JP2001151761A - Method for producing uracil of thymine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for inexpensively producing high-purity uracil and thymine in a high yield. SOLUTION: This method for producing uracil or thymine is characterized in that cyanoacetylurea or methylcyanoacetylurea is catalytically reduced in the presence of a palladium carbon catalyst in an aqueous solution of an organic acid.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing uracil or thymine. Both uracil and thymine are important intermediates as pharmaceutical ingredients such as anti-AIDS drugs,
In particular, thymine is also an important component of nucleic acids.

[0002]

2. Description of the Related Art Conventionally, as a method for producing pyrimidines by catalytic reduction of cyanoacetylureas, methylcyanoacetylurea is catalytically reduced in water in the presence of a platinum oxide catalyst (Adams catalyst) to produce thymine. (Bull. Inst. Nucl. Sci., 12, 1)
21 (1961); Am. Chem. Soc. , 5
5,1733, 1933), a method of producing uracil by catalytic reduction of cyanoacetylurea in an aqueous acetic acid solution in the presence of a nickel catalyst (CA 70: 1969, 87)
733h) A method of producing uracil at 20 to 70 ° C. by catalytically reducing cyanoacetylurea in an aqueous solution of a strong acid such as sulfuric acid or hydrochloric acid in the presence of a palladium carbon catalyst (JP-A-56-86172). Etc. are known.

[0003] However, these conventionally known methods have not been established as industrial methods for producing the desired pyrimidines, particularly thymine, at low cost and with good yield.

That is, the above method requires a large amount of a very expensive platinum-based catalyst and is not practical, and the yield of thymine is only as low as about 21 to 24%. Further, is a method in which a nickel catalyst is used in a large amount of 1.5 to 2 times the mass of the starting cyanoacetylurea, and the yield of uracil is as low as about 41%.

[0005] Alternatively, the raw material is decomposed in the reaction solution due to strong acidic conditions (pH: 0.1 or less) during the catalytic reduction. In particular, the raw material is changed to methylcyanoacetylurea by this method, and the reaction temperature is 70 ° C.
When thymine is produced by catalytic reduction as described above, the methylcyanoacetylurea is decomposed, and it is difficult to obtain the desired product in good yield.

[0006]

As described above, it is difficult to obtain the desired product in a high yield in any of the conventional methods for producing uracil and thymine, and in addition, a large amount of expensive catalyst is required. It is also not economical because it is used for

An object of the present invention is to solve the above-mentioned drawbacks in the production of uracil and thymine, and to provide a method for obtaining uracil and thymine in good yield and at low cost. .

[0008]

Means for Solving the Problems As a result of intensive studies to achieve the above object, the present inventors have found that cyanoacetylurea or palladium carbon can be obtained by using palladium carbon as a catalyst and an aqueous solution of an organic acid as a reaction solvent. In the case of catalytic reduction of methylcyanoacetylurea, the yield of the target product, uracil or thymine, is drastically improved even when a relatively inexpensive catalyst is used in a small amount. They have found that they can be obtained in high yield, and have completed the present invention.

That is, the present invention relates to a method for producing uracil, comprising catalytically reducing cyanoacetylurea in an aqueous solution of an organic acid in the presence of a palladium carbon catalyst. A method for producing thymine, which comprises catalytically reducing methylcyanoacetylurea in an aqueous solution of an organic acid; and a method for producing thymine, wherein the organic acid is acetic acid. The method according to any one of the above, wherein the pH of the reaction solution is 0.1 to 6 when the reaction is carried out, and the method according to any one of the above, wherein the catalytic reduction is performed at a temperature of 70 to 100 ° C. It is a manufacturing method of.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, the reaction raw material, cyanoacetylurea or methylcyanoacetylurea, is a substance which can be obtained by a known production method. For example, cyanoacetic acid or α-cyanopropionic acid is converted to urea. And a substance synthesized by reacting with acetic anhydride.

In the present invention, the palladium carbon catalyst used in the catalytic reduction reaction is not particularly limited, and examples thereof include those having a palladium content of 5% by mass or 10% by mass. Alternatively, it may be a dry product. These catalysts are commercially available as, for example, 5% Pd / C (50% wet product) NX type, K type, and E type (all are manufactured by NE Chemcat, trade name). Are also useful in the present invention.

