DE10237272A1 - Preparation of optically pure (3RS)-2-oxy-3-(2-thienyl)-propylamine compound, useful as drug intermediate for e.g. serotonin and norepinephrine uptake inhibitor duloxetine, by enantioselective Reformatsky type synthesis via new intermediate - Google Patents

Abstract

Preparation of (3R)- or (3S)-2-oxy-3-(2-thienyl)-propylamines (I) involves: (i) reacting a 2-thiophene-carboxaldehyde (II) with a reactive halo compound (III) and zinc in presence of an enantiomerically pure chiral auxiliary having at least two amino groups; (ii) adding water, acid or base or an alkylating, arylating, esterifying or silylating reagent; (iii) adding an amine (IV); and (iv) reducing product. Preparation of (3R)- or (3S)-2-oxy-3-(2-thienyl)-propylamines of formula (I) involves: (i) reacting a 2-thiophene-carboxaldehyde of formula (II) with a reactive halo compound of formula Hal-CR3R4-Y (III) and zinc in presence of an enantiomerically pure chiral auxiliary having at least two amino groups (provided that the protons present have a pKa of more than 20; (ii) adding water, acid or base or an alkylating, arylating, esterifying or silylating reagent; (iii) if Y is COOR1 or COOSi(Rs)3 adding an amine of formula NHR1R2 (IV); and (iv) reducing the product. R1, R2 = H or 1-30C hydrocarbyl ; R3 - R7 = halo or as defined for R1; Rx = H or 1-30C hydrocarbyl; W = H, alkyl, aryl, acyl or silyl; Y = CN or COZ; Z = OR1, OSi(Rs)3 or NR1R2; Rs = 1-30C hydrocarbyl; Hal = Cl, Br or I. The OW group in (I) is in alpha- or beta-configuration. 1-30C Hydrocarbyl either: (a) is optionally substituted by halo or CN; or (b) has one or more non-adjacent CH2 units replaced by O, CO, COO, OCO, OCOO, S or NRx; and/or (c) has one or more CH units replaced by N or P. Independent claims are included for the following new intermediates: (1) (3R)- or (3S)-2-oxy-3-(2-thienyl)-propionic acid amides, esters, silyl esters or nitriles of formula (V) (including mixtures of the (3R)- and (3S)-isomers in the case of amides) and (2) enantiomerically pure (3S)-3-hydroxy-3-(2-thienyl)-propionate esters of formula (VII). Q = CONR1R2, COOR1, COOSi(Rs)3 or CN; Ra = optionally halo- or cyano-substituted 2-30C hydrocarbyl; W' = H, alkyl, aryl, acyl, silyl or CORa. The OW group in (V) is in either the alpha- or beta-configuration, or may also be a mixture if Q = CONR1R2. When W is alkyl, aryl, silyl or CORa then Q is COOR1; and when R5 - R7 is H then Q is CN.

Description

The invention relates to a method and novel intermediates for the production of (3R) - or (3S) -3-oxy-3- (2-thiophene) propylamines.

Derivatives of (3R) - or (3S) -3-oxy-3- (2-thiophene) propylamines and especially (3R) - or (3S) -3-hydroxy-3- (2-thiophene) propylamines are important building blocks in the manufacture of pharmaceuticals Agents.

In particular, the derivatives of (3S) - (-) - 3-hydroxy-3- (2-thiophene) propylamine are important synthesis building blocks for the active pharmaceutical ingredient Duloxetine, an inhibitor of serotonin and norepinephrine uptake systems.

From B. A. Astleford, L. O. Weigel, Chirality Ind. II, pp. 101-105 (Ed .: A. N. Collins, G. N. Sheldrake, J. Crosby), Wiley: Chichester, 1997 and L.A. Sorbera, R.M. Castaner, J. Castaner, Drugs Fut. 2000, 25, p. 907 are two processes by splitting racemates and two enantioselective processes for the preparation of the N-dimethyl and the N-monomethyl derivative of (S) - (-) - 3-hydroxy-3- (2-thiophene) propylamine or the active ingredient duloxetine known.

However, these two procedures have a number of disadvantages: the manufacture of the optically active Connections by classical or enzymatic resolution, then the optically active isomer can only in a maximum yield of 50 based on the racemate. Through reracemization of the unwanted Although the yield of isomers can be improved, this step but is great associated economic effort. This and the low yields impair the economy of racemate resolution, especially in the execution on a technical scale.

The known manufacturing processes also include a variety of synthesis steps (more than four steps), being frequent expensive reagents are used. The relatively low overall yields over all Synthesis steps as well as the high reworking and raw material costs impair the economy of the multi-stage known from the prior art Additional procedure.

In an enantioselective previously known Manufacturing variant (B.A. Astleford, L.O. Weigel, Chirality Ind. II, pp. 101-105 (Ed .: A. N. Collins, G. N. Sheldrake, J. Crosby), Wiley: Chichester, 1997) Furthermore very large Amounts of a reaction component at very high dilution of the Reaction mixture can be used, resulting in very low concentrations or large Volumes and thus leads to very poor space-time yields and makes the manufacturing process uneconomical.

As an alternative manufacturing process would be a enantioselective Reformatsky synthesis conceivable for the construction of the chiral carbon skeleton, especially starting from 2-thiophenaldehyde and the addition of a chiral organo-zinc compound.

From M. Guette, J. Capillon, J.-P. Guette, Tetrahedron, 1973, 29, p. 3659 is an enantioselective Reformatsky synthesis of (S) - (-) - 3-hydroxy-3-phenylpropionic acid esters using benzaldehyde as a substrate in the presence of the chiral Ligands (-) - sparteine in the less coordinating solvents benzene and dimethoxymethane.

On the one hand, the process enables high enantioselectivities of up to 95 ± 3 % ee, on the other hand only very low chemical yields were possible of maximum 38 ± 7 % of theory can be achieved.

Pedrosa et al. (J.M. Andres, Y. Martin, R. Pedrosa, A. Perez-Encabo, Tetrahederon, 1997, 53, p. 3787) describe an enantioselective Reformatsky reaction with amino alcohols as chiral auxiliaries in Tetrahydrofuran. However, with high chemical yields up to 90% only moderate enantioselectivities of 22 to 62% ee achieved. The process is also based on use high surpluses of the Organozinc compound (Reformatsky reagent) and is therefore more economical and more technical Uninteresting view.

Seebach et al. describe an enantioselective Reformatsky reaction with chiral diamines as cosolvents with good chemical yields of up to 95%, but only low enantiomeric excesses of a maximum of 24.5% ee.

None of the prior art known enantioselective Reformatsky reactions the possibility the use of easily decomposable substrates such as 2-thiophenaldehyde as possible Educt in a Reformatsky reaction. As possible starting materials are first Line of simple aromatic aldehydes or ketones such as benzaldehyde and Acetophenone or aliphatic aldehydes described.

After R. D. Schuetz, W. H. Houff, J. Am. Chem. Soc. 1955, 77, p. 1836, the racemic compound (±) -3-Hydroxy-3- (2-thiophene) propionic acid ethyl ester in a Reformatsky synthesis using benzene as a solvent in a moderate yield be made by 62% of theory.

None of the known methods provides both high chemical and high optical yields. From The methods known from the prior art are therefore in particular for one large-scale and unsuitable for economic synthesis.

It was therefore the task of providing a universally applicable, enantioselective process which, as part of an asymmetric synthesis to (3R) - or (3S) -3-oxy-3- (2-thiophene) propylamines leads and solves the problems known from the prior art.

It was surprisingly found that asymmetric synthesis in the form of an enantioselective Reformatsky reaction using chiral, enantiomerically pure auxiliaries with at least two amine groups (amino auxiliaries) are particularly advantageous and can be performed with a variety of substrates.

wobei
R¹, R² unabhängig voneinander Wasserstoff oder einen gegebenenfalls halogen- oder cyanosubstituierten C_l-C₃₀-Kohlenwasserstoffrest bedeuten, in dem eine oder mehrere, einander nicht benachbarte Methyleneinheiten durch Gruppen -O-, -CO-, -COO-, -OCO-, oder -OCOO-, -S- oder -NR^x- ersetzt sein können und in dem eine oder mehrere Methineinheiten durch Gruppen -N= oder -P= ersetzt sein können und
R³, R⁴, R⁵, R⁶ und R⁷ unabhängig voneinander Wasserstoff, Halogen oder einen gegebenenfalls halogensubstituierten oder cyanosubstituierten C₁-C₃₀-Kohlenwasserstoffrest bedeuten, in dem eine oder mehrere, einander nicht benachbarte Methyleneinheiten durch Gruppen -O-, -CO-, -COO-, -OCO-, oder -OCOO-, -S- oder -NR^x- ersetzt sein können und in dem eine oder mehrere Methineinheiten durch Gruppen -N= oder -P= ersetzt sein können und
R^x Wasserstoff oder einen gegebenenfalls halogensubstituierten C₁-C₃₀-Kohlenwasserstoffrest bedeutet, 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 und
W Wasserstoff oder eine Alkyl-, Aryl-, Acyl- oder Silylgruppe bedeuten kann,
dadurch gekennzeichnet, dass

• (a) in einem ersten Schritt ein 2-Thiophencarbaldehyd der allgemeinen Formel (2)
  
  mit einer reaktiven Halogenverbindung der allgemeinen Formel (3a) Hal-CR³R⁴-Y (3a) wobei Y CN oder (C=O)-Z bedeuten kann und Z OR¹, OSi(R^Si)₃ oder NR¹R² bedeuten kann und R^Si unabhängig voneinander, gegebenenfalls halogensubstituierte oder cyanosubstituierte C₁-C₃₀-Kohlenwasserstoffreste bedeuten können, in denen eine oder mehrere, einander nicht benachbarte Methyleneinheiten durch Gruppen -O-, -CO-, -COO-, -OCO-, oder – OCOO-, -S- oder -NR^x- ersetzt sein können und in denen eine oder mehrere Methineinheiten durch Gruppen -N= oder -P= ersetzt sein können und Hal Chlor, Brom oder Iod bedeutet und Zink in Gegenwart eines chiralen enantiomerenreinen Auxiliars mit mindestens zwei Amin-Gruppen und der Maßgabe, dass vorhandene Protonen einen pK_a größer 20 haben, umgesetzt wird und anschließend Wasser, Säure oder Base oder ein Alkylierungs-Arylierungs-, Veresterungs- oder Silylierungsreagens zugegeben wird und
• (b) falls Y für (C=O)-Z steht mit der Maßgabe, dass Z für OR¹ oder OSi(R^Si)₃ steht ein Amin der allgemeinen Formel (4) NHR¹R² (4) zugegeben wird und
• (c) in einem abschließenden Schritt eine Reduktion durchgeführt wird.

The invention relates to a process for the preparation of (3R) - or (3S) -3-oxy-3- (2-thiophene) propylamines of the general formula (1a) or (1b),

in which
R ¹ , R ² independently of one another are hydrogen or an optionally halogen- or cyano-substituted C ₁ -C ₃₀ hydrocarbon radical in which one or more methylene units which are not adjacent to one another are represented by groups -O-, -CO-, -COO-, -OCO -, or -OCOO-, -S- or -NR ^x - can be replaced and in which one or more methine units can be replaced by groups -N = or -P = and
R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ independently of one another denote hydrogen, halogen or an optionally halogen-substituted or cyano-substituted C ₁ -C ₃₀ hydrocarbon radical in which one or more methylene units which are not adjacent to one another are represented by groups -O-, -CO-, -COO-, -OCO-, or -OCOO-, -S- or -NR ^x - can be replaced and in which one or more methine units can be replaced by groups -N = or -P = and
R ^x denotes hydrogen or an optionally halogen-substituted C ₁ -C ₃₀ hydrocarbon radical in which one or more methylene units which are not adjacent to one another are represented by groups -O-, -CO-, -COO-, -OCO- or -OCOO-, - S-, -NH- or - NC ₁ -C ₂₀ alkyl can be replaced and in which one or more methine units can be replaced by groups -N = or -P = and
W can denote hydrogen or an alkyl, aryl, acyl or silyl group,
characterized in that

• (a) in a first step a 2-thiophene carbaldehyde of the general formula (2)
  
  with a reactive halogen compound of the general formula (3a) Hal-CR ³ R ⁴ -Y (3a) where Y can mean CN or (C = O) -Z and Z can mean OR ¹ , OSi (R ^Si ) ₃ or NR ¹ R ² and R ^{Si can,} independently of one another, optionally be halogen-substituted or cyano-substituted C ₁ -C ₃₀ hydrocarbon radicals , in which one or more non-adjacent methylene units can be replaced by groups -O-, -CO-, -COO-, -OCO-, or - OCOO-, -S- or -NR ^x - and in which one or several methine units can be replaced by groups -N = or -P = and Hal means chlorine, bromine or iodine and zinc in the presence of a chiral enantiomerically pure auxiliary with at least two amine groups and the proviso that existing protons have a pK _a greater than 20, is reacted and then water, acid or base or an alkylation-arylation, esterification or silylation reagent is added and
• (b) if Y is (C = O) -Z with the proviso that Z is OR ¹ or OSi (R ^Si ) ₃ is an amine of the general formula (4) NHR ¹ R ² (4) is added and
• (c) a reduction is carried out in a final step.

