JP2001247538A - Method of producing amino acid derivative containing modified amino group and thiol group - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method of producing an amino acid derivative in which only an amino group is modified, in a high yield while suppressing the modification of thiol group or carboxyl group when modifying hydrogen atom on the amino group of the amino acid having thiol group in the molecule with an alkyloxycarbonyl group, an aralkyloxycarbonyl group, an aryloxycarbonyl group or the like. SOLUTION: The reaction of a haloformate represented by general formula [1]: XCOR...[1] (wherein, R is a lower alkoxy group, an aralkyloxy group or an aryloxy group; and X is a halogen atom) with an amino acid having a thiol group in the molecule in an aqueous medium is progressed while keeping the pH in the reaction system so as to be within the range of 7-9.5.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a hydrogen atom on an amino group of an amino acid having a thiol group in a molecule, which is useful as an intermediate for synthesizing various chemicals such as pharmaceuticals and agricultural chemicals, as an alkyloxycarbonyl group or an aralkyloxycarbonyl group. (Hereinafter, alkyloxycarbonyl group, aralkyloxycarbonyl group, aryloxycarbonyl group, etc. may be collectively referred to as “alkyloxycarbonyl group, etc.”). The present invention relates to a method for producing an amino acid derivative containing a thiol group having a modified amino group.

[0002]

2. Description of the Related Art Amino acid derivatives having a free carboxylic acid and a thiol group in a molecule are widely used as synthetic intermediates for pharmaceuticals, agricultural chemicals and the like. For example, with respect to penicillamine, one of amino acids having a thiol group in the molecule, International Publication No. WO 97/5108 discloses that
As penicillamine amide derivatives, compounds having antithrombin activity are indicated. Penicillamine derivatives having a free carboxylic acid in which the thiol group and amino group of penicillamine have been modified with various substituents have been used as intermediates for the production thereof.

[0003] Among such amino acid derivatives having a thiol group in the molecule, the amino group is modified with an alkyloxycarbonyl group and the like, and the thiol group is modified with an alkyl group, an aryl group, a cycloalkyl group and an aralkyl group. As a method for producing the amino acid derivative,
A method is known in which an amino group is modified with haloformate or the like, and then a thiol group is alkylated with an alkyl halide or the like. As a method for modifying the amino group of an amino acid with a haloformate or the like, a method of performing a reaction while maintaining the pH within a certain range is known.

For example, when modifying the nitrogen atom of aspartic acid with a benzyloxycarbonyl group, Japanese Patent Application Laid-Open No.
No. 14570 discloses that the reaction is carried out while maintaining the pH in the range of 10.75 to 11.75, and Japanese Patent Application Laid-Open No. 56-110661, etc., in the range of 12.0 to 13.5. Has been described.

[0005]

However, when the amino group of an amino acid having a thiol group in the molecule is modified with an alkyloxycarbonyl group or the like using a haloformate or the like under the above-mentioned strong basic conditions, Similarly, a reaction by-product modified with a thiol group or a carboxyl group in the amino acid by an alkyloxycarbonyl group or the like is obtained. Therefore, at present, it is difficult to obtain an amino acid derivative in which only an amino group is modified with an alkyloxycarbonyl group or the like in a high yield.

In view of the load imposed on purification, there is also a need for a production method capable of minimizing modification to a thiol group or a carboxyl group and obtaining an amino acid derivative modified only with an amino group in a high yield. Was.

[0007]

Means for Solving the Problems As a result of intensive studies, the present inventors have found that the amino group of an amino acid having a thiol group in the molecule can be converted to an alkyloxycarbonyl group or the like by using a haloformate or the like under basic conditions. The present inventors have found that the intended purpose can be achieved by maintaining the pH in the reaction system within a certain range in the reaction to be modified in the above, and thereby achieving the present invention.

That is, the gist of the present invention is based on the following general formula [1] which can be dissolved in an aqueous medium.

[0009]

Embedded image XCOR ... [1] (wherein, R represents a lower alkoxy group, an aralkyloxy group or an aryloxy group, and X represents a halogen atom), and a thiol group in the molecule. In a method for producing an amino acid derivative containing a thiol group in which an amino group is modified by reacting an amino acid containing thiol group with an amino acid in the presence of a base in an aqueous medium, the pH in the reaction system is in the range of 7 to 9.5. And a process for producing an amino acid derivative containing a thiol group in which an amino group is modified, characterized in that the reaction is carried out while maintaining the thiol group.

