NO134464B - - Google Patents

Description

The present invention relates to a new method

for the preparation of 1,4-benzodiazepine derivatives and their salts, namely compounds of the formula:

where R-^ is lower alkyl, halo-lower-alkyl, cyclo-lower-alkyl-lower-alkyl, lower-alkoxy-lower-alkyl or lower-alkylthio-lower-alkyl, X is hydrogen, halogen, nitro or trifluoromethyl, and Y is hydrogen or halogen.

The 1,4-benzodiazepine derivatives of formula I have beneficial effects as sedatives, anticonvulsants and muscle relaxants and are useful as pharmaceuticals. The purpose of the invention is to provide an industrially advantageous method for the production of these therapeutically valuable substances.

According to a known method for producing

ling of 1,4-benzodiazepine derivatives of the above formula (I), described in the Journal of Organic Chemistry, volume 28, page 2456

(1963), 1,yl-benzodiazepine-2-one derivatives of formula become:

where R^, X and Y have the same meanings as above, reduced with lithium aluminum tetrahydride. If, however, this known method is applied to the case where R, bound to the nitrogen atom in the 1-position in the above formula (II), is a substituent such as e.g. a methyl group, it is not practically possible to prepare a 2,3-dihydro-1,4-benzodiazepine derivative (e.g. a 1-methyl-2,3"dihydro-5-phenyl-7-chloro-1H- 1,4-benzodiazepine) which, on the other hand, is produced according to the present method.

According to recent publications (e.g. German Explanatory Document No. 1,958,742) it was found that upon reduction at low temperature of a compound where R^ bound to the nitrogen atom in the 1-position is a methyl group with lithium aluminum tetrahydride, the double bond in the group -C<=>N- in the 4- and 5-positions not reduced, while the carbonyl group (> C <=> 0) in the 2-position was only reduced to the hydroxyl group

0H

(- C<i>H ). Thus, the resulting compound did not become the intended 2,3-dihydro-1,4-benzodiazepine derivative (e.g. 1-methyl-2,3-dihydro-5-phenyl-7-chloro-1H-1,4- benzodiazepine) when the reaction temperature was increased further, but unknown products.

When X in the above formula (II) is furthermore a nitro group, the corresponding 2,3-dihydro-1,4-benzodiazepine derivative cannot be obtained with the known method because the nitro group is reduced by lithium aluminum tetrahydride.

As a result of extensive research to remedy the above disadvantages of the known processes, one now has, according to

the invention found a method for the production with a high yield of .1,4-benzodiazepine derivatives with the above formula whereby 1,4-benzodiazepine-2-one derivatives with the above formula (II) are reacted with diborane in the presence of an inert solvent.

With this method, even when X is a nitro group, a corresponding 1,4-benzodiazepine derivative can be prepared in high yield and with great purity; even when the substituent -. R]_ in the 1-position in formula (II) can by low-temperature reduction selectively produce a 2,3-dihydro-1,4-benzodiazepine derivative without reduction of the double bond in the group -C=N- in the 4- and 5-positions . Accordingly, the present method is a very advantageous commercial process.

The diborane used in the process can be added to the reaction mixture or can alternatively be formed continuously in the reaction mixture.

The solvent is chosen from among inert solvents that do not affect the reaction, e.g. ether, diethylene glycol dimethyl ether, tetrahydrofuran and the like.

The reaction takes place during cooling, but can, if necessary, be carried out under gentle heating.

2,3-dihydro-1H-1,4-benzodiazepine derivatives prepared by the above method can be isolated as acid addition salts by treatment with inorganic or organic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, succinic acid, acetic acid, maleic acid, fumaric acid, tartaric acid and the like.

The invention is further illustrated by means of the following examples.

Example 1

To a solution of 30 ml of 1.07 M diborane in tetrahydrofuran, 1.43 g of 1-methyl-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one was added with stirring at -15 to -10°C. After further stirring at -10°C for two hours, the reaction mixture was poured into 100 ml of ice water and 20 ml of concentrated hydrochloric acid was added. The mixture was refluxed for 1 hour. After cooling, the resulting red solution was neutralized with 28% aqueous ammonia and then -extracted with ether. The ether extract was washed with water and dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure. 1.35 g of 1-methyl-5-phenyl-7-chloro-2,3-dihydro-1H-1,4-benzodiazepine was obtained, which was recrystallized from n-hexane into prisms with m.p. 99.5 - 101.0°C.

