JPH08157431A - Production of n-alkoxycarbonylamino acid ester - Google Patents

Abstract

PURPOSE: To obtain the subject compound with low impurities in high yield in a simple operation. CONSTITUTION: A salt of an amino acid ester with acid is reacted with a dialkyl dicarbonate in the presence of an inorganic salt in an organic solvent compatible with water to produce a reaction liquor containing the objective N- alkoxycarbonylamino acid ester; the reaction liquor is then mixed with water so as to come to pH3.0-9.0 by such means as neutralization with an acid, and the objective N-alkoxycarbonylamino acid ester is isolated from the resultant mixture.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for industrially and easily producing N-alkoxycarbonyl amino acid esters.

[0002]

N-alkoxycarbonyl amino acid esters are useful compounds as synthetic intermediates for pharmaceuticals such as antibiotics. As a method for producing the N-alkoxycarbonyl amino acid ester, a method of reacting a dialkyl dicarbonate with an amino group of a salt of the amino acid ester with an acid is known. For example, a method of reacting amino acid ester hydrochloride with di-t-butyl dicarbonate in the presence of a stoichiometric amount of an organic base such as triethylamine or diisopropylethylamine (Journal of Medicinal Chemistry ( J. Med. Chem.) Vol. 26, No. 4, 549-5.
4 pages, 1986).

[0003]

However, in the above method, since the N-alkoxycarbonyl amino acid ester is to be isolated from the organic solvent, the organic base used for the neutralization and the ammonium by-produced by the neutralization are obtained. For the purpose of removing salts, washing operations with an acidic aqueous solution, a basic aqueous solution, and water must be performed, which requires a very complicated operation. Furthermore, it is necessary to separately treat a large amount of waste water containing ammonium salts.

In order to solve this problem, a method using an inorganic base was previously proposed (Japanese Patent Laid-Open No. 6-192207), but unreacted amino acid ester can be obtained only by separating the inorganic salt and distilling off the solvent. Impurities such as remain, resulting in N
-The purity of the alkoxycarbonyl amino acid ester was not yet satisfactory.

[0005]

In view of the above situation, the present inventors have further earnestly studied a method for producing an N-alkoxycarbonylamino acid ester containing few impurities by a simple operation and a high yield. As a result, a salt of an amino acid ester with an acid is reacted with a dialkyl dicarbonate in an organic solvent compatible with water in the presence of an inorganic base to obtain a reaction liquid containing an N-alkoxycarbonyl amino acid ester, and then It was found that N-alkoxycarbonyl amino acid ester can be isolated with high purity and high yield by mixing the reaction solution and water so as to have a specific pH, and completed the present invention.

That is, the present invention provides a salt of an amino acid ester with an acid and a dialkyl dicarbonate in the presence of an inorganic base.
A reaction solution containing an N-alkoxycarbonyl amino acid ester is obtained by reacting in an organic solvent compatible with water, and then the reaction solution and water are mixed so as to have a pH of 3.0 to 9.0. The method for producing an N-alkoxycarbonyl amino acid ester is characterized in that the N-alkoxycarbonyl amino acid ester is isolated from a mixed liquid of this reaction liquid and water.

In the present invention, known salts of amino acid esters with acids can be used without any limitation. As the amino acids constituting the amino acid ester,
Known compounds can be used without any limitation as long as they are compounds having at least one or more amino group or imino group and at least one or more carboxyl group in the molecule. In the case of an amino acid having two or more amino groups or imino groups in one molecule or a substituted amino group or a substituted imino group in which they are substituted with an alkyl group or the like,
Other amino or imino groups may be substituted as long as they have at least one amino or imino group. In the case of an amino acid having two or more carboxyl groups or substituted carboxyl groups in one molecule, at least one carboxyl group capable of ester bond is substituted with other carboxyl groups. May be.

