JPS588049A - Preparation of beta-chloroalanine - Google Patents

Abstract

PURPOSE:To prepare the titled compound (BCA) useful as a synthetic intermediate of cysteine, economically, in an industrial scale, by reacting aziridine-2- carboxylic acid salt (ADC) with HCl, separating BCA from the reaction products by crystallization, treating the filtrate with an alkali, and recycling the recovered ADC salt. CONSTITUTION:1mol of an alkali metal (e.g. Li, Na, K, etc.) salt, alkaline earth metal (Mg, Ca, etc.) salt, NH4 salt etc. of ADC is made to react with 2.0- 5.0mol of HCl in an aqueous medium at 0-100 deg.C for 1-50hr, and the produced is BCA separated by the selective crystallization and filtration. The recovered liquid is treated with an alkali metal hydroxide or alkaline earth metal hydroxide[e.g. NaOH, Ca(OH)2, etc.]or NH3, and the produced ADC salt is concentrated, diluted, or mixed with additional ADC salt to adjust the concentration, and is used as a raw material of the preceding reaction to obtain BCA in high efficiency.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing β-chloroalanine. For more details, see 1. In a method for producing β-chloroalanine by reacting aziridine-2-carboxylic acid salts with hydrogen chloride, the reaction is carried out using hydrogen chloride in a molar ratio of 2.0 to 5.0 to the aziridine-2-carboxylic acid salts. After conducting the reaction in an aqueous medium, β-chloroalanine is isolated from the reaction solution under conditions that selectively crystallize, and the recovered solution after isolating β-chloroalanine is treated with an alkali metal or alkaline earth metal. The present invention relates to a method for producing β-chloroalanine, characterized in that aziridine-2-carboxylic acid salts obtained by treatment with hydroxide or ammonia are recycled as raw materials.

β-chloroalanine is a physiologically active amino acid, and is also an extremely useful compound as a synthetic intermediate for cysteine and other drugs. However, conventionally,
Since there is no industrially advantageous method for producing β-chloroalanine, it is not always fully utilized. Known synthesis methods for β-chloroalanine include a method in which serine is used as a raw material and produced by esterification, chlorination, and hydrolysis (T, L, Wood, L, v, aq, M-idd
le-sworth, J. Bio, Ohem, No. 17
Volume 9, 529-Bagan-z, 't'949) and a method of producing chlorine derivatives by chlorination and decomposition by applying chlorine in an organic solvent (H, 1, Bagan-z, o, Dran
sch, Chem, Ber, Volume 93, Page 782 19
1960), but both methods use very expensive raw materials and are therefore not suitable as industrial production methods. On the other hand, a method for synthesizing β-chloroalanine by treating sodium aziridi/~2-carboxylic acid with hydrogen chloride (K, D, Gunderman
, G., Holtmann, H.-J., Rose, H., 5c.
Hulze, Chem, Ber, Volume 93, 16
32 pages.

1960) is publicly known.

However, this method requires a large excess of hydrogen chloride during the reaction, and the produced sodium chloride is mixed with β-chloroalanine hydrochloride and the by-product α-chloro-β-
An extraction operation is performed using alcohol to separate alanine from the mixture with hydrochloride, and the resulting mixture of β-chloroalanine hydrochloride and α-chloro-β-alanine hydrochloride is treated with ammonia. , further recrystallized from water and ethanol to isolate β-nichloroalanine. Even with this method, the isolation yield of β-chloroalanine is as low as 10%, and the isolation operation is extremely complicated, so it is not necessarily an advantageous production method from an industrial perspective. It's hard to say.

In addition, aziridine used as a raw material in the method of the present invention
Conventionally, as a method for producing 2-carboxylate from β-chloroalanine or α-chloro-β-alanine, for aziridine-2-carboxylic acid sodium salt, α-chloro-β-alanine hydrochloride is used as a raw material. compound in water,
After neutralization with an aqueous IJ solution, 1N hydroxide was added under heating to reflux so that the pH of the aqueous solution was maintained at 7 to z5 under the conditions that the initial concentration of the compound was 1% by weight. ) Method of manufacturing by dropping IJum aqueous solution (K, D
, Gundermann, Chem, Ber.

