JPS5815978A - Preparation of pyridopyrimidine drivative - Google Patents

Abstract

PURPOSE:To obtain a debenzylated product, in high yield, by the hydrogenative decomposition of an alkali salt of 2-(4-benzyl-1-piperazinyl)-8-alkyl-5,8-dihydro-5- oxopyridopyrimidine-6-carboxylic acid followed by neutralization. CONSTITUTION:The compound of formula II is prepare by the hydrogenative decomposition of the compound of formulaI(R<1>-R<3> are aryl or H, at least one of which is aryl; M is alkali metal or ammonium ion) in water or a water- containing medium (e.g. alcohol or DMF usually containing >=20wt% water) using a hydrogenation catalyst at 20-60 deg.C, followed by the neutralization of the decomposition product. Use of hydrogen in large excess is not desirable, and its amount is 1.0-1.1mol per 1mol of the compound of formulaI. The neutralization can be carried out by using a proper acid (e.g. HCl, acetic acid, etc.). EFFECT:High yield. The dangerous post-treatment of the catalyst is unnecessary. USE:Medicine.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing a pyridopyrimidine derivative represented by the general formula (wherein R4 is an alkyl group).

Several proposals have already been made regarding methods for producing the pyridopyrimidine derivative represented by the above formula (1), which is useful as a pharmaceutical in the form of anhydride or hexahydrate. A typical method is a method in which a compound represented by the general formula (wherein R5 is hydrogen or an alkyl group) is hydrogenolyzed in an organic solvent.

However, in this method, as far as commercially available catalysts are used, side reactions such as hydrogenation of the pyridopyrimidine nucleus occur, resulting in poor selectivity and yield of the target product. .

Additionally, palladium, platinum black, etc. are often used as catalysts, but these are dangerous as they can catch fire during the post-treatment stage of the reaction mixture.

The present inventors have investigated an improvement method that has a high yield and does not pose the risk of shrinkage, and has found that the above compound [
We have discovered a method for producing 1] with high yield. According to the present invention, salt is also used as a raw material, and usually, an alkali salt or an ammonium salt is synthesized by the method shown in Japanese Patent Application No. 55-925, and then directly subjected to isolation and purification operations. There is also the advantage that it can be used without

The present invention is based on the general formula (wherein R1, R2, and R3 are each an aryl group or hydrogen, and at least - is an aryl group.
is an alkali metal or ammonium ion) in water or a water-containing medium, and then neutralized to obtain R, R, and H of the above formula (1). The aryl group may be monosubstituted with a substituent such as an alkoxy group, an amino group, or an alkyl group. A specific example of the R2-0- group is 5 CH30CH2-1c2H5-/X)-a R2-1. Also, R4 is methyl, ethyl, 18
It is an alkyl group such as 0-propyl or n-propyl.

Furthermore, M is an alkali metal such as lithium, sodium, potassium or ammonium ion.

In the reaction, the compound of formula [I] may be formed in situ by the reaction of the corresponding free carboxylic acid with an alkali. Such alkalis include hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide;
Ammonia water, acetate such as lithium oxide, sodium oxide, and potassium oxide, carbonate such as lithium carbonate, sodium carbonate, and potassium carbonate, and the like can be used.

Hydrogenolysis of compounds of the formula [厘] is carried out in water or an aqueous medium at neutral or alkaline conditions. The water-containing medium is a mixture of water and other solvents, such as alcohols such as methanol, ethanol, and ethylene glycol, aprotic polar solvents such as dimethylformamide, and acetone, and usually contains about 20% by weight or more of water. It is preferable to use those containing

It is preferable to use a solution having a concentration of about 2 to 10% by weight of the compound of formula [Rin].

Hydrocracking is suitably carried out using a hydrogenation catalyst such as palladium, palladium on carbon, platinum on carbon, Raney nickel or the like.

In the hydrogenolysis reaction, the reaction temperature is preferably 10 to 10
A kneading temperature of 0°C, particularly about 20 to 60°C, is preferable.

In addition, it is not preferable to use a large excess amount of hydrogen in order to prevent side reactions, and for example, it is about 1.0 to 1.5 mol, particularly 1.0 to 1. It is preferred to use 6 (7) f)s in an amount close to the theoretical value, such as 1 mole. . . Reaction 0. Yo,
When the □2-8-''5 group is substituted with H, an alkali metal salt or ammonium salt of the target compound [1] is produced, and by neutralizing this, the target compound can be obtained.

An appropriate acid may be used to neutralize the hydrogenation reaction mixture. For example, by adjusting the pH to about 6 to 7 using an acid such as hydrogen chloride, acetic acid, or propionic acid, the target compound (1) can be converted into a trihydrate. Obtainable.

Also, before neutralizing the alkali metal salt or ammonium salt of the target compound (1), water is removed from the thread, and after dissolving the raw salt using an anhydrous organic solvent such as ethanol, dimethylformamide, chloroform, etc. By neutralizing with an acid such as hydrogen chloride, acetic acid, propionic acid, etc., the target compound (1) E can be obtained as an anhydride.

A specific example is shown below.

Example 1 2-(4-benzyl-1-piperazinyl)-8-ethyl-5,8-dihydro-5-oxopyride (2,3-d)
Pyrimidine - local phone ugliness 3.00g (7,6mmc
l) - Sodium hydroxide 0-53 g (8,2 mmo
l), 10% Pd-01, Og, and water 10.0 mA
' was placed in a reactor, and hydrogen was introduced while stirring at room temperature. After the calculated amount of hydrogen had been absorbed, the catalyst was separated and the p solution was adjusted to p)l=6.7 with acetic acid to precipitate pale yellow crystals. When this was collected and washed with water and methanol, 2-
2-20 g (yield: 81%) of (1-piperazinyl)-8-ethyl-5,8-dividor-5-oxopyrido(2,3-d)pyrimidine-6-carboxylic acid trihydrate was obtained. When this substance is recrystallized from DMF, the melting point is 253.
~256°C (263°C decomposition).

Example 2 Instead of using 10% Pd-0 in Example 1, 5% Pd-C was used.
The desired debenzylated product was obtained in a yield of 65%.

Example 3 2-(4-benzyl-1-piperazinyl)-8-ethyl-5,8-dihydro-5-oxopyrido [2,3-d]
Pyrimidine-6-carboxylic acid sodium salt 0.4'1g
(Immol), 5% pd-c O, 15gs and H
A mixture of 2O20m# was hydrolyzed in the same manner as in Example 1, and the desired debenzylated product was obtained in a yield of 58%.

Example 4 When a salt was used in place of the Na salt in Example 5, the desired debenzylated product was obtained in a yield of 67%.

Applicant: Mitsui Petrochemical Industries, Ltd. Agent Kazu Yamaguchi

Claims (1)

[Claims] (1) General formula (wherein R1, R2, and R3 are each an aryl group or hydrogen, and at least one is an aryl group.
is alkali metal or ammonium ion) in water or an aqueous medium, and then neutralized.