SU683618A3 - Method of the preparation of benzodiazepine derivatives - Google Patents

Description

- (CH2) 4 OR - (CH2) 5-. Target product is isolated with lime iriemamn.

The 3-fluorobenzodiazepines of the present invention have unexpectedly proven to be resistant to hydrolysis with both aqueous acids and aqueous bases, which makes them suitable, in particular, as pharmaceuticals.

The process can be carried out by dissolving or weighing the hydroxy compound in an inert solvent followed by the addition of a fluorinating agent. Inert solvent should be considered as such, not participating in the reaction; these include, for example, diethylene glycol dimethyl ether (diglyme), pentane, trichlorofluoromethane, and the like; preferred are chlorinated solvents, liquid at the reaction temperature, such as methylene chloride and chloroform. The product can be isolated from the reaction mixture and purified by conventional means. So the reaction mixture can be poured into water, the organic layer is separated and washed with water, then evaporated to dryness. The resulting crude 3-fluorobenzodiazepines can be further purified by recrystallization from the corresponding solvents.

The 3-hydroxybenzodiazepines used in this reaction are either known compounds or can be prepared by methods described in the literature.

Dialkylaminosulfur trifluorides can be obtained by reacting dialkylaminotrimethylsilane with sulfur trifluoride at low temperatures in an inert solvent. This method can be obtained diethylaminosulfur trifluoride, dimethylaminosulfur trifluoride, pyrrolidinosulfur trifluoride. When this reaction is carried out in trichlorofluoromethane at -70 ° C, high yields of the product of high purity are obtained, since the only by-product formed is fluorotrimethylsilane, easily separated low-boiling compound. These three trifluorides are stable products, can be distilled and stored in plastic bottles or cylinders at room temperature.

Diethylaminosulfur trifluoride. The dry round bottom flask with 4 neck bottles with a capacity of 1 l is equipped with a thermometer (from -100 to -f-SO C), a reflux condenser cooled by solid CO2 and protected from atmospheric influence with a solid tube, a tube for introducing gas above the liquid level and a magnetic stirrer. The flask is washed with dry nitrogen, then 300 ml of trichlorofluoromethane are added. When the nitrogen atmosphere is constant, the trichlorofluoromethane is cooled to -70 ° C with a CO2 and acetone solid bath, after which 119 g (1.1 mol) of sulfur trifluoride are added from the cylinder through the gas inlet tube, then the gas inlet tube is replaced A funnel (250 ml, with a pressure equalizer), loaded with a solution of 145 g (1 mol) of N, N-diethylamine-mimethylsilane in 90 ml of trichlorofluoromethane. This solution is added dropwise to the solution of sulfur trifluoride at a rate to withstand the temperature of the reaction mixture below (about 40 minutes). The cooled bath is removed, the reaction mixture is allowed to warm to room temperature. The refrigerator was replaced with a simple distillation unit, the solvent (bp 24 ° C) and fluorotrimethylsilane by-product (bp 17 ° C) were distilled into a well cooled receiving tank, carefully heating the reaction mixture to 45 ° C using a heating jacket. . The residual liquid from yellow to dark brown is passed, distilled under reduced pressure, through a column with a swirling tape to obtain 129-145 g (80-907o) of diethylaminosulfur trifluoride as a light yellow liquid; m.p. 46-47 ° C (10 mm Hg. Art.).

4-Fluorotriazolobenzodiazepines, like 4-fluoro-8-chloro-1-methyl-6-phenyl-4H-S-triazolo 4 ,, 1,4 benzodiazepine, can be prepared as follows.

A solution of 8-chloro-4-hydroxy-1-methyl-4H-5-triazolr 4 ,, 4 benzodiazepine in methylene chloride is treated with diethylaminosulfur trifluoride at -70 ° C, the reaction mixture is heated to -20 ° C and poured into water. 4-Fluoro-8-chloro-1-methyl-6-phenyl-4H-5trialose 4, 4 benzodiazepine was separated from the organic layer by evaporation of the solvent.

