EP2041070A1

EP2041070A1 - Method for producing optically active 3-aminocarboxylic acid esters

Info

Publication number: EP2041070A1
Application number: EP07787131A
Authority: EP
Inventors: Christoph JÄKEL; Wolf-Rüdiger KRAHNERT; Rocco Paciello; Wolfgang Siegel
Original assignee: BASF SE
Current assignee: BASF SE
Priority date: 2006-07-06
Filing date: 2007-07-05
Publication date: 2009-04-01
Also published as: WO2008003761A1; CN101484414B; JP5566103B2; CN101484414A; JP2009542603A; US20090299089A1

Abstract

The invention relates to a method for producing optically active 3-aminocarboxylic acid ester compounds. According to said method, an enantiomer mixture of a mono-N-acylated 3-aminocarboxylic acid ester, which mixture was previously enriched in an enantiomer, is subjected to deacylation and then to a further enantiomer enrichment by crystallization by adding an acidic salt-forming substance.

Description

Process for the preparation of optically active 3-amino carboxylic acid esters

description

The present invention relates to a process for the preparation of optically active 3-aminocarboxylic acid ester compounds, and their derivatives.

Asymmetric synthesis, d. H. Reactions in which a chiral moiety is generated from a prochiral, so that the stereoisomeric products (enantiomers or diastereomers) arise in unequal amounts, has gained immense importance, especially in the pharmaceutical industry, since often only a certain optically active isomer therapeutically active is. In this context, optically active intermediates of the active ingredients are becoming increasingly important. This also applies to 3-aminocarboxylic acid esters (formula I), as well as their derivatives and in particular also to 3-aminobutyric acid esters (formula II).

(Formula I) (Formula II)

Thus, there is a great need for effective synthetic routes to produce optically active compounds of general formulas I and II.

The literature describes several ways of preparing unsaturated 3-acetylamino-carboxylic acid esters. It is known that enamines are obtained from β-ketoesters by reaction with aqueous or gaseous ammonia. In a second step, an enamine thus produced can be N-acylated by reaction with acetic anhydride.

S.P.B. Ovenden et al. (J. Org. Chem. 1999, 64, 1140-1144) describe the one-step preparation of α-unsaturated 3-acetylaminocarboxylic esters by azeotropic dehydration of a p-toluenesulfonic acid-acidified solution of acetamide and a β-ketoester in toluene or benzene.

The hydrogenation of olefins or .beta.-substituted .alpha.-acylamidoacrylic acids is well known to the person skilled in the art and is described, for example, in US Pat. No. 3,849,480 or US Pat. No. 4,261,919. WS Knowles and MJ Sabacky disclose a general go for homogeneously catalyzed, asymmetric hydrogenation of olefins (especially of β-substituted α-acylamido-acrylic acids) in the presence of an optically active hydrogenation catalyst in which an optically active enantiomeric form is desired as a product and the metal of the catalyst complex is selected under Rh, Ir, Ru, Os, Pd and Pt.

Examples of the asymmetric hydrogenation of α-unsaturated 3-acetylaminocarboxylic acid derivatives to saturated 3-aminocarboxylic acid derivatives and to the chiral catalysts used therefor are described inter alia in WO 9959721, WO 001 18065, EP 967015, EP 1298136, WO 03031456 and in US Pat WO 03042135 discloses.

N.W. Boaz et al. describe in Org. Proc. Res. Develop. 2005, 9, p. 472 the direct deacylation of 2-Acetylaminocarbonsäurealkylestern to 2-aminocarboxylic acid alkyl esters. The reaction of the homologous 3-aminocarboxylic acid alkyl esters is not described.

The present invention is therefore based on the object to provide a simple and therefore economical process for the preparation of optically active 3-aminocarboxylic acid esters and derivatives thereof.

Surprisingly, it has now been found that the stated object is achieved by a process in which a simple N-acylated 3-aminocarboxylic acid ester is subjected to a deacylation and enantiomeric enrichment by crystallization.

The invention therefore provides a process for the preparation of optically active 3-aminocarboxylic acid ester compounds of the general formula I, and also their ammonium salts,

wherein

R ^{1 is} alkyl, cycloalkyl, heterocycloalkyl, aryl or hetaryl, and R ^{2 is} alkyl, cycloalkyl or aryl,

in which an enantiomer mixture enriched in an enantiomer of a singly N-acylated 3-aminocarboxylic acid ester of the general formula (Ib), O

R ³ ^ NH O (lb)

wherein R ¹ and R ^{2 have} the meanings given above and R ^{3 is} hydrogen, alkyl, cycloalkyl or aryl, by addition of an acidic salt former of a deacylation and a subsequent further Enantiomerenanreicherung by crystallization.

