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Method for producing irinotecan

A technology of irinotecan and production method, applied in the production field of irinotecan, can solve the problems of complex operation process, high production cost, long production cycle and the like, and achieve the effects of cost reduction, short reaction cycle and easy operation

Inactive Publication Date: 2011-05-25
SHANGHAI PUYI CHEM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, because high-purity SN38 is not easy to obtain economically in the market, the usual production process needs to adopt column chromatography in the refining process of irinotecan products. The production cycle is long, the operation process is complicated, and the labor intensity is high. Not only the production cost is high, The output is also low, so it is urgent to develop a more economical process suitable for mass production

Method used

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  • Method for producing irinotecan
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  • Method for producing irinotecan

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 2

[0028] Example 2 Purification raw material SN38 (7-ethyl-10-hydroxycamptothecin)

[0029] 1. Transfer 2000g of SN-38 crude product and 200L methanol to the heating kettle of the cold and hot reaction kettle, heat and reflux for 1.5h, then pump it into the cooling kettle to cool to room temperature, filter with suction, distill the filtrate to recover methanol, and use the filter residue in the next step.

[0030] 2. Transfer the filter residue from the previous step and 200L acetic acid to the heating kettle of the cold and hot reaction kettle, heat and reflux until all the solids are dissolved, and then suction filter to the cooling kettle to cool to room temperature, suction filter, distill the filtrate to recover acetic acid, and use the filter residue for the next step.

[0031] 3. Transfer the filter residue from the previous step and 200L ethanol to the heating kettle of the cold and hot reaction kettle, heat until all the solids are dissolved, pump it into the cooling ke...

Embodiment 3

[0032] Embodiment 3 condensation obtains irinotecan crude product

[0033] Prepare free 4-piperidinyl piperidine formyl chloride alkali: dissolve 2.2Kg of 4-piperidinyl piperidine formyl chloride hydrochloride in 10Kg of dichloromethane, add 1Kg of sodium bicarbonate and 5Kg of aqueous solution, and After stirring and reacting for 1 hour, the organic phase was separated and concentrated to remove the solvent, and 28 Kg of pyridine was added to dissolve it for later use.

[0034] Feeding reaction: put 20L pyridine into a clean 100L reactor, start the stirring device, stir fully, add 2Kg of SN-38 refined product, stir at room temperature for 1 hour, after it is completely dissolved, add the above-mentioned 4-piperidinylpiperidine methyl dropwise acid chloride solution. Add about 3 hours. After dropping, react at 25-30°C for 10 hours.

[0035] Post-processing: heating to 50°C, and distilling off pyridine under reduced pressure. After cooling to 40°C, add 50L of chloroform, fu...

Embodiment 4

[0036] Embodiment 4 salt refining

[0037] Feeding reaction: Add 35L deionized water to a 100L dissolution kettle, add 2Kg crude irinotecan, 0.7L concentrated hydrochloric acid, start the stirring device, heat to 50°C, and dissolve completely.

[0038] Post-treatment: Cool to 30°C, add 20L chloroform, stir well, separate layers, decolorize with activated carbon. Filter and concentrate the filtrate to 25L of water, cool and crystallize at 5°C, filter and wash with cold water. After drying, 2.1 Kg of white crystalline solid was obtained. The molar yield is 89%. HPLC analysis showed that the purity of the product was >99%, and the purity of the product was less than 0.1%.

[0039] In summary, the production method of irinotecan of the present invention eliminates the need for column chromatography in the refining process of irinotecan, shortens the production cycle, simplifies operations, reduces costs, increases yield, and is suitable for industrial scale production.

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Abstract

The invention provides a method for producing irinotecan, which comprises the following steps of: (1) purifying an initial raw material SN-38 to obtain a pure SN-38, and controlling the impurities in the pure SN-38 till the single impurity is less than 0.1 percent; and (2) condensing the pure SN-38 and free 4-piperidyl piperidine formyl chloride base and then refining to obtain the irinotecan, wherein column chromatography does not need to be adopted in the refining. Preferably, in the step (1), the initial raw material SN-38 is sequentially treated by adopting methanol, acetic acid and ethanol re-crystallization so as to obtain the pure SN-38; 10-hydroxycamptothecine in the impurities is controlled to be less than 0.05 percent; and the ratio of the free 4-piperidyl piperidine formyl chloride base to the pure SN-38 is at least 1.2:1. Because the column chromatography is not needed in the irinotecan refining process, the method for producing the irinotecan shortens the production period, simplifies the operation, reduces the cost, improves the yield and is suitable for industrialized scale production.

Description

technical field [0001] The present invention relates to the technical field of compound synthesis, more specifically, to the technical field of irinotecan synthesis, in particular to a production method of irinotecan. Background technique [0002] Irinotecan (Irinotecan) is one of camptothecin antineoplastic drugs. Piperidinyl] carboxyoxycamptothecin hydrochloride was developed by Japan Daiichi Seiyaku Company and Yakult Honsha Company. It was listed in Japan for the first time in 1994. It has been widely promoted in the world as an effective drug for metastatic colorectal cancer. It is formed by modifying the 7 and 10 positions of the camptothecin knot. [0003] The existing production method usually adopts the condensation of general purity SN-38 (7-ethyl-10-hydroxycamptothecin) and 4-piperidinylpiperidine formyl chloride hydrochloride to produce irinotecan. However, because high-purity SN38 is not easy to obtain economically in the market, the usual production process n...

Claims

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Application Information

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IPC IPC(8): C07D491/22
Inventor 王博
Owner SHANGHAI PUYI CHEM CO LTD
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