FI59100C - FOERBAETTRING FOER FOERFARANDE FOER FRAMSTAELLNING AV 12B-PHENYL-8,12B-DIHYDRO 4H- (1,3) OXATSINO (3,2 D) (1,4) BENZODIAZEPIN-4,7 (6H) -DIONER - Google Patents

Description

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Patent- och registerstyrelsen Arotkin utligd oeh utl.skrtftsn publkersd 27.02.81 (32) (33) (31) Requested • toikuut — Bugärd priorities 19-03- 7 ^

England-England (GB) 12068/71 * (71) Delmar Chemicals Limited, 9321 Airlie Street, Ville LaSalle, ^ Quebec, Canada (CA) (72) Vladimir Hach, Montreal, Quebec, Canada (CA) (74) Oy Kolster Ab (5I *) Improvement of the process for the preparation of 12b-phenyl-8,12b-dihydro-1 + HA, 3 / oxazino / 3,2 d7A A_7-benzodiazepineA, 7 (6H) -diones -Förbättring för farfarande för framställning av 12b-phenylyl-8, The present invention relates to an improvement in the process for 12b-phenyl-8,12b-dihydro-✓ 4H- / 1,3-oxazino [3, 6H] -diazerine [3, 6H] -dione. 2 dj / 1,4-bes-zodiazepine-4,7CGH) -dionexe of general formula

R

fl A

C1 / t N \ (IJ

_ / 0 C = 0 (Y Ή wy ch3 2 59100 wherein R represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a benzyl group in which process 5-phenyl-3H-1,4-benzodiazepin-2 (1H) -one of the general formula is

R

I "2 ci o wherein R is as defined above is reacted with a diketene of the general formula ch2 = c-ch2 (III) o-c = o in an inert organic solvent.

The above process for the preparation of compounds of formula I is known from U.S. Pat. No. 3,573,282. The compounds of formula I are known to have useful pharmacological properties, such as ataractic, sedative and anticonvulsant effects. The best known compound of formula I is 11-chloro-β, 12b-dihydro-2,8-dimethyl-12b-phenyl-4H- [1,3] oxazino-β, 2-dj [1,4] benzodiazepine-4,7 ( 6H) -dione, commonly known as ketazolam.

According to the aforementioned U.S. patent, compounds of formula I have previously been prepared by treating 5-phenyl-3H-1,4-benzodiazepin-2 (1H) -one of formula II with diketene, optionally prepared in situ, i. with oxygen halides and a strong base. According to this direct method, the benzodiazepine of formula II is heated in an inert organic solvent under a vertical condenser with a large excess of diketene (5-15 molar equivalents) for 1-1G hours. For example, 11-chloro-8,12b-dihydro-2,8-dimethyl-12b-phenyl-4H- [1,1:] oxazino [3,2-d] benzodiazepine-4,7 (6H) -dione is obtained by following the example of said patent. 2 procedures in 64% overall yield, heating under reflux for 18 hours a mixture of 7-chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2 (1H) -one and 50% by weight of diketene acetone solution.

59100

At the high temperature at which the reaction is carried out, the reaction component 11 has a tendency to polymerize, so that the product thus obtained has generally been impure. Because the compounds are intended to be used as drugs that may be used for long periods of time, such impurities are not desirable. These contaminants must therefore be carefully removed in order to obtain a useful medicinal product, and purification operations impair economy.

When preparing diketene in situ according to U.S. Patent 3,573,282, i.e. using an acyl halide and a strong base (see column 2, rows G □ -G11, the reaction is slow because the base acts as a hydrogen halide scavenger and not as a condensation catalyst.

"The process according to the invention is characterized in that the above reaction is carried out at a temperature of -10 to + 30 ° C and 0.1 to 10 molar equivalents, based on the benzodiazepine reactant, of a basic condensation catalyst and that the diketene reactant is present in an amount such that benzodiazepine and the molar ratio of diketene is 1: 1 to 1: 5, preferably 1: 1 to 1: 2.

The process according to the invention has several advantages over known processes = short reaction time, a small excess of diketene is sufficient, the yield is good and the product is pure.

A very preferred embodiment of this invention is the compound 11-chloro-8,12b-dihydro-2,8-dimethyl-12b-phenyl-4H, 1,3J oxazino- [3,2-d] [1,4-j] benzodiazepine-4,7 Preparation of (6H) -dione (ketazolam) by reacting 7-chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2 (1H) -one with diketene.

The reaction of the invention is carried out in an inert organic solvent, suitable solvents include, for example, acetone, benzene, chloroform, diethyl ether, tetrahydrofuran and any other organic solvent which does not significantly react with the reaction components or otherwise affect the course of the reaction.

Acetone is often the solvent of choice. In addition, liquid organic acids such as formic, acetic or propionic acids can also be used as solvents.

- The basic catalyst used in the process according to the invention should preferably be soluble in the chosen solvent. Suitable basic catalysts include organic bases such as triethylamine, trimethylamine, tributylamine, dimethylaniline, pyridine and quinoline. Inorganic bases such as zinc oxide or basic ion exchange resin can also be used (as suspensions). Preferred basic catalysts are tertiary amines, such as pyridine, which is a weak base with a basic dissociation constant of about 10. The preferred amount of the base to be used is between G, 1 to 10 molar equivalents, preferably between 0.1 and 2 molar equivalents, based on the benzodiazepine reaction component.

