JP2734096B2 - Method for producing 1,4-benzodiazepine derivative - Google Patents

Description

The present invention relates to a new method for producing a 1,4-benzodiazepine derivative useful as a sedative, an anxiolytic, or the like.

<Conventional technology> Conventionally, general formula (I) [In the formula, X represents a hydrogen atom or a halogen atom, and R represents an alkyl group which may be substituted. The method for producing a 1,4-benzodiazepine derivative represented by the following general formula (II): [Wherein, X has the same meaning as described above. Dimethyl sulfate as an alkylating agent,
A method of methylating sodium methylate as a deoxidizing agent in DMF is known (French Patent No. 2529203).
Is a compound represented by the general formula (I) or (II):
It is extremely weak to acids and alkalis due to the effect of the nitro group at the 7-position. For industrial production by conventional techniques, the base used has a strong basicity, which easily causes coloration and decolorization as well as ordinary purification. For example, a purification process such as recrystallization is required, so that it is not sufficient as an industrial production method.

Further, as a compound similar to the present invention, the following general formula (V) [In the formula, X represents a hydrogen atom or a halogen atom, and R represents an alkyl group which may be substituted. With respect to the 1,4-benzodiazepine derivative represented by
General formula (IV) [Wherein, X has the same meaning as described above. As a method for producing the compound represented by the formula (1), a method using sodium hydride or sodium methylate (JP-B-39-29776, JP-B-41-15580 and JP-B-48-26758), alkali A method using a metal carbonate and a quaternary ammonium salt (JP-A-63-8307)
No. 5 publication) is known.

However, even if these alkylation methods are applied directly to the compounds of the present invention and reacted, there are problems such as the formation of coloring components or tar components, and the desired desired products cannot be obtained.

<Problems to be Solved by the Invention> The inventors of the present invention have conducted an industrially advantageous study on a method for producing a 1,4-benzodiazepine derivative represented by the general formula (I), and as a result, a specific base has been identified. It has been found that the object can be achieved well by further lowering the reaction temperature by using, and the present invention has been completed.

<Means for Solving the Problems> The present invention provides a compound represented by the general formula (II): [In the formula, X represents a hydrogen atom or a halogen atom. And a compound represented by the general formula (III): RY (III) wherein R represents an alkyl group which may be substituted, and Y represents a halogen atom. In the presence of an alkali metal carbonate,
General formula (I) characterized in that the reaction is carried out at a temperature of 20 ° C. or less. Wherein X and R have the same meaning as described above. ] The method for producing a 1,4-benzodiazepine derivative represented by the following formula:

 Hereinafter, the method of the present invention will be described in more detail.

Examples of the alkali metal carbonate used in the method of the present invention include sodium carbonate, potassium carbonate, cesium carbonate and the like, and potassium carbonate and cesium carbonate are particularly preferable.

R in the general formulas (I) and (III) is specifically an alkyl group such as methyl, ethyl, propyl, butyl or the like or a substituted alkyl group, and the substituent is cycloalkyl such as cyclopropyl. Examples thereof include an alkyl group and a dialkylamino group such as diethylamino and dimethylamino.

Y in the general formula (III) is, for example, a halogen atom such as a bromine atom, a chlorine atom and an iodine atom.

The reaction in the method of the present invention is preferably performed in an inert solvent. Examples of the inert solvent used here include ketones such as acetone and methyl ethyl ketone, ethers such as ethylene glycol dimethyl ether (glyme), diethylene glycol dimethyl ether (diglyme), triethylene glycol dimethyl ether (triglyme), tetrahydrofuran (THF), and dioxane. And dimethylformamide (DM
F), dimethyl sulfoxide (DMSO), 1,3-dimethyl-
Aprotic polar solvents such as 2-imidazolidinone (DMI), N-methyl-2-pyrrolidone, acetonitrile and the like can also be used. These solvents can be used not only alone but also as a mixed solvent. Furthermore, the above solvent can be used in combination with other solvents, for example, halogenated hydrocarbons such as dichloromethane and dichloroethane, alkylbenzenes such as toluene and xylene, and cycloalkanes such as cyclohexane.

