DE1234731B - Process for the cleavage of DL-valine hydrohalides into the optically active enantiomers - Google Patents

Description

UNDESREPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. Cl .:

core

German class: 12 q- 6/01

Number: 1 234 731

File number: A 41488IV b / 12 q

Filing date: October 27, 1962

Opened on: February 23, 1967

Of the amino acids, like valine, generally only the L-isomer - the most common in nature occurring form - usable. Are such compounds using chemical methods synthesized, the end products represent almost constant racemates. There are already different Methods for resolving such racemates, especially dl-valine - including chemical or enzymatic ones Procedure falling - has been suggested.

In the chemical process, the acetate or ethyl ester of DL-valine is made by treatment with brucine (Ber., 39, p. 2320 [1906]), dibenzoyl-D-tartrate (Ber., 86, p. 1524 [1953]) or 1-a-phenylethylamine (J. Am. Chem. Soc, 73, p. 3363 [1951]) produced the diastereomers in their enantiomorphic forms due to differences split into properties such as solubility. In the enzymatic process, derivatives of DL-valine, such as B. Acetyl-DL-valine (J. Biol. Chem., 189, p. 447 [1951]), benzoyl-üL-valine (J. Am. Chem. Soc, 73, p. 452 [1951]), chloroacetyl-OL-valine, carbobenzoxy-DL-valine (J. Biol. Chem., 189, p. 447 [1951]) etc., treated with papain in the presence of aniline to give the anilide of the corresponding To produce L-valine derivatives. These DL-valine derivatives can then be converted into theirs by acylase, which asymmetrically hydrolyzes only the L-form of the valine derivatives enantiomorphic forms are cleaved (J. Biol. Chem., 194, p. 455 [1952]).

All of these methods have a number of disadvantages for industrial implementation, since they the use of relatively expensive reagents require the extraction of the acylase from organisms and usually require many arduous operations.

The invention relates to a method for the cleavage of DL-valine hydrohalides, which are also can be carried out industrially, in the optically active enantiomers, which is characterized in that one is a saturated or supersaturated solution of a DL-valine hydrohalide, optionally one of the two enantiomers in excess, with seed crystals of υ- or L-valine hydrohalide added, brings the solution in a known manner to crystallization and the crystals formed of the separates enantiomeric hydrohalide.

This is a new process for cleaving DL-valine in the form of a hydrohalide into the practically pure enantiomorphic forms and requires only cheap reagents and solvents and simple operations. The optically active valine hydrohalide or its monohydrate, the process obtained here for the cleavage of
DL-valine hydrohalides in the optically
active enantiomers

Applicant:

Ajinomoto Kabushiki Kaisha, Tokyo

Representative:

Dr. G. W. Lotterhos

and Dr.-Ing. H. W. Lotterhos, patent attorneys,

Frankfurt / M., Annastr. 19th

Named as inventor:

Susumu Tatsumi,

Ichiro Sasaji, Kanagawa-ken, Ko Ohno, Tokyo

(Japan)

can easily be neutralized to optically active valine in a known manner.

DL-glutamic acid has already become known from US Patents 2,987,543 and 2,898,358 in the form of their hydrochloride or hydrobromide in aqueous solution by inoculating with the hydrohalide of the corresponding optically active form into the optically active components to split. However, this cleavage method is not a chemical one, it is a purely physical process that has different laws than purely chemical processes obeys, is by no means generally applicable to amino acids and therefore no predictions about the crystallization behavior of amino acids other than glutamic acid.

Further experiments led to the surprising result that only the DL-valine hydrohalide with Success can be split into the enantiomorphic forms and this process does not affect others DL-valine derivatives or salts, for example the acyl derivatives and metal salts, ζ. B. the copper salt of valine.

DL-valine hydrohalide crystallizes from water or water-containing solutions in the form of its Hydrate off. For example, DL-valine hydrochloride crystallizes in the form of its monohydrate.

709 510/556

The hydrate loses water of crystallization gradually at 45 to 55 ⁰ C, on the other hand, which can quickly change back slightly in the presence of water in the hydrate at 10O ⁰ C, forming the hydratfreie form. The optically active valine hydrohalides have properties analogous to those of the racemates.

