JPH07233138A - Method for producing n-alkoxycarbonylamino acid ester - Google Patents

Abstract

PURPOSE:To provide a method for producing an N-alkoxycarbonylamino acid ester, capable of isolating the compound by a simple means from the reaction solution obtained by the reaction of an amino acid ester salt with a dicarbonate. CONSTITUTION:When an N-alkoxycarbonylamino acid ester is produced by reacting an amino acid ester salt (but excluding hydrochloride) with a decarbonate of the formula (R<1> is alkyl, alkenyl, aralkyl), the reaction is performed in the presence of an inorganic base, preferably a carbonic acid salt having a dehyration function, in an organic solvent slightly dissolving a salt produced by the neutralization of the inorganic salt in the reaction but capable of dissolving the produced objective compound. The organic solvent has a solubility of <=1g/100 cc, especially <=0.2g/100cc, for the salt, and a solubility of >=10g/100cc, especially >=30g/100cc, for the objective compound, and includes alcohols, ethers, nitriles, ketones, hydrocarbons, and chlorinated hydrocarbons.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for easily producing N-alkoxycarbonyl amino acid esters.

[0002]

2. Description of the Related Art Conventionally, there has been known a method of synthesizing an N-alkoxycarbonyl amino acid ester by reacting an amino group of a salt of an amino acid ester with a dicarbonate such as di-t-butyl dicarbonate. For example, a method is known in which an amino acid ester hydrochloride is reacted 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,
549-54, 1986).

[0003]

However, in the above method, since an organic base such as triethylamine or diisopropylethylamine is used, in order to remove salts of these organic bases from the reaction solution after the reaction, a reaction solvent of Dioxane was distilled off under reduced pressure, and after adding ethyl acetate, washing with water of an aqueous acid solution, aqueous base solution and water and liquid separation operation were carried out, which required a very complicated operation.

[0004]

SUMMARY OF THE INVENTION In view of the above situation, the inventors of the present invention have conducted extensive studies to easily produce N-alkoxycarbonyl amino acid esters, and as a result, have found that the salt of amino acid ester and dicarbonate are present in the presence of an inorganic base. It was found that the salt produced by neutralization of the inorganic base and the desired N-alkoxycarbonyl amino acid ester can be efficiently separated by reacting in a specific organic solvent below, and the present invention is completed. Came to.

That is, the present invention relates to a salt of an amino acid ester (excluding the hydrochloride) and the general formula (1)

[0006]

[Chemical 2]

(Wherein R ¹ is an alkyl group, an alkenyl group or an aralkyl group) is reacted with a dicarbonate to produce an N-alkoxycarbonylamino acid ester in the presence of an inorganic base. An N-alkoxycarbonyl amino acid ester characterized in that the reaction is carried out in an organic solvent in which an inorganic base is hardly neutralized during the reaction to form a salt, and the produced N-alkoxycarbonyl amino acid ester can be dissolved. Is a manufacturing method.

The dicarbonate used in the present invention is a compound represented by the above formula (1). Where R ¹
The alkyl group represented by is preferably a lower alkyl group such as a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group and a t-butyl group, and an alkenyl group is An allyl group is preferred, and a benzyl group is preferred as the aralkyl group.

Specific examples of the dicarbonate that can be preferably used in the present invention include dimethyl dicarbonate, diethyl dicarbonate, diisopropyl dicarbonate, diisobutyl dicarbonate, di-t-butyl dicarbonate, di-t-amyl dicarbonate. Carbonate, diallyl dicarbonate, dibenzyl dicarbonate, etc. can be mentioned.

The salt of the amino acid ester, which is the other raw material used in the present invention, has at least 1 in the molecule.
Any known compound can be used without any limitation as long as it is a salt of a compound having an ester bond formed by an esterification reaction of one or more amino groups or imino groups with a carboxyl group of an amino acid, with an acid other than hydrochloride. In the case of a salt of an amino acid ester 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, at least one amino group or imino group is even present. If it has, other amino group or imino group may be substituted with an alkyl group or the like.

In the present invention, the amino acid ester constituting the salt of such amino acid ester can be represented by the following general formula.