A synthetically particularly valuable Step of the method according to the invention is the establishment of a chiral center in the course of a Reformatsky reaction with high enantiomeric excesses in 3-position using a chiral auxiliary in the form of chiral, enantiomerically pure compounds with at least two amine groups.

When manufacturing the (3R) - or (3S) -3-oxy-3- (2-thiophene) propylamine derivatives by the method according to the invention can after step (a) (3R) - or (3S) -3-oxy-3- (2-thiophene) propionic acid derivatives and after the step (b) (3R) - or (3S) -3-oxy-3- (2-thiophene) propionic acid amide derivatives as valuable building blocks can be easily isolated.

Are used as reactive halogen compounds according to the invention directly α-halonitriles or α-halo amides used, the optional implementation according to the invention can also be used Amines of the general formula 4 are eliminated and the reduction directly of the intermediates which can be isolated after the first step.

R¹, R² unabhängig voneinander Wasserstoff oder einen gegebenenfalls halogen- oder cyanosubstituierten C₁-C₃₀-Kohlenwasserstoffrest bedeuten, in dem eine oder mehrere, einander nicht benachbarte Methyleneinheiten durch Gruppen -O-, -CO-, -COO-, -OCO-, oder -OCOO-, -S- oder -NR^x- ersetzt sein können und in dem eine oder mehrere Methineinheiten durch Gruppen -N= oder -P= ersetzt sein können und
R³, R⁴, R⁵, R⁶ und R⁷ unabhängig voneinander Wasserstoff, Halogen oder einen gegebenenfalls halogensubstituierten oder cyanosubstituierten C1-C30-Kohlenwasserstoffrest bedeuten, in dem eine oder mehrere, einander nicht benachbarte Methyleneinheiten durch Gruppen -O-, -CO-, -COO-, -OCO-, oder – OCOO-, -S- oder -NR^x- ersetzt sein können und in dem eine oder mehrere Methineinheiten durch Gruppen -N= oder -P= ersetzt sein können und
R^x Wasserstoff oder einen gegebenenfalls halogensubstituierten C₁-C₃₀-Kohlenwasserstoffrest bedeutet, 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 und
W Wasserstoff oder eine Alkyl-, Aryl-, Acyl- oder Silylgruppe bedeuten kann,
dadurch gekennzeichnet, dass

• (a) in einem ersten Schritt ein 2-Thiophencarbaldehyd der allgemeinen Formel (2)
  
  mit einer reaktiven Halogenverbindung der allgemeinen Formel (3b) Hal-CR³R⁹-(CO)-NR¹R² (3b) wobei Hal Chlor, Brom oder Iod bedeutet und Zink in Gegenwart eines chiralen, enantiomerenreinen Auxiliars mit mindestens zwei Amin-Gruppen mit der Maßgabe, dass vorhandene Protonen einen pK_a größer 20 haben, umgesetzt wird und anschließend Wasser, Säure oder Base oder ein Alkylierungs-Arylierungs-, Veresterungs- oder Silylierungsreagens zugegeben wird und
• (b) in einem zweiten Schritt eine Reduktion durchgeführt wird.

One possible embodiment of the invention is a process for the preparation of (3R) - or (3S) -3-oxy-3- (2-thiophene) propylamines of the general formula (1a) or (1b),

R ¹ , R ² independently of one another are hydrogen or an optionally halogen- or cyano-substituted C ₁ -C ₃₀ hydrocarbon radical in which one or more methylene units which are not adjacent to one another are represented by groups -O-, -CO-, -COO-, -OCO -, or -OCOO-, -S- or -NR ^x - can be replaced and in which one or more methine units can be replaced by groups -N = or -P = and
R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ independently of one another represent hydrogen, halogen or an optionally halogen-substituted or cyano-substituted C1-C30 hydrocarbon radical in which one or more methylene units which are not adjacent to one another are represented by groups -O-, -CO -, -COO-, -OCO-, or - OCOO-, -S- or -NR ^x - can be replaced and in which one or more methine units can be replaced by groups -N = or -P = and
R ^x denotes hydrogen or an optionally halogen-substituted C ₁ -C ₃₀ hydrocarbon radical in which one or more methylene units which are not adjacent to one another are represented by groups -O-, -CO-, -COO-, -OCO- or -OCOO-, - S-, -NH- or - NC ₁ -C ₂₀ alkyl can be replaced and in which one or more methine units can be replaced by groups -N = or -P = and
W can denote hydrogen or an alkyl, aryl, acyl or silyl group,
characterized in that

• (a) in a first step a 2-thiophene carbaldehyde of the general formula (2)
  
  with a reactive halogen compound of the general formula (3b) Hal-CR ³ R ⁹ - (CO) -NR ¹ R ² (3b) where Hal is chlorine, bromine or iodine and zinc is reacted in the presence of a chiral, enantiomerically pure auxiliary having at least two amine groups with the proviso that protons present have a pK _a greater than 20, and then water, acid or base or an alkylation Arylation, esterification or silylation reagent is added and
• (b) a reduction is carried out in a second step.

The chiral, enantiomerically pure compounds with at least two amine groups used as chiral auxiliaries in the process according to the invention must not have any acidic protons, in particular those with a pK _a less than 20, for example, in view of the reaction conditions during the Reformatsky reaction and in particular because of the addition of zinc Form of free amide functions NH-C = O or NH-SO ₂ or hydroxy functions. In particular, the use of large excesses of Reformatsky reagent is avoided.

Auxiliaries with at least one are preferred two secondary and / or tertiary Amine groups.

In particular, chiral, enantiomerically pure Preferred diamine compounds as auxiliaries, very particularly preferred Diamine compounds with secondary and / or tertiary Amine groups.

The amine groups of the chiral, enantiomerically pure Auxiliaries coordinate with the zinc atoms and complex the Reformatsky reagent - itself in the presence of polar and / or coordinating solvents. The resulting chiral Reformatsky reagent differentiates the re and si side of the Aldehyde substrate, leading to the formation of enantiomerically enriched products leads.

Particularly preferred chiral auxiliaries with at least two amine groups are (-) - sparteine, 3,7-diazabicyclo [3.3.1] nonane, (+) - / (-) - 1,1'-binaphthyl-2,2'- diamine and its derivatives, (+) / (-) - 2,2'-bipyridyls, (+) - / (-) - 2,2'-bipyrrolidines, (+) - / (-) - 1,2-diaminocyclohexane and its derivatives, chiral piperazines such as. B. (+) - / (-) - 2-isobutyl-5-isopropylpiperazine, amino-substituted dioxolanes such as. B. (+) - / (-) - 4,5-di (aminomethyl) -2,2-dimethyldioxolane, (+) - / (-) - 2- (aminomethyl) pyrrolidine and its derivatives, (+) - / (-) - 2- (2-pyridyl) pyrrolidine and its derivatives, ethylenediamine compounds such as B. (+) - / (-) - 1,2-diphenylethylene-1,2-ethylenediamine and its derivatives, (+) - / (- -1,2-di (tert-butyl) -1,2- ethylenediamine and its derivatives, (+) - / (-) - N, N'-bis (1-phenylethyl) -1,2-ethylenediamine and its derivatives or N, N'-bis (1-phenylethyl) -4,5-diamino-l, 7-octadiene and its derivatives, propylenediamine compounds such as. B. (+) - / (-) - N, N'-bis (1-phenylethyl) -1,2-propylenediamine and its derivatives, diaminobutane compounds such as. B. (+) - / (-) - 2,3-dialkoxy-l, 4-diaminobutane and its derivatives, diamino acid compounds, diamines derived from amino acids or diamines with ester, amide, ether, thioether, Thioester, alkoxy, aryloxy, silyloxy, nitrile, acetal and ketal functions.

For the inventive method is in particular (-) - sparteine as chiral Auxiliary particularly preferred.

By using (-) - spartein generally high enantiomeric excesses of (3S) -3-oxy-3- (2-thiophene) propylamines of the general formula (1a).

In particular, with (-) - spartein as a chiral auxiliary and with appropriate selection of the reaction components high enantiomeric excesses of (S) - (-) - 3-hydroxy-3- (2-thiophene) propylamine and achieve high yields. Possible Rection components for the preparation of the N-dimethyl or the N-monomethyl derivative of (S) - (-) - 3-hydroxy-3- (2-thiophene) propylamine according to the inventive method 2-thiophenaldehyde, methyl bromoacetate, Chlorosilane, (-) - sparteine and methyl or dimethylamine.

R¹, R² unabhängig voneinander Wasserstoff oder einen gegebenenfalls halogen- oder cyanosubstituierten C1-C30-Kohlenwasserstoffrest bedeuten, in dem eine oder mehrere, einander nicht benachbarte Methyleneinheiten durch Gruppen -O-, -CO-, -COO-, -OCO-, oder -OCOO-, -S- oder -NR^x- ersetzt sein können und in dem eine oder mehrere Methineinheiten durch Gruppen -N= oder -P= ersetzt sein können und
R^x Wasserstoff oder einen gegebenenfalls halogensubstituierten C₁-C₃₀-Kohlenwasserstoffrest bedeutet, 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 und
W Wasserstoff oder eine Alkyl-, Aryl-, Acyl- oder Silylgruppe bedeuten dadurch gekennzeichnet, dass

• (a) in einem ersten Schritt Thiophen-2-carbaldehyd mit einer reaktiven Halogenverbindung der allgemeinen Formel (3c) Hal-H₂C-Y (3c) wobei Y CN oder (C=O)-Z bedeuten kann und Z OR¹, OSi(R^Si)₃ oder NR1R2 bedeuten kann und R^Si unabhängig voneinander gegebenenfalls halogensubstituierte oder cyanosubstituierte C₁-C₃₀-Kohlenwasserstoffreste bedeuten können, in denen eine oder mehrere, einander nicht benachbarte Methyleneinheiten durch Gruppen -O-, -CO-, -COO-, -OCO-, oder -OCOO-, -S- oder -NR^x- ersetzt sein können und in denen eine oder mehrere Methineinheiten durch Gruppen -N= oder -P= ersetzt sein können und Hal Chlor, Brom oder Iod bedeutet und Zink in Gegenwart von (–)-Spartein umgesetzt wird und anschließend Wasser, Säure oder Base oder ein Alkylierungs-Arylierungs-, Veresterungs- oder Silylierungsreagens zugegeben wird und die dabei entstehenden Derivate der (S)-(–)-3-Hydroxy-3-(2-thiophen)propionsäure der allgemeinen Formel (6c)
  
• (b) falls Z für OR¹ oder OSi(R^Si)₃ steht ein Amin der allgemeinen Formel (4) NHR¹R² (4) zugegeben wird und zu (S)-(–)-3-Hydroxy-3-(2-thiophen)propionsäureamid oder dessen Derivaten der allgemeinen Formel (5c)
  
  umgesetzt werden und
• (c) in einem abschließenden Schritt eine Reduktion durchgeführt wird.

A particularly preferred embodiment of the process according to the invention is a process for the preparation of derivatives of (S) - (-) - 3-hydroxy-3- (2-thiophene) propylamine of the general formula 1c

R ¹ , R ² independently of one another are hydrogen or an optionally halogen- or cyano-substituted C1-C30 hydrocarbon radical in which one or more methylene units which are not adjacent to one another are represented by groups -O-, -CO-, -COO-, -OCO-, or -OCOO-, -S- or -NR ^x - can be replaced and in which one or more methine units can be replaced by groups -N = or -P = and
R ^x denotes hydrogen or an optionally halogen-substituted C ₁ -C ₃₀ hydrocarbon radical in which one or more methylene units which are not adjacent to one another are represented by groups -O-, -CO-, -COO-, -OCO- or -OCOO-, - S-, -NH- or - NC ₁ -C ₂₀ alkyl can be replaced and in which one or more methine units can be replaced by groups -N = or -P = and
W is hydrogen or an alkyl, aryl, acyl or silyl group, characterized in that

• (a) in a first step, thiophene-2-carbaldehyde with a reactive halogen compound of the general formula (3c) Hal-H ₂ CY (3c) where Y can mean CN or (C = O) -Z and Z can mean OR ¹ , OSi (R ^Si ) ₃ or NR1R2 and R ^Si independently of one another can optionally be halogen-substituted or cyano-substituted C ₁ -C ₃₀ hydrocarbon radicals in which one or more, non-adjacent methylene units can be replaced by groups -O-, -CO-, -COO-, -OCO-, or -OCOO-, -S- or -NR ^x - and in which one or more methine units by groups -N = or -P = can be replaced and Hal means chlorine, bromine or iodine and zinc is reacted in the presence of (-) - spartein and then water, acid or base or an alkylation-arylation, esterification or silylation reagent is added and the resulting derivatives of (S) - (-) - 3-hydroxy-3- (2-thiophene) propionic acid of the general formula (6c)
  
• (b) if Z is OR ¹ or OSi (R ^Si ) ₃ , an amine of the general formula (4) NHR ¹ R ² (4) is added and to (S) - (-) - 3-hydroxy-3- (2-thiophene) propionic acid amide or its derivatives of the general formula (5c)
  
  be implemented and
• (c) a reduction is carried out in a final step.

