BE724727A - - Google Patents

Description

  

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  "Derivatives of 1-alkyl-nitrobenzodiazepine"
Priority of nine patent applications filed in Japan on December 1, 1967, under N 77237/67, December 9, 1967, under N '79166/67, December 14, 1967, under N 80322/67, December 15 1967, under Nos. 80512/67 and 80513/67, on December 21, 1967, under N 82273/67, on December 28, 1967, under N 84961/67, on January 10, 1968, under N 1501/68, and on March 11, 1968, under N 16033/68.



   The present invention relates to a process for the preparation of benzodiazepine derivatives. More particularly, the invention relates to a process for the preparation of ben-

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 zodiazepine exerting: remarkable tranquilizing effects, muscle relaxation, spasmolytics and hypnotics, these derivatives corresponding to the formula
 EMI2.1
 wherein R represents a lower alkyl group of 1 to 4 carbon atoms and X represents a hydrogen or halogen atom.



   The benzodiazepine derivatives corresponding to formula (I) exert powerful tranquilizing, muscle relaxation, spasmolytic and hypnotic effects (see L.H. Sternbach et al: "J. Med. Chem.", 6, 261). Several processes are known for the preparation of these benzodiazepine derivatives, For example, a benzodiazepine derivative in low yield is obtained by reacting a 2-aminobenzophenone derivative with glycine hydrochloride or ethyl glycinate (see patent German No. 1,145,629), then by carrying out an alkylation (see LH Sternbach et al .: "J. Med. Chem." 6, 261).

   A benzodiazepine derivative is also prepared by treating a bromoacetamido-benzophenone derivative with ammonia and subjecting the resulting aminoacetamide derivative to cyclization (see German Patent No. 1,136,709), then to alkylation (see LH Sternbach). et al.: "J. Med.



    Chem. ", 6, 261; German Patent No. 1,136,709).



   In contrast to these methods, surprisingly, it has been found that a benzodiazepine derivative of formula (I) can be prepared smoothly and economically.

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 with high yield and high purity by reacting a 2-aminomethyl-indole derivative of formula
 EMI3.1
 wherein R and X have the same meanings as mentioned above or its salt with a suitable oxidizing agent. Heretofore, this method of transforming a compound with a pentagonal ring into a compound with a heptagonal ring by a ring expansion reaction has not yet been described or suggested in the literature. Therefore, the new method of the present invention is by no means obvious from the known methods and, moreover, it is very useful and unexpected.



   A new starting derivative of 2-amino-methylindole is easily prepared by reduction of an indole-2-carboxamide derivative or of an indole-2-carbonitrile derivative. The novel indole-2-carbonitrile derivative is prepared by dehydrating the indole-2-carboxamide derivative. The indole-2-carboxamide derivative is also a new compound which is prepared by amidation of indole-2-carboxylic acid derivatives in good yield. In addition, the indole'-2-carboxylic acid derivative is obtained, for example, by cyclization of a benzene-diazonium compound with an-benzyl-p-keto-acid ester derivative.



   All of these processes take place smoothly and give the desired products in high yields, so these processes are very useful in practice.



   An object of the present invention is to provide a new process for the preparation of the benzodiazepine derivative.

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 corresponding to formula (I).



   Another object of the present invention is to provide the novel indole derivative and the novel phenyl derivative. hydrazone, as well as the process for their preparation.



   Other objects of the present invention will emerge from the following description.



   In order to achieve these various objects, the present invention provides a process for preparing the benzodiazepine derivative corresponding to formula (I), this process consisting in reacting the 2-aminomethyl-indole derivative corresponding to formula ( II) or its salt with an oxidizing agent.



   The 2-aminomethyl-indole derivative of formula II, which is used in the present invention, is a new compound and is synthesized from a known compound.



   A synthetic scheme for the preparation of the benzodiazepine derivatives according to the present invention will be given below, but it is understood that this synthetic scheme is given merely by way of example and that the process of the present invention is not there not limited.

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 EMI5.1
 acid derivative compound of nitrophenyl-phenylpyruvic ester derivative nitrobenzene- of ss-keto-hydrazine diazonium acid
 EMI5.2
 

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 EMI6.1
 
In the above equations, R, R1 and R2 individually represent the same or different alkyl groups of 1 to 4 carbon atoms, R3 represents a hydrogen atom or the same alkyl group as in the case of R, R4 represents - feels a hydrogen atom or the same alkyl group as in the case of R1;

   X represents a hydrogen or halogen atom and Y represents a halogen atom.



   The process of the present invention will be illustrated in detail hereinafter in the order of the above-mentioned synthetic processes.

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  I. Preparation of the phenylhydrazone derivative (VII):
According to the present invention, the phenylhydrazone derivative (VII) is prepared by reacting the phenylhydrazine derivative (III) or its salt with the phenylpyruvic acid derivative (IV).



   Preferably, the reaction is carried out in the presence of an inert solvent, for example lower alkanols such as methanol, ethanol and the like, organic acids such as acetic acid and formic acid. The reaction is not particularly limited, but it is usually in the range between room temperature and the boiling point of the solvent employed. An acidic salt of nitrophenylhydrazine includes an inorganic acid salt such as a hydrochloride, hydrobromide or sulfate. Nitrophenylhydrazine (III) or its salt is used in an equimolar amount or more of the phenylpyruvic acid derivative.



   Among the phenylhydrazone (VII) derivatives obtained by the process of the present invention, there are the following compounds: p-nitrophenylhydrazone of methyl phenylpyruvate, p-nitrophenylhydrazone of ethyl phenylpyruvate, p-nitrophenylhydrazone of phenylpyruvate of tert-butyl, p-nitrophenylhydrazone from phenylpyruvic acid, m-nitrophenylhydrazone from phenylpyruvic acid, o-nitrophenylhydrazone from phenylpyruvic acid, N'-methyl-p-nitrophenylhydrazone from phenylpyruvic acid, (o-chlorophenyl) -pyruvic acid p-nitrophenylhydrazone, (o-fluorophenyl) pyruvic acid p-nitrophenylhydrazone,

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 (o-bromophenyl) pyruvic acid p-nitrophenylhydrazone,

   p-nitrophenylhydrazone from (p-chlorophenyl) pyruvic acid, p-nitrophenylhydrazone from (m-chlorophenyl) pyruvic acid, p-nitrophenylhydrazone from ethyl (o-chlorophenyl) pyruvate.



   Further, when the nitrobenzene-diazonium compound (V) is reacted with the keto-acid ester derivative (VI), the phenylhydrazone derivative of the formula is obtained.
 EMI8.1
 in which R1 and X have the same meanings as mentioned above.



   The phenylhydrazone derivative (VIIa) can be obtained by reacting the ester of the Ó-benzyl-ss-keto-acid derivative (VI) with the nitrobenzene-diazonium compound (V) in a suitable solvent, for example. 'water, methanol, ethanol or the like, in the presence of a base, for example caustic soda, caustic potash, potassium carbonate, sodium methoxide, sodium ethoxide, sodium acetate, potassium acetate or the like. The reaction takes place regularly.



   Due to the instability of the diazonium compound, the reaction can be carried out, preferably, below 10 C, more preferably below 5 C.



   Among the phenylhydrazone derivatives (VIIa), obtained by the process of the present invention, there are, for example, the following compounds:

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 methyl phenylpyruvate p-nitrophenylhydrazone, ethyl phenylpyruvate p-nitrophenylhydrazone, tert-butyl phenylpyruvate p-nitrophenylhydrazone, ethyl phenylpyruvate m-nitrophenylhydrazone, ethyl p-nitrophenyl hydrazone ethyl chlorophenyl) pyruvate, ethyl (o-bromophenyl) pyruvate p-nitrophenylhydrazone, ethyl (o-fluorophenyl) pyruvate p-nitrophenylhydrazone, ethyl (o-fluorophenyl) pyruvate p-nitrophenylhydrazone ethyl (m-chlorophenyl) pyruvate, ethyl (m-chlorophenyl) pyruvate p-nitrophenylhydrazone.



   Although two steric isomers of the phenylhydrazone derivative (VII) are observed, both isomers can be used for the next reaction step.



  II. Preparation of indole-2-carboxylic acid derivative (VIII):
The indole-2-carboxylic acid derivative (VIII) is prepared by heating the phenylhydrazone derivative (VII) with an acid, in a solvent.



   As solvents, lower alkanols such as methanol, ethanol, isopropanol and tert-butanol, aromatic solvents such as benzene, toluene, xylene, organic acids such as. formic acid and acetic acid or another organic solvent and an organic acid such as formic acid or acetic acid; an alcohol is particularly preferable for the reaction.



   As the acid, for example, a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and polyphosphoric acid is employed,

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 an organic acid such as formic acid and acetic acid or other acidic reagents, including Lewis acids such as zinc chloride, iron chloride, aluminum chloride and fluoride boron. The reaction is usually carried out at an elevated temperature.



   If, in the above case, a phenylhydrazone derivative of the formula is used
 EMI10.1
 in which R, R1 and X have the same meanings as those mentioned above, an indole-2-carboxylic acid derivative is obtained corresponding to the formula:
 EMI10.2
 in which R, R1 and X have the same meanings as those mentioned above. In addition, if a phenylhydrazone derivative of formula (VII) in which R3 R and R4. H (this phenylhydrazone derivative will be represented by formula (VII)), an indole-2-carboxylic acid derivative is obtained corresponding to the formula:
 EMI10.3
 in which R and X have the meanings mentioned above.

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   The indole-2-carboxylic acid derivative (VIII) can also be obtained directly by reacting the nitrophenylhydrazine (III) or its salt with the phenylpyruvic acid derivative (IV).



   The reaction can be carried out in a solvent, for example an alkanol such as methanol, ethanol, isopropanol and tert-butanol, an aromatic hydrocarbon such as benzene, toluene, xylene and the like, a organic acid such as formic acid and acetic acid and the like or still another inert organic solvent and the like, preferably in the presence of an acid catalyst, for example a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, polyphosphoric acid and the like, organic acid such as formic acid and acetic acid, Lewis acid such as zinc chloride, iron chloride, aluminum chloride, boron fluoride and the like are still a cation exchange resin.



   As the salt of the phenylhydrazine derivative (III), there may be employed, for example, an inorganic salt such as a hydrochloride, a hydrobromide or a sulfate or else an organic acid salt such as an acetate or an oxalate.



   The reaction is carried out under conditions analogous to those of the above preparation starting from the derivative of phenylhydrazone, to obtain a derivative of 2-carboxylic acid (VIII). However, when the reaction is carried out under mild conditions, the phenylhydrazone derivative (VII) is obtained. In this case, isolation of the compound (VII) is not necessarily required for this cyclization reaction.



