Patent Application
20090030235
The present invention relates to a method for fractionating compounds which have at least one alcohol and/or amino group.
Chiral alcohols and amines are starting materials which are in demand for example in fine chemistry and pharmaceutical chemistry. They are employed inter alia in tailored materials with nonlinear optical properties, as odorants and flavorings or as precursors for medicaments. There is a great interest in the most cost-effective provision of chiral alcohols that is possible. Chiral alcohols can be prepared and isolated in various ways. They can firstly be obtained directly or after appropriate chemical transformation from compounds which are naturally available, called the chiral pool. A further possibility for preparing chiral alcohols is by asymmetric synthesis, i.e. a reaction in which the resulting stereoisomeric products (enantiomers or diastereomers) result in unequal amounts. A further possibility is to obtain chiral alcohols starting from racemic alcohols by chiral discrimination in the sense of racemate resolution. Such a chiral discrimination is particularly advantageous when the corresponding racemic alcohol is readily available. Various methods for chiral discrimination of stereoisomeric alcohols are known. Thus, they can be subjected by means of enzymes, metal complexes or small organic molecules as catalysts to a kinetic racemate resolution in the sense of an enantiodifferentiation. However, the catalysts used are suitable only for a very limited number of alcohols and/or the high costs for producing the catalysts lead to the method being economically disadvantaged. It is moreover known to fractionate stereoisomeric alcohols by absorptive separation methods on optically active immobilized phases. In this connection, SMB chromatography (simulated moving bed chromatography) which enables stereoisomeric substance mixtures to be fractionated continuously into two different fractions is becoming increasingly important. One disadvantage of this technology derives from the relatively high costs of the chiral stationary phases to be used, and the need to use solvents from which the stereoisomers must be removed in a separate step. It is further known to fractionate racemic compounds with the aid of chiral discriminators (selectors) by distillation, specifically extractive rectification.
FR-A-2,176,621 describes a method for fractionating optical isomers by extractive distillation. This includes very generally the use of discriminators which are able to form complexes of differing stability with the optical antipodes in order to achieve a difference in relation to a physical property, specifically the boiling point.
EP-A-0970936 describes a method for fractionating optical isomers in which they are brought into contact in a countercurrent method with a discriminating liquid which comprises a discriminating agent, and with a diluent, and subjected to a fractionation of the optical isomers by absorptive separation, distillative separation or membrane separation. The chiral discriminators employed are saccharides and saccharide derivatives, especially cyclodextrins and cyclodextrin derivatives. A disadvantage of these discriminators is that they must be constructed in elaborate synthesis, leading to this method being economically disadvantaged.
The present invention is based on the object of providing a method which enables stereoisomeric compounds which have at least one alcohol, and/or amino group to be fractionated as economically as possible.
We have found that this object is achieved by a method for fractionating stereoisomeric compounds, specifically alcohols, by distillative separation in the presence of a chiral discriminator which is a metal complex which is derived from a compound of the general formula I
in which
“Chiral compounds” are in the context of the present invention compounds having at least one chirality center (e.g. having at least one asymmetric atom, in particular at least one asymmetric C atom or P atom), having a chirality axis, chirality plane or screw thread. The term “chiral discriminator” comprises discriminators which have at least one chiral ligand.
“Achiral compounds” are compounds which are not chiral.
A “racemic mixture” is also called “racemate” and refers to an equimolar mixture of two chemical compounds which are related to one another as image and mirror image.
The term “racemate resolution” refers to a separation of a racemic mixture into fractions which comprise the individual compounds which are related to one another as image and mirror image in pure or at least enriched form. There is thus a racemate resolution in the sense of the invention even if non-equimolar mixtures of the components are obtained.
“Stereoisomers” are compounds of identical constitution but different atomic arrangement in three-dimensional space.
“Enantiomers” are stereoisomers which are related to one another as image to mirror image. The enantiomeric excess (ee) obtained in an asymmetric synthesis results from the following formula: ee[%]=(R−S)/(R+S)×100. R and S are the descriptors of the CIP systems for the two enantiomers and represent the absolute configuration at the asymmetric atom. The enantiopure compound (ee=100%) is also referred to as “homochiral compound”.
The method of the invention leads to products which are enriched in a particular stereoisomer. The “enantiomeric excess” (ee) achieved is usually at least 1%.
“Diastereomers” are stereoisomers which are not enantiomers of one another.
The term “alkyl” hereinafter comprises straight-chain and branched alkyl groups. Preference is given in this connection to straight-chain or branched C1-C20-alkyl, more preferably C1-C12-alkyl, particularly preferably C1-C8-alkyl and very particularly preferably C1-C6-alkyl groups. Examples of alkyl groups are in particular methyl, ethyl, propyl, isopropyl, n-butyl, 2-butyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 2-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethylbutyl, 2-ethylbutyl, 1-ethyl-2-methylpropyl, n-heptyl, 2-heptyl, 3-heptyl, 2-ethylpentyl, 1-propylbutyl, n-octyl, 2-ethylhexyl, 2-propylheptyl, nonyl, decyl.
The term “alkyl” also comprises substituted alkyl groups which may generally have 1, 2, 3, 4 or 5, preferably 1, 2 or 3 and particularly preferably 1 substituent selected from the groups cycloalkyl, aryl, hetaryl, halogen, NE1E2, NE1E2E3+, COOH, carboxylate, —SO3H and sulfonate.
The term “alkylene” in the sense of the present invention stands for straight-chain or branched alkanediyl groups having preferably 1 to 6, in particular 1 to 4 carbon atoms. Included therein are methylene (—CH2—), ethylene (—CH2—CH2—), n-propylene (—CH2—CH2—CH2—), isopropylene (—CH2—CH(CH3)—) etc.
The term “cycloalkyl” comprises in the sense of the present invention unsubstituted and substituted cycloalkyl groups, preferably C3-C8-cycloalkyl groups such as cyclopentyl, cyclohexyl or cycloheptyl, which may in the case of substitution generally have 1, 2, 3, 4 or 5, preferably 1, 2 or 3 and particularly preferably 1 substituent preferably selected from the substituents mentioned for alkyl.
The term “heterocycloalkyl” in the sense of the present invention comprises saturated, cycloaliphatic groups having in general 4 to 7, preferably 5 or 6 ring atoms, in which 1 or 2 of the ring carbon atoms are replaced by heteroatoms, preferably selected from the elements oxygen, nitrogen and sulfur, and which may optionally be substituted, where in the case of substitution these heterocycloaliphatic groups may have 1, 2 or 3, preferably 1 or 2, particularly preferably 1 substituent selected from alkyl, aryl, COORf, COO−M+ and NE1E2, preferably alkyl. Examples which may be mentioned of such heterocycloaliphatic groups are pyrrolidinyl, piperidinyl, 2,2,6,6-tetramethylpiperidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, morpholidinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, piperazinyl-, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl.
