JP2001199951A - Method for producing N-alkoxycarbonyl amino acid ester - Google Patents

Abstract

(57) [Problem] To provide an advantageous method for producing N-alkoxycarbonyl amino acid ester on an industrial scale, which can efficiently remove impurities and satisfy productivity, operability, yield and quality. provide. An amino acid, an alcohol, and a sulfonic acid are reacted, and a sulfonic acid salt of the generated amino acid ester is neutralized with a base, and the sulfonic acid generated by the neutralization is neutralized with an organic solvent and water incompatible with water. The base salt and unreacted amino acids are removed to the aqueous phase, and the resulting free amino acid ester is extracted into the organic solvent phase, and then the obtained free amino acid ester-containing organic solvent phase is treated with dicarbonate. To obtain an organic solvent phase containing an N-alkoxycarbonyl amino acid ester.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an N-alkoxycarbonyl amino acid ester useful as a raw material for producing pharmaceuticals and the like.

[0002]

2. Description of the Related Art Conventionally, as a method for producing an N-alkoxycarbonyl amino acid ester, an amino acid is used as a starting material, an esterification reaction is performed using an alcohol, and the produced amino acid ester is obtained as an acid salt, which is then converted to a dicarbonate. A method is known which leads to the desired N-alkoxycarbonyl amino acid ester by reacting with N-alkoxycarbonyl amino acid ester.

[0003] In this case, although various acidic salts of amino acid esters are known, the acidic salts used industrially are mineral salts such as hydrochlorides and sulfates. Generally, the esterification reaction involves an amino acid,
The reaction is performed using an alcohol and a mineral acid or thionyl chloride.In the obtained reaction solution, in addition to the mineral acid salt of the target amino acid ester, a large amount of alcohol or generated water,
Contains extraneous substances such as excess mineral acids and sulfur dioxide, unreacted amino acids.

Japanese Patent Application Laid-Open No. 7-101928 describes a method of obtaining an N-alkoxycarbonyl amino acid ester by directly subjecting an esterification reaction solution obtained without removing these impurities to N-alkoxycarbonylation. However, in this case, the acquisition yield and quality of the target N-alkoxycarbonyl amino acid ester are likely to decrease. Further, in order to efficiently remove a large amount of inorganic salts and a considerable amount of related impurities, it is necessary to add a purification step, and although crystallization is particularly effective for purification, cumbersome operations such as crystal separation, drying, and pulverization are required. Has the disadvantage that operability, productivity, yield and the like are liable to decrease.

On the other hand, in order to remove the above-mentioned contaminants, a method of once isolating and purifying a mineral acid salt of an amino acid ester followed by N-alkoxycarbonylation is conceivable. However, this method is not preferable in terms of cost and productivity.

As described in Japanese Patent Application Laid-Open No. 7-145136, a method of converting a mineral acid salt of an amino acid ester into a free amino acid ester for isolation and purification is also known. Large amounts of inorganic bases and water are required to neutralize and remove mineral acids and sulfur dioxide, and it is extremely disadvantageous to extract extremely water-soluble free amino acid esters into an organic solvent phase in the presence of large amounts of water. .

As described above, the conventional method is not an industrial production method capable of efficiently removing contaminants and completely satisfying productivity, operability, yield and quality.

In addition, in addition to the above-mentioned problems, the conventional method for producing an N-alkoxycarbonyl amino acid ester uses a mineral acid such as hydrochloric acid and thionyl chloride. In addition, there is a problem that special equipment such as an exhaust gas treatment equipment needs to be installed.

[0009]

SUMMARY OF THE INVENTION In view of the above problems, it is an object of the present invention to provide an N-alkoxycarbonyl which can efficiently remove impurities and satisfy productivity, operability, yield and quality. It is an object of the present invention to provide an advantageous process for producing amino acid esters on an industrial scale.

[0010]

DISCLOSURE OF THE INVENTION The present inventors have conducted intensive studies on a process for producing an N-alkoxycarbonyl amino acid ester which is industrially advantageous, and as a result, reacted an amino acid, an alcohol and a sulfonic acid, and then produced the amino acid. By neutralizing the sulfonate of the ester with a base and converting it to the free amino acid ester and the salt of the base and sulfonic acid,
The extremely high water-soluble free amino acid ester can be efficiently extracted into the organic solvent phase, and further, by reacting the free amino acid ester contained in the obtained organic solvent phase with dicarbonate, It has been found that N-alkoxycarbonyl amino acid esters can be efficiently obtained by overcoming the problems. Furthermore, in the above method, it has been found that the yield of N-alkoxycarbonyl amino acid ester can be improved by reacting a free amino acid ester contained in an organic solvent phase substantially containing no alcohol with dicarbonate. .

