JP2915306B2 - Method for producing N-alkoxycarbonyl amino acid ester - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

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

[0002]

2. Description of the Related Art N-alkoxycarbonyl amino acid esters are useful as intermediates in the synthesis of pharmaceuticals such as antibiotics. As a method for producing this N-alkoxycarbonyl amino acid ester, a method has conventionally been known in which a dialkyl dicarbonate is reacted with an amino group of a salt of an amino acid ester with an acid. For example, a method of reacting an amino acid ester hydrochloride with di-t-butyl dicarbonate in an organic solvent in the presence of a stoichiometric amount of an organic base such as triethylamine or diisopropylethylamine (Journal of Medicinal Chemistry (Journal of Chem. J. Med. Chem.) 26, No. 4, 549-5.
4, 1986).

[0003]

However, in the above method, since the N-alkoxycarbonyl amino acid ester is to be isolated from an organic solvent, the organic base used for neutralization and ammonium by-produced by the neutralization are used. For the purpose of removing the salt, a washing operation 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 wastewater containing ammonium salts.

In order to solve this problem, a method using an inorganic base has been proposed before (JP-A-6-192207). However, an unreacted amino acid ester is obtained only by separating the inorganic salt and distilling off the solvent. And other impurities remain, resulting in N
The purity of the alkoxycarbonylamino acid ester was not one step satisfactory.

[0005]

Means for Solving the Problems In view of the above situation, the present inventors have further studied a method for producing an N-alkoxycarbonyl amino acid ester containing few impurities with a simple operation in 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 solution containing an N-alkoxycarbonyl amino acid ester. The inventors have found that N-alkoxycarbonyl amino acid esters can be isolated with high purity and high yield by mixing the reaction solution and water so as to have a specific pH, and have completed the present invention.

That is, the present invention provides a method for preparing a salt of an amino acid ester with an acid and a dialkyl dicarbonate in the presence of an inorganic base.
The reaction is carried out in an organic solvent compatible with water to obtain a reaction solution containing an N-alkoxycarbonyl amino acid ester. Then, the reaction solution and water are mixed so that the pH becomes 3.0 to 9.0. And isolating the N-alkoxycarbonyl amino acid ester from a mixture of the reaction solution 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,
As long as the compound has at least one or more amino groups or imino groups and at least one or more carboxyl groups in the molecule, known compounds can be used without any limitation. 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 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 addition, 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 another carboxyl group. You may.

Specific examples of amino acids that can be suitably used in the present invention include, for example, glycine, alanine and β-amino acid.
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,
Fatty neutral amino acids such as homoserine, isoserine, threonine, threonine, cystine, homocysteine, S-acetamidomethyl-cystine, methionine, homomethionine, asparagine, glutamine, and fatty acidic amino acids such as aspartic acid, glutamic acid, and homoglutamic acid , Lysine, arginine, hydroxylysine,
Orginin, aliphatic basic amino acids such as N-iminoethylornithine, phenylalanine, phenylglycine, aspartic acid-β-benzyl ester, S-benzyl-cysteine, 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, hydroxy Heterocyclic neutral amino acids such as proline and tryptophan,
Examples 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, amino acids having a hydroxyl group, such as serine, threonine, hydroxyphenylglycine, hydroxyproline,
An amino acid having a mercapto group such as cysteine, an acidic amino acid such as aspartic acid, a basic amino acid such as lysine and the like are particularly preferably used.

These amino acids may have a protected side chain functional group and may be a racemic mixture containing optical isomers. Further, a peptide in which two or more amino acids are connected can also be used in the present invention.

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

H—X—R (1) (where X is an amino acid residue and R is an alkyl group, alkenyl group or 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, alkenyl groups include allyl groups, and aralkyl groups include benzyl groups. Examples of these substituents include a halogen atom, an alkoxy group, an alkylthio group, a nitro group, a pyridyl group, a phthalimide group and the like. Examples of the alkyl group, alkenyl group, and aralkyl group substituted with these substituents include a trichloroethyl group, a β-methylthioethyl group, a p-nitrobenzyl group, a p-methoxybenzyl group, and a picolyl group.