   According to the present invention, among the derivatives

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 of indole-2-carboxylic acids (VIII), there are, for example, the following compounds: 5-nitro-3-phenyl-indole-2-carboxylic acid, 5-nitro-3-phenylindole-2 -methylcarboxylate, ethyl 5-nitro-3-phenylindole-2-carboxylate, tert-butyl 5-nitro-3-phenylindole-2-carboxylate, 6 (or 4) -nitro-3 -phenylindole-2-carboxylic acid, 7-nitro-3-phenylindole-2-carboxylic acid, 3- (o-chlorophenyl) -5-nitroindole-2-carboxylic acid, 3- (o-fluorophenyl ) -5-nitroindole-2-carboxylic,
 EMI12.1
 3- (o-bromophenyl) -5-nitroindole-2-carboxylic acid 3- (m-chlorophenyl) -5-nitroindole-2-carboxylic acid,
 EMI12.2
 3- (p-chlorophenyl) -S-nitroindole-2-carboxylic acid,

   1-methyl-5-nitro-3-phenylindole-2-carboxylic acid, 1-ethyl-5-nitro-3-phenylindole-2-carboxylic acid, 1-propyl-5-nitro-3- phenylindole-2-carboxylic acid, 3- (o-chlorophenyl) -1-nethyl-5-nitroindole-2-carboxylic acid, 3- (o-fluorophenyl) -l-methyl-5-nitroindole- 2-carboxylic.



   If, in the above case, a nitrophenylhydrazine derivative of formula
 EMI12.3
 in which R has the same meaning as mentioned above, as well as a phenylpyruvic acid derivative of -formula
 EMI12.4
 

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 in which X has the same meaning as that mentioned above, the indole-2-carboxylic acid derivative (VIIIb) is then obtained.



   As an alternative, one can obtain an indole-2-carboxylic acid derivative corresponding to the formula
 EMI13.1
 wherein R1 and X have the same meanings as mentioned above, by reacting the nitro-benzene-diazonium compound (V) with the P-keto-acid ester derivative (VI).



   When carrying out this process, the P-keto-acid ester derivative (VI) can be reacted with the nitrobenzene-diazonium compound (V) in the presence of a basic reagent such as sodium hydroxide, potassium hydroxide, sodium acetate, potassium acetate, sodium methoxide and sodium ethoxide in a suitable solvent such as water, methanol and ethanol so that the reaction proceeds easily. Due to the instability of the benzene diazonium compound, it is preferable to carry out the reaction below 10 C, more preferably below 5 C. Then, treatment of the reaction product with an acid gives rise to the formation. of the indole-2-carboxylic acid ester derivative of the formula (Ville). Preferably, however, the reaction product is isolated before the next step.

   Among the acids used in the process of the present invention, there are, for example, mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid,

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 phosphoric acid, polyphosphoric acid or the like, as well as other Lewis acids such as zinc chloride, ferrous chloride, aluminum chloride, stannous chloride, boron fluoride or the like.



   During this reaction, among the solvents, there are, for example, alkanols such as methanol, ethanol and isopropanol, aromatic hydrocarbons such as benzene, toluene and xylene, organic acids such as formic acid and acetic acid, as well as other organic solvents.



   According to the present invention, among the derivatives of indole-2-carboxylic acids (Ville), there are, for example, the following compounds: methyl 5-nitro-3-phenylindole-2-carboxylate, 5 ethyl -nitro-3-phenylindole-2-carboxylate, tert-butyl 5-nitro-3-phenylindole-2-carboxylate, ethyl 6 (or 4) -nitro-3-phenylindole-2-carboxylate , ethyl 7-nitro-3-phenylindole-2-carboxylate, 3- (o-chlorophenyl) -5-nitro-3-indole-2-carboxylate, 3- (o-bromophenyl) - Ethyl 5-nitro-3-indole-2-carboxylate, ethyl 3- (o-fluorophenyl) -5-nitroindole-2-carboxylate, 3- (m-chlorophenyl) -5-nitroindole-2- ethyl carboxylate, ethyl 3- (p-chlorophenyl) -5-nitroindole-2-carboxylate,
According to the method of the present invention,

   it is also possible to obtain an indole-2-carboxylic acid derivative
 EMI14.1
 in which R, R4 and X have the same meanings as

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 those mentioned above, by alkylating an indole-2-carboxylic acid derivative corresponding to the formula
 EMI15.1
 in which R4 and X have the same meanings as those mentioned above.



   This alkylation is carried out by treating an indole-2-carboxylic acid derivative of formula (VIIId) with an alkylating agent in the presence of an alkaline reagent. or after forming the metal salt with the alkaline reagent.



  Among the alkali reagents used in the process of the present invention are alkali metals, alkaline earth metals, alkali metal hydrides, alkaline earth metal hydrides, alkali metal hydroxides, metal hydroxides. alkaline earth metals, alkali metal amides and alkaline earth metal amides.



   The alkylation of an indole-2-carboxylic acid derivative of formula (VIIId) is carried out by treating it with the following compounds, for example an alkyl halide such as methyl iodide, d bromide ethyl, ethyl iodide and butyl bromide, an alkyl sulphate such as dimethyl sulphate and diethyl sulphate, an aromatic alkyl sulphonate such as paratoluene methyl sulphonate and a diazoalkane such as diazomethane.



   According to the present invention, among the derivatives of indole-2-carboxylic acids (Ville), there are, for example, the following compounds: ethyl 1-methyl-5-nitro-3-phenylindole-2-carboxylate,

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 EMI16.1
 methyl 1-methyl-5-nitro-3-phenylindole-2-carboxylate, ethyl 1-ethyl-5-nitro-3-phenylindole-2-darboxylate,
 EMI16.2
 ethyl 5-nitro-3-phenyl-1-propylindole-2.4carboxylate, 1-methyl-5-nitro-3-phenylindQle-2-carboxylic acid, 1-ethyl-5-nitro- 3-phenylindole-2-carboxylic acid, 1-methyl-6 (or 4) -nitro-3-phenylindole-2-carboxylic acid, 1-methyl-7-nitro-3-phenylindole-2-carboxylic acid, 3- (o-chlorophenyl) -1-methyl-5-nitroindole-2-carboxylic acid,
 EMI16.3
 3- (o-bromophenyl) -1-methyl-5-nitroindole-2-carboxyli acid.

   that, 3- (o-fluorophenyl) -1-methyl-S-nitroindole-2-carboxylic acid, 3- (m-chlorophenyl) -1-methyl-5-nitroindole-2-carboxy- acid lique,
 EMI16.4
 3- (P-chlorophenyl) -1-methyl-5-nitroindole-2-carboxylic acid.



   In addition, the indole-2-carboxylic acid derivative (VIIIb) can be obtained by the N-alkylation of an indole-2-carboxylic acid derivative of formula
 EMI16.5
 in which X has the meaning given above.



   According to the present invention, it is also possible to convert an indole-2-carboxylic acid derivative of the formula
 EMI16.6
 

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 in. in which R1, R3 and X have the same meanings as those mentioned above, to an indole-2-carboxylic acid derivative of the formula
 EMI17.1
 in which R3 and X have the same meanings as those mentioned above.



   The indole-2-carboxylic acid derivative corresponding to formula (VIIIf) is treated in water and / or in an alkanol such as methanol and ethanol, preferably in the presence of 'a hydrolyzing agent, to obtain the indole-2-carboxylic acid derivative corresponding to formula (VIIIg). Among the hydrolysing agents used in the present invention, there are, for example, mineral acids such as hydrochloric acid and sulfuric acid, hydroxides of alkali metals such as sodium hydroxide and potassium hydroxide. - sium, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkaline earth metal hydroxides, such as barium hydroxide and calcium hydroxide,

   as well as ammonium compounds such as ammonium hydroxide and the like. Alkali metal hydroxides or alkaline earth metal hydroxides are preferred. The reaction can be carried out even at room temperature, preferably at elevated temperature.



   In addition, the indole-2-carboxylic acid ester derivative (VIIIf) can also be hydrolyzed to an indole-2-carboxylic acid derivative (VIIIg) by treating it in an organic acid such as acetic acid. and propionic acid.,

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 preferably in the presence of a mineral acid.



   As an alternative, when is a tert-butyl group, the indole-2-carboxylic acid derivative (VIIIf) can also be converted into the desired carboxylic acid (VIIIg) by heating it with a mineral acid or toluene acid. sulfonic.



   According to the present invention, among the derivatives of indole-2-carboxylic acids (VIIIg), there are, for example, the following compounds: 5-nitro-3-phenylindole-2-carboxylic acid, 6-acid (or 4) -nitro-phenylindole-2-oarboxylic acid, 7-nitro-3-phenylindole-2-carboxylic acid,
 EMI18.1
 3- (o-ohlorophenyl) -5-nitroindole-2-carboxylic acid, 3- (o-chlorophenyl) -1-methyl-5-nitroindole-2-oarboxylic acid, 3- ( o-bromophenyl) -5-nitroindole-2-carboxylic acid, 3- (o-fluorophenyl) -5-nitroindole-2-carboxylic acid,
 EMI18.2
 3- (o-fluorophenyl) -1-methyl7, -5-nitro3ndole-2-.carbolic acid,
 EMI18.3
 3- (m-chlorophenyl) -5-nitroindol-2-carboxylic acid and 3- (p-chlorophenyl) - 5-nitroindole-2-carboxylic acid, l-methyl-5-nitro-3 -phenylindole-2-carboxylic acid,

     1-ethyl-5-nitro-3-phenylindole-2-carboxylic acid,
 EMI18.4
 1-propyl-5-nitro-3 phenylindole-2-carboxylic acid.



   Further, according to the process of the present invention, the indole-2-carboxylic acid derivative (Ville) can be converted into an indole-2-carboxylic acid derivative (VIIIb).



   According to the present invention, among the derivatives of indole-2-carboxylic acids (VIIIb), there are, for example, the following compounds:
 EMI18.5
 1-methyl-5-nitro-3-phenylindole-2-carboxylic acid, 1-ethyl-5-nitro-3-phenylindole-2-carboxylic acid,

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 1-methyl-6 (or 4) -nitro-3-phenylindole-2-carboxylic acid,
 EMI19.1
 1-methyl -? - nitro-3-phenylindole-2-carboxylic acid, l-propyl-5-nitro-3-phenylindole-2-carboxylic acid, 3- (o-chlorophenyl) -1 acid -methyl-5-nitroindole-2-crxboxy-. lic, 3- (o-bromophenyl) -1-methyl-5-nitroindole-2-oarboxyli- acid, µ- (o-fluorophenyl) -1-mebhyl-5-nitroindole-2-oanboxyli- acid that, µ- (m-chlonophenyl) -1-nethyl-5-nitnoindole-2-carboxylic acid, 3- (p-ehlonophenyl) -1-methyl-5-nitnoindole-2-oanboxyli- acid than.



