JPWO1999033785A1 - Methods for producing β-halogeno-α-aminocarboxylic acids, phenylcysteine derivatives, and intermediates thereof - Google Patents

Abstract

(57) [Abstract] An industrially advantageous method for producing β-hydroxy-α-aminocarboxylic acids is provided. Also provided is a method for producing optically active N-protected-S-phenylcysteine and its intermediates having high optical purity using this production method. A method for producing β-halogeno-α-aminocarboxylic acids or salts thereof is disclosed, in which the hydroxyl group of a β-hydroxy-α-aminocarboxylic acid (wherein the basicity of the amino group at the α-position is not masked by the presence of a substituent on the amino group) or its salt with an acid is treated with a halogenating agent. Also disclosed is a method for producing optically active N-protected-S-phenylcysteine represented by general formula (3) or a salt thereof by applying the above production method to optically active serine or a salt thereof, followed by treatment with an amino group-protecting agent and reaction with thiophenol under basic conditions.

Description

TECHNICAL FIELD The present invention relates to a method for producing a β-halogeno-α-aminocarboxylic acid or a salt thereof, which is useful as a pharmaceutical raw material, etc. The present invention also relates to a method for producing optically active N-protected-S-phenyl-L-cysteine or a salt thereof, which is useful as an intermediate for pharmaceuticals, particularly anti-AIDS drugs, and an intermediate therefor.

BACKGROUND ART Conventionally, as a method for producing β-halogeno-α-aminocarboxylic acids, the following methods, for example, have been known.

β-Hydroxy-α-aminocarboxylic acid is converted into a β-hydroxy-α-aminocarboxylic acid ester, which is then treated with phosphorus halide to halogenate the hydroxyl group to form a β-halogeno-α-aminocarboxylic acid ester, and then the ester group is hydrolyzed using hydrohalic acid to convert it into a β-halogeno-α-aminocarboxylic acid. Specifically, serine is converted into serine methyl ester hydrochloride, which is then treated with phosphorus pentachloride to form α-amino-β-chloropropionic acid methyl ester hydrochloride, which is then hydrolyzed using hydrochloric acid to convert it into α-amino-β-chloropropionic acid hydrochloride. The resulting α-amino-β-chloropropionic acid hydrochloride is isolated by concentrating the reaction mixture to dryness and then crystallizing the concentrated residue from a mixture of 1-propanol and hydrochloric acid [see, for example, CHIRALITY 8:197-200 (
1996).

β-Phenylserine hydrate is treated with thionyl chloride and then with concentrated hydrochloric acid to give β-chloro-β-phenylalanine [Gazzetta
Chimica Italiana 119 (1989) p. 215].

However, in the above-mentioned method, when halogenating the hydroxyl group at the β-position, a three-step reaction is usually carried out, in which the carboxyl group is protected, the hydroxyl group at the β-position is halogenated, and then the carboxyl group is deprotected. In this case, there are many drawbacks, such as the multi-step process, complicated operation, and low yield.

Furthermore, in the above method, a large amount of thionyl chloride is used as a solvent,
Therefore, there are drawbacks such as complicated operations, etc. Furthermore, the inventors' investigations have revealed that it is difficult to apply this method to the chlorination of serine, threonine, etc.

Thus, up to now, no efficient industrial method for producing β-halogeno-α-aminocarboxylic acids has been established.

On the other hand, the following methods have been known as methods for producing optically active S-phenylcysteine derivatives.

<Methods of Derivation from Serine> 1) A method of reacting serine with thiophenol by the action of tryptophan synthase (EP 754759). 2) A method of lactonization of a serine derivative with an azodicarboxylic acid ester [Journal of the American Chemical Society (J. Am. C.)].
chem. Soc., 1985, vol. 107, p. 7105; Synth. Commun., 1995, 25(16)
2475] 3) After converting the hydroxyl group of the N-protected serine ester derivative into a sulfonyloxy group,
Substitution with a thiophenyl group [Tetrahedron Letters (Tetrahedron Letters)]
Ron Lett.), 1987, Vol. 28, p. 6069; ibid., 1993,
34, p. 6607; EP 604185 A1] <Method of Derivation from a Source Other Than Serine> 4) A method of reacting cysteine with a phenyldiazonium salt in the presence of a copper salt [J. Org. Chem., 1999, 14, 1999]
958, Vol. 23, p. 1251] 5) A method of deriving from an aziridinecarboxylic acid derivative in the presence of a boron trifluoride ethyl ether complex [Bulletin of the Chemical Society of Japan (
Bull. Chcm. Soc. Jpn), 1983, vol. 56, p. 520] 6) A method of reacting cysteine with iodobenzene in the presence of a copper salt [Aust. J. Chem, 1983, vol. 56, p. 520]
5, vol. 38, p. 899] 7) A method of reacting dehydroalanine with a chiral nickel complex [Tetrahedron, 1988, vol. 44, p. 5507] Optically active serine, especially L-serine, is an easily available compound, so if L-serine can be used as a starting material and efficiently converted to an optically active S-phenylcysteine derivative, it could become a practical manufacturing method. However, the method using an enzyme in 1) and the method via a lactone derivative in 2) have problems in operability, productivity, safety in handling the reagents used, and economy. In addition, method 3) has problems in N
After converting the hydroxyl group of the protected serine ester derivative to a sulfonyloxy group, N,N-
The method involves a substitution reaction with a sodium salt of thiol in dimethylformamide, but the base used is a reagent such as sodium hydride or potassium hydride, which is relatively difficult to handle.
It was found that the yield of S-phenylcysteine ester was not necessarily high, and there was a problem in particular in that the optical purity was reduced.

On the other hand, all of the methods 4) to 7) that derive from sources other than serine require a lot of waste disposal, use raw materials that require careful handling or are expensive, or have low yields and productivity, and therefore cannot be said to be industrially advantageous methods.

In view of the above-mentioned current situation, an object of the present invention is to provide an industrially advantageous method for producing a β-halogeno-α-aminocarboxylic acid, and an industrially advantageous method for producing an optically active S-phenylcysteine derivative from optically active serine that is easily available industrially.

SUMMARY OF THE INVENTION The present inventors have conducted extensive research into industrially advantageous methods for producing β-halogeno-α-aminocarboxylic acids and, as a result, have surprisingly discovered an industrially advantageous production method in which β-halogeno-α-aminocarboxylic acids can be efficiently synthesized by treating β-hydroxy-α-aminocarboxylic acids or salts thereof with an acid with a halogenating agent.

On the other hand, in order to efficiently produce an optically active S-phenylcysteine derivative from optically active serine, i.e., L- or D-serine, the key point is how to prevent a decrease in optical purity when thiophenylating a compound in which the hydroxyl group of optically active serine is activated as a leaving group. The present inventors have conducted extensive studies, thinking that if it is possible to synthesize a carboxylic acid derivative in which the hydroxyl group of optically active serine is appropriately activated as a leaving group, and to efficiently thiophenylate it, it may be possible to achieve the above-mentioned object while suppressing racemization in an industrially advantageous manner. As a result, the above-mentioned β-halogeno
It has been discovered that optically active β-chloroalanine can be efficiently synthesized by utilizing a method for producing α-aminocarboxylic acid. There has been no prior knowledge of obtaining optically active β-chloroalanine by direct chlorination of optically active serine or a salt thereof, and the production method is therefore novel.

In addition, the optically active β-chloroalanine obtained above can be converted into optically active N-protected β-chloroalanine by treating it with an amino group protecting agent.
The present inventors have also found that this compound can be converted to optically active N-protected-S-phenylcysteine by reacting it with thiophenol under basic conditions, thereby completing the present invention. In particular, by using the above three steps, an optically active N-protected-S-phenylcysteine derivative can be produced in an industrially advantageous manner without substantially decreasing the optical purity of the starting material, optically active L- or D-serine.

That is, the present invention relates to a method for producing a β-halogeno-α-aminocarboxylic acid or a salt thereof, which comprises treating a β-hydroxy-α-aminocarboxylic acid (wherein the basicity of the amino group at the α-position is not masked by the presence of a substituent on the amino group) or a salt thereof with an acid with a halogenating agent to halogenate the hydroxyl group.

The present invention also provides a method for producing a compound represented by the following formula (1): from optically active serine or a salt thereof with an acid according to the above production method. and then treating the optically active β-chloroalanine or a salt thereof represented by the following general formula (2): (wherein R ¹ represents an amino-protecting group; ^{R 0} represents a hydrogen atom or
^{1 together with 1} represent an amino group-protecting group.
The present invention also provides a method for producing chloroalanine or a salt thereof.

The present invention further relates to a method for producing optically active N-protected-β-chloroalanine or a salt thereof according to the above-mentioned production method, and then reacting the resulting product with thiophenol under basic conditions.
The following general formula (3): (wherein R ¹ represents an amino-protecting group; ^{R 0} represents a hydrogen atom or
^{1 together with 1} represent an amino group-protecting group.
The present invention also provides a method for producing phenylcysteine or a salt thereof.

The present invention will be described in detail below.

