Cesium carbonate → 1-(2-(1-hydroxy-2-methylpropan-2-yloxy)-5-(4-((7R,8aS)-octahydro-5,5-dimethylindolizin-7-ylamino)-5-fluoropyrimidin-2-ylamino)-4-fluorophenyl)-4-methyl-1H-tetrazol-5(4H)-one

HRID 633395ノート

反応式

HRID 633395 の反応式
Cl.Cl[C:3]1[N:8]=[C:7]([NH:9][C@@H:10]2[CH2:18][C@H:17]3[N:13]([CH2:14][CH2:15][CH2:16]3)[C:12]([CH3:20])([CH3:19])[CH2:11]2)[C:6]([F:21])=[CH:5][N:4]=1.[NH2:22][C:23]1[C:24]([F:42])=[CH:25][C:26]([O:36][C:37]([CH3:41])([CH3:40])[CH2:38][OH:39])=[C:27]([N:29]2[C:33](=[O:34])[N:32]([CH3:35])[N:31]=[N:30]2)[CH:28]=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].[CH3:33][OH:34].[OH:39][CH2:38][C:37]([CH3:41])([O:36][C:26]1[CH:25]=[C:24]([F:42])[C:23]([NH:22][C:3]2[N:8]=[C:7]([NH:9][C@@H:10]3[CH2:18][C@H:17]4[N:13]([CH2:14][CH2:15][CH2:16]4)[C:12]([CH3:20])([CH3:19])[CH2:11]3)[C:6]([F:21])=[CH:5][N:4]=2)=[CH:28][C:27]=1[N:29]1[C:33](=[O:34])[N:32]([CH3:35])[N:31]=[N:30]1)[CH3:40]

参加物

8

反応物 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 86704489(7R,8aS)-N-(2-chloro-5-fluoropyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine hydrochlorideHCID 867044931-(5-amino-4-fluoro-2-(1-hydroxy-2-methylpropan-2-yloxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-one

生成物 2

HCID 21705897Ammonia methanol収率 1%HCID 718116361-(2-(1-hydroxy-2-methylpropan-2-yloxy)-5-(4-((7R,8aS)-octahydro-5,5-dimethylindolizin-7-ylamino)-5-fluoropyrimidin-2-ylamino)-4-fluorophenyl)-4-methyl-1H-tetrazol-5(4H)-one収率 101.9%

試薬・触媒・溶媒 2

HCID 167845palladium(II) acetate触媒HCID 312751,4-Dioxane溶媒

反応条件

温度
120 °C

実験手順

To a microwave vial, was added (7R,8aS)-N-(2-chloro-5-fluoropyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine hydrochloride (100 mg, 0.298 mmol, 1.00 equiv), 1-(5-amino-4-fluoro-2-(1-hydroxy-2-methylpropan-2-yloxy)phenyl)-4-methyl-1H-tetrazol-5(4H)-one (133 mg, 0.447 mmol, 1.50 equiv), rac-BINAP (38 mg, 0.0597 mmol, 0.200 equiv), Cs2CO3 (292 mg, 0.895 mmol, 3.00 equiv), Pd(OAc)2 (7 mg, 0.0298 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 1-(2-(1-hydroxy-2-methylpropan-2-yloxy)-5-(4-((7R,8aS)-octahydro-5,5-dimethylindolizin-7-ylamino)-5-fluoropyrimidin-2-ylamino)-4-fluorophenyl)-4-methyl-1H-tetrazol-5(4H)-one (compound 85) (85 mg, 51%) as a solid.

後処理

  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

出典と根拠

ORDレコード
ord-44c60660342e4d49a1d9d5b92884ebe2
出典データセット
uspto-grants-2016_04
特許番号
US09321763B2

反応ノート

読み込み中…