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Industrial synthesis method of water-soluble docetaxel derivative

A technology of docetaxel and synthetic method, which is applied in the direction of organic chemistry, can solve the problems of high production cost, achieve the effects of reducing solvent consumption, ensuring product quality, product yield and product quality

Inactive Publication Date: 2021-12-31
陈开云
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Problems solved by technology

[0004] Chinese patent 201510624350.X "Water-soluble docetaxel anticancer drug compound and its preparation method and application" adopts the reaction of docetaxel and polyethylene glycol monomethyl ether, diglycolate, etc. dissolved in anhydrous toluene The water-soluble docetaxel compound is obtained, but the method adopts carcinogenic toluene solvent, and the reaction substrate is finished product docetaxel, which has the disadvantage of high production cost

Method used

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  • Industrial synthesis method of water-soluble docetaxel derivative
  • Industrial synthesis method of water-soluble docetaxel derivative
  • Industrial synthesis method of water-soluble docetaxel derivative

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preparation example Construction

[0088] An industrial synthesis method of a water-soluble docetaxel derivative, comprising:

[0089] (R)-4-dimethylamino-2-fluoro-butyric acid hydrochloride synthesis steps; and water-soluble docetaxel synthesis steps.

[0090] (R)-4-dimethylamino-2-fluoro-butyric acid hydrochloride synthetic steps are as follows:

[0091] S1: Put α(-S)-hydroxy-γ-phthalimide-butyric acid into 2000L No. 1 reaction kettle, pump methanol into it, stir for 30min, then add thionyl chloride and stir at room temperature React to complete;

[0092] S2: the reaction solution is sent to No. 1 concentrator for concentration, centrifugal precipitation, and solvent recovery to obtain dry extract A;

[0093] S3: the dry extract A is loaded into No. 1 extraction kettle of 3000L, pumped into ethyl acetate for extraction, then pumped into saturated sodium bicarbonate solution for washing 2 times, and collecting and merging the washing liquid;

[0094] S4: pump the washing liquid into No. 1 liquid-liquid cent...

Embodiment

[0361] (R)-4-dimethylamino-2-fluoro-butyric acid hydrochloride synthetic steps are as follows:

[0362] (1), 2a synthetic process steps

[0363] a. Put 83.66 kg of α(-S)-hydroxyl-γ-phthalimide-butyric acid into a 2000L No. 1 reaction kettle, pump 1004L of methanol, stir for 30min, and then add dichloromethylene Sulfone 36.42L stirred and reacted at room temperature until complete;

[0364] b. Send the reaction solution to No. 1 concentrator for concentration, centrifuge precipitation, and recover the solvent to obtain dry filter cake A;

[0365] c. Put the dry filter cake A into No. 1 extraction kettle of 3000L, pump into 1673L of ethyl acetate for extraction, then pump into 502L of saturated sodium bicarbonate solution to wash twice, and collect the combined washing liquid;

[0366] d. Pump the washing liquid into the No. 1 liquid-liquid centrifugal extractor to separate the organic phase and the aqueous phase;

[0367] e. The organic phase was filtered, and the filtrate w...

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Abstract

The invention provides an industrial synthesis method of a water-soluble docetaxel derivative. The method is characterized in that 10-deacetylbaccatin III is used as a substrate, and the 10-deacetylbaccatin III and (R)-4-dimethylamino-2-fluoro-butyric acid hydrochloride are synthesized into the water-soluble docetaxel derivative. According to the method, a two-step synthesis technology, a centrifugal extraction separation technology, a recrystallization technology, a supercritical CO2 fluid drying technology and a full-automatic control technology are combined, synthesis and purification are carried out under the synergistic effect of the technologies, the water solubility of the water-soluble docetaxel derivative produced by the combined technology can reach 12 mg / ml or above, and the the water-soluble docetaxel derivative has about 2000 times higher solubility in water than docetaxel. A docetaxel injection prepared by the method does not use absolute ethyl alcohol or Tween-80 hydrotropy, and the docetaxel derivative is a water-soluble docetaxel derivative which is efficient, free of anaphylactic reaction and small in toxic and side effect. Therefore, the product has the characteristics of small toxic and side effects, low production cost, high product purity, high product yield and stable quality, and is suitable for industrial large-scale production.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis, and in particular relates to an industrial synthesis method of a water-soluble docetaxel derivative. Background technique [0002] Docetaxel, also known as docetaxel, molecular formula: C43H53NO14, molecular weight: 807.87922; is a lipophilic taxane antineoplastic drug, belonging to cytostatic drugs, by strengthening tubulin polymerization and inhibiting microtubule degradation Polymerization, forming stable non-functional microtubule bundles, thereby destroying the mitosis of tumor cells to achieve anti-tumor effects. The intracellular concentration of docetaxel is 3 times higher than that of paclitaxel, and the intracellular residence time is longer, so it has stronger anti-tumor activity than paclitaxel. It is mainly used clinically for the treatment of advanced breast cancer, ovarian cancer, non-small cell lung cancer, head and neck cancer, and small cell lung cancer; it als...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D305/14
CPCC07D305/14
Inventor 陈开云柏凤静
Owner 陈开云
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