Process for distillation recovery of 1, 1, 1, 3, 3, 3-hexafluoro-2-propanol (HFIP) from 4-substituted 1, 2, 3, 4-tetrahydroquinoline mixtures

Abstract

The invention relates to a process for the distillation recovery of 1, 1, 1, 3, 3, 3-hexafluoro-2-propanol (HFIP) from an initial mixture comprising 1, 1, 1, 3, 3, 3-hexafluoro-2-propanol and at least one 4-substituted 1, 2, 3, 4-tetrahydroquinoline, in which a protic solvent selected from the group consisting of water, alcohols having a boiling point of 115 DEG C or below at 1 bar and mixtures thereof is added to the initial mixture to obtain a distilled mixture, the distillation mixture is then distilled.

Description

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

[0002] 4-Substituted 1,2,3,4-tetrahydroquinolines are versatile intermediates in the synthesis of N-indanyl heteroarylcarboxamide fungicides, including the recently introduced pyrazolecarboxamide fungicide inpyrfluxam (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 process for preparing optically active 4-substituted 1,2,3,4-tetrahydroquinolines, which comprises hydrogenating the corresponding 4-substituted 1,2-dihydroquinoline in the presence of a transition metal catalyst having an optically active ligand. The asymmetric hydrogenation of 4-substituted NH-dihydroquinolines proceeds with moderate conversions (up to 62.6%) and enantioselectivities (up to 71.3% ee), while the conversions (up to 14%) and enantioselectivities (up to 31% ee) of N-acetyldihydroquinolines are even lower.

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

[0005] Brenek et al. reported a multi-step 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. The authors include 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 is the selective oxidation of 2-thioalkyl penems using urea-hydrogen peroxide in hexafluoroisopropanol. The article emphasizes that the use of hexafluoroisopropanol requires maximizing concentration and / or recycling the material to minimize the loss of this solvent (page 1353, bottom left column). Brenek et al. recommend the use of heptane cosolvent, which enables the development of a suitable recovery method for the expensive hexafluoroisopropanol by distillation (page 1353, right column, first and second paragraphs).

[0006] Unfortunately, separation of hexafluoroisopropanol from 4-substituted 1,2,3,4-tetrahydroquinolines is particularly difficult. This is believed to be due to the formation of hydrogen bonds between hexafluoroisopropanol and the 4-substituted 1,2,3,4-tetrahydroquinoline. Although distillation can recover some of the hexafluoroisopropanol, even the use of heptane as a co-solvent, as suggested by Brenek et al., does not give the desired high recovery. Distillation under harsh conditions, i.e., very high temperatures, is also not suitable because the 4-substituted 1,2,3,4-tetrahydroquinoline is not completely stable under these conditions and can form undesirable decomposition products.

[0007] Therefore, an object of the present invention is to provide a method for efficiently recovering 1,1,1,3,3,3-hexafluoro-2-propanol from a mixture of 1,1,1,3,3,3-hexafluoro-2-propanol and at least one 4-substituted 1,2,3,4-tetrahydroquinoline, wherein the method is capable of recovering as much 1,1,1,3,3,3-hexafluoro-2-propanol as possible, preferably to a certain extent that the remaining amount of 1,1,1,3,3,3-hexafluoro-2-propanol in the 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.

[0008] The above object is achieved by a method for recovering 1,1,1,1,3,3,3-hexafluoro-2-propanol by distillation from an initial mixture comprising 1,1,1,3,3,3-hexafluoro-2-propanol and a compound of formula (Ia) or (Ib),

[0009]

[0010] in

[0011] R 1 is selected from 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,

[0012] wherein the C1-C6-alkoxy group in the C1-C6-alkyl, C3-C6-cycloalkyl and C1-C6-alkoxy-C1-C6-alkyl moieties is optionally substituted with 1 to 3 substituents independently selected from halogen, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy and phenyl, wherein the phenyl group may be substituted with 1 to 5 substituents independently selected from halogen, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl and C1-C4-haloalkoxy, and

[0013] Among them, C6-C 14 -Aryl and C6-C 14 -C6-C in the aryl-C1-C4-alkyl moiety 14 - aryl is in each case unsubstituted or substituted by 1 to 5 substituents selected from halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy,

