Cesium carbonate → 4-(8-(2-(4,4-difluoropiperidin-1-yl)ethyl)-2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-9H-purin-6-yl)morpholine

HRID 1946057

반응식

HRID 1946057 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][C:17]([F:21])([F:20])[CH2:16][CH2:15]3)[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]>[F:20][C:17]1([F:21])[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][C:7]2[N:8]([CH3:11])[C:9]3[C:5]([N:6]=2)=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:3]=[C:2]([N:31]2[C:32]4[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=4[N:34]=[C:30]2[CH2:28][CH3:29])[N:10]=3)[CH2:15][CH2:16]1

참가 물질

7

반응물 4

HCID 10796Cesium carbonateHCID 158072-EthylbenzimidazoleHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 596055962-Chloro-8-[2-(4,4-difluoropiperidin-1-yl)ethyl]-9-methyl-6-morpholin-4-yl-9H-purine

생성물 1

HCID 596057654-(8-(2-(4,4-difluoropiperidin-1-yl)ethyl)-2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-9H-purin-6-yl)morpholine수율 64%

시약·촉매·용매 2

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

반응 조건

온도
120 °C

실험 절차

A mixture of 2-chloro-8-[2-(4,4-difluoropiperidin-1-yl)ethyl]-9-methyl-6-morpholin-4-yl-9H-purine (30 mg, 0.08 mmol), 2-ethylbenzimidazole (12 mg, 0.08 mmol), Pd2(dba)3 (1.7 mg, 2.5 mol %), Xphos (3.6 mg, 10 mol %) and Cs2CO3 (37 mg, 0.11 mmol) in dioxane (1.0 mL) was purged with argon gas then heated at 120° C., for 20 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 540 (25 mg, 64%) as a beige solid. LCMS: (Method I): RT 2.61 min; [M+H]+ 511.2. 1H NMR (400 MHz, CHCl3-d): δ 8.01-7.96 (m, 1 H), 7.78-7.74 (m, 1 H), 7.29-7.23 (m, 2 H), 4.68-4.02 (m, 4 H), 3.86 (t, J=4.8 Hz, 4 H), 3.78 (s, 3 H), 3.35 (q, J=7.5 Hz, 2 H), 3.12-2.99 (m, 4 H), 2.81-2.65 (m, 4 H), 2.15-1.99 (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-af69d6de5cfa4d37a771995d8135af3e
출처 데이터셋
uspto-grants-2013_03
특허 번호
US08394796B2

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