Method for distillative recovery of 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) from a mixture with 4-substituted 1,2,3,4-tetrahydroquinoline

Abstract

The present invention relates to a method for recovering 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) by distillation from an initial mixture containing at least one 4-substituted 1,2,3,4-tetrahydroquinoline, the method comprising adding a protic solvent selected from the group consisting of water, alcohols having a boiling point of 115° C. or less at 1 bar, and mixtures thereof to the initial mixture to obtain a distillation mixture, and subjecting the distillation mixture to distillation.

Description

[Technical Field]

[0001] The present invention relates to a process for the distillative recovery of 1,1,1,3,3,3-hexafluoro-2-propanol (hereinafter also referred to as hexafluoroisopropanol or HFIP) from a mixture comprising at least one 4-substituted 1,2,3,4-tetrahydroquinoline of formula (Ia) or (Ib) as specified below. [Background technology]

[0002] 4-Substituted 1,2,3,4-tetrahydroquinolines are versatile intermediates in the synthesis of N-indanylheteroarylcarboxamide fungicides, including the recently launched pyrazolecarboxamide fungicide inpirfluxam (EP 0 654 464, WO 2015 / 141564, WO 2019 / 185541, WO 2021 / 058457, WO 2021 / 058458). They can be obtained by hydrogenation of the corresponding 4-substituted 1,2-dihydroquinolines.

[0003] WO 2015 / 141564 describes a method for preparing optically active 4-substituted 1,2,3,4-tetrahydroquinolines, which involves 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 showed poorer conversions (up to 14%) and enantioselectivities (up to 31% ee).

[0004] WO 2019 / 185541, WO 2021 / 058457, and WO 2021 / 058458 disclose the enantioselective hydrogenation of the corresponding 4-substituted 1,2-dihydroquinolines in the presence of specific chiral iridium (P,N)-ligand catalysts, which provides improved conversion and enantioselectivity. The results are improved by performing the enantioselective hydrogenation in the presence of a suitable solvent. A particularly suitable solvent is the highly polar hexafluoroisopropanol. Although commercially available, its relatively high price may prevent its use in industrial-scale production processes in the agrochemical field unless the solvent can be efficiently recycled.

[0005] Brenek et al. reported a multistep preparation of the β-lactam antibiotic sulopenem in "Development of a Practical and Convergent Process for the Preparation of Sulopenem," Org. Process Res. Dev. 2012, 16(8), 1348-1359, in which Brenek, SJ, Caron, S., Chisowa, E., Delude, MP, Drexler, MT, Ewing, MD, Handfield, RE, Ide, ND, Nadkarni, DV, Nelson, JD, Olivier, M., Perfect, HH, Phillips, JE, Teixeira, JJ, Weekly, RM, and Zelina, JP. One reaction step involves selective oxidation of a 2-thioalkylpenem with urea and hydrogen peroxide in hexafluoroisopropanol. It is emphasized that the use of hexafluoroisopropanol requires maximizing the concentration and / or recycling this material to lose as little of this solvent as possible (page 1353, bottom of left column). Brenek et al. propose the use of a heptane co-solvent, which would allow the development of a suitable recycling process for the expensive hexafluoroisopropanol by distillation (page 1353, right column, first and second paragraphs). [Prior art documents] [Patent documents]

[0006] [Patent Document 1] European Patent Application Publication No. 0654464 [Patent Document 2] International Publication No. 2015 / 141564 [Patent Document 3] International Publication No. 2019 / 185541 [Patent Document 4] International Publication No. 2021 / 058457 [Patent Document 5] International Publication No. 2021 / 058458 [Non-patent literature]

[0007] [Non-Patent Document 1] Brenek et al., "Development of a Practical and Convergent Process for the Preparation of Sulopenem." Org. Process Res. Dev. 2012, 16(8), 1348-1359 Summary of the Invention [Problem to be solved by the invention]

[0008] Unfortunately, separation of hexafluoroisopropanol from 4-substituted 1,2,3,4-tetrahydroquinolines proved particularly difficult. This is believed to be due to the formation of hydrogen bonds between hexafluoroisopropanol and 4-substituted 1,2,3,4-tetrahydroquinolines. Distillation allows for partial recycling of hexafluoroisopropanol, but the necessary high recycling rates are not achieved, even when heptane is used as a cosolvent, as proposed by Brenek et al. Harsh conditions, i.e., distillation at very high temperatures, are also unsuitable because, under these conditions, 4-substituted 1,2,3,4-tetrahydroquinolines are not completely stable and undesirable decomposition products are formed.

