WO2009013553A1 - Method for recovering diphenylprolinol type catalysts with phase-tag groups, new catalysts recoverable by this method and their use - Google Patents

Method for recovering diphenylprolinol type catalysts with phase-tag groups, new catalysts recoverable by this method and their use Download PDF

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WO2009013553A1
WO2009013553A1 PCT/HU2008/000087 HU2008000087W WO2009013553A1 WO 2009013553 A1 WO2009013553 A1 WO 2009013553A1 HU 2008000087 W HU2008000087 W HU 2008000087W WO 2009013553 A1 WO2009013553 A1 WO 2009013553A1
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formula
catalyst
group
water
alkyl
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Tibor Soos
Zoltan Dalicsek
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H4 Sep Kft
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
    • B01J31/0271—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds also containing elements or functional groups covered by B01J31/0201 - B01J31/0231
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0201—Oxygen-containing compounds
    • B01J31/0202—Alcohols or phenols
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0201—Oxygen-containing compounds
    • B01J31/0204—Ethers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0201—Oxygen-containing compounds
    • B01J31/0211—Oxygen-containing compounds with a metal-oxygen link
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0215—Sulfur-containing compounds
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
    • B01J31/0235—Nitrogen containing compounds
    • B01J31/0237—Amines
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/40—Regeneration or reactivation
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/60—Reduction reactions, e.g. hydrogenation
    • B01J2231/64—Reductions in general of organic substrates, e.g. hydride reductions or hydrogenations
    • B01J2231/641—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes
    • B01J2231/643—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes of R2C=O or R2C=NR (R= C, H)
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/90—Catalytic systems characterized by the solvent or solvent system used
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/90—Catalytic systems characterized by the solvent or solvent system used
    • B01J2531/94—Fluorinated solvents

Definitions

  • the invention relates to a method for recovering diphenylprolinol type catalysts which carry phase-tag group ⁇ . Most of the catalysts recoverable by the method of the invention are new compounds; the invention also relates to these new compounds. Furthermore the invention relates to the use of catalysts with phase-tag groups in catalytic reactions.
  • X is hydrogen, hydroxy, C 1 -S alkoxy optionally interrupted in the alkyl chain by a single oxygen atom and/or by one or two sulphur atoms, or a group of formula
  • R', R" and R"' stand for identical or different Ci -3 alkyl groups or one of them may also represent phenyl group or a C 4-5 alkyl group;
  • Z is hydrogen or a Ci -6 alkyl group; and the wavy line indicates chirality (D or L); and complexes thereof are valuable catalysts for various asymmetric syntheses.
  • fluorous methodology is the most effective, which has brought a breakthrough by enabling to perform the reaction in homogeneous phase and simultaneously to recover the catalyst with high efficiency.
  • the essence of fluorous methodology is that "superhydrophobic" and at the same time chemically inert perfluoroalkyl groups with medium chain length (usually comprising 4-10 carbon atoms) are attached as phase-tags to the molecule of the catalyst to be recovered.
  • R 1 , R 2 and R 3 are independently selected from
  • adamantyl or ferrocenyl optionally substituted on the ring by one or more Ci- 4 alkyl and/or Ci -4 alkoxy, wherein said adamantyl or ferrocenyl group may be optionally attached to the rest of the molecule through a 1-4 membered chain composed of -O-, -S-, -CH 2 - and/or -C(CH 3 ) 2 - members; and (iv) C3- 1 0 alkyl, preferably C3-6 alkyl comprising preferably at least one branching in the alkyl chain, which
  • the invention relates to a method for recovering a catalyst of formula (II)
  • X is hydrogen, hydroxy, C 1-6 alkoxy optionally interrupted in the alkyl chain by a single oxygen atom and/or by one or two sulphur atoms, or a group of formula -0-Si(R', R", R"'), and in this latter formula R', R" and R 1 " stand for identical or different Ci -3 alkyl groups or one of them may also represent phenyl group or a C 4 - 5 alkyl group;
  • Y is hydrogen, hydroxy, mercapto (-SH), -OR, -SR or -O-CO-R, and in these latter formulae R is a hydrocarbyl group of up to 10 carbon atoms bearing optionally one or more halo and/or Ci -4 alkoxy substituents, with the proviso that when R represents a straight-chained hydrocarbyl group it may comprise up to 6 carbon atoms;
  • Z is hydrogen or a Ci -6 alkyl group
  • Ph 1 is a group of formula (a)
  • R 1 , R 2 and R 3 are independently selected from
  • adamantyl or ferrocenyl optionally substituted on the ring by one or more C 1 - 4 alkyl and/or C 1-4 alkoxy, wherein said adamantyl or ferrocenyl group may be optionally attached to the rest of the molecule through a 1-4 membered chain composed of -O-, -S-, -CH 2 - and/or -C(CH 3 ) 2 - members; and
  • a mixture comprising the catalyst is evaporated onto an aluminium oxide, silicate or aluminosilicate support or onto a reverse phase silica gel support all of nonporous surface, the components which differ from the catalyst are removed from the support by washing it with water or with a polar organic solvent comprising at least 20 % by volume of water, thereafter the catalyst is washed down from the support with a nonaqueous organic solvent, and, if desired, the catalyst is separated from the resulting solution; or
  • a mixture comprising the catalyst is distributed between a solvent system consisting of a water immiscible phase and of a polar phase comprising at least 20 % by volume of water, the water immiscible phase is separated, and, if desired, the catalyst is separated from the water immiscible phase.
  • Recovery of the catalyst of formula (II) is performed in one of the processing steps of the final reaction mixture. Sometimes recovery of the catalyst may be the first step of processing; however, other steps (e.g. total or partial removal of solids and/or of certain solvents) may also precede the recovery of the catalyst.
  • a complex of a compound of formula (II) has been used as catalyst in the reaction (as is the case e.g. in CBS reactions performed with oxazaborolidine complexes)
  • the complex is to be decomposed in a manner known per se prior to recovering the catalyst.
  • Method (1) of catalyst recovery can be recommended primarily for laboratory scale reactions.
  • Aluminium oxide, silicate or aluminosilicate support with nonporous surface to be used here may be e.g. ⁇ -aluminium oxide (corundum), ⁇ -alutninium oxide, glass beads, glass powder or any combination thereof.
  • reverse phase silica gel support (which has its usual meaning and relates to silica gel the surface of which has been modified with an apolar silylating agent) e.g. FSPE or DSC18 can be used.
  • An obvious requirement in connection with the support is that the mixture to be evaporated thereon should not swell the support. Corundum is a particularly preferred support.
  • the support is washed with water or with a polar organic solvent comprising at least 20 % by volume of water to remove the components other than the catalyst.
  • a polar organic solvent comprising at least 20 % by volume of water to remove the components other than the catalyst.
  • any solvent can be used which is able to dissolve at least 30 % by volume of water.
  • Most preferred organic solvents are those which are unlimitedly water miscible, such as methanol, ethanol, dimethyl formamide, dimethyl sulphoxide, acetonitrile.
