DD140036A1 - METHOD FOR THE PRODUCTION OF OPTICALLY ACTIVE AMINOSAURES AND THEIR DERIVATIVES - Google Patents

Abstract

The invention relates to a process for the preparation of optically active amino acids and their derivatives of general formula (R ind 1 R ind 2) -R ind 3-CH ind 2-CH (NHR ind 4) -COOR ind 5 by catalytic asymmetric hydrogenation of the corresponding unsaturated amino acid precursors in the presence of chiral metal complex catalysts. Optically active amino acids form valuable intermediates for the production of Pharmaca. According to the invention, optically active amino acids having an enantiomeric excess of up to 80% in the end product are obtained by reacting the prochiral amino acid precursors with chiral complex catalysts of rhodium (I), ruthenium or iridium complexes by reaction with bis (alkyl or arylphosphinous esters) of alkyl, Aralkyl or aryl-0,0-alkyliden- or -aralkyliden-glycopyranosiden or -furanosiden in a polar-apolar solvent mixture or in pure solvents at a catalyst-to-substrate ratio of 1:10 to 1: 1000 under hydrogen pressure of 0.1 to 100 atm and temperatures from -50 to +100 degrees C are hydrogenated asymmetrically.

Description

Process for the preparation of optically active amino acids and their derivatives

Field of application of the invention

The invention relates to a process for the preparation of optically active amino acids and their derivatives by catalytic asymmetric hydrogenation of the corresponding unsaturated amino acid precursors in the presence of metal complex catalysts with bisphosphinic acid esters as ligands. Optically active amino acids and their derivatives form valuable intermediates for the production of Pharmaca.

Characteristic of the known technical solutions

It is known that optically active amino acids from prochiral precursors can be obtained by homogenous catalytic asymmetric hydrogenation with complex catalysts _t the ligands having a center of chirality at the donor atom or in the vicinity of the donor atom _f "For example, Knowles u * Mitärb (Chem _e Technol), 197g. S, 590) for 3,4-Diox ^ -phenylalanine in 90% optical yield with the use of o-Anisylmethylcyclohexylphosphin as P-chiral ligand _e are particularly successful chelating bisphosphines as ligands for Rhodiurn (I) _'s optical yields of up to 80% by Kagan and co-workers _{e "(e} 0. AMSR Chem. Soc"., 9_4 (1972) 6429) were coated with 2 _i 3 ~ 0 Isopropylid3n '2 _"e 3-dihydroxs.-l _s 4-bis ( diphenylphosphino) butane (DIOP), whose center of chirality lies in the carbon skeleton of the phosphine ligand, has been exploited by Knowles

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of the chelate ligand (R, R) -I ^ -ethanothiyl-bis-i-methoxy / phenyl-phenylphosphine increase the optical yield of N-acetyl-phenylalanine to 96 % (US Pat. No. 4,008,281, 0. Amer. Chem. Soc (1977) 18, p. 5946) ,, chiral 1,2-bis (diphenylphosphinomethyl) cyclobutane, cyclopentane and cyclohexane derivatives have been prepared or used in several working groups (Aviron-Violet, BRD-OS 2 424 543j Tanaka and co-workers, Japan Kokai 76/101956 and 76/132190; systematic work by Glaser and Mitarb, in Tetrahedron Letters (1977) 29, S * 2527 and Tetrahedron Letters (1977) 52, 4635 u, 4639), where the enantiomeric excesses in small rings are particularly high and reach, for example, 91 % for N-acetylphenylalanine. However, Bosnich and Fryuk (3rd Amer. Chem. Soc., 89 (1977) 19, p 6262) has shown that with (2 S, 3 S) -Bis (diphenylphosphino) butane, ie without conformation stabilizing ring, almost enantiomerically pure amino acids can be represented, but DOPA only with 83 % optical yield and in the non-natural (R) form. A biphosphine obtained from a proline derivative over several stages also gives maximum optical yields of 91% N-acetylphenylalanine in the (R) -form (Achiwa, J " Amer. Chem. Soc., 98: 25 (1982), 8265).

Besides these particularly high enantiomeric excess producing chiral complex compounds, numerous other asymmetric complex catalysts have been used. So was by Morrison u. Al. (Amer. Chem. Soc., 93 (1971) 1301) proposed to use the diphenylrnenthylphosphine or neomenthylphosphine ligands in the form of the rhodium complexes for the catalytic reduction. A similar ligand, which also carries chiral phosphorus in addition to the chiral carbon skeleton of menthyl, has recently been used with 1-menthylmethylphenylphosphine (Fisher and M.: Tetrahedron Letters (1977) 29, p. Phosphinous acid esters of cellulose as chiral ligands for the rhodium-catalytic hydrogenation of amino acid precursors were first described by H. Pracejus u Bursian (DDR-WP 92 031).

