Trifluoroacetic acid → (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((methyl(3-(2-(5-(oxetan-3-yl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)tetrahydrofuran-3,4-diol

HRID 511671Notes

Reaction equation

HRID 511671 reaction equation
CC1(C)[O:6][C@@H:5]2[C@@H:7]([CH2:20][N:21]([CH3:41])[CH:22]3[CH2:25][CH:24]([CH2:26][CH2:27][C:28]4[NH:32][C:31]5[CH:33]=[CH:34][C:35]([CH:37]6[CH2:40][O:39][CH2:38]6)=[CH:36][C:30]=5[N:29]=4)[CH2:23]3)[O:8][C@@H:9]([N:10]3[CH:18]=[N:17][C:16]4[C:11]3=[N:12][CH:13]=[N:14][C:15]=4[NH2:19])[C@@H:4]2[O:3]1.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>O>[NH2:19][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[C:16]=1[N:17]=[CH:18][N:10]2[C@H:9]1[C@H:4]([OH:3])[C@H:5]([OH:6])[C@@H:7]([CH2:20][N:21]([CH3:41])[CH:22]2[CH2:25][CH:24]([CH2:26][CH2:27][C:28]3[NH:32][C:31]4[CH:33]=[CH:34][C:35]([CH:37]5[CH2:38][O:39][CH2:40]5)=[CH:36][C:30]=4[N:29]=3)[CH2:23]2)[O:8]1

Participants

5

Reactant 3

HCID 6422Trifluoroacetic acidHCID 11430Potassium Carbonate2×HCID 178484167HCID 178484167, compound

Product 1

HCID 178484170(2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-((methyl(3-(2-(5-(oxetan-3-yl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)tetrahydrofuran-3,4-diolYield 55%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent2×

Conditions

Temperature
0 °C

Procedure

To a cooled (ice bath) flask containing 9-((3aR,4R,6R,6aR)-2,2-dimethyl-6-((methyl(3-(2-(5-(oxetan-3-yl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)amino)methyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-amine (0.28 g, 0.42 mmol) was added a precooled (ice bath) solution of trifluoroacetic acid (6.4 mL, 84 mmol) in water (0.75 mL, 42 mmol). The reaction mixture was stirred for 5.75 h at 0° C.; HPLC/LC MS indicated nearly complete consumption of starting material. At 6 h the flask was removed from the cold bath and the volatiles were removed by distillation at rt. The residue was diluted with MeOH (15 mL) and treated with potassium carbonate (0.32 g, 2.3 mmol) and water (1 mL) and the mixture was stirred for 20 min at rt; pH 2. Additional potassium carbonate (0.20 g, 1.4 mmol) was added and the mixture was stirred for 20 min; pH 8-9. The solution was filtered through a fine frit, rinsing with MeOH, and the filtrate was concentrated in vacuo to afford a tan semi-solid. Purification by column chromatography (3×8 cm silica; 10-20% 7 N methanolic NH3/CH2Cl2) afforded the title compound (123 mg, 55%) as a nearly colorless glass: MS (ESI+) for C27H34N8O4 m/z 535.3 (M+H)+; MS (ESI−) for C27H34N8O4 m/z 533.3 (M−H)−; HPLC purity >95% (ret. time 1.765 min); 1H NMR (400 MHz, d4-MeOH) mixture of cis/trans isomers δH 8.29-8.25 (m, 1H), 8.21-8.17 (m, 1H), 7.51 (s, 1H), 7.47 (d, J=8.3 Hz, 1H), 7.26 (dd, J=1.6, 8.3 Hz, 1H), 6.00-5.96 (m, 1H), 5.11 (dd, J=5.8, 8.3 Hz, 2H), 4.81-4.76 (m, 2H), 4.73-4.68 (m, 1H), 4.40-4.31 (m, 1H), 4.27-4.13 (series of m, 2H), 3.13-3.03 (m, 0.4H), 2.86-2.66 (series of m, 4.6H), 2.30-1.80 (series of m, 8.6H), 1.55-1.40 (m, 1.4H).

Workup

  1. temperatureTo a cooled (ice bath) flask
  2. customconsumption of starting material
  3. customAt 6 h the flask was removed from the cold bath
  4. customthe volatiles were removed by distillation at rt
  5. additionThe residue was diluted with MeOH (15 mL)
  6. stirringthe mixture was stirred for 20 min at rt
  7. stirringthe mixture was stirred for 20 min
  8. filtrationThe solution was filtered through a fine frit
  9. washrinsing with MeOH
  10. concentrationthe filtrate was concentrated in vacuo
  11. customto afford a tan semi-solid
  12. customPurification by column chromatography (3×8 cm silica; 10-20% 7 N methanolic NH3/CH2Cl2)

Sources & evidence

ORD record
ord-72772348143e4625a4bc333aa5f23cd5
Source dataset
uspto-grants-2015_08
Patent number
US09096634B2

Reaction notes

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