2-(4-Boc-piperazinyl)-2-(3-methoxy-phenyl)acetic acid synthesis

Yield:868151-10-4 94%

Reaction Conditions:

in dichloromethane;Heating / reflux;

Steps:

2

tert-Butyl 4-[2-[[(3-cyano-2-methoxy-1-naphthyl)methyl](methyl)amino]-1-(3- methoxyphenyl)-2-oxoethyl]piperazine-1-carboxylate (123 mg, 0.22 mmol) was deprotected in 1:1 TFA:DCM (20 mL). After lh, the volatiles were removed under reduced pressure. The residue was dissolved in DCM, washed with sat. aq. NaHC03. The organic phase was dried over Na2SO4, 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 (83 mg, 82%). MS m/z 459.2 (M+H)+. 1H NMR (300.1 MHz, DMSO) 8 8.60 (s, 1H), 8.01 (d, J= 7.4 Hz, 1H), 7.96 (d, J= 8.2 Hz, 1H), 7.61 - 7.52 (m, 2H), 7.20 (t, J= 8.2 Hz, 1H), 6.97 (s, 2H), 6.83 (d, J= 8.2 Hz, 1H), 5.03 (dd, J= 21.3, 14.2 Hz, 2H), 4.43 (s, 1H), 3.95 (s, 3H), 3.69 (s, 3H), 2.71 - 2.69 (m, 7H), 2.43 - 2.41 (m, 4H). The citrate salt was formed by the addition of citric acid (16 mg, 1.0 equivalents) to a methanolic solution of the title compound (39 mg). Concentration under reduced pressure afforded the desired salt form of the product as a white foam. MS m/z 459.3 (M+H)(at). The requisite tert-butyl 4-[2-[[(3-cyano-2-methoxy-1- naphthyl)methyl](methyl)amino]-1-(3-methoxyphenyl)-2-oxoethyl]piperazine-1-carboxylate was synthesized using the following method. [4-(tert-Butoxycarbonyl)piperazin-1-yl](3-methoxyphenyl)acetic acid (100 mg, 0.28 mmol), 3-methoxy-4- [(methylamino)methyl]-2-naphthonitrile (64 mg, 0.28 mmol), HOBT (58 mg, 0.43 mmol), and 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide (66 mg, 0.34 mmol) were reacted together in DCM (10 mL) at RT overnight. The reaction mixture was partitioned between water (20 mL) and DCM (20 mL). The organic layer was washed with sat. aq. NaHC03, dried over Na2S04, filtered through a pad of diatomaceous earth and the volatiles were removed under reduced pressure. Chromatography of the residue on Si02 (0- 50% EtOAc:hexane) afforded the title compound as a white solid (123 mg, 77%). MS m/z 559.4 (M+H)+. 1H NMR (300.1 MHz, DMSO) No. 8.60 (s, 1H), 8.04 - 7.96 (m, 2H), 7.61 - 7.54 (m, 2H), 7.21 (t, J= 8.3 Hz, 1H), 6.97 - 6.95 (m, 2H), 6.84 (dd, J= 8.3, 2.1 Hz, 1H), 5.04 (s, 2H), 4.51 (s, 1H), 3.95 (s, 3H), 3.69 (s, 3H), 3.29 - 3.26 (m, 4H), 2.67 (s, 3H), 2.47 - 2.37 (m, 4H), 1.38 (s, 9H). The requisite [4-(tert-butoxycarbonyl)piperazin-1-yl](3-methoxyphenyl)acetic acid was synthesized using the following method. (3-Methoxyphenyl) boronic acid (345 mg, 1.61 mmol), tert-butyl piperazine-1- carboxylate (300 mg, 1.61 mmol) and glyoxylic acid monohydrate (148 mg, 1.61 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 (531 mg, 94%). MS m/z 351.1 (M+H)+, 295.1 (M+H-t-butyl). 1H NMR (300.1 MHz, DMSO) 8 12.39 (s, 0.2H), 7.27 (t, J= 8.4 Hz, 1H), 6.97 - 6.94 (m, 2H), 6.89 (d, J= 8.4 Hz, 1H), 3.97 (s, 1H), 3.74 (s, 3H), 3.36 - 3.26 (m, 10H [4H + H20]), 2.40 - 2.31 (m, 4H), 1.37 (s, 9H).

References:

WO2005/100325,2005,A1 Location in patent:Page/Page column 11-13