In addition, Tanaka u. Mitarb, three publications on the safeness of bisphosphonic acid esters of trans-cyclohexanediol (Chem. Comniun, (1975) 18, p. 735), trans-cyclopentanediol (Tetrahedron Letters (1977) 3, pp. 295-96) and a cellulose Derivatives (Chem. Letters (1976) 11, p. 1213) as chiral ligands for rhodium catalysts, the optical yield of N-acetylphenylalanine being 68.5 % or less (see also Oapan Kokai 76/101 956).

Recently were also atropisomeric 2.2 * derivatives of 1,1'-binaphthyl tested (Kumada u.Mitarb., Tetrahedron Letters (1977) 16, S _e 1389), where Bisdiphenylphosphinigsäureester of 2.2 * dihydroxy · !, 1 * -dinaphthyls gave the highest optical yields (76 % N-acetylphenylalanine) (Grubbs and De Vries ₈ Tetrahedron Letters (1977) 22, p. 1879).

Finally, chiral phosphinous acid amides also gave a maximum of 84 % enantiomeric excess in amino acids. (Fiorini et al., Mol. Catalysis i (1976) 6, p. 4511 G. Pracejus et al., Tetrahedron Letters (1977) 39, pp. 3497-3500). H.-Krause also succeeded in synthesizing a heterocyclic rhcdium-containing catalyst complex based on polystyrene bearing dimethylphosphine groups, with optical yields of up to 60 % being achieved (DDR-WP application WP C 07 C / 201 383). ,

All of these catalysts suffer from the disadvantage that they are either relatively difficult to synthesize, or in some cases chirally non-naturally occurring starting materials for the ligands, or give unsatisfactory optical yields or reaction rates,

Target represents the invention

It is the object of the invention to obtain simple and efficient amino acids and their derivatives by simple and efficient complex catalysts. The disadvantages of multi-stage and complicated syntheses for optically active starting products are thereby to be avoided.

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Explanation of the essence of the invention

The object is achieved by a process for the preparation of optically active amino acids and their derivatives of the general formula

(R ₁ R ₂ ) R ₃ CH ₂ -CH - COOR ₅ ,

in which R ₁ R _{2 are} H, OH, halogen, O-alkyl, O-acyl or

R ₁ -R ₂ : O-CH ₂ -Oj

R <3: H, alkyl, phenyl or phenyl substituted with R "R _O ;

R ₄ : acyl, benzoyl or phthaloyl (where the Η-atom on the

Nitrogen is substituted), R ₅ : H, alkyl or aryl;

by catalytic asymmetric hydrogenation of the corresponding unsaturated amino acid precursors in the presence of chiral metal complex catalysts, characterized in that the prochiral amino acid precursors with chiral complex catalysts of rhodium (I), ruthenium or iridium complexes by reaction with bis (alkyl or arylphosphinigsäureestern) of alkyl -, Aralkyl- or aryl-O, O ~ alkyliden- or -aralkyliden-glycopyranosiden or -furanosiden in a polar-apolar solvent mixture or in pure solvents at a catalyst-to-substrate ratio of 1:10 to 1: 1000 under hydrogen pressure of 0 , 1 to 100 atm and temperatures of -50 to +100 C are hydrogenated.

The chiral carbohydrate starting components for the phosphinous ester ligands are acetals and ketals, preferably the 4,6-benzilide compounds of the natural mono-, di- or oligosaccharides, in particular the methyl-4,6-O-benzylidene-8-glucopyranoside. Corresponding derivatives of "C 1-4 -anoseose and- C 1-5 -galactose or of the corresponding β-derivatives are also suitable." The aglycone used are O-aralkyl, O-aryl and O-alkyl, in particular methyl groups.

The free hydroxyl groups of these carbohydrate derivatives react with compounds of the trivalent phosphorus of the general formula

^R 6 ^R 7 ^PR 8

in the mean

Rg, R ₇ : H, alkyl, preferably tert-butyl, aralkyl, aryl, preferably phenyl, wherein R _β and R _{7 may be the} same or different;

Ro: N (alkyl) ₂ s halogen, preferably Cl; to the corresponding Bisphosphinigsäureestern.