[0009] One object of the present invention is therefore to provide an efficient method for recycling 1,1,1,3,3,3-hexafluoro-2-propanol from a mixture with at least one 4-substituted 1,2,3,4-tetrahydroquinoline, which method makes it possible to recover as much 1,1,1,3,3,3-hexafluoro-2-propanol as possible, to the extent that the residual amount of 1,1,1,3,3,3-hexafluoro-2-propanol in said mixture is less than 10% by weight, preferably less than 5% by weight, more preferably less than 1% by weight, more preferably less than 0.5% by weight, and most preferably less than 0.1% by weight. [Means for solving the problem]

[0010] The object of the above is to provide a process for the distillative recovery of 1,1,1,3,3,3-hexafluoro-2-propanol from an initial mixture comprising 1,1,1,3,3,3-hexafluoro-2-propanol and a compound of formula (Ia) or (Ib), comprising: [ka] [ka] R 1is C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy-C1-C6-alkyl, C3-C6-cycloalkyl, C6-C 14 -Aryl or C6-C 14 -aryl-C1-C4-alkyl, C1-C6-alkyl, C3-C6-cycloalkyl and C1-C6-alkoxy in the C1-C6-alkoxy-C1-C6-alkyl moiety may be substituted by 1 to 3 substituents independently selected from the group consisting of halogen, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy and phenyl, and phenyl may be substituted by 1 to 5 substituents independently selected from halogen, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl and C1-C4-haloalkoxy; C6~C 14 -aryl and C6-C 14 -C6-C in aryl-C1-C4-alkyl moiety 14 -aryl, in each case, is unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy, R 2 and R 3 are the same and are selected from the group consisting of hydrogen, C1-C6-alkyl, C1-C6-haloalkyl and C1-C6-alkoxy-C1-C6-alkyl, or R 2 and R 3 form together with the carbons to which they are attached a C3-C6-cycloalkyl ring, R 4is hydrogen, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkylamino, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-C1-C4-alkyl, C2-C6-alkenyloxy, 9-fluorenylmethyleneoxy, C6-C 14 -Aryl, C6-C 14 -Aryloxy, C6-C 14 -aryl-C1-C4-alkyloxy or C6-C 14 -aryl-C1-C4-alkyl, C6~C 14 -aryl, by itself or as part of a composite substituent, is unsubstituted or substituted with 1 to 5 substituents selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy, n is 0, 1, 2, 3 or 4; Each substituent R 5 is, if present, independently selected from the group consisting of halogen, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, hydroxyl, amino and -C(=O)-C1-C6-alkyl; a protic solvent selected from the group consisting of water, alcohols having a boiling point at 1 bar of not more than 115° C., and mixtures thereof, is added to the initial mixture to obtain a distillation mixture; The distillation mixture is distilled. This is achieved by the method.

[0011] Surprisingly, the addition of a protic solvent makes it possible to recover 1,1,1,3,3,3-hexafluoro-2-propanol by distillation from the mixture with the compound of formula (Ia) or (Ib) to such an extent that the residual amount of 1,1,1,3,3,3-hexafluoro-2-propanol in said mixture is less than 10% by weight, or even less than 0.1% by weight. DETAILED DESCRIPTION OF THE INVENTION

[0012] definition In the definitions of the symbols shown in the formulae above, generic terms were used that generally represent the following substituents:

[0013] halogen: Fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, more preferably fluorine or chlorine.

