DK145223B - METHOD FOR PREPARING 7-CHLOR-2,3-DIHYDRO-5-PHENYL-1H-1,4-BENZODIAZEPINE DERIVATIVES OR ACID ADDITION SALTS THEREOF - Google Patents

Description

(19) DENMARK (®M

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^ 02) PRESENTATION WRITING (11) 145223 B

DIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM

(21) Application No. 307V72 (51) lnt.CI * C 07 D 243/16 (22) Filing date 20 Jun. 1972 (24) Race day 20 Jun. 1972 (41) Aim. available 2J. December 1972 (44) Submitted Oct 11 1982 (86) International application # - (86) International filing day “(85) Continuation day - (62) Master application no -

(30) Priority Jun 22 1971 * 9106/71, CH

(71) Applicant F.HOFFMANN-LA ROCHE & CO. AKTIENGESELLSCHAFT, 4002 Basel, CH.

(72) Inventor Joseph Hellerbach, CH: Guldo Zanetti, CH.

(74) Associate Engineering Company Budde, Schou & Co.

(54) Process for the preparation of 7-chloro-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine derivatives or acid additon salts thereof.

The present invention relates to a particular process for the preparation of 7-chloro-2,3-dihydro-1-methyl-5-phenyl *

-1H-1,4-benzodiazepine or 7-chloro-2,3-dihydro-5-phenyl-1H-1,4-Q

2 -benzodiazepine or acid addition salts thereof. These known compound compounds have anticonvulsant, muscle relaxant and tranquilizing properties. They seem mentally relieving, mood-relieving and vegetatively regulating.

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

D

2 145223

R

N— CB - ^ - C N

C1 ^% ^ \ C = 0 I

ό in which R represents hydrogen or methyl is catalytically hydrogenated in the presence of Raney nickel or Raney cobalt, and the resulting compound is optionally converted into an acid addition salt useful for pharmaceutical purposes.

The catalytic hydrogenation of a compound of formula I can be carried out in an inert solvent. Examples of such inert solvents are alkanols, preferably methanol or ethanol, ethers, preferably dioxane, to which may be added water, or dimethylformamide. If the reaction is not carried out in an autoclave, it is conveniently carried out at a temperature between 10 ° C and 40 ° C. If working at higher temperatures, e.g. 100 ° C, the reaction is carried out in an autoclave. A particularly preferred reaction temperature is room temperature.

Hydrogenation can be carried out both at normal pressure and at elevated pressure. If the hydrogenation is carried out at elevated pressure, the reaction mixture must also be placed in an autoclave. Hydrogenation is particularly conveniently carried out at normal pressure.

The compounds of formula I, which in this process serve as starting material, are obtained from 2-methylamino-5-chloro-benzophenone or 2-amino-5-chloro-benzophenone by reaction with a haloacetonitrile. As haloacetonitriles, chloracetonitrile, bromoacetonitrile and iodoacetonitrile can be used. In this reaction, e.g. the chloroacetonitrile not only as a reaction participant, but also at the same time as a solvent.

Preferably, using chloroacetonitrile, an alkali metal bromide, preferably sodium bromide, or an alkali metal iodide, preferably sodium or potassium iodide, is added to the reaction mixture; preferably potassium iodide is added. However, there may also be other inert solvents, e.g. dimethylformamide, present. This reaction is conveniently carried out at elevated temperature, preferably at the boiling temperature of the reaction mixture.

Suitably at elevated temperature, preferably at the boiling temperature of the reaction mixture.

From the disclosure of U.S. Patent No. 3,243,427, it is known, e.g. processes for preparing 7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine and 7-chloro-2,3-dihydro-5-phenyl-1H-1,4 benzodiazepine. The practice of these synthesis methods has shown that these compounds, in part due to side reactions, are not obtained in such yields, which make these methods particularly attractive in the large-scale technique. These methods require, in part, a costly appliance supply or comprehensive precautions due to the use of toxic, corrosive or explosive reagents or reactants. Such drawbacks are avoided by the method of the present invention, which in the large art simply makes the intended compounds available from cheap starting materials.

The following examples further illustrate the process of the invention.

Example 1

A suspension of 11.4 g (2-benzoyl-4-chloro-N-methylanilino) -aceto-nitrile and ca. 5 g of Raney nickel are hydrogenated in 200 ml of alcohol until the hydrogen uptake has subsided. The catalyst is separated and the filtrate is evaporated to dryness in vacuo at 40 ° C. The residue is partially dissolved in 700 ml of boiling petroleum ether (40-45 ° C). The insoluble matter (1.0 g) is separated and the filtrate is heated to boiling with 1 g of activated carbon and filtered. The activated charcoal is further washed with 200 ml of boiling petroleum ether (40 ° -45 ° C). The filtrate is evaporated to ca. 100 ml. After standing overnight, the crystallized 7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine is extracted by suction, washed with petroleum ether (40-45 ° C) and dried. Mp. 100-101 ° C. Yield 70%.