As rhodium (I) ~ compounds, for example rhodium-carbonyl, rhodium-alkene, rhodium-phosphine or rhodium-diolefin complexes can be used, it being favorable that often complexed within the complex chlorine from the complex by formation of cationic complexes, z _e B _c by means of silver. tet.raf luoroborat, to remove *

The solution-forming chiral chelate complexes can be used directly for the hydrogenation or may be e.g. be isolated by precipitation from a solution in organic solvents with water.

The asymmetric hydrogenation of the amino acid precursors by the process according to the invention advantageously takes place at a catalyst / substrate ratio of 1: 100 in organic solvents such as methanol, ethanol, tetrahydrofuran or pioxane, preferably in ethanol or benzene / methanol mixtures at a hydrogen pressure of 1 to 60 atmospheres and a reaction temperature in the range of 15 to 25 ⁰ C.

The enantiomeric excesses of the amino acids can be up to 80 % in the final product * The workup is carried out at dan amino acid esters by concentration, hydrolysis with 17% HCl, formation of the sodium salts with bicarbonate _f extraction of the neutral parts with ethyl acetate, acidification with HCl and extraction of the amino acids with ethyl acetate, When using the prochiral acids, the workup is simplified because of elimination of the esterhydrolysQ step,. ,

-V- 2 05 13?

Exemplary embodiments Example 1

Reaction of methyl 4,6-O-benzylidene - '' - ^ - glucopyranoside (34 mmol) in 20 ml of inert pyridine with 15.4 ml of chlorodiphenylphosphine under strictly anaerobic conditions gives a rapidly durchkristallisierendes reaction mixture, from the methyl ~ , 6-benzylidene-2, 3-bis (0-diphenylphosphinyl) - * /, - glucopyranoside by extraction with ether and subsequent recrystallization from acetone in about 70 % yield is analytically pure isolated (mp.: 155 to 156, 5 ⁰ C).

With 0.1 mmol of this chelating ligand and 0.1 mVal of the dimeric rhodium-chloro-cyclooctadienkomplexes one prepares 10 ml of a stable benzene catalyst stock solution, of which 1 ml (containing 0.01 mmol in situ formed chelate) to 1 mmol06-Acetaminozimtsäuremethylester and 6.5 ml of benzene and 7.5 ml of methanol in an autoclave with Teflon insert is added. After shaking for 25 hours at 50 atm of hydrogen pressure and room temperature, N-acetylphenylalanine methyl ester is obtained quantitatively. After hydrolysis, an enantiomeric excess of 58.4 % (+) - (S) -N-acetylphenylalanine is detected.

Example 2: ·

Add 2 ml of air-free water to a solution of the complex of 1.3 mmol of methyl 4,6-O-benzylidene-bis-2,3-O- (diphenylphosphinyl) -5-glucopyranoside and 1.3 mM val the dimeric rhodium-chloro-cyclooctadienkomplexes in 20 ml of methanol / tetrahydrofuran mixture (1: 1) at 50 ⁰ C and slow

Cooling can be an orange colored chelate _s gain from the 0.01 mmol in 15 ml methanol / benzene mixture (1: 1) 1 mmol oL -Acetaminozimtsäuremethylester in 25 hours at 50 atm H ₂ and hydrogenated room temperature quantitatively. After hydrolysis of the ester, an enantiomeric excess of 59.8 % (+) - (S) -N-acetylphenylalanine is detected,

Example 3:

Analogously to Example 1, 1 mmol of α-acetaminocitic acid can be directly hydrogenated, whereby in 20 h at room temperature and 50 atm H _? the hydrogenation is quantitative and an enantiomeric excess of 57.0 % (+) - (S) -1! - acetylphenylalanine is obtained »

Example 4:

Analogously to Example 3, 1 mmol of α-acetaminocinnamic acid can also be hydrogenated quantitatively to N-acetylphenylalanine with a catalyst / substrate ratio of 1: 500 in 18 h at room temperature with 50 atm of H ₂ , where 55.8 % enantiomeric excess of (+) - (S) compound can be observed.

Example 5:

Analogously to Example 3 with a catalyst / substrate ratio of 1: 1000, 40 % enantiomeric excess of (+) - (S) -N'-acetylphenylalanine is obtained in 22 h at room temperature and 50 atm H at 91.0 % of chemical yield.

Example 6:

The hydrogenation of 1 mmol -Acetaminozimtsäure analogously to Example 2 leads in 20 h at room temperature under 50 atm H "in quantitative conversion to N-acetylphenylalanine, which contains 62.3 % of the (+) ~ (S) -enantiomers.

