JP2000297069A - Production of amino acid ester - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject compound useful as a raw material for producing a medicine, etc., simply, efficiently in high quality and in a high yield by reacting a salt of an amino acid and a base with a chlorosulfite ester. SOLUTION: A salt of an amino acid and a base (e.g. sodium salt of N- benzyloxycarbonyl-S-phenyl-L-cystine, etc.), in an amount of 1 equivalent is reacted with preferably 1-2 equivalents of a compound of the formula ClSOOR [R is a (substituted) alkyl, aryl or the like] to give an amino acid ester. The reaction is carried out in an organic solvent (e.g. toluene, etc.), preferably at 0 to 60 deg.C for 1-20 hours. The compound of the formula ClSOOR is obtained by reacting thionyl chloride with a hydroxy compound (e.g. methanol, etc.). The reaction is performed in an organic solvent preferably at -20 to 30 deg.C for several hours.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a process for producing an amino acid ester by reacting a salt of an amino acid and a base with a chlorosulfite, and more particularly, to reacting a salt of an optically active amino acid with a base with a chlorosulfite. And a method for producing an optically active amino acid ester. Amino acid esters, especially optically active amino acid esters, are useful as raw materials for producing pharmaceuticals and the like.

[0002]

2. Description of the Related Art Hitherto, as a method for directly esterifying a salt of a carboxy compound such as an amino acid and a base with a base, a method using a dialkyl sulfate or an alkyl halide under basic conditions is known (see "New Experimental Chemistry"). 14-II, 1
008, published by Maruzen Co., Ltd.). These methods are very simple because they can be esterified in one pot, but have a serious problem in handling on an industrial scale due to the high toxicity of commonly used dimethyl sulfate and methyl iodide. Further, it is not always a simple and efficient method for esterifying various salts of a carboxy compound and a base, and various reaction conditions suitable for a reaction substrate have been studied.

When an amino acid or a salt of an amino acid and a base is esterified, the reaction substrate or product is often unstable under acidic or basic conditions, and the reaction substrate or product is decomposed or racemized. There is a problem that yield and quality are reduced. For example, an optically active S-phenylcysteine ester in which an amino group is protected by a urethane-type protecting group, which is useful as a raw material of an intermediate for producing an HIV-protease inhibitor, is a compound that easily racemizes under basic conditions. .

[0004]

DISCLOSURE OF THE INVENTION In view of the above situation, the present invention provides a simple and efficient method for producing high-quality amino acid esters on an industrial scale from salts of various amino acids and bases in good yield. It is intended to provide a method.

[0005]

That is, the present invention is a method for producing an amino acid ester, comprising reacting a salt of an amino acid with a base with a chlorosulfite.
Hereinafter, the present invention will be described in detail.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, an amino acid ester is produced by reacting a salt of an amino acid with a base with chlorosulfite.

[0007] The salt of an amino acid and a base used in the present invention refers to a compound in which a hydrogen ion of a carboxyl group of an amino acid is replaced by a cation such as a metal ion or an ammonium ion. It is sufficient that at least one of the carboxyl groups contained in the amino acid forms a salt with a base, and the other carboxyl groups may be in an ester group or the like.

The form of the salt is not particularly limited, and may be a salt of an amino acid and an inorganic base or a salt of an amino acid and an organic base. Specifically, for example, lithium salt,
Examples thereof include alkali metal salts such as sodium salts and potassium salts; metal salts such as alkaline earth metal salts such as magnesium salts and calcium salts; and ammonium salts. Among them, a metal salt is preferable, an alkali metal salt is more preferable, and a sodium salt is more preferable.

The amino acid is not particularly limited, and basically includes at least one amino group or imino group in a molecule.
In addition, any compound having at least one carboxyl group may be used. According to the production method of the present invention, even when an optically active amino acid is used, an optically active amino acid ester can be obtained in a high yield without a decrease in optical purity.

