KR0167401B1 - A process for preparing benzodiazepine derivatives - Google Patents

Abstract

The present invention relates to a useful method of preparing benzodiazepines-3-carboxylic acid alkyl derivatives. More specifically, 5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid alkyl derivatives are obtained from 2-amino-benzoic acid derivatives. A simple, useful method of manufacturing.

Description

Method for preparing benzodiazepine derivative

The present invention relates to a useful method of preparing benzodiazepines-3-garboxylic acid alkyl derivatives. More specifically, 5,6-dihydro-5-methyl-6-oxer-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid ilkyl derivatives are prepared from 2-amino-benzoic acid derivatives. A simple, useful method of manufacturing.

8-Fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid ethyl (hereinafter referred to as flumagenyl) Was first synthesized in 1982 by the method described by Max Grekke et al. In U.S. Patent No. 4,316,839 and patented as a novel compound. Flumazenyl and its pharmaceutically acceptable acid addition salts and esters are useful for antagonizing the central sedative effects of benzodiazepines, which have physiological activities such as anticonvulsants, muscle relaxants, and the like. ) Was sold as a product. Various methods relating to the preparation of benzodiazepine-3-carboxylic acid alkyl derivatives, including flumazenyl, are disclosed in US Pat. No. 4,118,386, Belgium in particular 20833,2487 and Belgian patent 839,364, and collectively US Pat. Is described in

A typical synthesis method of imidazo [1,5-A] [1,4] diazepine of the general formula (2) including flumazenyl disclosed in U.S. Patent No. 4,316,839 is as follows. Now, the important process of the preparation method is a cyclization reaction between an imino phosphate or imino halide, which is an active form of an amide group, and alkyl isocyanate, which has a low yield. This method is illustrated below.

In the above formula, A represents a group selected from the group represented by the following (i), (ii) and (iii) with two carbon atoms represented by a and b;

And

The dashed lines represent double bonds in groups (i) and (ii);

R ₁ is methyl, ethyl or isopropyl;

R ₂ is hydrogen and R ₃ is lower alkyl;

R ₂ and R 3 together represent trimethylene or triphenylene;

R ₅ is hydrogen, halogen or trifluoromethyl;

R ₆ is hydrogen, halogen trifluoromethyl or lower alkyl;

X represents an exit group:

The carbon atom represented by C has an S- or R, S- configuration.

U. S. Patent No. 4,316, 839 also discloses several other methods of incorporation of imidazo [1,5-a] [1,4] diazepine of formula (2). Compounds of formula (2) from formylation or dehydrogenation of compounds represented by formulas (3), (4) and (5) prepared according to the methods disclosed in Belgian patents 833,248, 839,364, etc. Can be prepared. However, this manufacturing method has a disadvantage of having to go through a low yield and a long reaction path. This method is illustrated below.

In the general formula, A, the point islands R ₂₁ , R ₃₁ , R ₁₁ and X are as defined above.

An object of the present invention is to prepare a benzodiazepine-3-carboxylic acid alkyl derivative of the general formula (I) by a novel method.

In the above formula,

R ₁ is methyl, ethyl or isopropyl,

R ₂ and R ₃ are each hydrogen or lower alkyl having 1 to 6 carbon atoms,

R ₄ is hydrogen, halogen or trifluoromethyl,

The carbon atom represented by c has an S- or R, S- configuration.

The intermediate compound of the present invention is also novel. The present invention therefore provides novel intermediates in the preparation of the desired compound of formula (I).

The 2-amino-benzoic acid derivative of formula (II) is used as a starting material.

The compound of formula (II) is dissolved in an inert organic solvent such as acetonitrile, dimethyl sulfoxide, tetrahydrofuran, pyridine or dimethylformamide, preferably dimethylformamide, and then haloacetyl halide is added to 2-haloacetamido. A benzoic acid derivative is produced. Basic reactions such as carbonates such as sodium bicarbonate and potassium carbonate or hydroxides such as calcium hydroxide and potassium hydroxide sufficient to generate anions of 2-haloacetamidobenzosa derivatives, preferably by reaction with an aqueous sodium hydroxide solution 4,1-benzoxazepine-2,5-dione of general formula (III) which is crystallized directly from the mixture is obtained in good yield.