[0012]

[Chemical 3]

(However, X is an amino acid residue, and R ² is an alkyl group, an alkenyl group or an aralkyl group which may have a substituent.) As R ² in the general formula (2), An alkyl group, an alkenyl group, or an aralkyl group can be used without particular limitation. Particularly, as the alkyl group, a methyl group, an ethyl group, a propyl group, a t-butyl group, a cyclohexyl group, etc., and as the alkenyl group, an allyl group, etc. Examples of the aralkyl group include a benzyl group, a trimethylbenzyl group, a phenethyl group, and a diphenylmethyl group. Examples of these substituents include a halogen atom, an alkoxy group,
Examples thereof include 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
Examples thereof include trichloroethyl group, β-methylthioethyl group, p-nitrobenzyl group, p-methoxybenzyl group and picolyl group.

Specific examples of the amino acid that forms the basis of the salt of the amino acid ester that can be preferably used in the present invention include, for example, glycine, alanine, β-alanine, valine, norvaline, leucine, norleucine, isoleucine, phenylalanine and threonine. , Serine, homoserine, isoserine, proline, hydroxyproline, tryptophan, thyroxine, methionine, homomethionine, cystine, homocystine, α-aminobutyric acid, γ-aminobutyric acid, β-aminobutyric acid, α-aminoisobutyric acid, aspartic acid, asparagine, Glutamic acid, glutamine, lysine, ornithine, hydroxylysine, arginine, histidine, anticapsin, N-iminoethylornithine, α-amino-β- (2-imidazolidinyl) propionic acid, N-methylglycycin , Taurine, .gamma.-formyl -N- methyl-nor-valine, N- tosyl - arginine, N
-Benzyloxycarbonyl-arginine, aspartic acid-β-benzyl ester, S-acetamidomethyl-cysteine, S-benzyl-cysteine, glutamic acid-γ-benzyl ester, N-benzyloxycarbonyl-histidine, N-benzyloxycarbonyl-lysine , N-benzyloxycarbonyl-ornithine, O
-Benzyl-serine, O-benzyl-threonine, N-
Formyl-tryptophan, 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetic acid, 2- (2-amino-4-thiazolyl) -2-pentenoic acid, pipecolic acid, trans-4-aminomethyl-1. Examples thereof include cyclohexanecarboxylic acid, γ-amino-β-hydroxybutyric acid, and phenylglycine.

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

Further, in the present invention, the salt constituting the salt of the amino acid ester with an acid may be any known salt except for the hydrochloride. Specifically, mineral salts such as sulfate, methanesulfonic acid, benzenesulfonic acid, p
-Sulfonic acid salts such as toluenesulfonic acid and organic acid salts such as acetate can be mentioned.

The amount of the dicarbonate to be used with respect to the above-mentioned salt of the amino acid ester as a raw material is not economical if used in an excessively large amount. Therefore, it is usually 1 to 1 equivalent of amino group or imino group of the salt of amino acid ester to be protected. ~
5 equivalents, preferably 1 to 2 equivalents, more preferably 1 to
It may be selected in the range of 1.5 equivalents.

The above-mentioned reaction between the salt of amino acid ester and dicarbonate is carried out in the presence of an inorganic base. Specific examples of 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; carbonic acid. Carbonates such as sodium and potassium carbonate; bicarbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate. Particularly preferred are carbonates such as sodium carbonate and potassium carbonate which have a dehydrating action. Even if these inorganic bases are used alone,
You may use 2 or more types.

The amount of these inorganic bases to be used with respect to the salt of the amino acid ester is 1 gram equivalent or more, preferably 1 to 1 gram equivalent of the acid component of the amino acid ester salt.
You can choose in the range of 1.5 grams equivalent. When used in excess, for example, first add 1 gram equivalent of an inorganic base,
For the purpose of removing water generated by neutralization, a carbonate having a dehydrating action such as sodium carbonate or potassium carbonate may be added in excess.

In the present invention, the reaction between the above-mentioned salt of amino acid ester and dicarbonate makes it difficult to dissolve the salt formed by neutralization of the inorganic base during the reaction, and to generate the N-alkoxycarbonyl amino acid ester formed. It is carried out in a soluble organic solvent. Such an organic solvent preferably has a low solubility of the salt and a high solubility of the N-alkoxycarbonylamino acid ester produced in order to favorably separate the produced N-alkoxycarbonyl amino acid ester from the salt. For example, the solubility of the above salt is 1 g / 100 cc or less, 0.2 g / 100 c
c or less, and the solubility of the N-alkoxycarbonyl amino acid ester is 10 g / cc or more, preferably 30 g / cc.
An organic solvent having 100 cc or more can be preferably used. Solubility of salts and N-alkoxycarbonyl amino acid esters in such organic solvents is
-Since it varies somewhat depending on the type of alkoxycarbonyl amino acid ester, the selection of the organic solvent to be used may be appropriately determined according to the type of each compound produced, but generally, alcohols such as isopropyl alcohol and t-butanol are used. Ethers such as tetrahydrofuran, dioxane and diisopropyl ether; nitriles such as acetonitrile; ketones such as methyl ethyl ketone; hydrocarbons such as toluene; chlorinated hydrocarbons such as dichloromethane, dichloroethane, chloroform and the like can be preferably used. These organic solvents may be used alone, or may be used as a mixed solvent of two or more kinds at all.

