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Method for preparing irinotecan hydrochloride trihydrate pure product

A technology for irinotecan trihydrate and irinotecan, which is applied in the field of preparing pure irinotecan hydrochloride trihydrate, and can solve the problems of difficult elution by column chromatography, a large amount of solvent, and deterioration of irinotecan.

Inactive Publication Date: 2012-08-22
JIANGSU HONGDOUSHAN BIOLOGICAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the existing technology has technical defects such as pyridine has a foul smell, is easily oxidized and discolored, and high-temperature and reduced-pressure distillation is easy to cause irinotecan to deteriorate.
And the irinotecan hydrochloride crude product purification method reported in the prior art is mainly column chromatography, but because the adsorption of irinotecan hydrochloride is strong, column chromatography elution difficulty requires a large amount of solvent and longer elution time, It leads to long production cycle and heavy workload, which is not conducive to large-scale production
And the crystallization and purification method of irinotecan hydrochloride reported in the prior art has a crystallization method, that is, the crude product obtained from irinotecan free base after salification is through a recrystallization, and its purity, clarity of product solution, light transmittance and other technical indicators are difficult to meet the requirements
And the more commonly used irinotecan hydrochloride trihydrate crystallization method in the prior art, i.e. irinotecan hydrochloride is suspended in one or more than two kinds of mixed solvents earlier, after the solid of separation is dried, then by absorbing moisture from the air To obtain irinotecan hydrochloride trihydrate, this method cannot fully guarantee that the absorbed water is completely converted into real crystal water, and there is still adsorbed water in the irinotecan hydrochloride trihydrate product, so the product is unstable and prone to Chemical changes resulting in shorter shelf life

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] 1, the preparation of 4-piperidinyl piperidine carboxylic acid chloride

[0037] Add 0.33 equivalent of triphosgene to dichloromethane in an amount of 5 mL per gram of triphosgene to obtain a dichloromethane solution of triphosgene; use 1.0 equivalent of 4-piperidinyl piperidine as a solute, Add 3 mL of piperidine into dichloromethane to prepare a dichloromethane solution of 4-piperidinylpiperidine, and dropwise add triphosgene to the dichloromethane solution at 30°C, and stir at 30°C for 25h; The solution was concentrated under reduced pressure to a solid state, and 0.8 mL of dichloromethane and 3.0 equivalents of inorganic alkali sodium carbonate were added for every 1 mmol of 4-piperidinylpiperidine, stirred at 50°C for 1 h, and suction filtered, and the filtrate was reduced to Concentrate under reduced pressure to a solid state to obtain free 4-piperidinylpiperidine carboxylic acid chloride with a yield of 96.7% and GC: 99.8%.

[0038] Wherein, the GC conditions us...

Embodiment 2

[0062] The detection conditions and methods described in this example are all the same as in Example 1.

[0063] 1, the preparation of 4-piperidinyl piperidine carboxylic acid chloride

[0064] Add 0.8 equivalent of triphosgene to benzene in an amount of 20 mL per gram of triphosgene to obtain a benzene solution of triphosgene; use 1.0 equivalent of 4-piperidinyl piperidine as a solute, add 15 mL of 4-piperidinyl piperidine per gram The amount of benzene was added to prepare the benzene solution of 4-piperidinylpiperidine, and added dropwise to the benzene solution of triphosgene at 0°C, and stirred at 10°C for 35h; Add 1.2 mL of 1 mmol 4-piperidinylpiperidine to benzene, and 2.0 equivalents of organic base sodium methoxide, stir at 20°C for 1.5 h, filter with suction, and concentrate the filtrate to a solid state under reduced pressure to obtain free 4- Piperidinylpiperidinecarbonyl chloride, yield 95.9%, GC: 99.7%%.

[0065] 2. Preparation of irinotecan

[0066] Add 1.0 e...

Embodiment 3

[0070] The detection conditions and methods described in this example are all the same as in Example 1.

[0071] 1, the preparation of 4-piperidinyl piperidine carboxylic acid chloride

[0072] Add 0.55 equivalent of triphosgene to petroleum ether in an amount of 15 mL per gram of triphosgene to obtain a petroleum ether solution of triphosgene; use 1.0 equivalent of 4-piperidinylpiperidine as a solute, Add 10 mL of petroleum ether to prepare a petroleum ether solution of 4-piperidinylpiperidine, and add dropwise to the petroleum ether solution of triphosgene at 25°C, stir at 40°C for 20h; concentrate the reaction solution under reduced pressure to In solid state, add 0.3 mL of petroleum ether and 4.0 equivalents of organic base sodium ethoxide for every 1 mmol of 4-piperidinylpiperidine, stir at 25°C for 0.5 h, filter with suction, and concentrate the filtrate to a solid state under reduced pressure. That is, free 4-piperidinylpiperidinecarbonyl chloride was obtained with a y...

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Abstract

The invention relates to a method for preparing an irinotecan hydrochloride trihydrate pure product, which belongs to the field of medicinal chemistry. The method comprises the steps of first preparing dissociative 4-piperidyl piperidine formyl chloride, performing condensation reaction of the 4-piperidyl piperidine formyl chloride and 7-ethyl-10-hydroxycamptothecine with the presence of 4-dimethylamino piperidine or 4-dimethylamino pyridinium or analogues, and finally performing salifying to obtain an end-product. By means of the method, fetid and easily-discoloring piperidine participated condensation reaction is avoided, side reaction is decreased, the defects including increased period, large solvent dosage and the like caused by the fact that the product is purified through column chromatography are overcome, the purity and the yield of the product are improved, simultaneously color and luster of the product are improved, and the scale production is easy to achieve.

Description

technical field [0001] The invention relates to a method for preparing pure irinotecan hydrochloride trihydrate, belonging to the field of medicinal chemistry. Background technique [0002] Irinotecan hydrochloride is a drug of choice for the treatment of colorectal cancer. It has stronger antitumor activity and less neurotoxicity than camptothecin, and it is still effective for patients resistant to fluorouracil. Irinotecan hydrochloride was originally developed by Japan's Daiichi Seiyaku Company and Yakult Honsha Company using camptothecin as a raw material. It was first listed in Japan in 1994, and then listed in more than 100 countries around the world. The trihydrate of irinotecan hydrochloride is clinically used, and its molecular formula is C 33 h 38 N 4 o 6 ·HCl·3(H 2 O), its CAS registration number: 136572-09-3, is light yellow or yellow crystalline powder, and its structural formula is as follows: [0003] . [0004] The main synthetic route of irinotecan ...

Claims

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Application Information

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IPC IPC(8): C07D491/22
Inventor 龚喜周理洁王琼喻琼林
Owner JIANGSU HONGDOUSHAN BIOLOGICAL TECH
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