NL1013789C2 - New diastereomerically enriched phenylglycine amide derivatives useful in the preparation of enantiomerically enriched compounds such as alpha- and beta-amino acids and amines - Google Patents

Abstract

Diastereomerically enriched phenylglycine amide derivatives (I) are new. Diastereomerically enriched compounds of formula (I) are new. R1 = (un)substituted phenyl; R2, R3, R4 = different groups with R2 and R3 selected from H, (un)substituted (cyclo)alkyl, alkenyl, aryl, (a)cyclic heteroalkyl or heteroaryl with N, O or S atom(s) or -(CH2)n-COR6; R4 = CN, H, (un)substituted allyl, -C(R7R8)-CHR9OH or -C(R7R8)-COOR10; R5 = H or 1-6C alkyl; n = 0-6; R6 = OH, (un)substituted alkyl, aryl, alkoxy or amino; R7, R8, R9 = alkyl or aryl; and R10 = alkyl. An Independent claim is also included for the preparation of (I).

Description

- 1 - PN 3997

METHOD FOR DB PREPARATION OF EROMER 5 ENRICHED COMPOUNDS

The invention relates to a process for the preparation of an enantiomerically enriched compound of formula 1 r3 R-2-i-R4 NH xm (1) I ^ NH2

R1 "\ l

Rs O

in which Rj. a substituted or unsubstituted phenyl group, R2, R3 and R4 are each different and R2 and R3 are H, an unsubstituted or substituted (cyclo) alkyl, alkenyl, aryl, cyclic or heteroalkyl or heteroaryl group with one or more N, 0 or S atoms, or (CH2) n-COR6, where n = 0,1,2 ... 6 and R6 = OH, an unsubstituted or substituted alkyl, aryl, alkoxy- or amino group and R4 = CN, H, a substituted or unsubstituted (cyclo) alkyl, alkenyl, aryl, cyclic or non-cyclic heteroalkyl or heteroaryl group having one or more N, O or S atoms, and R5 is H or alkyl of 1-6 C atoms where an enantiomerically enriched phenylglycine amide of formula 2

1 0137 SS

- 2 - 15 / ° R, tC <2> K "NH * in which R 1 and R 5 have the above meanings, using a compound of formula 3 R 2 - c (0) - R 3 (3) wherein R 2 and R 3 above meaning, is converted to the corresponding Schiff base or the tautomeric enamine, and then the resulting Schiff base is converted to the compound of formula 1 using an alkali cyanide, a reducing agent (for example, H2) or an organometallic compound, (as shown in Fig. 1).

In this method, an enantiomerically enriched phenylglycine amide is used as an auxiliary chiral compound in diastereoselective reaction concepts. Some examples of processes in which chiral auxiliaries are used are known in the literature, for example enantiomerically enriched α-phenylglycinol and enantiomerically enriched α-methylbenzylamine.

A drawback of the known chiral auxiliary compounds is that they are very expensive and are therefore less suitable for commercial use, since the chiral auxiliary compounds are consumed.

The applicant has now found that the phenylglycine amides of formula (2), for example phenylglycine amide, p-hydroxyphenylglycine amide or o (methylphenylglycine amide), are particularly useful as chiral auxiliary compounds in the preparation of enantiomerically enriched compounds, in particular. Amino acids or derivatives thereof and amines This is all the more surprising since phenylglycine amides are known to be racemization sensitive.

Another major advantage of the invention is that in most cases the phenylglycine amide derivatives formed in the method according to the invention lead to crystalline products. This means that if compounds that are not entirely diastereomerically pure can be purified to enantiomerically pure compounds via a simple crystallization step. This is in contrast to the now customary chiral auxiliaries in which in many cases oils are obtained which, for example, whether or not derivatized, are separated by chiral chromatography.

Suitable compounds are, for example, aldehydes, ketones, keto acids, ketoesters, ketoamides and glyoxylic acid (derivatives), in particular pivaldehyde, methyl isopropyl ketone, acetophenone, sobutyraldehyde. pyruvic acid, trimethylpyruvic acid and ethyl acetoacetate.