Another object of the present invention is a process for the preparation of optically active 3-aminocarboxylic acid ester compounds of the general formula I ', as well as their derivatives,

wherein

R ^{1 is} alkyl, cycloalkyl, heterocycloalkyl, aryl, or hetaryl, and

R ^{2 'is} hydrogen, a cation equivalent M ⁺ , alkyl, cycloalkyl or aryl, in which a) a β-keto ester of the general formula 1.1

wherein R ¹ and R ^{2 have} the meanings given above,

a 1) having at least one carboxamide of the formula R ³ -C (O) NH 2, in which R ^{3 has} the abovementioned meaning, in the presence of an amidation catalyst, or a 2) with ammonia and then with a carboxylic acid derivative of the formula R ³ - C (O) X, in which X is halogen or a radical of the formula OC (O) R ⁴ , in which R ^{4 has} the meaning given above for R ³ , reacting the corresponding mixture of N-acylated, .alpha.-unsaturated (Z) - and (E) -3-aminocarboxylic acid esters, and optionally isolating the (Z) 3-aminocarboxylic acid ester of the general formula (La),

O

R ^J ^{^} NH O (La)

2

, R

R 'O

wherein R ¹ , R ² and R ^{3 have} the meanings given above,

b) subjecting the enamide (La) obtained in this reaction to an enantioselective hydrogenation in the presence of a chiral hydrogenation catalyst

Obtaining an enantiomerically enriched enantiomeric mixture of simply N-acylated β-aminocarboxylic acid esters of the general formula (Lb),

O

R ³ ^ NH O (lb)

wherein R ¹ , R ² and R ^{3 have} the meanings given above,

c) subjecting the obtained in the hydrogenation enantiomeric mixture of the compounds Lb by addition of an acidic salt former of a deacylation and subsequent further enantiomeric enrichment by crystallization and the thereby formed, with respect to a stereoisomer enriched ammonium salt of a 3-aminocarboxylic acid ester, and

d) optionally converting the isolated ammonium salt into the 3-aminocarboxylic acid ester, and

e) optionally converting the 3-aminocarboxylic acid ester into the free 3-aminocarboxylic acid or a salt thereof.

"Chiral compounds" in the context of the present invention are compounds having at least one chiral center (ie at least one asymmetric atom, eg at least one asymmetric C atom or P atom), with chirality axis, Chirality plane or helical turn. The term "chiral catalyst" includes catalysts having at least one chiral ligand.

"Achiral connections" are compounds that are not chiral.

A "prochiral compound" is understood to mean a compound having at least one prochiral center. "Asymmetric synthesis" refers to a reaction in which, from a compound having at least one prochiral center, a compound having at least one chiral center, a chiral axis, a plane of chirality, or a helical coil is generated, whereby the stereoisomeric products are formed in unequal amounts.

"Stereoisomers" are compounds of the same constitution but of different atomic order in three-dimensional space.

"Enantiomers" are stereoisomers that behave as image to mirror image to each other. The enantiomeric excess (ee) obtained in an asymmetric synthesis is given by the following formula: ee [%] = (RS) / (R + S) ^* 100. R and S are the descriptors of the CIP reaction. Systems for the two enantiomers and represent the absolute configuration of the asymmetric atom. The enantiomerically pure compound (ee = 100%) is also called "homochiral compound".

The process of the invention results in products that are enriched in a particular stereoisomer. The achieved "enantiomeric excess" (ee) is usually at least 3% higher than that of the N-acylated 3-aminocarboxylic acid ester. The achievable ee value with the method is usually at least 98%.

"Diastereomers" are stereoisomers that are not enantiomeric to one another.

Although other asymmetric atoms may be present in the compounds covered by the present invention, the stereochemical terms listed herein, unless expressly stated otherwise, refer to the carbon atom of the respective compounds corresponding to the asymmetric β-carbon atom in compound I or I '. If further stereocenters are present, they are neglected in the context of the present invention in the designation.

In the following, the term "alkyl" includes straight-chain and branched alkyl groups. Preferably, it is straight-chain or branched CrC ₂ O-alkyl, preferably CrCl ₂ alkyl, more preferably d-Cβ-alkyl, and especially preferably d-Ce-alkyl groups. Examples of alkyl groups are in particular methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 2-methylbutyl, 3-methylbutyl, 1, 2-dimethylpropyl , 1, 1-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 2-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2 , 3-dimethylbutyl,

1, 1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1, 1, 2-trimethylpropyl, 1, 2,2-trimethylpropyl, 1-ethylbutyl, 2-ethylbutyl, 1-ethyl-2-methylpropyl, n-heptyl, 2-heptyl, 3-heptyl, 2-ethylpentyl, 1-propylbutyl, n-octyl, 2-ethylhexyl, 2-methylheptyl, nonyl, decyl, 2-propylheptyl.

The term "alkyl" also includes substituted alkyl groups which are generally 1, 2, 3, 4 or 5, preferably 1, 2 or 3 and particularly preferably 1 substituent selected from the groups cycloalkyl, aryl, hetaryl, halogen, COOR ^f , CO ^" M ⁺ and NE can carry ¹ E ² , wherein R ^{f is} hydrogen, alkyl, cycloalkyl or aryl, M ^{+ is} a cation equivalent and E ¹ and E ^{2 are} independently hydrogen, alkyl, cycloalkyl or aryl.

The term "cycloalkyl" for the purposes of the present invention comprises both unsubstituted and substituted cycloalkyl groups, preferably Cs-Cβ-cycloalkyl groups, such as cyclopentyl, cyclohexyl or cycloheptyl, which in the case of a substitution, in general 1, 2, 3, 4 or 5, preferably 1, 2 or 3 and particularly preferably 1 substituent, preferably selected from alkyl and the substituents mentioned for alkyl, can carry.

