Sodium Bicarbonate → {2-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-5-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-methanol

HRID 646984Notes

Reaction equation

HRID 646984 reaction equation
[O:1]1CCCO[CH:2]1[C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)[CH:10]=[CH:9][C:8]=1[C:24]1[NH:28][C:27]2[CH:29]=[CH:30][C:31]([F:34])=[C:32]([CH3:33])[C:26]=2[N:25]=1.BrC1C=CC(OCCCC2CCN(C)CC2)=CC=1C1OCCCO1.C([Li])CCC.C([O-])(O)=O.[Na+].O1CCCOC1C1C=C(OCCCC2CCN(C)CC2)C=CC=1C=O.FC1C(C)=C(N)C(N)=CC=1>C1COCC1.CN(C=O)C.O>[F:34][C:31]1[CH:30]=[CH:29][C:27]2[NH:28][C:24]([C:8]3[CH:9]=[CH:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH:17]4[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)=[CH:12][C:7]=3[CH2:2][OH:1])=[N:25][C:26]=2[C:32]=1[CH3:33]

Participants

10

Reactant 6

HCID 516892Sodium BicarbonateHCID 220555474-Fluoro-3-methylbenzene-1,2-diamineHCID 575254714-[3-(4-Bromo-3-[1,3]dioxan-2-yl-phenoxy)-propyl]-1-methyl-piperidineHCID 575254722-{2-[1,3]Dioxan-2-yl-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-5-fluoro-4-methyl-1H-benzoimidazoleHCID 575254732-[1,3]Dioxan-2-yl-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-benzaldehydeHCID 178418339Butyllithium

Product 1

HCID 57525470{2-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-5-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-methanolYield 77%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolvent2×HCID 8028TetrahydrofuranSolvent

Procedure

2-{2-[1,3]Dioxan-2-yl-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-phenyl}-5-fluoro-4-methyl-1H-benzoimidazole. To a stirred solution of 4-[3-(4-bromo-3-[1,3]dioxan-2-yl-phenoxy)-propyl]-1-methyl-piperidine (4.82 g, 12.4 mmol, 1.0 equiv) in THF (62 mL) at −78° C. was added 2.5 M n-butyllithium in hexanes (22 mL, 55 mmol, 4.4 equiv). The resulting orange solution was stirred for 30 min then DMF (9.6 mL, 124 mmol, 10.0 equiv) was added. The solution was warmed to rt and stirred for 1.0 h then re-cooled to −78° C. and satd. aq. NaHCO3 was added. The mixture was warmed to rt, poured into water, and extracted with ethyl acetate. The combined extracts were dried (Na2SO4), filtered, and concentrated. The crude residue was partially purified by Method 2. The resultant 2-[1,3]dioxan-2-yl-4-[3-(1-methyl-piperidin-4-yl)-propoxy]-benzaldehyde (491 mg, 1.41 mmol, 1.0 equiv) was stirred with 4-fluoro-3-methyl-benzene-1,2-diamine (198 mg, 1.41 mmol, 1.0 equiv) and Na2S2O5 (350 mg, 1.84 mmol, 1.3 equiv) in DMF (7.0 mL) at 90° C. for 2 h. The mixture was loaded onto silica gel and purified by Method 2 to afford 509 mg (77%) of the title compound. MS (electrospray): mass calculated for C27H34FN3O3, 467.26. m/z found, 468.4 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.62 (d, J=8.5 Hz, 1H), 7.44-7.37 (m, 1H), 7.35 (d, J=2.7 Hz, 1H), 7.09-6.99 (m, 2H), 5.97 (s, 1H), 4.19-4.13 (m, 2H), 4.09 (t, J=6.4 Hz, 2H), 3.95-3.86 (m, 2H), 2.95-2.87 (m, 2H), 2.53 (s, 3H), 2.30 (s, 3H), 2.22-1.99 (m, 3H), 1.93-1.76 (m, 4H), 1.51-1.22 (m, 6H).

Workup

  1. stirringstirred for 1.0 h
  2. temperaturethen re-cooled to −78° C.
  3. temperatureThe mixture was warmed to rt
  4. extractionextracted with ethyl acetate
  5. dry with materialThe combined extracts were dried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe crude residue was partially purified by Method 2
  9. custompurified by Method 2

Sources & evidence

ORD record
ord-48a49909b5fa42dc812b828206559313
Source dataset
uspto-grants-2010_04
Patent number
US07705149B2

Reaction notes

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