[0014] R 2 and R 3 are identical and are selected from hydrogen, C1-C6-alkyl, C1-C6-haloalkyl and C1-C6-alkoxy-C1-C6-alkyl,

[0015] or

[0016] R 2 and R 3 Together with the carbon to which they are bound, they form a C3-C6-cycloalkyl ring,

[0017] R 4 is hydrogen, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-

[0018] Haloalkoxy, C1-C6-alkylamino, C2-C6-alkenyl, C2-C6-alkynyl,

[0019] C3-C6-cycloalkyl, C3-C6-cycloalkyl-C1-C4-alkyl, C2-C6-alkenyloxy,

[0020] 9-fluorenylmethyleneoxy, C6-C 14 -Aryl, C6-C 14 -Aryloxy, C6-C 14 -

[0021] Aryl-C1-C4-alkoxy or C6-C 14 - aryl-C1-C4-alkyl,

[0022] Among them, C6-C 14 -Aryl, by itself or as part of a composite substituent, is unsubstituted or substituted by 1 to 5 radicals selected from halogen, C1-C4-alkyl, C1-C4-haloalkyl,

[0023] C1-C4-alkoxy and C1-C4-haloalkoxy substituents,

[0024] n is 0, 1, 2, 3 or 4,

[0025] Each substituent R 5 , if present, is independently selected from halogen, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, hydroxy, amino and -C(=O)-C1-C6-alkyl,

[0026] The method is characterized in that a protic solvent selected from water, alcohols having 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, and then

[0027] The distillation mixture is subjected to distillation.

[0028] Unexpectedly, the addition of a protic solvent enables the distillation recovery of 1,1,1,3,3,3-hexafluoro-2-propanol from a mixture of 1,1,1,3,3,3-hexafluoro-2-propanol and a compound of formula (Ia) or (Ib), such that the remaining amount of 1,1,1,3,3,3-hexafluoro-2-propanol in the mixture is less than 10 wt %, or even less than 0.1 wt %.

[0029] definition

[0030] In the definitions of symbols given in the above formulae, collective terms are used which generally represent the following substituents:

[0031] halogen : fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, more preferably fluorine or chlorine.

[0032] alkyl : a saturated straight-chain or branched hydrocarbon substituent having 1 to 6, preferably 1 to 4, carbon atoms, such as, but not limited to, C1-C6-alkyl, such as methyl, ethyl, propyl (n-propyl), 1-methylethyl (isopropyl), butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, 1,1- Dimethylpropyl, 1,2-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl. In particular, the radical is C1-C4-alkyl, such as methyl, ethyl, propyl, 1-methylethyl (isopropyl), butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl) or 1,1-dimethylethyl (tert-butyl). Unless defined otherwise, this definition also applies to alkyl as part of a composite substituent, for example C3-C6 cycloalkyl-C1-C4-alkyl, C6-C 14 -aryl-C1-C4-alkyl, etc.

[0033] Alkenyl: an unsaturated straight or branched hydrocarbon substituent having 2 to 6, preferably 2 to 4 carbon atoms and one double bond at any position, such as (but not limited to) C2-C6-alkenyl, such as 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, 1-methylenyl, (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-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 In some embodiments, the group is vinyl, 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)vinyl, buta-1,3-dienyl, penta-1,4-dienyl, hexa-1,5-dienyl or methylhexadienyl. In particular, the group is vinyl or allyl. Unless defined otherwise, this definition also applies to alkenyl as part of a composite substituent.

[0034] Alkynyl: a straight or branched hydrocarbon substituent having 2 to 6, preferably 2 to 4 carbon atoms and a triple bond at any position, such as (but not limited to) C2-C6-ynyl, 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 In some embodiments, the alkynyl group is ethynyl, prop-1-ynyl, prop-2-ynyl, 1-ethylprop-3-ynyl, 1-ethylprop-2-ynyl, 1-ethylprop-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. In some embodiments, the alkynyl group is ethynyl, prop-1-ynyl, prop-2-ynyl, or 1-ethylprop-3-ynyl. This definition also applies to alkynyl as part of a composite substituent, unless defined elsewhere.

