Hydrochloric Acid → (E)-3-{3,4-dihydro-3-butyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4'-piperidin]-6-yl}-acrylic acid methyl ester hydrochloride

Participants

Reaction Steps

(E)-3-{1′-Tert-butoxycarbonyl-3,4-dihydro-3-butyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester (182 mg, 0.397 mmol, Intermediate 7) was treated with 4 M HCl in dioxane following the procedure described in Example 1 STEP C, to give (E)-3-{3,4-dihydro-3-butyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester hydrochloride (157 mg, 99%). Reaction with acetaldehyde (24 μl, 0.42 mmol) and NaCN(BH3) (26 mg, 0.42 mmol) following the procedure described in Example 71, Step A, gave (E)-3-{1′-ethyl-3,4-dihydro-3-butyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester (123 mg, 80%). The ester was hydrolyzed as described in Example 71, Step B, giving (E)-3-{1′-ethyl-3,4-dihydro-3-butyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid. The resulting acid was treated with NH2OTHP following the procedure described in Example 71, Step C, giving (E)-3-{1′-ethyl-3,4-dihydro-3-butyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide. Finally, removal of THP protecting group following the procedure described in Example 71, STEP C gave (E)-3-{1′-ethyl-3,4-dihydro-3-butyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-N-hydroxy-acrylamide that was purified by preparative LC-MS and obtained as trifluoroacetate salt (18 mg).

Provenance & Evidence