DE2033112A1 - Benzodiazepines prodn tranquillisers muscle - relaxant spasmolytics, anticonvulsants and - Google Patents

Abstract

Benzodiazepines (I): (where R1 is H, halogen, C1-4 alkyl, NO2 or CF3; R2 is H or halogen; R3 is H or C1-4 alkyl) are prepd. by (i) reacting the new cpd. (II): (where R4 is h or C1-4 alkyl; X is N-phthalimido) with ozone and reacting the reaction product with hydrazone (the intermediate ozonides are new) or (ii) heating the new cpd. (III): R1C6H4- -N=CR4-CH2C6H4R2 to form (II), which is treated as in (i).

Description

"1-Phthalimidoacylindole" Priority: April 16, 1969, Japan, No. 29 904/69 Benzodiazepines are valuable tranquilizers, muscle relaxants, antispasmodics, Anticonvulsants and hypnotics. They play an important role in medicine.

Several methods of making benzodiazepines are known. They are obtained, for example, by reacting an o-aminobenzophenone with a haloacetyl halide and subsequent reaction of the 2-haloacetamido compound obtained with ammonia or by heating an o-aminobenzophen, one with excess glycine ethyl ester hydrochloride in pyridine; compare

L. H. Sternbach et al., Journal of Organic Chemistry, Volume 27 (J962) Page 3788, German patents 1 145 626 and 1 136 709. This However, methods have the disadvantage that they are not universally applicable and the yields leave a lot to be desired in some cases.

The object of the invention was therefore to find new intermediates of benzodiazepines from which benzodiazepines can be produced smoothly and in high yield permit. This object is achieved by the invention.

The invention thus relates to 1-phthalimidoacylindoles of the general formula I in which R1 is a hydrogen or halogen atom, a C1-4-alkyl radical, a nitro or trifluoromethyl group, R2 is a hydrogen or halogen atom and R3 is a hydrogen atom or a C1-4-alkyl radical.

In the compounds of the general formula I, the mean halogen atoms Fluorine, chlorine, bromine and iodine atoms. The C1-4 alkyl radicals are the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl groups.

The 1-phthalimidoacylindoles can be prepared * by either a) an indole derivative of the general formula II in which R1 and R2 have the above meaning and R4 is a hydrogen atom or a C1-4-alkyl radical, with a phthalimidoacyl halide of the general formula III in which R3 has the above meaning and X is a halogen atom, acylated or b) Cifl 1-phthalimidoacylphenylhydrazone of the general formula IV in which R1, R2 and R3 have the above meaning and R4 is a hydrogen atom or a C1 4 -alkyl radical, heated to elevated temperatures. The acylation is preferably carried out in such a way that the indole of the general formula II is first treated with a basic metal compound to form the corresponding metal salt and then condensed this with a phthalimidoacyl halide of the general formula III.

Suitable basic metal compounds are, for example, sodium hydride and sodium amide and potassium amide. The reaction is preferably carried out in an organic solvent or solvent mixture carried out. Examples of suitable solvents are Dimethylformamide, benzene, toluene, xylene and their mixtures. The implementation can be at Room temperature or at temperatures below room temperature or at elevated temperatures Temperature.

The indole derivatives of the general formula II can, for example, by cyclization of phenylhydrazones of the general formula V in which R1, R2 and R4 have the above meaning. The compounds of the general formula VI can in turn by condensation of a phenylhydrazine of the general formula VI in which R1 has the above meaning, or its salt, with a compound of the general formula VII in which R2 and R4 have the above meaning.

The indole derivatives of the general formula II can also be used directly by reacting a phenylhydrazine of the general formula VI with a compound of the general formula VII without isolation of the phenylhydrazone of the general formula V can be produced.

In accordance with procedure b), the 1-phthalimidoacylindole derivatives of the general formula II can also be obtained by acylating a phenylhydrazone of the general formula V with a phthalimidoacyl halide of the general formula III and heating the resulting phthalimidoacylphenylhydrazone of the general formula IV in which R1, R2, R3 and R4 have the above meaning.