[0035] Alkylamino : monoalkylamino or dialkylamino, wherein monoalkylamino represents an amino group with an alkyl residue, and the alkyl residue has 1 to 6 carbon atoms and is connected to a nitrogen atom. Non-limiting examples include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino and tert-butylamino. Wherein dialkylamino represents an amino group with two independently selected alkyl residues, and the alkyl residue has 1 to 6 carbon atoms and is connected to a nitrogen atom. Non-limiting examples include N, N-dimethylamino, N, N-diethylamino, N, N-diisopropylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino, N-isopropyl-N-n-propylamino and N-tert-butyl-N-methylamino.

[0036] Alkoxy: a saturated straight or branched alkoxy substituent having 1 to 6, more preferably 1 to 4 carbon atoms, such as, but not limited to, C1-C6-alkoxy, such as 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 1-ethyl-1-methyl-propoxy and 1-ethyl-2-methyl-propoxy. This definition also applies to alkoxy as part of a composite substituent, unless defined otherwise.

[0037] Cycloalkyl : a monocyclic or polycyclic saturated hydrocarbon substituent having 3 to 12, preferably 3 to 8, more preferably 3 to 6 carbocyclic ring members, such as, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl and adamantyl. Unless otherwise defined, this definition also applies to cycloalkyl groups as part of a composite substituent, such as C3-C6-cycloalkyl-C1-C4-alkyl.

[0038] Halogenated alkyl : a linear or branched alkyl substituent (as described above) having 1 to 6, preferably 1 to 4 carbon atoms, wherein some or all of the hydrogen atoms in these groups are replaced by halogen atoms as described 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-trifluoropropan-2-yl. Unless otherwise defined, this definition also applies to haloalkyl as part of a composite substituent.

[0039] Haloalkenyl and haloalkynyl are defined similarly to haloalkyl, except that alkenyl and alkynyl groups are present as part of the substituent group rather than alkyl.

[0040] Haloalkoxy: linear or branched alkoxy substituents (as described above) having 1 to 6, preferably 1 to 4 carbon atoms, wherein some or all of the hydrogen atoms in these groups are replaced by halogen atoms as described 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. Unless otherwise defined, this definition also applies to haloalkoxy as part of a composite substituent.

[0041] 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 aromatic residue may be bonded to the superordinate general structure via any possible ring member. The aromatic residue is preferably selected from phenyl, 1-naphthyl, 2-naphthyl, 9-phenanthrenyl and 9-anthryl. Phenyl is particularly preferred.

[0042] The method of the present invention can efficiently separate hexafluoroisopropanol from the compound of formula (Ia) or (Ib).

[0043] Preferably, the compound of formula (Ia) or (Ib), in particular formula (Ia), wherein the substituents are defined as follows:

[0044] R 1 is C1-C6-alkyl or C6-C 14 - aryl-C1-C4-alkyl,

[0045] Among them, C6-C 14 -C6-C in the aryl-C1-C4-alkyl moiety 14 - aryl is unsubstituted or substituted by 1 to 5 substituents selected from halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy,

[0046] R 2 and R 3 are identical and are selected from C1-C4-alkyl,

[0047] R 4 is C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, phenyl or benzyl,

[0048] n is 0, 1, or 2,

[0049] Each substituent R 5 , if present, is independently selected from halogen, C1-C6-alkyl and C1-C6-haloalkyl.

[0050] More preferably, the compound of formula (Ia) or (Ib), in particular formula (Ia), wherein the substituents are defined as follows:

[0051] R 1 is a C1-C6-alkyl group,

[0052] R 2 and R 3 are identical and are selected from C1-C4-alkyl,

[0053] R 4 is C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, phenyl or benzyl,

[0054] n is 0, 1, or 2,

[0055] Each substituent R 5 , if present, is independently selected from halogen, C1-C6-alkyl and C1-C6-haloalkyl.

[0056] Even more preferably, compounds of formula (Ia) or (Ib), in particular formula (Ia), wherein the substituents are defined as follows:

[0057] R 1 is C1-C4-alkyl,

[0058] R 2 and R 3 Methyl,

[0059] R 4 is C1-C4-alkyl,

[0060] n is 0 or 1,

[0061] R 5 , if present, is fluorine.

[0062] Even more preferably, compounds of formula (Ia) or (Ib), in particular formula (Ia), wherein the substituents are defined as follows:

[0063] R 1 is methyl, ethyl or n-propyl,

[0064] R 2 and R 3 Methyl,

[0065] R 4is C1-C4-alkyl,

[0066] n is 0 or 1,

[0067] R 5 , if present, is fluorine.