  III. Preparation of indole-2-oarboxamide derivative (IX)
According to the process of the present invention, the indole-2-arboxamide derivative (IX) is prepared by reacting the indole-2-carboxylic acid derivative (VIIIg) or its reactive derivative with ammonia.



   The reactive derivative mentioned above is an acid chloride, an acid anhydride or an ester.



   Acid chloride is an indole-2-carboxylic halide derivative of the formula
 EMI19.2
 in which R3 and X have the same meanings as those mentioned above and in which -Hal represents a halogen atom; this chloride is obtained by reacting an indole-2-carboxylic acid derivative (VIIIg) with a halogenating agent in the presence or absence of a solvent.



   When this process is carried out, the derivative is treated

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 of indole-2-carboxylic acid of formula (VIIIg) with a halogenating agent in the absence of a solvent or in an inert solvent such as benzene, toluene, ether, chloroform, chloride of methylene and carbon tetrachloride. Among the halogenating agents used in the process of the present invention are, for example, thionyl chloride, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus oxychloride. phosphorus and phosgene.

   In this case, the reaction can be accelerated by adding a basic substance such as dimethylformamide. In addition, in this process, as the raw material, both a free carboxylic acid and the metal salt can be employed.



   The desired product is obtained by removing the solvent and excess halogenating agent, optionally by extraction with an inert solvent. Isolation or purification of the indole-2-carboxylic halide derivative is not always necessary to convert it to the indole-2-carboxamide derivative.



   The indole-2-carboxylic halide derivative of formula (VIIIh), in which R3 has the same meaning as R, is called "indole-2-carboxylic halide derivative" (VIIIi).



   Following the above process, the chloride, bromide or the like are obtained.



   According to the present invention, among the derivatives of indole-2-carboxylic halides (VIIIh), there are, for example, the following compounds: 5-nitro-3-phenylindole-2-carboxylic chloride, 6 (or 4 ) -nitro-3-phenylindole-2-carboxylic,

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 1-methyl-5-nitro-3-phenylindole-2-carboxylic chloride,
 EMI21.1
 1-ethyl-5-nitro-3-phenylindole-2-carboxylic chloride, 1-propyl-5-nitro-3-phenylindole-2-carboxylic chloride, 7-nitro-3-phenylindole-2-carboxylic chloride, 5-nitro-3-phenylindole-2-carboxylic bromide, 3- (o-chlorophenyl) -5-nitroindole-2-carboxylic chloride, 3- (o-bromophenyl) -S-nitroindole-2-carboxylic chloride,

     3- (o-fluorophenyl) -5-nitroindole-2-carboxylic chloride, 3- (p-chlorophenyl) -5-nitroindole-2-carboxylic chloride 3- (m-chlorophenyl) -5-nitroindole-2 -carboxylic.



   The esters of the indole-2-carboxylic acid derivative (VIIIg) used in the present invention include cyanomethyl ester and paranitrophenyl ester.



   Acid anhydrides such as a mixed anhydride of the type described in "Organic Reactions" volume 12, page 157 (1962) can be employed.



   Amidation of the indole-2-carboxylic acid derivative (VIIIg) or its reactive derivative is carried out by reacting it with ammonia.



   The amidation is advantageously carried out in the presence of a solvent. Among the solvents which can be used in the process of the present invention, there is, for example, an alcohol such as methanol or ethanol or else an organic solvent such as ether, acetone, benzene. , toluene, xylene, chlorobenzene or chloroform or even liquid ammonia.



   In the reaction of the present invention, ammonia can be used by introducing gaseous ammonia into a reaction mixture or by adding alcoholic ammonia (e.g., methanolic ammonia, ammonia).

 <Desc / Clms Page number 22>

 than ethanolic) or aqueous ammonia in the reaction mixture.



   Since the reaction usually takes place at room temperature, heating or cooling is not always necessary. However, the reaction can optionally be controlled by heating or cooling.



   According to the present invention, among the indole-2-carboxamide (IX) derivatives, there are, for example, the following compounds: 5-nitro-3-phenylindole-2-carboxamide, 6 (or 4 ) -nitro-3-phenylindole-2-carboxamide, 7-nitroindole-3-phenylindole-2-carboxamide, 1-methyl-5-nitro-3-phenylindole-2-carboxamide, 1-ethyl-5-nitro -3-phenylindole-2-carboxamide, 1-propyl-5-nitro-3-phenylindole-2-carboxamide,
 EMI22.1
 3- (o-chlorophenyl) -5-nitroindole-2-carboxamide, 3- (o-chlorophenyl) -1-methyl-5-nitroindole..2-ca.cboxamide, 3- (o-bromophenyl) - 5-nitroindole-2-carboxamide, 3- (o-fluorophenyl) -5-nitroindole-2-carboxamide, 3- (o-fluorophenyl) -l-methyl-5-nitroindole-2-carboxamide, 3- ( p-chlorophenyl) -S-nitroindole-2-carboxamide, 3- (m-chlorophenyl) -5-nitroindole-2-carboxamide,
Furthermore,

   according to the present invention, an indole-2-carboxamide of formula
 EMI22.2
 in which R and X have the same meanings as those mentioned above, by alkylating an indole-2-carboxamide derivative of the formula

 <Desc / Clms Page number 23>

 
 EMI23.1
 in which X has the same meaning as mentioned above. This N-alkylation can be carried out in a manner analogous to that described for the above-mentioned indole-2-carboxylic acid derivative (VIIId).



   According to the present invention, among the derivatives of indole-2-carboxamides (IXb), there are, for example, the following compounds:
 EMI23.2
 1-methyl-5-nitro-3-phenylindole-2-carboxamide, 1-ethyl-5-nitro-3-nhcnyl.indole-2-carboxamide, 1-propyl-5-nitro-3-phenylindole-2 -carboxamide, 3- (o-fluorphenyl) -l-methyl-5-nitroindole-2-carboxamide, 3- (o-chlorophenyl) -1-methyl-5-nitroindole-2-carboxamide, 3- (p -chlorophenyl) -1-methyl-5-nitroindole-2-carboxamide.



  IV. Preparation of the indole-2-carbonitrile derivative (X):
According to the present invention, a novel indole-2-carbonitrile derivative (X) is prepared by dehydrating an indole-2-carboxamide derivative (IX). The dehydration of indole-2-carboxamide (IX) is carried out by heating it in the presence of a dehydrating agent. Among the dehydrating agents used in the process of the present invention, there is a phosphorus halide such as phosphorus oxychloride, phosphorus trichloride or phosphorus pentachloride, or an acid chloride. such as p-toluenesulfonyl chloride, methyl-sulfonyl chloride, acetyl chloride, thionyl chloride, benzoyl chloride or carbobenzyl oxychloride. The reaction is carried out in the presence or absence of a solvent.

   The dehydrating agent

 <Desc / Clms Page number 24>

 itself can be used as a solvent. When the reaction is complete, the desired product is obtained from the reaction mixture.



   The following indole-2-carbonitrile (X) derivatives are obtained:
 EMI24.1
 1-methyl-5-nitro-3-phenylindo.e-.2-carbonitrile, 1-ethyl-5-nitro-3-phenylindole-2-carbonitrile,
 EMI24.2
 1-propyl, -5-nitro.-3-phenylindole-2-carbonitrile, 5-nitro-3-phenylindole-2-carbonitrile, 6 (or 4) -nitro-3-phenylindole-2-carbonitrile, 7-nitro-3-phenylindole-2-carbonitrile,
 EMI24.3
 3- (o-chlorophenyl) -5-nitroindole-2-carbonitrile, 3- (o-ohlorophenyl) -1-methyl-5-nitroindole-2-carbonitrile, 3- (o-bromophenyl) -5-nitroindole -2-carbonitrile,
 EMI24.4
 3- (o-fluorophenyl) -5-nitroindole-S-carbonitile, 3- (o-fluorophenyl) -l-methyl-5-nitroindol-2-carbonitrile, 3- (p-chlorophenyl) -1-methyl -5-nitroindole-2-carbonitrile, 3- (m-chlorophenyl)

  -5-nitroindole-2-carbonitrile.



   According to the process of the present invention, an indole-2-carbonitrile derivative of formula
 EMI24.5
 in which R and X have the same meanings as those mentioned above, by the N-alkylation of an indole-2-carbonitrile derivative corresponding to the formula
 EMI24.6
 in which X has the same meaning as mentioned above. This N-alkylation is carried out in a manner

 <Desc / Clms Page number 25>

 analogous to that described for the aforementioned indole-2-carboxylic acid derivative (VIIId).



  According to the present invention, among the indole-2-carbonitrile (Xb) derivatives, there are, for example, the following compounds:
 EMI25.1
 1-methyl-5-nitro-3-phenylindole-2-carbonitrile, 1-ethyl-5-nitro-3-phenylindole-2-carbonitrile, 1-propyl-5-nitro-3-phenylindole-2-carbonitrile ,
 EMI25.2
 3- (o-chlorophenyl) -1-methyl-5-nitroindole-2-carbonitri7.e '3- (o-fluorophenyl) -1-methyl-5-nitroindole-2-carbonitri..e' 3- (p-chlorophenyl) -l-methyl-5-nitroindole-2-carbonitrilee l-methyl-6 (or 4) -nitro-3-phenylindole-2-carbonitrile,
 EMI25.3
 1-methyl-7-nitro-3-pbenylindole-2-carbonitrile.



  V. Preparation of the derivative of 2-aminomethylindole (II):
According to the present invention, a new derivative of 2-aminomethylindole (II) or its salt is prepared by reducing the derivative of indole-2-carbonitrile (Xb). The reduction is carried out by reacting the indole-2-carbonitrile derivative (Xb) with a suitable reducing agent in a solvent.



   The reducing agent can be used, which can selectively reduce the cyano group to an aminomethyl group without altering the nitro group and / or the halogen atom.



   Among the reducing agents which can be used in the present invention, there are, for example, boron hydrides such as diborane, aluminum borohydride, calcium borohydride and sodium trimethoxy borohydride, as well as sodium borohydrides which have incorporated metal halides such as aluminum halides. Diborane is particularly preferred. When diborane is used as a reducing agent,

 <Desc / Clms Page number 26>

 diborane gas in the reaction mixture or diborane is formed in the reaction system. For example, the reduction is carried out using diborane formed from sodium borohydride and boron trifluoride or mercury chloride in the reaction system.

