Cesium carbonate → 8-(2-(2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)ethyl)-3-oxa-8-azabicyclo[3.2.1]octane

HRID 1946018

반응식

HRID 1946018 반응식
Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:14]3[CH:19]4[CH2:20][CH2:21][CH:15]3[CH2:16][O:17][CH2:18]4)[N:8]2[CH3:11])=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:3]=1.[CH2:28]([C:30]1[NH:31][C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1)[CH3:29].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]>[CH2:28]([C:30]1[N:31]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:14]4[CH:19]5[CH2:20][CH2:21][CH:15]4[CH2:16][O:17][CH2:18]5)[N:8]3[CH3:11])=[C:4]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[N:3]=2)[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1)[CH3:29]

참가 물질

7

반응물 4

HCID 10796Cesium carbonateHCID 158072-EthylbenzimidazoleHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 596059492-Chloro-9-methyl-6-morpholin-4-yl-8-[2-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)ethyl]-9H-purine

생성물 1

HCID 596061468-(2-(2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)ethyl)-3-oxa-8-azabicyclo[3.2.1]octane수율 52.4%

시약·촉매·용매 2

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

반응 조건

온도
120 °C

실험 절차

A mixture of 2-chloro-9-methyl-6-morpholin-4-yl-8-[2-(3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl)ethyl]-9H-purine (75 mg, 0.19 mmol), 2-ethylbenzimidazole (31 mg, 0.21 mmol), Pd2(dba)3 (4.4 mg, 2.5 mol %), Xphos (9.1 mg, 10 mol %) and Cs2CO3 (93 mg, 0.29 mmol) in dioxane (2.0 mL) was purged with argon gas then heated at 120° C., for 18 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/MeOH in DCM. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 20 mM triethylamine in water on a gradient of acetonitrile 30-90%) to give 511 (50 mg, 52%) as an off white solid. LCMS: (Method I): RT 2.49 min; [M+H]+ 503.2. 1H NMR (400 MHz, CHCl3-d): δ 8.02-7.97 (m, 1 H), 7.77-7.73 (m, 1 H), 7.29-7.22 (m, 2 H), 4.52-4.20 (m, 4 H), 3.86 (t, J=4.7 Hz, 4 H), 3.82 (s, 3 H), 3.79-3.65 (m, 2 H), 3.58-3.50 (m, 2 H), 3.35 (q, J=7.5 Hz, 2 H), 3.18-3.09 (m, 2 H), 3.09-2.99 (m, 2 H), 2.90-2.76 (m, 2 H), 2.07-1.88 (m, 4 H), 1.44 (t, J=7.5 Hz, 3 H)

후처리

  1. customwas purged with argon gas
  2. washwashed with MeOH
  3. washthe desired product eluted with 2 M NH3/MeOH in DCM
  4. customThe resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 20 mM triethylamine in water on a gradient of acetonitrile 30-90%)

출처 및 근거

ORD 기록
ord-9ea7a9b812414085a7754c3d581bbc9b
출처 데이터셋
uspto-grants-2013_03
특허 번호
US08394796B2

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