59100

The condensation reaction between benzodiazepine and diketene is remarkable as it proceeds rapidly at ambient temperature or even below 24-26 ° L, and surprisingly the reaction proceeds steadily to give good yields of the desired oxazinobenzodiazepines performed at -10 ° C to + 30 ° C. In general, the reaction is practically complete within an hour or even a short time. However, heating can be used if desired.

According to the present invention, the trawl ratio of 5-phenyl-3H-benzodiazepine-2MH) -one to diketene is in the range of 1: 1 to 1: 5, preferably between 1: 1 and 1: 2.

The product obtained is isolated and purified by conventional methods such as extraction, chromatography, trituration, crystallization and recrystallization.

The following examples of valcuring of the preferred compound, ketazolam, illustrate the improved process of this invention.

Example 1: 42 g (0.14 mol) of 7-chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2 (1H) -one, 360 ml of acetone as solvent and 90 ml ( 1.11 moles) of pyridine as a basic condensation catalyst. The resulting mixture was cooled to 5 ° C, after which 30 ml (0.39 mol) of diketene was added over one hour, during which time the contents of the flask were stirred. After the addition was complete, the solution was stirred for 1 hour at 5-10 ° ().

Then 3Θ00 ml of ice-cold water was added over 30 minutes, whereupon a solid precipitated. Stirring was continued for a further 30 minutes, keeping the contents of the flask at room temperature. The solid was then collected by filtration, washed with water and dried at room temperature to give 54.4 g (94.7%) of the desired 11-chloro-8,12b-dihydro-2,8-dimethyl-12b-phenyl-4H- [ "1,3] oxazino [3,2-d] [1,4] benzodiazepine-4,7 (6H) -dione.

A 50 g portion of this material was finely ground in 75 mL of acetone at 5 ° C, filtered, washed with acetone and dried at room temperature. Then 50 g of this acetone-washed product was dissolved in 1250 ml of acetone, 5 g of activated carbon (Norit) was added and the slurry was stirred for 10 minutes, then filtered, filtered through mass and passed into 3250 ml of water, stirred for 1 hour at room temperature, and filtered and dried in vacuo overnight to give 42.87 g (79% overall yield) of a white crystalline powder. IR, NMR and chromatographic analysis of this product showed it to be very pure, so the stability of the compound should be particularly good.

Example 2: 0.7 g (0.023 mol) of 7-chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2 (1H) -one was dissolved in 10 ml of acetic acid in a 50 ml flask. Then 1 ml (0.012 mol) of pyridine and 0.0 ml (0.0078 mol) of diketene were added and the reaction mixture was kept at a temperature between 0 ° C and 5 ° C for two hours with stirring. The temperature was then raised to room temperature (brother 2D - 25 ° C) and maintained there for a further two hours with occasional stirring.

The whole reaction mixture was then poured into 225 ml of cold water, stirred for 5 minutes, the precipitated white crystalline substance was filtered off, washed with water and dried at room temperature to give 0.75 g (yield 78.9%) of the desired 11-chloro-8. 12b-Dihydro-2,8-dimethyl-12b-phenyl-4H-d, 3j oxazino - (. 3,2-djf-1,4-benzodiazepine-4,7 (6H) -dione.

Example 3; 86.4 ml of glacial acetic acid and 4.8 ml of pyridine and 13.6 g (0.048 mol) of 7-chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2 (1H) -one were placed in a 1 liter ceramic neck ball. in small batches within 5 minutes. The mixture was cooled to 10-15 ° C and 29.6 g of a 50% diketene-acetone solution (0.176 mol) was added over 20 minutes maintaining the temperature at 10-15 ° C (cooling). Stirred for 3 hours at 15-20 ° C. The reaction mixture was slowly poured (15 min) into 340 ml of water (0-5 ° 0) to form a precipitate. After stirring at 0-5 ° C for 1 hour, the resulting 11-chloro-8,12b-dihydro-2,8-dimethyl-12b-phenyl-4H- [b] oxazino-3,2-d 1,4-Benzodiazepine -4,7 (6H) -dione was collected by filtration and washed with 100 ml of cold water. The filter cake was then dried at room temperature to give 17.0 g (96%) of a bleached crystalline powder.

Claims (1)

6,5100 Claim: Improvement of process 12h-phenyl-δ, 12b-dihydro-4H-Eβ, 1,2-oxoxyn.nu / 3.2 ijj (1,1 - · r. Zzobobiazepine i-4, 7 (6H) -). for the preparation of diones of the general formula R. N 0 1 \ K 2 (I) Cl / \ r --_ / C = D wherein R represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a benzyl group, wherein the 5-phenyl- 3H-1,4-Benzodiazepin-2 (1H) -one, elevated by the formula R ί> 2 (II) C1 O wherein R is as defined above, is reacted with a diketene of the general formula CH7 = C-CH7 (III) zp, Z oc = o in an inert organic solvent, characterized in that the reaction is carried out at a temperature of -1C to + 30 ° C and 0.1 to 10 molar equivalents, based on the benzodiazepine reagent, in the presence of a basic condensation catalyst and that the diketene reagent is present in an amount such that the molar ratio of benzodiazepine to diketene is 1: 1 to 1: 6, preferably 1: 1 to 1: 2.