Enantiomerically enriched compounds which can be particularly well prepared by the process according to the invention are, for example, the compounds of formula 1 with R 4 = CN. It has also been found that it is also possible to crystallize one of the two diastereomers preferentially, the other remaining in solution and epimerizing in situ. This means that independent of the intrinsic diastereomeric excess (obtained via asymmetric induction by the chiral auxiliary group) among the chosen 2>; J i; «. , conditions, full conversion to one diastereomer may occur.

The resulting amino nitrile can then be converted in various ways known for amino nitriles (Fig. 2) to amino acids, amino acid amides and amino acid esters, for example by acid hydrolysis, basic hydrolysis, enzymatic hydrolysis or metal-catalyzed hydrolysis. A suitable embodiment is for instance treatment with a strong acid at elevated temperature to the corresponding diacid, which subsequently yields the corresponding amino acid after hydrogenolysis according to known methods (for instance using H2 and a Pd / C, Pd (OH) 2 catalyst). .

The resulting amino nitrile can also be converted, for example, by treatment with a strong acid to the corresponding diamide, which subsequently yields the corresponding amino acid amide after hydrogenolysis of the auxiliary group. The amino acid amide can be converted to the corresponding amino acid by known methods (for example with a strong acid) if desired.

Another conversion is, for example, treatment of the obtained amino nitrile with a strong acid in alcohols (eg with methanol) to the corresponding mono- or diester, which subsequently yields the corresponding amino acid ester after hydrogenolysis of the auxiliary group. The amino acid ester can, if desired, be converted into the A U ü O · by known methods (for example with a strong acid). 0 »- 5 - corresponding amino acid.

Other compounds which can be suitably prepared by the process of the invention are, for example, amines via reduction of the Schiff base 5 followed by hydrogenolysis by known methods, for example using H2 and a Pd / C or a Pd (OH) 2 catalyst (Fig. 3).

Reduction of the Schiff base can, for example, take place with NaBH4, LiAlH4 or derivatives thereof (eg alkoxy derivatives such as NaBH (OAc) 3, with hydrogenation catalysts eg Pd, Pt or RaNi in combination with H2 or under transfer hydrogenation conditions. It has been found that in particular RaNi suitable catalyst is for hydrogenation reactions leading to high diastereoselectivities.

Also amines and amino acid derivatives can be made particularly well by means of selective addition of organometallic reagents, for example Zn, Cu or Mg derivatives, to the Schiff base. This is particularly true when starting with α-methylphenyl-glycine amide as a chiral auxiliary compound.

Suitable organometallic compounds are, for example, compounds of the form RM, R2M, RMX in which M stands, for example, for Mg, Zn, B, Cu, Li, or other known metals for this application, R for a substituted or unsubstituted (cyclo) alkyl-, aryl, alkenyl, or a cyclic heteroalkyl or heteroaryl group with one or more N, O, or S atoms, in particular dioxolane, dithian thiophene, furan or pyrol groups.

The compounds of formula 1 wherein R x, R 2, 1 U!) V i 6 - 6 - R 3, R 4, R 5, as previously defined are new compounds. The compounds are preferably obtained with a diastereoisomeric excess of 80%, in particular 90%, more in particular 98%. The invention also relates to such compounds.

In addition, it was found that, due to the crystalline behavior of the intermediate phenylglycine amide derivatives obtained, at incomplete diastereoselectivity, purification by one crystallization often leads to> 99% diastereomeric excess.

The phenylglycine derivatives obtained can be converted into the corresponding amines by hydrogenolysis with, for example, Pd.

