Ethanol → HCID 178451999, compound

HRID 913950Notes

Reaction equation

HRID 913950 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:14][CH2:15][C:16]3([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[CH2:12][F:13])[CH:10]=1)[NH:7][N:6]=[CH:5]2.[OH-].[Na+].C(O)C.C1C(=O)N([Cl:48])C(=O)C1>>[Cl:48][C:5]1[C:4]2[C:8](=[C:9]([C@H:11]([O:14][CH2:15][C:16]3([C:29]4[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=4)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[CH2:12][F:13])[CH:10]=[C:2]([Cl:1])[CH:3]=2)[NH:7][N:6]=1

Participants

5

Reactant 4

HCID 702EthanolHCID 14798Sodium Hydroxide2×HCID 31398Chlorosuccinimide2×HCID 57546100tert-Butyl 4-((1-(5-chloro-1H-indazol-7-yl)-2-fluoroethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate

Product 1

HCID 178451999HCID 178451999, compoundYield 74.9%

Procedure

To a solution of tert-butyl 4-((1-(5-chloro-1H-indazol-7-yl)-2-fluoroethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (90 mg, 0.178 mmol) and sodium hydroxide (4N in water) (0.056 mL, 0.222 mmol) in ethanol (1.7 mL, 29.1 mmol) at 0 C was added NCS (47.5 mg, 0.356 mmol), it was stirred at 0 C for 2 h when most S.M. converted to product. The reaction was treated with 0.03 ml of 4 N NaOH, 1 eq. of NCS and was stirred at 0 C for another 2 h., there is still some unreacted SM by TLC. The reaction was quenched by addition of aqueous ammonia and diluted with Et2O. The organic layer was washed with water (2×) then brine, dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (25% EtOAc/Hex) to give title compound (72 mg, 74.9% yield) as clear oil. 1H-NMR (CDCl3, 500 MHz) δ 7.57 (d, J=1.83, 1H), 7.28-7.25 (m, 2H), 7.09-7.06 (m, 3H), 4.6-4.4 (m, 3H), 3.77-3.6 (m, 2H), 3.51 (d, J=9.16 Hz, 1H), 3.39 (d, J=9.16 Hz, 1H), 3.08-2.95 (m, 2H), 2.27 (m, 1H), 2.05 (m, 1H), 1.86 (m, 1H), 1.74 (m, 1H), 1.43 (s, 9H); 13C-NMR (CDCl3, 126 MHz) δ 161.8 (d, J=247.6 Hz), 154.9, 137.8, 137.6, 134.4, 128.73, 127.67, 126.7, 122.2, 121.8, 119.0, 115.9, 115.8, 85.7, 84.3, 81.1, 80.9, 79.7, 42.5, 41.4, 32.4, 32.1, 31.7, 28.5, 22.7, 14.2. LC/MS (HPLC method 3): tR=4.12 min, 540.1(MH)+.

Workup

  1. stirringwas stirred at 0 C for another 2 h.
  2. customThe reaction was quenched by addition of aqueous ammonia
  3. additiondiluted with Et2O
  4. washThe organic layer was washed with water (2×)
  5. dry with materialbrine, dried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe crude product was purified by silica gel column chromatography (25% EtOAc/Hex)

Sources & evidence

ORD record
ord-19e646cb0ccf4c45bc1d6fab70f5cc45
Source dataset
uspto-grants-2011_09
Patent number
US08026257B2

Reaction notes

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