JP3285440B2 - 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 easily producing an N-alkoxycarbonyl amino acid ester.

[0002]

2. Description of the Related Art A method of synthesizing an N-alkoxycarbonyl amino acid ester by converting an amino acid ester into N-alkoxycarbonyl has been known. For example, a method is known in which a salt of an amino acid ester with an acid is reacted with di-t-butyl dicarbonate in an organic solvent in the presence of a stoichiometric amount of triethylamine (Journal of Organic Chemistry). (J. Org. Che
m. 50), No. 22, p. 4332-6, 1985
Year).

The salt of an amino acid ester with an acid used in such a reaction can be obtained, for example, by reacting an amino acid with an olefin and sulfuric acid. In addition,
In this method, the obtained reaction solution contains unreacted sulfuric acid in addition to the target amino acid ester sulfate. Therefore, in such a method for producing an amino acid ester sulfate , after the reaction is completed, an operation of isolating and purifying the generated amino acid ester sulfate is generally performed on the reaction solution. In this purification operation, usually, an aqueous solution of a base is added to the reaction solution, and the amino acid ester sulfate, which is a target substance, is once neutralized together with the sulfuric acid, and the neutralization is performed while the salt remains in the aqueous layer. , An amino acid ester released by the above method is extracted with an organic solvent that is not mixed with water, and the isolated amino acid ester is contacted with an acid to convert it into a stable acid salt again.

[0004]

However, the operation of purifying the amino acid ester sulfate is complicated, and the amino acid ester sulfate is first produced from the amino acid by the above-described amino acid esterification method. Then
Using this amino acid ester sulfate as a raw material, the N-
In the case of producing an N-alkoxycarbonyl amino acid ester by performing an alkoxycarbonylation reaction, it has hindered efficient production.

[0005] In addition, since the amino acid ester has a certain solubility in water, a considerable amount of the amino acid ester sulfate is not extracted into the organic solvent layer during the purification operation, and the amino acid ester is not dissolved in the aqueous layer. Remains and disappears. Therefore, even when an N-alkoxycarbonyl amino acid ester is produced using the above amino acid as a starting material,
If the extraction operation is not repeated using an excessively large amount of an organic solvent during the purification operation of the amino acid ester, loss of the amino acid ester to the aqueous layer occurs, and the N-alkoxycarbonyl amino acid ester is obtained in a satisfactory yield. Could not get.

[0006] From the above background, amino acids as raw materials
In producing an alkoxycarbonylamino acid ester, it has been desired to develop a method for obtaining the compound in a high yield by a simple operation.

[0007]

Means for Solving the Problems In view of the above-mentioned circumstances, the present inventors have intensively studied a method for producing an N-alkoxycarbonyl amino acid ester by a simple operation in a high yield. As a result, amino acids, olefins, and sulfuric acid react to
A reaction solution containing amino acid ester sulfate was obtained, and then
Reaction solution containing amino acid ester sulfate was neutralized with base
After that, the reaction solution containing the produced amino acid ester
It has been found that the above problems can be solved by mixing with dicarbonate represented by the general formula, and the present invention has been completed.

That is, the present invention relates to amino acids, olefins,
And sulfuric acid react to contain amino acid ester sulfate
A solution is obtained and then contains this amino acid ester sulfate
After neutralizing the reaction solution with a base, the resulting amino acid ester
And a reaction solution containing the general formula (1)

Embedded image (Provided that R ¹ is an alkyl group, an alkenyl group,
Is a alkyl group. ) To give N-alkoxy
A reaction solution containing a carbonyl amino acid ester is obtained.
-Reaction liquid containing alkoxycarbonyl amino acid ester
A method for producing an N-alkoxycarbonyl amino acid ester, wherein the isolation of an N-alkoxycarbonyl amino acid ester from N is carried out in the presence of water.

[0009]

Embedded image

(Wherein R ¹ is an alkyl group, an alkenyl group or an aralkyl group) to form an N-alkoxycarbonyl amino acid ester, and the N-alkoxy A method for producing an N-alkoxycarbonyl amino acid ester, comprising isolating the carbonyl amino acid ester in the presence of water.

