Process for preparing imidazo[1,5-A][1,5]benzodiazepines

• US 4,137,229 A
• Filed: 02/01/1978
• Issued: 01/30/1979
• Est. Priority Date: 03/07/1977
• Status: Expired due to Term

• Current Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Original Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Inventors: Walser, Armin, Fryer, Rodney I.
• Primary Examiner(s): Trousof, Natalie
• Assistant Examiner(s): Bond, Robert T.
• Application Number:
  US05/874,076
• Time in Patent Office: 363 Days
• Field of Search: 260/239.3 T
• US Class Current: 540/498
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: C07D 243/12 1,5-Benzodiazepines; Hydrogenated 1,5-benzodiazepines
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

The present invention concerns compounds of the formula ##STR1## wherein X is hydrogen or halogen; R₁ is hydrogen, halogen or trifluoromethyl; R₂ is hydrogen or lower alkyl; and R₃ is hydrogen, --COO lower alkyl or CON(R₄)₂ wherein R₄ is lower alkyl or hydrogen and may be different and the pharmaceutically acceptable salts thereof.

Also provided are methods for the preparation of these compounds as well as pharmaceutical formulations which contain the active compounds of this invention. The compounds of the formula illustrated above are useful as anxiolytics, anticonvulsants, muscle relaxants and sedative agents.

Claims

1. A process to produce a compound of the formula ##STR10## wherein X is hydrogen or halogen;

R₁ is hydrogen, halogen or trifluoromethyl;

R₂ is hydrogen or lower alkyl; and

R₃ is --COO lower alkyl or CON(R₄)₂ wherein R₄ is lower alkyl or hydrogen and may be different

which comprises;

A. reacting a compound of the formula ##STR11## wherein R₁ and X are as above with methylamine in the presence of titanium tetrachloride

B. nitrosating the product of (A) with nitrous acid or nitrosyl chloride in pyridine in an aliphatic or aromatic hydrocarbon solvent at from -30°

C. to room temperature;

C. condensing the product of (B) with the anion generated from malonic ester in a hydrocarbon solvent at from room temperature to 150°

C.;

D. hydrolyzing and selectively decarboxylating the product of (C) by utilizing an alkali metal or alkaline metal hydroxide at from room temperature to reflux temperature;

E. nitrosating the product of (D) with nitrous acid, nitrosyl chloride or a lower alkyl nitrite in the presence of a chlorinated hydrocarbon at from about -20°

C. to 100°

C.;

F. reducing the product of (E) to the amino intermediate by hydrogen/Raney Ni or zinc in acetic acid at room temperature to 80°

C.;

G. condensing the product of (F) to the closed ring compound by reaction with a reagent selected from the group consisting of orthoesters, amide acetals or orthoamides at from room temperature to reflux temperature;

H. converting the ester of (G) to the desired amide by reaction with lithium chloride in hexaalkylphosphorous triamide at from 180°

C. to 250°

C.