DE10359702B4 - Enantioselective process for the preparation of optically active alkynols - Google Patents

Abstract

method for the preparation of alpha-alkyne alcohols consisting of the reaction a carbonyl compound with a terminal alkyne in the presence a zinc sulfonate and an optically active aminoalcohol, thereby in that the optically active aminoalcohol and the zinc sulphonate in a molar ratio of (2 to 3): 1 are used.

Description

The The invention relates to an enantioselective process for the preparation of optically active alkynols (propargyl alcohols). Optically active Propargyl alcohols are important building blocks for the production of pharmaceutical agents and pesticides.

Out US 6,586,644 , JP 2003-261485 and NK Anand et al., J. Am. Chem. Soc., 2001, 123, p. 9687 discloses a catalytic process in which optically active alkynols are prepared enantioselectively by reacting aldehydes with terminal alkynes in the presence of a tertiary amine, an optically active aminoalcohol (N-methylephedrine) and zinc triflate ,

To this method can however, in most cases only either high chemical yields at comparatively low optical yields are achieved, such as 94% chemical yield at only 86% ee, or in cases achieved in the high optical yields, you get only low chemical yields, such as 99% ee with only 80% chemical Yield. Only with a few substrates is both the chemical as well as the optical yield satisfactory, but this allows Method does not provide universal access to a broad spectrum optically active alkynols with nevertheless high chemical and optical yields.

For an industrial However, applications are generally high-chemical methods Yields and enantioselectivities because of economical reasons desirable. It should be regularly optical Yields of> 97% ee available to be on costly measures to dispense with enantiomeric enrichment.

Out CN 1314333 and Z. Chen et al., Chem. Commun., 2002, p. 2098, discloses an enantioselective process for the preparation of optically active propargyl alcohols in which aldehydes having terminal alkynes in the presence of a base, in particular tertiary amines such as pyridine or triethylamine optically active aminoalcohol or aminoglycols and zinc triflate or Zinkdiflat be implemented. When catalytic use of zinc sulfonate and chiral ligand only enantioselectivities of a maximum of 74 to 91% ee can be achieved. For the above reasons, such a method is less interesting for industrial use for economic reasons.

In Org. Lett., 2002, 4, p. 3451, B. Jiang et al. a procedure, in the α-ketoester as activated ketone substrates with terminal alkynes in the presence of triethylamine, an aminoalcohol and zinc triflate to form of optically active tertiary Propargyl alcohols are reacted. Also in this process will be only enantioselectivities of a maximum of 73 to 94% ee achieved. Only in a few cases are they enough chemical and optical yields meet the high requirements of a economic process on an industrial scale.

None the method known from the prior art provides for a broad Spectrum of optically active propargyl alcohols both high chemical as well as high optical yields. The from the state of the art known processes are thus particularly for large-scale and economical synthesis of optically active alkynols little suitable.

It Therefore, the task was an economic, universal and large-scale feasible To provide methods that under an enantioselective Synthesis of highly enantiomerically enriched propargylic alcohols in high yields and thus solves the problems known from the prior art.

It was surprising found that the preparation of optically active alkynols by simple reaction of carbonyl compounds - especially aldehydes or reactive ketones - with terminal alkynes in the presence of optically active aminoalcohol auxiliaries and zinc sulfonate particularly advantageous and economical and with a big one Width of substrates performed can be.

object The invention is a process for producing optically active alpha-alkyne alcohols consisting of the reaction of a carbonyl compound with a terminal alkyne in the presence of a zinc sulfonate and an optically active aminoalcohol, characterized in that the optically active aminoalcohol and the zinc sulfate in a molar ratio of (2 to 3): 1 are used.

wobei
R¹ einen gegebenenfalls durch -Si(R^x)₃ oder -OSi(R^x)₃ substituierten oder hydroxy-, halogen-, nitro- oder cyanosubstituierten C₁-C₃₀-Kohlenwasserstoffrest, in dem eine oder mehrere Methyleneinheiten durch Gruppen -O-, -CO-, -COO-, -OCO-, oder -OCOO-, -S-, -NR^y- oder -NSi(R^x)₃- ersetzt sein können und in dem eine oder mehrere Methineinheiten durch Gruppen -N= oder -P= ersetzt sein können, bedeutet und
R² ausgewählt wird aus der Gruppe enthaltend Wasserstoff, -COR¹, -COOR¹, -CONR¹R³, -CN, -C(X)_n(R³)_3-n, C(R³)(OR¹)₂ und
R³ Wasserstoff oder einen gegebenenfalls durch -Si(R^x)₃ oder -OSi(R^x)₃ substituierten oder hydroxy-, halogen-, nitro- oder cyanosubstituierten C₁-C₃₀-Kohlenwasserstoffrest, in dem eine oder mehrere Methyleneinheiten durch Gruppen -O-, -CO-, -COO-, -OCO-, oder -OCOO-, -S-, -NR^y- oder -NSi(R^x)₃- ersetzt sein können und in dem eine oder mehrere Methineinheiten durch Gruppen -N= oder -P= ersetzt sein können, bedeutet und
R^x Wasserstoff oder einen gegebenenfalls halogensubstituierten C₁-C₃₀-Kohlenwasserstoffrest, in dem eine oder mehrere Methyleneinheiten durch Gruppen -O-, -CO-, -COO-, -OCO- oder -N-C₁-C₂₀-Alkyl ersetzt sein können, bedeutet und
R^y Wasserstoff oder einen gegebenenfalls halogen- oder hydroxysubstituierten C₁-C₃₀-Kohlenwasserstoffrest, in dem eine oder mehrere, einander nicht benachbarte Methyleneinheiten durch Gruppen -O-, -CO-, -COO-, -OCO-, oder -OCOO-, -S-, -NH- oder -N-C₁-C₂₀-Alkyl ersetzt sein können und in dem eine oder mehrere Methineinheiten durch Gruppen -N= oder -P= ersetzt sein können, bedeutet und
x für Fluor, Chlor oder Brom und
n für 1, 2 oder 3 steht,
bestehend aus der Umsetzung
einer Carbonylverbindung der allgemeinen Formel (2) R¹R²C=O (2)mit einem Alkin der allgemeinen Formel (3) H-C≡C-R³ (3) in Gegenwart eines Zinksulfonates und einem optisch aktivem Auxiliar der allgemeinen Formel (4)

wobei
R¹ und R³ die oben benannte Bedeutung haben und
R⁴, R⁵, R⁶, R⁷, R⁸ und R⁹ unabhängig voneinander ausgewählt werden aus der Gruppe enthaltend Wasserstoff oder einen gegebenenfalls durch -Si(R^x)₃ oder -OSi(R^x)₃ substituierten oder hydroxy-, halogen-, nitro- oder cyanosubstituierten C₁-C₃₀-Kohlenwasserstoffrest, in dem eine oder mehrere Methyleneinheiten durch Gruppen -O-, -CO-, -COO-, -OCO-, oder -OCOO-, -S-, -NR^y- oder -NSi(R^x)₃- ersetzt sein können und in dem eine oder mehrere Methineinheiten durch Gruppen -N= oder -P= ersetzt sein können, und
m für 0, 1 oder 2 steht.A preferred embodiment of the invention is a process for the preparation of compounds the general formula (1),

