JPH08333333A - Production of 1-(3-chloro-(2s)-methylpropionyl)-pyrrolidine-(2s)-carboxylic acid - Google Patents

Abstract

PURPOSE: To simply and efficiently obtain high-quality 1-[3-chloro-(2S)- methylpropionyl]-pyrrolidine-(2S)-carboxylic acid as crystal in good yield. CONSTITUTION: 3-Chloro-2-D-methylpropionyl chloride in an amount of <=1. 05 times by mol based on L-proline is reacted with L-proline and a deacid condensing agent while adding 3-chloro 2-D-methylpropionyl chloride to a basic aqueous solution containing L-proline and a deacid condensing agent and maintaining conditions of pH>=10 and >=0.01kW/m<3> during whole reaction period to produce 1-[3-chloro(2S)-methylpropionyl]-pyrrolidine-(2S)-carboxylic acid and then, the product is crystallized by acidifying the resultant reaction liquid to pH<=3.

Description

Detailed Description of the Invention

[0001]

The present invention relates to N- (D-α-methyl-), which is known as an antihypertensive agent under the general name of captopril.
β-mercaptopropionyl) -L-proline (alias:
1- [3-mercapto- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid or N-
(3-Mercapto-2-D-methylpropionyl) -L
1- [3, which is useful as an intermediate for the production of proline)
-Chloro- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid (alias: N- (3-chloro-
2-D-methylpropionyl) -L-proline).

[0002]

PRIOR ART 1- [3-Chloro- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid to N- (D-α-methyl-β-mercaptopropionyl)
A method for producing -L-proline is described in, for example, JP-A-61 / 61
No. 183263, Japanese Patent Publication No. 63-40424, and the like.

Further, as a method for producing 1- [3-chloro- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid, 3-chloro-2-methylpropionyl chloride and L-proline are prepared. A method based on the Schotten-Baumann reaction is known.

For example, Japanese Examined Patent Publication No. 60-56705 has a general description of the Schotten-Baumann reaction between an ω-halogenalkylcarbonyl halide and L-proline. Detailed description and examples of this reaction are given. , 1- [3-chloro-
(2S) -Methylpropionyl] -pyrrolidine- (2
There is also no indication of how to isolate the S) -carboxylic acid.

Further, Chemical and Pharmaceutical Bulletin (Chem. Pharm. Bull.)
30 (9), 3139-3146 (1982), 3
-Chloro-2-D-methylpropionyl chloride and L-
1- [3 by the Schotten-Baumann reaction with proline
-Chloro- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid was synthesized, the reaction mixture was acidified with hydrochloric acid, then extracted with ethyl acetate and concentrated to give a syrup which was ethyl acetate / Crystallization with n-hexane for purification is described, and US Pat. No. 4,371,699 describes 3-chloro-2-D-.
1- [3-chloro- (2S) was obtained by the Schotten-Baumann reaction between methylpropionyl chloride and L-proline.
-Methylpropionyl] -pyrrolidine- (2S) -carboxylic acid was synthesized, the reaction mixture was acidified with phosphoric acid and then extracted with ethyl acetate, the solvent was removed to give a white solid, which was ethyl acetate / n -Crystallization and purification with hexane are described.

Thus, the schotten of 3-chloro-2-D-methylpropionyl chloride and L-proline
There are several reports on a method for producing 1- [3-chloro- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid using the Baumann reaction.

[0007]

As a result of various studies using the above method, the present inventors have found that after the reaction, 1- [3-
In order to isolate and purify chloro- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid into crystals, there is no good solvent as an extraction solvent because of its high distribution rate and the crystallization solvent. There is no suitable solvent as a result, as a result it is necessary to use a large amount of organic solvent or a mixed solvent that is difficult to recover and reuse, there is a yield loss during extraction and purification operations, and it is possible to crystallize well. It is difficult, and it takes a long time to crystallize as an oily substance, and even if the oily substance crystallizes, a large amount of deposits occur in the crystallizer, and the amount of precipitated crystals is not sufficient. It turned out that

That is, according to the methods known so far, even if the Schotten-Baumann reaction of 3-chloro-2-D-methylpropionyl chloride and L-proline is carried out without any problem, a large amount of organic solvent or mixture is used. Time consuming due to the use of solvents, separation and concentration of organic solvents,
Waiting time for oil to crystallize, difficulty in crystal separation due to poor crystal quality, low yield of crystals, special device for suppressing adhesion to crystallization can, large amount Production on a commercial scale, such as a large device for using the solvent of the above, the need for multiple devices from reaction to crystallization (crystallization) and purification (reaction can, extraction can, adsorption equipment and crystallization can) In the above, there are various problems to be improved, and the effective method for overcoming these problems is not known until now.

