CN106632124A - Synthesis method of 5,5'-di(acetic ether)-3,3'-bi-1,2,4-oxadiazole - Google Patents

Synthesis method of 5,5'-di(acetic ether)-3,3'-bi-1,2,4-oxadiazole Download PDF

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Publication number
CN106632124A
CN106632124A CN201611084276.8A CN201611084276A CN106632124A CN 106632124 A CN106632124 A CN 106632124A CN 201611084276 A CN201611084276 A CN 201611084276A CN 106632124 A CN106632124 A CN 106632124A
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reaction
connection
oxadiazoles
oxadiazole
glyoxime
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CN106632124B (en
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黄晓川
郭涛
王子俊
刘敏
邱少君
姚冰洁
李洪丽
姜俊
唐望
吕英迪
张彦
陈志强
石强
郑晓东
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Xian Modern Chemistry Research Institute
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Photoreceptors In Electrophotography (AREA)

Abstract

The invention discloses a synthesis method of 5,5'-di(acetic ether)-3,3'-bi-1,2,4-oxadiazole. The structural formula of the 5,5'-di(acetic ether)-3,3'-bi-1,2,4-oxadiazole is disclosed in the specification. By using diamidoglyoxime and ethyl chloroformylacetate as raw materials, the method comprises the following steps: (1) sequentially adding glycol dimethyl ether and pyridine into a reaction bulb, stirring uniformly, adding the diamidoglyoxime in batches, stirring until the solid is completely dissolved, dropwisely adding the ethyl chloroformylacetate, and carrying out reaction at 30-50 DEG C for 20-40 minutes; (2) heating the reaction solution obtained in the step (1) to 80-120 DEG C, continuing the reaction for 1-3 hours, pouring the reaction solution into water, and carrying out chloroform extraction, drying, reduced pressure distillation and the like to obtain the 5,5'-di(acetic ether)-3,3'-bi-1,2,4-oxadiazole. The synthesis method disclosed by the invention is easy to operate, and has higher reaction yield. The method is mainly used for synthesizing 5,5'-di(acetic ether)-3,3'-bi-1,2,4-oxadiazole.

