JPS5822040B2 - Method for producing homopyriimidazole derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing homopyriimidazole derivatives,
More specifically, the present invention relates to a new method for producing 3-carbamoyl-4-oxo-6-methyl-6,7,8,9-tetrahydrohomopyrimidazole represented by formula (1).

The compound of formula (1) produced by the present invention itself has anesthetic-enhancing, antipyretic, and analgesic effects and is useful as a pharmaceutical, as well as an intermediate for producing related pharmaceuticals.

The conventional method for producing the compound of formula (1) is to ring-close α,α'-picolyl aminomethylene malonic acid diethyl ester in the coexistence of a large amount of phosphorus oxychloride and a small amount of polyphosphoric acid to form 3-carboethoxy- 4-oxo-6-methylhomopyrimidazole was obtained (see Japanese Patent Publication No. 49-39278), and this compound was then reduced to give 3-carboethoxy-4-oxo-6-methyl-6,7,8,9 - Obtained tetrahydrohomopyrimidazole (Special Publication No. 46-43
(Refer to Publication No. 390), and finally, this carboxylic acid ester is left in concentrated ammonia water for a long time to amidate to give the formula (1
) is known (see Japanese Patent Publication No. 49-39278).

The present inventors have conducted various studies in order to develop an industrially advantageous manufacturing method for the compound of formula (1), and as a result, α,α'-picolyl amino methylene malonide, IJ, represented by formula (3)
If a heating reaction is carried out in the coexistence of poly-IJ-IJ-acid, the formula (2
) 3-carbamoyl-4-oxo-6-methylhomopyrimidazole represented by formula (1) is produced in high yield, and this compound is easily converted into 3-carbamoyl-4-oxo represented by formula (1) by ordinary catalytic reduction. -6-Methyl-6,7,8,9-tetrahydrohomopyrimidazole.

According to the present invention, conventional ring closure, reduction 2 and amidation 3
The target compound of formula (1) can be advantageously produced by shortening a method consisting of steps to two steps of heating and reduction.

Next, embodiments of the present invention will be described in detail below.

α- of formula (3) used as a starting material in the present invention
α'-Hycolylaminomethylenemalononitrile is a new compound that has not been described in any literature, but it can be produced with high purity in good yield by reacting it with 2-aminopicolinth lower alkoxymethylenemalonnitrile without a solvent or in an inert solvent. can be obtained.

The reaction is almost completed by adding the starting material compound of formula (3) into polyhydric acid and stirring at a temperature of about 100°C to 140°C until it dissolves, and the 3-carbamoyl- of formula (2) is added. 4-oxo-6-methyl homopolyimidazole is produced in high yield.

The exact reaction mechanism that explains the immediate formation of the compound of formula (2) in this heating reaction is unclear, but it is likely that 3-cyano-4-imino-6-methylhomopyrimidazole is the starting material. This is presumed to be due to the fact that this is immediately hydrolyzed by the poly-IJ acid coexisting in the same reaction system.

The reaction product was cooled to room temperature, transferred to about 10 to 40 times the amount of water, and after removing insoluble matter from P, alkali was added to make solution F weakly alkaline. etc. Re.

A highly pure compound of formula (2) is obtained by crystallization.

3-carbamoyl-4- from the compound of formula (2)
The reduction step for obtaining oxo-6-methyl-6,7,8,9-tetrahydrohomopyrimidazole can be carried out by a conventional catalytic hydrogenation method.

- For example, the desired compound of the formula Y can be suitably obtained using palladium activated carbon in the presence of an inorganic or organic acid in a lower alcohol solvent at normal pressure or room temperature.

The compound of formula (1) can be hydrolyzed in the presence of an inorganic acid to give the corresponding carboxylic acid, which can also be esterified if desired.

Hereinafter, the present invention will be explained in more detail by showing reference examples and examples.