Detailed Disclosure of the Invention The β-hydroxy-α-aminocarboxylic acid used in the present invention is not particularly limited, but basically, one in which the basicity of the amino group is not blocked by the presence of a substituent such as an acyl-type amino group-protecting group is used. The β-hydroxy-α-aminocarboxylic acid is α-amino-β-hydroxypropionic acid (
The amino group has a basic skeleton (also called serine) in which one, two, or three of the three hydrogen atoms on the carbon chain other than the amino group, hydroxyl group, and carboxyl group in the basic skeleton may be substituted with other groups, as long as the substitution does not adversely affect the halogenation reaction. Furthermore, as described above, one or two of the hydrogen atoms of the amino group may be substituted with a substituent (e.g., an alkyl group, an aralkyl group, an aryl group, etc.), as long as the substitution does not adversely affect the halogenation reaction and does not impair its basicity.

Representative examples of β-hydroxy-α-aminocarboxylic acids include serine, threonine, allothreonine, β-phenylserine, etc. Salts of β-hydroxy-α-aminocarboxylic acids with acids are not particularly limited, and include:
Examples of salts include serine hydrochloride, threonine hydrochloride, allothreonine hydrochloride, and β-phenylserine hydrochloride. The salts may be prepared in advance and isolated, or may be prepared in a reaction vessel or generated during the reaction. When these β-hydroxy-α-aminocarboxylic acids are used, the products are β-halogeno-α-aminopropionic acid (i.e., β-halogenoalanine),
β-halogeno-α-aminobutyric acid, β-halogeno-β-phenyl-α-aminopropionic acid (i.e., β-halogenophenylalanine), etc.
The above β-hydroxy-α-aminocarboxylic acid may be optically active.

Examples of the halogenating agent used in the present invention include thionyl halides and phosphorus halides, specifically thionyl chloride, thionyl bromide, phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride, phosphorus tribromide, etc., but from the viewpoint of reaction yield and ease of handling, thionyl halides are preferred, and thionyl chloride is particularly preferred. The amount of the halogenating agent used is determined based on the amount of the substrate β-hydroxy-α
The amount of the β-hydroxy-α-aminocarboxylic acid or its salt with an acid is, for example, 1 to 10 times by mole, preferably 1 to 4 times by mole, and more preferably 1 to 2 times by mole. The amount is basically the number of moles per basic skeleton unit of the β-hydroxy-α-aminocarboxylic acid. For example, when the molecule contains a plurality of the basic skeleton units,
Alternatively, if the other substituent is or contains a group that consumes a halogenating agent, an increase of a corresponding equivalent amount may be necessary.

The treatment using a halogenating agent in the production method of the present invention is preferably carried out in a solvent. In this case, the solvent may be, for example, 1,2-dimethoxyethane, 1,4
- dioxane, tetrahydrofuran, diethylene glycol dimethyl ether,
Ether solvents such as triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, polyethylene glycol dimethyl ether, t-butyl methyl ether, dibutyl ether, diethyl ether, and other aprotic solvents such as acetonitrile, methylene chloride, and ethyl acetate are preferred. These may be used alone or in combination of two or more. Among these, ether solvents are preferred, and ether solvents that are compatible with water, such as 1,2-dimethoxyethane, 1,4-dioxane, tetrahydrofuran, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, and polyethylene glycol dimethyl ether, are particularly preferred. Needless to say, other solvents can be used in combination within the range that does not have an adverse effect.

The treatment using the halogenating agent can be carried out under the condition of adding an amine or a salt thereof. The amine or the salt thereof is not particularly limited, and examples thereof include triethylamine, trimethylamine, diisopropylethylamine, tetramethylethylenediamine, pyridine, dimethylaminopyridine, imidazole, triethylamine hydrochloride, trimethylamine hydrochloride, diisopropylethylamine hydrochloride, etc. Among them, tertiary amines such as trimethylamine and triethylamine or salts thereof are preferred, and triethylamine or its hydrochloride is more preferred.

The amount of the amine or salt thereof added is preferably 0.1 to 30 mol %, more preferably 1 to 10 mol %, based on the substrate β-hydroxy-α-aminocarboxylic acid or salt thereof.

In the present invention, a more preferred method for achieving a high reaction yield is to carry out the treatment with the above-mentioned halogenating agent, preferably thionyl chloride, in the presence of hydrogen halide, preferably hydrogen chloride (gas). The amount of hydrogen halide used is, for example, about 1 molar equivalent or more relative to the β-hydroxy-α-aminocarboxylic acid, preferably more than 2.0 molar equivalents, and more preferably about 3 molar equivalents or more. Generally, the treatment can be carried out extremely effectively when about 3 to 10 molar equivalents or more of hydrogen halide is used. As described above, the amount used is basically interpreted as the number of molar equivalents per basic skeleton unit of β-hydroxy-α-aminocarboxylic acid (note that a hydrohalide salt of β-hydroxy-α-aminocarboxylic acid corresponds to the presence of 1.0 molar equivalent of hydrogen halide relative to the β-hydroxy-α-aminocarboxylic acid). The hydrogen halide concentration in the reaction solution is, for example, about 1 mol or more per 1 L of solvent, preferably about 2 mol or more, and more preferably about 3 mol or more. The treatment can also be carried out effectively at a concentration below the saturated concentration of hydrogen halide in the reaction system. The above treatment can be carried out under the condition of adding an amine or a salt thereof.

A simple example of the reaction procedure will be specifically described. For example, a suspension of β-hydroxy-α-aminocarboxylic acid (e.g., L-serine) and 1,4-dioxane is nearly saturated or completely saturated with hydrogen chloride gas, and then thionyl chloride is added. After the addition is complete, the reaction mixture is stirred at room temperature to 100°C, preferably at 40 to 80°C,
A β-chloro-α-aminocarboxylic acid [for example, L-α-amino-β-chloropropionic acid (also called β-chloro-L-alanine)] can be produced by moderate to vigorous stirring, preferably for 0.5 to 30 hours, more preferably 1 to 20 hours.

The β-halogeno-α-aminocarboxylic acid obtained by the above halogenation may be isolated before use in the next step, or may be used as it is without isolation.

The above-mentioned β-halogeno-α-aminocarboxylic acid can be isolated by, for example, a method such as column chromatography, which is commonly used for isolating amino acids, but preferably, it can be isolated simply and efficiently by the following method.

When the β-halogeno-α-aminocarboxylic acid is isolated as its hydrohalide salt such as its hydrochloride, precipitation of the target product progresses as the treatment with the halogenating agent progresses (i.e., reactive crystallization progresses), and therefore, after the reaction, the target product can be collected very simply and in high yield by separating the product directly or by concentrating the reaction solution and using a general solid-liquid separation procedure such as filtration or centrifugation. Needless to say, during isolation, components with relatively low boiling points, such as sulfur dioxide, excess hydrogen halide such as hydrogen chloride, and unreacted halogenating agent such as thionyl halide remaining in the reaction solution after the halogenation reaction, can be reduced or removed in advance, if necessary.
The reaction solvent can also be recovered by concentrating the reaction solution.

When the β-halogeno-α-aminocarboxylic acid is isolated in a free state, the acid present in the reaction mixture after the halogenation reaction is oxidized with a base, preferably lithium hydroxide,
The β-halogeno-α-
The target product can be easily collected by precipitating the aminocarboxylic acid and dissolving the resulting salt in the medium, followed by separation using a common solid-liquid separation procedure such as filtration, centrifugation, etc. Since the conversion of the acid to the salt is generally preferably carried out in the presence of water, it is preferable to use an organic solvent that is compatible with water as the organic solvent, thereby reducing the amount of the water-soluble compound β-halogeno-α-aminocarboxylic acid dissolved, i.e., increasing the amount of precipitation.

Specific examples of the water-compatible organic solvent include 1,2-dimethoxyethane, 1,4-dioxane, tetrahydrofuran, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, polyethylene glycol dimethyl ether,
Examples of suitable solvents include, but are not limited to, acetonitrile, methanol, ethanol, n-propanol, isopropanol, t-butanol, acetone, etc. Among these, acetone is particularly preferred from the viewpoints of increasing the amount of precipitated β-halogeno-α-aminocarboxylic acid, which is a water-soluble compound, obtaining crystals with good properties, ease of handling, and low cost.

Since the β-halogeno-α-aminocarboxylic acid has a high solubility in water, in order to increase the amount of precipitation, the amount of coexisting water is reduced, the volume ratio of the water-compatible organic solvent to water is set to 1 or more, and the final cooling temperature is set to a low temperature, preferably 10
It is preferable to keep the temperature at or below 0° C., more preferably at or below 0° C. The coexistence of lithium chloride or the like tends to increase the solubility of the β-halogeno-α-aminocarboxylic acid, and in order to maximize the amount of precipitation, it is effective to use acetone in combination.

When precipitating the β-halogeno-α-aminocarboxylic acid, a basic lithium compound is added to convert the coexisting acid into a salt, and accordingly, the reaction solution is preferably adjusted to a weakly acidic to neutral range, specifically, to a value around the isoelectric point of the β-halogeno-α-aminocarboxylic acid. When the β-halogeno-α-aminocarboxylic acid is α-amino-β-halogenopropionic acid or α-amino-β-halogenobutyric acid, the pH is preferably adjusted to around 4 to 7.