In the present invention, the acid constituting these amino acid esters and salts may be any known acid. Specific examples 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, known dialkyl dicarbonates to be reacted with the above-mentioned salts of amino acid esters with acids are used without particular limitation. Alkyl groups are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t
A lower alkyl group having 1 to 4 carbon atoms such as -butyl group is preferred. Illustrative examples include dimethyl dicarbonate,
Examples thereof include diethyl dicarbonate, diisopropyl dicarbonate, diisobutyl dicarbonate, di-t-butyl dicarbonate, and di-t-amyl dicarbonate.

When the amount of the dialkyl dicarbonate used is less than 1 equivalent relative to the salt of the amino acid ester with the acid, the remaining amino acid ester and the like are mixed into the formed N-alkoxycarbonyl amino acid ester. The amount is at least 1 equivalent to 1 equivalent of the amino group or imino group of the salt with the acid of the ester, but it is preferably used in the range of 1 to 1.5 equivalents in view of economy and the like.

The above-mentioned reaction of a salt of an amino acid ester with an acid and a dialkyl dicarbonate is carried out in the presence of an inorganic base.
The reaction is performed in an organic solvent compatible with water. Specific examples of inorganic bases that can be suitably used in the present invention include sodium hydroxide, alkali metal hydroxides such as potassium hydroxide, calcium hydroxide, alkaline earth metal hydroxides such as magnesium hydroxide, and carbonic acid. Examples thereof include carbonates such as sodium and potassium carbonate, and bicarbonates such as sodium bicarbonate and potassium bicarbonate. In particular, carbonates such as sodium carbonate and potassium carbonate, and bicarbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, 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 irrespective of the properties of the base such as bulk specific gravity.

The amount of the inorganic base to be used is usually preferably at least 1 equivalent to 1 equivalent of the acid component of the salt with the acid of the amino acid ester. In order to completely neutralize the acid component in the salt with the acid of the amino acid ester, and in view of economy, the acid component of the salt with the acid of the amino acid ester is 1.0 to 1.5 to 1 equivalent of the acid component. A range of equivalents is preferred.

When the production method of the present invention is carried out subsequent to the esterification reaction of an amino acid as described later, a reaction containing a salt of an amino acid ester obtained by the esterification reaction of the amino acid with an acid is carried out. The liquid contains an excess of a strong acid such as hydrogen chloride used in the esterification reaction or sulfur dioxide generated by thionyl chloride.
In such a case, the inorganic base is used by adding an amount capable of completely neutralizing the free acidic components contained in the reaction solution to the amount based on the acid component of the salt with the acid of the amino acid ester. It is common.

The organic solvent compatible with water is not particularly limited, but is preferably alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, nitriles such as acetonitrile, and the like.
Ketones such as acetone can be used.
Since there is no fear of transesterification, an alcohol of the same type as the alcohol residue of the ester is preferably used.
The amount of the organic solvent at the time of the reaction is not particularly limited, but is preferably 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 the acid from the viewpoint of ease of stirring and reaction rate. preferable.

In the present invention, the method for causing 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 at all. 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 that used for the reaction solution and a different organic solvent can be used without limitation. In this case, the amount of the organic solvent used for the suspension is not particularly limited, but considering the ease of stirring and liquid transfer, economy, etc., 40 to 40 parts by weight of the inorganic base is considered.
It is preferably from 500 to 500 parts by weight.

The order of mixing the salt of the amino acid ester with the acid, the dialkyl dicarbonate and the inorganic base is not particularly limited, and the mixing may be carried out in any order. In order to minimize the decomposition of the dialkyl dicarbonate, it is preferable to mix the inorganic base with the organic solution of the salt with the acid of the amino acid ester by the above method, and then further mix the dialkyl dicarbonate,
The inorganic base and the dialkyl dicarbonate may be mixed simultaneously with the organic solution of the salt of the amino acid ester with the acid, or the inorganic base may be mixed after the dialkyl dicarbonate is mixed first. In addition, while observing the reaction between the dialkyl dicarbonate and the amino acid ester, the inorganic base may be mixed in several portions without any problem.