That is, the present invention relates to amino acids, alcohols,
And a sulfonic acid, and a sulfonic acid salt of the amino acid ester produced is neutralized with a base, and a salt of the sulfonic acid and the base generated by the neutralization using an organic solvent and water that are incompatible with water, and unreacted While removing amino acids to the aqueous phase,
The resulting free amino acid ester is extracted into an organic solvent phase, and then the resulting organic solvent phase containing the free amino acid ester is reacted with dicarbonate to form N-alkoxycarbonyl, thereby converting the N-alkoxycarbonyl amino acid ester. The present invention relates to a method for producing an N-alkoxycarbonyl amino acid ester, which comprises obtaining a contained organic solvent phase.

Further, the present invention provides the above-mentioned production method,
The present invention also relates to a method for producing an N-alkoxycarbonyl amino acid ester, wherein the organic solvent phase containing a free amino acid ester to be subjected to the alkoxycarbonylation reaction is an organic solvent phase containing substantially no alcohol.

Hereinafter, the present invention will be described in detail.

First, the esterification reaction of an amino acid will be described. In the esterification reaction, first, an amino acid, an alcohol and a sulfonic acid are reacted.

The amino acids that can be used in the present invention basically need only have at least one amino group or imino group and at least one carboxyl group in the molecule. In the case of having two or more amino groups or imino groups in the molecule or having two or more carboxyl groups, other amino groups having at least one amino group or imino group and one carboxyl group The groups or imino groups and carboxyl groups may have been converted to other functional groups. For example, a hydrogen atom of an amino group or an imino group may be substituted with an alkyl group or the like, and a carboxyl group may be converted into an amide or an ester.

Specific examples of amino acids that can be used in the present invention
Examples include, for example, glycine, alanine, 3-chloro
Alanine, β-alanine, valine, norvaline, leucine
, Norleucine, isoleucine, alloisoleucine,
Phenylalanine, homophenylalanine, tyrosine,
Diiodotyrosine, threonine, allothreonine, sericin
, Homoserine, isoserine, proline, hydroxy
Loline, 3,4-dehydroproline, tryptophan,
Thyroxine, methionine, homomethionine, cystine,
Homocystine, α-aminobutyric acid, β-aminobutyric acid, γ-
Aminobutyric acid, α-aminoisobutyric acid, aspartic acid,
Spartic acid-β-cyclohexyl ester, asparagus
Formic acid-β-methyl ester, aspartic acid-β-a
Sopropyl ester, aspartic acid-β-benzyl
Stelu, glutamic acid, glutamic acid-γ-cyclohexyl
Sil ester, glutamic acid-γ-methyl ester,
Glutamic acid-γ-isopropyl ester, glutamic acid
-Γ-benzyl ester, lysine, hydroxylysine,
Ornithine, hydroxyornithine, arginine, hiss
Thidine, anti-capsin, N^Five-Iminomethylornichi
, Α-amino-β- (2-imidazolidyl) propio
Acid, taurine, γ-formyl-N-methylnorval
N^g-Tosyl arginine, N^g-Benzyloxyca
Rubonyl arginine, S-acetamidomethyl cysteine
, S-phenylcysteine, S-benzylcysteine
N, ethionine, N^im-Benzyloxycarbonyl hiss
Thidine, N ⁶-Benzyloxycarbonyl lysine, N^Five−
Benzyloxycarbonyl ornithine, O-benzylse
Phosphorus, O-benzylthreonine, Nⁱⁿ-Formyl trip
Tophan, 2- (2-amino-4-thiazolyl) -2-
Hydroxyiminoacetic acid, 2- (2-amino-4-thiazo
(Lyl) -2-methoxyiminoacetic acid, 2- (2-amino-
4-thiazolyl) -2-glyoxyacetic acid, 2- (2-a
Mino-4-thiazolyl) -2-pentenoic acid, 3-amino
-2-hydroxy-4-phenylbutyric acid, 3-amino-3
-Phenylpropionic acid, phenylglycine, 4-hydrido
Roxyphenylglycine, 4-chlorophenylglyci
, 4-chlorophenylalanine, cyclohexylala
Nin, cyclohexylglycine, 3- (1-naphthyl)
Alanine, 3- (2-naphthyl) alanine, creatine
Azetidine-2-carboxylic acid, orsylalanine,
Ergothioneine, lanthionine, 1-methylhistidine
And 3-methylhistidine.

Further, compounds in which the hydrogen atom of the amino group of these amino acids is substituted with an alkyl group, for example, a methyl group, etc., also correspond to the amino acids usable in the present invention.

In the present invention, amino acids having 4 or more carbon atoms can be particularly preferably used from the viewpoint of efficiently extracting the produced amino acid ester into an organic solvent phase, and more preferably phenylalanine and the like. And an amino acid having an aromatic ring. Usually, an amino acid having one amino group or imino group and one carboxyl group (neutral amino acid) is preferably used.

