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A preparation process and organic base technology, applied in the field of everolimus preparation process, can solve the problems of low conversion rate and rapamycin utilization rate, unfavorable everolimus, unrecoverable and other problems, and achieve stable and reliable reaction results , reduce degradation, improve the effect of reaction conversion
Active Publication Date: 2014-06-11
SHANGHAI INST OF PHARMA IND CO LTD +1
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The reaction yield is greatly improved (intermediate A yield is 30%), but the conversion rate of the first step reaction and the utilization rate of rapamycin are all lower than CN201010017955 (only 30% of intermediate A is obtained, which is not recovered or cannot reclaiming rapamycin), the second step reaction continues to use US5665772, the purity of the crude everolimus of gained is lower, is unfavorable for obtaining high-purity everolimus with higher yield
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Embodiment 1
[0029] Embodiment 1. Synthesis of Intermediate A
[0030] Dissolve rapamycin (29.99g) and N,N‐diisopropylethylamine (25.75g) in toluene (80mL), heat to 60°C, add trifluoromethanesulfonic acid 2‐(tert-butyl Dimethylsilyloxy)ethyl ester (48.44g), reacted for 4.5h, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain intermediate A (23.35 g, yield: 66.4%), and rapamycin (5.03 g, recovery: 16.8%) was recovered. Example 2. Synthesis of Everolimus
Embodiment 2
[0031] Dissolve intermediate A (12.98g) in 240ml of acetone, add 48ml of 0.5M hydrochloric acid, react at 20°C for 0.5h, extract with ethyl acetate, and concentrate to obtain crude everolimus (12.35g), HPLC Chromatographic detection showed that the purity of the crude product was greater than 90%. 1HNMR (CDCl3): δ0.71(1H, dd), 0.83~1.60(m), 1.64(3H, s), 1.73(3H, s), 1.75~2.40(m), 2.52‐2.90(m), 3.00 ~3.20 (5H, s and m), 3.32 (3H, s), 3.35‐3.48 (5H, s and d), 3.52‐3.95 (8H, m), 4.18 (1H, m), 5.08‐5.60 (4H, m), 5.84‐6.40 (4H, m).
Embodiment 3
[0032] Example 3. Synthesis of Everolimus
[0033] Dissolve intermediate A (1.00g) in 20ml of acetone, add 4ml of 0.5M hydrochloric acid, react at 35°C for 0.25h, extract with ethyl acetate, concentrate to obtain crude everolimus (0.98g), and perform high performance liquid chromatography Tests showed that the crude product had a purity of 82%.
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Abstract
The invention provides a preparation technology for everolimus. The preparation method comprises the two steps of: 1) reacting sirolimus with 2-(tert-butyldiMethylsilyloxy) ethyl trifluoromethane sulfonate in the presence of proper solvent and organic base, to obtain an intermediate A; 2) reacting the intermediate A with inorganic acid in an organic solvent to obtain everolimus, wherein the organic base used in the step 1) is selected from large-steric hindrance or non-nucleophilic bases such as triethylamine, N,N-diisopropylethylamine, 1,8-diazabicycloundec-7-ene or N-methylmorpholine, acid used in the step 2) is hydrochloric acid, sulfuric acid or phosphoric acid. According to the technology, the total yield in the two steps and the purity of a final product are greatly improved as compared with those reported by the existing literature, the process route is short, the reaction conditions are mild, and the reaction result is also stable and reliable.
Description
technical field [0001] The invention belongs to the field of pharmaceutical synthesis, and in particular relates to a preparation process of everolimus. Background technique [0002] Everolimus is an orally effective derivative of rapamycin developed by Novartis, Switzerland, and belongs to a new generation of macrolide immunosuppressants and antitumor drugs. Everolimus was first launched in Sweden in 2003, as an immunosuppressant to prevent rejection in organ transplantation and as a coating drug for drug coating of vascular stents. Everolimus was approved by the European Medicines Agency (EMEA) and the US Food and Drug Administration (FDA) in 2008 and 2009, respectively, as an antineoplastic drug for the treatment of breast cancer, neuroendocrine tumors and renal cell carcinoma. The structural formula of everolimus is derived from 40‐OH of rapamycin to 40‐O‐(2‐hydroxyethyl), so everolimus is also called 40‐O‐(2‐hydroxyethyl)‐Rapa Mycin. [0003] [0004] Patent US566...
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