The compound of general formula (IV) used in this method can also be manufactured from the compound of general formula (III) by using the well-known method. See US Patent No. 4,118,386.

Examples of the leaving group represented by the symbol X as the compound of the general formula (IV) include, for example, a phosphinyl group, a halogen atom, an alkylthio group, an aralkylthio group, an n-nitrosoalkylamino group, an alkoxy group, and the like which are easily removable. Indicates.

The 1,3-dipole dicyclization addition reaction between the compound of formula (IV) and an isocyanoacetic acid alkyl derivative to prepare benzoxazepinone of formula (V) is carried out in an inert solvent such as diethylformamide. , Methylphosphate triamide, dimethylsulfoxide, tetrahydrofuran or other suitable inert organic solvent), in the presence of a base strong enough to produce anions of isocyanoacetic acid alkyl. Suitable bases used here include alkali metal alkoxides (e.g. sodium methoxide or potassium tert-butoxide), alkali metal hydrides (e.g. sodium hydride), alkali metal amides (e.g. lithium amide or lithium diisopropylamide). ), Tertiary amines (e.g. triethylamine). This reaction is conveniently carried out at temperatures between -40 ° C and room temperature.

The general formula (V) benzoxazepinone in which the imidazole ring is thus produced is a convenient novel intermediate for preparing benzodiazepine-3-carboxylic acid alkyl derivatives such as flumazenyl.

Among the inert solvents (as mentioned above), hydroxyalkylamines of the general formula (VI) are preferably produced by treating the compound of the general formula (V) with a lower alkylamine such as methylamine in a dimethylformamide solvent. Compound is yielded.

Halogenated reagents such as thionyl chloride, phosphorus oxychloride or phosphorus trichloride of alcohol are preferably used in an inert solvent (as mentioned above) in the hydroxyalkylamine compound of formula (VI). Is treated with thionyl chloride to give the chloroalkyl compound of formula (VII) in a good yield.

Alkali metal alkoxides (e.g. sodium methoxide or potassium tert-butoxide), alkali metal hydrides (e.g. sodium hydride), alkali metals under inert solvents (as mentioned above), preferably in dimethylformamide solvent Bases such as amides (such as lithium amide or lithium diisopropylamide), tertiary amines (such as triethylamine), are preferably chloro of formula (VII) treated with a base such as sodium ethoxide, sodium hydride, etc. 5,6-dihydroxy-5-methyl-6-oxo-4H-ididazo [1,5-a] [1,4] benzodiazepine-3 of formula (1) in good yield from the cyclization of alkyl compounds -Carboxylic acid alkyl derivatives are obtained.

The hydroxyalkylamine compound of formula (VI) prepared from the benzooxazinpinone of formula (V) is cyclized above to give 5,6-dihydro-5-methyl-6-oxo- of formula (I). The method for preparing 4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid alkyl derivative was carried out after conversion into a chloroalkyl compound of formula (VII) in a two step process.

In a convenient manner, a hydroxyalkalamine compound of the formula (VI) is prepared in solution from benzoxazepionone of the general formula (V) by a reaction which is first treated with an alkylamine in one reactor, and a halogenated reagent of the alcohol is added thereto. Addition of chloroalkyl compound of formula (VII) is obtained in good yield. If this is cyclized in the presence of a base, it is possible to prepare the compound of the general formula (I) in a good yield in a shortened process.

Pharmaceutically acceptable acid addition salts and esters of flumazenyl thus obtained can be easily prepared according to known methods.

The reaction path of the present invention is illustrated as follows.

In the above formula,

R ₁ is methyl, ethyl or isopropyl,

R ₂ and R ₃ are each hydrogen or lower alkyl having 1 to 6 carbon atoms,

R ₄ is hydrogen, halogen or trifluoromethyl,

The carbon atom represented by C has S- or R, S- configuration.

The following examples illustrate the present invention in more detail. However, these examples do not limit the scope of the present invention.

Example 1

Synthesis of 7-fluoro-4,1-benzoxazepine-2,5- (1H, 3H) -dione

In a solution of 1.94 g (12.5 mmol) of 2-amino-5-fluorobenzoic acid in 4 ml dimethylformamide, 2.52 g (13.75 mmol) bromoacetyl bromide was added while maintaining the temperature below 40 ° C. over 10 minutes. do. The solution is stirred for 30 minutes and a solution dissolved in 1.12 g of sodium hydroxide 28 ml of water at 45 DEG C or lower is added. The mixture is slowly heated to 60 ° C. over 1 hour, held for 1 hour and cooled to 5 ° C. 2.22 g (yield 91%) of crystalline solid 7-fluoro4,1-benzoxazepine 2,5- (1H, 3H) -dione having a melting point of 186 占 폚 are obtained.