   When reducing with diborane, preferably, a solvent such as ether, tetrahydrofuran, dioxane, dyglyme or the like can be employed. As a rule, the reaction is carried out at a temperature between room temperature and the boiling point of the solvent employed. When the reaction is complete, the excess reducing agent is decomposed, for example, by adding water or an acid such as hydrochloric acid. The 2-aminomethylindole derivative (II) can be obtained in the form of the corresponding salt by treatment with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or acid. phosphoric acid, or an organic acid such as acetic acid or formic acid.

   The 2-aminomethylindole (II) derivatives or their salts exert hypoglycemic activity.



   According to the present invention, among the 2-aminomethylindole derivatives (II), there are, for example, the following compounds: 2-aminomethyl-1-ethyl-5-nitro-3-phenylindole, 2-aminomethyl-1 -methyl-5-nitro-3-phenylindole,
 EMI26.1
 2-aminomthyl-'1-propyl-5-nitro-3-phenylindole, 2-aminomethyl-3- (o-chlorophenyl) -1-màthyi-5-nitroindole, 2-aminomethyl-3- (o-fluorophenyl ) -1-methyl-5-nitroindolet 2-aminomethyl-3- (o-bromophenyl) -1-methyl-5-nitroindole, 2-aminomethyl-3- (p-chlorophnyl) -1-mc: thyl-5 -nitroindole, 2-aminomethyl-1-methyl-6 (or 4) -nitro-3-phenylindole,

 <Desc / Clms Page number 27>

 
 EMI27.1
 2-aminomethyl-1-methyl-7-nitro-3-phenylindole, as well as their hydrochlorides, hydrobromides, sulphates, phosphates and acetates.



  VI. Preparation of the benzodiazepine derivative (I):
According to the process of the present invention, the benzodiazepine derivative (I) is prepared by reacting the 2-aminomethylindole derivative (II) or its salt with an oxidizing agent.



   When carrying out the process for preparing the benzodiazepine derivatives according to the present invention, a 2-aminomethylindole derivative corresponding to formula (II) or its salt is reacted with a suitable oxidizing agent, for example ozone, hydrogen peroxide, a peracid (eg, performic acid, peractic acid and perbenzoic acid), chromic acid, potassium permanganate or the like. However, the oxidizing agent used in the process of the invention is not however limited to those mentioned above by way of example. As a rule, the reaction is easily carried out at room temperature. Sometimes it is found that a higher or lower temperature is more satisfactory.

   Chromium trioxide is preferred as an oxidizing agent. Preferably, the reaction can be carried out in the presence of a solvent. The solvent is selected from water, methanol, ethanol, acetone, carbon tetrachloride, acetic acid, sulfuric acid or other strong solvents. The oxidizing agent is used in a stoichiometric amount or more.



   When the oxidation is carried out with chromium trioxide in acetic acid, it is preferable to use twice the molar amount or more of chromium trioxide at room temperature. We dissolve a derivative of

 <Desc / Clms Page number 28>

   2-Aminomethylindole or its salt such as hydrochloride, hydrobromide, sulfate, nitrate, acetate and the like or it is suspended in a solvent and, while stirring, an oxidizing agent is added thereto. Typically, the reaction is completed within 24 hours. Likewise, the crude benzodiazepine derivative can be separated from the reaction mixture.



  The product can optionally be purified by recrystallization from a suitable solvent such as ethanol, isopropanol and the like.



   According to the present invention, the benzodiazepine derivative (I) is treated with an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid, or else; an organic acid such as maleic acid, fumaric acid, succinic acid, formic acid or acetic acid, so as to obtain its salt.



   According to the present invention, the following benzodiazepine derivatives are obtained: 1-methyl-5-phenyl-7-nitro-1,3-dihydro-2H-1,4-benzodiazepine-2-one,
 EMI28.1
 1-ethyl-S-phenyl-7-nitro-13-dihydro-2H-14-benzodiazepine-2-one, 2-methyl-S- (o-chlorophenyl) -7-nitro3-.dihydro-2H-14 - benzodiazepine-2-one, T.-methyl-5- (o-fluorophenyl) -7-nitrol, 3-dihydro-2H-l, 4-benzodiazepine-2-one, 1-propyl-5-phen- * 1-7-nitro-113-dihydro-2H-1,4-benzodiazepine-2-one.



   The present invention will be illustrated below in more detail with reference to examples, which however in no way limit the scope of the invention.

 <Desc / Clms Page number 29>

 



  Example 1
To an ice-cooled solution consisting of 150 g of ethyl α-benzylacetoacetate in 700 ml of ethanol is added, in portions, 236 ml of an aqueous solution of potassium hydroxide to 50%, while cooling, then 1390 ml of ice-cold water are added to the mixture. % to this mixture, a cold solution of a diazonium salt, prepared from 96 g of p-nitro-aniline, 278 ml of concentrated hydrochloric acid, 278 ml of water and a solution is added dropwise. of 48 g of sodium nitrite in 140 ml of water. After addition, the reaction mixture is stirred for 10 minutes while cooling and extracted with ether.

   The ether layer was dried over sodium sulfate, then the ether was evaporated to give 216 g (96.6%) of ethyl phenylpyruvate p-nitrophenylhydrazone, as an oil, which partially solidified. when left to stand overnight. The solid is recrystallized from ethanol to give the Ó isomer with a melting point of 110-114 C.



  IR spectrum cm-1 :) N-H 3330 (in paraffin); C-O 1729 (in paraffin).



  Analysis for C17H17O4N3 Calculated t C 62.38, H 5.24, N 12.83% Found t C 62.35, H 5.15, N 12.72%
To a solution of 111.1 g of this crude oily p-nitrophenylhydra-zone of ethyl phenylpyruvate in 400 ml of ethanol is introduced dry hydrochloric acid gas for 40 minutes, while raising the temperature to 64 ° C. The mixture was cooled and filtered to obtain 49.8 g of the P-isomer of ethyl phenylpyruvate p-nitrophenylhydrazone with a melting point of 121-124 C. By recrystallization.

 <Desc / Clms Page number 30>

 Satation in ethanol gives the product with a melting point of 125.5 - 129.5 C, IR spectrum cm-1: N-H 3220 (in paraffin); C-O 1694 (in paraffin).



  Analysis for C17H17O4N3 Caclulate: C 62.38, H 5.24, N 12.83 Found: C 62.44, H 4.93, N 12.64%.



   In the same way, the following compounds are prepared: p-nitrophenylhydrazone of methyl phenylpyruvate, p-nitrophenylhydrazone of tert-butyl phenylpyruvate, m-nitrophenylhydrazone of ethyl phenylpyruvate, p-nitrophdnylhydrazone of (o ethyl chlorophenyl) pyruvate, ethyl (o-bromophenyl) pyruvate p-nitrophényhydrazone, ethyl (o-fluorophenyl) pyruvate p-nitrophenylhydrazone,
 EMI30.1
 ethyl (p-chlorophenyl) pyruvate p-nitrophenyihydrazone, ethyl (m-chlorophlnyl) pyruvate p-nitrophonyihydrazone.



  Example 2
To a solution of 22.5 g of phenyl-pyruvic acid in 500 ml of ethanol, 21 g of p-nitrophenylhydrazine is added and the mixture is heated under reflux for 30 minutes., When the reaction is complete, the mixture is heated. eliminates the solvent under reduced pressure, to quantitatively obtain the p-nitrophenylhydra-zone of phenylpyruvic acid in the form of the mixture of the form ce and the form ss.



  Example 3
To a solution of 22.5 g of phenylpyruvic acid in 500 ml of ethanol, 21 g of p-nitrophenylhydrazine is added and the mixture is heated under reflux for 30 minutes. We concentrate

 <Desc / Clms Page number 31>

 be the mixture obtained, then it is cooled. The precipitate was collected by filtration to obtain 12 g of the p-nitrophenylhydrazone form of phenylpyruvic acid. Recrystallization from ethanol gives fine pale yellow needles with a melting point of 191-192 C (decomposition).



  IR spectrum cm-1: N-H 3260 (in paraffin)
C-O 1669 (in paraffin) UV spectrum: # EtoH: 382 m (¼ 31.100) max
The filtrate was further concentrated to obtain 28 g of the form (3 of p-nitrophenylhydrazone of phenyl-pyruvic acid mp 177 - 179 ° C. by recrystallization from benzene to obtain fines. yellow needles with a melting point of 185 - 186 C (decomposition).



  IR spectrum cm-1: N-H 3310 (in paraffin)
C-O 1714 (in paraffin) UV spectrum: max: 372 m (28,800)
In the same way, the following compounds are prepared: p-nitrophenylhydrazone of methyl phenylpyruvate, p-nitrophenylhydrazone of tcrt-butyl phenylpyruvate, p-nitrophenylhydrazone of ethyl phenylpyruvate, m-nitrophenylhydrazone of phenylpyruvic acid, o-nitrophenylhydrazone from phenylpyruvic acid, N'-methyl-p-nitrophenylhydrazone from phenylpyruvic acid, p-nitrophenylhydrazone from (o-chlorophenyl) pyruvic acid, p-nitrophenylhydrazone from ( o-bromophenyl) pyruvic,

     (o-fluorophenyl) pyruvic acid p-nitrophenylhydrazone, (p-chlorophenyl) pyruvic acid p-nitrophenylhydrazone, (m-chlorophenyl) pyruvic acid p-nitrophenylhydrazone.

 <Desc / Clms Page number 32>

 



  Example 4
For 4 hours, a suspension of 1 g of the ss isomer of p-nitrophenylhydrazone of ethyl phenylpyruvate in 40 ml of 50% formic acid is heated under reflux. The solvent was removed under reduced pressure and the residue washed in a small amount of ethanol to give 0.75 g of ethyl 5-nitro-3-phenylindole-2-carboxylate with a melting point of 235. - 237 C (decomposition).



  Example 5
For 2 hours, a mixture of 32.7 g of p-nitrophenylhydrazone of ethyl phenylpyruvate, 200 ml of acetic acid and 200 ml of concentrated hydrochloric acid is heated under reflux. After cooling, the solid was collected by filtration, washed with water to obtain 23.8 g of ethyl 5-nitro-3-phenylindole-2-carboxylate.



  Example 6
For 4 hours, a suspension of 40 g of p-nitrophenylhydrazone of phenylpyruvic acid in 1.5 liters of 50% formic acid is heated under reflux. The solvent was removed under reduced pressure and the residue washed with ethanol to give 37 g of 5-nitro-3-phenylindole-2-carboxylic acid. Recrystallization from ethanol gives orange-yellow crystals with a melting point of 299 C (decomposition).