The (hetero) alkyl or alkoxy groups mentioned in the context of this invention preferably have 1-20 C atoms, in particular 1-5 C atoms, the alkenyl groups preferably have 2-20, in particular 2- 9 C atoms and the (hetero) aryl groups 2-20, in particular 3-8 C atoms. The (hetero) alkyl, alkoxy, alkenyl, aryl, heteroaryl or amino groups may, if desired, be singly or multiply substituted with, for example, halogen, in particular chlorine or bromine, an alkyl or aryl group with, for example, 1-10 C- atoms, and / or an alkoxy or acyloxy group with, for example, 1-10 C atoms.

The invention will now be elucidated on the basis of the examples without, however, being limited thereby.

013789

Examples

Example I

- 7 -

Strecker reaction with aldehyde 5 Addition of KCN to Schiff base of (R) -phenylglycine amide and 2,2-dimethylpropanal.

To 7.5 g (50 mmol) (R) -phenylglycine amide suspended in 50 ml water was added 3.0 ml (50 mmol) glacial acetic acid at 70 ° C. Then 4.3 g (50 mmol) of 2,2-dimethylpropanal and 3.25 g (50 mmol) of KCN were added at the same temperature.

The mixture was stirred at a temperature of 70 ° C for 24 hours. After cooling to 30 ° C, the solid was filtered off and washed with 10 ml of water. 10.4 g (42.5 mmol, 85%) of (R, S) -aminonitrile as white solid were obtained.

Absolute configuration was determined after conversion to 98% (S) -t-leucine (R, S) -aminonitrile, determined by 1 H NMR analysis, 1 H NMR (CDCl 3): 0.94 (s, 9H, tBu), 2, 66 (d, 1H, NH), 2.77 (d, 1H, CHCN), 4.37 (s, 1H, CHPh), 5.36 (broad s, 1H, CONH) 5.90 (broad s, 1H , CONH), 7.16-7.36 (m, 5H, Ar).

Other isomer (R, R) 25 X H NMR (CDCl3): 1.04 (s, 9H, tBu), 1.79 (d, 1H, NH), 3.21 (d, 1H, CHCN), 4.37 (s, 1H, CHPh), 6.27 (broad s, 1H, CONH) 6.66 (broad S, 1H, CONH), 7.16-7.36 (m, 5H, Ar).

i 1 C 7 R 9 - 8 -

Example II

Strecker reaction with aldehyde

Addition of KCN to Schiff base of (S) -phenylglycine amide and 2,2-dimethylpropanal.

5 To 7.5 g (50 mmol) (S) -phenylglycine amide suspended in 50 ml water was added 3.0 ml (50 mmol) glacial acetic acid at 70 ° C. Then 4.3 g (50 mmol) of 2,2-dimethylpropanal and 3.25 g (50 mmol) of KCN were added at the same temperature. The mixture was stirred at a temperature of 70 ° C for 24 hours. After cooling to 30 ° C, the solid was filtered off and washed with 10 ml of water.

10.7 g (43.3 mmol, 87.3%) (5.5) -aminonitrile as white solid was obtained. Absolute configuration was determined after comparison with the conversion of the (R, S) -aminonitrile to (S) - t-leucine: (5.5) -aminonitrile: de 98%, determined by 1 H NMR analysis, 1 H NMR (CDCl 3): 1.05 (s, 9H, tBu), 1.81 (d, 1H, NH), 3.19 (d, 1H, CHCN), 4, 35 (s, 1H, CHPh), 6.26 (broad s, 1H, CONH) 6.59 (broad, 1H, CONH), 7.10-7.38 (m, 5H,

Ar).

Example III

25 Strecker reaction with ketone

Addition of NaCN to Schiff base of (R) -phenylglycine amide and 3,4-dimethoxyphenylacetone

To 18.6 g (100 mmol) (R) -phenylglycine amide. HCl salt in 15 ml of MeOH and 25 ml of H 2 O was added at 9-10 9-25 ° C, 16.5 g of 30 % NaCN in water (100 mmol) and 19.3 g (100 mmol 3,4-dimethoxyphenylacetone) The clear solution was stirred at 20-25 ° C. After 82 hours, the resulting crystals were filtered off and washed with 3 x 5 ml of methanol / water (v / v 70:30).