The term "heterocycloalkyl" in the context of the present invention comprises saturated, cycloaliphatic groups having generally 4 to 7, preferably 5 or 6, ring atoms in which 1 or 2 of the ring carbon atoms are replaced by heteroatoms, preferably selected from the elements oxygen, nitrogen and sulfur and which may optionally be substituted, wherein in the case of a substitution, these heterocycloaliphatic groups 1, 2 or 3, preferably 1 or 2, more preferably 1 substituent selected from alkyl, cycloalkyl, aryl, COOR ^f , COO ^" M ⁺ and NE ¹ E ² , preferably alkyl, where R ^{f is} hydrogen, alkyl, cycloalkyl or aryl, M ^{+ is} a cation equivalent and E ¹ and E ² are each independently hydrogen, alkyl, cycloalkyl or aryl Heterocycloaliphatic groups are pyrrolidinyl, piperidinyl, 2,2,6,6-tetramethylpiperidinyl, imidazolidinyl, pyrazolidinyl, oxazolidine yl, morpholidinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, piperazinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl. The term "aryl" for the purposes of the present invention comprises unsubstituted and substituted aryl groups, and is preferably phenyl, ToIyI, XyIyI, mesityl, naphthyl, fluorenyl, anthracenyl, phenanthrenyl or naphthacenyl, particularly preferably phenyl or naphthyl, said aryl groups im In case of a substitution in general 1, 2, 3, 4 or 5, preferably 1, 2 or 3 and particularly preferably 1 substituent selected from the groups alkyl, alkoxy, nitro, cyano or halogen, can carry.

The term "hetaryl" for the purposes of the present invention comprises unsubstituted or substituted heterocycloaromatic groups, preferably the groups pyridyl, quinolinyl, acridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, indolyl, purinyl, indazolyl, benzotriazolyl , 1, 2,3-triazolyl, 1, 3,4-triazolyl and carbazolyl, these heterocycloaromatic groups in the case of a substitution generally 1, 2 or 3 substituents selected from the groups alkyl, alkoxy, acyl, carboxyl, Carboxylate, -SO ₃ H, sulfonate, NE ¹ E ² , alkylene-NE ¹ E ² or halogen, where E ¹ and E ^{2 have} the meanings given above.

The above explanations concerning the terms "alkyl", "cycloalkyl", "aryl", "heterocycloalkyl" and "hetaryl" apply correspondingly to the terms "alkoxy", "cycloalkoxy", "aryloxy", "heterocycloalkoxy" and "hetaryloxy ".

The term "acyl" in the context of the present invention represents alkanoyl or aroyl groups having generally 2 to 11, preferably 2 to 8, carbon atoms, for example the acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl, hepta noyl, 2-ethylhexanoyl, 2-propylheptanoyl, benzoyl, naphthoyl or trifluoroacetyl group.

"Halogen" is fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine.

M ⁺ represents a cation equivalent, ie a monovalent cation or the single positive charge fraction of a multiple cation. These include z. Li, Na, K, Ca and Mg.

As described above, the processes according to the invention make it possible to prepare optically active compounds of the general formula I and II, and to prepare their derivatives.

R ¹ is preferably C ₁ -C ₆ -alkyl, C ₃ -C ₇ -cycloalkyl or C ₆ -C ₄ -aryl, which may optionally be substituted as described above. In particular, R ^{1 is} methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclohexyl or phenyl, especially methyl. R ² is preferably unsubstituted or substituted C ₁ -C ₆ -alkyl, C ₃ -C ₇ -cycloalkyl or C ₆ -C ₄ -aryl. Particularly preferred radicals R ² are methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, cyclohexyl, phenyl and benzyl.

R ² is hydrogen, M ⁺ , as well as the meanings given for R ² .

R ³ is hydrogen, alkyl, cycloalkyl or aryl, in particular hydrogen, methyl, ethyl, trifluoromethyl, benzyl and phenyl.

According to the invention, an enantiomeric mixture of the compounds I.sub.b is subjected to deacylation by addition of an acidic salt-forming agent and subsequent further enantiomeric enrichment by crystallization, and the ammonium salt of a 3-aminocarboxylic acid ester enriched with respect to a stereoisomer is isolated.

It is a characteristic feature of the process according to the invention that in the isomer mixture of compounds of the general formula I.b used for deacylation, the corresponding enantiomer or, starting from chiral β-ketoesters, also diastereomers are present in non-negligible amounts. Advantageously, the process thus enables the preparation of optically active compounds of general formula I, starting from mixtures of isomers of compounds of general formula I.b, as they are obtainable for example from the precursor compounds by conventional asymmetric hydrogenation of enamides.

Usually, in this process step enantiomeric mixtures are used which are already enriched in one enantiomer. The ee value of these mixtures is preferably greater than 75% and particularly preferably greater than 90%.

In a preferred embodiment of the process according to the invention, the deacylation is carried out in an alcoholic solvent.

