prior art processes. The process should allow the preparation of the desired enantiomer in high yield and high enantiomeric purity with few process steps and few purification steps. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] EP0654464 issue [Patent Document 2] WO2011 / 162397 issue [Patent Document 3] WO2012 / 084812 issue [Patent Document 4] WO2015 / 197530 issue [Patent Document 5] EP3103789 issue [Patent Document 6] WO2015 / 141564

[0008] The above object is achieved by a process for preparing a compound of formula (Ia) or (Ib), [ka] During the ceremony, R 1 is C 1 -C 6 -Alkyl, C 1 -C 6 -Haloalkyl, C 1 -C 6 -Alkoxy-C 1 -C 6 -Alkyl, C 3 -C 6 -Cycloalkyl, C 6 -C 14 -aryl, or C 6 -C 14 -Aryl-C 1 -C 4 -alkyl, Here, C 1 -C 6 -Alkyl, C 3 -C 6 -cycloalkyl and C 1 -C 6 -Alkoxy-C 1 -C 6 -C in alkyl moiety 1 -C 6 -Alkoxy is halogen, C 1 -C 4 -Alkoxy, C 1 -C 4 -Haloalkyl, C 1 -C 4 -haloalkoxy and phenyl, wherein phenyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C 1 -C 4 -Alkyl, C 1 -C 4 -Alkoxy, C 1 -C 4 -haloalkyl and C 1 -C 4-haloalkoxy, and C in each case 6 -C 14 -aryl and C 6 -C 14 -Aryl-C 1 -C 4 -C in alkyl moiety 6 -C 14 Aryl is unsubstituted or is selected from the group consisting of halogen, C 1 -C 4 -Alkyl, C 1 -C 4 -Haloalkyl, C 1 -C 4 -Alkoxy and C 1 -C 4 -haloalkoxy; R 2 and R 3 are the same, hydrogen, C 1 -C 6 -Alkyl, C 1 -C 6 -haloalkyl and C 1 -C 6 -Alkoxy-C 1 -C 6 -alkyl; or R 2 and R 3 together with the carbon to which they are attached form C 3 -C 6 - forming a cycloalkyl ring, R 4 is hydrogen, C 1 -C 6 -Alkyl, C 1 -C 6 -Haloalkyl, C 1 -C 6 -Alkoxy, C 1 -C 6 -Haloalkoxy, C 1 -C 6 -Alkylamino, C 2 -C 6 -Alkenyl, C 2 -C6 -Alkynyl, C 3 -C 6 -Cycloalkyl, C 3 -C 6 -Cycloalkyl-C 1 -C 4 -Alkyl, C 2 -C 6 -Alkenyloxy, 9-fluorenylmethyleneoxy, C 6 -C 14 -aryl, C 6 -C 14 -aryloxy, C 6 -C 14 -Aryl-C 1 -C 4 -Alkyloxy or C 6 -C 14 -Aryl-C 1 -C 4 -alkyl, Here, C 6 -C 14 -Aryl, as such or as a part thereof, is unsubstituted or substituted with halogen, C 1 -C 4 -Alkyl, C 1 -C 4 -Haloalkyl, C 1 -C 4 -Alkoxy and C1-C 4 -haloalkoxy; n is 0, 1, 2, 3 or 4; Each substituent R 5 If present, halogen, C 1 -C 6 -Alkyl, C 1 -C 6 -Haloalkyl, C 1 -C 6 -Alkoxy, hydroxy, amino, and -C(=O)-C 1 -C 6 -alkyl; The method comprises: enantioselective hydrogenation of a compound of formula (II) in the presence of a chiral iridium catalyst, [ka] In the formula, the substituent R 1 , R 2 , R 3 , R 4 , R 5 and the integer n is as defined for compounds of formula (Ia) or (Ib), The chiral iridium catalyst is characterized in that it comprises a chiral ligand of formula (IIIa) or (IIIb); [ka] In the formula, R 6 is a group of expressions [ka] where ** represents the bond to the 6,7-dihydro-5H-cyclopenta[b]pyridine moiety; R 13 is hydrogen, methyl or ethyl, R 14 is C 1 -C 6 -alkyl, R 7 is hydrogen, R 8 is C 1 -C 4 -alkyl or phenyl, where phenyl is unsubstituted or is selected from the group consisting of halogen, C 1 -C 4 -Alkyl, C 1 -C 4 -Haloalkyl, C 1 -C 4 -Alkoxy and C 1 -C 4 -haloalkoxy; R 9 and R 10 is C 1 -C 6-Alkyl, C 3 -C 8 - independently selected from the group consisting of cycloalkyl, piperidinyl and pyridyl, R 9 and R 10 together with the phosphorus atom to which they are attached, form G 1 or G 2 Forming a group, [ka] wherein the bonds identified by "x" and "y" are both attached directly to the phosphorus atom; p and q are independently selected from 0, 1 and 2; R 11 and R 12 is independently 1 -C 6 -alkyl and phenyl, the groups being selected from halogen, C 1 -C 4 -Alkyl, C 1 -C 4 -alkoxy and phenyl, which may be substituted with 1 to 5 substituents selected from the group consisting of 1 or 2 C 1 -C 4 - optionally substituted with an alkyl substituent; R 9 and R 10 together with the phosphorus atom to which they are attached, form G 3 Forming a group, [ka] Here, the bonds identified by "u" and "v" both attach directly to the phosphorus atom.

[0009] Surprisingly, it has been found that optically active 4-substituted 1,2,3,4-tetrahydroquinolines (Ia and Ib) can be prepared in high yields and with excellent enantioselectivities by enantioselective hydrogenation of the corresponding 4-substituted 1,2-dihydroquinolines (II) in the presence of chiral iridium (P,N)-ligand catalysts.

[0010] definition In the definitions of the symbols given in the formula above, collective terms have been used which generally represent the following substituents:

[0011] Halogen: fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, more preferably fluorine or chlorine.

[0012] Alkyl: A saturated, linear or branched hydrocarbyl group having 1 to 6, preferably 1 to 4, carbon atoms, such as, but not limited to, C 1 -C 6 -alkyl groups, such as methyl, ethyl, propyl (n-propyl), 1-methylethyl (iso-propyl), butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 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. In particular, the groups are 1 -C 4-alkyl groups, for example methyl, ethyl, propyl, 1-methylethyl (isopropyl), butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl) or 1,1-dimethylethyl (tert-butyl) groups. This definition, unless otherwise defined, also includes alkyl as part of a complex substituent, for example C 3 -C 6 -Cycloalkyl-C 1 -C 4 -Alkyl, C 6 -C 14 -Aryl-C 1 -C 4 -Alkyl etc. are also applicable.