The method according to the invention is preferred in a solvent carried out.

As a solvent for the process according to the invention all for the inert solvent suitable for the Reformatsky reaction. A summary of suitable solvents is for example in A. Fürstner, Synthesis 1989, p. 571 included.

Particularly preferred solvents are in particular diethyl, dipropyl, dibutyl ether, diisopropyl ether, Methyl tert-butyl ether, dimethoxymethane, diethoxymethane, dimethoxyethane, Diethoxyethane, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, Diethylene glycol dipropyl ether, diethylene glycol dibutyl ether, triethylene glycol dimethyl ether, Triethylene glycol diethyl ether, triethylene glycol dibutyl ether, methylene chloride as well as mixtures of the aforementioned compounds and mixtures the above-mentioned compounds with the solvents benzene, toluene, Ethylbenzene, propylbenzene, isopropylbenzene, butylbenzene, xylene, Mixture of xylene isomers, trimethylbenzene, pentane, hexane, octane, isooctane, Nonane, nonane fraction, Cyclohexane, cycloheptane, cyclooctane, dimethylcyclohexane, ethylcyclohexane, Propylcyclohexane, butylcyclohexane, petroleum spirit and paraffin.

To achieve high yields if possible short reaction times and thus high space-time yields and at the same time high enantioselectivities to achieve, tetrahydrofuran, 2-methyltetrahydrofuran, 2,5-dimethyltetrahydrofuran, 2,5-dimethoxytetrahydrofuran, 1,4-dioxane, carboxylic acid ester, Amines, acid amides, ketones, polar aprotic solvents, halogenated hydrocarbons or mixtures of the solvents mentioned to the reaction mixture or optionally to those mentioned above solvents or solvent mixtures added.

Tetrahydrofuran is preferred, 2-methyltetrahydrofuran, 2,5-dimethyltetrahydrofuran, 2,5-dimethoxytetrahydrofuran and 1,4-dioxane, especially tetrahydrofuran and 1,4-dioxane.

Preferably added carboxylic acid esters, Amines, acid amides, Ketones, polar aprotic solvents or halogenated hydrocarbons are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-hexyl, n-pentyl, i-pentyl acetate, propionate and butyrate, 2-acetic acid-2-ethoxyethyl ester, Pyridine, N-acetylpyrrolidine, N-acetylpyrrole, N-acetylsuccinimide, Tetramethylurea, N, N'-dimethylethyleneurea, tetramethylguanidine, Acetone, methyl ethyl ketone, diethyl ketone, isopropyl methyl ketone, isopropyl ethyl ketone, Acetonitrile, propionitrile, butyronitrile, dimethylformamide, diethylformamide, Dimethylacetamide, diethylacetamide, 1-methyl-2-pyrrolidone, dimethyl sulfoxide, Methylene chloride or mixtures of the aforementioned solvents.

In particular, dimethylformamide, 1-methyl-2-pyrrolidone and tetrahydrofuran or mixtures thereof preferred, especially tetrahydrofuran.

The use of tetrahydrofuran, Mixtures containing tetrahydrofuran and polar solvents is for the course of the reaction, the yields and enantioselectivities of vitally important.

The aforementioned solvents or their mixtures are suitable for all steps of the method according to the invention.

Further objects of the invention are while of the method according to the invention isolatable and obtainable by the inventive method Intermediates, which in turn are valuable enantiomerically enriched or enantiomerically pure synthesis building blocks, in particular for the construction of Drug libraries based on the 2-substituted one Thiophene as basic body, represent.

The advantages of the process according to the invention are that the synthesis of derivatives of (3S) - or (3R) -3-hydroxy-3- (2-thiophene) propylamine (end products) can be carried out particularly economically, especially when carried out on an industrial scale. since the end products and the available intermediates in high yields with high purities and high optical purities (Ena tiomers excess) can be prepared enantioselectively with respect to the 3-oxy position.

Compared to the state of the art known process for the preparation of (S) - (-) - 3-hydroxy-3- (2-thiophene) propylamine by splitting racemates can by the asymmetric according to the invention Process the isomer of the desired handedness and a big one Number of derivatives (universality) in high yields very inexpensive and be manufactured economically.

In addition, according to the method of the invention the end products and numerous synthetically valuable intermediates in very short reaction times and very good space-time yields economical win.

The method according to the invention also includes in contrast to the methods known from the prior art a small number of synthesis stages, which is the manufacturing process due to lower rework and raw material costs and at the same time higher Yields based on the end products are also particularly economical makes interesting.

The chiral used can also be used enantiomerically pure auxiliaries very easily when working up the reaction mixture recover and isolate the products in high yields and reuse what the inventive method in particular the implementation on a technical scale particularly inexpensive and economical.

For example, (-) - Spartein when working up the reaction mixture and isolating the products in very high yield of> 90 % win back and reuse.

The C ₁ -C ₃₀ hydrocarbon radicals for R ¹ and R ² are preferably 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 can be substituted by F, Cl, Br, J, CN and C ₁ -C ₁₀ alkoxy radicals and C ₁ -C ₁₀ alkylamino radicals; Aryl, aralkyl, alkaryl, aralkenyl, alkenylaryl radicals in which one or more methine units can be replaced by groups -N = or -P =, and methylene units by -O-, - S-, -NH- and which are substituted can be by F, Cl, Br, J, CN, C ₁ -C ₁₀ alkoxy and C ₁ -C ₁₀ alkylamino and on the ring by C ₁ -C ₁₀ alkyl and in the ring the heteroatoms -O-, - S- or -NH- can wear.

Particularly preferred radicals R ¹ and R ² are hydrogen, methyl, ethyl, propyl, butyl, tert-butyl, phenyl, benzyl, acetyl, benzyloxycarbonyl and tert-butyloxycarbonyl.

The C1-C30 hydrocarbon radicals for R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are preferably 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 can be substituted by F, Cl, Br, J, CN and C ₁ -C ₁₀ -alkoxy radicals and also C ₁ -C ₁₀ -alkylamino radicals; Aryl, aralkyl, alkaryl, aralkenyl, alkenylaryl radicals in which one or more methine units can be replaced by groups -N = or -P =, and methylene units by -O-, - S-, -NH- and which are substituted can be by F, Cl, Br, J, CN, C ₁ -C ₁₀ alkoxy and C ₁ -C ₁₀ alkylamino and on the ring by C ₁ -C ₁₀ alkyl and in the ring the heteroatoms -O-, - S- or -NH- can wear.

Particularly preferred radicals R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are hydrogen, methyl, ethyl, propyl, butyl, tert-butyl, phenyl, benzyl, acetyl, benzyloxycarbonyl, tert-butyloxycarbonyl and halogen, in particular hydrogen and methyl.

Preferred radicals for R ^x are 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 can be substituted by F, Cl, Br, I, CN and C ₁ -C ₁ 0-alkoxy radicals and C ₁ -C ₁ 0-alkylamino; Aryl, aralkyl, alkaryl, aralkenyl, alkenylaryl radicals in which one or more methine units can be replaced by groups -N = or -P =, and methylene units by -O-, - S-, -NH- and which are substituted can be by F, Cl, Br, J, CN, C ₁ -C ₁₀ alkoxy and C ₁ -C ₁₀ alkylamino and on the ring by C ₁ -C ₁₀ alkyl and in the ring the heteroatoms -O-, - S- or -NH- can wear.

Particularly preferred radicals for R ^x are hydrogen, methyl, ethyl, propyl, butyl, tert-butyl, phenyl and benzyl, in particular hydrogen and methyl.

The C ₁ -C ₃₀ hydrocarbon radicals for R ^Si are preferably 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 can be substituted by F, Cl, Br, J, CN and C ₁ -C ₁₀ alkoxy radicals and C ₁ -C ₁₀ alkylamino radicals; Aryl, aralkyl, alkaryl, aralkenyl, alkenylaryl radicals in which one or more methine units can be replaced by groups -N = or -P =, and methylene units by -O-, - S-, -NH- and which are substituted may be replaced by F, Cl, Br, I, CN, C ₁ -C _{1 0} -alkoxy and C ₁ -C ₁₀ alkylamino groups and the ring by C ₁ -C _{1 0} alkyl groups and in the ring the heteroatoms -O- , -S- or -NH- can wear.

Particularly preferred radicals for R ^Si are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, vinyl, phenyl and benzyl.

Preferred radicals for W are Hydrogen, benzyl, methyl, ethyl, acetyl, propionyl, benzoyl, Trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, phenyl and 1-naphthyl.

Particularly preferred radicals for W are Hydrogen, benzyl, acetyl, propionyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl and 1-naphthyl, especially hydrogen, acetyl, propionyl, trimethysilyl and 1-naphthyl.

As reactive halogen compounds of the general formula (3a) or (3b) are preferably reactive α-haloacetic acid derivatives used.

Reactive α-haloacetic acid derivatives of the general formula (3a) are preferred, in which Y is (C = O) -Z and Z is OR ¹ and OSi (R ^Si ) ₃ and R ¹ and R ^{Si are} preferred from those described above Embodiments can be selected.

As reactive halogen compounds of the general formula (3a) or (3b) are in particular chlorine or Bromine compounds, Hal being for Bromine or chlorine, very particularly preferably bromine compounds, wherein Hal for Bromine is used.

Particularly preferred embodiments for reactive Halogen compounds are α-bromoacetic acid esters or bromoacetonitrile.

When using bromoacetonitrile or its derivatives, the correspondingly obtained β-oxynitriles by reduction into a compound of the general formula (1a) or (1b) implemented. The optional implementation according to the invention with Amines can naturally be omitted here.

Possible embodiments for reactive bromine compounds are also reaction products of α-haloacetic acid derivatives with silanes, such as, for example, compounds of the type [Br-CH ₂ (C = O) -O] ₂ Si (R ^Si ) ₂ or [Br-CH ₂ (C = O ) -OSi (R ^Si ) ₂ -CH ₂ ] ₂ , where R ^Si is intended to have the meaning given above, in particular the preferred embodiments described above. The Reformatsky regiments are then obtained from these by implementation with zinc.

Preferred embodiments of the 2-thiophenecarbaldehyde of the general formula (2) are substituted with alkyl, aryl or alkoxy groups 2-thiophene carbaldehydes, especially with methyl, ethyl or phenyl groups substituted 2-thiophenecarbaldehydes, the unsubstituted base 2-thiophene carbaldehyde is very particularly preferred.

In the first reaction step of the process according to the invention is first zinc in a solvent or Solvent mixture submitted and then a mixture, optionally dissolved in one Solvent, the Add reactive halogen compound and the chiral auxiliary.

Zinc and that is preferred first chiral auxiliary in a solvent or solvent mixture submitted and subsequently the reactive halogen compound, optionally dissolved in one Solvent, under Formation of an organozinc halide of the general formula (3a) or (3b), where Hal is intended to mean halogen zinc here.

Zinc is particularly preferred first in a solvent or solvent mixture submitted and then the reactive halogen compound, optionally dissolved in one Solvent, to form an organozinc halide of the general formula (3a) or (3b), where Hal is intended to mean halogen zinc here. The chiral auxiliary is then added to this mixture, if necessary solved in a solvent.

The implementation is carried out in the presence of a carried out under the reaction conditions inert solvent that optionally mixed with tetrahydrofuran or one or more polar other solvent before or after adding zinc or the chiral auxiliary or others Reagents or additives or optionally together with zinc or the chiral auxiliary or other reagents or additives is added.

The organozinc halides produced first of the general formula (3a) or (3b), where Hal here is halogen zinc should mean, if necessary after adding the chiral auxiliary, also initially stored stably and possibly to a later one Time to be reacted. They represent valuable, for the enantioselective Reformatsky reaction excellent reagents.

To the mixtures obtained from Organozinc halides of the general formula (3a) or (3b), wherein Hal is supposed to mean halogen zinc here, and the chiral auxiliary then a thiophene-2-carbaldehyde of the general formula (2) is added, possibly solved in a solvent. Alternatively, you can the mixtures of the organozinc halides obtained, also into one Thiophene-2-carbaldehyde of the general formula (2), if appropriate solved in a solvent, be added.

It is also possible to add organozinc halides a mixture of the thiophene-2-carbaldehyde of the general formula (2) and the chiral auxiliary or add the organozinc halides to a mixture of the thiophene-2-carbaldehyde of the general formula (2) and add to the chiral auxiliary.

