4,4'-(6-Chloropyrimidine-2,4-diyl)dimorpholine → Buparlisib

HRID 1043812ノート

反応式

HRID 1043812 の反応式
[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:10]=[C:9](Cl)[N:8]=2)[CH2:3][CH2:2]1.[F:20][C:21]([F:39])([F:38])[C:22]1[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][N:25]=[C:24]([NH2:37])[CH:23]=1>COCCOC.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:39][C:21]([F:20])([F:38])[C:22]1[C:27]([C:9]2[CH:10]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:12]=[C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[N:8]=2)=[CH:26][N:25]=[C:24]([NH2:37])[CH:23]=1

参加物

7

反応物 2

HCID 6863344,4'-(6-Chloropyrimidine-2,4-diyl)dimorpholineHCID 574164995-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)pyridin-2-amine

生成物 1

HCID 16654980Buparlisib

試薬・触媒・溶媒 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)触媒HCID 80711,2-Dimethoxyethane溶媒HCID 8857Ethyl Acetate溶媒HCID 10340Sodium Carbonate溶媒

反応条件

温度
90 °C

実験手順

Argon gas was bubbled through a heterogeneous mixture of 2,4-dimorpholino-6-chloropyrimidine (4.1 g, 14.3 mmol) and 4-(trifluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (16.5 g, 57.3 mmol) in 1,2-dimethoxyethane and 2M Na2CO3 (3:1) for 20 minutes. 1,1′-Bis(diphenylphosphino)ferrocene palladium(II) chloride (292 mg, 0.36 mmol) was added and the high pressure glass vessel containing the mixture was sealed. The reaction mixture was then heated at 90° C. for 15 hours, cooled and diluted with EtOAc (300 mL). The organic solution was washed with 300 mL of a mixture of water: Na2CO3(sat.):NH4OH(conc.)=5:4:1, then NH4Cl(sat.), and brine (2×), dried over Na2SO4, filtered and concentrated. The crude material was purified by SiO2 chromatography (50-90% EtOAc/hexanes with 0.1% TEA) resulting in 5.62 g (95%) of 4-(trifluoromethyl)-5-(2,6-dimorpholinopyrimidin-4-yl)pyridin-2-amine as an off-white solid. LCMS (m/z): 411.3 (MH+); 1H NMR (CDCl3): δ 8.27 (s, 1H), 6.78 (s, 1H), 5.97 (s, 1H), 4.77 (bs, 2H), 3.59-3.80 (m, 12H), 3.58-3.61 (m, 4H).

後処理

  1. additionthe high pressure glass vessel containing the mixture
  2. customwas sealed
  3. temperaturecooled
  4. washThe organic solution was washed with 300 mL of a mixture of water
  5. dry with materialNa2CO3(sat.):NH4OH(conc.)=5:4:1, then NH4Cl(sat.), and brine (2×), dried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe crude material was purified by SiO2 chromatography (50-90% EtOAc/hexanes with 0.1% TEA)
  9. customresulting in 5.62 g (95%) of 4-(trifluoromethyl)-5-(2,6-dimorpholinopyrimidin-4-yl)pyridin-2-amine as an off-white solid

出典と根拠

ORDレコード
ord-fb8e2f41c0374b048b2dda4945be32a3
出典データセット
uspto-grants-2013_10
特許番号
US08563549B2

反応ノート

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