The amino group or imino group of the amino acid may be protected with a protecting group. The protective group is not particularly limited, and may be a protective group in organic synthesis second edition (PROTECTIVE GRO).
UPS IN ORGANICSYNTHESIS 2
nd Ed. ), John Wiley & Sons Publishing (1991)
) Can be selected from general amino or imino group protecting groups described in US Pat. Preferably, it is a urethane-type protecting group or an acyl-type protecting group in that the basicity of the amino group can be sufficiently shielded. Specifically, benzyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, acetyl, tosyl, benzoyl, phthaloyl, (3
S) -Tetrahydrofuranyloxycarbonyl group, 3-hydroxy-2 in which a hydroxyl group may be protected
-Methylbenzoyl group and the like. Among them, a urethane-type protecting group is more preferred, and an aralkyloxycarbonyl group or a lower alkoxycarbonyl group is still more preferred. Particularly preferred are a benzyloxycarbonyl group, a tert-butoxycarbonyl group, an ethoxycarbonyl group and a methoxycarbonyl group, and among them, a benzyloxycarbonyl group is preferred.

Such a salt of an amino acid and a base can be obtained by reacting the amino acid with a base such as a metal hydroxide salt or ammonia by a conventionally known method.

The salt of an amino acid and a base which can be used in the present invention is not particularly limited, and various ones can be suitably used. Particularly preferred is a salt in which an amino group is protected. S-phenylcysteine (N
-Protected-S-phenylcysteine) and a base. In addition, S-phenylcysteine in which the protecting group for the amino group is protected by a urethane-type protecting group (preferably an alkoxycarbonyl group or a benzyloxycarbonyl group having an alkyl group having 1 to 4 carbon atoms) or an ester thereof (preferably having a carbon number of 1 to 4). 1-4 alkyl esters)
Are described in WO 96/23756, EP 604185A.
As described in No. 1 and the like, it is an important compound as a raw material of an intermediate for producing an HIV-protease inhibitor.

A salt of this amino-protected S-phenylcysteine (N-protected-S-phenylcysteine) with a base (preferably one in which the amino group is protected by a urethane-type protecting group, more preferably benzyloxy Protected by a carbonyl group) can be produced by the method described in Japanese Patent Application No. 11-013388.
For example, under basic conditions (preferably pH 8 or more) and an amount of an inorganic salt (preferably having an inorganic salt concentration with respect to water of sufficient amount) to salt out a salt of N-protected-S-phenylcysteine and a base. Alanine (preferably β-chloroalanine in which the amino group is protected with a urethane-type protecting group) in which the amino group is protected and has a leaving group at the β-position in an aqueous medium containing 5% by weight or more. It can be produced by treating with thiophenol to synthesize N-protected-S-phenylcysteine and simultaneously salting out the obtained N-protected-S-phenylcysteine from the reaction mixture as a salt with a base. . The salt of an amino acid and a base produced by the above method is usually preferably used as an anhydrous salt. However, when water coexists, the reaction may be performed after azeotropic removal of water using a solvent.

The chlorosulfite used in the production method of the present invention is a compound represented by the general formula: ClSOOR. The substituent R in the general formula is not particularly limited,
Examples thereof include a substituted or unsubstituted alkyl group and a substituted or unsubstituted aryl group. The alkyl group is
It may be any of a primary, secondary or tertiary alkyl group. These substituents may have an unsaturated group or a ring structure,
The ring structure may be not only an alicyclic ring but also a heterocyclic ring or an aromatic ring. Among them, an alkyl group having 1 to 3 carbon atoms or a benzyl group is preferable, and more preferably 1 to 3 carbon atoms.
Alkyl group, specifically, a methyl group, an ethyl group,
It is an n-propyl group or an isopropyl group. This substituent R is introduced into an amino acid to form an amino acid ester.

The above-mentioned chlorosulfite can be generally obtained by reacting thionyl chloride with a hydroxy compound. This method is suitable when the chlorosulfite is a primary alkyl or aryl ester. When the chlorosulfite is a secondary alkyl ester, it can also be obtained by reacting a dialkyl sulfite with thionyl chloride. When the chlorosulfite is neopentyl chlorosulfite, it can be obtained by reacting neopentyl trimethylsilyl ether with thionyl chloride.