Specific examples of amino acids that can be preferably used in the present invention include, for example, glycine, alanine, β-
Alanine, valine, norvaline, leucine, norleucine, isoleucine, α-aminobutyric acid, β-aminobutyric acid,
γ-aminobutyric acid, α-aminoisobutyric acid, N-methylglycine, γ-formyl-N-methylnorvaline, serine,
Aliphatic neutral amino acids such as homoserine, isoserine, threonine, threonine, cystine, homocystine, S-acetamidomethyl-cystine, methionine, homomethionine, asparagine and glutamine, and fatty acid amino acids such as aspartic acid, glutamic acid and homoglutamic acid , Lysine, arginine, hydroxylysine,
Ornithine, aliphatic basic amino acids such as N-iminoethylornithine, phenylalanine, phenylglycine, aspartic acid-β-benzyl ester, S-benzyl-cystine, O-benzylserine, N-benzyloxycarbonyl-lysine, tyrosine, Aromatic neutral amino acids such as thyroxine and diiodotyrosine, aromatic basic amino acids such as N-tosylarginine and N-benzyloxycarbonyl-arginine, aromatic acidic amino acids such as β-phenylglutamic acid, proline and hydroxy. Heterocyclic neutral amino acids such as proline and tryptophan,
Examples thereof include heterocyclic basic amino acids such as histidine, and heterocyclic acidic amino acids such as γ-carboxyproline. Furthermore, amino acids having high solubility in water, for example, serine, threonine, hydroxyphenylglycine, hydroxyproline, and other amino acids having a hydroxyl group,
Particularly preferred are amino acids having a mercapto group such as cysteine, acidic amino acids such as aspartic acid, and basic amino acids such as lysine.

The functional groups of the side chains of these amino acids may be protected, or they may be a racemic mixture containing optical isomers. Moreover, a peptide in which two or more amino acids are linked can also be used in the present invention.

In the present invention, the amino acid ester composed of such amino acids is preferably one represented by the following general formula.

H—X—R (1) (wherein X is an amino acid residue and R is an alkyl group, an alkenyl group or an aralkyl group which may have a substituent.) In the general formula (1) As R, an alkyl group, an alkenyl group or an aralkyl group can be used without any limitation. Particularly, as the alkyl group, a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group,
Examples thereof include those having 1 to 4 carbon atoms such as i-butyl group and t-butyl group, examples of alkenyl group include allyl group, and examples of aralkyl group include benzyl group. Examples of these substituents include a halogen atom, an alkoxy group, an alkylthio group, a nitro group, a pyridyl group and a phthalimido group. Examples of the alkyl group, alkenyl group and aralkyl group substituted with these substituents include a trichloroethyl group, β-methylthioethyl group, p-nitrobenzyl group, p-methoxybenzyl group and picolyl group.

In the present invention, any known acid may be used as the acid constituting the salt with the amino acid ester. Specific examples thereof include mineral acids such as hydrochloric acid and sulfuric acid, sulfonic acids such as methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, and carboxylic acids such as acetic acid.

In the present invention, as the dialkyl dicarbonate to be reacted with the salt of the above amino acid ester with an acid, known ones can be used without particular limitation. The alkyl group is a methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, t
A lower alkyl group having 1 to 4 carbon atoms such as -butyl group is preferable. Specifically, dimethyl dicarbonate,
Examples thereof include diethyl dicarbonate, diisopropyl dicarbonate, diisobutyl dicarbonate, di-t-butyl dicarbonate and di-t-amyl dicarbonate.

If the amount of the dialkyl dicarbonate to be used with respect to the salt of the amino acid ester with an acid is less than 1 equivalent, the remaining amino acid ester and the like are mixed in the produced N-alkoxycarbonyl amino acid ester. The amount is 1 equivalent or more with respect to 1 equivalent of the amino group or imino group of the salt of the ester with an acid, but it is preferably used in the range of 1 to 1.5 equivalents in consideration of economical efficiency and the like.

The reaction of the salt of the above amino acid ester with an acid and the dialkyl dicarbonate is carried out in the presence of an inorganic base.
It is carried out in an organic solvent compatible with water. Specific examples of the inorganic bases that can be preferably used in the present invention include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide and magnesium hydroxide, and carbonic acid. Examples thereof include carbonates such as sodium and potassium carbonate, and bicarbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate. In particular, carbonates such as sodium carbonate and potassium carbonate, bicarbonates such as sodium hydrogencarbonate and potassium hydrogencarbonate, etc., which hardly cause hydrolysis during neutralization, are preferably used. These inorganic bases may be used alone or in combination of two or more. Further, it can be used regardless of the properties of the base such as bulk specific gravity.

The amount of the inorganic base used is usually preferably 1 equivalent or more per 1 equivalent of the acid component of the salt of the amino acid ester with an acid. In order to completely neutralize the acid component in the salt of the amino acid ester with an acid and in consideration of economy, 1.0 to 1.5 per 1 equivalent of the acid component of the salt of the amino acid ester with an acid is taken into consideration. A range of equivalents is preferred.

