JPS61152645A - Optical resolution of beta-chloro-dl-alanine - Google Patents

Abstract

PURPOSE:To carry out the optical resolution of the titled compound useful as synthetic intermediate of various pharmaceuticals and agricultural chemicals, etc., by dissolving beta-chloro-DL-alanine in an aqueous solution of hydrochloric acid, and crystallizing the compound from the solution as a monohydrochloride under specific condition. CONSTITUTION:beta-Chloro-DL-alanine (abbreviated as DL-ClAla) is dissolved in an aqueous solution of hydrochloric acid, and the objective optically active beta-chloroalanine monohydrochloride is crystallized from the solution under the condition to attain the solution saturated or supersaturated with DL-ClAla monohydrochloride (e.g. by cooling the solution). Concretely, a saturated or supersaturated hydrochloric acid solution of DL-ClAla monohydrochloride is inoculated with a crystal of optically active beta-chloroalanine monohydrochloride as a seed crystal to effect the preferential crystallization of the same kind of optically active isomer.

Description

[Detailed description of the invention] [Industrial application field] The present invention is directed to β-chloro-DL-alanine (hereinafter referred to as β-chloro-DL-alanine).

It is simply abbreviated as DL-0LALa. ) regarding the optical separation method. To be more specific, unexploded #J is DL-
cthtat” monohydrochloride.

[Conventional technology]

β-chloroalanine (OLA/a) Ld is an amino acid that has physiological activity by itself l) j) (J, Bio
l, Ohem,.

252, p. 3170), for example, β-chloro-L-
Alanine (hereinafter abbreviated as L-CtAta) is a precursor for enzymatically producing β-substituted amino acids, while β-chloro-D-alanine (hereinafter abbreviated as D-02A
It is abbreviated as ta. ) It is known as an inhibitor of the enzyme in the ridge, and is used in research on enzyme mechanisms.

β-chloroalanine is also a compound useful as a synthetic intermediate for the antibiotic cycloserine, the sulfur-containing amino acid cysteine, and other pharmaceuticals and agricultural chemicals.

β-Chloroalanine is produced by converting chloroacetaldehyde into bisulfite or sulfite adduct in an aqueous solution using chloroacetaldehyde as a raw material.
This can be industrially synthesized by reacting it with ammonia and then with hydrocyanic acid or its salt to give α-aminoniβ-chloropropionitrile, followed by acidic hydrolysis (Japanese Patent Publication No. 5a-2214oi), but D L −
There have been no reports on the method of dividing czAzak into optically active substances, and therefore β-
It is limited to the use of chloroalanine, and L-C2
In reality, when At& and D -C6ALa are required, they are chemically derived from L-serine or D-serine. However, serine is not only expensive as a raw material, but also serine's β-hydro-? The 7-group chlorination reaction has a low yield and cannot be said to be an industrially advantageous method.

[Problem that the invention seeks to solve]

An object of the present invention is to provide a method for optically resolving DL-01Atat, thereby opening the way to the production of various derivatives from optically active β-chloroalanine. That is, methods for synthesizing optically active serine, cysteine, S-carboxymethyl cysteine, etc. from optically active β-chloroalanine without racemization are already known, and in order to achieve the object of the present invention, It is extremely significant.

[Means for solving the problem and methods for optically resolving functional α-amino acids include (1) physical methods; (2)
A number of biochemical and (3) chemical methods are known.

Since C1 and ALa are α-amino acids that do not exist in nature, the biochemical method (2) of enzymatic resolution using microbial sieves is expected to be difficult.
Partitioning using physicochemical methods was investigated.

First, from a solution of CjtALth racemic body, 0 body and 5 body are
crystallizes as separate crystals (racemic mixture).

Further, repeated studies were conducted to find the conditions under which one of the two preferentially crystallizes.

The raw bottom crystals from the aqueous solution of D L -CIALa are
It has been found that preferential crystallization from an aqueous solution is impossible for crystals of so-called racemic compounds.

