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

HRID 1445169Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1445169
[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]

Komponenten

10

Edukt 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

Produkt 1

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

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 962WaterLösungsmittelHCID 6228DimethylformamideLösungsmittel2×HCID 8028TetrahydrofuranLösungsmittel

Versuchsvorschrift

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).

Aufarbeitung

  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

Quellen und Nachweise

ORD-Eintrag
ord-f28fae1c4e7a46508537c6bc483ff375
Quelldatensatz
uspto-grants-2010_02
Patentnummer
US07662966B2

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