[0009]

In order to solve the above-mentioned problems, the present inventors have obtained 1- by the Schotten-Baumann reaction of 3-chloro-2-D-methylpropionyl chloride with L-proline. [3-chloro- (2S)-
Methylpropionyl] -pyrrolidine- (2S) -carboxylic acid is not extracted by using an organic solvent for crystallization, but a good quality product is obtained from the Schotten-Baumann reaction solution in good yield, easily and efficiently. Earnestly studied repeatedly about the method of obtaining it as a crystal. As a result, in particular,
Difficulty in crystallization of 1- [3-chloro- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid in an aqueous solution, poor crystallinity and low crystal recovery rate
During the Schotten-Baumann reaction, 3-chloro-2-methylpropionyl chloride or 1- [3-chloro- (2S)-
3-chloro-2-methylpropionic acid or 1-, which is considered to be a byproduct of a hydrolysis reaction or dehydrochlorination reaction from methylpropionyl] -pyrrolidine- (2S) -carboxylic acid
This is due to the coexistence of by-products such as methacryloyl-pyrrolidine- (2S) -carboxylic acid (also known as N-methacryloyl-L-proline), and 3-chloro-2-D-methylpropionyl chloride and L-. In the Schotten-Baumann reaction with proline, even if the reaction is not carried out in a non-aqueous system in order to suppress the above-mentioned hydrolysis reaction and the like, if a specific reaction condition is selected in an aqueous solution, it can be compared with a conventionally known reaction method. Then, the above-mentioned hydrolysis reaction and the like can be significantly suppressed, and the desired 1- [3-chloro- (2S) -methylpropionyl] -pyrrolidine-
(2S) -carboxylic acid can be synthesized, and
Acidification of the reaction mixture gives very good quality 1- [3-chloro- (2S) -methylpropionyl]-.
It was found that pyrrolidine- (2S) -carboxylic acid can be precipitated in a high yield, and it is not necessary to use an organic solvent, nor is it necessary to perform complicated isolation / purification, which is very simple, efficient and economical. The method for producing 1- [3-chloro- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid has been completed.

That is, the present invention relates to 3-chloro-2-D
1 from -methylpropionyl chloride and L-proline
In the method for producing-[3-chloro- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid, the amount of 3- (3-chloro- (2S) -pyrrolidine- (2S) -carboxylic acid is 1.05 times or less with respect to L-proline.
While adding chloro-2-D-methylpropionyl chloride to a basic aqueous solution containing L-proline and a deoxidizing condensing agent, pH 9.5 or more and stirring strength 0.01 during the entire reaction period.
a method for producing 1- [3-chloro- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid, characterized in that the reaction is carried out while maintaining the condition of kW / m ³ or more (claim 1), From 3-chloro-2-D-methylpropionyl chloride and L-proline, 1- [3-chloro-
(2S) -Methylpropionyl] -pyrrolidine- (2
In the method for producing (S) -carboxylic acid, the amount of 3-chloro-2-D is 1.05 times or less the molar amount of L-proline.
While adding methylpropionyl chloride to a basic aqueous solution containing L-proline and a deoxidizing condensing agent, while maintaining the conditions of pH 9.5 or more and stirring strength 0.01 kW / m ³ or more during the entire reaction period. After reaction, 1- [3-chloro- (2
S) -Methylpropionyl] -pyrrolidine- (2S)-
After producing the carboxylic acid, the obtained reaction solution is acidified to pH 3 or less to crystallize 1- [3-chloro- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid. 1- [3-chloro- (2
S) -Methylpropionyl] -pyrrolidine- (2S)-
Method for producing carboxylic acid (claim 2), sodium hydroxide, potassium hydroxide, lithium hydroxide as a deoxidizing condensing agent,
The production method according to claim 2 (claim 3) in which sodium carbonate, potassium carbonate or lithium carbonate is used and the acidification is carried out using sulfuric acid or hydrochloric acid, and the reaction solution is acidified to pH 2 or lower. A manufacturing method (claim 4),
The concentration of 1- [3-chloro- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid during acidification is 10% (w / v) or more with respect to water. 6. The production method according to claim 4 (claim 5), the temperature during the deoxidation condensation reaction and / or the crystallization is 60 ° C. or lower, and the temperature is such that the solution does not freeze. (Claim 6), wherein 1.02 times or less molar amount of 3-chloro-2-D-methylpropionyl chloride relative to L-proline is used.
The production method according to 5 or 6 (claim 7), and the reaction between 3-chloro-2-D-methylpropionyl chloride and L-proline are carried out under conditions of stirring strength of 0.1 kW / m ³ or more. The manufacturing method according to 1, 2, 3, 4, 5, 6, or 7 (claim 8).

[0011]

EXAMPLES The manufacturing method of the present invention will be described in detail.

In the present invention, 3-chloro-2-D-
From methylpropionyl chloride and L-proline by the Schotten-Baumann reaction, 1- [3-chloro- (2
S) -Methylpropionyl] -pyrrolidine- (2S)-
A carboxylic acid is produced, in which case 3-chloro-2-D is added to a basic aqueous solution containing L-proline and a deoxidizing condensing agent.
-Methylpropionyl chloride is added.