If the amount of the catalyst used in the present invention is too small, the rate of reduction of the raw material with hydrogen is slow, and if too much is used, it leads to an increase in cost. Therefore, the raw material cyanoacetylurea or methyl cyano is used. Usually 1 to 10% by mass based on the amount of acetylurea (d
(converted in terms of y minutes). Also,
In the present invention, the palladium carbon catalyst used for the reaction,
It is fully possible to use it repeatedly in the next reaction.

In the present invention, the catalytic reduction reaction is carried out in an aqueous solution of an organic acid under an atmosphere of hydrogen gas, and the hydrogen gas is blown into the reaction solution or fed into the gas phase of the upper phase of the reaction solution. However, it does not matter which one.

The hydrogen pressure during the reduction reaction can be increased under pressure. However, in order to prevent side reactions from occurring and to obtain the desired product in good yield, the reaction is performed at normal pressure. Is preferred.

The organic acids include acetic acid, propionic acid, succinic acid, lactic acid and the like. Among them, in the present invention, it is preferable to carry out catalytic reduction in an aqueous solution of acetic acid, and under these conditions, when catalytically reducing cyanoacetylurea or methylcyanoacetylurea,
Extremely high purity crystals can be obtained with very high yield.

The aqueous solution of an organic acid as a reaction solvent preferably has an organic acid concentration of 0.01 to 80% by mass in the aqueous solution. If the pH is too low, the decomposition of the raw material is accelerated.If the pH is too high, the thymine yield is extremely reduced due to the decomposition of the raw material and the generation of by-products. Is preferably from 0.1 to 6, and more preferably from 0.3 to 5.

In the catalytic reduction reaction according to the present invention, an organic acid aqueous solution is not prepared as a reaction solvent from the beginning, but an aqueous solvent is used and an organic acid is appropriately added thereto to adjust the pH to the above range. It is also possible to make the reaction proceed.

In the present invention, the concentration of the starting material cyanoacetylurea or methylcyanoacetylurea in the aqueous solution of the organic acid is adjusted to achieve a high yield, a short reaction time and good stirring efficiency. 0.1 to 3
0 mass%, more preferably 1 to 10 mass%
Use the amount

Depending on the amount of the organic acid in the organic acid aqueous solution and the raw material concentration, the reaction solution may be uniform except for the catalyst or may be in a slurry state. In the case of uniformity, the catalyst is separated by hot filtration, and in the case of a slurry, alkali water such as aqueous sodium hydroxide solution is added until the catalyst becomes uniform, and then the catalyst is filtered.

The reaction temperature in the catalytic reduction of the present invention is not particularly problematic in terms of product quality and yield even when the reaction is carried out at the boiling point of the reaction solvent, but if the reaction temperature is lower than 70 ° C., the reaction proceeds slowly.
Since the yield of the target compound is also deteriorated, it is preferable to perform the reaction in the range of 70 to the boiling point of the reaction solvent, and more preferably 75 to 100.
It is more preferable to carry out in the range of ° C.

The time required for the catalytic reduction is not fixed depending on the reaction temperature, the raw material concentration in the reaction solution, etc., but is usually in the range of 3 to 30 hours.

[0022]

EXAMPLES The method for producing uracil or thymine in the present invention will be described in more detail with reference to examples. In the following, all percentages are by mass except where otherwise specified, and the component analysis in the reaction solution was obtained from the results of quantitative analysis by HPLC.

Example 1 15.0 g (0.10 mol) of methylcyanoacetylurea having a purity of 94.2%, 40.0 g of acetic acid, and 508.1 g of pure water were placed in a reactor having an internal volume of 1 liter and stirred. did. The pH of the solution at this time was 2.2. Here, a palladium carbon catalyst having a palladium content of 5% (5% Pd
A / C NX type (50% wet product) (manufactured by NE Chemcat, trade name) (1.41 g) was added, and the gas phase was replaced with nitrogen and further replaced with hydrogen. The temperature of the reaction solution was raised to 80 ° C., and stirring was continued at normal pressure for 5 hours. Next, after replacing the gas phase with nitrogen, the catalyst was separated by filtration at a liquid temperature of about 70 ° C., and the obtained filtrate was analyzed. As a result, thymine was produced at a yield of 90 mol% with respect to the raw material methylcyanoacetylurea. It was confirmed that it was generated.