21.6 g (61.1 mmol, 61%) of aminonitrile as a white solid of> 98%, determined by NMR analysis, were obtained.

1 H NMR (CDCl3): 1.48 (s, 3H, CH3), 2.60 (s, 1H, NH), 2.81 (s, 2H, CH2), 3.82 (s, 3H, OCH3) , 3.86 (s, 3H, OCH3), 4.47 (s, 1H, CHPh), 6.05 (broad s, 1H, CONH), 6.70 (broad s, 1H, CONH), 6.84 -6.90 (m, 3H, Ar), 7.26-7.38 (m, 5H, Ar).

Other isomer (only peaks determining the diastereomeric excess are given) XH NMR (CDCl3): 1.18 (s, 3H, CH3), 3.47 (s, 3H, OCH3), 3.50 (s .3H, 0CH3).

Example IV

20 Hydrolysis of the aminonitrile of (R) -phenylglycine amide and 2,2-dimethylpropanal, conversion to diamide

To a solution of 9.4 g (38.4 mmol) of aminonitrile in 50 ml of dichloromethane, 56 ml of concentrated H 2 SO 4 was added at about -10 ° C at a rate such that the temperature remains between -10 and 0 ° C. The mixture was then stirred at 20-25 ° C for 16 hours. After pouring the mixture on ice and neutralizing with 2% NH 3 / H 2 O, it was extracted with 3 x 200 ml ethyl acetate. The combined ethyl acetate layers 30 were dried over MgSO 4, filtered and, after evaporation,

i U 1 O t O W

- 10 - 9.5 g (36.1 mmol, 94%) (R, S) -diamide were obtained as a white solid X H NMR (CDCl 3): 0.87 (s, 9H, tBu), 2.46 (broad s, 1H, NH), 2.53 (broad s, 1H, CH), 4.08 (s, 1H, CH), 6.35 (broad s, 1H, CONH) 6.40 (broad s .2H, CONH2), 6.51 (broad s, 1H, CONH) 7.15-7.40 (m, 5H, Ar).

Example V

Hydrolysis of the amino nitrile of (R) -phenylglycine amide and 2,2 dimethylpropanal, conversion to diacid.

10.0 g (40.8 mmol) aminonitrile was added with stirring to 50 ml concentrated H 2 SO 4 at a rate such that the temperature remained below 40 ° C. The mixture was stirred at 20-25 ° C for 5 hours and then added dropwise to 100 ml of water. Then this reaction mixture was stirred at 70 ° C for 24 hours. After cooling to 25-30 ° C, NH3-25% was added to pH = 2, with crystallization of the amino diacid. The solid was filtered off and washed with 2 x 5 ml of water.

After drying, 8.0 g (30.2 mmol, 74.1%) (R, S) -amino diacid were obtained as a light yellow solid.

1 H NMR (D 2 O): 1.04 (s, 9H, tBu), 3.43 (s, 1H, CH CH 3), 4.84 (s, 1H, CHAr), 7.40-7.51 (m, 5H, Ar) 25

Example VI

Hydrogenolysis of the amino diamide of (R) -phenylglycine amide and 2,2-dimethylpropanal: synthesis of (S) -2-amino-3,3-dimethylbutanamide 30 9.0 g (36.7 mmol) aminodiamide was added ί λ 4 o 7 7 9 5 u F c - ^ - - 11 - dissolved in 250 ml 96% ethanol and then 0.5 g 10% Pd / C added. The mixture was hydrogenated at 0.2 MPa H 2 and 20-25 ° C for 20 hours. After removal of the Pd / C by filtration over celite, the solution was evaporated under reduced pressure. The crude reaction mixture was purified by column chromatography (SiO2, dichloromethane / methanol 9: 1). 2.2 g (46%) (S) -2-amino-3,3-dimethylbutanamide as a solid was obtained

10 1 H NMR (CDCl 3): 0.96 (s, 9H, tBu), 1.48 (broad s, 2H

NH2), 3.07 (s, 1H, CH), 5.49 (broad s, 1H, CONH) 6.50 (broad s, 1H, CONH).

