Cesium carbonate → 4-(2-(2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)ethyl)-1-isopropylpiperazin-2-one

HRID 1946006노트

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HRID 1946006 반응식
Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][N:17]([CH:20]([CH3:22])[CH3:21])[C:16](=[O:23])[CH2:15]3)[N:8]2[CH3:11])=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:3]=1.[CH2:30]([C:32]1[NH:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1)[CH3:31].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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]>[CH2:30]([C:32]1[N:33]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:14]4[CH2:19][CH2:18][N:17]([CH:20]([CH3:21])[CH3:22])[C:16](=[O:23])[CH2:15]4)[N:8]3[CH3:11])=[C:4]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:3]=2)[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1)[CH3:31]

참가 물질

7

반응물 4

HCID 10796Cesium carbonateHCID 158072-EthylbenzimidazoleHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 596059634-[2-(2-Chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)ethyl]-1-isopropylpiperazin-2-one

생성물 1

HCID 596058904-(2-(2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)ethyl)-1-isopropylpiperazin-2-one수율 44%

시약·촉매·용매 2

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

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온도
120 °C

실험 절차

A mixture of 4-[2-(2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)ethyl]-1-isopropylpiperazin-2-one (51 mg, 0.12 mmol), 2-ethylbenzimidazole (20 mg, 0.13 mmol), Pd2(dba)3 (2.8 mg, 2.5 mol %), Xphos (5.8 mg, 10 mol %) and Cs2CO3 (59 mg, 0.18 mmol) in dioxane (1.5 mL) was purged with argon gas then heated at 120° C., for 19 h, in a sealed tube. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by flash chromatography (Si—PCC, 0-10% 2 M NH3/MeOH in DCM) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 20 mM triethylamine in water on a gradient of acetonitrile 20-98%) to give 493 (28 mg, 44%) as an off white solid. LCMS: (Method I): RT 2.75 min; [M+H]+ 532.3. 1H NMR (400 MHz, CHCl3-d): δ 8.01-7.96 (m, 1H), 7.80-7.76 (m, 1 H), 7.28 (m, 2 H), 4.91-4.82 (m, 1 H), 4.5-4.21 (m, 4 H), 3.87 (t, J=4.7 Hz, 4 H), 3.77 (s, 3 H), 3.37 (q, J=7.5 Hz, 2 H), 3.29 (s, 2 H), 3.26 (t, J=5.4 Hz, 2 H), 3.08-3.01 (m, 2 H), 3.00-2.93 (m, 2 H), 2.81 (t, J=5.4 Hz, 2 H), 1.45 (t, J=7.5 Hz, 3 H), 1.14 (d, J=6.9 Hz, 6 H)

후처리

  1. customwas purged with argon gas
  2. washwashed with MeOH
  3. washthe desired product eluted with 2 M NH3 in MeOH
  4. customThe resulting residue was purified by flash chromatography (Si—PCC, 0-10% 2 M NH3/MeOH in DCM)

출처 및 근거

ORD 기록
ord-55c41a777bac4f49894c98945792c22e
출처 데이터셋
uspto-grants-2013_03
특허 번호
US08394796B2

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