93.1640 (1960)), but the reaction operation is complicated, such as the reaction concentration being limited to a low concentration, the need for heating and refluxing, and the need to control the pH of the reaction solution. Therefore, it is difficult to say that it is an industrially satisfactory method.

As a result of intensive studies on the reaction between aziridine-2-carboxylic acid or its salts and hydrogen chloride, the present inventors found that the reaction between aziridine-2-carboxylic acid or its salts and hydrogen chloride led to is produced together with α-chloro-β-alanine, in which case it is not necessary to use a large excess of hydrogen chloride relative to aziridine-2-carboxylic acid or its salts, and it is sufficient to use a stoichiometric amount or a small excess of hydrogen chloride, It has been found that only β-chloroalanine can be selectively crystallized and separated from the resulting reaction solution.

Furthermore, β-chloroalanine and α-chloro-β- after isolating β-chloroalanine crystallized from the reaction solution
By treating the recovered solution containing alanine with an alkali metal or alkaline earth metal hydroxide, or ammonia under extremely mild conditions, aziridine-2 is regenerated.
The inventors have discovered that β-chloroalanine can be produced by discovering a solution and water scale containing the aziridine-2-carboxylic acid salt and reacting it with hydrogen chloride again using the aziridine-2-carboxylic acid salt as a raw material, thereby achieving the present invention.

In the method of the present invention, the target β-chloroalanine precipitates directly from the reaction mixture, so no special operation is required for separation from by-products, and industrially pure β-chloroalanine can be obtained. Moreover, β-chloroalanine, which is not isolated and is dissolved in solution, and the by-product α-chloro-β-alanine, which can be easily isolated by r-filtration, can be easily isolated by the novel method completed by the present inventors. Good, it does not require pH control or heating like known technology, and it can be converted into aziridine-2-carboxylate with a simple reaction operation and at a high concentration, and this aziridine-2-carboxylate can be recycled as a raw material. It is an extremely valuable manufacturing method industrially, as it has many advantages such as:

In the method of the present invention, aziridine-2-carboxylic acid salts are used as raw materials. Examples of the aziridine-2-carboxylic acid salts include salts of alkali metals such as lithium, sodium and potassium, salts of alkaline earth metals such as magne/lamb and calcium, and ammonium salts.

Such aziridine-2-carboxylic acid salts are α-chloro-β-aminopropionitrile hydrochloride or α-amino-β-chloropropionitrile hydrochloride with alkali metals such as lithium, sodium, potassium, magnesium , can be easily synthesized in high yield by reacting with a hydroxide of an alkaline earth metal such as calcium.

The hydrogen chloride used in the method of the present invention is usually concentrated hydrochloric acid. There is no problem in blowing hydrogen chloride gas into the system if necessary. The amount of hydrogen chloride used is aziridine-2-
20 to 25 molar ratio to carboxylic acid alkali metal salt and ammonium salt, preferably 205 to 2.6
Molar ratio, ld4. to aziridine-2-carboxylic acid alkaline earth metal salt. o to 5.0 molar ratio, preferably 4.05 to 4.8 molar ratio. If the amount of hydrogen chloride used is less than 20 molar ratio to the alkali metal salt and ammonium salt of aziridine-2-carboxylic acid, and less than 4.0 molar ratio to the alkaline earth metal salt of aziridine-2-carboxylic acid, the reaction yield will decrease. The isolation yield of β-chloroalanine also decreases. Also, the amount of hydrogen chloride used is 2.2% relative to the alkali metal salt and ammonium salt of aziridine-2-carboxylic acid.
If the molar ratio exceeds 5.0 molar ratio with respect to the alkaline earth metal salt of aziridine-2-carboxylic acid, the isolation yield of β-chloroalanine will decrease significantly, which is not preferable.

In the process of the invention, the reaction of the aziridine-2-carboxylic acid salts with hydrogen chloride is carried out in an aqueous medium, particularly preferably in an aqueous medium. The amount of solvent used during the reaction is
There are no particular restrictions. Therefore, β
- The reaction may be carried out below or above the crystallization concentration range of chloroalanine. However, in order to crystallize β-chloroalanine from the reaction solution, it is necessary to adjust the concentration of the reaction solution such as dilution or concentration. - It is preferable to use the amount necessary to achieve a concentration range that allows chloroalanine to crystallize.