Next, 9.0% of a 49% aqueous sulfuric acid solution was added to the above filtrate.
After adding g, the temperature was raised to 70 ° C. under reduced pressure, about 490 g of an aqueous acetic acid solution was distilled off, and the obtained solution was adjusted to pH 7 by adding a 5% aqueous sodium hydroxide solution. Crystals were precipitated at a solution temperature of 10 ° C., filtered and washed with water to obtain 15.4 g of thymine-containing crystals. It is then dried and has a purity of 99.1.
% Thymine white crystals, 10.8 g (0.085 mol). The yield of taking out the crystals was 85 mol% based on the starting material methylcyanoacetylurea.

Example 2 12.5 g (0.0886 mol) of methylcyanoacetylurea having a purity of 94.2%, 15.9 g of acetic acid, and 455.1 g of pure water were placed in the same reactor as in Example 1, and stirred. did. The pH of the solution at this time was 2.3. Here, a palladium carbon catalyst having a palladium content of 5% (5% Pd
/ C NX type (51% wet product), manufactured by NE Chemcat, trade name) 1.29 g was added, and the gas phase was replaced with nitrogen and then further replaced with hydrogen. The temperature of the reaction solution was raised to 80 ° C., and stirring was continued at normal pressure for 7 hours. Then, after the gas phase was replaced with nitrogen, the catalyst was separated by filtration at a liquid temperature of about 60 ° C., and the obtained filtrate was analyzed. It was confirmed that it was generated.

Next, 7.8% of a 49% aqueous sulfuric acid solution was added to the filtrate.
After adding g, the temperature was raised to 70 ° C. under reduced pressure to distill off about 435 g of an aqueous acetic acid solution, and the obtained liquid was adjusted to pH 7 by adding a 5% aqueous sodium hydroxide solution. Crystals were precipitated at a solution temperature of 10 ° C., filtered and washed with water to obtain 13.1 g of thymine-containing crystals. It is then dried and has a purity of 99.6.
9.54 g (0.0753 mol) of thymine white crystals were obtained. The yield of taking out the crystals was 85 mol% based on the starting material methylcyanoacetylurea.

Example 3 A reactor having an internal volume of 0.5 liter was charged with 15.0 g (0.107 mol) of methylcyanoacetylurea having a purity of 93.5%, 17.3 g of acetic acid, and 69.5 g of pure water. ,
Stirred. The pH of the solution at this time was 1.9. Here, a palladium carbon catalyst (5% palladium content)
% Pd / C NX type (51% wet product), manufactured by NE Chemcat, trade name) (1.50 g) was added, and the gas phase was replaced with nitrogen and further replaced with hydrogen. The temperature of the reaction solution was raised to 80 ° C., and stirring was continued at normal pressure for 15 hours. At 70 ° C., 91 g of a 22% aqueous sodium hydroxide solution was added to the obtained reaction solution to homogenize the components other than the catalyst.
As a result of analyzing the reaction solution, it was confirmed that thymine was produced in a yield of 88 mol% with respect to the starting material methylcyanoacetylurea.

Next, the reaction solution was filtered at 70 ° C. to remove the catalyst, 33 g of a 41% aqueous sulfuric acid solution was added, and the mixture was cooled to 10 ° C., and the precipitated crystals were separated by filtration. 16.5 g of crystals were obtained. This was then dried, and 11.3 g of 99.5% pure thymine white crystals.
(0.0888 mol). Crystal take-out yield is
83 mol% based on the raw material methylcyanoacetylurea
Met.

Example 4 13.4 g (0.10 mol) of cyanoacetylurea having a purity of 95.0% and acetic acid 4 in a reactor having an internal volume of 1 liter.
0.0 g and 508.1 g of pure water were added and stirred.
The pH of the solution at this time was 2.2. Here, a palladium carbon catalyst having a palladium content of 5% (5% Pd / C
NX type (50% wet product), manufactured by NE Chemcat, Inc. (1.41 g) was added, and the gas phase was replaced with nitrogen and further replaced with hydrogen. When the temperature of the reaction solution is 80
C. and the stirring was continued for 5 hours under normal pressure. Then, after replacing the gas phase with nitrogen, the catalyst was filtered off at a liquid temperature of about 70 ° C., and the obtained filtrate was analyzed. As a result, uracil was produced in a yield of 91 mol% based on the starting material cyanoacetylurea. It was confirmed that.