The following examples illustrate the preparation of compounds of the present invention. Parts are given by weight.

Example 1. 3-Fluoro-1,3-digdro-7-chloro-5-phenyl-2H-1, 4-benzodiazepin-2-one.

Carefully stirred suspension of 10 g (0.03 mol) of 3-hydroxy-1,3-dihydro-7-chloro-5-phenyl-2H-1, 4-benzodiazepin-2-one in 500 ml of methylene chloride is cooled to -70 ° WITH. Then 25 ml (0.2 mol) of diethylaminosulfur trifluoride are added dropwise with moisture and air. After the addition is complete, the bath of dry ice-acetone is removed, the contents of the flask are allowed to warm to about 10 ° C for about 25 minutes, after which the reaction mixture is rapidly cooled by pouring into a beaker containing 400-500 ml of ice water. (If the reaction mixture is allowed to warm to 25 ° C, none of the desired products are formed). Then the mixture is intensively stirred for 7-10 minutes. The organic layer was separated, dried over magnesium sulfate, and evaporated under reduced pressure to obtain a light orange powder. The product is dissolved in hot benzene, treated with decolorizing wood

charcoal and filtered hot. Upon addition to benzene solution of heptane with ice cooling, the title compound crystallizes out as a beloto powder 8.19 g (82%); m.p. 190- 199 ° C (with decomposition).

Read more information for C, N.OCLMUR. %: C, 62.40; 62.77; H 3.49; 3.97; N 9.70; 9.29.

Found,%; 62.72; H 4.01; N 9.31.

Example 2. 3-Fluoro-1,3-dihydro-1-methyl-7-HLOR-5 - phenyl-2H-, 4-benzodiazepin-2-one.

A. A solution of 12.1 g (0.04 mol) of 3-hydroxy-1,3-dihydro-1-methyl - 7-chloro-5-phenyl - 2H-1,4-benzodiazine-2-one in 25 ml of anhydrous methylene chloride is added dropwise m is added over 15 minutes to a stirred solution of 12.6 ml (0.1 mol) of diethylaminosulfur trifluoride in 300 ml of anhydrous clapping methylene, cooled to -70 ° C. The reaction mixture is allowed to warm slowly over 45 minutes to 5 ° C, then poured into 500 ml of ice and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulphate and evaporated to dryness under reduced pressure to give 10.9 g (yield 90%) of the crude product as a light yellow residue. By recrystallization from heptane, 8.48 g (yield 70%) of the compound are obtained in the form of colorless crystals; m.p. 138-140 ° C.

Example 3. 3-Fluoro-1,3-dihydro-7-chloro-5 (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one.

Thoroughly stir the suspension 3.0 g (0.01 mol) of 3-hydroxy-1,3-dihydro-7-chloro-5- (2 fluorophenyl) -2H-1,4-benzodiazepin-2-one in 150 ml of methylene chloride is cooled to -70 ° C, after which 7.5 ml (0.06 mol) of trifluorond dethylaminosulfur are added dropwise over 10 minutes. The reaction mixture is then allowed to warm slowly over 26 minutes to -10 ° C and poured into 200 ml of ice water. The organic layer was separated, dried over magnesium sulfate, and evaporated to dryness under reduced pressure, to give 2.95 g (98%) of a crude product. By recrystallization from benzene - heptane, 2.00 g (67%) of the title compound are obtained in the form of impure white and light crystals; m.p. 206-207 ° С (with decomposition).

Example 4. 3-Fluoro-1,3-dihydro-1-ethyl-7-chloro-5-phenyl-2H-1, 4-benzodiazepin-2-one.