in which
R ^{1 is} an optionally substituted by -Si (R ^x ) ₃ or -OSi (R ^x ) ₃ or hydroxy, halogen, nitro or cyano-substituted C ₁ -C ₃₀ hydrocarbon radical in which one or more methylene units represented by groups -O -, -CO-, -COO-, -OCO-, or -OCOO-, -S-, -NR ^y - or -NSi (R ^x ) ₃ - may be replaced and in which one or more methine units by groups -N = or -P = can be replaced, means and
R ^{2 is} selected from the group consisting of hydrogen, -COR ¹ , -COOR ¹ , -CONR ¹ R ³ , -CN, -C (X) _n (R ³ ) _3-n , C (R ³ ) (OR ¹ ) ₂ and
R ^{3 is} hydrogen or an optionally substituted by -Si (R ^x ) ₃ or -OSi (R ^x ) ₃ or hydroxy, halogen, nitro or cyano-substituted C ₁ -C ₃₀ hydrocarbon radical in which one or more methylene units by groups -O-, -CO-, -COO-, -OCO-, or -OCOO-, -S-, -NR ^y - or -NSi (R ^x ) ₃ - may be replaced and in which one or more methine units by groups -N = or -P = can be replaced, means and
R ^{x is} hydrogen or an optionally halogen-substituted C ₁ -C ₃₀ -hydrocarbon radical in which one or more methylene units may be replaced by groups -O-, -CO-, -COO-, -OCO- or -NC ₁ -C ₂₀ -alkyl , means and
R ^{y is} hydrogen or an optionally halogen- or hydroxy-substituted C ₁ -C ₃₀ -hydrocarbon radical in which one or more, non-adjacent methylene units are represented by -O-, -CO-, -COO-, -OCO- or -OCO- groups. , -S-, -NH- or -NC ₁ -C ₂₀ -alkyl and in which one or more methine units may be replaced by groups -N = or -P =, and
x for fluorine, chlorine or bromine and
n is 1, 2 or 3,
consisting of the implementation
a carbonyl compound of the general formula (2) R ¹ R ² C = O (2) with an alkyne of the general formula (3) HC≡CR ³ (3) in the presence of a zinc sulfonate and an optically active auxiliary of the general formula (4)

in which
R ¹ and R ^{3 have} the abovementioned meaning and
R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ^{9 are} independently selected from the group consisting of hydrogen or an optionally substituted by -Si (R ^x ) ₃ or -OSi (R ^x ) ₃ or hydroxy-, halogen, nitro or cyano-substituted C ₁ -C ₃₀ -hydrocarbon radical in which one or more methylene units are represented by -O-, -CO-, -COO-, -OCO-, or -OCO-, -S-, -NR ^y - or -NSi (R ^x ) ₃ - may be replaced and in which one or more methine units may be replaced by groups -N = or -P =, and
m is 0, 1 or 2.

erhalten.In a typical embodiment of the process according to the invention, compounds in the optical configuration of the general formulas (1a) or (1b) are synthesized in this way in the course of an enantioselective reaction.

receive.

The C ₁ -C ₃₀ -hydrocarbon radicals for R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ^x and R ^y can be configured linear or branched, cyclic or containing cyclic groups ,

The C ₁ -C ₃₀ -hydrocarbon radicals for R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ^x and R ^y are preferably linear, branched or cyclic, saturated or unsaturated C C ₁ -C ₂₀ -alkyl, C ₂ -C ₂₀ -alkenyl, C ₂ -C ₂₀ -alkynyl, C ₅ -C ₂₀ -acetalalkenyl, C ₃ -C ₂₀ -alkoxycarbonylalkyl radicals, which may be substituted by F, Cl, Br, J, CN, NO ₂ , OH, C ₁ -C ₁₀ -alkoxy radicals, C ₁ -C ₆ -trialkylsilyl radicals, C ₁ -C ₆ -trialkylsilyloxy radicals, triarylsilyl radicals, C ₁ -C ₆ -triaryllyilyloxy radicals, C ₁ - C ₁₀ -alkylamino radicals, C ₁ -C ₆ -trialkylsilylamino radicals and C ₁ -C ₆ -trialkylsilyl-C ₁ -C ₁₀ -alkylamino radicals and in which methylene units may be replaced by -O-, -S-, -NR ^y -, aryl -, aralkyl, alkaryl, aralkenyl, Alkenylarylreste, in which one or more methine units by groups -N = or -P =, and in which methylene units may be replaced by -O-, -S- or -NR ^y - and which may be substituted by F, Cl, Br, J, CN, NO ₂ , C ₁ -C ₁₀ -alko xyrenes, C ₁ -C ₁₀ -alkylamino radicals and C ₁ -C ₁₀ -alkyl radicals and in the ring can carry the heteroatoms -O-, -S- or -NR ^y -.

Particularly preferred radicals R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, butyl, sec-butyl tert-butyl, n-pentyl, n-heptyl, n-octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, allyl, vinyl, phenyl, naphthyl, benzyl, furyl, piperidinyl, pyrrolidinyl, quinolinyl, pyridyl, piperazinyl, Imidazolyl, pirimidinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolyl, isothiazolyl, indolyl, triazinyl, thienyl, thiophenyl, which are represented by methyl, ethyl, n-propyl, isopropyl, butyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, n-octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, allyl, vinyl, phenyl, naphthyl, furyl, piperidinyl, pyrrolidinyl, quinolinyl, pyridyl, piperazinyl, imidazolyl, pirimidinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolyl, Isothiazolyl, indolyl, triazinyl, thienyl, thiophenyl, fluorine, chlorine, bromine, nitro, cyano, hydroxy, methoxy, ethoxy, phenoxy, Trimethylsilyl, triethylsilyl, triisopropylsilyl, triphenylsilyl, tert-butyldimethylsilyl, trimethylsilyloxy, triethylsilyloxy, triisopropylsilyloxy, triphenylsilyloxy, tert-butyldimethylsilyloxy, acetyl, acetoxy, propionyl, amino, N, N-dimethylamino, N-benzyl, N-acetylamino, N- Acetyl-N-methylamino, N-benzyloxycarbonylamino, tert-butyloxycarbonylamino, as well as acetyl, amino, N, N-dimethylamino, N-benzyl, N-acetylamino, N-acetyl-N-methylamino-, N-benzyloxycarbonylamino, tert-butyloxycarbonylamino, nitro, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, methoxy, ethoxy, phenoxy, Acetoxy, benzyloxy, trimethylsilyl, tert-butyldimethylsilyl, trimethylsilyloxy, triethylsilyloxy-triisopropylsilyloxy, tert-butyldimethylsilyloxy, fluoro, chloro, bromo, iodo, and cyanophenyl and naphthyl.

