DK142456B - Analogous process for the preparation of 1,4-benzodiazepine derivatives or salts thereof. - Google Patents

Description

(11) PUBLICATION MANUAL 142456 DENMARK (Bi) Int. Cl.3 C 07 O 243/26 f (21) Application No. 24 78/69 (22) Filed on May 6, 19 ^ 9 (24) Running Day, May 6, I969 (44) The application submitted and the writ published on 5 · DOV · I 9θϋ

DIRECTORATE OF

PATENT AND TRADE BRANDS <30> Priority Dedicated from d8n

May 7, 1968, 727556 US

Mar 12 1969, 806702, US

(71) F. HOFFMANN-LA ROCHE & CO. AICTIENGESELLSCHÅFT, Grenzacherstrasse 124-184, Basel, CH.

(72> Inventor: Rodney Ian Fryer, 5 Eton Drive, North Caldwell, N.J., US:

Leo Henryk Sternbach, 10 Woodmont Road, Upper Montclair, N.J., US.

(74) Plenipotentiary at the hearing:

The engineering company Budde, Schou & Co.

(54) Analogous process for the preparation of 1,4-benzodiazepine levitates or salts thereof.

The present invention relates to an analogous process for the preparation of novel 1,4-benzodiazepine derivatives of the general formula -cr fX> ά in which R1 represents halogen and R represents haloalkanoyl, alkoxyalkanoyl, optionally with alkyl, alkoxy or halogen substituted benzoyl, optionally with alkyl, alkoxy or halogen substituted pyridylcarbonyl, the monobasic residue of a dibasic alkanoic or alkenoic acid or its salts, the residue of an alkenoic acid, a carbamate or phosphate residue, wherein alkyl, alkoxy and alkanoyl may contain 1-7 carbon atoms, and the alkenic acid may contain 4-7 carbon atoms and an ethylenic double bond, wherein the monobasic residue of a dibasic alkanoic or alkenoic acid may contain 4-7 carbon atoms, or salts of these compounds.

The term "alkyl" encompasses straight and branched chain alkyl groups having 1-7, preferably 1-4 carbon atoms such as methyl, ethyl, isobutyl and isopropyl. The term "alkoxy" also includes straight-chain and branched groups having 1-7, preferably 1-4 carbon atoms, such as methoxy and ethoxy. The term "halogen" or "halide" encompasses all four halogens, viz. chlorine, bromine, fluorine and iodine, unless otherwise indicated. The term "alkanoyl" encompasses straight-chain or branched groups having 1-7 carbon atoms, such as methylcarbonyl, ethylcarbonyl and isopropylcarbonyl.

Examples of the groups encompassed by the substituent R of formula I include haloalkanoyl groups such as haloacetyl, halo propionyl, e.g. 3-chloropropionyl, halogenobutryl, e.g. 4'-chlorobutyryl, and alkoxyalkanoyl such as methoxyacetyl and ethoxyacetyl.

Examples of alkyl, alkoxy or halogen substituted benzoyl groups are alkylbenzoyl (p-alkylbenzoyl), di-alkoxybenzoyl such as dimethoxybenzoyl and tri-alkoxybenzoyl such as trimethoxybenzoyl. Examples of optionally alkyl, alkoxy or halogen substituted pyridylcarbonyl groups are groups derived from picolinic acid, isonicotinic acid and nicotinic acid which may be unsubstituted or substituted as defined above.

Suitable substituted acids of pyridine are e.g. alkoxynicotinic acid such as 2-methoxynicotinic acid, halogenicotinic acid such as 2,4- or 5-bromnicotinic acid, 3-alkylisonicotinic acid. The term "the monobasic residue of a dibasic alkanoic or alkenoic acid" includes the monobasic residues of dibasic alkanoic acids such as succinic acid and the monobasic residues of dibasic alkanoic acids such as maleic and glutaric acid. Salts of the latter can be prepared with suitable bases such as alkali metal alkoxides, e.g. sodium.

A carbamate group, i.e. -CONH alkyl, can be introduced using an alkyl isocyanate, such as methyl isocyanate, as the esterification component. A phosphate group may be introduced by esterification with e.g.

polyphosphoric acid, phosphorus oxychloride or ethylthiophosphate.

Preferably R 2 represents chlorine and R is preferably fluorine or chlorine.

Furthermore, it is preferred to prepare compounds wherein R is chlorine, R is fluorine, and R is N 1 -CO 2%., A carbamate group or the balance of a dibasic alkanoic or alkenoic acid, or salts thereof.

