tert-Butyl 4-(methylamino)piperidine-1-carboxylate → Methyl 4-({1-[(tert-butoxy)carbonyl]piperidin-4-yl}(methyl)amino)-3,6-dichloropyridine-2-carboxylate

HRID 2208796Notes

Reaction equation

HRID 2208796 reaction equation
[Cl:1][C:2]1[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1Cl.[CH3:14][NH:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1>CN(C=O)C>[C:25]([O:24][C:22]([N:19]1[CH2:18][CH2:17][CH:16]([N:15]([CH3:14])[C:7]2[CH:6]=[C:5]([Cl:9])[N:4]=[C:3]([C:10]([O:12][CH3:13])=[O:11])[C:2]=2[Cl:1])[CH2:21][CH2:20]1)=[O:23])([CH3:28])([CH3:27])[CH3:26]

Participants

4

Reactant 2

HCID 15380702tert-Butyl 4-(methylamino)piperidine-1-carboxylateHCID 22677534Methyl 3,4,6-trichloropyridine-2-carboxylate

Product 1

HCID 86719553Methyl 4-({1-[(tert-butoxy)carbonyl]piperidin-4-yl}(methyl)amino)-3,6-dichloropyridine-2-carboxylateYield 18%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

To a stirred solution of methyl 3,4,6-trichloropyridine-2-carboxylate (310 mg, 1.29 mmol) in DMF (5 ml) was added TEA (359 μl, 2.58 mmol) followed by tert-butyl 4-(methylamino)piperidine-1-carboxylate (276 mg, 1.29 mmol) and the reaction mixture was heated at 100° C. for 4 h. The reaction mixture was then cooled to room temperature and poured onto water (50 ml), followed by extraction of the product into TBME (3×50 ml), washing of the combined organics with brine (50 ml), drying with Na2SO4 and evaporation. The crude product was then purified over a 10 g silica Isolute column eluting with a gradient of 0% to 50% EtOAc in heptane to afford the title compound as a white solid (95 mg, 18%). LC-MS 95%, 2.29 min (3.5 minute LC-MS method), m/z=418.1/419.8, 1H NMR (500 MHz, Chloroform-d) δ 6.87 (s, 1H) 4.12-4.34 (m, 2H) 3.99 (s, 3H) 3.69-3.80 (m, 1H) 2.79 (s, 3H) 2.64-2.77 (m, 2H) 1.75 (br. s., 4H) 1.48 (s, 9H).

Workup

  1. temperatureThe reaction mixture was then cooled to room temperature
  2. additionpoured onto water (50 ml)
  3. extractionfollowed by extraction of the product into TBME (3×50 ml)
  4. washwashing of the combined organics with brine (50 ml)
  5. dry with materialdrying with Na2SO4 and evaporation
  6. customThe crude product was then purified over a 10 g silica Isolute column
  7. washeluting with a gradient of 0% to 50% EtOAc in heptane

Sources & evidence

ORD record
ord-24dd0126d52246519ed33dd525e260a6
Source dataset
uspto-grants-2016_06
Patent number
US09376422B2

Reaction notes

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