A solution of 3.5 g (0.01 mol) of 3-hydroxy-1,3-dihydro-1-ethyl-7-chloro-5-phenyl-2H-1,4-benzodiazepn-2-one in 7 ml of anhydrous methylene chloride 3.53 ml (0.028 mol) of diethylaminosulfur trifluoride in 84 ml of anhydrous methylene chloride, cooled to -70 ° C, are added dropwise to the stirred solution. The reaction mixture is allowed to slowly warm to 5 ° C, then pouring into 150 ml of ice and water. the organic layer is separated, washed with water, dried over anhydrous magnesium sulphate and evaporated to dry n: d under reduced pressure to obtain 2.84 g (yield 90%)

raw product in the form of light yellow crystals. By recrystallization of this compound with 200 ml of heptane, 1.81 g (yield 57%) of the compound are obtained; m.p. 156-158 ° C.

Calculated for C, 7Hb ,,%; C, 64.46; H 4.46; F 6.00; N 8.84.

Found,%; C, 64.46; H 4.71; F 6.57; N 8.67.

Example 5. 3-Fluoro-1,3-dihydro-1-methyl 7-chloro-5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one.

A solution of 1.4 g of 3-oxo-1,3-dihydro-1-methyl 7-chloro-5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one in 10 ml of methylene chloride

To the stirred solution is added dropwise 1.5 ml of diethylaminosulfur fluoride in 50 ml of CHLORINE methylene, cooled to -70 ° C. The solution is allowed to slowly warm to 5 ° C, then pouring into 100 ml

ice water. The lower organic layer is separated, dried over anhydrous magnesium sulphate and evaporated to dryness under reduced pressure. The residue was recrystallized from heptane to give 1.17 g of the compound as cream-colored crystals; m.p. 91-95 ° C.

Calculated CieHiiClF N.Oo,%; C, 59.91; H 3.46; F 11.85; N 8.74.

Found,%; C 60.00; H 3.57; F 11.55;

N 8.69.

Example 6. 3-Fluoro-7-bromo-1,3-dngidro-5phenyl-2H-1, 4-benzodnazepin-2-one.

A thoroughly stirred suspension of 6.0 g (0.018 mol) of 7-bromo-1,3-dihydroxy-5-phenyl-2H-1, 4-benzodiazhesh-2-it in 250 ml of methylene chloride is cooled to -70 ° C, 7.5 ml (0.06 mol) of diethylaminosulfur trifluoride are then added dropwise. The reaction mixture is allowed to slowly warm to -10 ° C.

for 30 minutes, keeping at this temperature for 20 minutes until the small amount of the solid is dissolved. The reaction mixture is poured into 500 ml and stirred until it turns yellow. The organic layer is separated, dried over magnesium sulphate and evaporated to dryness under reduced pressure. The residue is dissolved in 300 ml of hot benzene and filtered while hot.

The filtrate is mixed with 400 ml of hexane and cooled. The separated crystals are collected on a filter, washed with hexane, and air dried to give 5.28 g (88%) of the compound as colorless crystals;

so nl 207-209 ° С (with decomposition). One

the sample is dried in a vacuum oven for ana, lisa.

Fit for Cl-.HidBrFNoO,%; C, 54.07;

H 3.03; N 8.41; F 5.70, - - Found,%; C 54.31; H 3.17; - N 8.40;

F 5.62.

7-Bromo-1,3-dihydro-3-oxy-5 - phenyl -2Hj 1,4-benzodiazepin-2-one, as used above, is prepared as follows. A sample of 10.0 g (0.03 mol) of 7-bromo-1,3-dihydro-5-phenyl-2H-1, 4 - PS benzodiazepin-2-one-4-oxide

portions were added to 50 ml of trifluoroacetic acid anhydride, after which the reaction mixture was stirred for 2 hours at room temperature. The suspended solid is collected on a filter, washed thoroughly with pentane and dried in vacuo over potassium hydroxide pellets to yield 12.8 g (99%) of the above compound as a white crystalline powder; m.p. 181-183 ° C.

Calculated CuHioBrFsNsOa,%: C 47.79; H 2.36; N 6.56.

Found,%: C 47.66; H 2.33; N 6.26.