Next, we investigated the conditions under which C1Ata itself would crystallize as a racemic mixture by varying the pH and temperature of the aqueous solution and forming many different types of salts. It was found that the crystallization process was difficult because the crystallization process was difficult.

On the other hand, 02Ata was found to be stable in an aqueous hydrochloric acid solution, so the solid-liquid equilibrium of the C1At1a crystal in an aqueous hydrochloric acid solution was measured. Obtain fL order.

In other words, raw hydrochloride (0 tAta 9
11C1) t-formed, and as a result of Xi@diffraction, this compound was found to be a racemic compound. However, when the concentration of hydrochloric acid exceeds a certain level (more than 24% at 20°C), the liquid base changes to monohydrochloric acid salt (C1At&-HCl), and the result of monohydrochloric acid mri X-ray diffraction shows that it is a racemic mixture. It turned out that it would be possible to apply the method, and based on this knowledge, the invention was completed.

That is, in the present invention, β-chloro-DL-alanine is made into a hydrochloric acid aqueous solution, and this solution is β-chloro-DL.

- A method for optical resolution of β-eICI alanine characterized by crystallizing optically active β-chloroalanine monohydrochloride m in a state where alanine hydrochloride is saturated or supersaturated.

In the optical resolution method of the present invention, it is safe to perform the Shimada operation under the condition that the liquid bottom composition in the aqueous hydrochloric acid solution is maintained as a monosalt shield salt. The average concentration can be determined experimentally, and for example, at 10°C it is 23% by weight, and at 20°C it is 24% by weight as mentioned above. However, this value varies depending on the equilibrium composition, and in actual operations under non-equilibrium conditions, the metastable region is taken into consideration, and the crystallization operation is performed at a hydrochloric acid concentration with some margin to ensure the precipitation of monohydrochloride crystals. It's good.

Since adjusting the hydrochloric acid concentration during the dividing operation is complicated and slow, a method is adopted in which separately produced C1ot&.Hat crystals are dissolved in an aqueous solution of hydrochloric acid of a constant concentration (for example, 5%).

Note that it is not preferable to dissolve C2AZa-HC6 crystals in pure water and perform crystallization operations such as cooling or concentration, since raw hydrochloride will precipitate, whether it is a racemic form or an optically active form.

D Any ordinary means such as a method of gradually supplying the solution may be used.

The temperature at which the crystallization operation is performed is desirably 70°C or lower, since 06Ata gradually decomposes even in a hydrochloric acid water bath at temperatures above 80°C.

In order to obtain high optical purity, the degree of supersaturation of D L -CLALIL is desirably as low as possible, and a range that is commensurate with the crystal growth rate and that does not involve nucleation is required.

Specifically, in the method of the present invention, β-chloro-
By inoculating optically active β-chloroalanine monohydrochloride crystals as seed crystals into a saturated or supersaturated aqueous hydrochloric acid solution of DL-alanine monohydrochloride, and preferentially crystallizing the optically active substance of the same type. Optical separation can be performed.

At this time, in order to prevent nucleation, it is preferable to inoculate seed crystals at the saturation point of the racemate and then bring it to a supersaturated state.

There are no particular restrictions on the seed crystals to be inoculated, and even those with low optical purity can be divided, but the operation will be complicated.

When dry monohydrochloride is used as a seed crystal, nucleation tends to occur, which causes a decrease in optical purity.

When using crystals with low optical purity or dry crystals as seed crystals, it is necessary to perform a pretreatment of inoculating the seed crystals into an unsaturated solution, and then bring the seed crystals to a supersaturated state.

The preferential crystallization method according to the present invention is based on the growth of crystals, but each crystal is generally a polyhedron with its own crystal habit, and the growth rate of each face is usually different. Furthermore, the particle size of the formed crystals also varies depending on the solubility and temperature. Furthermore, the crystal habit of the optically active form may differ depending on whether it is crystallized from a solution containing the racemic form or when it is crystallized from a solution containing only one of the optically active forms.