The reaction temperature ranges from 0 to ioO<0>C, preferably from 0 to 50<0>C. The reaction time varies depending on the reaction conditions, but is usually 1 to 50 hours, preferably 2 to 25 hours.

The end point of the reaction can be quickly and easily determined using analytical means such as high performance liquid chromatography.

β-chloroalanine is selectively crystallized from the reaction solution obtained by the reaction as described above.

The conditions necessary to selectively crystallize β-chloroalanine include β-chloroalanine and α-chloroalanine in the reaction solution.
These are the concentration and crystallization temperature of chloro-β-alanine.

In order to crystallize β-chloroalanine from the reaction solution, β-chloroalanine and α-chloro-β in the reaction solution must be
- Adjust the total concentration of alanine. This adjustment varies depending on the aziridine-2-carboxylic acid salts used as raw materials, and is as follows depending on the raw materials used.

(1) When using lithium aziridine-2-carboxylate, 10 to 47% by weight, preferably 27 to 46% by weight; (2) When using sodium aziridine-2-carboxylate, 8 to 28% by weight, preferably 15 to 27% by weight, (5) 8 to 25% by weight when using potassium aziridine-2-carboxylate, preferably 12 to 24% by weight, (4) When using magnesium aziridine-2-carboxylate, 10 to 41% by weight, preferably 26 to 40% by weight, (5) When using aziridine-2-carbo/calcium acid, 10 to 46% by weight -\ preferably 20 to 45% by weight
(6) When ammonium aziridine-2-carboxylate is used, 8 to 61% by weight, preferably 18 to 30% by weight
This is the concentration range.

Therefore, if the chlorination reaction is carried out within the crystallization concentration range shown for each aziridine-2-carboxylic acid salt above, no adjustment is necessary; however, if the chlorination reaction is carried out outside the crystallization concentration range, , the reaction solution is concentrated or diluted to adjust the crystallization concentration to the above range depending on each aziridine-2-carboxylic acid salt. If β-chloroalanine is crystallized at a concentration lower than the lower limit concentration shown for each aziridine-2-carboxylic acid salt, the isolation yield of β-chloroalanine will decrease, and
If the concentration is exceeded, by-products (α-chloro-
β-alanine) and the produced inorganic salts may be mixed in, so this is not preferable.

The temperature at which β-chloroalanine is crystallized from the reaction solution whose concentration has been adjusted as described above is usually in the range of -30 to 40°C, preferably -20 to 30°C.

If crystallization is carried out below the lower limit of this temperature range, by-products etc. will be mixed in, and if the temperature exceeds the upper limit, the isolated yield of β-chloroalanine will drop to zero, which is undesirable. There is no particular limit to the time required for crystallization. 0.5 to 8 in the above temperature range
Crystallization is sufficiently completed in 0 hours, usually 1 to 50 hours.

End of crystallization.

The point can also be quickly and easily determined by analytical means such as high-performance liquid chromatography.

Since β-chloroalanine is selectively separated as a precipitate from the reaction solution in the above method, it can be easily isolated by r-filtration. Even if trace amounts of impurities are attached to the obtained β-chloroalanine crystals, these can be removed by washing with a small amount of cold water and/or an organic solvent miscible with water. Examples of the organic solvent used here include alcohols such as methanol, ethanol, n-propanol, isopropanol, and tert-butanol, acetone, dioxane, and tetrahydrofuran.

In the method of the present invention, □
After the crystallized β-chloroalanine is isolated and obtained, β-chloroalanine and α-chloro-β-alanine dissolved in the recovery liquid are subjected to a ring-closing reaction with a base to form aziridine-2-carboxylic acid salts, This is again used as the above raw material to produce β-chloroalanine.

