tert-Butyl 4-((1-(5-cyclopropyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate → HCID 57546036, compound

HRID 913872Notes

Reaction equation

HRID 913872 reaction equation
[CH:1]1([C:4]2[CH:5]=[C:6]3[C:10](=[C:11]([CH:13]([O:15][CH2:16][C:17]4([C:30]5[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=5)[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]4)[CH3:14])[CH:12]=2)[NH:9][N:8]=[CH:7]3)[CH2:3][CH2:2]1.C1(C2C=C(C(OCC3(C4C=CC(F)=CC=4)CCN(C(OC(C)(C)C)=O)CC3)C)C3C(=CN(COCC[Si](C)(C)C)N=3)C=2)CC1>FC(F)(F)C(O)=O>[CH:1]1([C:4]2[CH:5]=[C:6]3[C:10](=[C:11]([CH:13]([O:15][CH2:16][C:17]4([C:30]5[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=5)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[CH3:14])[CH:12]=2)[NH:9][N:8]=[CH:7]3)[CH2:3][CH2:2]1

Participants

4

Reactant 2

HCID 57545980tert-Butyl 4-((1-(5-cyclopropyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylateHCID 57546075HCID 57546075, compound

Product 1

HCID 57546036HCID 57546036, compound

Reagents, catalysts & solvents 1

HCID 6422Trifluoroacetic acidSolvent

Procedure

Enantiomer B of tert-Butyl 4-((1-(5-cyclopropyl-1H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate. Enantiomer B of tert-Butyl 4-((1-(5-cyclopropyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate(46 mg, 0.074 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 1.6 mL) and stirred at room temperature for 4 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 product was eluted with 2 M ammonia in methanol and concentrated to give 30 mg of Enantiomer B of 5-cyclopropyl-7-(1-((4-(4-fluorophenyl)piperidin-4-yl)methoxy)ethyl)-1H-indazole (quant.). The crude amine (30 mg, 0.076 mmol) in dichloromethane (2 mL) was cooled to 0° C. and treated with di-tert-butyl dicarbonate (33.3 mg, 0.152 mmol). The reaction was stirred at 0° C. for 1 h and was quenched by addition of 2 M ammonia in methanol and concentrated. The residue was purified by column chromatography (25% EtOAc/Hex) to give 28 mg (74.4%) as oil. 1H-NMR (CDCl3, 300 MHz) δ 7.85 (s, 1H), 7.23 (m,2H), 7.03 (m, 3H), 6.76 (s, 1H), 4.46 (q, J=6 Hz, 1H), 3.57-3.75 (m, 2H), 3.32 (d, J=9 Hz, 1H), 3.22 (d, J=9 Hz, 1H), 2.9-3.1(m, 2H), 2.01-2.22 (m,2H), 1.65-1.8 (m, 2H), 1.37-1.41 (m, 12H), 0.91 (m, 2H), 0.64 (m, 2H); Mass spec.: 494.48 (MH)+.

Workup

  1. concentrationThe reaction was concentrated
  2. customThe cartridge was flushed with several volumes of methanol which
  3. washThe product was eluted with 2 M ammonia in methanol
  4. concentrationconcentrated

Sources & evidence

ORD record
ord-4d2660ca7afd4774a0d2b96fccca6529
Source dataset
uspto-grants-2011_09
Patent number
US08026257B2

Reaction notes

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