Trichloroacetonitrile → Tert-butyl 4-((1-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1h-benzo[d]imidazol-4-yl)ethoxy)methyl)-4-phenylpiperidine-1-carboxylate

1-(6-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-4-yl)ethanol (336 mg, 0.91 mmol) was converted to the corresponding trichloroacetimidate ester using trichloroacetonitrile (0.15 mL), DBU (0.02 mL) in CH2Cl2:cyclohexane (1:3, 2 mL) following a reported procedure (Kuethe, J. T. et. al. J. Org. Chem. 2006, 71, 7378-7390). TLC analysis (SiO2, EtOAc:hexane, 7:3) indicated approximately 10% of starting material with the formation of a less polar product. The reaction mixture was worked up as described in the cited reference. The crude product was purified by SiO2 chromatography using a linear gradient of EtOAc:hexane (3:22) to EtOAc on biotage instrument on a 25M cartridge. Fractions containing the less polar imidate ester were combined and evaporated in vacuo. The residue obtained weighed (363 mg, 78%). This was used in the next step as follows: Azeotropically dried (heptane) sample of imidate (354 mg, 0.69 mmol) was dissolved in dichloroethane (2 mL) and to this tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (200 mg, 1.0 equiv) and heptane (0.5 mL) were added. The clear solution was cooled to −15° C. (dry ice-ethyleneglycol bath) under N2 and to the resulting suspension HBF4 (3 drops ˜10-15 μL) was added. After stirring for 5 min, the cooling bath was changed to Ice-water bath and stirring continued for another 1 h. The reaction mixture was warmed to room temperature for 1 h. At the end 0.71 mL of 1N aq. NaOH was added and stirred for 10 min. Diluted with EtOAc (40 mL) and more water (30 mL) and extracted. Organic layer was dried (Na2SO4) and evaporated. The crude product was purified by SiO2 chromatography using a linear gradient of EtOAc:hexane (3:22) to EtOAc on biotage instrument on a 25M cartridge. Fractions containing required product and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate as contaminant were purified by preparative HPLC (Method 17). Fractions containing the required product were combined and evaporated in vacuo. The residue was converted to free base using ammonium hydroxide to give tert-butyl 4-((1-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-4-yl)ethoxy)methyl)-4-phenylpiperidine-1-carboxylate (34 mg) as racemate. 1H NMR (500 MHz, MeOD) δ ppm 8.28 (s, 1 H), 7.70 (d, J=1.8 Hz, 1 H), 7.33-7.41 (m, 4 H), 7.21-7.28 (m, 1 H), 7.08 (d, J=1.5 Hz, 1 H), 5.62 (s, 2 H), 5.01 (q, J=6.4 Hz, 1 H), 3.66-3.78 (m, 2 H), 3.55 (t, J=7.9 Hz, 2 H), 3.40 (d, J=9.2 Hz, 1 H), 3.31 (d, 1 H, partial overlap with solvent signal), 2.96-3.15 (m, 2 H), 2.12-2.27 (m, 2 H), 1.83-1.98 (m, 2 H), 1.46 (s, 9 H), 1.40 (d, J=6.4 Hz, 3 H), 0.88 (t, J=7.9 Hz, 2 H), −0.07 (s, 9 H). 644(MH)+.

1. customThe crude product was purified by SiO2 chromatography
2. additionFractions containing the less polar imidate ester
3. customevaporated in vacuo
4. customThe residue obtained
5. additionwere added
6. customthe cooling bath was changed to Ice-water bath
7. stirringstirring
8. waitcontinued for another 1 h
9. stirringstirred for 10 min
10. extractionextracted
11. dry with materialOrganic layer was dried (Na2SO4)
12. customevaporated
13. customThe crude product was purified by SiO2 chromatography
14. additionFractions containing required product and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate as contaminant
15. customwere purified by preparative HPLC (Method 17)
16. additionFractions containing the required product
17. customevaporated in vacuo

ORD-Eintrag

ord-c759a8e9a18c44eb9101386da2bf314e

Quelldatensatz

uspto-grants-2011_09

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08026257B2