Example 7: ·

The hydrogenation of 1 mmol of X-Acetaminozimtsäuremethylester according to Example 1 using the analogous recoverable methyl-4 _i 6 ~ benzyliden ~ 2.3 "to ~ O ~ (diphenylphosphinyl) ~ galactopyranoside as Cheiatliganden for the catalyst leads in 20h of reaction at room temperature and 50 atm. to 94 % chemical yield of N-acetylphenylalanine methyl ester with an excess of the (+) - (! 3) ~ enantiomer of 54.4 % e .

- β - 2 05 137

Example 8:.

0.5 mmol of p-acetoxy-m-methoxy-c-acetaminocinnamic acid is hydrogenated with 0.5 l of catalyst stock solution according to Example 1, but in 15 ml of absolute ethanol in 19 h at 55 atm HU and room temperature to 86 % , while 79 , 4 % enantiomeric excess of (+) (Sj-p-acetoxy-m-methoxy-N-acetyl-phenylalanine as DOPA precursor.

Example 9:

The quantitative hydrogenation of 1 mmol -Acetaminozimtsäure analogously to Example 2, but in 15 ml of methanol at 55 atm H_ and room temperature in 20 h leads to an enantiomeric excess of 63.6 % of (*) - (S) -N-acetylphenylalanine.

Example 10:

Analogously to Example 9, but with 15 ml of ethanol as solvent, an enantiomeric excess of 71.4 % of (+) - (S) -N-acetylphenylalanine is obtained,

Example 11:.

From a catalyst stock solution containing 2 mMol Rh ₂ (CpH) ₂ Cl "7 and 1 mmol of methyl 4,6-benzylidene-2,3-bis-0- (diphenylphosphinyl) -jC" "^ -glucopyranoside in 15 ml of benzene, 0.15 ml of 1 mmol of c / acetaminocinnamic acid in 15 ml of ethanol are added, and after shaking at 15 ° C. and 55 atm of Hp for 21 hours, the hydrogenation is quantitative and, after working up, N-acetylphenylalanine is obtained with an enantiomeric excess of (+ ) - (S) compound of 70.5 % .

Example 12:.

Analogously to Example 11, but with the addition of 1 mmol of triethylamine, 10 h at 25 C and 30 atm of H ₂ gives only an enantiomeric excess of 11 _e 7 % (+) ~ (S) -N-acetylphenylalanine.

Example 13:

Analogously to Example 12, but in dioxane as solvent, the (-) - (R) -enantiomer of N-acetylpher.ylalanine is obtained with 12 % optical yield,

, - 9 » SL Ί * **

Example 14:

3 ml of the catalyst stock solution of Example 11 are with

Stirred 4 ml of a solution of 0.2 mmol of silver tetrafluoroborate in toluene two days * 3.5 ml of the supernatant solution will be "added Z'-acetaminocinnamic acid in 3 ml benzene and 7.5 ml of ethanol" to 1 mM at 25 ⁰ C and 1 atmHp is the reaction in 25 min quantitative, enantiomeric excess 72%

N ~ acetylphenylalanine _e

Example 15:

2 ₅ 5 ml of the catalyst stock solution of Example 1. are allowed to stand with 1 ml of toluene AgBF.-solution (containing 0.05 mmol) for 20 h * 2 _e 8 ml of the resulting supernatant solution (containing 0.02 mmol of rhodium) are added to a solution of 1 mmol of α-acetaminocinnamic acid in 7, Added 5 ml of methanol and 3.7 ml of benzene. At 25 C and 1 atm HL · the reaction is quantitative in 12 min »Enantiomeric excess 68.9% (+) - (S) -N-acetylpheny! Alanine»

Example 16:

10 ml of the catalyst stock solution of Example 1 are mixed with a solution of 0.15 mmol AgBF. stand in 3 ml of toluene for 20 h »1.3 ml of the supernatant solution (containing 0.01 mmol of rhodium) come to a solution of 1 mmol <pC ~ acetaminocinnamic acid in 13 _? 7 ml ethanol "At 25 ° C and 1 atm H ₂ , the reaction is quantitative in 12 min. Enantiomeric excess 71.6 % (+) - (S) ~ N-acetylphenylalanine. .

Example 17:

0.33 ml of the activated by AgBF ₄ catalyst solution from Example 16 are added to a solution of 1 mmol "^ -Acetaminc-» cinnamic acid in 14 ^ 7 ml of ethanol, at 25 ⁰ C and 1 atm of H ₂ , the reaction in 65 min quantitative: Enantiomeric excess 75.3 % (. + -. - (S) -N-acetylphenylalanine.

