Resolution of P-Hydroxyphenyl-2-Alkoxypropionic Acids

Abstract

The present invention is aimed at a process for the preparation of enantiomerically enriched compounds of general formula (I). These are obtained by classical resolution of the corresponding acid using a chiral amino base in organic solvents.

Description

EXAMPLES

Preparation of the (S,S)-Ammonium Salt

78.4 g (0.4 mol) of racemic (R,S)-3-(4-hydroxyphenyl)-2-methoxypropionic acid are dissolved in 400 ml of methyl isobutyl ketone and 160 ml of isopropanol. The solution is warmed to 50° C. and at this temperature 36.4 g (0.4 mol) of (S)-(+)-2-amino-l-butanol are added dropwise in the course of 15 minutes. The reaction mixture is slowly cooled to room temperature. At 30° C., seed crystals are added. The reaction mixture is stirred for 12 h at RT. The precipitated (S,S)-ammonium salt is filtered off at RT. The filter cake is washed with 20 ml of acetone and subsequently dried in vacuo at 400C. 45.9 g (40%) of (S,S)-ammonium salt of (S)-3-(4-hydroxyphenyl)-2-methoxypropionic acid and (S)-(+)-2-amino-1-butanol are obtained.

Cleavage of the (S,S)-Ammonium Salt

45.9 g of (S,S)-ammonium salt are dissolved in 250 ml of DI-water. With stirring, about 16 ml of concentrated hydrochloric acid (36% strength) are added dropwise such that a pH of pH=0.8-1 is established. The aqueous phase is extracted three times with 275 ml each of MIBK. The combined extracts are completely concentrated in vacuo at 50° C. The resulting oil slowly crystallizes completely. 33.0 g of crude (S)-3-(4-hydroxyphenyl)-2-methoxypropionic acid having an optical purity of ee=92.0% are obtained. The oil can also be made to crystallize in a controlled manner. To this end, the oil is dissolved in 75 ml of methyl tert-butyl ether at 40-50° C. and then 125 ml of cyclohexane are slowly added dropwise with stirring. The solution is slowly cooled to room temperature. At 30° C., seed crystals are added. After 4 h at RT, the product is filtered off and the filter cake is washed with 10 ml of the methyl tert-butyl ether/cyclohexane mixture. After drying in vacuo at 50° C., 30.0 g (38%) of (S)-3-(4-hydroxyphenyl)-2-methoxypropionic acid are obtained. Optical purity ee>99%. Chemical purity>99%

45.9 g of (S,S)-ammonium salt are dissolved in 250 ml of DI-water. With stirring, about 16 ml of concentrated hydrochloric acid (36% strength) are added dropwise such that a pH of pH=0.8-1 is established. The aqueous phase is extracted three times with 275 ml each of MIBK. The combined extracts are concentrated down to a residual volume of 420 ml in vacuo.

Neutralization of the (S)-3-(4-hydroxyphenyl)-2-methoxy-propionic Acid Using Sodium Acetate

420 ml of the (S)-3-(4-hydroxyphenyl)-2-methoxypropionic acid solution from above are treated with stirring with a solution of 16.32 g of sodium acetate in 136 ml of methanol. After addition of seed crystals, the mixture is stirred for 12 h at room temperature. The precipitated product is filtered off and the filter cake is washed twice with 20 ml each of MIBK. The product is dried in vacuo at 50° C. in the course of 12 h. 30.2 g (34.8%) of sodium (S)-3-(4-hydroxyphenyl)-2-methoxypropionate are obtained. Optical purity ee=95-97%. Chemical purity >99%.

Improvement of the Optical Purity

10 g of sodium (S)-3-(4-hydroxyphenyl)-2-methoxypropionate having an optical purity of ee=95% are resuspended with stirring in 40 ml of methanol at 40° C. After cooling to RT, the product is isolated by filtration. The filter cake is washed with 5 ml of cold methanol and subsequently dried in vacuo at 50° C. in the course of 12 h. 9 g of sodium (S)-3-(4-hydroxyphenyl)-2-methoxypropionate having an optical purity of ee=99.6% are obtained.

Preparation of the (R,R)-Ammonium Salt

19.9 g (0.1015 mol) of (R)-3-(4-hydroxyphenyl)-2-methoxy-propionic acid are dissolved in 150 ml of MTBE. At RT, 9.05 g (0.1015 mol) of (R)-(−)-2-amino-l-butanol are slowly added dropwise with stirring. The reaction mixture is stirred for 4 h at RT. The precipitate is filtered off and the filter cake is washed with 10 ml of MTBE. After drying, 26 g (90%) of crystalline (R,R)-ammonium salt are obtained.

The following experiments demonstrate that both the (R,S)-ammonium salt and the (S,R)-ammonium salt were obtained in the form of oils which show no tendency at all to crystallize.

Preparation of the (R,S)-Ammonium Salt

19.9 g (0.1015 mol) of (R)-(−)-3-(4-hydroxyphenyl)-2-methoxypropionic acid are dissolved in 150 ml of MTBE. At RT, 9.05 g (0.1015 mol) of (S)-(+)-2-amino-1-butanol are added dropwise with stirring, the product separating as an oil. The mixture was stirred for 12 h at RT. A two-phase mixture resulted. After phase separation, the lower phase was separated off and freed of volatile constituents in vacuo. 31.8 g of spectroscopically homogeneous product result in the form of an oil which shows no tendency at all to crystallize. The experiments were repeated in various solvents. In all cases, it was not possible to achieve any crystallization.

Preparation of the (S,R)-Ammonium Salt

13.72 g (0.07 mol) of (S)-3-(4-hydroxyphenyl)-2-methoxypropionic acid are dissolved in 100 ml of MTBE and 6.2 g (0.07 mol) of (R)-(−)-2-amino-1-butanol are added dropwise at RT with stirring, the product separating as an oil. The mixture was stirred for 12 h at RT. A two-phase mixture resulted.

After phase separation, the lower phase was separated off and freed in vacuo of volatile constituents. 22.3 g of spectroscopically homogeneous product resulted in the form of an oil which showed no tendency at all to crystallize.

The experiments were repeated in various solvents. In all cases, it was not possible to achieve any crystallization.

Claims

1. Process for the preparation of enantiomerically enriched compounds of the general formula (I)

2. Process according to claim 1, wherein R=methyl or ethyl.

3. Process according to claim 1, wherein the organic solvent used is a mixture of ketones and alcohols.

4. Process according to Claim 1, wherein the molar ratio between (I) where X=H and 2-amino-1-butanol is in the ratio 1 to 0.4-1.

5. Salt of (S)-3-(4-hydroxlphenyl)-2-(C1-C8)-alkyloxy-propionic acid and (S)-(+)-2-amino-1-butanol.

6. Salt of (R)-3-(4-hydroxyphenyl)-2-(C1-C8)-alkyloxy-propionic acid and (R)-(−)-2-amino-1-butanol.

7. A method for the preparation of bioactive compounds which comprises utilizing the salt of claim 5 as a starting substance.

8. Process for the preparation of enantiomerically enriched compounds of the general formula (I) comprising forming a salt of the compound of general formula (I) in which X=H with enantiomerically pure 2-amino-1-butanol in an organic solvent or solvent mixture selected from the group consisting of alcohols, esters, ketones and ethers; andcrystallizing the salt from the organic solvent or solvent mixture;

9. A method for the preparation of bioactive compounds which comprises utilizing the salt of claim 6 as a starting substance.