An alcoholic solvent used according to the invention is understood as meaning both pure alcohols and solvent mixtures which contain alcohols. In particular, these are methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol and cyclohexanol, and mixtures thereof with inert solvents, such as aromatics, for example toluene, and chlorinated hydrocarbons, dichloromethane or chloroform , With particular preference it is a compound of the formula R ² -OH, where R ^{2 has the} same meaning as in the product of the formula I or II. In a further preferred embodiment of the process according to the invention, at least one ester as solvent or a solvent mixture comprising at least one ester is added for the enantiomeric enrichment by crystallization. The ester is preferably alkyl acetates, in particular alkyl acetates of the formula CH ₃ C (O) OR ² , where R ^{2 has} the meaning given above. R ² particularly preferably has the same meaning as in the reacted N-acylated 3-aminocarboxylic acid ester of the formula (Ib). Specifically, the ester is methyl acetate or ethyl acetate.

In a specific embodiment of the invention, after deacylation, the solvent or solvent mixture used in the deacylation is partially or completely removed by a customary method known to the person skilled in the art, especially by a distillative process. Subsequently, a suitable solvent or solvent mixture, especially consisting of one or comprising an ester, is added to the residue for the enantiomeric enrichment by crystallization. Preferably, the solvent used for the enantiomeric enrichment by crystallization is added to a concentrated (i.e., a saturated or nearly saturated) solution of the 3-aminocarboxylic acid ester compound. If appropriate, the residual content of the solvent used in the deacylation is then further reduced by a process known to the person skilled in the art, preferably by distillation. Particularly preferably, the residual content of the solvent used in the deacylation is reduced to less than 5%.

Preferably, the deacylation is carried out at a temperature of at least 60 ° C, more preferably at least 75 ° C. For the subsequent crystallization, this temperature can be lowered.

The pressure in the deacylation is generally within a range of ambient pressure up to 25 bar. When using alcoholic solvents, the pressure is preferably in a range of 1 to 10 bar. The subsequent crystallization can be carried out at atmospheric pressure.

In a preferred embodiment of the present invention, the salt former used for deacylation and for subsequent crystallization is selected from achiral acidic compounds. Examples of suitable salt formers are acids which have a greater acid strength than acetic acid in the aqueous medium and form ammonium salts with the saturated .beta.-aminocarboxylic acid esters. Advantageously, the precipitation of the salts and their subsequent isolation leads to an increase in the optical purity. Preferably, the resulting salts of these salt formers are selected from benzoate, oxalate, phosphate, sulfate, hydrogen oxalate, hydrogen sulfate, formate, lactate, fumarate, chloride, bromide, trifluoroacetate, p-toluenesulfonate and methanesulfonate. Particularly preferred are p-toluenesulfonate and methanesulfonate.

When using such salt formers, ee values of at least 98% are generally achieved for the isolated ammonium salt.

In a particularly preferred embodiment of the process according to the invention, p-toluenesulfonate or methanesulfonate is used for the deacylation and subsequent crystallization as salt formers and the alcoholic solvent used for the deacylation comprises a compound of the formula R ² -OH, where R ^{2 has} the meaning given above.

The temperature in the enantiomeric enrichment by crystallization is generally in the range between melting point and boiling point of the solvent or solvent mixture used. In a suitable embodiment, the temperature in the course of the crystallization can be increased one or more times and / or lowered to initiate the crystal formation and / or to complete the precipitation of the desired enantiomer.

Advantageously, the solid isolated after the enantiomer-enriching crystallization has an ee value of at least 97.0% and in particular greater than 98%.

When N-acylated 3-aminocarboxylic acid esters with an ee value of 95% are used, ee values of at least 98% are generally achieved after deacylation for the corresponding ammonium salts.

The product of the formula I or II obtained in the crystallization can be subjected to a work-up (see the following statements on process steps d) and e)).

Another object of the invention relates to a process comprising the reaction steps a) to c) described below and optionally d) and e).

Stage a) In one embodiment of step a) of the process according to the invention, a β-keto ester of formula 1.1 is reacted with at least one carboxamide of the formula R ³ -C (O) NH ₂ in the presence of an amidation catalyst to remove the water of reaction to give a 3-aminocarboxylic acid ester of formula Ia implemented (step a.1).

In the case of the carboxylic acid amides of the formula R ³ -C (O) NH _2, preference is given in step a.1 to acetamide, propionamide, benzoic acid amide, formamide or trifluoroacetamide, in particular to benzoic acid amide or acetamide.

Suitable solvents for step a.1 are those which form a low-boiling azeotrope with water, from which the water of reaction can be removed by separation methods known to those skilled in the art (such as, for example, azeotropic distillation). In particular, these are aromatics such as toluene, benzene, etc., ketones such as methyl isobutyl ketone or methyl ethyl ketone, etc., and haloalkanes such as chloroform. Preference is given to using toluene.

Suitable amidation catalysts are, for example, acids such as p-toluenesulfonic acid, methanesulfonic acid, sulfuric acid or the like. Preferably, p-toluenesulfonic acid is used.

The reaction in process step a.1 preferably takes place at a temperature in the range from 20 to 110.degree. C., particularly preferably from 60 to 90.degree. Particularly preferably, the temperature is above the boiling point of the solvent used under normal conditions.

