Triethylamine → 1,1-Dimethylethyl 4-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate

HRID 423690Notes

Reaction equation

HRID 423690 reaction equation
CS(Cl)(=O)=O.[OH:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.C(N(CC)CC)C.[Br:28][C:29]1[N:34]=[CH:33][C:32](O)=[CH:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>O.CN(C=O)C.C(Cl)Cl>[Br:28][C:29]1[N:34]=[CH:33][C:32]([O:6][CH2:7][CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:31][CH:30]=1

Participants

9

Reactant 5

HCID 8471TriethylamineHCID 11430Potassium CarbonateHCID 31297Methanesulfonyl chlorideHCID 27628652-Bromo-5-hydroxypyridineHCID 2764081Tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate

Product 1

HCID 579302011,1-Dimethylethyl 4-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylateYield 42.3%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

Methanesulfonyl chloride (1.8 mL, 23.4 mmol) was added to a mixture of 1,1-dimethylethyl 4-(hydroxymethyl)-1-piperidinecarboxylate (4.8 g, 22.3 mmol), triethylamine (3.4 mL, 24.5 mmol), and CH2Cl2 (100 mL) at 0° C. The mixture stirred at 0° C. for 1 h. The mixture was washed with water. The organics were dried over MgSO4, filtered, and the filtrate was concentrated. The resulting residue was charged with 6-bromo-3-pyridinol (3.88 g, 22.3 mmol), K2CO3 (6.16 g, 44.6 mmol), DMF (50 mL), and was stirred at 90° C. overnight. The mixture was cooled to ambient temperature, and was set at ambient temperature overnight. The mixture was charged with water, and was stirred at ambient temperature for 4 h. The resulting tan precipitate was filtered, washed with water, and air-dried. The precipitate was purified by chromatography on a silica gel column using 0 to 10% MeOH/CH2Cl2 to give 3.6 g (43%) of 1,1-dimethylethyl 4-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate as a white solid, and 3.5 g of 1,1-dimethylethyl 4-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate that contained impurities. The impure batch was repurified by chromatography on a silica gel column using 0 to 2.5% MeOH/CH2Cl2 to give 2.8 g (34%) of 1,1-dimethylethyl 4-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate as an off-white solid which still contained a ˜17% impurity. 1H NMR (400 MHz, CDCl3): δ 8.02 (d, 1H, J=3.0 Hz), 7.34 (d, 1H, J=8.7 Hz), 7.06 (dd, 1H, Ja=8.7 Hz, Jb=3.1 Hz), 4.15 (d, 2H, J=10.3 Hz), 3.80 (d, 2H, J=6.3 Hz), 2.72 (t, 2H, J=12.4 Hz), 2.01-1.85 (m, 1H), 1.79 (d, 2H, J=12.8 Hz), 1.44 (s, 9H), 1.32-1.13 (m, 2H); LRMS (ESI), m/z 371/373 (M+H).

Workup

  1. washThe mixture was washed with water
  2. dry with materialThe organics were dried over MgSO4
  3. filtrationfiltered
  4. concentrationthe filtrate was concentrated
  5. stirringwas stirred at 90° C. overnight
  6. temperatureThe mixture was cooled to ambient temperature
  7. waitwas set at ambient temperature overnight
  8. stirringwas stirred at ambient temperature for 4 h
  9. filtrationThe resulting tan precipitate was filtered
  10. washwashed with water
  11. customair-dried
  12. customThe precipitate was purified by chromatography on a silica gel column

Sources & evidence

ORD record
ord-535a434f4d64494a9fa04c59e8bdd06a
Source dataset
uspto-grants-2012_01
Patent number
US08101634B2

Reaction notes

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