The acylation of the phenylhydrazone of the general formula V with the Phthalimidoacyl halide of the general formula III is in the presence of an acid acceptor carried out. The acid acceptor is used in at least an equimolar amount. Examples of suitable acid acceptors are inorganic bases, such as alkali metal hydroxides or carbonates, or tertiary organic bases such as pyridine, triethylamine, tributylamine, N-methylpiperidine or dimethylaniline. The reaction is preferably carried out in the presence an organic solvent or a solvent mixture carried out. Examples of suitable solvents are benzene, toluene, ether; Tetrahydrofuran, Pyridine, dioxane or mixtures thereof. These organic solvents can also in the form of mixtures with water when used as an inorganic base Acid acceptor is used. The reaction is usually carried out at temperatures ton about / -20 ° C and room temperature. You can also use it at elevated temperatures work.

The phthalimidoacylphenylhydrazones of the general formula IV can converted into the 1-phthalimidoacylindoles of the general formula I by cyclization will. The reaction is preferably carried out in the presence of at least catalytic amounts filtered through an acid. Examples of suitable acids are mineral acids such as Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and polyphosphoric acid, organic acids, such as acetic acid and formic acid, and Lewis acids, such as zinc chloride, Aluminum chloride, tin tetrachloride and boron trifluoride, or mixtures thereof. The implementation can be carried out in the presence or absence of a solvent. Suitable Solvents are lower aliphatic alcohols such as methanol, ethanol and isopropanol or tert-butanol, aromatic hydrocarbons such as benzene, toluene or xylene, lower carboxylic acids, such as formic acid and acetic acid, or other organic solvents, such as chloroform or cyclohexane. The reaction is carried out by heating the reaction mixture at elevated temperatures, preferably at temperatures of 50 to 250 ° Ct.

The conversion of the l-phthalimidoacylindoles of the general formula I into benzodiazepines of the general formula VIII takes place via the ozonide of the general formula IX R1, R2, R3 and R4 have the above meanings.

The ozonolysis of 1-Phthalimidoacylindole can be done with ozone or a Mixture of ozone with oxygen, nitrogen or air can be carried out.

For this purpose the 1-PhthalimidoacylindoSe ground the general Formula I or their acid addition salts dissolved in an organic solvent or suspended and treated with ozone until about 1 molar equivalent of ozone is absorbed istc Examples of suitable solvents are acetic acid, formic acid, methanol, Carbon tetrachloride, methylene chloride, chloroform and ethyl acetate. Ozonolysis can be at room temperature, at temperatures below room temperature or at elevated temperatures Temperature. It is not required as an intermediate Ozonide formed from the reaction.

Mixture isolate to take it to the next stage with the hydrazine derivative to implement.

When reacting the ozonide intermediate with a hydrazine derivative, how Hydrazine hydrate or phenylhydrazine, the corresponding benzodiazepine is obtained. The hydrazine derivative is at least equimolar to the 1-phthalimidoacylindole or the corresponding ozonide is used. The reaction is generally in the presence a solvent or solvent mixture carried out. Examples of suitable Solvents are methanol, ethanol, isopropanol, chloroform, dimethyl sulfoxide, Water and their mixtures. The reaction is carried out at a temperature in the range of carried out about room temperature to the boiling point of the solvent used.

The preparable benzodiazepines can by reaction with a Acid, e.g. a mineral acid such as hydrochloric acid, hydrobromic acid, Sulfuric acid, nitric acid or phosphoric acid, or an organic acid such as Maleic acid, fumaric acid, succinic acid, or acetic acid, into the corresponding acid addition salts are transferred.