[0014] Alkyl: Saturated, linear or branched hydrocarbyl substituents having 1 to 6, preferably 1 to 4, carbon atoms, such as (but not limited to) 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. C1-C6-alkyl, such as propyl, 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, said groups are C1-C4-alkyl groups, such as 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 applies to alkyl as part of a complex substituent, such as C3-C6-cycloalkyl-C1-C4-alkyl, C6-C6-cycloalkyl-C1-C4-alkyl, C6-C6-cycloalkyl-C1-C4-alkyl, C6-C6-cycloalkyl-C1-C4-alkyl, C6-C6-cycloalkyl-C1-C4-alkyl, C6-C6-cycloalkyl-C1-C4-cyclo ... 14 The same also applies to -aryl-C1-C4-alkyl.

[0015] Alkenyl:Unsaturated, linear or branched hydrocarbyl substituents having 2 to 6, preferably 2 to 4, carbon atoms in any position and one double bond, such as (but not limited to) 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 pent-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-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-methylpent-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 C2-C6-alkenyl such as (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, the group is vinyl or allyl. This definition also applies to alkenyl as part of a compound substituent, unless otherwise defined.

[0016] Alkynyl:Straight-chain or branched hydrocarbyl substituents having 2 to 6, preferably 2 to 4, carbon atoms in any position and one triple bond, such as (but are not limited to) 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 C2-C6 alkynyl such as 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, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl. This definition also applies to alkynyl as part of a compound substituent, unless defined otherwise.

[0017] Alkylamino:Monoalkylamino or dialkylamino, where monoalkylamino refers to an amino radical having one alkyl residue of 1 to 6 carbon atoms attached to the nitrogen atom. Non-limiting examples include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, and tert-butylamino. Dialkylamino refers to an amino radical having two independently selected alkyl residues of 1 to 6 carbon atoms attached to the nitrogen atom. Non-limiting examples include N,N-dimethylamino, N,N-diethylamino, N,N-diisopropylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl-Nn-propylamino, and N-tert-butyl-N-methylamino.

[0018] Alkoxy: Saturated, straight chain or branched alkoxy substituents having 1 to 6, more preferably 1 to 4, carbon atoms, such as (but not limited to) 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-methyleth ... C1-C6-alkoxy such as 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 defined otherwise.

[0019] Cycloalkyl:Monocyclic or polycyclic saturated hydrocarbyl substituents 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 also applies to cycloalkyl, such as C3-C6-cycloalkyl-C1-C4-alkyl, as part of a compound substituent, unless otherwise defined.

[0020] Haloalkyl: Straight-chain or branched alkyl substituents (specified above) having 1 to 6, preferably 1 to 4, carbon atoms in which some or all of the hydrogen atoms have been replaced by halogen atoms as specified above, such as (but not limited to) C1-C3-haloalkyl, such as 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.

[0021] 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.

[0022] Haloalkoxy:and straight or branched alkoxy substituents (as specified above) having 1 to 6, preferably 1 to 4, carbon atoms, in which some or all of the hydrogen atoms are replaced by halogen atoms as specified above, such as (but not limited to) C1-C3-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.

[0023] Aryl: Monocyclic, bicyclic, or tricyclic aromatic or partially aromatic substituents having 6 to 14 carbon atoms, such as (but not limited to) phenyl, naphthyl, tetrahydronaphthyl, indenyl, and indanyl. Attachment to the superordinate general structure can be via any available 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.

[0024] The process according to the invention makes it possible to efficiently separate hexafluoroisopropanol from compounds of formula (Ia) or (Ib).

[0025] Preferably, compounds of formula (Ia) or (Ib), especially (Ia), are those in which the substituents are defined as follows: R 1 is C1-C6-alkyl or C6-C 14 -aryl-C1-C4-alkyl, C6~C14 -C6-C in aryl-C1-C4-alkyl moiety 14 -aryl is unsubstituted or substituted with 1 to 5 substituents selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy, R 2 and R 3 are the same and are selected from C1-C4 alkyl, R 4 is C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, phenyl, or benzyl, n is 0, 1, or 2; Each substituent R 5 When present, is independently selected from the group consisting of halogen, C1-C6-alkyl and C1-C6-haloalkyl.