   In the same way, the following compounds are prepared: methyl 5-nitro-3-phenylindole-2-carboxylate, tert-butyl 5-nitro-3-phenylindole-2-carboxylate, 6 (or 4) - ethyl nitro-3-phenylindole-2-carboxylate, 7-nitro-3-phenylindole-2-carboxylic acid,
 EMI32.1
 3- (o-chlorophenyl) -5-nitroindole-2-canboxylic acid,

 <Desc / Clms Page number 33>

 3- (o-bromophenyl) -5-nitroindole-2-carboxylic acid, 3- (o-fluorophenyl) -5-nitroindole-2-carboxylic acid, 3- (p-chlorophenyl) -5 -nitroindole-2-carboxylic acid,
 EMI33.1
 3 '- (m-chlorophenyl) -5-nitroindole-2-carboxylic acid.



    Example?
A mixture of 7.1 g of p-nitroaniline, 20.9 g of concentrated hydrochloric acid and 20 ml of water in solution is heated, then it is cooled to 0 C. To the mixture is added, dropwise. drop, a solution of 3.7 g of sodium nitrite in 7 ml of water at a temperature below 0 ° C. and the mixture is stirred for 10 minutes. To the mixture was added 11.7 g of sodium acetate and the mixture was stirred for 30 minutes below 5 C. The resulting mixture was added dropwise to an ice-cooled solution of 11 g of a-. ethyl benzylacetoacetate and 14.7 g of anhydrous potassium acetate in methanol, while stirring, below, 3 C; stirring is continued for two additional hours below 10 C.

   The reaction mixture is extracted with 200 ml of ether. The ether layer is washed with water, dried over sodium sultate and evaporated to give an oil.



   To the oily residue, 50 ml of isopropyl alcohol and 50 ml of concentrated hydrochloric acid are added and the mixture is refluxed for 5 hours. After cooling, the precipitate was collected by filtration, washed with water and dried to obtain 8.8 g of ethyl 5-nitro-3-phenyl-indole-2-carboxylate.



  Example 8
A mixture of 7.1 g of p-nitroaniline, 20.9 g of concentrated hydrochloric acid and 20 ml of water is heated in

 <Desc / Clms Page number 34>

 solution, then cooled to 0 C. The mixture is subjected to diazotization by adding dropwise a solution of 3.7 g of sodium nitrite in 7 ml of water below 0 C.



  To the mixture was added 11.7 g of sodium acetate and the mixture was stirred for 30 minutes below 5 C. The resulting mixture was added dropwise to an ice-cooled solution of 11 g of Ó-. ethyl benzylacetoacetate and 14.7 g of anhydrous potassium acetate in methanol below 3 C, while stirring. The reaction mixture is stirred for one hour below 10 ° C. and heated under reflux for 4 hours. After cooling, the solid is separated and triturated with methanol and water to obtain ethyl phenylpyruvate p-nitrophenylhydrazone (14.5 g) with a melting point of 108 - 117 C,
This hydrazone is heated with 45 ml of isopropyl alcohol and 45 ml of concentrated sulfuric acid. After heating under reflux for 5 hours, the reaction mixture is cooled.

   The solid was collected by filtration, washed with water and dried to obtain 10.5 g of ethyl 5-nitro-3-phenylindole-2-carboxylate with a melting point of 218 C.



   Using the process of Examples 7 and 8, the following compounds were prepared in the same manner, methyl 5-nitro-3-phenylindole-2-carboxylate, tert-5-nitro-3-phenylindole-2-carboxylate. -butyl, ethyl 6 (or 4) -nitro-3-phenylindole-2-carboxylate, ethyl 7-nitro-3-phenylindole-2-carboxylate, 3- (o-chlorophenyl) -5- ethyl nitroindole-2-carboxylate, ethyl 3- (o-bromophenyl) -5-nitroindole-2-carboxylate,
 EMI34.1
 ethyl 3- (o-fluorophenyl) -5-nitroindole-2-carboxylate,

 <Desc / Clms Page number 35>

 ethyl 3- (m-chlorophenyl) -5-nitroindole-2-carboxylate, ethyl 3- (p-chlorophenyl) -S-nitroindole-2-carboxylate,
Example 9
Has a solution of 22.5 g of phenylpyruvic acid in
500 ml of ethanol,

     21 g of p-nitrophenylhydazine are added. The mixture is heated under reflux for 3.0 minutes and the solvent evaporated. To the residue, 1.5 liters of 50% aqueous formic acid are added and the mixture is heated under reflux for 4 hours. The solvent is removed under reduced pressure to obtain a residue which is washed with ethanol to obtain
 EMI35.1
 n qUéuit1tt :: 1.vment of rr, rttra.3pha'yindQe ¯ carboxylic acid, with a melting point of 297 C (decomposition).



  Recrystallization from ethanol gives yellow-orange crystals with a melting point of 299 ° C (decomposition).



  Analysis for C15H10O4N2 Calculated: C 63.83, H 3.57, N 9.92% Found: C 63.40, H 3.51, N 10.02 Example 10
For two hours, a mixture of 25 g of phenylpyruvic acid, 23 g of p-nitro-phenylhydrazine, 480 ml of acetic acid and 450 ml of concentrated hydrochloric acid is heated. The reaction mixture is cooled and poured into ice water. The precipitate was collected by filtration, washed with water and dried to obtain 40 g of 5-nitro-3-phenylindole-2-carboxylic acid. A sample is recrystallized from ethanol to obtain crystals with a melting point of 299 ° C (decomposition).



  Example 11
Has a solution of 112.6 g of p-nitrophenylhydrazine

 <Desc / Clms Page number 36>

 and 119.2 g of phenylpyruvic acid in 2 liters of acetic acid, 2 liters of concentrated hydrochloric acid are added, while stirring. The mixture is heated under reflux for one hour, then cooled. The precipitate is collected by filtration, washed with water and dried to give 168.2 g of 5-nitro-3-phenylindole-2-carboxylic acid with a melting point of 287. 'C (decomposition).



   Using the process of Examples 9 to 11, the following compounds were prepared in the same manner!
 EMI36.1
 eze 5-n.txc -... nylindcle - methyl ar3rxe *, '1-methy3 -nit, ro-3phenyllndle ... methyl carkoxylate,
 EMI36.2
 '' tert-butyl 5-nitro-3-phenylindole-2-earboxylate, 6 (or 4) -nitro-3-phenylindole-2-carboxylic acid, '' 7-nitro-3-phenylindole-2 -carboxylic, 3- (o-chlorophenyl) -5-nitroindole-2-carboxylic acid,
 EMI36.3
 3- (o-chlorophenyl) -1-metyl-5-nitroindole-2-carboxylic acid, 3- (o-bromophenyl) -5-nitroindole-2-carboxylic acid, 3- (o-fluorophenyl) -5-nitroindole-2-carboxylic acid, 3- (o-fluorophenyl) -1-methyl-5-nitroindole-2-carboxylic acid, 3- (m-chlorophenyl) acid

  -5-nitroindole-2-carboxylic acid, 3- (p-chlorophenyl) -5-nitroindole-2-carboxylic acid, 1-ethyl-5-nitro-3-phenylindole-2-carboxylic acid, 1-methyl-5-nitro-3-phenylindole-2-carboxylic acid.



  Example 12
To a solution of 2.7 g of potassium hydroxide in 50 ml of isopropyl alcohol and 1 ml of water, 6.2 g of ethyl 5-nitro-3-phenylindole-2-carboxylate is added and one adds heated. the mixture at reflux for 45 hours. We concentrate the mixture

 <Desc / Clms Page number 37>

 and the residue is dissolved in water. The cooled solution is acidified with concentrated hydrochloric acid while cooling. By filtration, the precipitate formed is collected, washed well with water and dried to obtain 5.5 g of 5-nitro-3-phenylindole-2-carboxylic acid with a melting point. of 287 C (decomposition).



   In the same way, the following compounds are prepared: 6 (or 4) -nitro-phenylindole-2-carboxylic acid, 7-nitro-3-phenylindole-2-carboxylic acid, 3- (o -chlorophenyl) -S-nitroindole-2-carboxylic,
 EMI37.1
 3- (o-chlurophenyl) -l-methyl-5-nitroindole-2-carboxylic acid, 3- (o-bromophenyl) -5-nitroindole-2-carboxylic acid,
 EMI37.2
 3- (o-fluorophenyl) -5-nitroindole-2-carboxylic acid, 3- (o-fluorophenyl) -l-methyl-5-nitroindole-2-carboxylic acid, 3- ( m-chlorophenyl) -5-nitroindole-2-carboxylic acid, 3- (p-chlorophenyl) -5-nitroindole-2-carboxylic acid, l-methyl-5-nitro-3-phenylindole-2-carboxylic acid , 1-ethyl-5-nitro-3-phenylindole-2-carboxylic acid.



  Example 13
Is heated, in solution, a mixture of 28.2 g of 5-nitro-3-phenylindole-2-carboxylic acid, 150 ml of acetone and 45 g of an aqueous solution of potassium hydroxide at 50 %. To the solution was added 25.2 g of dimethyl sulfate dropwise while stirring and the mixture was heated under reflux for 1 hour. When the reaction is complete, the reaction mixture is cooled and the crystalline product is collected by filtration, washed with acetone and dissolved in 150 ml of water, while heating.

   We acidify

 <Desc / Clms Page number 38>

 the solution with hydrochloric acid and the precipitate is collected by filtration, washed with water and dried to obtain 26.6g of 1-methyl-5-nitro-3-phenyl-indole- acid. 2-carboxylic with a melting point of 250-251 C (decomposition).



   The following compounds were prepared in the same manner:
 EMI38.1
 1-ethyl..5-nitro-3-phcnyl, indole-2-car3oxylic acid, 1-methyl-6 (or 4) -nitro-3-phenylindole-2-carboxylic acid, 1- methyl-7-nitro-3-phenylindole-2-carboxylic, 3- (o-chlorophenyl) -1-methyl-5-nitroindole-2-carboxylic acid,
 EMI38.2
 3- (o-bromophenyl) -1-methyl-5-nitroindole-2-carboxylic acid, 3- (o-fluorophenyl) -1-methyl-5-nitroindole-2-carboxylic acid, 3- (m-chlorophenyl) -1-methyl-5-nitroindole-2-carboxylic acid, 3- (p-chlorophenyl) -1-methyl-S-nitroindole-2-carboxylic acid.



  Example14
A mixture of 6.2 g of ethyl 5-ni-tro-3-phenylindole-2-carboxylate, 20 ml of acetone and a solution of 5.3 g of hydroxide is heated in solution. of potassium in 5 ml of water, then cooled to 30 ° C. To the mixture, 5.1 g of dimethyl sulfate is added dropwise and the mixture is heated under reflux for 4 hours. The acetone is removed under reduced pressure and the residue is dissolved in 300 ml of water. The solution is treated over charcoal and filtered. The filtrate is acidified with hydrochloric acid while cooling and the precipitate is collected by filtration.