The starting material can be prepared by one of the four following methods: (A) A solution of 123 g (0.5 mole) of 2-methylamino-5-ehlorobenzophenone in 320 ml of chloraeetonitrile is boiled for 20 hours, excluding moisture and reflux. The dark solution is poured into 1.5 L of ice water. Sodium bicarbonate is added to the mixture for slightly alkaline reaction and extracted with 1 L of acetic ester. Wash the vinegar solution with 750 ml of water and extract the aqueous solutions again with 1 liter of vinegar ester. The acetic ester phases are combined, dried over magnesium sulfate, filtered and evaporated to dryness in vacuo at 40 ° C. The residual oil (150 g) is dissolved in a 150 ml cyclohexane-methylene anhydride mixture (1: 3) and chromatographed on 2.5 kg of silica gel (Merck). Elution of the column with a mixture of cyclohexane and methylene chloride (1: 3), after discarding the first fractions, gives (2-benzoyl-4-chloro-N-methylanilino) acetonitrile, which is recrystallized from ether. Mp. 68-69 ° C. Yield 52%.

(B) To a mixture of 24.6 g of 2-methylamino-5-chlorobenzophenone and 83 g of potassium iodide in 150 ml of absolute dimethylformamide is added dropwise 37 * 8 with stirring and exclusion of humidity at 2 ° C. g ehloroacetonitrile. The mixture is stirred an additional 17 hours at 100 ° C and then evaporated to dryness in vacuo at 70 ° C. A solution of 80 g of sodium thiosulfate in 400 ml of water is added to the residue and the precipitated product is extracted with 2 x 300 ml of vinegar ester. The vinegar ester phases are washed with 2 x 300 ml water, combined, dried over magnesium sulfate and evaporated to dryness in vacuo at 40 ° C. The residue is dissolved in 50 ml of methanol. After standing for 20 hours at 4 ° C, the crystallized (2-benzoyl-4-chloro-N-methylanilino) -acetonitrile is separated off, washed with a little methanol and dried. Mp. 68-69 ° C. The mother liquor is freed from the solvent at 40 ° C in vacuo. The residue is dissolved in a 50 ml methylene chloride-cyclohexane mixture (3: 1) and chromatographed on 500 g of silica gel (Merck). Elution of the column with a mixture of methylene chloride and cyclohscan (3: 1) gives additional (2-benzoyl-4-chloro-N-methylanilino) -aetonitrile, mp 68-69 ° C. Yield 81%.

(C) To a mixture of 24.6 g of 2-methylamino-5-chlorobenzophenone and 75 g of sodium iodide in 150 ml of absolute dimethylformamide is added dropwise at 100 ° C 37 with stirring and exclusion of moisture, 8 g ehloroacetonitrile. The mixture is further stirred for 7 hours at 100 ° C and then evaporated to dryness in vacuo at 70 ° C. A solution of 80 g of sodium thiosulfate in 400 ml of water is added to the residue and the precipitated product is extracted with 2 x 300 ml of vinegar ester. The vinegar ester phases are washed with 2 x 300 ml of water, combined, dried over magnesium sulfate and evaporated to dryness in vacuo at 40 ° C. The residue is dissolved in a 100 ml methylene chloride-cyclohexane mixture (3: 1) and chromatographed on 1 kg of silica gel (Merck). Elution of the column with a mixture of methylene chloride and cyclohexane (3: 1) gives (2-benzoyl-4-chloro-N-methylanilino) -acetonitrile, m.p. 68_69 ° C. Yield 67%.

