JPH07101928A - Production of n-alkoxycarbonylamino acid ester - Google Patents

Abstract

PURPOSE:To provide an industrially useful method for the production of an N-alkoxycarbonylamino acid ester from an amino acid with a simple operation in high yield. CONSTITUTION:An amino acid, an alcohol (preferably 1-10C alcohol) is reacted with a strong acid having a pKa of <=2.0 (preferably <=1.0) in aqueous solution or thionyl chloride at -20 to +80'C the obtained reaction liquid is neutralized with a base, the resultant amino acid ester is reacted with a dicarbonate of the formula (R<1> is alkyl, alkenyl or aralkyl) to obtain an N-alkoxycarbonylamino acid ester and the compound is separated from the reaction system in the presence of water. The separation of the compound in the presence of water is carried out e.g. by crystallization or extraction with an organic solvent (e.g. dichloroethane or toluene) incompatible with water and capable of dissolving the objective compound. In the above separation process, the slurry concentration of the N-alkoxycarbonylamino acid ester is preferably <=20% and the salt concentration in the liquid is preferably 5-25%.

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, a method of N-alkoxycarbonylating an amino acid ester to synthesize an N-alkoxycarbonyl amino acid ester is known. For example, a method is known in which an amino acid ester acid salt 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,
4, 549-54, 1986).

The amino acid ester acid salt used in such a reaction is obtained by reacting an amino acid with an alcohol and a strong acid or thionyl chloride.
At this time, the reaction solution obtained by the above reaction contains unreacted strong acid or by-produced hydrogen chloride and sulfur dioxide. An operation of isolating and purifying the salt is performed. As this refining operation, for example, the unreacted alcohol is distilled off from the reaction solution to azeotropically remove the coexisting substance with the alcohol.

[0004]

When an amino acid ester acid salt is first produced from an amino acid as a raw material and then an N-alkoxycarbonylamino acid ester is produced from the amino acid ester acid salt by the above-mentioned method, It has been desired to improve the yield of this N-alkoxycarbonyl amino acid ester with respect to the amino acid.

Further, the purification treatment of the amino acid ester acid salt, which is carried out when the amino acid ester acid salt is produced from an amino acid, is a method of distilling off the alcohol, for example, by replenishing the reaction solution with alcohol several times. Therefore, complicated processing such as repeated processing is required. Therefore, even in the case of producing an N-alkoxycarbonyl amino acid ester using such an amino acid as a raw material, if the residual coexisting substances such as strong acid are removed at the end of the esterification reaction of the amino acid, the reaction operation becomes complicated. There was a problem.

[0006] From the above background, N is obtained by using amino acid as a raw material.
-When producing an alkoxycarbonyl amino acid ester, it has been desired to develop a method for obtaining the compound with a simple operation and a high yield.

[0007]

SUMMARY OF THE INVENTION In view of the above situation, the inventors of the present invention have made extensive studies in order to produce an N-alkoxycarbonyl amino acid ester with a simple operation and a high yield. As a result, the reaction solution obtained by reacting an amino acid, an alcohol, and a strong acid or thionyl chloride is neutralized, and the obtained amino acid ester is reacted with a dicarbonate represented by a specific general formula to produce an N-alkoxycarbonylamino acid. It was found that the above problems can be solved by producing an ester and isolating the N-alkoxycarbonyl amino acid ester in the presence of water, and completed the present invention.

That is, the present invention relates to amino acids, alcohols,
And a reaction solution obtained by reacting a strong acid or thionyl chloride with a base to neutralize the resulting amino acid ester with the general formula (1)

[0009]

[Chemical 2]

(Wherein R ¹ is an alkyl group, an alkenyl group or an aralkyl group) is reacted with the dicarbonate to produce an N-alkoxycarbonylamino acid ester, and the N-alkoxyamino acid ester from the reaction solution is reacted. A method for producing an N-alkoxycarbonyl amino acid ester, which comprises isolating the alkoxycarbonyl amino acid ester in the presence of water.

The alcohol used for esterification of the amino acid in the present invention is not particularly limited, but preferably has 1 to 10 carbon atoms. Specific examples include methanol, ethanol, n-propanol, i-propanol, n-butanol, i-butanol, n-hexanol and cyclohexanol.

The amino acid used in the present invention is at least one amino group or imino group in the molecule,
Known compounds can be used without any limitation as long as they are compounds having a carboxyl group. 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, at least one amino group or even imino group is contained. If so, the other amino group or imino group may be substituted with an alkyl group or the like.