 <Desc / Clms Page number 39>

 tion, washed well with water and dried to obtain 5.1 g of 1-methyl-5-nitro-3-phenylindole-2-carboxylic acid with a melting point of 260 C (decomposition ).



  Analysis for C16H12O4N2 Calculated: C 64.86, H 4.08, N 9.46 Found t C 65.08, H 3.93, N 9.29%.



   In the same way, the following compounds were prepared:
 EMI39.1
 acid -thy, - nitro-3.ph:ny,.ndals-.2-oarboxylicuet!. 1-methyl-6 (or 4) -nitro.3.-phenylindole-2-c & rbox: Eliq 1 acid -methyl-7-n3.tro 3.phenylindole..2-carboxy, .que, 3- (o-chlorophenyl) -1-methyl-5-nitroindole-2-carboxylic acid,
 EMI39.2
 3- (o-bromophenyl) -1-methyl-S-nitroindole-2-carboxylic acid, 3- (o-fluorophenyl) =, - methyl-5-nitro3ndole-2 carboxylic acid, 3 .. (m-chlorophenyl) -1 methyl-5-nitroindole-2-carboxylic acid, 3- (p-chlorophenyl) -1-methyl-5-nitroindole-2-carboxylic acid, Example 15
A mixture of 163.1 g of 5-nitro-3-phenylindole-2-carboxylic acid and 420 ml of thionyl chloride is heated to reflux for one hour.

   The excess thionyl chloride is removed under reduced pressure to quantitatively obtain 5-nitro-3-phenylindole-2-carboxylic chloride having a melting point of 192.5-194.5 C after recrystallization from sodium chloride. methylene.



  Example 16
Heated under reflux for one hour, a mixture of

 <Desc / Clms Page number 40>

 
23.7 g of 1-methyl-5-nitro-3-phenylindole-2-carboxylic acid and 47.6 g of thionyl chloride. The excess thionyl chloride is removed under reduced pressure to quantitatively obtain 1-methyl-5-nitro-3-phenylindole-2-carboxylic acid, as a yellow solid. Recrystallization from dichloroethane gives yellow prisms with a melting point of 197-198 C.



   Using the process of Examples 15 and 16, the following compounds are prepared in the same manner: 6 (or 4) -nitro-3-phenylindole-2-carboxylic chloride, 7-nitro-3- chloride phenylindole-2-carboxylic, 5-nitro-3-phenylindole-2-carboxylic bromide,
 EMI40.1
 3- (Q-chlorophenyl) -5-nitxoindoae-2-carbdxy2.cue chloride, 3- (o-bromophenyl) -5-nitroindole-2-carboxylic chloride,
 EMI40.2
 3- (o-fluorophenyl) -5-nitroindole-2-carboxylic chloride, 3- (p-chlorophenyl) -5-nitroindole-2-carboxylic chloride, 3- (m-chlorophenyl) -S-nitroindole- chloride 2-carboxylic chloride, 1-ethyl-5-nitro-3-phenylindole-2-carboxylic chloride, 1-propyl-5-nitro-3-phenylindole-2-carboxylic chloride.



  Example 17
A mixture is heated at reflux for 30 minutes. 27.5 g of 5-nitro-3-phenylindole-2-carboxylic acid and 115 g of thionyl chloride. The excess thionyl chloride is removed under reduced pressure to obtain a residue, which is dissolved in 400 ml of anhydrous tetrahydrofuran.



  Gaseous ammonia is introduced into the solution while cooling with ice. The precipitate is collected by filtration, washed with water, then with ethanol and dried to obtain 14.5 g of 5-nitro-3-phenylindole-2-carboxamide at one point. of 299-302 C. One concentrates

 <Desc / Clms Page number 41>

 the tetrahydrofuran layer to dryness under reduced pressure and the residue washed successively with water, ethanol and ether, then dried to obtain an additional 12.1 g of 5- nitro-3-phenylindole-2-carboxamide with a melting point of 295.5-297 C.



   Recrystallization from methanol gives an analytical sample with a melting point of 302 C.



  Analysis for C15H11O3N3 Calculated: C 64.05, H 3.94, N 14.94% Found: C 64.13, H 3.89, N 14.15 Example 18
A mixture of 168.0 g of 5-nitro-3-phenylindole-2-carboxylic acid and 710 g of thionyl chloride is heated under reflux for 1.5 hours. The excess thionyl chloride is removed under reduced pressure and the residue is suspended in 2 liters of dry toluene. Gaseous ammonia is introduced into the suspension for 2 hours. The precipitate was collected by filtration, washed with water and ether and dried to obtain 160.4 g of 5-nitro-3-phenylindole-2-carboxamide.



  Example 19
A mixture of 5.0 g of 1-methyl-1-5-nitro-3-phenylindole-2-carboxylic acid and 20 g of thionyl chloride is heated under reflux for two hours. The excess thionyl chloride is removed under reduced pressure. The residue is suspended in 40 ml of dry toluene and gaseous ammonia is introduced into the suspension while cooling. The yellow precipitate was collected by filtration, washed well with water and dried to obtain 3.2 g of 1-methyl-5-nitro-3-phenylindole-2-carboxamide of a

 <Desc / Clms Page number 42>

 mp 245-247 C.



   Using the process of Examples 17 to 19, the following compounds are prepared in the same manner: 6 (or 4) -nitro-3-phenylindole-2-carboxamide, 7-nitroindole-3-phenylindole- 2-carboxamide, 1-ethy1-5-nitro-3-phenylindole-2-carboxamide, 1-propyl-5-nitro-3-phenylindole-2-carboxamide,
 EMI42.1
 3- (o-chlorophenyl) -5-nitroindole-2-carboxamide, 3- (o-ahlorophenyl) -l-methyl-5-nitroindole-2-carboxamide, 3- (o-bromophenyl) -S- nitroindole-2-carboxamide, 3- (o-fluorophenyl) -5-nitroindole-2-carboxamide,
 EMI42.2
 3- (o-fluorophenyl) -1-methyl-5-nitroindole-.2-carboxamide 3- (p-chlorophenyl) -5-nitroindole-2-carboxamide, 3- (m-chlorophenyl) -5-nitroindole -2-carboxamide.



  Example 20
In solution, a mixture of 28.1 g of 5-nitro-3-phenylindole-2-carboxamide, 100 ml of acetone and 23 g of a 50% aqueous solution of potassium hydroxide is heated. and cooled to 40 ° C. To the mixture was added, dropwise, 18.9 g of dimethyl sulfate, while stirring.



  After addition, the mixture is heated under reflux for one hour, then cooled in an ice bath. The precipitate was collected by filtration, washed with cold acetone, then with water and dried to obtain 19.3 g.
 EMI42.3
 1-methyl-5-nitro-3-phônylindole-2-carboxamide with a melting point of 248-249 C.



   Methylation is carried out with methyl iodide instead of dimethyl sulfate in the above method, after forming the sodium salt with sodium hydride in dimethylformamide, to obtain 1-methyl-5 -nitro-

 <Desc / Clms Page number 43>

 3-phenylindole-2-carboxamide with a melting point of 247-249 C.



   In the same way, the following compounds were prepared: 1-ethyl-5-nitro-3-phenylindole-2-carboxamide,
 EMI43.1
 2-prapyl-.5-nitro-3-phenylindole-2-carboxamide, 3- (o-fluorophenyl) -l-methyl-to-nitroindole-2-carboxamide, 3-.fo + chlorophenyl) -l- methyl-5-nitroindole-2-carboxamide, 3- (p-chlorophényi) -i-methyl-5-nitroindole-2-carboxamide.



   Example 21
Heated to reflux for 30 minutes :, a mixture of 13.5 g of 5-nitro-3-phenylindole-2-carboxamide and 59 g of phosphorus oxychloride. The reaction mixture is poured onto crushed ice while stirring. The precipitate was collected by filtration, washed with water and dried to obtain 11 g of 5-nitro-3-phenylindole-2-carbonitrile with a melting point of 261 C. By recrystallization from methanol, pale yellow needles with a melting point of 263-264 C.



  Analysis for C15H9O2N3:.



  Calculated: C 68.44, H 3.45, N 15.95% Found: C 68.61, H 3.07, N 16.19%.



  Example 22
Heated to reflux for 20'minutes, a mixture of. 1.5 g of 1-methyl-5-nitro-3-phenylindole-2-carboxamide and 8 g of phosphorus oxychloride. The mixture is cooled and poured over crushed ice. The solid was collected by filtration, washed with water and dried to obtain 1.4 g of 1-methyl-5-nitro-3-phenylindole-2-carbonitrile with a melting point of. 218-220 C.



   Using the process of Examples 21 and 22, the following compounds are prepared in the same manner

 <Desc / Clms Page number 44>

 1-ethyl-5-nitro-3-phenylindole-2-carbonitrile,
 EMI44.1
 1-propyl-5-nitro-3-phenylindole-2-carbonitrile, 6 (or 4) -nitro-3-phenylindole-2-carbonitrile, 7-nitro-3-phenylindole-2-carbonitrile, 3- (o-chlorophenyl) -5-nitroindole-2-carbonitrile,
 EMI44.2
 3 - (o-chlorophenyl) -1-methvl-5.nitroindole-2-carbonitrile, 3- (o-bromophenyl) -S.-nitroindole-2-carbonitrile, 3- (o-fluorophenyl) -5 -nitroindole-2-carbonitrile, 3 -. (c-fluoraphenyl) .- 1-methyx-5-nitroindole-.2-carborit.e, 3- (p-chlorophenyl) -l-1nethyl-5-nitroindole- 2-carbonitrile, 3- (m-chlorophenyl) -5-nitroindole-2 * -carbonitrile.



  Example 23
To an ice-cooled suspension consisting of 20 g of 5-nitro-3-phenylindole-2-carbonitrile in 70 ml of acetone is added a solution of 14.3 g of potassium hydroxide in 14. , 3 ml of water. 18.6 g of dimethyl sulfate are added dropwise to the solution obtained. The temperature rose to 43 ° C. After the addition, the mixture was stirred for 30 minutes and cooled. The precipitate is collected by filtration, washed with water and dried to give 20.7 g of 1-methyl-5-nitro-3-phenylindole-2-carbonitrile with a melting point of. 222-223 C. Recrystallization gives an analytical sample with a melting point of 222.5-223.5 C.



   Methylation is carried out with methyl iodide instead of dimethyl sulfate in the above method, after forming the sodium salt with sodium hydride in dimethylformamide to obtain 1-methyl-5- Nitro-indole-2-carbonitrile with a melting point of 222-223 C.



