JPH10310567A - Crystallization method of 3-amino-2- (N-alkoxycarbonyl) aminopropionic acid ester / substituted benzenesulfonic acid salt - Google Patents

Abstract

(57) [Summary] [Problem] From a reaction solution. 3-amino-2-, which is the target substance
(N-alkoxycarbonyl) aminopropionate / substituted benzenesulfonate is efficiently recovered. SOLUTION: In a poor solvent containing 3-amino-2- (N-alkoxycarbonyl) aminopropionate / substituted benzenesulfonate, 3-amino-2- (N-alkoxycarbonyl) aminopropionate / substitution is carried out. In the method of crystallizing a benzenesulfonate, crystallization is performed under the conditions that the content of water in the solvent is 1% by weight or less and the content of alcohol having 1 to 4 carbon atoms is 5% by weight or less.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to 3-amino-2-
The present invention relates to the production of (N-alkoxycarbonyl) aminopropionate / substituted benzenesulfonate. This compound is useful as a synthetic intermediate for pharmaceuticals, pesticides, and the like, for example, “Bioorganic &
Medicinal Chemistry Lette
rs, Vol. 6, No. 3,339 (1996), which is useful as an intermediate of a raw material for producing a drug represented by the following formula (4).

[0002]

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(Wherein, R represents an alkyl group having 1 to 4 carbon atoms)

[0004]

2. Description of the Related Art As a method for producing an amino acid ester / sulfonate, a method by transesterification between an amino acid and a sulfonic acid ester is known. For example, the magazine "Bull. Chem. Soc. Jpn., Vol. 5"
2 (6), 1879 (1979)], amino acids and p
-Ethyl toluene sulfonate in an ethanol solvent,
After performing the reaction under reflux for 24 to 30 hours, the ethanol of the solvent was distilled off, and diethyl ether was added to crystallize the amino acid ethyl ester / p-toluenesulfonate,
A method for obtaining this by filtration is disclosed.

A method is also known in which an amino acid and a sulfonic acid are reacted with an intended ester of an amino acid ester / sulfonate in an alcohol solvent corresponding to the target. Magazine "Int. J. Peptide Protei
n Res. 23,111 (1984) "discloses that after reacting an amino acid with p-toluenesulfonic acid monohydrate in ethanol for 24 hours under reflux, the ethanol is distilled off, and diethyl ether is added to give the amino acid. A method for crystallizing ethyl ester / p-toluenesulfonate and obtaining the same is disclosed.

[0006]

However, these methods are not preferred in terms of safety, since they use diethyl ether, which is a special flammable substance, when removing amino acid ethyl ester / p-toluenesulfonate. However, this method is not suitable for production on an industrial scale. In addition, using these methods as objects, the formula (1)

[0007]

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Wherein R ¹ is a straight-chain or branched carbon atom
And R ² may be a straight-chain or branched alkyl group having 1 to 5 carbon atoms, and R ³ may be a branched or halogen atom having 1 to 5 carbon atoms. Represents an alkyl group, a halogen atom or a hydrogen atom. When applied to the method for producing 3-amino-2- (N-alkoxycarbonyl) aminopropionic acid ester / substituted benzenesulfonate represented by the formula (1), crystallization does not occur or crystals in a sticky state are formed. When precipitated, a salt having good reproducibility and good properties could not be taken out.
The present invention relates to an industrially feasible 3-amino-2- (N-
Alkoxycarbonyl) aminopropionate
A method for producing a substituted benzenesulfonate is provided.