Here, a method for preparing chlorosulfite by reacting thionyl chloride with a hydroxy compound will be described. The hydroxy compound to be used is not particularly limited, for example, substituted or unsubstituted alcohols,
Substituted or unsubstituted phenols can be exemplified. The alcohols may be primary, secondary or tertiary alcohols. These hydroxy compounds may have an unsaturated group or a ring structure, and the ring structure may be not only an alicyclic structure but also a heterocyclic or aromatic ring. Among them, alcohols having 1 to 3 carbon atoms or benzyl alcohol are preferable, and alcohols having 1 to 3 carbon atoms are more preferable, and specific examples thereof include methanol, ethanol, n-propanol and isopropanol.

The amount of the hydroxy compound used is not particularly limited, and it is sufficient to use about 1 equivalent or more per 1 equivalent of thionyl chloride. Generally, an excess of the hydroxy compound is used. Chlorosulfites can also be prepared using a large excess of the hydroxy compound as the reaction solvent.

The reaction solvent is not particularly limited, and examples thereof include aromatic hydrocarbon solvents, ether solvents and the like, in addition to the above-mentioned hydroxy compound which also serves as a reaction substrate and a reaction solvent. When these are used, the amount of the hydroxy compound used can be minimized.

The reaction temperature is not particularly limited, and the reaction can generally be performed at a low temperature of about 40 ° C. or less. The temperature is preferably about -20 ° C to 30 ° C, and when prepared at this temperature, the reaction is usually completed within several hours.

The chlorosulfite prepared as described above may be isolated by distillation or the like and used in the esterification reaction of the present invention. However, it is preferable to use a solution containing chlorosulfite prepared by reacting thionyl chloride with a hydroxy compound as it is in the esterification reaction of the present invention. In this case, a solution in which low boiling components such as thionyl chloride coexisting in the solution are removed by evaporation can be used.

Next, the esterification reaction of the present invention, that is, the reaction between a salt of an amino acid and a base and a chlorosulfite will be described. In this reaction, the reaction system can be maintained under suitable acidic or neutral conditions, and even when amino acids or amino acid esters are unstable under strongly acidic or basic conditions, they can be decomposed. It is possible to produce an amino acid ester with high yield and high quality while protecting from the racemization.

Although the amount of the chlorosulfite used depends on the type of the reaction substrate, generally, about 1 equivalent or more is used per 1 equivalent of the salt of the amino acid and the base. There is no particular upper limit, but it is generally 20 equivalents or less. Preferably 1
It is used in the range of 10 to 10 equivalents, more preferably in the range of 1 to 2 equivalents. However, the amount of the chlorosulfite or, in some cases, the amount of the thionyl chloride and the hydroxy compound is adjusted so that the reaction suitably proceeds according to the properties of the reaction substrate to obtain a high-quality target product. It is more preferable to maintain appropriate conditions in the reaction system.

The reaction solvent for the esterification is not particularly limited, and the above-mentioned hydroxy compound can be used also as the reaction solvent. However, the use of the hydroxy compound using an aromatic hydrocarbon solvent, an ether solvent or the like can be used. The amount can be minimized.

The reaction temperature is not particularly limited by the type of the reaction substrate, but is preferably 8 in order to minimize side reactions.
0 ° C. or lower, more preferably −20.
The temperature is in the range of from 70C to 70C, more preferably from 0C to 60C.

The time required for the above reaction varies depending on the type and amount of the salt between the amino acid and the base, the amount of chlorosulfite, the reaction temperature and the like. Usually, the reaction can be made to proceed almost quantitatively in 1 to 20 hours.

From the reaction solution thus obtained, the desired product can be easily separated and purified using generally known operations. For example, an insoluble component is filtered, degassed or concentrated to remove a volatile component, and a solution containing the target substance or the target substance can be easily obtained. After degassing and / or neutralization as desired, the target substance is extracted into an organic solvent to transfer unnecessary components to the aqueous phase to obtain a solution containing the target substance, which is concentrated if necessary. By doing so, the desired product can be obtained.

