Ethyl Acetate → Methyl 1-(4-cyano-3-fluorophenyl)-6-oxo-4-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)-1,6-dihydropyridazine-3-carboxylate

HRID 386566노트

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HRID 386566 반응식
Cl.[C:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([O:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:12]([C:24]([O:26][CH3:27])=[O:25])=[N:11]2)=[CH:6][C:5]=1[F:28])#[N:3].CCN(C(C)C)C(C)C.Cl[C:39]1[N:44]=[CH:43][C:42]([CH2:45][CH2:46][CH3:47])=[CH:41][N:40]=1.CCOC(C)=O>CN1C(=O)CCC1>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([O:17][CH:18]3[CH2:19][CH2:20][N:21]([C:39]4[N:44]=[CH:43][C:42]([CH2:45][CH2:46][CH3:47])=[CH:41][N:40]=4)[CH2:22][CH2:23]3)[C:12]([C:24]([O:26][CH3:27])=[O:25])=[N:11]2)=[CH:6][C:5]=1[F:28])#[N:3]

참가 물질

6

반응물 4

HCID 8857Ethyl AcetateHCID 81531DiisopropylethylamineHCID 27357842-Chloro-5-propylpyrimidineHCID 67446633methyl 1-(4-cyano-3-fluorophenyl)-6-oxo-4-(piperidin-4-yloxy)-1,6-dihydropyridazine-3-carboxylate HCl

생성물 1

HCID 44621041Methyl 1-(4-cyano-3-fluorophenyl)-6-oxo-4-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)-1,6-dihydropyridazine-3-carboxylate수율 32.5%

시약·촉매·용매 1

HCID 13387N-methyl-2-pyrrolidone용매

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온도
95 °C

실험 절차

To a stirring solution of methyl 1-(4-cyano-3-fluorophenyl)-6-oxo-4-(piperidin-4-yloxy)-1,6-dihydropyridazine-3-carboxylate HCl (37.2 mg, 0.10 mmol) in NMP (3 mL) at room temperature under argon was added DIPEA (38.8 mg, 0.30 mmol) and 2-chloro-5-propylpyrimidine (23.5 mg, 0.15 mmol). The resulting reaction mixture was heated at 95° C. under argon overnight. 15 mL of EtOAc was added to the reaction mixture. The reaction mixture was washed with water (15 mL), and brine (15 mL). Organic phase was dried (MgSO4), filtered and concentrated. The crude product was directly purified by preparative HPLC (C18 column; 10-100% methanol in water without TFA) to give methyl 1-(4-cyano-3-fluorophenyl)-6-oxo-4-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)-1,6-dihydropyridazine-3-carboxylate (16 mg, white solid, 32%). 1H NMR (400 MHz, CDCl3) δ ppm 0.56-1.12 (m, 3H) 1.37-1.67 (m, 2H) 1.70-2.20 (m, 4H) 2.39 (q, J=7.47 Hz, 2H) 3.64-4.09 (m, 7H) 4.02-4.40 (m, 1H) 4.40-4.95 (m, 1H) 6.31 (s, 1H) 7.45-7.91 (m, 3H) 7.91-8.46 (m, 2H). MS (ESI) 493 (M+H).

후처리

  1. customThe resulting reaction mixture
  2. washThe reaction mixture was washed with water (15 mL), and brine (15 mL)
  3. dry with materialOrganic phase was dried (MgSO4)
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe crude product was directly purified by preparative HPLC (C18 column; 10-100% methanol in water without TFA)

출처 및 근거

ORD 기록
ord-a782519f712f4bfcb4659fbb77fe74c6
출처 데이터셋
uspto-grants-2013_02
특허 번호
US08372837B2

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