  • the water/organic solvent mixture comprises preferably about 50 % by volume of water.
  • the catalyst of formula (II) is used typicaly in reactions wherein polar components are involved (e.g.
  • liquid hydrocarbons such as hexane, cyclohexane
  • ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran
  • chlorinated liquid hydrocarbons such as dichloromethane, chloroform
  • organic solvents which are unlimitedly water miscible, such as methanol, ethanol, dimethyl formamide, dimethyl sulphoxide, acetonitrile are also applicable.
  • the resulting solution optionally can be recycled directly into the catalytic reaction.
  • the catalyst can be separated in a manner known per se, e.g. by evaporation.
  • Method (2) of the catalyst recovery can be recommended mainly for industrial processes.
  • the key element of this method is the provision of the two- phase liquid system, wherein the aqueous phase should contain at least 20 % by volume of water. It has been observed, unexpectedly, that the compounds of formula (II) are much more sensitive to the presence of water with regard to their solubility and distribution coefficient than the starting substances and end products of the catalyzed reaction, which can be attributed to the presence of the phase-tag groups R 1 , R 2 and R 3 . The presence of the prescribed minimum amount of water
  • the aqueous phase may be pure water. In most instances, however, the aqueous phase also comprises a water miscible organic solvent in an amount sufficient to dissolve the non-catalyst components.
  • the water miscible solvents should be able to dissolve at least 20 % by volume of water.
  • Particularly preferred representatives of water miscible solvents are polar solvents with unlimited water miscibility, such as methanol, ethanol, dimethyl formamide, dimethyl sulphoxide and acetonitrile.
  • the water content of the water/organic solvent mixture is preferably at least 30 % by volume, particularly preferably about 50 % by volume.
  • the aqueous phase may be the reaction mixture or the pre-processed reaction mixture itself, the water content of which is adjusted to the prescribed value.
  • water immiscible phase which sharply separate from the aqueous phase, i.e. which do not form either real or colloidal solutions with the aqueous phase.
  • water immiscible means that not more than 1 % by volume of water can be dissolved by the solvent concerned. It is preferred if the water immiscible solvent is also immiscible with the organic solvent present in the aqueous phase.
  • Liquid hydrocarbons e.g. hexane, cyclohexane, methyl- cyclohexane
  • certain ethers e.g.
  • diisopropyl ether hybridic fluorinated solvents comprising not more than 4 perfluorinated units (e.g. perfluorobutyl-ethyl-ether) and 3,5-bis(trifluoromethyl)-benzene are suitable examples of water immiscible solvents.
  • the further catalysts of formula (II) and their complexes, furthermore complexes of compounds of formula (II) wherein Ph 1 is 3,5-bis(trifluoro-methyl)- phenyl and at the same time Y and Z stand for hydrogen and X stands for hydroxy, methoxy or tetramethylsiliyloxy, are new compounds.
  • the invention also relates to these new compounds.
  • hydrocarbyl group used in connection with R in the definition of the compounds of formula (II) refers to saturated, unsaturated, aromatic, open- chain and cyclic hydrocarbyl groups and all possible combinations thereof, of which the followings are mentioned as examples: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, alkylphenyl, phenylalkyl, alkylcycloalkyl, cycloalkylalky, cycloalkylphenyl and the like.
  • Ph 1 may represent preferably a group of formula
  • R 1 and R2 are as defined above.
  • one of R 1 and R 2 may also represent hydrogen, however, it is more preferred when both R 1 and R 2 are other than hydrogen.
  • Compounds of formula (II) wherein R 1 and R 2 are the same are particularly preferred.
  • this alkyl grop may comprise preferably 3-6 carbon atoms and comprises preferably at least one branching in the alkyl chain.
  • a particularly preferred representative of the alkyl groups is tertiary butyl.
  • the number of carbon atoms contained in the straight- chained alkyl groups is preferably 3.
  • the new catalysts of formula (II) can be prepared by any method used for the preparation of structurally related substances, e.g. by those disclosed in the cited references dealing with compounds of formula (I) and with the known members of compounds of formula (II). According to a suitable method a compound of formula (III)
  • Est is an esterifying group and Y is as defined above, is reacted with a compound of formula (IV)
  • the invention also relates to the use of a compound of formula (II), wherein X, Y, Z, Ph 1 and the wavy line are as defined above with the proviso that when Y and Z are hydrogen and at the same time X is hydroxy, methoxy or thetramethylsilyloxy, Ph 1 may only be other than 3,5-bis(trifluoromethyl)-phenyl, as a catalyst in a catalytic reaction requiring the use of a compound of formula (I) or of a complex thereof.
  • These catalytic reactions are performed by methods well known in the art, e.g.
  • the invention relates to the use of the oxazaborolidine complex of a compound of formula (II), wherein Y and Z are hydrogen, X is hydroxy or trimethylsilyloxy and Ph 1 is 3,5-bis(trifluoromethyl)-phenyl, in a catalytic asymmetric CBS reduction.
  • asymmetric CBS reduction is performed as disclosed in the literature with the difference that the oxaborolidine complex of a compound of formula (II) as defined n this paragraph is used as catalyst instead of the oxaborolidine complex of a compound of formula (I) recommended in the literature.
  • water is excluded from the reaction mixture prior to the processing steps.
  • oxazaborolidine complex was prepared by dissolving 105.0 mg (0.2 mmoles) of bis[3,5-bis(trifluoro-methyl)-phenyl]-pyrrolidin-2-yl-methanol in 2 ml of dry tetrahydrofuran, adding 24.9 mg (28 ⁇ l, 0.24 mmoles) of trimethyl borate, and stirring the reaction mixture at room temperature for 1 hour.
  • Support/filler 1 Phenyl- 1 -(Naphthalene- 1-(Pyridin- 1-(4-Chloro- -ethanol -2-yl)-ethanol -3-yl)-ethanol phenyQ-ethanol
  • magnesium powder 801 mg (33 mmoles) were weighed into a two-necked flask which was previously dried with heating and flushed with argon, and a condenser was fitted to the flask.
  • the magnesium powder was activated with iodine, thereafter 35 ml of dry tetrahydrofuran were added.
  • 8.97 g (30 mmoles) of 5-bromo-1 , 1 -di-(tert-butyl)-2-methoxy-benzene were dissolved in 5 ml of dry tetrahydrofuran, and the solution was introduced into the flask within 30 minutes, under keeping the mixture in boiling.
  • Example 2 The method described in Example 2 was followed with the difference that oxazaborolidine complex of bis[3,5-di-(tert-butyl)-4-methoxy-phenyl]-pyrrolidin-2-yl- methanol was used as catalyst. Aftr performing the reaction and quenching the oxazoborolidine complex the reaction mixture was evaporated onto 1 g of corundum. The thus treated support was placed onto a filler as given in Table 3, and the support/filler assembly was washed five times with a 1 :1 v/v mixture of acetonitrile and water (2 ml each) in order to remove the non-catalyst components of the reaction mixture.