The above-mentioned 3-chloro-2-D-methylpropionyl chloride can be obtained from Japanese Examined Patent Publication (Kokoku) No. 62-32181 or Chemical and Pharmaceutical Bulletin 30.
(9), 3139-3146 (1982), and the like, for example, D-β-hydroxyisobutyric acid or a salt thereof is converted to a phosphorus chloride compound such as phosphorus trichloride, phosphorus pentachloride or phosphorus oxychloride. Or by treatment with a chlorinating agent such as thionyl chloride.

The 3-chloro-2-D-methylpropionyl chloride used may be used in an unpurified form,
Those obtained by removing low-boiling components such as thionyl chloride and those isolated and purified by a method such as vacuum distillation under a nitrogen stream are preferred.

Examples of the deoxidizing condensing agent include bases generally used in the Schotten-Baumann reaction, for example, organic bases such as triethylamine and pyridine, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate. Examples thereof include inorganic bases such as lithium carbonate, but are not limited thereto. These may be used alone or in combination of two or more. Of these, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate acidify the reaction mixture and 1- [3-chloro-
(2S) -Methylpropionyl] -pyrrolidine- (2
In crystallizing the S) -carboxylic acid, it is preferable from the viewpoint of easy disposal of the salt produced and the salting out effect of the salt produced. Especially, sodium hydroxide, potassium hydroxide and lithium hydroxide are preferable.

The solvent for the basic aqueous solution is usually
Water is used and only water is used as a solvent, so that the reaction concentration and crystallization concentration can be increased, no harmful organic solvent is used, and post-treatment including wastewater treatment is easy. A mixture of water and an organic solvent may be used, although it is preferable in that it can be increased. Generally, in order to suppress side reactions in the Schotten-Baumann reaction, or for extraction and removal of unreacted raw materials and side reaction products, the above organic solvent may be used, but in the present invention, There is a great advantage in that it is not necessary to use any organic solvent.

When a mixture of water and an organic solvent is used as a solvent, the system may be a system in which an organic solvent miscible with water and water are uniformly mixed, or an organic solvent immiscible with water. A non-uniform two-layer system of a solvent and water may be used, but L
-A heterogeneous two-layer system of water and an organic solvent that is immiscible with water from the viewpoints that the solubility of proline is kept high and the reaction is carried out at a high concentration, the recovery rate during crystallization is increased, and the recovery of the solvent is easy. Is preferred.

Examples of the organic solvent include ethers such as diethyl ether and tetrahydrofuran, halogenated hydrocarbons such as methylene chloride and dichloroethane, hydrocarbons such as toluene, methylcyclohexane and n-hexane, ethyl acetate and isopropyl acetate. Fatty acid esters such as, nitriles such as acetonitrile,
Alcohols such as methanol, ethanol and propanol, ketones such as acetone and methyl ethyl ketone,
Examples thereof include aprotic polar solvents such as dimethylformamide, dimethyl sulfoxide, and N-methylpyrrolidone, but are not limited thereto.

The basic aqueous solution is an aqueous solution which is made basic by a deoxidizing condensing agent added together with L-proline to water as a solvent or a mixture of water and an organic solvent. It is not necessary to add a base to make it acidic, but in order to facilitate adjustment of the pH during the reaction period, disodium hydrogen phosphate, hydrochloric acid, boric acid, etc. are added to form a basic aqueous solution having a buffering property. You may use what was done. Further, a surfactant, a phase transfer catalyst or the like may be added to the basic aqueous solution, if necessary.
A part of the deoxidizing condensing agent is used to make the carboxylic acid group of L-proline into a salt.

The basic aqueous solution containing L-proline to which 3-chloro-2-D-methylpropionyl chloride is added and a deoxidizing condensing agent is a basic aqueous solution containing L-proline in a predetermined amount of deoxidizing condensation. The agent may be allowed to coexist in advance, and it may be added to a basic aqueous solution containing L-proline in an amount of 3
When 3-chloro-2-D-methylpropionyl chloride is added, either sequentially or in divided additions of the deoxidizing condensing agent required according to the addition of -chloro-2-D-methylpropionyl chloride. The deoxidizing condensing agent may be present in an amount required for the above.

It is to be noted that it is preferable to add all L-proline from the beginning so as to suppress the formation of by-products and ensure a high yield.
It is preferable from the viewpoint of easy operability.

For the addition of 3-chloro-2-D-methylpropionyl chloride, 3-chloro-2-D-methylpropionyl chloride may be added as it is, for example, by dissolving it in an inert liquid such as methylene chloride or tetrahydrofuran. It may be added, but it must be carried out by a method of adding it into a basic aqueous solution containing L-proline and a deoxidizing condensing agent. For example, L-proline is added in the presence of 3-chloro-2-D-methylpropionyl chloride and a deoxidizing condensing agent, or L-proline is deoxidized and condensing in 3-chloro-2-D-methylpropionyl chloride. If other addition methods such as adding agents are selected, 3-
Since a large amount of by-products such as chloro-2-methylpropionic acid and 1-methacryloyl-pyrrolidine- (2S) -carboxylic acid (also known as N-methacryloyl-L-proline) are formed, 1- [3 -Chloro- (2S)-
Fatal problems in terms of isolation and purification occur, such as difficulty in crystallization of methylpropionyl] -pyrrolidine- (2S) -carboxylic acid and reduction in yield.