Example VII

Hydrogenolysis of the amino diacid of (R) -phenylglycine amide and 2,2-dimethylpropanal 2.0 gr (7.5 mmol) amino diacid was added to 70.0 ml of water, followed by 1 eq HCl gas. After adding 0.2 g of 5% Pd / C, the reaction mixture was hydrogenated at 0.4 MPa H 2 and 50 ° C for 17 hours.

After filtration of the catalyst, the reaction mixture was extracted 3x with 50 ml of butyl acetate. The water layer was then applied to a Dowex 50 Wx8 column in the NH4 + form. The column was washed with 150 ml H 2 O and then eluted with ca 200 ml 10% aqueous NH 3.

After evaporation and drying, 0.84 g (6.4 mmol, 85.5%) (S) -2-amino-3,3-dimethylbutanoic acid ((S) -t-leucine) was obtained as a white solid 30 XH NMR (D20): 1.06 (s, 9H, tBu), 3.44 (s, 1H, CH) 1 013 7 8 9

Example VIII

- 12 -

Hydrolysis of (S) -2-amino-3,3-dimethylbutanamide: Synthesis of (S) -2-amino-3,3-dimethylbutanoic acid ((S) -t-leucine) 5 2.0 g (15.4 mmol ) (S) -2-amino-3,3-dimethylbutanamide was heated at 100 ° C in 500 ml 6N HCl for 24 hours. After cooling to 20-25 ° C, the mixture was applied to a Dowex 50 Wx8 column in the NH4 + form. The column was washed with 250 ml of water and then eluted with ca 400 ml of 10% aqueous NH3. After evaporation and drying, 1.7 g (86%) (S) -2-amino-3,3-dimethylbutanoic acid ((S) -t-leucine) were obtained XH NMR (D20): 1.06 (s, 9H, tBu), 3.44 (s, 1H, CH)

Example IX

Synthesis of the Schiff base of (R) -phenylglycine amide and 3,3-dimethyl-2-butanone

To 7.5 g (50 mmol) (R) -phenylglycine amide, 10.0 g (100 mmol) of 3,3-dimethyl-2-20 butanone, 40 ml of toluene, 50 ml of cyclohexane and 0.1 g (0, 53 mmol) p-toluenesulfonic acid. The mixture was heated to reflux (ca 90 ° C) with stirring. The water formed was collected during the reaction by 4A sieves in a soxhlett apparatus. After about 48 hours, the solution was evaporated under reduced pressure.

11.2 g (48.2 mmol, 97%) of Schiff's base as a white solid were obtained and used as such in the next step without purification.

XH NMR (DMSO-d6): 1.15 (s, 9H, t-Bu), 1.75 (s, 3H, Me), 4.85 (s, 1H, aH), 7.2-7, 4 (m, 5H-arom) 1013789 - 13 -

Example .. X

Reduction of Schiff base of (R) -phenylglycine amide and 3,3-dimethyl-2-butanone with Pt / C and H2 11.2 g (48.2 mmol) Schiff base of (R) -5 phenylglycine amide and 3.3 dimethyl butanone was dissolved in 100 ml of absolute ethanol and then 0.2 g of 5% Pt / C was added. The mixture was hydrogenated at 5 bar H 2 and 20 ° C for 5 hours. After removal of the Pt / C by filtration, the solution was evaporated under reduced pressure. The resulting yellow oil was dissolved in 100 ml of ethyl acetate and washed with 2 x 20 ml of water. After drying over MgSO4, the solution was evaporated again and then crystallized from 90 ml hexane. The solid was filtered, washed with 2 x 10 ml hexane and dried to constant weight.

Yield: 6.6 g (57% of (R) -phenylglycine amide). 1 H NMR showed only one stereoisomer (R, S) 1 H NMR (CDCl 3): 0.9 (s, 9H, tBu); 1.0 (d, 3H, Me), 2.35 (q, 1H, CHN), 4.25 (s, 1H, aH), 5.6-5.8 (s, 1H, NH), 7 25-7.40 (m, 5H, ar).

