Cesium carbonate → (S)-3-[6-(5-cyano-6-methoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carboxylic acid tert-butyl ester

HRID 242310

반응식

HRID 242310 반응식
[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[C:15]3[CH2:23][NH:22][CH2:21][CH2:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[CH:26]=[N:27][C:28]([O:33][CH3:34])=[C:29]([CH:32]=1)[C:30]#[N:31].C(=O)([O-])[O-].[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>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].O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[C:15]3[CH2:23][N:22]([C:25]4[CH:26]=[N:27][C:28]([O:33][CH3:34])=[C:29]([C:30]#[N:31])[CH:32]=4)[CH2:21][CH2:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

참가 물질

7

반응물 4

HCID 10796Cesium carbonateHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 263699225-Bromo-2-methoxynicotinonitrileHCID 57495303(S)-3-(5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester2회

생성물 1

HCID 57495310(S)-3-[6-(5-cyano-6-methoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carboxylic acid tert-butyl ester수율 39.3%

시약·촉매·용매 2

HCID 9811564Bis(dibenzylideneacetone)palladium촉매HCID 312751,4-Dioxane용매

반응 조건

온도
110 °C

실험 절차

To a glass vial was added (S)-3-(5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 7) (630 mg, 1.97 mmol), 5-bromo-2-methoxynicotinonitrile (419 mg, 1.97 mmol), cesium carbonate (1281.0 mg, 3.93 mmol), tris(dibenzylideneacetone)dipalladium(0) (180 mg, 0.20 mmol), X-Phos (319 mg, 0.67 mmol) and anhydrous dioxane (10.0 mL). The vial was flushed with a stream of argon for 15 sec and capped. The mixture was heated with stirring for 1 h at 110° C. and then stirred at room temperature for 18 h. Diluted with CH2Cl2 (100 mL) and water (30 mL) and filtered through a celite pad. The organic phase was separated by filtering through a phase separation tube and concentrated in vacuo. Purified by flash chromatography on silica gel with heptanes/EtOAc, 80/20 to 0/100 to give (S)-3-[6-(5-cyano-6-methoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carboxylic acid tert-butyl ester as a brown gum (350 mg, 39% yield) LCMS: [M+H]+=453.6, Rt(7)=1.29 min.

후처리

  1. customThe vial was flushed with a stream of argon for 15 sec
  2. customcapped
  3. temperatureThe mixture was heated
  4. stirringstirred at room temperature for 18 h
  5. additionDiluted with CH2Cl2 (100 mL) and water (30 mL)
  6. filtrationfiltered through a celite pad
  7. customThe organic phase was separated
  8. filtrationby filtering through a phase separation tube
  9. concentrationconcentrated in vacuo
  10. customPurified by flash chromatography on silica gel with heptanes/EtOAc, 80/20 to 0/100

출처 및 근거

ORD 기록
ord-ea213d696ed048aa9746e6dec2745986
출처 데이터셋
uspto-grants-2014_02
특허 번호
US08653092B2

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