The process of the present invention is characterized by a compound of the general formula

° C2H4 H

RK 2 Ac = n-cr 1 2 in which R and R are as defined above are acylated in a manner known per se to introduce haloalkanoyl, alkoxyalkanoyl, optionally with alkyl, alkoxy or halogen substituted benzoyl, optionally with alkyl , alkoxy or halogen substituted pyridylcarbonyl, a monobasic residue of a dibasic alkanoic or alkenoic acid, an acid residue of an alkenoic acid or a carbamate or phosphate residue wherein the number of carbon atoms in said groups or residues is as indicated above and a compound formed if desired is converted into a salt thereof.

Examples of suitable acylating agents for esterification of compounds of formula II are isonicotinoyl chloride, benzoyl chloride, 4-methylbenzoyl chloride, 3,4,5-trimethoxybenzoyl chloride, 4

14245 G

succinic anhydride, isonicotinic acid, picolinic acid, maleic anhydride, glutaric anhydride, methyl isocyanate, ethyl isocyanate and strong inorganic acids such as acidic phosphates, for example, polyphosphoric acid, ethylthiophosphate and phosphorus oxychloride.

From the above it is clear that also organic acids substituted with halogen, alkyl or alkoxy can be used as acylating agents. Examples include haloacetic acids such as chloroacetic acid and alkoxyacetic anhydride, such as ethoxy-acetic anhydride, 4-alkylbenzoyl chloride, such as 4-methylbenzoyl chloride, 3,4,5-trimethoxybenzoyl chloride, 2-, 4- or 5-halo-nicotinic acid, e.g. . 5-bromnicotinic acid and 2-, 4- or 5-alkoxynicotinic acid such as 2-methoxynicotinic acid.

The esterification reaction takes place according to known methods. The esterification may e.g. is carried out with an acidic agent such as an acid anhydride or an acid halide, e.g. benzoyl halide, such as 3,4,5-trimethoxybenzoyl chloride, or nicotinoyl halide, when left at room temperature, especially when pyridine or the like is used as a solvent.

The reaction conditions for the esterification of a compound of formula II are not critical and can be readily selected by any person skilled in the art, depending on the aggravating agent used at all times.

When a terminally free acid group is present in the 1-position of a compound of formula I (when a dibasic acid or a derivative thereof is used as an acyl group-providing reagent), it can be treated by a conventional base such as sodium hydroxide or potassium hydroxide. , potassium carbonate, alkali metal alkoxides such as sodium methoxide are converted into corresponding benzodiazepines of formula I which carry a COOA group at the end of the 1-position side chain, in which A represents the cation of the base used. Preferably, A means sodium or potassium,

The esterification reaction can be carried out in a conventional organic solvent such as dimethylformamide, pyridine or a hydrocarbon such as toluene. However, it is preferred, as far as possible, to perform the esterification in the presence of pyridine. In addition, if an acid anhydride is used as an acyl group-providing reagent, this anhydride can also serve as a reaction medium. The reaction is preferably carried out at room temperature, however, it can also be worked above or below room temperature, depending on the reagent used.

Particularly preferred esters are those with high water solubility. These esters, which as the substituent R of formula I, have a nicotinoyl, succinoyl or phosphate group, are particularly important because of their high solubility in water, which they exhibit in pharmaceutically useful acid addition salts. These particularly preferred esters are prepared by esterification of compounds of formula II with a reagent containing a nicotinoyl, succinoyl or phosphate group.

According to the invention, it is particularly advantageous to use the present process for the preparation of the compounds N-methyl-2- [7-chloro-5- (2-fluorophenyl) -2,3-dihydro-2-oxo-1H-1,4 benzodiazepin-1-yl] ethylcarbamate, 1- (2-nicotinoyloxyethyl) -7-chloro-5- (2-fluorophenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one, 2- [7-Chloro-5- (2-fluorophenyl) -2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-1-yl] ethylsuccinate or 7-chloro-1- (2 -hydroxyethyl) -5- (2-fluorophenyl) - 1,3-dihydro-2H-1,4-benzodiazepin-2-one-o-phosphoric acid, because these compounds have been found to be particularly prominent in the therapeutic effects discussed below.

Compounds of formula I are useful as sedatives as they have a pronounced sleep-inducing effect. These compounds, as well as their pharmaceutically usable salts, may be administered according to individual needs and doses adapted to each case. The administration may be given orally or parenterally in the form of tablets, suspensions, solutions, capsules and dragees.

