Hydrochloric Acid → 3,4-Dihydro-3-amino-2H-1-benzopyran

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Reaction Steps

The compounds of this invention are prepared by various means. The compounds of this invention wherein R3 is hydrogen, R1 is hydrogen, ethyl or propyl, cyclopropylmethyl or cyclobutylmethyl and R2 is --CH2 cycloalkylC3-8, alkylC2-8, --(CH2)q --R4, or --CH2CH2O(CH2)rCH3 are prepared by refluxing one equivalent of a salicyl aldehyde of formula C-1 (see Chart 1) with one and one-half equivalents of 2-nitroethanol in amylacetate in the presence of one and one-half equivalents of din-propylamine hydrochloride followed by azeotropic distillation for 12 hours in a Dean-Stark apparatus to give the 3-nitrochromene of formula C-3. The 3-nitrochromene is reduced with cyanoborohydride or zinc and HCl to give the 3-aminochromane of C-4. The 3-aminochromane of C-4 can be acylated with an appropriate acid halide, e.g., acid chloride, of the formula RyCOhalide wherein Ry is alkylC1-7, --(CH2)tR4 wherein t is 1 or 2, cycloalkylC3-8 or --CH2O(CH2)mCH3 wherein R5 and m have the meanings in Formula I to give the chromane amides of formula C-5. Also the aminochromane of formula C-4 can be treated with methyl iodide to give the compound of formula C-6 wherein R14 is hydrogen and R15 is methyl or can be treated with formaldehyde in water in the presence of NaBH3CN and a few drops of glacial acetic acid at pH5 to give the corresponding dimethylated compounds. The compounds of formulas C-5 and C-6 can be converted to the corresponding compounds of formulas C-7 and C-8 wherein R is F, Cl, CF3, NR5R6, NR7C(=O)R8, NR9C(=O)OR10, or NR11C(=O)NR12R13 as follows:

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