L-proline and 3-chloro-2-D-when 3-chloro-2-D-methylpropionyl chloride is added to a basic aqueous solution containing L-proline and a deoxidizing condensing agent to react with each other The proportion of methylpropionyl chloride is 3-chloro-2-D-methylpropionyl chloride in 1.05 times or less, preferably 1.02 times or less, and more preferably 1.01 times that of L-proline. It is not more than the molar amount, not less than 0.8 times the molar amount, further not less than 0.9 times the molar amount, and especially not less than 0.95 times the molar amount. When the proportion of 3-chloro-2-D-methylpropionyl chloride is higher than the above proportion, a hydrolysis reaction of 3-chloro-2-D-methylpropionyl chloride to 3-chloro-2-methylpropionic acid It becomes difficult to obtain high quality 1- [3-chloro- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid by crystallization after the reaction. On the other hand, 3-chloro-2
If the proportion of -D-methylpropionyl chloride is less than the above proportion, an excessive amount of L-proline is used, which is uneconomical such that the yield for L-proline decreases.

The pH when 3-chloro-2-D-methylpropionyl chloride is added to a basic aqueous solution containing L-proline and a deoxidizing condensing agent and reacted is pH 9.5 during the entire reaction period. As described above, usually about 14 to 15 or less is adopted. If the pH becomes less than 9.5 during the reaction period, 3
3 from -chloro-2-D-methylpropionyl chloride
-The number of hydrolysis reactions to chloro-2-methylpropionic acid increases. When the pH exceeds 14 to 15, particularly when the reaction temperature is high, by-products tend to increase and the yield tends to decrease.

As mentioned above, the pH during the entire reaction period was adjusted to 9.
It is necessary to hold at least 5 and, for this reason,
In the case of an alkali metal hydroxide, a deoxidizing condensing agent is added to an aqueous solution containing L-proline in an amount of at least about 2.1 times the amount of L-proline in advance, added in portions, or added sequentially. Etc. are added. The upper limit of the addition amount of the deoxidizing condensing agent is about 2.3 times the molar amount in the case of the alkali metal hydroxide, and use in excess of this amount is uneconomical.

The temperature for carrying out the deoxidation condensation reaction is as follows:
A temperature below 60 ° C at which the solution does not freeze, generally about 0
A range of 50 ° C is adopted. If the reaction temperature exceeds 60 ° C., the yield tends to decrease due to an increase in by-products, especially under conditions of high alkali concentration.

The addition rate of 3-chloro-2-D-methylpropionyl chloride or its solution is preferably such that the generated heat can be removed and an excessive temperature rise does not occur. When the reaction rate cannot keep up with the addition rate of 3-chloro-2-D-methylpropionyl chloride, a side reaction (particularly 3-chloro-2
From 3-D-methylpropionyl chloride to 3-chloro-2
Since the ratio of (hydrolysis reaction to -D-methylpropionic acid) is increased, it is not preferable to add them all at once, but depending on the addition amount, etc., the addition of the entire amount is usually completed over several minutes to several hours. As described above, the unreacted 3-chloro-2-
It is preferred that D-methylpropionyl chloride is not present in the system for a long time. The target of the addition rate is that the reaction temperature is about 6 when stirring at a predetermined stirring intensity.
It is preferable that the temperature can be maintained at 0 ° C. or lower, generally about 0 to 50 ° C.

The stirring strength when 3-chloro-2-D-methylpropionyl chloride is added to a basic aqueous solution containing L-proline and a deoxidizing condensing agent and reacted is as follows.
0.01 kW / m ³ or more, preferably about 0.1 kW / m ³
The above is more preferably about 0.5 kW / m ³ or more, and the larger the stirring strength is, the more preferable. However, the upper limit is about 5 kW / m ³ due to limitations in terms of the capacity and power consumption of the stirrer. is there. When the stirring intensity is less than the above value, the hydrolysis rate of 3-chloro-2-D-methylpropionyl chloride is relatively high, and therefore, the reaction between the added 3-chloro-2-D-methylpropionyl chloride and L-proline. The rate of occurrence of is reduced. Surprisingly, the reaction with L-proline, which is the desired reaction, becomes extremely predominant among the reactions between 3-chloro-2-D-methylpropionyl chloride and water or L-proline due to the increase in stirring intensity.

The agitation intensity is the agitation required power Pv per unit volume, and is expressed by the formula: Pv = N _p × N ³ × d ⁵ × ρ ÷ V = 2πNT / V N _p : Power number [-] N: Stirring number [s ^-1 ] d: Stirring blade diameter [m] ρ: Reaction liquid density [kg / m ³ ] V: Reaction liquid amount [m ³ ] T: Torque [Ws]

After the addition of 3-chloro-2-D-methylpropionyl chloride is completed, it is preferable to maintain the above preferable reaction conditions until the reaction is almost completed. Usually, the reaction is almost completed within 1 hour after the addition is completed.