A specific example of a simple procedure for isolating the above-mentioned β-halogeno-α-aminocarboxylic acid in a free state is as follows: after the halogenation reaction, preferably, components with relatively low boiling points, such as sulfur dioxide remaining in the reaction solution, excess hydrogen halide such as hydrogen chloride, and unreacted halogenating agent such as thionyl chloride, are reduced or removed in advance, and then the pH is adjusted at low temperature using a basic lithium compound such as lithium hydroxide or lithium carbonate, preferably lithium hydroxide, and a small amount (preferably a minimum amount) of water, and the precipitated β-halogeno-α-aminocarboxylic acid is isolated using a medium containing a water-compatible organic solvent, which is the solvent for the halogenation reaction, preferably a water-compatible ether as the main solvent. The resulting β-halogeno-α-carboxylic acid is collected, or after the halogenation reaction, components with relatively low boiling points, such as sulfur dioxide, excess hydrogen halide such as hydrogen chloride, and unreacted halogenating agent such as thionyl chloride, remaining in the reaction solution are reduced or removed in advance, and the reaction solvent is replaced with a small amount (preferably a minimum amount) of water at a low temperature. If necessary, treatment with an adsorbent such as activated carbon or filtration of insoluble matter is performed for the purpose of removing impurities or decolorization. Thereafter, the pH is adjusted at a low temperature using a basic lithium compound such as lithium hydroxide or lithium carbonate, preferably lithium hydroxide, and a small amount (preferably a minimum amount) of water, and the β-halogeno-α-carboxylic acid is extracted with the water-compatible organic solvent, preferably acetone, in combination.
The aminocarboxylic acid is sufficiently precipitated so that it can be collected.

Furthermore, when the β-halogeno-α-aminocarboxylic acid is subjected to the next step without isolation, it is preferable to reduce or remove in advance components with relatively low boiling points remaining in the reaction liquid after the halogenation reaction, such as sulfur dioxide, excess hydrogen halide such as hydrogen chloride, and unreacted halogenating agent such as thionyl chloride, and to replace the reaction solvent with water at low temperature, and, if necessary, adjust the pH with a base such as sodium hydroxide or lithium hydroxide.Furthermore, if necessary, for the purposes of removing impurities and decolorization, treatment with an adsorbent such as activated carbon or filtration of insoluble matter can be carried out, and the resulting aqueous liquid can be used as containing the β-halogeno-α-aminocarboxylic acid.

Next, a preferred method for purifying and isolating the above-mentioned β-halogeno-α-aminocarboxylic acid will be described. This method is a method for purifying and isolating the β-halogeno-α-aminocarboxylic acid in a free state. In the following method (1), a β-halogeno-α-aminocarboxylic acid can be used, and in the following method (2), a β-halogeno-α-aminocarboxylic acid or a salt thereof can be used. The salt of the β-halogeno-α-aminocarboxylic acid is preferably a hydrohalide salt such as a hydrochloride salt. Needless to say, the above-mentioned β-halogeno-α-aminocarboxylic acid can be optically active.

(1) A β-halogeno-α-aminocarboxylic acid is crystallized using water as a good solvent and a water-compatible organic solvent as a poor solvent. Preferably, the β-halogeno-α-aminocarboxylic acid is crystallized from an aqueous solution of the β-halogeno-α-aminocarboxylic acid in the presence of a water-compatible organic solvent. If necessary, treatment with an adsorbent such as activated carbon or filtration of insoluble matter can be combined for the purpose of removing impurities or decolorizing.

(2) Aqueous solutions containing β-halogeno-α-aminocarboxylic acid and hydrogen halide are converted into salts using a basic lithium compound such as lithium hydroxide or lithium carbonate to convert the (hydrogen halide) acid, and the β-halogeno-α-aminocarboxylic acid is precipitated in a free state using water as a good solvent and a water-compatible organic solvent as a poor solvent. Basically, the aforementioned technique for isolating β-halogeno-α-aminocarboxylic acid in a free state from a halogenation reaction solution can be utilized. Preferably, first, β-halogeno-α-aminocarboxylic acid or its salt (preferably a hydrohalide such as hydrochloride) is allowed to coexist with an aqueous solution of hydrohalic acid such as hydrochloric acid or water, and preferably dissolved. The pH is usually adjusted to:
It is preferable to set the pH to 3 or less, preferably 2 or less, to minimize the amount of water required for fluidization, preferably dissolution. Next, if necessary, treatment with an adsorbent such as activated carbon or filtration of insoluble matter is carried out for the purpose of removing impurities and decolorization. While adjusting the pH using a basic lithium compound such as lithium hydroxide or lithium carbonate, the hydrohalic acid is converted into a salt (lithium halide such as lithium chloride) soluble in organic solvents and water, and
A water-compatible organic solvent is used as a poor solvent to precipitate the β-halogeno-α-aminocarboxylic acid while leaving the salt unprecipitated, and then the salt is separated using a general solid-liquid separation procedure such as filtration or centrifugation. Alternatively, a β-halogeno-α-aminocarboxylic acid or its salt (preferably its hydrohalide salt such as hydrochloride) is first dissolved in a medium consisting of water or an aqueous solution of a hydrohalic acid such as hydrochloric acid and a water-compatible organic solvent. The pH after dissolution is usually 3 or less, preferably 2 or less. Next, if necessary, treatment with an adsorbent such as activated carbon or filtration of insoluble matter is carried out for the purpose of removing impurities and decolorization. The pH is adjusted using a basic lithium compound such as lithium hydroxide or lithium carbonate (if a hydrohalic acid is present, it is converted into a salt), and the β-halogeno-α-aminocarboxylic acid or its salt is then separated.
The aminocarboxylic acid is precipitated, and the salt (lithium halide such as lithium chloride) formed is not precipitated but remains, and is then separated using a general solid-liquid separation procedure such as filtration or centrifugation.

Specific examples of the water-compatible organic solvent used in the above (1) and (2) include 1,2-dimethoxyethane, 1,4-dioxane, tetrahydrofuran, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, polyethylene glycol dimethyl ether, acetonitrile, methanol, ethanol,
Examples of alcohols that can be used include, but are not limited to, n-propanol, isopropanol, t-butanol, acetone, etc. Among these, acetone is particularly preferred from the viewpoints of increasing the amount of precipitated β-halogeno-α-aminocarboxylic acid, which is a water-soluble compound, obtaining crystals with good properties, ease of handling, and low cost.

Since β-halogeno-α-aminocarboxylic acid has high solubility in water, in order to increase the amount of precipitation, it is preferable to reduce the amount of coexisting water, to set the volume ratio of the water-compatible organic solvent to water to 1 or more, and to maintain the final cooling temperature at a low temperature, preferably 10° C. or below, more preferably 0° C. or below. The coexistence of lithium chloride or the like tends to increase the solubility of β-halogeno-α-aminocarboxylic acid, and the use of acetone is effective in maximizing the amount of precipitation of β-halogeno-α-aminocarboxylic acid.

The pH during crystallization or precipitation of the β-halogeno-α-aminocarboxylic acid is preferably adjusted to a range from weakly acidic to neutral, specifically, to about the isoelectric point of the β-halogeno-α-aminocarboxylic acid. When the β-halogeno-α-aminocarboxylic acid is α-amino-β-halogenopropionic acid or α-amino-β-halogenobutyric acid, the pH is preferably adjusted to about pH 4 to 7.

The most preferred hydrohalic acid is hydrogen chloride (hydrochloric acid), and the most preferred basic lithium compound is lithium hydroxide or lithium carbonate, with lithium hydroxide being particularly preferred.

Since the β-halogeno-α-aminocarboxylic acid is not necessarily stable, it is preferable to pay attention to contact with bases, such as contacting with water or an aqueous medium at an acidic to neutral pH, etc. In general, it is preferable to handle it under acidic to neutral conditions, for example, at a pH of 7 or less, at low temperatures.

According to the method of the present invention, a β-halogeno-α-aminocarboxylic acid can be efficiently synthesized from a β-hydroxy-α-aminocarboxylic acid in a single reaction step, and a high-quality β-halogeno-α-aminocarboxylic acid or a salt thereof can be isolated in high yield. Furthermore, when this reaction is carried out using an optically active β-hydroxy-α-aminocarboxylic acid, an optically active β-halogeno-α-aminocarboxylic acid having the same configuration as the substrate can be obtained without substantial racemization and while maintaining its optical purity.

The optically active β-
To convert chloroalanine to optically active N-protected-S-phenylcysteine,
[0003] Two methods are considered: treatment with an amino group-protecting agent followed by thiophenylation; and thiophenylation followed by treatment with an amino group-protecting agent. However, the inventors' investigations have revealed that the method of treatment with an amino group-protecting agent followed by thiophenylation is preferable from the standpoints of yield and operability. The method of treatment with an amino group-protecting agent followed by thiophenylation does not provide a satisfactory yield, particularly because optically active β-chloroalanine is unstable under thiophenylation conditions.

The method for producing optically active N-protected-β-chloroalanine or a salt thereof of the above general formula (2) in the present invention comprises treating optically active serine or a salt of optically active serine and an acid with a chlorinating agent to produce optically active β-chloroalanine or a salt thereof, and then treating it with an amino group-protecting agent.
The reaction to obtain chloroalanine or a salt thereof can be carried out in the same manner as described above.