205 137

Example 18:

0.65 ml of the activated catalyst solution of Example 16

(containing 0 _f 005 mmol of rhodium) come to a solution

of 0.5 mmol of p-acetoxy-m-methoxy-α-acetaminocinnamic acid in 13.7 ml of ethanol. At 25 ⁰ C and 1 atm H ₂ is the reaction

in 12 min quantitative «Enantiomeric excess 70.8% (+) - (S) ·

ρ-acetoxy-m-methoxybenzaldehyde N-acetylamino phenylalanine.

Example 19:

The procedure is analogous to Example 14, but using only 0.7 ml of AgBF. Reacted catalyst solution, At room temperature and 55 atm H _? the enantiomeric excess of (+) - (S) -N-acetylphenylalanine is 73.3 /

Example 20:

Reaction of phenyl-4,6-O-benzylidene-β-D-glucopyranoside (34 mmol) in 15 ml of inert pyridine with 15.4 ml of chlorodiphenylphosphine under strictly anaerobic conditions gives a rapidly crystallizing reaction mixture. from which

D-glucopyranoside can be obtained by analysis with benzene in 64% yield analytically pure (mp.: 157.5 to 160 ⁰ C) ₀ .

1 eq of this chelating ligand and 1 mVal of the dimeric rhodium »chlorocyelooctadienkomplexes yield in 100 ml of benzene, a chelate ₄ from the addition of 5 ml of a toluene solution of 1.08 mmol of silver tetrafluoroborate at 80 C within 10 minutes, the chlorine quantitatively as silver chloride can be precipitated. From the decanted solution shed orange-red crystals of the rhodium cyclooctadxen ligand tetrafluoroborate complex which are stable to OQr air, washed twice with 8 ml benzene and dried in vacuo at 100.degree Yield of animal without further recrystallization of analytically pure substance 62.7 %

From this catalyst, O ₄ olmoles are added to a solution of 1 mM oil of acetaminoclinic acid in 15 ml anaerobic ethanol. The hydrogenation is quantitative at 25 ° C. and 1 atm tL in 25 minutes. Enantioroerenüberschuß 93 % (+) ~ (S) »= N ~ acetyl» phenylalanine *

Example 21?

OjOl iTiMol of the cationic chelate complex described in Example 20 are added to a solution of 1 mmol Z - ^ - acetaminocinnic acid in 15 ml of anaerohem ethanol. For the catalytically active catalyst complex, the reaction is started by stirring at room temperature under 1 atm of hydrogen for two minutes then continued at -15 ^V C, with a half-life of 35 min, the substrate is hydrogenated, yielding 98 μl (• frJ-iSJ-N-acetylphenylalanine with an enantiomeric excess of 97 % !).

205 137

Example 22:

However, 5 mmol of ZX- acetaminocinnamic acid are used as in Example 21, with the substrate being hydrogenated to 98 % with a half-life of 180 min, the optical yield of (+) - (S) -N-acetylphenol alanine is 96%,

   '/

 Example 23 $

O ₁ mmol of the cationic chelate complex described in Example 20 are added to a suspension of 20 mmol Z *> * C - acetaminocinnamic acid in 15 mmol anaerobic ethanol and

at 25 C and 1 atm of hydrogen with a half-life oft -

φ 110 minutes with stirring to N-acetyl-phenylalanine hydrogenated, wherein the optical yield of the (+) - (S) -enantiomer was 86% "

Example 24:. '

O ₄ mmol of the cationic chelate complex described in Example 20 are added to a solution of 1 mmol of p-acetoxy-m-methoxy-Z'-c-acetaminocinnamic acid in 15 ml of dioxane and at 25 C under 1 atm of hydrogen with a half-life of 8 min hydrogenated, enantiomeric excess 88 % (+) - (S) -p-acetoxy-m-methoxy ~ N -acetylphenylalanine,

Example 25:

The procedure is analogous to Example 24 and 15 ml of anaerobic diethyl ether was added to hydrogenate at 0 ⁰ C after being prehydrated for 2 min at room temperature. Half-life of 90 min, an optical yield of 89 % (+) - (S) -p-acetoxy-m-methoxy-N-acetyl-phenyl alanine is achieved. "

Example 26:

The procedure is analogous to Example 25 at -15 ⁰ C and at a half life of 140 min, an optical yield of 90 % (HO ^ CSJ-p-Acstoxy-m-methoxy-N-acetyl-phenylalanip achieved,

13 2 O 5 1 ί

Example 27:

The procedure is analogous to Example 24 but in 15 ml of ethanol. At a half-life of 27 min, an enantiomeric excess of 87 % (+) - (S) - p is hydrogenated acetoxy-m-methoxy-N-acetylphenylalanine.

