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

Inactive Publication Date: 2012-07-25
SANOFI SA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, homogeneous catalytic hydrogenation using transition metal complexes is very expensive due to noble metals (e.g. rhodium or ruthenium) and complexed organic ligands, complex metal and ligand recovery, often low substrat

Method used

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  • Process for the production of artemisinin intermediates
  • Process for the production of artemisinin intermediates
  • Process for the production of artemisinin intermediates

Examples

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Example Embodiment

[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...

Example Embodiment

[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...

Example Embodiment

[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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Abstract

This application relates to a process for the production of (2R)-dihydroartemisinic acid or (2R)-dihydroartemisinic acid esters from artemisinic acid or artemisinic acid esters, respectively, by diimine hydrogenation of the exocyclic CC-double bond, and use of said process in the production of the antimalarial drug artemisinin.

Description

[0001] Cross References to Related Applications [0002] This application claims priority under 35 U.S.C. §119 to U.S. Provisional Patent Application 61 / 241,744, filed September 11, 2009, which is hereby incorporated by reference in its entirety. Background technique [0003] Malaria is a tropical disease common in Africa, Southeast Asia and South America. An estimated 300-500 million people are infected with malaria, making it one of the world's leading infectious diseases. In 2006, an estimated 1.5 to 2.7 million deaths were caused by malaria and most of the deaths occurred in children under 5 years of age. Disease control is hampered by the emergence of multidrug-resistant strains of the parasite Plasmodium falciparum. Therefore, the development of new antimalarial drugs and alternative methods of preparing antimalarial drugs are important world health goals. One of these antimalarial drugs is artemisinin of formula II, [0004] [0005] That is, sesquiterpene lacton...

Claims

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Application Information

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IPC IPC(8): C07C51/36C07C57/26C07C67/303C07C69/608C07D493/18
CPCC07B2200/07C07D493/20C07C67/303C07C51/36C07D493/18C07C2102/28C07C2602/28A61P33/06C07C57/26C07C69/608
Inventor V.克拉夫特G.克雷奇马K.罗森
Owner SANOFI SA
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