[0009]

Means for Solving the Problems As a result of intensive studies to solve these problems, the present invention has found that the water content or the alcohol content in the crystallization liquid has an extremely large effect on crystallization. By strictly defining these, it is possible to obtain 3-amino-2-
It has been found that (N-alkoxycarbonyl) aminopropionate / substituted benzenesulfonate can be obtained with high reproducibility and high yield. Further, as a result of studying a poor solvent used for crystallization, a method using an industrially feasible solvent was found, and the present invention was completed. The present invention relates to formula (1)

[0010]

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Wherein R ¹ is a straight-chain or branched carbon atom
And R ² may be a straight-chain or branched alkyl group having 1 to 5 carbon atoms, and R ³ may be a branched or halogen atom having 1 to 5 carbon atoms. Represents an alkyl group, a halogen atom or a hydrogen atom. 3-amino-2- (N-alkoxycarbonyl) aminopropionate in a poor solvent containing a substituted benzenesulfonate represented by the formula: In the method for crystallizing a substituted benzenesulfonate, crystallization is performed under the condition that the content of water in a solvent is 1% by weight or less and the content of an alcohol having 1 to 4 carbon atoms is 5% by weight or less. A crystallization method is provided.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail. Reaction: 3-amino-2- (N-alkoxycarbonyl) aminopropionic acid ester / substituted benzenesulfonate represented by the above formula (1) is converted to a compound represented by the formula (2)

[0013]

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(Wherein R ¹ is a linear or branched carbon atom having 1 carbon atom)
And represents alkyl groups 4 to 4. 3-amino-2 represented by the formula:
-(N-alkoxycarbonyl) aminopropionic acid derivative and a compound represented by the formula (3)

[0015]

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(Wherein R ² is an alkyl group having 1 to 5 carbon atoms which may be linear or branched, and R ³ may be a C 1 to C 5 branched or halogen atom. A substituted benzenesulfonic acid derivative represented by an alkyl group, a halogen atom or a hydrogen atom) with toluene, xylene, or the same ester portion (R ¹ ) of the resulting salt represented by the formula (1). It is obtained by reacting in a solvent such as alcohol having an alkyl group.

The 3-amino-2- (N
-Alkoxycarbonyl) aminopropionic acid derivative as R ¹ alkyl group includes methyl group, ethyl group, n-
Propyl, i-propyl, n-butyl, i-butyl and the like. R ² of the substituted benzenesulfonic acid derivative represented by the formula (3) is a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, an n-amyl. R ³ represents a lower alkyl group which may be branched such as a methyl group or an ethyl group; a lower haloalkyl group such as a trifluoromethyl group; a halogen such as chlorine or bromine. Atoms and hydrogen atoms.

The amount of the substituted benzenesulfonic acid derivative may theoretically be used in an equimolar amount with respect to 1 mol of the 3-amino-2- (N-alkoxycarbonyl) aminopropionic acid derivative. 1.0-3.
Used in the range of 0 mol. The reaction is usually carried out with 3-amino-
It is carried out by charging 2- (N-alkoxycarbonyl) aminopropionic acid and a substituted benzenesulfonic acid derivative in a solvent, heating and stirring. At this time, the substituted benzenesulfonic acid derivative used is in a free acid state (R ³ =
In the case of H), it is necessary to add alcohol necessary for esterification.

As a reaction solvent, a solvent in which diaminopropionic acids and substituted benzenesulfonic acid derivatives as raw materials are used is used. At this time, the raw material does not need to be completely dissolved, but only needs to be partially dissolved. Specific examples of the solvent used include alcohols having the same alkyl group as the ester moiety to be formed, and hydrocarbon solvents such as toluene and xylene. Usually, the above-mentioned alcohols and toluene are used.

The amount of the solvent used should be the minimum amount that allows stirring, and is usually used 5 to 20 times by weight based on the diaminopropionic acid derivative. Although it depends on the solvent used, when the temperature is low, a long time is required until the reaction is completed. Therefore, the reaction is preferably carried out at 40 ° C. or more, and more preferably at 50 to 70 ° C., from the viewpoint of reactivity and economy.
The time required for the reaction of the present invention varies depending on the reaction temperature and the type of solvent used, but is usually about 10 to 30 hours.

Crystallization: In the present invention, the reaction product is usually taken out by concentrating the solvent in the reaction solution, adding a poor solvent, and adding 3-amino-2- (N (Alkoxycarbonyl) aminopropionate / substituted benzenesulfonate is precipitated as crystals, and this is obtained by filtration.