Example 28:

0.01 mmol of the cationic chelate complex described in Example 20 are added to a suspension of 1 mmol 3 _{t of} 4-dimethoxy-Zo ^ acetaminocinnamic acid in 15 ml of ethanol. ** At 25 ° C., under 1 atm of hydrogen with a half-life W hydrogenated for 7 min to a 3 ^ -Dimethoxy-N-acetylphenylalanin- ^ mixture with / * << 7 _D - + 49.3 (c 2.9 EtOH). Ί

Example 29:

Analogously to Example 23, but in 15 ml of dioxane as solvent, a hydrogenation product with / "° -7 _D = * 45.8 (c 3.2 EtOH) is obtained with a half-life of 19 min."

Example 30:

0.01 mmol of the cationic chelate complex described in Example 20 are added to a suspension of 1 mmol of 3,4-dimethoxy-Z - ^ - aceto-anyncinnamic acid methyl ester in 15 ml of ethanol. At 25 ° C., under 1 atm of hydrogen with a half-life from 31 min to a 3,4-dimethoxy-N-acetylphenylalanine methyl ester mixture with / ^ O ⁷ _D - + 17.4 (c 2.0 EtOH).

Example 31:

Analogously to Example 30 "but in 15 ml of dioxane as solvent, a hydrogenation product with C <7 _U " + 14.5 (c 1.9 EtOH) is obtained with a half-life of 31 min.

¹⁴ 205 137

Example 32:

0.01 mmol of the cationic chelate complex described in Example 21 are added to a suspension of 1 mmol of 3,4-. Dirnethoxy-Z-ocf-acetaminozimtsäureethylester in 15 ml of ethanol. At 25 ⁰ C is hydrogenated under 1 atm of hydrogen with a half-life of 21 min to a 3,4-N-acetylphenylalanine ethyl ester Diroethoxy-mixture with '/ WJ = + 14.8 (c 2.0 EtOH).

Example 33:

Analogously to Example 32, but in 15 ml of dioxane as solvent, a hydrogenation product with / O £ J _D = + 15.9 (c 2.0 EtOH) is obtained with a half-life of 31 min.

Example 34 :: · _:

0.01 mmol. Of the cationic Che.latkomplexes described in Example 21 are added to a suspension of 1 mmol of 3,4-dimethoxy-Zb £ - benzoylaminocinnamic acid in 15 ml of ethanol. Hydrogenated at 25 C under 1 atm of hydrogen with a half-life of 65 min to give a 3,4-dimethoxy-N-benzoylphenyl-elanine mixture with ~ 4 / _D = 80.1 (c 2.0 CHCl ₃ ).

Example 35:

Analogously to Example 34, but in 15 ml of dioxane as solvent, with a half-life of 32 min, a hydrogenation product with £ * k? _D "- + 81.3 (c 2.1 CHCl ₃ ).

Example 35:

0.01 mmol of the cationic chelate complex, described under Example 21 are added to a solution of 1 mmol of 3,4-dimethoxy-Z ^ tx -benzoylaminozimtsäuremethylester in 15 ml of ethanol, "at 25 ⁰ C under 1 atm of hydrogen with a half-life of Hydrogenated for 19 min to a 3,4 ~ dimethoxy ~ N-benzoyiphenylalanine methyl ester mixture with / * <= 47 _D = + 7§, 6 (c 2.1 CHCl ₃ ). ,

5 137

is χ, ν ο

Example 37:

Analogously to Example 36, but in 15 ml of dioxane as solvent, a hydrogenation product with / V_ / _D '' ·· + 55.8 (c 2.4 CHCl ₃ ) is obtained with a half-life of 23 min.

Example 38 :.

0.01 mmol of the cationic chelate complex described in Example 21 are added to a solution of 1 ml of 3,4-dimethoxy-Z - ^ '- Benzoylarnimzimtsäureethylester in 15 ml of ethanol at 25 C under 1 atm of hydrogen with a half-life of 21 min to a 3,4-dimethoxy-N ~ benzoylphenylalaninethylester ~ hydrogenated mixture with / "<4 / _D = + 67.8 (c 2.0 CHCi ₃ ).

Example 39:

In analogy to Example 58, but in 15 ml of dioxane as solvent, a hydrogenation product having a half-life of 32 minutes is obtained with <** _Ό = + 63.0 (c 2.0 CHCl ₃ ).

vo, in'v

¹⁴ 20 5 137

Example 32:.