If the separately produced optically active material is t-sieved to have a uniform particle size and the seed crystals do not meet the above conditions, the initial crystallization may not proceed smoothly.

Therefore, it is preferable to directly crystallize the seed crystals in an aqueous hydrochloric acid solution. In other words, the optically active substance is dissolved in a solution of the racemate to be separated, and only the optically active substance is first crystallized by cooling, etc. If this is used as a seed crystal, the crystal habit and particle size are uniform, and the other crystals are initially separated. Nucleation of the optically active substance can be prevented, and the split crystallization operation can proceed smoothly.

As described above, in the second specific method of the present invention, either β-chloro-D-alanine or β-riol-L-alanine is obtained from a supersaturated aqueous hydrochloric acid solution of β-chloro-DL-alanine monohydrochloride. Optical resolution is performed by crystallizing the optically active monohydrochloride salt present in excess of one of the two and using it as a seed crystal, and growing this crystal.

When only one optically active form is crystallized from a racemic solution by the method of the present invention and its crystal 5c is grown, the other active form becomes excessive in the solution and becomes supersaturated. If the degree of A saturation is too high, nucleation of the other optically active substance will occur, resulting in failure of optical resolution, so care must be taken. The extent to which supersaturation is actually allowed varies depending on the shape of the crystallization tank, stirring conditions, particle size distribution of seed crystals, etc.
It is necessary to determine this experimentally.

In the case of the optical separation method of the present invention, if crystallization is performed using a complete mixing tank type crystallization tank and using an anchor type stirring blade with a large blade diameter to ensure that the particle-based Reynolds number is sufficiently large, the crystallization can be carried out at 5°C. It is possible to achieve a temperature supersaturation degree of , is sufficiently stable even during solid-liquid separation, and can be operated without crystallization of the other optically active substance.

Since the mother liquor separated from one optically active ftp contains an excess of the other optically active substance, D L -CIAta・HO4
The splitting operation can be carried out in a similar manner either in tO4 or without supplementation, by inoculating the seed crystals present in excess, or by crystallizing the seed crystals in solution.

In addition, in the present invention, as a third specific method, β-chloro-
Into a saturated or supersaturated aqueous hydrochloric acid solution of DL-alanine monohydrochloride, β-chloro-L-alanine monohydrochloride with significantly different particle sizes was simultaneously added as seed crystals. It is also possible to inoculate, grow each crystal, and then separate the crystals for optical resolution by sieving.

Optically active β-chloroalanine can be obtained by bathing the optically active monohydrochloride separated by the method of the present invention in water and adjusting it to pas and s with an alkali using the conventional method. However, when using it as a base material for other derivatives (G,
It can also be used in the monohydrochloride form.

[Examples] Hereinafter, typical examples and comparative examples of the optical separation method of the present invention will be shown and explained in more detail, but these are intended to facilitate understanding of the present invention. The invention is not limited to these examples.

Example 1 D in a crystallization tank (10/,) equipped with an anchor-type stirring blade
Dissolve 5 kg of L -CjLALa-1101 crystals in 57 kg of 5% aqueous hydrochloric acid solution, and further dissolve L -0tAta -F.
500 tons of i01 crystals were mixed and heated to 45°C. After the crystals are completely dissolved, do not stir until the liquid temperature is t-25℃.
The mixture was cooled for 2 hours until L-form was crystallized. Then,
The mixture was cooled from 25° C. to 20° C. over 3 hours with stirring, and then immediately separated from each other to obtain 660 tt of L-form crystals. The specific optical rotation is [α]D=4.02 (0=:10.
The optical purity was determined by 100%.

When the ν liquid was further cooled to 15° C. and the precipitated crystals were separated from each other, 9 crystals 2091 were obtained.

The specific optical rotation of this substance is [C3”1=-sq s (c=
10, INHC2), and the optical purity was 1j97.7%.