The reaction temperature of such an amino acid ester salt with an acid and a dialkyl dicarbonate is not particularly limited, but if the temperature is too high, the starting dialkyl dicarbonate and the product are decomposed.
In consideration of the range of 80 ° C., workability, and the like, the range is preferably 0 to 60 ° C.

The reaction can be carried out under any of normal pressure, increased pressure and reduced pressure. The time required for the reaction varies depending on the reaction temperature and the type of the amino acid used as the raw material. ~ 120 hours. The reaction can be performed in either a batch system or a continuous system.

The reaction of the above-mentioned salt of an amino acid ester with an acid and a dialkyl dicarbonate gives a reaction solution containing an N-alkoxycarbonyl amino acid ester.
Thus, the greatest feature of the present invention is that when isolating an N-alkoxycarbonyl amino acid ester from the reaction solution, the reaction solution and water are mixed at a pH of 3.0 to 9.0, preferably 4.0 to 9.0. It is to mix to 8.0.

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

At this time, it is important that the pH of the mixture of the reaction solution containing the N-alkoxycarbonylamino acid ester and water is adjusted to 3.0 to 9.0. That is, the inorganic base is also present in the reaction solution containing the N-alkoxycarbonyl amino acid ester. This inorganic base is also soluble in water, but when the reaction solution containing the N-alkoxycarbonyl amino acid ester is mixed with water in the presence of the inorganic base, the mixed solution exhibits strong basicity. , The hydrolysis reaction proceeds in the ester portion of the N-alkoxycarbonyl amino acid ester. The hydrolysis reaction not only reduces the yield of the N-alkoxycarbonyl amino acid ester, but also causes a problem that the hydrolysis product is mixed into the N-alkoxycarbonyl amino acid ester. Under the above circumstances, the present invention suppresses the hydrolysis reaction by adjusting the mixture of the reaction solution containing the N-alkoxycarbonyl amino acid ester and water to the specific pH as described above. It is.

Here, the pH of the mixture of the reaction solution containing the N-alkoxycarbonyl amino acid ester and water is 9.0.
When it is larger than this, the hydrolysis reaction of the ester proceeds, while when the pH is less 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 mixing amount of water in the reaction solution containing the N-alkoxycarbonyl amino acid ester is not particularly limited, but the purity and the yield of the obtained N-alkoxycarbonyl amino acid ester are not limited. Considering goodness, it is most preferable to use 50 to 2000 parts by weight based on 100 parts by weight of the N-alkoxycarbonyl amino acid ester.

In the present invention, the pH of a mixture of a reaction solution containing N-alkoxycarbonyl amino acid ester and water is adjusted.
Is not particularly limited, and may be adjusted by any method.

For example, after mixing the above reaction solution and water,
Examples of the method 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 the method of neutralization, known methods 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 in water in advance, etc. Can be mentioned.

The method of removing the inorganic base in advance is not particularly limited. Specifically, the specific gravity such as centrifugal sedimentation, decantation, etc. is utilized by utilizing the fact that the inorganic base is hardly soluble in an organic solvent. Differential separation, centrifugal filtration, pressure filtration,
It is preferable to remove by a filtration method such as normal pressure filtration and reduced pressure filtration. At this time, the separated inorganic base may be extracted with an organic solvent to recover the attached N-alkoxycarbonyl amino acid ester. According to such a method, when the reaction solution from which the inorganic base has been removed in advance and water are mixed, p
H becomes 7.0 to 9.0.

The pH of 3.0 to 3.0 obtained by the above method.
The mixture of 9.0 contains an organic solvent compatible with water 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, the mixed solution is converted to N
There is no problem in isolating the alkoxycarbonylamino acid ester, but depending on the type of the salt of the amino acid used with the acid, the isolation yield may be reduced. As far as possible, the organic solvent is preferably distilled off.