[0026] More preferred compounds of formula (Ia) or (Ib), especially (Ia), are those in which the substituents are defined as follows: R 1 is C1-C6-alkyl, R 2 and R 3 are the same and are selected from C1-C4 alkyl, R 4 is C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, phenyl, or benzyl, n is 0, 1, or 2; Each substituent R 5 When present, is independently selected from the group consisting of halogen, C1-C6-alkyl and C1-C6-haloalkyl.

[0027] Even more preferred compounds of formula (Ia) or (Ib), especially (Ia), are those in which the substituents are defined as follows: R 1 is C1-C4-alkyl, R 2and R 3 is methyl, R 4 is C1-C4-alkyl, n is 0 or 1, R 5 When present, is fluorine.

[0028] Even more preferred compounds of formula (Ia) or (Ib), especially (Ia), are those in which the substituents are defined as follows: R 1 is methyl, ethyl, or n-propyl, R 2 and R 3 is methyl, R 4 is C1-C4-alkyl, n is 0 or 1, R 5 When present, is fluorine.

[0029] Even more preferred compounds of formula (Ia) or (Ib), especially (Ia), are those in which 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, is fluorine.

[0030] The most preferred compounds of formula (Ia) or (Ib), especially (Ia), are those in which the substituents are defined as follows: R 1 is methyl, R 2 and R 3 is methyl, R 4 is methyl, n is 0.

[0031] The total amount of 1,1,1,3,3,3-hexafluoro-2-propanol and the compound of formula (Ia) or (Ib) in the initial mixture subjected to the method according to the present invention is preferably at least 90% by weight, more preferably at least 95% by weight, even more preferably at least 97% by weight, even more preferably at least 98% by weight, even more preferably at least 99% by weight, and most preferably at least 99.5% by weight, based on the weight of the initial mixture. In other words, the initial mixture contains any component other than 1,1,1,3,3,3-hexafluoro-2-propanol and the compound of formula (Ia) or (Ib) in an amount of preferably less than 10% by weight, more preferably less than 5% by weight, even more preferably less than 3% by weight, even more preferably less than 2% by weight, even more preferably less than 1% by weight, and most preferably less than 0.5% by weight, based on the weight of the initial mixture. When two, three or more compounds of formula (Ia) or (Ib) are present in the initial mixture, the ranges outlined above apply to the total amount of 1,1,1,3,3,3-hexafluoro-2-propanol and all compounds of formula (Ia) or (Ib).

[0032] The amount of any protic solvent present in the initial mixture is preferably less than 0.5% by weight, more preferably less than 0.2% by weight, even more preferably less than 0.1% by weight, even more preferably less than 0.05% by weight, and most preferably less than 0.01% by weight, based on the weight of the initial mixture.

[0033] A particularly preferred initial mixture is one resulting from the synthesis of a compound of formula (Ia) or (Ib) by enantioselective hydrogenation of the corresponding 4-substituted 1,2-dihydroquinoline in the presence of a chiral iridium (P,N) ligand catalyst, as described in WO 2019 / 185541, WO 2021 / 058457 or WO 2021 / 058458.

[0034] The amount of 1,1,1,3,3,3-hexafluoro-2-propanol in the initial mixture is preferably at most 20% by weight, more preferably at most 15% by weight, even more preferably at most 12% by weight, even more preferably at most 10% by weight, and even more preferably at most 5% by weight, based on the weight of the initial mixture.