In a preferred embodiment of the present invention, the amino acid containing a thiol group in the molecule is represented by the following general formula [2]:

[0011]

Embedded image (Wherein, A represents a single bond, a methylene group or an ethylene group, and R ₁ and R ₂ each independently represent a hydrogen atom or a lower alkyl group). An amino acid derivative containing a modified thiol group is represented by the following general formula [3]

[0012]

Embedded image (Wherein, R, A, R1 and R2 have the same meanings as described above), wherein the aqueous medium is a mixture containing water and a water-soluble organic solvent. Wherein the reaction temperature is 5 to 40 ° C .; the amount of haloformate is 0.8 to 1.3 with respect to the amino acid containing a thiol group in the molecule.
The above-mentioned production method, wherein the molar ratio is p;
The above method, wherein H is maintained in a range of 8 to 9; wherein X represents a chlorine atom and R represents an n-propyloxy group in the general formula [1]. In the general formula [2], A represents a single bond, and R ₁ and R ₂ each represent a methyl group; and in the general formula [3], R represents an n-propyloxy group. Wherein A represents a single bond and R ₁ and R ₂ each represent a methyl group.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION The haloformate of the present invention is represented by the following general formula [1]

[0014]

## STR7 ## wherein X is a compound which satisfies the formula (1), wherein R represents a lower alkoxy group, an aralkyloxy group or an aryloxy group, and X represents a halogen atom, and is soluble in an aqueous medium. If there is, it is not particularly limited.

In the general formula [1], the lower alkoxy group means an alkoxy group having a carbon number at which the compound represented by the general formula [1] can be dissolved in an aqueous medium and which may be branched. And, for example, a methyloxy group,
Ethyloxy group, n-propyloxy group, isopropyloxy group, n-butyloxy group, isobutyloxy group,
Examples thereof include an s-butyloxy group, a t-butyloxy group, an n-pentyloxy group, an isopentyloxy group, a neopentyloxy group, a t-pentyloxy group, and an n-hexyloxy group. Preferred are a methyloxy group, an ethyloxy group, an n-propyloxy group, an isopropyloxy group, an n-butyloxy group, an isobutyloxy group, and a t-butyloxy group, and more preferred is an n-propyloxy group.

The aralkyloxy group is an aralkyloxy group having a carbon number at which the compound represented by the general formula [1] can be dissolved in an aqueous medium, and examples thereof include a benzyloxy group and a phenethyloxy group. As
A benzyloxy group.

In the general formula [1], the aryloxy group is an aryloxy group having a carbon number at which the compound represented by the general formula [1] can be dissolved in an aqueous medium. , A tolyloxy group, a pyridyloxy group and the like, preferably a phenyloxy group.

In the above general formula [1], a halogen atom means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom,
Examples include an astatine atom and the like, preferably a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and more preferably a chlorine atom.

Specific examples of the compound represented by the above general formula [1] include, for example, methylchloroformate, ethylchloroformate, n-propylchloroformate, isopropylchloroformate, n-butylchloroformate. , T-butyl chloroformate, phenyl chloroformate, benzyl chloroformate and the like,
Preferably, n-propylchloroformate is used.

The amount of the haloformate used is 0.8 to 1.3 based on the amino acid containing a thiol group in the molecule.
The molar ratio is preferably 0.9 to 1.1.

On the other hand, in the present invention, the amino acid containing a thiol group in the molecule is not particularly limited, and various amino acids can be mentioned. One example is the following general formula [2]

[0022]

Embedded image (Wherein, A represents a single bond, a methylene group or an ethylene group, and R ₁ and R ₂ each independently represent a hydrogen atom or a lower alkyl group).

In the above formula [2], the lower alkyl group is an alkyl group having a carbon number at which the compound represented by the formula [2] can be dissolved in an aqueous medium and which may be branched. And, for example, a methyl group, an ethyl group,
Propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, neopentyl, t-pentyl, hexyl, etc., preferably methyl, ethyl Group, propyl group and isopropyl group.

Specific examples of the compound represented by the general formula [2] include, for example, cysteine and penicillamine.

In the present invention, the amino acid derivative containing a thiol group in which the amino group is modified includes, for example, the following general formula [3]

[0026]

Embedded image (Wherein, R, A, R1 and R2 each have the same meaning as described above).

In the present invention, the reaction using the haloformate represented by the general formula [1] and penicillamine as an example of the amino acid represented by the general formula [2] proceeds according to the following reaction formula.