The alcohol which can be used in the present invention is
Although not particularly limited, usually an alcohol having 1 to 10 carbon atoms is preferable, and specifically, methanol, ethanol,
Examples thereof include n-propanol, i-propanol, n-butanol, i-butanol, n-hexanol, cyclohexanol, and benzyl alcohol.

The amount of the alcohol used is not particularly limited, but is preferably at least 1 equivalent to 1 equivalent of the amino acid. Generally, since this esterification reaction is carried out by reacting the alcohol, amino acid and sulfonic acid in a large excess of alcohol medium, the amino acid 1
The amount of alcohol used relative to the equivalent is usually about 5 equivalents or more. Although the upper limit of the amount of alcohol used is not particularly limited, it is usually about 50 equivalents or less, preferably about 30 equivalents or less, more preferably about 20 equivalents or less from the viewpoint of economy.

In addition, to minimize the amount of alcohol used,
In order to reduce the amount of alcohol brought into the N-alkoxycarbonylation reaction, the reaction may be carried out while azeotropically dehydrating water produced by the reaction using an organic solvent azeotropic with water such as toluene.

The sulfonic acid that can be used in the present invention is not particularly limited. Examples thereof include methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, butanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, Examples thereof include 1-phenylethanesulfonic acid and a substituted product thereof.

As will be described later, from the viewpoint of keeping the solubility of the sulfonate produced by the neutralization high in water and extracting the amino acid ester produced by minimizing the amount of water used into the organic solvent phase, the number of carbon atoms must be as follows. 1-4 sulfonic acids,
In particular, methanesulfonic acid is most preferred.

The amount of the sulfonic acid to be used may be at least 1 equivalent to 1 equivalent of an amino group or an imino group capable of forming a salt with the sulfonic acid in the amino acid molecule.
Equivalents, preferably 1.2 to 3 equivalents are used.

In the present invention, an amino acid can be used as a sulfonate of an amino acid. Particularly, a racemic amino acid (for example, DL-phenylglycine, DL-4-hydroxyphenylglycine, etc.) can be optically active. Sulfonic acid (for example, d-camphorsulfonic acid,
It is also possible to use an optically active amino acid sulfonate obtained by optical resolution with (-)-1-phenylethanesulfonic acid or a substituted product thereof). In this case, the use amount (addition amount) of the sulfonic acid may be appropriately increased or decreased so that the amount of the sulfonic acid finally contained in the esterification reaction solution falls within the above range.

Further, when the sulfonic acid is used as a mixture with an alcohol or an ether, it is possible to suppress the corrosiveness and solidification of the sulfonic acid to the metal without losing the effectiveness of the acid catalyst or the like originally possessed by the sulfonic acid (Japanese Patent Application No. Hei 10-284,197). 2000-007
175), which is advantageous in terms of equipment and operability.

In this case, the alcohol which can be suitably mixed with the sulfonic acid is not particularly limited, but is preferably an alcohol having 1 to 10 carbon atoms, and specifically, methanol, ethanol, n-propanol, i-propanol, n-propanol. Butanol, i-butanol, n-hexanol, cyclohexanol, benzyl alcohol and the like can be mentioned. Generally, it is preferable to use the same alcohol as the alcohol used in the esterification reaction to suppress the generation of unnecessary by-products.

Examples of the ethers which can be suitably mixed with the sulfonic acid include, for example, cyclic ethers having a 5- to 6-membered ring, chain ethers each composed of two independent C1 to C4 alkyl groups, and mono-ethers. And / or poly-alkylene glycol ethers, and more specifically, cyclic ethers such as tetrahydrofuran and 1,4-dioxane, chain ethers such as diisopropyl ether and methyl t-butyl ether, and monoethylene glycol. Examples include alkylene glycol ethers such as dimethyl ether, monoethylene glycol diethyl ether, polyethylene glycol dimethyl ether, and polyethylene glycol diethyl ether. Among them, it is preferable to use an ether having high affinity for sulfonic acid, particularly an ether having compatibility with water, such as tetrahydrofuran.

The amount of the above-mentioned alcohol or ether that can be mixed with the sulfonic acid may be appropriately varied depending on the type of the sulfonic acid and the degree of the desired effect.
Although not particularly limited, it is usually about 5% by weight or more, preferably about 10% by weight or more, based on the weight of the sulfonic acid.

The reaction temperature in the amino acid esterification reaction that can be performed in the present invention is not particularly limited.
It can be selected from the range of freezing point to boiling point of the reaction system.
A range of 0 ° C, preferably about 20-120 ° C, more preferably about 30-80 ° C is selected.

Next, a method for obtaining an organic solvent phase containing a free amino acid ester will be described.

The esterification reaction solution obtained as described above generally contains, in addition to the target amino acid ester,
Unreacted amino acids coexist as sulfonates.