The term “aryl” comprises in the sense of the present invention unsubstituted and substituted aryl groups, and preferably stands for phenyl, tolyl, xylyl, mesityl, naphthyl, fluorenyl, anthracenyl, phenanthrenyl or naphthacenyl, 4′-biphenylyl, 3′-biphenylyl, 2′-biphenyl particularly preferably phenyl, 4′-biphenyl or naphthyl, where these aryl groups in the case of substitution may generally have 1, 2, 3, 4 or 5, preferably 1, 2 or 3 and particularly preferably 1 substituent selected from the groups alkyl, alkoxy, carboxyl, carboxylate, —SO3H, sulfonate, NE1E2, alkylene-NE1E2, nitro, cyano or halogen.
The term “hetaryl” comprises in the sense of the present invention unsubstituted or substituted heterocycloaromatic groups, preferably the groups pyridyl, quinolinyl, acridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, indolyl, purinyl, indazolyl, benzotriazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl and carbazolyl, where these heterocycloaromatic groups may in the case of substitution generally have 1, 2 or 3 substituents selected from the groups alkyl, alkoxy, acyl, carboxyl, carboxylate, —SO3H, sulfonate, NE1E2, alkylene-NE1E2 or halogen. The above explanations of the terms “alkyl”, “cycloalkyl”, “aryl”, “heterocycloalkyl” and “hetaryl” apply correspondingly to the terms “alkoxy”, “cycloalkoxy”, “aryloxy”, “heterocycloalkoxy” and “hetaryloxy”.
The term “acyl” stands in the sense of the present invention for alkanoyl or aroyl groups having in general 2 to 11, preferably 2 to 8 carbon atoms, for example for the acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl, heptanoyl, 2-ethylhexanoyl, 2-propylheptanoyl, benzoyl or naphthoyl group.
The radicals E1 to E12 are selected independently of one another from hydrogen, alkyl, cycloalkyl and aryl. The groups NE1E2, NE4E5, NE7E8 and NE10E11 preferably stand for N,N-dimethylamino, N-ethyl-N-methylamino, N,N-diethylamino, N,N-dipropylamino, N,N-diisopropylamino, N,N-di-n-butylamino, N,N-di-t-butylamino, N,N-dicyclohexylamino or N,N-diphenylamino.
Halogen stands for fluorine, chlorine, bromine and iodine, preferably for fluorine, chlorine and bromine.
A cation equivalent means a singly charged cation or the fraction of a multiply charged cation which corresponds to a single positive charge. Preference is given to the use of alkali metal, especially Na+, K+, Li+ ions or onium ions such as ammonium, mono-, di-, tri-, tetraalkylammonium, phosphonium, tetraalkylphosphonium or tetraaryl-phosphonium ions.
In a preferred embodiment, the substituents R1 and R2 and/or R3 and R4 in compounds of the general formula I are groups which are not connected together. R1, R2, R3 and R4 are preferably selected independently of one another from groups of the formulae II.a to II.c
In a preferred embodiment, the radicals R1, R2, R3 and R4 are selected from radicals of the formula II.a in which Ra, Rb and Rc are independently of one another hydrogen, C1-C4-alkyl, particularly preferably methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl, C1-C4-alkoxy, preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, aryl, preferably phenyl, halogen, preferably fluorine or chlorine, trifluoromethyl, methoxycarbonyl or ethoxycarbonyl. In a preferred embodiment, Ra, Rb and Rc are hydrogen.
In a further preferred embodiment, the radicals R1, R2, R3 and R4 are selected from radicals of the formula II.b in which Ra, Rb, Rc, Rd, Re and Rf are independently of one another hydrogen, C1-C4-alkyl, particularly preferably methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl, C1-C4-alkoxy, preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, halogen, preferably fluorine or chlorine, trifluoromethyl, methoxycarbonyl or ethoxycarbonyl. Preferably one, two or three of the radicals Ra to Rf are selected independently of one another from C1-C4-alkyl, particularly preferably methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl, C1-C4-alkoxy, preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, halogen, preferably fluorine or chlorine, trifluoromethyl, methoxycarbonyl or ethoxycarbonyl, and the remaining radicals Ra to Rf are hydrogen. In a preferred embodiment, Ra, Rb, Rc, Rd, Re and Rf are hydrogen.
In a further preferred embodiment, the radicals R1, R2, R3 and R4 are selected from radicals of the formula II.c, in which Ra, Rb, Rc, Rd, Re and Rf are independently of one another hydrogen, C1-C4-alkyl, particularly preferably methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl, C1-C4-alkoxy, preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, halogen, preferably fluorine or chlorine, trifluoromethyl, methoxycarbonyl or ethoxycarbonyl. Preferably one, two or three of the radicals Ra to Rf are selected independently of one another from C1-C4-alkyl, particularly preferably methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl, C1-C4-alkoxy, preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, halogen, preferably fluorine or chlorine, trifluoromethyl, methoxycarbonyl or ethoxycarbonyl, and the remaining radicals Ra to Rf are hydrogen. In a preferred embodiment, Ra, Rb, Rc, Rd, Re and Rf are hydrogen.
It is particularly preferred for R1, R2, R3 and R4 all to be phenyl, all to be 4-biphenylyl or all to be 2-naphthyl.
In a further preferred embodiment, R1 and R2 and/or R3 and R4 together with the carbon atom to which they are bonded are a 5- to 8-membered heterocycle which is optionally additionally fused one, two or three times to cycloalkyl, heterocycloalkyl, aryl or hetaryl, where the heterocycle and, if present, the fused groups may independently of one another each have one, two, three or four substituents which are selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, hetaryl, hydroxy, thiol, polyalkylene oxide, polyalkyleneimine, alkoxy, halogen, COOH, carboxylate, SO3H, sulfonate, NE4E5, NE4E5E6A−, nitro, alkoxycarbonyl, acyl or cyano, in which E4, E5 and E6 are in each case identical or different radicals selected from hydrogen, alkyl, cycloalkyl and aryl, and A− is an anion equivalent.
The bridging group X is preferably selected from groups of the formulae C═O, C═S and CR5R6 in which
R5 and R6 together with the carbon atom to which they are bonded are a 5- to 8-membered heterocycle which optionally is additionally fused one, two or three times to cycloalkyl, heterocycloalkyl, aryl or hetaryl, where the heterocycle and, if present, the fused groups may, independently of one another each have one, two, three or four substituents which are selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, hetaryl, hydroxy, thiol, polyalkylene oxide, polyalkyleneimine, alkoxy, halogen, COOH, carboxylate, SO3H, sulfonate, NE13E14, NE13E14E15A−, nitro, alkoxycarbonyl, acyl or cyano, in which E4, E5 and E6 are in each case identical or different radicals selected from hydrogen, alkyl, cycloalkyl and aryl, and A− is an anion equivalent.
R5 and R6 are preferably both C1-C4-alkyl and in particular both methyl.
Preferred compounds of the formula I are those selected from compounds of the formula I.1
in which R1, R2, R3, R4, R5 and R6 have the meanings indicated previously.