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  • Engineering & Computer Science (AREA)
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Abstract

The invention relates to a method for recovering a catalyst of formula (II), wherein X1 Y, Z and Ph1 are as defined in the description and in the claims, wherein (1) a mixture comprising said catalyst is evaporated onto a support, and the support is washed first with an aqueous polar solvent and then with a nonaqueous solvent, or (2) a mixture comprising said catalyst is treated with a two-phase liquid system consisting of an aqueous polar phase and of a water immiscible phase: The catalysts of formula (II) comprise phase-tag groups, thus they appear preferentially in a nonaqueous phase, which renders them fully recoverable from a homogeneous reaction mixture. Most of the catalysts of formula (II) are new; the invention also relates to these new compounds.

Description

METHOD FOR RECOVERING DIPHENYLPROLJNOL TYPE CATALYSTS WITH PHASE-TAG GROUPS, NEW CATALYSTS RECOVERABLE BY THIS METHOD
AND THEIR USE
The invention relates to a method for recovering diphenylprolinol type catalysts which carry phase-tag groupδ. Most of the catalysts recoverable by the method of the invention are new compounds; the invention also relates to these new compounds. Furthermore the invention relates to the use of catalysts with phase-tag groups in catalytic reactions.
Diphenylprolinol compounds of formula (1)
Figure imgf000002_0001
wherein
X is hydrogen, hydroxy, C1-S alkoxy optionally interrupted in the alkyl chain by a single oxygen atom and/or by one or two sulphur atoms, or a group of formula
-O-Si(R', R", R1"), and in this latter formula R', R" and R"' stand for identical or different Ci-3 alkyl groups or one of them may also represent phenyl group or a C4-5 alkyl group;
Z is hydrogen or a Ci-6 alkyl group; and the wavy line indicates chirality (D or L); and complexes thereof are valuable catalysts for various asymmetric syntheses.
Thus e.g. the oxazaborolidine complex of diphenylprolinol [alternatively termed as bis(phenyl)-(pyrrolidin-2-yl)-methanoI; X = -OH, Z = H] has been widely utilized for enantioselective reduction of ketones [CBS reduction; J. Am. Chem. Soc. 1987,
109:5551 and 7925; Angew. Chem. Int. Ed. 1998, 37:1986-2012]; the methyl ester and trimethyl silyl ester of diphenylprolinol (X = -OME or -OTMS, Z = H) are catalysts of enantioselective Michael additions [Organic Letters 2005, 7(19):4253-
4256 and references cited therein]; whereas N-methyl-diphenyl-prolinol (X = -OH, Z = Me) has been utilized in asymmetric diethylzinc and diphenylzinc addition reactions [Chem. Eur. J. 2005, 11 :945].
These catalysts are expensive, therefore their simple and economic recovery is highly desirable, particularly when industrial scale syntheses are concerned. According to recent methods the catalysts have been recovered by chromatography, or sometimes they have been precipitated as hydrochlorides which have been converted then into the free bases. Both methods are uneconomic on industrial scale. In principle the catalyst could be bound to a solid support which would enable an easy recovery of the catalyst by filtration. However, when a solid supported catalyst is used the homogeneous reaction turns heterogeneous, which changes the dynamics of the reaction (primarily the time requirement is increased), frequently affects the enantioselectivity of the reaction and runs with numerous operational problems.
Of the efforts made so far to avoid the problems caused by heterogeneous reactions the so-called fluorous methodology is the most effective, which has brought a breakthrough by enabling to perform the reaction in homogeneous phase and simultaneously to recover the catalyst with high efficiency. The essence of fluorous methodology is that "superhydrophobic" and at the same time chemically inert perfluoroalkyl groups with medium chain length (usually comprising 4-10 carbon atoms) are attached as phase-tags to the molecule of the catalyst to be recovered. These groups do not affect the activity of the catalyst, simultaneously they enable the recovery of the catalyst during the processing of the homogeneous reaction mixture by a two-phase perfluoro/organic liquid/liquid extraction or by a reverse phase extraction performed with perfluoro silica gel [Tetrahedron Lett. 2006, 47:5131-5134; Organic Letters 2005, 7(15):3243-3246 and references cited therein]. Despite of its numerous advantages fluorous methodology has nowadays got out of the centre of interest. The main reasons for this are as follows: (1) The perfluorinated solvents utilized are not only highly expensive but their biological degradation may last for even 26000 years. These substances are now regarded as environmentally hazardous with a strong initiative for their withdrawal from circulation. (2) Recently increasing attention is paid to the biological accumulation of so-called long chain perfluorinated compounds. Although their exact biological effects have not yet beel elucidated, it is rather distressing that these comounds, like DDT, accumulate in the living organism and are excreted to a very low extent. Upon this observation the Environment Protection Office of the United States has already ordered the manufacturers to reduce the production of compounds comprising perfluoro phase-tags with more than 5 carbon atoms (by 2010 a reduction of 90 % is to be achieved) and to terminate their production by 2015.
The aim of our work has been to provide phase-tag groups which enable efficient and economical recovery of the catalyst and simultaneously eliminate the disadvantages of the fluorous methodology discussed above.
Now it has been found unexpectedly that when replacing both phenyl groups of the diphenylprolinol compounds by groups of formula (a)
Figure imgf000004_0001
wherein
R1, R2 and R3 are independently selected from
(i) trifluoromethyl;
(ii) 1 ,1 ,2,2-tetrafluoroethoxy (-0-CF2CF2H);
(iii) adamantyl or ferrocenyl optionally substituted on the ring by one or more Ci-4 alkyl and/or Ci-4 alkoxy, wherein said adamantyl or ferrocenyl group may be optionally attached to the rest of the molecule through a 1-4 membered chain composed of -O-, -S-, -CH2- and/or -C(CH3)2- members; and (iv) C3-10 alkyl, preferably C3-6 alkyl comprising preferably at least one branching in the alkyl chain, which
(α) is attached to the rest of the molecule through -O- or -S-, or (β) in the absence of such a linking atom is attached to the rest of the molecule with a chain member of the formula -CH2-, -C(CH3V, -C(CH3)(C2H5)- or -C(C2H5)2-, furthermore one or two of R1, R2 and R3 may also stand for hydrogen; and the group of formula (a) may bear optionally one or more further -OR and/or -SR substituents, wherein R is a hydrocarbyl group of up to 10 carbon atoms bearing optionally one or more halo and/or Ci-4 alkoxy substituents, with the proviso that when R represents a straight-chained hydrocarbyl group it may comprise up to 6 carbon atoms; catalysts are obtained which enable one to perform the catalytic reaction in a homogeneous medium without affecting the activity of the parent catalysts of formula (I), and which can be recovered easily upon processing the reaction mixture.
Compounds wherein the hydrogen in position 4 of the pyrrolidine ring has been replaced by various organic substituents are similarly easily recoverable.
