Acetic Acid → ethyl 3-(3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)amino)cyclobutyl)propanoate

HRID 511573

Reaction equation

HRID 511573 reaction equation
[NH2:1][CH2:2][C@@H:3]1[C@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@H:6]2[C@H:5]([N:13]2[CH:21]=[N:20][C:19]3[C:14]2=[N:15][CH:16]=[N:17][C:18]=3[NH2:22])[O:4]1.O=[C:24]1[CH2:27][CH:26]([CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:25]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.O>[NH2:22][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[C:19]=1[N:20]=[CH:21][N:13]2[C@H:5]1[C@@H:6]2[O:10][C:9]([CH3:12])([CH3:11])[O:8][C@@H:7]2[C@@H:3]([CH2:2][NH:1][CH:24]2[CH2:25][CH:26]([CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:27]2)[O:4]1

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 5003444Sodium cyanoborohydrideHCID 113012155'-Amino-5'-deoxy-2',3'-O-(1-methylethylidene)-adenosineHCID 67775333Ethyl 3-(3-oxocyclobutyl)propanoate2×

Product 1

HCID 67774002ethyl 3-(3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)amino)cyclobutyl)propanoate

Reagents, catalysts & solvents 2

HCID 887MethanolSolvent2×HCID 962WaterSolvent

Procedure

A mixture of 9-((3aR,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-amine (0.50 g, 1.6 mmol) and ethyl 3-(3-oxocyclobutyl)propanoate (0.27 g, 1.6 mmol) in methanol (10 mL) was treated with acetic acid (0.09 mL, 2 mmol) at rt and the flask was evacuated and flushed with nitrogen (×3). The reaction mixture was treated at rt with sodium cyanoborohydride (0.26 g, 4.1 mmol), which afforded instant gas evolution and a nearly colorless, clear solution in a few minutes. The reaction mixture was stirred for 1 h at rt; HPLC/LC MS indicated a ˜2:1 mixture of product to starting amine. At 1.5 h additional ethyl 3-(3-oxocyclobutyl)propanoate (66 mg, 0.39 mmol) in MeOH (1.0 mL) was added and the reaction mixture was stirred at rt for 30 min; HPLC/LC MS indicated ˜70% conversion and some dialkylation. At 2 h 15 min water (4.0 mL) was added and the mixture was concentrated in vacuo. The residual aqueous layer was diluted with saturated aqueous sodium bicarbonate (10 mL, to pH 9) and extracted with CH2Cl2 (3×15 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo to afford the reductive amination product as a white foam, which was carried on without further purification: MS (ESI+) for C22H32N6O5 m/z 461.1 (M+H)+, 483.1 (M+Na)+.

Workup

  1. customthe flask was evacuated
  2. customflushed with nitrogen (×3)
  3. customafforded instant gas evolution
  4. waita nearly colorless, clear solution in a few minutes
  5. additiona ˜2:1 mixture of product
  6. stirringthe reaction mixture was stirred at rt for 30 min
  7. concentrationthe mixture was concentrated in vacuo
  8. additionThe residual aqueous layer was diluted with saturated aqueous sodium bicarbonate (10 mL, to pH 9)
  9. extractionextracted with CH2Cl2 (3×15 mL)
  10. dry with materialThe combined organics were dried (Na2SO4)
  11. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-d69bc03d0ff54dee9800da2645ab4ef0
Source dataset
uspto-grants-2015_08
Patent number
US09096634B2

Linked notes

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