While the addition of the reactive halogen compound of the general formula (3a) or (3b) and optionally the chiral auxiliary are kept Temperature preferably the exothermic reaction if necessary cooling at a predetermined value. The upper temperature limit by the boiling point of the solvent used, such as Tetrahydrofuran (bp .: 66 ° C) or ethyl acetate (bp: 78 ° C) be limited. With higher boiling solvents such as 1,4-dioxane (bp: 100-102 ° C) the temperature of the reaction preferably by cooling controlled.

The reaction is preferably at Temperatures of –20 up to +150 ° C, particularly preferably at 0 to 110 ° C, in particular at 30 to 80 ° C, if appropriate performed under reflux.

In a particularly preferred embodiment of the process according to the invention, the reak tion performed at reflux below 60 ° C.

While the addition of the chiral auxiliary to the organozinc halides of the general formula (3a) or (3b), where Hal here means halogen zinc should hold if necessary, the temperature of the exothermic reaction cooling preferably at a predetermined value. The addition is preferably made at Temperatures from –80 up to +100 ° C, particularly preferred at -20 up to +60 ° C, especially at 0 to 30 ° C.

The addition of the thiophene-2-carbaldehyde of the general formula (2) for mixing the organozinc halide of the general formula (3a) or (3b), where Hal here is halogen zinc should mean, and the chiral auxiliary or the addition of the reaction mixture to thiophene-2-carbaldehyde of the general formula (2) and optionally of the chiral auxiliary is preferably carried out at temperatures from -110 to +100 ° C, especially preferred at -80 up to +40 ° C, especially at –40 up to +10 ° C.

After the addition of everyone involved Components leaves preferably 30 to 24 hours, more preferably 1 to 18 h, in particular 2 to 10 h, to react to the reaction to complete.

Excess zinc metal can be separated by filtration. It is also possible to use excess zinc in the optionally used for the hydrolysis of the reaction mixture Dissolve acid.

After implementation, the Reaction mixture usually at temperatures of –110 up to +60 ° C, particularly preferred from -40 up to +10 ° C optionally after adding an water-immiscible organic Solvent, preferred Toluene, methylene chloride, ethyl acetate or tert-butyl methyl ether by adding water, an aqueous Acid or Base hydrolyzes, forming zinc compounds and zinc salts dissolve. Alternatively, the reaction mixture can be added to water, one aqueous Acid or Add base.

This way you get the corresponding 3-hydroxy derivatives as valuable intermediates.

Z OR¹ bedeutet und
R¹ und R^x die oben genannten Bedeutungen haben sollen.
R¹ und R^x können insbesondere aus den oben genannten bevorzugten Ausführungsformen ausgewählt werden.The invention accordingly further provides the enantiomerically pure (S) -3-hydroxy-3- (2-thiophene) esters of the general formula (7) which can be obtained by using reactive halogen ester compounds and aqueous, acidic or alkaline workup by the process according to the invention.

Z OR ¹ means and
R ¹ and R ^x should have the meanings given above.
R ¹ and R ^x can in particular be selected from the preferred embodiments mentioned above.

R ¹ particularly preferably represents methyl, ethyl, propyl or benzyl.

Preferred bases are ammonia and organic amines such as trialkylamines and alkanolamines.

Preferred acids are Brönstedt acids, in particular strong acids, such as boric, tetrafluoroboric, nitric acid, nitrous acid, phosphoric acid, phosphorous Acid, hypophosphorous acid, Sulfuric acid, sulphurous acid, Peroxosulfur., Salt, river, hydrogen iodide, hydrogen bromide, Perchloric acid, hexafluorophosphoric acid, Benzenesulfone, p-toluenesulfone, methanesulfone, trifluoromethanesulfone and carboxylic acids, such as Chloroacetic, trichloroacetic, vinegar, acrylic, benzoic, trifluoroacetic, Lemon, croton, ants, fumar, malein, malon, gallus, Itaconic, lactic, tartaric, oxalic, phthalic and succinic acids.

In particular, ammonia, hydrochloric acid, sulfuric acid, acetic acid or citric acid, preferably ammonia, hydrochloric acid, sulfuric acid and acetic acid used. The acid or base can be in concentrated form or in the form of a dilute aqueous solution be used.

As an alternative to hydrolysis, it is possible to use the Reaction mixture usually at temperatures of –110 up to +100 ° C, particularly preferred from -40 up to +50 ° C with an alkylation or arylation reagent, an esterification reagent (Acylation) or a silylation reagent, optionally in the presence a solvent, to move. The arylated, silylated, alkylated, 3-oxy positions thus obtained or esterified (acylated) intermediates can then after hydrolysis or optionally directly from the mixture z. B. by distillation, Extraction or crystallization can be easily isolated.

These intermediates in the form of alkylated, arylated, silylated or esterified in the 3-oxy position (3R) - or (3S) -3-oxy-3- (2-thiophene) propionic acid amides, -ester or -silylester in turn represent valuable intermediates (Intermediate products).

It is also possible to use the reaction mixture optionally containing the intermediate products without further working up insoluble after separation Ingredients and solvent to be used directly in the next step.

wobei
R¹, R², R³, R⁴, R⁵, R⁶ und R⁷ die oben genannten Bedeutungen haben sollen und
R^x einen gegebenenfalls halogensubstituierten Cl-C30-Kohlenwasserstoffrest bedeutet, 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 knnen und in dem eine oder mehrere Methineinheiten durch Gruppen -N= oder -P= ersetzt sein können und
W Wasserstoff oder eine Alkyl-, Aryl-, Acyl- oder Silylgruppe bedeuten kann.
R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R^x und W können insbesondere aus den oben genannten bevorzugten Ausführungsformen ausgewählt werden.The invention further provides the (3R) - or (3S) -3-oxy-3- (2-thiophene) amides of the general formula (5a) obtainable by using reactive halogen compound of the general formula (3b) by the process according to the invention. or (5b) or mixtures thereof

in which
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ should have the meanings given above and
R ^x denotes an optionally halogen-substituted Cl-C30 hydrocarbon radical in which one or more methylene units which are not adjacent to one another are represented by groups -O-, -CO-, -COO-, -OCO-, or -OCOO-, -S-, - NH- or -NC ₁ -C ₂₀ alkyl can be replaced and in which one or more methine units can be replaced by groups -N = or -P = and
W can be hydrogen or an alkyl, aryl, acyl or silyl group.
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ^x and W can in particular be selected from the preferred embodiments mentioned above.

R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are particularly preferably hydrogen.

R ¹ and R ² are particularly preferably hydrogen, methyl, ethyl, propyl or benzyl.

W is particularly preferred here for hydrogen, Acetyl and trimethylsilyl.

wobei
Z OR¹ bedeutet und
R¹, R³, R⁴, R⁵, R⁶, R⁷ und R^x die oben genannten Bedeutungen haben sollen und
W für eine Alkyl-, Aryl-, oder Silylgruppe oder eine Acylgruppe (C=O)-R^Ac steht, mit der Maßgabe, dass R^Ac für einen gegebenenfalls halogen- oder cyanosubstituierten C₂-C₃₀-Kohlenwasserstoffrest steht.
R¹, R³, R⁴, R⁵, R⁶, R⁷ und R^x können insbesondere aus den oben genannten bevorzugten Ausführungsformen ausgewählt werden.The invention furthermore relates to the (3R) - or (3S) -3-oxy-3- (2-thiophene) esters of the general formula (6a) or (6b) obtainable by using reactive halogen ester compounds by the process according to the invention.

in which
Z OR ¹ means and
R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ^x should have the meanings given above and
W stands for an alkyl, aryl or silyl group or an acyl group (C = O) -R ^Ac , with the proviso that R ^{Ac stands} for an optionally halogen or cyano-substituted C ₂ -C ₃₀ hydrocarbon radical.
R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ^x can in particular be selected from the preferred embodiments mentioned above.

R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are particularly preferably hydrogen.

R ¹ particularly preferably represents hydrogen, methyl, ethyl, propyl or benzyl.

R ^Ac is particularly preferably ethyl, propyl or benzyl.

W can also be from the above preferred embodiments selected become.

W is particularly preferred here for hydrogen, Propionyl and trimethylsilyl.

wobei
Z OSi(R^Si)₃ bedeutet und
R³, R⁴, R⁵, R⁶, R⁷, R^x und R^Si die oben genannten Bedeutungen haben sollen und
W Wasserstoff oder eine Alkyl-, Aryl-, Acyl- oder Silylgruppe bedeuten kann.The invention furthermore relates to the (3R) - or (3S) -3-oxy-3- (2-thiophene) silylesters of the general formula (8a) or (8b) which can be obtained by using reactive halosilyl ester compounds by the process according to the invention.

in which
Z OSi (R ^Si ) ₃ means and
R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ^x and R ^Si should have the meanings given above and
W can be hydrogen or an alkyl, aryl, acyl or silyl group.

R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ^x , R ^Si and W can in particular be selected from the preferred embodiments mentioned above.

R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are particularly preferably hydrogen.

W is particularly preferred here for hydrogen, Acetyl and trimethylsilyl.

R ^si is particularly preferably methyl, ethyl, propyl or tert-butyl.

wobei
R³, R⁴ und R^x die oben genannten Bedeutungen haben sollen und
W Wasserstoff oder eine Alkyl-, Aryl-, Acyl- oder Silylgruppe bedeuten kann.Another object of the invention are the β-oxynitriles (3R) or (3S) -3-oxy-3- (2-thiophene) propiononitrile of the general formula (9a) obtainable by using α-halonitriles as reactive halogen compounds by the process according to the invention ) or (9b)

in which
R ³ , R ⁴ and R ^x should have the meanings given above and
W can be hydrogen or an alkyl, aryl, acyl or silyl group.

R ¹ , R ⁴ and W can in particular be selected from the preferred embodiments mentioned above. R ³ and R ⁴ are particularly preferably hydrogen. W particularly preferably represents hydrogen, acetyl and trimethylsilyl.

As alkylation or arylation, Esterification or silylation reagents find all suitable, Reagents well known to those skilled in the art Use.

Preferred alkylating agents are Methyl, ethyl, propyl, butyl, benzyl chloride, bromide and iodide.

Preferred arylation reagents are fluorobenzene, 1-fluoro-4-trifluorobenzene, 1-fluoronaphthalene, chlorobenzene, 1-chloro-4-trifluorobenzene, and 1-chloronaphthalene.

Preferred esterification reagents are acetyl chloride, bromide and acetic anhydride.

Preferred silylation reagents are trimethyl-, -ethyl-, propyl-, -butylchlorosilane and tert-butyldimethylchlorosilane.

Optionally, the reaction mixture after the reaction is hydrolyzed by adding an aqueous acid or base become.

If silyl compounds with Y = (C = O) -Z and Z = OSi (R ^Si ) ₃ are used as reactive halogen compounds of the general formula (3a), where R ^Si can have the meanings given above, then hydrolysis is followed by the above conditions mentioned carboxylic acids of the general formula (8a) or (8b), where Z here means OH.

Before the aqueous, acidic or alkaline workup of the reaction mixture, the silyl compounds obtained are preferably first mixed with alcohols of the general formula R ¹ OH or amines of the general formula (4), if appropriate in the presence of hydrogen halide, optionally after subsequent hydrolytic workup or reaction of the reaction mixture with an alkylation, arylation, esterification or silylation reagent carboxylic acid ester of the general formula (6a) or (6b) with Z = OR ¹ or their derivatives or carboxamides of the general formula (5a) or (5b) with Z = NR ¹ R ² or their derivatives can be obtained.

When using amines of the general formula (4) and preparing carboxamides of the general formula (5a) or (5b) with Z = NR ¹ R ² from the silyl esters prior to working up, the second reaction step of the process according to the invention is omitted and the process is advantageously carried out directly the compounds of the general formula (5a) or (5b).

The first and the second reaction step of the method according to the invention are thus advantageously carried out in a single reaction step the total number of reaction steps is shortened and the process according to the invention in contrast to the methods known from the prior art makes it particularly economical.

The intermediates thus obtained can last from the organic phase of the reaction mixture be isolated after phase separation. These can be isolated from the organic phase by known, commonly used methods such as extraction, distillation, crystallization or by means of chromatographic methods. In most cases, the crude product obtained after removal of the solvent is of very high purity and can be used directly in the subsequent second reaction step.

If necessary, crystalline Intermediates of the general formulas before further implementation in the second reaction step for further enantiomer enrichment if necessary recrystallized. The reaction products are used for recrystallization preferably in the form of their raw products in a suitable solvent solved and optionally by inoculation with an enantiomerically pure compound recrystallized.

It has been found that this is chiral amino auxiliaries when working up the reaction mixture of isolate the first reaction step as a zinc-containing solid and can be recovered from it in high yields. The workup can preferably aqueous, acidic, alkaline or with a silylating reagent.

In particular, recovery when using (-) - spartein perform as auxiliary with high yields.

The chiral is particularly preferred Amino auxiliaries, especially (-) - sparteine, in the hydrolysis of the reaction mixture by adding an aqueous Acid as Salt isolated.