[0035] An initial mixture containing 1,1,1,3,3,3-hexafluoro-2-propanol in an amount greater than 20% by weight, based on the weight of the initial mixture, can also be subjected to the method according to the present invention. However, if a large amount of 1,1,1,3,3,3-hexafluoro-2-propanol is present in the initial mixture, a portion of it can be easily recovered by simple distillation without the need to add a protic solvent. Therefore, if 1,1,1,3,3,3-hexafluoro-2-propanol is present in the initial mixture in an amount greater than 20% by weight, it is preferable to remove a portion of 1,1,1,3,3,3-hexafluoro-2-propanol by distillation without adding a protic solvent until the level of 1,1,1,3,3,3-hexafluoro-2-propanol reaches a threshold for efficient further distillation, for example, until the amount of 1,1,1,3,3,3-hexafluoro-2-propanol reaches a maximum of 20% by weight. It is preferred to add a protic solvent at this stage and further distill the resulting distillation mixture.

[0036] The weight ratio of 1,1,1,3,3,3-hexafluoro-2-propanol to the compound of formula (Ia) or (Ib) in the initial mixture is preferably from 1:4 to 1:100, more preferably from 1:6 to 1:100.

[0037] The protic solvent added to the initial mixture is preferably selected from the group consisting of water, methanol, ethanol, 1-propanol, 2-propanol, and mixtures thereof, more preferably selected from the group consisting of water, methanol, ethanol, 2-propanol, and mixtures thereof, and the most preferred protic solvent is water.

[0038] The amount of protic solvent added to the initial mixture is preferably 1 to 300% by weight, more preferably 1 to 200% by weight, even more preferably 2 to 150% by weight, even more preferably 2 to 100% by weight, and most preferably 3 to 50% by weight, based on the weight of the initial mixture. When the protic solvent is a mixture of two, three or more solvents selected from the group consisting of water and alcohols with a boiling point of 115°C or less at 1 bar, the ranges outlined above apply to the amounts of each mixture, i.e., the total amount of protic solvents that are part of the protic solvent mixture.

[0039] Preferably, the distillation is carried out at a pressure of 0.05 to 1.2 bar, more preferably 0.3 to 1.1 bar, even more preferably 0.5 to 0.9 bar, and most preferably 0.6 to 0.8 bar. Generally, a lower pressure will facilitate the distillation and allow a lower distillation temperature to be chosen.

[0040] The distillation is preferably carried out at a temperature of 80 to 150°C, more preferably 90 to 140°C, and most preferably 100 to 140°C.

[0041] As will be readily understood by those skilled in the art, the distillation time can vary widely depending on various factors, particularly the scale of the distillation, i.e., the amount of distillation mixture being distilled, the distillation pressure, and the distillation temperature, but is generally between 0.5 and 48 hours. The shorter the time required to achieve the desired level of HFIP recovery, the more economically advantageous it is. Therefore, the distillation time is preferably less than 24 hours, more preferably less than 12 hours, and most preferably less than 6 hours.

[0042] The process according to the invention may be carried out in the presence of an aprotic additive selected from aliphatic hydrocarbons having 1 to 12 carbon atoms and mixtures thereof, which may be added to the initial mixture and / or the distillation mixture. Preferably, the aprotic additive is selected from aliphatic hydrocarbons having 1 to 12 carbon atoms and mixtures thereof. 10 -Alkanes, C1-C 10 -Alkenes, C3-C 12-Cycloalkanes, C3-C 12 -cycloalkenes, and mixtures thereof, more preferably selected from pentane, hexane, heptane, octane, pentene, hexene, heptene, octene, cyclohexane, methylcyclohexane, dimethylcyclohexane, ethylcyclohexane, and mixtures thereof, even more preferably selected from heptane, cyclohexane, methylcyclohexane, and mixtures thereof. Most preferably, the aprotic additive is methylcyclohexane.

[0043] When present, the aprotic additive is preferably added in an amount to achieve a content of aprotic additive in the distillation mixture of 1 to 400% by weight, preferably 1 to 300% by weight, more preferably 5 to 200% by weight, and most preferably 5 to 100% by weight, based on the weight of the distillation mixture. If the aprotic additive is a mixture of two, three or more additives, the ranges outlined above apply to the amounts of each mixture, i.e., the total amount of aprotic additives that are part of the aprotic additive mixture.

[0044] Preferably, the distillation is carried out using a distillation column.