The charged concentration is 3-chloro-2 with respect to the solvent.
The total amount of -D-methylpropionyl chloride is generally in the range of about 1 to 70% (w / v), but productivity and acidification of the reaction mixture may lead to 1- [3-chloro- (2
S) -Methylpropionyl] -pyrrolidine- (2S)-
Considering the recovery rate, quality, and fluidity of slurry when crystallizing and separating carboxylic acid, it is usually about 5 to 50.
% (W / v), more preferably 10 to 40% (w / v).

The reaction mixture thus obtained is usually obtained by mixing 1- [3-chloro- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid formed as a salt with about 10 to a solvent. Since it exists at a concentration of 80% (w / v), preferably about 15 to 60% (w / v), it can be obtained as crystals by neutralizing and acidifying with an acid as it is in an aqueous solution. . Of course, it may be neutralized and acidified with an acid, then extracted with an organic solvent and crystallized if necessary. Further, after unreacted substances and by-products are extracted and removed in advance, it is acidified to obtain the objective. 1- [3-chloro- (2S) -methylpropionyl]-
Pyrrolidine- (2S) -carboxylic acid may be extracted or crystallized in a pure state. If necessary, further reaction (production of derivative) as it is without obtaining crystals.
May be used.

1- [3-] can be obtained by a method of neutralizing or acidifying the reaction mixture as it is, or by extracting and removing unreacted materials and by-products in advance.
Chloro- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid can be simply obtained by precipitating it as high-quality crystals with good physical properties.

As the acid used for the neutralization and acidification, it is preferable to use a mineral acid such as hydrochloric acid or sulfuric acid. In particular, when an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide or an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate is used as a deoxidizing condensing agent during the Schotten-Baumann reaction. In the meantime, by neutralizing and acidifying with hydrochloric acid or sulfuric acid,
In addition to producing inorganic salts (chlorides and sulfates of alkali metals such as sodium chloride and sodium sulfate) that are easy to dispose of, the salting out effect of the produced inorganic salts causes 1-
The recovery rate of [3-chloro- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid can be increased. Usually, it is not necessary to increase the amount of water, so concentrated hydrochloric acid or concentrated sulfuric acid, or a solution obtained by diluting these slightly with water is used. Of course, other acids may be used.

In order to increase the precipitation rate of 1- [3-chloro- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid, the pH is about 3 or less, preferably p.
It is preferable to acidify to H2 or less, more preferably to pH1 or less.

The reaction mixture used for acidification can be obtained not only in terms of quality but also 1- [3-chloro- (2S)
-Methylpropionyl] -pyrrolidine- (2S) carboxylic acid, 3-chloro-2-methylpropionic acid and 1-methacryloyl-pyrrolidine-from the viewpoints of easiness of crystallization, filterability, crystallinity and precipitation rate. The total amount of by-products such as (2S) -carboxylic acid (also known as N-methacryloyl-L-proline) is 1- [3-chloro- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid. It is preferably about 3.5% by weight or less, particularly about 2% by weight or less. Such a low amount of by-products can be successfully achieved by the production method of the present invention.

The acidification rate may be, for example, in the range of several minutes to several hours and is not particularly limited. It may be acidified for a longer period of time.

As a method of acidification, the reaction mixture may be added to an acid solution, but usually, in order to obtain good crystals, an acid is added to the reaction mixture or a reaction with the acid is performed in water. The method of adding the mixture is preferred.

The stirring for neutralization or acidification is also not particularly limited, and may be arbitrarily selected from mild stirring to very vigorous stirring.

The temperature at the time of acidification is preferably about 60 ° C. or lower so as to crystallize well without oiling. Usually, while effectively removing heat generated during acidification, the solution is acidified and crystallized at a temperature of about 60 ° C. or lower at which the solution does not freeze, usually about 0 to 50 ° C. Finally, it is more preferable to sufficiently crystallize at 20 ° C or lower, preferably 10 ° C or lower.

1- [3-chloro- (2S) -methylpropionyl] -pyrrolidine- (2 relative to water during acidification
The concentration of S) -carboxylic acid depends on the productivity and 1- [3-chloro- (2S) -methylpropionyl] -pyrrolidine-
Considering the recovery rate in the case of crystallizing and separating the (2S) -carboxylic acid, it is usually performed at about 5% (w / v) or more. In particular, at about 10% (w / v) or more, 1- [3
Since the dissolution rate of -chloro- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid can be considerably reduced and the amount of precipitation can be increased, it may be necessary to separately concentrate and distill off water. It is possible to secure a sufficient recovery rate without complicated operations such as coexistence of more inorganic salts such as sodium chloride, sodium sulfate and ammonium sulfate. Usually, considering the viscosity and fluidity of the slurry, it is preferably carried out at about 10 to 80% (w / v), preferably about 15 to 60% (w / v).

As an acidification method, a hydrogen-supplying ion exchange resin can be used.

The following is an example of the simplest and preferred embodiment of the present invention.