Process step a.1 is usually carried out at a pressure of 0.01 to 1.5 bar, in particular 0.1 to 0.5 bar. If appropriate, the aminocarboxylic acid ester obtained in step a.1 can be purified by customary methods known to the person skilled in the art, eg. B. be subjected to distillation.

In an alternative embodiment, a β-ketoester of the formula 1.1 is reacted with aqueous ammonia and then with a carboxylic acid derivative of the formula R ³ -C (O) X to give the N-acylated, β-unsaturated (Z) -3-aminocarboxylic acid ester (Ia), in which X is halogen or a radical of the formula OC (O) R ⁴ , in which R ^{4 has} the meaning given above for R ³ (step a.2).

The carboxylic acid derivative is preferably selected from carboxylic acid chlorides, wherein X is chlorine and R ^{3 has} the meaning given above, or carboxylic anhydrides, wherein X is OC (O) R ⁴ and R ^{4 is} preferably the same meaning As R ³ possesses, particularly preferably the carboxylic acid derivatives are acetyl chloride, benzoyl chloride or acetic anhydride.

The acylation in step a.2 is preferably carried out at a temperature in the range from 20 ° C. to 120 ° C., more preferably at a temperature in the range from 60 ° C. to 90 ° C.

The acylation in step a.2 is carried out in a polar solvent or a mixture of a polar solvent with a non-polar solvent, preferably the polar solvent is a carboxylic acid of the formula R ³ COOH or a tertiary amine, as nonpolar Solvents are particularly suitable haloalkanes and aromatics, particularly preferably used as the solvent acetic acid or triethylamine.

The acylation in step a.2 can be carried out using a catalyst, this can be used both in catalytic amounts and stoichiometrically or as a solvent, preferably non-nucleophilic bases, such as tertiary amines, more preferably these are triethylamine and / or di - methylaminopyridine (DMAP).

Optionally, in steps a.1 and a.2, the (Z) -3-aminocarboxylic acid ester is obtained as a mixture with the (E) -3-aminocarboxylic acid ester and optionally further acylation products. In this case, the (Z) -3-aminocarboxylic acid ester of formula I.a will be isolated by methods known to those skilled in the art. A preferred method is separation by distillation.

Stage b)

The α-unsaturated (Z) -3-aminocarboxylic acid ester compounds of the formula Ia obtained in step a can subsequently undergo enantioselective hydrogenation in the presence of a chiral hydrogenation catalyst to give a enantiomerically enriched enantiomeric mixture of simply N-acylated β-aminocarboxylic acid esters of the general formula (Ib) be subjected.

Preferably, in stage b), the hydrogenation catalyst used is at least one complex of a transition metal of groups 8 to 11 of the Periodic Table of the Elements, which comprises at least one chiral, phosphorus atom-containing compound as ligand. The hydrogenation is preferably carried out using a chiral hydrogenation catalyst which is capable of hydrogenating the α-unsaturated, N-acylated 3-aminocarboxylic acid ester (La) used, with preference for the desired isomer. The compound of the formula Ib obtained in step b) preferably has an ee value of at least 75%, particularly preferably at least 90%, after the asymmetric hydrogenation. However, such a high enantiomeric purity is often not necessary in the process according to the invention since, according to the process of the invention, a further enantiomeric enrichment takes place in the subsequent deacylation and crystallization step. However, the ee value of the compound 1b is preferably at least 75%.

The process according to the invention preferably allows the enantioselective hydrogenation at substrate / catalyst ratios (s / c) of at least 1000: 1, particularly preferably at least 5000: 1 and in particular at least 15000: 1.

For the asymmetric hydrogenation, preference is given to using a complex of a group 8, 9 or 10 metal with at least one of the ligands mentioned below. Preferably, the transition metal is selected from Ru, Rh, Ir, Pd or Pt. Particular preference is given to catalysts based on Rh and Ru. Especially preferred are Rh catalysts.

The phosphorus-containing compound used as ligand is preferably selected from bidentate and polydentate phosphine, phosphinite, phosphonite, phosphoramidite and phosphite compounds.

For hydrogenation, preference is given to catalysts which have at least one ligand selected from compounds of the following formulas,

TangPhos DuanPhos PhanePhos

or their enantiomers, where Ar is optionally substituted phenyl, preferably Toyl or Xylyl.

Particularly preferred are bidentate compounds of the aforementioned classes of compounds. In particular, P-chiral compounds such as DuanPhos, TangPhos or Binapine are preferred.

