Formaldehyde → (+/-)-5-chloro-7-(1-((4-(4-fluorophenyl)-1-methylpiperidin-4-yl)methoxy)ethyl)-1H-indole-3-carbonitrile

(±)-tert-butyl 4-((1-(5-chloro-3-cyano-1H-indol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (70 mg, 0.137 mmol) was stirred in TFA (2 mL, 26.0 mmol) at 0° C. for 20 minutes. The solvent was evaporated at a bath temperature of 23° C. The residue was taken up in Ethanol (5 mL), then triethylamine (1 mL), formaldehyde (0.102 mL, 1.367 mmol) and sodium triacetoxyborohydride (87 mg, 0.410 mmol) were added. The reaction was stirred 1 hour, then solvent was evaporated. The residue was taken up in aqueous sodium bicarbonate (10 mL) and extracted with ethyl acetate (4×10 mL). The organic phase was dried with MgSO4 and evaporated. The residue was purified by chromatography on SiO2 with 3%-5%% 2M ammonia in methanol/dichloromethane to give (±)-5-chloro-7-(1-((4-(4-fluorophenyl)-1-methylpiperidin-4-yl)methoxy)ethyl)-1H-indole-3-carbonitrile (55 mg, 0.129 mmol, 94% yield) as a clear oil. 1H-NMR (CDCl3, 400 MHz) δ 8.27 (bs, 1H), 7.56 (d, J=1.8 Hz, 1H), 7.27 (m, 2H), 7.14 (d, J=2.8 Hz, 1H), 7.08 (t, J=8.5 Hz, 2H), 6.93 (d, J=1.8 Hz, 1H), 4.55 (q, J=6.5 Hz, 1H), 4.55 (m, 1H), 3.19 (d, J=8.6 Hz, 1H), 2.62 (m, 1H), 2.52 (m, 2H), 2.35 (m, 1H), 1.95-2.20 (m, 2H), 1.86 (m, 1H), 1.48 (m, 1H), 1.41 (d, J=6.5 Hz, 3H). LC/MS (HPLC method 4): tR=2.84 min, 426.14(MH)+.

1. customThe solvent was evaporated at a bath temperature of 23° C
2. customsolvent was evaporated
3. extractionextracted with ethyl acetate (4×10 mL)
4. dry with materialThe organic phase was dried with MgSO4
5. customevaporated
6. customThe residue was purified by chromatography on SiO2 with 3%-5%% 2M ammonia in methanol/dichloromethane

ORD record

ord-ada85f864add4f9cbf07d7a70af0f65d

Source dataset

uspto-grants-2011_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08026257B2