Example 2

Synthesis of 3-carboethoxy-5,6-dihydro-8-fluoro-4H-imidazo [1,5-a] [1,4] benzoxazepin-6-one

0.585 g (3 mmol) of 7-fluoro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5 (1H) -dione and 3.51 ml (27.6 mmol) of 8 ml chloroform mixture Heated to reflux with reflux with dimethylaniline and 0.438 ml (4.5 mmol) of phosphorus oxychloride for 1 hour. The solution is poured into 1.998 g of sodium bicarbonate and 12 ml of water mixture and stirred for 30 minutes. The mixture is extracted twice with chloroform and then the chloroform phase is washed with water and dried in the presence of magnesium sulfate. After removal of the solvent, 4.48 g of the corresponding imino chloride yellow solution in dimethylaniline are obtained.

4.48 g of iminochloride solution in dimethylaniline prepared above was added to 3.75 ml of dimethylformamide at room temperature with 0.627 ml (4.5 mmol) of triethylamine and 0.492 ml (4.5 mmol) of ethyl isocyanate acetate. Drop by. After stirring overnight at room temperature, the light brown solution is diluted with water and then extracted three times with chloroform.

The chloroform extracts were combined, washed five times with water, dried in the presence of magnesium sulfate and evaporated. The residue was crystallized with ethyl acetate to give 0.475 g (t-rate 55%) of 3-carboethoxy-5,6-dihydro-8-fluoro-4H-imidazo having a melting point of 168 ° C to 170 ° C. 1,5-a] [1,4] benzoxazepin-6-one is obtained.

Example 3

Synthesis of 1- (4-fluoro-2-N-methylcarbamoylphenyl) -2-hydroxymethylimidazole-3-carboxylic acid ethyl

0.203 g (0.7 mmol) 3-carboethoxy-5,6-dihydro-8-fluoro-4H-imidazo [1,5-a] [1,4] benzooxa on 1 ml of dimethylformamide The zepin-6-on solution is treated with 0.400 ml of 30% methylamine methanol solution and the solution is stirred for 1 hour. The reaction is poured into water and extracted with ethyl acetate. The extract is dried in the presence of magnesium sulfate and evaporated. The residue was crystallized with ethyl acetate to give 0.214 g (95% yield) of 1- (4-fluoro-2-N-methylcarbamoylphenyl) -2-hydroxymethylimide having a melting point of 128 ° C to 130 ° C. Obtain sol-3-carboxylic acid ethyl.

Example 4

Synthesis of 2-chloromethyl-1- (4-fluoro-2-N-methylcarbamoylphenyl) imidazole-3-carboxylic acid ethyl

0.17 g (1.5 mmol) thionyl in 0.161 g (0.5 mmol) 1- (4-fluoro-2-N-methylcarbamoylphenyl) -2-hydroxymethylamidazole solution on 1 ml dimethylformamide Treat with chloride and stir the solution for 30 minutes. The reaction is poured into water and extracted with ethyl acetate. The extract is dried in the presence of magnesium sulfate and evaporated. The residue was crystallized with ethyl acetate to yield 0.161 g (yield 95%) of 2-chloromethyl-1- (4-fluoro-2-N-methylcarbamoylphenyl) imidazole- having a melting point of 145 ° C (decomposition). Obtain 3-ethyl carboxylate.