A particularly preferred radical for R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ is, in addition to the above, hydrogen, wherein in the optically active auxiliary of the general formula (4) only three of the four radicals R ⁴ , R ⁵ , R ⁸ and R ⁹ may be hydrogen at the same time.

Preferred radicals for R ² are those in which R ¹ and R ^{3 are selected} from the abovementioned preferred embodiments of R ¹ and R ³ .

Preferred radicals X in R ² are fluorine and chlorine.

Preferred radicals R ^x are hydrogen, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, norbornyl, allyl, vinyl, phenyl, naphthyl, benzyl, methoxy, ethoxy, propoxy, Phenoxy, in particular methyl, ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, norbornyl and phenyl.

Preferred radicals for R ^y are hydrogen and linear, branched or cyclic C ₁ -C ₂₀ -alkyl, C ₂ -C ₂₀ -alkenyl, C ₅ -C ₂₀ -acetalalkenyl, C ₃ -C ₂₀ -alkoxycarbonylalkyl radicals which are substituted can be by F, Cl, Br, J, NO ₂ , CN, OH and C ₁ -C ₁₀ -alkoxy radicals and C ₁ -C ₁₀ -alkylamino radicals and in which methylene units may be replaced by -O-, -S-, -NH-, aryl- , Aralkyl, alkaryl, aralkenyl, alkenylaryl radicals in which one or more methine units can be replaced by -N = or -P = groups, and in which methylene units can be replaced by -O-, -S-, -NH- and substituted can be represented by F, Cl, Br, J, NO ₂ , CN, OH, C ₁ -C ₁₀ alkoxy and C ₁ -C ₁₀ alkylamino radicals and by C ₁ -C ₁₀ alkyl radicals and in the ring the heteroatoms -O -, -S- or -NH- can carry.

Particularly preferred radicals for R ^y are hydrogen, methyl, ethyl, n-propyl, isopropyl, butyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, allyl, vinyl, phenyl, naphthyl, benzyl, hydroxy , Acetyl, acetoxy, propionyl, benzyloxycarbonyl, tert-butyloxycarbonyl, in particular hydrogen, methyl, allyl, benzyl, acetyl, benzyloxycarbonyl and tert-butyloxycarbonyl.

When Carbonyl compounds, in particular those of the general formula (2) can Aldehydes or keto compounds, in particular activated, reactive Keto compounds (reactive ketones) are used.

at Use of aldehydes as the carbonyl component is obtained after the inventive method secondary alpha-alkyne alcohols, while Keto compounds to tertiary alpha-alkyne alcohols to lead.

When Aldehydes can aliphatic and aromatic aldehydes, optionally suitably substituted used become.

When activated ketones are generally diketones, ketoesters, ketoamides, Ketonitrile, haloketones and their derivatives are suitable α-keto esters are suitable and α-haloketones.

Possibly The aldehydes or reactive ketones are used before they are used Purified by distillation or recrystallization (in particular at technical starting materials with purities <90 wt .-%).

When Alkyne component, in particular those of the general formula (3), can generally terminal alkynes are used. In a possible embodiment the method according to the invention can also be gaseous Acetylene be reacted.

It has proved its worth, the alkyne, especially those of the general formula (3), with the Carbonyl compound, especially those of the general formula (2) in molar ratio (0.5 to 5): 1, in particular (1 to 1.5): 1 implement.

Basically the inventive method both with stoichiometric Use of aminoalcohol auxiliary and / or zinc sulfonate or even with excess of aminoalcohol auxiliary and / or zinc sulfonate based on the carbonyl compound. For economic reasons establish however, is the catalytic and thus substoichometric use of aminoalcohol auxiliary and / or zinc sulfonate based on the carbonyl compound.

When Auxiliary, in particular those of the general formula (4), for the enantioselective Reaction generally optically active amino alcohols are used (Aminoalcohol auxiliary).

Basically an optically active auxiliary, as well as a mixture of different optical auxiliaries are used, in particular mixtures of below preferred and particularly preferred embodiments.

When optically active aminoalcohol auxiliary, especially those of general formula (4), a β-aminoalcohol having m = 0 is preferably used. Particularly preferred embodiments of the aminoalcohol auxiliary are optically active N-methylephedrine compounds, optically active 2-dimethylamino-1-phenylethanol compounds, optically active 1-dimethylamino-3,3-dimethylbutan-2-ol compounds and optically active 2-dimethylaminopropan-1-ol compounds, where either the (+) or the forms are used and thus the R or the S-shape of the desired Product can be produced.

Especially is commercially available (+) - and (-) - N-methylephedrine or (+) - and (-) - 2-dimethylamino-1-phenylethanol.

In principle, one or mixtures of several optically active and equivalent auxi be used.

Becomes (+) - N-Methylephedrine and / or (+) - 2-dimethylamino-1-phenylethanol as Auxiliary for the reaction of phenylacetylene with cyclohexylcarbaldehyde or Isobutyraldehyde used, then you get the R-configuration of the alkynol. Will (-) - N-Methylephedrine and / or (-) - 2-dimethylamino-1-phenylethanol used, so receives the S configuration of the alkynol.

It has proved its worth, the optically active amino alcohol auxiliary, in particular one of general formula (4), with the carbonyl compound, in particular one of the general formula (2) in the molar ratio (0.01 to 3): 1 implement. Preference is given to a molar ratio from (0.03 to 0.6): 1, in particular from (0.05 to 0.4): 1 (catalytic Commitment).

To the method according to the invention the reaction of the alkyne with the carbonyl compound in the presence a zinc sulfonate promoted. As preferred embodiments zinc sulfonates find zinc trifluoromethanesulfonate (zinc triflate) and zinc difluoromethanesulfonate (zinc diflate) use, especially preferably zinc triflate. To increase the activity, the zinc sulfonate before implementation the reaction by heating at 80-150 ° C under reduced Pressure dried.

It has proved its worth, the zinc sulfonate with the carbonyl compound in the molar ratio (0.001 to 3): 1 implement. Preference is given to a molar ratio of (0.01 to 0.6) 1, in particular from (0.03 to 0.3): 1 (catalytic use).

It was now surprisingly found that the enantioselective synthesis of the alpha-alkyne alcohols, in particular those of the general formula (1), by the process according to the invention in the presence of an optically active auxiliary and zinc sulfonate with particularly high optical yields of regularly> 97% ee and at the same time very high chemical Yields go, if opposite the known from the prior art method to the addition further basic additives, in particular tertiary amines is deliberately omitted. Presumably, these yield increases are on it attributed to that according to the inventive method no additional achiral base - in particular tertiary Nitrogen bases with known dimensions high zinc affinity - in addition the chiral auxiliary competes for zinc as the promoter of the reaction.