Reference Example 1 10.8 g of 2-aminopicoline and 12.2.9 g of ethoxymethylenemalonitrile are heated and stirred on an oil bath at 100° C. for 15 minutes.

When the reactant is cooled and recrystallized from ethanol and water, α, α
'-Picolyl aminomethylene malonitrile 17.2
g to i.

Yield 94.5% Melting point 186.0-186.5℃ Elemental analysis value as Cl0H3N4 C% N% N/16 Calculated value 65.20 4.38 30.42 Actual value 65.36 4.67 30.32 Example 1 10 g of poly-IJ IJ acid (manufactured by Wako Tsumugi Kogyo Co., Ltd.) was heated to 140°C on an oil bath, and 460 ~ of α,α'-picolilaminomethylenemalonitrile was added thereto and stirred for 40 minutes.

After the reaction, the mixture is cooled, dissolved in 50 TL of water to remove insoluble matter, sodium bicarbonate is added to make the r solution alkaline, 20 ml of water is added, and the mixture is left in a cool place overnight.

The precipitated crystals were washed several times with water and then recrystallized from methanol and water to obtain 3-carbamoyl-4-oxo-6-methylhomopyrimidazole 288yn&.

Yield 56.0% Melting point 263-264°G Elemental analysis value as C1oH302N3 C% N% N% Calculated value 59.10 4.46 20.68 Actual value 59.28 4.75 20.89 Example 2 3 - Caltumamoyl-4-oxo-6-1 + 1.42.9 ruhomopyrimidazole was suspended in 50 ml of methanol, 2 ml of concentrated hydrochloric acid and 5001 n of 5% palladium on activated carbon.
After introducing hydrogen gas at room temperature and atmospheric pressure for 2 hours, the insoluble matter was removed, and the F solution was evaporated to dryness under reduced pressure. 30 ml of water was added to the residue to dissolve it. After adding sodium hydrogen carbonate to make it alkaline and removing the precipitated crystals,
Ethyl acetate is added to the tear fluid for extraction, the organic layer is dried over magnesium sulfate, the desiccant is removed, the residue is evaporated to dryness under reduced pressure, and this is recrystallized from ethanol to obtain 3- Carbamoyl-4-oxo-6-methyl-6,7,8,9-tetrahydrohomopyrimidazole 435η is obtained.

Yield 30.0% Melting point 192-193°C Elemental analysis value as C1oH1302N3 C% H
% N% Calculated value 57.96 6.32 20.08 Actual value 58.09 6.32 19.88 Reference example
2 Dissolve 2.07 g of the compound obtained in Example 2 in a mixture of 100 ml of water and 50 TL of concentrated hydrochloric acid, heat under reflux for 1 hour and 30 minutes, then 5% hydroxide) Adjust the pH to about 3 with IJum and leave to cool. .

When the precipitated crystals are washed several times with water and then recrystallized from benzene,
3.30 g of 4-oxo-6-methyl-6,7,8,9-tetrahydrohomopyrimidazole-3-carboxylic acid are obtained.

Yield 72.1% Melting point 142-145°C Cl1! Elemental analysis value C% as HI3 o3N2
H% N% Calculated value 57.68 5.8,1 13.45 Actual value 57.57 5.95 13.61□ This product easily corresponds in high yield when heated to reflux in the presence of hydrochloric acid in methanol. It can be converted to the methyl ester 3-carbomethoxy-4-oxo-6-methyl-6,7,8,9-tetrahydrohomopyrimidazole.

When recrystallized from ethyl acetate, it has a melting point of 114°C.

Claims (1)

[Claims] 1 α, α′-Picolylaminomethylenemalononitrile was subjected to a heating reaction in the presence of polyacid, and the obtained 3-
A method for producing 3°-carbamoyl-4-oxo-6-methyl 6.7,8°9-tetrahydrohomopyrimidazole, which comprises reducing carbamoyl-4-oxo-6-methylhomopyrimidazole.