[0045] If an aprotic additive is added, it is preferred to use a water separator, preferably a Dean-Stark apparatus, downstream of the distillation column to separate the aprotic additive phase from the distillate and recycle all or part of it to the distillation mixture.

[0046] [Table 1]

[0047] [Example]

[0048] [Examples 1 to 11] 143 g of hexafluoroisopropanol (HFIP) was mixed with 1357 g of (4R)-1-(2,2,4-trimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (R-THQA), which already contained 0.4% w / w MCH and 0.5% w / w HFIP, to obtain a final HFIP content of 10% w / w. From this homogeneous mixture, 200 g was taken for each experiment, and the respective amounts of additives were added to each (Table 1). Each resulting distillation mixture was stirred at 700 mbar for 1 h at 110 or 130 °C oil bath temperature (respective temperatures are shown in Table 1) using a standard distillation bridge equipped with a 500 mL round-bottom flask and a Liebig condenser. The distillate was collected. If a two-phase distillate was received, the lower HFIP-containing phase was separated. 19 By weighing and analyzing the HFIP content in the distillate (or its respective lower phase) by F quantitative NMR (internal standard, alcystine), the percentage of HFIP recovered can be calculated. The results are shown in Table 1.

[0049] [Table 2]

[0050] Examples 1 to 11 show that the addition of 10 g of water (Examples 2 and 5) and 20 g of water (Examples 1, 3, 4, and 6), corresponding to 5 and 10% by weight, respectively, relative to the weight of the initial HFIP / R-THQA mixture, enables the distillative recovery of HFIP from an HFIP / R-THQA mixture containing 10% HFIP by weight. Thus, even under relatively mild distillation conditions (110 °C, 700 mbar), the HFIP content can be reduced to well below 10% by weight by 1 h. In contrast, when no solvent is added (Examples 7 and 10) or the aprotic solvent MCH (Examples 8 and 10) or heptane (Example 9) is added, HFIP is not recovered under the respective distillation conditions.

[0051] [Examples 12 to 19] For each experiment, 200 g of the mixture of R-THQA with 10% HFIP (prepared as in Examples 1-11) was taken and the respective amounts of additives were added (Table 2). The resulting mixture was stirred at 700 mbar and an oil bath temperature of 130 °C for 1 h using a standard distillation bridge equipped with a 500 mL round-bottom flask and a Liebig condenser. The distillate was collected. 19 By weighing and analyzing the HFIP content in the distillate by F quantitative NMR (internal standard, alcysteine), the percentage of HFIP recovered can be calculated. The results are shown in Table 2.

[0052] [Table 3]

[0053] Examples 12 to 19 show that the addition of an alcohol having a boiling point of 115°C or less at 1 bar (Examples 12 to 15) also allows for the distillative recovery of HFIP from HFIP / R-THQA mixtures containing 10% HFIP by weight, but when n-butanol (boiling point 118°C at 1 bar, Example 16) or another higher-boiling alcohol (Examples 17 and 18) or a protic solvent (Example 19) is added, little or no HFIP is recovered under the respective distillation conditions.

