Hydrochloric Acid → HCID 69218508, compound

A mixture of 4-methyl-3-(1-{[4-(2,4,5-trifluorophenoxy)phenyl]methyl}(4-piperidyl)) phenylamine (70 mg, 0.164 mmol), piperidine-1,3-dicarboxylic acid 1-tert-butyl ester (113 mg, 0.492 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 188 mg, 0.492 mmol) and diisopropylethylamine (85 mg, 0.657 mmol) in dimethylformamide (5 mL) was stirred at room temperature for 18 h. The mixture was partitioned between water (20 mL) and CH2Cl2 (2×20 mL). The combined organic layers were washed with water (2×20 mL) and saturated brine (20 mL) then dried over MgSO4 and concentrated in vacuo to give a gummy solid. This was dissolved in methanol (3 mL) and methanolic hydrogen chloride (1 M, 4 mL) was added and stirring was continued for 18 h. The reaction mixture was concentrated in vacuo to yield a gum. This was dissolved in CH2Cl2 and applied to a SCX cartridge (5 g) and eluted with CH2Cl2:methanol, 1:1 then methanolic ammonia (1.6 M):CH2Cl2, 1:1 to yield N-[4-methyl-3-(1-{[4-(2,4,5-trifluorophenoxy)phenyl]methyl}(4-piperidyl))phenyl]-3-piperidylcarboxamide (88 mg, 100% yield). This was dissolved in acetonitrile (2 mL) and water (1 mL) and formaldehyde (37%, 75 μL, 0.921 mmol) followed by sodium cyanoborohydride (11 mg, 0.184 mmol) and the resulting mixture was stirred at room temperature for 1 h. This was partitioned between CH2Cl2 (2×10 mL) and saturated aqueous NaHCO3 (20 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to yield the crude product which was applied to a SCX cartridge (5 g) and eluted with CH2Cl2:methanol (1:1) then methanolic ammonia to give a gum. Purification on silica (silica gel 60, ca 20 mL) eluting with CH2Cl2:methanol:triethylamine, 195:4:1 gave the free base as a glassy solid. This was dissolved in methanol (2 mL) and methanolic hydrogen chloride (1.25 M, 4 mL) was added. The solution was concentrated in vacuo to give (1-methyl(3-piperidyl))-N-[4-methyl-3-(1-{[4-(2,4,5-trifluorophenoxy)phenyl]methyl}(4-piperidyl))phenyl]carboxamide dihydrochloride (45 mg, 50% yield) as a gummy solid. LCMS (method A): 6.91 min, 552.3 (M+H)+; 1H NMR (D6-DMSO) δ 10.94 (br s, 1H), 10.72 (br s, 1H), 10.29 (s, 1H), 7.84 (td, J=10.8, 7.7 Hz, 1H), 7.65 (m, 2H), 7.60 (dt, J=11.0, 7.9 Hz, 1H,), 7.42 (d, J=2.1 Hz, 1H), 7.38 (dd, J=8.1, 2.1 Hz, 1H), 7.09 (m, 3H), 4.28 (d, J=5.1 Hz, 2H), 3.40 (m, 4H), 3.04 (m, 4H), 2.91 (m, 2H), 2.74 (d, J=4.8 Hz, 3H), 2.24 (s, 3H), 2.00 (m, 3H), 1.86 (m, 4H), 1.48 (m, 1H).

1. customThe mixture was partitioned between water (20 mL) and CH2Cl2 (2×20 mL)
2. washThe combined organic layers were washed with water (2×20 mL) and saturated brine (20 mL)
3. dry with materialthen dried over MgSO4
4. concentrationconcentrated in vacuo
5. customto give a gummy solid
6. stirringstirring
7. waitwas continued for 18 h
8. concentrationThe reaction mixture was concentrated in vacuo
9. customto yield a gum
10. washeluted with CH2Cl2

ORD record

ord-50c9e3b1c93c412e87c9521a0591a4bf

Source dataset

uspto-grants-2008_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07446204B2