In the general formula (2), R ¹ represents an amino-protecting group. The amino-protecting group can be selected from the group consisting of the amino-protecting groups described in Protective Groups in Organic Synthesis, 2nd Edition.
sis. 2nd Ed.), Theodora W. Green (Theodora
W. Green, John Wiley & Sons
Examples of the protecting group include benzyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, t-butoxycarbonyl, acetyl, tosyl, benzoyl, and phthaloyl groups, as described in "Protein-Based Fluorescent Chemistry" (1990) by John Wiley & Sons. Although a (3S)-tetrahydrofuranyloxycarbonyl group and a 3-hydroxy-2-methylbenzoyl group in which the hydroxy group may be protected are also within the scope of the protecting group selection, the benzyloxycarbonyl group is preferred.

R ⁰ in the above general formula (2) usually represents a hydrogen atom, but may also represent an amino-protecting group such as a phthaloyl group together with R ¹ above.

The amino group-protecting agent is not particularly limited as long as it corresponds to the amino group-protecting group and is a common amino group-protecting agent, and examples thereof include benzyl chloroformate, ethyl chloroformate, methyl chloroformate, di-tert-butyl dicarbonate, benzoyl chloride, acetyl chloride, p-toluenesulfonyl chloride, phthalic anhydride, N-carbethoxyphthalimide, etc. In addition, (3S)-tetrahydrofuranyl chloroformate, 3-hydroxy-2-(2-methyl-2-propanol)-2-one whose hydroxyl group may be protected,
Methylbenzoyl chloride and the like are also within the scope of selection, with benzyl chloroformate being preferred among them.

The treatment with the amino group-protecting agent may be carried out using isolated optically active β-chloroalanine, but as described above, it is preferable to obtain an aqueous medium containing optically active β-chloroalanine and then treat this aqueous medium with the amino group-protecting agent to protect the amino group. In either case, a base is used, and examples of the base that can be used include sodium hydroxide and potassium carbonate. The treatment with the amino group-protecting agent can be carried out in either water and/or an organic solvent.

In this case, the solvent is not particularly limited, and examples thereof include 1,2-dimethoxyethane, 1,
Examples of solvents that can be used include ether solvents such as 4-dioxane, tetrahydrofuran, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, polyethylene glycol dimethyl ether, t-butyl methyl ether, dibutyl ether, and diethyl ether; and other aprotic solvents such as acetonitrile, methylene chloride, ethyl acetate, acetone, and toluene.

To be more specific, carbobenzyloxylation is taken as an example of the method for protecting the amino group. For example, a base such as sodium hydroxide or potassium carbonate is added to an aqueous medium containing optically active β-chloroalanine, preferably at a temperature of from 0°C to 30°C, more preferably at 5°C or lower, to maintain the pH at 8 to 13, preferably 9 to 12, more preferably 9 to 10, and then the reaction mixture is heated at a temperature of from 0°C to 30°C, more preferably at a temperature of from 0°C to 30°C, more preferably at 5°C or lower.
More preferably, benzyl chloroformate is added in an amount of 1 to 2 molar equivalents, preferably about 1.0 molar equivalent, relative to the substrate at 5° C. or less, and the reaction is carried out at a temperature of 1 to 2° C. at which the solvent does not freeze.
The reaction is carried out by stirring for preferably 1 to 30 hours at 30° C., more preferably at 5° C. or lower. If necessary, the reaction solution can be washed with an organic solvent that is immiscible with water or an aqueous medium, such as toluene, in order to remove unreacted benzyl chloroformate and by-produced benzyl alcohol.

The optically active N-protected-β-chloroalanine obtained as described above can be isolated, for example, by a conventional extraction procedure followed by column chromatography or the like.

The method for producing optically active N-protected-S-phenylcysteine or a salt thereof of the above general formula (3) in the present invention comprises treating optically active serine or a salt of optically active serine and an acid with a chlorinating agent to obtain optically active β-chloroalanine, then treating with an amino group protecting agent to produce optically active N-protected-β-chloroalanine or a salt thereof, and further reacting with thiophenol under basic conditions. In the above general formula (3), ^R0 and ^R1 are the same as the above-mentioned examples of ^R0 and ^R1 . In this production method, the reactions up to obtaining optically active N-protected-β-chloroalanine or a salt thereof can be carried out in the same manner as above.

The thiophenylation of the optically active N-protected-β-chloroalanine can be carried out using the optically active N-protected-β-chloroalanine isolated as described above. Alternatively, the thiophenylation can be carried out by adjusting the pH of the reaction solution after treatment with the amino group-protecting agent, adding thiophenol directly thereto, and carrying out the reaction in the reaction solution.

The step of reacting the optically active N-protected-β-chloroalanine with thiophenol can be carried out under basic conditions in water and/or an organic solvent. The organic solvent is not particularly limited, and examples thereof include ether solvents such as 1,2-dimethoxyethane, 1,4-dioxane, tetrahydrofuran, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, polyethylene glycol dimethyl ether, t-butyl methyl ether, dibutyl ether, and diethyl ether; and other aprotic solvents such as acetonitrile, methylene chloride, ethyl acetate, acetonitrile, and toluene.

The amount of thiophenol used is usually 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, per mole of optically active N-protected-B-chloroalanine.
More preferably, it is about 1.5 molar equivalents.

To carry out the thiophenylation under basic conditions, it is preferable to add an inorganic base as the base. The inorganic base is not particularly limited, and examples thereof include sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, and sodium hydroxide. An alkaline pH buffer can also be used.

The amount of the base used varies depending on the base used, but in the case of sodium hydroxide or sodium carbonate, for example, it is 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, per mole of optically active N-protected-β-chloroalanine.
The yield tends to decrease under strongly alkaline conditions due to side reactions. After the reaction is completed, the product can be isolated by, for example, acidifying the reaction mixture with hydrochloric acid, sulfuric acid, or the like, extracting it with an organic solvent such as ethyl acetate, concentrating it, and then subjecting it to column chromatography or the like.

The thiophenylation can be carried out by, for example, reacting optically active N-protected-β-chloroalanine with
Preferably, the thiophenylation can be carried out by adding a base such as sodium hydroxide or sodium carbonate to a solution of 5 to 30 w/v % water at a temperature of 0 to 30° C. to adjust the pH to preferably 9 to 11, and then adding 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, of thiophenol relative to the optically active N-protected-β-chloroalanine, followed by stirring at a temperature of preferably 30 to 90° C., more preferably 40 to 70° C. The order of addition of the reagents is not necessarily limited to the above, and the thiophenylation can also be carried out by, for example, adding a base to an aqueous solution of thiophenol and optically active N-protected-β-chloroalanine, or by simultaneously adding thiophenol and a base to an aqueous solution of optically active N-protected-β-chloroalanine.

In the production method of the present invention, the three steps of treating optically active serine or a salt of optically active serine and an acid with a chlorinating agent, treating the obtained optically active β-chloroalanine with an amino group-protecting agent, and reacting the obtained optically active N-protected β-chloroalanine with thiophenol under basic conditions are carried out without isolating the intermediate product, thereby enabling the optically active N-protected-S-phenylcysteine derivative to be obtained simply and efficiently.Furthermore, the two steps of treating optically active β-chloroalanine with an amino group-protecting agent and reacting the obtained optically active N-protected β-chloroalanine with thiophenol under basic conditions can also be carried out without isolating the intermediate product.

The optically active N-serine obtained from the optically active serine or a salt thereof by the production method of the present invention
Protected-S-phenylcysteine was obtained in a yield of 98% e.e. without purification such as crystallization.
In other words, according to the method of the present invention, optically active N-protected-S-phenylcysteine having the same configuration as the substrate can be obtained from optically active serine or a salt thereof without substantial racemization and while maintaining the optical purity.

The optically active N-protected-S-phenylcysteine obtained by the present invention, particularly N-
Carbobenzyloxy-S-phenyl-L-cysteine is a compound that is very useful as an intermediate for, for example, HIV protease inhibitors (WO9532185).

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be explained in more detail below by way of examples, but the present invention is not limited to these examples.

Example 1: Preparation of B-chloro-L-alanine hydrochloride. 5.0 g (0.0476 mol) of L-serine was added to 50 ml of 1,4-dioxane, and hydrogen chloride gas was introduced into the solution while stirring at room temperature. At this time, the amount of hydrogen chloride in the solution was 14.5 g (0.3977 mol). 12.5 g (0.1051 mol) of thionyl chloride was slowly added to the solution, and the internal temperature was raised to 50°C.
The temperature was adjusted to °C. After stirring for about 6 hours, the solution was concentrated to about half its volume. The concentrated solution was cooled to 0 to 10 °C, and 50 ml of water was slowly added to maintain this temperature. HPLC analysis of this solution revealed that 6.9 g (0.0431 mol) of β-chloro-L-alanine hydrochloride had been produced (production yield: 91 mol%).

Example 2: Preparation of β-chloro-L-alanine hydrochloride. 5.0 g (0.0476 mol) of L-serine was added to 50 ml of 1,4-dioxane, and hydrogen chloride gas was introduced into the solution with stirring at room temperature. At this time, the amount of hydrogen chloride in the solution was 11.2 g (0.3072 mol). 6.2 g (0.0521 mol) of thionyl chloride was slowly added to the solution, and the internal temperature was raised to 45°C.
The temperature was adjusted to °C. After stirring for about 20 hours, the solution was concentrated to about half its volume. The concentrated solution (slurry) was filtered, and the cake was washed with 10 ml of 1,4-dioxane. The wet crystals were dried under reduced pressure (40 °C, 10 mmHg or less) to obtain dry crystals. The obtained crystals were analyzed by HPLC, and the yield of pure β-chloro-L-alanine hydrochloride was found to be 7.2 g (0.0450 mol).