   In the same way, the following compounds are prepared:
 EMI44.3
 1-ethyl-5-nitro-3-phenylindole-2-carbonitrile,

 <Desc / Clms Page number 45>

 
 EMI45.1
 1-propyl-5-nitro-3-phenylindole-2-carbonitrile, 3 .. (o-chlorophenyl) -1-methyl7.-5-nitroindole-2-carbonitrile '3- (o-fluorophenyl) -1 -methyl-5-nitroindole-2-carbonitrile, 3- (p-chlorophenyl) -1-methyl-5-nitroindole-2-carbonitrile, 1-methyl-6 (or 4) -nitro-3-phenylindole-2 -carbonitrile,
 EMI45.2
 1-methyl-7-nitro-3-phenylindole-2-carbonitrile.



  Example 24
To a suspension of 135 g of 1-methyl-5-nitro-3-phenyl-indole-2-carbonitrile in 2.5 liters of dry tetrahydrofuran, 46.4 g of powdered sodium borohydride is added.



  To the mixture was added dropwise a solution of 231 g of boron etherate / trifluoride in 500 ml of dry tetrahydrofuran, while stirring for more than 30 minutes. After the addition, stirring is continued for a further two hours. To the reaction mixture is added dropwise 600 ml of water, then 600 ml of concentrated hydrochloric acid, while stirring and cooling in ice. The resulting mixture is neutralized with 1.1 liter of ammonium hydroxide. The organic layer is separated and the aqueous phase is extracted with ether. The extracts are combined with the organic layer, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue is heated to reflux with 1500 ml of ethanol. After cooling, the solid is removed by filtration.

   The filtrate is concentrated and cooled with ice. By filtration, the precipitate thus formed was collected and dried to obtain 108.3 g of crude 2-aminomethyl-1-methyl-5-nitro-indole. This crude product is used in the next step without further purification.



   An analytical sample is obtained as follows:

 <Desc / Clms Page number 46>

 
The crude product (10 g) is heated in solution with
100 ml of glacial acetic acid. The solution is cooled and, by filtration, the crystals obtained are collected, washed with glacial acetic acid and carbon tetrachloride; they are dried to obtain 5.5 g of yellow needles with a melting point of 196-198 C. By recrystallization from isopropyl alcohol, yellow plaques with a melting point of 196-198 C are obtained. .



   The crystals are neutralized with ammoniacal water and extracted with chloroform. The extracts were combined, dried over sodium sulfate and concentrated to give 2-aminomethyl-1-methyl-5-nitroindole mp 157-158 C.



   IR spectrum :) paraffin: 3390, 1612, 1602, 1570, 1510 cm-1
Example 25
To a solution of 6.1 g of crude 2-aminomethyl-1methyl1-5-nitroindole obtained in Example 22, in 200 ml of ethanol, 20 ml of 20% ethanolic hydrochloric acid is added. The mixture was cooled and the precipitate was collected by filtration, washed with hot ethanol and dried to give 4.4 g of 2-aminomethyl-1-methyl-5-nitroindole hydrochloride. melting point 270.5-273 C.



   Analysis for C16H15O2N3HC1:
Calculated: C 60.48, H 5.08%
Found: C 60.28, H 5.26%.



   IR spectrum: max: 1616, 1607, 1570,1520 cm-1
Example 26
To a suspension of 73.9 g of 1-methyl-5-nitro-3-phenylindole-2-carbonitrile in 1.5 liters of dry tetrahydrofuran is added dropwise a solution of 126 g.

 <Desc / Clms Page number 47>

 of boron trifluoride / etherate in 220 ml of dry tetrahydrofuran, while stirring for two hours. After addition, stirring is continued for a further 3 hours. 370 ml of water are added dropwise to the reaction mixture, followed by 370 ml of concentrated hydrochloric acid, while stirring and cooling in ice.



   By filtration, the precipitate formed is collected, washed with water, then with ethanol and dried to obtain 56.3 g of crude 2-aminomethyl-1-methyl-5-nitroindole hydrochloride. 'a melting point of 263-267 C.



   Using the methods of Examples 24 to 26, the following compounds are prepared in the same manner: 2-aminomethyl-1-ethyl-5-nitro-3-phenylindole, 2-aminomethyl-1-propyl-5- nitro-3-phenylindole, 2-aminomethyl-3- (o-chlorophenyl) -1-methyl-S-nitroindole, 2-aminomethyl-3- (o-fluorophenyl) -l-methyl-5-nitroindole,
 EMI47.1
 2-aminomthyl-3- (o-bromophenyl) -l-mthyl-5-nitroindolel 2-aminomethyl-3- (p-chloroph nyl) -1-müthyl-S-nitroindole, 2-aminomethyl-1-methyl -6 (or 4) -nitro-3-phenylindole;
 EMI47.2
 2-aminomethyl-2-methyl-7-nitro-3-phenylindol.e, as well as their hydrochlorides, hydrobromides, sulphates, phosphates and acetates.



  Example 27
To a suspension of 6.5 g of 2-aminomethy1-1-methyl-5-nitro-3-phenylindole in 65 ml of glacial acetic acid, a solution of 6.5 g of anhydride is added dropwise. chromic acid in 6.5 ml of water at 20 C while stirring. The mixture was stirred at room temperature overnight, then 195 ml of water was added thereto. To the mixture is added dropwise 100 ml of 28% ammoniacal water with stirring and stirring.

 <Desc / Clms Page number 48>

 cooling.

   By filtration, the precipitate formed is collected, washed with water and dried to obtain 5.9 g of a crude product having a melting point of 135-140 ° C. By fractional recrystallization from ethanol, 3.8 g of 1-methyl-7-nitro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one are obtained in the form of yellow plaques with a dot of melting of 153-156 C. By further recrystallization in the same solvent, pale yellow plaques with a melting point of 156-156.5 C. are obtained.



  Example 28
To a mixture of 8.1 g of 2-amino-methyl-1-methyl-5-nitro-3-phenylindole hydrochloride and 80 ml of glacial acetic acid is added dropwise a solution of 8 g of chromic anhydride in 8 ml of water at 23-30 C, while stirring. The mixture is stirred overnight at room temperature. To the mixture was added 240 ml of water, then 125 ml of 28% aqueous ammonia was added dropwise while stirring and cooling. The precipitate is collected by filtration and washed with water. By recrystallization from 70 ml of ethanol, 4.1 g of 1-methyl-
 EMI48.1
 7-nitro-5-phônyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one with a melting point of 156-157 C.



  Example 29 To a suspension of 10 g of 2-amino-methyl-1-methyl-5-nitro-3-phenylindole hydrochloride and 100 ml of glacial acetic acid, a solution of 8.8 g is added dropwise. chromic anhydride in 8.8 ml of water at 16-21 C while stirring. The mixture is stirred at room temperature overnight. By filtration, the precipitate obtained is collected, washed with glacial acetic acid and carried out.

 <Desc / Clms Page number 49>

 dried to give 5 g of a yellow-brown solid with a melting point of 181-183 C. The solid (9.5 g) was added to dilute aqueous ammonia with stirring.

   The precipitate was collected by filtration, washed with water and dried to obtain 5.6 g of 1-methyl-7-nitro-5-phenyl-1,3-dihydro-2H-1,4-. benzodiazepine-2-one with a melting point of 149-156 C. By treatment with activated carbon and recrystallization from ethanol, 3.85 g of almost colorless plaques with a melting point are obtained. from 156-158 C.



  Example 30
A stream of ozonated oxygen is passed through a mixture of 10 g of 2-aminomethyl-1-methyl-5-nitro-3-phenylindole and 120 ml of glacial acetic acid, at 20-25 ° C. The reaction mixture is added dropwise over a period of 3.5 hours to a solution of 150 ml of 28% ammoniacal water and 300 ml of water while cooling, and the mixture is extracted with chloroform. The combined extracts were washed with ether, dried over sodium sulfate and evaporated under reduced pressure, the residue dissolved in 100 ml of hot ethanol After cooling, insoluble material was removed by decantation. The ethanolic solution is concentrated under reduced pressure.

   The residue was subjected to chromatography on silica gel and eluted with benzene to afford 2-methyl-amino-5-nitro-benzophenone. By additional elution with chloroform, the
 EMI49.1
 1-methyl-7-nitro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-one.



  Example 31
To a mixture of 98 g of chromic anhydride, 98 ml of water and 980 ml of glacial acetic acid is added, by

 <Desc / Clms Page number 50>

 portions, 98 g of 2-aminomethyl-1-methyl-5-nitro-3-phenylindole, at 25-26 C, while stirring. The mixture is stirred at room temperature for 18 hours. The reaction mixture is added dropwise to an ice-cooled solution of 1.3 liters of 28% ammoniacal water and 6 liters of ice-cold water, below 10 ° C.

   The precipitate was collected by filtration, washed with water and dried to obtain 163.9 g of 1-methyl-7-nitro-5-phenyl-1,3-dihydro-2H-1,4-. crude benzodiazepine-2-one with a melting point of 133-140 "C ,,
This crude product (10 g) is dissolved in 20 ml of dimethylformamide. The solution is treated over activated carbon and filtered. Gaseous hydrochloric acid is passed through the filtrate.



   By filtration, the precipitate formed is collected, washed with dimethylformamide and ethanol and dried to obtain 1-methyl-7-nitro-5-phenyl-1,3-dihydro-2H-1 hydrochloride. , 4-Benzodiazepin-2-one mp 227-234 C (decomposition). The hydrochloride is suspended in 30 ml of water and neutralized with ammoniacal water, while stirring, to obtain 6.5 g of 1-methyl-.
 EMI50.1
 ? -nitro-S-phenyl - ,, 3-dihydro-2H -.'-benzodiazepine-2-ane. Recrystallization from ethanol gives 5.7 g of the pure product with a melting point of 156-158 C.



   Using the process of Examples 27 to 31, the following compounds are prepared in the same manner:
 EMI50.2
 1-ethyl-7-nitro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-one, 1-m (thyl-8-nitro-5-phenyl-lt3- dihydro-2H-1,4-benzodiazepine-2-one,

 <Desc / Clms Page number 51>

 
 EMI51.1
 1-methyl-9-nitro-5-phenyl-1,3-dihydro-2H-ip4-benzodiazd-pine-2-one, 5- (o-chlorophenyl) -1.-methyl-7-nitro-. , 3-d.hydro-2H-.f1-benzodiazepin-2-one,
 EMI51.2
 5- (o-bromophényi) -1-methyl-7-nitro-1,3-dihydro-2H-1,4-benzodiazepine-2-one,
 EMI51.3
 5- (o-fluorophenyl) -l-methyl-7-nitro-1,? - dihydro-2H-1,4-benzodiazepin-2-one,
 EMI51.4
 5- (p-chloraphenyl) -1-methyl-7-nitro-1,3-dihydro-2H-1,4-benzodiazepin-2-one.

