Method for synthesizing camptothecin serving as active intermediate of anti-tumor medicament
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A synthetic method and technology of camptothecin, applied in the field of drug synthesis, can solve the problems of camptothecin shortage and exhaustion, extraction pollution, low efficiency, etc., and achieve the effect of low cost, efficient route and high efficiency
Inactive Publication Date: 2013-08-28
NANJING YIBEIJIA TECH
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Problems solved by technology
[0009] At present, the camptothecin required for the production of various drugs mainly depends on the semi-synthesis of natural S-CPT, and the camptothecin, which is a national second-class protected plant species, is also in short supply and exhausted, and the pollution is serious during extraction
Recently, reports on the total synthesis of S-CPT emerge in endlessly, but the synthesis methods often have defects such as low efficiency, long route, and high cost.
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Embodiment 1
[0027]
[0028] Add 10ml of DMF (0.13mol) to the reaction flask, cool in an ice bath, and slowly add 30ml of POCl dropwise to the reaction flask 3 (0.33mol), control the temperature not to exceed 5°C. After dropping, add compound 1 (acetanilide) (5.20g, 38.5mmol) to the reaction solution, control the temperature at 80-90°C, stir the reaction for 8-10h, and drop to At room temperature, the reaction solution was poured into a beaker filled with ice water, stirred, suction filtered, and vacuum-dried to obtain compound 2 (5.90 g, 30.8 mmol, 80%) as a pale yellow solid.
Embodiment 2
[0030]
[0031] Dissolve 5.90g of compound 2 (30.8mmol) in 50ml of THF, cool down to 0°C, and add NaBH in batches to the reaction flask 4 (1.71g, 45mmol), stirred and reacted for 3-5 hours after the addition, added ice water dropwise to the reaction flask, poured out the reaction solution, suction filtered, and dried to obtain light yellow solid compound 3 (5.84g, 30.2mmol, 98 %).
Embodiment 3
[0033]
[0034] Add compound 3 (5.84g, 30.2mmol), Et 3 N (15.18g, 0.15mol) and 100ml of THF were stirred for 0.5h, TsCl (11.54g, 60.4mmol) was added at room temperature, stirred at room temperature for 16-24h, the reaction solution was suction filtered, and the filtrate was dried with anhydrous magnesium sulfate. Suction filtration, precipitation under reduced pressure, and purification by column chromatography (EtOAc / n-hexane=1:5) gave compound 4 as a white solid (9.76 g, 28.1 mmol, 93%).
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Abstract
The invention discloses a novel synthetic method for camptothecin serving as an intermediate of anti-tumor medicament irinotecan hydrochloride and various functional medicament camptothecin derivatives. According to the technical scheme, the method mainly comprises the following steps of: (1) obtaining a compound 2 from a compound 1; (2) obtaining a compound 3 from the compound 2; (3) obtaining a compound 4 from the compound 3; (4) obtaining a compound 6 from a compound 5; (5) obtaining a compound 7 from the compound 6; (6) obtaining a compound 8 from the compound 7; (7) obtaining a compound 9 from the compound 8; (8) obtaining a compound 10 from the compounds 4 and 9; and (9) obtaining a compound 11 from the compound 10, namely (20S)-camptothecin. By adopting the technical scheme, the method can be used for efficiently completing full synthesis of the camptothecin with short route based on simple commercial raw materials by using common reagents and simple operation.
Description
technical field [0001] The invention belongs to the technical field of medicine synthesis, and specifically relates to a novel synthesis method of camptothecin, which can be used as an intermediate of antitumor drug irinotecan hydrochloride and various functional drug camptothecin derivatives. Background technique [0002] In 1966, American scientists Wall and Wani first isolated (20S)-camptothecin (S-CPT) from Camptotheca acuminata endemic to my country. Thereafter, the structure of S-CPT was identified by various analytical techniques, and its molecule was confirmed to have a unique pentacyclic structure and 20S chiral center (Figure 1). [0003] [0004] Figure1(20S)-The structural formula of camptothecin [0005] Due to the extremely poor solubility of camptothecin in water and other physiologically compatible solvents, the soluble sodium salt of camptothecin was first used in clinical applications, but its antitumor effect was significantly reduced, and the soluble ...
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