The simple and effective recovery of the chiral auxiliary, in particular of (-) - sparteine, makes the process according to the invention particularly economical.

Preferably the chiral auxiliary, especially (-) - sparteine, by hydrolysis with hydrochloric acid, sulfuric acid or acetic acid isolated.

Alternatively, it is also possible that chiral auxiliary, especially (-) - sparteine, on hydrolysis the reaction mixture together by adding an aqueous base isolate with the intermediate from the first reaction step and subsequently by adding an aqueous Acid to To implement, separate and recover ammonium salt.

The auxiliary, especially (-) - spartein, can be freed of impurities by distillation before reuse and be cleaned.

By distillation, the auxiliary, in particular (-) - spartein recovered in very high yield. (-) - Spartein is particularly preferred reinserted without cleaning by distillation.

The chiral is also preferred Auxiliary, especially (-) sparteine, after reaction of the reaction mixture with a silylation reagent isolated as a solid.

Surprisingly it has now been found that the chiral auxiliary, in particular (-) - Spartein, at Implementation of the reaction mixture with trialkylhalosilane, in particular with trimethylchlorosilane, as a solid in the form of a zinc-containing Isolate salt, can be separated off by filtration and recovered to> 90. The simple and effective recovery of the chiral auxiliary, in particular of (-) - sparteine, makes the process according to the invention particularly economical.

(-) - Spartein is particularly preferred by reacting the reaction mixture with trimethylchlorosilane as Silylation reagent isolated as a solid and then regenerated.

It has been proven that the zinc with the reactive Halogen compound of the general formula (3a) or (3b) and the 2-thiophene carbaldehyde and the chiral auxiliary in a molar ratio (1st to 3): (1 to 2): 1: (0.1 to 2.5), especially (1.1 to 1.7) : (1 to 1.3): 1: (0.1 to 1.5).

Zinc is generally in the form of foils, tape, chip, powder or dust form or in the form of zinc wool used. The presence of other metals such as copper, silver or Mercury is not required. In particular, zinc is in shape of commercially available commercial Zinc powder or zinc dust is used, zinc of high purity is preferred of at least 99.995%, particularly preferred is zinc dust which consists of Zinc with a purity of at least 99,995% is obtained.

In order to achieve high product yields and purities, it has proven useful to activate the zinc before adding the reactive halogen compound of the general formula (3a) or (3b) or the chiral auxiliary or their mixture. Known methods, for example those mentioned in the summary by A. Fürstner, Synthesis 1989, p. 571, are suitable for zinc activation. Washing of the zinc with acid, activation by iodine as in EP-A-562 343 described and the activation by trimethylchlorosilane, wherein the activation by trimethylchlorosilane is particularly preferred because of its simple feasibility and the increased yields, product purities and selectivities and the suppression of side reactions. The activation of zinc by trimethylchlorosilane in the solvent diethyl ether is known from G. Picotin, P. Miginiac, J. Org. Chem. 1987, 52, p. 4796.

To activate zinc with trimethylchlorosilane, the zinc is introduced into the solvent or solvent mixture, then trimethylchlorosilane is added and the mixture is heated for 10 min to 2 h, preferably 10 to 45 min, at temperatures from 30 to 150 ° C., in particular at 40 to 120 ° C. , preferably heated at 50 to 80 ° C. It has proven useful to use zinc with trimethylchlorosilane in a molar ratio of 1: (0.01 to 0.5), in particular 1: (0.05 to 0.3) with heating to the desired temperature.

To activate the reaction mixture can also additives such as copper, chrome, manganese, cobalt, bismuth, Samarium, scandium, indium, titanium, cerium, tellurium, tin, lead, Antimony, germanium, aluminum, magnesium, palladium, nickel and mercury compounds or mixtures thereof, if appropriate be used.

The pressure range of the reaction is not critical and can be varied within wide limits. The pressure is usually 0.01 to 20 bar, the reaction under normal pressure (atmospheric pressure) is preferred carried out.

The reaction is preferred under Inertization with protective gas, such as nitrogen or argon. The Reaction can be continuous or batchwise, preferably batchwise carried out become.

In the second reaction step of the process according to the invention become the intermediate compounds produced in the first reaction step in the form of alkylated, arylated, silylated in the 3-oxy position or esterified (3R) - or (3S) -3-oxy-3- (2-thiophene) propionic acid esters or -silyl esters with amines of the general formula (4) to (3R) - or (3S) -3-oxy-3- (2-thiophene) propionic acid amides or their derivatives implemented. Preferably the liquid or gaseous Amines of the general formula (4) undiluted or optionally dissolved in one organic solvents or in water or in a mixture of an organic solvent and water, optionally under acidic conditions or adding others Bases to the intermediates obtained from the first reaction step, possibly solved in a solvent, added.

Are also preferred from the Intermediates obtained in the first reaction step, if appropriate solved in a solvent, to the amines, optionally dissolved in a solvent or solvent mixture, added.

It is also possible to use the second reaction step under elevated To perform pressure. The reaction is preferred in a pressure range between atmospheric pressure and carried out 1000 bar, a pressure range between atmospheric pressure is particularly preferred and 100 bar, especially up to 10 bar.

The temperature of the reaction is preferably maintained while the addition of the amines or that obtained from the first reaction step Intermediate products, if necessary by cooling, on a predetermined Value. The reaction is preferably carried out at temperatures from -110 to +200 ° C, particularly preferred at -60 up to +150 ° C, especially at –20 up to +80 ° C carried out.

If necessary, is before implementation with amines of the general formula (4) an activation of the from Intermediates obtained in the first reaction step. So can for example carboxylic acids of the general formula (6a) or (6b), where Z here is OH should z. B. 1,1'-carbonyldiimidazole activated first and then with reacted with the amines. Those from are preferred intermediates obtained in the first reaction step without activation reacted with the amines of the general formula (4).

If necessary, it is also possible to Implementation to the (3R) - or (3S) -3-Oxy-3- (2-thiophene) propionic acid amides with dialkylaluminium amides perform. The person skilled in the art is aminating carboxylic acid derivatives and their conditions known.

Preferably, in the second reaction step of the process according to the invention, the intermediates obtained from the first reaction step can also be reacted with hydroxylamine, hydrazine or their derivatives such as B. O-methylhydroxylamine or phenylhydrazine, optionally dissolved in a solvent, to N-hydroxy- (3R / 3S) -3-oxy-3- (2-thiophene) propionic acid amide, (3R / 3S) -3-oxy-3- (2-thiophene) propionic acid hydrazide or its derivatives of the general formula (5a) or (5b) are reacted with R ¹ = OH, OR ³ or NHR ³ .

It is preferably also possible in the first reaction step of the process according to the invention as reactive halogen compounds of the general formula (3b) carboxamides or their derivatives with Y = (C = O) -Z and Z = - NR1R2, -NR ¹ Si (R ^Si ) ₃ and -NSi (R ^Si ) ₃ Si (R ^Si ) ₃ , where R ¹ , R ² and R ^Si are intended to have the meaning given above, in particular the preferred embodiments mentioned above. This advantageously leads directly to (3R) - or (3S) -3-oxy-3- (2-thiophene) propionic acid amides, in particular those of the general formula (5a) or (5b). The first and the second reaction step of the process according to the invention are thus advantageously carried out in a single reaction step, which shortens the total number of reaction steps and, in contrast to the previously known multistage processes, makes the process according to the invention particularly economical owing to lower reworking and raw material costs.

Alternatively, reactive halogen compounds of the general formula (3b) or their derivatives with Y = (C = O) -Z and Z = -NR ¹ -OR ² or -NR ¹ -NR ² R ^{3 can} also be N-oxy-carboxamides or carboxylic acid hydrazides or their derivatives are used, the radicals R ¹ and R2 here also being able to also represent Si (R ^Si ) ₃ and otherwise R ¹ , R ² , R ³ and R ^{Si should have} the abovementioned meanings, in particular for the abovementioned preferred ones Embodiments should stand.

It is also preferably possible, in the first reaction step of the process according to the invention, after the reaction and after-reaction have taken place, the reaction mixture usually at temperatures from -110 to +60 ° C, particularly preferably from -40 to 0 ° C optionally after adding a water-immiscible organic solvent such as. B. methylene chloride, ethyl acetate, tert-butyl methyl ether or toluene with amines of the general formula (4) directly to (3R) - or (3S) -3-oxy-3- (2-thiophene) propionamides or their derivatives. The liquid or gaseous amines of the general formula (4) are preferably added to the reaction mixture in undiluted form or, if appropriate, dissolved in an organic solvent or in water or in a mixture of an organic solvent and water. The corresponding connections are advantageously reached directly. The first and second reaction steps of the process according to the invention are thus advantageously carried out in a single reaction step, which shortens the total number of reaction steps and makes the process according to the invention particularly economical, in contrast to the previously known multistage processes.

After the addition of everyone involved Leaves reactants preferably another 5 minutes to 24 hours, particularly preferably 50 minutes react to 18 h, in particular 20 min to 8 h, to complete the reaction to complete.

It was found that the implementation the intermediates obtained from the first reaction step with amines of the general formula (4) already at temperatures between -20 and +30 ° C very quickly complete within 5 to 30 min runs. The short reaction times make the process particularly attractive execution on a technical scale very economical.

Surprisingly it was also found that the from the first reaction step Intermediates obtained with amines of the general formula (4) in the absence of solvents or other additives at elevated pressure up to 10 bar quickly and with unexpectedly high product purities and yields runs at very high space-time yields. This does the procedure especially when performing on a technical scale very economical.

After implementation, the Reaction mixture of the second reaction step usually at temperatures from -110 up to +200 ° C, particularly preferred at -60 up to +100 ° C, especially at –20 up to +60 ° C optionally after adding an water-immiscible organic solvent such as B. methylene chloride, ethyl acetate, tert-butyl methyl ether or Toluene by adding an aqueous Acid worked up. Alternatively, the reaction mixture can also be converted into an aqueous one Add acid.

Preferred acids are Brönstedt acids, in particular strong acids, such as boric, tetrafluoroboric, phosphoric acid, phosphorous acid, hypophosphorous Acid, Sulfuric acid, sulphurous acid, Peroxosulfur, salt, river, hydrogen iodide, hydrogen bromide, Perchloric acid, hexafluorophosphoric acid, Benzenesulfone, p-toluenesulfone, methanesulfone, trifluoromethanesulfone and carboxylic acids, such as chloroacetic, trichloroacetic, vinegar, trifluoroacetic, lemon and formic acid.

In particular, hydrochloric acid, sulfuric acid, acetic acid or citric acid, preferably hydrochloric acid and acetic acid used. The acid can be in a concentrated form or in the form of a. dilute aqueous solution become.

The one after the second reaction step obtained (3R) - or (3S) -3-oxy-3- (2-thiophene) propionic acid amides are finally isolated from the organic or aqueous phase. The manufactured products can according to known, usually methods used such as extraction, distillation, crystallization or be isolated using chromatographic methods.

The following are particularly preferred obtained in the second reaction step (3R) - or (3S) -3-oxy-3- (2-thiophene) propionic acid amides after the reaction, even without adding an aqueous acid or an organic solvent or water or other treatment of the reaction mixture directly from the reaction mixture, if appropriate after adding a suitable one Solvent through Extraction, distillation, crystallization or by means of chromatographic Methods won.

Alternatively, it is preferred possible, after the reaction from the reaction mixture organic solvent or water optionally together with excess amine of the general formula (4) usually at temperatures of –80 up to +150 ° C, particularly preferred at -40 up to +120 ° C, in particular at 20 up to +70 ° C by distillation, if necessary under reduced pressure, partially or completely to remove. The (3R) - or (3S) -3-Oxy-3- (2-thiophene) propionic acid amides are then obtained from the concentrated reaction mixture, optionally after adding a solvent or an aqueous one Acid isolated. The manufactured products can from the organic or aqueous Phase after known, usually methods used such as extraction, distillation, crystallization or be isolated using chromatographic methods.

Preference is given to the reaction mixture also more gaseous Hydrogen chloride introduced, excess amines of the general Formula (4) are converted into ammonium salts. The ammonium salts can optionally removed from the reaction mixture by filtration become. The (3R) - or (3S) -3-oxy-3- (2-thiophene) propionic acid amides obtained in the second reaction step can from the organic or aqueous Phase after known, usually methods used such as extraction, distillation, crystallization or be isolated using chromatographic methods.

In the second reaction step, crystalline (3R) - or (3S) -3-oxy-3- (2-thiophene) propionic acid ami de obtained, then the crystallization is preferably initiated and promoted by seeding with the pure compounds.

Surprisingly it has now been found that this is particularly preferred, for example by the method according to the invention N-methyl- (S) - (-) - 3-hydroxy-3- (2-thiophene) propionic acid amide which can be prepared by crystallization after distilling off water and excess methylamine from the reaction mixture directly or if necessary by seeding and if necessary in Presence of solvents Toluene, tert-butyl methyl ether, Methylene chloride, ethyl acetate, methanol, ethanol or tetrahydrofuran can be isolated in high yield and purity.