When the production method of the present invention is carried out subsequently to the esterification reaction of an amino acid as described below, the reaction of the salt of the amino acid ester obtained by the esterification reaction of the amino acid with an acid is contained. The liquid contains excessive sulfur dioxide generated due to strong acid such as hydrogen chloride used in the esterification reaction or thionyl chloride.
In such a case, the inorganic base is used by adding to the amount of the acid salt of the above amino acid ester with respect to the acid component, and further adding an amount sufficient to completely neutralize the free acidic component contained in this reaction solution. Is common.

The organic solvent compatible with water is not particularly limited, but preferably, alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, nitriles such as acetonitrile,
Ketones such as acetone can be used, and further,
Since there is no fear of transesterification reaction, alcohols of the same type as the alcohol residue of the ester are preferably used.
The amount of the organic solvent during the reaction is not particularly limited, but in the range of 50 to 500 parts by weight with respect to 100 parts by weight of the salt of the amino acid ester with an acid, from the viewpoint of easiness of stirring, reaction rate and the like. preferable.

In the present invention, the method of allowing the above-mentioned inorganic base to be present in the reaction solution of the salt of the amino acid ester with the acid and the dialkyl dicarbonate is not limited in any way. For example, the inorganic base may be suspended in an organic solvent and mixed with the reaction solution, or the inorganic base itself may be mixed. When an organic solvent is used, the same organic solvent as the organic solvent used as the reaction solution and a different organic solvent can be used without limitation. In that case, the amount of the organic solvent used for suspension is not particularly limited, but in consideration of easiness of stirring and liquid transfer, economy, etc., it is 40 with respect to 100 parts by weight of the inorganic base.
It is preferably about 500 parts by weight.

The order of mixing the salt of the amino acid ester with an acid, the dialkyl dicarbonate and the inorganic base is not particularly limited, and the order may be any order. In order to minimize the decomposition of the dialkyl dicarbonate, it is preferable to mix the organic solution of the salt of the amino acid ester with the acid, the inorganic base by the above method, and then further mix the dialkyl dicarbonate,
The inorganic base and the dialkyl dicarbonate may be simultaneously mixed with an organic solution of a salt of an amino acid ester with an acid, or the dialkyl dicarbonate may be mixed first and then the inorganic base. Also, while watching the reaction between the dialkyl dicarbonate and the amino acid ester, it is possible to mix the inorganic base in several times.

The reaction temperature of the salt of the amino acid ester with an acid and the dialkyl dicarbonate is not particularly limited, but if the temperature is too high, the raw material dialkyl dicarbonate and the product are decomposed.
Considering the range of 80 ° C, workability, etc., the range of 0 to 60 ° C is preferable.

The reaction pressure may be normal pressure, increased pressure or reduced pressure, and the time required for the reaction varies depending on the reaction temperature and the type of the starting amino acid, but is usually 30 minutes. ~ 120 hours range. The reaction can be carried out batchwise or continuously.

A reaction solution containing an N-alkoxycarbonyl amino acid ester can be obtained by the reaction of the salt of the amino acid ester with an acid and the dialkyl dicarbonate.
Therefore, the most important feature of the present invention is that when the N-alkoxycarbonylamino acid ester is isolated from the reaction solution, the pH of the reaction solution and water is 3.0 to 9.0, preferably 4.0. It is to mix so that it may become 8.0.

That is, in the reaction solution containing the N-alkoxycarbonyl amino acid ester, in addition to the compound, a salt formed by neutralizing the acid component of the salt of the amino acid ester with an acid, the remaining amino acid ester, etc. Impurities coexist. Thus, the salts and impurities such as amino acid esters are well soluble in water, while the N-alkoxycarbonyl amino acid esters have low solubility in the water. By mixing the reaction liquid containing the alkoxycarbonylamino acid ester with water, the N-alkoxycarbonylamino acid ester can be easily isolated.

At this time, it is important that the pH of the mixed liquid of the reaction liquid containing the N-alkoxycarbonyl amino acid ester and water is adjusted to 3.0 to 9.0. That is, the inorganic base also coexists in the reaction liquid containing the N-alkoxycarbonyl amino acid ester. This inorganic base also dissolves well in water, but when the reaction liquid containing the N-alkoxycarbonyl amino acid ester is mixed with water in the presence of the inorganic base, the mixed liquid exhibits strong basicity. The hydrolysis reaction proceeds in the ester portion of the N-alkoxycarbonyl amino acid ester. The hydrolysis reaction not only lowers the yield of the N-alkoxycarbonyl amino acid ester, but also causes a problem that the hydrolysis product is mixed in the N-alkoxycarbonyl amino acid ester. In the above situation, the present invention suppresses the hydrolysis reaction by mixing the reaction liquid containing the N-alkoxycarbonyl amino acid ester with water as described above to the specific pH. Is.

