Process for the production of artemisinin intermediates
An in-situ preparation, diimine technology, applied in the preparation of carboxylate, organic chemistry methods, chemical instruments and methods, etc., can solve the problems of trace catalyst poison sensitivity, high cost, low substrate and catalyst loading, etc. The effect of good product purity and high overall yield
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[0084] Example 1: Synthesis of dihydroartemisinic acid Ia in methanol at 65°C by producing diimine from HOSA and sodium methoxide
[0085] 0.248 g (0.001 mol) artemisinic acid IIIa was dissolved in 10 mL MeOH. Then 0.432 g (0.008 mol) of sodium methoxide was added. The reaction mixture was heated to reflux (65°C) and 0.628 g (0.005 mol) of hydroxylamine-O-sulfonic acid (HOSA) was added in portions. After the addition was complete, the reaction mixture was stirred at the same temperature for another 1 hour until RP-HPLC analysis showed that the starting material was completely consumed. The reaction mixture was acidified to pH 2 with dilute aqueous hydrochloric acid. The product was extracted with MTBE, dried with magnesium sulfate and the solvent was evaporated to give 0.22 g (93%) of the title compound, which crystallized on standing. by 1 H-NMR and HPLC / MS analysis determined that the diastereomer ratio in the unpurified product was greater than 96:4, which confirmed the des...
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[0095] Example 2: Synthesis of dihydroartemisinic acid Ia by generating diimine from hydroxylamine and HOSA in methanol at 40-50°C
[0096] 5.3g (0.08mol) hydroxylamine (50% in water) and 15.1g (0.12mol) HOSA (dissolved in 25mL water) were continuously added to a solution of 4.69g (0.02mol) artemisinic acid IIIa in 10mL MeOH, while using The 5N NaOH aqueous solution keeps the pH constant at pH 9. The temperature range is 40℃-50℃. After the addition was complete, the reaction mixture was stirred for another hour until no change in pH was detected. RP-HPLC analysis confirmed the complete consumption of artemisinic acid Ia. The reaction mixture was then acidified to pH 2 with dilute aqueous hydrochloric acid. The product was extracted with MTBE, dried with magnesium sulfate and the solvent was evaporated to give 4.8 g (100%) of the title compound, which crystallized on standing. by 1 The ratio of diastereomers in the unpurified product detected by H-NMR and LC / MS analysis was 96...
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[0097] Example 3: Synthesis of dihydroartemisinic acid Ia by generating diimine from hydroxylamine and HOSA / NaOH in methanol at a temperature between -5°C and 0°C
[0098] Dissolve 2.34 g (0.01 mol) Artemisinic acid IIIa in 20 mL MeOH. Then 1.98 g (0.03 mol) hydroxylamine (50% in water) and 5.65 g (0.045 mol) HOSA (dissolved in 10 mL water) were continuously added while maintaining pH 9 with a 32% aqueous NaOH solution. Adjust the temperature between -5°C and 0°C. After the addition was complete, the reaction mixture was stirred for another hour until no pH change was detected. RP-HPLC analysis confirmed the complete consumption of artemisinic acid. The reaction mixture was then acidified to pH 2 with dilute aqueous hydrochloric acid. The product was extracted with MTBE, dried with magnesium sulfate and the solvent was evaporated to give 2.25 g (95%) of the title compound, which crystallized on standing. by 1 The ratio of diastereomers in the unpurified product detected by H-...
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