Other isomer: 0.8 (s, 9H, tBu), 0.95 (d, 3H, Me), 4.20 (q, 1H, CHN), 4.18 (s, 1H, aH), 7.25-7 .40 (m, 5H, ar).

25

Example XI

Reduction of Schiff base from (R) -phenylglycine amide and 3-methyl-2-butanone with RaNi and H2.

4.0 g (18.3 mmol) of the Schiff base of (R) -30 phenylglycine amide and 3-methyl-2-butanone were dissolved 1013789 - 14 - in 50 ml of absolute ethanol and 5 g of wet RaNi (previously washed) were added. with 3 x 30 ml absolute ethanol). The mixture was then hydrogenated with 0.1 MPa H 2. The conversion was monitored over time.

5 After about 7 days, the conversion was almost complete. The catalyst was removed by filtration and then evaporated under reduced pressure.

3.8 g (17.3 mmol, 94.5%) of amine as one diastereomer were obtained.

10

Example XII

Hydrogenolysis of amino amides; synthesis of (S) -3,3-dimethyl-2-butylamine.HCl 6.6 g (28.2 mmol) amino amide was dissolved in 100 ml absolute ethanol and then 0.3 g 10% Pd / C added. The mixture was hydrogenated at 0.5 MPa H 2 and 50 ° C for 20-24 hours. After cooling and filtration of the Pd / C over Celite, 3 ml of 37% HCl was added. The pH of the mixture was then about 3.5.

The solution was then evaporated under reduced pressure and the resulting oil was taken up in 50 ml of H 2 O. The water layer was then extracted with 4 x 25 ml ethyl acetate to remove phenylacetamide. The water layer was then evaporated and residual water removed from the residue by adding 2 x 30 ml absolute ethanol and distilling. The residue was then crystallized from 50 ml of ethyl acetate.

The solid was filtered, washed with 10 ml of ethyl acetate and dried to constant 1013783-15 weight.

3.6 g (26.2 mmol, 93.3%) (S) -3,3-dimethyl-2-butylamine.HCl were obtained.

The rotation of the product indicated that the S isomer 5 had been formed.

Using chiral HPLC determined the enantiomeric excess: e.e. (S) = 99% X H NMR (DMSO-dg): 0.95 (s, 9H, tBu), 1.15 (d, 3H, Me), 2.95 (q, 1H, CHN), 8.0 (broad, 3H, NH 3 Cl.

10

Example XIII

Synthesis of Schiff base from (R) -phenylglycine amide and isobutyraldehyde

5.4 g (50 mmol) of (R) -phenylglycine amide 15 in 100 ml of dichloromethane were added with 5.4 g (50 mmol) of isobutyraldehyde and 0.7 g of 4A sieves. The mixture was stirred at 20-25 ° C for 4 hours. After filtration, the solution was evaporated.

10.8 g (45.0 mmol, 95%) of Schiff base of (R) -phenylglycine amide and isobutyraldehyde as a white solid were obtained.

XH NMR (CDCl3): 1.06 (m, 6H), 2.46 (m, 1H), 4.67 (s, 1H), 5.68 (bs, 1H), 6.90 (bs, 1H) , 7.21-7.37 (m, 5H), 7.60 (d, 1Η) α-Η).

25

Example XIV

Allylation of Schiff base of (R) -phenylglycine amide and isobutyraldehyde

To a mixture of 4.8 g (20.0 mmol) of 30 Schiff base of (R) -phenylglycine amide and 1 n'i 'noi i .:' '- 16 - isobutyraldehyde and activated Zn (2 eq) in 100 ml of dry THF was added with stirring 2.4 g (20 mmol) of allyl bromide to produce an exothermic reaction. The mixture was stirred at 20-25 ° C for 1 hour and then 100 ml of a saturated aqueous NaHCO 3 solution was added. 100 ml of ethyl acetate were added to this. After separating the ethyl acetate layer, the water layer was extracted again with 100 ml of ethyl acetate. After drying over 10 MgSO 4, filtration and evaporation, 4.3 g (15.4 mmol, 77%) of the homoallylamine were obtained.