From 3-chloro-2-D-methylpropionyl chloride and L-proline, 1- [3-chloro- (2
S) -Methylpropionyl] -pyrrolidine- (2S)-
In the method for producing carboxylic acid, a molar amount of 3-chloro-2- is about 0.95 to 1.02 times that of L-proline.
D-methylpropionyl chloride can be theoretically obtained 1
An amount of water, L-proline and deprotonated such that the concentration of-[3-chloro- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid is about 10-80% (w / v) with respect to water. While adding to an aqueous solution of an alkali metal hydroxide (sodium hydroxide, potassium hydroxide or lithium hydroxide) as an acid condensing agent, at that time, during the entire reaction period,
The reaction temperature is 50 ° C. or lower, the temperature at which the aqueous solution does not freeze, the stirring strength is 0.1 kw / m ³ or more, and the reaction pH is about 2.1 to about a total amount of alkali metal hydroxide as a deoxidizing condensing agent with respect to L-proline. It was obtained after preparing 1- [3-chloro- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid by reacting with a 2.3-fold molar amount while maintaining at 9.5 or more. The reaction solution was acidified to pH 2 or lower with hydrochloric acid or sulfuric acid at 50 ° C. or lower at a temperature at which the aqueous solution did not freeze to give 1- [3-chloro- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid. It is crystallized and finally cooled to around 0 to 10 ° C. to increase the amount of precipitation and then separated and obtained.

1- [3-chloro- (2S) -methylpropionyl] -pyrrolidine (2
The aqueous slurry of (S) -carboxylic acid is separated into crystals and a filtrate by a general method such as centrifugation or pressure filtration, and if necessary, washed with a suitable solvent such as cold water, and under normal pressure. Dried by air flow drying or vacuum drying, 1- [3-chloro- (2S) -methylpropionyl] -pyrrolidine-
(2S) -carboxylic acid is obtained.

Hereinafter, the production method of the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.

Example 1 20.4 g of L-proline was added to 170 ml of water, and a 30 wt% NaOH aqueous solution was slowly added to adjust the pH to 11. While maintaining this solution at about 10 ° C. under stirring, 3-
Chloro-2-D-methylpropionyl chloride 25.0
g was added dropwise over 30 minutes, and after completion of the addition, stirring was continued for 1 hour. The pH of the reaction solution during the reaction is 30% by weight NaOH.
The pH was adjusted to 11 by dropping the aqueous solution. The stirring intensity was about 1 kW / m ³ , and the amount of NaOH used was L
-2.1 times the molar amount of proline.

As a result of analyzing the reaction solution by high performance liquid chromatography, the yield of 1- [3-chloro- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid was 99 mol%.

Further, 3-chloro-2-D-methylpropionyl chloride to 3-chloro-2-D-methylpropionic acid and 1-methacryloyl-pyrrolidine- (2
The ratio of S) -carboxylic acid produced was 0.0 mol% (0.0 wt% (ratio to 1- [3-chloro- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid, The same shall apply hereinafter)) and 0.3 mol%
(0.3% by weight).

Example 2 The procedure of Example 1 was repeated except that the pH of the reaction solution was always kept at 13.5. The amount of NaOH used was 2.2 times the molar amount of L-proline.

As a result of high performance liquid chromatography analysis of the reaction solution, the yield of 1- [3-chloro- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid was 99 mol%.

Further, 3-chloro-2-D-methylpropionyl chloride to 3-chloro-2-D-methylpropionic acid and 1-methacryloyl-pyrrolidine- (2
The proportions of S) -carboxylic acid formed were 0.0 mol% (0.0 wt%) and 0.2 mol% (0.2 wt%), respectively.

Example 3 The same procedure as in Example 1 was repeated except that the pH of the reaction solution was always kept at 10. The amount of NaOH used was 2.1 times the molar amount of L-proline.

As a result of high performance liquid chromatography analysis of the reaction solution, the yield of 1- [3-chloro- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid was 97 mol%.

Further, 3-chloro-2-D-methylpropionyl chloride to 3-chloro-2-D-methylpropionic acid and 1-methacryloyl-pyrrolidine- (2
The proportions of S) -carboxylic acid formed were 2.0 mol% (1.1 wt%) and 0.3 mol% (0.3 wt%), respectively.

Comparative Example 1 The procedure of Example 1 was repeated, except that the pH of the reaction solution was constantly maintained at 9. The amount of NaOH used was 2.0 times the molar amount of L-proline.

As a result of analyzing the reaction solution by high performance liquid chromatography, the yield of 1- [3-chloro- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid was 90 mol%.

Further, 3-chloro-2-D-methylpropionyl chloride to 3-chloro-2-D-methylpropionic acid and 1-methacryloyl-pyrrolidine- (2
The proportions of S) -carboxylic acid formed were 8.2 mol% (4.6% by weight) and 0.5 mol% (0.4% by weight), respectively.

Example 4 The procedure of Example 1 was repeated, except that the stirring strength of the reaction solution was maintained at about 0.1 kW / m ³ .

As a result of analyzing the reaction solution by high performance liquid chromatography, the yield of 1- [3-chloro- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid was 98 mol%.

Further, 3-chloro-2-D-methylpropionyl chloride to 3-chloro-2-D-methylpropionic acid and 1-methacryloyl-pyrrolidine- (2
The proportions of S) -carboxylic acid formed were 1.7 mol% (0.9 wt%) and 0.4 mol% (0.3 wt%), respectively.

