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Gemcitabine hydrochloride purifying method

A technology of gemcitabine hydrochloride and a purification method, which is applied in the field of purification of antitumor drug gemcitabine hydrochloride, can solve problems such as difficulty in purifying gemcitabine hydrochloride crude product, and achieve the effects of optimizing product quality, improving purity and high yield

Active Publication Date: 2012-09-12
NANJING CHENGONG PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Next, bis(trimethylsilyl)cytosine is condensed onto ribose. This reaction is a well-known nucleophilic substitution reaction. The SN1 unimolecular nucleophilic substitution reaction and the SN2 bimolecular nucleophilic substitution reaction exist simultaneously, which also makes the α-terminal group Isomers are easy to appear, which brings certain difficulties to the purification of crude gemcitabine hydrochloride, and the use of crude gemcitabine hydrochloride with low purity has potential safety hazards in clinical practice

Method used

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  • Gemcitabine hydrochloride purifying method
  • Gemcitabine hydrochloride purifying method

Examples

Experimental program
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Effect test

Embodiment 1

[0020] a) Dissolve 100g (0.33mol) of crude gemcitabine hydrochloride in 1000mL of water, slowly add saturated ammonia water, stir the reaction until the pH is 8.5, and produce gemcitabine precipitate, filter it with suction, and dry it in vacuum at 45°C to obtain 82g (0.31mol) of gemcitabine. Rate 94%;

[0021] b) Dissolve 82g of gemcitabine obtained in the previous step in 410mL of pure methanol, add 4.1g of activated carbon, stir at 30°C for 0.5 hours, filter for decarburization, and collect the filtrate;

[0022] c) The above-mentioned filtrate is separated and purified by a chromatographic column to obtain a gemcitabine hydrochloride refined product, wherein the mobile phase used in the chromatographic column is acetone and an aqueous hydrochloric acid solution with a pH of 2 to 3, the volume ratio of acetone to aqueous hydrochloric acid is 30:70, and the stationary phase The filler is silica gel, the flow rate is 4.6mL / min, and the column temperature is 20°C. The filtrat...

Embodiment 2

[0024] a) Dissolve 100g (0.33mol) of crude gemcitabine hydrochloride in 1000ml of water, slowly add saturated sodium hydroxide solution, stir the reaction until the pH is 9.0, and produce gemcitabine precipitates, filter through suction, and dry under vacuum at 45°C to obtain 84g (0.32mol) of gemcitabine ), yield 97%;

[0025] b) Dissolve 84g of gemcitabine obtained in the previous step in 500mL of ethanol with a purity of 99.5%, add 4.2g of activated carbon, stir at 25°C for 1.0 hour, filter for decarburization, and collect the filtrate;

[0026] c) Separating and purifying the above filtrate with a chromatographic column to obtain refined gemcitabine hydrochloride, wherein the mobile phase used in the chromatographic column is acetonitrile and aqueous hydrochloric acid with a pH of 2 to 3, the volume ratio of acetonitrile to aqueous hydrochloric acid is 50:50, and the stationary phase is The filler is aluminum oxide, the flow rate is 6mL / min, and the column temperature is 25...

Embodiment 3

[0028] a) Dissolve 100g (0.33mol) of crude gemcitabine hydrochloride in 1000mL of water, slowly add sodium methoxide, stir the reaction until the pH is 8, produce gemcitabine precipitate, filter by suction, and dry under vacuum at 45°C to obtain 82g (0.31mol) of gemcitabine. Rate 94%;

[0029] b) Dissolve 82g of gemcitabine obtained in the previous step in 410mL of pure isopropanol, add 4.1g of activated carbon, stir at 20°C for 1.5 hours, filter for decarburization, and collect the filtrate;

[0030] c) The above-mentioned filtrate is separated and purified by a chromatographic column to obtain a gemcitabine hydrochloride refined product, wherein the mobile phase used in the chromatographic column is acetonitrile and an aqueous hydrochloric acid solution with a pH of 2 to 3, the volume ratio of acetonitrile and aqueous hydrochloric acid is 45:55, and the stationary phase The filler is silica gel, the flow rate is 8 mL / min, and the column temperature is 30°C. The filtrate was...

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Abstract

The invention relates to a gemcitabine hydrochloride purifying method. The gemcitabine hydrochloride purifying method comprises the following steps: a), dissolving a gemcitabine hydrochloride coarse product into water, regulating the pH of the solution to 8-9 by adding alkali, stirring and reacting, and extracting to obtain gemcitabine; b), dissolving the gemcitabine into an alcohol solution, with the concentration of 0.1-0.2g / mL, adding activated carbon, filtering, and collecting filtrate; c), separating the filtrate with a preparing chromatographic column, wherein a fluid phase used by the chromatographic column is acetone or acetonitrile and a hydrochloric acid solution, the volume ratio of acetone or acetonitrile to the hydrochloric acid solution is 30-50: 70-50, and a stationary phase filler is silica or aluminum oxide; collecting filtrate; and drying to obtain a gemcitabine hydrochloride refined product. Through acid-base reaction, activated carbon adsorption, and separation and purification of the preparing chromatographic column, the purity of the gemcitabine hydrochloride is improved, the quality of a prepared product is optimized and the safety of clinical medicine is ensured; and the method is simple in process and low in cost and is applicable to industrial production.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical engineering, and in particular relates to a purification method of an antineoplastic drug gemcitabine hydrochloride. Background technique [0002] Gemcitabine hydrochloride (gemcitabine hydrochloride) is a difluoronucleoside anti-metabolite anticancer drug developed by Eli Lilly Company of the United States that disrupts cell replication. It mainly acts on tumor cells in the DNA synthesis phase, that is, S phase cells. It was first listed in the Netherlands, Sweden, Finland and South Africa in December 1995. In May 1996, it was approved by the FDA for the treatment of pancreatic cancer and non-small cell lung cancer. It is sold in the US market under the trade name "Gemzar", and the specifications are 0.2g / bottle and 1g / bottle. CAS of gemcitabine hydrochloride: 122111-03-9, chemical name: 4-amino-1-(3,3-difluoro-4-hydroxy-5-hydroxymethyltetrahydrofuran-2-yl)-1H-pyrimidine-2- Ketone hydroc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/073C07H1/06
Inventor 郭昭
Owner NANJING CHENGONG PHARM CO LTD
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