The benzodiazepine derivatives prepared by the process of the invention exhibit a surprisingly better sedative effect than the structurally closely related compound 7-chloro-1,3-dihydro-1- (2-hydroxyethyl) -5-phenyl-2H-1,4-benzodiazepine 2-on, known from United States Patent No. 3,391,138. This relationship has been demonstrated by a number of trials, namely slope trials, pot shock trials, and unaesthetized cat trials.

Compounds of formula I form pharmaceutically useful salts (depending on the substituent present in the 1 position at all times) with both inorganic and organic, pharmaceutically useful acids and bases, e.g. hydrochloric, hydrobromic, nitric, sulfuric, phosphoric, citric, formic, acetic, succinic, methanesulfonic, p-toluenesulfonic, ammonia, amines such as tertiary amines, e.g. triethylamine, alkali metal hydroxides such as sodium and potassium hydroxide and alkali metal alkoxides such as sodium methoxide.

The following examples illustrate the process of the invention.

Example 1

To a solution of 5 g (0.0151 mol) of 7-chloro-5- (2-fluorophenyl) -1- (2-hydroxyethyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one Into 6 ml of dry toluene is added 2.95 g (0.0302) of maleic anhydride and heated for 5 hours with stirring to reflux. The reaction mixture is cooled and poured into 40 ml of ether and 300 ml of dilute ammonium hydroxide. The phases are separated and the basic phase is acidified with acetic acid. The crude product is extracted with 2 x 100 ml of dichloromethane and evaporated to dryness. The residual oil is dissolved in 100 ml of dichloromethane, washed with 2 x 100 ml of water and 100 ml of saturated brine, dried over anhydrous sodium sulfate and evaporated to dryness. The product is crystallized from isopropanol and recrystallized twice from a mixture of dichloromethane and hexane to give pale yellow prisms of 2- / 7-chloro-5- (2-fluorophenyl) -2,3-dihydro-2-oxo-1H -1,4-Benzodiazepin-1-ylT-ethylmaleinate, m.p. 15> 157 ° C.

The starting material can be prepared as follows: A) To a solution of 10 g (0.0 ^ 46 mol) of 7-chloro-5- (2-fluorophenyl) -1,3,3-dihydro-2H-3,4-benzodiazepine 2-one hydrochloride in 25 ml of M, N-dimethylformamide is added 10.6 ml of a solution of 0.0415 mol of sodium methoxide in methanol. The solution is stirred for 30 minutes at room temperature, then 8.7 g (0.0692 mol) of 2-bromethanol are added. The reaction mixture is heated at 80 ° C for 2 hours and then poured into 200 ml of water. The reaction products are filtered off, dissolved in 100 ml of dichloromethane, washed with 2 x 100 ml of water and saturated brine, dried over sodium sulfate and evaporated. The residual oil (10.5 g) is crystallized from ether and the ether phase is filtered. The mother liquor is evaporated, dissolved in benzene and filtered over 200 g of silica gel. The silica is eluted with ether 7 until all impurities have been removed and then methanol is used as the eluent to give 7-chloro-5- (2-fluorophenyl) -1- (2-hydroxyethyl) -1,3 dihydro-2H-l, 4-benzodiazepin-2-one. After removal of the solvent, the product is obtained as an oil. An excess of ethanolic hydrochloric acid is added and then ether is added to precipitate the salt. Three times recrystallization of the salt from a mixture of methanol and ether gives slightly yellow prisms of 7-chloro-1- (2-hydroxyethyl) -5- (2-fluorophenyl) -1,5-dihydro-2H-1,4 -benzodiazepine-2-one hydrochloride, m.p. 194-196 ° C (dec.).