Example 5 Example 5 was repeated except that the stirring strength of the reaction solution was maintained at about 0.01 kW / m ³ .

As a result of analyzing the reaction solution by high performance liquid chromatography, the yield of 1- [3-chloro- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid was 94 mol%.

Further, 3-chloro-2-D-methylpropionyl chloride to 3-chloro-2-D-methylpropionic acid and 1-methacryloyl-pyrrolidine- (2
The proportions of S) -carboxylic acid formed were 4.8 mol% (2.7 wt%) and 0.6 mol% (0.5 wt%), respectively.

Comparative Example 2 20.4 g of L-proline was added to 7.10 g of NaOH and 87 of water.
ml to the mixture. While maintaining the solution at 0 to 5 ° C. under stirring, an aqueous solution (87 ml of water) of 25.0 g of 3-chloro-2-D-methylpropionyl chloride and 7.10 g of NaOH was simultaneously added over 30 minutes, and after the addition was completed. Stirring was continued for another hour. The stirring intensity was about 0.5 kW / m ³ , and the initial pH of the reaction solution was around 13, but it decreased to 5 in the latter half of the reaction.

As a result of high performance liquid chromatography analysis of the reaction mixture, the yield of 1- [3-chloro- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid was 92 mol%.

Further, 3-chloro-2-D-methylpropionyl chloride to 3-chloro-2-D-methylpropionic acid and 1-methacryloyl-pyrrolidine- (2
The proportions of S) -carboxylic acid formed were 6.9 mol% (3.8 wt%) and 0.4 mol% (0.3 wt%), respectively.

Comparative Example 3 20.5 g of L-proline was added to 180 ml of 2N NaOH. With stirring this solution at about 0 ° C., 25.0 g of 3-chloro-2-D-methylpropionyl chloride
Was added dropwise over 30 minutes, and after completion of the addition, stirring was continued for 1 hour. The stirring intensity was about 0.5 kW / m ³ , but the pH of the reaction solution in the latter half of the reaction dropped to 5.

As a result of analyzing the reaction solution by high performance liquid chromatography, the yield of 1- [3-chloro- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid was 91 mol%.

Further, 3-chloro-2-D-methylpropionyl chloride to 3-chloro-2-D-methylpropionic acid and 1-methacryloyl-pyrrolidine- (2
The proportions of S) -carboxylic acid formed were 7.3 mol% (4.1% by weight) and 0.7 mol% (0.6% by weight), respectively.

Example 6 The reaction-terminated liquid (1- [3
-Chloro- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid is contained as 16.4 g) under stirring with 35% HCl added dropwise over 10 minutes to pH 0. When set to 5, crystals were satisfactorily deposited. Continue stirring for an additional hour and then filter to 1-
[3-Chloro- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid 15.8 g (recovery rate 96
%).

Chloro-2-D-methylpropionic acid and 1-methacryloyl-pyrrolidine-in the obtained crystals
The contents of (2S) -carboxylic acid were 0.0% by weight and 0.1% by weight, respectively.

Example 7 1- [3-chloro- (2S)-was obtained in the same manner as in Example 1 except that the pH of the reaction solution was always maintained at 10.5.
Methylpropionyl] -pyrrolidine- (2S) -carboxylic acid 7.10 g (0.3% by weight of 3-chloro-2-D-methylpropionic acid and 1-methacryloyl-pyrrolidine- (2S) -carboxylic acid 0.3% by weight 50 g of the reaction-completed liquid containing
When Cl was added dropwise over 10 minutes to reach pH 0.5,
Crystals were well precipitated. After stirring for 1 hour, the mixture was separated by a centrifuge. After washing with a small amount of cold water, vacuum drying, and 1- [3-chloro- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid 6.67 g
(Recovery rate 94%) was acquired.

The contents of 3-chloro-2-D-methylpropionic acid and 1-methacryloyl-pyrrolidine- (2S) -carboxylic acid in the obtained crystals were 0.0% by weight and 0.1% by weight, respectively. there were. The melting point of the obtained crystals is 1
31 to 132 ° C, specific rotation [α] _D ²⁵ is -102 ° (C
= 2.0, EtOH), and Chemical and Pharmaceutical Bulletin 30 (9), 3139-3.
146 (1982).

Example 8 1- [3-chloro- (2S) -methylpropionyl] -pyrrolidine- (obtained by the same method as in Example 1 except that the pH of the reaction solution was always maintained at 9.6. Completion of reaction containing 7.10 g of 2S) -carboxylic acid (including 2.1% by weight of 3-chloro-2-D-methylpropionic acid and 0.3% by weight of 1-methacryloyl-pyrrolidine- (2S) -carboxylic acid) While maintaining about 50 g of the liquid under stirring at about 5 ° C as in Example 7, 35% HCl was added dropwise over 10 minutes to adjust the pH to 0.1.
When set to 5, crystals were satisfactorily deposited. After stirring for 1 hour, the mixture was separated by a centrifuge. After washing with a small amount of cold water, it was vacuum dried to obtain 6.57 g (recovery rate 93%) of 1- [3-chloro- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid.