The olefin used for the esterification of amino acids in the present invention is not particularly limited, but preferably has 2 to 10 carbon atoms. Specifically, ethylene, propylene, 1-butene, 2-butene, isobutylene, 1-pentene, 2-pentene, isopentene,
Examples thereof include 1-hexene, 2-hexene, isohexene, and cyclohexene.

The amino acid used in the present invention comprises at least one amino group or imino group in the molecule,
A known compound can be used without any limitation as long as it has a carboxyl group. In the case of an amino acid having two or more amino groups or imino groups or a substituted amino group or a substituted imino group substituted by an alkyl group or the like in one molecule, it has at least one amino group or even imino group. If so, another amino group or imino group may be substituted with an alkyl group or the like.

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, 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-
Examples thereof include 1-cyclohexanecarboxylic acid, γ-amino-β-hydroxybutyric acid, phenylglycine, and 4-hydroxyphenylglycine.

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.

In the present invention, such an esterification reaction of an amino acid is carried out by reacting the amino acid, the olefin, and sulfuric acid to produce an amino acid ester sulfate. Here, the amount of the olefin is not particularly limited, but is preferably at least 1 equivalent to 1 equivalent of the amino acid. Normal,
This esterification reaction is generally performed by dissolving or suspending an amino acid and concentrated sulfuric acid in an organic solvent, and further dissolving an olefin to saturation.

In the present invention, the amount of sulfuric acid used is not particularly limited, but is preferably at least 1 equivalent, more preferably 1 to 3 equivalents, per equivalent of the amino acid.

In the present invention, the solvents used for esterification of amino acids are specifically exemplified by ethers such as dioxane and tetrahydrofuran; chlorinated solvents such as dichloromethane and dichloroethane; and hydrocarbons such as toluene. Used for

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

In the reaction solution obtained by the above esterification reaction, unreacted sulfuric acid coexists in addition to the target amino acid ester sulfate.

In the present invention, after the amino acid ester sulfate is formed in this way, a base is added to the reaction solution to neutralize the amino acid ester sulfate. By this neutralization, in addition to the amino acid ester sulfate, sulfuric acid coexisting in the esterification reaction solution is also neutralized, and the amino acid ester and sulfate are formed in the solution. Here, the base used for neutralization is not particularly limited, but specific examples of a base that can be preferably used include organic amines such as triethylamine and diisopropylethylamine, and alkali metals such as sodium hydroxide and potassium hydroxide. Examples thereof include hydroxides, alkaline earth metal hydroxides such as calcium hydroxide and magnesium hydroxide, carbonates such as sodium carbonate and potassium carbonate, and bicarbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate. These bases may be used as they are, or may be used after being dissolved or suspended in water or an organic solvent.

The amount of the base used for neutralization can be selected in the range of 0.8 to 2 gram equivalents, preferably 1 to 1.5 gram equivalents, for 1 gram equivalent of sulfuric acid used for the esterification reaction of the amino acid. I just need. When an aqueous solution of a base is used for neutralization, the pH of the aqueous solution obtained by the neutralization is preferably 5 to 5.
13, more preferably, an amount that leads to 6 to 11.

In the present invention, the neutralization is carried out using a base itself or a solution or suspension of a base whose solvent component is the same as the solvent used in the esterification reaction of the amino acid. In this case, since the solvent component of the neutralized liquid has a substantially single composition, an arbitrary amount thereof may be recovered by a method such as distillation under reduced pressure after neutralization. Here, in order to recover and reuse the solvent, it is preferable to use a base that does not generate water during the neutralization as the base used for the neutralization. When the amino acid is recovered after neutralization in this way, the amino acid used has a hydroxyl group in the molecule, such as serine,
It is preferable to use a compound which does not condense the hydroxyl group of the amino acid and the carboxyl group of another amino acid to produce a dimer ester by-product during the distillation under reduced pressure.

