The reaction of ethyl o-fluorophenylpyruvate (I) with p-chloro-N1-cyclopropylmethylphenylhydrazine (II) in refluxing ethanol gives the corresponding phenylhydrazone (III), which is cyclized by treating with HCl in hot ethanol yielding ethyl 1-cyclopropylmethyl-3-(2-fluorophenyl)-5-chloroindole-2-carboxylate (IV). The hydrolysis of (IV) with KOH in refluxing ethanol affords the corresponding free acid (V), which by treatment with refluxing SOCl2 is converted into the acyl chloride (VI). The reaction of (VI) with ammonia in water gives rise to the corresponding amide (VII), which by reduction with LiAlH4 in ether yields 1-cyclopropylmethyl-2-aminomethyl-3-(2-fluorophenyl)-5-chloroindole (VIII). Finally, this compound is treated with CrO3 in acetic acid. The reaction of amide (VII) with refluxing POCl3 yields the nitrile (IX), which can be reduced with LiAlH4 in ether affording the 2-aminomethyl compound (VIII) already obtained.
The reaction of o-fluorophenylpyruvate (I) with p-chlorophenylhydrazine (X) in refluxing ethanol gives ethyl o-fluorophenylpyruvate p-chlorophenylhydrazone (XI), which is cyclized by treatment with dry HCl in refluxing ethanol yielding ethyl 3-(2-fluorophenyl)-5-chloroindole-2-carboxylate (XII). The N-alkylation of (XII) with cyclopropylmethyl bromide (A) by means of KOH in refluxing acetone affords compound (IV) of the preceding sequence.
The condensation of p-chlorophenyldiazonium chloride (from p-chloroaniline (XIII) and NaNO2-HCl) and ethyl o-fluorobenzylacetoacetate (XIV) in methanol-water gives ethyl alpha-(o-fluorobenzyl)-alpha-(p-chlorophenylazo) acetoacetate (XV), which is cyclized to indole (XII) by means of H2SO4 in refluxing isopropanol.
The hydrolysis of 3-(2-fluorophenyl)-5-chloroindole-2-carboxylate (XII) with KOH in refluxing ethanol affords the corresponding free acid (XVI), which by treatment with refluxing SOCl2 is converted into the acyl chloride (XVII). The reaction of (XVII) with NH3 in ether yields the amide (XVIII), which by N-alkylation with cyclopropylmethyl bromide (A) by means of NaH in DMF gives rise to the alkylated amide (VII) already obtained.
The dehydration of the amide (XVIII) with refluxing POCl3 gives the corresponding nitrile (XIX), which by reduction with LiAlH4 in ether is converted into the 2-aminomethyl derivative (XX). The treatment of (XX) with CrO3 in acetic acid yields 5-(2-fluorophenyl)-7chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXI) (1,10), which is finally N-alkylated with cyclopropylmethy bromide (A) by means of phenyllithium in THF.
a) By cyclization of 2-cyclopropylmethylamino-5-chloro-2'-fluorobenzophenone (XXII) with 2,5-oxazolidinedione (XXIII) by means of dry HCl in CH2Cl2-ether. b) By dehydrogenation of 1-cyclopropylmethyl-5-(2-fluorophenyl)-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one (XXIV) by means of hexamethylenetetramine in refluxing acetic acid or by means of S or also by irradiation with a mercury lamp in DMS. c) By cyclization of 5-chloro-2'-fluoro-2-[N-cyclopropylmethyl-N-[2-(p-toluenesulfonyloxy)acetyl]amino]benzophenone (XXV) by means of NH3 in chloroform. d) By cyclization of the aminobenzophenone (XXII) with 2-chloro-1,3,2-oxazaphospholidin-5-one (XXVI) (prepared in situ from glycine and PCl3). e) By cyclization of 5-chloro-2'-fluoro-2-[N-cyclopropylmethyl-N-(benzyloxycarbonylacetyl)amino]benzophenone (XXVII) by means of HBr in acetic acid. f) By cyclization of 5-chloro-2'-fluoro-2-[N-cyclopropylmethyl-N-(aminoacetyl)amino]benzophenone (XXVIII) by means of aqueous ammonia.