Specific examples of amino acids that can be preferably used in the present invention include, for example, glycine, alanine and β-.
Alanine, valine, norvaline, leucine, norleucine, isoleucine, phenylalanine, tyrosine, diiodotyrosine, 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, glutamic acid, homoglutamic 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, 4-hydroxyphenylglycine and the like can be mentioned. 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.

In the present invention, the esterification reaction of such an amino acid is carried out by reacting the amino acid, the alcohol, and a strong acid or thionyl chloride to produce an amino acid ester acid salt. The amount of the alcohol used is not particularly limited, but is preferably 1 equivalent or more per 1 equivalent of the amino acid. Usually, this esterification reaction is generally carried out by reacting the alcohol with an amino acid and a strong acid or thionyl chloride in a large excess of alcohol medium.

As the above-mentioned strong acid, known ones used in the esterification reaction of amino acids can be used without any limitation. Preferably, pK in aqueous solution
It is preferable to use an acid having a of 2.0 or less, preferably 1.0 or less. Here, when the acid is a polybasic acid such as sulfuric acid, the pKa of the acid means a value in the first stage dissociation in which the value is the smallest. In addition, such a small pK
Even if the compound having an acidic group of a is a compound having a basic group such as an amino group at the same time as an amino acid, it does not exhibit strong acidity as a whole molecule, and is therefore distinguished from the strong acid in the present invention. . Specific examples of the strong acid preferably used in the present invention include mineral acids such as hydrogen chloride and sulfuric acid, and organic acids such as p-toluenesulfonic acid, benzenesulfonic acid and methanesulfonic acid. In the present invention, it is most preferable to react hydrogen chloride or thionyl chloride with an amino acid and an alcohol. The amount of the strong acid or thionyl chloride used to react with the amino acid or alcohol is not particularly limited, but is preferably 1 equivalent or more per 1 equivalent of the amino acid. When hydrogen chloride is used as a strong acid, the hydrogen chloride is usually blown into an alcohol serving as a reaction medium until saturated. Other strong acids such as sulfuric acid and thionyl chloride are usually preferably used in the range of 1 to 5 equivalents per 1 equivalent of the amino acid.

In the esterification reaction of such an amino acid, it is general to simultaneously act three raw materials of amino acid, alcohol, and strong acid or thionyl chloride. When the esterification reaction is carried out using thionyl chloride, For this, thionyl chloride and alcohol may be previously reacted, and the reaction product may be reacted with an amino acid. In particular, when an amino acid having a hydroxyl group in the molecule such as serine is used as the amino acid, it is preferable to adopt a method of previously reacting thionyl chloride with an alcohol as described above to improve the yield of the target esterification reaction. It is preferable from the viewpoint of improving.

The reaction temperature in the esterification reaction of the amino acid is not particularly limited, but it is usually the freezing point of the system to 100 ° C.
Is suitable, and preferably in the range of -20 to 80 ° C. The time required for the reaction varies depending on the reaction temperature, the starting alcohol and the type of amino acid, but is usually in the range of 1 to 120 hours.

The reaction solution obtained by the above esterification reaction contains unreacted strong acid, or hydrogen chloride and sulfur dioxide which are by-products when thionyl chloride is used, in addition to the target amino acid ester acid salt. Coexist.

In the present invention, after the amino acid ester acid salt is thus produced, the esterification reaction solution is neutralized with a base. Here, the neutralization with the base may be carried out by bringing the base itself into contact with the esterification reaction solution as it is, but generally, the base is made into a solution or suspension with water and / or an organic solvent, This is preferably carried out by contacting with the above esterification reaction liquid. Here, the base is not particularly limited, but specific examples of bases that can be preferably used include organic amines such as triethylamine and diisopropylethylamine, sodium hydroxide, base metal hydroxides such as potassium hydroxide, Calcium hydroxide,
Examples thereof include basic earth metal hydroxides such as magnesium hydroxide, carbonates such as sodium carbonate and potassium carbonate, and bicarbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate.

When such a base is used by being dissolved or suspended in an organic solvent, the organic solvent is not particularly limited, but specifically, methanol, ethanol, isopropanol, t-butanol, dichloromethane, 1,2
-Dichloroethane, ethyl acetate, toluene, diisopropyl ether and the like are used. It is preferable to use the same alcohol as that used in the esterification reaction of the amino acid selected from methanol, ethanol and the like.

The amount of the base used for the neutralization is sufficient as long as it can substantially neutralize the acidic component in the esterification reaction solution, and normally, the amount of the gram equivalent of the acidic component in the reaction solution is 0. A gram equivalent of 8 to 2.0 times, preferably 1 to 1.5 times is preferable. For example, in the case of neutralizing with an aqueous solution of a base, the pH of the solution obtained by the neutralization is preferably 4 to 13, and more preferably 5 to 11.

