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

HRID 872062노트

반응식

HRID 872062 반응식
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

참가 물질

9

반응물 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

생성물 1

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

시약·촉매·용매 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)촉매HCID 8857Ethyl Acetate용매HCID 312751,4-Dioxane용매2회

반응 조건

온도
120 °C

실험 절차

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.

후처리

  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)

출처 및 근거

ORD 기록
ord-84b8d71ba46c4cdcbac1e48df49d08dc
출처 데이터셋
uspto-grants-2015_03
특허 번호
US08975261B2

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