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 1050454ノート

反応式

HRID 1050454 の反応式
[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]

参加物

9

反応物 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

生成物 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)benzamide収率 30.1%

試薬・触媒・溶媒 2

HCID 962Water溶媒HCID 6228Dimethylformamide溶媒

実験手順

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.

後処理

  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

出典と根拠

ORDレコード
ord-bbaacf05fa054bd49f551bc1139939bf
出典データセット
uspto-grants-2016_07
特許番号
US09382234B2

反応ノート

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