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

Specific examples of the dicarbonate which can be preferably used in the present invention include dimethyldicarbonate, diethyldicarbonate, diisopropyldicarbonate, diisobutyldicarbonate, di-t-butyldicarbonate, di-t-amyldicarbonate. Carbonate, diallyl dicarbonate, dibenzyl dicarbonate, etc. can be mentioned.

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

The reaction temperature in the N-alkoxycarbonylation 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 ° C., preferably 0. ~ 8
It is preferably in the range of 0 ° C.

The reaction pressure in the N-alkoxycarbonylation reaction can be any of atmospheric pressure, pressurization and depressurization, and the time required for the reaction varies depending on the reaction temperature and the type of the starting amino acid. It is usually in the range of 1 to 120 hours. The reaction can be carried out batchwise or continuously.

By the way, the neutralization reaction of the esterification reaction solution of the amino acid is carried out by a base solution or a solution or suspension of the base itself, or a solvent component of which is the same alcohol as the alcohol used as a raw material in the esterification reaction of the amino acid. , The reaction medium of the N-alkoxycarbonylation reaction is predominantly occupied by the same alcohol as that used in the esterification reaction of this amino acid. Therefore, in such a case, before or after the N-alkoxycarbonylation reaction is started, an arbitrary amount of alcohol in the reaction medium is recovered by distillation under reduced pressure, etc. It may be used as an alcohol raw material for the esterification reaction. When the amino acid used is an amino acid having a hydroxyl group in the molecule such as serine, such recovery is particularly performed after the completion of the N-alkoxycarbonylation reaction because the by-product of the amino acid dimer ester can be prevented. Is preferred.

In the case of recovering alcohol in this manner, as the base used for neutralizing the esterification reaction solution of the above amino acid, water is not generated by the neutralization of sodium carbonate, potassium carbonate, etc. It is preferable to use one having a water adsorption capacity. When such a base is used, water is not generated during the neutralization of the esterification reaction solution of the above amino acid, and water slightly by-produced when the esterification reaction of the above amino acid is carried out with a strong acid is also adsorbed to the base. Therefore, the reaction medium of the N-alkoxycarbonylation reaction can be recovered substantially anhydrous and can be reused as it is as an alcohol raw material for the esterification reaction of the amino acid.

By the above N-alkoxycarbonylation reaction, N-alkoxycarbonyl amino acid ester is produced. In this reaction solution, the solvent is an alcohol derived from unreacted raw materials of the esterification reaction and by-products of the N-alkoxycarbonylation reaction, or a solution or suspension of water or an organic solvent of a base in the neutralization step. When used, the above alcohol and water and / or water derived from this neutralization solution
Alternatively, it is a mixed solution with an organic solvent. In addition to the above N-alkoxycarbonyl amino acid ester, this solution contains a salt produced by neutralization of an acid salt of an amino acid ester and neutralization of a strong acid or sulfur dioxide coexisting in the esterification reaction solution of an amino acid. Coexist. In some cases, unreacted raw materials and intermediate products such as amino acids and amino acid esters also remain.

Since such salts and the above-mentioned amino acids, amino acid esters and the like are well soluble in water, on the other hand, N-alkoxycarbonyl amino acid esters are difficult to dissolve in water.
In the present invention, the presence of water in the reaction solution obtained by the N-alkoxycarbonylation reaction utilizes the difference in the solubility of such salts and N-alkoxycarbonylamino acid ester in water, The N-alkoxycarbonyl amino acid ester can be easily isolated from the reaction solution. The isolation method is not particularly limited, but specifically, a method of crystallizing crystals of N-alkoxycarbonyl amino acid ester from the reaction solution, or a method incompatible with water and Examples include a method of mixing an organic solvent in which the N-alkoxycarbonylamino acid ester is dissolved with the reaction solution, and extracting the N-alkoxycarbonylamino acid ester into the organic solvent layer. Thus, in the present invention, when the N-alkoxycarbonyl amino acid ester is isolated by utilizing the difference in solubility between the salt and the N-alkoxycarbonyl amino acid ester in water, the compound is Due to the salting-out effect of the salt coexisting in the reaction solution, the salt is efficiently crystallized from the reaction solution, or due to the high dissolved concentration of the salt, the salt is efficiently extracted from the reaction solution into the organic solvent layer. Therefore, in the production method of the present invention, the isolation of the N-alkoxycarbonyl amino acid ester from the N-alkoxycarbonylation reaction solution as described above is performed in the presence of water to obtain the compound in high yield. Will be possible.

