JP2002121183A - How to close amino acids - Google Patents

Abstract

PROBLEM TO BE SOLVED: To improve the method of cyclizing an amino acid in order to produce a ring-closing compound used as an intermediate or a reagent intermediate for drug production from an amino acid, and to improve the yield and purity of the product. It is an object to increase the reaction time, shorten the reaction time, do not require a catalyst, and do not generate by-products. SOLUTION: The temperature is 100 ℃ ~ 400 ℃, the pressure is 5MPa ~.
The amino acid is dehydrated by bringing high-temperature and high-pressure water of 100 MPa into contact with the amino acid, thereby closing the amino acid.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for cyclizing an amino acid, and more particularly, to a method for cyclizing an amino acid in order to produce a cyclized compound used as an intermediate or a reagent intermediate for the production of a pharmaceutical product from the amino acid. Regarding improvement.

[0002]

2. Description of the Related Art Conventionally, intermediates and reagent intermediates for the production of pharmaceuticals have been produced from raw materials containing amino acids. It is produced by a ring closure reaction.

For example, 7-membered ε-caprolactam is used as a raw material for polyamide-based synthetic fibers (nylon), and 2-piperidone and 2-pyrrolidone are used as pharmaceutical intermediates.

The production of intermediates and reagent intermediates for the production of pharmaceuticals by such a ring closure reaction is described, for example, in Tetra hedr.
On Letters, vol. 38, No. 4, 677-680 (1997), the reaction has conventionally been carried out at about 60 ° C. using a catalyst.

[0005]

However, such a conventional method has the following problems. Poor yield of manufactured product. Poor purity of manufactured product. Long reaction time. A catalyst is required for the ring closure reaction. By-products are formed.

SUMMARY OF THE INVENTION The present invention has been made to solve the above-mentioned problems, and it is an object of the present invention to increase the yield and purity of a product, shorten the reaction time, do not require a catalyst, and do not generate by-products. As an issue.

[0007]

SUMMARY OF THE INVENTION The present invention has been made to solve such a problem, and means for solving the problem includes a temperature of 100 ° C. to 400 ° C. and a pressure of 5 MPa.
By contacting high-temperature high-pressure water of 100 MPa with an amino acid, the amino acid is dehydrated to close the amino acid.

The temperature of the high-temperature high-pressure water is 100 ° C. as described above.
To 400 ° C, more preferably 200 ° C to 300 ° C.

[0009] The pressure of the high-temperature and high-pressure water is 5 MPa to 100 MPa as described above, but is more preferably 10 MPa to 50 MPa.

Although the number of carbon atoms in the main chain of the amino acid is not particularly limited, it is preferably 5 to 9.

The amino acids include, for example, 6-aminohexanoic acid, 5-amino-n-valeric acid, 4-amino-n
-Any butyric acid or a mixture of two or more of these is used.

Examples of the substance formed by ring-closing these amino acids include ε-caprolactam, 2-piperidone, 2-pyrrolidone, and a mixture of two or more of these.

[0013]

Embodiments of the present invention will be described below.

Example 1 In this example, 6-aminohexanoic acid (molecular weight 131.17) was used as an amino acid, and ε-
Caprolactam was produced.

The manufacturing method will be described first.
In a 6 ml stainless steel high-pressure vessel,
Charge 0.16 mmol of aminohexanoic acid and water, and raise the temperature to 150
℃ ~ 300 ℃ (423K ~ 573K) range, and set the pressure
The reaction was allowed to proceed for 1 hour at 30 MPa.

As a result, ε-caprolactam, a 7-membered lactam, was produced. The reaction formula is as shown in the following formula (1).

[0017]

Embedded image

Table 1 shows the change in the amount of ε-caprolactam produced based on the temperature change, and FIG. 1 shows the change in the yield based on the temperature change. In FIG. 1, the temperature is indicated only by the absolute temperature.

[0019]

[Table 1]

As is clear from Table 1 and FIG. 1, the yield reached 90% at the maximum at a temperature of 280 ° C. (553 K).
The raw material (mg) in Table 1 is the total weight of the raw material amino acid and water. Hereinafter, notations in all tables are the same.

Example 2 In this example, 5-amino-n-valeric acid (molecular weight 117.15) was used as an amino acid,
-Piperidone (δ-valerolactam) was prepared.

The manufacturing method will be described first.
In a stainless steel high-pressure vessel with an inner volume of 6 ml, 5-
0.16 mmol of amino-n-valeric acid and water were charged and the temperature was adjusted to 15
The reaction was carried out for 1 hour at a temperature of 0 ° C. to 300 ° C. and a pressure of 30 MPa.

As a result, 2-piperidone (δ-valerolactam), which is a 6-membered lactam, was produced. The reaction formula is as shown in the following formula (2).