The distillation may be carried out by either normal pressure or reduced pressure. However, in order to minimize the hydrolysis of the N-alkoxycarbonyl amino acid ester, it is preferable to perform distillation under reduced pressure. The distillation of the organic solvent may be performed in advance before mixing the reaction solution containing the N-alkoxycarbonyl amino acid ester with water.

The concentration of the N-alkoxycarbonyl amino acid ester in the thus obtained mixture is as follows:
Although there is no particular limitation, too much water leads to a decrease in the isolation yield in the separation step, and if the concentration is high, operation problems such as liquid transfer occur, so that it is 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-alkoxycarbonylamino acid ester from the above-mentioned 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 mix an organic solvent that dissolves the N-alkoxycarbonylamino acid ester with this mixture and extract the compound into an organic solvent layer 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. Known methods can be used for separating the precipitated crystals without limitation. For example, they may be separated by filtration, centrifugation or the like.
If necessary, washing with water or an organic solvent can be performed during these separation operations.

On the other hand, when the N-alkoxycarbonyl amino acid ester is isolated by an extraction operation using 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 any 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 extracted by a known method such as distilling off the organic solvent.

The method for producing an N-alkoxycarbonyl amino acid ester of the present invention may be carried out in the esterification reaction solution following the amino acid esterification reaction. Thereby, an N-alkoxycarbonyl amino acid ester can be efficiently produced from an amino acid. A known method can be applied to the amino acid esterification reaction without any 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 of the method 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 an organic solvent compatible with water in the presence of an inorganic base, and the pH of the reaction solution is adjusted. By an industrially easy operation of obtaining an N-alkoxycarbonyl amino acid ester from a mixed solution with water, an N-alkoxycarbonyl amino acid ester can be obtained with high purity and high yield. Therefore, the present invention is industrially extremely useful as a method for producing an N-alkoxycarbonyl amino acid ester.

[0040]

Hereinafter, the present invention will be described with reference to examples.
The present invention is not limited to these embodiments.

Example 1 L-Proline methyl ester hydrochloride 82.8 g (0.5
Mol) of methanol in 250 ml of sodium carbonate 64 g (0.6 g) previously placed in a four-necked flask.
Mol) in a suspension of 50 ml of methanol under stirring at 10 ° C.
It was dropped below. Further, 109 g (0.5 mol) of di-t-butyl dicarbonate was added dropwise under ice-cooling, followed by a reaction at room temperature for 12 hours. Next, 250 g of alcohol was distilled off under reduced pressure. 800 ml of water is mixed with this residual liquid,
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 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 determined by high performance liquid chromatography (hereinafter HP
LC) was 0.5% or less. In addition, L-proline methyl ester, which is an amino acid ester, was quantified by HPLC and found to be 0.5% or less.

Examples 2 to 8 and Comparative Example 1 The procedure of Example 1 was repeated except that the reaction was carried out using the inorganic base shown in Table 1 and the pH was adjusted to the value shown in Table 1. . 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. The pH of the mixture of the reaction solution containing N-butoxycarbonyl-L-proline methyl ester and the pH not adjusted was 10.6.
Met. The yield of N-butoxycarbonyl-L-proline methyl ester was 86%. The content of Nt-butoxycarbonyl-L-proline, which is a hydrolysis product, was determined by HPLC to be 2.0%. Further, L-proline methyl ester, which is an amino acid ester, was determined by HPLC to be 0.5% or less.

Comparative Example 3 In a four-necked flask, 82.8 g (0.5 mol) of L-proline methyl ester hydrochloride, 64 g of sodium carbonate
(0.6 mol) and 250 ml of chloroform, and 109 g of di-t-butyl dicarbonate under ice-cooling.
(0.5 mol) was added dropwise, followed by reaction at room temperature for 24 hours. After suction filtration of the reaction solution, 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 determined by HPLC to be 2.0%
Met.

Comparative Example 4 A 4-neck flask was charged with 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.
Further, 109 g of di-t-butyl dicarbonate under ice cooling.
(0.5 mol) was added dropwise, followed by reaction at room temperature for 24 hours. After suction filtration of the reaction solution, the solvent was distilled off, and 200 ml of hexane was added for crystallization. The obtained crystals were separated by suction filtration to give 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 determined by HPLC to be 1.5%.

