JP2821564B2 - Method for producing quinazolinone derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing a quinazolinone derivative. More specifically, afloqualone [6-amino-2-fluoromethyl-, which acts on the central nervous system and is used as a minor tranquilizer and a muscle relaxant, is used.
3- (2-methylphenyl) -4 (3H) -quinazolinone].

[0002]

2. Description of the Related Art Conventionally, quinazolinone derivatives according to the present invention have been prepared from 2-fluoromethyl-3- (2-methylphenyl) -6 as a starting compound.
-Nitro-4 (3H) -quinazolinone is subjected to a reduction reaction. Since this compound has a nitro group and a fluoromethyl group, it must be a mild reaction in which fluorine of the fluoromethyl group does not easily cause dehalogenation and must selectively reduce the nitro group. As the reduction reaction, a method of using a combination of a polyvalent metal powder or a chloride thereof with a mineral acid or an organic acid (JP-B-55-16508, JP-B-54-43513, 3-407
No. 4 gazette) and a catalytic reduction method (Japanese Patent Publication No. 52-1559).
No. 9) is exclusively adopted.

As the polyvalent metal, tin, iron, zinc and the like, and as the chloride thereof, stannous chloride and the like are suitably used as main reducing agents. In such a method using a combination of a polyvalent metal powder or a chloride thereof with a mineral acid or an organic acid, it is possible to selectively reduce a nitro group to an amino group with almost no dehalogenation. Although it is possible, the amount of metal used is not small, and industrial disposal of metal becomes a problem, which may cause environmental problems. In the method of catalytic reduction, palladium / carbon, palladium / barium sulfate, palladium / black,
The reaction is performed in a hydrogen atmosphere in the presence of a reducing catalyst such as Raney nickel, Raney cobalt, and platinum oxide. In this method, the dehalogenation is suppressed to some extent by the activity of the catalyst, but the control is difficult and a dehalogenated product is easily generated. When a dehalogenated product is formed, it is difficult to separate the dehalogenated product from a dehalogenated product which is not dehalogenated and selectively reduced to an amino group with a nitro group.
In Japanese Patent No. 5599, the separation is carried out by column chromatography.
2.5%, which is not an industrially advantageous production method.

[0004] It is an object of the present invention to readily dehalogenate the fluorine of the fluoromethyl group in the starting compound, 2-fluoromethyl-3- (2-methylphenyl) -6-nitro-4 (3H) -quinazolinone. A mild reaction that does not occur, and by selectively reducing the nitro group, the desired compound 6-amino-2-fluoromethyl-3-
It is to provide a method for producing (2-methylphenyl) -4 (3H) -quinazolinone simply and industrially advantageously.

[0005]

Means for Solving the Problems The present inventors have made intensive studies to solve the above-mentioned problems, and as a result, have reached the present invention. That is, the gist of the present invention is 2-fluoromethyl-3- (2-
6-amino-2-fluoromethyl-3- (2-methylphenyl) -6-nitro-4 (3H) -quinazolinone reduced with hydrosulfite
Methylphenyl) -4 (3H) -quinazolinone.

[0006]

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The method of the present invention is carried out under neutral or alkaline conditions. When the reaction medium becomes acidic, hydrosulfite decomposes into sodium sulfite and does not act as a reducing agent. As a reaction medium, water or an aqueous system to which an alkaline substance is added is used. The alkaline substance may be either an organic compound or an inorganic compound. For example, aqueous ammonia, sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium acetate or their potassium salts are exemplified.

The amount of hydrosulfite used is usually about 1 to 6 moles, preferably 3 to 4 moles, per mole of the starting compound. If it is less than 3 moles, the yield decreases, and if it is more than 4 moles, there is no corresponding increase in the yield.

The solvent used in this step is a reaction of a non-aqueous solvent such as a halogenated hydrocarbon such as methylene chloride or dichloroethane, an aromatic hydrocarbon such as benzene, toluene or xylene, or a hydrophilic solvent such as methanol or ethanol. Any solvent may be used as long as it does not participate in the reaction. This step is usually performed at a temperature of 5 to 100 ° C. for 30 minutes to 5 hours, preferably 2 minutes.
The reaction is completed by reacting at a temperature of 0 to 40 ° C for 2 to 3 hours. If the temperature is lower than 5 ° C., the reactivity decreases, and
If the temperature exceeds ℃, there is a tendency that by-products increase, which is not preferable.