In the present invention, the resulting sulfonate of the amino acid ester is neutralized with a base, and an organic solvent incompatible with water is used to neutralize the sulfonic acid-base salt formed by neutralization.
In addition to removing the unreacted amino acids into the aqueous phase, the generated free amino acid esters are efficiently extracted into the organic solvent phase. The salt of sulfonic acid and base formed by neutralization is extremely water-soluble, so that the amount of water required to dissolve it can be minimized, and the extraction efficiency of highly water-soluble free amino acid ester into the organic solvent phase is maximized. Be transformed into

In the above operation, for example, after neutralizing the esterification reaction solution, extraction may be performed using an organic solvent that is not compatible with water, or an organic solvent that is not compatible with water may be added to the esterification reaction solution. After mixing, the mixture may be neutralized and extracted.Further, neutralization and extraction may be performed after removing part or all of the alcohol component in the esterification reaction solution, and finally the free amino acid The procedure is not limited as long as an organic solvent phase containing an ester can be obtained. However, from the viewpoint of stabilization of the indicated pH value at the time of neutralization (pH adjustment), the neutralization is preferably performed in the presence of an alcohol component.

The base used in the neutralization operation is not particularly limited, but is usually an inorganic base, for example, an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, or an alkali metal hydroxide such as sodium carbonate or potassium carbonate. Examples thereof include carbonates, alkali metal hydrogencarbonates such as sodium hydrogencarbonate and potassium hydrogencarbonate. Also, hydroxides and carbonates of other metals can be suitably used.

The above-mentioned neutralization operation may be carried out by bringing the base itself into contact with the esterification reaction solution. Alternatively, the base may be mixed with water and / or an organic solvent and brought into contact with the esterification reaction solution. . Usually, an alkali metal hydroxide such as sodium hydroxide and potassium hydroxide, an alkali metal carbonate such as sodium carbonate and potassium carbonate, and an alkali metal bicarbonate such as sodium hydrogen carbonate and potassium hydrogen carbonate are used as an aqueous solution. It is suitable from the viewpoint of operability. Above all,
Most preferably, an aqueous solution of an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide (for example, about 5 to 20N) is used.

When the above base is used by mixing with an organic solvent, the organic solvent is not particularly limited, but specific examples include methanol, ethanol, i-propanol, ethyl acetate, toluene, diisopropyl ether and the like. Can be. When using alcohol,
It is preferable to use the same alcohol as that used in the esterification reaction.

It is preferable that the above bases are mixed with careful stirring or the like so as not to become locally strong basic.

The amount of the base used for the neutralization is generally an amount for neutralizing the sulfonic acid in the esterification reaction solution, but the sulfonic acid is non-volatile under the operating conditions, and is different from hydrogen chloride gas. Since it does not volatilize, it can be neutralized by adding an equivalent to a small excess of a base equivalent to the sulfonic acid used in the esterification reaction. Usually, 1 to 2 times, preferably 1 to 2 times the gram equivalent number of sulfonic acid in the reaction solution.
1.5 times.

When the neutralization operation is performed using pH as an index,
If the pH is too low, the extraction efficiency is poor. On the other hand, if the pH is too high, the decomposition of the amino acid ester proceeds, so that it is preferable to neutralize the ester to approximately basic conditions. The lower limit is usually p
It is H8 or more, preferably pH 9 or more, and the upper limit is preferably pH 12 or less, more preferably pH 11 or less. That is, a pH of about 8 to 12, preferably a pH of 9 to 1
Neutralize so as to be around 1.

In general, the temperature of the neutralization operation (including the temperature at the time of contact with water during neutralization) is too high.
℃ or less, preferably 20 ℃ or less, more preferably 10 ℃
It is desirable to carry out the following.

The organic solvent which is not compatible with water is not particularly limited, but in order to provide a reaction environment suitable for the N-alkoxycarbonylation reaction in the next step, both free amino acid ester and dicarbonate are dissolved. In order to further reduce the amount of alcohol (and the amount of water) coexisting during the N-alkoxycarbonylation reaction, for example, when the organic solvent phase containing a free amino acid ester is separated from the aqueous phase, It is preferable to use an organic solvent having a water solubility of 10% by weight or less, preferably 5% by weight or less, more preferably 2% by weight or less.

Specific examples of the organic solvent incompatible with water include, for example, ethyl acetate, propyl acetate, butyl acetate,
According to the present invention, free amino acid esters can be efficiently extracted into an organic solvent phase using not only esters such as isobutyl acetate but also aromatic hydrocarbons having low polarity, and benzene, toluene and xylene can be efficiently extracted. And the like.

Among these water-insoluble organic solvents,
Those having a higher boiling point than the alcohol used in the esterification reaction are more convenient because the alcohol can be efficiently concentrated and removed or the solvent can be replaced. Among the above organic solvents, toluene is most preferably used.