[0013] Alkenyl: An unsaturated, linear or branched hydrocarbyl group having 2 to 6, preferably 2 to 4, carbon atoms and one double bond at any position, such as, but not limited to, C 2 -C 6-alkenyl, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, isopropenyl, homoallyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, ( Z)-Pent-2-enyl, (E)-Pent-1-enyl, (Z)-Pent-1-enyl, 3-Methylbut-3-enyl, 2-Methylbut-3-enyl, 1-Methylbut-3-enyl, 3-Methylbut-2-enyl, (E)-2-Methylbut-2-enyl, (Z)-2-Methylbut-2-enyl, (E)-1-Methylbut-2-enyl, (Z)-1-Methylbut-2-enyl, (E)-3-Methylbut-1-enyl, (Z)-3-Methylbut-1-enyl, (E)-2-Methylbut-1-enyl, (Z)-2-Methylbut-1-enyl, (E)-1-Methylbut-2-enyl Chillbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl, (E)-3,3-dimethylprop-1-enyl, (Z)-3,3-dimethylprop-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl , 4-methylpent-4-enyl, 3-methylpent-4-enyl, 2-methylpent-4-enyl, 1-methylpent-4-enyl, 4-methylpent-3-enyl, (E)-3-methylpent-3-enyl, (Z)-3-methylpent-3-enyl, (E)-2-methylpent-3-enyl, (Z)-2-methylpent-3-enyl, (E)-1-methylpent-3-enyl, (Z)-1-methylpent-3-enyl, (E)-4-methylpent-2-enyl, (Z)-4-methylpent-2-enyl, (E)-3-methylpent-2-enyl,(Z)-3-methylpent-2-enyl, (E)-2-methylpent-2-enyl, (Z)-2-methylpent-2-enyl, (E)-1-methylpent-2-enyl, (Z)-1-methylpent-2-enyl, (E)-4-methylpent-1-enyl, (Z)-4-methylpent-1-enyl, (E)-3-methylpent-1-enyl, (Z)-3-methylpent-1-enyl, (E)-2-methylpent-1-enyl, (Z)-2-methyl pent-1-enyl, (E)-1-methylpent-1-enyl, (Z)-1-methylpent-1-enyl, 3-ethylbut-3-enyl, 2-ethylbut-3-enyl, 1-ethylbut-3-enyl, (E)-3-ethylbut-2-enyl, (Z)-3-ethylbut-2-enyl, (E)-2-ethylbut-2-enyl, (Z)-2-ethylbut-2-enyl, (E)-1-ethylbut-2-enyl, (Z)-1-ethylbut-2-enyl , (E)-3-ethylbut-1-enyl, (Z)-3-ethylbut-1-enyl, 2-ethylbut-1-enyl, (E)-1-ethylbut-1-enyl, (Z)-1-ethylbut-1-enyl, 2-propylprop-2-enyl, 1-propylprop-2-enyl, 2-isopropylprop-2-enyl, 1-isopropylprop-2-enyl, (E)-2-propylprop-1-enyl, (Z)-2-propylprop-1-enyl, (E) -1-propylprop-1-enyl, (Z)-1-propylprop-1-enyl, (E)-2-isopropylprop-1-enyl, (Z)-2-isopropylprop-1-enyl, (E)-1-isopropylprop-1-enyl, (Z)-1-isopropylprop-1-enyl, 1-(1,1-dimethylethyl)ethenyl, buta-1,3-dienyl, penta-1,4-dienyl, hexa-1,5-dienyl or methylhexadienyl. In particular, said groups are vinyl or allyl. This definition also applies to alkenyl as part of a compound substituent, unless otherwise defined.

[0014] Alkynyl: a straight or branched hydrocarbyl substituent having 2 to 8, preferably 2 to 6, more preferably 2 to 4 carbon atoms and one triple bond at any position, such as, but not limited to, C 2 -C6 Alkynyl, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, 1-methylprop-2-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 3-methylpent-4-ynyl, 2-methylpent- 4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl, or 3,3-dimethylbut-1-ynyl groups. In particular, said alkynyl groups are ethynyl, prop-1-ynyl, or prop-2-ynyl. This definition also applies to alkynyl as part of a compound substituent, unless otherwise defined.

[0015] Alkylamino: monoalkylamino or dialkylamino, where monoalkylamino represents an amino group having one alkyl residue with 1-4 carbon atoms attached to the nitrogen atom. Non-limiting examples include methylamino, ethylamino, n-propylamino, isopropyl-amino, n-butylamino, and tert-butylamino. Wherein dialkylamino represents an amino residue having two independently selected alkyl residues, each having 1-4 carbon atoms attached to the nitrogen atom. Non-limiting examples include N,N-dimethyl-amino, N,N-diethyl-amino, N,N-diisopropylamino, N-ethyl-N-methylamino, N-methyl-Nn-propyl-amino, N-isopropyl-Nn-propylamino, and N-tert-butyl-N-methylamino.

[0016] Alkoxy: A saturated linear or branched alkoxy substituent having 1 to 6, more preferably 1 to 4, carbon atoms, such as, but not limited to, C 1 -C 6 Alkoxy, for example, methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, 1,1-dimethylethoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, hexoxy, 1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy and 1-ethyl-2-methylpropoxy. This definition also applies to alkoxy as part of a compound substituent, unless otherwise defined.

[0017] Cycloalkyl: A monocyclic or polycyclic saturated hydrocarbyl substituent having 3 to 12, preferably 3 to 8, more preferably 3 to 6 carbon ring members, such as, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, and adamantyl. This definition does not include cycloalkyl as part of a composite substituent, such as, unless otherwise defined, C 3 -C 6 -Cycloalkyl-C 1 -C 4 -applies to alkyl.

[0018] Haloalkyl: A straight or branched alkyl substituent having 1 to 6, preferably 1 to 4, carbon atoms (as specified above) in which some or all of the hydrogen atoms of these groups are replaced with halogen atoms as specified above, such as, but not limited to, C 1 -C 3 Haloalkyl, for example, chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl and 1,1,1-trifluoroprop-2-yl. This definition also applies to haloalkyl as part of a compound substituent, unless otherwise defined.

[0019] Haloalkenyl and haloalkynyl are defined similarly to haloalkyl, except that instead of an alkyl group, an alkenyl and alkynyl group are present as part of the substituent.

[0020] Haloalkoxy: a straight or branched chain alkoxy substituent having 1 to 6, preferably 1 to 4, carbon atoms (as specified above), in which some or all of the hydrogen atoms of these groups are replaced by halogen atoms as defined above, such as, but not limited to, C 1 -C 3 -haloalkoxy, such as chloromethoxy, bromomethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorofluoromethoxy, dichlorofluoromethoxy, chlorodifluoromethoxy, 1-chloroethoxy, 1-bromoethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy and 1,1,1-trifluoroprop-2-oxy. This definition also applies to haloalkoxy as part of a compound substituent, unless otherwise defined.

[0021] Aryl: a monocyclic, bicyclic or tricyclic aromatic or partially aromatic substituent having 6 to 14 carbon atoms, such as, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indenyl and indanyl. The bond to the higher general structure can be carried out via any possible ring member of the aryl residue. Aryl is preferably selected from phenyl, 1-naphthyl, 2-naphthyl, 9-phenanthryl and 9-anthracenyl. Phenyl is particularly preferred.

[0022] The term "enantioselective" as used herein intends that one of the two possible enantiomers of the hydrogenation product is preferably formed, i.e., the enantiomer of formula (Ia) or the enantiomer of formula (Ib). "Enantioselectivity" or "ee" indicates the degree of enantioselectivity:

[0023]

number

[0024] The predominant enantiomer can be controlled by the choice of chiral ligand, for example by choosing a chiral ligand of formula (IIIa) or the opposite enantiomer (a ligand of formula (IIIb)).

[0025] The process according to the invention is used to prepare compounds of formula (Ia) or (Ib), preferably (Ia).

[0026] Preferred are compounds of formula (Ia) or (Ib), especially (Ia), in which the substituents are defined as follows: R 1 is C 1 -C 6 -Alkyl or C 6 -C 14 -Aryl-C 1 -C 4 -alkyl, Here, C 6 -C 14 -Aryl-C 1 -C 4 -C in alkyl moiety 6 -C 14 Aryl is unsubstituted or is selected from the group consisting of halogen, C 1 -C 4 -Alkyl, C 1 -C 4 -Haloalkyl, C 1 -C 4 -Alkoxy and C 1 -C 4 -haloalkoxy; R 2 and R 3 are identical, C 1 -C 4 -alkyl, R 4 is C 1 -C 4 -Alkyl, C 1 -C 4 -Haloalkyl, C1 -C 4 -Alkoxy, C 1 -C 4 -haloalkoxy, phenyl or benzyl; n is 0, 1 or 2; Each substituent R 5 If present, halogen, C 1 -C 6 -Alkyl and C 1 -C 6 -haloalkyl.