According to the method of the present invention, an amino acid ester can be produced by easily and efficiently esterifying a salt of an amino acid and a base while suppressing a side reaction, and the yield is 90%.
As described above, preferably, almost quantitative yield can be expected. An advantage of the present invention is that amino acids or amino acid esters can be suitably applied even to compounds that are unstable under acidic or basic conditions. For example, as a salt of an optically active amino acid and a base, a salt of an optically active S-phenylcysteine in which the amino group is protected (preferably with a urethane-type protecting group) and a base, specifically N-benzyloxycarbonyl-S Even when the sodium salt of -phenyl-L-cysteine is used, the desired optically active amino acid ester can be produced without lowering the optical purity.

[0028]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

Example 1 1.71 thionyl chloride was added to 1.01 g of methanol under ice cooling.
g was added dropwise while maintaining the internal temperature at 10 ° C. or lower. This solution was stirred for 30 minutes under ice cooling to prepare a methanol solution of methyl chlorosulfite.

The whole amount of the methanol solution of methyl chlorosulfite was added to ice-cooled N-benzyloxycarbonyl-S-
4. dry crystals of the sodium salt of phenyl-L-cysteine
It was added to a suspension consisting of 01 g (4.08 g pure) and 8.04 g methanol. The reaction solution was heated at 40 ° C. for 3 hours.
Then, the reaction was carried out at the same temperature for 3 hours. When a very small amount of the reaction solution was sampled and analyzed by HPLC, the raw materials had completely disappeared.

Next, the solvent in the reaction solution was replaced with toluene at 40 ° C. under reduced pressure, and insolubles were removed by filtration to obtain 22.42 g of a toluene solution. This toluene solution is
It contained 4.01 g (100% yield) of N-benzyloxycarbonyl-S-phenyl-L-cysteine methyl ester. No decrease in optical purity was observed.

Example 2 1.71 thionyl chloride was added to 1.01 g of methanol under ice cooling.
g was added dropwise while maintaining the internal temperature at 10 ° C. or lower. This solution was stirred for 30 minutes under ice cooling to prepare a methanol solution of methyl chlorosulfite.

On the other hand, N-benzyloxycarbonyl-S
5.01 g (4.08 g) of dry crystals of sodium salt of -phenyl-L-cysteine were suspended in 8.09 g of toluene, and the solution was heated to about 40 ° C.

This N-benzyloxycarbonyl-S-
The whole amount of the previously prepared methanol solution of methyl chlorosulfite was added to the toluene suspension of the sodium salt of phenyl-L-cysteine, and the mixture was further reacted at the same temperature for 3 hours.
When a very small amount of the reaction solution was sampled and analyzed by HPLC, the raw materials had completely disappeared.

14.75 g of the obtained reaction solution was cooled to 25 ° C., and 7 mL of water was mixed (pH: about 0). The organic layer obtained by separating the aqueous layer was heated to 40 ° C., washed with 3.18 g of a 5% aqueous sodium hydrogen carbonate solution (pH: about 8),
Washed twice with 5 mL of 5% aqueous sodium chloride solution (pH
About 7). Further, the distillation of toluene was started at an internal temperature of 60 to 70 ° C., and finally, the internal pressure was 20 mmHg and the internal temperature was 66 ° C.
4.07 g of an oily substance of -benzyloxycarbonyl-S-phenyl-L-cysteine methyl ester was obtained. After adding tetrahydrofuran thereto, insolubles were removed by filtration to obtain 9.39 g of a solution of N-benzyloxycarbonyl-S-phenyl-L-cysteine methyl ester in tetrahydrofuran. This tetrahydrofuran solution is N-benzyloxycarbonyl-S-phenyl-L
-Cysteine methyl ester 4.01 g (yield 100
%). No decrease in optical purity was observed.