The recovery liquid used in this reaction process is the r liquid in which the crystallized β-chloroalanine has been separated; Since it contains alanine, it is treated with an alkali metal or alkaline earth metal hydroxide or ammonia to close the ring and form acridi-2-
Obtain a carboxylate solution. As the hydroxide of the alkali metal or alkaline earth metal used here, bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, and calcium hydroxide are used.

The amount of the base to be used is 2 equivalents or more based on hydrogen chloride neutralization and β-chloroalanine and α-chloro-β-alanine in the solution. The upper limit of the amount to be used is not particularly limited, but it is not economically advantageous to use a significantly excessive amount, and it is usually sufficient to use up to 5 equivalents.

This reaction can be carried out in water or a water-containing organic solvent. Therefore, the solvent of the recovery liquid can be water or a combination of water and an organic solvent miscible with water. Organic solvents miscible with water include methanol, ethanol, n-flobanol, isoprono(nol, ter
Alcohols such as t-butanol, cellosolve, methylselonol, etc., acetone, dioxane, tetrahydrofuran, etc. can be mentioned, so as mentioned above, the recovered solution contains the washing solution obtained by washing the f-separated β-chloroalanine with an organic solvent. This reaction can be carried out even if

When water and an organic solvent are used together in the reaction, the ratio of water to organic solvent can be arbitrarily selected. The amount of water or water-containing organic solvent to be used is 200 to 200 times, preferably 5 to 100 times, relative to β-chloroalanine and α-chloro-β-alanine.
It's double the amount. The reaction temperature is 0 to 100°C, preferably 20°C.
~80℃.

The reaction time varies depending on the various reaction conditions, but from 05 to
It takes 50 hours, usually 2.0 to 30 hours to complete.

The end point of the reaction can be quickly and easily determined by thin layer chromatography. Aziridine produced
The 2-carboxylic acid salt is obtained in the form of an aqueous solution by removing water and/or the organic solvent under normal pressure or reduced pressure and, if necessary, removing inorganic salts precipitated during concentration.

The aqueous solution of aziridine-2-carboxylate thus obtained can be used as a raw material for the first-stage reaction of the method of the present invention, and its concentration can be adjusted by concentrating or diluting it, or by adding new aziridine-2-carboxylate. Then, β-chloroalanine can be produced again by reacting it with hydrogen chloride under the above reaction conditions.

As described above, the method of the present invention makes it possible to effectively utilize β-chloroalanine and α-chloro-β-alanine in the f solution after isolating β-chloroalanine. -This is an industrially extremely valuable method for producing β-chloroalanine that can efficiently produce chloroalanine.

The method of the present invention will be explained below using Examples.

Example 1 A 32% aqueous solution 11z92 of sodium aziridine-2-carboxylate was washed with a small amount of 35% tanol stirred under water cooling to obtain β-chloroalanine 17f. Yield 39% versus sodium aziridine-2-carboxylate. Melting point 142℃
(Decomposition) Next, add 6 parts of an aqueous solution of sodium hydroxide to the washing solution.
40 t was added and the reaction was carried out at 45°C for 6 hours.

The resulting solution was concentrated by distilling off methanol and water under reduced pressure, and the precipitated inorganic salt was filtered to obtain 55 vol of a 32% aqueous solution of potassium cyacyridine-2-carboxylate. This solution was added to 375f of water-cooled 35% hydrochloric acid and treated in the same manner as above to obtain 7.69 g of β-chloroalanine. The total yield of β-chloroalanine was 51% based on the initially used sodium aziridine-2-carboxylate at 24.6f.

Example 2 28% aqueous solution 1 of potassium aziridine-2-carboxylate
94t was added over 1 hour to 35% hydrochloric acid, 942g, which had been stirred under water cooling. Thereafter, the reaction was carried out at room temperature for 10 hours, and the reaction solution was ice-cooled for 4 hours.

The precipitated crystals were filtered and washed with a small amount of methanol to obtain 20.7 t of β-chloroalanine.

f 10% aqueous solution of potassium hydroxide in 277v of washing liquid 361
1 was added, and the mixture was reacted at 50°C for 5 hours. The obtained solution was concentrated by distilling off methanol and water under reduced pressure, and the precipitated inorganic salt was filtered to obtain 84f of a 31-thi aqueous solution of potassium lyasiridine-2-carboxylate. This solution was added to 6Of 35% hydrochloric acid stirred under water cooling, and treated in the same manner as above to obtain 8.92 β-chloroalanine.