In the method of the invention for fractionating stereoisomeric compounds, specifically alcohols, there is preferably use of a metal complex derived from a metal of group Ia, IIa, IIIa, IVa or Va, of group Ib to VIIIb, of the lanthanides or the actinides. The metal is preferably selected from B, Al, Ga, In, Tl, Si, Ge, Sn, Pb, As, Sb, Bi, Ti, Zr, V, Cr, Mo, W, Mn, Fe, Ru, Os, Co, Rh, Ir, Ni, Pd, Pt, Cu, Ag, Au, Zn and Cd. The metal is in particular Al, Ga, In.
If the compound to be fractionated is a stereoisomeric monoalcohol, the metal is preferably a metal which is capable of forming a stable trivalent oxidation state. These are preferably selected from Al, Ga and In. The metal is then in particular Al.
If the compound to be fractionated is a stereoisomeric compound having two functional groups which are selected from alcohol and/or amino groups, metals preferably suitable as metal are those capable of forming a stable tetravalent oxidation state. These include in particular Ti, Zr, Ge, Sn. The metal is then in particular titanium.
In this embodiment, the compounds to be fractionated are then selected in particular from diols, amino alcohols and diamines. These preferably have two hydroxyl groups or two amino groups or one hydroxyl group and one amino group in each case in the α and β position relative to one another. Suitable compounds are mentioned below.
In addition to the ligands of the formula I described above, the discriminators may also have at least one further ligand which is preferably selected from alcohols, thiols, amines, halides, alkanes, carboxylates, acetylacetonate, aryl- or alkylsulfonates, hydride, N-containing heterocycles, aromatic and heteroaromatic compounds.
The metal complex employed as chiral discriminator is preferably selected from compounds of the general formula I.a
in which
In an alternative preferred embodiment, L is selected from optionally substituted phenols. Substituted phenols may preferably have 1, 2, 3 or 4 substituents which are selected from the substituents mentioned at the outset for “aryl”. In this connection, preferred phenols have at least one substituent in position 2. The substituents of the phenols are preferably selected from C1-C4-alkyl, particularly preferably methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl, C1-C4-alkoxy, preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, halogen, preferably fluorine or chlorine, trifluoromethyl, methoxycarbonyl or ethoxycarbonyl. Unsubstituted phenols are further preferred.
In a particularly preferred embodiment, L is selected from alcohols or phenols which have a higher boiling point than the racemate to be separated.
The metal complex is preferably prepared by employing an aluminum trialcoholate such as aluminum ethoxide (aluminum triethoxide), aluminum n-propoxide, aluminum isopropoxide, aluminum n-butoxide, aluminum sec-butoxide, aluminum tert-butoxide, aluminum phenolate, etc.
The metal complex employed as chiral discriminator is preferably selected from compounds of the general formula I.b
in which
In an alternative preferred embodiment, L is selected from optionally substituted phenols. Substituted phenols may preferably have 1, 2, 3 or 4 substituents which are selected from the substituents mentioned at the outset for “aryl”. In this connection, preferred phenols have at least one substituent in position 2. The substituents of the phenols are preferably selected from C1-C4-alkyl, particularly preferably methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl, C1-C4-alkoxy, preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, halogen, preferably fluorine or chlorine, trifluoromethyl, methoxycarbonyl or ethoxycarbonyl. Unsubstituted phenols are further preferred.
In a particularly preferred embodiment, L is selected from alcohols or phenols which have a higher boiling point than the racemate to be separated.
The metal complex is preferably prepared by employing an aluminum trialcoholate such as aluminum ethoxide (aluminum triethoxide), aluminum n-propoxide, aluminum isopropoxide, aluminum n-butoxide, aluminum sec-butoxide, aluminum tert-butoxide, aluminum phenolate, etc. or a titanium tetraalcoholate such as titanium ethoxide, titanium n-propoxide, titanium isopropoxide, titanium n-butoxide, titanium sec-butoxide, titanium tert-butoxide, titanium phenolate, etc.
The metal complex employed as chiral discriminator is preferably selected from compounds of the general formula I.b1or I.b2
in which
Some suitable discriminators are shown by way of example below
The chiral discriminators employed according to the invention lead to a boiling point difference of the stereoisomeric compounds, specifically alcohols, which have at least one alcohol and/or amino group (e.g. where enantiomeric compounds are involved) or to an increase in a preexistent boiling point difference of the stereoisomeric compounds, specifically alcohols, which have at least one alcohol and/or amino group (e.g. where diastereomeric compounds are involved).
The mixture employed for the fractionation preferably comprises two stereoisomeric compounds, specifically alcohols. The stereoisomeric compounds are preferably enantiomers of an alcohol.
The stereoisomeric compounds are particularly preferably alcohols of the general formula (III)
where
The stereoisomeric compounds of the general formula (III) are in particular the enantiomers of these compounds.
Suitable alkyl, cycloalkyl, heterocycloalkyl, aryl and hetaryl substituents are those mentioned at the outset.
Alkyl is preferably C1-C8-alkyl. Cycloalkyl is preferably C3-C8-cycloalkyl. Aryl is preferably phenyl or naphthyl, specifically phenyl.
The substituents R5 and R6 are preferably independently of one another unsubstituted or optionally halogen-substituted C1-C4-alkyl, specifically optionally substituted benzyl, or optionally halogen-, cyano-, nitro-, C1-C4-alkyl- or C1-C4-alkoxy-substituted aryl, in particular optionally substituted phenyl or naphthyl. R7 in this embodiment is preferably hydrogen.