In most cases, these are by distance of the solvent obtained crude products of the second reaction step in the form of (3R) - or (3S) -3-oxy-3- (2-thiophene) propionic acid amides of very high purity and can then immediately used in the subsequent third reaction step become.

If necessary, in the second Crystalline (3R) - or (3S) -3-oxy-3- (2-thiophene) obtained in the reaction step propionic acid amides before further implementation in the third reaction step for enantiomer enrichment recrystallized. For recrystallization, they are preferred in Form their crude products dissolved in a suitable solvent and optionally recrystallized by seeding with enantiomerically pure compound.

Surprisingly it has now been found that this is particularly preferred, for example by the method according to the invention producible N-methyl- (S) - (-) - 3-hydroxy-3- (2-thiophene) propionic acid amide with 91% ee by a recrystallization step from acetone, methyl ethyl ketone or tetrahydrofuran up to> 98 % ee enrichment.

It is also preferably possible to (3R) - or (3S) -3-hydroxy-3- (2-thiophene) obtained in the second reaction step propionic acid amides, optionally directly from the reaction mixture after the reaction is complete at temperatures of –110 up to +100 ° C with an alkylation or Arylating reagent such as 1-fluoronaphthalene, one Esterification reagent or a silylation reagent and optionally a solvent to move.

The so obtained, in 3-oxy position alkylated, arylated, esterified (acylated) or silylated Products, can then after hydrolysis or optionally directly from the mixture be isolated by distillation, extraction or crystallization.

As alkylation or arylation, Esterification or silylation reagents find all suitable, Reagents well known to those skilled in the art Use.

The alkylation, arylation, Esterification or silylation reagent can be preferred selected from the compounds described above, especially those above described preferred embodiments.

It is also preferably possible to obtain (3R) - or (3S) -3-oxy-3- (2-thiophene) propionic acid amides, in particular propionic acid amides of ammonia, obtained from the second reaction step by exchanging the amide-NH ₂ - or -NHR ¹ - Group, wherein R ¹ is intended to have the meaning given above, with primary or secondary amines of the general formula (4) to convert carboxamides of primary or secondary amines. The person skilled in the alkylation deamination reaction of carboxylic acid amides and their conditions well known (eg. For example, from J. March, Advanced Organic Chemistry, ^3rd Edition, Wiley, New York 1985).

It is also preferably possible to obtain (3R) - or (3S) -3-oxy-3- (2-thiophene) propionic acid amides, in particular ammonia propionic acid amides, from the second reaction step by N-alkylation of the amide-NH2- or -NHR ¹ -Convert group with suitable reagents in N-monosubstituted or N-disubstituted carboxamides. N-alkylation of carboxamides and their conditions are well known to those skilled in the art.

In the third reaction step of the process according to the invention the (3R) - or (3S) -3-Oxy-3- (2-thiophene) propionic acid amides by reduction (3R) - or (3S) -3-oxy-3- (2-thiophene) propylamines or their derivatives of the general formula (1a) or (1b).

Preferably the liquid or solid amides from the second reaction step undiluted or possibly solved in a solvent to suitable reducing agents, optionally dissolved or suspended in a solvent, added.

Suitable ones are also preferred Reducing agent, optionally dissolved or suspended in one Solvent, to the amides from the second reaction step, optionally dissolved in one Solvent, added or, when using gaseous hydrogen as a reducing agent, initiated. The conditions of the reduction of carboxamides and nitriles are well known in the art.

All are used as reducing agents for the reduction of carboxamides, -hydrazides, N-hydroxycarboxamides or their derivatives and nitriles suitable reducing agents. The person skilled in the art is suitable for reducing agents from the Well known in the art.

The (3R) - or (3S) -3-oxy-3- (2-thiophene) propionic acid amides are preferably reduced by borane or diborane, alan, silanes, complex metal hydrides or homogeneous or heterogeneous catalytic reduction by hydrogen and also by all hydrogen-liberating ones reducing agent. Diborane, borane, alan or their derivatives are particularly preferred, it being possible for individual hydrogen atoms to be replaced by alkyl radicals, borane complexes with Lewis bases, preferably with the Lewis bases ammonia, tert-butylamine, N, N-diethylaniline, dimethylamine, N-ethyldiisopropylamine, 2,6-lutidine, N-methylmorpholine, N-phenylmorpholine, morpholine, 4- (dimethylamino) pyridine, pyridine, triethylamine, trimethylamine, dimethyl sulfide, diphenylphosphine, triphenylphosphine, tributylphosphine, 1,4-oxathiane, tetrahydrofuran and 1 , 5-thioxane or the reducing agents trichlorosilane, triethylsilane, tripropylsilane, tributylsilane or complex metal hydrides of aluminum and boron, optionally in the form of their complexes with Lewis bases, in particular lithium aluminum hydride, sodium aluminum hydride, sodium borohydride, lithium borohydride, calcium borohydride and their derivatives, whereby individual alcoholate be replaced as in sodium aluminum bis (2-methoxyethoxy dihydride), Vitride ^®, or cyanide can as well as amino aluminum hydrides. Lithium aluminum hydride and sodium aluminum bis (2-methoxyethoxy dihydride) (Vitrid®) are particularly preferred. If appropriate, the reduction is carried out in the presence of suitable activating additives, catalysts or solvents. A summary of this can be found, for example, in the prior art in J. Malek, Org. React. 1988, 36, p. 249.

Possibly before reduction the (3R) - or (3S) -3-oxy-3- (2-thiophene) propionic acid amides or their derivatives such. B. the N-hydroxy or hydrazide derivatives an activation and conversion of the compounds into an easier one reducible connection necessary. For example, the amides or their derivatives triethyloxonium tetrafuoroborate in activated O-alkyl derivatives implemented and then be reduced. Activated carboxamide derivatives are, for example also the α-alkylthioimmonium and α-chloroimmonium compounds.

The (3R) - or (3S) -3-oxy-3- (2-thiophene) propionic acid amides are preferred reduced without activation.

The temperature of the reaction is preferably maintained while the addition of the (3R) - or (3S) -3-oxy-3- (2-thiophene) propionic acid amides or the reducing agents optionally by cooling at a predetermined value. The reaction is preferably at Temperatures from –80 up to +300 ° C, particularly preferred at -40 up to +150 ° C, especially at –10 up to +800 ° C carried out.

As a solvent for the third Reaction step (reduction) can all suitable, well-known to the person skilled in the art from the prior art, under the conditions of reduction from the second reaction step obtained amides or their derivatives, inert solvents can be used. A summary of suitable solvents can be found, for example in J. Male k, Org. React. 1988, 36, p. 249.

Preferred solvent for the third Reaction step (reduction) are alcohols such as B. methanol, ethanol, Butanol, propanol, isopropanol, ethers such as diethyl ether, 1,4-dioxane, dimethoxymethane, dimethoxyethane, tert-butyl methyl ether and tetrahydrofuran, aromatic hydrocarbons, halogenated aliphatic hydrocarbons or mixtures of the above Solvent.

Particularly preferred solvents for the third reaction step (reduction) are ethers such as Diethyl ether, 1,4-dioxane, dimethoxymethane, dimethoxyethane, tert-butyl methyl ether and tetrahydrofuran.

It is also preferably possible without previous isolation of those obtained from the second reaction step Amides directly after the second reaction step of the process according to the invention after the reaction and post-reaction, the reaction mixture preferably at temperatures from -80 to +300 ° C, especially preferred at -40 up to +150 ° C, especially at –10 up to +80 ° C optionally after adding a suitable solvent with a reducing agent to convert directly to the amines of the general formulas (1a) or (1b) or reduce. In this case, reducing agents are preferably used together with a solvent added to the reaction mixture. This is advantageous directly to the compounds of the general formulas (1a) or (1b). The second and the third reaction step of the method according to the invention are thus advantageous together without isolation of intermediates carried out, what the inventive method makes it particularly economical.

After the addition of everyone involved Components leaves preferably another 5 minutes to 12 hours, particularly preferably 50 minutes react to 6 h, in particular 20 min to 3 h, to complete the reaction to complete.

After implementation, the Reaction mixture usually at temperatures of –80 up to +150 ° C, particularly preferred at -60 up to +80 ° C, especially at –20 up to +40 ° C optionally after adding an water-immiscible organic Solvent, preferably methylene chloride, ethyl acetate, tert-butyl methyl ether or toluene or by adding water or an aqueous Base or acid worked up. Alternatively, the reaction mixture can be added to water or an aqueous Base or acid enforce. The reaction mixture is particularly preferably one aqueous Base added.

Preferred bases are sodium, potassium, Lithium, magnesium or Calcium hydroxide, ammonia and organic amines such as trialkylamines and alkanolamines.

Preferred acids are Brönstedt acids, in particular strong acids, such as boric, tetrafluoroboric, phosphoric acid, phosphorous acid, hypophosphorous Acid, Sulfuric acid, sulphurous acid, Peroxosulfur, salt, river, hydrogen iodide, hydrogen bromide, Perchloric acid, hexafluorophosphoric acid, Benzenesulfone, p-toluenesulfone, methanesulfone, trifluoromethanesulfone and carboxylic acids, such as chloroacetic, trichloroacetic, vinegar, trifluoroacetic, lemon and formic acid.

In particular, sodium, potassium, Magnesium and calcium hydroxide, ammonia, hydrochloric acid, sulfuric acid or Acetic acid, preferably sodium hydroxide, hydrochloric acid and sulfuric acid used. The acid or base can be in concentrated form or in the form of a dilute aqueous solution be used.

The one after the third reaction step (Reduction) obtained products (end products) of the general formulas (1a) or (1b) are the organic or aqueous Phase isolated. When working up with an aqueous acid, the products of the general dissolve Formulas (1a) or (1b) in the aqueous Phase from which they, if necessary after extraction of unwanted Ingredients with organic solvent, after treatment with aqueous Base can be won. The manufactured products can according to known, usually methods used such as extraction, distillation, crystallization or be isolated using chromatographic methods.

Are crystalline end products of general formulas (1a) or (1b), then the crystallization preferably initiated by seeding with the pure compounds and favored.

If necessary, crystalline End products of the general formulas (1a) or (1b) for enantiomer enrichment recrystallized. The end products are preferred for recrystallization dissolved in the form of their crude products in a suitable solvent and, if appropriate recrystallized by seeding with enantiomerically pure compound.

It has now surprisingly been found that, for example, the method according to the invention particularly easy to prepare N-methyl- (S) - (-) - 3-hydroxy-3- (2-thiophene) propylamine enrich with 88% ee through a recrystallization step up to> 99% ee leaves. For the Recrystallization are called solvents Ethers, preferably diethyl ether, dipropyl ether, diisopropyl ether, Dibutyl ether or tert-butyl methyl ether, halogenated hydrocarbons and mixtures of ethers and halogenated hydrocarbons or mixtures of the abovementioned solvents or more polar solvents, preferably acetone, methyl ethyl ketone, ethyl acetate, ethylene glycol monomethyl ether or tetrahydrofuran with non-polar solvents, preferably Hexane, cyclohexane, petroleum ether, benzene or toluene are used.

Diethyl ethers are particularly suitable, Diisopropyl ether, dibutyl ether, tert-butyl methyl ether, tetrahydrofuran and ethylene glycol monomethyl ether.

It was surprisingly found that that's about the inventive method particularly easy to prepare N-methyl- (S) - (-) - 3-hydroxy-3- (2-thiophene) propylamine with 88% ee from tert-butyl methyl ether, a mixture of tert-butyl methyl ether and methylene chloride, a mixture of ethylene glycol monomethyl ether and tert-butyl methyl ether or a mixture of ethylene glycol monomethyl ether, Tetrahydrofuran and tert-butyl methyl ether in a recrystallization enriched to 99 ee.

The recrystallization surprisingly proceeds with very little product loss of up to <8% by weight and at very high concentrations up to> 30% by weight, what the enrichment is very, especially when carried out on a technical scale makes economical. Advantageously, this can be achieved by enrichment Enantiomerically enriched product by crystallization economical and inexpensive be converted into highly enantiomerically enriched or enantiomerically pure product.

This is particularly preferred in the third Liquid step obtained reaction Crude product directly from the solvents or solvent mixtures mentioned above, if necessary crystallized by inoculation and enriched at the same time.

It is also possible to liquid end products of the general Implement formula (1a) or (1b) in crystalline salts, which are then used for Enantiomeric enrichment can be recrystallized. Suitable salts are, for example, hydrochlorides, bromides, oxalates or carboxylates the benzoic acid, by the reaction of the end products with hydrogen chloride, hydrogen bromide, oxalic acid or benzoic acid be preserved.

In most cases, this is by distance of the solvent obtained crude end product of the general formula (1a) or (1b) of very high or sufficiently high purity and can immediately be used in subsequent reactions. So you can for example, the production of the active ingredient duloxetine by etherification the hydroxy group of particularly advantageous by the process according to the invention preparable N-methyl- (S) - (-) - 3-hydroxy-3- (2-thiophene) propylamine with 1-fluoronaphthalene.

