NO754025L - - Google Patents

Description

Method for the production of

7-Chloro-1-(diethylamino)-ethyl-7-5-(o-fluorophenyl)-1,3-dihydro-2H-1H-benzodiazepine-2-one.

The invention relates to a new process for the preparation of 7-chloro-1-(2-(diethylamino)-ethyl7-5-(o-fluoro-phenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one with the formula

which is a known compound that is used as a drug with hypnotic properties.-

It is known to prepare similar benzodiazepinones by carrying out a Grignard reaction on a benzodiazepine-<J>j-oxide; but if this known method is tried to be used for the preparation of compound I, a yield of less than 5% is obtained, possibly because the execution of a Grignard reaction with the o-bromobenzene halide usually results in the formation of a quantity of the highly reactive benzyne3 which gives side reactions s which reduce the yield of the desired compound.

It has now been shown that the compound I can be prepared in high yield with a minimum of side reactions, if the Grignard reaction is carried out in a special way.

According to the invention, the compound I is prepared by 7-chloro-1-[_<_>2-(diethylamino)-ethyl7-1J3-dihydro-2H-1,<i>1-benzodiazepine-2-one-4-oxide (II ) is subjected to an in situ Grignard reaction with o-fluorophenylmagnesium bromide in the presence of 1,2-dibromoethane, and from the resulting 7-chloro-1-_/~2-(diethylamino)-ethyl_17-5-(o-fluorophenyl) -1,3,4,5-tetrahydro-4-hydroxy-2H-1,4-benzodiazepin-2-one (III) is separated from water.

a

The procedure is illustrated by the following reaction schemes:

In a preferred embodiment of the method, the synthesis according to the invention is carried out without isolation of any intermediate product.

The Grignard reaction is preferably carried out at a temperature between ^0 and 60°C, especially at H0-^2°C, as this has been shown in a minimum of impurities in the resulting product.

In the preparation of the Grignard reagent from 1-bromo-2-fluorobenzene, an excess of 25-50%, preferably 30-461, of the latter compound is suitably used with regard to achieving maximum yield, without the amount of impurities in the intermediate III being increased disproportionately.

Application of an excess of magnesium ensures

a uniform reaction course from the beginning to the end of the Grignard reaction.

The starting substance II is a new compound which is prepared from the known 7-chloro-1,3-dihydro-2H-1,1-1-benzodiazepine-2-one-4-oxide and 2-chloroethyl-1-diethylamine.

The water separation from compound III is preferably carried out with phenyl isocyanate. Other water splitting agents that can be used are sodium methoxide in methanol and 1,4-dimethylpiperazine.

The new compounds II and III are also covered by the invention.

The procedure shall be explained in more detail with the help of some examples.

Example 1.

7-Chloro-1-(diethylamino)-ethyl7-1,3-dihydro-2H-1,3-benzodiazepine-one-T-oxide (II).

For the preparation of the above-mentioned starting material, 7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one-4-oxide (80.0 g, 0.380 mol) was added to a solution of sodium methoxide (prepared of 9*66 g (0.420 mol) of sodium, and 200 ml of methanol and evaporation of 150 ml of methanol) in methanol (50 ml) and N,N-dimethylformamide (800 ml). The clear solution, which became cloudy after 30 seconds, was stirred for 30 minutes at room temperature. A solution of 2-chlorotriethylamine (prepared from the hydrochloride (72.3 g, 0.420 mol)) in dry toluene (440 ml) at 5°C was added in one portion and the mixture heated for 1 hour on a water bath (100 °C). The resulting bright orange colored suspension was evaporated on a water bath (70°C) under reduced pressure to dryness. To the evaporation residue was added methylene chloride (300 ml) and the resulting suspension was poured into a mixture of ice (1000 g), water (1000 ml) and 3 N hydrochloric acid (133 ml, 0.400 mol). The aqueous phase was separated, washed with methylene chloride (200 + 200 ml) and adjusted to a pH between 9 and 10 at 0°C with 3 N sodium hydroxide (133 ml, 0.400 mol). The separated oil was extracted with methylene chloride (200 + 200 + 200 ml). The combined methylene extracts were dried with "Drierite" (Siccon Fluca). Removal of the methylene chloride on a water bath (40°C), finally at a pressure below 15 mm Hg, gave 99j3 g (84%) of compound II as a tea-colored oil. This oil (99 3 3 g) was dissolved in hot ether (200 ml) and the solution cooled and allowed to stand for 48 hours at -30°C. The crystal cake formed was isolated by decantation of the above ethereal mother liquor, washed with cold ether (15 + 15 ml) and dissolved in hot methanol (30 ml). Ether (300 ml) was added and the solution was stored until the next day at -20°C. The separated crystalline precipitate was filtered off, washed with cold ether (25 + 25 ml) and dried (20°C, 0.5 mm Hg), whereby the! 48.0 g (4l$) of compound II appeared as white crystals with a melting point of 87-89°C. The mother liquor and the washings were evaporated to dryness on a water bath (45°C) under reduced pressure and the evaporation residue was crystallized from ether (100 ml) at -20°C and isolated as above yielding 23.4 g (20%) of compound II as slightly yellowish crystals with a melting point of 86-88°C. The two-fold yield of II was thus 71.4 g (61%). A sample with a melting point of 88-90°C was analysed. 7-Chloro-W 2-(diethylamino)-ethyl/-5-(o-fluorophenyl)-1,3,4,5~;tetrahydro-4-hydroxy-2H-1,4-benz,odiazepin-2-one (III);A stirred suspension of magnesium filings (1.32 g, 0.055 mol) in a mixture of 1,2-dibromoethane (1.0 g, 0.005 mol) and tetrahydrofuran (.10 mL) was heated in a dry flask to approx. 60°C until the initial evolution of ethylene. A solution of compound II (4.7 g, 0.015 mol) in a mixture of 1,2-Dibromoethane (4.6 g, 0.025 mol), 1-bromo-2-fluorobenzene (3.5 g, 0.0.2 mol) and tetrahydrofuran (30 mL) were added dropwise with stirring at 56-58°C within 35 minutes. The resulting dark red-brown solution was stirred and cooled over 1 hour to 30°C. The resulting viscous solution was added in one portion with stirring to 0.5 N hydrochloric acid (300 mL, 0.15 mol) at 5°C. The resulting almost clear reddish-brown solution was adjusted to pH 10 with 40% sodium hydroxide (15 ml). The resulting emulsion was • extracted with ether (100 + 100 + 100 ml) and the combined ether extracts dried over anhydrous magnesium sulfate. The brown filtrate was evaporated to dryness leaving an oily substance (5.4 g). This was dissolved in a mixture of chloroform and methanol (9=1) to a solution containing 0.10 g/ml. 4 ml of this solution was poured onto four plates prepared for thin-layer chromatography (20 x 20 cm, 2 mm layer of Merck silica gel F 254). The development took place with ethertriethylamine (19:1) for about 3 hours. An appropriate band was removed and extracted with chloroform-ethanol (9:1) (100 + 100 + 100 ml).. The filtrate was evaporated to dryness to give a*brownish semi-crystalline oil (0.33 g)•