Example 2 :■''_-■,„■'•

To a suspension of 2.28 g of sodium borohydride in 35 ml of tetrahydrofuran, a solution of 13.0 g of boron trifluoride etherate in 10 ml of tetrahydrofuran was added dropwise with stirring under 10°C and the mixture was stirred at room temperature for 45 min. A solution of 1.43 g of 1-methyl-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one in 10 ml of tetrahydrofuran was added dropwise to the mixture at -15 to -12.5°C within 5 min. and the mixture was stirred at -15°C for 22 hours. The reaction mixture was poured into 100 ml of ice water and 20 ml of concentrated hydrochloric acid was added. The mixture was refluxed for 30 min., cooled and neutralized with concentrated ammonia. The tetrahydrofuran layer was separated and the aqueous layer extracted with ether. The combined organic layers were washed with water and dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure to give 1.4 g of 1-methyl-5-phenyl-7-chloro-2,3-dihydro-1H-1,4- benzodiazepine.

Example 3

To a solution of 30 ml of 1.07 M diborane in tetrahydrofuran, 1.48 g of 1-methyl-5-phenyl-7-nitro-1,3-dihydro-2H-1,4-benzodiazepine-2- on at -13 to -8°C, and the mixture was further stirred at -8°C for 1 hour and 45 minutes. The reaction mixture was poured into ice water and 20 ml of concentrated hydrochloric acid was added. The mixture was refluxed for 1 hour. After cooling, the solution was neutralized with 28% ammonia and extracted with chloroform. The chloroform extracts were washed with water and dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure. The residue was divided into a 20% solution of hydrochloric acid in ethyl alcohol and boiled at reflux for 10 min. The alcohol was distilled off under reduced pressure and the residue distributed between water and chloroform. The chloroform layer was separated, washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and 1.34 g of 1-methyl-5-phenyl-7~nitro-2,3-dihydro-1H-1,4-benzodiazepine was obtained, which was recrystallized from isopropyl alcohol to yellow flakes with m.p. . 186 - 187°C.

In a similar manner the following compounds were prepared: 1-methyl-5-phenyl-7-trifluoromethyl-2,3-dihydro-1H-1,4-benzodiazepine, pale yellow prisms after recrystallization from n-hexane, m.p. 150.5 - 152°C.

1-methyl-5-phenyl-7-bromo-2, 3-d-ihydro-1H-1,4-benzodiazepine, yellow prisms after recrystallization from n-hexane, m.p. 105°C,

1-methyl-5-(o-fluorophenyl)-7-chloro-2,3-dihydro-1H-1,4-benzodiazepine hydrochloride, m.p. 246 - 247°C (decomp.) after recrystallization from methanol-acetone. 1-ethoxymethyl-5-phenyl-7-chloro-2,3-dihydro-1H-1,4-benzodiazepine citrate, m.p. 136 - 140°C after recrystallization from ethyl alcohol-ether,

1-methylthiomethyl-5-phenyl-7-chloro-:2,3-dihydro-1H-1,4-.benzodiazepine maleate, m.p. 158 - 159°C after recrystallization from isopropyl alcohol,

1-methyl-5-(o-chlorophenyl)-7-chloro-2,3-dihydro-1H-1,4-benzodiazepine, m.p. 93 - 9^.5°C,

1-methyl-5-(o-fluorophenyl)-7-chloro-2,3-dihydro-1H-1,4-benzodiazepine, m.p. 91 92.5°C,

1-cyclopropylmethyl-5-(o-chlorophenyl)-7-chloro-2,3~ dihydro-1H-1,4-benzodiazepine, m.p. 88 - 89°C,

1-cyclopropylmethyl-5-phenyl-7-trifluoromethyl-2,3-dihydro-1H-1,4-benzodiazepine hydrochloride m.p. 244 - 246°C (decomp.).

Example 4

To a solution of 50 ml of 1.07 M diborane in tetrahydrofuran, 1.43 g of 1-methyl-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one was added with stirring at room temperature and the mixture was boiled under reflux and stirring for 7.5 hours. After standing overnight, 5 mL of water was added followed by 5 mL of concentrated hydrochloric acid to decompose the excess diborane, and the mixture was refluxed for 1 hour. After cooling, the solution was neutralized with concentrated ammonia and extracted with ether. The ether extract was washed with water and dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure. The residue was recrystallized from n-pentane to give 1.30 g of 1-methyl-5-phenyl-7-chloro-2H3,5,5-tetrahydro-1H-1,4-benzodiazepine, m.p. 66 - 68°C.

Example 5

To a suspension of 4.12 g of sodium borohydride in 50 ml of tetrahydrofuran, a solution of 22.64 g of boron trifluoride etherate in 20 ml of tetrahydrofuran was added dropwise and with stirring at a temperature of 10°C or lower.