[0028]

Embedded image (In the formula, R and X have the same meanings as described above.)

In the present invention, an amino acid having a thiol group in a molecule as described above is reacted with haloformate in an aqueous medium in the presence of a base. The base used in the present invention is not particularly limited. For example, an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate, or triethylamine, trimethylamine Or an organic base such as pyridine or aniline.

As the aqueous medium, a substantially water-only solvent or a mixed solvent of water and an organic solvent which is water-soluble and dissolves haloformate is used. As the organic solvent used in the case of the mixed solvent, for example,
Examples thereof include tetrahydrofuran, dioxane, methanol, ethanol, isopropanol, t-butanol, N, N-dimethylformamide and the like. For example, the usage ratio to water is 0.1 to 3 volume ratio, preferably 0.5 to 3%.
1.5 volume ratio. The amount of the aqueous medium used is, for example, 3 to 2 with respect to the amino acid containing a thiol group in the molecule.
It is 0 times by weight.

In the present invention, when the reaction between the amino acid containing a thiol group in the molecule and the haloformate is carried out in the presence of a base, the pH in the reaction system is adjusted to 7 to 7 at the beginning of the reaction.
It is essential to start the reaction after adjusting to 9.5, preferably 7 to 9, more preferably 8 to 9, and to carry out the reaction while maintaining the pH during the reaction. When a reaction between an amino acid having a thiol group in the molecule represented by the general formula [2] and a haloformate is carried out in the presence of a base, H-X is by-produced with the progress of the reaction. Although the pH in the inside gradually decreases, the present invention is characterized in that the reaction is allowed to proceed while maintaining the pH in the above specific range.

When the pH value during the reaction is higher than 9.5, the reaction with the haloformate proceeds at the thiol group or the carboxyl group which is a reaction by-product, and not only the amino group but also the thiol group or the carboxyl group. The generation of by-products in which even the group is modified increases, and it is not possible to obtain an amino acid derivative containing a thiol group in which only the desired amino group is modified in high yield. On the other hand, when the value of pH is smaller than 7, the substitution reaction rate on the amino group decreases, which is not practical.

Therefore, to carry out the reaction of the present invention, usually, an amino acid containing a thiol group in a molecule is charged into an aqueous medium, and a base is added thereto to adjust the pH in the system to a desired value. After that, a preferred form is one in which the haloformate and the base are added dropwise to advance the reaction so that the pH does not exceed the desired range.

The reaction temperature of the present invention is 5 to 4
The temperature is 0 ° C, preferably 10 to 30 ° C, and the reaction time is usually about 0.5 to 5 hours.

The reaction mixture is usually made acidic and then
For example, the desired amino acid derivative can be obtained by extracting with a suitable organic solvent which can be separated from water such as toluene and concentrating it. Of course, the extracted solution can be used as it is for the next reaction.

[0036]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to the following examples unless it exceeds the gist thereof.

Example 1 A 300 mL glass reactor equipped with a stirrer, pH meter, temperature controller, reflux condenser and two dropping funnels was charged with 30 g (0.2 mol) of D-penicillamine and 180 mL of water. After cooling the temperature to 10 ° C., the pH in the system was adjusted to 8.6 with a 30% aqueous potassium hydroxide solution. At this time, the consumed 30% aqueous potassium hydroxide solution was 27.5 g (0.15 mol as potassium hydroxide). Then, n
-24.6 g (0.2 mol) of propyl chloroformate
Was added dropwise over 30 minutes, and stirring was continued for another 30 minutes to carry out the reaction. During this reaction, the pH in the reaction system
Was maintained between 8.5 and 8.9 by dropwise addition of a 30% aqueous potassium hydroxide solution. The 30% aqueous potassium hydroxide solution used for maintaining the pH was 57.1 g (0.31 mol as potassium hydroxide). Also, during the reaction,
The temperature in the system was maintained between 10 and 15 ° C.

After completion of the reaction, the mixture was analyzed by high performance liquid chromatography to obtain the results shown in Table 1.

Examples 2 to 3 Table 1 shows the results when the pH in the reaction system was adjusted to the value shown in Table 1 in Example 1 and the same reaction was carried out.

Comparative Example 1 Table 1 shows the results obtained in the same manner as in Example 1 except that 0.27 mol of potassium carbonate was present in the reaction system as a base to be used in the reaction from the beginning of the reaction. The pH of the reaction system at this time was 10.4 (early stage of the reaction) to 8.6.
(At the end of the reaction).

