Tonapofylline → 3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-propionic acid chloromethyl ester

HRID 480136Notes

Reaction equation

HRID 480136 reaction equation
[O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:27])[N:3]1[CH2:28][CH2:29][CH3:30].C(=O)(O)[O-].[Na+].S(Cl)(O[CH2:40][Cl:41])(=O)=O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O.ClCCl>[Cl:41][CH2:40][O:25][C:24](=[O:26])[CH2:23][CH2:22][C:17]12[CH2:20][CH2:21][C:14]([C:7]3[NH:6][C:5]4[C:4](=[O:27])[N:3]([CH2:28][CH2:29][CH3:30])[C:2](=[O:1])[N:10]([CH2:11][CH2:12][CH3:13])[C:9]=4[N:8]=3)([CH2:19][CH2:18]1)[CH2:15][CH2:16]2

Participants

7

Reactant 3

HCID 216466TonapofyllineHCID 516892Sodium BicarbonateHCID 2733556Chloromethyl chlorosulfate

Product 1

HCID 670789293-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-propionic acid chloromethyl esterYield 86%

Reagents, catalysts & solvents 3

HCID 94433Tetrabutylammonium hydrogen sulfateCatalystHCID 962WaterSolventHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

A mixture of 3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-propionic acid (208 mg, 0.5 mmol), sodium bicarbonate (168 mg, 2 mmol), and tetra-n-butylammonium hydrogensulfate (17 mg, 0.05 mmol) in water (5 ml) and dichloromethane (5 ml) was stirred vigorously at 0° C. After 10 min, to the reaction mixture was added a solution of chloromethyl chlorosulfate in dichloromethane (1 ml) and allowed to ambient temperature and continued to stir vigorously. After a couple of hours, the organic layer was separated and washed with brine. The organic extracts were dried over sodium sulfate. After the solvent was removed in vacuo, the residue was purified by column chromatography on SiO2 using ethyl/hexane (1:5) as an eluent to give (200 mg, yield 86%) 3-[4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-propionic acid chloromethyl ester. MS (M+1 465)

Workup

  1. customallowed to ambient temperature
  2. stirringto stir vigorously
  3. waitAfter a couple of hours
  4. customthe organic layer was separated
  5. washwashed with brine
  6. dry with materialThe organic extracts were dried over sodium sulfate
  7. customAfter the solvent was removed in vacuo
  8. customthe residue was purified by column chromatography on SiO2

Sources & evidence

ORD record
ord-4e92cd6f410c48cd8439d0bed4f066c7
Source dataset
uspto-grants-2003_11
Patent number
US06649600B1

Reaction notes

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