7-chloro-1-(2-(diethylamino)-ethyl)-7-5-(o-fluorophenyl)-1,3-. dihydro- 2H- 1, 4- benzodiazepine- 2- one, dihydrochloride ( I). Compound III (0.24 g, 0.590 mmol) was dissolved in dry pyridine (2 mL) at 20 °C. Freshly distilled phenyl isocyanate (0.13 mL, 1.2 mmol) was added in one portion with stirring. The clear solution was refluxed until CO 2 evolution ceased (about 40 minutes). The clear, light tea colored solution was evaporated on a water bath (60°C) under reduced pressure to dryness. The light brown, semi-crystalline evaporation residue was stirred for 5 minutes with methylene chloride (3 mL). The suspension was filtered and the crystals washed with methylene chloride (0.3 + 0.3 ml) and dried (80°C), thereby yielding 0.110 g of carbanilide (88%), melting point 243°C. Filtrate and washing liquid were subjected to preparative thin layer chromatography on a 1.50 mm layer of Merck silica gel PF 254 on a glass plate (height 20 cm, width 45 cm), which was activated by heating to 120°C for 30 minutes. The development took place with ether-triethylamine (95=5), whereby at least 4 compounds could be separated. The 30 mm wide, colorless band in the middle of the chromatogram (the position fixed in ultraviolet light) was removed from the plate and extracted for 3 hours with ether in a Soxleth type apparatus. The ether extract was dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure on a water bath (45°C). The resulting oil (0.214 g) was dried by standing overnight at 50°C and 0.4 mm Hg to give 0.208 g (91%) of compound I as a pale yellow oil. The IR spectrum of a sample thereof (5% in'CHCl-j) was identical to the spectrum of an authentic sample. 100 mg (0.258 mmol) of the oil was dissolved in 0.99 N methanolic hydrochloric acid solution (0.58 mL, 0.57 mmol). The addition of dry ether (5 ml) and stirring for 90 minutes gave a white suspension. The crystals were filtered off, washed with dry ether (1+1 ml) and dried (50°C, 0.5 mm Hg, 2 hours), thereby yielding 102 mg of I (86%). Melting point and mixed melting point with authentic sample was 196-206°C during decomposition (the literature states melting point 190-220°C during decomposition). The IR spectrum (in KBr) was the same as for an authentic sample.. Calculated for C12H.23C1FN3.0.2 HC1(460 .8):

Example 2.

This example shows the preparation of the dihydrochloride of compound I without isolation of the intermediates.

