Diisopropylethylamine → Tert-butyl 4-(2-chloro-6-(3,3-difluoropyrrolidin-1-yl)pyridin-4-yl)piperidine-1-carboxylate

HRID 1057043Notes

Reaction equation

HRID 1057043 reaction equation
Cl.[F:2][C:3]1([F:9])[CH:8]=C[CH:6]=[N:5][CH2:4]1.Cl[C:11]1[CH:16]=[C:15]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH:14]=[C:13]([Cl:30])[N:12]=1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O.C(OCC)(=O)C>[Cl:30][C:13]1[CH:14]=[C:15]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH:16]=[C:11]([N:5]2[CH2:6][CH2:8][C:3]([F:2])([F:9])[CH2:4]2)[N:12]=1

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 900150733,3-Difluoropyridine hydrochlorideHCID 90015259Tert-butyl 4-(2,6-dichloropyridin-4-yl)piperidine-1-carboxylate

Product 1

HCID 90067487Tert-butyl 4-(2-chloro-6-(3,3-difluoropyrrolidin-1-yl)pyridin-4-yl)piperidine-1-carboxylateYield 47%

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Procedure

A solution of 3,3-difluoropyridine hydrochloride (533 mg, 3.72 mmol, 3.18 equiv), tert-butyl 4-(2,6-dichloropyridin-4-yl)piperidine-1-carboxylate (1.00 g, 1.17 mmol, 1 equiv), and N,N-diisopropylethylamine (1.23 mL, 7.03 mmol, 6.00 equiv) in N-methylpyrrolidinone (2.3 mL) was heated at 130° C. in the microwave (CEM) for 1.5 h. The reaction mixture was diluted with ethyl acetate (50 mL), and the resulting solution was washed with saturated aqueous ammonium chloride solution (2×20 mL). The aqueous washes were extracted with ethyl acetate (25 mL). The combined organic was washed with water (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (4:1 heptane/ethyl acetate) provided product as a clear oil (220 mg, 47% yield). 1H NMR (400 MHz, CDCl3): 6.51 (s, 1H), 6.03 (s, 1H), 4.25 (m, 2H), 3.83 (t, J=13.1 Hz, 2H), 3.67 (t, J=7.3 Hz, 2H), 2.77 (m, 2H), 2.42-2.58 (m, 3H), 1.78 (m, 2H), 1.53-1.62 (m, 2H), 1.48 (s, 9H).

Workup

  1. washthe resulting solution was washed with saturated aqueous ammonium chloride solution (2×20 mL)
  2. extractionThe aqueous washes were extracted with ethyl acetate (25 mL)
  3. washThe combined organic was washed with water (25 mL)
  4. dry with materialdried over anhydrous sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customPurification by flash column chromatography (4:1 heptane/ethyl acetate)

Sources & evidence

ORD record
ord-654f6b5618ac4a579209a2c660adf643
Source dataset
uspto-grants-2016_07
Patent number
US09399636B2

Reaction notes

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