JPS5826353B2 - 1- Thicampyride (2,3-D) Pyrimidine -2,4(1H,3H)- - Google Patents

Description

Detailed Description of the Invention The present invention is based on the general formula (I) (wherein R is (1) a phenyl group, (2) a halogen atom,
Lower alkyl group, lower alkoxy group, nitro group, phenyl group substituted with trifluoromethyl group, (3) benzyl group, (4) benzyl group substituted with halogen atom, (
5) 1=substituted pyrido[2.3-d]pyrimidine 2.4 (IH.3H
)-dione derivative production method.

More specifically, the compound represented by the general formula (n) (wherein R has the same meaning as above, and X means a hydroxyl group, a lower alkoxy group, and an amino group) has the general formula (III) NH2COY (III) (In the formula, Y means an amino group or a lower alkoxy group) is reacted directly at a reaction temperature of 160 to 260°C in the presence or absence of a monohydric alcohol or a polyhydric alcohol, This invention relates to a method for producing the compound represented by (I).

To explain in more detail about R and A phenyl group substituted with 1 to 2 lower alkoxy groups, nitro groups, or trifluoromethyl groups, etc., at any position can be substituted with a benzyl group,
Or a lower alkyl group such as a halogen atom such as chlorine, fluorine, or bromine, a lower substituted benzyl group such as methoxy or ethoxy, a cycloalkyl group is a cyclohexyl group or a lower alkyl-substituted cyclohexyl group, and a lower alkoxy group of X is methoxy. , ethoxy, propoxy*, and other lower alkoxy groups.

In addition, examples of the compound represented by the general formula (m) and dust include urea, urethane, etc.

The present inventors have previously conducted various studies regarding methods for producing 1-monosubstituted pyrido[2.3-d)pyrimidine-2.4(IH.3H)-dione derivatives.

As a result, we have discovered a method of ring-closing a 2-aminonicotinamide derivative and a carbonate ester in the presence of a metal compound such as sodium ethylate, and are already applying for a patent for this method.

However, this method involves various risks when applied to industrial production because it uses metal compounds such as sodium ethylate and flammable organic solvents such as alcohol, and it requires expensive carbonate esters. There were various drawbacks such as high cost due to the use of .

Therefore, the present inventors developed a method using inexpensive raw materials and a simple method to obtain 1-monosubstituted pyrido[2.3-d)pyrimidine-2.4(L
As a result of research and examination to find a method for industrially producing H.3H)-dione derivatives, we found that the compounds represented by the general formula (II) and the compound represented by the general formula (III) were mixed with methyl alcohol, ethyl alcohol, In the presence of alcohols such as monohydric alcohols such as n-propyl alcohol, n-7'' alcohol, and amyl alcohol, and polyhydric alcohols such as ethylene glycol, propylene glycol, diethylene glycol, dipropylene glycol, and polypropylene glycol. They discovered a method for producing the target compound in good yield simply by heating the reaction or directly heating and melting it, and completed the present invention.

The production method is easy to operate and proceeds without solvent,
In addition, the cost of raw materials is low and there is little risk, making it a very advantageous method for businesses.

The reaction formula of the method of the present invention is as follows.

To carry out this reaction, the reaction proceeds even in the absence of a solvent, but
Preferably, the reaction is carried out in a nitrogen atmosphere in the presence of a polyhydric alcohol such as ethylene glycol, propylene glycol, diethylene glycol, dipropylene glycol, or polypropylene glycol.

The reaction temperature is suitably 160 to 260°C, especially 180°C.
~250°C is optimal.

Further, a reaction time of 3 to 10 hours is sufficient.

The target compound obtained by the method of the present invention itself has pharmacological activities such as analgesic action and anti-inflammatory action, and also has remarkable analgesic action and
It is a compound useful as an intermediate for 1,3-disubstituted pyridopyrimidinedione derivatives that have pharmacological effects such as anti-inflammatory and central nervous system depressant effects.

EXAMPLES The present invention will be specifically explained below with reference to Examples.

Example 1 2-anilinonicotinic acid 21.4f? and 60i of urea were reacted at 180 to 220°C for 4 hours.

The lumpy reaction product was pulverized and the soluble material was eluted with boiling water and filtered.

Next, it was dissolved in a 2% caustic soda solution, the insoluble matter was separated, the liquid was neutralized with dilute hydrochloric acid, the precipitated crystals were recrystallized with dimethylformamide, and a colorless prismatic l-phenylpyrid[2.3d]pyrimidine-2. 15.4f of 4(IH·3H)-dione was obtained.

The melting point of this substance was 315°C or higher, and its infrared absorption spectrum matched that of a separately synthesized standard.

Example 2 2-(m-)lifluoromethylanilino)nicotinamide 28g, urea 601, diethylene glycol 80r
rLl under stirring at 180-220°C for 2 hours, then at 240°C.
The reaction was carried out at ~250°C for 3 hours.

After cooling, water was added to the reaction product, the precipitated crystals were collected, the solid matter was dissolved in a 2% caustic soda solution, and the insoluble matter was removed from house to house.
When the liquid was neutralized with dilute hydrochloric acid, crystals were precipitated.

The crystals were recrystallized from a mixed solvent of acetone and methanol to form colorless prismatic crystals of 1-(mtrifluoromethylphenyl)pyrido[2.3d]pyrimidine-2.4(1H
-20.8r of 3H)-dione was obtained.

The melting point of this material was 260-261°C.

Example 3 2-Benzylaminonicotinic acid 22. sy, Uvtan 90P mixture at 180-200°C for 2 hours, then 2 hours.
The reaction was carried out by heating at 20 to 240°C for 3 hours.

After cooling, boiling water was added to the reaction product to elute soluble substances, and the same post-treatment as in Example 1 was carried out to obtain colorless prismatic crystals of 1-benzylpyrido[2.3-d]pyrimidine-2.4( 16.41 of IH.3H)-dione was obtained.

The melting point of this material was 198-199°C.

Example 4 2-(m-fluoroanilino)nicotinic acid 23.2f
, urea 60'? and dipropylene glycol 40 mA'
were reacted in a nitrogen atmosphere at 180-200°C for 2 hours with stirring, then at 220-240°C for 4 hours.

After cooling, boiling water was added to the reaction mixture to elute the soluble substances, filtration was carried out under hot water, and the same post-treatment as in Example 1 was carried out to obtain colorless prismatic crystals of 1-(m-fluorophenyl)pyrid[2.3-d]pyrimidine. -2・4(IH・3H)-dione 17.7f?
I got it.

The melting point of this substance was 315°C or higher, and its infrared absorption spectrum matched that of a separately synthesized standard.

Examples 5-24 According to the method of Examples 1-4, the compounds shown in the following table were obtained in good yields.

Claims (1)

[Claims] 1 General formula (wherein R is (1) a phenyl group, (2) a halogen atom,
Lower alkyl group, lower alkoxy group, nitro group, phenyl group substituted with trifluoromethyl group, (3) benzyl group, (4) benzyl group substituted with halogen atom, (
5) Add a cycloalkyl group to a compound represented by the general formula % (wherein, Y means an amino group and a lower alkoxy group) 160 to 260 directly in the presence or absence of a monohydric or polyhydric alcohol.
1 represented by the general formula (wherein R has the same meaning as above) characterized in that the reaction is carried out at a reaction temperature of °C.
Monosubstituted pyrido[2,3-d]pyrimidine-2,4 (1H
- A method for producing a 3H)-dione derivative.