In the present invention, the reaction temperature is an important factor, and the preferable reaction temperature is 20 ° C or lower, more preferably 15 ° C or lower.

The amount of the alkali metal carbonate used as a catalyst is 1 to 10 times, preferably 2 to 5 times the molar amount of the raw material compound (II).

The amount of the inert solvent to be used is appropriately determined depending on the charged amount of the raw material compound, the used amount of the catalyst, the state of stirring, and the like, and is usually 2 to 20 times by weight, preferably 3 to 5 times the weight of the raw material compound (II). Weight times.

In the method of the present invention, a further catalyst, for example,
The purpose can be achieved without further using a quaternary ammonium salt or the like, but if necessary, these may be used in combination.

The isolation of the 1,4-benzodiazepine derivative (I), which is the object of the present invention, is carried out by removing the excess alkali metal carbonate, generated salt and the like by filtration, extraction and washing with water after completion of the reaction, And can be easily isolated by crystallization.

<Effect of the Invention> According to the method of the present invention, it is possible to obtain a desired product of a preferable pale yellow prism crystal which does not need to be purified anymore in a high yield.

<Example> Hereinafter, the method of the present invention will be described in more detail with reference examples and examples.

Reference Example 1 A reaction vessel equipped with a stirrer and a condenser was charged with 10 g of 7-nitro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (VI) and sodium methylate 6.1.
g, 4.3 g of methyl bromide and 40 g of DMF were added, followed by stirring at 0 to 5 ° C for 12 hours. Raw material (VI) was 0.5%.

Dichloroethane and water were added, and the dichloroethane portion was separated. The dichloroethane extract was washed with water, and dichloroethane was distilled off. Crystallized from isopropyl alcohol, 1,3-dihydro-7-nitro-5 having a melting point of 158-161 ° C.
-Phenyl-1-methyl-1,4-benzodiazepine-2
9.3 g of -on (VII) were obtained. The crystals were yellow.
Recrystallization was performed using isopropyl alcohol to obtain pale yellow prism crystals. Although the reaction proceeded quantitatively, finally, the yield of (VII) was 7.9 g (yield 75
%)Met.

Reference Example 2 A reaction vessel equipped with a stirrer and a condenser was charged with 10 g of 7-nitro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (VI), 14.7 g of potassium carbonate, 4.3 g of methyl bromide, 0.5 g of benzyltriethylammonium chloride and 40 g of acetone were added, and the mixture was stirred at room temperature (about 25 ° C.). The raw material (VI) became 0.2% in 2 hours, but the reaction mass turned brown.

Dichloroethane and water were added, and the dichloroethane portion was separated. During this time, a tar-like substance was formed as an intermediate layer, which separated to the aqueous layer side. The dichloroethane extract was washed with water, and dichloroethane was distilled off. Crystallized from isopropyl alcohol to give 1,3-dihydro-7-nitro-5-phenyl-1-methyl-1,4 with a melting point of 158-161 ° C.
-8.8 g of benzodiazepin-2-one (VII) were obtained. The crystals were yellow. Recrystallization was performed using isopropyl alcohol to obtain pale yellow prism crystals. The amount of (VII) obtained by this method was 7.9 g (yield 75%).

Example 1 A reaction vessel equipped with a stirrer and a condenser was charged with 10.6 g of 7-nitro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (VI) and 15.6 g of potassium carbonate. , 4.3 g of methyl bromide and 40 g of acetone.
Stirred for hours. Raw material (VI) was 0.5%.

After completion of the reaction, dichloroethane and water were added, and the dichloroethane portion was separated. The dichloroethane extract was washed with water, dichloroethane was distilled off, and the residue was crystallized from isopropyl alcohol to give 1,3-dihydro-7 having a melting point of 158-161 ° C.
10.1 g of -nitro-5-phenyl-1-methyl-1,4-benzodiazepin-2-one (VII) were obtained as pale yellow prism crystals. This did not require repurification and was a 91% yield.