(D) A mixture of 12.5 g of 2β-methylamino-5-chlorobenzophenone and 55.5 g of iodoacetonitrile in 50 ml of absolute dimethylformamide is stirred at 100 ° C for 6 hours, excluding moisture. The dimethylformamide o is removed in vacuo at 70 ° C and a solution of 25 g of sodium thiosulfate in 500 ml of water is added to the residue. The precipitated product is extracted with 2 x 500 ml vinegar ester. The acetic ester phases are washed with 2 x 50 ml of water, combined, dried over magnesium sulfate and evaporated in vacuo at 40 ° C. The residue is dissolved in 50 ml of methanol. After standing for 20 hours at 4 ° C, the crystallized (2-benzoyl-4-chloro-N-methylanilino) -acetonitrile is separated off, washed with a little methanol and dried. Mp. 68-69 ° C. The mother liquor is evaporated to dryness in vacuo at 40 ° C. The residue is dissolved in a 50 ml methylene chloride-cyclohexane mixture (5: 1) and chromatographed on 200 g of silica gel (Merck). Elution of the column with a mixture of methylene chloride and cyclohexane (5: 1) gives additional (2-benzoyl-4-chloro-N-methylanilino) -acetonitrile, m.p. 68-69 ° C. Yield 65%.

Example 2

A suspension of 8.5 g of (2-benzoyl-4-chloro-N-methylanilino) -acetonitrile and 4 g of Raney cobalt is hydrogenated in 200 ml of alcohol at 60 ° C and 50 ato. The catalyst is separated and the filtrate is evaporated to dryness in vacuo. The residue is dissolved in 50 ml of vinegar ester and chromatographed on 200 g of silica gel (Merck). Elution of the column with vinegar ester gives 7-chloro-1-methyl-5-phenyl-2,5-dihydro-1H-1,4-benzodiazepine, m.p. 100-101 ° C. Yield 64%.

Example 5

A suspension of 2.6 g of N- (2-benzoyl-4-chlorophenyl) glycinonitrile and ca. 1 g of Raney nickel is hydrogenated in 100 ml of alcohol until hydrogen uptake subsides. The catalyst is separated and the filtrate is evaporated to dryness in vacuo. The residue is dissolved in 20 ml of vinegar ester - methanol mixture (9: 1) and chromatographed on 50 g of silica gel (Merck). Elution of the column with a mixture of vinegar ester and methanol (9: 1) gives 7-chloro-5-phenyl-1,2-dihydro-5H-1,4-benzodiazepine, m.p. 172-175 ° C. Yield 28%.

The starting material can be prepared by one of the following three methods: (A) A solution of 25.1 g of 2-amino-5-chlorobenzophenone in 65 ml of chloroacetonitrile is boiled under moisture exclusion for 2 1/2 hours at reflux. The dark red solution is poured into 500 ml of ice water.

6 145223

Sodium bicarbonate is added to the mixture for slightly alkaline reaction. The precipitated precipitate is separated and discarded. The filtrate is extracted with 2 x 250 ml vinegar ester. The acetic ester phases are washed with 100 ml of water, combined, dried over magnesium sulfate, filtered and evaporated in vacuo to dryness. The residue is dissolved in 100 ml of eyclohexane. After standing for 50 minutes at room temperature, the crystallized N- (2-benzoyl-4-chlorophenyl) glycinonitrile is separated, washed with eyclohexane and recrystallized from methanol. Mp. 174-176 ° C.

Yield 9.6%.

(B) To a mixture of 23.2 g of 2-amino-5-chlorobenzophenone and 85 g of potassium iodide in 150 ml of aboslut dimethylformamide is added dropwise at 100 ° C 37 with stirring and exclusion of moisture over a period of 2 1/2 hours. 8 g ehloroacetonitrile. The mixture is further stirred for 6 hours at 100 ° C and then evaporated in vacuo at 70 ° C. To the residue is added a solution of 80 g of sodium thiosulfate in 400 ml of water and the precipitated product is extracted with 2 x 400 ml of vinegar ester. The vinegar ester phases are washed with 2 x 300 ml water, combined, dried over magnesium sulfate and evaporated to dryness at 40 ° C in vacuo. Recrystallization of the residue from 400 ml of acetic acid-cyelohexane mixture (1: 4) gives N- (2-benzoyl-4-ehlorophenyl) glycinonitrile, m.p. 174-176 ° C. Yield 62.5%.

(C) A mixture of 23.2 g of 2-amino-5-chlorobenzophenone and 33 * 3 g of iodoacetonitrile in 50 ml of absolute dimethylformamide is stirred at 100 ° C for 6 hours, excluding moisture. The dimethylformamide o is removed in vacuo at 70 ° C and a solution of 25 g of sodium thiosulfate in 300 ml of water is added to the residue. The precipitated product is extracted with 2 x 400 ml of vinegar ester. The vinegar ester phases are washed with 2 x 200 ml water, combined, dried over magnesium sulfate and evaporated in vacuo at 40 c. Recrystallization of the residue from 400 ml vinegar ester - cyclohexane mixture (1: 4) gives N- ) -glycino-nitrile, m.p., 174-17β ° 0, Yield 63%.