Example 9 In the same manner as in Example 1, L-proline methyl ester hydrochloride was reacted with di-t-butyl dicarbonate.
Next, the obtained reaction solution was filtered to remove an excessive 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 the residual liquid, the pH of the resulting mixed liquid was 7.8. This mixture was subjected to extraction using 150 ml of ethyl acetate. The ethyl acetate layer was washed with 100 ml of water, and 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 as a hydrolysis product was determined to be not more than 0.5% by HPLC. The content of L-proline methyl ester, which is an amino acid ester, was determined to be 0.5% or less by HPLC.

Examples 10 to 13 The same procedures as in Example 1 were carried out except that the N-alkoxycarbonyl amino acid ester shown in Table 2 was obtained in the solvent shown in Table 2 using the salt of the amino acid ester shown in Table 2. The same operation was performed. Table 3 shows the results.

[0049]

[Table 2]

Examples 14 to 15 The same procedure as in Example 13 was carried out except that the compounds shown in Table 3 were used as the dialkyl dicarbonates to obtain the respective N-alkoxycarbonyl amino acid esters shown in Table 3. Table 3 shows the dialkyl dicarbonate used and the yield.
It was shown to.

[0051]

[Table 3]

Example 16 A four-necked flask equipped with a stirrer and a thermometer was charged with 66 g (0.5 mol) of L-hydroxyproline and 250 ml of methanol.
and thionyl chloride 125
g (1.05 mol) was added and reacted at room temperature for 6 hours.
The obtained reaction solution was added dropwise to a suspension of 91.8 g (0.85 mol) of sodium carbonate and 100 ml of methanol at 10 ° C. or lower with stirring in a four-necked flask in advance. Further, di-t-butyl dicarbonate 10 was added under ice cooling.
9 g (0.5 mol) were added dropwise, followed by sodium carbonate 3
0.5 g (0.3 mol) was added and reacted 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 was added to the filtrate which was firstly filtered. Then 25
After 0 g of alcohol was distilled off under reduced pressure, 300 ml of water was mixed. The pH of this mixture was 7.8. Further, 500 g of the solvent was concentrated under reduced pressure. The solution was cooled to 4 ° C. for crystallization, and the crystals were collected by filtration and 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 hydrolysis product Nt-butoxycarbonyl-L-hydroxyproline content is:
It was 0.5% or less as determined by HPLC. The L-hydroxyproline methyl ester content, which is an amino acid ester, was determined by HPLC,
It was 0.5% or less.

Examples 17 to 19 The same procedures as in Example 16 were carried out except that the N-alkoxycarbonyl amino acid esters shown in Table 4 were obtained using the amino acids shown in Table 4. Table 4 shows the results.

[0054]

[Table 4]

Continuation of front page (56) References JP-A-62-181297 (JP, A) JP-A-6-192207 (JP, A) JP-A-47-9597 (JP, A) JP-A-2-306947 (JP, A) JP-A-3-261748 (JP, A) JP-A-5-213839 (JP, A) JP-A-6-41031 (JP, A) JP-A-6-49005 (JP, A) Edition Experimental Chemistry Lecture 22 Organic Synthesis IV-Acids, Amino Acids and Peptides-", Maruzen Co., Ltd., November 30, 1992, p. 234-235 (58) Fields investigated (Int. Cl. ⁶ , DB name) C07C 229/12 C07C 227/18 CA (STN) CAOLD (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. A reaction solution containing an N-alkoxycarbonyl amino acid ester by reacting a salt of an amino acid ester with an acid and a dialkyl dicarbonate in an organic solvent compatible with water in the presence of an inorganic base. Next, the reaction solution and water are mixed so that the pH becomes 3.0 to 9.0, and an N-alkoxycarbonyl amino acid ester is isolated from the mixture of the reaction solution and water. A method for producing an N-alkoxycarbonyl amino acid ester.