Suspension 10 g (0.023 mol) of 7-bromo-1,3-dihydro-5-phenyl-3 - triforcetoxy-2H-1,4benzodiazepin-2-one in a mixture of 130 ml of ethanol and 130 ml of 5% aqueous sodium bicarbonate 20 h stirred at room temperature (25 ° C). The suspended solid is collected on a filter, washed with water and recrystallized from ethanol to give 6.5 g (85%) of 7-bromo-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepia-2one in the form of colorless tiles; m.p. 190-192 ° C.

Calculated for Ci6HnBrN2O2,%: C54.40; H 3.35; N 8.46.

Found,%: C 54.61; H 3.51; N 8.47.

Example 7. 3-Fluoro-7-bromo-5- (2-fluorophenyl) -1,3-dihydro-2H-1,4-bisodiazepia2-one.

A stirred suspension of 4.2 g (0.012 mol) of 7-bromo-5- (2-fluorophenyl) -1,3-dihydro-3-hydroxy-2H-1, 4-benzodiazepin-2-one in 200 ml of methylene chloride is cooled to -70 ° C, then 5 ml (0.04 mol) of diethylaminosulfur trifluoride was added dropwise. The reaction mixture is allowed to warm to 10 ° C, being held at this temperature until the main solid is dissolved. The reaction mixture was poured into ice-cold water and stirred vigorously, the organic layer was separated, washed with water, dried over magnesium sulphate and evaporated to dryness under reduced pressure. The residue is recrystallized from benzene-hexane to give 3.12 g of the compound as light yellow crystals; m.p. 195-197 ° C (with decomposition).

Calculated for CisHgBrFgNzO,%: C, 51.30; H 2.58; F 10.81; N 7.98.

Found,%: C 51.50; H 2.69; F 10.53; N 8.05.

The 7-bromo-5- (2-fluorophenyl) -1,3-dihydro-3 used above - OXI-2H - 1,4-benzodiazepin-2-one is prepared as follows.

9.5 g (0.027 mol) of 7-bromo-5- (2-fluorophenyl) -1.3-digidro-2H-1,4-benzodiazepin-2on-4-oxide is added portionwise in 50 ml of trifluoroacetic anhydride then the reaction mixture is stirred for 90 minutes. The resulting weighed solid is collected on a filter, washed with hf, thinly with menthane and dried with KOH hell under vacuum. 9.72 g (80%) of 7-bromo-5- (2fluorophenyl) -1,3-dihydro-3-trifluoroacetoxy-2H-1, 4-benzodiazepin-2-one are obtained in the form of an impure white crystalline powder; m.p. 175-177 ° C (with decomposition).

Calculated Ci7H9BrF4N2O3,%: C 45.86; H 2.04; F 17.70; N 6.29.

Found,%; C, 44.55; H 1.91; F 18.00; N 6.31.

Suspension 9.5 g (0.021 mol) of 7-bromo-5- (2fluorophenyl) -1.3 - dihydro-3-trifluoroacetoxy-2H-1, 4-benzodiazepin-2-one in a mixture of 130 ml of ethanol and 130 ml of aqueous 5% ного ика sodium bicarbonate is stirred at 25 ° C. The suspended solid is collected on a filter, washed with water, air dried and recrystallized from ethanol to give 4.54 g (62%) of 7-bromo-5 - (2-fluorophenyl) -1,3-dihydro-3-hydroxy-2H -1,4-benzodiazeip-2-oia as colorless crystals; m.p. 196-198 ° C.

Ci5HioBrFN202 calculated,%: C 51.59; H 2.89; F 5.44; N 8.02.

Found,%: C 51.63; H 2.97; F 5.41; N 7.89.

Example 8. 3-Fluoro-7-chloro-5- (2-chlorfeiyl) -1,3 - dihydro-2H-1,4 - benzodiazepin2-one.