Based on the above, the invention relates to a method for recovering a catalyst of formula (II)
Figure imgf000005_0001
wherein
X is hydrogen, hydroxy, C1-6 alkoxy optionally interrupted in the alkyl chain by a single oxygen atom and/or by one or two sulphur atoms, or a group of formula -0-Si(R', R", R"'), and in this latter formula R', R" and R1" stand for identical or different Ci-3 alkyl groups or one of them may also represent phenyl group or a C4-5 alkyl group;
Y is hydrogen, hydroxy, mercapto (-SH), -OR, -SR or -O-CO-R, and in these latter formulae R is a hydrocarbyl group of up to 10 carbon atoms bearing optionally one or more halo and/or Ci-4 alkoxy substituents, with the proviso that when R represents a straight-chained hydrocarbyl group it may comprise up to 6 carbon atoms;
Z is hydrogen or a Ci-6 alkyl group;
Ph1 is a group of formula (a)
Figure imgf000006_0001
wherein
R1, R2 and R3 are independently selected from
(i) trifluoromethyl;
(ii) 1 ,1 ,2,2-tetrafluoroethoxy (-0-CF2CF2H);
(iii) adamantyl or ferrocenyl optionally substituted on the ring by one or more C1-4 alkyl and/or C1-4 alkoxy, wherein said adamantyl or ferrocenyl group may be optionally attached to the rest of the molecule through a 1-4 membered chain composed of -O-, -S-, -CH2- and/or -C(CH3)2- members; and
(iv) C3-io alkyl, preferably C3^ alkyl comprising preferably at least one branching in the alkyl chain, which
(α) is attached to the rest of the molecule through -O- or -S-, or (β) in the absence of such a linking atom is attached to the rest of the molecule with a chain member of the formula -CH2-, -C(CH3)2-, -C(CH3)(C2H5)- or -C(C2H5);?-, furthermore one or two of R1, R2 and R3 may also stand for hydrogen; and the group of formula (a) may bear optionally one or more further -OR and/or -SR substituents, wherein R is a hydrocarbyl group of up to 10 carbon atoms bearing optionally one or more halo and/or Ci-4 alkoxy substituents, with the proviso that when R represents a straight-chained hydrocarbyl group it may comprise up to 6 carbon atoms; and the wavy line indicates chiraiity (D or L), where the relative configuration of the groups attached to the chiral carbon atom is preferably trans; from mixtures comprising said catalyst.
According to the method of the invention
(1) a mixture comprising the catalyst is evaporated onto an aluminium oxide, silicate or aluminosilicate support or onto a reverse phase silica gel support all of nonporous surface, the components which differ from the catalyst are removed from the support by washing it with water or with a polar organic solvent comprising at least 20 % by volume of water, thereafter the catalyst is washed down from the support with a nonaqueous organic solvent, and, if desired, the catalyst is separated from the resulting solution; or
(2) a mixture comprising the catalyst is distributed between a solvent system consisting of a water immiscible phase and of a polar phase comprising at least 20 % by volume of water, the water immiscible phase is separated, and, if desired, the catalyst is separated from the water immiscible phase.
Recovery of the catalyst of formula (II) is performed in one of the processing steps of the final reaction mixture. Sometimes recovery of the catalyst may be the first step of processing; however, other steps (e.g. total or partial removal of solids and/or of certain solvents) may also precede the recovery of the catalyst. When a complex of a compound of formula (II) has been used as catalyst in the reaction (as is the case e.g. in CBS reactions performed with oxazaborolidine complexes), the complex is to be decomposed in a manner known per se prior to recovering the catalyst.
Method (1) of catalyst recovery can be recommended primarily for laboratory scale reactions. Aluminium oxide, silicate or aluminosilicate support with nonporous surface to be used here may be e.g. α-aluminium oxide (corundum), γ-alutninium oxide, glass beads, glass powder or any combination thereof. As reverse phase silica gel support (which has its usual meaning and relates to silica gel the surface of which has been modified with an apolar silylating agent) e.g. FSPE or DSC18 can be used. An obvious requirement in connection with the support is that the mixture to be evaporated thereon should not swell the support. Corundum is a particularly preferred support. Following the evaporation step the support is washed with water or with a polar organic solvent comprising at least 20 % by volume of water to remove the components other than the catalyst. For this purpose in principle any solvent can be used which is able to dissolve at least 30 % by volume of water. Most preferred organic solvents are those which are unlimitedly water miscible, such as methanol, ethanol, dimethyl formamide, dimethyl sulphoxide, acetonitrile. The water/organic solvent mixture comprises preferably about 50 % by volume of water. As the catalyst of formula (II) is used typicaly in reactions wherein polar components are involved (e.g. addition reactions of aldehydes, synthesis of alcohols), the components which 'differ from the catalyst evaporated onto the surface of the support can be safely washed down with these polar liquids. It is, however, very surprising that when utilizing an aqueous wash the catalyst of formula (II) remains on the support, firmly adhering onto its surface. When the components which differ from the catalyst has been washed down, washing is continued with an organic solvent in order to remove the catalyst from the support. For this purpose e.g.. liquid hydrocarbons (such as hexane, cyclohexane), ethers (such as diethyl ether, diisopropyl ether, tetrahydrofuran), chlorinated liquid hydrocarbons (such as dichloromethane, chloroform) can be used; however, organic solvents which are unlimitedly water miscible, such as methanol, ethanol, dimethyl formamide, dimethyl sulphoxide, acetonitrile are also applicable. Depending on the nature of the solvent applied, the resulting solution optionally can be recycled directly into the catalytic reaction. However, if desired, the catalyst can be separated in a manner known per se, e.g. by evaporation.
Method (2) of the catalyst recovery can be recommended mainly for industrial processes. The key element of this method is the provision of the two- phase liquid system, wherein the aqueous phase should contain at least 20 % by volume of water. It has been observed, unexpectedly, that the compounds of formula (II) are much more sensitive to the presence of water with regard to their solubility and distribution coefficient than the starting substances and end products of the catalyzed reaction, which can be attributed to the presence of the phase-tag groups R1, R2 and R3. The presence of the prescribed minimum amount of water
(20 % by volume) is already sufficient to ensure that the compound of formula (II) selectively accumulates in the water immiscible phase, whereas the other components of the mixture to be processed, being substances with some polarity, remain in the aqueous phase.
If the solubilities of the non-catalyst components of the mixture to be processed make it possible, the aqueous phase may be pure water. In most instances, however, the aqueous phase also comprises a water miscible organic solvent in an amount sufficient to dissolve the non-catalyst components. The water miscible solvents should be able to dissolve at least 20 % by volume of water. Particularly preferred representatives of water miscible solvents are polar solvents with unlimited water miscibility, such as methanol, ethanol, dimethyl formamide, dimethyl sulphoxide and acetonitrile. The water content of the water/organic solvent mixture is preferably at least 30 % by volume, particularly preferably about 50 % by volume. Optionally the aqueous phase may be the reaction mixture or the pre-processed reaction mixture itself, the water content of which is adjusted to the prescribed value.