[0024]

Embedded image

Table 2 shows the change in the amount of δ-valerolactam produced based on the temperature change, and FIG. 1 shows the change in the yield based on the temperature change.

[0026]

[Table 2]

As is clear from Table 2 and FIG. 1, the yield reached the maximum of 90% at a temperature of 220 ° C. (493 K).

Example 3 In this example, 4-amino-n-butyric acid (molecular weight: 103.12) was used as an amino acid,
Pyrrolidone (butyrolactam) was produced.

The manufacturing method will be described first.
In a 6 ml stainless steel high-pressure vessel,
0.16 mmol of amino-n-butyric acid and water were charged, and the temperature was 150
℃ ~ 300 ℃ range, set the pressure to 30MPa
The reaction was allowed to run for hours.

As a result, 2-pyrrolidone (butyrolactam), which is a 5-membered ring lactam, was produced. The reaction formula is as shown in the following formula (3).

[0031]

Embedded image

Table 3 shows the change in the amount of butyrolactam produced according to the temperature change, and FIG. 1 shows the change in the yield according to the temperature change.

[0033]

[Table 3]

As is clear from Table 3 and FIG. 1, the yield reached the maximum of 90% at a temperature of 220 ° C. (493 K).

As is apparent from FIG. 1, the peak of the maximum yield of the reaction for producing the 7-membered lactam ε-caprolactam is higher than that of the 6-membered lactam δ-valerolactam and the 5-membered lactam. The peak of the maximum yield of the production reaction of lactam butyrolactam was shifted to the lower temperature side.

(Embodiment 4) In this embodiment, the first embodiment will be described.
Ε-caprolactam was produced from 6-aminohexanoic acid in the same manner as described above.

The manufacturing method is the same as in Example 1, except that the temperature is set in the range of 200 ° C. to 300 ° C. (473 K to 573 K).
The reaction was performed for 1 hour at a pressure of 15 MPa.

Table 4 shows the change in the amount of ε-caprolactam produced based on the temperature change, and FIG. 2 shows the change in the yield based on the temperature change.

[0039]

[Table 4]

As is clear from Table 4 and FIG. 2, the yield was 87% at the maximum at a temperature of 300 ° C. (573 K).

(Embodiment 5) In this embodiment, the second embodiment will be described.
Δ-Valerolactam was produced from 5-amino-n-valeric acid in the same manner as described above.

The production method was the same as in Example 2, except that the reaction was carried out for 1 hour at a pressure of 15 MPa.

Table 5 shows the change in the amount of δ-valerolactam produced based on the temperature change, and FIG. 2 shows the change in the yield based on the temperature change. In FIG. 2, the temperature is indicated only by the absolute temperature.

[0044]

[Table 5]

As is clear from Table 5 and FIG. 2, when the temperature was 275 ° C. (548 K) and 300 ° C. (573 K), the maximum yield was 93%.

(Embodiment 6) In this embodiment, the third embodiment will be described.
Butyrolactam was produced from 4-amino-n-butyric acid in the same manner as in 1.

The production method was the same as in Example 3, except that the reaction was carried out for 1 hour at a pressure of 15 MPa.

Table 6 shows the change in the amount of butyrolactam produced based on the temperature change, and FIG. 2 shows the change in the yield based on the temperature change.

[0049]

[Table 6]

As is clear from Table 6 and FIG. 2, the yield reached the maximum of 92% at a temperature of 250 ° C. (523 K).

As is apparent from FIG. 2, the reaction for producing ε-caprolactam, which is a 7-membered ring lactam, was 200
Although the yield was low around ℃, the 6-membered lactam δ
In the reaction for producing valerolactam and butyrolactam which is a 5-membered ring lactam, a high yield was obtained even at around 200 ° C.

Example 7 In this example, as raw materials
6-aminohexanoic acid, 5-amino-n-valeric acid, 4-
A mixture containing 0.16 mmol of amino-n-butyric acid and water were charged into a stainless steel high-pressure vessel having an inner volume of 6 ml,
The temperature was set to 220 ° C. (493 K), the pressure was set to 5 MPa, and the reaction was allowed to proceed for 1 hour.

As a result, 35.8 mg of ε-caprolactam was obtained,
75.9 mg of δ-valerolactam, 59.8 mg of butyrolactam
Generated.

The product was analyzed by gas chromatography to confirm that no other reaction by-products were generated.

(Display of plots against reaction pressure) ε-caprolactam, δ-valerolactam,
When the yields of butyrolactam and the reaction pressure are plotted again, the results are as shown in FIG.

As is clear from FIG. 3, in the range of 10 to 30 MPa, it was found that the lower the pressure of each product, the higher the yield. However, there was no extreme change.