The poor solvent is 3-amino-2- (N
-Alkoxycarbonyl) aminopropionate / substituted benzenesulfonate is not particularly limited as long as it is difficult to dissolve. Usually, hydrocarbon solvents such as hexane, heptane and toluene, tetrahydrofuran, tert
Ether solvents such as -butyl methyl ether and halogen solvents such as methylene chloride and chloroform are used. Among them, preferred are tert-butyl methyl ether and toluene. The poor solvent is used in an amount of 2 to 10 times the weight of the salt represented by the formula (1).

In this crystallization method, the product 3-
Amino-2- (N-alkoxycarbonyl) aminopropionic acid ester / substituted benzenesulfonate is easily soluble in water and alcohol, and when it is contained in the reaction solution, crystallization is significantly affected. Therefore, it is necessary to strictly control these contents during crystallization. That is, (1) when the reaction solution contains alcohol, the alcohol is distilled off, and the content after addition of the poor solvent is adjusted to 5% by weight or less. (2) When water is contained in the reaction solution due to the raw material or the reaction, reduce the water to 1% by weight or less. Examples of a method for achieving this include azeotropic dehydration with another solvent, use of a desiccant such as an inorganic salt or a resin, and an appropriate method may be used in some cases. By performing these operations, a crystal with good reproducibility and good properties can be obtained. A method of adding an appropriate amount of seed crystals during crystallization is also effective in shortening the crystallization time.

Use: The salt represented by the formula (1) is useful as an intermediate for pharmaceuticals and agricultural chemicals. For example, a process for producing a medicine represented by the above formula (4) using this salt as a raw material will be described below.

[0025]

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[0026]

The present invention will be described in more detail with reference to the following examples. (Example 1) 1.11 liter of methanol, (S)-
61.5 g of 3-amino-2- (Nn-butoxycarbonyl) aminopropionic acid and 61.7 g of methyl p-toluenesulfonate were charged into a two-liter four-necked flask, and refluxed (about 63 to 64 ° C.). ) For 20 hours. Next, after removing 1.09 liter of methanol from the reaction solution, the reaction solution was cooled to 25 ° C. To this, 0.40 liter of tert-butyl methyl ether was charged and stirred at room temperature for 2 hours. At this time, 1 g of a seed crystal was added to promote crystal growth. here,
The water content is 0.1% by weight or less, and the methanol content is 3.
It was 8% by weight.

The precipitated crystals were separated by filtration, washed with 0.1 liter of tert-butyl methyl ether, and then washed at 40 ° C.
Under reduced pressure to obtain 100 g of methyl (S) -3-amino-2- (Nn-butoxycarbonyl) aminopropionate / p-toluenesulfonate. The purity of the obtained crystals was 94%, and the yield was 85%.

Example 2 1.11 L of methanol, 61.5 g of (S) -3-amino-2- (Nn-butoxycarbonyl) aminopropionic acid, and p-
61.7 g of methyl toluenesulfonate was charged into a two-liter four-necked flask and reacted under reflux (about 63 to 64 ° C.) for 20 hours. Next, after distilling off 0.90 liter of methanol from the reaction solution, toluene 0.40
A liter was charged, and residual methanol was azeotropically distilled off with toluene, and it was confirmed that the methanol content was 2% by weight or less and the water content was 400 ppm. Next, the reaction solution was cooled to 30 ° C., and after adding 1 g of seed crystals, the reaction solution was cooled to 5 ° C. over 5 hours and aged for 2 hours. The precipitated crystals were separated by filtration, and tert-butyl methyl ether was added.
After washing with 0.1 liter, dried under reduced pressure at 40 ° C,
82.4 g of methyl (S) -3-amino-2- (Nn-butoxycarbonyl) aminopropionate / p-toluenesulfonate was obtained. The purity of the obtained crystals is 98
% And the yield was 70%.

Comparative Example 1 0.22 L of methanol, 12.3 g of (S) -3-amino-2- (Nn-butoxycarbonyl) aminopropionic acid, and p-
12.3 g of methyl toluenesulfonate is charged into a 500 ml four-necked flask and refluxed (about 63 to 6).
(4 ° C.) for 20 hours. Next, after distilling off 0.21 liter of methanol from the reaction solution, the reaction solution was cooled to 25 ° C. To this, 0.08 liter of tert-butyl methyl ether was charged and stirred at room temperature for 2 hours. At this time, the water content in the solution is 0.1% by weight or less,
The methanol content was 8.2% by weight.