It is obvious to one skilled in the art that only those liquids or liquid mixtures can be used as water immiscible phase which sharply separate from the aqueous phase, i.e. which do not form either real or colloidal solutions with the aqueous phase. The term "water immiscible" means that not more than 1 % by volume of water can be dissolved by the solvent concerned. It is preferred if the water immiscible solvent is also immiscible with the organic solvent present in the aqueous phase. Liquid hydrocarbons (e.g. hexane, cyclohexane, methyl- cyclohexane), certain ethers (e.g. diisopropyl ether) hybridic fluorinated solvents comprising not more than 4 perfluorinated units (e.g. perfluorobutyl-ethyl-ether) and 3,5-bis(trifluoromethyl)-benzene are suitable examples of water immiscible solvents.
The selection of the individual water miscible/water immiscible solvent pairs for a given water content is within the routine knowledges of one skilled in the art. Having appropriately selected the two-phase liquid mixture, a simple liquid- -liquid extraction is performed, thereafter the water immiscible phase is separated. Depending on the nature of the solven(ts) used in the water immiscible phase, sometimes the resulting solution can be introduced directly into the catalytic reaction; if necessary, however, the catalyst of formula (II) can be separated from it by known methods (e.g. by evaporation).
We have observed that the catalyst of formula (II) can be recovered almost quantitatively with the method of the invention. The catalytic activity of the thus recovered catalyst (.e. the rate and enantioselectivity of the catalyzed reaction) remains unchanged even after repeated cycles of recovery, -
Of the catalysts of formula (II) compounds wherein Ph1 is 3,5-bis(trifluoro- methyl)-phenyl and at the same time Y and Z stand for hydrogen and X stands for hydroxy, methoxy or trimethylsilyloxy, have been disclosed in the literature [Angew. Chem. Int. Ed. 2006, 45(47):7876-7880]. Complexes of these compounds, particularly the oxazaborolidine complexes usable for CBS reactions, have, however, not been disclosed. These known compounds, like those of formula (I), have been utilized as catalysts in asymmetric syntheses. However, none of the references which deal with the utilization of these compounds refer to that the known compounds could be recovered from their mixtures by the method of the invention. The respective references either do not deal with the recovery of the catalyst, or they suggest a chromatographic processing.
The further catalysts of formula (II) and their complexes, furthermore complexes of compounds of formula (II) wherein Ph1 is 3,5-bis(trifluoro-methyl)- phenyl and at the same time Y and Z stand for hydrogen and X stands for hydroxy, methoxy or tetramethylsiliyloxy, are new compounds. The invention also relates to these new compounds.
The term "hydrocarbyl group" used in connection with R in the definition of the compounds of formula (II) refers to saturated, unsaturated, aromatic, open- chain and cyclic hydrocarbyl groups and all possible combinations thereof, of which the followings are mentioned as examples: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, alkylphenyl, phenylalkyl, alkylcycloalkyl, cycloalkylalky, cycloalkylphenyl and the like.
In the compounds of formula (II) Ph1 may represent preferably a group of formula
Figure imgf000011_0001
wherein R1 and R2 are as defined above. As it has been stated before, one of R1 and R2 may also represent hydrogen, however, it is more preferred when both R1 and R2 are other than hydrogen. Compounds of formula (II) wherein R1 and R2 are the same are particularly preferred.
When any of R1, R2 and R3 stands for a C3-10 alkyl group, this alkyl grop may comprise preferably 3-6 carbon atoms and comprises preferably at least one branching in the alkyl chain. A particularly preferred representative of the alkyl groups is tertiary butyl. The number of carbon atoms contained in the straight- chained alkyl groups is preferably 3.
The new catalysts of formula (II) can be prepared by any method used for the preparation of structurally related substances, e.g. by those disclosed in the cited references dealing with compounds of formula (I) and with the known members of compounds of formula (II). According to a suitable method a compound of formula (III)
Figure imgf000011_0002
wherein Est is an esterifying group and Y is as defined above, is reacted with a compound of formula (IV)
PIr-Mg-Ha! (IV),
wherein Ph1 is as defined above and Hal stands for halogen, under Grignard conditions, and the -COOEst group of the resulting compound of formula (V)
Figure imgf000012_0001
is split off. According to an other possibility a phosgene compound of formula (Vl)
Figure imgf000012_0002
wherein Y is as defined above, is used as starting substance, and this is reacted with a compound of formula (IV). In both instances compounds of formula (II) are obtained wherein Z is hydrogen and X is hydroxy. If desired, these compounds can be converted into other compounds of formula (II) wherein Z and X represent other groups, by utilizing conventional alkylation and reduction methods. If desired, group Y of a resulting compound can be converted into an other Y group by known reactions (e.g. introduction of hydroxy group, ether formation, splitting of an ether group, etc.).
The invention also relates to the use of a compound of formula (II), wherein X, Y, Z, Ph1 and the wavy line are as defined above with the proviso that when Y and Z are hydrogen and at the same time X is hydroxy, methoxy or thetramethylsilyloxy, Ph1 may only be other than 3,5-bis(trifluoromethyl)-phenyl, as a catalyst in a catalytic reaction requiring the use of a compound of formula (I) or of a complex thereof. These catalytic reactions are performed by methods well known in the art, e.g. by those disclosed in the cited references, with the difference that a compound of formula (II) as defined here or a complex thereof is used as catalyst instead of the catalyst of formula (I) or a complex thereof recommended in the literature. As a further obvious amendment, water is excluded from the reaction mixture prior to the processing steps.
Finally, the invention relates to the use of the oxazaborolidine complex of a compound of formula (II), wherein Y and Z are hydrogen, X is hydroxy or trimethylsilyloxy and Ph1 is 3,5-bis(trifluoromethyl)-phenyl, in a catalytic asymmetric CBS reduction. Again, the asymmetric CBS reduction is performed as disclosed in the literature with the difference that the oxaborolidine complex of a compound of formula (II) as defined n this paragraph is used as catalyst instead of the oxaborolidine complex of a compound of formula (I) recommended in the literature. As a further obvious amendment, water is excluded from the reaction mixture prior to the processing steps.
Further details of the invention are illustrated by the following Examples.
