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Method for preparing vinorelbine tartrate with vinblastine sulfate

A technology of vinblastine sulfate and tartrate, which is applied in the field of manufacturing chemical substances or medicines, can solve the problems of low product purity, low efficiency, and many side reactions, and achieve the goal of increasing total yield, improving efficiency, and improving utilization rate Effect

Inactive Publication Date: 2010-06-09
HUAZHONG UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The invention provides a method for synthesizing vinorelbine tartrate with vinblastine sulfate, which solves the problems of many side reactions, low purity and low efficiency of the existing method for synthesizing vinorelbine tartrate

Method used

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  • Method for preparing vinorelbine tartrate with vinblastine sulfate
  • Method for preparing vinorelbine tartrate with vinblastine sulfate
  • Method for preparing vinorelbine tartrate with vinblastine sulfate

Examples

Experimental program
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Effect test

Embodiment 1

[0029] (1) Dehydration reaction steps:

[0030] Add C to a 250ml reaction bottle 2 o 2 Cl 2 20.0ml, under nitrogen protection, be cooled to 0 ℃, under stirring, after dripping the triethanolamine solution of 60ml, add the triethanolamine solution 70ml that contains vinblastine sulfate 16g (vinblastine sulfate 65%, HPLC detects), be warming up to 30 ℃, reacted for 12 hours to obtain anhydrovinblastine and 6'-N b -oxide-leurosine solution.

[0031] (2) Purification treatment steps

[0032] After step (1), add 750ml of ice water (5 times the volume of the reaction solution) to the resulting solution, adjust the pH to 11 with ammonia water, extract three times with chloroform, combine the organic phases, and concentrate the organic phases to dryness. The dehydrated product obtained is dissolved in methanol at 40°C: in the solution of water=5:1 (V / V), freezes and crystallizes in a refrigerator at 0°C, filters to obtain 8.96g of dehydrated vinblastine sulfate (dehydrated vinbla...

Embodiment 2

[0048] (1) Dehydration reaction steps:

[0049] Add BF to a 250ml reaction bottle 3 24ml, under nitrogen protection, cooled to 0 ℃, under stirring, after the pyridine solution of 60ml was added dropwise, added the pyridine solution 76ml containing vinblastine sulfate 16g (vinblastine sulfate 65%, HPLC detection), warming up to 4 ℃, reaction 6 hours, to obtain anhydrovinblastine and 6'-N b -oxide-leurosine solution.

[0050] (2) Purification treatment steps

[0051] After step (1) is finished, add 480ml of ice water (3 times the volume of the reaction solution) to the resulting solution, adjust the pH to 8.5 with ammonia water, extract three times with n-hexane, combine the organic phases, and concentrate the organic phases to dryness. The dehydrated product obtained is dissolved in methanol at 60°C: in the solution of water=4:1 (V / V), 6°C refrigerator freezes and crystallizes, filters, obtains dehydrated vinblastine sulfate 8.33g (dehydrated vinblastine sulfate has a purity...

Embodiment 3

[0067] (1) Dehydration reaction steps:

[0068] Add SOCl to a 150ml reaction bottle 2 12.0ml, under the protection of nitrogen, cool down to 0 ℃, under stirring, after adding 36ml of dimethylformamide solution dropwise, add dimethylformamide containing vinblastine sulfate 10g (vinblastine sulfate 65%, HPLC detection) Solution 32ml, warming up to 20 ℃, reacted for 10 hours, obtained containing anhydrovinblastine and 6'-N b -oxide-leurosine solution.

[0069] (2) Purification treatment steps

[0070] After the step (1) is finished, add 320ml of ice water (4 times the volume of the reaction solution) to the resulting solution, adjust the pH to 10 with ammonia water, extract three times with dichloromethane, combine the organic phases, and concentrate the organic phases to dryness. The dehydrated product obtained is dissolved in methanol at 50°C: in the solution of water=2:1 (V / V), 4°C refrigerator freezes and crystallizes, filters, obtains dehydrated vinblastine sulfate 5.62g ...

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Abstract

A method for synthesizing vinorelbine tartrate by vinblastine sulfate belongs to the chemical substance or medicine manufacturing method, solving the problems of the prior synthesis method of vinorelbine tartrate including more side reaction, low product purity and low efficiency. The invention comprises the steps of dehydration reaction, purification treatment, bromization ring contraction integral reaction, separation, refining and by-product processing. The purification treatment step makes use of the separation technology according to which a silica gel dry column is combined with a reversed phase column, and then adopts a high-yield Sephadex LH-20 column which is refined to obtain vinorelbine tartrate with the purity more than 99.5 percent; therefore, separation efficiency is greatlyincreased and technical overall yield is raised to 36 percent through combining with the by-product processing step.

Description

technical field [0001] The invention belongs to the manufacturing method of chemical substances or medicines, in particular to a method for synthesizing vinorelbine tartrate with vinblastine sulfate as raw material. Background technique [0002] Catharanthus roseus (L).G.Don is an important medicinal plant of the genus Vinca in the family Apocynaceae. It contains 100 More than alkaloid components, most of which have biological activity, vinblastine and vincristine are currently one of the most widely used natural plant anti-tumor drugs. However, the clinical application of these two alkaloids is limited due to their greater stimulation to the nervous system and local normal tissues after injection. Therefore, it has become necessary to obtain new alkaloids with better antitumor effect and lower toxicity through chemical synthesis and other methods. The new-generation anticancer drugs vinorelbine and vinflunine, which have come out and are widely used, are obtained through ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D519/04
CPCY02P20/10
Inventor 余龙江赵春芳李硕吴泽强熊茵
Owner HUAZHONG UNIV OF SCI & TECH