IR, ¹ H-NMR, ¹³ C-N of the obtained β-chloro-L-alanine hydrochloride
The MR was completely consistent with that of β-chloro-L-alanine hydrochloride from Aldrich.

Example 3: Preparation of β-chloro-L-alanine. The milky white crystals obtained in the same manner as in Example 2 (purity 95.2% by weight, containing 3.6 g, 0.0225 mol as β-chloro-L-alanine hydrochloride) were dissolved in 14 ml of water.
The mixture was added to 1 L of water and slurried. About 2 g of concentrated hydrochloric acid was slowly added to the slurry to completely dissolve it. 0.1 g of 50% activated carbon was added to the solution, and the mixture was stirred at room temperature for about 1
The mixture was stirred for 10 minutes, and the activated carbon was filtered under reduced pressure and washed with 1 ml of water to obtain a filtrate.
The filtrate was cooled to 0-10°C, and then, while maintaining the temperature, a saturated aqueous solution of lithium hydroxide was slowly added to adjust the pH to 5.5, forming a slurry. 42 ml of acetone was slowly added to the slurry to precipitate sufficient crystals, and then -
The mixture was cooled to 10 to 0°C and kept at this temperature for about 1 hour. The precipitated crystals were filtered and mixed with 14 ml of acetone.
The cake was washed with 10 ml of ethanol to obtain wet crystals. The wet crystals were dried under reduced pressure (40°C, 10 ml
The crystals were subjected to a pressure of 1000 kJ/min (less than 1000 kJ/min) to obtain 2.65 g of white crystals of β-chloro-L-alanine. HPLC analysis of the crystals revealed that the purity was 99.9% by weight, and the pure amount of β-chloro-L-alanine was 2.65 g (0.0214 mol).

The optical purity of the obtained β-chloro-L-alanine was determined by HPLC as described below.
The result of measurement by C analysis was 99.9% ee or more.

<Analysis conditions> Column: Tosoh TSK-Gel Enantio L1 (4.6 mm x 250
mm) Mobile phase: 0.5 M aqueous _CuSO4 solution/acetonitrile = 80/20 Column temperature: 40°C Detection wavelength: 254 nm Flow rate: 1.0 ml/min Retention time β-chloro-L-alanine 9.3 min β-chloro-D-alanine 7.8 min Example 4 Preparation of β-chloro-L-alanine 30.0 g (0.2855 mol) of L-serine was dissolved in 600 ml of 1,4-dioxane.
Hydrogen chloride gas was introduced into the solution added to the flask at room temperature while stirring.
The amount of hydrogen chloride in the liquid was 133.1 g (3.6508 mol). 40.8 g (0.3426 mol) of thionyl chloride was slowly added to this liquid, and the internal temperature was then adjusted to 40° C. After stirring for approximately 20 hours, this liquid (slurry) was concentrated to approximately half its volume. This concentrated liquid (slurry) was cooled to 0-10° C., and 200 ml of water was slowly added while maintaining this temperature to dissolve the precipitate. This liquid was further concentrated to approximately 200 g, and then 3.0 g of 50% hydrated activated carbon was added, and
The mixture was stirred at room temperature for about 10 minutes. The activated carbon was filtered under reduced pressure and washed with 10 ml of water. The filtrate was then concentrated to about 120 g.
After cooling to ° C., saturated aqueous lithium hydroxide solution was slowly added while maintaining this temperature, adjusting the pH to 5.5 and forming a slurry. 600 ml of acetone was slowly added to this slurry to precipitate sufficient crystals, and then the mixture was cooled to -10 to 0 ° C. and maintained for about 1 hour. The precipitated crystals were filtered under reduced pressure and the cake was washed with 100 ml of acetone to obtain wet crystals. The wet crystals were dried under reduced pressure (40 ° C., 10 mmHg or less) to obtain 32.6 g of β-chloro-L-alanine crystals. The crystals were analyzed by HPLC.
Analysis revealed that the purity was 99.8% by weight and the pure amount of β-chloro-L-alanine was 3
The weight was 2.5 g (0.2625 mol).

Example 5: Preparation of β-chloro-D-alanine hydrochloride. 5.0 g (0.0476 mol) of D-serine was added to 50 ml of 1,4-dioxane, and hydrogen chloride gas was introduced into the solution with stirring at room temperature. At this time, the amount of hydrogen chloride in the solution was 11.5 g (0.3154 mol). 6.2 g (0.0521 mol) of thionyl chloride was slowly added to the solution, and the internal temperature was raised to 45°C.
The temperature was adjusted to °C. After stirring for about 20 hours, the solution was concentrated to about half its volume. The concentrated solution (slurry) was filtered, the cake washed with 10 ml of 1,4-dioxane, and the wet crystals were dried under reduced pressure (40 °C, 10 mmHg or less) to obtain dry crystals. The obtained crystals were analyzed by HPLC, and the yield of pure β-chloro-D-alanine hydrochloride was found to be 7.0 g (0.0438 mol). The optical purity of the thus obtained β-chloro-D-alanine hydrochloride was measured in the same manner as in Example 3 and was found to be 99.9% ee or more.

Example 6: Preparation of β-chloro-L-alanine hydrochloride. 5.0 g (0.0476 mol) of L-serine was dissolved in 50 ml of the reaction solvent shown in Table 1.
Hydrogen chloride gas was introduced into the solution at room temperature while stirring to saturate the hydrogen chloride. 12.5 g (0.1051 mol) of thionyl chloride was slowly added to this solution, and the mixture was reacted under the conditions shown in Table 1. The reaction solution (slurry) was then concentrated to approximately half its volume. The concentrated solution was cooled to 0-10°C, and 50 ml of water was slowly added while maintaining this temperature. This solution was analyzed by HPLC to determine the yield of β-chloro-L-alanine hydrochloride. The results are shown in Table 1.

Example 7: Preparation of (αS,βR)-α-amino-β-hydroxybutyric acid hydrochloride. 10.14 g (0.0851 mol) of L-threonine was dissolved in 1,4-dioxane.
Hydrogen chloride gas was introduced into the solution, which had been added to 100 ml of ethanol at room temperature while stirring. At this time, the amount of hydrogen chloride in the solution was 15.5 g (0.4251 mol). 12.2 g (0.1022 mol) of thionyl chloride was slowly added to the solution, and then
The internal temperature was adjusted to 50°C. After stirring for about 10 hours, the solution was concentrated to about half its volume. The concentrated liquid (slurry) was filtered, the cake was washed with 20 ml of 1,4-dioxane, and the wet crystals were dried under reduced pressure (40°C, 10 mmHg or less) to obtain dry crystals. The obtained crystals were analyzed by HPLC, and the yield of pure (αS,βR)-α-amino-β-hydroxybutyric acid hydrochloride was 12.2 g (0.0701
mol). [α] _D ²⁰ +16.1° (c=1.0, water) (lit. [
α] _D ²⁰ +17.8° (c=1.0, water) [CHIRALITY 9,656
~660, (1997)].

Example 8: Preparation of (αS,βR)-α-amino-β-hydroxybutyric acid. Milky white crystals [purity 94.9% by weight, (αS,
βR)-α-amino-β-hydroxybutyric acid hydrochloride 5.0 g, 0.0287
The resulting mixture (containing 100 mol) was added to 19 ml of water to form a slurry. Approximately 2.8 g of concentrated hydrochloric acid was slowly added to the slurry to completely dissolve it. 0.05 g of 50% hydrous activated carbon was added to the solution.
1 g of activated carbon was added and stirred at room temperature for approximately 10 minutes. The activated carbon was filtered under reduced pressure and washed with 1 ml of water to obtain a filtrate. After cooling the filtrate to 0-10°C, saturated aqueous lithium hydroxide solution was slowly added while maintaining the temperature to adjust the pH to 5.5, forming a slurry. 58 ml of acetone was slowly added to the slurry, and the pH was adjusted to 5.5.
After sufficient crystallization, the mixture was cooled to -10 to 0°C and maintained for approximately 1 hour. The precipitated crystals were filtered, and the cake was washed with 19 ml of acetone to obtain wet crystals. The wet crystals were dried under reduced pressure (40°C, 10 mmHg or less) to obtain 3.75 g of white crystals of (αS, βR)-α-amino-β-chlorobutyric acid. HPLC analysis of the crystals revealed a purity of 99.8% by weight, and the pure amount of (αS, βR)-α-amino-β-chlorobutyric acid was 3.74 g (0.02272 mol). mp 176°C (dec
omp) (lit,mp 176°C (decomp) ["Pharmaceutical Research", 33, 4
28-437, (1961)].

The IR and ^1H -N spectra of the obtained (αS,βR)-α-amino-β-chlorobutyric acid crystals were
MR and ¹³ C-NMR were performed using (αS, βR)-α
The crystal structure was completely identical to that of β-amino-β-chlorobutyric acid crystals.