It is also possible to obtain end products of the general formula (1a) or (1b) obtained, if appropriate directly from the reaction mixture after the reaction has ended or after working up, usually at from 110 to +150 ° C. using an alkylating or arylating reagent, an esterification re agent (acylation) or a silylation reagent, if appropriate in the presence of a solvent. The alkylated, arylated, silylated or esterified (acylated) products obtained can then be isolated after hydrolysis or, if appropriate, directly from the mixture by distillation, extraction or crystallization.

The amine group -NR ¹ R ² and / or the oxy group -OW of the end products of the general formula (1a) or (1b) obtained can be alkylated, arylated, silylated or esterified (acylated), where appropriate W and / or optionally at least one Radical R ¹ or R ² here should stand for hydrogen and otherwise W, R ¹ and R ² may have the meanings given above.

For example, an amino group in a compound of general formula (1a) or (1b) with an alkylating reagent, preferably methyl chloride or bromide be converted into a mono- or dimethylamino group.

For example, it is also possible to use a Hydroxy group in 3 position in a compound of general formula (1a) or (1b) with an arylating reagent, preferably 1-fluoronaphthalene.

As alkylation or arylation, Esterification or silylation reagents find all suitable, Reagents well known to those skilled in the art Use.

The alkylation, arylation, Esterification or silylation reagent can be preferred selected from the compounds described above, especially those above described preferred embodiments.

All of the above symbols of the above Formulas have their meanings independent of each other.

In the following examples, unless otherwise stated, all quantities and percentages by weight, all pressures 0.10 MPa (abs.) And all temperatures 20 ° C.

Example 1:

Preparation of (S) - (-) - 3-hydroxy-3- (2-thiophene) propionic acid methyl ester (1st reaction step)

At room temperature were in one Three-necked flask with reflux condenser, internal thermometer, Dropping funnel and stirrer 9 g zinc dust (138 mmol) in 70 ml tetrahydrofuran under a nitrogen blanket submitted. After adding 2.3 ml of trimethylchlorosilane, heated the mixture is kept at 60 ° C. for 15 minutes and then dripped within 7 min at <65 ° C 20.4 g bromoacetate (134 mmol) neat to. Then the mixture was stirred for 15 min and with 20 ml of 1-methyl-2-pyrrolidone added. After cooling to 0 ° C were 32.6 g (-) - sparteine (139 mmol) neat added, the temperature rising to 8 ° C. After the clear Mix for 10 min at 40 ° C touched was cooled one to –20 ° C and added 12.4 g thiophene-2-carbaldehyde (111 mmol) neat to. The clear reaction mixture was then stirred at -20 ° C for 8 h, then at this temperature with 35 ml of 20% hydrochloric acid to a pH of 2 acidified and stirred for 10 minutes, the temperature of the mixture rising to 0 ° C. Then 150 ml Water added. Precipitated sparteine salt was suctioned off and twice with 40 ml of ethyl acetate washed (Spartein could be> 90% recovered). After separation the organic phase, the aqueous phase was extracted with 50 ml of ethyl acetate and then separated the organic phase. The organic phase was then at -10 ° C for 10 min stirred with 20 ml of concentrated ammonia solution. After phase separation the solvent largely distilled off in vacuo and the residue washed with 20 ml of water. After phase separation, drying and removal of solvent in vacuo was (S) - (-) - 3-hydroxy-3- (2-thiophene) propionic acid methyl ester in a yield of 19.8 g (96% of theory) and a purity of> 94% and 91% ee (HPLC) receive. The crude product obtained with a boiling point of 89 ° C (0.6 mbar) was used immediately in the subsequent second reaction step.

Example 2:

Preparation of (S) - (-) - 3-Hydroxy-3- (2-thiophene) propionic acid ethyl ester (1st reaction step)

At room temperature, 9 q of zinc dust (138 mmol) in 60 ml of tetrahydrofuran were placed in a three-necked flask equipped with a reflux condenser, internal thermometer, dropping funnel and stirrer under a nitrogen blanket. After 2.3 ml of trimethylchlorosilane had been added, the mixture was warmed to 60 ° C. for 15 min and then 22.4 g of ethyl bromoacetate (134 mmol) were added undiluted at <65 ° C. within 7 min. Then the mixture was stirred for 15 minutes. After cooling to 0 ° C., 60 ml of dimethylformamide were added and then 32.6 g (-) - sparteine (139 mmol) were added undiluted, the temperature rising to 8 ° C. After the clear mixture had been stirred at 10 ° C. for 10 min, the mixture was cooled to −20 ° C. and 12.4 g of thiophene-2-carbaldehyde (111 mmol) were added undiluted. The clear reaction mixture was then stirred at -20 ° C. for 8 h, then at this temperature with 35 ml of 20% hydrochloric acid to a pH of 2 acidifies and stirred for 10 min, the temperature of the mixture rising to 0 ° C. Then 150 ml of water was added. Precipitated sparteine salt was filtered off with suction and washed twice with 40 ml of ethyl acetate each time (sparteine could be recovered> 90%). After the organic phase had been separated off, the aqueous phase was extracted with 50 ml of ethyl acetate and the organic phase was then separated off. The organic phase was then stirred at -10 ° C for 10 min with 20 ml of concentrated ammonia solution. After phase separation, drying and removal of solvent in vacuo, (S) - (-) - 3-hydroxy-3- (2-thiophene) propionic acid ethyl ester was obtained in a yield of 20.9 g (94% of theory) and a purity of> 94 and 89% ee (HPLC) obtained. The crude product obtained was used immediately in the subsequent second reaction step.

Example 3:

Production of (S) - (-) - 3- (2-thiophene) -3-trimethylsiloxypropionic acid methyl ester (1st reaction step)

At room temperature, 5 g of zinc dust (77 mmol) in 30 ml of tetrahydrofuran were placed in a three-necked flask equipped with a reflux condenser, internal thermometer, dropping funnel and stirrer under a nitrogen blanket. After 1.2 ml of trimethylchlorosilane had been added, the mixture was warmed to 55 ° C. for 15 minutes and then 10.9 g of methyl bromoacetate (71 mmol) were added undiluted at <65 ° C. in the course of 7 minutes. Then the mixture was stirred for 10 minutes. After cooling to 20 ° C., 30 ml of tetrahydrofuran were added and then 17 g (-) - sparteine (72 mmol) were added undiluted at 0 ° C., the temperature rising to 10 ° C. The mixture was cooled to −15 ° C. and 6.6 g of thiophene-2-carbaldehyde (60 mmol) were added undiluted. The reaction mixture was then stirred at -15 ° C for 20 h, then 8 g of trimethylchlorosilane (74 mmol) were added at this temperature, the temperature of the mixture rising to 10 ° C and a precipitate being formed. The mixture was then stirred at 20 ° C. for 1 h, half of the organic solvent was distilled off in vacuo, 70 ml of pentane were added to the residue, the mixture was stirred for 30 minutes and cooled to 0 ° C. Precipitated sparteine salt was filtered off with suction and washed twice with 50 ml each of pentane (sparteine could be recovered to> 90). The organic product phase was washed with 5 ml of saturated sodium bicarbonate solution. washed. After phase separation, drying and removal of solvent in vacuo, (S) - (-) - 3- (2-thiophene) -3-trimethylsiloxypropionic acid methyl ester was obtained in a yield of 15 g (98% of theory) and a purity of> 95 % and 89% ee (HPLC) obtained. Rotation value: α _D = 54.3 (20 ° C, methylene chloride, c = 4). The crude product obtained was used immediately in the subsequent second reaction step.

Example 4:

Preparation of (S) - (-) - 3-methoxy-3- (2-thiophene) propionic acid methyl ester (1st reaction step)

At room temperature were in one Three-necked flask with reflux condenser, internal thermometer, Dropping funnel and stirrer 5 g zinc dust (77 mmol) in 30 ml tetrahydrofuran under nitrogen protective gas submitted. After adding 1.2 ml trimethylchlorosilane, heated the mixture is kept at 55 ° C. for 15 minutes and then dripped within 7 min at <65 ° C 10.9 g bromoacetate (71 mmol) neat to. Then the mixture was stirred for 10 minutes. After cooling down 20 ° C were 30 ml of tetrahydrofuran added and subsequently at 0 ° C 17 g (-) - sparteine (72 mmol) undiluted added, the temperature rising to 10 ° C. It was cooled to -15 ° C and added 6.6 g of thiophene-2-carbaldehyde (60 mmol) undiluted. The reaction mixture was subsequently Stirred at -15 ° C for 20 h, then 10.5 g of methyl iodide (74 mmol) were added at this temperature, the temperature of the mixture rising to 0 ° C.

The mixture was then 1 h at 20 ° C touched, organic solvent in half in a vacuum distilled off and to 0 ° C. cooled. Precipitated sparteine salt was suctioned off and twice with 50 ml of pentane washed (sparteine could be> 90% recovered). The organic Product phase became saturated with 5 ml Sodium bicarbonate solution. washed. After phase separation, drying and removal of solvent in vacuo was (S) - (-) - 3-methoxy-3- (2-thiophene) propionic acid methyl ester obtained in a yield of 11.1 g (92% of theory) and 89% ee (HPLC).

Example 5:

Preparation of (S) - (-) - 3-acetoxy-3- (2-thiophene) propionic acid methyl ester (1st reaction step)

At room temperature, 5 g of zinc dust (77 mmol) in 30 ml of tetrahydrofuran were placed in a three-necked flask equipped with a reflux condenser, internal thermometer, dropping funnel and stirrer under a nitrogen blanket. After 1.2 ml of trimethylchlorosilane had been added, the mixture was warmed to 55 ° C. for 15 minutes and then 10.9 g of methyl bromoacetate (71 mmol) were added undiluted at <65 ° C. in the course of 7 minutes. Then the mixture was stirred for 10 minutes. After cooling to 20 ° C., 30 ml of tetrahydrofuran were added and then 17 g (-) - sparteine (72 mmol) were added undiluted at 0 ° C., the temperature rising to 10 ° C. The mixture was cooled to −15 ° C. and 6.6 g of thiophene-2-carbaldehyde (60 mmol) were added undiluted. The reaction mixture was then stirred at -15 ° C for 20 h, then 5.8 g of acetyl chloride (74 mmol) were added at this temperature, the temperature of the mixture rising to 10 ° C. The mixture was then stirred at 20 ° C. for 1 h, half of the organic solvent was distilled off in vacuo, 70 ml of pentane were added to the residue, the mixture was stirred for 30 minutes and cooled to 0 ° C. Precipitated sparteine salt was filtered off with suction and washed twice with 50 ml each of pentane (sparteine could be recovered to> 90). The organic product phase was washed with 5 ml of saturated sodium bicarbonate solution. washed. After phase separation, drying and removal of solvent in vacuo, (S) - (-) - 3-acetoxy-3- (2-thiophene) propionic acid methyl ester was obtained in a yield of 13.1 g (93% of theory) and 89% ee ( HPLC) obtained. The crude product obtained was used immediately in the subsequent second reaction step.

Example 6:

Preparation of (S) - (-) - 3-hydroxy-3- (2-thiophene) propiononitrile (1st reaction step)

At room temperature were in one Three-necked flask with reflux condenser, internal thermometer, Dropping funnel and stirrer 10 g zinc dust (154 mmol) in 60 ml tetrahydrofuran under nitrogen protective gas submitted. After adding 1.2 ml trimethylchlorosilane, heated the mixture is kept at 55 ° C. for 15 minutes and then dripped within 7 min at <65 ° C 17.1 g Bromessigsäurenitril (142 mmol) neat to. After cooling to 0 ° C became 34 g (-) - sparteine (144 mmol) neat added, the temperature rising to 5 ° C. It was cooled to -15 ° C and added 13.3 g of thiophene-2-carbaldehyde (120 mmol) undiluted. The reaction mixture was subsequently Stirred at -15 ° C for 24 h, then at this temperature with 40 ml of 20% hydrochloric acid to a pH of 2 acidified and stirred for 10 minutes, the temperature of the mixture rising to 0 ° C. Then 80 ml Water and 80 ml of ethyl acetate were added. The mixture was filtered and separated solid washed with ethyl acetate. After separation the organic phase, the aqueous phase was extracted with 50 ml of ethyl acetate and then separated the organic phase. The organic phase was then at -10 ° C for 10 min stirred with 30 ml of concentrated ammonia solution and after phase separation washed again with 20 ml of water. After phase separation, drying and removal of solvent in vacuo became (S) - (-) - 3-hydroxy-3- (2-thiophene) propiononitrile in a yield of 16 g (88% of theory) and a purity of> 96 and 92% ee (HPLC) receive.