Next, 9.0% of a 49% aqueous sulfuric acid solution was added to the above filtrate.
After adding g, the temperature was raised to 70 ° C. under reduced pressure, about 490 g of an aqueous acetic acid solution was distilled off, and the obtained solution was adjusted to pH 7 by adding a 5% aqueous sodium hydroxide solution. Crystals were precipitated at a solution temperature of 10 ° C., separated by filtration and washed with water to obtain 13.7 g of uracil hydrated crystals. It is then dried and has a purity of 99.
9.7 g (0.086 mol) of 2% uracil white crystals were obtained. The yield of taking out the crystals was 85 mol% based on the starting material cyanoacetylurea.

Comparative Example 1 Into the same reactor as in Example 1, 12.5 g (0.0886 mol) of methylcyanoacetylurea having a purity of 94.2% and 487.0 g of pure water were charged and stirred. The pH of the solution at this time was 7. Here, a palladium carbon catalyst having a palladium content of 5% (5% Pd / C NX type (5
1% wet product); made by NE Chemcat, trade name)
1.29 g was added, the gas phase was replaced with nitrogen, and further replaced with hydrogen. The temperature of the reaction solution was raised to 80 ° C., and stirring was continued at normal pressure for 7 hours. Next, after the gas phase was replaced with nitrogen, the catalyst was filtered off at a liquid temperature of about 60 ° C., and the obtained filtrate was analyzed. As a result, thymine was produced in an amount of 37 mol% based on the raw material methylcyanoacetylurea. Was.

Comparative Example 2 12.5 g (0.0886 mol) of methylcyanoacetylurea having a purity of 94.2%, 28.7 g of acetic acid and 455.1 g of pure water were placed in the same reactor as in Example 1, and stirred. did. The pH of the solution at this time was 2.3. To this, 6.25 g of Raney nickel catalyst was added, the gas phase was replaced with nitrogen, and further replaced with hydrogen. The temperature of the reaction solution is 80 ° C
, And stirring was continued for 7 hours under normal pressure. Next, after replacing the gas phase with nitrogen, the catalyst was filtered off at a liquid temperature of about 60 ° C., and the obtained filtrate was analyzed. As a result, thymine was produced at 75 mol% with respect to the raw material methylcyanoacetylurea. Was.

Comparative Example 3 Into the same reactor as in Example 1, 12.5 g (0.0886 mol) of methylcyanoacetylurea having a purity of 94.2%, 303.3 g of pure water, and 101.7 g of a 1N aqueous solution of sulfuric acid were placed. And stirred. At this time, the pH of the solution was less than 0.1. Here, a palladium carbon catalyst having a palladium content of 5% (5% Pd / C NX type (51% wet product);
1.29 g of a product of NE Chemcat (trade name) was added, and the gas phase was replaced with nitrogen, and further replaced with hydrogen. The temperature of the reaction solution was raised to 80 ° C., and stirring was continued at normal pressure for 7 hours. Next, after the gas phase was replaced with nitrogen, the catalyst was filtered off at a liquid temperature of about 60 ° C., and the obtained filtrate was analyzed. As a result, thymine was produced in an amount of 54 mol% with respect to the raw material methylcyanoacetylurea. Was.

[0034]

As described above, according to the present invention, the catalytic reduction of cyanoacetylurea or methylcyanoacetylurea in the presence of a small amount of a relatively inexpensive catalyst provides
It is possible to obtain uracil or thymine with a purity of well over 99% in very good yield and at low cost.

 ────────────────────────────────────────────────── ─── Continued on the front page (72) Inventor Mitsuaki Senda 580-32 Nagaura, Sodegaura-shi, Chiba Mitsui Chemicals, Inc. F-term (reference) 4H039 CA42 CH20

Claims (5)

[Claims] 1. A method for producing uracil, comprising the step of catalytically reducing cyanoacetylurea in an aqueous solution of an organic acid in the presence of a palladium carbon catalyst. 2. A method for producing thymine, comprising catalytically reducing methylcyanoacetylurea in an aqueous solution of an organic acid in the presence of a palladium carbon catalyst. 3. The method according to claim 1, wherein the organic acid is acetic acid. 4. The process according to claim 1, wherein the pH of the reaction solution at the time of performing the catalytic reduction is 0.1 to 6. 5. The production method according to claim 1, wherein the catalytic reduction is performed at a temperature of 70 to 100 ° C.