Process for the synthesis of 4H-imidazo [1,5-a] [1,4] benzodiazepines, in particular midazolam and salts thereof
AssigneeF.I.S. Fabbrica Italiana Sintetici S.p.A.
InventorsAndrea Castellin, Michele Maggini, Paola Donnola
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Abstract
The present invention refers to a process for the preparation of 4H-imidazo[1,5-a][1,4]benzodiazepines, in particular Midazolam, through an efficient and selective decarboxylation reaction of the derivative compound of the 5-aminomethyl-1-phenyl-1H-imidazole-4-carboxylic acid of formula (II) avoiding the formation of the 6H-imidazo[1,5-a][1,4]benzodiazepines by-products and the ensuing process for the isomerization of a 4H-imidazo[1,5-a][1,4]benzodiazepine product.
Claims15
Process for the preparation of 4H-imidazo[1,5-a][1,4]benzodiazepine of formula (I) or a salt thereof:
- wherein R is selected from the group consisting of H, CH3, CH2OH and C2H5;
- X1 and X2 are independently selected from H and halogen;
- comprising the following steps:
- hydrolysis of the compound of formula (III):
- wherein R, X1 and X2 have the same meaning above specified,
- to give the compound of formula (II)
- wherein HA is an inorganic acid,
- decarboxylation of the compound of formula (II) to give the compound of formula (I) or a salt thereof.
Compound of formula (II):
- wherein R is selected from the group consisting of H, CH3, CH2OH and C2H5;
- X1 and X2 are independently selected from H and halogen, and HA is an inorganic acid.
Process for the preparation of a compound of formula (I) or a salt thereof:
- wherein R is selected from the group consisting of H, CH3, CH2OH and C2H5;
- X1 and X2 are independently selected between H and halogen;
- comprising the decarboxylation of the compound of formula (II)
- wherein R, X1 and X2 have the same meanings above specified and HA is an inorganic acid.
A method for the preparation of Midazolam of formula (IV) or a salt thereof:
- comprising decarboxylation of the compound of formula (V)
Dependencies are inferred from the claim text.