Example 2 A reaction vessel equipped with a stirrer and a condenser was charged with 7-nitro-5- (o-fluorophenyl) -1,3-dihydro-2H.
10 g of 1,4-benzodiazepin-2-one (VIII), 13.9 g of potassium carbonate, 4.3 g of methyl bromide and 40 g of acetone were added, followed by stirring at 14 to 15 ° C. for 12 hours. Raw material (VIII) is 0.5
%Met.

After completion of the reaction, dichloroethane and water were added, and the dichloroethane portion was separated. The dichloroethane extract was washed with water, dichloroethane was distilled off, and the residue was crystallized from isopropyl alcohol to give 1,3-dihydro-7 having a melting point of 170-172 ° C.
9.42 g of -nitro-5- (o-fluorophenyl) -1-methyl-1,4-benzodiazepin-2-one (IX) was obtained as pale yellow prism crystals. This did not require repurification and was a 90% yield.

Example 3 In a reaction vessel equipped with a stirrer and a condenser, 10.6 g of 7-nitro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (VI) and 36.8 g of cesium carbonate were added. Then, 4.3 g of methyl bromide, 30 g of acetone and 30 g of dichloromethane were added, and the mixture was stirred at 15 ° C. for 18 hours. Raw material (VI) was 0.5%.

After completion of the reaction, dichloromethane and water were added, and the dichloromethane portion was separated. The dichloromethane extract was washed with water, dichloromethane was distilled off, and the residue was crystallized from isopropyl alcohol to give 1,3-dihydro-7 having a melting point of 158-161 ° C.
-Nitro-5-phenyl-1-methyl-1,4-benzodiazepin-2-one (VII) 10.0 g was obtained as pale yellow prism crystals. This did not require repurification and was a 90% yield.

Example 4 A reaction vessel equipped with a stirrer and a condenser was charged with 7-nitro-5- (o-fluorophenyl) -1,3-dihydro-2H.
10 g of 1,4-benzodiazepin-2-one (VIII), 13.9 g of potassium carbonate, 4.3 g of methyl bromide and 40 g of glyme were added, and the mixture was stirred at 13 to 14 ° C. for 13 hours. Raw material (VIII) is 0.5
%Met.

After completion of the reaction, dichloroethane and water were added, and the dichloroethane portion was separated. The dichloroethane extract was washed with water to distill off dichloroethane, and then crystallized from isopropyl alcohol to give 1,3-dihydro-7 having a melting point of 170-172 ° C.
9.41 g of -nitro-5- (o-fluorophenyl) -1-methyl-1,4-benzodiazepin-2-one (IX) was obtained as pale yellow prism crystals. This did not require repurification and was a 90% yield.

Example 5 A reaction vessel equipped with a stirrer and a condenser was charged with 10 g of 7-nitro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (VI), 14.7 g of potassium carbonate, 4.3 g of methyl bromide, 0.1 g of benzyltriethylammonium chloride and 40 g of acetone were added, and the mixture was stirred at 5 ° C. The raw material (VI) became 0.2% in 5 hours.

After completion of the reaction, dichloroethane and water were added, and the dichloroethane portion was separated. The dichloroethane extract was washed with water, dichloroethane was distilled off, and the residue was crystallized from isopropyl alcohol to give 1,3-dihydro-7 having a melting point of 158-161 ° C.
9.45 g of -nitro-5-phenyl-1-methyl-1,4-benzodiazepin-2-one (VII) were obtained as pale yellow prism crystals. This did not require repurification and was a 90% yield.

Claims (2)

(57) [Claims] 1. A compound of the general formula (II) [In the formula, X represents a hydrogen atom or a halogen atom. And a compound represented by the general formula (III): RY (III) wherein R represents an alkyl group which may be substituted, and Y represents a halogen atom. In the presence of an alkali metal carbonate,
General formula (I) characterized in that the reaction is carried out at a temperature of 20 ° C. or less. [Wherein, X and R have the same meaning as described above. ] The manufacturing method of the 1, 4- benzodiazepine derivative represented by these. 2. The method according to claim 1, wherein the reaction is carried out in an inert solvent.