1 H NMR (CDCl 3): 0.72 (d, 3H), 0.85 (d, 3H), 1.87 (m, 2H), 2.17 (m, 1H), 2.37 (m, 1H) , 4.25 (s, 1H), 5.03 (s, 1H), 5.07 (d, 1H), 5.76 (m, 1H), 6.02 (s (wide, 1H), 15 7 20-7.34 (m, 6H).

XH NMR showed only one stereoisomer.

1013789

Claims (9)

1 U 1 ^ 1 - 19 - where R1 is OH, NH2 or alkoxy. 1. Process for the preparation of an enantiomerically enriched compound of formula 1 R 3 R 2 - 1 - R 4 nh o) I, NH 2 R 1, 1 R 5 wherein R 1 is a substituted or unsubstituted phenyl group, R 2, R 3 and R4 are each different and R2 and R3 represent H, a substituted or unsubstituted (cyclo) alkyl, alkenyl, aryl, cyclic heteroalkyl-15 or heteroaryl group having one or more N, O or S atoms, or (CH2) n-COR6, where n = 0,1,2 ..... 6 and R6 = OH, which is unsubstituted or substituted alkyl, aryl, alkoxy, or amino group, R4 = CN, H, a substituted or unsubstituted (cyclo) alkyl, alkenyl, aryl, cyclic or non-cyclic heteroalkyl or heteroaryl group with one or more N, O or S atoms R5 is H or alkyl of 1-6 carbon atoms. an enantiomer enriched λ - ··. · ·· · 'n Q - 18 - phenylglycine amide of formula 2 ΐ / ° R 1 - C - (T <2> Ah,' NH 2 5 in which Rx and R5 have the above meanings, with using a compound of formula 3 R2 - C (O) - R3 (3) 10 wherein R2 and R3 have the above meaning, is converted into the corresponding Schiff base and then the resulting Schiff base is converted into the enantiomerically enriched compound of formula 1 using an alkali cyanide, a reducing agent or an organometallic compound. The method then claim 1 wherein R 4 represents CN and wherein the resulting nitrile of formula 1 is isolated via crystallization. 3. Process according to claim 1 or 2, wherein the obtained enantiomerically enriched nitrile is subsequently converted into the corresponding acid, amide or ester and the acid, amide or ester thus obtained is converted by hydrogenolysis into the corresponding, enantiomerically enriched 25 amino acid derivative with formula 4 R 3 o 2 - i-cf, (4) | xRl nh2 „-M £ / O ^ 4. Process according to claim 1, wherein R4 is H, wherein the obtained compound of formula 1 is subsequently converted by hydrogenolysis into an enantiomerically enriched compound of formula 5 h2n h R / 'b, <5) in which R2 and R3 are the same have meaning as in claim 1 with the proviso that they are each dissimilar to H. Process according to claim 1, wherein R4 represents an unsubstituted or substituted (cyclo) alkyl, alkenyl, aryl, cyclic or non-cyclic heteroalkyl or heteroaryl group having one or more N, 0 or S atoms, wherein subsequently the resulting compound of formula 1 is hydrogenated to an enantiomerically enriched compound of formula 6 H 2 N R 1 (6) r / nR 3 wherein R 2 and R 3 have the same meaning as in claim 1, except that they are each unequal to R 4. 6. A compound of formula 1 wherein R 1, R 2, R 3, R 4 and R 5 are described above. Compounds according to claim 6 with a diastereomeric excess greater than 80%. 1 0 13 7 89 - 20 - Compounds according to claim 7 with a diastereomeric excess greater than 90%. Compounds according to claim 8 with a diastereomeric excess greater than 98%. 5 1 f> <: · 'q o