In the present invention, the method of allowing water to be present in the N-alkoxycarbonylation reaction solution is not particularly limited. For example, when the esterification reaction solution of the amino acid is neutralized with an aqueous solution of a base, the above N
-Since the alkoxycarbonylation reaction liquid already contains a large amount of water derived from the aqueous solution, the isolation operation can be carried out without particular attention. On the other hand, when the neutralization of the esterification reaction solution of the amino acid is carried out using the base itself or a solution or suspension of the base in an organic solvent, the reaction solution is obtained as it is in a substantially anhydrous state. At that time, water may be mixed with the reaction solution at the time of the isolation operation. Here, the content of water in the reaction solution is not particularly limited, but is not limited to the above N-
Considering the isolation efficiency of the alkoxycarbonyl amino acid ester, it is preferably 40% by weight or more, and more preferably 60% by weight or more at the time of crystal precipitation or compound extraction.

In the present invention, when the N-alkoxycarbonyl amino acid ester is isolated from the reaction solution containing water by the above-mentioned crystallization, the operation is
The reaction may be carried out by cooling the reaction solution with the solvent composition as it is, or if necessary by removing the organic solvent such as alcohol by a method such as distillation under reduced pressure. If the amount of the liquid during the crystallization is too small, it is difficult to stir and transfer the liquid. Therefore, the amount of the N-alkoxycarbonylamino acid ester slurry concentration should be 30% or less, further 20% or less. Is preferred. Further, in order to perform crystallization efficiently, it is preferable that the salt concentration in the liquid is 3 wt% or more, and further 5 wt% to 25 wt%. The crystallization temperature is usually from the freezing point of the system to 40 ° C, preferably from 0 to 30 ° C. The precipitated crystals can be separated by a known method such as filtration or centrifugation. If necessary, further washing with water 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. Specific examples include dichloromethane, 1,2-dichloroethane, chloroform, toluene, ethyl acetate, diisopropyl ether and the like. When such an organic solvent is mixed, the reaction solution may be subjected to distilling off the organic solvent already contained such as alcohol by a method such as distilling under reduced pressure. In that case, if the amount of the liquid before mixing the organic solvent is too small, it is difficult to stir, so that the slurry concentration of the N-alkoxycarbonylamino acid ester should be 30% or less, and even 20% or less. Preferably there is. Moreover, in order to perform extraction efficiently, the salt concentration in the liquid is 3 w.
It is preferably t% or more, and more preferably 5 wt% to 25 wt%. The extract can be further washed with water if necessary. The N-alkoxycarbonyl amino acid ester can be obtained by distilling off the organic solvent from the extract thus obtained. Further, N-alkoxycarbonyl amino acid ester may be crystallized from the extract by a known method.

[0034]

INDUSTRIAL APPLICABILITY According to the present invention, the reaction solution obtained by reacting an amino acid, an alcohol, and a strong acid or thionyl chloride is directly neutralized, and the obtained amino acid ester and dicarbonate are reacted by a simple operation. , N-alkoxycarbonyl amino acid ester can be obtained in high yield. Therefore, the present invention is industrially extremely useful as a method for producing an N-alkoxycarbonyl amino acid ester.

[0035]

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

Example 1 Glycine 3 was added to a four-necked flask equipped with a stirrer and a thermometer.
7.5 g (0.5 mol) and 400 ml of ethanol were added, and the mixture was blown under stirring at 10 ° C. until dry hydrogen chloride was saturated. The container was tightly closed and left at room temperature for 2 days. The obtained reaction solution was added dropwise to 1 L of a 1N aqueous solution of sodium hydroxide, which had been placed in a 4-necked flask, under ice-cooling stirring. A 2N sodium hydroxide aqueous solution was appropriately added dropwise so that the pH was 7 to 9 during the addition. After the dropping was completed, 98.1 g (0.45 mol) of di-t-butyl dicarbonate was added dropwise under ice cooling, and the mixture was reacted at room temperature for 12 hours. Thereafter, ethanol and t-butanol produced were added so that the water content of the reaction solution was 96.
Distilled off under reduced pressure to give a weight percentage of 400
Extraction operation was performed using ml. The dichloromethane layer was washed with 100 ml of water, and the dichloromethane was distilled off under reduced pressure.
82.2 g of oily Nt-butoxycarbonylglycine ethyl ester was obtained. The yield was 81.0%.

