JPS6130575A - Preparation of 4-hydroxy-6-methylpyrimidine - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as an intermediate for drugs, agricultural chemicals, etc. industrially advantageously without producing a heavy metal compound as a by-product, by using inexpensive 3-aminocrotonamide as a raw material, reacting it with a formic ester in the presence of a base. CONSTITUTION:3-Aminocrotonamide is used as a raw material, and reacted with a formic ester in the presence of a base such as sodium methylate, etc. at 40- 180 deg.C, especially at 60-160 deg.C in a solvent such as methanol, ethylene glycol dimethyl ether, etc., to give the aimed compound. An amount of the base used is preferably 0.5-5mol, especially 1-3mol based on 1mol 3-aminocrotonamide, the starting raw material. Methyl formate, cyclohexyl formate, etc. may be cited as the formic ester, an amount of it used is preferably >=1mol based on 1mol starting raw material, and it can be used also as a solvent.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a method for producing 4-hydroxy-6-methylpyrimidine.

4-Hydroxy-6-methylpyrimidine is a medicine.

It is useful as an intermediate for pesticides and other products.

[Problems to be solved by conventional technology and invention]

Conventionally, 4-hydroxy-6-methylpyrimidine was produced by reacting acetoacetate and thiourea to produce 4-hydroxy-2-mercapto-6-
Synthesize methylpyrimidine.

It is known that θ is produced by desulfurizing this with Raney nickel (Org, Syn, Vol. 3).
5.80).

However, this method produced a large amount of nickel sulfide and was not industrially satisfactory.

Furthermore, a method for obtaining 2-substituted-4-hydroxy-6-methylpyrimidine from O-aminocrotonamide and esters in the presence of a base is known.

There is a description in a certain magazine, 90, 509 (1970).

It is stated that monoaminocrotonamide 4-hydroxy-6-methylpyrimidine could not be obtained.

[Means for solving problems]

The present invention provides a method for producing 4-hydroxy-6-methylpyrimidine from 3-aminocrotonamide and formic acid esters in high yield.

According to the present invention, 4-hydroxy-6-amide is reacted with a formate in the presence of a base.
A method of making methylpyrimidine is provided.

〔Effect of the invention〕

The method according to the present invention does not produce by-products of heavy metal compounds, and 4-hydroxy-6-methylpyrimidine can be industrially advantageously produced using inexpensive 6-aminocrotonamide as a raw material.

The present invention will be explained in detail below.

The O-aminocrotonamide used in the present invention is 2, for example, Tetrahedron, 2-Ro, 2965 (
It can be easily synthesized from diketene and ammonia by the method described in (1967).

Specific examples of the base used in the present invention include sodium alcoholades such as sodium methylate, sodium ethylate, sodium butylade, and sodium cyclohexilade, and potassium alcoholades such as potassium t-butylate. The amount of the base to be used is preferably 0.5 to 5 mol, particularly 1 to 3 mol, per 1 mol of 3-aminocrotonamide as a starting material.

Examples of formic acid esters used in the present invention include methyl formate, ethyl formate, and inbutyl formate.

Formic acid alkyl esters such as inbutyl formate, n-hexyl formate, n-octyl formate, nclopentyl formate,
Examples include cycloargyl formate esters such as cyclohexyl formate, alkenyl formate esters such as allyl formate, and alkynyl formate such as propargyl formate. The reaction temperature for formic acid ester is 40 to 180°C, especially 60°C.
~160°C is preferred.

In addition to formic acid esters, solvents used in the present invention include methanol, ethanol, isopropyl alcohol, n-butyl alcohol, cyclohexyl alcohol,
Alcohols such as allyl alcohol, methoxyethanol, and ethoxyethanol, and ethylene glycol dimethyl ether.

Di-n-butyl ether, tetrahydrofuran.

Ethers such as dioxane, dimethylformhokind,
N,N-dimethylformamide is mentioned.

These solvents can be used alone or in combination of two or more in the reaction.

〔Example〕

Next, examples of the present invention will be shown. Note that the yield of the target product on each side is based on 3-aminocrotonamide.

Example 1 3-aminocrotonamide 3 in a 100-proof Erlenmeyer flask
．． 0 f/ (0.03 mol) and ethyl formate 6.5y (
O, OS mol) was charged, and metallic sodium 1.47 (0
, 06 mol) dissolved in 20 ml of absolute ethanol was added thereto, and the mixture was heated under reflux for 5 hours. After the reaction is complete.

After neutralizing with acetic acid, filtering the precipitate and washing with ethanol, the filtrate was concentrated and purified by column chromatography to obtain white crystals of 1.82 JF (m, p, 146-148
4-hydroxy-6-methylpyrimidine (yield: 55 °C) was obtained.

Example 2 The reaction was carried out in the same manner as in Example 1 except that 5.27 (0.07 mol) of ethyl formate was charged, and as a result of the same treatment, 2.
74S' 4-hydroxy-6-methylpyrimidine (m
, p, 147-149°C). The yield was 8 pieces.

Example 6 ” A 100me Erlenmeyer flask was charged with 5mJ of absolute ethanol and 20ml of anhydrous dioxane, and NaHl, 49
(0.06 mol) was added and after stirring for 1 hour, 3-aminocrotonamide 3. Of (0,03 mol).

5.29 (0.07 mol) of ethyl formate was added, and the mixture was heated under reflux for 5 hours. After the reaction was completed, the same procedure as in Example 1 was carried out to obtain 2.38 j/d of 4-hydroxy-6-methylpyrimidine (yield: 72 g).

Example 4 2.5 ml of isobutyl alcohol was placed in a 100 mA' Erlenmeyer flask, and Na, Ho, 7 f (0,
0.03 mol) and dissolved, 6-aminocrotonamide 3,,Oy (0.03 mol) and isobutyl formate 5.
．． 22 (0.05 mol) was added thereto, and the mixture was heated under reflux for 9 hours.

After the reaction was completed, the same procedure as in Example 1 was carried out to obtain 1.57 of the desired product (yield: 45%).

Example 5 1 (25 m/! of cyclohexanol was charged into a 10 + + l Erlenmeyer flask +' NaHl, 4 f (0
, 06 mol) was added and heated to dissolve, and then 3-aminocrotonamide 3. Of (0.03 mol) and 11.5 g (0.09 mol) of cyclohexyl formate were added, and 140
'C for 6 hours. After the reaction was completed, the same procedure as in Example 1 was carried out to obtain the desired product with a yield of 61%.

Example 6 6. Erlenmeyer flask with 100 penalties. Of (0,06 mol)
Aminocrotonamide and 25 mJ of ethyl formate were charged, 20.1 methanol solution in which NaOCH33,2f (0.06 mol) was dissolved was added, and the mixture was heated under reflux for 10 hours. After the reaction was completed, the same procedure as in Example 1 was carried out,
The desired product was obtained with a yield of 77%.

Claims (1)

[Claims] 4-Hydroxy-6-, which is characterized by reacting 3-aminocrotonamide with formic acid ester in the presence of a base.
Method for producing methylpyrimidine.