[0027] More preferred are compounds of formula (Ia) or (Ib), especially (Ia), in which the substituents are defined as follows: R 1 is C 1 -C 6 -alkyl, R 2 and R 3 are identical, C 1 -C 4 -alkyl, or R 2 and R 3 together with the carbon to which they are attached, C 3 -C 6 - forming a cycloalkyl ring, R 4 is C 1 -C 4 -Alkyl, C 1 -C 4 -haloalkyl, phenyl or benzyl; n is 0, 1 or 2; Each substituent R 5 If present, halogens and C 1 -C 6 -alkyl.

[0028] Even more preferred are compounds of formula (Ia) or (Ib), especially (Ia), in which the substituents are defined as follows: R 1is methyl, ethyl or n-propyl, R 2 and R 3 is methyl, R 4 is C 1 -C 4 -alkyl, n is 0, 1 or 2; Each substituent R 5 If present, halogens and C 1 -C 6 -alkyl.

[0029] Most preferred are compounds of formula (Ia) or (Ib), especially (Ia), wherein the substituents are defined as follows: R 1 is methyl or n-propyl, R 2 and R 3 is methyl, R 4 is methyl, n is 0 or 1, Substituent R 5 When present, it is fluorine.

[0030] The process according to the invention comprises the enantioselective hydrogenation of a compound of formula (II). 1 , R 2 , R 3 , R 4 , R 5 and the integer n is as defined for compounds of formula (Ia) or (Ib), respectively.

[0031] The enantioselective hydrogenation of a compound of formula (II) is carried out in the presence of a chiral iridium catalyst containing a chiral ligand of formula (IIIa) or (IIIb).

[0032] In a preferred embodiment of the process according to the invention, the substituents of formulae (Ia), (Ib), (II), (IIIa) and (IIIb) are defined as follows: R 1 is C 1 -C 6 -Alkyl or C 6 -C 14 -Aryl-C 1 -C 4 -alkyl, Here, C 6 -C 14 -Aryl-C 1 -C 4 -C in alkyl moiety 6 -C 14 Aryl is unsubstituted or is selected from the group consisting of halogen, C 1 -C 4 -Alkyl, C 1 -C 4 -Haloalkyl, C 1 -C 4 -Alkoxy and C 1 -C 4 -haloalkoxy; R 2 and R 3 are identical, C 1 -C 4 -alkyl, R 4 is C 1 -C 4 -Alkyl, C 1 -C 4 -Haloalkyl, C 1 -C 4 -Alkoxy, C 1 -C 4 -haloalkoxy, phenyl or benzyl; n is 0, 1 or 2; Each substituent R 5 If present, halogen, C 1 -C 6 -Alkyl and C 1 -C 6 -haloalkoxy; R 6 is a group of expressions [ka] where ** represents the bond to the 6,7-dihydro-5H-cyclopenta[b]pyridine moiety; R 13 is hydrogen, methyl or ethyl, R 14 is C 1 -C 4 -alkyl, R 7 is hydrogen, R 8 is C 1 -C 4 alkyl or phenyl, where phenyl is unsubstituted or has 1 to 5 C 1 -C 4 - substituted with alkyl substituents, R 9 and R 10 are each independently selected from the group consisting of isopropyl, tert-butyl, cyclopentyl, cyclohexyl and piperidin-1-yl.

[0033] In a more preferred embodiment of the process according to the invention, the substituents of formulae (Ia), (Ib), (II), (IIIa) and (IIIb) are defined as follows: R 1 is C 1 -C 6 -alkyl, R 2 and R 3 are identical, C 1 -C 4 -alkyl, R 4 is C 1 -C 4 -Alkyl, C 1 -C 4 -Haloalkyl, C 1 -C 4 -Alkoxy, C 1 -C 4 -haloalkoxy, phenyl or benzyl; n is 0, 1 or 2; Each substituent R 5 If present, halogen, C 1 -C6 -Alkyl and C 1 -C 6 -haloalkyl; R 6 is a group of expressions [ka] where ** represents the bond to the 6,7-dihydro-5H-cyclopenta[b]pyridine moiety; R 13 is ethyl, R 14 is methyl, R 7 is hydrogen, R 8 is methyl, R 9 and R 10 are independently selected from the group consisting of cyclohexyl and piperidin-1-yl.

[0034] In the most preferred embodiment of the process according to the invention, the substituents of formulae (Ia), (Ib), (II), (IIIa) and (IIIb) are defined as follows: R 1 is C 1 -C 4 -alkyl, R 2 and R 3 is methyl, R 4 is C 1 -C 4 -alkyl, n is 0 or 1, R 5 is fluorine, if present; R 6 is 2,6-diethyl-4-methylphenyl, R 7 is hydrogen, R 8 is methyl, R 9 and R 10 are both cyclohexyl.

[0035] Depending on whether compound (Ia) or (Ib) is the desired product, the ligand of formula (IIIa) or (IIIb) is selected.

[0036] Preferred are ligands of formula (IIIa) and (IIIb), in which the substituents are defined as follows: R 6 is 2,6-diethyl-4-methylphenyl, R 7 is hydrogen, R 8 is methyl, R 9 and R 10 are both cyclohexyl.

[0037] Preferably, the chiral iridium catalyst is selected from the group consisting of [IrL*(COD)]Y and [IrL*(nbd)]Y, wherein L* is a chiral ligand of formula (IIIa) and (IIIb), COD stands for 1,5-cyclooctadiene nbd stands for norbornadiene, and Y is [B(R 18 ) 4 ] - , P.F. 6 - and [Al{OC(CF 3 ) 3} 4 ] - is a non-coordinating anion selected from the group consisting of [ka] In the formula, R 18 is selected from fluorine and phenyl, which is unsubstituted or 1 -C 4 -Alkyl, C 1 -C 4-substituted with 1 to 5 substituents selected from haloalkyl and halogen;

[0038] More preferred are chiral iridium catalysts of the formula [IrL*(COD)]Y and [IrL*(nbd)]Y, where Y is [Al{OC(CF 3 ) 3} 4 ] - or [B(R 18 ) 4 ] - and R 18 is phenyl, unsubstituted or substituted with 1 to 5 substituents selected from fluorine and trifluoromethyl.

[0039] Even more preferred are chiral iridium catalysts of general formulae (Va) and (Vb): [ka] During the ceremony R 6 is 2,6-diethyl-4-methylphenyl, R 7 is hydrogen, R 8 is methyl, R 9 and R 10 are both cyclohexyl, Y is [B(R 18 ) 4 ] - and [Al{OC(CF 3 ) 3} 4 ] - is a non-coordinating anion selected from the group consisting of Here, R 18 is 3,5-bis(trifluoromethyl)phenyl.

[0040] Most preferred is a chiral iridium catalyst of general formula (Va): [ka] R 6 is 2,4,6-trimethylphenyl, R 7 is hydrogen, R 8 is methyl, R 9 and R 10 are both cyclohexyl, Y is a compound of formula (VII) 3 ) 3} 4 ] - It is.

[0041] The amount of iridium catalyst used is preferably in the range of 0.001 mol % to 5 mol %, more preferably 0.001 mol % to 4 mol %, most preferably 0.002 mol % to 3 mol %, especially 0.005 mol % to 1.0 mol %, based on the amount of compound of formula (II).