0.01 mmol of the cationic chelate complex described in Example 21 are added to a suspension of 1 mmol of 3,4-dinethoxy-Zt ^ T-acetaminozimtsäureethylester in 15 ml of ethanol. Hydrogenated at 25 C under 1 atm of hydrogen with a half-life of 21 min to a 3,4-dimethoxy-N-acetylphenylalanine ethyl ester mixture with C ⁰ ^ J - + 14.8 (c 2.0 EtOH).

Example 33:

Analogously to Example 32, but in 15 ml of dioxane as the solvent, a hydroti product with a half-life of 31 minutes is obtained, with O.sub.jl _D = + 15.9 (c 2.0 EtOH).

Example 34:

0.01 mmol of the cationic chelate complex described in Example 21 are added to a suspension of 1 mmol of 3,4-dimethoxy-Z-5'-benzoylaminocinnamic acid in 15 ml of ethanol. Hydrogenated at 25 C under 1 atm of hydrogen with a half-life of 65 min to a 3,4-dimethoxy-N-benzoylphenylalanine mixture with / _D 47 = 80.1 (c 2.0 CHCl ₃ ).

Example 35:

Analogously to Example 34, but in 15 ml of dioxane as solvent, a hydrogenation product with fc07 _Q = + 81.3 (c 2.1 CHCl ₃ ) is obtained with a half-life of 32 min.

Example 36:

0.01 mmol of the cationic chelate complex described in Example 21 are added to a solution of 1 mmol of 3,4-dimethoxy-Z - ^ - benzoylamimzimtsäuremethylester in 15 ml of ethanol. At 25 ⁰ C unter.1 atm of hydrogen with a half-time of 19 min is a 3,4-dimethoxy-N-benzoylphenylalanxnmethylester mixture with / * </ _D - * · 76.6 (c 2.1 CHCl ₃₎ hydrogenated "

20. Ji] ifi9 / ü * 7 Ji ^ i (15

15 "£ Il D

Example 37:

A hydrogenation product is obtained with a half-life of 23 min, as in Example 36, but in 15 ml of dioxane as solvent, with / * e £ J _D - ¹ '+ 55.8 (c 2.4 CHCl ₃ ).

Example 38s.

0.01 mmol of the cationic chelate complex described in Example 21 are added to a solution of 1 mmol of ethyl 3,4 ~ dimethoxy ^ Z - ^ - benzoylamino - cinnamate in 15 ml of ethanol. At 25 ° C., hydrogen is added under 1 atm to a half - life of 21 min a 3,4-dimethoxy-N-benzoylphenylalanine ethyl ester mixture with / "<47 _D = + 67.8 (c 2 * 0 CHCl ₃ ) hydrogenated,

Example 3.9:

Analogously to Example 38, but in 15 ml of dioxane as the solvent, a hydrogenation product with / X / _D = + 63.0 (c 2.0 CHCl ₃ ) is obtained with a half-life of 32 min.

C. U. vK'i IJi J ¹ 'toi - £ "χ

Table:

Ex j initial used ^ Rh (COD) Cl7 ₂ Rh (I ) - Substrate 15 ml Lo , sungsmit- EtOH Catalyst / atm H T ⁰ C Time optical Configu · component complex tt tel MeOH substratum H yield ration f.d.Ligan EtOH Ό / Ay " the η Bzl: MeOH = l: .l EtOH 50 1 glc t " AE H EtOH 1: 100 50 15 25 58.4 (+ WS) 2 glc η a) AE H dioxane 1: 100 50 15 25 59.8 (+) - (S) 3 glc. tt A H Benzene 3 ml 1: 100 50 15 20 57.0 (+) - (S) 4 glc H A M Toluene 3.5 ml 1: 500 50 15 18 55.8 (+) - (S) 5 glc H A M MeOH 7.5 ml. 1: 1000 50 15 22 40.0 °) (+) - (S) 6 glc H a) A N Bzl: MeOH = l: l, 2 1: 100 50 15 20 62.; 3 (+ WS) 7 gal ^ Rh (CH) C17 ₂ AE EtOH 1: 100 55 15 20 54.4 (+ WS) 8th glc Cm - Cm · β ft D EtOH 1: 100 55 15 19 79.4 ^d > (+) - (s) 9 glc M a) A EtOH 1: 100 55 15 20 63.6 (+) - (S) 10 glc η ^a ) A EtOH 1: 100 55 15 20 71.4 (+) - (S) 11 glc A -Acetaminozimtsäure; AE = 1: 100 30 15 21 70.5 '(+ WS). 12 glc A-NEt ₃ 1: 100 30 25 10 11.7 (+ WS) 13 glc A-NEt ₃ 1: 100 1 25 10 12.0 (-) - (R) 14 , glc • ι b) A 1:10 25 0.4 72.0 (+) - (S) , .- _; N  j M 1 .15 glc ^ Rh. (C ₂ H ₄ ) ₂ ci7 ₂ b) A 1:50 1 25 0.2 68.9 (+) - (S) 16 glc Substrate: A = b) A 1: 100 1 25 0.2 71.6 (+ WS) 17 glc b) A 1: 400 1 25 1 75.3 (+) - (S) 18 glc b) D 1: 100 55 25 0.2 70.8 (+) - (S) 19 glc b) A 1:50 15 20 73.3 (+) - (s) Remarks: z- χ Z- c'-acetaminocinnamic acid methyl ester}

