1,2-Dichloroethane → Ammonium Hydroxide

Participants

Reaction Steps

A solution of N-[2-(3,5-difluorophenyl)-2-({[(7S)-2′-oxo-1′,2′,6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-3-yl]methyl}amino)propyl]-2-methylalanine from Step D (150 mg, 0.262 mmol), EDC (60.4 mg, 0.315 mmol), HOBT (48.2 mg, 0.315 mmol), and DIEA (0.229 mL, 1.31 mmol) in DMF (5 mL) was stirred for 16 h. The reaction mixture was diluted with saturated aqueous NaHCO3 (20 mL) and extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH:NH4OH—100:0:0 to 90:10:1, to give the title compound as a mixture of diastereomers. The mixture of diastereomers were resolved by HPLC, utilizing a Chiralpak AS-H column and eluting with MeOH:CO2—20:80. The first major peak to elute was (7S)-3-{[(2R)-2-(3,5-Difluorophenyl)-2,5,5-trimethyl-6-oxopiperazin-1-yl]methyl}-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one, isomer A, and the second major peak to elute was (7S)-{[(2R)-2-(3,5-Difluorophenyl)-2,5,5-trimethyl-6-oxopiperazin-1-yl]methyl}-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one, isomer B, the title compound. MS: m/z=554 (M+1). HRMS: m/z=554.2365; calculated m/z=554.2362 for C32H30F2N5O2.

Provenance & Evidence