After the reaction is almost completed, excess hydrosulfite is decomposed by acidifying the reaction solution. In this case, mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid, and strong acids of organic acids such as trifluoroacetic acid are exemplified. However, hydrogen chloride gas is blown into a saturated state in consideration of reactivity and post-reaction treatment. Alternatively, a method of dropping concentrated sulfuric acid is desirable. Also, this operation is preferably performed at room temperature or less,
When the temperature is high, by-products are easily generated.

Next, the reaction solution is neutralized with an alkaline substance such as an aqueous sodium hydroxide solution, and the target compound is extracted by separating the organic layer. The thus-obtained target compound of the present invention can be easily purified by appropriately using known purification means for organic compounds, for example, means such as filtration, extraction, and recrystallization. For example, if necessary, recrystallization from methanol or ethyl acetate, or dissolving in an aqueous hydrochloric acid solution, washing with methylene chloride, neutralizing again, and collecting the precipitated crystals by filtration to give 69.7% or more pure crystals. -Amino-2-fluoromethyl-
3- (2-Methylphenyl) -4 (3H) -quinazolinone can be obtained.

[0012]

EXAMPLES The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples. Example 1 2-fluoromethyl-3- (2-methylphenyl) -6
-Nitro-4 (3H) -quinazolinone 20.0 g (0.
(064 mol), 100 ml of methylene chloride, 20 g of 29% aqueous ammonia and 100 ml of water were added, and 40.0 g (0.23 mol) of hydrosulfite was added in portions at room temperature. After stirring at 20 to 40 ° C for 2 to 3 hours, 89 g of hydrogen chloride was blown while maintaining the temperature at 20 ° C or lower. The mixture was neutralized again with an aqueous sodium hydroxide solution, and the methylene chloride layer was separated.
After removing the insolubles in the methylene chloride layer by filtration, the mixture was concentrated to obtain 15.7 g of 6-amino-2-fluoromethyl-3- (2-methylphenyl) -4 (3H) -quinazolinone (yield). 87.0%, purity 98.2%).

Example 2 50.0 g of 2-fluoromethyl-6-nitro-3- (2-methylphenyl) -4 (3H) -quinazolinone (0.
16 mol), 500 ml of methanol, 28.7 g of 29% aqueous ammonia and 21.3 g of water were added, and 85 g (0.49 mol) of hydrosulfite was added in portions at room temperature. 2
After stirring at 0 to 30 ° C for about 2 to 3 hours, 100.8 g (0.98 mol) of 98% sulfuric acid was added dropwise while maintaining the temperature at 20 ° C or lower. After stirring for about 3 hours, the reaction solution was filtered to remove inorganic salts. The filtrate was concentrated, redissolved in 300 ml of methylene chloride, and washed with water. Furthermore, it is extracted with hydrochloric acid aqueous solution,
After washing with methylene chloride, the mixture was neutralized again with aqueous ammonia and extracted with methylene chloride. The extract was concentrated to give 6-amino-
2-fluoromethyl-3- (2-methylphenyl) -4
38.2 g of (3H) -quinazolinone was obtained (yield 84.
5%).

[0014]

According to the method of the present invention, the nitro group can be selectively reduced without the fluorine of the fluoromethyl group of the starting compound undergoing dehalogenation. Moreover, this method does not have the problem of industrial disposal of metals as in the conventional method using a polyvalent metal, and is a target compound in a higher yield than when a catalyst for catalytic reduction is used. This is an industrially advantageous method by which 6-amino-2-fluoromethyl-3- (2-methylphenyl) -4 (3H) -quinazolinone can be obtained.

Claims (1)

(57) [Claims] 1. A method of reducing 2-fluoromethyl-3- (2-methylphenyl) -6-nitro-4 (3H) -quinazolinone using hydrosulfite. A method for producing methyl-3- (2-methylphenyl) -4 (3H) -quinazolinone.