Comparative Example 1 Glycine 3 was placed in a four-necked flask equipped with a stirrer and a thermometer.
7.5 g (0.5 mol) and 400 ml of ethanol were added, and the mixture was blown under stirring at 10 ° C. until dry hydrogen chloride was saturated. The container was tightly closed and left at room temperature for 2 days. The operation of distilling off the solvent from this reaction solution under reduced pressure, adding 50 ml of ethanol and distilling off under reduced pressure was repeated 4 times, and the residue was crystallized with ethanol / ether. The obtained crystals were placed in a 4-necked flask in advance, and a 0.5N sodium hydroxide aqueous solution 1
It was added to L under stirring with ice cooling. Furthermore, under ice cooling, di-t-
Butyldicarbonate 98.1 g (0.45 mol) was added dropwise, and the mixture was reacted at room temperature for 12 hours. The water content of the reaction solution was 96% by weight. An extraction operation was performed on this reaction liquid using 400 ml of dichloromethane. The dichloromethane layer was washed with 100 ml of water and the dichloromethane was distilled off under reduced pressure to obtain 73.4 g of oily Nt-butoxycarbonylglycine ethyl ester. The yield was 72.3%.

Example 2 L-hydroxyproline (66.0 g, 0.5 mol) and methanol (25) were placed in a four-necked flask equipped with a stirrer and a thermometer.
0 ml was added, and thionyl chloride 62.
5 g (0.53 mol) was added and reacted at room temperature for 12 hours. The resulting reaction solution was added dropwise to 1 L of a 1.2 M sodium carbonate aqueous solution previously placed in a 4-neck flask at 10 ° C. or lower with stirring. The pH of the solution at the end of dropping is 9.
It was 6. Furthermore, 109 g (0.5 mol) of di-t-butyl dicarbonate was added dropwise under ice cooling, and the mixture was reacted at room temperature for 12 hours. Thereafter, methanol and the produced t-butanol were distilled off under reduced pressure so that the water content of the reaction solution would be 96% by weight, and the precipitated crystals were collected by filtration.

The funnel was washed with 200 ml of water and dried to obtain 107 g of Nt-butoxycarbonyl-L-hydroxyproline methyl ester crystals. Yield 8
It was 7.3%.

Comparative Example 2 In a four-necked flask equipped with a stirrer and a thermometer, 66.0 g (0.5 mol) of L-hydroxyproline and 25 methanol.
0 ml was added, and thionyl chloride 62.
5 g (0.53 mol) was added and reacted at room temperature for 12 hours. The solvent was distilled off under reduced pressure from this reaction solution, and methanol 10
The operation of adding 0 ml and evaporating under reduced pressure was repeated 4 times, and the residue was crystallized with methanol / ether. The obtained crystals were added to 1 L of a 0.28 M sodium carbonate aqueous solution which had been placed in a 4-neck flask in advance under ice-cooling stirring. The pH of the solution at the end of the dropping was 9.6. Furthermore, 109 g (0.5 mol) of di-t-butyl dicarbonate under ice cooling
Was dropped and reacted at room temperature for 12 hours. The water content of the reaction solution was 96% by weight, and the crystals precipitated in the reaction solution were collected by filtration. The funnel was washed with 200 ml of water and dried to obtain 96.8 g of crystals of Nt-butoxycarbonyl-L-hydroxyproline methyl ester. The yield is 79.
It was 0%.

Examples 3 to 6 250 ml of methanol was placed in a four-necked flask equipped with a stirrer and a thermometer, and thionyl chloride 6 was added at 0 ° C. or lower with stirring.
2.5 g (0.53 mol) was added and reacted at 0 ° C or lower for 15 minutes. Thereafter, 0.5 mol of the amino acid shown in Table 1 was added, and the mixture was reacted at room temperature for 12 hours. The obtained reaction solution was added dropwise to 1 L of a 1.2 M aqueous potassium carbonate solution, which had been placed in a 4-neck flask in advance, at 10 ° C. or lower with stirring. Furthermore, 109 g of di-t-butyl dicarbonate under ice cooling
(0.5 mol) was added dropwise, and the mixture was reacted at room temperature for 12 hours.
Thereafter, the methanol and the produced t-butanol were distilled off under reduced pressure so that the water content of the reaction solution would be 80% by weight,
Extraction operation was performed using 500 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 each N-alkoxycarbonyl amino acid ester shown in Table 1. The raw material amino acids used and the yield are shown in Table 1.

[0042]

[Table 1]

Examples 7 to 8 N-alkoxycarbonyl amino acid esters shown in Table 2 were obtained in the same manner as in Example 5 except that the compounds shown in Table 2 were used as the dicarbonate. The dicarbonate used and the yield are shown in Table 2.