Examples of monoalcohols which can be employed in the method of the invention and which may be mentioned are
(RS)1-phenylethanol, (RS)-2-butynol, (RS)-2-pentynol, (RS)1-phenylpropanol,
(RS)1-(4-chlorophenyl)ethanol, (RS)1-(4-chlorophenyl)propanol,
(RS)2-chloro-1-phenylethanol, (RS)3-chloro-1-phenylpropanol,
(RS)2-chloro-1-(4-chlorophenyl)ethanol, (RS)3-chloro-1-(4-chlorophenyl)propanol,
(RS)2-chloro-1-(3-chlorophenyl)ethanol, (RS)3-chloro-1-(3-chlorophenyl)propanol,
(RS)2-chloro-1-(2-chlorophenyl)ethanol, (RS)3-chloro-1-(2-chlorophenyl)propanol,
(RS)1-(4-nitrophenyl)ethanol, (RS)1-(4-nitrophenyl)propanol, (RS) 1-naphthylethanol,
(RS)1-naphthylpropanol, (RS)1-(6-methoxynaphthyl)ethanol,
(RS)1-(6-methoxynaphthyl)propanol, (RS)2-chloro-1-naphthylethanol,
(RS)3-chloro-1-naphthylpropanol, (RS)2-chloro-1-(6-methoxynaphthyl)ethanol,
(RS)3-chloro-1-(6-methoxynaphthyl)propanol, (RS )1-(4-methylpheny )ethanol,
(RS)1-(4-methylphenyl)propanol, (RS)2-chloro-1-(4-methylphenyl)ethanol,
(RS)3-chloro-1-(4-methylphenyl)propanol, (RS)1-(4-ethylphenyl)ethanol,
(RS)1-(4-ethylphenyl)propanol, (RS)2-chloro-1-(4-ethylphenyl)ethanol,
(RS)3-chloro-1-(4-ethylphenyl)propanol, (RS)1-(4-methoxyphenyl)ethanol,
(RS)1-(4-methoxyphenyl)propanol, (RS)2-chloro-1-(4-methoxyphenyl)ethanol,
(RS)3-chloro-1-(4-methoxyphenyl)propanol, (RS)1-(2-methylphenyl)ethanol,
(RS)1-(2-methylphenyl)propanol, (RS)2-chloro-1-(2-methylphenyl)ethanol,
(RS)3-chloro-1-(2-methyl phenyl)propanol, (RS)1-(2-ethylphenyl)ethanol,
(RS)1-(2-ethylphenyl )propanol, 2-chloro-1-(2-ethylphenyl)ethanol,
(RS)3-chloro-1-(2-ethylphenyl)propanol, (RS)1-(2-methoxyphenyl)ethanol,
(RS)1-(2-methoxyphenyl )propanol, 2-chloro-1-(2-methoxyphenyl)ethanol,
(RS)3-chloro-1-(2-methoxyphenyl)propanol, (RS)1-(3-methylphenyl)ethanol,
(RS)1-(3-methylphenyl)propanol, (RS)2-chloro-1-(3-methylphenyl)ethanol,
(RS)3-chloro-1-(3-methyl phenyl)propanol, (RS) 1-(3-ethylphenyl )ethanol,
(RS)1-(3-ethylphenyl)propanol, (RS)2-chloro-1-(3-ethylphenyl)ethanol,
(RS)3-chloro-1-(3-ethylphenyl)propanol, (RS )1-(3-methoxyphenyl)ethanol,
(RS)1-(3-methoxyphenyl )propanol, (RS)2-chloro-1-(3-methoxyphenyl)ethanol,
(RS)3-chloro-1-(3-methoxyphenyl)propanol and (RS)1-(1,3)-benzodioxoleethanol.
In a further preferred form, the mixture employed for the fractionation comprises stereoisomeric compounds in particular selected from diols, amino alcohols and diamines. These preferably have two hydroxyl groups or two amino groups or one hydroxyl group and one amino group in each case in α and β position relative to one another. The stereoisomeric compounds are preferably enantiomers or diastereomers.
The stereoisomeric compounds are particularly preferably compounds of the general formula (IV)
where
Suitable alkyl, cycloalkyl, heterocycloalkyl, aryl and hetaryl substituents are those mentioned at the outset.
Alkyl is preferably C1-C8-alkyl. Cycloalkyl is preferably C3-C8-cycloalkyl. Aryl is preferably phenyl or naphthyl, specifically phenyl.
Particularly preferred compounds of the formula (IV) are those in which n is 0.
R12 and R13 are further independently of one another preferably hydrogen or C1-C6-alkyl, where the radicals R12 and R13 may be identical or different from one another. Examples which may be mentioned of stereoisomeric compounds which can be employed in the method of the invention and have two functional groups, which may be alcohol and/or amine, which are in α and β positions relative to one another are racemic mixtures of 1,2-propanediol, 3-chloro-1,2-propanediol, 3-bromo-1,2-propanediol, 1,2-butanediol, 2,3-butanediol, 1,4-dichloro-2,3-butanediol, 2-methyl-2,3-butanediol, 1,2-pentanediol, 1,2-cyclopentanediol, trans-1,2-cyclopentanediol, 1,2-hexanediol, 1,2-cyclohexanediol, trans-1,2-cyclohexanediol, 3,3-dimethyl-1,2-butanediol, 1,2-heptanediol, 2,3-heptanediol, 1,2-cycloheptanediol, trans-1,2-cycloheptanediol, 1,2-octanediol, 7-octene-1,2-diol, 1-phenyl-1,2-ethanediol, 1-phenyl-1,2-propanediol, 2-phenyl-1,2-propanediol, 1-isopropenyl-4-methyl-1,2-cyclohexanediol, 1,2,3,4-tetrahydro-2,3-naphtalenediol, 2-amino-3-hydroxybutanol (threoninol), 1-amino-2-propanol, 2-amino-1-propanol, 1-amino-2-butanol, 2-amino-1-butanol, 2-amino-2-methyl-1-propanol, 2-amino-3-methyl-1-butanol (valinol), 2-amino-1-pentanol, 2-amino-4-methylmercapto-1-butanol (methioninol), 2-amino-3-methyl-1-pentanol (isoleucinol), 2-amino-4-methyl-1-pentanol (leucinol), 2-amino-3,3-dimethyl-1-butanol (tert-leucinol), 2-amino-1-hexanol, 2-aminocyclohexanol, 2-ethylamino-1-butanol, 2-amino-1-phenylethanol, 2-amino-2-phenylethanol (α-phenylglycinol), 2-amino-3-phenyl-1-propanol (phenylalanol), 2-amino-1-phenyl-1-propanol, 2-amino-3-(p-chlorophenyl)-1-propanol, 2-benzylamino-1-propanol, 2-amino-2-methyl-3-phenyl-1-propanol, 1-amino-2-indanol, 2-amino-1-indanol, 3-amino-1,2,3,4-tetrahydro-2-naphthol, 2-amino-3-(a-imidazolyl)propanol (histidinol), 2-(hydroxymethyl)pyrrolidine (prolinol), 1,2-propylenediamine, 2-methyl-1,2-propanediamine, 1,2-cyclopentanediamine, trans-1,2-cyclopentanediamine, 1,2-cyclohexanediamine, trans-1,2-cyclohexanediamine, 1,1-di(4-anisyl)-2-iso-propylethylenediamine (daipen), 1,3-butanediol, 1,3-pentanediol, 2,2,4-trimethyl-1,3-pentanediol, 1,3-cyclohexanediol, 2-methyl-2,4-pentanediol, 2,4-pentanediol, 3-methyl-2,4-pentanediol, 1,3-cyclohexanediamine and 3-amino-2-methyl-1-phenyl-1-propanol.
The method of the invention is carried out by the stereoisomers to be fractionated being brought into contact with a chiral discriminator as described previously and subjected simultaneously and/or subsequently to a distillative separation.
The boiling point difference induced by the discriminators employed according to the invention between the stereoisomeric compounds to be fractionated makes fractionation by distillation possible. This can take place in principle by conventional distillation methods known to the skilled worker. Suitable apparatuses for distillative workup comprise distillation columns such as tray columns which may be equipped with bubble caps, perforated plates, perforated trays, valves, side offtakes, etc., evaporators, such as thin-film evaporators, Sambay evaporators etc. and combinations thereof.
