Cesium carbonate → 4-((7R,8aS)-octahydro-5,5-dimethylindolizin-7-ylamino)-2-(4-(1-hydroxy-2-methylpropan-2-yloxy)-2-fluoro-5-(4,5-dihydro-4-methyl-5-oxotetrazol-1-yl)phenylamino)pyrimidine-5-carbonitrile

HRID 633394노트

반응식

HRID 633394 반응식
Cl.[CH3:2][C:3]1([CH3:22])[CH2:11][C@H:10]([NH:12][C:13]2[C:18]([C:19]#[N:20])=[CH:17][N:16]=[C:15](Cl)[N:14]=2)[CH2:9][C@H:8]2[N:4]1[CH2:5][CH2:6][CH2:7]2.[NH2:23][C:24]1[C:25]([F:43])=[CH:26][C:27]([O:37][C:38]([CH3:42])([CH3:41])[CH2:39][OH:40])=[C:28]([N:30]2[C:34](=[O:35])[N:33]([CH3:36])[N:32]=[N:31]2)[CH:29]=1.C1C=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.C([O-])([O-])=O.[Cs+].[Cs+]>CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1>[NH3:4].[CH3:34][OH:35].[CH3:2][C:3]1([CH3:22])[CH2:11][C@H:10]([NH:12][C:13]2[C:18]([C:19]#[N:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:29]=[C:28]([N:30]4[C:34](=[O:35])[N:33]([CH3:36])[N:32]=[N:31]4)[C:27]([O:37][C:38]([CH3:41])([CH3:42])[CH2:39][OH:40])=[CH:26][C:25]=3[F:43])[N:14]=2)[CH2:9][C@H:8]2[N:4]1[CH2:5][CH2:6][CH2:7]2

참가 물질

8

반응물 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 867044914-((7R,8aS)-octahydro-5,5-dimethylindolizin-7-ylamino)-2-chloropyrimidine-5-carbonitrile hydrochlorideHCID 867044931-(5-amino-4-fluoro-2-(1-hydroxy-2-methylpropan-2-yloxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-one

생성물 2

HCID 21705897Ammonia methanol수율 1%HCID 718115974-((7R,8aS)-octahydro-5,5-dimethylindolizin-7-ylamino)-2-(4-(1-hydroxy-2-methylpropan-2-yloxy)-2-fluoro-5-(4,5-dihydro-4-methyl-5-oxotetrazol-1-yl)phenylamino)pyrimidine-5-carbonitrile수율 78.6%

시약·촉매·용매 2

HCID 167845palladium(II) acetate촉매HCID 312751,4-Dioxane용매

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온도
120 °C

실험 절차

To a microwave vial, was added 4-((7R,8aS)-octahydro-5,5-dimethylindolizin-7-ylamino)-2-chloropyrimidine-5-carbonitrile hydrochloride (100 mg, 0.292 mmol, 1.00 equiv), 1-(5-amino-4-fluoro-2-(1-hydroxy-2-methylpropan-2-yloxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-one (130 mg, 0.438 mmol, 1.50 equiv), rac-BINAP (37 mg, 0.0584 mmol, 0.200 equiv), Cs2CO3 (286 mg, 0.877 mmol, 3.00 equiv), Pd(OAc)2 (7 mg, 0.0292 mmol, 0.100 equiv), and dioxane (3 mL). The microwave vial was capped and sonicated under vacuum for 5 min. The reaction mixture was heated in the microwave at 120° C. for 3 h. The cooled reaction mixture was filtered using a pad of celite and rinsed with dioxane, and the filtrate was concentrated. The crude product was purified by flash chromatography and eluted with DCM:2M NH3/MeOH=100:0 to 95:5 using 1% 2M NH3/MeOH increments to provide 4-((7R,8aS)-octahydro-5,5-dimethylindolizin-7-ylamino)-2-(4-(1-hydroxy-2-methylpropan-2-yloxy)-2-fluoro-5-(4,5-dihydro-4-methyl-5-oxotetrazol-1-yl)phenylamino)pyrimidine-5-carbonitrile (compound 84) (65 mg, 39%) as a solid.

후처리

  1. customThe microwave vial was capped
  2. customsonicated under vacuum for 5 min
  3. customThe cooled reaction mixture
  4. filtrationwas filtered
  5. washrinsed with dioxane
  6. concentrationthe filtrate was concentrated
  7. customThe crude product was purified by flash chromatography
  8. washeluted with DCM

출처 및 근거

ORD 기록
ord-a75182aa91b542ac885a4c9a70dc7e95
출처 데이터셋
uspto-grants-2016_04
특허 번호
US09321763B2

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