Examples of those producible from the intermediates of the invention Benzodiazepines are 5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one, 5-phenyl-7-chloro-1 , 3-dihydro-2H-1, 4-benzodiazepin-2-one, 5-phenyl-7-bromo-1,3-dihydro-2H-1,4-benzodiazepin-2-ones 5-phenyl-7-nitro-1, 3-dihydro-2H-1, 4-benzodiazepin-2-one, 5-phenyl-7-trifluoromethyl-1,3-dihydro-2H-1,4-benzodiazepine-2- on, 5-phenyl-7-methyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one, 3-methyl-5-phenyl-7-chloro-t, 3-dihydro-2H-1,4- benzodiazepin-2-one, 5- (o-chlorophenyl) -7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one, 5- (o-chlorophenyl) -7-nitro-1,3-dihydro-2H- 1,4-benzodiazepin-2-one, 5- (oZ orphenyl) -7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one, 5- (o-fluorophenyl) -7-nitro-1,3-dihydro-2H-1,4-benzodiazepine -2-on and 5- (p-chlorophenyl) -7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one.

The examples illustrate the invention.

Example 1 A mixture of 20 g of phthaloylglycine and 35.2 g of thionyl chloride is refluxed for 1 hour. Thereafter, excess thionyl chloride distilled off under reduced pressure. The residue is washed with anhydrous toluene added and the solution medium distilled off under reduced pressure. You get 22.4 g of phthalimidoacetyl chloride as an oil.

The product obtained is dissolved in 80 ml of anhydrous tetrahydrofuran, and the solution is added dropwise to a solution of 20 g of phenylacetaldehyde-p-chlorophenylhydrazone added free tetrahydrofuran and 7.7 g of pyridine to below 0 ° C. in 160 ml of water.

The mixture is then stirred below OOC for 5 hours and then Left to stand at 0 ° C for 15 hours. The reaction mixture is then filtered and washed with ether. The filtrates and wash solutions are combined, and so is the solvent is distilled off under reduced pressure. There are 47.4 g of phenylacetaldehyde-N1-phthalimidoacetyl-N1- (p-chlorophenyl -) - hydrazone received as a syrup that slowly solidifies. After recrystallization from ethanol platelets are obtained which melt at 169.5 to 171.5 ° C. According to the procedure Phenylacetaldehyde-p-chlorophenylhydrazone used is produced as follows: One Suspension of 28.8 g of p-chlorophenylhydrazine in 150 ml of ethanol is mixed with 30 ml of acetic acid offset. Thereafter, the mixture is added dropwise with 27.5 g of phenylacetaldehyde 10 to 150C offset. The mixture is 1 hour at 10 to 15 0C and then Stirred for 15 minutes at 72 to 780C. The solvent is under reduced pressure distilled off and the residue with 500 ml of ether, 50 ml of 28% aqueous ammonia solution and then mixed with 100 ml of water. The ethereal solution is washed with water and then saturated with sodium chloride solution and dried over sodium sulfaf. The solvent is then distilled off. The oily residue is made from n-hexane recrystallized. Yield 45.7 g of phenylacetaldehyde-p-chlorophenylhydrazone from F. 76 to 79 0C. According to the method described above, the following compounds are produced: Phenylacetaldehyde-N1-phthalimidoacetyl-N1- (p-bromophenyl) -hydrazone, Phenylacetaldehyde-N1-phthalimide-acetyl-N1-phenyl-hydrazone, 1 1 phenylacetaldehyde phthalimidoacetyl-Nl- (p-nitrophenyl) hydrazone, phenylacetaldehyde-N1-phthalimidoacetyl-N1- (p-trifluoromethylphenyl ) -hyurazon, (o-chlorophenyl) -acetaldehyde-N1-phthalimidoacetyl-N1- (p-chlorophenyl) -l'drazn, (o-Chlorophenyl) acetaldehyde-N1-phthalimidoacetyl-N1- (p-nitrophenyl) 4ydrazone, (o-fluorophenyl) acetaldehyde-N1-phthalimidoacetyl-N1- (p-chlorophenyl) hydrazone and (p-chlorophenyl) acetaldehyde-N1-phthalimidoacetyl-N1- (p-chlorophenyl) hydrazone.

Example 2 A mixture of 0.5 g of phenylacetaldehyde-N - (phthalimidoacetyl) -N1- (p-chlorophenyl) hydrazone and 0.5 g of zinc chloride is heated to 21500 with stirring. After cooling it will 20 ml of water are added to the product. The mixture is heated to reflux.