[0042] The chiral iridium catalyst is [Ir(COD)Cl] 2 , can be prepared by methods known in the art from a chiral ligand of formula (IIIa) or (IIIb) and an iridium(I) catalyst precursor, such as an alkali salt of a non-coordinating anion (S. Kaiser et al., Angew. Chem. Int. Ed. 2006, 45, 5194-5197; W. J. Drury III et al., Angew. Chem. Int. Ed. 2004, 43, 70-74).

[0043] The process according to the invention involves the enantioselective hydrogenation of a compound of formula (II).

[0044] Preferably, the hydrogenation is carried out with hydrogen gas at a pressure of 1-300 bar, preferably 3-200 bar, most preferably 20-150 bar.

[0045] The hydrogenation is carried out at a temperature within the range of preferably 20°C to 130°C, more preferably 30°C to 100°C.

[0046] Suitable solvents are halogenated alcohols such as 2,2,2-trifluoroethanol, hexafluoroisopropanol (1,1,1,3,3,3-hexafluoro-2-propanol) and tetrafluoropropanol (2,2,3,3-tetrafluoro-1-propanol), halogenated hydrocarbons such as chlorobenzene, dichlorobenzene, dichloromethane, chloroform, tetrachloromethane, dichloroethane and trichloroethane, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, methyl tert-amyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane and anisole, and esters such as ethyl acetate, isopropyl acetate, and mixtures thereof.

[0047] Preferred solvents are selected from the group consisting of 2,2,2-trifluoroethanol, hexafluoroisopropanol, 1,2-dichloroethane, tetrafluoropropanol, 1,4-dioxane, isopropyl acetate, toluene, and mixtures thereof.

[0048] More preferred solvents are selected from the group consisting of 2,2,2-trifluoroethanol, hexafluoroisopropanol, 1,2-dichloroethane, tetrafluoropropanol, and mixtures thereof.

[0049] Particularly preferred are 2,2,2-trifluoroethanol and hexafluoroisopropanol.

[0050] Most preferred is hexafluoroisopropanol.

[0051] The process according to the invention may optionally be carried out in the presence of an additive selected from the group consisting of Bronsted acids and Lewis acids.

[0052] In a preferred embodiment of the method according to the invention, the additive is selected from the group consisting of hexafluorophosphoric acid, acetic acid, trifluoromethylsulfonic acid, water, pentafluorophenol, 3,5-bis(trifluoromethyl)phenol, tetrafluoroboric acid, tetrafluoroboric acid diethyl ether complex, Nafion, Amberlyst, 1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-ol, triphenylborane, tris[3,5-bis(trifluoromethyl)phenyl]borane, tris(2,3,4,5,6-pentafluorophenyl)borane, borane tetrahydrofuran complex, boric acid, aluminum(III) trifluoromethanesulfonate, zinc(II) trifluoromethanesulfonate, scandium(III) trifluoromethanesulfonate, aluminum(III) fluoride, titanium(IV) isopropoxide, trimethylaluminum, boron trifluoride, complexes of boron trifluoride, and mixtures thereof.

[0053] Suitable complexes of boron trifluoride are complexes of boron trifluoride with organic solvents, such as dialkyl ethers or alcohols, and complexes of boron trifluoride with organic acids, such as carboxylic acids. Preferred boron trifluoride complexes are selected from the group consisting of boron trifluoride-diethyl ether complex, boron trifluoride acetate complex, and boron trifluoride n-propanol complex.

[0054] In a more preferred embodiment of the method according to the invention, the additive is selected from the group consisting of hexafluorophosphoric acid, pentafluorophenol, 3,5-bis(trifluoromethyl)phenol, tetrafluoroborate diethyl ether complex, triphenylborane, tris[3,5-bis(trifluoromethyl)phenyl]borane, tris(2,3,4,5,6-pentafluorophenyl)borane, aluminum(III) trifluoromethanesulfonate, scandium(III) trifluoromethanesulfonate, aluminum(III) fluoride, titanium(IV) isopropoxide, trimethylaluminum, boron trifluoride, complexes of boron trifluoride, and mixtures thereof, wherein the complexes of boron trifluoride are preferably selected from the group consisting of boron trifluoride-diethyl ether complex, boron trifluoride acetate complex, and boron trifluoride n-propanol complex.

[0055] In an even more preferred embodiment of the method according to the invention, the additive is selected from the group consisting of hexafluorophosphoric acid, pentafluorophenol, 3,5-bis(trifluoromethyl)phenol, triphenylborane, tris[3,5-bis(trifluoro-methyl)phenyl]borane, tris(2,3,4,5,6-pentafluorophenyl)borane, aluminum(III) trifluoromethanesulfonate, scandium(III) trifluoromethanesulfonate, aluminum(III) fluoride, titanium(IV) isopropoxide, trimethylaluminum, boron trifluoride, complexes of boron trifluoride and mixtures thereof, wherein the complexes of boron trifluoride are preferably selected from the group consisting of boron trifluoride-diethyl ether complex, boron trifluoride acetate complex and boron trifluoride n-propanol complex.

[0056] In the most preferred embodiment of the method according to the invention, the additive is selected from the group consisting of aluminum(III) trifluoromethanesulfonate, scandium(III) trifluoromethanesulfonate, tris(2,3,4,5,6-pentafluorophenyl)borane, hexafluorophosphoric acid, boron trifluoride and complexes of boron trifluoride, where the complexes of boron trifluoride are preferably selected from the group consisting of boron trifluoride diethyl ether complex, boron trifluoride acetate complex, and boron trifluoride n-propanol complex.

[0057] The amount of additive selected from the group consisting of Bronsted acids and Lewis acids used is preferably in the range of 0.1 mol % to 10 mol %, more preferably 0.2 mol % to 5 mol %, most preferably 0.3 mol % to 2 mol %, in particular 0.4 mol % to 1 mol %, based on the amount of the compound of formula (II).

[0058] Abbreviations and acronyms: TIFF0007660101000013.tif192166

[0059] Preparation of iridium catalyst [ka]

[0060] Ligand precursors (enantiomerically enriched secondary alcohols) were prepared according to known literature procedures such as those disclosed in Kaiser et al., Angew. Chem. Int. Ed. 2006, 45, 5194-5197 or DH Woodmansee Chem. Sci 2010, 1, 72. Ligand and iridium complexes were prepared by modified procedures based on the same literature precedents:

[0061] Standard Procedure Procedure for ligand synthesis (under Ar): A solution of the alcohol precursor in THF (0.25 mmol in 5.0 mL of THF) was cooled to -78 °C and n-BuLi (0.1 mL of a 2.5 M solution of n-BuLi in hexanes; 0.25 mmol; 1 equiv.) was added dropwise to the continuously stirred solution. After the addition was complete, the solution was allowed to warm to room temperature and stirred at this temperature for an additional 30 min. The solution was cooled again to -78 °C and R 9 R 10 PCl (0.25 mmol, 1 equiv.) was added continuously to the stirred solution. The mixture was allowed to warm to room temperature and then heated to 50° C. and kept at this temperature overnight. 31 The theoretical yield of the ligand was calculated using P-NMR, and the ligand was used in the next step without further purification.

[0062] Complexation method (under Ar): Add [Ir(COD) 2 ]BARF (BARF = tetrakis[3,5-bis(trifluoromethyl)phenyl]-borate) (1 equivalent as a solid, based on theoretical yield) was added. The resulting mixture was heated to 50°C and held at this temperature for 3 hours.

[0063] Workup (under air): After cooling to room temperature, the reaction solution was rotary evaporated onto silica and loaded onto a column of silica. Minor components were eluted with pentane / diethyl ether, followed by the desired complex with DCM. The solvent was then evaporated under reduced pressure.