The amount of the organic solvent used is not particularly limited, but is preferably an amount sufficient to dissolve the entire amount of the produced N-alkoxycarbonyl amino acid ester.

The reaction temperature in this reaction is not particularly limited, but if the temperature is too high, the raw material dicarbonate and the product are decomposed. Therefore, the freezing point of the system is usually in the range of 100 to 100 ° C., preferably 10 to 80 ° C. It is preferably in the range.

The reaction pressure can be any of normal pressure, increased pressure and reduced pressure, and the time required for the reaction varies depending on the reaction temperature, the type of organic solvent and the type of salt of the amino acid ester as the raw material. , Usually in the range of 1 to 120 hours. The reaction can be carried out batchwise or continuously.

After the N-alkoxycarbonyl amino acid ester is produced in this manner, the N-alkoxycarbonyl amino acid ester is isolated. According to the method of the present invention, the by-produced salt is precipitated as a solid, and thus the desired N-alkoxycarbonyl amino acid ester and the salt can be separated by a known method such as filtration or centrifugation. If necessary before filtration, centrifugation, etc., for example, if the reaction solvent is incompatible with water,
You may perform two simple water washes. When the reaction solvent is compatible with water, the water generated by the neutralization may be distilled off azeotropically in the reaction solvent. Furthermore, the reaction solvent can be removed by a simple method such as evaporation under reduced pressure. When the obtained N-alkoxycarbonyl amino acid ester needs to be further purified, it may be purified by a known method such as crystallization and decantation.

The N-alkoxycarbonyl amino acid ester obtained in the present invention has the following formula having a structure in which the amino group of the salt of the starting amino acid ester is reacted with dicarbonate to protect the amino group.

[0026]

[Chemical 4]

(Wherein R is an alkyl group, an alkenyl group or an aralkyl group, and Am is a residue obtained by removing an amino group from an amino acid ester). Specific examples include alkoxycarbonyl amino acid alkyl ester, alkoxycarbonyl amino acid alkenyl ester, alkoxycarbonyl amino acid aralkyl ester, alkenyloxycarbonyl amino acid alkyl ester, alkenyloxycarbonyl amino acid alkenyl ester, alkenyloxycarbonyl amino acid aralkyl ester, aralkyloxycarbonyl amino acid. They are alkyl ester, aralkyloxycarbonyl amino acid alkenyl ester, and aralkyloxycarbonyl amino acid aralkyl ester.

[0028]

INDUSTRIAL APPLICABILITY According to the present invention, a dicarbonate and a salt of an amino acid ester are reacted in a specific organic solvent in the presence of an inorganic base to form an N-alkoxycarbonyl amino acid ester, The salt produced at the same time can be easily removed by a known means such as filtration,
Furthermore, the organic solvent is simply removed by distillation under reduced pressure,
The desired N-alkoxycarbonyl amino acid ester can be isolated. Therefore, the present invention is industrially extremely useful as a method for obtaining an N-alkoxycarbonyl amino acid ester.

[0029]

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

Example 1 L-proline benzyl ester p-toluenesulfonate 37.7 was placed in a four-necked flask equipped with a stirrer and a thermometer.
g (0.1 mol), chloroform (100 mL), potassium carbonate (8.29 g, 0.06 mol), and di-t
-Butyl dicarbonate at 25 ° C 22.9 g (0.1
(05 mol) was added and reacted at the same temperature for 24 hours. The reaction solution was filtered to remove excess inorganic base and the generated potassium p-toluenesulfonate, and then the solvent was distilled off under reduced pressure to obtain 45.5 g of oily Nt-butoxycarbonyl-L-prolinebenzyl ester. It was The yield was 95.3%, and the content of potassium p-toluenesulfonate was 0.5% by weight or less. The solubility of potassium p-toluenesulfonate in chloroform is 0.2 g / 100 cc or less, and the solubility of Nt-butoxycarbonyl-L-prolinebenzyl ester is 10 g / 100 cc or more.