Reference Example 1 : Alternative Synthesis of (αS,βR)-α-Amino-β-Chlorobutyric Acid: Threonine was converted to threonine methyl ester hydrochloride using thionyl chloride and methanol, which was then treated with thionyl chloride to give α-amino-β-chlorobutyric acid methyl ester hydrochloride, which was then hydrolyzed with hydrochloric acid to give α-amino-β-chloropropionic acid hydrochloride. The resulting α-amino-β-chloropropionic acid hydrochloride was crystallized and isolated in the same manner as in Example 8.

Example 9: Preparation of β-chloro-L-alanine hydrochloride. 6.7 g (0.0473 mol) of L-serine hydrochloride was dissolved in 50 mL of 1,4-dioxane.
6.8 g (0.0572 mol) of thionyl chloride was added to the solution in ml at room temperature.
After slowly adding the above, the internal temperature was adjusted to 60°C. After stirring for about 3 hours, the solution was concentrated to about half its original volume. The concentrated solution was cooled to 0-10°C, and 50 ml of water was slowly added while maintaining this temperature. When the solution was analyzed by HPLC, 4.6 g (0.0287 m) of β-chloro-L-alanine hydrochloride was found to be present.
It was confirmed that 61 mol % of tetrahydrofuran (2,3-diol) was produced (production rate: 61 mol %).

Comparative Example 1 20.0 g (0.1903 mol) of L-serine was dissolved in 49.8 g (0.1903 mol) of thionyl chloride.
The mixture was added to a solution of 100 ml of β-chloro-L-alanine (4187 mol), heated to 60° C., and stirred for 6 hours. After hydrolysis, the solution was analyzed by HPLC. No peak for β-chloro-L-alanine was observed, but peaks for unreacted L-serine and various impurities were observed.

Comparative Example 2 15.0 g (0.1427 mol) of L-serine was added to 150 ml of toluene,
Hydrogen chloride gas was bubbled into the solution at room temperature until it was saturated. 37.0 g of thionyl chloride was added to the solution.
After adding 14.4 g (0.3140 mol), the mixture was heated to 80°C and stirred for 20 hours. After hydrolysis of this solution, HPLC analysis revealed various impurity peaks, with only a trace of β-chloro-L-alanine peak. (The reaction solution contained tar-like substances and was colored pitch black.) Comparative Example 3: 15.0 g (0.1427 mol) of L-serine was added to 150 ml of methylene chloride, and hydrogen chloride gas was blown in at room temperature to saturate the mixture. 3 g of thionyl chloride was added to this solution.
After adding 7.4 g (0.3140 mol) of N-carbobenzyloxy-β-chloro-L-alanine, the mixture was heated to 40°C and stirred for 16 hours. After hydrolysis of this solution, HPLC analysis revealed various impurity peaks, with only a trace of β-chloro-L-alanine peak. (The reaction solution contained tar-like substances and was colored pitch black.) Example 10: Preparation of N-carbobenzyloxy-β-chloro-L-alanine. 0.4 g (2.84 mmol) of L-serine hydrochloride and 0.02 g of triethylamine were added.
9 g (0.28 mmol) of thionyl chloride was suspended in 4 ml of diethylene glycol dimethyl ether, and the suspension was heated at room temperature under a nitrogen gas atmosphere with 0.67 g (5.68 mmol) of thionyl chloride.
After stirring at 60°C for 2 hours, 8 ml of water was added while maintaining the temperature of the reaction solution at 15°C or below, and the mixture was stirred at room temperature for 30 minutes.
After adjusting the pH to around 10, 0.956 g (5.68 g) of benzyl chloroformate was added.
After standing overnight at room temperature, the mixture was washed with ethyl acetate, and the resulting aqueous layer was ice-cooled, acidified with 50% sulfuric acid, and extracted with ethyl acetate. The solvent was evaporated, and the residue was purified by column chromatography to obtain 0.3 g (1.16 mmol, 41%) of N-carbobenzyloxy-β-chloro-L-alanine.

^1H NM of the obtained N-carbobenzyloxy-β-chloro-L-cysteine
The R and IR results were as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 3.85-4.06
(m, 2H), 4.80-4.82 (m, 1H), 5.14 (s, 2H), 5.
70 (d, J=7.8Hz, 1H), 7.36 (s, 5H) IR (neat) 3034, 1720, 1516, 1456, 1203, 106
6,855,754,698 (cm ⁻¹ ) Example 11 Preparation of N-carbobenzyloxy-β-chloro-L-alanine 0.4 g (2.84 mmol) of L-serine hydrochloride and 0.02 g of triethylamine were dissolved.
9 g (0.28 mmol) of the suspension was suspended in 4 ml of 1,2-dimethoxyethane, and 0.67 g (5.68 mmol) of thionyl chloride was added dropwise at room temperature under a nitrogen gas atmosphere. After stirring at 60°C for 2 hours, 8 ml of water was added while maintaining the reaction solution at 15°C or below, and the mixture was stirred at room temperature for 30 minutes. Further, 1.6 g of potassium carbonate was added to adjust the pH
= 10, and then 0.956 g (5.68 mmol) of benzyl chloroformate
The mixture was left at room temperature overnight, then cooled on ice and acidified with 50% sulfuric acid. HPLC analysis of the resulting solution revealed that N-carbobenzyloxy-β-chloro-L-alanine was obtained in a yield of 42% (1.18 mmol). The analytical conditions are as follows:

Analysis conditions (N-carbobenzyloxy-β-chloro-L-alanine/N-carbobenzyloxy-L-serine) Column: YMC-Pack ODS-A A-303 (250 mm x 4.6 m
Mobile phase: phosphate buffer (pH 3.0):acetonitrile = 60:40. Flow rate: 1.0 ml/min. Sample injection volume: 20 μl. Sample solvent: acetonitrile. Retention times: 6.2 min (N-carbobenzyloxy-β-chloro-L-alanine) 3.9 min (N-carbobenzyloxy-L-serine). Example 12 : Preparation of N-carbobenzyloxy-β-chloro-L-alanine. 0.1 g (0.71 mmol) of L-serine hydrochloride and 7.2 m triethylamine were dissolved in 100 ml of acetonitrile.
g (0.07 mmol) of the suspension was suspended in a solvent consisting of 1 ml of acetonitrile/0.1 ml of diethylene glycol dimethyl ether, and 0.167 g (1.42 mmol) of thionyl chloride was added dropwise at room temperature under a nitrogen gas atmosphere. After stirring at 60°C for 2 hours, 2 ml of water was added while keeping the temperature of the reaction solution below 15°C, and the mixture was stirred at room temperature for 3 hours.
The mixture was stirred for 10 minutes. 0.4 g of potassium carbonate was added to adjust the pH to about 10, and then 0.239 g (1.52 mmol) of benzyl chloroformate was added dropwise. The mixture was left overnight at room temperature, then cooled on ice, and acidified with 50% sulfuric acid. HPLC analysis of the resulting solution was carried out in the same manner as in Example 11, and the yield was 34% (0.24 mmol).
ol) to give N-carbobenzyloxy-β-chloro-L-alanine.

Example 13 Preparation of N-carbobenzyloxy-S-phenyl-L-cysteine 0.108 g (0.42
mmol) was dissolved in 0.5 ml of water, and then 0.097 g (
Then, 0.054 g (0.50 mmol) of thiophenol was added dropwise under a nitrogen gas atmosphere at room temperature. After stirring at 60° C. for 2 hours, the mixture was cooled on ice and acidified with 1N hydrochloric acid. After extraction with ethyl acetate, the solvent was distilled off and the mixture was purified by column chromatography to give N-carbobenzyloxy-S-phenyl-
0.112 g (0.34 mmol, 81%) of L-cysteine was obtained. The optical purity of the obtained compound was 98% e.e. or higher. The optical purity was determined using HPLC. The analytical conditions are as follows:

Optical purity analysis conditions (N-carbobenzyloxy-S-phenyl-L-cysteine/N-carbobenzyloxy-S-phenyl-D-cysteine) Column: DAICEL CHIRALPAK AS (250 mm x 4.6 mm)
Mobile phase: (hexane/t-butyl methyl ether/trifluoroacetic acid=800/
200/2):ethanol = 85:15 Flow rate: 1.2 ml/min Sample injection volume: 10 μl Temperature: 35°C Sample solvent: (hexane/t-butyl methyl ether/trifluoroacetic acid = 8
00/200/2):ethanol = 80:20 Retention time: 4.5 min (N-carbobenzyloxy-S-phenyl-L-cysteine) 5.6 min (N-carbobenzyloxy-S-phenyl-D-cysteine) ¹ H NMR of the obtained N-carbobenzyloxy-S-phenyl-L-cysteine
The R and IR results were as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm); 3.41 (dd, J
=5.1, 14.2Hz, 2H), 4.61-4.63(m, 1H), 5,07
(s, 2H), 5.56 (d, J=7.3Hz, 1H), 7.17-7.55 (
m, 10H) IR (neat) 3036, 1686, 1532, 1281, 1059, 737
(cm ⁻¹ ) Example 14 Preparation of N-carbobenzyloxy-S-phenyl-L-cysteine N-carbobenzyloxy-β-chloro-L-alanine 0.091 g (0.35
(mmol) was dissolved in 0.45 ml of water, and then 0.06 mmol of sodium bicarbonate was added.
5 g (0.77 mmol) of N-carbobenzyloxy-S-phenyl-L-cysteine was added. Subsequently, 0.046 g (0.42 mmol) of thiophenol was added dropwise under a nitrogen gas atmosphere at room temperature, and the mixture was stirred at 60°C for 2 hours, then cooled on ice and acidified with 1N hydrochloric acid. After extraction with ethyl acetate, the solvent was distilled off and the mixture was purified by column chromatography to obtain 0.097 g (0.29 mmol, 84%) of N-carbobenzyloxy-S-phenyl-L-cysteine. As a result of HPLC analysis using the same method as in Example 13, the optical purity of the obtained product was 98% e.e. or higher.

