Succinic anhydride → Artesunate

HRID 1839856Notes

Reaction equation

HRID 1839856 reaction equation
[CH3:1][C@H:2]1[C@@H:12]2[CH2:13][CH2:14][C@:15]3([CH3:19])[O:17][O:18][C@:11]42[C@H:5]([C@@H:6]([CH3:20])[C:7]([O:9][C@@H:10]4[O:16]3)=[O:8])[CH2:4][CH2:3]1.[BH4-].[Na+].C[C@H]1[C@@H]2CCC3(C)O[O:39][C@:32]42[C@H:27]([C@@H:28](C)[C@@H:29]([OH:41])[O:30][C@@H]4O3)CC1.C1(=O)OC(=O)CC1>O1CCOCC1.O.O1CCCC1>[CH3:1][C@H:2]1[C@@H:12]2[CH2:13][CH2:14][C@@:15]3([CH3:19])[O:17][O:18][C@:11]42[C@H:5]([C@@H:6]([CH3:20])[C@H:7]([O:8][C:32]([CH2:27][CH2:28][C:29]([OH:41])=[O:30])=[O:39])[O:9][C@@H:10]4[O:16]3)[CH2:4][CH2:3]1

Participants

8

Reactant 4

HCID 7922Succinic anhydrideHCID 456410Npc182939HCID 4311764Sodium borohydrideHCID 9838675Qing Hau Sau2×

Product 1

HCID 6917864Artesunate

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 312751,4-DioxaneSolvent

Procedure

In the process of the present invention, artemisinin and the catalyst, polyhydroxy compound or cation exchange resin were stirred in 1,4-dioxan or tetrahydrofuran for 5 minutes. Sodium borohydride was added slowly at room temperature (20-35° C.) and the reaction mixture was stirred for about 0.5-2 hours at room temperature. After completion of the reduction of artemisinin, without workup or the isolation of the dihydroartemisinin, succinic anhydride was added in the presence of a base at room temperature (20-35° C.). The reaction mixture was stirred further for about 1-3 hours at room temperature (20-35° C.). After completion of the esterification reaction, cold water was added. The Applicants experimentally found that if the pH of the solution is maintained between 6-7, it is conducive for extraction with ethyl acetate n-hexane mixture. Hence, the pH of the solution is adjusted between 6 to 7 by adding acetic acid. The solution having pH of 6-7 was then extracted with mixture of ethyl acetate n-hexane (3-4 times). The combined extract was washed with water. The ethyl acetate-hexane extract was dried over anhydrous sodium sulphate and removal of the solvent furnished impure artesunic acid. Silica gel column chromatography (1:4-5 ratio) of the impure artesunic acid using 20-30% ethyl acetate in n-hexane as an eluant furnished pure artesunic acid in 85-96% w/w yield.

Workup

  1. stirringThe reaction mixture was stirred further for about 1-3 hours at room temperature (20-35° C.)
  2. additionwas added
  3. temperatureis maintained between 6-7, it
  4. extractionis conducive for extraction with ethyl acetate n-hexane mixture
  5. additionby adding acetic acid
  6. extractionwas then extracted with mixture of ethyl acetate n-hexane (3-4 times)
  7. extractionThe combined extract
  8. washwas washed with water
  9. extractionThe ethyl acetate-hexane extract
  10. dry with materialwas dried over anhydrous sodium sulphate and removal of the solvent

Sources & evidence

ORD record
ord-e40cbcb701e048f6a1e7c025a358379d
Source dataset
uspto-grants-2004_01
Patent number
US06677463B1

Reaction notes

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