Reference Example 1 N-benzyloxycarbonyl
Preparation of sodium salt of -S-phenyl-L-cysteine Aqueous solution containing 7.47 g of β-chloroalanine 86.
To 23 g, 11.35 g of benzyloxycarbonyl chloride (1.1 times mol with respect to β-chloroalanine) was added to 15 g of the mixture while maintaining the pH at 9.7 with a 30% aqueous sodium hydroxide solution at about -5 to 0 ° C. while stirring. The reaction was carried out dropwise over time. The reaction solution obtained by further reacting for 3 hours was washed with 50 ml of toluene.

13.98 g of sodium chloride was added to the reaction solution.
(25% by weight with respect to water), and the mixture was adjusted to pH 1 with a 30% aqueous sodium hydroxide solution under a nitrogen atmosphere at about 40 ° C. with stirring.
9.82 g of thiophenol (β-
(1.5 times the molar amount of chloroalanine) over 2 hours. As the reaction proceeds, the N-
Benzyloxycarbonyl-S-phenyl-L-cysteine was precipitated as a sodium salt, and the reaction system became a slurry.

To the reaction solution slurry obtained by reacting for 20 hours, 65 ml of toluene was added, and the mixture was stirred at about 40 ° C. under a nitrogen atmosphere for 1 hour. Then, crystals were separated by suction filtration, and the crystals were separated with toluene and a saturated aqueous solution of sodium chloride. After successive washing, 31.48 g of wet crystals were obtained. The wet crystals contained 18.17 g (90% yield) of sodium salt of N-benzyloxycarbonyl-S-phenyl-L-cysteine, and the apparent purity by HPLC was 99.0 area%. Further, 14.98 g of the obtained wet crystal was dried under reduced pressure (1.
３０30 mmHg, 20-40 ° C., 20 hours) to obtain 10.62 g of dry crystals.

[0039]

According to the present invention, since it has the above-mentioned structure, it can be easily and efficiently obtained with high yield from a salt of an amino acid and a base.
High quality amino acid esters can be produced. In particular, a high-quality optically active amino acid ester can be produced easily and efficiently from a salt of an optically active amino acid and a base with good yield.

Claims (10)

[Claims] 1. A method for producing an amino acid ester, comprising reacting a salt of an amino acid with a base with a chlorosulfite. 2. The method according to claim 1, wherein the salt between the amino acid and the base is a salt between an optically active amino acid and a base. 3. The chlorosulfite ester is methyl chlorosulfite, ethyl chlorosulfite, n-propyl chlorosulfite or isopropyl chlorosulfite.
The manufacturing method as described. 4. The method according to claim 1, wherein the chlorosulfite is a solution containing a chlorosulfite prepared by reacting thionyl chloride with a hydroxy compound. 5. The method according to claim 1, wherein the reaction is carried out at a temperature of 80 ° C. or lower. 6. The method according to claim 1, wherein the salt of the amino acid and the base is an alkali metal salt of the amino acid. 7. The method according to claim 6, wherein the alkali metal salt of the amino acid is a sodium salt of the amino acid. 8. The salt of an amino acid and a base is a salt of a base with S-phenylcysteine in which an amino group is protected by a urethane-type protecting group and a base.
The manufacturing method as described. 9. A salt of S-phenylcysteine in which the amino group is protected with a urethane-type protecting group and a salt of the S-phenylcysteine in which the amino group is protected with a urethane-type protecting group under basic conditions.
In an aqueous medium in which a sufficient amount of an inorganic salt is present for salting out a salt of phenylcysteine and a base, β-chloroalanine having an amino group protected with a urethane-type protecting group is treated with thiophenol to give an amino acid. Synthesizing S-phenylcysteine in which the group is protected with a urethane-type protecting group and simultaneously salting out the resulting S-phenylcysteine in which the amino group is protected with a urethane-type protecting group from the reaction mixture as a salt with a base. The method according to claim 8, which is obtained by the following method. 10. The method according to claim 8, wherein the urethane-type protecting group is a benzyloxycarbonyl group.