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Synthesis method of triphenyl-n-(colchicine amido) butylphosphonium chloride and its application in antitumor drugs

A technology of narciscine amide and triphenyl chloride, which is applied in the synthesis field of triphenyl-n-butylphosphonium chloride, can solve the problems of high toxicity of colchicine, limited application, animal death, etc., and achieves Improve the efficiency of drug action, reduce the dosage, and overcome the effect of excessive toxicity

Active Publication Date: 2020-11-13
HUBEI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the toxicity of colchicine is too large (LD50=1.6mg / kg), which often produces certain side effects, which may cause nausea, loss of appetite, abdominal distension, and even intestinal paralysis, constipation and gastric bleeding in severe cases
In addition, excessive injection can also cause animal death
This limits its application to some extent

Method used

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  • Synthesis method of triphenyl-n-(colchicine amido) butylphosphonium chloride and its application in antitumor drugs
  • Synthesis method of triphenyl-n-(colchicine amido) butylphosphonium chloride and its application in antitumor drugs

Examples

Experimental program
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Effect test

Embodiment 1

[0041] A kind of synthetic method of triphenyl chloride-4-(colchicine amido) butylphosphonium compound of the present embodiment comprises the steps:

[0042] (1) Synthesis of N-Boc colchicine

[0043] Dissolve 1.04g (2.6mmol) colchicine in 15ml of dichloromethane solution after dry distillation, then add 0.35g (2.91mmol) 4-dimethylaminopyridine, 0.42ml (2.91mmol) to the three-necked flask successively triethylamine. Stir and reflux and slowly dropwise add 3.20 g (14.66 mmol) of Boc anhydride to the solution, react for 6 h, and monitor the progress of the reaction by TLC. After the reaction was complete, the solvent was distilled off under reduced pressure and separated by column chromatography to obtain 0.93 g of a light yellow solid with a yield of 68.72%. m.p.: 87.3—89.6°C. IR(KBr)cm -1 :3653.34,2974.62,2934.58,2836.21,1737.32,1679.84,1618.21,1588.59,1488.51,1460.13,1435.05,1407.35,1370.32,1324.04,1283.67,1252.04,1141.28,1092.32,1021.12,1001.58,982.51,923.07,846.03,774....

Embodiment 2

[0053] A kind of synthetic method of triphenyl chloride-3-(colchicine amido) butylphosphonium compound of the present embodiment is basically the same as Example 1, the difference is only in:

[0054] (1) the chloroalkyl chloride that the present embodiment adopts is 3-chlorobutyryl chloride;

[0055] (2) The process of step (4) and step (5) is different:

[0056] (4) Synthesis of N-3-chlorobutyryl deacetylcolchicine

[0057] Take 0.50 g of deacetylcolchicine prepared in step (3), dissolve 0.15 ml of triethylamine in 10 ml of chloroform, stir in an ice-water bath, and add 0.15 ml of 3-chlorobutyryl chloride dropwise into the solution. After reacting for 2 hours, remove the ice-water bath and heat to condense to reflux, and react for 1.5 hours. The progress of the reaction was monitored by TLC. After the reaction was complete, the pH was adjusted to neutral with triethylamine, and the solvent was distilled off under reduced pressure. Column chromatography separated to obtai...

Embodiment 3

[0061] A kind of synthetic method of triphenyl chloride-2-(colchicine amido) butylphosphonium compound of the present embodiment is basically the same as Example 1, the difference is only in:

[0062] (1) the chloroalkyl chloride that present embodiment adopts is 2-chlorobutyryl chloride;

[0063] (2) The process of step (4) and step (5) is different:

[0064] (4) Synthesis of N-2-chlorobutyryl deacetylcolchicine

[0065] Take 0.50 g of deacetylcolchicine prepared in step (3), dissolve 0.125 ml of triethylamine in 10 ml of chloroform, stir in an ice-water bath, and add 0.125 ml of 2-chlorobutyryl chloride dropwise into the solution. After reacting for 2 hours, remove the ice-water bath, heat and condense to reflux, and react for 2 hours. The progress of the reaction was monitored by TLC. After the reaction was complete, the pH was adjusted to neutral with triethylamine, and the solvent was distilled off under reduced pressure. Separated by column chromatography, 0.38 g of ...

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Abstract

The invention relates to a synthetic method of a triphenyl-n-(colchicine amido)butylphosphonium chloride compound and application of the compound in an antitumor medicine, belonging to the technical field of organic synthesis. Colchicine derived from plants, as a raw material, is subjected to structure modification with 4-dimethylaminopyridine, trifluoroacetic acid and the like in order to convertthe colchicine into colchamine; and then the colchamine reacts with chloroalkyl chloride and triphenylphosphine in order to synthesize the target compound having higher antitumor activity and lower toxicity. The phosphonium structure of the target compound has a cell metabolism interference effect and a targeted enrichment effect on malignant cells, and can greatly reduce the dosage and improve the medicine function efficiency. A step-by-step elution process is introduced to a preparation process and a selected specific eluent ensures purity of a final product. The prepared phosphonium compound is low in toxicity and high in efficiency and is expected to be an antitumor medicine.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and relates to the synthesis and application of a fluorine-containing phosphorus nitrogen compound (FPN). More specifically, the invention relates to a triphenyl-n-(colchicine amido)butyl chloride Synthesis method of base phosphonium compound and its application in antineoplastic drugs. Background technique [0002] Malignant tumor is a common and frequently-occurring disease that seriously threatens human health. Worldwide, more than 7 million people die from malignant tumors every year. Cancer is becoming the number one killer of human beings. Because tumor cells have the characteristics of proliferation and metastasis, radiotherapy, chemotherapy and surgical treatment cannot achieve the goal of radical cure. Due to individual differences, toxic side effects, drug dependence and other problems in chemotherapy technology, there has been an urgent need for new, high-efficiency and lo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/54A61K31/66A61P35/00
CPCA61P35/00C07F9/5442
Inventor 娄兆文周莉肖春芬肖成林陈兰张杰
Owner HUBEI UNIV
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