Next, in the present invention, without isolating and purifying the compound from the reaction solution in which the amino acid ester was formed by the above neutralization, the dicarbonate represented by the above formula (1) was continuously added to the reaction solution. To perform an N-alkoxycarbonylation reaction of the amino acid ester. here,
The amino acid ester is a compound having a considerably higher solubility in water and a significantly lower solubility in an organic solvent as compared with the N-alkoxycarbonyl amino acid ester formed by the N-alkoxycarbonylation reaction,
It is a compound that has a relatively large loss to an aqueous layer or the like in an isolation and purification operation such as extraction with an organic solvent. Therefore, in the present invention, the reaction solution obtained by the esterification reaction of the amino acid as described above is directly subjected to the N-alkoxycarbonylation reaction, thereby not only simplifying the production operation but also simplifying the production operation. The disappearance of the compound caused by performing the purification operation is eliminated, and as a result,
A significant improvement in the yield of the desired N-alkoxycarbonyl amino acid ester is achieved.

In addition, the N-alkoxycarbonylation reaction solution thus obtained is not subjected to the purification operation of the neutralized solution of the esterification reaction solution of the amino acid, in addition to the N-alkoxycarbonyl amino acid ester. A considerable amount of sulfate coexists. Sulfates dissolve well in water,
On the other hand, since N-alkoxycarbonyl amino acid esters are hardly soluble in water, in the present invention, if water is contained in the reaction solution obtained by the N-alkoxycarbonylation reaction, such sulfates and N-alkoxy Utilizing the difference in solubility of carbonyl amino acid esters 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 N-alkoxycarbonyl amino acid ester crystals from the reaction solution, or a method in which water is mixed with water in a reaction solution containing water. By mixing an organic solvent that is compatible and dissolves the N-alkoxycarbonyl amino acid ester, or by mixing water with a reaction solution in which the organic solvent is a solvent component, an N-alkoxy is added to the organic solvent layer. A method of extracting a carbonyl amino acid ester is exemplified. Thus, when the N-alkoxycarbonyl amino acid ester is isolated by utilizing the difference in solubility of the sulfate and the N-alkoxycarbonyl amino acid ester in water in this manner, this compound is Efficient crystallization from the reaction solution due to the salting out effect of sulfate coexisting in the reaction solution to be produced, or efficient extraction from the reaction solution into the organic solvent layer due to the high dissolved concentration of the salt . Therefore, in the production method of the present invention, the yield of N-alkoxycarbonyl amino acid ester is further improved by the salting out effect of the sulfate.

In the present invention, the dicarbonate used for N-alkoxycarbonylation is a compound represented by the above formula (1). In the formula, the alkyl group represented by R ¹ is not particularly limited, but is a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group,
A lower alkyl group such as an i-butyl group and a t-butyl group is preferable, an alkenyl group is preferably an allyl group, 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 amount of dicarbonate used relative to the amino acid ester is not economical if it is used in an excessively large amount.
It may be selected in the range of 2 equivalents, more preferably 1 to 1.5 equivalents.

The N-alkoxycarbonylation reaction is carried out in water or
Or without limitation in organic or mixed solvents
In the present invention, the amino acid
Amino acids obtained through a telluration reaction and a subsequent neutralization reaction
The reaction solution containing steal is reacted with the N-alkoxycarbonylation reaction.
When the reaction is performed, various solvents are further replenished.
A reaction may be performed. It also contains this amino acid ester.
The reaction liquid is distilled off by distilling off any amount of the solvent under reduced pressure.
Or replenish it with other solvents after such evaporation.
May be subjected to the N-alkoxycarbonylation reaction.
No.

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. ~ 8
Preferably it is in the range of 0 ° C.

The reaction pressure in the N-alkoxycarbonylation reaction can be carried out at any of normal pressure, increased pressure, and reduced pressure. The time required for the reaction varies depending on the reaction temperature and the kind of the amino acid used as the raw material. Usually, it is in the range of 1 to 120 hours. The reaction can be performed in either a batch system or a continuous system.

In the present invention, when the solvents used in the N-alkoxycarbonylation reaction, the esterification reaction of amino acids and the neutralization reaction are the same, the solvent of the N-alkoxycarbonylation reaction solution is used. Since the components have almost a single composition, an arbitrary amount thereof may be recovered by a method such as distillation under reduced pressure after the reaction. Here, in order to recover and reuse the solvent, it is preferable to use a base that does not generate water during the neutralization as the base used for the neutralization.