Example 1
Preparation of bisr3,5-bis(trifluoromethyl)-phenyll-pyrrolidin-2-yl-methanol (L isomer, known compound)
2.08 g (85.56 mmoles) of magnesium powder were weighed into a two- necked flask wich was previously dried with heating and flushed with argon, and a condenser was fitted to the flask. The magnesium powder was activated with iodine, thereafter 80 ml of dry diethyl ether were added. 21.54 g (73.52 mmoles) of 1-bromo-3,5-bis(trifluoromethyl)-benzene were dissolved in 20 ml of dry diethyl ether, and the solution was introduced into the flask within 30 minutes, under keeping the mixture in boiling. The mixture was refluxed then for 2 additional hours, then cooled to O0C, and a solution of 5.69 g (28.28 mmoles) of N-(ethoxycarbonyl)- 2-(methoxycarbonyl)-pyrrolidine (L isomer) in 20 ml of dry diethyl ether was added. The reaction mixture was stirred at O0C overnight, then quenched with 100 ml of saturated aqueous ammonium chloride when cold. The organic phase was separated, and the aqueous phase was extracted three times with chloroform (100 ml each). The organic phases were combined, dried over sodium sulphate, and evaporated then under reduced pressure. The crude product was recrystallized from methyl-cyclohexane to otbain 15.88 g (94.0 %) of 2-[bis-(3,5-bis(trifluoro- methyl)-phenyl)-hydroxymethyl]-pyrrolidine-1-carboxylic acid ethyl ester as an off white crystalline solid. [α]D 27 = -45° (c = 1 ,0, chloroform).
IR (KBr): 3365, 2991, 2361 , 1666, 1278, 1170, 1125, 895, 844, 704, 628 cm"1
400 ml of 2.0 M methanolic potassium hydroxide solution were added to 14.44 g (24.18 mmoles) of the intermediate obtained as described above. After 5 hours of refluxing the reaction mixture was evaporated under reduced pressure, 200 ml of distilled water were added to the residue, and the mixture was extracted four times with dichloromethane (100 ml each). The organic phases were combined, dried over sodium sulphate, and evaporated then under reduced pressure. 12.16 g (95.8 %) of the title compound were obtained as an off white crystalline solid. [α]D 27 = -55° (c = 1 ,0, chloroform).
IR (KBr): 3419, 2988, 2924, 2880, 1628, 1468, 1377, 1281 , 1167, 1133, 901 , 892, 844, 713, 704, 683 cm"1.
Example 2
Use of the oxazaborolidine complex of bisrS^-bisftrifluoromethvD-phenvH- pyrrolidin-2-yl-methanol (L isomer) in asymmetric CBS reductions under recovering the bisr3,5-bis(trifluoromethylVphenyl1-pyrrolidin-2-yl-methanol
The catalytic activity of the oxazaborolidine complex of bis[3,5-bis(trifluoro- methyl)-phenyl]-pyrrolidin-2-yl-methanol and the recoverability of bis[3,5-bis(tri- fluoromethyl)-phenyl]-pyrrolidin-2-yl-methanol was tested in the preparation of four asymmetric alcohols [1-phenyI-ethano.l, 1-(naphthalene-2-yl)-ethanol, 1-(pyridin-3- yl)-ethanol and 1-(4-chloro-phenyl)-ethanol] by CBS reduction. First the oxazaborolidine complex was prepared by dissolving 105.0 mg (0.2 mmoles) of bis[3,5-bis(trifluoro-methyl)-phenyl]-pyrrolidin-2-yl-methanol in 2 ml of dry tetrahydrofuran, adding 24.9 mg (28 μl, 0.24 mmoles) of trimethyl borate, and stirring the reaction mixture at room temperature for 1 hour. Thereafter 0.21 ml of a 10 molar solution of DMS-BH3 (2 mmoles) were added to the mixture comprising the oxaborolidine complex at room temperature under argon, and then a solution of 2.0 mmoles of the ketone to be reduced in 2 ml of dry tetrahydrofuran were added dropwise within 1 hour using a feeding pump. The reaction mixture was stirred then for 1 additional hour.
Thereafter the oxazaborolidine complex was quenched by cooling the mixture to O0C and introducing slowly 2 ml of methanol. ' After 40 minutes the reaction mixture was evaporated onto 1 g of support (corundum or γ-aluminium oxide). The resulting treated support was placed onto 1 g of a filling agent as listed in Table 1, and the support/filling agent assembly was washed five times with 2 ml each of a 1 :1 mixture of methanol and water [when 1-(naphthalene-2-yl)-ethanol was prepared, the washing agent was a 1 :1 mixture of dimethyl formamide and water]. With this operation the non-catalyst components of the reaction mixture were removed. The washes were combined and the bis[3,5-bis(trifluoro-methyl)- phenyl]-pyrrolidin-2-yl-methanol content of the aqueous wash was determined by gas chromatography. The results are listed in Table 1.
Thereafter washing of the support/filling agent assembly was continued with 5 portions of diethyl ether (2 ml each). These washes were also combined, and the bis[3,5-bis(trifluoro-methyl)-phenyl]-pyrrolidin-2-yl-methanol content of the organic wash was determined by gas chromatography. The results are listed in Table 2.
As it appears from the data of the Tables, 84-97 % of the introduced bis[3,5- bis(trifluoro-methyl)-phenyl]-pyrrolidin-2-yl-methanol could be recovered by the method of the invention. The most favourable results were obtained with corundum. Table 1
Amount of bisr3,5-bis(trifluoro-methyl)-phenyll-pyrrolidin-2-yl-methanol in the aqueous wash
When preparing
Support/filler 1-Phenyl- 1-(Naphthalene- 1-(Pyridin- 1-(4-Chloro- -ethanol -2-vD-ethanol -3-vO-ethanol phenvD-ethanol
Corundum/DSC18 3.3 mg nd nd 1.6 mg
Corundum/ 5.7 mg 0.15 mg 2.8 mg 2.7 mg Corundum
Y-AI2(VFSPE 14.9 mg α-AfeOa/DSCIδ 4.0 mg
Table 2
Bis[3,5-bis(trifluoro-methvO-phenyl]-pyrrolidin-2-yl-methanol recovered in the organic wash
When preparing
Support/filler 1 -Phenyl- 1 -(Naphthalene- 1-(Pyridin- 1-(4-Chloro- -ethanol -2-yl)-ethanol -3-yl)-ethanol phenyQ-ethanol
Corundum/DSC18 96.9 mg 100.0 mg 100.0 mg 98.5 mg
Corundum/ 94.6 mg 99.9 mg 97.3 mg 97.4 mg Corundum
Y-AI2(VFSPE 85.8 mg α-AI2θ3/DSC18 96.2 mg
The above test series have been repeated with the difference that instead of diethyl ether the same amount of tetrahydrofuran was used to wash down bis[3,5- bis(trifluoro-methyl)-phenyl]-pyrrolidin-2-yl-methanol. The results were similar to those listed in Tables 1 and 2.
The above reaction for the preparation of 1-(pyridin-3-yl)-ethanol was repeated under scaling up by 12.5, i.e.1315 mg of bis[3,5-bis(trifluoro-methyl)- phenyl]-pyrrolidin-2-yl-methanol were used in the reaction. The mixture obtained upon quenching the oxazoioborolidine complex was evaporated, and an 1:1 mixture of acetonitrile and water and hexane were added to the mixture. After the liquid/liquid extraction the hexane phase was separated and evaporated. 1304 mg (99.46 %) of bis[3,5-bis(trifluoro-methyl)-phenyl]-pyrrolidin-2-yl-methanol were recovered.