It is, of course, also possible to employ an inert solvent for bringing the discriminator into contact with the stereoisomeric compounds to be fractionated and/or for the separation. The preferred solvent in this connection is one which makes it possible to carry out the distillation, as described in detail below, as extractive distillation. Examples of solvents which are ordinarily suitable are aromatic compounds such as toluene and xylenes, hydrocarbons or mixtures of hydrocarbons. Also suitable are halogenated, in particular chlorinated, hydrocarbons or aromatic compounds, such as 2-chloronaphthalene. Further suitable solvents are esters of aliphatic or aromatic carboxylic acids with alkanols, for example Texanol® (2,2,4-trimethyl-1,3-pentanediol monobutyrate) or palatinols. Suitable solvents are moreover ethers, preferably diaryl ethers, such diphenyl ether, and dialkyl ethers, such as di-n-butyl ether or polyethers, for example Lutrols® (polyethylene glycol). Suitable solvents are moreover carboxamides such as N,N-dialkylcarboxamides, e.g. dimethylformamide and dimethylacetamide, and dimethylacetanilide or carbolactams such as N-alkylcarbolactams, e.g. N-methylpyrrolidone. Also suitable are sulfur-containing solvents such as dimethyl sulfoxide or sulfolane. It is also possible to use industrial white oils, thermal oils and heat-transfer fluids such as Marlotherms®, Dowtherms®, Therminol® as solvents. It is also possible to employ ketones such as cyclohexanone etc. It is also possible to use as solvents so-called “ionic liquids”. These are liquid salts, for example N,N′-dialkylimidazolium salts such as N-butyl-N′-methylimidazolium salts, tetraalkyl-ammonium salts such as tetra-n-butylammonium salts, N-alkylpyridinium salts such as n-butylpyridinium salts, tetraalkylphosphonium salts such as trishexyl(tetradecyl)-phosphonium salts, e.g. the tetrafluoroborates, acetates, tetrachloroaluminates, hexafluorophosphates, chlorides and tosylates. The racemate to be separated may itself serve as a further suitable solvent.
In a preferred embodiment of the method of the invention, the separation takes place by extractive distillation. Extractive distillation is a method known in principle for fractionating mixtures of components which differ only slightly in their relative volatilities or which boil azeotropically. Extractive distillation is carried out by adding an additional (selective) solvent, also referred to as extractant, which preferably has a higher boiling point than the mixture to be fractionated.
The additional solvent preferably employed for the extractive distillation has a boiling point at the pressure under which the fractionation takes place which is at least 5° C., particularly preferably at least 10° C., higher than the boiling point of the highest-boiling stereoisomer.
Additional solvents suitable for the extractive distillation are those mentioned previously.
The additional solvent preferably employed is one in which the chiral discriminator employed has, under the fractionation conditions, a solubility of at least 20 g/l, in particular of at least 50 g/l.
The method can be carried out under atmospheric pressure or under reduced or elevated pressure. The method is preferably carried out under reduced pressure in such a way that the temperature at the top of the column is less than 200° C., preferably less than 150° C., particularly preferably less than 100° C.
The distillation according to the invention normally takes place under a pressure in the range from 0.01 to 900 mbar, preferably from 0.1 to 500 mbar.
The extractive distillation in the presence of the discriminator can be repeated more than once. The number of repetitions depends on the desired purity of the enantiomeric or diastereomeric products and can be determined by the skilled worker by methods known per se.
The invention is explained in more detail by means of the following, non-restrictive examples.
Separation of racemic 1-phenylethanol using the chiral selector generated from (4R,5R)-(bishydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane and Al(O-isopropyl)3
50 ml of diphenyl ether are added to 15 mmol (7.0 g) of (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane and 15 mmol (3.1 g) of aluminum triisopropoxide in a glove box. The resulting suspension is stirred at 90° C. under protective gas for 15 min. Subsequently, 30 mmol (3.7 g) of racemic 1-phenylethanol are added, stirring is continued for 90 min and then the resulting isopropanol is distilled off under about 20 mbar. Then, at 90° C. under 1 mbar, about 1 ml of phenylethanol is distilled off. Examination of the sample by chiral GC shows a composition of 58% (R)-1-phenylethanol and 42% (S)-1-phenylethanol. After hydrolysis of the distillation residue, the 1-phenylethanol remaining in the residue is examined by chiral GC. A composition of 46.6% (R)-phenylethanol and 53.4% (S)-phenylethanol is found.
GC: Column switching with precolumn: 25 m*0.25 mm Optioma-1 (Macherey & Nagel)
FD=0.5 μm, and chiral column: 30 m*0.25 mm BGB174S (BGB-Analytikvertrieb)
FD=0.25 μm; oven temp.: 115° C. 12′, 5°/*, 200° C.; precolumn: 1.4 bar H2, chiral column: 1.1 bar H2; column switching: at 1.9 min to chiral column; RT of R-1-phenylethanol=9.4 min; RT of S-1-phenylethanol=9.8 min.
Separation of racemic 1-phenylethanol using the chiral selector generated from (4R,5R)-bis(hydroxydi(4′-biphenylyl)methyl)-2,2-dimethyl-1,3-dioxolane and Al(O-isopropyl)3
50 ml of diphenyl ether are added to 15 mmol (7.0 g) of (4R,5R)-bis(hydroxydi(4′-bi-phenylyl)methyl)-2,2-dimethyl-1,3-dioxolane and 15 mmol (3.1 g) of aluminum triisopropoxide in a glove box. The resulting suspension is stirred at 90° C. under protective gas for 15 min. Subsequently, 30 mmol (3.7 g) of racemic 1-phenylethanol are added and about 1 ml of phenylethanol is distilled off. Examination of the sample by chiral GC shows a composition of 53.4% (R)-1-phenylethanol and 46.6% (S)-1-phenylethanol.
GC: Column switching with precolumn: 25 m*0.25 mm Optioma-1 (Macherey & Nagel)
FD=0.5 μm, and chiral column: 30 m*0.25 mm BGB174S (BGB-Analytikvertrieb)
FD=0.25 μm; oven temp.: 115° C. 12′, 5°/*, 200° C.; precolumn: 1.4 bar H2, chiral column: 1.1 bar H2; column switching: at 1.9 min to chiral column; RT of R-1-phenylethanol=9.4 min; RT of S-1-phenylethanol=9.8 min.
Separation of rac.-1,2-propanediol using the chiral selector generated from (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane and Ti(O-isopropyl)4
6.5 mmol (3.0 g) of (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane and 6.5 mmol (1.83 g) of titanium tetraisopropoxide are put into 20 ml of diphenyl ether in a glove box. The resulting yellow solution is stirred under protective gas at 90° C. for 60 min. This is followed by addition of 13 mmol (0.98 g) of rac.-1,2-propanediol and stirring for a further 10 min, and then the resulting isopropanol is distilled out under about 20 mbar. Subsequently, about 0.75 g of a mixture of diphenyl ether and 1,2-propanediol is distilled out at 1 mbar and 90° C. The enantiomeric excess determined by gas chromatography (Chirasil Dex CB, TFA derivatization) for (S)-1,2-propanediol is 16%.
Separation of rac.-1,2-propanediol using the chiral selector generated from (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane and Ti(O-isopropyl)4
6.5 mmol (3.0 g) of (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane and 6.5 mmol (1.83 g) titanium tetraisopropoxide are put into 20 ml of diphenyl ether in a glove box. The resulting yellow solution is stirred under protective gas at 90° C. for 60 min. This is followed by addition of 26 mmol (1.96 g) of rac.-1,2-propanediol and stirring for a further 10 min, and then the resulting isopropanol is distilled out under about 20 mbar. Subsequently, about 0.75 g of a mixture of diphenyl ether and 1,2-propanediol is distilled out at 1 mbar and 90° C. The enantiomeric excess determined by gas chromatography (Chirasil Dex CB, TFA derivatization) for (S)-1,2-propanediol is 7.4%.