[0068] Even more preferably, compounds of formula (Ia) or (Ib), in particular formula (Ia), wherein the substituents are defined as follows:

[0069] R 1 is methyl or n-propyl,

[0070] R 2 and R 3 Methyl,

[0071] R 4 Methyl,

[0072] n is 0 or 1,

[0073] Substituent R 5 , if present, is fluorine.

[0074] Most preferably, the compound of formula (Ia) or (Ib), in particular formula (Ia), wherein the substituents are defined as follows:

[0075] R 1 Methyl,

[0076] R 2 and R 3 Methyl,

[0077] R 4 Methyl,

[0078] n is 0.

[0079] In the initial mixture subjected to the process of the present invention, the total amount of 1,1,1,3,3,3-hexafluoro-2-propanol and the compound of formula (Ia) or (Ib) 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%, based on the weight of the initial mixture. In other words, the initial mixture preferably contains 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 of any components other than 1,1,1,3,3,3-hexafluoro-2-propanol and the compound of formula (Ia) or (Ib), based on the weight of the initial mixture. If two, three or more compounds of formula (Ia) or (Ib) are present in the initial mixture, the above range refers to the total amount of 1,1,1,3,3,3-hexafluoro-2-propanol and all compounds of formula (Ia) or (Ib).

[0080] The amount of any protic solvent in the initial mixture is preferably less than 0.5 wt%, more preferably less than 0.2 wt%, even more preferably less than 0.1 wt%, even more preferably less than 0.05 wt%, most preferably less than 0.01 wt%, based on the weight of the initial mixture.

[0081] Particularly preferably, the initial mixture is a product mixture obtained 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 WO2021 / 058458 to synthesize a compound of formula (Ia) or (Ib).

[0082] The amount of 1,1,1,3,3,3-hexafluoro-2-propanol in the initial mixture is preferably at most 20 wt%, more preferably at most 15 wt%, even more preferably at most 12 wt%, even more preferably at most 10 wt%, even more preferably at most 5 wt%, based on the weight of the initial mixture.

[0083] Furthermore, an initial mixture containing more than 20% by weight of 1,1,1,3,3,3-hexafluoro-2-propanol, based on the weight of the initial mixture, can also be subjected to the process according to the invention. However, if a large amount of 1,1,1,3,3,3-hexafluoro-2-propanol is present in the initial mixture, part of it can be easily recovered by simple distillation without the addition of a protic solvent. Therefore, if the amount of 1,1,1,3,3,3-hexafluoro-2-propanol in the initial mixture exceeds 20% by weight, it is preferred to remove part of the 1,1,1,3,3,3-hexafluoro-2-propanol by distillation without adding a protic solvent until its content reaches a threshold value for efficient further distillation, for example until the content of 1,1,1,3,3,3-hexafluoro-2-propanol is at most 20% by weight. It is preferred to add a protic solvent at this stage and to subject the resulting distillation mixture to a further distillation.

[0084] 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 1:4 to 1:100, more preferably 1:6 to 1:100.

[0085] The protic solvent added to the initial mixture is preferably selected from water, methanol, ethanol, 1-propanol, 2-propanol and mixtures thereof, more preferably selected from water, methanol, ethanol, 2-propanol and mixtures thereof. The most preferred protic solvent is water.

[0086] The amount of protic solvent added to the initial mixture is preferably 1 to 300 wt %, more preferably 1 to 200 wt %, even more preferably 2 to 150 wt %, even more preferably 2 to 100 wt %, most preferably 3 to 50 wt %, based on the weight of the initial mixture. If the protic solvent is a mixture of two, three or more solvents selected from water and alcohols having a boiling point of 115° C. or less at 1 bar, the above ranges refer to the amount of the corresponding mixture, i.e. the sum of the amounts of protic solvents as part of the protic solvent mixture.

[0087] 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, most preferably 0.6 to 0.8 bar. Generally, reducing the pressure facilitates the distillation and enables the selection of a lower distillation temperature.

[0088] Preferably, the distillation is carried out at a temperature of 80 to 150°C, more preferably 90 to 140°C, most preferably 100 to 140°C.

