JP3285398B2 - Method for producing urethane compound - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for easily producing a urethane compound.

[0002]

2. Description of the Related Art A method of synthesizing a urethane compound having a structure in which an amino group is protected by reacting an amino group of an amino acid ester hydrochloride with a dicarbonate such as di-t-butyl dicarbonate is known. . For example, a method is known in which an amino acid ester hydrochloride is reacted 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 O.). medical·
Chemistry (J. Med. Chem.) 26 volumes, 4
Pp. 549-54, 1986).

[0003]

However, in the above-mentioned method, since organic bases such as triethylamine and diisopropylethylamine are used, after the reaction, salts of these organic bases are removed from the reaction solution by washing with water or the like. A liquid separation operation was performed, and a very complicated operation was required.

[0004]

Means for Solving the Problems In view of the above situation, the present inventors have conducted intensive studies to easily produce a urethane compound. As a result, the present inventors have found that an amino acid ester hydrochloride and a dicarbonate can be converted to a specific compound in the presence of an inorganic base. The inventors have found that by reacting in an organic solvent, an inorganic salt generated by the reaction of an inorganic base can be efficiently separated from a target urethane compound, thereby completing the present invention.

That is, the present invention relates to an amino acid ester hydrochloride having the general formula (1)

[0006]

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(Where R ¹ is an alkyl group, an alkenyl group or an aralkyl group). In the method for producing a urethane compound, the inorganic base reacts with the dicarbonate in the presence of an inorganic base. A method for producing a urethane compound, characterized in that a reaction is carried out in an organic solvent which is difficult to dissolve an inorganic salt generated by neutralization therein and dissolves a generated urethane compound.

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, a t-butyl group, and an alkenyl group is An allyl group is preferred, and an aralkyl group is preferably a benzyl group.

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

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

The amino acid ester hydrochloride that can be used in the present invention can be represented by the following general formula.

[0012]

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(Where X is an amino acid residue, R ² is an alkyl group, an alkenyl group or an aralkyl group which may have a substituent, and n is a number of 1 or more.) As R ^{2 in} 2), an alkyl group, an alkenyl group, or an aralkyl group can be used without any particular limitation. Particularly, as the alkyl group, a methyl group, an ethyl group, a propyl group, a t-butyl group, a cyclohexyl group and the like can be used. An alkenyl group includes an allyl group and the like, and an aralkyl group includes a benzyl group, a trimethylbenzyl group, a phenethyl group and a diphenylmethyl group.These substituents include a halogen atom, an alkoxy group,
Examples include an alkylthio group, a nitro group, a cyano group, a carbamoyl group, a pyridyl group, and a phthalimide 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, picolyl group, phthalimidomethyl group and the like.

The amino acid which can be suitably used in the present invention and which is the base of the amino acid ester hydrochloride is specifically shown as follows:
For example, glycine, alanine, β-alanine, valine,
Norvaline, leucine, norleucine, isoleucine,
Phenylalanine, threonine, serine, homoserine,
Isoserine, proline, hydroxyproline, tryptophan, thyroxine, methionine, homomethionine, cystine, homocystine, α-aminobutyric acid, γ-aminobutyric acid, β-aminobutyric acid, α-aminoisobutyric acid, asparagine, glutamine, lysine, ornithine, hydroxylysine Arginine, histidine, anticapsin, N-iminoethylornithine, α-amino-β- (2-imidazolidinyl) propionic acid, N-methylglycine, taurine, γ-formyl-N-methylnorvaline, 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-cyclohexanecarboxylic acid, γ -Amino-β-hydroxybutyric acid, phenylglycine and the like.

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

The amount of dicarbonate used for the amino acid ester hydrochloride as the raw material described above is not economical if it is used in an excessively large amount. Therefore, it is usually 1 to 1 equivalent of the amino group or imino group of the amino acid ester hydrochloride to be protected. The amount may be selected in the range of 5 to 5 equivalents, preferably 1 to 2 equivalents, and more preferably 1 to 1.5 equivalents.

The reaction between the amino acid ester hydrochloride and dicarbonate is carried out in the presence of an inorganic base. Specific examples of inorganic bases that can be suitably 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; Carbonates such as sodium and potassium carbonate; bicarbonates such as sodium bicarbonate and potassium bicarbonate;

The amount of the inorganic base to be used for the amino acid ester hydrochloride is 1% of the amino acid ester hydrochloride hydrochloride.
One equivalent or more, preferably in the range of 1 to 1.1 equivalents, may be selected.

In the present invention, the reaction between the amino acid ester hydrochloride and the dicarbonate is difficult to dissolve the inorganic salt formed by neutralization of the inorganic base during the reaction, and can dissolve the urethane compound formed. It is performed in an organic solvent. Such an organic solvent preferably has a low solubility of the inorganic salt and a high solubility of the generated urethane compound in order to satisfactorily separate the generated urethane compound and the inorganic salt. For example, the solubility of the inorganic salt is 0.1
g / 100 cc or less, preferably 0.01 g / 100 c
c or less, and the solubility of the urethane compound is 1 g / 100.
An organic solvent having an amount of at least cc, preferably at least 10 g / 100 cc can be suitably used. Specific examples of the organic solvent that can be preferably used in the present invention include alcohols such as isopropyl alcohol and t-butanol; ethers such as tetrahydrofuran, dioxane and diisopropyl ether; nitriles such as acetonitrile; ketones such as methyl ethyl ketone; Hydrocarbons such as toluene and hexane; and chlorinated hydrocarbons such as dichloromethane, dichloroethane and chloroform. These organic solvents may be used alone or in combination of two or more.