[0064] The following specific catalysts were synthesized and characterized: [ka]

[0065] Table 1 [Table 1] [ka]

[0066] Va-1 The reaction was carried out according to the standard procedure described above. The complex was obtained as an orange solid (282 mg, [Ir(COD) 2 ]BARF was used to isolate the β-amyloid β-amyloid 76% of ...

[0067] 1 H-NMR (300 MHz, CD 2 Cl 2 ): δ (ppm) = 7.73 (s, 8H), 7.56 (s, 4H), 7.23 (s, 1H), 7.14 (s, 1H), 7.00 (s, 1H), 5.62 (dd, J = 8.0, 5.6 Hz, 1H), 5.46-5.39 (m, 1H), 4.32 (dd, J = 7.4, 3.4 Hz, 1H), 3.36-3.27 (m, 1H), 3.19-3.06 (m, 2H), 3.01-2.91 (m, 2H), 2.80 (dq, J = 14.9, 7.4 Hz, 1H), 2.59-2.43 (m, 2H), 2.43-2.15 (m, 7H), 2.15-0.83 (m, 36H), 0.66-0.48 (m, 1H). 31 P-NMR (122 MHz, CD 2 Cl 2 ) δ (ppm) = 119.00. 19 F-NMR (282 MHz, CD 2 Cl 2 ) δ (ppm) = -62.87. HR-MS (ESI) m / z C 40 H 58 NOPIr [M] + Calculated value 792.3880, analyzed value 792.3903.

[0068] Va-2 A solution of the respective alcohol precursor in THF (0.25 mmol, in 5.0 mL of THF) was cooled to -78 °C and n-BuLi (0.1 mL of a 2.5 M solution of n-BuLi in hexanes; 0.25 mmol; 1 equiv.) was added dropwise to the continuously stirred solution. After the addition was complete, the solution was allowed to warm to room temperature and stirred at this temperature for an additional 30 min. The solution was cooled again to -78 °C and Cy was added dropwise to the hexane. 2 PCl (0.25 mmol, 1 equiv.) was added continuously to the stirred solution. The mixture was allowed to warm to room temperature and then heated to 50° C. and kept at this temperature overnight. After the reaction was cooled to room temperature, the THF was removed, dried under reduced pressure, and [Ir(COD)Cl] was obtained. 2 (0.125 mmol) and DCM (5.0 ml) were added to the tube and stirred at 50 °C for 2 h. The reaction mixture was then treated with Li{Al[OC(CF 3 ) 3 ] 4} (0.275 mmol) was added and stirred at room temperature overnight. The reaction solution was rotary evaporated onto silica, loaded onto a column of silica prepared with DCM and chromatographed with n-heptane / DCM:1 / 1 to give an orange solid (140 mg, 32%).

[0069] 1 H-NMR (300 MHz, CD 2 Cl 2 ) δ = 7.27 (s, 1H), 7.18 (s, 1H), 7.04 (s, 1H), 5.66 (dt, J = 8.0, 3.8 Hz, 1H), 5.50-5.44 (m, 1H), 4.40-4.31 (m, 1H), 3.46-3.26 (m, 1H), 3.25-2.91 (m, 4H), 2.91-2.77 (m, 1H), 2.57-2.52 (m, 2H), 2.50-2.20 (m, 7H), 2.19-1.78 (m, 13H), 1.70-1.53 ​​(m, 5H), 1.49-1.02 (m, 18H), 0.62 (s, 1H). 31 P-NMR (122 MHz, CD 2 Cl 2 ) δ = 119.02. 19 F-NMR (282 MHz, CD2 Cl 2 ) δ = -75.74. HR-MS (ESI) m / z C 45 H 60 NOPIr [M] + Calculated value 792.3880, analyzed value 792.3903.

[0070] Va-3 The reaction was carried out according to the standard procedure described above. The complex was obtained as an orange solid (162 mg, [Ir(COD) 2 ]BARF based on the 42%).

[0071] 1 H-NMR (300 MHz, CD 2 Cl 2 ) δ = 7.80-7.65 (m, 8H), 7.65-7.41 (m, 10H), 7.17 (s, 1H), 7.04 (s, 1H), 5.70-5.65 (m, 1H), 5.53-5.47 (m, 1H), 4.42-4.35 (m, 1H), 3.43-3.32 (m, 2H), 3.27-3.09 (m, 2H), 3.09-2.93 (m, 1H), 2.86 (dq, J = 14.8, 7.4 Hz, 1H), 2.55-2.48 (m, 2H), 2.38 (s, 3H), 2.27-1.46 (m, 19H), 1.46-0.74 (m, 18H) , 0.69 - 0.52 (m, 1H). 31 P-NMR (122 MHz, CD 2 Cl 2 ) δ = 119.07. 19 F-NMR (282 MHz, CD 2 Cl 2 ) δ = -62.87. HR-MS (ESI)M / z C 45 H 60 NOPIr[M] + Calculated value 854.4036, analyzed value 854.4073.

[0072] Va-4 ClP-(S)-BINOL (0.25 mmol, freshly prepared) and [Ir(COD) 2The reaction was carried out using ]BARF (287 mg, 0.225 mmol) according to the standard procedure described above. The complex could be isolated as an orange solid (104 mg) after three column chromatography runs using heptane / DCM:1 / 1. 31 PNMR still shows 4 peaks with the major one at 117.72 ppm (approximately 80% purity). HRMS shows the desired complex is present.

[0073] 31 P-NMR (122 MHz, CD 2 Cl 2 ) δ = 120.36, 117.72, 114.61, 92.27. 19 F-NMR (282 MHz, CD 2 Cl 2 ) δ = -62.85. HR-MS (ESI) m / z C 48 H 48 NO 3 PIr [M] + Calculated value 910.2996, analyzed value 910.3026.

[0074] Va-5 The reaction was carried out according to the standard procedure described above using 1,1'-(chlorophosphanediyl)dipiperidine (0.25 mmol, freshly prepared). The complex could be isolated as a red solid (149 mg). 31 PNMR has 6 peaks with the major peaks at 102.35 and 98.87 ppm (2:3). HRMS shows the desired complex is present.

[0075] 31 P-NMR (122 MHz, CD 2 Cl 2 ) δ = 102.35, 101.96, 101.40, 98.87, 98.46, 98.35. 19 F-NMR (282 MHz, CD 2 Cl 2 ) δ = -62.87. HR-MS (ESI) m / z C 39 H58 N 3 OPIr [M] + Calculated value 808.3941, analyzed value 808.3958.

[0076] Va-6 A solution of the respective alcohol precursor in THF (0.25 mmol, in 5.0 mL of THF) was cooled to -78 °C and n-BuLi (0.1 mL of a 2.5 M solution of n-BuLi in hexanes; 0.25 mmol; 1 equiv.) was added dropwise to the continuously stirred solution. After the addition was complete, the solution was allowed to warm to room temperature and stirred at this temperature for an additional 30 min. The solution was cooled again to -78 °C and Cy was added dropwise to the hexane. 2 PCl (0.25 mmol, 1 equiv.) was added continuously to the stirred solution. The mixture was allowed to warm to room temperature and then heated to 50° C. and kept at this temperature overnight. After the reaction was cooled to room temperature, the THF was removed, dried under reduced pressure, and [Ir(COD)Cl] was obtained. 2 (0.125 mmol) and DCM (5.0 ml) were added to the tube and stirred at 50° C. for 2 hours. Then, KPF 6 (0.25 mmol) was added and stirred at room temperature overnight. The reaction solution was rotary evaporated onto silica, loaded onto a column of silica prepared with DCM, and chromatographed with EtOAc / DCM:1 / 10 to give an orange solid (130 mg, 55%) after two column chromatography runs.

