Diisopropylethylamine → Tert-butyl 4-[(3,6-dichloro-2-{[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]carbamoyl}pyridin-4-yl)(methyl)amino]piperidine-1-carboxylate

HRID 2208798Notes

Reaction equation

HRID 2208798 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:26])[C:15]2[CH:20]=[C:19]([Cl:21])[N:18]=[C:17]([C:22](O)=[O:23])[C:16]=2[Cl:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH2:69][CH2:70][C:71]1[C:72](=[O:79])[NH:73][C:74]([CH3:78])=[CH:75][C:76]=1[CH3:77]>CN(C=O)C>[Cl:25][C:16]1[C:17]([C:22](=[O:23])[NH:69][CH2:70][C:71]2[C:72](=[O:79])[NH:73][C:74]([CH3:78])=[CH:75][C:76]=2[CH3:77])=[N:18][C:19]([Cl:21])=[CH:20][C:15]=1[N:14]([CH3:26])[CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 2724699PyBOPHCID 70638443-(Aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-oneHCID 867195544-({1-[(Tert-butoxy)carbonyl]piperidin-4-yl}(methyl)amino)-3,6-dichloropyridine-2-carboxylic acid

Product 1

HCID 86719555Tert-butyl 4-[(3,6-dichloro-2-{[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]carbamoyl}pyridin-4-yl)(methyl)amino]piperidine-1-carboxylate

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a stirred solution of 4-({1-[(tert-butoxy)carbonyl]piperidin-4-yl}(methyl)amino)-3,6-dichloropyridine-2-carboxylic acid (75 mg, 0.19 mmol) in DMF (2 ml) cooled to 0° C. h was added DIPEA (48 μl, 0.28 mmol) followed by PyBOP (116 mg, 0.22 mmol) and 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (89% purity, 35 mg, 0.2 mmol). The reaction mixture was then stirred at room temperature for 16 h after which the reaction was poured onto water (30 ml) and extracted with EtOAc (3×50 ml) after which the combined organics were washed with brine (50 ml) and dried (Na2SO4) and evaporated. The crude product was purified using a 5 g silica Isolute column eluting with a gradient of 0% to 100% EtOAc in heptane to afford the title compound as a white solid which contained ˜45% w/w tripyrrolidinophosphene oxide by NMR—this compound was used in the next stage of the synthesis without any further purification. LC-MS 93%, 1.97 min (3.5 minute LC-MS method), m/z=538.0/539.45/542.05, 1H NMR (500 MHz, Chloroform-d) δ 10.03 (br. s, 1H), 8.13-7.97 (m, 1H), 6.79 (s, 1H), 5.87 (s, 1H), 4.50 (d, J=6.1 Hz, 2H), 4.16 (br. m, 2H), 3.78-3.62 (m, 1H), 2.72 (s, 3H), 2.65 (br. m, 2H), 2.35 (s, 3H), 2.22 (s, 3H), 1.73-1.63 (m, 4H), 1.44 (s, 9H).

Workup

  1. additionwas poured onto water (30 ml)
  2. extractionextracted with EtOAc (3×50 ml) after which the combined
  3. washorganics were washed with brine (50 ml)
  4. dry with materialdried (Na2SO4)
  5. customevaporated
  6. customThe crude product was purified
  7. washeluting with a gradient of 0% to 100% EtOAc in heptane

Sources & evidence

ORD record
ord-596ba57a859745b99e5ddaa47efcc6fe
Source dataset
uspto-grants-2016_06
Patent number
US09376422B2

Reaction notes

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