The enantioselectivities of the products obtained in the catalytic reactions were determined by HPLC on Chiracel OJ or Chiracel OD column, utilizing a 95:5 or 90:10 mixture of hexane and isopropanol as eluting agent. The following results were obtained: 1 -phenyl-ethanol: ee = 94 %; 1-(4-chloro-phenyl)-etanol: ee = 95 %; 1-(naphthalene-2-yl)-etanol: ee = 94 %;
1-(pyridin-3-yl)-ethanol: ee = 98 % (small scale reaction); 97 % (large scale reaction).
Example 3
Preparation of bisr3,5-dKtert-butyl)-4-methoχy-phenyl1-pyrrolidin-2-yl- methanol (L isomer: new compound)
801 mg (33 mmoles) of magnesium powder were weighed into a two-necked flask which was previously dried with heating and flushed with argon, and a condenser was fitted to the flask. The magnesium powder was activated with iodine, thereafter 35 ml of dry tetrahydrofuran were added. 8.97 g (30 mmoles) of 5-bromo-1 , 1 -di-(tert-butyl)-2-methoxy-benzene were dissolved in 5 ml of dry tetrahydrofuran, and the solution was introduced into the flask within 30 minutes, under keeping the mixture in boiling. The mixture was ref luxed then for 2 additional hours, then cooled to O0C, and a solution of 2.41 g (12 mmoles) of N-(ethoxycarbonyl)-2- (methoxycarbonyl)-pyrrolidine (L isomer) in 5 ml of dry tetrahydrofuran was added. The reaction mixture was allowed to warm slowly to room temperature, and stirred overnight. The mixture was quenched with 50 ml of saturated aqueous ammonium chloride solution. The organic phase was separated, and the aqueous phase was extracted three times with chloroform (30 ml each). The organic phases were combined, dried over sodium sulfate, and evaporated under reduced pressure. 6.21 g (85.0 %) of 2-[bis-(3,5-di-(tert-butyl)-4-methoxy-phenyl)-hydroxymethyl]-pyrroldin- 1-carboxylic acid ethyl ester were obtained as a white substance which was difficult to crystallize. This substance was used in the next step without additional purification. TLC (Merck silica gel 60 F254, hexane/ethyl acetate 9:1) Rf = 0.64.
1H NMR (300 MHz, CDCI3): δ = 7.26 (s, 2H), 7.17 (s, 2H), 4.92 (m, 1 H), 4.18 (m, 2H), 3.68 (s, 3H), 3.64 (s, 3H), 3.35 (m, 1H), 2.78 (m, 1 H), 2.09 (m, 1H)1 1.84 (m, 1 H), 1.42 (m, 1 H), 1.39 (s, 18H), 136 (s, 18H), 1.25 (t, J=7.0 Hz, 3H), 0.73 (m, 1 H) ppm.
160 ml of 2.0 M methanolic potassium hydroxide solution were added to 6.0 g (9.84 mmoles) of the intermediate obtained as described above. After 5 hours of refluxing the reaction mixture was evaporated under reduced pressure, 80 ml of distilled water were added to the residue, and the mixture was extracted four times with dichloromethane (40 ml each). The organic phases were combined, dried over sodium sulphate, and evaporated then under reduced pressure. 4.97 g (94 %) of the title compound were obtained as a white crystalline substance. TLC (Merck silica gel 60 F254, hexane:ethyl acetate 9:1) Rf = 0.47.
1H NMR (300 MHz, CDCI3): δ = 7.30 (s, 2H), 7.20 (s, 2H), 4.43 (dd, J=5.4 and 10.2 Hz), 3.72 (m, 1H), 3.66 (s, 6H), 3.26 (m, 1H), 1.85 (m, 3H)1 1.39 (s, 18H), 1.37 (S, 18H), 1.16 (m, 1 H) ppm.
Example 4
Use of the oxazaborolidine complex of bisr3,5-di-(tert-butyl)-4-methoxy- phenyn-pιrrolidin-2-yl-methanol (L isomer) in asymmetric CBS reductions under recovering the bisr3,5-di-(tert-butylV4-methoxy-phenyl1-pyrrolidin-2-yl-methanol
The method described in Example 2 was followed with the difference that oxazaborolidine complex of bis[3,5-di-(tert-butyl)-4-methoxy-phenyl]-pyrrolidin-2-yl- methanol was used as catalyst. Aftr performing the reaction and quenching the oxazoborolidine complex the reaction mixture was evaporated onto 1 g of corundum. The thus treated support was placed onto a filler as given in Table 3, and the support/filler assembly was washed five times with a 1 :1 v/v mixture of acetonitrile and water (2 ml each) in order to remove the non-catalyst components of the reaction mixture. Thereafter washing of the support/filler assembly was continued with five portions of tetrahydrofuran (2 ml each). These latter washes were combined, and the amount of bis[3,5-di-(tert-butyl)-4-methoxy-phenyl]- pyrrolidin-2-yl-methanol present was determined by gas chromatography. The percentage recovery is given in Table 3.
Table 3
Bisf3,5-di-rtert-butvl)-4-methoxv-Phenvll-pvrrolidin-2-vl-methanol recovered in the organic wash
When preparing
Support/filler 1-Phenyl- 1-(Naphthalene- 1-(Pyridin- 1-(4-Chloro- -ethanol -2-vlVethanol -3-vlVethanol phenvO-ethanol
Corundum/DSC 18 94.6 % 97.3 % 95.2 % 93.8 %
Corundum/ 92.8 % 95.2 % 93.3 % 92.7 % Corundum

Claims

What we claim is:
1. A method for recovering a catalyst of formula (II)
Figure imgf000020_0001
wherein
X is hydrogen, hydroxy, C-i-β alkoxy optionally interrupted in the alkyl chain by a single oxygen atom and/or by one or two sulphur atoms, or a, group of formula
-O-Si(R\R",R"'), and in this latter formula R', R" and R"' stand for identical or different Ci-3 alkyl groups or one of them may also represent phenyl group or a C4-s alkyl group;
Y is hydrogen, hydroxy, mercapto (-SH), -OR, -SR or -O-CO-R, and in these latter formulae R is a hydrocarbyl group of up to 10 carbon atoms bearing optionally one or more halo and/or CM alkoxy substituents, with the proviso that when R represents a straight-chained hydrocarbyl group it may comprise up to 6 carbon atoms;
Z is hydrogen or a C1-6 alkyl group;
Ph1 is a group of formula (a)
Figure imgf000020_0002
wherein
R1, R2 and R3 are independently selected from
(i) trifluoromethyl;
(ii) 1 ,1,2,2-tetrafluoroethoxy (-0-CF2CF2H);
(iii) adamanty! or ferrocenyl optionally substituted on the ring by one or more Ci-4 alkyl and/or Ci-4 alkoxy, wherein said adamantyl or ferrocenyl group may be optionally attached to the rest of the molecule through a 1-4 membered chain composed of -O-, -S-, -CH2- and/or -C(CH3)2- members; and
(iv) C3-10 alkyl, preferably C3-6 alkyl comprising preferably at least one branching in the alkyl chain, which
(α) is attached to the rest of the molecule through -O- or -S-, or (β) in the absence of such a linking atom is attached to the rest of the molecule with a chain member of the formula -CH2-, -C(CH3)2-, -C(CH3)(C2H5)- or -C(C2H5)2-, furthermore one or two of R1, R2 and R3 may also stand for hydrogen; and the group of formula (a) may bear optionally one or more further -OR and/or -SR substituents, wherein R is a hydrocarbyl group of up to 10 carbon atoms bearing optionally one or more halo and/or Ci-4 alkoxy substituents, with the proviso that when R represents a straight-chained hydrocarbyl group it may comprise up to 6 carbon atoms; and the wavy line indicates chirality (D or L), where the relative configuration of the groups attached to the chiral carbon atom is preferably trans; from mixtures comprising said catalyst; characterized in that
(1) a mixture comprising the catalyst is evaporated onto an aluminium oxide, silicate or aluminosilicate support or onto a reverse phase silica gel support all of nonporous surface, the components which differ from the catalyst are removed from the support by washing it with water or with a polar organic solvent comprising at least 20 % by volume of water, thereafter the catalyst is washed down from the support with a nonaqueous organic solvent, and, if desired, the catalyst is separated from the resulting solution; or
(2) a mixture comprising the catalyst is distributed between a solvent system consisting of a water immiscible phase and of a polar phase comprising at least 20 % by volume of water, the water immiscible phase is separated, and, if desired, the catalyst is separated from the water immiscible phase.