Separation of rac.-2-amino-1-propanol using the chiral selector generated from (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane and Ti(O-isopropyl)4
6.5 mmol (3.0 g) of (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane and 6.5 mmol (1.83 g) of titanium tetraisopropoxide are put into 20 ml of diphenyl ether in a glove box. The resulting yellow solution is stirred under protective gas at 90° C. for 60 min. This is followed by addition of 13 mmol (0.97 g) of rac.-2-amino-1-propanol and stirring for a further 10 min, and then the resulting isopropanol is distilled out under about 20 mbar. Subsequently, about 0.75 g of a mixture of diphenyl ether and 2-amino-1-propanol is distilled out at 1 mbar and 90° C. The enantiomeric excess determined by gas chromatography (Chirasil Dex CB, TFA derivatization) for (S)-2-amino-1-propanol is 6.3%.
Separation of rac.-1-phenylethanol using a chiral selector generated from (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane and Al(O-isopropyl)3 (selector: alcohol ratio 0.5:1)
6.4 mmol (3.0 g) of (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane and 6.4 mmol (1.31 g) of aluminum triisopropoxide are put into 20 ml of diphenyl ether in a glove box. The resulting suspension is stirred under protective gas at 90° C. for 60 min. This is followed by addition of 12.8 mmol (1.56 g) of racemic 1-phenylethanol and stirring for a further 10 min. The resulting isopropanol is then distilled out under about 20 mbar. Subsequently, 1.2 g of a mixture of (R)-1-phenylethanol and (S)-1-phenylethanol are obtained as distillate at 1 mbar and 90° C. The enantiomeric excess determined by chiral gas chromatography (BGB174S, BGB-Analytikvertrieb) for (R)-1-phenylethanol was 12.0%.
Separation of rac.-1-phenylethanol using a chiral selector generated from (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane and Al(O-isopropyl)3 (selector: alcohol ratio 2:1)
9.9 mmol (4.6 g) of (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane and 9.9 mmol (2.02 g) of aluminum triisopropoxide are put into 30 ml of diphenyl ether in a glove box. The resulting suspension is stirred under protective gas at 90° C. for 60 min. This is followed by addition of 4.95 mmol (0.60 g) of racemic 1-phenylethanol and stirring for a further 10 min, and then the resulting isopropanol is distilled out under about 20 mbar. Subsequently, 1.0 g of a mixture of (R)-1-phenylethanol and (S)-1-phenylethanol is obtained as distillate at 1 mbar and 90° C. The enantiomeric excess determined by gas chromatography (BGB174S, BGB-Analytikvertrieb) for (R)-1-phenylethanol was 33.8% ee.
Separation of rac.-1-phenylethanol using a chiral selector generated from (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane and Al(O-isopropyl)3 (selector: alcohol ratio 3:1)
39.0 mmol (18.0 g) of (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane and 39.0 mmol (7.96 g) of aluminum triisopropoxide are put into 60 ml of diphenyl ether in a glove box. The resulting suspension is stirred under protective gas at 90° C. for 60 min. This is followed by addition of 13 mmol (1.56 g) of racemic 1-phenylethanol and stirring for a further 10 min, and then the resulting isopropanol is distilled out under about 20 mbar. Subsequently, 2.35 g of a mixture of (R)-1-phenylethanol and (S)-1-phenylethanol is obtained as distillate at 1 mbar and 90° C. The enantiomeric excess determined by gas chromatography (BGB174S, BGB-Analytikvertrieb) for (R)-1-phenylethanol was 14.8% ee.
Separation of rac.-1-phenylethanol using a chiral selector generated from (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane and Al(O-isopropyl)3 (selector: alcohol ratio 4:1)
52.0 mmol (24.0 g) of (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane and 52.0 mmol (10.5 g) of aluminum triisopropoxide are put into 80 ml of diphenyl ether in a glove box. The resulting suspension is stirred under protective gas at 90° C. for 60 min. This is followed by addition of 13 mmol (1.56 g) of racemic 1-phenylethanol and stirring for a further 10 min, and then the resulting isopropanol is distilled out under about 20 mbar. Subsequently, 3.7 g of a mixture of (R)-1-phenylethanol and (S)-1-phenylethanol is obtained as distillate at 1 mbar and 90° C. The enantiomeric excess determined by gas chromatography (BGB174S, BGB-Analytikvertrieb) for (R)-1-phenylethanol was 13.4% ee.
Separation of rac.-4-methylphenylethanol using a chiral selector generated from (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane and Al(O-isopropyl)3 (selector:alcohol ratio 1:1)
13.0 mmol (6.0 g) of (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane and 13.0 mmol (2.62 g) of aluminum triisopropoxide are put into 40 ml of diphenyl ether in a glove box. The resulting suspension is stirred under protective gas at 90° C. for 60 min. This is followed by addition of 13 mmol (1.75 g) of racemic 1-(4-methylphenyl)ethanol and stirring for a further 10 min. Subsequently, the resulting isopropanol is distilled out under about 20 mbar. Then, at 1 mbar and 90° C., 2.65 g of distillate are obtained. Investigation of the distillate by chiral gas chromatography (BGB-Analytikvertrieb BGB-174S) revealed an enantiomeric excess of 23.6%.
Separation of rac.-4-chlorophenylethanol using a chiral selector generated from (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane and Al(O-isopropyl)3 (selector:alcohol ratio 1:1)
13.0 mmol (6.0 g) of (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane and 13.0 mmol (2.62 g) of aluminum triisopropoxide are put into 40 ml of diphenyl ether in a glove box. The resulting suspension is stirred under protective gas at 90° C. for 60 min. This is followed by addition of 13 mmol (2.02 g) of racemic 1-(4-chlorophenyl)ethanol and stirring for a further 10 min. Subsequently, the resulting isopropanol is distilled out under about 20 mbar. Then, at 1 mbar and 90° C., 1.4 g of a mixture of the enantiomers of 1-(4-chlorophenyl)ethanol as distillate are obtained. Investigation of the distillate by chiral gas chromatography (BGB-Analytikvertrieb BGB-174S) revealed an enantiomeric excess of 7.3%.
Separation of rac.-4-fluorophenylethanol using a chiral selector generated from (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane and Al(O-isopropyl)3 (selector:alcohol ratio 1:1)
13.0 mmol (6.0 g) of (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane and 13.0 mmol (2.62 g) of aluminum triisopropoxide are put into 40 ml of diphenyl ether in a glove box. The resulting suspension is stirred under protective gas at 90° C. for 60 min. This is followed by addition of 13 mmol (1.80 g) of racemic 1-(4-fluorophenyl)ethanol and stirring for a further 10 min. Subsequently, the resulting isopropanol is distilled out under about 20 mbar. Then, at 1 mbar and 90° C., 1.25 g of a mixture of the enantiomers of 1-(4-fluorophenyl)ethanol as distillate are obtained. Investigation of the distillate by chiral gas chromatography (BGB-Analytikvertrieb BGB-174S) revealed an enantiomeric excess of 9.1%.
