Vinorelbine preparation method

A technique for vinorelbine and dehydrated vinblastine, which is applied in the field of synthesis and purification of vinorelbine, can solve problems such as high market price, and achieve the effects of less solvent consumption, improved reaction rate, and short production cycle

Inactive Publication Date: 2006-04-26
NORTHEAST FORESTRY UNIVERSITY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because the structure of its carantatin ring is different from other vinblastine alkaloids, the original 9-membered ring is changed to an 8-membered ring, which makes it less neurotoxic and stronger than vinblastine, vincristine, vinblastine, etc. antitumor activity, and its market price is expensive

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0024] Embodiment 1: Vinblastine sulfate (a) prepares dehydrated vinblastine (b)

[0025]

[0026] Weigh 2 g of vinblastine sulfate, dissolve it in 30 ml of anhydrous N, N-dimethylformamide under the protection of nitrogen, and drop into N, N-dimethylformamide solution of thionyl chloride (4 ml of chlorinated Dissolve sulfoxide in 10ml of N,N-dimethylformamide), ultrasonic cavitation reaction at room temperature for about 80min, stop the reaction when TLC tracked to no raw material point, add 160ml of ice water, adjust pH to 9 with ammonia water, extract with ether 3 times , 120ml each time, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 40°C, N 2 Methanol recrystallization under protection gave 1.26 g of dehydrated vinblastine with a purity of 82% and a yield of 59.2%.

Embodiment 2

[0027] Embodiment 2: Dehydrovinblastine (b) prepares dehydrovinblastine-N-oxide (c)

[0028]

[0029] Weigh 1.25 g of dehydrated vinblastine, dissolve it in 37 ml of anhydrous dichloromethane, add a methylene chloride solution of m-chloroperoxybenzoic acid (0.37 g of m-chloroperoxybenzoic acid is dissolved in 18.5 ml of methylene chloride), and Ultrasonic cavitation reaction for 10min, pour the reaction solution into 11ml of saturated sodium carbonate solution, extract with 185ml of chloroform, wash with an equal volume of saturated sodium chloride solution, dry the chloroform layer with anhydrous sodium sulfate, filter, and recover under reduced pressure at 40°C Solvent, the residue was obtained.

Embodiment 3

[0030] Example 3: Preparation of Vinorelbine from Dehydrated Vinblastine-N-Oxide

[0031]

[0032] Dissolve the above residue in 7.4ml of anhydrous dichloromethane under the protection of nitrogen, add 1ml of trifluoroacetic anhydride at 0°C, keep warm for 30min by ultrasonic cavitation reaction, and recover the solvent under reduced pressure (without heating) to obtain the residue. Dissolve in 29.6ml of tetrahydrofuran, add 0.11ml of water, conduct ultrasonic cavitation reaction at room temperature for 30min, pour the reaction solution into 25ml of saturated sodium chloride solution, extract with 150ml of chloroform, wash with saturated sodium chloride solution until pH = 7, and wash the chloroform layer with Dry over anhydrous sodium sulfate, filter, and recover the solvent from the filtrate under reduced pressure to obtain a residue of 0.73 g with a purity of 71% and a yield of 42.2%.

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PUM

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Abstract

The present invention provides new process of synthesizing and purifying vinorelbine. The new process adopts vinblastine sulfate as material and through ultrasonic cavitation, and rather than stirring, negative pressure dry column chromatography to purify and obtain high purity vinorelbine. The purified vinorelbine may be used as material for synthesizing vinorelbine tartrate as clinical medicine. The said process has high vinorelbine purity over 98 % and total yield over 24 %, greatly shortened reaction period and high reaction efficiency, and is suitable for industrial production.

Description

Technical field: [0001] The invention relates to a preparation and purification process of anticancer drug vinorelbine. In particular, it relates to a method for synthesizing and purifying vinorelbine by ultrasonic cavitation and negative pressure dry column chromatography. Background technique: [0002] Vinorelbine (trade name Navelbine) is a drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with advanced non-small cell lung cancer (NSCLC). It is the first-line treatment drug for patients with advanced non-small cell lung cancer. It is also the drug of choice in the treatment of breast cancer, lymphoma and ovarian cancer. It is registered and sold in many countries in Europe and the United States. Because the structure of its carantatin ring is different from other vinblastine alkaloids, the original 9-membered ring is changed to an 8-membered ring, which makes it less neurotoxic and stronger than vinblastine, vincristine, vinblasti...

Claims

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Application Information

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IPC IPC(8): C07D519/04A61P35/00C07D471/16C07D471/18
Inventor 祖元刚张琳付玉杰赵修华祖柏实牛卉颖
Owner NORTHEAST FORESTRY UNIVERSITY
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