A stirred suspension of magnesium filings (1.18 g, 0.049 mol) in a mixture of 1,2-dibromoethane (1.5 g, 0.008 mol) and tetrahydrofuran (20 mL, absolutely free of water and peroxide) was heated under nitrogen in a dry flask to 60°C for initial evolution of ethylene. A solution of compound II (1.49 g, 0.0048 mol) in a mixture of 1,2-dibromoethane (2.5 g, 0.013 mol), 1-bromo-2-fluorobenzene (1.22 g, 0.007 mol) and tetrahydrofuran (20 ml, absolutely free of water and peroxide) were then added dropwise with stirring at 40-42°C during 45 minutes. The resulting dark red-brown solution was heated to 50°C and stirred at this temperature for 30 minutes. The resulting viscous mixture was added in one portion to ice-mixed 0.14 N hydrochloric acid (150 mL, 0.021 mol). The resulting reddish-yellow cloudy solution was filtered to remove unreacted magnesium (0.4 g recovered). The solution's pH value was set to approx. 5 with 3 N NaOH (2 ml) and then the solution was extracted continuously for 6 hours with methylene chloride.

The methylene chloride extract was washed with 20% KHCO 3

(50 ml + 50 ml), dried over anhydrous calcium sulfate and filtered. The light brown filtrate was evaporated for approx. 150 ml. Methanol (50 ml) was added, activated charcoal (0.2 g) was added and the suspension was boiled with stirring and reflux for 4.0 minutes. The filtrate from this was stirred with silica gel (3 g, Merck type G) for 10 minutes. The filtrate from this was evaporated to dryness (70°C, 10 mm Hg).

The remaining oil was dissolved in dry pyridine (12 mL) at 20°C. Freshly distilled phenyl isocyanate (1.0 mL, 0.009 mol) was added in one portion to the stirred solution.

The dark brownish solution was heated slowly with stirring under nitrogen to reflux (45 minutes). Development of C02 started at approx. 80°C. Refluxing was continued for 30 minutes and then evaporated to dryness on a water bath (70°C, 10 mm Hg) over 10 minutes. The suspension was filtered and the crystals washed with methylene chloride (3+3 ml) and dried (100°C, 10 mm Hg) to give 0.64 g of slightly reddish carbanilide, mp 238-241°C. The filtrate was evaporated to dryness on a water bath (70°C, 10 mm Hg).

The remaining oil was dissolved in 2-propanol

(10 ml) on gentle heating. To the stirred, dark brown solution was added a 4.6 N solution of hydrochloric acid in 2-propanol (5 ml) in one portion. Diethyl ether (ca. 15 mL) was added slowly to the solution with stirring. At the beginning. After the precipitation of a brownish, tarry product, the ether feed was stopped, a few crystals of compound I were added, and the mixture was boiled for a few minutes under reflux until the precipitate was dissolved. Stirring was continued and upon cooling began after a few minutes' course of precipitation of the dihydrochloride of compound I. Ether (5 ml) was added slowly and the suspension stirred for 1 hour. Filtration and washing with cold 2-propanol ether (1:1) respectively

(2+2 ml) and ether (2+2 ml) followed by drying (100°C, 10 mm Hg, 4 hours) gave 1.00 g of slightly colored crystals with melting point 199-203°C, corresponding to a total yield of '46%.

Claims (6)

1. Process for the production of 7-chloro-1-[2-(diethylamino)-ethyl]-5-'(o-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one, characterized in that 7-chloro-1-(diethylamino)-ethyl-1/-1,3-dihydro-2H-1,4-benzodiazepine-2-one-4-oxide is subjected to a Grignard reaction in situ with o-fluorophenylmagnesium bromide in presence of 1,2-dibromoethane, and from the resulting 7-chloro-1-_/ 2-(diethylamino)-ethyl_17-5-(o-fluorophenyl)-1,3,4,5-tetrahydro-4-hydroxy-2H-1,4-benzodiazepine- 2-on split water. 2. Method according to claim 1, characterized in that the reactions are carried out without isolation of intermediate products. 3. Method according to claim 1 or 2, characterized in that the Grignard reaction is carried out at a temperature between 40 and 60°C, preferably at 40-42°C. 4. Method according to claims 1-3, characterized in that an excess of l-bromo-2-fluorobenzene of 25-50%, preferably 30-40%, is used for the preparation of the Grignard reagent. 5. Method according to claims 1-4, characterized in that the water separation takes place with f-eny isocyanate, sodium methoxide in methanol or 1,4-dimethylpiperazine. 6.- Intermediate product for the production of the 7-chloro-1-[2-(diethylamino)-ethyl]-5- (o-fluorophenyl)- 1,3-dihydro-2H-1,4-benzodiazepine-2-one, kar' acteri- . especially in that its chemical composition is 7-Chloro-l- _/""!= (diethylamino)-ethyl 17-1,3-dihydro-2H-1,4-benzodiazepine-2-qn= 4-oxide. 7- Intermediate product for the preparation of the 7-chloro-1-[2-(diethylamino)-ethyl-7-5-(o-fluorophenyl)-1,3-dihydro-2H-1 4-benzodiazepine-2-one referred to in claim 1 , characterized in that its chemical composition is 7_chloro-1-1_ 2-(diet<y>lamino)-ethyl75-(o-fluoro-phenyl)-1,3} 4,5-tetrahydro-4-hydroxy-2H-1 ,4-benzodiazepine-2-one.