In the process of the invention, all solvents can be used as solvents in which valine hydrohalide or its hydrate can be dissolved and from their solutions the dissolved substance can be brought to crystallization as a hydrate or in the hydrate-free form. Some examples are:

Water, alcohols with 1 to 5 carbon atoms, ethyl alcohols, whose Η atoms in / ^ - position through Alkoxy groups are substituted with 1 or 2 carbon atoms, water-containing ketones, aqueous Solutions with a halide content of less than 35% and / or their mixtures.

The solution of dl-valine hydrohalide prepared using these solvents becomes seeded according to the invention with crystals of the hydrohalide of one of the optical isomers. as Seed crystals can be both optically active valine hydrohalides as hydrates or in hydrate-free form Shape can be used. The seed crystals are usually present in an amount greater than 0.3% based on the weight of the solution, applied.

In the method according to the invention, a solution can also be assumed that the Hydrohalide of the racemate mixed with the hydrohalide of one of the two optically active ones Contains isomers. In this case, the optically active isomer present in excess crystallizes preferentially out of the solution, according to a particular embodiment of the invention in this case a Inoculation with optically active isomer is not always necessary.

However, it has proven to be useful to carry out the inoculation with the optically active isomer, if a more even split is to be achieved. In this case, one amount of seed crystal is sufficient less than 0.3% based on the weight of the solution.

To bring about and maintain a saturated or supersaturated state in the racemate solution various previously known measures can be applied individually or together, e.g.

1. cooling the solution,

2. Concentrate the solution,

3. Addition of solvents which have a low dissolving power for valine hydrohalide, but with the valine hydrohalide solution are miscible,

4. Addition of substances containing common ions, d. H. in the present case halogen ions.

The solution is conveniently stirred during the crystallization, although this is not always necessary is.

If the cleavage is carried out with cooling of the solution, the upper temperature limit is then at the boiling point of the solution - but usually at a temperature below the boiling point and worked above about 20 ° C - and the lower temperature limit below the temperature the saturation point of a given solution, at about 50 ° C or less.

If the cleavage is carried out with the addition of a solvent, the choice of the one to be added should be made Solvent in terms of the type of solvent used to make the DL-valine hydrohalide solution had been used. Are z. B. isopropanol or glycol monomethyl ether has been used to prepare the solution

ίο the ethyl ether is a suitable solvent to reduce the solubility of the solute. In the method of connecting with a common Add ions can be gases or aqueous solutions of hydrogen halides or halides or their aqueous solutions can be used.

Appropriately, the process is interrupted before the precipitated crystals a lot of about 10% based on the weight of the solution

so have achieved and the precipitated crystals separated from the solution.

The after the completion of the crystallization of the hydrohalide of one antipode and separation the mother liquor obtained from the crystals contains an excess of the other antipode, which subsequently can also be obtained from the mother liquor using the process of the invention or more expediently after dissolving additional dl-valine hydrohalide or its hydrate in the

3 "Mother liquor. The process of the invention can thus be done repeatedly by alternating one and then the other of the enantiomorphs Forms used for inoculation in appropriate concentrations and racemic after each stage Mixture adds, with all of the dl-valine hydrohalide or its hydrate completely and usable can be split into its optically active components.

example 1

150 g of an aqueous solution at 30 ° C., saturated with monohydrate of DL-valine hydrochloride, was gradually cooled to 29.5 ° C. with stirring and inoculated with 3.0 g of monohydrate of L-valine hydrochloride. Thereafter, the mixture was gradually further cooled at a rate of 1 ° C per 10 minutes. After reaching 25.5 ° C., the developed crystals were filtered off and the mother liquor adhering to the crystals was removed by adsorption on filter paper over a period of 3 days. The amount of crystal obtained was 5.5 g and its specific rotation [<x] ² S = + 13.24 ° (C = 2, H ₂ O). Because the specific rotation

of the pure monohydrate of L-valine hydrochloride [α] 20 = + 14.24 ° (C = 2, H ₂ O), the crystals obtained have an optical purity of 93.0%.

5.5 g of monohydrate of DL-valine hydrochloride were dissolved in the mother liquor at 45 ° C., the solution obtained was gradually cooled to 29.5 ° C., inoculated with 3.0 g of monohydrate of D-valine hydrochloride and the mixture obtained treated further in the manner described above. 5.3 g of crystals with a specific rotation of [oi \ ² § = -14.10 ° (C = 2, H ₂ O) were obtained. It was the monohydrate of D-valine hydrochloride, which had an optical purity of 90.0%.

