Di-tert-butyl dicarbonate → HCID 57546011, compound

HRID 913947Notes

Reaction equation

HRID 913947 reaction equation
[Cl:1][C:2]1[CH:10]=[C:9]([C@H:11]([O:13][CH2:14][C:15]2([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH3:12])[C:8]2[C:4](=[CH:5][N:6](COCC[Si](C)(C)C)[N:7]=2)[CH:3]=1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C@H:11]([O:13][CH2:14][C:15]3([C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[CH3:12])[CH:10]=1)[NH:7][N:6]=[CH:5]2

Participants

4

Reactant 2

HCID 90495Di-tert-butyl dicarbonateHCID 57546164HCID 57546164, compound

Product 1

HCID 57546011HCID 57546011, compound

Reagents, catalysts & solvents 1

HCID 6422Trifluoroacetic acidSolvent

Procedure

(R)-tert-Butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (850 mg, 1.375 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 30 mL) and stirred at room temperature for 4 h. The reaction was concentrated, loaded onto a strong cation exchange cartridge (4×2 g cartridges) in methanol, and flushed with several volumes of methanol which were discarded. The product was eluted with 2M ammonia in methanol and concentrated. The crude piperidine was dissolved in dichloromethane (10 mL), and treated with di-tert-butyl dicarbonate(0.48 mL, 2.062 mmol). The reaction was quenched by addition of ethylene diamine (200 mg) in dichloromethane (2 mL). The reaction was concentrated and purified by column chromatography (25%→37% ethyl acetate/n-hexane) to give 650 mg (97%) as a white foam solid. 1H-NMR (CDCl3, 500 MHz) δ 9.66 (bs, 1H), 7.90 (s, 1H), 7.57 (d, J=1.8 Hz, 1H), 7.26 (dd, J=8.9, 5.5 Hz, 2H), 7.07 (dd, J=8.9, 8.6 Hz, 2H), 6.98 (d, J=1.5 Hz, 1H), 4.49 (q, J=6.4 Hz, 1H), 3.74 (m, 2H), 3.38 (d, J=9.2 Hz, 1H), 3.25 (d, J=9.2 Hz, 1H), 3.22 (bs, 2H), 3.05 (m, 1H), 2.97 (m, 1H), 2.26 (m, 1H), 2.06 (m, 1H), 1.84 (m, 1H), 1.73 (m, 1H), 1.43 (m. 12H); 13C NMR (75 MHz, CDCl3) δ ppm 171.0, 161.5 (d, J=247 Hz), 154.8, 137.9, 137.8, 135.4, 133.7, 128.5 (d, J=7.5 Hz), 127.3, 125.9, 124.6, 124.0, 118.9, 115.5 (d, J=21 Hz), 79.4, 78.5, 78.1, 60.3, 41.0, 39.8 (br), 32.3, 32.0, 28.3, 22.0, 20.9, 14.1. Mass spec.: 488.17 (MH)+.

Workup

  1. concentrationThe reaction was concentrated
  2. customflushed with several volumes of methanol which
  3. washThe product was eluted with 2M ammonia in methanol
  4. concentrationconcentrated
  5. dissolutionThe crude piperidine was dissolved in dichloromethane (10 mL)
  6. customThe reaction was quenched by addition of ethylene diamine (200 mg) in dichloromethane (2 mL)
  7. concentrationThe reaction was concentrated
  8. custompurified by column chromatography (25%→37% ethyl acetate/n-hexane)
  9. customto give 650 mg (97%) as a white foam solid

Sources & evidence

ORD record
ord-8c71bd420e6d48c39398a4197e58bfa0
Source dataset
uspto-grants-2011_09
Patent number
US08026257B2

Reaction notes

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