Example 2 In the same crystallization tank as in Example 1, DL-C1ALl!
L・Hat's 5-dihydrochloric acid aqueous solution (# degree 5 [19%) 9.
9 klil to L-C1Ath-HOl 560
f was dissolved and the liquid temperature was brought to 45°C. The mixture was cooled from 45° C. to 25° C. over 2 hours with stirring, and a small amount of L-form seed crystals were added midway through to generate nuclei, and the L-form was crystallized.

Next, it was cooled from 25°C to 24°C for 1 hour and from 24°C to 20°C for 2 hours, and then immediately filtered to obtain 749t crystals of the L form. Optical purity is 95%.

In the F solution, D L -CIALa-HCL 400 f, some 5-thihydrochloric acid aqueous solution and D -C1ALh-HCL 3
80? was replenished, the temperature was raised to 45°C, and the same crystallization operation was performed to obtain 9 698 f5. Optical purity is 98%.

Example 3 In the same crystallization tank as Example 1, D Xa -CLAla-H
Add 9t-5% hydrochloric acid aqueous solution to CL crystal 5 at 7 o'clock, and add 30
It was warmed to ℃ to completely dissolve it. Next, when cooled to 25°C, 500~40~60 mesh crystals of L-CLAta-HOl were obtained. After inoculating and stirring at 25°C for 30 minutes, cool to 20°C over 3 hours. The grown crystals were filtered to obtain 670t L-form crystals. The optical purity was 94.1%.

Comparative Example D L -CLALh-HOL crystal t-2. Dissolved in 0% hydrochloric acid aqueous solution at 45°C to make a solution with a concentration of t-65.3! When the liquid temperature reaches 40°C, L -C2Ata-HO
6 crystals were placed in 250 ft. and cooled to 355° C. over 55 hours. The grown crystal was t-filtered to obtain a 350i crystal, which had an optical purity of 70%.

During the crystallization operation, the optical rotation of the solution was measured and the result was that the racemic product remained and no changes were observed during the process, resulting in an unsuccessful resolution. The obtained crystal was found to be contaminated with D L -C1At -Hacz 2>E according to elemental analysis, infrared spectrum and X-ray diffraction pattern.

〔Effect of the invention〕

The present invention provides a method for optically resolving D L -0/Ata t for the first time by crystallizing it as a monohydrochloride in an aqueous hydrochloric acid solution.
This greatly paved the way for the use of Ata as a synthetic intermediate for various pharmaceuticals and pharmaceuticals.

[Brief explanation of drawings]

FIG. 1 is a solid-liquid equilibrium curve of β-chloro-DL-alanine in an aqueous hydrochloric acid solution at 20°C. i-th box

Claims (1)

[Claims] 1) When β-chloro-DL-alanine is dissolved in hydrochloric acid and the solution is saturated or supersaturated with respect to β-chloro-DL-alanine monohydrochloride, the optically active β
- A method for optical resolution of β-chloroalanine, characterized by crystallizing chloroalanine monohydrochloride. 2) A saturated or supersaturated aqueous hydrochloric acid solution of β-chloro-DL-alanine monohydrochloride is inoculated with crystals of optically active β-chloroalanine monohydrochloride as seed crystals, and the optically active form of the same species is preferentially seeded. The optical separation method according to claim 1, which comprises crystallizing. 3) Crystallizing the optically active monohydrochloride present in excess of either β-chloro-D-alanine or β-chloro-L-alanine from a supersaturated aqueous hydrochloric acid solution of β-chloro-DL-alanine monohydrochloride. An optical separation method according to claim 1. 4) Add β-chloro-DL-alanine monohydrochloride of different particle sizes to a saturated or supersaturated aqueous hydrochloric acid solution.
L-alanine monohydrochloride and β-chloro-D-alanine
2. The optical resolution method according to claim 1, wherein monohydrochloride is simultaneously inoculated as a seed crystal, each crystal is allowed to grow, and then the separated crystals are sieved.