Next, in the present invention, the method of allowing water to be present in the reaction solution obtained by the N-alkoxycarbonylation reaction is not particularly limited. For example,
If the esterification reaction solution of the amino acid is neutralized using an aqueous solution of a base, the N-alkoxycarbonylation reaction solution already contains a large amount of water derived from the aqueous solution. The isolation operation can be performed without special care. On the other hand, when the esterification reaction solution of the amino acid is neutralized using the base itself or a solution or suspension of the base in an organic solvent, the reaction solution is obtained in a substantially anhydrous state as it is. When you are
Water may be added to the reaction solution during such an isolation operation. Here, the content of water in the reaction solution is not particularly limited. However, in consideration of the efficiency of isolation of the N-alkoxycarbonyl amino acid ester, when the crystal is precipitated or the compound is extracted. It is preferably at least 40% by weight, more preferably at least 60% by weight.

In the present invention, when the N-alkoxycarbonyl amino acid ester is isolated from the reaction solution in which water is present by the above-mentioned crystallization, the operation is as follows:
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 by a method such as distillation under reduced pressure. If the amount of the solution at the time of crystallization is too small, it is difficult to stir and transfer the solution.
The amount is preferably 0% or less, more preferably 20% or less. In order to perform crystallization efficiently,
The sulfate concentration in the liquid is 3 wt% or more, and more preferably 5 wt% or more.
Preferably, it is 25 wt%. The crystallization temperature is preferably selected from the range of usually from the freezing point of the system to 40 ° C, more preferably from 0 to 30 ° C. The precipitated crystals can be separated by a known method, for example, filtration, centrifugation or the like. If necessary, further water washing can be performed during these separation operations.

On the other hand, when the N-alkoxycarbonyl amino acid ester is isolated by the above-mentioned 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 are used without particular limitation. Specific examples include dichloromethane, 1,2-dichloroethane, chloroform, toluene, ethyl acetate, diisopropyl ether and the like. When mixing such an organic solvent, the organic solvent already contained as a reaction solvent may be previously distilled off from the reaction solution by a method such as distillation under reduced pressure, if necessary. In this case, if the amount of the liquid before mixing the organic solvent is too small, it is difficult to stir the mixture. Preferably, there is. Further, in order to perform the extraction efficiently, it is preferable that the sulfate concentration in the liquid is 3 wt% 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. The N-alkoxycarbonyl amino acid ester may be crystallized from the extract by a known method.

[0035]

According to the present invention, amino acids, olefins and sulfuric acid are reacted to contain amino acid ester sulfates.
The amino acid ester sulfate is then removed.
After neutralizing the reaction solution containing the
The reaction solution containing ter is mixed with dicarbonate to obtain
Containing N-alkoxycarbonyl amino acid esters
From the reaction solution, the N-alkoxycarbonyl amino acid ester
Can be obtained in a high yield by a simple operation of isolating N-alkoxycarbonyl amino acid in the presence of water . Therefore, the present invention is industrially extremely useful as a method for producing an N-alkoxycarbonyl amino acid ester.

[0036]

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

Example 1 37.5 g (0.5 mol) of glycine, 400 ml of dioxane and 98 g (1 mol) of concentrated sulfuric acid were placed in an eggplant flask.
While cooling in a dry ice / acetone bath, isobutylene 56
g (1 mol) was blown in. It was sealed and left at room temperature for 1 day. The obtained reaction solution was added dropwise to 1 L of a 2N aqueous sodium hydroxide solution previously placed in a four-necked flask with stirring under ice-cooling. After completion of the dropwise addition, 87.2 g (0.4 mol) of di-t-butyl dicarbonate was added dropwise under ice cooling, and the mixture was cooled to room temperature at room temperature.
Allowed to react for hours. Then dioxane and the formed t-
Butanol was distilled off under reduced pressure, and an extraction operation was performed using 400 ml of dichloromethane. Dichloromethane layer is added to water 100
After washing twice with water, dichloromethane was distilled off under reduced pressure to obtain 77.4 g of oily Nt-butoxycarbonylglycine-t-butyl ester. The yield was 67%.