[0044]

[Table 2]

Example 9 L-hydroxyproline 66.0 g (0.5 mol) and methanol 25 were placed in a four-necked flask equipped with a stirrer and a thermometer.
0 ml was added, and thionyl chloride 62.
5 g (0.53 mol) was added and reacted at room temperature for 12 hours. The obtained reaction solution was placed in a 4-neck flask in advance, and 1.2 mol of sodium carbonate was added to methanol 250
The solution was suspended in ml and added dropwise with stirring at 10 ° C or lower. Furthermore, di-t-butyl dicarbonate 10 under ice cooling
9 g (0.5 mol) was added dropwise, and the mixture was reacted at room temperature for 12 hours. Thereafter, methanol and the produced t-butanol were distilled off under reduced pressure, water was added so that the water content of the reaction solution was 87% by weight, and the precipitated crystals were collected by filtration.

The funnel was washed with 200 ml of water and dried to obtain 105 g of Nt-butoxycarbonyl-L-hydroxyproline methyl ester crystals. Yield 8
It was 5.7%.

Comparative Example 3 In a four-necked flask equipped with a stirrer and a thermometer, 66.0 g (0.5 mol) of L-hydroxyproline and 25 methanol.
0 ml was added, and thionyl chloride 62.
5 g (0.53 mol) was added and reacted at room temperature for 12 hours. The solvent was distilled off under reduced pressure from this reaction solution, and methanol 10
The operation of adding 0 ml and evaporating under reduced pressure was repeated 4 times, and the residue was crystallized with methanol / ether. The obtained crystals were added to a solution of 0.28 mol of sodium carbonate suspended in 500 ml of methanol, which had been placed in a 4-neck flask in advance, under ice-cooling stirring. Furthermore, under ice cooling
-Butyldicarbonate 109 g (0.5 mol) was added dropwise and the reaction was carried out at room temperature for 12 hours. Thereafter, methanol and the produced t-butanol were distilled off under reduced pressure, water was added so that the water content of the reaction solution was 87% by weight, and the precipitated crystals were collected by filtration. The funnel was washed with 200 ml of water and dried to obtain 96.0 g of Nt-butoxycarbonyl-L-hydroxyproline methyl ester crystals. Yield 7
It was 8.4%.

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[Procedure amendment]

[Submission date] November 24, 1993

[Procedure Amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0028

[Correction method] Change

[Correction content]

In the case of recovering alcohol in this manner, as the base used for neutralizing the esterification reaction solution of the above amino acid, one which does not generate water due to neutralization and has a water adsorbing ability Is preferably used.
When such a base is used, water is not generated during the neutralization of the esterification reaction solution of the above amino acid, and water slightly by-produced when the esterification reaction of the above amino acid is carried out with a strong acid is also adsorbed to the base. Therefore, the reaction medium of the N-alkoxycarbonylation reaction can be recovered substantially anhydrous and can be reused as it is as an alcohol raw material for the esterification reaction of the amino acid. ─────────────────────────────────────────────────── ───

[Procedure amendment]

[Submission date] December 9, 1993

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be amended] Claims

[Correction method] Change

[Correction content]

[Claims]

[Chemical 1] (However, R ¹ is an alkyl group, an alkenyl group or ara
It is a rukyll group. ) Mixed with dicarbonate
Contains N-alkoxycarbonyl amino acid ester
A reaction solution was obtained, and this N-alkoxycarbonylamino acid
A method for producing an N-alkoxycarbonyl amino acid ester, which comprises isolating the N-alkoxycarbonyl amino acid ester from a reaction liquid containing a stell in the presence of water.

[Procedure Amendment 2]

[Document name to be amended] Statement

[Correction target item name] 0007

[Correction method] Change

[Correction content]

[0007]

SUMMARY OF THE INVENTION In view of the above situation, the inventors of the present invention have made extensive studies in order to produce an N-alkoxycarbonyl amino acid ester with a simple operation and a high yield. As a result, a reaction solution containing an amino acid ester acid salt by reacting an amino acid, an alcohol, and a strong acid or thionyl chloride.
And then reacting with the amino acid ester acid salt
After neutralizing the solution with a base,
A reaction solution and a dicarbonate represented by a specific general formula
Mix and mix N-alkoxycarbonyl amino acid ester
It was found that the above problems can be solved by obtaining a reaction liquid containing the above and isolating the N-alkoxycarbonyl amino acid ester in the presence of water, and completed the present invention.

[Procedure 3]

[Document name to be amended] Statement

[Correction target item name] 0008

[Correction method] Change

[Correction content]

That is, the present invention relates to amino acids, alcohols,
And a strong acid or thionyl chloride to react
A reaction solution containing the telluric acid salt is obtained, and the amino acid
After neutralizing the reaction solution containing the stearic acid salt with a base,
Reaction liquid containing general amino acid ester and general formula (1)

[Chemical 1] (However, R ¹ is an alkyl group, an alkenyl group or ara
It is a rukyll group. ) Mixed with dicarbonate
Contains N-alkoxycarbonyl amino acid ester
A reaction solution was obtained, and this N-alkoxycarbonylamino acid
A method for producing an N-alkoxycarbonyl amino acid ester, which comprises isolating the N-alkoxycarbonyl amino acid ester from a reaction solution containing a stell in the presence of water.