Separation of rac.-3-(trifluoromethyl)phenylethanol using a chiral selector generated from (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane and Al(O-isopropyl)3 (selector:alcohol ratio 1:1)
13.0 mmol (6.0 g) of (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane and 13.0 mmol (2.62 g) of aluminum triisopropoxide are put into 40 ml of diphenyl ether in a glove box. The resulting suspension is stirred under protective gas at 90° C. for 60 min. This is followed by addition of 13 mmol (2.50 g) of racemic 1-(3-trifluoromethylphenyl)ethanol and stirring for a further 10 min. Subsequently, the resulting isopropanol is distilled out under about 20 mbar. Then, at 1 mbar and 90° C., 1.25 g of a mixture of the enantiomers of 1-(3-trifluoromethylphenyl)ethanol as distillate are obtained. Investigation of the distillate by chiral gas chromatography (BGB-Analytikvertrieb BGB-174S) revealed an enantiomeric excess of 27.8%.
Optical purification of 1-phenylethanol (28% ee) using a chiral selector generated from (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane and Al(O-isopropyl)3 (selector:alcohol ratio 2:1)
26.0 mmol (12.0 g) of (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane and 26.0 mmol (5.25 g) of aluminum triisopropoxide are put into 60 ml of diphenyl ether in a glove box. The resulting suspension is stirred under protective gas at 90° C. for 60 min. This is followed by addition of 13 mmol (1.56 g) of phenylethanol with an (R)-1-phenylethanol enantiomeric excess of 28% ee, and stirring for a further 10 min. Subsequently, the resulting isopropanol is distilled out under about 20 mbar. Then 1.10 g of a mixture of (R)-1-phenylethanol and (S)-1-phenylethanol are obtained as distillate at 1 mbar and 90° C. Investigation of the distillate by chiral gas chromatography (BGB-Analytikvertrieb BGB-174S) revealed an (R)-1-phenylethanol enantiomeric excess of 49.1%.
Optical purification of 1-phenylethanol with 47% ee using a chiral selector generated from (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane and Al(O-isopropyl)3 (selector:alcohol ratio 2:1)
26.0 mmol (12.0 g) of (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane and 26.0 mmol (5.25 g) of aluminum triisopropoxide are put into 60 ml of diphenyl ether in a glove box. The resulting suspension is stirred under protective gas at 90° C. for 60 min. This is followed by addition of 13 mmol (1.56 g) of phenylethanol with an (R)-1-phenylethanol enantiomeric excess of 47% ee, and stirring for a further 10 min. Subsequently, the resulting isopropanol is distilled out under about 20 mbar. Then 1.10 g of a mixture of (R)-1-phenylethanol and (S)-1-phenylethanol are obtained as distillate at 1 mbar and 90° C. Investigation of the distillate by chiral gas chromatography (BGB-Analytikvertrieb BGB-174S) afforded an (R)-1-phenylethanol enantiomeric excess of 59.0%.
Optical purification of 1-phenylethanol with 66% ee using a chiral selector generated from (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane and Al(O-isopropyl)3 (selector:alcohol ratio 2:1)
26.0 mmol (12.0 g) of (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane and 26.0 mmol (5.25 g) of aluminum triisopropoxide are put into 60 ml of diphenyl ether in a glove box. The resulting suspension is stirred under protective gas at 90° C. for 60 min. This is followed by addition of 13 mmol (1.56 g) of 1-phenylethanol with an (R)-1-phenylethanol enantiomeric excess of 66% ee, and stirring for a further 10 min. Subsequently, the resulting isopropanol is distilled out under about 20 mbar. Then 1.10 g of a mixture of (R)-1-phenylethanol and (S)-1-phenylethanol are obtained as distillate at 1 mbar and 90° C. Investigation of the distillate by chiral gas chromatography (BGB-Analytikvertrieb BGB-174S) revealed an (R)-1-phenylethanol enantiomeric excess of 72.8%.
Optical purification of phenylethanol with 76% ee using a chiral selector generated from (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane and Al(O-isopropyl)3 (selector:alcohol ratio 2:1)
26.0 mmol (12.0 g) of (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane and 26.0 mmol (5.25 g) of aluminum triisopropoxide are put into 60 ml of diphenyl ether in a glove box. The resulting suspension is stirred under protective gas at 90° C. for 60 min. This is followed by addition of 13 mmol (1.56 g) of 1-phenylethanol with an (R)-1-phenylethanol enantiomeric excess of 76% ee, and stirring for a further 10 min. Subsequently, the resulting isopropanol is distilled out under about 20 mbar. Then 1.10 g of a mixture of (R)-1-phenylethanol and (S)-1-phenylethanol are obtained as distillate at 1 mbar and 90° C. Investigation of the distillate by chiral gas chromatography (BGB-Analytikvertrieb BGB-174S) revealed an (R)-1-phenylethanol enantiomeric excess of 83.0%.
Optical purification of phenylethanol with 82% ee using a chiral selector generated from (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane and Al(O-isopropyl)3 (selector:alcohol ratio 2:1)
26.0 mmol (12.0 g) of (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane and 26.0 mmol (5.25 g) of aluminum triisopropoxide are put into 60 ml of diphenyl ether in a glove box. The resulting suspension is stirred under protective gas at 90° C. for 60 min. This is followed by addition of 13 mmol (1.56 g) of 1-phenylethanol with an (R)-1-phenylethanol enantiomeric excess of 82% ee, and stirring for a further 10 min. Subsequently, the resulting isopropanol is distilled out under about 20 mbar. Then 1.10 g of a mixture of (R)-1-phenylethanol and (S)-1-phenylethanol are obtained as distillate at 1 mbar and 90° C. Investigation of the distillate by chiral gas chromatography (BGB-Analytikvertrieb BGB-174S) revealed an (R)-1-phenylethanol enantiomeric excess of 86.3%.
Optical purification of phenylethanol with 86% ee using a chiral selector generated from (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane and Al(O-isopropyl)3 (selector:alcohol ratio 2:1)
26.0 mmol (12.0 g) of (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane and 26.0 mmol (5.25 g) of aluminum triisopropoxide are put into 60 ml of diphenyl ether in a glove box. The resulting suspension is stirred under protective gas at 90° C. for 60 min. This is followed by addition of 13 mmol (1.56 g) of 1-phenylethanol with an (R)-1-phenylethanol enantiomeric excess of 86% ee, and stirring for a further 10 min. Subsequently, the resulting isopropanol is distilled out under about 20 mbar. Then 1.10 g of a mixture of (R)-1-phenylethanol and (S)-1-phenylethanol are obtained as distillate at 1 mbar and 90° C. Investigation of the distillate by chiral gas chromatography (BGB-Analytikvertrieb BGB-174S) revealed an (R)-1-phenylethanol enantiomeric excess of 89.9%.
