1-Methyl-1H-indole-3-carbaldehyde → HCID 67071752, compound

Participants

Reaction Steps

A suspension of (±)-(E)-3-[4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]acrylic acid methyl ester (284 mg, 0.88 mmol, Intermediate 1) in 1 M Na2CO3, was stirred for 10 min, then extracted with DCM and treated with N-methyl-indol-3-carbaldehyde (167 mg, 1.06 mmol) and NaBH(OAc)3 (297 mg, 1.32 mmol) following the procedure described in Example 2, step A, giving (±)-(E)-3-[1′(1-methyl-1H-indol-3-ylmethyl)-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-acrylic acid methyl ester (191 mg, 0.44 mmol, 42%) as a white solid. The resulting ester was hydrolyzed as described in Example 2, step B, giving (±)-(E)-3-[1′(1-methyl-1H-indol-3-ylmethyl)-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-acrylic acid (51 mg, 0.11 mmol, 25%) as an orange solid (hydrochloride salt). The product was suspended in DCM (3 ml), TEA (0.025 ml, 0.31 mmol) was added, and the clear solution was treated with NH2OTHP following the procedure described in Example 2, step C, giving (E)-3-[1′(1-methyl-1H-indol-3-ylmethyl)-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (53 mg, 0.10 mmol, 91%) as a light yellow solid. The compound was then dissolved in DCM (3 ml) and treated with 1 M HCl in diethyl ether (3 ml) as described in Example 2, step D, giving a light brown solid after aqueous workup and column chromatography (eluent: DCM/MeOH 9:1) (10 mg, 22%, free base)

Provenance & Evidence