The mother liquor obtained in this way was kept at 15 ° C. with occasional stirring, the precipitated crystals were separated off from the solution and dried at 80 ° C. for 72 hours without washing. The amount of crystals obtained was 3.5 g and the specific rotation [<x] ² _D ° = + 13.06 ° (C = 2, H ₂ O). Since the specific rotation of pure L-valine hydrochloride is H ² _D ° = + 15.91 ° (C = 2, H ₂ O), the crystals obtained provided L-valine hydrochloride with an optical purity of 82.1% represent.

Example 2

137 g of an isopropyl alcohol solution saturated with DL-valine hydrochloride (water content 0.5%) at 55 ° C. was gradually cooled to 53 ° C. with stirring, inoculated with 1.7 g of L-valine hydrochloride, and the mixture obtained with it a rate of 3 ° C per 10 minutes with stirring for a further 50 minutes and the precipitated crystals separated and dried. The amount of crystals obtained was 4.0 g "and its optical rotation [a] ² ₀ ° = + 13.6 ° (C = 2, H ₂ O). Therefore, the obtained crystals were L-valine hydrochloride in an optical purity of 85.5%.

4, OgDL-VaHnhydrochloride were added to the mother liquor obtained and the solution was treated in the manner described above, with the exception that 6 g of D-valine hydrochloride were used instead of 1.7 g of L-valine hydrochloride for the inoculation became. 4.5 g of D-valine hydrochloride with a specific rotation of [oc] ™ = -14.0 ° (C = 2, H ₂ O) (optical purity 88.1%) were obtained.

Example 3

23 g of DL-valine hydrochloride were completely dissolved in 40 g of ethylene monomethyl ether at 70 to 80 ° C., then the solution obtained was treated with activated charcoal to decolorize and left to stand at room temperature (27 ° C.). At a solution temperature of 45 ° C., the solution was inoculated with 0.7 g of L-valine hydrochloride and the resulting mixture was allowed to cool at room temperature for 10 minutes while stirring. The crystals were filtered off, quickly washed with ether and dried. 1.6 g of L-valine hydrochloride with an optical purity of 84.9% ([a]% ° = + 13.5 ° [C = 2, H ₂ O]) were obtained.

Example 4

150 g of a saturated DL-valine hydrochloride solution, for the preparation of which monohydrate of DL-valine hydrochloride had been dissolved to saturation in a 16% strength aqueous sodium chloride solution at 40 ° C., were gradually cooled to 39.8 ° C., at 2.0 g of monohydrate of L-valine hydrochloride were inoculated, the mixture obtained was cooled for a further 25 minutes with stirring at a rate of 1 ° C. per 10 minutes, and the crystals obtained were further treated in the manner described in Example 1. 4.5 g of monohydrate of L-valine hydrochloride with an optical purity of 71% (Mc? = + 10.1 ° [C = 2, H ₂ O]) were obtained.

The mother liquor was kept at 40 ° C. with occasional stirring, the precipitated crystals were filtered off and dried at 80 ° C. for 72 hours. 3.1 g of D-valine hydrochloride with an optical purity of 68% (Mc? = -10.8 ° [C = 2, H ₂ O]) were obtained.
5

Example 5

In 200 g of saturated DL-valine hydrochloride solution, for their production DL-valine hydrochloride in

If 17.5% hydrochloric acid had been dissolved to saturation at 54.5 ° C., 2.0 g of L-valine hydrochloride were completely dissolved at 70 ° C. and the resulting solution was gradually cooled down in the manner described in Example 1. After reaching 51 ° C., the precipitated crystals were filtered off, washed quickly with isopropyl alcohol and dried. 4.42 g of crystals were obtained with a specific rotation of [x] f = -J-11.6 ° (C = 2, H ₂ O).

Examples

In 50 g of ethylene glycol monomethyl ether, 20 g of DL-valine hydrochloride were completely dissolved at 28 ° C. and the solution was treated with active animal charcoal to decolorize. After adding 0.7 g of L-valine hydrochloride, 30 g of ethyl ether were added dropwise within 15 minutes. The precipitated crystals were filtered off, washed with isopropyl alcohol and dried. There were obtained 1.74 g of crystals having a specific rotation of [α] ² ₀ = + 13.3 ° ° (C = 2, H ₂ O) and an optical purity of 83.6%.