(Other Examples) The types of amino acids used in the present invention are limited to 6-aminohexanoic acid, 5-amino-n-valeric acid, 4-amino-n-butyric acid and the like in the above examples. It is not something to be done.

However, in order to produce a ring-closing compound by causing a ring-closing reaction, those having about 5 to 9 carbon atoms are preferred.

The temperature range of the high-temperature and high-pressure water is not limited to the above embodiments, but may be in the range of 100 ° C. to 400 ° C.

Below 100 ° C., the desired ring-closed compound can hardly be produced without a catalyst, while at 400 ° C.
This is because, in the above, the raw material amino acid and the generated ring-closing compound may be inadvertently decomposed.

However, in order to obtain a high yield and to further enhance the effect of preventing the product from being carelessly decomposed,
The temperature is preferably in the range of 0 ° C to 300 ° C.

Further, the pressure of the high-temperature and high-pressure water is not limited to 30 MPa or 15 MPa in each of the above-mentioned embodiments, but may be 5 to 100 MPa.

When the pressure is 5 MPa or less, the desired ring-closed compound can hardly be produced without a catalyst such as another chemical substance. On the other hand, when the pressure is 100 MPa or more, it is not suitable for the actual situation of a real apparatus using high-temperature and high-pressure water. .

However, in order to obtain a high yield or the like, 10MP
The pressure is preferably set to a to 50 MPa.

Further, experiments were conducted with the charged amount of amino acid at the time of the reaction in addition to 0.16 mmol for each component and 0.85 mmol, and it was also confirmed that the same yield was obtained irrespective of the charged amount.

Further, the kind of the ring-closing compound produced is
Ε-caprolactam, 2-piperidone, 2
-It is not limited to pyrrolidone, and other ring-closing compounds may be used.

Furthermore, in the above embodiment, stainless steel was used as the material of the high-pressure vessel, but it is particularly desirable to use Hastelloy C steel. When a container having an inner wall made of Hastelloy C steel is used, the inner wall has a catalytic action, so that the reaction proceeds quickly.

[0068]

As described above, the present invention has a temperature of 100 ° C.
This method involves dehydration of amino acids by contacting high-temperature, high-pressure water with a pressure of 5 MPa to 100 MPa at ~ 400 ° C with the amino acids to dehydrate the amino acids, thereby significantly increasing the yield and purity of the product as compared with the conventional method. There is an effect that can be.

Further, there is an effect that the reaction time for carrying out the ring closure reaction can be significantly shortened as compared with the conventional case.

Further, unlike the conventional ring-closing reaction of amino acids, no catalyst such as a chemical substance is required, and therefore, there is an effect that the production cost of intermediate products of drugs and reagents can be reduced as compared with the conventional case. .

Further, there is an effect that no side reaction occurs and no by-product is generated.

[Brief description of the drawings]

FIG. 1 is a graph showing a correlation between a change in temperature and a change in yield at 30 MPa.

FIG. 2 is a graph showing a correlation between a change in temperature and a change in yield at 15 MPa.

FIG. 3 is a graph showing a correlation between a change in pressure at 300 ° C. and a change in yield.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Kazuaki Hata 2217-43 Hayashi-cho, Takamatsu-shi, Kagawa Prefecture Inside the High-Temperature-High-Pressure Fluid Research Institute (72) Inventor Shinkichi 2217-43 43 Hayashi-cho, Takamatsu-shi, Kagawa High-temperature, high-pressure flow F-term in the Body Engineering Laboratory (reference) 4C034 DE03 4C054 AA02 BB01 CC01 DD23 EE01 FF01 4C069 AB11 BC12

Claims (6)

[Claims] 1. A temperature of 100 ° C. to 400 ° C. and a pressure of 5 MPa to
A method for closing a ring of an amino acid, comprising contacting 100 MPa of high-temperature and high-pressure water with the amino acid to dehydrate the amino acid and to close the amino acid. 2. The method for cyclizing amino acids according to claim 1, wherein the temperature of the high-temperature high-pressure water is 200 ° C. to 300 ° C. 3. The method according to claim 1, wherein the pressure of the high-temperature and high-pressure water is 10 MPa to 50 MPa. 4. The method for ring-closing an amino acid according to claim 1, wherein the main chain of the amino acid has 5 to 9 carbon atoms. 5. The method according to claim 5, wherein the amino acid is 6-aminohexanoic acid,
2. It is any one of -amino-n-valeric acid and 4-amino-n-butyric acid, or a mixture of two or more thereof.
5. The method for cyclizing an amino acid according to any one of claims 1 to 4. 6. A substance produced by cyclizing an amino acid,
The method for cyclizing amino acids according to any one of claims 1 to 5, wherein the method is any one of ε-caprolactam, 2-piperidone, and 2-pyrrolidone, or a mixture of two or more thereof.