Suitable chiral ligands which coordinate to the transition metal via at least one phosphorus atom are known to the person skilled in the art and are commercially available, for example, from Chiral Quest ((Princeton) Inc., Monmouth Junction, NJ). The naming of the previously exemplified chiral ligands corresponds to their commercial designation. Chiral transition metal complexes can be prepared in a manner known to the person skilled in the art (for example Uson, Inorg. Chim. Acta 73, 275 1983, EP-A-0 158 875, EP-A-437 690) by reacting suitable ligands with complexes of the metals, containing labile or hemilabile ligands. Complexes such as Pd ₂ (dibenzylideneacetone) ₃ , Pd (OAc) ₂ (Ac = acetyl), RhCl ₃ , Rh (OAc) ₃ , [Rh (COD) Cl] ₂ , [Rh (COD) OH] can be used as precatalysts. ₂ , [Rh (COD) OMe] ₂ (Me = methyl), Rh (COD) acac, Rh ₄ (CO) i ₂ , Rh ₆ (CO) i ₆ , [Rh (COD) ₂ )] X, Rh ( acac) (CO) ₂ (acac = acetylacetonato), RuCl ₃ , Ru (acac) ₃ , RuCl ₂ (COD), Ru (COD) (methallyl) ₂ , Ru (Ar) I ₂ and Ru (Ar) Cl ₂ , Ar = aryl, both unsubstituted and substituted, [Ir (COD) Cl] ₂ , [Ir (COD) ₂ ] X, Ni (allyl) X can be used. Instead of COD (= 1, 5-cyclooctadiene) also NBD (= norbornadiene) can be used. Preference is given to [Rh (COD) Cl] ₂ , [Rh (COD) ₂ ] IX, Rh (acac) (CO) ₂ , RuCl ₂ (COD), Ru (COD) (methallyl) ₂ , Ru (Ar) Cl ₂ , Ar = aryl, both unsubstituted and substituted, and the corresponding systems with NBD instead of COD. Particularly preferred are [Rh (COD) ₂ )] X and [Rh (NBD) ₂ ) IX.

X can be any anion known to those skilled in the art and generally useful in asymmetric synthesis. Examples of X are halogens such as Cl ^" , Br ^" or I ^" , BF ₄ ^" , CIO ₄ ^" , SbF ₆ ^" , PF ₆ ^" , CF ₃ SO ₃ ^" , BAr ₄ ^" . Preferred for X are BF ₄ ^" , PF ₆ ^" , CF ₃ SO ₃ ^" , SbF ₆ ^" .

The chiral transition metal complexes can either be generated in situ before the actual hydrogenation reaction in the reaction vessel or else be generated separately, isolated and then used. It may happen that at least one solvent molecule attaches to the transition metal complex. The customary solvents (for example methanol, diethyl ether, tetrahydrofuran (THF), dichloromethane, etc.) for the complex preparation are known to the person skilled in the art.

Phosphine, phosphinite, phosphonite, phosphoramidite and phosphite-metal or metal-LM complexes (LM = solvent) with at least one labile or hemilabile ligand are suitable precatalysts from which the actual hydrogenation under the conditions of hydrogenation Catalyst is generated.

The hydrogenation step (step b) of the process according to the invention is carried out usually at a temperature from -10 to 150 ⁰ C, preferably at O to 120 ⁰ C and particularly preferably at 10 to 70 ⁰ C.

The hydrogen pressure can be varied within a range between 0.1 bar and 600 bar. This is preferably in a pressure range of 0.5 to 20 bar, more preferably between 1 to 10 bar. Suitable solvents for the hydrogenation reaction of enamides 1a are all solvents known to those skilled in the art for asymmetric hydrogenation. Preferred solvents are lower alkyl alcohols such as methanol, ethanol, isopropanol, as well as toluene, THF, ethyl acetate. In the process according to the invention, ethyl acetate or THF is particularly preferably used as the solvent.

The hydrogenation catalysts (or pre-catalysts) described above can also be suitably, for. B. by attachment via suitable as anchor groups functional groups, adsorption, grafting, etc. to a suitable carrier, eg. Example of glass, silica gel, resins, polymer carriers, etc., are immobilized. They are then also suitable for use as solid phase catalysts. Advantageously, the catalyst consumption can be further reduced by these methods. The catalysts described above are also suitable for a continuous reaction, z. B. after immobilization, as described above, in the form of Festphasenkatalysato- reindeer.

In a further embodiment, the hydrogenation in stage b is carried out continuously. The continuous hydrogenation can be carried out in one or preferably in several reaction zones. Multiple reaction zones may be formed by multiple reactors or by spatially distinct regions within a reactor. When using multiple reactors may each be the same or different reactors. These may each have the same or different mixing characteristics and / or be subdivided by internals one or more times. The reactors can be interconnected as desired, z. B. parallel or in series.

Suitable pressure-resistant reactors for the hydrogenation are known to the person skilled in the art. These include the commonly used reactors for gas-liquid reactions, such. B. tubular reactors, tube bundle reactors, stirred tank, gas circulation reactors, bubble columns, etc., which may be filled or divided by internals.

Step c)

With regard to step c) reference is made to the statements made at the outset for the crystallization by adding an acidic salt former.

Step d)

If desired, the ammonium salts isolated in the enantiomer-enriching crystallization can be subjected to a further work-up. This is how it is For example, to release the optically active compound of formula I, the product of the crystallization with a suitable base, preferably NaHCθ ₃ , NaOH, KOH bring into contact. In a suitable procedure, the product of the crystallization is dissolved or suspended in water and then the pH is adjusted by base addition to about 8 to 12, preferably about 10. To isolate the free 3-aminocarboxylic acid ester, it is possible to add the basic solution or suspension with a suitable organic solvent, e.g. Example, an ether, such as methyl butyl ether, a hydrocarbon or hydrocarbon mixture, for. As an alkane, such as pentane, hexane, heptane, or an alkane mixture, ligroin or petroleum ether, or aromatics, such as toluene to extract. A preferred extractant is toluene. In this procedure, the 3-amino acid ester can be obtained almost quantitatively, while also maintaining the ee value.