B) A solution of 1 g (0.00346 mole) of 7-chloro-5- (2-fluorophenyl) -3H-1,4-benzodiazepin-2 (1H) -one in 15 ml of dry Ν, Ν-dimethylformamide is treated with 0.9 ml (0.00415 mol) of a 4.69 N solution of sodium methoxide in methanol. The mixture is stirred for half an hour and then a solution of 0.45 g (0.0105 mole) of ethylene oxide in 5 ml of dry N, N-dimethyl formamide is added. The reaction mixture is stirred for 2 hours at room temperature and for 1 hour at 60 ° C. The solvent is removed under reduced pressure and the residue is treated with 1.5 g (0.015 mole) of succinic anhydride and 50 ml of toluene. The solution is heated to reflux for 3 hours, then cooled in an ice bath, basified with ammonium hydroxide (pH = 9) and the phases separated. The aqueous phase is treated with 5 ml of 3 N sodium hydroxide solution. The mixture is first acidified with concentrated hydrochloric acid after 30 minutes and then made basic with ammonium hydroxide. The product is extracted into 100 ml of dichloromethane which is washed with 50 ml of saturated brine, dried over anhydrous sodium sulfate and evaporated to dryness. The residual oil is dissolved in 15 ml of benzene and filtered over 50 g of silica gel. The silica gel is eluted with 200 ml of benzene and then with 250 ml of ethyl acetate. The ethyl acetate fraction is evaporated to dryness, dissolved in 5 ml of ethanol and treated with an excess of ethanolic hydrochloric acid. Ether is added and 7-chloro-1- (2-hydroxyethyl) -5- (2-fluorophenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one hydrochloride is separated. such as pale yellow prisms with m.p. 195-197 ° C (closed tube) by filtration.

Example 2

A solution of 1.6 g (0.00371 mol) of crude 2- / 7-ehloro-5- (2-fluoro-phenyl) -2,3-dihydro-2-oxo-1H-1,4-benzodiazepine-1 -yl7-ethylmaleinate in 10 ml of methanol is treated with 0.7 ml (0.00328 mol) of 4.69 N sodium methoxide in methanol and the solution is evaporated to dryness. The residual oil is triturated with ether and the residue is crystallized from a mixture of ethanol and ether. After recrystallization from a mixture of methanol and ether, slightly yellow prisms of 2- / 7-chloro-5- (2-fluorophenyl) -2,3-dihydro-2-oxo-1H-1,4-benzodiazepine-1 are obtained. -yl7-ethylmalei-sodium sodium salt, m.p. 143-147 ° C. It has been found that this sample retains methanol at 100 ° C, but after recrystallization from a mixture of methanol acetone, the product is obtained methanol free as pale yellow prisms with m.p. 220-222 ° C.

Example 3

A solution of 4 g (0.0121 mol) of 7-chloro-5- (2-fluorophenyl) -1 - (2-hydroxyethyl) -1,3-chlorohydro-2H-1,4-benzodiazepin-2-one 40 ml of dry pyridine is treated with 8.2 g (0.0362 mol) of 3,4,5-trimethoxybenzoyl chloride and the mixture is allowed to stand at room temperature for 16 hours. The solvent is distilled off and the residue is dissolved in 100 ml of dichloromethane. The solution is washed with 100 ml of 5 # potassium arbonate solution and 50 ml of saturated brine, dried over anhydrous sodium sulfate and evaporated to dryness. Recrystallization of the residue from methanol and then from a mixture of dichloromethane and hexane gives white prisms of 2- / T-chloro-5- (2-fluorophenyl) -2,3-dihydro-2-oxo-1H-1,4-benzodiazepine - 1-yl7-ethyl-3,4,5-trimethoxybenzoate, m.p. L6L-L63 ° C.

Example 4

A solution of 4 g (0.012 mol) of 7-chloro-5- (2-fluorophenyl) -1 - (2-hydroxyethyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one in 15 ml Dry pyridine is treated with 20 ml of methyl isocyanate and the reaction mixture is heated on a steam bath for 2 hours. The solvent is removed at reduced pressure and the residue is dissolved in 50 ml of dichloromethane. The solution is washed with 50 ml of dilute ammonium hydroxide and 25 ml of saturated brine, dried over anhydrous sodium sulfate and evaporated to dryness to give N-methyl-2- / 7-chloro-5- (2-fluorophenyl) -2,3-dihydro-hydrochloride. 2-oxo-1H-1,4-benzodiazepin-1-yl7-ethylcarbamate as an oil.

The resulting oil is dissolved in 10 ml of ethanol and an excess of ethanolic hydrochloric acid is added. The solution is evaporated to dryness and the residue is crystallized first from a mixture of isopropanol and ether and then from a mixture of methanol and ether to give the hydrochloride as slightly yellow prisms with m.p. 175 ° -18 ° C (in a small closed tube).