A thoroughly stirred suspension of 6.8 g (0.021 mol) of 8-chloro-5- (2-chlorophenyl) -3-oxy1, 3-dihydro-2H-1,4-benzodiazepin-2-one in 350 ml of methylene chloride is cooled in an atmosphere nitrogen to -72 ° C. Diethylaminosulfur trifluoride (10.5 ml, 0.80 mol) was added dropwise over 10 minutes at a temperature of from -72 to -70 ° C. The slurries were allowed to slowly warm to -10 ° C over 30 minutes, then it was poured into 500 ml of ice water with vigorous stirring. The organic layer is separated, dried over magnesium sulfate and evaporated to give 7.8 g of an orange-yellow solid which is dissolved in benzene and allowed to crystallize, giving 3.59 g of the compound as white crystals; m.p. 210-211 ° C (with decomposition) 95% purity according to high pressure liquid chromatography and UV analysis. A second batch is prepared by adding n-hexane (1.7 g).

Example 9. 3-Fluoro-1,3-dihydro-7-nitro5-feiil-2H-1, 4-benzodiazepin-2-one.

Thoroughly stir the suspension of 3.6 g (0.012 mol) of 1,3-dihydro-3-hydroxy-7-nitro-5phenyl-2H-1, 4-benzodiazepin-2-.zh in 200 ml of methylene chloride is cooled to -70 ° C Then 5 ml (0.04 mol) of diethylaminosulfur trifluoride are added dropwise. The reaction mixture is allowed to slowly warm to-° C; at this temperature, the entire solid product dissolves. The reaction mixture is poured into 400 ml of ice-water, the organic layer is separated, washed with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue is recrystallized from benzene 3-Oxybenzodiazepion

ten

Table

Trifluoride

3-Fluorobenzodiazepinone dialkylaminosulfur

N

Bl

(, C2H5) gM5Kz

Cl

he

2H5)

Cl

,

jC.

 R

 with.

but:

Oih

y

g

SNS

OJ:

ig:

NSFj

1СгН5) г113Гз

Cl

otTlSFj

.

zs

(sns)

oc; Oz-n

Cl

(SNZ) 2M8Rz

0.11

CH,

v-nj

CHi-OT I

 G.

 6

CK2 l .- bi,

Cl

eleven

Trifluoride

4-Oxytriazolo benzodiazepine dialkylaminosulfur

12

table 2

4-fluorotriazolobenzodiazepine

+ Et2NSF3

EfoNSF,

EtoNSF,

heptane to give 3.0 g (83%) of the compound as colorless crystals; m.p. 174-175 ° C (with decomposition).

Calculated for CisHioFNsOs,%: C, 60.20; H 3.37; F 6.35; N 14.04.

Found,%: C 60.02; H 3.43; F 6.21; N 13.88.

Example 10. 4-Fluoro-8-chloro-1-methyl-6-phenyl-4H-5 - triazolo 4, 1.4 benzodiazepine.

A solution of 5.0 g (0.014 mol) of 8-chloro-4-oxy-1-methyl-4H-3 - triazolo 4,3-a - 1.4 benzodiazepine methanol solvate in 250 ml of methylene chloride is cooled to -70 ° C, after which for 10 ml of 10 ml of diethylaminosulfur trifluoride are added. The reaction mixture is heated to -20 ° C for 20 minutes, maintaining this temperature for 20 minutes. It is then poured into 500 ml of ice-cold water. The aqueous mixture is neutralized with sodium bicarbonate, the organic layer is separated, washed with water, dried over magnesium sulfate, and evaporated to dryness, to give 4.1 g of the compound; m.p. 232- 235 ° С (with decomposition).

In tab. 1 shows additional compounds that can be obtained using the corresponding 3-hydroxy compounds as starting material according to the method of the invention.

On the table. 2 shows additional 4-fluorotriazolobenzodiazepines which can be obtained using the corresponding 4-hydroxy starting material.

Claims (1)

1. US patent No. 3.490.695, cl. 260- 239.9, publ. 1969.