Cesium carbonate → 4-{[(1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl]methoxy}-2-methyl-5-(2-methyl-1,3-thiazol-5-yl)pyrimidine

HRID 872062ノート

反応式

HRID 872062 の反応式
Br[C:2]1[C:3]([O:9][CH2:10][C@H:11]2[CH2:13][C@@H:12]2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][N:15]=2)=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:46]1[S:50][C:49]([CH3:51])=[N:48][CH:47]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C@H:12]2[CH2:13][C@@H:11]2[CH2:10][O:9][C:3]2[C:2]([C:46]3[S:50][C:49]([CH3:51])=[N:48][CH:47]=3)=[CH:7][N:6]=[C:5]([CH3:8])[N:4]=2)=[N:15][CH:16]=1

参加物

9

反応物 5

HCID 10796Cesium carbonateHCID 517044Potassium AcetateHCID 2733548Bis(pinacolato)diboraneHCID 132286635-Bromo-2-methyl-1,3-thiazoleHCID 710613855-bromo-4-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyrimidine

生成物 1

HCID 714887054-{[(1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl]methoxy}-2-methyl-5-(2-methyl-1,3-thiazol-5-yl)pyrimidine

試薬・触媒・溶媒 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)触媒HCID 8857Ethyl Acetate溶媒HCID 312751,4-Dioxane溶媒2 回

反応条件

温度
120 °C

実験手順

A mixture of 5-bromo-4-{[(1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl]-methoxy}-2-methylpyrimidine (MM3) (35 mg, 0.10 mmol), bis(pinacolato)diboron (27.9 mg, 0.11 mmol), potassium acetate (39 mg, 0.40 mmol) and PdCl2(dppf) (14.6 mg, 0.020 mmol) in dioxane (0.6 mL) under N2 was heated at 120° C. for 2 hours. A solution of 5-bromo-2-methyl-1,3-thiazole (26.7 mg, 0.15 mmol) in dioxane (0.2 mL) was added followed by aqueous cesium carbonate (2 M, 0.15 mL, 0.30 mmol). The resulting mixture was heated at 120° C. for 14 hours. The mixture was cooled to ambient temperature, diluted with EtOAc (5 mL), washed with sodium bicarbonate (1 mL) and brine (1 mL), dried over MgSO4, filtered and concentrated. The resulting residue was purified by reverse phase chromatography (Waters Sunfire Prep C18 OBD, 5-45% acetonitrile in water with 0.1% TFA modifier) to afford the title compound as a white, gummy solid. 1H NMR (500 MHz, DMSO): δ 8.83 (s, 1 H), 8.20 (s, 1 H), 8.14 (d, J=2.9 Hz, 1 H), 7.31-7.25 (m, 2 H), 4.56 (dd, J=11.2, 6.9 Hz, 1 H), 4.37 (dd, J=11.2, 7.6 Hz, 1 H), 3.78 (s, 3 H), 2.62 (s, 3 H), 2.54 (s, 3 H), 2.22 (dt, J=8.6, 4.6 Hz, 1 H), 1.78 (s, 1 H), 1.24-1.18 (m, 1 H), 1.11-1.05 (m, 1 H); HRMS m/z (M+H) 369.1386 found, 369.1380 required.

後処理

  1. temperatureThe resulting mixture was heated at 120° C. for 14 hours
  2. temperatureThe mixture was cooled to ambient temperature
  3. washwashed with sodium bicarbonate (1 mL) and brine (1 mL)
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe resulting residue was purified by reverse phase chromatography (Waters Sunfire Prep C18 OBD, 5-45% acetonitrile in water with 0.1% TFA modifier)

出典と根拠

ORDレコード
ord-84b8d71ba46c4cdcbac1e48df49d08dc
出典データセット
uspto-grants-2015_03
特許番号
US08975261B2

反応ノート

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