Example 5 9 142A56 Into a 2-liter flask with thermometer, stirrer, reflux condenser, drying tube, nitrogen supply tube and drip funnel, place 100 g (0.346 mole) of 7-ehloro-5- (2-fluorophenyl) -1,3-dihydro-2H-hydrochloride. 1,4-benzodiazepin-2-one hydroehloride and 400 ml of dry Ν, Ν-dimethylformamide. The solution is stirred under a slow stream of nitrogen and 23.2 g (0.692 mol) of a 50 # sodium hydride dispersion in mineral oil are added. After 20 minutes, the solution in an ice bath is cooled to 5 ° C and 130 g (0.04 mole) of 2-bromomethanol in 100 ml of dry Ν, Ν-dimethylformamide are added dropwise over 20 minutes. The nitrogen stream is shut off and the reaction mixture is heated to 100 ° C for 5 hours and then rinsed into a 3-liter flask with benzene and evaporated under reduced pressure to dryness. The 7-ehloro-5- (2-fluoro-phenyl) -1 ~ (2-hydroxyethyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one thus formed is placed in a 3-liter three-necked flask with 750 ml of benzene, then 100 ml (0.719 mol) of triethylamine and 100 g (1.0 mol) of succinic anhydride are added and the reaction is stirred for 16 hours at room temperature. The mixture is rinsed in a 3-liter flask with benzene and evaporated in vacuo to dryness. The dark oil is dissolved in 750 ml of benzene and then treated with shaking or stirring with 450 ml of water. Then a mixture of 55 ml of ice and water is added to bring the temperature down to ea. 10 ° C. The solution is basified (pH = 8.5) with 175 ml of a 50 $ potassium carbonate solution with stirring to prevent foaming and then transferred into a separatory funnel. The phases are separated and the aqueous phase is extracted with 2 x 600 ml of benzene. The benzene solutions are combined, washed with 200 ml of saturated brine, dried over anhydrous sodium sulfate and evaporated in vacuo to dryness to give an oil of 2- / 7-chloro-5 ”(2-fluorophenyl) -2,3-dihydro-2- oxo-lH-l, 4-benzo-diazepine-l-yl7-ethylsuccinate, potassium salt.

Example 6

A solution of 5 g (0.0151 mol) of 7-chloro-1- (2-hydroxyethyl) -5- (2-fluorophenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one hydrochloride in 60 ml of pyridine is treated with 8 g (0.044 mole) of nicotinoyl chloride hydrochloride and the solution is heated for 2 hours with stirring on a steam bath. The pyridine is separated in vacuo and the residue is dissolved in 100 ml of dichloromethane, washed with 10 # potassium carbonate solution (2 x 75 ml) of U2456 10 and 75 ml of a saturated brine, dried over anhydrous sodium sulfate and evaporated to dryness. The oil is crystallized from ether and recrystallized from methanol to give white prisms of 1- (2-nicotinoyl-oxyethyl) -7-chloro-5- (2-fluorophenyl) -1,3-dihydro-2H-1,4-benzodiazepine - 2-on with m.p. 138-L40 ° C.

Example 7

A solution of 10 g (0.05 mol) of 7-chloro-5 ~ (2-fluorophenyl) -1- (2-hydroxyethyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one Treat 100 ml of benzene with 4 g of succinic anhydride and 4 ml of triethylamine. After standing for 18 hours at room temperature, the solvent is removed under reduced pressure. The residue is dissolved in 100 ml of dilute potassium carbonate solution and washed with 100 ml of ether and the aqueous phases are acidified with acetic acid. The liquid is decanted off and the residual oil is dissolved in 100 ml of dichloromethane. The solution is washed with 100 ml of water, dried over anhydrous sodium sulfate and evaporated to dryness. 2- [Chloro-5- (2-fluorophenyl) -2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-1-yl7'-ethylsuccinate crystallizes from ether. After recrystallization from a mixture of methanol and ether, the product is obtained as white prisms with m.p. 152-156 ° C,

Example 8

To a solution of 15 g (0.045 mol) of 7-chloro-5- (2-fluorophenyl) -1- (2-hydroxyethyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one in 200 To xylene, 12.8 g (0.135 mole) of ehloroacetic acid are added and the solution is heated to reflux for 4 hours. The reaction mixture is cooled, washed with 10 $ potassium carbonate solution (3 x 75 mol) and water (3 x 75 ml), dried over anhydrous sodium sulfate and evaporated to dryness. The residue is dissolved in dichloromethane (50 ml), filtered over 100 g of Plorisil and eluted with 500 ml of ether. The solvent is evaporated and the residue is recrystallized twice from a mixture of dichloromethane petroleum ether to give white prisms of 7-r-chloro-L · (2-chloroacetoxyethyl) -5- (2-fluorophenyl) -1,3r-dihydro -2H-1,4-benzodiazepin-2-one, m.p. 135-137 ° C.