Example 5

2-chloromethyl-1- from 3-carboethoxy-5,6-dihydro-8-fluoro-4H-imidazo [1,5-a] [1,4] benzoxazepin-6-one Synthesis of (4-fluoro-2-N-methylcarbamoylphenyl-imidazole-3-carboxylic acid ethyl

0.203 g (0.7 mmol) 3-carboethoxy-5,6-dihydro-8-fluoro-4H-imidazo [1,5-a] [1,4] benzooxa on 1 ml of dimethylformamide The Zepin-6-one solution is treated with 0.400 ml of 30% methylamine methanol solution and the solution is stirred for 1 hour. 0.250 g (2.1 mmol) of thionyl chloride of 1- (4-fluoro-2-N-methylcarbamoylphenyl) -2-hydroxymethylamidazole-3-carboxylic acid ethyl having excess methylamine removed in vacuo Treatment and the solution is stirred for 30 minutes. The reaction is poured into water and extracted with ethyl acetate. The extract is dried in the presence of magnesium sulfate and evaporated. The residue was crystallized with ethyl acetate to give 0.221 g (yield 93%) of 2-chloromethyl-1- (4-fluoro-2-N-methylcarbamoylphenyl) imidazole- having a melting point of 145 ° C (decomposition). Obtain 3-carboxylic acid ethyl.

Example 6

8-Fluoro-5,6-dihydro-5-methyl-6 from 2-chloromethyl-1- (4-fluoro-2-N-methylcarbamoylphenyl) imidazole-3-carboxylic acid ethyl Synthesis of -oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid ethyl

0.075 g (1.1 mmol) of 0.340 g (1 mmol) 2-chloromethyl-1- (4-fluoro-2-N-methylcarbamoylphenyl) imidazole-3-carboxylic acid ethyl and 3 ml ethanol mixture Heat boil for 30 minutes under reflux with sodium ethoxylated). The mixture is poured into water and extracted with ethyl acetate. The extract is dried in the presence of magnesium sulfate and evaporated. The residue was crystallized with ethyl acetate to yield 0.294 g (yield 97%) of 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1 having a melting point of 201 to 203 ° C. , 5-a] [1,4] benzodiazepine-3-carboxylic acid ethyl is obtained.

Claims (5)

Treating a compound of formula (V) with a lower alkylamine in an inert solvent to prepare a hydroxyalkylamine compound of formula (VI), Compound of formula (VI) is prepared by addition of a halogenating reagent of alcohol to prepare a compound of formula (VII), A method for preparing a benzodiazepine-3-carboxylic acid alkyl derivative of formula (I) and pharmaceutically acceptable acid addition salts or esters thereof by ring closure of the compound of formula (VII) in the presence of a base. In the above formula, R ₁ is methyl, ethyl or isopropyl; R ₂ and R ₃ are each hydrogen or lower alkyl having 1 to 6 carbon atoms, and R ₄ is hydrogen, halogen or trifluoromethyl; Carbon atoms represented by C have an S- or R, S- configuration. The compound of formula (V) according to claim 1, wherein the compound of formula (V) is a starting material of 2-amino-benzoic acid derivative By cyclization under basic conditions to prepare the compound of formula (III), After adding leaving group X to the compound of formula (III) to prepare a compound of formula (IV), Wherein X represents a phosphinyl group, a halogen atom, an alkylthio group, an aralkylthio group, an n-nitrosoalkylamino group, an alkoxy group. Benzodiazepine-3-carboxylic acid alkyl derivatives of general formula (I) and pharmaceuticals thereof, characterized in that benzoxazepinone derivatives are prepared in general formula (V) by reacting alkyl isocyanate acetate in the presence of a strong base in an inert solvent. Method for preparing acid addition salts or esters as is acceptable. The benzodiazepine-3-carboxylic acid alkyl derivative of general formula (I) according to claim 1 or 2, wherein the base uses an alkali metal alkoxide, an alkali metal hydride, an alkali metal amide tertiary amine or the like. Processes for preparing pharmaceutically acceptable acid addition salts or esters. The benzodiazepine of formula (I) according to claim 1 or 2, wherein the inert solvent is acetonitrile, pyridine, diethylformamide, hexamethylphosphate triamide, dimethyl sulfoxide, tetrahydrofuran, or the like. -Carboxylic acid alkyl derivatives and pharmaceutically acceptable acid addition salts or acid esters thereof. Reaction intermediates used in the modification of benzodiazepines-3-carboxylic acid alkyl derivatives of general formula (I) represented by general formula (V) and pharmaceutically acceptable acid addition salts or esters thereof Wherein R ₁ is methyl, ethyl or isopropyl; R ₂ is hydrogen or lower alkyl having 1 ⁶ carbon atoms, R ₄ is hydrogen, halogen or trifluoromethyl; Carbon atoms represented by C have an S- or R, S- configuration.