The water-insoluble substances are filtered off and washed with water and dried. Yield 0.45 g of 1- (phthalimidoacetyl) -3-phenyl-5-chloroindole. yield 93.5% of theory. After recrystallization from ethanol, the light yellow ones melt Prisms at 232 to 2340 Example 3 A mixture of 15 g of phenylacetaldehyde-N1- (phthalimidoacetyl) -N1 - (p-chlorophenyl) hydrazone and 75 g of polyphosphoric acid are stirred for 10 minutes heated to 1800C. The reaction mixture is then cooled and poured into water. The crystals formed are filtered off, washed with water and dried. Yield 13.7 g of 1- (phthalimidoacetyl) -3-phenyl-5-chloroindole. Yield 95% of theory. After recrystallization from ethanol, the light yellow prisms melt at 232 bis 23400.

The following compounds are produced in a similar manner: l-phthalimidoacetyl-3-phenylindole, l-phthalimidoacetyl-3-phenyl-5-bromoindole, 1-phthalimidoacetyl-3-phenyl-5-nitroindole, l-Phthalimidoacetyl-3- (o-chlorophenyl ) -5-chloroindole, 1-phthalimidoacetyl-3- (o-chlorophenyl) -5-nitroindole, l-phthalimidoacetyl-3- ( o-fluorophenyl) -5-chloroindole and l-phthalimidoacetyl-3- (p-chlorophenyf3-5 example 4 A cooled solution of 15 g of 2-methyl-3-phenyl-5-chloroindole in dimethylformamide is mixed with 3.24 g of a 63% sodium hydride dispersion in mineral oil with cooling offset. The mixture is then stirred at -5 ° C. for 2 hours. After that, will the mixture with a solution of 22.4 g of phthalimidoacetyl chloride in 100ml toluene at -5 to from added. When the addition is complete, the mixture becomes 2 Stirred for hours at -1 ° C and then left to stand in the refrigerator for 15 hours. The precipitated crystals of 1- (phthalimidoacetyl) -2-methyl-3-phenyl-5-chloroindole are filtered off, washed with ether and dried. After recrystallization from Dimethylformamide melts the light yellow needles at 254 to 255 ° C. The filtrate is poured into water, and the precipitated crystals are filtered off, washed with ether and dried. Further amounts of the indole are obtained.

The 2-methyl-3-phenyl-5-chloroindole used according to the process is prepared as follows: A mixture of 25 g of p-chlorophenylhydrazine hydrochloride and 50 g of phenylacetone are heated to 80 ° C. for 2 hours and stirred.

The mixture is then filtered and the filtrate under reduced pressure Distilled pressure. The 2-methyl-3-phenyl-5-chloroindole of bp 170 bis is obtained 175 ° C / 0.5 to 0.6 torr; F. 78 to 830C. After recrystallization from aqueous ethanol the crystals melt at 84 to 8600.

In a similar way, the following connections can be made: 1- (Phthalimidoacetyl) -2-methyl-3-phenylindole, 1- (Phthalimidoacetyl) -2-methyl-3-phenyl-5-bromoindole, 1- (Phthalimidoacetyl) -2-methyl-3-phenyl-5-nitroindole, 1- (Phthalimidoacetyl) -2-methyl-3- (o-chlorophenyl) -5-chloroindole, 1- (Phthalimidoacetyl) -3- (o-chlorophenyl) -5-nitroindole, 1- (Phthalimidoacetyl) -2-methyl-3- (o-fluorophenyl) -5-chloroindole, 1- (Phthalimida'acetyl) -3- (p-chlorophenyl) -5-chloroindole, 1- (Phthalimidoacetyl) -3-phenyl-5-chloroindole, 1- (phthalimidoacetyl) -3-phenyl-5-nitroindole, 1- (phthalimidoacetyl) -3-phenyl-5-methoxyindole and 1- (α-phthalimidopropionyl) -3-phenyl-5-chloroindole.