U2456 11

Example 9

A solution of 15 g (0.045 mol) of 7-chloro-5- (2-fluorophenyl) -1 - (2-hydroxyethyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one in 17.0 ml The xylene is treated with 11.1 g (0.09 mol) of isonicotinic acid and the solution is heated at reflux for 56 hours. The reaction mixture is cooled with 100 ml of 10 $ potassium carbonate solution and then washed with 100 ml of water. The xylene solution is extracted with 1 N hydrochloric acid (2 x 75 ml), the acid phases are combined, washed with 100 ml of ether and basified with apnonium hydroxide. The product is extracted into 100 ml of diehiormethane, which is washed with 50 ml of saturated brine, dried over anhydrous sodium sulfate and evaporated to dryness. The oil is recrystallized from ether and recrystallized from a mixture of dichloromethane and petroleum ether to give white chips of 7-chloro-5- (2-fluorophenyl) -1- (2-isonicotinoyloxyethyl) -1,3-dihydro-2H 1,4-benzodiazepin-2-one, m.p. 138-L42 ° C.

Example 10 4 g (12.0 mmol) of 7-ehloro-5- (2-fluorophenyl) -1- (2-hydroxyethyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one are dissolved in 21 ml of anhydrous pyridine and I50 ml of dry ether and the solution is cooled to -10 ° C. Another solution of 1.2 ml of phosphorus oxychloride in 75 ml of ether is added over half an hour with stirring from a dropping funnel with pressure equalization. The temperature is kept for another 2 hours below 0 ° C and then allowed to rise. After a further 1 hour, 300 ml of ice-water mixture and 15.0 ml of ether are added and after 1 hour the phases are separated. The aqueous phase is evaporated in vacuo at 30 ° C and the pH is adjusted to 3.2. The organic matter is absorbed in a 100 ml 30 $ aqueous suspension of acid washed NORIT. The aqueous phase is removed and the charcoal is washed with the four-fold volume of water which has the slightly acidic pH of the original solution. The phosphate is then desorbed with a 1: 1 mixture of ethanol and water containing 0.3 $ concentrated ammonia in 5 x 100 ml batches.

The combined filtrates are evaporated to a very hydroscopic oil, concentrated with absolute ethanol, and finally sometimes rubbed with ethyl ether. The resulting powder is kept in a vacuum desiccator to give 7-chloro-1- (2-hydroxyethyl) -5- (2-fluorophenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one -o-phosphoric acid diammonium salt in the form of a non-crystalline material. The corresponding monosodium salt exhibits a m.p. at 194-196 ° C after crystallization from methanol.

Example 11 12 T42A56

A solution of 4,4-g (0.0131 mol) of 7-chloro-5- (2-fluorophenyl) -1- (2-hydroxyethyl) -1,3-dicyl <3ro-2H-1,4-benzodiazepine -2-one and 2.0 g (0.01.31 mol) of 2-methoxynicotinic acid in 100 ml of xylene are heated at reflux for 58 hours. The reaction mixture is cooled and washed with 75 ml of 1N hydrochloric acid, which is then extracted with 50 ml of ether. The ether is combined with the xylene fraction and washed with 100 ml of dilute ammonium hydroxide and 50 ml of saturated brine, dried over anhydrous sodium sulfate and evaporated in vacuo to dryness to give 7-ehloro-1,3 'dihydro-5- (2-fluorophenyl) -L- (2-methoxynicotinoyloxyethyl) -2H-l, 4-benzodiazepin-2-one. The oil is dissolved in 100 ml of benzene, 5 ml (0.039 mol) of a 7.8 N ethanolic hydrochloric acid solution is added and the solution is evaporated in vacuo to dryness. The residue is crystallized from a mixture of acetone and ether and then recrystallized from a mixture of methanol and ether to give pale yellow prisms of 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -1 - (2 -methoxyniaotinoyloxyethyl) -2H-1,4-benzodiazepin-2-one dihydrochloride, m.p. 154-158 ° C (closed tube).

