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

HRID 1445169ノート

反応式

HRID 1445169 の反応式
[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]

参加物

10

反応物 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

生成物 1

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

試薬・触媒・溶媒 3

HCID 962Water溶媒HCID 6228Dimethylformamide溶媒2 回HCID 8028Tetrahydrofuran溶媒

実験手順

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).

後処理

  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

出典と根拠

ORDレコード
ord-f28fae1c4e7a46508537c6bc483ff375
出典データセット
uspto-grants-2010_02
特許番号
US07662966B2

反応ノート

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