JPS6119626B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing 4-amino-2-methylpyrimidine, which is a raw material for vitamin _B1 and other pharmaceuticals, in a high yield in one reaction step using inexpensive raw materials. So far known methods for producing 4-amino-2-methylpyrimidine include 2-ethoxycarbonimidoyl acetate derived from cyanoacetate or 2-formylacetic acid derived from formate and acetate. Either of the esters is reacted with acetamidine derived from acetonitrile to form 4-amino-6-hydroxy-2-
There are methods that lead to the desired 4-amino-2-methylpyrimidine through methylpyrimidine, bromination, and reduction, and methods that treat 2,6-dibromopyridine with potassium amide in liquid antinia, but in the former, the reaction is The disadvantage is that the process is complicated and the total yield is very low, and the latter has the disadvantage that the raw materials are expensive and the yield is low. The inventors of the present invention have conducted extensive research to find a method for producing 4-amino- ² -methylpyrimidine that does not have the drawbacks mentioned above. The desired product 4 can be obtained in good yield through just one reaction step from a certain acetonitrile and at least one member selected from formamide, formimidate, formamidine, and 1,3,5-triazine, which are also obtained at low cost. -Amino-2-methylpyrimidine could be obtained, and based on this knowledge, the present invention was accomplished. The present invention is characterized in that one compound selected from formamide, formimidate, formamidine, and 1,3,5-triazine, or a mixture of a plurality of them, is reacted with acetonitrile. -A method for producing amino-2-methylpyrimidine, the reactions comprising:
It only progresses when heated under a pressure of 1000Kg/cm2 or ^more . That is, none of the reactions proceed at all under normal pressure, but slight progress is observed when the pressure is increased to 1000 Kg/cm ² . Economic reaction rate is 2000
This is achieved by applying pressure to Kg/cm ² or more.
There is no particular upper limit to the pressure. The higher the pressure, the higher the reaction rate, but between 2000Kg/cm ² and 12000Kg/cm ²
A pressure range of 100 to 100% is technically and economically suitable. High pressure can be generated by filling a pressure-resistant reaction vessel with a raw material mixture or a capsule containing the raw material mixture whose internal volume can change depending on external pressure, and then introducing a gas or liquid high-pressure medium. A method of pressurizing directly or through a movable bulkhead,
A method of pressurizing the raw material mixture using a high-pressure pump,
There are various methods, such as sealing the raw material liquid in a pressure-resistant reaction vessel at a low temperature and then heating it to generate high pressure due to thermal expansion of the liquid. 50℃ for reaction temperature
Below 200°C, the reaction is extremely slow, and above 200°C the target 4-amino-2-methylpyrimidine undergoes deterioration, so a temperature range of 80 to 200°C is appropriate. The reaction time depends on the pressure, temperature, amount of catalyst, etc., but usually 5 to 100 hours is sufficient. These reactions are promoted by lower alcohols, especially methanol, and the addition of ammonia improves the yield of 4-amino-2-methylpyrimidine. Therefore, methanol or ammonia or both are usually added at the same time as a catalyst in an amount ranging from several mol % to an equimolar amount. Methanol may also be used in large amounts to serve as a reaction solvent. In this reaction, any solvent inert to the reaction may be used freely. In this reaction, formamide is Since it is presumed to react, formamide 1
Approximately 3 moles of acetonitrile may be used, but the exact optimum number of moles is determined experimentally for each reaction condition. The formimidate used in this reaction is represented by the general formula HC(NH)OR, and R is generally known to be a lower alkyl group, and its type is not limited. It is usually supplied in the form of a salt and is either neutralized to the free base with an alkali prior to use or mixed with other raw materials and solvents and then added with a calculated amount of alkali to generate the free base in the reaction mixture. What reacts according to formula (2) Since it is estimated that the
Around twice the molar amount of acetonitrile is used. Since formamidine is normally supplied in the form of a salt, it is used as a free base by neutralization as in the case of formimidate described above. Formula (3) It is estimated that the reaction proceeds at The molar ratio of formamidine and acetonitrile is usually around 1:2 and varies to some extent. 1,3,5-
Triazines are usually produced from alkali cyanide or formimidate. The reaction is estimated to proceed according to equation (4). Therefore, about 6 for 1,3,5-triazine
Use twice the molar amount of acetonitrile. As a result of the present invention, 4-amino-2-methylpyrimidine can be supplied at a much lower cost than before through just one reaction step, so it is important to develop various new synthetic routes using this product as a raw material. is possible. For example, this one can easily be converted into 4-amino-5-halogeno-2-methylpyrimidine,
It can lead to 4-amino-5-cyano-2-methylpyrimidine, which is an intermediate in producing vitamin _B1 . This is considered to contribute to reducing the production cost of vitamin _B1 . Next, the present invention will be explained in more detail with reference to Examples. Parts shown in each example represent parts by weight. The percentage indicating the yield is based on the estimated reaction formula (1) ~ already described in the present invention.
This is the theoretical yield based on (4), and is per raw material compound shown in the first term of each formula. Note that the yield shown in each example does not necessarily mean the highest yield under optimal reaction conditions. Example 1 1 part of formamide, 2.73 parts of acetonitrile, 1.42 parts of methanol, and 0.038 parts of ammonia (molar ratio 1:3:2:0.1) were melt-sealed in a capsule made of fluorine-based plastic (Aflon), which was then filled into a pressure-resistant reaction vessel. Then add ethylene glycol to the container.
A pressure medium consisting of an equal amount of water was injected until a predetermined pressure was reached, and then the container was externally heated to raise the internal temperature to 140°C, and the temperature was then maintained at the same temperature for 20 hours. During this time, the pressure inside the container was maintained at a predetermined constant pressure by partially withdrawing and press-fitting the pressure medium. After 20 hours had elapsed, the container was cooled, the pressure was removed, the capsule was removed and opened, and the contents were analyzed by high performance liquid chromatography and gas chromatography. The yield of the target 4-amino-2-methylpyrimidine at each predetermined reaction pressure was as shown in the following table.