So receives one by the method according to the invention (R) -1-cyclohexyl-3-phenyl-2-propyn-1-ol with 98% yield> 98% ee (see also example 2a). Under analogous conditions but in Presence of tertiary Amine base triethylamine, N.K. Anand et al., J. Am. Chem. Soc., 2001, 123, p. 9687, however, in a chemical yield of 95% yield only an enantiomeric excess of 89% ee (see also Comparative Example 2b).

The Absence of basic additives, in particular of tertiary amines, is for Achieving very high optical yields at the same time high decisive for chemical yields.

In some cases it has proven itself the procedure additionally in the presence of a secondary amine perform.

So was in an alternative embodiment the method according to the invention demonstrated that the enantioselective synthesis of the alpha-alkyne alcohols, in particular those of the general formula (1), by the process according to the invention in the presence of an optically active auxiliary and zinc sulfonate also then with particularly high enantioselectivities of regularly> 97% ee and simultaneously Very high chemical yields occur when secondary amines be used. The secondary Amines do not form enamines here with aldehydes and ketones By-products and impurities lead. In the presence of secondary amines no impurities are formed, but the secondary amines effect the formation of the desired Alkynols with, opposite the previously known method using tertiary amines (triethylamine, pyridine), higher Enantioselectivity.

When secondary Amines are generally linear, cyclic, aliphatic and aromatic amines, in particular dialkyl, diaryl and alkylarylamines.

Examples of particularly suitable secondary amines are diethyl, dipropyl, diisopropyl, dibutyl, diisobutyl, di-tert-butyl, methyl tert-butyl, ethyl tert-butyl, ethyl isopropylamine, 2, 2,6,6-tetramethylpiperidine and diphenylamine. In particular, sterically demanding bases such as diisopropylamine and 2,2,6,6-tetramethylpiperidine.

It has proven itself generally, the secondary one Amine with the carbonyl compound, in particular one of the general Formula (2), in molar ratio (0.01 to 1.5): 1, particularly preferably (0.05 to 0.6): 1 implement.

Prefers becomes the method according to the invention but without the addition of a secondary Amines performed.

The Implementation can basically in the presence or absence of a solvent, preferred is the implementation in the presence of a solvent.

suitable solvent are generally hydrocarbons, halogenated hydrocarbons, linear and cyclic ethers, di- and oligoethers, esters and polar aprotic solvents and their mixtures.

preferred solvent are selected from the group containing pentane, hexane, heptane, octane, cyclohexane, Benzene, toluene, chlorobenzene, dichloromethane, diethyl ether, methyl tert-butyl ether, dimethoxymethane and ethane, diethoxymethane and ethane, tetrahydrofuran, tetrahydropyran, Dioxane, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, Ethyl acetate, acetonitrile, propionitrile, dimethylformamide or mixtures two or more of these solvents. Particularly preferred solvents are toluene, diethyl ether, methyl tert-butyl ether and methylene chloride or mixtures thereof, particularly preferably toluene.

Becomes the reaction is carried out in the presence of a solvent, then the concentration of the mixture should be greater than 5% by weight based on the used carbonyl compound, in particular 8 to 40 % By weight.

The inventive method is generally at temperatures from 0 to + 110 ° C, preferably at 10 to 80 ° C, especially at 20 to 60 ° C, optionally with reflux and optionally with reduced Pressure performed.

The Duration of implementation is usually 0.25 to 24 hours, especially 1 to 10 hours.

Of the Pressure range of the reaction is not critical and can continue within Limits are varied. The pressure is usually 0.01 to 20 bar, the reaction is preferably carried out under normal pressure (atmospheric pressure) carried out.

The Reaction is preferably carried out under inerting with an inert protective gas, in particular nitrogen or argon. The reaction can be continuous or discontinuously, preferably batchwise.

In a particularly preferred embodiment the method according to the invention is the reaction at substoichiometric or catalytic use of the optically active aminoalcohol auxiliary of (0.05 to 0.5): 1 and of zinc sulfonate of (0.03 to 0.2) : 1 in mol. Equivalents based on the carbonyl compound, in particular those of the general Formula (2), between 40 and 60 ° C, at reaction times between 1 and 6 h, in toluene as solvent, in a concentration of 8 to 40% by weight based on the carbonyl compound carried out. That way you can especially high product yields and purities as well as very high ee up to> 98% ee at economic reaction and at the same time achieve particularly high space-time yields.

to Preparation of the alpha-alkyne alcohols, especially those of the general Formula (1) or alpha-alkyne alcohols in the optical configurations of general formula (1a) or (1b) is the order of addition the reaction components and the solvent in general not mandatory. In a typical embodiment the method according to the invention becomes common first zinc sulfonate in the agitator submitted and in a vacuum at elevated Temperature dried. Subsequently the optically active auxiliary is added and optionally one solvent added. It is also possible, to submit the optically active auxiliary, then add the zinc sulfonate and to dry the mixture. Subsequently, if necessary, a solvent be added. The drying can also alternatively in the presence of solvent carried out be by azeotropic distillation.

The Mixture of zinc sulfonate, auxiliary and optionally solvent is stirred for 1 to 3 h, preferably 2 h at 10 to 30 ° C (premix to form the active zinc complex). The premix is omitted in particular in substoichiometric, catalytic use of zinc sulfonate and optically active auxiliary on the carbonyl compound. The mixture is then added to the alkyne and last adds to the carbonyl compound too. Alternatively, it is also possible first to add the carbonyl compound and then the alkyne. The reaction mixture will follow until the complete Reaction optionally stirred with heating.

To Completion of the reaction is the reaction mixture for isolation of the alpha-alkyne alcohol according to customary Methods such as extraction, chromatography, Crystallization or distillation, optionally after previous hydrolytic workup, in particular by addition of water, aqueous Acid or aqueous Base.

During the Product isolation can the optically active auxiliary and optionally the zinc sulfonate recovered and reintroduced into the process, what the procedure especially when performing on an industrial scale makes it particularly economical and environmentally friendly.

In a possible Work-up procedure is optionally after previous removal of the solvent used for the reaction first a polar solvent and subsequently optionally another, with the polar solvent or reaction solvent immiscible, preferably nonpolar solvent added and an extraction of the desired Product reaches the nonpolar phase while the optically active Auxiliary and the zinc sulfonate predominantly in the polar phase. The workup and separation the reusable reagents of the desired product are then passed through a phase separation.