Example 15 Preparation of N-carbobenzyloxy-S-phenyl-L-cysteine 0.137 g (0.53%) of N-carbobenzyloxy-β-chloro-L-alanine
After dissolving 0.68 ml of thiophenol (1 mmol) in water, 0.58 ml of 2N aqueous sodium hydroxide solution was added.
After stirring at 60°C for 2 hours, the mixture was cooled on ice and acidified with 1N hydrochloric acid. After extraction with ethyl acetate and distillation of the solvent, the mixture was purified by column chromatography to give N-carbobenzyloxy-S-phenyl-
0.107 g (0.32 mmol, 61%) of L-cysteine was obtained. HPLC analysis in the same manner as in Example 13 revealed that the optical purity of the obtained product was 98%.
% e.e. or more.

Example 16: Preparation of N-carbobenzyloxy-S-phenyl-L-cysteine. 10.0 g (70.6 mmol) of L-serine hydrochloride and 0.0 g of triethylamine were mixed.
73g (7.1mmol) of diethylene glycol dimethyl ether 100ml
The mixture was dissolved in 16.8 g (141.2 m) of thionyl chloride at room temperature under a nitrogen gas atmosphere.
After stirring at 60°C for 2 hours, 200 ml of water was added while maintaining the temperature of the reaction system at 15°C or below, and the mixture was stirred at room temperature for 30 minutes. Furthermore, 50 g of potassium carbonate was added to adjust the pH to around 10, and then 17.9 g (1 mol) of benzyl chloroformate was added dropwise.
After allowing the mixture to stand overnight at room temperature, 10 g of potassium carbonate was added again to adjust the pH to around 10, and then 10.7 g (97.1 mmol) of thiophenol was added dropwise at room temperature under a nitrogen gas atmosphere. After stirring at 60°C for 2 hours, the mixture was ice-cooled and acidified with 50% sulfuric acid. After extraction with ethyl acetate and distillation of the solvent, purification by column chromatography yielded 8.7 g (26.2 mmol, 37%) of N-carbobenzyloxy-S-phenyl-L-cysteine. HPLC analysis using the same method as in Example 13 showed that the optical purity of the obtained product was 98%.
% e.e. or more.

Example 17 Preparation of N-carbobenzyloxy-S-phenyl-L-cysteine 15.7 g (98.1 mmol) of β-chloro-L-alanine hydrochloride was dissolved in 160 ml of water.
The internal temperature was cooled to 0 to 5°C, and with strong stirring, about 36 g of a 30 wt% aqueous solution of sodium hydroxide was added dropwise to adjust the pH to 10.
While maintaining the temperature at 200°C, 20.5 g (120.0 mmO) of benzyl chloroformate was added under vigorous stirring.
After adding dropwise the solution of 1) over 1 hour, stirring was continued for 4 hours.
About 16 g of a t% aqueous solution of sodium hydroxide was added dropwise to adjust the pH of the reaction solution to 9.5 to 10.
The temperature was maintained at 0.5. The N-carbobenzyloxy-β-chloro-L
The amount of alanine was determined by HPLC to be 25.1 g (97.5 mmol).

To the resulting reaction mixture, 22.0 g (20%) of thiophenol was added under a nitrogen atmosphere with vigorous stirring.
During this time, about 200 ml of a 30 wt % aqueous solution of sodium hydroxide was added dropwise.
6 g of HCl was added dropwise to maintain the pH of the reaction solution at 9.7 to 10.3.
The internal temperature was raised to 50° C., and the reaction was carried out for 3.5 hours. During this time, about 1 g of a 30 wt % aqueous solution of sodium hydroxide was added dropwise to maintain the pH of the reaction solution at 9.7 to 10.3.
To the resulting reaction solution, about 20 g of concentrated hydrochloric acid was slowly added dropwise over 3 hours under nitrogen atmosphere with vigorous stirring, and the pH of the slurry was adjusted to 3. The precipitated crystals of N-carbobenzyloxy-S-phenyl-L-cysteine were filtered under reduced pressure, washed twice with 100 ml of water, and thoroughly drained to obtain wet crystals of N-carbobenzyloxy-S-phenyl-L-cysteine [net content of N-carbobenzyloxy-S-phenyl-L-cysteine: 29%].
.8 g (89.9 mmol)] was obtained.
The optical purity of phenyl-L-cysteine was 99.9% e.e.

Comparative Example 4 : Preparation of S-phenyl-L-cysteine 2.23 g (0.0042 mol) of 20 wt % aqueous sodium carbonate solution was added to 0.97 g (0.0088 mol) of thiophenol, and the mixture was stirred at room temperature for 0.5 hours.
A solution consisting of 20 wt % sodium carbonate and water was added and reacted for 5 hours. During this time, the pH of the reaction solution was adjusted by adding 5.14 g (0.0097 mol) of a 20 wt % aqueous solution of sodium carbonate.
The H was maintained at 8 to 10. To the resulting reaction solution, 30 ml of toluene was added under a nitrogen atmosphere.
20 ml of water and about 3 g of concentrated hydrochloric acid were added to adjust the pH to 0.5. After separating the organic layer, the aqueous layer was washed twice with 30 ml of toluene to remove residual thiophenol, yielding 34.3 g of an aqueous solution of S-phenyl-L-cysteine.

The resulting aqueous solution was analyzed by HPLC, revealing that the yield of pure S-phenyl-L-cysteine was 0.45 g (0.0023 mol, yield 26.0%) and that β-chloro-L-alanine had been significantly decomposed.

INDUSTRIAL APPLICABILITY The present invention has the above-mentioned constitution, and therefore, it is possible to obtain β-halogenated ...
α-Aminocarboxylic acids and optically active N-protected α-aminocarboxylic acids useful as pharmaceutical intermediates
It is now possible to produce S-phenylcysteine and its intermediates simply and efficiently on a commercial scale by an industrially advantageous method.

[Procedure Amendment] Submission of a copy of amendments under Article 34 of the Patent Cooperation Treaty

[Submission date] November 8, 1999 (11.8.1999)

[Procedural Correction 1]

[Name of document to be corrected] Statement

[Item to be amended] Claims

[Correction method] Change

[Correction details]

[Claims]

[Procedural Correction 2]

[Name of document to be corrected] Statement

[Item name to be corrected] 0022

[Correction method] Change

[Correction details]

[0022] Example 7: Preparation of (αS,βR)-α-amino-β-chlorobutyric acid hydrochloride. 10.14 g (0.0851 mol) of L-threonine was dissolved in 1,4-dioxane.
Hydrogen chloride gas was introduced into the solution, which had been added to 100 ml of ethanol at room temperature while stirring. At this time, the amount of hydrogen chloride in the solution was 15.5 g (0.4251 mol). 12.2 g (0.1022 mol) of thionyl chloride was slowly added to the solution, and then
The internal temperature was adjusted to 50°C. After stirring for about 10 hours, the solution was concentrated to about half its volume. The concentrated liquid (slurry) was filtered, the cake was washed with 20 ml of 1,4-dioxane, and the wet crystals were dried under reduced pressure (40°C, 10 mmHg or less) to obtain dry crystals. The obtained crystals were analyzed by HPLC, and the yield of pure (αS,βR)-α-amino-β-chlorobutyric acid hydrochloride was 12.2 g (0.0701 m
ol). [α] _D ²⁰ +16.1° (c=1.0, water) (lit. [α
] _D ²⁰ +17.8° (c=1.0, water) [CHIRALITY 9,656~
660, (1997)]. Example 8 Preparation of (αS,βR)-α-amino-β-chlorobutyric acid. Milky white crystals [purity 94.9 wt.%, (αS,
βR)-α-amino-β-hydroxybutyric acid hydrochloride 5.0 g, 0.0287
The resulting mixture (containing 100 mol) was added to 19 ml of water to form a slurry. Approximately 2.8 g of concentrated hydrochloric acid was slowly added to the slurry to completely dissolve it. 0.05 g of 50% hydrous activated carbon was added to the solution.
1 g of activated carbon was added and stirred at room temperature for about 10 minutes.

───────────────────────────────────────────────────────── Continued from the front page (51) Int.Cl. ⁷ Identification Symbol FI C07C 323/58 C07C 323/58 // C07M 7:00 (81) Designated States EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), CN, IN, JP, KR, SG, US (72) Inventor Ueda Yasuyoshi 140-15 Waku, Aboshi-ku, Himeji-shi, Hyogo-ken, Japan (72) Inventor Murao Hiroshi 1-12-30 Nishihata, Takasago-shi, Hyogo-ken, Japan (Note) This publication is based on the gazette published internationally by the International Bureau of Patents (WIPO). The effect of the international publication of the Japanese patent application (Japanese utility model registration application) related to this publication arises pursuant to Article 184-10, Paragraph 1 of the Patent Act (Article 48-13, Paragraph 2 of the Utility Model Act), and is unrelated to this publication.