[0077] 1 H-NMR (300 MHz, CD 2 Cl 2 ) δ = 7.37-7.02 (m, 3H), 5.74-5.56 (m, 1H), 5.52-5.46 (m, 1H), 4.47-4.30 (m, 1H), 3.45-3.21 (m, 1H), 3.19-2.92 (m, 3H), 2.66 (s, 3H), 2.63-2.48 (m, 2H), 2.44 (s, 3H), 2.40-2.19 (m, 2H), 2.16-1.70 (m, 15H), 1.68-1.46 (m, 6H), 1.41-1.28 (m, 13H), 1.18-0.95 (m, 5H), 0.71-0.58 (m, 1H). 31P-NMR (122 MHz, CD 2 Cl 2 ) δ = 118.42, -127.01, -132.85, -138.70, -144.55, -150.39, -156.24, -162.09. 19 F-NMR (376 MHz, CD 2 Cl 2 ) δ = -72.64, -74.52. HR-MS (ESI) m / z C 41 H 60 NOPIr [M] + Calculated value 806.4036, analyzed value 806.4061.

[0078] Va-7 The reaction was carried out using CgPBr (0.25 mmol, freshly prepared) according to the standard procedure described above. The complex could be isolated as an orange solid (120 mg). 31 PNMR shows two peaks. HRMS shows the desired complex is present.

[0079] 31 P-NMR (122 MHz, CD 2 Cl 2 ) δ = 89.41, 83.71. 19 F-NMR (282 MHz, CD 2 Cl 2 ) δ = -62.86. HR-MS (ESI) m / z C 35 H 46 NO 4 PIr [M] + Calculated value 768.2788, analyzed value 768.2816.

[0080] Va-8 The reaction was carried out according to the standard procedure described above using 2-(tert-butylchlorophosphanyl)pyridine (0.25 mmol). The complex could be isolated as a red solid (196 mg). 31 PNMR has two peaks at 107.59 and 102.97 ppm (1:1.4). HRMS shows the desired complex is present.31 P-NMR (122MHz, CD 2 Cl 2 ) δ=107.59, 102.97. 19 F-NMR (282MHz, CD 2 Cl 2 ) δ=-62.83. HR-MS(ESI)M / z C 34 H 43 N 2O PIr[M]+ calculated value 719.2737, analyzed value 719.2757.

[0081] Va-9 A solution of the respective alcohol precursor in THF (0.25 mmol, in 5.0 mL of THF) was cooled to -78 °C and n-BuLi (0.1 mL of a 2.5 M solution of n-BuLi in hexanes; 0.25 mmol; 1 equiv.) was added dropwise to the continuously stirred solution. After the addition was complete, the solution was allowed to warm to room temperature and stirred at this temperature for an additional 30 min. The solution was cooled again to -78 °C and Cy was added dropwise to the hexane. 2 PCl (0.25 mmol, 1 equiv.) was added continuously to the stirred solution. The mixture was allowed to warm to room temperature and then heated to 50° C. and kept at this temperature overnight. After the reaction was cooled to room temperature, the THF was removed, dried under reduced pressure, and [Ir(COD)Cl] was obtained. 2 (0.125 mmol) and DCM (5.0 ml) were added to the tube and stirred at 50 °C for 2 h. The reaction mixture was then treated with Li{Al[OC(CF 3 ) 3 ] 4} (0.275 mmol) was added and stirred at room temperature overnight. The reaction solution was rotary evaporated onto silica, loaded onto a column of silica prepared with DCM and chromatographed with n-heptane / DCM:1 / 1 to give an orange solid (122 mg, 28%).

[0082] 1 H-NMR (300 MHz, CD 2 Cl 2) δ = 7.40-7.12 (m, 4H), 5.67-5.63 (m, 1H), 5.50-5.42 (m, 1H), 4.43-4.36 (m, 1H), 3.39-3.30 (m, 1H), 3.25-2.90 (m, 3H), 2.67 (s, 3H), 2.60-2.42 (m, 4H), 2.42-2.18 (m, 2H), 2.13-1.99 (m, 5H), 1.96-1.71 (m, 9H), 1.65-1.52 (m, 5H), 1.45-1.01 (m, 12H), 0.69-0.53 (m, 1H). 31 P-NMR (121 MHz, CD 2 Cl 2 ) δ = 118.81. 19 F-NMR (282 MHz, CD 2 Cl 2 ) δ = -75.74. HR-MS (ESI) m / z C 37 H 52 NOPIr [M] + Calculated value 750.3416, analyzed value 750.3420.

[0083] Va-10 287mg of [Ir(COD) 2 The reaction was carried out according to the procedure described above using 0.225 mmol of [Ir(COD)]BARF. The complex was obtained as an orange solid (148 mg, [Ir(COD)] 2 ]BARF was used to isolate the 40% nucleotides.

[0084] 1 H-NMR (300 MHz, CD 2 Cl 2): δ (ppm) = 7.91-7.46 (m, 12H), 7.21 (s, 1H), 7.09 (s, 1H), 6.94 (s, 1H), 5.67-5.63 (m, 1H), 5.46-5.41 (m, 1H), 4.38-4.36 (m, 1H), 3.36-3.32 (m, 1H), 3.19-2.85 (m, 3H), 2.64 (s, 3H), 2.53-2.46 (m, 2H), 2.41 (s, 3H), 2.35 (s, 3H), 2.31-2.18 (m, 2H), 2.19-1.83 (m, 14H), 1.68-1.54 (m, 6H), 1.38-1.20 (m, 5H), 1.14-0.97 (m, 5H), 0.68-0.56 (m, 1H). 31 P-NMR (122 MHz, CD 2 Cl 2 ) δ = 118.64. 19 F-NMR (282 MHz, CD 2 Cl 2 ) δ = -62.87. HR-MS (ESI) m / z C 38 H 54 NOPIr [M]+ calculated 764.3572, analyzed 764.3577.

[0085] Va-11 The reaction was carried out according to the procedure described above. The complex was obtained as an orange solid (274 mg, [Ir(COD) 2 ]BARF was used to isolate the 5'-amino acid sequence (73%).

[0086] 1 H-NMR (300 MHz, CD 2 Cl 2): δ (ppm) = 7.79-7.66 (m, 8H), 7.56 (s, 4H), 7.29 (s, 1H), 7.23 (s, 1H), 7.13 (s, 1H), 5.65 (td, J = 5.9, 2.2 Hz, 1H), 5.46-5.40 (m, 1H), 4.42-4.36 (m, 1H), 3.38-3.30 (m, 1H), 3.19-2.86 (m, 3H), 2.65 (s, 3H), 2.59-2.44 (m, 2H), 2.42 (s, 3H), 2.38-1.54 (m, 20H), 1.46-0.98 (m, 21H), 0.70-0.58 (m, 1H). 31 P-NMR (122 MHz, CD 2 Cl 2 ) δ (ppm) = 118.67. 19 F-NMR (282 MHz, CD 2 Cl 2 ) δ (ppm) = -62.86. HR-MS (ESI) m / z C 41 H 60 NOPIr [M]+ calculated value 806.4042, analyzed value 806.4053.

[0087] Va-12 287mg of [Ir(COD) 2 The reaction was carried out according to the procedure described above using 0.225 mmol of ]BARF. The complex was obtained as an orange solid (298 mg, [Ir(COD) 2 ]BARF was used to isolate the 82% genotype.