In a preferred work-up method is optionally from the Two-phase system, which experience has shown, especially when using an at least six-fold amount of a solvent such as Toluene based on the weight of the carbonyl compound forms, the Solvent through Distillation, optionally under reduced pressure and at elevated temperature between 30 and 120 ° C, away. To the remaining residue becomes a polar solvent such as acetonitrile, propionitrile, dimethylformamide, Methanol, ethylene glycol or acetic acid, preferably acetonitrile, added. Subsequently becomes the optically active Alkinolprodukt with one with the polar solvent immiscible non-polar or low-polar solvent extracted, wherein the biggest part of the zinc sulfonate and the auxiliary remain in the polar phase, while the wished Product is extracted. The nonpolar or poorly polar extractant is preferably selected from the group consisting of hydrocarbons, such as pentane, hexane, heptane, octane, cyclohexane, toluene, benzene or Ethers, such as diisopropyl ether, dibutyl ether or methyl tert-butyl ether selected. Particularly preferred are pentane, hexane, heptane, cyclohexane, toluene and dibutyl ether.

is that for the reaction solvent used in the process according to the invention one for the Extraction usable nonpolar or less polar solvent, especially toluene or benzene, then optionally eliminating the previous distillative Removal of for the reaction used solvent.

The Alkynol product can subsequently by extraction, chromatography, crystallization or distillation, optionally by prior hydrolysis by water, aqueous acid or Base can be isolated from the non-polar or low-polar phase, again residues of the auxiliary can be recovered.

In In a particularly preferred form of work-up, the reaction takes place in toluene, which subsequently removed by distillation and the remaining residue with acetonitrile as polar solvent and pentane, hexane, heptane or dibutyl ether as a nonpolar solvent is offset. In the pentane, hexane, heptane or dibutyl ether phase accumulates the desired Product on while the optically active auxiliary and the zinc sulfonate predominantly in the acetonitrile phase.

The in this way obtained alkynol crude products are of very high Purity and can usually further processed without further purification and as starting materials used for the production of pharmaceuticals and agrochemicals become.

For the recovery and reuse of the zinc sulfonate and the auxiliary from the polar phase, the polar solvent is removed by distillation. The residue contains zinc sulfonate and high purity auxiliary and can be reintroduced into the synthesis process (recycling), if necessary after Restore the original stoichiometry by adding small amounts of zinc sulfonate and auxiliary.

The Extraction process and recovery of zinc sulfonate and auxiliary for the renewed use in the synthesis process make the inventive method particularly economical and resource and environmentally friendly.

The Advantages of the method according to the invention in particular, that the process is the synthesis of the optical active alkynols (alpha-alkyne alcohols), in particular those of general formula (1), with particularly high and compared to the method known from the prior art significantly better ee permitting at the same time very high chemical yields. Just with catalytic use of optically active auxiliary and zinc sulfonate Compared to the previously known methods with up to 10% points enantiomeric excess (ee) higher ee achieves what additional, downstream measures makes it unnecessary to enantiomeric enrichment.

Becomes the reaction of the alkyne with the carbonyl compound only in the presence of the optically active auxiliary and zinc sulfonate and without further Addition of excipients, in particular tertiary amine performed designed the work-up, isolation of the product and recovery of the auxiliary and zinc sulfonate procedurally unproblematic, efficient and economical. Unlike the ones from the state known in the art is a complicated separation of the basic Amino alcohol auxiliaries of other basic additives, in particular tertiary Amin no longer by distillation, extraction or crystallization necessary. For example, in the case of acidic hydrolytic work-up the aminoalcohol auxiliary unproblematic from the aqueous Phase recovered become.

moreover allows the extractive separation of the product from the polar amino alcohol-zinc sulfonate phase a technically simple and very efficient product isolation at the same time, very high recycling rates of zinc sulphonate and aminoalcohol auxiliary. This makes the process is particularly economical and environmentally friendly.

All The above symbols of the above formulas have their meanings each independently on.

In the following examples are, unless stated otherwise, all quantities and percentages by weight, all pressures 0.10 MPa (abs.) And all temperatures 20 ° C. The examples serve the further illustration of the method according to the invention and are in no way as a limitation consider.

Example 1a:

Preparation of (S) -1-cyclohexyl-3-phenyl-2-propyn-1-ol

At room temperature, 270 mg of zinc triflate (0.75 mmol, 10 mol%) were placed in a three-necked flask equipped with internal thermometer, dropping funnel and stirrer under nitrogen blanketing and dried at 120 ° C and 0.5 mbar for 2 h. After 403 mg of (-) - N-methylephedrine (2.25 mmol, 30 mol%) and 7.5 ml of toluene were added at 23 ° C., the mixture was stirred for 15 min at 23 ° C., then 918 mg of phenylacetylene (9 mmol, 120 mol%) and stirred again at 23 ° C for 15 min. Then, 840 mg of cyclohexylcarbaldehyde (7.5 mmol, 100 mol%) was added. The mixture was then heated to 50 ° C and stirred for 2 h. After cooling to 25 ° C, the mixture was treated with 6 ml of concentrated ammonia and 30 ml of ether, stirred for 10 min and then separated the organic phase. The organic phase was then stirred for 10 minutes with 15 ml of 1 N hydrochloric acid. After phase separation, the hydrochloric acid aqueous phase was extracted with 30 ml of ether. The organic ether phases were combined. After drying and removal of solvent in vacuo, (S) -1-cyclohexyl-3-phenyl-2-propyn-1-ol was obtained in a yield of 1.59 g (98% of theory) and 97% ee (HPLC, Chiracel OD-H, 10% i-PrOH in hexane, 0.5 ml / min, 208 nm, t _r 7.0 (R isomer), 15.0 (S isomer)).

Example 1b - Comparative Example

Preparation of (S) -1-cyclohexyl-3-phenyl-2-propyn-1-ol in the presence of triethylamine according to N.K. Anand et al., J. Am. Chem. Soc., 2001, 123, p. 9687.

At room temperature, in a three-necked flask with internal thermometer, dropping funnel and stirrer 270 mg of zinc triflate (0.75 mmol, 10 mol%) are initially introduced under nitrogen blanketing and dried at 120 ° C. and 0.5 mbar for 2 h. After 148 mg (-) - N-methylephedrine (0.825 mmol, 11 mol%), 7.5 ml of toluene and 189 mg of triethylamine (1.875 mmol, 25 mol%) were added at 23 ° C, the mixture was stirred for 15 min 23 ° C, then added 918 mg of phenylacetylene (9 mmol, 120 mol%) and stirred for another 15 min at 23 ° C. Then, 840 mg of cyclohexylcarbaldehyde (7.5 mmol, 100 mol%) was added. The mixture was then heated to 50 ° C and stirred for 2 h. After working up as described in Example 1a, (S) -1-cyclohexyl-3-phenyl-2-propyn-1-ol was obtained in a yield of 1.56 g (96% of theory) and 92% ee.

