Acetic Acid → 5-Chloro-7-(1-((4-(4-fluorophenyl)-1-methylpiperidin-4-yl)methoxy)ethyl)-1-methyl-1h-benzo[d]imidazol-2(3h)-one trifluoroacetic acid salt

HRID 914041노트

반응식

HRID 914041 반응식
[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]([O:23][CH2:24][C:25]2([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[CH2:30][CH2:29][N:28]([C:31](OC(C)(C)C)=O)[CH2:27][CH2:26]2)[CH3:22])[C:5]2[N:9]([CH3:10])[C:8](=[O:11])[N:7](COCC[Si](C)(C)C)[C:6]=2[CH:20]=1.C([BH3-])#N.[Na+].C(O)(=O)C.[F:53][C:54]([F:59])([F:58])[C:55]([OH:57])=[O:56]>>[F:53][C:54]([F:59])([F:58])[C:55]([OH:57])=[O:56].[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]([O:23][CH2:24][C:25]2([C:38]3[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=3)[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]2)[CH3:22])[C:5]2[N:9]([CH3:10])[C:8](=[O:11])[NH:7][C:6]=2[CH:20]=1

참가 물질

5

반응물 4

HCID 176Acetic AcidHCID 6422Trifluoroacetic acidHCID 5003444Sodium cyanoborohydrideHCID 57546215tert-Butyl 4-((1-(6-chloro-3-methyl-2-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate

생성물 1

HCID 251612285-Chloro-7-(1-((4-(4-fluorophenyl)-1-methylpiperidin-4-yl)methoxy)ethyl)-1-methyl-1h-benzo[d]imidazol-2(3h)-one trifluoroacetic acid salt

실험 절차

tert-Butyl 4-((1-(6-chloro-3-methyl-2-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (26 mg, 0.040 mmol) was dissolved in trifluoroacetic acid (40% in dichloromethane, 1 mL) and stirred at room temperature for 1 h. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The crude piperidine was eluted with 2M ammonia in methanol and concentrated. The crude product was dissolved in acetonitrile (1 mL) and treated with formalin (50 μL) followed quickly by sodium cyanoborohydride (5.0 mg, 0.08 mmol). To this was added two small drops of acetic acid over 5 minutes. The reaction was concentrated and the residue taken up in ethyl acetate, washed with saturated sodium bicarbonate, then brine, dried over magnesium sulfate, and concentrated. The crude product was dissolved in ethanol (10 mL) and heated at reflux overnight. The reaction was concentrated and purified by preparative HPLC (28% B isocratic method, TFA/ACN) to give 10.3 mg (47%). 1H-NMR (CD3OD, 500 MHz) δ 7.44 (m, 1.5H), 7.35 (m, 0.5H), 7.14 (m, 1.5H), 7.06 (m, 0.5H), 6.90-7.20 (m, 1H), 6.78 (d, J=2.1 Hz, 0.6H), 6.68 (m, 0.3H), 4.99 (m, 1H), 3.35-3.52 (m, 5H), 3.30 (d, J=9.2 Hz, 1H), 2.55-3.00 (m, 6H), 2.05 (m, 2H), 1.30-1.50 (m, 3H). Mass spec.: 432.1 (MH)+.

후처리

  1. concentrationThe reaction was concentrated
  2. customThe cartridge was flushed with several volumes of methanol which
  3. washThe crude piperidine was eluted with 2M ammonia in methanol
  4. concentrationconcentrated
  5. dissolutionThe crude product was dissolved in acetonitrile (1 mL)
  6. additiontreated with formalin (50 μL)
  7. concentrationThe reaction was concentrated
  8. washwashed with saturated sodium bicarbonate
  9. dry with materialbrine, dried over magnesium sulfate
  10. concentrationconcentrated
  11. dissolutionThe crude product was dissolved in ethanol (10 mL)
  12. temperatureheated
  13. temperatureat reflux overnight
  14. concentrationThe reaction was concentrated
  15. custompurified by preparative HPLC (28% B isocratic method, TFA/ACN)
  16. customto give 10.3 mg (47%)

출처 및 근거

ORD 기록
ord-e56a244ed9e74e9386ee15f78326d59a
출처 데이터셋
uspto-grants-2011_09
특허 번호
US08026257B2

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