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1,4-diacyl-3,6-diphenyl-1,4-dihydrotetrazine compound as well as preparation method and application thereof

A compound and diphenyl technology, applied in the field of pharmaceutical synthesis, can solve the problems of long synthetic route, inability to obtain, low yield, etc., and achieve the effects of easy operation, favorable for industrial production and high yield

Active Publication Date: 2013-06-12
TAIZHOU VOCATIONAL & TECHN COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This type of compound is synthesized with 1,6-dihydro-s-tetrazine and isocyanate as raw materials, and its synthetic process route has the following disadvantages: the synthetic route is long and the yield is low, and the inventors have found through research that this type of compound can only be produced in The 1,4-position s-tetrazine compounds can only be obtained when the 3,6 positions are replaced by alkyl groups, and the 1,4-substituted compounds cannot be obtained if the 3,6 positions are replaced by aryl groups
Another example is the preparation method of an existing 3,6-diaryl-1,2-dihydro-s-tetrazine-1,2-dicarboxylate compound (Rao, G.W. et al., Organic Chemistry, 2004, 24 (12), 1622-1625) using 3,6-diaryl-1,2-dihydro-s-tetrazine as raw material to react with chloroformate, expecting to obtain 3,6-diaryl-1,4-di Hydrogen-s-tetrazine-1,4-dicarboxylates, but unexpectedly only 3,6-diaryl-1,2-dihydro-s-tetrazine-1,2-dicarboxylates
It can be seen that how to obtain 1,4-substituted s-tetrazine compounds when the 3 and 6 positions are substituted by an aryl group cannot be well solved in the prior art, and there is no report of such compounds in the prior art. Reports on antitumor activity

Method used

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  • 1,4-diacyl-3,6-diphenyl-1,4-dihydrotetrazine compound as well as preparation method and application thereof
  • 1,4-diacyl-3,6-diphenyl-1,4-dihydrotetrazine compound as well as preparation method and application thereof
  • 1,4-diacyl-3,6-diphenyl-1,4-dihydrotetrazine compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] 1,4-Diacetyl-3,6-diphenyl-1,4-dihydro-s-tetrazine (Ⅰ-1)

[0034]

[0035] The preparation method of the above-mentioned 1,4-diacetyl-3,6-diphenyl-1,4-dihydro-s-tetrazine compound is as follows:

[0036] Add 0.8g (3.4mmol) of 3,6-diphenyl-1,2-dihydro-s-tetrazine and 0.85g (6.8mmol) of basic catalyst 4-(N,N-dimethylamino)pyridine into the reactor Then, add 20mL of chloroform solvent, under the condition of stirring, cool down to 0°C, then start to drop 0.53g (6.8mmol) of acetyl chloride (as a preference, first dissolve 0.53g of acetyl chloride in 10mL of chloroform solution and then dropwise), after the dropwise addition, continue to control the temperature at 0°C, and carry out the acylation reaction for 15 hours. The treatment is to remove the incompletely reacted alkaline catalyst, let it stand, separate layers, collect the organic phase, and then wash the organic phase with 30mL of 10% sodium hydroxide aqueous solution, and use alkali to remove the unreacted catal...

Embodiment 2

[0044] 1,4-dipropionyl-3,6-diphenyl-1,4-dihydro-s-tetrazine (Ⅰ-2)

[0045]

[0046] The preparation method of the above-mentioned 1,4-dipropionyl-3,6-diphenyl-1,4-dihydro-s-tetrazine compound is as follows:

[0047] Add 0.8g (3.4mmol) of 3,6-diphenyl-1,2-dihydro-s-tetrazine and 0.54g (6.8mmol) of basic catalyst pyridine into the reactor, and then add 20mL of dichloromethane solvent , under stirring conditions, lower the temperature to -5°C, then start to drop propionyl chloride 0.64g (6.97mmol) (as a preference, first dissolve 0.64g propionyl chloride in 10mL dichloromethane before adding dropwise), drop After the completion, continue to control the temperature at -5°C to carry out the acylation reaction for 16 hours. After the acylation reaction is completed, add 30mL of 10% dilute hydrochloric acid solution for washing. The purpose of treating with dilute hydrochloric acid is to remove unreacted Complete basic catalyst pyridine, stand still, separate layers, collect the ...

Embodiment 3

[0055] 1,4-Dibutyryl-3,6-diphenyl-1,4-dihydro-s-tetrazine (Ⅰ-3)

[0056]

[0057] The preparation method of the above-mentioned 1,4-dibutyryl-3,6-diphenyl-1,4-dihydro-s-tetrazine compound is as follows:

[0058] Add 0.8g (3.4mmol) of 3,6-diphenyl-1,2-dihydro-s-tetrazine and 0.70g (6.97mmol) of basic catalyst triethylamine into the reactor, and then add 30mL ethyl acetate Ester solvent, under the condition of stirring, lower the temperature to -10°C, then start to add 0.76g (7.14mmol) of butyryl chloride dropwise (as a preference, first dissolve 0.76g of butyryl chloride in 10mL of ethyl acetate and then add dropwise), drop After the addition is complete, continue to control the temperature at -10°C to carry out the acylation reaction for 20 hours. After the acylation reaction is completed, add 40 mL of 10% by mass aqueous dilute hydrochloric acid solution to wash and remove the unreacted basic catalyst. Ethylamine, stand still, separate layers, collect the organic phase, a...

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Abstract

The invention relates to a 1,4-diacyl-3,6-diphenyl-1,4-dihydrotetrazine compound as well as a preparation method and an application of the 1,4-diacyl-3,6-diphenyl-1,4-dihydrotetrazine compound, and belongs to the technical field of drug synthesis. Due to the compound disclosed by the invention, a compound of formula II (X is halogen and R is C1-C5 alkyl or benzyl) and a compound of formula III are acylated to acquire a 1,4-diacyl-3,6-diphenyl-1,4-dihydrotetrazine compound. The compound disclosed by the invention has the advantage of high biological activity, especially has a high inhibition effect on tumor cells, can be used for realizing the anti-tumor effect and can be applied to an anti-tumor medicament; and meanwhile, the method disclosed by the invention has the advantages of simple technical process, completion in one-step reaction, wild conditions, easiness in operation and high product yield.

Description

technical field [0001] The invention relates to a 1,4-diacyl-3,6-diphenyl-1,4-dihydro-s-tetrazine compound and a preparation method and application thereof, belonging to the technical field of pharmaceutical synthesis. Background technique [0002] S-tetrazine compounds have a wide range of biological activities, especially in recent years, the advantages of dihydro-s-tetrazine derivatives in anticancer activity have attracted the attention of many scholars and researchers. [0003] At present, there are many studies on dihydro-s-tetrazine compounds. For example, a Chinese patent application (publication number: CN1223259A) has announced a new type of 3,6-dimethyl-1,4-dihydro-s-tetrazine-1,4 -Dicarboxamide compounds have strong antitumor activity. This type of compound is synthesized with 1,6-dihydro-s-tetrazine and isocyanate as raw materials, and its synthetic process route has the following disadvantages: the synthetic route is long and the yield is low, and the inventor...

Claims

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Application Information

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IPC IPC(8): C07D257/08A61K31/395A61P35/00
Inventor 杨珍珍徐峰柯中炉蒋军荣陈江飞胡惟孝奚立民
Owner TAIZHOU VOCATIONAL & TECHN COLLEGE
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