ES376528A1 - Benzodiazepine derivatives and manufacture thereof - Google Patents

Abstract

Procedure for the preparation of benzodiazepine derivatives of the general formula **(See formula)** in which R1 means halogen or nitro; R2 signifies phenyl, halophenyl or pyridyl; R3 signifies hydrogen, alkyl, hydroxyalkyl, acyloxyalkyl, haloalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or carboalkoxy; R4 signifies alkoxy, haloalkoxy, monoalkylaminoalkoxy, dialkylaminoalkoxy, hydroxyalkyloxy, alkoxyalkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl; R5 signifies hydrogen or hydroxyl; and R6 signifies hydrogen or carboalkoxy; and in the case that R5 means hydrogen, the nitrogen atom in position 4 can carry an oxygen atom, and of the salts of these compounds, characterized by: a) reacting a compound of the general formula **(See formula)** where R1, R2 and R6 have the same meaning as before, or a respective 4-oxide, with a compound of the general formula **(See formula)** where stands for hydrogen, alkyl, haloalkyl, carboalkoxy or acyloxyalkyl; R8 signifies alkoxy, haloalkoxy, alkylthio or alkoxyalkylthio; and X stands for halogen, O well b) reacting a compound of the general formula **(See formula)** where R1 and R2 have the same meaning as before, with a vinyl ether of the general formula CH2 = CH-O-R9 V where R9 signifies alkyl; O well **(See formula)** where R1, R2 and R5 have the same meaning as before, R10 signifies hydrogen, alkyl, hydroxyalkyl, haloalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or acyloxyalkyl; and R11 has the same meaning as explained for R4, but one at least of the R10 and R11 substituents means a monohaloalkyl or monohaloalkoxylic group and, in the case that R5 signifies hydrogen, the nitrogen atom in position 4 can carry an oxygen atom, with a monoalkylamine or dialkylamine; O well d) alkylating a compound of the general formula **(See formula)** where R1 and R2 have the same meaning as before; R12 signifies alkoxy, monoalkylaminoalkoxy, dialkylaminoalkoxy, alkoxyalkoxy, alkylthio or aminoalkoxy; R13 signifies hydrogen, alkyl, monoalkylaminoalkyl, dialkylaminoalkyl or aminoalkyl, but one of at least one of the substituents R12 and R13 signifies an aminoalkoxy, monoalkylaminoalkoxy, aminoalkyl or monoalkylaminoalkyl group, or a respective 4-oxide; O well **(See formula)** where R1 and R2 have the same meaning as before; R14 signifies alkoxy, monoalkylaminoalkoxy, dialkylaminoalkoxy, alkoxyalkoxy, alkylthio or a protected monoalkylaminoalkoxy group; and R15 means hydrogen, alkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acyloxyalkyl or a protected monoalkylaminoalkyl group, but one of at least one of the R14 substituents, and R15 means a protected monoalkylaminoalkoxy or monoalkylaminoalkyl group, or of a respective 4-oxide, the protecting group; O well f) in a compound of the general formula **(See formula)** where R1, R2, R5 and R6 have the same meaning as before, but also, in the case of R5 meaning hydrogen, the nitrogen atom in position 4 can carry an oxygen atom; R16 stands for alkoxy, monohaloalkoxy, monoalkylaminoalkoxy, dialkylaminoalkoxy, hydroxyalkoxy, alkoxyalkoxy, or alkylthio; and R17 stands for hydrogen, alkyl, hydroxyalkyl, monohaloalkyl, carboalkoxy, monoalkylaminoalkyl, dialkylaminoalkyl or acyloxyalkyl, but one at least of R16 and R17 substituents means monohaloalkoxy or monohaloalkyl, replacing aliphatically linked halogen atoms with hydroxy groups; O well g) in a compound of the general formula **(See formula)** where R1, R2, R5 and R6 have the same meaning as before; R18 signifies alkylthio; and R19 means hydrogen, alkyl, hydroxyalkyl, haloalkyl, carboalkoxy