Example 7

In 50 g of isopropyl alcohol (water content of 4 weight percent) were 36 DL-valine hydrobromide g dissolved and the solution cooled at 7O ⁰ C. After 43 ⁰ C was reached, the solution was mixed with 1.0 g L-valine hydrobromide ([a] _D ² ° = 12.8 ° [C = 4, H ₂ O]) and the mixture seeded with stirring to Chilled 36 ° C, which took 15 minutes. The precipitated crystals were filtered off, washed with a small amount of isopropyl alcohol and dried. There were 4.25 g of crystals with a

optical purity of M ² _D ° = + 7.2 ° (C = 4, H ₂ O) was obtained.

Example 8

In 80 g of a solvent mixture of water and methanol (1: 1 parts by weight) 100 g of monohydrate of DL-valine hydrochloride and 3.0 g of L-valine hydrochloride were completely dissolved at 35 ° C. and the solution obtained in this way at 10 Maintained up to 15 ° C with occasional stirring. The precipitated crystals were filtered, washed with a small amount of isopropyl alcohol and dried at 8O ⁰ C, which required 72 hours. There was added 5.8 g L-valine hydrochloride having a specific rotation of [a] ² ₀ = + 11.50 ° ° (C = 2, H ₂ O) was obtained with an optical purity of 72.3%.

The mother liquor was placed in a refrigerator overnight and the precipitated crystals were treated in the manner described above. 1.1 g of D-valine hydrochloride with a specific rotation of [a]% ° = -14.60 ° (C = 2, H ₂ O) and an optical purity of 91.8% were obtained.

i 234

Example 9

70 g of monohydrate of DL-valine hydrochloride were dissolved in 100 g of acetone (water content 30 percent by weight) at 35 ^° C. and the resulting solution was cooled down; when 26 ° C. had been reached, 3.0 g of L-valine hydrochloride were added as seed crystals and the mixture was further cooled to 24.5 ° C., which took 15 minutes with vigorous stirring. The resulting slurry was filtered and the crystals were dried at 80 ° C. for 72 hours. 5.2 g of L-valine hydrochloride with a specific rotation of [«] ² ₀ ° = + 13.50 ° (C = 2, H ₂ O) and an optical purity of 84.9% were obtained.

In the manner described in Example 8, 1.8 g of crystalline monohydrate of D-valine hydrochloride in optical purity of 89.9% ([ajb ° = -14.30 ° [C = 2, H ₂ O]) were obtained from the Mother liquor obtained.

Example 10

20 g of DL-valine hydrochloride were dissolved in 50 g of isoamyl alcohol (water content 5 percent by weight) at 80 ° C. and the solution was left to cool. When they had a temperature of 30 ° C, it was added 1.5 g of monohydrate of L-valine hydrochloride, and the obtained mixture is cooled within 15 minutes with vigorous stirring to 2O ⁰ C. The crystals were filtered off from the resulting slurry and treated further in the manner described in Example 8. 4.9 g of L-valine hydrochloride with a specific rotation of [<x] ² _D ° = + 14.40 ° (C = 2, H ₂ O) and an optical purity of 90.5% were obtained.

In the manner described in Example 8, 2.1 g of crystalline n-valine hydrochloride were obtained from the mother liquor. Specific rotation [oc] ² _D ° = -14.15 ° (C = 2, H ₂ O), optical purity 88.9%.

Claims (3)

Patent claims: 1. Process for the cleavage of iiL-valine hydrohalides in the optically active enantiomers, characterized in that one is a saturated or supersaturated solution of a DL-valine hydrohalide, which may contain one of the two enantiomers in excess contains, mixed with seed crystals of d- or L-valine hydrohalide, the solution in itself in a known manner brings to crystallization and the crystals of the enantiomeric hydrohalide formed separates. 2. The method according to claim 1, characterized in that the solvent used is water, Alcohols with 1 to 5 carbon atoms, ethyl alcohols, whose Η-atoms in / i-position through Alkoxy groups are substituted with 1 or 2 carbon atoms, water-containing ketones, aqueous solutions with a halide content of less than 35% and / or mixtures thereof used. 3. Process according to Claims 1 and 2, characterized in that for the case that one starts from a solution which contains one of the two enantiomers in excess, the Processes carried out without the addition of seed crystals. Considered publications:
U.S. Patent Nos. 2,898,358, 2,987,543. 709 510/556 2.67 Bundesdruckerei Berlin