Description

The synthetic method of 5,5 '-ethyl diacetate base -3,3 '-connection -1,2,4- oxadiazoles
Technical field
The present invention relates to a kind of synthetic method of -1,2,4- oxadiazole analog derivatives of connection, more particularly to a kind of 5,5 '-diethyl The synthetic method of acetoacetic ester base -3,3 '-connection -1,2,4- oxadiazoles.
Background technology
5,5 '-ethyl diacetate base -3,3 '-connection -1,2,4- oxadiazoles are -3,3 '-connection -1 of nitroform base of synthesis 5,5 '-two, 2,4- oxadiazoles, 5,5 '-two together with dinitro methyl -3,3 '-connection -1,2,4- oxadiazoles and 5,5 '-two together with fluorine dinitro methyl -3,3 ' - The key intermediate of the energy-containing compounds such as connection -1,2,4- oxadiazoles.《Synthesis of C-Azolylacetic acid esters based on carbethoxyethylacetimidate》(Russian chemical bulletin,1990,39 (9):1888-1895) disclose a kind of synthetic method of 5,5 '-ethyl diacetate base -3,3 '-connection -1,2,4- oxadiazoles.《5, 5′-Bis-(trinitromethyl)-3,3′-bi-(1,2,4-oxadiazole):a stable ternary CNO- compound with high density》The synthetic method is continued to use.Its synthesis step is as follows：
(1) under room temperature condition, 0.017mol diaminourea glyoxime and 0.063mol malonic acid are separately added into in reaction bulb Diethylester, at 150～160 DEG C 30min is reacted；
(2) reaction system is warming up into 170 DEG C to continue to react after 2h, vacuum distillation is gone out excessive diethyl malonate, And obtain 5 by pillar layer separation, and 5 '-ethyl diacetate base -3, -1,2,4- oxadiazoles of 3 '-connection, yield is 23%.
The synthetic method is raw material using diaminourea glyoxime and diethyl malonate, and diethyl malonate is also while conduct Solvent, Jing high-temperature heatings cyclization reaction obtains 5,5 '-ethyl diacetate base -3, -1,2,4- oxadiazoles of 3 '-connection.The synthetic method Selectivity it is poor, target compound need to be obtained using pillar layer separation, and yield is relatively low, only 23%.
The content of the invention
In order to overcome shortcomings and deficiencies of the prior art, the present invention provide a kind of process is simple and yield it is higher 5,5 '- Ethyl diacetate base -3,3 '-connection -1,2,4- oxadiazole synthetic methods.
Because reaction raw materials are diethyl malonate employed in documents, reactivity is strong, it is therefore desirable to compared with React at high temperature, but this necessarily increases the generation of side reaction, significantly reduces reaction selectivity and yield.The present invention Method replaces the diethyl malonate employed in documents as reaction raw materials using chloroformyl ethyl acetate, using chloromethane , there is coupling cyclization with the reaction of diaminourea glyoxime at a lower temperature anti-in highly active chloroformyl in ethyl acetoacetic acid ethyl ester Should.
The structural formula of 5,5 ' involved by the inventive method-ethyl diacetate base -3,3 '-connection -1,2,4- oxadiazoles is as follows：
The route that the inventive method synthesizes 5,5 '-ethyl diacetate base -3,3 '-connection -1,2,4- oxadiazoles is as follows：
The present invention 5,5 '-ethyl diacetate base -3, the synthetic method of -1,2,4- oxadiazoles of 3 '-connection is comprised the following steps：
Under the conditions of (1) 25 DEG C, glycol dimethyl ether and pyridine are added sequentially in reaction bulb, it is to be mixed it is uniform after, point Batch diaminourea glyoxime is added, stirred to being completely dissolved；Chloroformyl ethyl acetate, 30～50 DEG C of conditions are added dropwise in resulting solution 20～40min of lower reaction；The molal volume ratio of diaminourea glyoxime, chloroformyl ethyl acetate, pyridine and glycol dimethyl ether For：10mmol：10～40mmol：5～30mmol：25～50ml；
(2) step (1) gained reactant liquor is warming up into 80～120 DEG C, continues to react after 1～3h, pour reactant liquor into water In, the step such as Jing chloroform extractions, drying and vacuum distillation obtains 5,5 '-ethyl diacetate base -3, -1,2,4- Evil bis- of 3 '-connection Azoles.
Currently preferred 5,5 '-ethyl diacetate base -3, the synthetic method of -1,2,4- oxadiazoles of 3 '-connection, including it is following Step：
Under the conditions of (1) 25 DEG C, glycol dimethyl ether and pyridine are added sequentially in reaction bulb, it is to be mixed it is uniform after, point Criticize and add diaminourea glyoxime, stir to after being completely dissolved, chloroformyl ethyl acetate is added dropwise, under the conditions of 40 DEG C 30min is reacted；Two The molal volume ratio of amino glyoxime, chloroformyl ethyl acetate, pyridine and glycol dimethyl ether is：10mmol：25mmol： 25mmol：30ml；
