Acetoxyacetyl chloride → 3-Acetyloxyacetyl-2-carbomethoxyindolizine

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Reaction Steps

Following the procedure of Example 3, reaction of 2-carbomethoxyindolizine with acetoxyacetyl chloride gave 3-acetyloxyacetyl-2-carbomethoxyindolizine (IX). Reaction of IX with 1.5 equiv of anhydrous hydrazine in dry ethanol gave 4-hydroxymethylpyridazino[4,5-b]indolizin-1-one which upon refluxing with excess POCl3 gave 1-chloro-4-chloromethylpyridazino[4,5-b]indolizine (X). Compound X (1.0 g, 4.0 mmol) was combined with excess N,N-diethylaminopropylamine (2.68 mL, 17 mmoL) in N-methylpyrrolidinone (2 mL) containing TEA (0.74 mL, 1.2 equiv.) and 1.2 equiv. of ammonium chloride (vigorous initial reaction with gas evolution). When the reaction subsided the stirred reaction mixture was heated at 100° C. overnight. After cooling to room temperature, the volatiles were removed by vacuum distillation. The residue was dissolved in methylene chloride and extracted with water (3 times), dried (MgSO4), and the solvent evaporated. The residue was purified by flash column chromatography on silica gel eluting with 20% methanol in methylene chloride containg 2% ammonium hydroxide. The isolated free base was converted to the tetra hydrochloride salt using ethereal HCl in ether m.p. 120°-123° C.

Provenance & Evidence