[Procedure amendment 4]

[Document name to be amended] Statement

[Correction target item name] 0034

[Correction method] Change

[Correction content]

[0034]

According to the present invention, an amino acid, an alcohol, and a strong acid or thionyl chloride are reacted to give an amino acid.
A reaction solution containing the ester acid salt was obtained, and then the amino acid
Reaction solution containing acid ester acid salt was directly neutralized with base
After that , the N-alkoxycarbonyl amino acid ester can be obtained in a high yield by a simple operation of reacting the reaction solution containing the produced amino acid ester with dicarbonate. Therefore, the present invention is industrially extremely useful as a method for producing an N-alkoxycarbonyl amino acid ester. ─────────────────────────────────────────────────── ───

[Procedure amendment]

[Submission date] March 3, 1994

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be amended] Claims

[Correction method] Change

[Correction content]

[Claims]

[Chemical 1] (However, R ¹ is an alkyl group, an alkenyl group or an aralkyl group.) Is mixed with a dicarbonate to obtain a reaction solution containing an N-alkoxycarbonyl amino acid ester, and the N-alkoxycarbonyl amino acid ester is added to the reaction solution. A method for producing an N-alkoxycarbonyl amino acid ester, which comprises isolating the N-alkoxycarbonyl amino acid ester from a reaction solution containing the same in the presence of water.

[Procedure Amendment 2]

[Document name to be amended] Statement

[Name of item to be corrected] 0002

[Correction method] Change

[Correction content]

[0002]

2. Description of the Related Art Conventionally, a method of N-alkoxycarbonylating an amino acid ester to synthesize an N-alkoxycarbonyl amino acid ester is known. 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,
4, 549-54, 1986).

[Procedure 3]

[Document name to be amended] Statement

[Name of item to be corrected] 0003

[Correction method] Change

[Correction content]

The amino acid ester hydrochloride used in such a reaction is obtained by reacting an amino acid with an alcohol and a strong acid or thionyl chloride.
Note that this time, the reaction solution obtained by the above reaction, because it contains unreacted materials or by-product hydrogen chloride and sulfur dioxide of a strong acid after completion of the reaction, the reaction liquid, the resulting amino acid ester hydrochloride An operation of isolating and purifying the salt is performed. As this refining operation, for example, the unreacted alcohol is distilled off from the reaction solution to azeotropically remove the coexisting substance with the alcohol.

[Procedure amendment 4]

[Document name to be amended] Statement

[Correction target item name] 0004

[Correction method] Change

[Correction content]

[0004]

According to the above-mentioned method, amino acid is used as a raw material to first prepare an amino acid ester .
When producing a salt with an acid and then producing an N-alkoxycarbonyl amino acid ester from the salt of the amino acid ester, it is desired to improve the yield of the N-alkoxycarbonyl amino acid ester with respect to the amino acid. It was

[Procedure Amendment 5]

[Document name to be amended] Statement

[Name of item to be corrected] 0005

[Correction method] Change

[Correction content]

In addition, from amino acid to amino acid ester acid
Of the amino acid ester applied when a salt with
For example, in the case of a method of distilling off the alcohol, the salt refining treatment requires a complicated treatment such as the fact that the reaction liquid must be replenished with the reaction liquid several times and then repeated. Therefore, N-
Even in the case of producing an alkoxycarbonyl amino acid ester, if the residual coexisting substances such as strong acid are to be removed at the end of the esterification reaction of the amino acid, there is a problem that the reaction operation becomes complicated.

[Procedure correction 6]

[Document name to be amended] Statement

[Correction target item name] 0007

[Correction method] Change

[Correction content]

[0007]

SUMMARY OF THE INVENTION In view of the above situation, the inventors of the present invention have made extensive studies in order to produce an N-alkoxycarbonyl amino acid ester with a simple operation and a high yield. As a result, the reaction solution obtained by reacting the amino acid, alcohol, and strong acid or thionyl chloride is neutralized with a base, and then the raw solution is added.
With the reaction liquid containing the amino acid ester formed and a specific general formula
Mix with the indicated dicarbonate to give N-alkoxy
It was found that the above-mentioned problems can be solved by obtaining a reaction liquid containing a rubonyl amino acid ester and isolating the N-alkoxycarbonyl amino acid ester in the presence of water, and completed the present invention.