Steps)

Optionally, the 3-aminocarboxylic acid esters may be derivatized using methods known to those skilled in the art. Possible derivatizations include, for example, saponification of the ester or stereoselective reduction of the carboxyl carbon to an optically active alcohol.

Thus, derivatives of compounds of formula I 'according to the invention include, for example, ammonium salts of 3-aminocarboxylic acid esters, free carboxylic acids wherein R ^{2 is} hydrogen, salts of free carboxylic acid wherein R ^{2 is} M ⁺ , and optically active 3-aminoalcohols.

In a specific embodiment, the process described above is used to prepare optically active compounds of the formula II, or their ammonium salts, with the following absolute configuration, or for the preparation of the enantiomers of these compounds or salts,

wherein R ^{2 is} C 1 -C ₆ alkyl. These compounds and their salts are obtained in high optical purity, in particular with an ee value of at least 98%.

Examples

Example 1 Preparation of (R) -3-aminobutyric acid methyl ester

a) Synthesis of (ZJ-N-acetyl-S-aminocrotonic acid methyl ester

A solution of methyl acetoacetate (580 g, 5 mol), acetamide (295 g, 5 mol) and p-toluenesulfonic acid monohydrate (19 g, 0.1 mol) in toluene (1 L) at a reflux temperature of 80 ° C and heated to a pressure of 300 mbar on a water separator until no further reaction water left more and by GC analysis, the complete reaction was confirmed

(24 hours). After cooling the reaction mixture to 25 ° C, the organic phase was washed with water (2 x 375 mL). The combined aqueous phases were then extracted with toluene (500 mL), the combined organic phases combined and the toluene removed under reduced pressure. The crude product thus obtained was purified by distillation under reduced pressure

(15 mbar) over a short column at a head temperature of 105 ° C cleaned. (ZJ-N-acetyl-S-aminocrotonic acid methyl ester (380 g, 2.38 mmol) was obtained in 98% purity (GC), the yield being 47%.

b) Synthesis of (R) -N-acetyl-3-aminobutyric acid methyl ester

Under protective gas was (Z) -N-acetyl-3-aminocrotonsäuremethylester (200 g, 1, 27 mmol) dissolved in THF (200 g) and degassed by brief evacuation of the reaction vessel. After addition of [Rh (COD) DuanPhos] OTf (31.5 mg, 0.042 mmol), the resulting solution was transferred to a 1.2 L autoclave while maintaining the inert gas atmosphere. The autoclave was rinsed twice with a hydrogen pressure of 5 bar and then heated at this hydrogen pressure to 70 ° C and stirred for 20 h. By GC analysis of the reaction output, a conversion of 99.5% was determined with a content of (R) -N-acetyl-3-aminobutyrate of 99.2%. The ee value was 95.1% ee.

c) Synthesis of (R) -3-aminobutyric acid methyl ester x p-toluenesulfonic acid

From a according to step b) obtained solution of (R) -N-acetyl-3-aminobutter- acid methyl ester (37.5 g) in THF (43 mL), the solvent was removed under reduced pressure at a temperature of 50 ° C. The residue was taken up in methanol (94 mL) with p-toluenesulfonic acid monohydrate (53.8 g). mixed and stirred for 12 h at 100 ° C under autogenous pressure. After cooling the reaction solution and venting, the methanol was removed under reduced pressure at 50 ° C. The residue was treated at 50 ° C with methyl acetate (1 12 ml_) and then slowly cooled to 0-5 ° C. The precipitated product was isolated by filtration, washed with cold methyl acetate and then dried in vacuo.

The structure of the compound was verified by NMR spectroscopy. The content of the compound was determined by titration with a base. The enantiomeric purity was determined after derivatization by gas chromatography on a chiral phase. The derivatization of amino acids and their derivatives to determine the enantiomeric purity is known in the art.

The analysis of the reaction products was carried out by GC according to the following method:

Determination of Conversion:

Separation column: 25 m ^* 0.32 mm OV 1, FD = 0.5 μm, 50 °, 2 ', 207', 300 °, 45 '.

Starting material: 8.1 min; Product: 8,3 min

ee determination:

Guard column: 25 m ^* 0.25 mm Optima-1, FD = 0.5 μm; Chir. Column: 30m ^* 25mm BGB 174S;

FD = 0.25 μm; Temp. Program: 140 ° C, 12 '; 10 ° C / min, 200 ° C, 2 min; CoI 1 .:

Ramp pressure: 1.7 bar H2 (4.6 ml / '); 1, 7 min, 10 bar / min, 1, 9 bar, 0.2 min; 10bar / min; 1, 4 bar; CoI 2 .: Const. Press., 1, 3 bar H2 (2.7 ml / min).