The amount of the organic solvent used is not particularly limited, but is preferably an amount sufficient to dissolve the entire amount of the urethane compound formed.

The reaction temperature in this reaction is not particularly limited. However, if the temperature is too high, the starting material dicarbonate and the product are decomposed, so that the temperature usually falls within the range of the freezing point of the system to 100 ° C., preferably 10 to 80 ° C. Preferably, it is in the range.

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, the type of the organic solvent and the type of the raw material amino acid ester hydrochloride. , Usually in the range of 1 to 120 hours. The reaction can be performed in either a batch system or a continuous system.

After the formation of the urethane compound in this manner, the urethane compound is isolated. According to the method of the present invention, the separation of the inorganic salt and the urethane compound intended for the by-product inorganic salt to be precipitated as a solid can be performed by a known method such as filtration or centrifugation,
Further, the solvent can be removed by a simple method of distilling off. When it is necessary to further purify the obtained urethane compound, it may be purified by a known method such as crystallization or decantation.

The urethane compound obtained in the present invention has a structure in which the amino group of the amino acid ester hydrochloride as a raw material is reacted with dicarbonate to protect the amino group.

[0025]

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(Where R ¹ 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 an alkoxycarbonyl amino acid alkyl ester, an alkoxycarbonyl amino acid alkenyl ester, an alkoxycarbonyl amino acid aralkyl ester, an alkenyloxycarbonyl amino acid alkyl ester, an alkenyloxycarbonyl amino acid alkenyl ester, an alkenyloxycarbonyl amino acid aralkyl ester, and an aralkyloxycarbonyl amino acid. Alkyl esters, aralkyloxycarbonylamino acid alkenyl esters or aralkyloxycarbonylamino acid aralkyl esters.

[0027]

According to the present invention, a dicarbonate and an amino acid ester hydrochloride are reacted in a specific organic solvent in the presence of an inorganic base to form a urethane compound, and then the inorganic compound formed simultaneously. The salt can be easily removed by a known means such as filtration, and the desired urethane compound can be isolated by a simple method of removing the organic solvent by distillation. Therefore, the present invention is industrially extremely useful as a method for obtaining a urethane compound having a structure in which the amino group of an amino acid ester is protected.

[0028]

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

Example 1 In a four-necked flask equipped with a stirrer and a thermometer, 15.6 g (0.1 mol) of L-serine methyl ester hydrochloride, 100 mL of chloroform, and 6.91 g of potassium carbonate (0.09 g) were added.
5 mol), and 21.8 g (0.1 mol) of di-t-butyl dicarbonate was added at 25 ° C., and reacted at the same temperature for 24 hours. After filtering the reaction solution to remove potassium chloride, the solvent was distilled off to obtain 21.2 g of oily Nt-butoxycarbonyl-L-serine methyl ester. The yield was 96.7% and the content of potassium chloride was 0.1% by weight or less. The solubility of potassium chloride in chloroform is 0.01 g / 100 cc or less, and the solubility of Nt-butoxycarbonyl-L-serine methyl ester is 10 g / 100 cc or more.

Examples 2 to 4 The same procedures as in Example 1 were carried out except that the urethane compounds shown in Table 1 were obtained using the amino acid ester hydrochloride shown in Table 1. The results are shown in Table 1. In each case, the content of potassium chloride in the product was 0.1% by weight or less, and the solubility of the formed urethane compound in chloroform was 10 g / 100 cc or more.

[0031]

[Table 1]

Examples 5 to 8 The same procedures as in Example 1 were carried out except that the inorganic bases shown in Table 2 were used. The results are shown in Table 2. In any case, the content of the inorganic salt in the product is 0.1% by weight or less, and the solubility of the inorganic salt generated by the reaction of various inorganic bases with chloroform is 0.01 g / 100 cc or less, The formed Nt-butoxycarbonyl-L-
The solubility of serine methyl ester was 10 g / 100 cc or more.

[0033]

[Table 2]

Examples 9 to 13 The same operation as in Example 1 was carried out except that the organic solvents shown in Table 3 were used. Table 3 shows the results. In each case, the content of potassium chloride in the product was 0.1% by weight or less, and the solubility of potassium chloride in various organic solvents was 0.01 g / 100 cc or less.
The solubility of t-butoxycarbonyl-L-serine methyl ester was 10 g / 100 cc or more.

[0035]

[Table 3]

──────────────────────────────────────────────────の Continued on the front page (58) Fields surveyed (Int. Cl. ⁷ , DB name) C07C 269/04 C07C 271/22 CA (STN)

Claims (1)

(57) [Claims] (1) an amino acid ester hydrochloride having the general formula (1): (Where R ¹ is an alkyl group, an alkenyl group or an aralkyl group). In the method for producing a urethane compound represented by the formula ( ¹ ), the inorganic base is added during the reaction in the presence of the inorganic base. A method for producing a urethane compound, characterized in that the reaction is carried out in an organic solvent that is difficult to dissolve the inorganic salt formed by the addition and that can dissolve the urethane compound to be formed.