Example 2a:

Preparation of (R) -1-cyclohexyl-3-phenyl-2-propyn-1-ol.

at Room temperature were in a three-necked flask with internal thermometer, Dropping funnel and stirrer under Nitrogen blanket 182 mg zinc triflate (0.5 mmol, 20 mol%) and 2 h at 120 ° C and 0.5 mbar dried. After at 25 ° C 225 mg of (+) - N-methylephedrine (1.25 mmol, 50 mol%) and 7.5 ml of toluene added were stirred the mixture for 2 h at 25 ° C, continued afterwards 306 mg of phenylacetylene (3 mmol, 120 mol%) and stirred again 15 min at 25 ° C. Then, 280 mg of cyclohexylcarbaldehyde (2.5 mmol, 100 mol%) was added. you heated the mixture afterwards to 50 ° C and stirred 3 h. After working up as described in Example 1a, (R) -1-cyclohexyl-3-phenyl-2-propyn-1-ol in a yield of 530 mg (98% of theory) and 98.4% ee.

Example 2b - Comparative Example

Preparation of (R) -1-cyclohexyl-3-phenyl-2-propyn-1-ol in the presence of triethylamine according to N.K. Anand et al., J. Am. Chem. Soc., 2001, 123, p. 9687.

at Room temperature were in a three-necked flask with internal thermometer, Dropping funnel and stirrer under Nitrogen blanket 180 mg of zinc triflate (0.5 mmol, 20 mol%) and 2 h at 120 ° C and 0.5 mbar dried. After at 25 ° C 100 mg (+) - methylephedrine (0.55 mmol, 22 mol%) were added, The mixture was kept at 0.5 mbar for 30 min. Subsequently were 2.5 ml of toluene and 126 mg of triethylamine (1.25 mmol, 50 mol%) was added and man stir the mixture for 2 h at 25 ° C, continued afterwards 306 mg of phenylacetylene (3 mmol, 120 mol%) and stirred again 15 min at 25 ° C. Then, 280 mg of cyclohexylcarbaldehyde (2.5 mmol, 100 mol%) was added. you heated the mixture afterwards to 50 ° C and stirred 3 h at 50 ° C. To Work-up as described under Example 1a (R) -1-cyclohexyl-3-phenyl-2-propyn-1-ol in a yield of 515 mg (95% of theory) and 89% ee.

N. K. Anand et al., J. Am. Chem. Soc., 2001, 123, p. 9687 (R) -1-Cyclohexyl-3-phenyl-2-propyn-1-ol at a reaction temperature of 23 ° C and a reaction time of 5 h and otherwise identical reaction conditions in a yield of 94% d. Th. And 86% ee.

Example 3a:

Preparation of (R) -1,5-diphenyl-2-pentyne-1-ol.

Analogously to Example 1a, using 270 mg of zinc triflate (0.75 mmol, 30 mol%), 269 mg of (+) - N-methylephedrine (1.5 mmol, 60 mol%), 306 mg of phenylacetylene (3 mmol, 120 mol%). ) and 265 mg of benzaldehyde (2.5 mmol, 100 mol%) in 2.5 ml of toluene at a reaction temperature of 25 ° C and a reaction time of 10 h under otherwise identical conditions (R) -1,5-diphenyl-2-pentyne-1 in a yield of 437 mg (84% of theory) and 94% ee (HPLC, Chiracel OD-H, 10% i-PrOH in hexane, 0.5 ml / min, 208 nm, t _r 14.0 (R Isomer), 24.9 (S-isomer)).

Example 3b - Comparative Example

Preparation of (R) -1,5-diphenyl-2-pentyne-1-ol in the presence of triethylamine according to N.K. Anand et al., J. Am. Chem. Soc., 2001, 123, p. 9687.

Using Example 270, using 270 mg zinc triflate (0.75 mmol, 30 mol%), 148 mg (+) - N-methylephedrine (0.825 mmol, 33 mol%), 190 mg triethylamine (1.88 mmol, 75 mol%). ), 306 mg of phenylacetylene (3 mmol, 120 mol%) and 265 mg of benzaldehyde (2.5 mmol, 100 mol%) in 2.5 ml of toluene at a reaction temperature of 25 ° C and a reaction time of 10 h under otherwise identical conditions (R. ) -1,5-di phenyl-2-pentin-1-ol in a yield of 360 mg (69% of theory) and 85% ee.

Example 4:

Preparation of (S) -1-cyclohexyl-3-phenyl-2-propyn-1-ol (extractive workup, recycling of sulfonate and auxiliary)

at Room temperature were in a three-necked flask with internal thermometer, Dropping funnel and stirrer under Nitrogen blanket 270 mg of zinc triflate (0.75 mmol, 10 mol%) and 2 h at 120 ° C and 0.5 mbar dried. After at 23 ° C 403 mg (-) - N-methylephedrine (2.25 mmol, 30 mol%) and 7.5 ml of toluene were added, the mixture was stirred the mixture for 15 min at 23 ° C, continued afterwards 918 mg of phenylacetylene (9 mmol, 120 mol%) and stirred for another 15 min at 23 ° C. Then were Added 840 mg of cyclohexylcarbaldehyde (7.5 mmol, 100 mol%). you heated the mixture afterwards to 50 ° C and stirred 2 h. Subsequently became the solvent Distilled off toluene at 10 mbar and a temperature of 55 ° C. The residue was added with 20 ml of acetonitrile and the polar phase with 130 ml of heptane extracted continuously in an extractor for 4 h. The upper Heptane product phase was separated (the lower acetonitrile phase was stored), washed with 10 ml of 1 N hydrochloric acid, dried and finally distilled off the extractant in vacuo. (S) -1-cyclohexyl-3-phenyl-2-propyn-1-ol was obtained in a yield of 1.57 g (97% of theory) and 97% ee. For reuse of zinc triflate and (-) - N-methylephedrine the solvent Acetonitrile from the lower acetonitrile phase in vacuo at Temperature of 60 ° C distilled off. The residue contains 90 mol% of zinc triflate used and 80 mol% of the used (-) - N-Methylephedrine. To Restore the original one stoichiometry by topping up, the mixture of zinc triflate and (-) - N-methylephedrine again to prepare (S) -1-cyclohexyl-3-phenyl-2-propyn-1-ol at the same enantioselectivity be used.

Example 5:

Preparation of (R) -1-cyclohexyl-3-phenyl-2-propyn-1-ol

at Room temperature were in a three-necked flask with internal thermometer, Dropping funnel and stirrer under Nitrogen blanket 500 mg zinc triflate (1.38 mmol, 0.55 mol equiv.) Submitted and 2 h at 120 ° C and Dried 0.5 mbar. After 540 mg (+) - N-methylephedrine at 25 ° C (3 mmol, 1.2 mol equiv.) added were kept the mixture at 0.5 mbar for 30 min. Subsequently were Added 7.5 ml of toluene and one touched the mixture for 2 h at 25 ° C, continued afterwards 306 mg of phenylacetylene (3 mmol, 1.20 mol equiv.) To and stirred again 15 min at 25 ° C. Then, 280 mg of cyclohexylcarbaldehyde (2.5 mmol, 1.00 mol equiv.) Was added. you stir the mixture afterwards 2 h at 25 ° C. After working up as described in Example 1a, (R) -1-cyclohexyl-3-phenyl-2-propyn-1-ol in a yield of 530 mg (98% of theory) and 99% ee.