Claims

1. A method for distilling and recovering 1,1,1,3,3,3-hexafluoro-2-propanol from an initial mixture containing 1,1,1,3,3,3-hexafluoro-2-propanol and a compound of formula (Ia) or (Ib), 【Chemistry 1】 (Ia) 【Chemistry 2】 (Ib) R １ is C １ to C ６ -alkyl, C １ to C ６ -haloalkyl, C １ to C ６ -alkoxy-C １ to C ６ -alkyl, C ３ to C ６ -cycloalkyl, C ６ to C １４ -aryl, or C ６ to C １４ -aryl-C １ to C ４ selected from the group consisting of -alkyl, Said C １ ~C ６ - Alkyl, C ３ ~C ６ -Cycloalkyl, and the C １ ~C ６ -Alkoxy-C １ ~C ６ - The C in the alkyl portion １ ~C ６ - Alkoxy is a halogen, C １ ~C ４ - Alkoxy, C １ ~C ４ - Haloalkyl, C １ ~C ４ - May be substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxys and phenyl, wherein the phenyl is a halogen, C １ ~C ４ - Alkyl, C １ ~C ４ - Alkoxy, C １ ~C ４ - Haloalkyl, and C １ ~C ４ - May be substituted with 1 to 5 substituents independently selected from the haloalkoxy, Said C ６ ~C １４ - Aryl and the C ６ ~C １４ -Aryl-C １ ~C ４ - The C in the alkyl portion ６ ~C １４ - In each case, the aryl is either unsubstituted or a halogen, C １ ~C ４ - Alkyl, C １ ~C ４ - Haloalkyl, C １ ~C ４ - Alkoxy and C １ ~C ４ - Substituted with 1 to 5 substituents selected from the group consisting of haloalkoxys, R ２ and R ３ They are the same, hydrogen, C １ ~C ６ - Alkyl, C １ ~C ６ - Haloalkyl and C １ ~C ６ -Alkoxy-C １ ~C ６ - Selected from the group consisting of alkyl groups, or R ２ and R ３ C ３ -C ６ - Forms 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 ~C ６ -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, and Said C ６ ~C １４ - The aryl is either unsubstituted, either by itself or as part of a complex substituent, or a halogen, C １ ~C ４ - Alkyl, C １ ~C ４ - Haloalkyl, C １ ~C ４ - Alkoxy and C １ ~C ４ - Substituted with 1 to 5 substituents selected from the group consisting of haloalkoxys, 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, hydroxyl, amino and -C(=O)-C １ ~C ６ - Independently selected from the group consisting of alkyls, A protic solvent selected from the group consisting of water, alcohols with a boiling point of 115°C or less at 1 bar, and mixtures thereof is added to the initial mixture to obtain a distillation mixture. A method for distilling the aforementioned distillation mixture.

2. R １ C １ ~C ６ -It is alkyl, R ２ and R ３ They are the same, C １ ~C ４ - Selected from alkyl groups, R ４ 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 - Independently selected from the group consisting of haloalkyls, The method according to claim 1.

3. R １ C １ ~C ４ -It is alkyl, R ２ and R ３ It is methyl, R ４ C １ ~C ４ -It is alkyl, n is either 0 or 1, R ５ If present, it is fluorine. The method according to claim 1.

4. R １ It is methyl, R ２ and R ３ It is methyl, R ４ It is methyl, n is 0. The method according to claim 1.

5. The method according to claim 1, wherein the total amount of 1,1,1,3,3,3-hexafluoro-2-propanol and the compound of formula (Ia) or (Ib) in the initial mixture is at least 90% by weight of the initial mixture.

6. The method according to claim 1, wherein the amount of 1,1,1,3,3,3-hexafluoro-2-propanol in the initial mixture is up to 20% by weight relative to the weight of the initial mixture.

7. The method according to claim 1, wherein the protic solvent is selected from the group consisting of water, methanol, ethanol, 1-propanol, 2-propanol, and mixtures thereof.

8. The method according to claim 1, wherein the protic solvent is water.

9. The method according to claim 1, wherein the amount of protic solvent added to the initial mixture is 1% to 300% by weight relative to the weight of the initial mixture.

10. The method according to claim 1, wherein the distillation is carried out at a pressure of 0.05 bar to 1.2 bar.

11. The method according to claim 1, wherein the distillation is carried out at a temperature of 80°C to 150°C.

12. The method according to claim 1, wherein the distillation mixture is distilled for 0.5 to 48 hours.

13. The method according to claim 1, wherein an aprotic additive selected from aliphatic hydrocarbons having 1 to 12 carbon atoms and mixtures thereof is added to the initial mixture or the distillation mixture.

14. The method according to claim 13, wherein the aprotic additive is added in an amount such that the content of the aprotic additive in the distillation mixture reaches 1 to 400% by weight relative to the weight of the distillation mixture.

15. The method according to claim 1, wherein the distillation is carried out using a distillation column.

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