Next, in order to promote crystal growth, a seed crystal
0.2 g was added. The precipitated crystals are filtered off and tert
After washing with 0.1 liter of -butyl methyl ether, the obtained crystals were sticky and had poor properties and were difficult to handle. The obtained crystals were dried at 40 ° C. under reduced pressure to obtain 95.0 g of methyl (S) -3-amino-2- (Nn-butoxycarbonyl) aminopropionate / p-toluenesulfonate. The purity of the obtained crystals is 8
5% and the yield was 70%.

Comparative Example 2 0.22 liter of methanol, 12.3 g of (S) -3-amino-2- (Nn-butoxycarbonyl) aminopropionic acid, and p-
12.3 g of toluenesulfonic acid monohydrate was charged into a 500 ml four-neck flask and refluxed (about 63
６４64 ° C.) for 24 hours. Next, 0.21 liter of methanol was distilled off from the reaction solution,
The reaction was cooled until. To this, 0.08 liter of tert-butyl methyl ether was charged. At this time, the water content was 1.2% by weight, and the methanol content was 3.6% by weight. Here, a seed crystal to promote crystal growth
0.2 g was added and the mixture was stirred at room temperature for 2 hours, but no crystals were precipitated. The mixture was further cooled to 5 ° C. and stirred for 4 hours, but did not crystallize.

[0032]

Industrial Applicability According to the present invention, it has become possible to industrially produce diaminopropionate sulfonic acid salts useful as intermediates for medicines and agricultural chemicals.

 ────────────────────────────────────────────────── ─── Continued on the front page (72) Inventor Ken Okamoto 1-1 Kurosaki Shiroishi, Yawatanishi-ku, Kitakyushu City, Fukuoka Prefecture Inside the Research Laboratory, Kurosaki Works, Mitsubishi Chemical Corporation

Claims (5)

[Claims] (1) Formula (1) (Wherein, R ¹ is a linear or branched alkyl group having 1 to 4 carbon atoms, R ² is an alkyl group which may be linear or branched having 1 to 5 carbon atoms, and R ³ is 1 to 4 carbon atoms. 5 represents an alkyl group, a halogen atom or a hydrogen atom which may contain a branch or a halogen atom.)
In a poor solvent containing (N-alkoxycarbonyl) aminopropionate / substituted benzenesulfonate, 3-
In a method for crystallizing an amino-2- (N-alkoxycarbonyl) aminopropionate / substituted benzenesulfonate, the content of water in a solvent is 1% by weight or less,
A crystallization method, wherein the crystallization is performed under the condition that the content of an alcohol having 1 to 4 carbon atoms is 5% by weight or less. 2. A method according to claim 1, wherein 3-amino-2- (N
-Alkoxycarbonyl) aminopropionic acid ester / substituted benzenesulfonate is represented by the formula (2): (Wherein, R ¹ represents a linear or branched alkyl group having 1 to 4 carbon atoms.) A 3-amino-2- (N-alkoxycarbonyl) aminopropionic acid derivative represented by the formula (3) ) (Wherein, R ² represents an alkyl group having 1 to 5 carbon atoms which may be linear or branched; R ³ represents an alkyl group having 1 to 5 carbon atoms which may contain a branched or halogen atom; A substituted benzenesulfonic acid derivative represented by a halogen atom or a hydrogen atom) with toluene, xylene, or the same alkyl group as the ester portion (R ¹ ) of the resulting salt represented by the formula (1). The crystallization method according to claim 1, which is obtained by reacting in a solvent such as an alcohol. 3. The crystallization method according to claim 1, wherein R ¹ is an n-butyl group, and R ² and R ³ are methyl groups. 4. The crystallization method according to claim 1, wherein tert-butyl methyl ether is used as the poor solvent. 5. The method according to claim 1, wherein toluene is used as the poor solvent.