D. E. Frantz et al., J. Am. Chem. Soc., 2000, 122, p. 1806 (R) -1-Cyclohexyl-3-phenyl-2-propyn-1-ol using triethylamine under otherwise identical reaction conditions in a yield of 99% d. Th. And 96% ee.

Example 6a:

Preparation of (R) -1-cyclohexyl-3-phenyl-2-propyn-1-ol in the presence of (+) - 2-dimethylamino-1-phenylethanol.

Analogous Example 1a was carried out using 270 mg zinc triflate (0.75 mmol, 30 mol%), 248 mg of (+) - 2-dimethylamino-1-phenylethanol (1.5 mmol, 60 mol%), 306 mg of phenylacetylene (3 mmol, 120 mol%) and 280 mg of cyclohexylcarbaldehyde (2.5 mmol, 100 mol%) in 7.5 ml of toluene under otherwise identical conditions (R) -1-cyclohexyl-3-phenyl-2-propyn-1-ol in a yield of 530 mg (98% of theory) and 96% ee.

Example 6b - Comparative Example

Preparation of (R) -1-cyclohexyl-3-phenyl-2-propyn-1-ol in the presence of (-) - 2-dimethylamino-1-phenylethanol and triethylamine according to N.K. Anand et al., J. Am. Chem. Soc., 2001, 123, p. 9687.

Analogously to Example 1b, using 270 mg of zinc triflate (0.75 mmol, 30 mol%), 136 mg of (+) - 2-dimethylamino-1-phenylethanol (0.825 mmol, 33 mol%), 189 mg of triethylamine (1.88 mmol, 75 mol%), 306 mg of phenylacetylene (3 mmol, 120 mol%) and 280 mg of cyclohexylcarbaldehyde (2.5 mmol, 100 mol%) in 7.5 ml of toluene under otherwise identical conditions (R) -1-cyclohexyl-3-phenyl-2-propyne-1 -ol in a yield of 514 mg (95% of theory) and 89% ee.

Example 7:

Preparation of (R) -4-methyl-1-phenyl-1-pentyne-3-ol.

Using 1100 mg zinc triflate (3.07 mmol, 1.10 mol equiv.), 1100 mg (+) - N-methylephedrine (6.14 mmol, 2.40 mol equiv.), 340 mg phenylacetylene (3.35 mmol, 1.20 mol Equiv.) And 200 mg of isobutyraldehyde (2.79 mmol, 1.00 mol equiv.) In 8.5 ml of toluene under otherwise identical conditions (R) -4-methyl-1-phenyl-1-pentyne-3-ol in 476 yield mg (98% of theory) and 97% ee (HPLC, Chiracel OD-H, 10% i-PrOH in hexane, 0.5 ml / min, 208 nm, t _r 6.5 (R isomer), 10.6 (S) Isomer)).

D. E. Frantz et al., J. Am. Chem. Soc., 2000, 122, p. 1806 (R) -4-methyl-1-phenyl-1-pentyne-3-ol using triethylamine under otherwise identical reaction conditions in a yield of 95% d. Th. And 90% ee.

Example 8:

Preparation of (S) -1-cyclohexyl-3-phenyl-2-propyn-1-ol

Analogous Example 1a was carried out using 270 mg zinc triflate (0.75 mmol, 10 mol%), 371 mg of (-) - N-dimethylaminophenylethanol (2.25 mmol, 30 mol%), 918 mg of phenylacetylene (9 mmol, 120 mol%) and 840 mg of cyclohexylcarbaldehyde (7.5 mmol, 100 mol%) under otherwise identical conditions (S) -1-cyclohexyl-3-phenyl-2-propyn-1-ol in one Yield of 1.58 g (98% of theory) and 95% ee obtained.

Example 9:

Preparation of (S) -1-cyclohexyl-2-heptyn-1-ol

Analogous Example 1a was carried out using 270 mg zinc triflate (0.75 mmol, 10 mol%), 403 mg (-) - N-methylephedrine (2.25 mmol, 30 mol%), 738 mg of 1-hexyne (9 mmol, 120 mol%) and 840 mg cyclohexylcarbaldehyde (7.5 mmol, 100 mol%) under otherwise identical conditions Conditions (S) -1-cyclohexyl-2-heptyn-1-ol in a yield of 1.43 g (96% of theory) and 98% ee were obtained.

Example 10:

Preparation of (S) -1-cyclohexyl-3-triisopropylsilyl-2-propyn-1-ol

Analogous Example 1a was carried out using 270 mg zinc triflate (0.75 mmol, 10 mol%), 403 mg (-) - N-methylephedrine (2.25 mmol, 30 mol%), 1638 mg of triisopropylsilylacetylene (9 mmol, 120 mol%) and 840 mg Cyclohexylcarbaldehyde (7.5 mmol, 100 mol%) with otherwise identical Conditions (S) -1-cyclohexyl-3-triisopropylsilyl-2-propyn-1-ol in a yield of 2.16 g (98% of theory) and 98% ee.

Example 11:

Preparation of (S) -1-cyclohexyl-5-methoxy-2-pentyne-1-ol

Analogous Example 1a was carried out using 270 mg zinc triflate (0.75 mmol, 10 mol%), 403 mg (-) - N-methylephedrine (2.25 mmol, 30 mol%), 756 mg of 1-methoxy-3-butyne (9 mmol, 120 mol%). and 840 mg of cyclohexylcarbaldehyde (7.5 mmol, 100 mol%) under otherwise identical conditions (S) -1-cyclohexyl-5-methoxy-2-pentyne-1-ol in a yield of 1.44 g (98% of theory) and 97% ee.

Example 12:

Preparation of (3S) -4-ethyl-1-phenyl-1-octyn-3-ol

Using Example 1 a, using 270 mg zinc triflate (0.75 mmol, 10 mol%), 403 mg (-) - N-methylephedrine (2.25 mmol, 30 mol%), 918 mg phenylacetylene (9 mmol, 120 mol%). ) and 960 mg of rac. 2-ethylhexanal (7.5 mmol, 100 mol%) under otherwise identical conditions as a diastereomer mixture of (3S, 4S) -4-ethyl-1-phenyl-1-octyn-3-ol and (3S, 4R) -4-ethyl 1-phenyl-1-octyn-3-ol in a yield of 1.63 g (95% of theory) and 94% ee.

Example 13:

Preparation of (3S) -1-phenyl-1-decyn-3-ol

Analogous Example 1a was carried out using 270 mg zinc triflate (0.75 mmol, 10 mol%), 403 mg (-) - N-methylephedrine (2.25 mmol, 30 mol%), 918 mg phenylacetylene (9 mmol, 120 mol%) and 960 mg of octanal (7.5 mmol, 100 mol%) at a reaction temperature from 40 ° C under otherwise identical conditions, (3S) -1-phenyl-1-decin-3-ol in one Yield of 1.67 g (97% of theory) and 97% ee.