Example 7:

Preparation of N-methyl- (S) - (-) - 3-hydroxy-3- (2-thiophene) propionic acid amide (2nd reaction step)

At room temperature were in one Three-necked flask with internal thermometer, dropping funnel and stirrer underneath Nitrogen blanket 19.8 g of (5) - (-) - 3-hydroxy-3- (2-thiophene) propionic acid methyl ester (94%, 100 mmol) from Example 1. After cooling to -10 ° C one added 11 ml of a 41% methylamine solution in water (129 mmol) and stirred the mixture for 4 h at 0 ° C. Subsequently 90 ml of acetone were added and organic solvent was distilled together with water at 40 ° C in a vacuum. After the mixture was concentrated to about 40-50 g by inoculation with N-methyl- (S) - (-) - 3-hydroxy-3- (2-thiophene) propionic acid amide (> 99% ee) crystallization at 45 ° C initiated the product. After cooling the mixture to -10 ° C Filtered precipitate, washed with 15 ml of cold acetone and dried. N-methyl- (S) - (-) - 3-hydroxy-3- (2-thiophene) propionamide was in a yield of 15.1 g (82% of theory) with a melting point from 99 ° C and 96% ee (HPLC) was obtained.

Example 8:

Preparation of N-methyl- (S) - (-) - 3-hydroxy-3- (2-thiophene) propionic acid amide (2nd reaction step)

At room temperature were in one Three-necked flask with internal thermometer, dropping funnel and stirrer underneath Nitrogen blanket 145 g (S) - (-) - 3- (2-thiophene) -3-trimethylsiloxypropionic acid methyl ester (564 mmol), prepared according to Example 3, and 160 ml of methanol added. After cooling to 0 ° C added one 54 g of methylamine (1.7 mol) were added to the clear mixture and the mixture was stirred Mix for 3 h at 40 ° C. Subsequently was methanol along with excess methylamine distilled off. N-methyl- (S) - (-) - 3-hydroxy-3- (2-thiophene) propionic acid amide was in a yield of 103 g (99 d. Th.) and a purity of> 95% and 89% ee (HPLC) obtained.

Example 9:

Preparation of N-methyl- (S) - (-) - 3-hydroxy-3- (2-thiophene) propylamine (3rd reaction step)

At room temperature were in one Three-necked flask with reflux condenser, internal thermometer, Dropping funnel and stirrer under nitrogen protective gas 109 g of N-methyl- (S) - (-) - 3-hydroxy-3- (2-thiophene) propionic acid amide (587 mmol), prepared according to Example 8, in 1 1 tetrahydrofuran solved. Then 29 g of lithium aluminum hydride (764 mmol) were added in 30 min 260 ml of tetrahydrofuran at a temperature of <30 ° C metered in with evolution of hydrogen. After complete addition heated by lithium aluminum hydride the mixture is kept at 50 ° C. for 3 hours, cooled to 0 ° C and hydrolyzed with 70 ml of water, forming a Precipitation came. The suspension was stirred at 20 ° C for 30 min. The Precipitate was filtered off and four times with 100 ml of tetrahydrofuran washed. After drying over Sodium sulfate became the solvent distilled off in vacuo. N-methyl- (S) - (-) - 3-hydroxy-3- (2-thiophene) propylamine was in the form of an oil, that slowly crystallized, in a yield of 90.5 g (90% d. Th.) And 89% ee (HPLC) obtained and immediately recrystallized.

Example 10:

Preparation of N-methyl- (S) - (-) - 3-hydroxy-3- (2-thiophene) propylamine (3rd reaction step)

At room temperature, 375 g of Na-Al reductides (70% strength in toluene, "Vitride ^® solution") were placed in a three-necked flask with a reflux condenser, internal thermometer, dropping funnel and stirrer under a nitrogen blanket. A solution of 87 q of N-methyl- (S) - (-) - 3-hydroxy-3- (2-thiophene) propionic acid amide (470 mmol) was removed at a temperature of 20 to 30 ° C. with evolution of hydrogen within 45 min. prepared according to Example 8, metered in 770 ml of tetrahydrofuran. After another 45 min. at 25 to 30 ° C the mixture was heated to 40 ° C for 2 h. For hydrolysis, the solution, cooled to 0 ° C., was poured into a mixture of 700 ml of NaOH (15% in water) and 100 ml of tetrahydrofuran. The solution was stirred at 20 ° C. for a further 30 min. To recover 820 ml of tetrahydrofuran, the mixture was concentrated in vacuo. The remaining aqueous phase was extracted three times with 750 ml of methyl tert-butyl ether. The combined organic extracts were washed with 10 ml of water and the methyl tert-butyl ether was removed in vacuo. The residue was taken up in 80 ml of hot methyl tert-butyl ether and heated to reflux for 30 min. Cooling to 0 ° C. gives N-methyl- (S) - (-) - 3-hydroxy-3- (2-thiophene) propylamine in the form of colorless crystals with a yield of 73 g (91% of theory) and a purity of> 99% and 97% ee (HPLC).

Example 11:

Preparation of N-methyl- (S) - (-) - 3-hydroxy-3- (2-thiophene) propylamine by recrystallization

At room temperature, 50 g of N-methyl- (S) - (-) - 3-hydroxy-3- (2-thiophene) propylamine (292 mmol. Were in a three-necked flask with reflux condenser, internal thermometer, dropping funnel and stirrer at a temperature of 55 ° C. ), prepared according to Example 9, dissolved in 130 ml of methyl tert-butyl ether. The clear solution was inoculated with crystals of N-methyl- (S) - (-) - 3-hydroxy-3- (2-thiophene) propylamine with> 99% purity and> 99% ee and slowly cooled to 0 ° C. The precipitate formed was filtered off, washed with 70 ml of cold methyl tert-butyl ether and dried. N-methyl- (S) - (-) - 3-hydroxy-3- (2-thiophene) propylamine was obtained in a yield of 44 g (88% of theory) and> 98% ee (HPLC). The compound has a melting point of 73 ° C. Rotation value: α _D = –12.9 (35 ° C, MeOH, c = 4.2).

Analogous recrystallization from diisopropyl ether and diethyl ether provide N-methyl- (S) - (-) - 3-hydroxy-3- (2-thiophene) propylamine in a yield of 90 and 87% of theory Th. And 97.5 and 96.5% ee (HPLC).

Example 12:

Preparation of N-methyl- (S) - (-) - 3-hydroxy-3- (2-thiophene) propylamine by recrystallization

At room temperature were in one Three-necked flask with reflux condenser, internal thermometer, Dropping funnel and stirrer at a temperature of 50 ° C 50 g of N-methyl- (S) - (-) - 3-hydroxy-3- (2-thiophene) propylamine (292 mmol), prepared according to Example 9, dissolved in 750 ml of 2-butanone. The clear solution was made with crystals of N-methyl- (S) - (-) - 3-hydroxy-3- (2-thiophene) propylamine with> 99% purity and> 99% ee inoculated and slowly cooled to -10 ° C. educated Precipitate was filtered off, washed with 50 ml of cold 2-butanone and dried. N-methyl- (S) - (-) - 3-hydroxy-3- (2-thiophene) propylamine was in a yield of 43 g (86% of theory), a purity of> 99% and> 98% ee (HPLC) and an mp of 72.5 ° C receive.

Example 13:

Preparation of N-methyl- (S) - (-) - 3-hydroxy-3- (2-thiophene) propylamine by recrystallization

At room temperature were in one Three-necked flask with reflux condenser, internal thermometer and stirrer at a temperature of 53 ° C 80 g of N-methyl- (S) - (-) - 3-hydroxy-3- (2-thiophene) propylamine (467 mmol, 90% ee) in a mixture of 80 ml of methyl tert-butyl ether and 40 ml of ethylene glycol monomethyl ether added and 30 min backflow heated. When cooling slowly to 0 ° C receives man N-methyl- (S) - (-) - 3-hydroxy-3- (2-thiophene) propylamine in the form of colorless crystals in a yield of 73.6 g (92% of theory Th.) And a purity of> 99 % and 97% ee (HPLC).

Claims (13)

Process for the preparation of (3R) - or (3S) -3-oxy-3- (2-thiophene) propylamines of the general formula (1a) or (1b),

where R ¹ , R ² independently of one another are hydrogen or an optionally halogen- or cyano-substituted Cl-C30 hydrocarbon radical in which one or more methylene units which are not adjacent to one another are represented by groups -O-, -CO-, -COO-, -OCO- , or -OCOO-, -S- or -NR ^x - can be replaced and in which one or more methine units can be replaced by groups -N = or -P = and R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ independently of one another are hydrogen, halogen or an optionally halogen-substituted or cyano-substituted C ₁ -C ₃₀ hydrocarbon radical in which one or more methylene units which are not adjacent to one another are represented by groups -O-, -CO-, -COO-, -OCO-, or -OCOO-, -S- or -NR ^x - can be replaced and in which one or more methine units can be replaced by groups -N = or -P = and R ^{x is} hydrogen or an optionally halogen-substituted C ₁ -C ₃₀ hydrocarbon radical in which one or more, each other non-adjacent methylene units can be replaced by groups -O-, -CO-, -COO-, -OCO-, or -OCOO-, -S-, -NH- or -NC ₁ -C ₂₀ alkyl and in which one or several methine units can be replaced by groups -N = or -P = and W can denote hydrogen or an alkyl, aryl, acyl or silyl group, characterized in that (a) in a first step a 2-thiophenecarbaldehyde of the general formula (2)

with a reactive halogen compound of the general formula (3a) Hal-CR ³ R ⁴ -Y (3a) where Y can mean CN or (C = O) -Z and Z can mean OR ¹ , OSi (R ^Si ) ₃ or NR ¹ R ² and R ^{Si can,} independently of one another, optionally be halogen-substituted or cyano-substituted C ₁ -C ₃₀ -hydrocarbon radicals, in which one or more non-adjacent methylene units can be replaced by groups -O-, -CO-, -COO-, -OCO-, or -OCOO-, -S- or -NR ^x - and in which one or more Methine units can be replaced by groups -N = or -P = and Hal means chlorine, bromine or iodine and zinc in the presence of a chiral, enantiomerically pure auxiliary having at least two amine groups, with the proviso that protons present have a pK _a greater than 20, is reacted and then water, acid or base or an alkylation-arylation, esterification or silylation reagent is added and (b) if Y is (C = O) -Z with the proviso that Z is OR ¹ or OSi (R ^Si ) ₃ is an amine of the general formula (4) NHR ¹ R ² (4) is added and c) a reduction is carried out in a final step. A method according to claim 1, in which as reactive halogen compounds Bromine compounds are used. Process according to Claims 1 to 2, in which α-bromocarboxylic acid esters are used as the reactive halogen compounds become. A method according to claim 1 to 3, characterized in that the reaction in the presence of (-) - sparteine performed as a chiral auxiliary becomes. A method according to claim 1 to 4, characterized in that the products obtained after the second or third reaction step be recrystallized. A method according to claim 1 to 5, characterized in that Zinc from the reaction solution the chiral auxiliary is separated in a solid. A method according to claim 1 to 6, characterized in that the chiral auxiliary used from the separated from the reaction solution recovered zinc-containing solid becomes. A method according to claim 1 to 7, characterized in that the products obtained from an enantiomer enrichment by recrystallization be subjected. (3R) - or (3S) -3-oxy-3- (2-thiophene) amides of the general formula (5a) or (5b) or their mixtures

 in which R¹. R², R³, R⁴, R⁵, R⁶ and R⁷ should have the meaning according to claim 1 and R^x an optionally halogen-substituted C₁-C₃₀hydrocarbyl means in which one or more methylene units which are not adjacent to one another by groups -O-, -CO-, -COO-, -OCO-, or -OCOO-, -S-, -NH- or -N-C₁-C₂₀-Alkyl can be replaced and in which one or more Methine units can be replaced by groups -N = or -P = and W Is hydrogen or an alkyl, aryl, acyl or silyl group can. (3R) - or (3S) -3-oxy-3- (2-thiophene) ester of the general formula (6a) or (6b) where

Z is OR ¹ and R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ^x are intended to have the meaning according to claim 1 and W is an alkyl, aryl or silyl group or an acyl group (C = O) -R ^Ac with the proviso that R ^{Ac stands} for an optionally halogen-substituted or cyano-substituted C ₂ -C ₃₀ hydrocarbon radical. Enantiomerically pure (3S) -3-hydroxy-3- (2-thiophene) esters of the general formula (7)

where Z is OR ¹ and R ¹ and R ^x are intended to have the meaning according to claim 1. (3R) - or (3S) -3-oxy-3- (2-thiophene) silylester of the general formula (8a) or (8b)

where Z is OSi (R ^Si ) ₃ and R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ^x and R ^Si are to be as defined in claim 1 and W is hydrogen or an alkyl, aryl, acyl or or can mean silyl group. (3R) - or (3S) -3-oxy-3- (2-thiophene) propiononitriles of the general formula (9a) or (9b) where

R ³ , R ⁴ and R ^x are intended to have the meaning according to Claim 1 and W is hydrogen or an alkyl, aryl, acyl or can mean silyl group.