2. A method as claimed in claim 1, characterized in that in variant (1) corundum is used as support.
3. A method as claimed in claim 1 or 2, characterized in that in variant (1) a polar organic solvent comprising at least 30 % by volume of water is used to remove the non-catalyst components.
4. A method as claimed in any of claims 1 to 3, characterized in that in variant (1) an about 1 :1 v/v mixture of water and a polar organic solvent is used to remove the non-catalyst components.
5. A method as claimed in any of claims 1 to 4, characterized in that in variant (1) methanol, ethanol, dimethyl formamide, dimethyl sulphoxide or acetonitrile is used as polar organic solvent to remove the non-catalyst components.
6. A method as claimed in any of claims 1 to 5, characterized in that in variant (1) a hydrocarbon, an ether, a chlorinated hydrocarbon or an organic solvent with unlimited water miscibility is used as nonaqueous solvent to wash down the catalyst.
7. A method as claimed in claim 1 , characterized in that in variant (2) a polar phase comprising at least 30 % by volume of water is used.
8. A method as claimed in claim 1 or 7, characterized in that in variant (2) an about 1 :1 v/v mixture of water and an organic solvent of unlimited water miscibility is used as aqueous polar phase.
9. A method as claimed in any of claims 1 , 7 and 8, characterized in that in variant (2) an about 1/1 mixture of water and methanol, ethanol, dimethyl formamide, dimethyl sulphoxide or acetonitrile is used as aqueous polar phase.
10. A method as claimed in any of claims 1 and 7 to 9, characterized in that in variant (2) a hydrocarbon, an ether, a hybridic fluorinated solvent comprising not more than 4 perfluorinated units or 3,5-bis(trifluoromethyl)-benzene is used as water imiscible phase.
11. A catalyst of formula (II)
Figure imgf000023_0001
wherein
X is hydrogen, hydroxy, C1^ alkoxy optionally interrupted in the alkyl chain by a single oxygen atom and/or by one or two sulphur atoms, or a group of formula
-0-Si(R1, R", R"'), and in this latter formula RJ, R" and R'" stand for identical or different Ci-3 alkyl groups or one of them may also represent phenyl group or a C4-S alkyl group;
Y is hydrogen, hydroxy, mercapto (-SH), -OR, -SR or -O-CO-R, and in these latter formulae R is a hydrocarbyl group of up to 10 carbon atoms bearing optionally one or more halo and/or Ci-4 alkoxy substituents, with the proviso that when R represents a straight-chained hydrocarbyl group it may comprise up to 6 carbon atoms;
Z is hydrogen or a Ci-6 alkyl group;
Ph1 is a group of formula (a)
Figure imgf000023_0002
wherein
R1, R2 and R3 are independently selected from
(i) trifluoromethyl;
(ii) 1 ,1,2,2-tetrafluoroethoxy (-0-CF2CF2H);
(iii) adamantyl or ferrocenyl optionally substituted on the ring by one or more Ci-4 alkyl and/or Ci-4 alkoxy, wherein said adamantyl or ferrocenyl group may be optionally attached to the rest of the molecule through a 1-4 membered chain composed of -O-, -S-, -CH2- and/or -C(CH3^- members; and (iv) C3-10 alkyl, preferably C3-6 alkyl comprising preferably at least one branching in the alkyl chain, which
(α) is attached to the rest of the molecule through -O- or -S-, or (β) in the absence of such a linking atom is attached to the rest of the molecule with a chain member of the formula -CH2-, -C(CH3)2-, -C(CH3)(C2H5)- or -C(C2H5V, furthermore one or two of R1, R2 and R3 may also stand for hydrogen; and the group of formula (a) may bear optionally one or more further -OR and/or -SR substituents, wherein R is a hydrocarbyl group of up to 10 carbon atoms bearing optionally one or more halo and/or C1-4 alkoxy substituents, with the proviso that when R represents a straight-chained hydrocarbyl group it may comprise up to 6 carbon atoms; and the wavy line indicates chirality (D or L), where the relative configuration of the groups attached to the chiral carbon atom is preferably trans; with the proviso that when Y and Z represent hydrogen and at the same time X is hydroxy, methoxy or trimetlylsililoxy, Ph1 may only represent a group other than 3,5-bis(trifluoromethyl)-phenyl, complexes of the catalysts defined above, furthermore complexes of catalysts of formula (II) wherein Y and Z represent hydrogen, X is hydroxy, methoxy or trimethylsililoxy and Ph1 is 3,5-bis(trifluoromethyl)-phenyl.
12. Compounds as claimed in claim 11 wherein Ph1 is a group of formula (ai)
Figure imgf000024_0001
13. Compounds as claimed in claim 12, wherein R1 nd R2 in formula (ai) are the same.
14. Compounds as claimed in claim 13, wherein R1 and R2 in formula (a-i) are the same and represent trif luoromethyl, tert-butyl, adamantyl or phenanthrenyl.
15. Use of a compound as claimed in claim 11 as catalyst in a catalytic reaction requiring the use of a compound of formula (I) or a complex thereof
Figure imgf000025_0001
wherein X, Z and the wavy line are as defined in claim 11.
16. Use of the oxazaborolidine complexes of a catalyst of formula (II), wherein X is hydroxy or trimethylsililoxy and Ph1 is 3,5-bis(trifluoromethyl)-phenyl, in a catalytic asymmetric CBS reduction.
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