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

HRID 1445169노트

반응식

HRID 1445169 반응식
[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]

참가 물질

10

반응물 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

생성물 1

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

시약·촉매·용매 3

HCID 962Water용매HCID 6228Dimethylformamide용매2회HCID 8028Tetrahydrofuran용매

실험 절차

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).

후처리

  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

출처 및 근거

ORD 기록
ord-f28fae1c4e7a46508537c6bc483ff375
출처 데이터셋
uspto-grants-2010_02
특허 번호
US07662966B2

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