Example 14:

Preparation of (3S) -6-benzyloxy-1-phenyl-1-hexyn-3-ol

Analogous Example 1a was carried out using 270 mg zinc triflate (0.75 mmol, 10 mol%), 403 mg (-) - N-methylephedrine (2.25 mmol, 30 mol%), 918 mg phenylacetylene (9 mmol, 120 mol%) and 1335 mg of 4-benzyloxybutanal (7.5 mmol, 100 mol%) at a reaction temperature from 35 ° C and a reaction time of 8 h under otherwise identical conditions (3S) -6-benzyloxy-1-phenyl-1-hexyne-3-ol in a yield of 2.03 g (97% of theory) and 96% ee.

Example 15:

Preparation of ethyl (2R) -2-methyl-2-hydroxy-4-phenyl-3-butyric acid

Analogous Example 1a was carried out using 540 mg zinc triflate (1.50 mmol, 20 mol%), 806 mg (-) - N-methylephedrine (4.50 mmol, 60 mol%), 1530 mg phenylacetylene (15 mmol, 200 mol%) and 870 mg of pyruvic acid ethyl ester (7.5 mmol, 100 mol%) at a reaction time of 24 h under otherwise identical conditions (2R) -2-methyl-2-hydroxy-4-phenyl-3-butyric acid ethyl ester in a yield of 0.98 g (60% of theory) and 95% ee.

• (*) Ausbeute und ee in Gegenwart von Triethylamin nach N. K. Anand et al., J. Am. Chem. Soc., 2001, 123, S. 9687 bzw. D. E. Frantz et al., J. Am. Chem. Soc., 2000, 122, S. 1806.

Table 1 compares the enantioselectivities and yields of Examples 1 to 15 obtained by the process according to the invention to the corresponding values obtainable with the processes known from the prior art (addition of triethylamine). Table 1

• (*) Yield and ee in the presence of triethylamine according to NK Anand et al., J. Am. Chem. Soc., 2001, 123, p. 9687 and DE Frantz et al., J. Am. Chem. Soc., 2000, 122, p. 1806.

Claims (9)

Process for the preparation of alpha-alkyne alcohols consisting of the reaction of a carbonyl compound with a terminal alkyne in the presence of a zinc sulphonate and an optically active aminoalcohol, characterized in that the optically active aminoalcohol and the zinc sulphonate in a molar ratio of (2 to 3): 1 are used. Process according to Claim 1 for the preparation of compounds of the general formula (1),

where R ^{1 is} a C ₁ -C ₃₀ -hydrocarbon radical which is unsubstituted or substituted by -Si (R ^x ) ₃ or -OSi (R ^x ) ₃ or in which one or more methylene units are substituted by hydroxyl, halogen, nitro or cyano. O-, -CO-, -COO-, -OCO-, or -OCOO-, -S-, -NR ^y - or -NSi (R ^x) ₃ - may be replaced and in which one or more methine groups by - N = or -P = may be replaced, and R ^{2 is} selected from the group consisting of hydrogen, -COR ¹ , -COOR ¹ , -CONR ¹ R ³ , -CN, -C (X) _n (R ³ ) _{3 -n} , C (R ³ ) (OR ¹ ) ₂ and R ^{3 is} hydrogen or an optionally substituted by -Si (R ^x ) ₃ or -OSi (R ^x ) ₃ or hydroxy-, halogen-, nitro- or cyano-substituted C ₁ -C ₃₀ -hydrocarbon radical in which one or more methylene units by groups -O-, -CO-, -COO-, -OCO-, or -OCOO-, -S-, -NR ^y - or -NSi (R ^x) ₃ - may be replaced and in which one or more methine units may be replaced by groups -N = or -P =, bede and R ^{x is} hydrogen or an optionally halogen-substituted C ₁ -C ₃₀ -hydrocarbon radical in which one or more methylene units is replaced by -O-, -CO-, -COO-, -OCO- or -NC ₁ -C ₂₀ -alkyl groups and R ^{y is} hydrogen or an optionally halogen- or hydroxy-substituted C ₁ -C ₃₀ -hydrocarbon radical in which one or more, non-adjacent methylene units are represented by -O-, -CO-, -COO-, -OCO- groups. , or -OCOO-, -S-, -NH- or -NC ₁ -C ₂₀ -alkyl and in which one or more methine units may be replaced by groups -N = or -P =, and x is fluorine , Chlorine or bromine and n is 1, 2 or 3, consisting of the reaction of a carbonyl compound of the general formula (2) R ¹ R ² C = O (2) with an alkyne of the general formula (3) HC≡CR ³ (3) in the presence of a zinc sulfonate and an optically active auxiliary of the general formula (4)

wherein R ¹ and R ^{3 have} the abovementioned meaning and R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ^{9 are} independently selected from the group consisting of hydrogen or optionally by -Si (R ^x ) ₃ or -OSi (R ^x ) ₃ substituted or hydroxy-, halogen-, nitro- or cyano-substituted C ₁ -C ₃₀ -hydrocarbon radical in which one or more methylene units are represented by -O-, -CO-, -COO-, -OCO- , or -OCOO-, -S-, -NR ^y - or -NSi (R ^x ) ₃ - may be replaced and in which one or more methine units may be replaced by groups -N = or -P =, and m is 0 , 1 or 2 stands. Process according to Claim 1 or 2, characterized in that compounds in the optical configuration of the general formulas (1a) or (1b)

receives. Method according to one or more of claims 1 to 3, characterized in that the terminal alkyne with the carbonyl compound in molar ratio (1 to 1.5): 1 is implemented. Method according to one or more of claims 1 to 4, characterized in that as an optically active auxiliary a or more connections selected from the group comprising (+) - N-methylephedrine, (-) - N-methylephedrine, (+) - 2-dimethylamino-1-phenylethanol or (-) - 2-dimethylamino-1-phenylethanol becomes. Method according to one or more of claims 1 to 5, characterized in that the zinc sulfonate from the group containing zinc trifluoromethanesulfonate or zinc difluoromethanesulfonate is selected. Method according to one or more of claims 1 to 6, characterized in that the zinc sulfonate in a molar ratio to Carbonyl compound of (0.03 to 0.3): 1 and the optically active Auxiliary in a molar ratio to the carbonyl compound of (0.05 to 0.4): 1 is used. Method according to one or more of claims 1 to 7, characterized in that the workup optionally after previous removal of the solvent used for the reaction by addition of a polar solvent and optionally a immiscible with the polar solvent nonpolar solvent done by extraction and phase separation. A method according to claim 8, characterized in that the reaction is carried out in toluene, the toluene is then removed by distillation, as the polar solvent acetonitrile and as a non-polar solvent Pentane, hexane or heptane is added.