[0089] As will be readily appreciated by those skilled in the art, the distillation time may vary widely depending on a number of factors, in particular the scale of the distillation, i.e. the amount of distillation mixture to be distilled, the distillation pressure and the distillation temperature, but is generally between 0.5 and 48 hours. For economic reasons, the time required to achieve the desired level of HFIP recovery is as short as possible. Thus, preferably the distillation time is less than 24 hours, more preferably less than 12 hours, and most preferably less than 6 hours.

[0090] The process according to the invention can optionally be carried out in the presence of an aprotic additive selected from aliphatic hydrocarbons having 1 to 12 carbon atoms and mixtures thereof, which additive can be added to the initial mixture and / or the distillation mixture. Preferably, the aprotic additive is selected from C1-C 10 -Alkanes, C1-C 10 -Olefins, C3-C 12 -Cycloalkanes, C3-C 12 - cycloolefins 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.

[0091] If an aprotic additive is present, it is preferably added in such an amount that the content of aprotic additive in the distillation mixture is from 1 to 400% by weight, preferably from 1 to 300% by weight, more preferably from 5 to 200% by weight, most preferably from 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 above ranges refer to the amounts of the corresponding mixture, i.e. the sum of the amounts of aprotic additives that are part of the aprotic additive mixture.

[0092] Preferably, the distillation is carried out using a distillation column.

[0093] If an aprotic additive is added, a water separator, preferably a Dean-Stark apparatus, is preferably used downstream of the distillation column in order to separate the aprotic additive phase from the distillate and recycle it in its entirety or in part into the distillation mixture.

[0094] Abbreviations and Acronyms:

[0095] nd Undetermined h Hour HFIP Hexafluoroisopropanol MCH Methylcyclohexane QNMR Quantitative NMR spectroscopy R-THQA (4R)-1-(2,2,4-Trimethyl-3,4-dihydroquinolin-1(2H)-yl)ethanone w / w By weight Example

[0096] Embodiment 1-11:

[0097] 143 g of hexafluoroisopropanol (HFIP) were 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 of MCH and 0.5% w / w of HFIP, giving a final HFIP content of 10% w / w. From this homogeneous mixture, 200 g were taken per experiment and the corresponding amount of additives (Table 1) were added. Each of the resulting distillation mixtures was stirred for 1 h at an oil bath temperature of 110° C. or 130° C. (the respective temperatures are indicated in Table 1) at 700 mbar using a 500 mL round-bottom flask and a standard distillation bridge with a Liebig condenser. The distillate was collected. If a two-phase distillate was obtained, the lower phase comprising HFIP was separated off. By 19 The HFIP content in the distillate (or its respective lower phase) was weighed and analyzed by F quantitative NMR (internal standard: alsystin), and the percentage of HFIP recovered could be calculated. The results are shown in Table 1.

[0098] Table 1:

[0099]

[0100]

[0101] Examples 1-11 show that the addition of 10 g of water (Examples 2 and 5) and 20 g of water (Examples 1, 3, 4, 6), corresponding to 5 wt % and 10 wt %, respectively, based on the weight of the initial HFIP / R-THQA mixture, enables the distillation recovery of HFIP from a HFIP / R-THQA mixture containing 10 wt % HFIP. Thus, even under relatively mild distillation conditions (110° C., 700 mbar) over 1 h, the HFIP content can be reduced to well below 10 wt %. In contrast, if no solvent is added (Examples 7 and 10) or an aprotic solvent MCH (Examples 8 and 10) or heptane (Example 9) is added, HFIP cannot be recovered under the corresponding distillation conditions.

[0102] Embodiment 12-19:

[0103] From a mixture of 10% w / w HFIP in R-THQA (prepared in the same manner as in Examples 1-11), 200 g was taken for each experiment and the corresponding amount of additives (Table 2) was added. The resulting mixture was stirred for 1 h at an oil bath temperature of 130°C at 700 mbar using a 500 mL round bottom flask and a standard distillation bridge with a Liebig condenser. The distillate was collected. 19The HFIP content in the distillate was weighed and analyzed by F quantitative NMR (internal standard: alsystin), and the percentage of HFIP recovered could be calculated. The results are shown in Table 2.

