1,2-Dichloroethane → 5-chloro-N-((2,6-dimethyl-4-oxo-1,4-dihydropyridin-3-yl)methyl)-2-methyl-3-((1-(pyrimidin-4-yl)piperidin-4-yl)oxy)benzamide

HRID 1050454Notes

Reaction equation

HRID 1050454 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)[CH2:15][CH2:14]2)[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:26][CH2:27][C:28]1[C:33](=[O:34])[CH:32]=[C:31]([CH3:35])[NH:30][C:29]=1[CH3:36].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.C([O-])(O)=O.[Na+]>O.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)[CH2:15][CH2:14]2)[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([NH:26][CH2:27][C:28]1[C:33](=[O:34])[CH:32]=[C:31]([CH3:35])[NH:30][C:29]=1[CH3:36])=[O:9]

Participants

9

Reactant 6

HCID 111,2-DichloroethaneHCID 79724-MethylmorpholineHCID 181649HOAtHCID 516892Sodium BicarbonateHCID 902729075-Chloro-2-methyl-3-((1-(pyrimidin-4-yl)piperidin-4-yl)oxy)benzoic acidHCID 902732273-(aminomethyl)-2,6-dimethylpyridin-4(1H)-one hydrochloride

Product 1

HCID 769019525-chloro-N-((2,6-dimethyl-4-oxo-1,4-dihydropyridin-3-yl)methyl)-2-methyl-3-((1-(pyrimidin-4-yl)piperidin-4-yl)oxy)benzamideYield 30.1%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

A 20 mL vial was charged with 5-chloro-2-methyl-3-((1-(pyrimidin-4-yl)piperidin -4-yl)oxy)benzoic acid (72.0 mg, 0.207 mmol), 3-(aminomethyl)-2,6-dimethylpyridin -4(1H)-one hydrochloride (46.9 mg, 0.248 mmol), EDC (59.5 mg, 0.311 mmol), HOAt (47.9 mg, 0.311 mmol), N,N-dimethylformamide (3 mL) and N-methylmorpholine (0.341 mL, 3.11 mmol). The reaction mixture was stirred for 2 days, at which time it was added drop-wise to a rapidly stirring solution of saturated NaHCO3 (25 mL) and water (10 mL). The resulting cloudy mixture was stirred at room temperature 4 h, then filtered. The collected solid was dried under high vacuum and purified by reverse phase HPLC (Column: Phenomenex Gemini-NX axia, 30×100, 5μ, C18. Eluent: 5-25% acetonitrile/0.1% formic acid in water, 7 minute gradient). The resulting sticky, glassy solid was dissolved in MeOH (6 mL) and DCM (2 mL), then concentrated in vacuo. The resulting residue was then dissolved with DCM (1 mL) and concentrated in vacuo. The residue was partitioned between DCM (20 mL) and saturated NaHCO3 (6 mL) and water (3 mL). The aqueous layer was filtered and the solid dried under vacuum for 20 min to give 5-chloro -N-((2,6-dimethyl-4-oxo-1,4-dihydropyridin-3-yl)methyl)-2-methyl-3-((1-(pyrimidin-4-yl)piperidin-4-yl)oxy)benzamide (30 mg, 0.062 mmol, 30.1% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.02 (br. s., 1H), 8.49 (s, 2H), 8.18 (d, J=6.32 Hz, 1H), 7.19 (d, J=2.02 Hz, 1H), 6.88 (dd, J=1.01, 6.32 Hz, 1H), 6.83 (d, J=1.77 Hz, 1H), 5.86 (s, 1H), 4.78 (tt, J=3.82, 7.17 Hz, 1H), 4.20 (d, J=4.80 Hz, 2H), 3.80-3.97 (m, 2H), 3.52-3.69 (m, 2H), 2.29 (s, 3H), 2.14 (s, 3H), 2.07 (s, 3H), 1.87-2.01 (m, 2H), 1.54-1.71 (m, 2H). MS(ES) [M+H]+ 482.2.

Workup

  1. stirringThe resulting cloudy mixture was stirred at room temperature 4 h
  2. filtrationfiltered
  3. customThe collected solid was dried under high vacuum
  4. custompurified by reverse phase HPLC (Column: Phenomenex Gemini-NX axia, 30×100, 5μ, C18. Eluent: 5-25% acetonitrile/0.1% formic acid in water, 7 minute gradient)
  5. dissolutionThe resulting sticky, glassy solid was dissolved in MeOH (6 mL)
  6. concentrationDCM (2 mL), then concentrated in vacuo
  7. dissolutionThe resulting residue was then dissolved with DCM (1 mL)
  8. concentrationconcentrated in vacuo
  9. customThe residue was partitioned between DCM (20 mL) and saturated NaHCO3 (6 mL) and water (3 mL)
  10. filtrationThe aqueous layer was filtered
  11. customthe solid dried under vacuum for 20 min

Sources & evidence

ORD record
ord-bbaacf05fa054bd49f551bc1139939bf
Source dataset
uspto-grants-2016_07
Patent number
US09382234B2

Reaction notes

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