[0088] 1 H-NMR (300 MHz, CD 2 Cl 2): δ (ppm) = 7.80-7.52 (m, 12H), 7.42-7.19 (m, 3H), 7.12 (d, J = 7.5 Hz, 1H), 5.65 (td, J = 5.6, 2.6 Hz, 1H), 5.48-5.42 (m, 1H), 4.43-4.37 (m, 1H), 3.38-3.30 (m, 1H), 3.21-2.89 (m, 3H), 2.67 (s, 3H), 2.58-2.45 (m, 2H), 2.42 (s, 3H), 2.38-2.16 (m, 2H), 2.13-2.05 (m, 3H), 2.02-1.89 (m, 4H), 1.84 (s, 3H), 1.81-1.72 (m, 2H), 1.64-1.49 (m, 3H), 1.39-1.19 (m, 8H), 1.12-0.99 (m, 4H), 0.68-0.56 (m, 1H). 31 P-NMR (122 MHz, CD 2 Cl 2 ) δ = 118.80. 19 F-NMR (282 MHz, CD 2 Cl 2 ) δ = -62.88. HR-MS (ESI) m / z C 37 H 52 NOPIr [M]+ calculated value 750.3416, analyzed value 750.3420.

[0089] Working Example The reaction was carried out in a metal autoclave. The reaction mixture was subjected to HPLC (Chiralpak IC column, 95 / 5 heptane / ethanol, 1 mL / min) or SFC (OZ-H column, supercritical CO 2 The extracts were analyzed via chromatography (2.5% methanol in 100 mL / min).

[0090] Examples 1 to 12 The Ir-complex (at the given catalyst loading) and 0.64 g of 1-(2,2,4-trimethyl-1-quinolyl)ethanone (3 mmol) were placed in an 8 mL autoclave vial containing a PTFE-coated stir bar. The autoclave vial was closed using a screw cap with a septum and flushed with argon (10 min). Hexafluoroisopropanol (HFIP, 4 mL) was added to the vial through the septum. The vial was placed in an argon-containing autoclave and the autoclave was flushed with argon (10 min). The autoclave was pressurized with hydrogen gas (10 bar) and subsequently depressurized to atmospheric pressure three times. After this, the autoclave was pressurized to 60 bar hydrogen pressure and placed in a suitable alumina block. After heating to 85° C., the reaction was held at this temperature for the specified time. After cooling to room temperature and depressurization, the vials were removed from the autoclave and the reaction results were determined by GC-FID analysis (diluted with EtOH) and the enantiomeric excess was determined by HPLC analysis. Typical values ​​are shown.

[0091] Table 2 [Table 2]

[0092] Examples 13 to 18: The Ir-complex (given catalyst loading) and 2.56 g of 1-(2,2,4-trimethyl-1-quinolyl)ethanone (12 mmol) were placed in a 25 mL autoclave. The autoclave was flushed with argon (10 min). Hexafluoroisopropanol (HFIP, 16 mL) was added to the autoclave. The autoclave was pressurized with hydrogen gas (10 bar) and subsequently depressurized to atmospheric pressure three times. After this, the autoclave was pressurized to 60 bar hydrogen pressure and placed in a suitable alumina block. After heating to 85° C., the reaction was kept at this temperature for a given time. After cooling to room temperature and depressurization, the reaction results were determined by GC-FID analysis (diluted with EtOH) and the enantiomeric excess was determined by HPLC analysis.

[0093] Table 3 [Table 3]

[0094] Examples 19 to 48: Ir-complex Va-1 (given catalyst loading) and 0.64 g of 1-(2,2,4-trimethyl-1-quinolyl)ethanone (3 mmol, purified by heptane:water washing + crystallization) were placed in an 8 mL autoclave vial containing a PTFE-coated stir bar. The autoclave vial was closed using a screw cap with a septum and flushed with argon (10 min). Hexafluoroisopropanol (HFIP, 4 mL) and additives (given loading) were added to the vial through the septum. The vial was placed in an argon-containing autoclave and the autoclave was flushed with argon (10 min). The autoclave was pressurized with hydrogen gas (10 bar) and subsequently depressurized to atmospheric pressure three times. After this, the autoclave was pressurized to 60 bar hydrogen pressure and placed in a suitable alumina block. After heating to 85 °C, the reaction was held at this temperature for the given time. After cooling to room temperature and depressurization, the vials were removed from the autoclave and the reaction results were determined by GC-FID analysis (diluted with EtOH) and the enantiomeric excess was determined by HPLC analysis. Typical values ​​are shown.

[0095] Table 4 [Table 4] TIFF0007660101000021.tif221162

[0096] Examples 49 to 54 Ir-complex Va-1 (given catalyst loading) and 1-(2,2,4-trimethyl-1-quinolyl)ethanone (given amount; purified by heptane:water washing + crystallization) were placed in a 25 mL autoclave. The autoclave was flushed with argon (10 min). Hexafluoroisopropanol (1.33 mL per mmol of 1-(2,2,4-trimethyl-1-quinolyl)ethanone) and additives (given loading) were added to the autoclave. The autoclave was pressurized with hydrogen gas (10 bar) and subsequently depressurized to atmospheric pressure three times. After this, the autoclave was pressurized to 60 bar hydrogen pressure and placed in a suitable alumina block. After heating to 85 °C, the reaction was kept at this temperature for a given time. After cooling to room temperature and depressurization, the reaction results were determined by GC-FID analysis (diluted with EtOH) and the enantiomeric excess was determined by HPLC analysis.

[0097] Table 5 [Table 5]

[0098] Examples 55 to 56 The Ir complex (identified and catalyst loading given) and 0.64 g of 1-(2,2,4-trimethyl-1-quinolyl)ethanone (3 mmol, purified by heptane:water wash + crystallization) were placed in an 8 mL autoclave vial containing a PTFE-coated stir bar. The autoclave vial was closed using a screw cap with a septum and flushed with argon (10 min). Hexafluoroisopropanol (HFIP, 4 ml) and BF 3 *OEt 2[1 mol % relative to 1-(2,2,4-trimethyl-1-quinolyl)ethanone] was added to the vial through the septum. The vial was placed in an argon-containing autoclave and the autoclave was flushed with argon (10 min). The autoclave was pressurized with hydrogen gas (10 bar) and subsequently depressurized to atmospheric pressure three times. After this, the autoclave was pressurized to 60 bar hydrogen pressure and placed in a suitable alumina block. After heating to 85° C., the reaction was kept at this temperature for a given time. After cooling to room temperature and depressurization, the vial was removed from the autoclave and the reaction results were determined by GC-FID analysis (diluted with EtOH) and the enantiomeric excess was determined by HPLC analysis. Typical values ​​are shown.

[0099] Table 6 [Table 6]

[0100] Examples 57 to 60 Ir complex Va-1 (0.02 mol%, 0.6 μmol) and 0.64 g of 1-(2,2,4-trimethyl-1-quinolyl)ethanone (3 mmol, purified by heptane:water washing + crystallization) were placed in an 8 mL autoclave vial containing a PTFE-coated stir bar. The autoclave vial was closed using a screw cap with a septum and flushed with argon (10 min). 2,2,2-trifluoroethanol (TFE, 4 ml) and BF 3 *OEt 2 (given loading amount) was added to the vial through the septum. The vial was placed in an argon-containing autoclave and the autoclave was flushed with argon (10 min). The autoclave was pressurized with hydrogen gas (10 bar) and subsequently depressurized to atmospheric pressure three times. After this, the autoclave was pressurized to 60 bar hydrogen pressure and placed in a suitable alumina block. After heating to 85° C., the reaction was kept at this temperature for 3 h. After cooling to room temperature and depressurization, the vial was removed from the autoclave and the reaction results were determined by GC-FID analysis (diluted with EtOH) and the enantio-excess was determined by HPLC analysis. Typical values ​​are shown.

