Triethylamine → Benzyl 4-((5-chloro-2-pivalamidopyridin-4-ylamino)methyl)piperidine-1-carboxylate

HRID 384691Notes

Reaction equation

HRID 384691 reaction equation
Cl[C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=1.[NH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:20][CH2:19]1.C(N(CC)CC)C>CN1C(=O)CCC1.CO>[NH3:5].[Cl:8][C:7]1[C:2]([NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:25])[CH2:20][CH2:19]2)=[CH:3][C:4]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[N:5][CH:6]=1

Participants

7

Reactant 3

HCID 8471TriethylamineHCID 10538422N-(4,5-Dichloropyridin-2-yl)pivalamideHCID 219554994-Aminomethyl-1-N-Cbz-piperidine

Product 2

HCID 222AmmoniaHCID 59613350Benzyl 4-((5-chloro-2-pivalamidopyridin-4-ylamino)methyl)piperidine-1-carboxylateYield 150%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
210 °C

Procedure

A capped microwave reaction vial containing a solution of N-(4,5-dichloropyridin-2-yl)pivalamide (0.38 g, 1.54 mmol) (Synthesis 153-B), benzyl 4-(aminomethyl)piperidine-1-carboxylate (0.76 g, 2 eq) and triethylamine (0.43 mL, 2 eq) in NMP (3 mL) was heated at 210° C. for 1.75 hr under microwave irradiation, and then allowed to cooled. The reaction mixture was diluted with MeOH and adsorbed onto Isolute SCX-II acidic resin (10 g). The resin was washed with methanol, then 2M ammonia in methanol. The basic fractions were concentrated and the crude product was further purified by column chromatography, using a Biotage 40+silica column eluted with a gradient of EtOAc in hexane. The product contained residual NMP which was removed by a second ion exchange purification on Isolute SCX-II acidic resin, eluting with methanol, then 2M ammonia in methanol, to give benzyl 4-((5-chloro-2-pivalamidopyridin-4-ylamino)methyl)piperidine-1-carboxylate as a light yellow gum (0.53 g, 68%).

Workup

  1. customA capped microwave reaction
  2. temperatureto cooled
  3. washThe resin was washed with methanol
  4. concentrationThe basic fractions were concentrated
  5. customthe crude product was further purified by column chromatography
  6. washeluted with a gradient of EtOAc in hexane
  7. customwas removed by a second ion exchange purification on Isolute SCX-II acidic resin
  8. washeluting with methanol

Sources & evidence

ORD record
ord-14a2a0b553454013974030c97d989fce
Source dataset
uspto-grants-2013_02
Patent number
US08367658B2

Reaction notes

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