[Table] Example 2 1 part of formamide, 2.73 parts of acetonitrile, 0.71 parts of methanol, 0.019 parts of ammonia (molar ratio 1:3:1:0.05), and 3.2 parts of tetrahydrofuran
12,000 parts of the mixture was treated in the same manner as in Example 1.
Results of reaction at 100℃ for 63 hours at Kg/cm ² 4
-Yield of amino-2-methylpyrimidine is 50.5%
It was hot. Example 3 1 part of formamide, 2.73 parts of acetonitrile, 0.36 parts of methanol, and 0.0095 parts of ammonia (molar ratio 1:3:0.5:0.025) were encapsulated in a polyethylene capsule, and heated in the same manner as in Example 1 at 80°C and 12800~
When kept at 11600Kg/ ^cm2 for 40 hours, 4-amino-
2-methylpyrimidine was produced in a yield of 34.3%. Example 4 A mixture of 1 part of formamide, 1.37 parts of acetonitrile, 0.53 parts of methanol and 0.014 parts of ammonia (molar ratio 1:1.5:0.75:0.038) was prepared in the same manner as in Example 1 at 100°C and 13000 to 10400 Kg/ ^cm2 . When kept for a week, the yield of 4-amino-2-methylpyrimidine was 28.9%. However, this yield is 57.6% when converted to acetonitrile. Solid matter was filtered out from the reaction product and extracted with 1,4-dioxane to obtain 0.57 parts of a crude product. After repeated recrystallization with methanol, a white 4
0.45 part of pure -amino-2-methylpyrimidine was obtained. The melting point was 207.8°C. Values known so far range from 203 to 206°C. Elemental analysis value as C ₅ H ₇ N ₃ C% H% N% Theoretical value 55.03 6.47 38.50 Experimental value 54.68 6.49 38.27 Example 5 1 part of ethylformimidate hydrochloride, 0.75 part of acetonitrile and 0.073 part of methanol (molar ratio 1 :2:0.25) into a polyethylene capsule, and while stirring to form a slurry, add 2.9 mol/
A solution of sodium ethylate in ethanol is added dropwise until it is neutralized using thymolphthalein as an indicator, and the capsule is melt-sealed. This was reacted in the same manner as in Example 1 and under the same conditions as in Example 2. As a result, the yield of 4-amino-2-methylpyrimidine was
It was 44.5%. Example 6 1 part formamidine hydrochloride, acetonitrile
When 1.02 parts (molar ratio 1:2) of the mixed slurry was neutralized with sodium ethylate and treated in the same manner as in Example 5, 4-amino-2-methylpyrimidine was produced in a yield of 37.7%. Example 7 1 part 1,3,5-triazine, acetonitrile
3.04 parts, methanol 1.18 parts, ammonia 0.032 parts (molar ratio 1:6:3:0.5) and tetrahydrofuran.
5.34 parts was added, sealed in a polyethylene capsule, and reacted under the same conditions as in Example 2. Result 4-
The yield of amino-2-methylpyrimidine was 20.9%.

Claims (1)

[Claims] 1. A 4-amine characterized by reacting at least one compound selected from formamide, formimidate, formamidine, and 1,3,5-triazine with acetonitrile at a reaction pressure of 1000 Kg/cm ² or more. -A method for producing 2-methylpyrimidine.