Acetonitrile → 1-(4-(tert-butyl)phenyl)-3-(3-((((3aR,4R,6R,6aR)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(methyl)amino)propyl)urea

HRID 2284545Notes

Reaction equation

HRID 2284545 reaction equation
CS(O[CH2:6][CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1)=[O:11])(=O)=O.C(N(CC)C(C)C)(C)C.[CH3:32][O:33][C:34]1[CH:63]=[C:62]([O:64][CH3:65])[CH:61]=[CH:60][C:35]=1[CH2:36][NH:37][C:38]1[C:39]2[CH:46]=[CH:45][N:44]([C@H:47]3[C@H:54]4[C@H:50]([O:51][C:52]([CH3:56])([CH3:55])[O:53]4)[C@@H:49]([CH2:57][NH:58][CH3:59])[O:48]3)[C:40]=2[N:41]=[CH:42][N:43]=1.C(#N)C.S([O-])(=O)(=O)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.C(OCC)C>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:10]([NH:9][CH2:8][CH2:7][CH2:6][N:58]([CH2:57][C@@H:49]2[C@@H:50]3[C@@H:54]([O:53][C:52]([CH3:56])([CH3:55])[O:51]3)[C@H:47]([N:44]3[C:40]4[N:41]=[CH:42][N:43]=[C:38]([NH:37][CH2:36][C:35]5[CH:60]=[CH:61][C:62]([O:64][CH3:65])=[CH:63][C:34]=5[O:33][CH3:32])[C:39]=4[CH:46]=[CH:45]3)[O:48]2)[CH3:59])=[O:11])=[CH:14][CH:15]=1)([CH3:22])([CH3:21])[CH3:20]

Participants

8

Reactant 5

HCID 6342AcetonitrileHCID 81531DiisopropylethylamineHCID 85257MethanesulfonateHCID 67818376HCID 67818376, compoundHCID 867023653-(3-(4-(Tert-butyl)phenyl)ureido)propyl methanesulfonate

Product 1

HCID 678145181-(4-(tert-butyl)phenyl)-3-(3-((((3aR,4R,6R,6aR)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(methyl)amino)propyl)ureaYield 62%

Reagents, catalysts & solvents 2

HCID 67553Tetrabutylammonium IodideCatalyst3×HCID 21584169Diethylether ethylacetateSolvent

Conditions

Temperature
65 °C

Procedure

A mixture of 3-(3-(4-(tert-butyl)phenyl)ureido)propyl methanesulfonate (224 mg, 0.682 mmol), tetra-n-butylammonium iodide (252 mg, 0.682 mmol) and N,N-diisopropylethylamine (120 μL, 0.67 mmol) was treated with N-(2,4-dimethoxybenzyl)-7-((3aR,4R,6R,6aR)-2,2-dimethyl-6-((methylamino)methyl)tetrahydrofuro[3,4-d][1,3]-dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (320 mg, 0.68 mmol) in acetonitrile (7.8 mL, 150 mmol) and the solution was heated at 65° C. After 16.5 h at 65° C., HPLC indicated the reaction was about 78-85% complete. An additional 60 mg of mesylate (in 0.4 mL CH3CN) and 67 mg of TBAI were added and continued heating for 7 h. The reaction mixture was cooled to room temperature and concentrated. The crude residue was purified by flash chromatography (60 g silica gel, 3-7% 7N NH3 in CH3OH/CH2Cl2) to yield the product contaminated with TBAI. The material was dissolved in 20 mL 1/1 ethyl acetate/ethyl ether and washed with three 10 mL portions of H2O. The organic phase was dried over Na2SO4, filtered and concentrated to yield the title compound (295 mg, 62%) as a foam: MS (ESI+) for C38H51N7O6 m/z 702.2 (M+H)+: (ESI−) for C38H51N7O6 m/z 700.3 (M−H)−; HPLC purity 96% (ret. time, 3.69 min).

Workup

  1. temperaturecontinued heating for 7 h
  2. temperatureThe reaction mixture was cooled to room temperature
  3. concentrationconcentrated
  4. customThe crude residue was purified by flash chromatography (60 g silica gel, 3-7% 7N NH3 in CH3OH/CH2Cl2)
  5. customto yield the product
  6. washwashed with three 10 mL portions of H2O
  7. dry with materialThe organic phase was dried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated

Sources & evidence

ORD record
ord-2aeae2bb44184cbe88cc982c1b565b8b
Source dataset
uspto-grants-2015_09
Patent number
US09145438B2

Reaction notes

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