The total yield of β-chloroalanine was 5% compared to the initially charged potassium aziridine-2-carboxylate in 2961.
It was 6%.

Example 3 2192 of a 37% aqueous solution of ammonium aziridine-2-carboxylate was added to 229f of 35% hydrochloric acid with stirring under water cooling.
The mixture was added over a period of time, and then reacted at room temperature for 23 hours. 4. Cool the reaction solution on ice for 5 hours, filter the precipitated β-chloroalanine, and wash with a small amount of methanol.
52 β-chloroalanine was obtained. Next, F washing liquid 51.3
Add 9 to 29fi' of 10% ammonia water and mix 6 at room temperature.
The reaction was allowed to proceed for 0 hours, and the solvent was distilled off and concentrated under reduced pressure to remove the precipitated inorganic salt, thereby obtaining 30% aqueous solution 18f of ammonium aziridine-2-carboxylate.

β-chloroalanine t8sF was obtained by treatment in the same manner as above using 35-thihydrochloric acid 162. The total yield of β-chloroalanine was 50% based on the ammonium aziridine-2-carboxylate initially charged in six sweats.

Example 4 21.22 kg of calcium aziridine-2-carboxylate was added to 55% hydrochloric acid 501F stirred under water cooling, and then reacted at room temperature for 6 hours. The reaction solution was ice-cooled for 5 hours, and the precipitated crystals were collected by filtration and washed with a small amount of methanol to obtain 8.92% of β-chloro-alanine.

Next, the washing solution was mixed with a suspension of 280 f of calcium hydroxide.
t, and the mixture was reacted at 60°C for 7 hours. The obtained solution was filtered to remove excess calcium hydroxide, and concentrated under reduced pressure to obtain 33% aqueous solution 32f of calcium aziridine-2-carboxylate.

This solution was added to water-cooled 35% hydrochloric acid 279, and treated in the same manner as above to obtain 4.1 ft of β-chloroalanine. The total yield of β-chloroalanine was 50% of the calcium aziridine-2-carboxylate initially used in 15f.

Example 5 2361 of a 32% aqueous solution of sodium aziridine-2-carboxylate was added over 2 hours to 168 f of 65% hydrochloric acid heated to 40°C. Thereafter, the reaction was carried out at 40 to 45°C for 1 hour, and the reaction solution was cooled at -16°C for 2 hours. Precipitated β
- Chloroalanine was filtered out and washed with a small amount of inpropatol to obtain 39 grams of β-chloroalanine. Yield 4
5% to sodium aziridine-2-carboxylate.

Next, a 10% sodium hydroxide solution 3882 was added to the washing liquid, and the mixture was reacted at 45° C. for 4 hours.

The obtained solution was concentrated by distilling off impronosinol and water under reduced pressure, and the precipitated inorganic salt was filtered to obtain a 32% aqueous solution of sodium aziridine-2-carboxylate.
I got 51. By adding this solution to 35-thihydrochloric acid 857 and reacting in the same manner as above, β-chloroalanine 181
I got it.

The total yield of β-chloroalanine was 64% based on the sodium aziridine-2-carboxylate initially used in 551.

Example 6 The method of Example 1 was repeated. From the second time onward, a new sodium aziridine-2-carboxylate aqueous solution was added to adjust the concentration and amount to be the same as the first time.The results are shown in Table 1.

First time 48.8 59 2 47.5, 38.53
48.0 38.64 48
．． 2 37.9 Note 2. The yield for each run is shown.

Patent applicant: Mitsui Toatsu Chemical Co., Ltd.

Claims (1)

[Claims] 1) Aziridine-2-carboxylate in an aqueous medium from 20 to
Aziridine-2-carboxylic acid obtained by reacting with hydrogen chloride at a molar ratio of 5.0 and treating with alkali metal or alkaline earth metal hydroxide or ammonia to selectively crystallize the produced β-chloroalanine. A method for producing β-chloroalanine characterized by recycling an acid salt as a raw material