Here, the pH of the mixed liquid of the reaction liquid containing the N-alkoxycarbonyl amino acid ester and water is 9.0.
When it is higher, the hydrolysis reaction of the ester proceeds, while when the pH is lower than 3.0, the hydrolysis reaction of the ester proceeds and the elimination reaction of the alkoxycarbonyl group also proceeds.

In the present invention, the amount of water mixed into the reaction solution containing the N-alkoxycarbonyl amino acid ester is not particularly limited, but the purity and yield of the obtained N-alkoxycarbonyl amino acid ester may be varied. In consideration of goodness, it is most preferable to use it in the range of 50 to 2000 parts by weight with respect to 100 parts by weight of N-alkoxycarbonyl amino acid ester.

In the present invention, the pH of the mixed liquid of the reaction liquid containing N-alkoxycarbonyl amino acid ester and water
Is adjusted to 3.0 to 9.0 without any particular limitation, and any method may be used.

For example, after mixing the above reaction liquid with water,
Examples thereof include a method of neutralizing the mixed solution with an acid, and a method of removing an inorganic base from the reaction solution before mixing the reaction solution containing the N-alkoxycarbonyl amino acid ester with water.

As a neutralization method, a known method can be generally used. For example, a method of directly adding a mineral acid such as hydrogen chloride or sulfuric acid to the reaction solution, or a method of adding a solution diluted with water in advance. Can be mentioned.

The method of removing the inorganic base in advance is not particularly limited, but specifically, the fact that the inorganic base is poorly soluble in an organic solvent is used, and specific gravity such as centrifugal sedimentation and decantation is used. Difference separation method, centrifugal filtration, pressure filtration,
It is preferably removed by a filtration method such as atmospheric filtration or vacuum filtration. At this time, the separated inorganic base may be extracted with an organic solvent to collect the attached N-alkoxycarbonyl amino acid ester. When the reaction liquid from which the inorganic base has been removed in advance is mixed with water by such a method, p of the mixed liquid is
H becomes 7.0 to 9.0.

The pH obtained by the above method is from 3.0 to
The mixed solution of 9.0 contains the water-compatible organic solvent used as a reaction medium in the reaction of the salt of the amino acid ester with the acid and the dialkyl dicarbonate. In the present invention, when the organic solvent is contained, N
-There is no problem in isolating the alkoxycarbonyl amino acid ester, but the isolation yield may decrease depending on the type of the salt of the amino acid used with the acid. As far as possible, it is preferable to distill off the organic solvent.

The method for distilling off may be either atmospheric pressure or reduced pressure, but it is preferable to distill off under reduced pressure in order to suppress hydrolysis of the N-alkoxycarbonylamino acid ester as much as possible. This removal of the organic solvent may be carried out in advance before mixing the reaction liquid containing the N-alkoxycarbonyl amino acid ester with water, which may be a problem.

The concentration of the N-alkoxycarbonyl amino acid ester in the thus obtained mixed liquid is
There is no particular limitation, but if too much water leads to a reduction in the isolation yield in the separation step, and if the concentration is high, operating problems such as liquid transfer will occur, so preferably 5 to 70% by weight, More preferably, it is in the range of 10 to 60% by weight.

In the present invention, the isolation of the N-alkoxycarbonyl amino acid ester from the above mixed solution is not particularly limited, but usually, the compound is crystallized from the mixed solution or is incompatible with water. It is preferable to carry out by mixing an organic solvent which dissolves the N-alkoxycarbonyl amino acid ester with this mixed solution and extracting the compound into the organic solvent layer which is incompatible with water.

When the N-alkoxycarbonyl amino acid ester is isolated by crystallization, the crystallization temperature is usually from the freezing point of the system to 70 ° C.
It is preferable to adopt from the range of 40 ° C. A known method can be used for separating the precipitated crystals without limitation. For example, you may isolate | separate by filtration, centrifugation, etc.
If necessary, further washing with water or washing with an organic solvent can be performed during these separation operations.

On the other hand, when the isolation of the N-alkoxycarbonyl amino acid ester is carried out by an extraction operation with an organic solvent which is incompatible with water and dissolves the N-alkoxycarbonyl amino acid ester, the organic solvent is Those having the above properties can be used without particular limitation. Specifically, halogenated aliphatic hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform, aromatic hydrocarbons such as toluene, halogenated aromatic hydrocarbons such as chlorobenzene, and esters such as ethyl acetate. And ethers such as diisopropyl ether. The N-alkoxycarbonyl amino acid ester separated by extraction may be taken out by a known method such as distilling off the organic solvent.

