4-chloro-N-methylpiperidine → HCID 66749527, compound

HRID 2402081Notes

Reaction equation

HRID 2402081 reaction equation
[Mg].Cl[CH:3]1[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1.[Cl:10][C:11]1[CH:46]=[CH:45][C:14]([C:15]([C:17]2[CH:18]=[C:19]([C:35]3[CH:40]=[CH:39][N:38]=[C:37]([NH:41][C:42](=[O:44])[CH3:43])[CH:36]=3)[S:20][C:21]=2[C:22]2[N:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:23]=2)=[O:16])=[CH:13][CH:12]=1>O1CCCC1>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([OH:16])([CH:3]2[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]2)[C:17]2[CH:18]=[C:19]([C:35]3[CH:40]=[CH:39][N:38]=[C:37]([NH:41][C:42](=[O:44])[CH3:43])[CH:36]=3)[S:20][C:21]=2[C:22]2[N:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:34])[CH3:33])[N:23]=2)=[CH:45][CH:46]=1

Participants

5

Reactant 3

HCID 793424-chloro-N-methylpiperidineHCID 5462224Magnesium2×HCID 66749619HCID 66749619, compound

Product 1

HCID 66749527HCID 66749527, compoundYield 44.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
45 °C

Procedure

A 25 mL round bottom flask charged with magnesium turnings (23.0 mg, 0.947 mmol) was flame-dried. To the flask was added tetrahydrofuran (1.00 mL) and a drop of 1,2-dibromoethane. The mixture was heated to 45° C. for 10 min and cooled to rt. To the mixture was added 4-chloro-N-methylpiperidine (126 mg, 0.947 mmol). The reaction was stirred at 35° C. under an atmosphere of nitrogen for 12 hrs. The mixture turned cloudy, and magnesium turnings eventually disappeared, as the reaction progressed. To a solution of N-{4-[4-(4-chlorobenzoyl)-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-thienyl]pyridin-2-yl}acetamide (113 mg, 0.204 mmol) in tetrahydrofuran (1.00 mL) was added the pre-prepared Grignard reagent solution dropwise at 0° C. In 3 hrs, the reaction was warmed to rt. In another 3 hrs, the reaction was quenched with water and distributed between NaHCO3(aq) saturated solution and EtOAc. The aqueous layer was extracted with EtOAc (×2). The combined organic layer was dried and concentrated. Purification on a silica gel column (gradient elution, 1-20% MeOH) provided N-(4-{4-[(4-chlorophenyl)(hydroxy)(1-methylpiperidin-4-yl)methyl]-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-thienyl}pyridin-2-yl)acetamide as a yellow solid (59.0 mg, 44.3% yield). LCMS: (AA) ES+ 653, 655; NMR (400 MHz, CDCl3) δ 8.77-8.66 (s, 1H), 8.60-8.49 (s, 1H), 8.31-8.23 (d, J=5.3 Hz, 1H), 8.15-8.08 (m, 2H), 7.66-7.60 (s, 1H), 7.34-7.23 (m, 3H), 7.17-7.08 (d, J=8.7 Hz, 2H), 5.45-5.38 (s, 2H), 3.63-3.51 (m, 2H), 3.49-3.44 (s, 3H), 3.02-2.90 (d, J=10.8 Hz, 1H), 2.90-2.78 (d, J=11.2 Hz, 1H), 2.28-2.20 (m, 4H), 2.20-2.09 (m, 1H), 2.07-1.95 (m, 1H), 1.96-1.78 (m, 2H), 1.76-1.58 (qd, J=12.7, 3.8 Hz, 1H), 1.16-1.07 (d, J=12.5 Hz, 1H), 0.99-0.85 (m, 2H), 0.02-1-0.04 (s, 9H).

Workup

  1. customwas flame-dried
  2. additionTo the flask was added tetrahydrofuran (1.00 mL)
  3. temperaturecooled to rt
  4. waitIn 3 hrs
  5. temperaturethe reaction was warmed to rt
  6. waitIn another 3 hrs
  7. customthe reaction was quenched with water
  8. extractionThe aqueous layer was extracted with EtOAc (×2)
  9. customThe combined organic layer was dried
  10. concentrationconcentrated
  11. customPurification
  12. washon a silica gel column (gradient elution, 1-20% MeOH)

Sources & evidence

ORD record
ord-24cb450eea7f4459bce66de5cc80e549
Source dataset
uspto-grants-2014_08
Patent number
US08796271B2

Reaction notes

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