 

Claims (1)

R E V E N D I C A T I O N S 1. Process for preparing a benzodiazepine derivative corresponding to the formula EMI51.5 in which R represents an alkyl group of 1 to 4 carbon atoms and X represents a hydrogen or halogen atom, characterized in that it corsists in reacting a 2-aminomethylindole derivative corresponding to the formula EMI51.6 in which R and X have the same meanings as those mentioned above, or its salt, with an oxidizing agent. <Desc / Clms Page number 52> 2. Method according to claim 1, characterized in that the oxidizing agent is chromic acid or ozone, 3. Process for the preparation of a benzodiazepine derivative corresponding to the formula EMI52.1 in which R represents an alkyl group of 1 to 4 carbon atoms and X represents a hydrogen or halogen atom or its salt, characterized in that it consists in reacting, with a reducing agent, a derivative of indole-2-carbonitrile corresponding to the formula EMI52.2 in which R and X have the same meanings as those mentioned above, to prepare a 2-amino-methylindole derivative of the formula EMI52.3 in which R and X have the same meanings as those mentioned above, then reacting, with an oxidizing agent, the obtained 2-aminomethylindole derivative or its salt. 4. Method according to claim 3, characterized in that the reducing agent is diborane. <Desc / Clms Page number 53> 5. Process according to claim 3, characterized in that the indole-2-carbonitrile derivative (Xb) is prepared by treating an indole-2-carbonitrile derivative corresponding to the formula. EMI53.1 wherein X has the same meaning as mentioned in claim 3, together with an alkylating agent. 6. A method according to claim 5, characterized in that the alkylating agent is a dialkyl sulfate or an alkyl halide. 7. Process for the preparation of a benzodiazepine derivative corresponding to the formula EMI53.2 in which R represents an alkyl group of 1 - 4 carbon atoms and X represents a hydrogen or halogen atom, characterized in that it consists in reacting, with a dehydrating agent, a derivative of indole-2-carboxamide corresponding to the formula EMI53.3 in which R and X have the same meanings as those <Desc / Clms Page number 54> mentioned above, to prepare @ an indole-2-carbonitrile derivative of the formula EMI54.1 in which R and X have the same meanings as those mentioned above, reacting the indole-2-carbonitrile derivative thus obtained with a reducing agent to form a 2-aminomethylindole derivative of the formula EMI54.2 in which R and X have the same meanings as those mentioned above, then reacting said 2-aminomethylindole derivative or its salt with an oxidizing agent. 8. The method of claim 7, characterized in that the dehydrating agent is phosphorus oxychloride. 9. Process according to claim 7 ′ characterized in that the indole-2-carboxamide derivative (IXb) is prepared by treating an indole-2-carboxamide derivative corresponding to the formula. EMI54.3 in which X has the same meaning as in claim 7, with an alkylating agent. 10. The method of claim 9, characterized <Desc / Clms Page number 55> in that the alkylating agent is a dialkyl sulfate or an alkyl halide. 11. Process for preparing a benzodiazepine derivative corresponding to the formula EMI55.1 in which R represents an alkyl group of 1 - 4 carbon atoms and X represents a hydrogen or halogen atom, characterized in that it consists in reacting, with ammonia, an indole derivative 2-carboxylic acid corresponding to the formula EMI55.2 in which R and X have the same meanings as those mentioned above, or its reactive derivative, to prepare an indole-2-carboxamide derivative corresponding to the formula EMI55.3 in which R and X have the same meanings as those mentioned above, reacting said indole-2-carboxamide derivative with a dehydrating agent to form an indole-2-carbonitrile derivative of the formula <Desc / Clms Page number 56> EMI56.1 in which R and X have the same meanings as those mentioned above, reacting the indole-2-carbonitrile derivative thus obtained with a reducing agent to obtain a 2-aminomethylindole derivative corresponding to the formula EMI56.2 in which R and X have the same meanings as those mentioned above, then reacting the 2-amino-methylindole derivative thus obtained, or its salt, with an oxidizing agent. 12. The method of claim 11, characterized in that the reactive derivative of the derivative of indole-2-carboxylic acid (VIIIb) is a derivative of an indole-2-carbonyl halide corresponding to the formula. EMI56.3 in which R and X have the same meanings as those mentioned above and -Hal represents a halogen atom, which is obtained by reacting the indole-2-carboxylic acid derivative (VIIIb) with an agent d 'halogenation. 13. The method of claim 12, characterized in that the halogenating agent is thionyl chloride. 14. The method of claim 11, characterized in that the derivative of indole-2-carboxylic acid is prepared. <Desc / Clms Page number 57> (VIIIb) by treating an indole-2-carboxylic acid derivative of the formula EMI57.1 wherein X has the same meaning as recited in claim 11, together with an alkylating agent. ' 15. The method of claim 14, characterized in that the alkylating agent is a dialkyl sulfate. 16. The method of claim 11, characterized in that the derivative of indole-2-carboxylic acid (VIIIb) is prepared by reacting, with an acid, a phenyl-hydrazone derivative corresponding to the formula. EMI57.2 wherein R and X 'have the same meanings as in claim 11. 17. Process according to claim 11, characterized in that an indole-2-carboxylic acid derivative (VIIIb) is prepared by treating an indole-2-carboxylic acid derivative corresponding to the formula (Ville) with an agent. alkylation, in the presence of a twice equimolar amount or more of an alkylene agent. 18. The method of claim 16, characterized in that the derivative of phenylhydrazone (VIIc) is prepared by reacting a derivative of nitrophenylhydrazine corresponding to the formula. <Desc / Clms Page number 58> EMI58.1 in which R has the same meaning as in claim 16, with a phenylpyruvic acid derivative of the formula EMI58.2 in which X has the same meaning as in claim 16. 19. The method of claim 11, characterized in that the derivative of indole-2-carboxylic acid (VIIIb) is prepared by reacting a nitrophenylhydrazine derivative corresponding to the formula. EMI58.3 in which R has the same meaning as in claim 11, with a phenylpyruvic acid derivative of the formula EMI58.4 in which X has the same meaning as in claim 11. 20. A process for preparing a benzodiazepine derivative corresponding to the formula <Desc / Clms Page number 59> EMI59.1 in which R represents an alkyl group of 1 - 4 carbon atoms and X ′ represents a hydrogen or halogen atom, characterized in that it consists in converting an indole-2-carboxylic acid derivative corresponding to to the formula EMI59.2 in which R and X have the same meanings as those mentioned above and R1 represents an alkyl group of 1-4 carbon atoms, to an indole-2-carboxylic acid derivative of the formula EMI59.3 in which R and X have the same meanings as those mentioned above, reacting the indole-2-carboxylic acid derivative thus obtained, or its reactive derivative, with ammonia, for preparing an indole-2-carboxamide derivative of the formula EMI59.4 in which R and X have the same meanings as those <Desc / Clms Page number 60> mentioned above, reacting the indole-2-carboxamide derivative with a dehydrating agent to form an indole-2-carbonitrile derivative of the formula EMI60.1 wherein R and X have the same meanings as those mentioned above, reacting said indole-2-carbonitrile derivative with a reducing agent to prepare a 2-aminomethylindole derivative of the formula EMI60.2 in which R and X have the same meanings as those mentioned above, then reacting said 2-aminomethylindole derivative with an oxidizing agent. 21. The method of claim 20, characterized in that the derivative of indole-2-carboxylic acid (Villa) is prepared by treating an indole-2-carboxylic acid derivative corresponding to the formula ' EMI60.3 wherein X and R1 have the same meanings as in claim 20, with an alkylating agent. 22. The method of claim 21, characterized in that the alkylating agent is a dialkyl sulfate or an alkyl halide. <Desc / Clms Page number 61> 23. The method of claim 20, characterized in that the derivative of indole-2-carboxylic acid (Villa) is prepared by reacting a derivative of nitrophenylhydrazine. answering the formula EMI61.1 in which R has the same meaning as in claim 20, with a phenylpyruvic acid derivative of the formula EMI61.2 wherein X and R1 have the same meanings as in claim 20. 24. Process for the preparation of a benzodiazepine derivative corresponding to the formula EMI61.3 in which R represents an alkyl group of 1 to 4 carbon atoms and X represents a hydrogen or halogen atom, characterized in that it consists in reacting, with an acid, a phenylhydrazone derivative corresponding to the formula EMI61.4 <Desc / Clms Page number 62> -in which R and X have the same meanings as those mentioned above and R1 represents an alkyl group of 1-4 carbon atoms, to form an indole-2-carboxylic acid derivative corresponding to the formula EMI62.1 in which R, R1 and X have the same meanings as those mentioned above, converting indole-2-carboxylic acid into an indole-2-carboxylic acid derivative having the formula EMI62.2 wherein R and X have the same meanings as mentioned above, reacting the indole-2-carboxylic acid derivative or its reactive derivative with ammonia, to prepare an indole-2-carboxamide derivative responding to the formula EMI62.3 in which R and X have the same meanings as those mentioned above, reacting the indole-2-carboxamide derivative with a dehydrating agent to form an indole-2-carbonitrile derivative of the formula <Desc / Clms Page number 63> EMI63.1 in which R and X have the same meanings as those mentioned above, reacting the indole-2-carbonitrile derivative with a reducing agent, to prepare a 2-aminomethylindole derivative of the formula EMI63.2 in which R and X have the same meanings as those mentioned above, then reacting the 2-amino-methylindole derivative, or its salt, with an oxidizing agent. 25. The method of claim 24, characterized in that the derivative of phenylhydrazone (VIIb) is prepared by reacting a derivative of nitrophenylhydrazine corresponding to the formula EMI63.3 in which R has the same meaning as in claim 24, with a phenylpyruvic acid derivative of the formula EMI63.4 wherein R1 and X have the same meanings as in claim 24. 26. 2-aminomethylindole derivative of the formula <Desc / Clms Page number 64> EMI64.1 wherein R represents an alkyl group of 1 to 4 carbon atoms and X represents a hydrogen or halogen atom. 27. Indole-2-carbonitrile derivative corresponding to the formula EMI64.2 in which R represents an alkyl group of 1 - 4 carbon atoms and X represents a hydrogen or halogen atom. 28. Indole-2-carboxamide derivative corresponding to the formula EMI64.3 wherein R represents an alkyl group of 1 to 4 carbon atoms and X represents a hydrogen or halogen atom. 29. Indole-2-carboxylic halide derivative having the formula EMI64.4 in which R represents an alkyl group of 1 - 4 carbon atoms, X represents a hydrogen or halogen atom and Hal represents a halogen atom. 30. Indole-2-carboxylic acid derivative responding to <Desc / Clms Page number 65> EMI65.1 in which R represents an alkyl group of 1 - 4 carbon atoms and X represents a hydrogen or halogen atom.