Examples 2 to 5 The procedure of Example 1 was repeated, except that the N-alkoxycarbonyl amino acid ester shown in Table 1 was obtained using the salt of the amino acid ester shown in Table 1. The results are shown in Table 1. In each case, the salt content in the product was 0.5% by weight or less, and the solubility of the produced N-alkoxycarbonyl amino acid ester in chloroform was 10 g / 100 cc or more.

[0032]

[Table 1]

Examples 6 to 9 The procedure of Example 1 was repeated, except that the inorganic bases shown in Table 2 were used in the amounts shown in Table 2. In the case of using two kinds of inorganic bases, 1 gram equivalent of a base other than sodium carbonate was first added, and after 30 minutes, an excess amount of sodium carbonate was added. The results are shown in Table 2. In each case, the content of the salt in the product was 0.5% by weight or less, and the solubility of the salt produced by neutralization of various inorganic bases in chloroform was 0.2 g / 100 cc or less. Nt
The solubility of -butoxycarbonyl-L-proline benzyl ester in chloroform was 10 g / 100 cc or more.

[0034]

[Table 2]

Examples 10 to 13 The same operations as in Example 1 were carried out except that the organic solvents shown in Table 3 were used. The results are shown in Table 3. In each case, the content of potassium p-toluenesulfonate in the product was 0.5% by weight or less, and the p-toluenesulfonate content in various organic solvents was
-Solubility of potassium toluene sulfonate 0.2g / 1
The solubility of the produced Nt-butoxycarbonyl-L-proline benzyl ester in various organic solvents was 10 g / 100 cc or more.

[0036]

[Table 3]

Examples 14 to 15 N-alkoxycarbonyl was carried out in the same manner as in Example 1 except that the compounds shown in Table 1 were used instead of di-t-butyldicarbonate as the dicarbonate. -L-proline benzyl ester was obtained. The results are shown in Table 4.

In each case, the content of potassium p-toluenesulfonate in the product is 0.5% by weight or less,
The solubility of the produced N-alkoxycarbonyl-L-proline benzyl ester in chloroform was 10 g / 10.
It was 0 cc or more.

[0039]

[Table 4]

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[Procedure amendment]

[Submission date] March 18, 1994

[Procedure Amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0020

[Correction method] Change

[Correction content]

In the present invention, the reaction between the above-mentioned salt of amino acid ester and dicarbonate makes it difficult to dissolve the salt formed by neutralization of the inorganic base during the reaction, and to generate the N-alkoxycarbonyl amino acid ester formed. It is carried out in a soluble organic solvent. Such an organic solvent preferably has a low solubility of the salt and a high solubility of the N-alkoxycarbonylamino acid ester produced in order to favorably separate the produced N-alkoxycarbonyl amino acid ester from the salt. For example, the solubility of the above salt is 1 g / 100 cc or less, preferably 0.2 g
/ 100 cc or less, and the solubility of the N-alkoxycarbonyl amino acid ester is 10 g / cc or more, preferably 30 g / 100 cc or more, an organic solvent can be suitably used. Salts and N for such organic solvents
-The solubility of the alkoxycarbonyl amino acid ester is
The organic solvent to be used may be appropriately selected depending on the type of each compound to be formed, since it varies depending on the type of the salt and the N-alkoxycarbonyl amino acid ester, but generally, isopropyl alcohol, t
-Alcohols such as butanol; tetrahydrofuran,
Ethers such as dioxane and diisopropyl ether;
Nitriles such as acetonitrile; ketones such as methyl ethyl ketone; hydrocarbons such as toluene; chlorinated hydrocarbons such as dichloromethane, dichloroethane and chloroform can be preferably used. These organic solvents may be used alone, or may be used as a mixed solvent of two or more kinds at all.

Claims (1)

[Claims] 1. A salt of an amino acid ester (excluding hydrochloride) and a compound represented by the general formula (1): (However, R ¹ is an alkyl group, an alkenyl group, or an aralkyl group.) In the method for producing an N-alkoxycarbonylamino acid ester, which comprises reacting with a dicarbonate represented by the formula, A method for producing an N-alkoxycarbonyl amino acid ester, characterized in that the reaction is carried out in an organic solvent in which a salt produced by neutralization during the reaction is difficult to dissolve and an N-alkoxycarbonyl amino acid ester produced is soluble. .