Incidentally, these organic solvents incompatible with water may be allowed to coexist from the esterification reaction, if necessary.

The temperature at which the organic solvent phase containing the amino acid ester is separated from the aqueous phase is generally determined by the solubility of the free amino acid ester in the organic solvent phase and the presence or absence of meniscus during the phase separation. However, for example, about 0 to 100 ° C., usually about 10 to 50
It may be carried out at a temperature of ° C.

From the viewpoint of suppressing the decomposition of dicarbonate in the subsequent N-alkoxycarbonation reaction, the organic solvent phase containing the amino acid ester thus obtained is an organic solvent phase containing substantially no alcohol. Preferably, there is. Here, the “organic solvent phase substantially free of alcohol” is an organic solvent phase in which the alcohol content does not adversely affect the N-alkoxycarbonylation reaction. It means an organic solvent phase that does not decompose. Although it depends on the reaction concentration and the concentration of the amino acid ester, it generally means that the alcohol concentration in the organic solvent phase is 5% by weight or less.

Therefore, the organic solvent phase containing the free amino acid ester can reduce a part or all of its components in the step up to the N-alkoxycarbonylation reaction if necessary. The alcohol component is
In general, the concentration can be reduced by concentration distillation or solvent replacement or washing with water. However, concentration distillation or solvent replacement is effective.

Next, the N-alkoxycarbonylation reaction will be described.

By mixing the organic solvent phase containing the free amino acid ester with dicarbonate, the free amino acid ester reacts with dicarbonate to form N-
An organic solvent phase containing an alkoxycarbonyl amino acid ester can be obtained.

Dicarbonate is represented by the general formula (ROCO)
A compound represented by ₂ O, wherein R represents, for example, a methyl group, an ethyl group, an i-propyl group, an n-butyl group,
Examples include alkyl groups such as -butyl group and t-amyl group, alkenyl groups such as allyl group, and aralkyl groups such as benzyl group.

Specific examples of the dicarbonate which can be suitably used in the present invention include dimethyl dicarbonate, diethyl dicarbonate, diisopropyl dicarbonate, di-n-butyl dicarbonate, diisobutyl dicarbonate, di-t-butyl dicarbonate, Examples thereof include t-amyl dicarbonate, diallyl dicarbonate, dibenzyl dicarbonate and the like.

The amount of the dicarbonate to be used for the amino acid ester may be about 1 equivalent with respect to 1 equivalent of the amino group or imino group used for the alkoxycarbonylation reaction, and is usually 0.95 to 1.05 equivalent, preferably 0 to 1 equivalent. .9
It is 8 to 1.02 equivalents, more preferably 1.00 equivalent.

The reaction temperature in the N-alkoxycarbonylation reaction is not particularly limited. However, if the temperature is high, the decomposition of dicarbonate tends to proceed, so that the freezing point of the reaction system is usually 100 to 100 ° C., preferably -20 to 80 ° C. , More preferably in the range of 0 to 60 ° C.

The organic solvent phase containing the N-alkoxycarbonyl amino acid ester thus obtained may be further subjected to an acidic condition (usually, if necessary) for the purpose of avoiding traces of unreacted amino acid ester. It can be washed with water at a pH of 5 or less, preferably pH 0 to 4). Washing under acidic conditions not only removes unreacted amino acid esters, but also has very good liquid separation during washing, as compared to washing under neutral conditions.

[0056]

BEST MODE FOR CARRYING OUT THE INVENTION

[0057]

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples and the like, but the present invention is not limited to these examples.

Example 1 (Methyl esterification reaction of L-phenylalanine)
33.0 g (0.200 mol) of phenylalanine was suspended in 160 ml (4.0 mol) of methanol. Under an internal temperature of about 20 to 30 ° C., 38.4 g of methanesulfonic acid was added thereto while stirring at a required stirring power of 50 W / m ³ or less.
(0.400 mol) and 6.4 g of tetrahydrofuran
Was added over about 10 minutes, whereby L-phenylalanine was rapidly dissolved. Further power required for stirring 50
The reaction was carried out while slightly refluxing while stirring at W / m ³ or less. After 5 hours, the reaction had already reached equilibrium.

As a result of HPLC analysis of this reaction solution, L-
The molar ratio of phenylalanine / L-phenylalanine methyl ester was 2/98, and the yield of L-phenylalanine methyl ester was 35.1 g (0.19).
6 mol, the yield from L-phenylalanine is 98 mol
1%).

