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

HRID 1050451Notes

Reaction equation

HRID 1050451 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([O:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:20][CH2:21][C:22]1[C:27](=[O:28])[CH:26]=[C:25]([CH3:29])[NH:24][C:23]=1[CH3:30].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.C([O-])(O)=O.[Na+]>C(Cl)Cl.O.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([NH:20][CH2:21][C:22]1[C:27](=[O:28])[CH:26]=[C:25]([CH3:29])[NH:24][C:23]=1[CH3:30])=[O:9]

Participants

10

Reactant 6

HCID 111,2-DichloroethaneHCID 79724-MethylmorpholineHCID 181649HOAtHCID 516892Sodium BicarbonateHCID 902727855-chloro-2-methyl-3-((tetrahydro-2H-pyran-4-yl)oxy)benzoic acidHCID 902732273-(aminomethyl)-2,6-dimethylpyridin-4(1H)-one hydrochloride

Product 1

HCID 769019515-chloro-N-((2,6-dimethyl-4-oxo-1,4-dihydropyridin-3-yl)methyl)-2-methyl-3-((tetrahydro-2H-pyran-4-yl)oxy)benzamideYield 45.5%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

A 20 mL vial was charged with 5-chloro-2-methyl-3-((tetrahydro-2H-pyran-4-yl)oxy)benzoic acid (72.0 mg, 0.266 mmol), 3-(aminomethyl)-2,6-dimethylpyridin -4(1H)-one hydrochloride (60.2 mg, 0.319 mmol), EDC (76 mg, 0.399 mmol), HOAt (61.5 mg, 0.399 mmol), N,N-dimethylformamide (3 mL) and N-methylmorpholine (0.351 mL, 3.19 mmol). The reaction was stirred for 16 h, at which time it was added drop-wise to a rapidly stirred solution of saturated NaHCO3 (25 mL) and water (10 mL) and stirred at room temperature 1 h. The solid was collected via vacuum filtration and dried under vacuum. Purification of the residue by reverse phase HPLC (Column: Phenomenex Gemini-NX axia, 30×100, 5μ, C18; Eluent: 20-55% acetonitrile/0.1% formic acid in water, 5 min gradient) gave a sticky, glassy solid. This residue was dissolved with DCM (20 mL) and washed with a saturated NaHCO3 (6 mL) and water (3 mL). The aqueous was extracted with DCM (2×20 mL) and the combined organic layers were filtered through MgSO4 and Na2SO4 and concentrated to give 5-chloro-N-((2,6-dimethyl-4-oxo -1,4-dihydropyridin-3-yl)methyl)-2-methyl-3-((tetrahydro-2H-pyran-4-yl)oxy)benzamide (49 mg, 0.121 mmol, 45.5% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.21 (t, J=4.93 Hz, 1H), 7.15 (d, J=2.02 Hz, 1H), 6.80 (d, J=2.02 Hz, 1H), 5.87 (s, 1H), 4.66 (tt, J=4.04, 7.96 Hz, 1H), 4.19 (d, J=5.05 Hz, 2H), 3.73-3.89 (m, 2H), 3.51 (ddd, J=3.03, 8.59, 11.62 Hz, 2H), 2.31 (s, 3H), 2.16 (s, 3H), 2.07 (s, 3H), 1.86-2.00 (m, 2H), 1.49-1.66 (m, 2H). MS(ES) [M+H]+ 405.1.

Workup

  1. stirringstirred at room temperature 1 h
  2. filtrationThe solid was collected via vacuum filtration
  3. customdried under vacuum
  4. customPurification of the residue by reverse phase HPLC (Column: Phenomenex Gemini-NX axia, 30×100, 5μ, C18; Eluent: 20-55% acetonitrile/0.1% formic acid in water, 5 min gradient)
  5. customgave a sticky, glassy solid
  6. washwashed with a saturated NaHCO3 (6 mL) and water (3 mL)
  7. extractionThe aqueous was extracted with DCM (2×20 mL)
  8. filtrationthe combined organic layers were filtered through MgSO4 and Na2SO4
  9. concentrationconcentrated

Sources & evidence

ORD record
ord-b874c75809c4490db991a1be5b75de45
Source dataset
uspto-grants-2016_07
Patent number
US09382234B2

Reaction notes

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