(R) -3-N-acetylaminobutyric acid methyl ester: 9.87 min

(S) -3-N-Acetylaminobutyric acid methyl ester: 10.51 min

Claims

claims

1. A process for preparing optically active 3-aminocarboxylic acid ester compounds of general formula I, and their ammonium salts,

wherein

R ^{1 is} alkyl, cycloalkyl, heterocycloalkyl, aryl, or hetaryl, and

R ^{2 is} alkyl, cycloalkyl or aryl,

in which an enantiomer mixture enriched in one enantiomer of a singly N-acylated 3-aminocarboxylic acid ester of the general formula (l.b),

O

R ³ ^ NH O (lb)

wherein R ¹ and R ^{2 have} the meanings given above and R ^{3 is} hydrogen, alkyl, cycloalkyl or aryl, by addition of an acidic Salzbild- ners a deacylation and subsequent further enantiomer enrichment by crystallization.

2. Process for the preparation of optically active 3-aminocarboxylic ester

Compounds of general formula I ', and derivatives thereof,

wherein

R ^{1 is} alkyl, cycloalkyl, heterocycloalkyl, aryl, or hetaryl, and

wherein R ¹ and R ^{2 have} the meanings given above,

a 1) with at least one carboxylic acid amide of the formula R ³ -C (O) NH 2, in which R ^{3 has} the abovementioned meaning, in the presence of an amidation catalyst, or a 2) with ammonia and then with a carboxylic acid derivative of the formula R ³ -C ( O) X, in which X is halogen or a radical of the formula OC (O) R ⁴ , in which R ^{4 has} the meaning given above for R ³ ,

to give the corresponding N-acylated, .alpha.-unsaturated

(Z) -3-aminocarboxylic acid ester of general formula (La),

wherein R ¹ , R ² and R ^{3 have} the meanings given above,

b) subjecting the enamide (La) obtained in this reaction to an enantioselective hydrogenation in the presence of a chiral hydrogenation catalyst, to obtain a enantiomerically enriched mixture of enantiomers of simply N-acylated β-aminocarboxylic acid esters of the general formula (Lb),

O

R ^J ^{^} NH O (Lb)

2

, R

R ¹ "^ (D ^'

wherein R ¹ , R ² and R ^{3 have} the meanings given above, c) subjecting the obtained in the hydrogenation enantiomeric mixture of compounds lb by addition of an acidic salt former of a deacylation and subsequent further enantiomeric enrichment by crystallization and the resulting formed with respect to a stereoisomer enriched ammonium salt of a 3-amino carboxylic acid ester, and

3. The method of claim 2, wherein a ß-ketoester of formula 1.1 with at least one carboxylic acid amide of the formula R ³ -C (O) NH 2, in the presence of an amidation tion catalyst with removal of the water of reaction to a 3-amino carboxylic acid ester of the formula La is implemented ,

4. The method according to any one of the preceding claims, wherein the deacylation is carried out in an alcoholic solvent.

5. The method according to any one of the preceding claims, wherein the enantiomer-enriching crystallization is carried out with the addition of an ester.

6. The method according to any one of claims 1 to 5, wherein the salt former used for deacylation and for crystallization is selected from achiral acidic compounds.

A process according to claim 6, wherein the salt former is selected from p-toluenesulfonic acid, methanesulfonic acid, benzoic acid, oxalic acid, phosphoric acid, sulfuric acid, hydrogenoxalate, hydrogensulfate, formic acid, lactic acid, fumaric acid, hydrochloric acid, hydrobromic acid and trifluoroacetic acid.

8. The method according to any one of claims 1 to 7, wherein for deacylation and for crystallization p-toluenesulfonic acid or methanesulfonic acid is used as a salt former and the alcoholic solvent used for the deacylation comprises a compound of formula R ² -OH, wherein R ^{2 has} the previously given meaning has.

9. The method according to any one of claims 2 to 8, wherein as the hydrogenation catalyst at least one complex of a transition metal of groups 8 to 11 of the Periodic Table of the Elements is used, which comprises as ligand at least one chiral, phosphorus atom-containing compound.

10. The method of claim 9, wherein the transition metal is selected from Ru, Rh, Ir, Pd or Pt.

1 1. The method of claim 9 or 10, wherein the catalyst comprises at least one ligand selected from bidentate and polydentate phosphine,

Phosphinite, phosphonite, phosphoramidite and phosphite compounds.

12. The method of claim 11, wherein the catalyst comprises at least one ligand selected from compounds of the following formulas,

or their enantiomers, wherein Ar is optionally substituted phenyl, preferably ToIyI or XyIyI.

13. The method according to any one of claims 2 to 12, wherein at least one of the method steps is operated continuously.

14. The method of claim 13, wherein the hydrogenation is operated continuously.

15. The method according to claim 1 or 2, wherein R ¹ is d-Cg-alkyl and R ² and R ^{3 have} the meanings mentioned in claim 1.

16. The method according to claim 1 or 2, wherein R ^{3 is} methyl and R ¹ and R ^{2 have} the meanings mentioned in claim 1.

17. The method according to any one of the preceding claims, wherein the isolated after crystallization solid has an ee value of at least 98%.

18. The method according to any one of the preceding claims, wherein one obtains an optically active compound of the formula II or their ammonium salts with the following absolute configuration or the optically active enantiomer of this compound or salts

wherein R ^{2 is} C _r C ₆ alkyl.