JPS5973558A - Ureido derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:2-Ureido-4,5-dimethoxybenzoic acid amide shown by the formula I . USE:Useful as an intermediate for synthesizing drugs. For example, useful as an intermediate for synthesizing a guinazoline antihypertensive. PROCESS:2-Amino-4,5-dimethoxybenzoic acid amide shown by the formula II is reacted with an alkali metal cyanate (e.g., sodium cyanate, potassium cyanate, etc.) in an acidic solvent such as acetic acid, hydrochloric acid, sulfuric acid, etc. at 0-100 deg.C, preferably at 15-30 deg.C for 30min-24hr to give a compound shown by the formula I . This compound is then treated with an alkali to give 2,4-dihydroxy-6,7-dimethoxyquinazoline.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to 2-ureido-4,5-dimethoxybenzoic acid amide represented by the formula, which is useful as a pharmaceutical synthesis intermediate, and a method for producing the same.

As a quinazoline antihypertensive agent, for example, a drug of the following formula [A], commonly referred to as brazosin hydrochloride, described in U.S. Patent No. 3,511,836, is known. 2.4-dihydroxy-6
, 7-simethoxyquinazoline is an important synthetic intermediate. The present inventors have diligently investigated the Shingetsu 1 manufacturing method for 2,4-dihydroxy-6,7-simethoxyquinazoline, and as a result, have completed the present invention.

Conventional methods for synthesizing 2,4-dihydroxy-6,7-simethoxyquinazoline include a method in which 2-ureido-4.5-dimethoxybenzoic acid is treated with sodium hydroxide (Jour, Ohem, Soc.).

1948, 1rss). However, this method has a low reaction yield of only 2844%, and is therefore not suitable as an actual production method.

The present inventors prepared 2-amino-4,5-dimethoxybenzoic acid amide [Ohim, Ther, 2,231 (1967)]
] to obtain a new compound, 2-ureido-4,5-dimethoxybenzoic acid amide (1), which was then treated with an alkali to yield 2,4-dihydrox 7-8. represented by the formula. A manufacturing method for obtaining 7-simethoxyquinazoline has been discovered.

2-Amino-4゜5-dimethoxybenzoic acid amide (U)
In the reaction to obtain 2-ureido-4,5-dimethoxybenzoic acid amide (I), the acidic solvent used is formic acid,
Organic acids such as acetic acid and propionic acid, hydrohalic acids such as hydrochloric acid, hydrobromic acid and hydroiodic acid, and mineral acids such as sulfuric acid are used, but acetic acid is preferably used.

This reaction is carried out by contacting 2-amino-4,5-dimethoxybenzoic acid amide with an alkali metal cyanate salt in the presence of the above-mentioned acidic solvent. As the alkali metal cyanate salt used, sodium cyanate, potassium cyanate, etc. are used. The reaction can be gradually progressed by dissolving the alkali metal cyanate in water or an aqueous alkali hydroxide solution and dropping the solution dropwise. The reaction temperature is 0 to 100°C, preferably 15 to 30°C, and the reaction time is 30 minutes to 24 hours, depending on the reaction temperature.

After the reaction is complete, the crystals of the desired compound (I) are collected by filtration. If necessary, it can be purified by conventional methods such as recrystallization.

2-ureido-4,5-dimethoxybenzoic acid amide (1
) to obtain 2,4-dihydroxy-6,7-dimethquine quinazoline [phase] is accomplished in a basic solution. Examples of the alkali used include alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, and calcium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; and organic bases such as trimethylamine. and aliphatic tertiary amines such as triethylamine; pyridines such as pyridine and picoline; and aliphatic cyclic amines such as N-methylmorpholine and N-methylpiperidine. The solvent to be used is not particularly limited as long as it does not participate in this reaction, and includes, for example, water; alcohols such as methanol and ethanol; aliphatic tertiary amines such as trimethylamine and triethylamine; pyridines such as pyridine and picoline;
Aliphatic cyclic amines such as N-methylmorpholine and N-methylpiperidine are used, but preferably water is used.

The amount of base used is determined by the amount of base used to react with 2-ureido-4,5
-1 to 4 times the molar amount of dimethoxybenzoic acid amide,
When the base is used also as a solvent, it can be used in a large amount. The reaction temperature is 20 to 130°C, but a method in which the reaction is carried out at the boiling point of the solvent used is preferred. The reaction time varies depending on the type of solvent used and the reaction temperature, but is usually 15 minutes to 8 hours. After the reaction is completed, the target compound (2) is collected from the reaction mixture according to a conventional method. For example, the desired product can be obtained by etching the edges with acids such as acetic acid, hydrochloric acid, sulfuric acid, etc. and counting the precipitated crystals. The obtained target product can be purified by a conventional method, for example, a recrystallization method, if necessary.

EXAMPLES Next, the present invention will be specifically explained with reference to Examples, but these Examples are not intended to limit the present invention.

Example 1 2-Ureido-4,5-dimethoxybenzoic acid amide 2.49 liters of 2-amino-4,5-dimethoxybenzoic acid amide 1B was added to 1010 liters of acetic acid, stirred and dissolved, and 100.7 f of potassium cyanate was added at room temperature. Water 425WLl (7
) Actual value: C! ,53.92:H,4,63;N,12
．． 56 was completely dissolved in 20 minutes. - At night, the precipitated crystals are removed, washed with water, and dried to obtain the target product 174.
I got 3f.

Melting point: 260°C or higher Elemental analysis (a) Calculated value as C1°Hl 3N304: 0,50.21; H, 5,48; N, 17.
56 Actual value: C! ,50.18;H,548:N,1
7.37 Example 2゜Purine water 2.1 and 35% sodium hydroxide 735ml! and 2-ureido-4,5-dimethoxybenzoic acid amide 17
4.3 t was added and heated under reflux for 30 minutes.

After cooling, vinegar was added to the reaction solution and the mixture was boiled.

The precipitated crystals were collected, washed with water, and dried to obtain 160.2 f of the desired product.

Melting point 260℃ or higher Elemental analysis (%) Calculated value as 01oH1oN204: 0,54.05:H,4,54:'H,12,
61(8) Patent applicant: Sankyo Co., Ltd. Agent: Patent attorney Shoji Kashide

Claims (1)

[Claims] 11) 2-ureido-4,5-dimethoxybenzoic acid amide represented by the formula. (2) 2-ureido-4,5 represented by the formula characterized in that 2-amino-4,5-dimethoxybenzoic acid amide represented by the formula is reacted with an alkali metal cyanate salt under acidic conditions. - A method for producing dimethoxybenzoic acid amide. (3) Production of 2,4-dihydroxy-6,7-simethoxyquinazoline represented by the formula, characterized by treating 2-ureido-4,5-dimethoxybenzoic acid amide represented by the formula with a base. Law.