Comparative Example 1 In Example 1, the glycine esterification reaction solution was changed to 2N
The same operation as in Example 1 was performed up to the operation of neutralizing with an aqueous sodium hydroxide solution. After neutralization, dioxane was distilled off under reduced pressure, and glycine-t-butyl ester was extracted with 400 ml of dichloromethane. Then, the dichloromethane layer was separated, and 87.2 g (0.4 mol) of di-t-butyl dicarbonate was added dropwise under ice cooling, and the mixture was reacted at room temperature for 12 hours. The obtained reaction solution was washed twice with 100 ml of water, and the solvent was distilled off under reduced pressure to obtain 61.2 g of oily Nt-butoxycarbonylglycine-t-butyl ester. The yield was 53%.

Example 2 58.0 g (0.5 mol) of L-proline, 400 ml of dichloromethane and 98 g (1 mol) of concentrated sulfuric acid were placed in an eggplant flask, and 56 g (1 mol) of isobutylene was cooled in a dry ice / acetone bath. Was infused. It was sealed and left at room temperature for 1 day. 106 g (1 mol) of sodium carbonate previously placed in a four-necked flask with the obtained reaction solution
Is suspended in 300 ml of dichloromethane.
The solution was added dropwise at 10 ° C. or lower with stirring. Further, 87.2 g (0.4 mol) of di-t-butyl dicarbonate was added dropwise under ice cooling, and the mixture was reacted at room temperature for 12 hours. Thereafter, the reaction solution was diluted with water 10
After washing twice with 0 ml, dichloromethane was distilled off under reduced pressure.
Oily Nt-butoxycarbonyl-L-proline-t
97.6 g of butyl ester were obtained. The yield was 72%.

Example 3 66.0 g of L-hydroxyproline was placed in an eggplant-shaped flask.
(0.5 mol), 400 ml of dioxane, 98 g of concentrated sulfuric acid
(1 mol), and 56 g (1 mol) of isobutylene was blown while cooling in a dry ice / acetone bath. It was sealed and left at room temperature for 1 day. The obtained reaction solution was added dropwise to 1.5 L of a 0.67 M aqueous solution of sodium carbonate at 10 ° C. or lower while stirring in a four-necked flask in advance.
Further, 87.2 g of di-t-butyl dicarbonate under ice cooling.
(0.4 mol) was added dropwise and reacted at room temperature for 12 hours.
Thereafter, dioxane and generated t-butanol were distilled off under reduced pressure, and the precipitated crystals were collected by filtration. 200ml on a funnel
The crystals were washed with water and dried to obtain 106 g of crystals of Nt-butoxycarbonyl-L-hydroxyproline-t-butyl ester. The yield was 74%.

Examples 4 and 5 The procedure of Example 2 was repeated except that the compounds shown in Table 1 were used as amino acids to obtain the respective N-alkoxycarbonyl amino acid esters shown in Table 1. The amino acids used and the yields are shown in Table 1.

[0042]

[Table 1]

Examples 6 and 7 The procedure of Example 2 was repeated, except that the compounds shown in Table 2 were used as the dicarbonates, to obtain the respective N-alkoxycarbonyl amino acid esters shown in Table 2. Table 2 shows the dicarbonate used and the yield.

[0044]

[Table 2]

Claims (1)

(57) [Claims] (1) reacting an amino acid, an olefin and sulfuric acid;
To obtain a reaction solution containing the amino acid ester sulfate.
Then, the reaction solution containing this amino acid ester sulfate is added with a base.
After neutralization, the reaction solution containing the generated amino acid ester
General formula (1) (Provided that R ¹ is an alkyl group, an alkenyl group,
Is a alkyl group. ) To give N-alkoxy
A reaction solution containing a carbonyl amino acid ester is obtained.
-Reaction liquid containing alkoxycarbonyl amino acid ester
A process for producing an N-alkoxycarbonyl amino acid ester, comprising isolating the N-alkoxycarbonyl amino acid ester from the compound in the presence of water.