After stirring for one hour at room temperature and then cooling, a solution of 5.0 g of 1-(3-methylthioethyl)-5-phenyl-7-chloro-1,3-dihydro-2H-1,4- benzodiazepine-2-one in 50 ml of tetrahydrofuran. The reaction mixture was stirred for 3.5 hours at -12 to ~8°C.

The reaction mixture was poured into 300 ml of ice water. After adding 100 ml of concentrated hydrochloric acid, the mixture was boiled under reflux for 30 min., then cooled and neutralized with concentrated ammonia water. The tetrahydrofuran layer was separated and the aqueous layer was extracted with ether. The organic solvent layers were combined, washed with water, dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure to give 5.8 g of an oily residue.

The oily residue was dissolved under heating in 25 ml of acetic anhydride. After standing for 1 hour at room temperature, addition of ice-water and neutralization with concentrated ammonia water, the solution was extracted with ether. The ether layer was re-extracted with 1N hydrochloric acid. The hydrochloric acid layer was neutralized with concentrated ammonia water and extracted with ether.

After drying over anhydrous sodium sulfate, the ether was removed by distillation under reduced pressure and this gave 3)8 g (79.2%) of oily 1-(g-methylthioethyl)-5-phenyl-7-chloro-2,3-dihydro- 1H-1,4-benzodiazepine. IR absorption: l6l0, 1570, 1550 cm ^.

The oily 1-(g-methylthioethyl)-5-phenyl-7-chloro-2,3-dihydro-1H-1,4-benzodiazepine obtained was oxidized with 15% hydrogen peroxide in glacial acetic acid and recrystallized from isopropanol to give l-( (g-methylsulfinylethyl)-5-phenyl-7-chloro-2,3-dihydro-1H-1,4-benzodiazepine, m.p. 170-171°C.

Example 6

To a suspension of 0.94 g of sodium borohydride in 20 ml of tetrahydrofuran, a solution of 5.19 g of boron trifluoride etherate in 5 ml of tetrahydrofuran was added dropwise and with stirring at a temperature of 10°C or lower. After stirring for 1 hour at room temperature and then cooling, a solution of 1.0 g of 1-(g-ethoxyethyl-5-(o-fluorophenyl)-7-chloro-1,3-dihydro-2H-) was added dropwise to this mixture 1,4-benzodiazepine-2-one in 5 ml of tetrahydrofuran The reaction mixture was stirred for 10 hours at from -5 to 2°C.

To the reaction mixture was added dropwise

10 ml of ice-water at from -10 to 0°C, then 10 ml of concentrated hydrochloric acid and the whole was refluxed for 30 min. After cooling and neutralization with concentrated ammonia water, the tetrahydrofuran layer was separated and the aqueous layer was extracted with ether. The organic solvent layers were combined, washed with water, dried over anhydrous sodium sulfate and the solvent removed by distillation under reduced pressure to give 1.5 g of an oily residue.

The oily residue was dissolved under heating in

5 ml of acetic anhydride. After standing for 1 hour at room temperature, addition of ice-water and neutralization with concentrated ammonia, the solution was extracted with ether. The ether layer was re-extracted with 0.24 N hydrochloric acid. The hydrochloric acid was neutralized with concentrated ammonia water and extracted with ether. After drying over anhydrous sodium sulfate, the ether was removed by distillation under reduced pressure to give 0.75 g (78.0%) of the oily compound 1-(3-ethoxyethyl)-5-(o-fluorophenyl)-7-chloro- 2,3-dihydro-1H-1,4-benzodiazepine.

This oily residue was dissolved in 3 ml of isopropyl alcohol and 1 ml of 21.3% hydrochloric acid-isopropyl alcohol was added to the solution. After standing, precipitated crystals were filtered off and this gave 1-(3-ethoxyethyl)-5-(o-fluorophenyl)-7~chloro-2,3-dihydro-1H-1,4-benzodiazepine hydrochloride, in the form of yellow needles and with sm.p. 206-208°C.

Claims (1)

Process for the preparation of 1,4-benzodiazepine derivatives with the formula: where R^ is lower-alkyl, halo-lower-alkyl, cyclo-lower-alkyl-lower-alkyl, lower-alkoxy-lower-alkyl or lower-alkylthio-lower-alkyl, X is hydrogen, halogen, nitro or trifluoromethyl, and Y is hydrogen or halogen, characterized by reacting a 1,4-benzodiazepine-2-one derivative with the formula: where R-^, X and Y have the meaning given above, with diborane in an inert solvent.