(Acquisition of Organic Solvent Phase Containing Free L-Phenylalanine Methyl Ester) The above reaction solution was concentrated under reduced pressure at an internal temperature of about 20 to 30 ° C. to a solution weight of 140 g. Further, after adding 80 ml of toluene, the solution weight 14
The operation of concentrating under reduced pressure to 0 g was repeated twice. afterwards,
80 ml of toluene was added, the mixture was cooled to an internal temperature of about 0 ° C., and at an internal temperature of about 0 to 5 ° C., 40 ml of water was added, followed by 40 ml (0.4 mol) of a 10N aqueous sodium hydroxide solution for neutralization. The pH of this solution was 9-10. The aqueous phase was separated at an internal temperature of about 20 to 25 ° C. to obtain an organic solvent phase containing 33.6 g of L-phenylalanine methyl ester. On the other hand, the aqueous phase was further extracted with 160 ml of toluene to obtain 1.1 g of L-phenylalanine methyl ester.
An organic solvent phase was obtained.

The obtained two organic solvent phases are combined and HPL
As a result of C analysis, L-phenylalanine was not detected,
The content of L-phenylalanine methyl ester is 3
4.7 g (0.194 mol, yield from L-phenylalanine: 95 mol%). When the organic solvent phase was analyzed by GC, the methanol concentration was 1% by weight.
It was below.

(Nt-Butoxycarbonylation Reaction of Free L-Phenylalanine Methyl Ester) The above organic solvent phase was stirred at an internal temperature of about 20 to 25 ° C. and required stirring power of 50 W /
While stirring under m ³ , 42.35 g (0.194 mol) of di-t-butyl dicarbonate and toluene 4
g of the mixture was slowly added dropwise over about 20 minutes.
With the required power of stirring of 0 W / m ³ or less, the internal temperature is about 20 to 25 ° C.
The reaction had already reached equilibrium after 5 hours.

The obtained organic solvent phase was analyzed by HPLC to find that L-phenylalanine methyl ester / Nt-
The molar ratio of butoxycarbonyl-L-phenylalanine methyl ester was 0.3 / 99.7. Note that L
-Phenylalanine and Nt-butoxycarbonyl-
L-phenylalanine was not detected.

(Adjustment of Concentration of Nt-Butoxycarbonyl-L-phenylalanine Methyl Ester Containing Solution)
It concentrated under reduced pressure to g. As a result of HPLC analysis of this concentrated solution, the content of Nt-butoxycarbonyl-L-phenylalanine methyl ester was found to be 53.6 g (0.19 g).
2 mol) (the yield from free L-phenylalanine methyl ester was 99 mol%, and the yield from L-phenylalanine was 96 mol%).

Example 2 (Synthesis of Nt-butoxycarbonyl-L-phenylalanine methyl ester from L-phenylalanine) 38.4 g of methanesulfonic acid used in Example 1
(0.400 mol) and 6.4 g of tetrahydrofuran
Was mixed with 38.4 g of methanesulfonic acid (0.400 m
ol), the same procedure as in Example 1 was carried out, except that N-
An organic solvent phase containing t-butoxycarbonyl-L-phenylalanine methyl ester was obtained.

As a result of HPLC analysis of the organic solvent phase,
The molar ratio of L-phenylalanine methyl ester / Nt-butoxycarbonyl-L-phenylalanine methyl ester was 0.5 / 99.5 (from L-phenylalanine to Nt-butoxycarbonyl-L-phenylalanine methyl ester). Is 96 mol%).

Example 3 (Washing of Nt-butoxycarbonyl-L-phenylalanine methyl ester-containing organic solvent phase with acidic water) 1/10 of the organic solvent phase obtained in Example 2
At 0 ° C., 17 ml of water was added, and the mixture was adjusted to pH 2-3 with stirring using 0.5N hydrochloric acid. After stirring for about 5 minutes,
On standing, the aqueous phase was separated. The remaining organic solvent phase is HPL
As a result of C analysis, the molar ratio of L-phenylalanine methyl ester / Nt-butoxycarbonyl-L-phenylalanine methyl ester was 0.01 or less / 99.99.
That was all.

The organic solvent phase was mixed with water 1 at an internal temperature of about 20 ° C.
7 ml was added and stirred for about 5 minutes. The pH at this time is 4 ~
It was 5. After standing, the aqueous phase was separated, and the remaining organic solvent phase was analyzed by HPLC. The molar ratio of L-phenylalanine methyl ester / Nt-butoxycarbonyl-L-phenylalanine methyl ester was 0.01 or less / 9.
It was 9.99 or more.

The organic solvent phase is heated at an internal temperature of about 20 to 30 ° C.
The solution was concentrated under reduced pressure to a solution weight of 12 g. This concentrated solution is HPL
As a result of C analysis, N
No decomposition of -t-butoxycarbonyl-L-phenylalanine methyl ester was observed.