or acyloxyalkyl, but in case R5 means hydrogen, the nitrogen atom in position 4 can carry an oxygen atom, oxidize the alkylthio group converting it into an alkylsulfinyl or alkylsulfonyl group ; O well h) cyclizing a compound of the general formula **(See formula)** where R1, R2, R3, R4 and R6 have the same meaning as before; O well i) hydrolyzing a compound of the general formula **(See formula)** where R1, R2, R3, R4 and R6 have the same meaning as before, while R20 signifies an acyl group; O well j) deoxygenate a compound of the general formula **(See formula)** where R1, R2, R3 and R6 have the same meaning as before, while R21 stands for alkoxy, haloalkoxy, monoalkylaminoalkoxy, dialkylaminoalkoxy, hydroxyalkoxy, alkoxyalkoxy or alkylthio; O well k) dehydrating a compound of the general formula **(See formula)** where R1, R2 and R6 have the same meaning as before; R22 stands for alkoxy, dialkylaminoalkoxy, alkoxyalkoxy or alkylthio; and R23 signifies hydrogen, alkyl, carboalkoxy, dialkylaminoalkyl or acyloxyalkyl; O well l) oxidizing or dehydrogenating at the 4,5 link a compound of the general formula **(See formula)** where R1, R2 and R6 have the same meaning as before; R24 signifies alkoxy, monoalkylaminoalkoxy, dialkylaminoalkoxy, hydroxyalkoxy or alkoxyalkoxy; and R25 signifies hydrogen, alkyl, hydroxyalkyl, carboalkoxy, monoalkylaminoalkyl, dialkylaminoalkyl or acyloxyalkyl; O well m) saponifying and decarboxylating a compound of the general formula **(See formula)** where R1, R2, R4 and R5 have the same meaning as before; R26 means alkyl, R27 signifies hydrogen, alkyl, hydroxyalkyl, haloalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or acyloxyalkyl; and in the case that R5 means hydrogen, the nitrogen atom in position 4 can carry an oxygen atom; O well n) oxidizing a compound of the general formula **(See formula)** where R1, R2, R3, R4 and R26 have the same meaning as before, to convert it to the 3-hydroxy compound; O well o) make it a compound of the general formula **(See formula)** where R1, R2, R6 and R25 have the same meaning as before, R28 means acyl; and R29 means alkoxy, monoalkylaminoalkoxy, dialkylaminoalkoxy, hydroxyalkoxy, alkoxyalkoxy or alkylthio, with a base, in the respective compound 4,5 dehydro; O well p) become a compound of the general formula **(See formula)** where R1, R2 and R6 have the same meaning as before; R30 signifies a mesyl or tosylic group; R31 signifies hydrogen, alkyl, hydroxyalkyl, carboalkoxy, dialkylaminoalkyl or acyloxyalkyl; and R32 signifies alkoxy, dialkylaminoalkoxy, hydroxyalkoxy, alkoxyalkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl, with a strong base, in the respective 4,5-dehydro compound; O well q) rearranging a compound of the general formula **(See formula)** where R1, R2, R3, R4 and R6 have the same meaning as before, converting it into the respective 4,5-dehydro compound; O well r) treating a compound of the general formula where R1, R2 and R6 have the same meaning as before, R40 represents hydroxyalkyl and R41 represents alkoxy, haloalkoxy, dialkylaminoalkoxy, alkoxyalkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl, or a respective 4-oxide, with an acylating agent; O well s) in a compound of the general formula **(See formula)** where R1, R2 and R6 have the same meaning as before, R42 represents haloalkyl and R43 represents alkoxy, dialkylaminoalkoxy, alkoxyalkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl, or a respective 4-oxide, converting the aliphatically linked halogen atom to an acyloxylic group; and/or t) if desired, converting a resulting compound to a salt. (Machine-translation by Google Translate, not legally binding)