The method for producing the N-alkoxycarbonyl amino acid ester of the present invention may be carried out in the esterification reaction liquid subsequent to the esterification reaction of the amino acid. Thereby, an N-alkoxycarbonyl amino acid ester can be efficiently produced from an amino acid. A known method can be applied to the esterification reaction of the amino acid without particular limitation. Specifically, a method of reacting an amino acid with a chlorosulfonic acid ester obtained by reacting an alcohol with thionyl chloride in an alcohol solution,
A method of reacting an acid chloride obtained by reacting an amino acid with thionyl chloride and an alcohol, a method of reacting an amino acid with an alcohol in the presence of an acid, or in the presence of an acid,
Examples thereof include a method of reacting an amino acid with an alkyl olefin.

[0039]

According to the present invention, a salt of an amino acid ester with an acid is reacted with a dialkyl dicarbonate in the presence of an inorganic base in an organic solvent compatible with water to adjust the pH, and The N-alkoxycarbonyl amino acid ester can be obtained in high purity and high yield by an industrially easy operation of obtaining the N-alkoxycarbonyl amino acid ester from a mixed solution with water. Therefore, the present invention is industrially extremely useful as a method for producing an N-alkoxycarbonyl amino acid ester.

[0040]

EXAMPLES The present invention will be described below with reference to examples.
The invention is not limited to these examples.

Example 1 L-proline methyl ester hydrochloride 82.8 g (0.5
A solution of 250 mol of methanol in 250 ml of methanol was placed in a four-necked flask in advance.
Mol) in a suspension of 50 ml of methanol under stirring at 10 ° C.
Dropped below. Furthermore, 109 g (0.5 mol) of di-t-butyl dicarbonate was added dropwise under ice cooling, and then the mixture was reacted at room temperature for 12 hours. Next, 250 g of alcohol was distilled off under reduced pressure. To this residual liquid, mix 800 ml of water,
Further, 1M hydrochloric acid was added to adjust the pH to 7.0, and an extraction operation was performed using 150 ml of ethyl acetate. The ethyl acetate layer was washed with 100 ml of water, and the ethyl acetate was distilled off under reduced pressure to obtain 111 g of Nt-butoxycarbonyl-L-proline methyl ester. The yield was 97%. The hydrolysis product, Nt-butoxycarbonyl-L-
Proline content is measured by high performance liquid chromatography (hereinafter HP
It was 0.5% or less when quantified by LC). In addition, L-proline methyl ester, which is an amino acid ester, was 0.5% or less as determined by HPLC.

Examples 2 to 8 and Comparative Example 1 The same operation as in Example 1 was carried out except that the reaction was carried out using the inorganic bases shown in Table 1 and the pHs shown in Table 1 were adjusted. . Table 1 shows the results.

[0043]

[Table 1]

Comparative Example 2 The procedure of Example 1 was repeated except that the pH was not adjusted to obtain 98.6 g of N-butoxycarbonyl-L-proline methyl ester. In addition, the pH of the reaction liquid containing N-butoxycarbonyl-L-proline methyl ester which does not adjust pH and water is 10.6.
Met. The yield of N-butoxycarbonyl-L-proline methyl ester was 86%. The content of Nt-butoxycarbonyl-L-proline as a hydrolysis product was 2.0% as determined by HPLC. The amount of L-proline methyl ester, which is an amino acid ester, was 0.5% or less as determined by HPLC.

Comparative Example 3 In a four-necked flask, 82.8 g (0.5 mol) of L-proline methyl ester hydrochloride and 64 g of sodium carbonate were added.
(0.6 mol) and chloroform (250 ml) were added, and di-t-butyl dicarbonate (109 g) was added under ice cooling.
(0.5 mol) was added dropwise, and then the mixture was reacted at room temperature for 24 hours. After the reaction solution was filtered by suction, all the solvent was distilled off to obtain 111 g of Nt-butoxycarbonyl-L-proline methyl ester. The yield was 95%. The content of L-proline methyl ester, which is an amino acid ester, was 2.0% when quantified by HPLC.
Met.