[0104] Table 2:

[0105]

[0106] Examples 12-19 show that the addition of alcohols having a boiling point of 115° C. or less at 1 bar (Examples 12-15) also allows the distillation recovery of HFIP from a HFIP / R-THQA mixture containing 10 wt. % HFIP. However, if n-butanol (boiling point 118° C. at 1 bar, Example 16) or other higher boiling alcohols (Examples 17 and 18) or protic solvents (Example 19) are added, no or almost no HFIP can be recovered under the corresponding distillation conditions.

Claims

1. A method for recovering 1,1,1,3,3,3-hexafluoro-2-propanol by distillation from an initial mixture comprising 1,1,1,3,3,3-hexafluoro-2-propanol and a compound of formula (Ia) or (Ib), in R 1 Selected from 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, wherein the C1-C6-alkoxy in the C1-C6-alkyl, C3-C6-cycloalkyl and C1-C6-alkoxy-C1-C6-alkyl moieties are optionally substituted with 1 to 3 substituents independently selected from halogen, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-haloalkoxy and phenyl, The phenyl group may be substituted by 1 to 5 groups independently selected from halogen, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl and C1-C4-haloalkoxy substituents, and Among them, C6-C 14 -Aryl and C6-C 14 -C6-C in the aryl-C1-C4-alkyl moiety 14 -Aryl is in each case unsubstituted or substituted by 1 to 5 radicals selected from halogen, C1-C4-alkyl, Substituted by C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy substituents, R 2 and R 3 are identical and are selected from hydrogen, C1-C6-alkyl, C1-C6-haloalkyl and C1-C6-alkoxy-C1-C6-alkyl, or R 2 and R 3 Together with the carbon to which they are bound, they form a C3-C6-cycloalkyl ring, R 4 is 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-alkoxy or C6-C 14 - aryl-C1-C4-alkyl, Among them, C6-C 14 -Aryl, by itself or as part of a composite substituent, is unsubstituted or substituted by 1 to 5 radicals selected from halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy substituents, n is 0, 1, 2, 3 or 4, Each substituent R 5 , if present, is independently selected from halogen, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, hydroxy, amino and -C(=O)-C1-C6-alkyl, in, To the initial mixture is added a protic solvent selected from water, an alcohol having a boiling point of 115° C. or less at 1 bar, and a mixture thereof to obtain a distillation mixture, and then The distillation mixture is subjected to distillation.

2. The method according to claim 1, wherein R 1 is a C1-C6-alkyl group, R 2 and R 3 are identical 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, and Each substituent R 5 , if present, is independently selected from halogen, C1-C6-alkyl and C1-C6-haloalkyl.

3. The method according to claim 1, wherein R 1 is C1-C4-alkyl, R 2 and R 3 Methyl, R 4 is C1-C4-alkyl, n is 0 or 1, and R 5 If present, it is fluorine.

4. The method according to claim 1, wherein R 1 Methyl, R 2 and R 3 Methyl, R 4 is a methyl group, and n is 0.

5. The process according to any one of claims 1 to 4, 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, based on the weight of the initial mixture.

6. The process according to any one of claims 1 to 5, wherein the amount of 1,1,1,3,3,3-hexafluoro-2-propanol in the initial mixture is at most 20% by weight, based on the weight of the initial mixture.

7. The process according to any one of claims 1 to 6, wherein the protic solvent is selected from water, methanol, ethanol, 1-propanol, 2-propanol and mixtures thereof.

8. The process according to any one of claims 1 to 7, wherein the protic solvent is water.

9. The process according to any one of claims 1 to 8, wherein the amount of the protic solvent added to the initial mixture is from 1% to 300% by weight, based on the weight of the initial mixture.

10. The process according to any one of claims 1 to 9, wherein the distillation is carried out at a pressure of 0.05 bar to 1.2 bar.

11. The process according to any one of claims 1 to 10, wherein the distillation is carried out at a temperature of 80 to 150°C.

12. The process according to any one of claims 1 to 11, wherein the distillation mixture is distilled for 0.5 to 48 hours.

13. The process according to any one of claims 1 to 12, 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 process according to claim 13, wherein the aprotic additive is added in such an amount that the content of the aprotic additive in the distillation mixture is 1 to 400% by weight, based on the weight of the distillation mixture.

15. The process according to any one of claims 1 to 14, wherein the distillation is carried out using a distillation column.

Images