The contents of 3-chloro-2-D-methylpropionic acid and 1-methacryloyl-pyrrolidine- (2S) -carboxylic acid in the obtained crystals were 0.1% by weight and 0.1% by weight, respectively. there were.

Comparative Example 4 1- [3-chloro- (2S) -methylpropionyl] -pyrrolidine- (obtained by the same method as in Example 1 except that the pH of the reaction solution was always kept at 8.5. Completion of reaction containing 7.10 g of 2S) -carboxylic acid (including 8.9% by weight of 3-chloro-2-D-methylpropionic acid and 0.3% by weight of 1-methacryloyl-pyrrolidine- (2S) -carboxylic acid) While maintaining about 50 g of the liquid under stirring at about 5 ° C as in Example 7, 35% HCl was added dropwise over 10 minutes to adjust the pH to 0.1.
When it was set to 5, a semi-solid sticky substance was separated. The stirring was continued for another hour, but it did not change. When this was separated with a centrifuge, the separability was very poor, and some oily substances passed to the filtrate side. After washing with a small amount of cold water and vacuum drying, it has a high adhesiveness 1-
5.4 g (recovery rate 76%) of [3-chloro- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid solid was obtained.

The contents of 3-chloro-2-D-methylpropionic acid and 1-methacryloyl-pyrrolidine- (2S) -carboxylic acid in the obtained solid were 1.2% by weight and 0.2% by weight, respectively. there were.

Example 9 As in Example 7, the reaction-terminated liquid (1) obtained in Example 5 was used.
Containing 5.0 g of-[3-chloro- (2S) -methylpropionyl-pyrrolidine- (2S) -carboxylic acid)
Was crystallized, separated, washed and dried to give 1- [3-chloro- (2S) -methylpropionyl] -pyrrolidine-
(2S) -carboxylic acid (4.6 g, recovery rate 92%) was obtained.

The content of 3-chloro-2-D-methylpropionic acid and 1-methacryloyl-pyrrolidine- (2S) -carboxylic acid in the obtained crystals was 0.2% by weight. The melting point of this crystal is 130 to 131.
° C.

[0081]

According to the present invention, 3-chloro-2-D-
Starting from methylpropionyl chloride and L-proline as starting materials, 1- [3-chloro- (2
S) -Methylpropionyl] -pyrrolidine- (2S)-
A carboxylic acid can be easily and efficiently obtained.

Claims (8)

[Claims] 1. From 3-chloro-2-D-methylpropionyl chloride and L-proline, 1- [3-chloro-
(2S) -Methylpropionyl] -pyrrolidine- (2
In the method for producing (S) -carboxylic acid, the amount of 3-chloro-2-D is 1.05 times or less the molar amount of L-proline.
While adding methylpropionyl chloride to a basic aqueous solution containing L-proline and a deoxidizing condensing agent, while maintaining the conditions of pH 9.5 or more and stirring strength 0.01 kW / m ³ or more during the entire reaction period. 1-characterized by reacting
Process for producing [3-chloro- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid. 2. 1- [3-Chloro-) from 3-chloro-2-D-methylpropionyl chloride and L-proline
(2S) -Methylpropionyl] -pyrrolidine- (2
In the method for producing (S) -carboxylic acid, the amount of 3-chloro-2-D is 1.05 times or less the molar amount of L-proline.
While adding methylpropionyl chloride to a basic aqueous solution containing L-proline and a deoxidizing condensing agent, while maintaining the conditions of pH 9.5 or more and stirring strength 0.01 kW / m ³ or more during the entire reaction period. After reaction, 1- [3-chloro- (2
S) -Methylpropionyl] -pyrrolidine- (2S)-
After producing the carboxylic acid, the obtained reaction solution is acidified to pH 3 or less to crystallize 1- [3-chloro- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid. 1- [3-chloro- (2
S) -Methylpropionyl] -pyrrolidine- (2S)-
A method for producing a carboxylic acid. 3. The process according to claim 2, wherein sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate or lithium carbonate is used as the deoxidizing condensing agent, and the acidification is carried out using sulfuric acid or hydrochloric acid. Method. 4. The production method according to claim 2, wherein the reaction solution is acidified to pH 2 or less. 5. 1- [3-chloro- (2S) upon acidification
The method according to claim 2, 3 or 4, wherein the concentration of -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid is 10% (w / v) or more with respect to water. 6. The method according to claim 1, 2, 3, 4 or 5, wherein the temperature during the deoxidation condensation reaction and / or the crystallization is 60 ° C. or lower and the solution does not freeze. 7. The production method according to claim 1, wherein 3-chloro-2-D-methylpropionyl chloride is used in an amount of 1.02 times or less the molar amount of L-proline. . 8. The reaction between 3-chloro-2-D-methylpropionyl chloride and L-proline is carried out with stirring strength of 0.1.
Claim 1,2,3 implemented in kW / m ³ or more conditions,
The manufacturing method according to 4, 5, 6 or 7.