Example 5 A suspension of 1.0 g of 1- (phthalimidoacetyl) -3-phenyl-5-chloroindole in 20 ml of acetic acid is ozonated with an ozone-oxygen mixture at 200C for 4 hours. The precipitated crystals are filtered off, washed with acetic acid and taken under dried under reduced pressure. Yield 0.6 g of the ozonide with a melting point of 168 to 1700C (decomposition). Another yield of 0.3 g is obtained from the filtrate after adding water.

0.9 g of the ozonide are in a mixture of 10 ml and chloroform 10 ml of ethanol suspended. The suspension is with 0.35 g of hydrazine hydrate and 3.5 mL of water are added and the mixture is stirred at room temperature for 2 hours. After that, the received Let the solution stand for 15 hours. The solvent is then reduced under Distilled off pressure and the residue mixed with ether and water and extracted. The aqueous layer is with Ether extracted. The ether solutions are combined and extracted with 5% hydrochloric acid. The combined hydrochloric acids Extracts are made alkaline with 10% sodium hydroxide solution and then with Ether extracted. The combined ether extracts are washed with saturated sodium chloride solution washed and then evaporated under reduced pressure. You get that 5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one from F.

202 to 205 ° C (decomposition).

Example 6 According to Example 5, but using 1- (phthalimidoacetyl) -3- (o-fluorophenyl) -5-chloroindole instead of l- (phthalimidoacetyl) -3-phenyl-5-chloroindole, one obtains 5- (o-fluorophenyl) -7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one, after recrystallization from ethanol at 204 to 20 @ ° C @ilzt.

Example 7 According to Example 5, but using 1- (phthalimidoacetyl) -3-phenyl-S-bromoindole instead of l- (phthalimidoacetyl -) - 3-phenyl-5-chibrindol, one obtains 5-phenyl-7-bromo-1,3-dihdr-i-1,4-benzodiazepin-2-one, which melts after recrystallization from acetone at 220 to 221 ° C.

The following compounds are prepared in a similar manner: 5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one, 5-phenyl-7-nitro-1,3-dihydro-2H-1,4-benzodiazepin-2-one, 5- (o-chlorophenyl) -7-chloro-1,3-dihydro-2H-1,4- benzodiazepin-2-one, 5- (p-chlorophenyl) -7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one and 5- (o-chlorophenyl) -7-nitro-1,3-dihydro-2H- 1,4-benzodiazepin-2-one.

Example 8 A suspension of 1.0 g of 1- (phthalimidoacetyl) -2-methyl-3-phenyl-5-chloroindole in 20 ml of acetic acid is treated with a mixture of ozone and oxygen for 2 hours Room temperature ozonated.

The mixture is stirred for a further 2 hours and then fil- ' trotted. The filtrate is poured into water, and the separated crystals are filtered off, washed with water and dried under reduced pressure. Yield 0.98 g of the ozonide with a melting point of 98 to 109 ° C (decomposition).

The ozonide is dissolved in a lPr mixture of 1.1 ml of chloroform and 1.1 ml Dissolved ethanol. 0.03 g of hydrazine hydrate and .g ml of water are added to the solution and left to stand at room temperature. Then the solvent is reduced Distilled pressure. The residue is mixed with 10 ml of water, 10 ml of ether and 0.2 ml 28% ammonia solution added and shaken.

The aqueous solution is extracted with ether. The combined ether extracts are extracted with 5 pointer hydrochloric acid, the combined hydrochloric acid extracts are Made alkaline with aqueous ammonia solution, extracted with ether and dried over sodium sulfate dried. The solvent is then distilled off. What remains is 5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiaze pin-2-on.

Claims (1)

Patent claim 1-Phthalimidoacylindole of the general formula (I) in which R1 is a hydrogen or halogen atom, a C1-4-alkyl radical, a nitro or trifluoromethyl group, R2 is a hydrogen or halogen atom and R3 and R4 are hydrogen atoms or C1-4-alkyl radicals.