Example 12

A solution of 3S3 g (0.01 mole) of 7-chloro-5- (2-fluorophenyl) -1 - (2-hydroxyethyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one and 2.0 g (0.01 mole) of 5-bromnicotinic acid in 100 ml of xylene is heated at reflux for 48 hours. The reaction mixture is cooled and washed with 75 ml of 1 N hydrochloric acid, thereby removing the unreacted starting material. The aqueous phase is extracted with 50 ml of ether which is combined with the xylene solution and washed with 100 ml of dilute ammonium hydroxide and 50 ml of saturated brine, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue is crystallized from ether and recrystallized from a mixture of dichloromethane and hexane to give white prisms of 7-chloro-1- (5-bromnicotinoyloxyethyl) -1,3-dihydro-5- (2-fluorophenyl) -2H -1,4-benzo-diazepin-2-one, m.p. L40-L43 ° C.

Example 13

One. solution of 10 g (0.030 mol) of 7-chloro-5- (2-fluorophenyl) -1 - (2-hydroxyethyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one in 100 ml of dry benzene is treated with 6 ml (0.0428 mol) of triethylamine and 6.3 g (0.033 mol) of ethoxyacetic anhydride. After standing for 18 hours at room temperature, the solvent is removed in vacuo and the residue is dissolved in 100 ml of dichloromethane and washed with 100 ml of 10% potassium carbonate solution and 50 ml of saturated brine, dried over anhydrous sodium sulfate and evaporated to dryness. 7-Chloro-1,1-dihydro-1- (2-ethoxyacetoxyethyl) 5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one as an oil. The oil is dissolved in 100 ml of benzene, treated with 6 ml (0.0468 mol) of a solution of 7.8 N ethanolic hydrochloric acid and then evaporated to dryness. The residue is recrystallized from a mixture of acetone and ether to give slightly yellow prisms of 7-chloro-1,3-dihydro-1- (2-ethoxyethoxyethoxyethyl) -5- (2-fluoro-phenyl) -2H-1,4-benzodiazepine -2-one hydrochloride, m.p. 154-158 ° C (closed tube).

Example 14 4 g (12.0 mol) of 7-chloro-5- (2-fluorophenyl) -1- (2-hydroxyethyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one are dissolved in 21 ml of anhydrous pyridine and 150 ml of dry ether and the solution is cooled to -10 ° C. A solution of 1.2 ml of phosphorus oxychloride in 75 ml of ether is added over half an hour with stirring from a dropping funnel with pressure equalization. The temperature is kept for another 2 hours below 0 ° C and then allowed to rise. After another hour, add 500 ml in s-water-blur and 150 ml ether and after 1 hour the phases are separated. The aqueous phase is carefully concentrated in vacuo at J> 0 ° C - to avoid spraying and the pH is adjusted to 5.2. The organic material is absorbed in 100 ml of a 50 $ aqueous suspension of acid-washed NORIT. The aqueous phase is removed and the charcoal is washed with the quadruple amount of water which is adjusted to the slightly acidic pH of the original solution. The phosphate is then desorbed with a 1: 1 mixture of ethanol and water containing 0.1% concentrated ammonia in 5 x 100 ml batches. The combined filtrates are concentrated to a very hydroscopic oil, concentrated with absolute ether and then sometimes rubbed with ethyl ether. The resulting powder is kept in a vacuum desiccator to give 7-chloro-1- (2-hydroxyethyl) -5- (2-fluorophenyl) -1,5-dihydro-2H-1,4-benzodiazepin-2-one. o-phosphoric acid - diammonium salt in the form of a non-crystalline material. The corresponding monosodium salt exhibits a m.p. at 194-196 ° C after crystallization from methanol.

Example 15 14 142456

A solution of 0-552 g (1 mmol) of 7-chloro-5- (2-fluorophenyl) -1 - (2-hydroxyethyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one 6 ml of dry pyridine are mixed with 0.795 g (5 mmol) of an SO₂ pyridine addition product and the suspension is shaken overnight at room temperature. The residue formed after removal of the solvent in vacuo at 25 ° C. Dissolve in water and adjust to a pH of 7 with saturated BafOH® solution. An equal volume of ethanol is added and BaSO 2 is centrifuged. The above liquid as well as the ethanol used to wash the precipitate (50 $) are combined and evaporated in vacuo to dryness and the residue is dissolved in 95 $ ethanol. The insoluble material is centrifuged. from, the ethanol solution is evaporated and the residue is dissolved in 1 ml of water. Chromatograph on a diethylaminoethyl (DEAE) cellulose (biearbonate) column, 2 x 20 cm, with a linear gradient for water 0.3 moles pH 7 TEABIC (triethylammonium bicarbonate) of 1500 ml total volume. Fractions 161-235 contain 7-chloro-5- (2-fluorophenyl) -2,3-dihydro-2-oxo-1H-1,4-benzodiazepine-1-ethyl-hydrogen sulfate-triethylamine salt, and the fraction 201- 235 is evaporated to give a yellow, glassy product with = 311 m / u Optical density at 311 m / x = 400 corresponding to approximately 0.18 mmol (calculated at 220 m / ^).

