Triethylamine → HCID 57546017, compound

HRID 913835Notes

Reaction equation

HRID 913835 reaction equation
[C:1]([C:3]1[N:4](COCC[Si](C)(C)C)[N:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:8]=[C:7]2[CH:16]([O:18][CH2:19][C:20]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)[CH3:17])#[N:2].FC(F)(F)C(O)=O.C(Cl)Cl.C(=O)(OC(C)(C)C)OC(C)(C)C.C(N(CC)CC)C>ClCCl.N.CO>[C:1]([C:3]1[C:11]2[C:6](=[C:7]([CH:16]([O:18][CH2:19][C:20]3([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[CH3:17])[CH:8]=[C:9]([C:12]([F:14])([F:15])[F:13])[CH:10]=2)[NH:5][N:4]=1)#[N:2]

Participants

8

Reactant 4

HCID 8471TriethylamineHCID 10219638Carbonic acid, bis(1,1-dimethylethyl) esterHCID 21863450Trifluoroacetic acid methylene chlorideHCID 57545974HCID 57545974, compound

Product 1

HCID 57546017HCID 57546017, compound

Reagents, catalysts & solvents 3

HCID 222AmmoniaCatalystHCID 887MethanolSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

(±)-tert-Butyl 4-((1-(3-cyano-5-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethoxy)methyl)-4-phenylpiperidine-1-carboxylate (95 mg, 0.14 mmol) was treated with a trifluoroacetic acid/methylene chloride mixture (1:1, 2 mL) for 3 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. The solvent was concentrated to afford a crude product which was dissolved in dichloromethane (3 mL), cooled to 0° C., and treated with di-tert-butyl carbonate (63 mg, 0.29 mmol) and triethylamine (30 μL, 0.22 mmol). After 1 h, the reaction was treated with a few drops of 2 M ammonia in methanol and concentrated. The residue was dissolved in ethyl acetate, washed with water (2×), brine (2×), dried over sodium sulfate, filtered and concentrated. Flash chromatography on silica gel (15% ethyl acetate/hexanes) afforded 40 mg (53%). 1H-NMR (CDCl3, 500 MHz) δ 7.99 (s, 1H), 7.38-7.46 (m, 3H), 7.31-7.33 (m, 3H), 4.70 (q, J=6.7 Hz, 1H), 4.46 (m, 2H), 3.78-3.79 (m, 2H), 3.55 (d, J=8.9 Hz, 1H), 3.35 (d, J=8.9 Hz, 1H), 2.98-3.12 (m, 2H), 2.08-2.40 (m, 2H), 1.68-1.87 (m, 2H), 1.46 (m, 3H), 1.43 (s, 9H). Mass spec.: 529.19 (MH)+.

Workup

  1. customThe solvent was removed in vacuo
  2. washAfter washing the column with several volumes of methanol
  3. washthe product was eluted
  4. washby washing the column with 2 M ammonia in methanol
  5. concentrationThe solvent was concentrated
  6. customto afford a crude product which
  7. concentrationconcentrated
  8. dissolutionThe residue was dissolved in ethyl acetate
  9. washwashed with water (2×), brine (2×)
  10. dry with materialdried over sodium sulfate
  11. filtrationfiltered
  12. concentrationconcentrated
  13. customFlash chromatography on silica gel (15% ethyl acetate/hexanes) afforded 40 mg (53%)

Sources & evidence

ORD record
ord-ad72f94190574521be544043cefaf110
Source dataset
uspto-grants-2011_09
Patent number
US08026257B2

Reaction notes

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