| 82% |
In dichloromethane;Heating / reflux; |
tert-Butyl 4- {1-(3-chloro-4-fluorophenyl)-2-[(3-cyano-2-methoxy-1- naphthyl)methoxy]ethyl}piperazine-1-carboxylate (100 mg, 0.18 mmol) was dissolved in DCM (2 mL) and TFA (2 mL) was added. After 2h the volatiles were removed under reduced pressure. The residue was taken up in EtOAc (20 mL) and washed with sat. aq. NaHC03 (20 mL). The organic phase was dried over Na2S04, filtered through a pad of diatomaceous earth and the volatiles removed under reduce pressure. Chromatography of the residue on Si02 (0- 5% 2 M NH3 in MeOH: DCM) afforded the title compound as an off-white solid (81.6 mg, 79%). The citrate salt was formed by the addition of citric acid (1.0 equivalents) to a methanolic solution of the title compound. Concentration under reduced pressure afforded the desired salt form of the product as an off-white powder. MS m/z 454.4 (M+H) +. ¹H NMR (300.1 MHz, DMSO + TFA) No. 8.64 (s, 1H), 8.08 (t, J= 7.6 Hz, 2H), 7.80 (dd, J= 1.9, 7.1 Hz, 1H), 7.72 (t, J= 7.1 Hz, 1H), 7.64 (t, J= 7.6 Hz, 1H), 7.55 - 7.45 (m, 2H), 5.06 (dd, J= 15.4, 11.0 Hz, 2H), 4.78 (t, J= 5.0 Hz, 1H), 4.20 (d, J= 5.0 Hz, 2H), 3.99 (s, 3H), 3.41 - 3.34 (m, 6H), 3.23 - 3.19 (m, 2H), 2.75 (dd, J= 33.0, 15.4 Hz, 4H), 1.83 (s, 1H). The requisite tert-butyl 4-{1-(3-chloro-4-fluorophenyl)-2-[(3-cyano-2-methoxy-1- naphthyl)methoxy]ethyl}piperazine-1-carboxylate was synthesized using the following method. tert-Butyl 4-[1-(3-chloro-4-fluorophenyl)-2-hydroxyethyl]piperazine-1-carboxylate (65 mg, 0.18 mmol) was dissolved in THF (1.8 mL). 4-(Iodomethyl)-3-methoxy-2- naphthonitrile (70 mg, 0.22 mmol) was added followed by NaH (9 mg, 0.36 mmol). After reacting at RT overnight, water (60 mL) was added. The mixture was extracted with EtOAc (40 mL). The organic phase was dried over Na2S04, filtered through a pad of diatomaceous earth and the volatiles removed under reduce pressure. Chromatography of the residue on Si02 (0-30% EtOAc: hexane) afforded the title compound (99 mg). MS m/z 554.6 (M+H)+. The requisite tert-butyl 4- [ 1 -(3 -chloro-4-fluorophenyl)-2-hydroxyethyl]piperazine- I - carboxylate was synthesized using the following method. Borane-methyl sulfide complex (2M in THF, 1.07 mL) was added to a solution of [4- (tert-butoxycarbonyl)piperazin-1-yl](3-chloro-4-fluorophenyl)acetic acid (200 mg, 0.54 mmol) in THF (3 mL). After 30 min at RT the reaction was heated to reflux for 4h. After cooling the reaction to RT, MeOH (10 mL) was slowly added. After stirring overnight the volatiles were removed under reduced pressure. Chromatography of the residue on Si02 (0- 50% EtOAc:hexane) afforded the title compound (160 mg, 83%). MS m/z 359.3 (M+H)+, 303.2 (M+H-t-butyl). The requisite [4-(tert-butoxycarbonyl)piperazin-1-yl](3-chloro-4-fluorophenyl)acetic acid was synthesized using the following method. (3-Chloro-4-fluorophenyl) boronic acid (440 mg, 2.52 mmol), tert-butyl piperazine-1-carboxylate (469 mg, 2.52 mmol) and glyoxylic acid monohydrate (232 mg, 2.52 mmol) were reacted together in DCM (10 mL) at reflux overnight. The volatiles were removed under reduced pressure. Chromatography of the residue on Si02 (0-10% MeOH: DCM) afforded the title compound (767 mg, 82%). MS m/z 373.1 (M+H)+, 317.1 (M+H-t-butyl). ¹H NMR (300.1 MHz, DMSO) 6 12.80 (s, 0.6H), 7.59 (d, J= 7.2 Hz, 1H), 7.42 (d, J= 7.2 Hz, 2H), 4.09 (s, 1H), 3.30 (s, 2H), 3.16 (s, 2H), 2.35 (m, 4H), 1.38 (s, 9H). |
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