Example 4 (Methyl esterification reaction of L-phenylalanine)
40.0 g (0.242 mol) of phenylalanine was suspended in 100 ml of methanol. Internal temperature about 20-30 ° C
Under a required power of 50 W / m3 or less, a mixed solution of 46.5 g (0.484 mol) of methanesulfonic acid and 8.2 g of tetrahydrofuran was added thereto over a period of about 10 minutes. Was dissolved. Further, the reaction was carried out while slightly refluxing while stirring at a power required for stirring of 50 W / m3 or less. After 5 hours, the reaction had already reached an equilibrium.

As a result of HPLC analysis of this reaction solution, L
The molar ratio of -phenylalanine / L-phenylalanine methyl ester was 3/97, and the amount of L-phenylalanine methyl ester produced was 42.1 g (0.2
35 mol, 97 m yield from L-phenylalanine
ol%).

(Acquisition of Organic Solvent Phase Containing Free L-Phenylalanine Methyl Ester) The above reaction solution was added at an internal temperature of about 0 to 7 ° C., 25 ml of water was added, and 65 g of a 30% by weight aqueous sodium hydroxide solution was added. And neutralized.
The pH of this solution was 10-11.

Thereafter, at an internal temperature of about 20 to 25 ° C., 200 ml of toluene was added and extracted, and the aqueous phase was separated to obtain an organic solvent phase containing 36.3 g of L-phenylalanine methyl ester. On the other hand, the aqueous phase was further extracted with 200 ml of toluene to obtain an organic solvent phase containing 4.6 g of L-phenylalanine methyl ester.

The obtained two organic solvent phases are combined and HPL
As a result of C analysis, L-phenylalanine was not detected,
The content of L-phenylalanine methyl ester is 4
0.9 g (0.228 mol, yield from L-phenylalanine: 94 mol%).

Next, the obtained organic solvent phase was concentrated to 273 g of the organic solvent phase. Thereafter, solvent replacement was carried out under reduced pressure while adding 80 ml of toluene to the organic solvent phase while keeping the volume almost constant, and the methanol content in the organic solvent phase was reduced to 1% by weight or less.

(Nt-butoxycarbonylation reaction of free L-phenylalanine methyl ester) Di-t-butyl dicarbonate was added to the above organic solvent phase at an internal temperature of about 20 ° C. and a required power of 50 W / m 3 or less. 49.8 g (0.
228 mol) was slowly added dropwise. 5 hours later, water 1
50 ml was added, and the pH was adjusted to 2 with 35% hydrochloric acid.
After standing, the aqueous phase was separated, and the obtained organic solvent phase was washed with water 15
After washing with 0 ml, the solution was concentrated under reduced pressure to a solution weight of 131 g.

As a result of HPLC analysis of the organic solvent phase finally obtained, the content of Nt-butoxycarbonyl-L-phenylalanine methyl ester was 62.7 g (0.224 mol, free L-phenylalanine). The yield from methyl ester is 98%, and the yield from L-phenylalanine is 93%). In addition, L-phenylalanine, L-phenylalanine methyl ester and Nt-
Butoxycarbonyl-L-phenylalanine was not detected.

Comparative Example 1 (Washing of Organic Solvent Phase Containing Nt-Butoxycarbonyl-L-phenylalanine Methyl Ester with Neutral Water) The internal temperature was reduced to 1/10 of the organic solvent phase obtained in Example 2. 2
At 0 ° C., 17 ml of water was added, and the mixture was stirred for about 5 minutes. The pH at this time was about 7. After standing, the aqueous phase was separated, and the remaining organic solvent phase was analyzed by HPLC. As a result, L-phenylalanine methyl ester / Nt-butoxycarbonyl-
The molar ratio of L-phenylalanine methyl ester is 0.3
/99.7. An internal temperature of about 20 ° C.
Below, 17 ml of water was added, and the mixture was stirred for about 5 minutes. P at this time
H was about 7.

After standing, the aqueous phase was separated, and the remaining organic solvent phase was analyzed by HPLC. The molar ratio of L-phenylalanine methyl ester / Nt-butoxycarbonyl-L-phenylalanine methyl ester was 0.1 / 0.1 99.9
Met. It should be noted that the liquid separation property was poor as compared with (the washing of the organic solvent phase containing Nt-butoxycarbonyl-L-phenylalanine methyl ester with acidic water) of Example 3, and the emery and the turbidity of the organic solvent phase during washing were poor. It was remarkable.

Reference Example 1 2 g of various solvents were added to 18 g of methanesulfonic acid at room temperature. A SUS304 test piece is immersed in this mixture,
The test pieces were stored at 40 ° C. for 1 week in a nitrogen atmosphere, and the test pieces were examined for corrosion (degree of erosion). The results are shown in Table 1.

[0081]

[Table 1] Reference Example 2 In a 100 ml eggplant flask equipped with a cooling tube,
1.0 g of di-t-butyl dicarbonate and the solvent shown in Table 2 were added, and the mixture was maintained under predetermined conditions, and the residual ratio of di-t-butyl dicarbonate was examined. The results are shown in Table 2.