Example 16 500 mg (2-mmol) of dilithium S- (ethyl) thiophosphate is converted to the pyridinium salt (Dowex 50 pyridinium). The pyridinium salt is kept anhydrous at high vacuum concentration with anhydrous pyridine. To the dry residue is added 552 mg (1 mmol) of 7-chloro-5- (2-fluorophenyl) -1- (2-hydroxyethyl) -1,5-dihydro-2H-1,4-benzodiazepin-2-one , 800 mg (4 mmol) of dicyclohexylcarbodiimide and 10 ml of anhydrous pyridine. The reaction mixture is shaken for 24 hours in the dark. 5 ml of water are added and the reaction mixture is allowed to stand overnight. The dicyclohexylurea is filtered off and washed with anhydrous pyridine. The filtrate is evaporated to remove pyridine and the residue is dissolved in water (2 ml) and adjusted to a pH of 8 with dilute ammonium hydroxide. The solution is placed on a 4 x 40 cm column of DEAE-Cellulose DE-25 (bicarbonate form) and washed with one linear gradient of 2 liters of triethylammonium bicarbonate (0.2 mol, pH 7.2) in the reservoir and 2 liters of water. mixing vessel. 20 ml fractions are collected at a flow rate of 5 ml per minute.

142456 15

Fractions 100-220 contain the product which is identified by paper chromatography (70 parts acetonitrile, JO parts 0.1 N ammonium chloride, pH 9, ascending). The fractions are combined, evaporated to an oily residue and dissolved in 10 ml of water. A solution containing 1.2 g of Ig in acetone (10 ml) is added and the mixture is allowed to stand for J hours. The solution is extracted with 6 x JO ml ether, the aqueous phase is evaporated and the pH is adjusted to J, 2 Activated Nori.t (70 ml of a J0% suspension) is added and the mixture is allowed to stand for 15 minutes at 0 ° C. The charcoal is filtered off and washed with water. The product is desorbed twice with a mixture of 100 ml of water, 100 ml of ethanol and 0.6 ml of concentrated ammonia. The filtrate is evaporated and concentrated with ether with an oil. After grating with ether, a yellowish powder of 7-chloro-1- (2-hydroxyethyl) ~ 5 ~ (2-fluorophenyl) -1,3-dihydro-2H-1,4-benzo-diazepin-2-one- o-phosphoric acid diammonium salt in the form of a non-crystalline material. The corresponding monosodium salt exhibits m.p. at 194-196 ° C after crystallization from methanol.

Claims (2)

142456 16 Patent Claims. An analogous process for the preparation of 1,4-benzodiazepine derivatives of the general formula C ^HOROR y> 1/12 in which R and R are halogen and R is haloalkanoyl, alkoxyalkanoyl, optionally with alkyl, alkoxy or halogen substituted benzoyl ,. optionally with alkyl, alkoxy or halogen substituted pyridylcarbonyl, the monobasic residue of a dibasic alkanoic or alkenoic acid or its salts, the residue of an alkenoic acid, a carbamate or phosphate residue, wherein alkyl, alkoxy and alkanoyl may contain 1-7 carbons. bp atoms, and the alkenic acid may contain 4-7 carbon atoms and an ethylenic double bond, wherein the monobasic residue of a dibasic alkanoic or alkenoic acid may contain 4-7 carbon atoms, or salts thereof, characterized in that a compound of the general formula 2Η4 ° * 0. N - or j0 (> I R2 "Ίί 12 in which R and R are as defined above are acylated in a manner known per se to introduce haloalkanoyl, alkoxyalkanoyl, optionally with alkyl, alkoxy or halogen substituted benzoyl, optionally with alkyl, alkoxy or halogen substituted pyridylcarbonyl, a monobasic residue of a dibasic alkanoic or alkenoic acid, an acid residue of an alkenoic acid or a carbamate or phosphate residue, wherein the number of carbon atoms in said groups or residues is as indicated above, and a formed compound if desired is converted into a salt thereof.