[0101] Table 7 [Table 7]

[0102] Comparative Example The Ir-complex (at the given catalyst loading) and 0.64 g of 1-(2,2,4-trimethyl-1-quinolyl)ethanone (3 mmol) were placed in an 8 mL autoclave vial containing a PTFE-coated stir bar. The autoclave vial was closed using a screw cap with a septum and flushed with argon (10 min). Hexafluoroisopropanol (HFIP, 4 mL) was added to the vial through the septum. The vial was placed in an argon-containing autoclave and the autoclave was flushed with argon (10 min). The autoclave was pressurized with hydrogen gas (10 bar) and subsequently depressurized to atmospheric pressure three times. After this, the autoclave was pressurized to 60 bar hydrogen pressure and placed in a suitable alumina block. After heating to 85° C., the reaction was held at this temperature for the specified time. After cooling to room temperature and depressurization, the vials were removed from the autoclave, and the reaction results were determined by GC-FID analysis (diluted with EtOH) and the enantiomeric excess was determined by HPLC analysis.

[0103] Table 8 [Table 8]

[0104] This set of experimental results shows the superiority of complexes Va-1 and Va-2. Va-2 gives a slightly higher conversion than Va-1 after 6 hours with 0.01 mol% of catalyst. Va-1 gives a significantly higher conversion than Va-10 (= Va-10 from WO2019 / 185541A1) after 17 hours with 0.01 mol% of catalyst. Va-10 gives a similar performance to Va-13 (= Va-1 from WO2019 / 185541A1), but only 1 / 4 of the amount of catalyst was used. It must therefore be considered superior to Va-13. Va-13 gives a superior conversion compared to the Ir catalyst (I) from DE112015001290T5. Furthermore, all catalysts Va give superior enantioselectivities (>95% ee) compared to Ir catalyst (1) from DE112015001290T5 (81.7% ee). Catalyst Va-1 gives higher conversions (93.1 vs. 84%) than Ir catalyst (1) from DE112015001290T5, even at one-tenth the catalyst loading (0.01 vs. 0.1 mol%).

[0105] [ka]

Claims

1. A process for preparing a compound of formula (Ia) or (Ib) comprising the steps of: 【Chemistry 1】 During the ceremony, R １ is C １ -C ６ - alkyl, R ２ and R ３ are identical, and C １ -C ４ - alkyl, R ４ is C １ -C ４ -Alkyl, C １ -C ４ -Haloalkyl, C １ -C ４ -Alkoxy, C １ -C ４ -haloalkoxy, phenyl or benzyl, n is 0, 1 or 2; Each of the substituents R ５ is, when present, a halogen, C １ -C ６ -Alkyl and C １ -C ６ -haloalkyl, The process comprises the enantioselective hydrogenation of a compound of formula (II) in the presence of a chiral iridium catalyst, 【Chemistry 2】 In the formula, the substituent R １ , R ２ , R ３ , R ４ , R ５ and integer n is as defined for compounds of formula (Ia) or (Ib), The chiral iridium catalyst is characterized in that it comprises a chiral ligand of formula (IIIa) or (IIIb); 【Chemistry 3】 In the formula, R ６ is 2,6-diethyl-4-methylphenyl, R ７ is hydrogen, R ８ is methyl, R ９ and R １０ are independently selected from the group consisting of cyclohexyl and piperidin-1-yl; method.

2. 2. The method of claim 1 , R １ is C １ -C ４ - alkyl, R ２ and R ３ is methyl, R ４ is C １ -C ４ - alkyl, n is 0 or 1; R ５ is fluorine, if present; R ６ is 2,6-diethyl-4-methylphenyl, R ７ is hydrogen, R ８ is methyl, R ９ and R １０ are both cyclohexyl. method.

3. 3. The method according to claim 1 or 2, The chiral iridium catalyst is represented by the general formula (Va) or (Vb): 【Chemistry 4】 During the ceremony R ６ is 2,6-diethyl-4-methylphenyl, R ７ is hydrogen, R ８ is methyl, R ９ and R １０ are both cyclohexyl, Y is [B(R １８ ) ４ ] － and [Al{OC(CF ３ ) ３ } ４ ] － is a non-coordinating anion selected from the group consisting of 【Chemistry 5】 Here, R １８ is 3,5-bis(trifluoromethyl)phenyl; method.

4. The method according to any one of claims 1 to 3, The chiral iridium catalyst is represented by general formula (Va): 【Chemistry 6】 R ６ is 2,6-diethyl-4-methylphenyl, R ７ is hydrogen, R ８ is methyl, R ９ and R １０ are both cyclohexyl, Y is an alkyl group represented by the formula (VII): ３ ) ３ } ４ ] － That is, method.

5. The process according to any one of claims 1 to 4, wherein the process is carried out in the presence of an additive selected from the group consisting of Bronsted acids, Lewis acids and mixtures thereof.

6. 6. The method of claim 5, wherein the additive is selected from the group consisting of hexafluorophosphoric acid, pentafluorophenol, 3,5-bis(trifluoromethyl)phenol, triphenylborane, tris[3,5-bis(trifluoromethyl)phenyl]borane, tris(2,3,4,5,6-pentafluorophenyl)borane, aluminum(III) trifluoromethanesulfonate, scandium(III) trifluoromethanesulfonate, aluminum(III) fluoride, titanium(IV) isopropoxide, trimethylaluminum, boron trifluoride, complexes of boron trifluoride, and mixtures thereof.

7. The process according to any one of claims 1 to 6, wherein the hydrogenation is carried out with hydrogen gas at a pressure of from 1 to 300 bar.

8. The process according to any one of claims 1 to 7, wherein the amount of chiral iridium catalyst used is in the range of 0.001 mol % to 5 mol % based on the amount of compound of formula (II).

9. A process according to any one of claims 1 to 8, wherein the hydrogenation is carried out at a temperature in the range of from 20°C to 130°C.

10. A method according to any one of claims 5 or 6, wherein the amount of additive used is in the range of 0.1 mol % to 10 mol %.

11. The chiral iridium catalyst is selected from the group consisting of chiral iridium catalysts of general formulae (Va) and (Vb): 【Chemistry 7】 [During the ceremony R ６ is 2,6-diethyl-4-methylphenyl, R ７ is hydrogen, R ８ is methyl, R ９ and R １０ are both cyclohexyl, Y is [B(R １８ ) ４ ] － and [Al{OC(CF ３ ) ３ } ４ ] － is a non-coordinating anion selected from the group consisting of 【Chemistry 8】 Here, R １８ is 3,5-bis(trifluoromethyl)phenyl.

12. 12. The chiral iridium catalyst according to claim 11, wherein the chiral iridium catalyst is a chiral iridium catalyst of general formula (Va): 【Chemistry 9】 [During the ceremony R ６ is 2,6-diethyl-4-methylphenyl, R ７ is hydrogen, R ８ is methyl, R ９ and R １０ are both cyclohexyl, Y is [B(R １８ ) ４ ] － where R １８ is 3,5-bis(trifluoromethyl)phenyl.

13. 12. The chiral iridium catalyst according to claim 11, wherein the chiral iridium catalyst is a chiral iridium catalyst of general formula (Va): 【Chemistry 10】 [During the ceremony R ６ is 2,6-diethyl-4-methylphenyl, R ７ is hydrogen, R ８ is methyl, R ９ and R １０ are both cyclohexyl, Y is an alkyl group represented by the formula (VII): ３ ) ３ } ４ ] － is a non-coordinating anion.

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