Comparative Example 2 Table 1 shows the results when the same reaction was carried out as in Example 1 except that the pH in the reaction system was adjusted to the value shown in Table 1.

[0042]

[Table 1] Table 1 * 1: Analyzed by high performance liquid chromatography using absolute calibration curve method * 2: Analyzed by high performance liquid chromatography in area%

The by-products 1 and 2 were obtained by LC
According to the -MS measurement, it is presumed that the hydrogen atom of the thiol group or carboxyl group of penicillamine was replaced with an n-propyloxycarbonyl group.

Example 4 Table 2 shows the results when the reaction was carried out in the same manner as in Example 1 except that a mixed solvent of 90 mL of tetrahydrofuran and 90 mL of water was used instead of 180 mL of water.

The initial addition amount and dropping amount of the aqueous sodium hydroxide solution when adjusting the pH were different, but the total amount was almost the same as in Example 1.

Examples 5 to 6 Table 2 shows the results obtained in the same manner as in Example 4 except that the mixing ratio of tetrahydrofuran and water was adjusted to the value shown in Table 2 and the reaction was carried out in the same manner.

[0047]

[Table 2] Table 2 * 1 and * 2 have the same meaning as in Table 1.

Examples 7 and 8 Table 3 shows the results when the reaction was carried out in the same manner as in Example 4 except that the temperature in the system during the reaction was adjusted to the value shown in Table 3.

[0049]

[Table 3] Table 3 * 1 and * 2 have the same meaning as in Table 1.

From the results of the above Examples and Comparative Examples, it is understood that in the present invention, it is important to maintain the pH in the reaction system within the range defined by the present invention from the beginning of the reaction to the end of the reaction. .

[0051]

According to the present invention, the pH in the reaction system is determined in the presence of a base.
Is kept in a specific range, and an amino acid containing a thiol group in the molecule is reacted with a haloformate to produce an amino acid derivative containing a thiol group having an amino group modified.

According to the present invention, the production of a reaction by-product can be suppressed as compared with the case where the pH is not adjusted, and the target compound in which only the amino group is modified can be obtained in a high yield.

 ────────────────────────────────────────────────── ─── Continuing on the front page (72) Susumu Sato Inventor F-term 4H006 AA02 AC56 AC63 BC10 BC16 BC31 RA04 RB04 TA04 TB55 inside Kurosaki Factory 1-1 Kurosaki Joishi, Yawatanishi-ku, Kitakyushu-shi, Fukuoka Prefecture

Claims (10)

[Claims] 1. The following general formula [1] dissolvable in an aqueous medium: XCOR ... [1] (wherein, R represents a lower alkoxy group, an aralkyloxy group or an aryloxy group, and X represents a halogen By reacting the haloformate represented by the formula (1) with an amino acid containing a thiol group in the molecule in an aqueous medium in the presence of a base to give an amino acid derivative containing a thiol group having a modified amino group. A method for producing an amino acid derivative containing a thiol group in which an amino group has been modified, wherein the reaction is allowed to proceed while maintaining the pH in the reaction system in the range of 7 to 9.5 in the production method. 2. An amino acid containing a thiol group in the molecule,
The following general formula [2] (2) wherein A represents a single bond, a methylene group or an ethylene group, and R ₁ and R ₂ each independently represent a hydrogen atom or a lower alkyl group. Recipe. 3. An amino acid derivative containing a thiol group having a modified amino group is represented by the following general formula [3]: (Wherein, R, A, R1 and R2 each have the same meaning as described above).
Production method described in 1. 4. The method according to claim 1, wherein the aqueous medium is a mixture containing water and a water-soluble organic solvent. 5. The method according to claim 1, wherein the reaction temperature is 5 to 40 ° C. 6. The method according to claim 1, wherein the amount of the haloformate is 0.8 to 1.3 times the amount of the amino acid containing a thiol group in the molecule. 7. The process according to claim 1, wherein the pH in the reaction system is maintained in the range of 8 to 9. 8. The method according to claim 1, wherein in the general formula [1], X represents a chlorine atom, and R represents an n-propyloxy group. 9. The method according to claim 2, wherein in the general formula [2], A represents a single bond, and R ₁ and R ₂ represent a methyl group. 10. The compound according to claim 3, wherein in the general formula [3], R represents an n-propyloxy group, A represents a single bond, and R ₁ and R ₂ represent a methyl group. The production method according to any of the above.