Binap, (A+-)- → 2-methyl-6-(((1S,2S)-2-(1-methyl-1H-pyrazol-3-yl)cyclopropyl)methoxy)-4-((2-methylthiazol-5-yl)methylamino)pyridazin-3(2H)-one

HRID 530791노트

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HRID 530791 반응식
[CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][CH2:10][C:11]2[S:12][C:13]([CH3:16])=[N:14]N=2)=[CH:5][C:4]([O:17][CH2:18][C@H:19]2[CH2:21][C@@H:20]2[C:22]2[CH:27]=[CH:26]C(C)=C[N:23]=2)=[N:3]1.C[C:30]1SC(CN)=C[N:34]=1.[CH:37]1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C(#N)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][CH2:10][C:11]2[S:12][C:13]([CH3:16])=[N:14][CH:37]=2)=[CH:5][C:4]([O:17][CH2:18][C@H:19]2[CH2:21][C@@H:20]2[C:22]2[CH:27]=[CH:26][N:34]([CH3:30])[N:23]=2)=[N:3]1

참가 물질

9

반응물 4

HCID 634876Binap, (A+-)-HCID 19046689(2-Methyl-1,3-thiazol-5-yl)methanamineHCID 23676156Sodium t-butoxideHCID 904543862-methyl-4-((5-methyl-1,3,4-thiadiazol-2-yl)methylamino)-6-(((1S,2S)-2-(5-methyl pyridin-2-yl)cyclopropyl)methoxy)pyridazin-3(2H)-one

생성물 1

HCID 904543882-methyl-6-(((1S,2S)-2-(1-methyl-1H-pyrazol-3-yl)cyclopropyl)methoxy)-4-((2-methylthiazol-5-yl)methylamino)pyridazin-3(2H)-one

시약·촉매·용매 4

HCID 9811564Bis(dibenzylideneacetone)palladium촉매HCID 962Water용매2회HCID 1140Toluene용매HCID 6342Acetonitrile용매

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온도
85 °C

실험 절차

To the solution of 4-bromo-2-methyl-6-(((1S,2S)-2-(1-methyl-1H-pyrazol-3-yl)cyclo propyl)methoxy)pyridazin-3(2H)-one (made according to Example 1, by replacing ((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methanol with ((1S,2S)-2-(1-methyl-1H-pyrazol-3-yl)cyclopropyl)methanol, 27 mg, 0.08 mmol) in toluene (2 mL) under N2, (2-methylthiazol-5-yl)methanamine (13 mg, 0.096 mmol), Pd2(dba)3 (7 mg, 0.008 mmol), BINAP (7 mg, 0.012 mmol) and NaOtBu (9 mg, 0.096 mmol) were added. After the reaction mixture was stirred at 85° C. for 4 h, 15 mL water was added. The mixture was extracted with EtOAc (3×10 mL). The combined organics were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by reverse phase chromatography (X bridge Prep C18OBD, 40-60% acetonitrile in water with 10 mmol NH4HCO3 modifier) to afford the title compound as an oil. 1H NMR (400 MHz, MeOD) δ 7.56 (s, 1H), 7.42 (d, 1H), 5.96 (d, 1H), 5.89 (s, 1H), 4.59 (s, 2H), 4.15-5.11 (m, 1H), 4.04-4.01 (m, 1H), 3.81 (s, 3H), 3.63 (s, 3H), 2.66 (s, 3H), 1.95-1.89 (m, 1H), 1.61-1.53 (m, 1H), 1.01-0.95 (m, 2H); LRMS m/z (M+H) 387.1 found, 387.15 required.

후처리

  1. extractionThe mixture was extracted with EtOAc (3×10 mL)
  2. dry with materialThe combined organics were dried over MgSO4
  3. filtrationfiltered
  4. concentrationconcentrated in vacuo

출처 및 근거

ORD 기록
ord-190e2045a1704dc59ffceca9812852c4
출처 데이터셋
uspto-grants-2016_05
특허 번호
US09353104B2

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