D = p-acetoxy-m-methoxy-Z - ^ - acetaminocinnamic acid; glc = <£. D-glucose; gal == tD galactose,

a) The chiral catalyst complex was used in isolated form

b) Catalyst activated by AgBF addition to the catalyst stock solution

c) Chemical yield 91%. d) Chemical yield 86 %

In all other cases the chemical yield is practically 100 %.

Claims (10)

invention claim 1. A process for the preparation of optically active amino acids and their derivatives of the general formula (R "R _O ) R" CH _O - CH COOR ₁ . in the mean RR ₂ : H, OH, halogen, O-alkyl, O-acyl or R ₁ -R ₂ : 0-CH ₂ -O ₁ R ~: H, alkyl, phenyl or phenyl substituted with R ₁ R ₀ ; R ^: acyl, benzoyl or phthaloyl (wherein the H atom is substituted on the nitrogen) ι R ₅ : H, alkyl or aryl σ by catalytic asymmetric hydrogenation of the corresponding unsaturated amino acid precursors in the presence of chiral metal complex catalyst Gn, characterized in that the prochiral amino acid precursors with chiral coriiplex catalysts of rhodium (I), ruthenium or iridium complexes by reaction with bis (alkyl or arylphosphinigsäureestern) of alkyl, aralkyl - or aryl-0,0-alkylidene- or -aralkyliden-glycopyranosiden or -furanosiden in a polar-apolar solvent mixture or in pure solvents. a catalyst-to-substrate ratio of 1:10 to 1: 1000 under hydrogen pressures of 0.1 to 100 atm and temperatures of -50 to +100 ⁰ C are asymmetrically hydrogenated. 2. The method according to item 1, characterized in that are used as chiral carbohydrate starting components for the Phosphinigsäureesterliganden the 4 _i 6-Benzilidenverbindungen the mono ~, di- or oligosaccharides. 3 »A method according to item 1 and 2, characterized · in that as carbohydrate starting components Met.hyl-4j, 6-0-benzylidene-oC - 63-glucopyranoside or" appropriate. Derivatives of y - ^ -mannose and οό-cd - »galactose and their ß-derivatives are used« / 205 13 / 4 «method according to item 1 to 3, characterized in that act as aglycone for the glycosides of the ligands used 0-aralkyl, O-aryl or O-alkyl groups. 5 · Process according to item 1 to 4, characterized in that as bisphosphinous acid ester reaction products of the compounds of trivalent phosphorus of the general "Formula R ₆ R ₇ PR ₈ , in the mean R, R_: H, alkyl, aralkyl, aryl, where R _β and R _{7 may be} identical or different, R ₈ : N (alkyl) ₂ , halogen, be used with the free hydroxyl groups of carbohydrate derivatives · 6 _# Process according to items 1 to 5, characterized in that all rhodium (I) compounds rhodium carbonyl, rhodium alkene, rhodium phosphine,. or rhodium diolefins in complexes. 7. The method according to item 1 to 6, characterized in that the obtained in situ chiral metal complex catalysts are used. 8. The method according to item 1 to 6, characterized in that the obtained chiral metal complex catalysts are isolated in pure form. 9. The method according to item 1 to 8, characterized in that the metal complexes used are activated by conversion into cationic complexes. 10. The method according to item 1 to 9, characterized in that the asymmetric hydrogenation of the amino acid precursors at a catalyst to substrate ratio of 1: 100 in organic solvents such as methanol, ethanol, tetrahydrofuran or dioxane, preferably in ethanol or benzene / methanol mixtures , at a hydrogen pressure of 1 to 60 atm and a reaction temperature in the range of 15 to 25 ⁰ C is performed.