Comparative Example 4 Into a four-necked flask, 90.8 g (0.5 mol) of L-hydroxyproline methyl ester hydrochloride, 64 g (0.6 mol) of sodium carbonate and 250 L of chloroform were placed,
Furthermore, 109 g of di-t-butyl dicarbonate under ice cooling
(0.5 mol) was added dropwise, and then the mixture was reacted at room temperature for 24 hours. After the reaction solution was suction filtered, the solvent was distilled off, and 200 ml of hexane was added for crystallization. The obtained crystals were separated by suction filtration, and Nt-butoxycarbonyl-
L-hydroxyproline methyl ester 104.2 g
I got The yield was 85%. The content of L-hydroxyproline methyl ester, which is an amino acid ester, was 1.5% as determined by HPLC.

Example 9 In the same manner as in Example 1, L-proline methyl ester hydrochloride was reacted with di-t-butyl dicarbonate.
Then, the obtained reaction solution was filtered to remove excess inorganic base by filtration, and 250 g of alcohol was distilled off from the filtrate under reduced pressure. When 800 ml of water was mixed with this residual liquid, the pH of the resulting mixed liquid was 7.8. This mixed solution was extracted with 150 ml of ethyl acetate. The ethyl acetate layer was washed with 100 ml of water and the ethyl acetate was distilled off under reduced pressure to obtain 111 g of Nt-butoxycarbonyl-L-proline methyl ester. The yield was 97%. The content of Nt-butoxycarbonyl-L-proline, which is a hydrolysis product, was 0.5% or less as determined by HPLC. Moreover, the content rate of L-proline methyl ester which is an amino acid ester was 0.5% or less when quantified by HPLC.

Examples 10 to 13 Example 1 to Example 1 except that the amino acid ester salts shown in Table 2 were used and the N-alkoxycarbonyl amino acid ester shown in Table 2 was obtained in the solvent shown in Table 2. The same operation was performed. Table 3 shows the results.

[0049]

[Table 2]

Examples 14 to 15 N-alkoxycarbonyl amino acid esters shown in Table 3 were obtained in the same manner as in Example 13 except that the compounds shown in Table 3 were used as the dialkyl dicarbonates. The dialkyl dicarbonate used and the yield are shown in Table 3.
It was shown to.

[0051]

[Table 3]

Example 16 In a four-necked flask equipped with a stirrer and a thermometer, 66 g (0.5 mol) of L-hydroxyproline and 250 of methanol were added.
Add ml, and stir at 10 ° C or below under stirring to thionyl chloride 125
g (1.05 mol) was added, and the mixture was reacted at room temperature for 6 hours.
The obtained reaction liquid was added dropwise to a suspension of 91.8 g (0.85 mol) of sodium carbonate and 100 ml of methanol, which had been placed in a 4-neck flask in advance, at 10 ° C. or lower with stirring. Furthermore, di-t-butyl dicarbonate 10 under ice cooling
9 g (0.5 mol) was added dropwise, and then sodium carbonate 3
0.5g (0.3mol) was added and it was made to react at room temperature for 12 hours. Next, the precipitated inorganic salt and excess inorganic base were separated by centrifugation, the salt was washed with 100 ml of methanol, and the washing solution was added to the filtrate first filtered. Then 25
After 0 g of alcohol was distilled off under reduced pressure, 300 ml of water was mixed. The pH of this mixed solution was 7.8. Further, 500 g of the solvent was concentrated under reduced pressure. The solution was cooled to 4 ° C. for crystallization, the crystals were collected by filtration, washed with 100 ml of water,
After drying, 115 g of crystals of Nt-butoxycarbonyl-L-hydroxyproline methyl ester were obtained. The yield was 94%. The content of Nt-butoxycarbonyl-L-hydroxyproline, which is a hydrolysis product, is
It was 0.5% or less as determined by HPLC. The content of L-hydroxyproline methyl ester, which is an amino acid ester, was quantified by HPLC,
It was 0.5% or less.

Examples 17 to 19 The same operations as in Example 16 were carried out except that the amino acids shown in Table 4 were used to obtain the N-alkoxycarbonyl amino acid esters shown in Table 4. The results are shown in Table 4.

[0054]

[Table 4]

Claims (1)

[Claims] 1. A reaction solution containing an N-alkoxycarbonyl amino acid ester is obtained by reacting a salt of an amino acid ester with an acid and dialkyldicarbonate in the presence of an inorganic base in an organic solvent compatible with water, Next, the reaction liquid and water are mixed so as to have a pH of 3.0 to 9.0, and the N-alkoxycarbonyl amino acid ester is isolated from the mixed liquid of the reaction liquid and water. Process for producing N-alkoxycarbonyl amino acid ester.