Claims (44)

[Claims] [Claim 1] A method for producing a β-halogeno-α-aminocarboxylic acid or a salt thereof, which comprises treating a β-hydroxy-α-aminocarboxylic acid (wherein the basicity of the amino group at the α-position is not masked by the presence of a substituent on the amino group) or a salt thereof with an acid with a halogenating agent to halogenate the hydroxyl group. 2. The method of claim 1, wherein the halogenating agent is thionyl halide. 3. The method according to claim 2, wherein the thionyl halide is thionyl chloride. 4. The method of claim 1, 2 or 3, wherein the amount of the halogenating agent used is 1 to 10 times the molar amount of the β-hydroxy-α-aminocarboxylic acid. 5. The method according to claim 1, wherein the treatment with the halogenating agent is carried out using a solvent containing an ether solvent. 6. The method according to claim 5, wherein the ether solvent is an ether solvent that is compatible with water. [Claim 7] The manufacturing method described in claim 6, wherein the ether-based solvent that is miscible with water is at least one selected from the group consisting of 1,2-dimethoxyethane, 1,4-dioxane, tetrahydrofuran, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether and polyethylene glycol dimethyl ether. 8. The method according to claim 1, wherein the treatment is carried out with a halogenating agent in the presence of hydrogen halide. 9. The method according to claim 8, wherein the amount of hydrogen halide used is more than 2.0 molar equivalents relative to the amount of β-hydroxy-α-aminocarboxylic acid. 10. The method according to claim 8 or 9, wherein the hydrogen halide gas is completely saturated or nearly saturated before the treatment with the halogenating agent. 11. The method according to claim 8, 9 or 1, wherein the hydrogen halide is hydrogen chloride.
0. The manufacturing method according to claim 0. 12. The process according to claim 1, wherein the treatment is carried out with a chlorinating agent in the presence of an amine or a salt thereof. 13. The method according to claim 12, wherein the amine is a tertiary amine. [Claim 14] A manufacturing method described in any one of claims 1 to 13, wherein after treatment with a halogenating agent, the coexisting acid is converted into a salt with a basic lithium compound, and the salt is dissolved in a medium consisting of water and an organic solvent compatible with water, thereby precipitating the β-halogeno-α-aminocarboxylic acid in a free state. 15. The method of claim 14, wherein the ether solvent that is miscible with water is at least one selected from the group consisting of 1,2-dimethoxyethane, 1,4-dioxane, tetrahydrofuran, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, polyethylene glycol dimethyl ether, acetonitrile, methanol, ethanol, n-propanol, isopropanol, t-butanol, and acetone. 16. The method of claim 1, wherein the water-compatible organic solvent is acetone.
6. The manufacturing method according to claim 5. 17. The method according to claim 14, 15 or 16, wherein the volume ratio of the water-compatible organic solvent to water is 1 or more. 18. The method according to any one of claims 14 to 17, wherein the final cooling temperature during precipitation is 10° C. or less.
18. The method of manufacturing according to any one of items 17 to 18. 19. The method of claim 14, wherein after the treatment with a halogenating agent, low boiling components present in the reaction solution are reduced or removed before precipitating the target product. 20. A method for producing a β-halogeno-α-aminocarboxylic acid according to any one of claims 1 to 13, wherein after treatment with a halogenating agent, the precipitated hydrogen halide salt of β-halogeno-α-aminocarboxylic acid is collected directly or after concentration from the reaction mixture. 21. A method for producing a β-halogeno-α-aminocarboxylic acid according to any one of claims 1 to 13, wherein after the treatment with a halogenating agent, the reaction solvent is replaced with water to obtain an aqueous liquid containing the β-halogeno-α-aminocarboxylic acid. 22. The method according to any one of claims 1 to 21, wherein the β-hydroxy-α-aminocarboxylic acid is serine, threonine, allothreonine or β-phenylserine. 23. The method according to claim 22, wherein the β-hydroxy-α-aminocarboxylic acid is serine. 24. The method according to any one of claims 1 to 23, wherein the β-hydroxy-α-aminocarboxylic acid is an optically active substance. 25. The method according to claim 23 or 24, wherein the β-hydroxy-α-aminocarboxylic acid is L-serine. 26. A method for producing a β-halogeno-α-aminocarboxylic acid (wherein the basicity of the amino group at the α-position is not masked by the presence of a substituent on the amino group) in a solvent containing water as a good solvent,
β-, characterized in that crystallization is carried out using a water-compatible organic solvent as a poor solvent.
A method for purifying and isolating halogeno-α-aminocarboxylic acids. 27. The water-compatible organic solvent according to claim 26, wherein the water-compatible organic solvent is acetone.
4. A method for purifying and isolating the β-halogeno-α-aminocarboxylic acid according to claim 1. 28. A method for purifying and isolating a β-halogeno-α-aminocarboxylic acid according to claim 27, wherein the β-halogeno-α-aminocarboxylic acid is precipitated in a free state by crystallization using acetone as a poor solvent from an aqueous solution of a hydrohalic acid containing the β-halogeno-α-aminocarboxylic acid, the hydrohalic acid being converted into a salt using a basic lithium compound. 29. A method for purifying and isolating a β-halogeno-α-aminocarboxylic acid according to claim 26, 27 or 28, wherein the volume ratio of the water-compatible organic solvent to water during crystallization is 1 or more. 30. The method according to any one of claims 26 to 30, wherein the final cooling temperature during crystallization is 10°C or less.
30. A method for purifying and isolating a β-halogeno-α-aminocarboxylic acid according to any one of 29. [Claim 31] A method for purifying and isolating a β-halogeno-α-aminocarboxylic acid described in any one of claims 26 to 30, wherein the β-halogeno-α-aminocarboxylic acid is β-chloroalanine, β-chloro-α-aminobutyric acid, or β-chloro-β-phenyl-α-aminopropionic acid. 32. The method for purifying and isolating a β-halogeno-α-aminocarboxylic acid according to claim 31, wherein the β-halogeno-α-aminocarboxylic acid is β-chloroalanine. 33. The method for purifying and isolating a β-halogeno-α-aminocarboxylic acid according to any one of claims 26 to 32, wherein the β-halogeno-α-aminocarboxylic acid is an optically active substance. 34. The method for purifying and isolating a β-halogeno-α-aminocarboxylic acid according to claim 32 or 33, wherein the β-halogeno-α-aminocarboxylic acid is β-chloro-L-alanine. 35. A method for producing a compound represented by the following formula (1): from optically active serine or a salt thereof with an acid, according to the production method described in claim 1: and then treating the resulting product with an amino group-protecting agent, (wherein R ¹ represents an amino-protecting group; ^{R 0} represents a hydrogen atom or
1, together with ¹ , represent an amino group-protecting group. 36. The method according to claim 35, wherein the optically active β-chloroalanine is produced according to the method according to any one of claims 2 to 25. 37. The amino group protecting agent is benzyl chloroformate, and the optically active N
37. The method for producing the protected β-chloroalanine according to claim 35 or 36, wherein R ⁰ is a hydrogen atom and R ¹ is a carbobenzyloxy group in general formula (2). 38. A process for producing an optically active N-protected-β-chloroalanine or a salt thereof according to the process of claim 35, followed by reacting thiophenol with a compound represented by the following general formula (3): (wherein R ¹ represents an amino-protecting group; ^{R 0} represents a hydrogen atom or
1, together with ¹ , represent an amino group-protecting group. 39. The optically active N-protected-B-chloroalanine according to claim 36.
39. The method of claim 38, which is produced according to the method of claim 38. 40. The amino group protecting agent is benzyl chloroformate, and the optically active N
The -protected-S-phenylcysteine is a compound represented by the general formula (3), wherein R ⁰ is a hydrogen atom and R ¹ is a carbobenzyloxy group.
9. The method of manufacture according to claim 9. 41. The method of any one of claims 38 to 40, wherein the treatment of optically active serine or a salt of optically active serine with an acid with a chlorinating agent, the treatment with an amino group protecting agent, and the thiophenylation are carried out without isolating the intermediate product. 42. An optically active β-chloroalanine or a salt thereof is treated with an amino group protecting agent to obtain a compound represented by the following general formula (2): (wherein R ¹ represents an amino-protecting group; ^{R 0} represents a hydrogen atom or
and then reacting thiophenol with the compound represented by the following general formula ( ³ ):
; (wherein R ¹ represents an amino-protecting group; ^{R 0} represents a hydrogen atom or
1, together with ¹ , represent an amino group-protecting group. 43. The amino group protecting agent is benzyl chloroformate, and the optically active N
The optically active N-protected-β-chloroalanine and the optically active N-protected-S-phenylcysteine are represented by the general formula (2) and the general formula (3), respectively, wherein R ⁰ is a hydrogen atom,
43. The method according to claim 42, wherein R ¹ is a carbobenzyloxy group. 44. The method according to claim 42 or 43, wherein the treatment with an amino group-protecting agent and the thiophenylation are carried out without isolating the intermediate product.