[0082]

[Table 2]

[0083]

The N-alkoxycarbonyl amino acid ester can be produced on an industrial scale with good productivity, operability, yield and quality.

 ────────────────────────────────────────────────── ─── Continued on front page (72) Inventor Yasuyoshi Ueda 140-15 F-term (reference) 4H006 AA02 AC48 AC56 AD16 BA52 BA66 BB10 BB11 BB31 BB44 BB46 RA06 RB04

Claims (21)

[Claims] An amino acid, an alcohol, and a sulfonic acid are reacted, the resulting sulfonic acid salt of the amino acid ester is neutralized with a base, and the sulfonic acid generated by neutralization using an organic solvent and water that are incompatible with water. And the base salt and unreacted amino acid are removed to the aqueous phase, and the formed free amino acid ester is extracted into the organic solvent phase. A method for producing an N-alkoxycarbonyl amino acid ester, comprising reacting a carbonate to N-alkoxycarbonyl to obtain an organic solvent phase containing the N-alkoxycarbonyl amino acid ester. 2. The organic solvent phase containing a free amino acid ester to be subjected to the N-alkoxycarbonylation reaction is an organic solvent phase containing substantially no alcohol.
The method for producing an N-alkoxycarbonyl amino acid ester according to the above. 3. A method in which a part or all of an alcohol component is concentrated and distilled off in a step until an organic solvent phase substantially containing no alcohol and containing a free amino acid ester is subjected to an N-alkoxycarbonylation reaction. 3. The method for producing an N-alkoxycarbonyl amino acid ester according to claim 2, which is obtained by solvent replacement. 4. The N-alkoxy according to claim 1, 2 or 3, wherein the organic solvent phase containing the N-alkoxycarbonyl amino acid ester is washed with water under acidic conditions to remove unreacted amino acid ester into the aqueous phase. A method for producing a carbonyl amino acid ester. 5. The method for producing an N-alkoxycarbonyl amino acid ester according to claim 1, wherein the water-insoluble organic solvent is a water-insoluble organic solvent having a higher boiling point than the alcohol used. Law. 6. The method for producing an N-alkoxycarbonyl amino acid ester according to claim 1, wherein the organic solvent incompatible with water is an aromatic hydrocarbon solvent. 7. The method for producing an N-alkoxycarbonyl amino acid ester according to claim 6, wherein the aromatic hydrocarbon solvent is toluene. 8. The method for producing an N-alkoxycarbonyl amino acid ester according to claim 1, wherein the sulfonic acid is methanesulfonic acid. 9. The method for producing an N-alkoxycarbonyl amino acid ester according to claim 1, wherein the amino acid is phenylalanine. 10. The method for producing an N-alkoxycarbonyl amino acid ester according to claim 1, wherein the dicarbonate is di-t-butyl dicarbonate. 11. The N according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, wherein the alcohol is methanol.
-A method for producing an alkoxycarbonyl amino acid ester. 12. A sulfonic acid produced by reacting an amino acid, an alcohol and a sulfonic acid, neutralizing a sulfonic acid salt of the produced amino acid ester with a base, and using an organic solvent and water which are incompatible with water. An amino acid characterized in that, while removing a salt of a base and an unreacted amino acid into an aqueous phase, and extracting a generated free amino acid ester into an organic solvent phase, an organic solvent phase containing a free amino acid ester is obtained. Method for producing esters. 13. The method for producing an amino acid ester according to claim 12, wherein the organic solvent phase containing a free amino acid ester is an organic solvent phase containing substantially no alcohol. 14. An organic solvent phase substantially free of alcohol and containing a free amino acid ester, wherein the organic solvent phase is obtained by concentrating and distilling off or replacing a part or all of the alcohol component. 14. The method for producing an amino acid ester according to claim 13, which is an organic solvent phase containing no. 15. The process for producing an amino acid ester according to claim 12, wherein the water-insoluble organic solvent is a water-insoluble organic solvent having a higher boiling point than the alcohol used. 16. The method for producing an amino acid ester according to claim 12, wherein the organic solvent incompatible with water is an aromatic hydrocarbon solvent. 17. The method for producing an amino acid ester according to claim 16, wherein the aromatic hydrocarbon is toluene. 18. The sulfonic acid is methanesulfonic acid.
A method for producing an amino acid ester according to claim 12, 13, 14, 15, 16, or 17. (19) the method for producing an amino acid ester according to the above (12), (13), (14), (15), (16), (17) or (18); 20. The method according to claim 12, wherein the dicarbonate is di-t-butyl dicarbonate.
20. The method for producing an amino acid ester according to 7, 18 or 19. 21. The method according to claim 1, wherein the alcohol is methanol.
2, 13, 14, 15, 16, 17, 18, 19, or 2
0. The method for producing an amino acid ester according to 0.