Optical purification of phenylethanol with 91% ee using a chiral selector generated from (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane and Al(O-isopropyl)3 (selector:alcohol ratio 2:1)
26.0 mmol (12.0 g) of (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane and 26.0 mmol (5.25 g) of aluminum triisopropoxide are put into 60 ml of diphenyl ether in a glove box. The resulting suspension is stirred under protective gas at 90° C. for 60 min. This is followed by addition of 13 mmol (1.56 g) of 1-phenylethanol with an (R)-1-phenylethanol enantiomeric excess of 91% ee, and stirring for a further 10 min. Subsequently, the resulting isopropanol is distilled out under about 20 mbar. Then 1.10 g of a mixture of (R)-1-phenylethanol and (S)-1-phenylethanol are obtained as distillate at 1 mbar and 90° C. Investigation of the distillate by chiral gas chromatography (BGB-Analytikvertrieb BGB-174S) revealed an (R)-1-phenylethanol enantiomeric excess of 92.4%.
Optical purification of 1-phenylethanol with 92.5% ee using a chiral selector generated from (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane and Al(O-isopropyl)3 (selector:alcohol ratio 2:1)
26.0 mmol (12.0 g) of (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane and 26.0 mmol (5.25 g) of aluminum triisopropoxide are put into 60 ml of diphenyl ether in a glove box. The resulting suspension is stirred under protective gas at 90° C. for 60 min. This is followed by addition of 13 mmol (1.56 g) of 1-phenylethanol with an (R)-1-phenylethanol enantiomeric excess of 92.5% ee, and stirring for a further 10 min. Subsequently, the resulting isopropanol is distilled out under about 20 mbar. Then 1.10 g of a mixture of (R)-1-phenylethanol and (S)-1-phenylethanol are obtained as distillate at 1 mbar and 90° C. Investigation of the distillate by chiral gas chromatography (BGB-Analytikvertrieb BGB-174S) revealed an (R)-1-phenylethanol enantiomeric excess of 94.7%.
Optical purification of phenylethanol with 94.2% ee using a chiral selector generated from (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane and Al(O-isopropyl)3 (selector:alcohol ratio 2:1)
26.0 mmol (12.0 g) of (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane and 26.0 mmol (5.25 g) of aluminum triisopropoxide are put into 60 ml of diphenyl ether in a glove box. The resulting suspension is stirred under protective gas at 90° C. for 60 min. This is followed by addition of 13 mmol (1.56 g) of 1-phenylethanol with an (R)-1-phenylethanol enantiomeric excess of 94.2% ee, and stirring for a further 10 min. Subsequently, the resulting isopropanol is distilled out under about 20 mbar. Then 1.10 g of a mixture of (R)-1-phenylethanol and (S)-1-phenylethanol are obtained as distillate at 1 mbar and 90° C. Investigation of the distillate by chiral gas chromatography (BGB-Analytikvertrieb BGB-174S) revealed an (R)-1-phenylethanol enantiomeric excess of 95.4%.
Separation of rac.-trans-1,2-diaminocyclohexane using a chiral selector generated from (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane and Ti(O-isopropyl)4
6.5 mmol (3.0 g) of (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane and 6.5 mmol (1.83 g) of titanium tetraisopropoxide are put into 20 ml of diphenyl ether in a glove box. The resulting yellow solution is stirred under protective gas at 90° C. for 60 min. This is followed by addition of 26 mmol (2.94 g) of racemic trans-1,2-diaminocyclohexane and stirring for a further 10 min, and then the resulting isopropanol is distilled out under about 20 mbar. Subsequently, about 0.8 g of a mixture of diphenyl ether and 1,2-diaminocyclohexane is distilled out at 1 mbar and 90° C. The enantiomeric excess determined by gas chromatography (Chirasil Dex CB, TFA derivatization) for (S,S)-1,2-trans-diaminocyclohexane was 12.9%.
Separation of rac.-1,2-propanediol using a chiral selector generated from (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane and Ti(O-isopropyl)4 in the presence of 2-tert-butyl-4-methoxyphenol and 3-tert-butyl-4-methoxyphenol
6.5 mmol (3.0 g) of (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane, 6.5 mmol (1.83 g) of titanium tetraisopropoxide and 13 mmol (2.32 g) of a mixture of 2-tert-butyl-4-methoxyphenol and 3-tert-butyl-4-methoxyphenol are put into 20 ml of diphenyl ether in a glove box. The resulting orange solution is stirred under protective gas at 90° C. for 60 min. This is followed by addition of 13 mmol (0.99 g) of rac.-1,2-propanediol and stirring for a further 10 min. The resulting isopropanol is then distilled out under about 20 mbar. Subsequently, about 1.0 g of a mixture of diphenyl ether and 1,2-propanediol is distilled out at 1 mbar and 90° C. The enantiomeric excess determined by gas chromatography (BGB-174S, TFA derivatization) for (S)-1,2-propanediol was 9.2%.
Separation of rac.-1,2-propanediol using a chiral selector generated from (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane and Ti(O-isopropyl)4 in the presence of didodecylamine
6.5 mmol (3.0 g) of (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane, 6.5 mmol (1.83 g) of titanium tetraisopropoxide and 13 mmol (4.6 g) of didodecylamine are put into 20 ml of diphenyl ether in a glove box. The resulting clear solution is stirred under protective gas at 90° C. for 60 min. This is followed by addition of 26 mmol (1.98 g) of rac.-1,2-propanediol and stirring for a further 10 min. The resulting isopropanol is then distilled out under about 20 mbar. Subsequently, about 3.15 g of a mixture of diphenyl ether and 1,2-propanediol is distilled out at 1 mbar and 90° C. The (S)-1,2-propanediol enantiomeric excess determined by gas chromatography (BGB-174S, TFA derivatization) was 17.6%.
Separation of rac.-1,2-propanediol using a chiral selector generated from (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane and Ti(O-isopropyl)4 in the presence of dodecylamine
6.5 mmol (3.0 g) of (4R,5R)-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane, 6.5 mmol (1.83 g) of titanium tetraisopropoxide and 13 mmol (2.41 g) of dodecylamine are put into 20 ml of diphenyl ether in a glove box. The resulting clear solution is stirred under protective gas at 90° C. for 60 min. This is followed by addition of 26 mmol (1.98 g) of rac.-1,2-propanediol and stirring for a further 10 min. The resulting isopropanol is then distilled out under about 20 mbar. Subsequently, 2.3 g of a mixture of diphenyl ether and 1,2-propanediol is distilled out at 1 mbar and 90° C. The (S)-1,2-propanediol enantiomeric excess determined by gas chromatography (BGB-174S, TFA derivatization) was 14.8%.
| Number | Date | Country | Kind |
|---|---|---|---|
| 10 2005 046 917.5 | Sep 2005 | DE | national |
| 06113819.4 | May 2006 | EP | regional |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP2006/066910 | 9/29/2006 | WO | 00 | 3/19/2008 |
