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 530791ノート

反応式

HRID 530791 の反応式
[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

参加物

9

反応物 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

生成物 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

試薬・触媒・溶媒 4

HCID 9811564Bis(dibenzylideneacetone)palladium触媒HCID 962Water溶媒2 回HCID 1140Toluene溶媒HCID 6342Acetonitrile溶媒

反応条件

温度
85 °C

実験手順

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.

後処理

  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

出典と根拠

ORDレコード
ord-190e2045a1704dc59ffceca9812852c4
出典データセット
uspto-grants-2016_05
特許番号
US09353104B2

反応ノート

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