[Procedure Amendment 7]

[Document name to be amended] Statement

[Correction target item name] 0008

[Correction method] Change

[Correction content]

That is, the present invention relates to amino acids, alcohols,
And a reaction solution obtained by reacting a strong acid or thionyl chloride with a salt.
Neutralized with a group, and then the reaction solution containing the produced amino acid ester and the general formula (1)

[Procedure Amendment 8]

[Document name to be amended] Statement

[Correction target item name] 0010

[Correction method] Change

[Correction content]

(However, R ¹ is an alkyl group, alkenyl
A group or an aralkyl group. ) Dicarbone
N-alkoxycarbonyl amino acid
A reaction liquid containing a stell was obtained, and this N-alkoxycarbon
The method for producing an N-alkoxycarbonyl amino acid ester is characterized in that the N-alkoxycarbonyl amino acid ester is isolated from the reaction liquid containing the amino acid ester in the presence of water.

[Procedure Amendment 9]

[Document name to be amended] Statement

[Correction target item name] 0014

[Correction method] Change

[Correction content]

In the present invention, the esterification reaction of such an amino acid is carried out by reacting the amino acid, the alcohol, and a strong acid or thionyl chloride to form a salt of the amino acid ester with an acid . The amount of the alcohol used is not particularly limited, but is preferably 1 equivalent or more per 1 equivalent of the amino acid. Usually, this esterification reaction is generally carried out by reacting the alcohol with an amino acid and a strong acid or thionyl chloride in a large excess of alcohol medium.

[Procedure Amendment 10]

[Document name to be amended] Statement

[Correction target item name] 0018

[Correction method] Change

[Correction content]

The reaction solution obtained by the above esterification reaction contains a salt of the target amino acid ester with an acid , an unreacted strong acid, or hydrogen chloride by-produced when thionyl chloride is used. Sulfur dioxide coexists.

[Procedure Amendment 11]

[Document name to be amended] Statement

[Correction target item name] 0019

[Correction method] Change

[Correction content]

In the present invention, after the salt of the amino acid ester with the acid is thus formed, the esterification reaction solution is
Neutralize with base. Here, the neutralization with the base may be carried out by bringing the base itself into contact with the esterification reaction solution as it is, but generally, the base is made into a solution or suspension with water and / or an organic solvent, This is preferably carried out by contacting with the above esterification reaction liquid. Here, the base is not particularly limited, but specific examples of bases that can be preferably used include organic amines such as triethylamine and diisopropylethylamine, sodium hydroxide,
Basic metal hydroxides such as potassium hydroxide, basic earth metal hydroxides such as calcium hydroxide and magnesium hydroxide, carbonates such as sodium carbonate and potassium carbonate, bicarbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate. Etc. can be mentioned.

[Procedure Amendment 12]

[Document name to be amended] Statement

[Name of item to be corrected] 0029

[Correction method] Change

[Correction content]

By the above N-alkoxycarbonylation reaction, N-alkoxycarbonyl amino acid ester is produced. In this reaction solution, the solvent is an alcohol derived from unreacted raw materials of the esterification reaction and by-products of the N-alkoxycarbonylation reaction, or a solution or suspension of water or an organic solvent of a base in the neutralization step. When used, the above alcohol and water and / or water derived from this neutralization solution
Alternatively, it is a mixed solution with an organic solvent. In addition to the above N-alkoxycarbonyl amino acid ester, this solution is neutralized with a salt of the amino acid ester with an acid , and with a strong acid or sulfur dioxide coexisting in the amino acid esterification reaction solution. The generated salt coexists.
In some cases, unreacted raw materials and intermediate products such as amino acids and amino acid esters also remain.

[Procedure Amendment 13]

[Document name to be amended] Statement

[Correction target item name] 0034

[Correction method] Change

[Correction content]

[0034]

According to the present invention, a reaction solution obtained by reacting an amino acid, an alcohol, and a strong acid or thionyl chloride is prepared.
The N-alkoxycarbonyl amino acid ester can be obtained in high yield by a simple operation in which the reaction solution containing the produced amino acid ester is reacted with the dicarbonate directly after neutralization with a base . Therefore, the present invention provides a method for producing an N-alkoxycarbonyl amino acid ester,
It is extremely useful industrially.

Claims (1)

[Claims] 1. A reaction solution obtained by reacting an amino acid, an alcohol, and a strong acid or thionyl chloride is neutralized with a base,
The resulting amino acid ester and the general formula (1): (However, 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, and the N-alkoxycarbonylamino acid from the reaction solution is reacted. A process for producing an N-alkoxycarbonyl amino acid ester, which comprises isolating the ester in the presence of water.