(2) step (1) gained reactant liquor is heated into 100 DEG C, continues to react after 2h, reactant liquor is poured into water, Jing chlorine The steps such as imitative extraction, dry and vacuum distillation obtain 5,5 '-ethyl diacetate base -3,3 '-connection -1,2,4- oxadiazoles.
Advantages of the present invention：
It is an advantage of the current invention that replacing the diethyl malonate in documents as anti-using chloroformyl ethyl acetate Raw material is answered, compared with documents, reaction temperature is reduced, the selectivity of the reaction is improve, pillar layer separation purification is saved Step, makes reaction easily operated, and reaction yield is 62%, higher than documents value 23%.
Specific embodiment
By the following examples the invention will be further described, but the present invention is not limited by the following example.
The synthesis of embodiment 1 5,5 '-ethyl diacetate base -3,3 '-connection -1,2,4- oxadiazoles
Under the conditions of (1) 25 DEG C, glycol dimethyl ether 30ml and pyridine 1.6g are added sequentially in reaction bulb, it is to be mixed equal After even, diaminourea glyoxime 1.2g is dividedly in some parts, is stirred to after being completely dissolved, chloroformyl ethyl acetate 3.0g, 40 DEG C of bars are added dropwise 30min is reacted under part；
(2) step (1) gained reactant liquor is continued to be heated to 100 DEG C, continues to react after 2h, reactant liquor is poured into water, The steps such as Jing chloroform extractions, drying and vacuum distillation obtain 5,5 '-ethyl diacetate base -3,3 '-connection -1,2,4- oxadiazoles 1.92g, yield is 62%.
Structural Identification：
Elementary analysis：
Molecular formula：C12H14N4O6
Theoretical value：C 46.45,H 4.55,N 18.06；
Measured value：C 46.51,H 4.52,N 18.10.
Infrared (KBr, cm-1)：3473,3376,3180,2976,1751,1659,1587,1543,1447,1405,1394, 1369,1343,1317,1253,1199,1185,1114,1038,1019,939,911,876,810,791,752,648,623, 573,508,439.
1H nuclear-magnetism (CDCl3, ppm)：1.2 (t, 6H, CH3), 4.08 (s, 4H, CH2), 4.17 (q, 4H, CH2O)；
13C nuclear-magnetism (CDCl3, ppm)：175.776,174.106,166.745,62.161,31.127,14.362.
Above-mentioned analyze data confirm the material obtained by the synthetic method be strictly 5,5 '-ethyl diacetate base -3,3 ' - Connection -1,2,4- oxadiazoles.
Embodiment 2
Under the conditions of (1) 25 DEG C, glycol dimethyl ether 25ml and pyridine 0.4g are added sequentially in reaction bulb, it is to be mixed equal After even, diaminourea glyoxime 1.2g is dividedly in some parts, is stirred to after being completely dissolved, chloroformyl ethyl acetate 1.5g, 30 DEG C of bars are added dropwise 40min is reacted under part；
(2) step (1) gained reactant liquor is continued to be heated to 80 DEG C, continues to react after 3h, reactant liquor is poured into water, Jing The steps such as chloroform extraction, drying and vacuum distillation obtain 5,5 '-ethyl diacetate base -3,3 '-connection -1,2,4- oxadiazoles 1.86g, yield is 60%.
Embodiment 3
Under the conditions of (1) 25 DEG C, glycol dimethyl ether 40ml and pyridine 2.0g are added sequentially in reaction bulb, it is to be mixed equal After even, diaminourea glyoxime 1.2g is dividedly in some parts, is stirred to after being completely dissolved, chloroformyl ethyl acetate 4.5g, 40 DEG C of bars are added dropwise 20min is reacted under part；
(2) step (1) gained reactant liquor is continued to be heated to 100 DEG C, continues to react after 2h, reactant liquor is poured into water, The steps such as Jing chloroform extractions, drying and vacuum distillation obtain 5,5 '-ethyl diacetate base -3,3 '-connection -1,2,4- oxadiazoles 1.92g, yield is 62%.
Embodiment 4
Under the conditions of (1) 25 DEG C, glycol dimethyl ether 50ml and pyridine 2.4g are added sequentially in reaction bulb, it is to be mixed equal After even, diaminourea glyoxime 1.2g is dividedly in some parts, is stirred to after being completely dissolved, chloroformyl ethyl acetate 6.0g, 40 DEG C of bars are added dropwise 40min is reacted under part；
(2) step (2) gained reactant liquor is continued to be heated to 120 DEG C, continues to react after 3h, reactant liquor is poured into water, The steps such as Jing chloroform extractions, drying and vacuum distillation obtain 5,5 '-ethyl diacetate base -3,3 '-connection -1,2,4- oxadiazoles 1.83g, yield is 59%.

Claims (2)

1. one kind 5,5 '-ethyl diacetate base -3, the synthetic method of -1,2,4- oxadiazoles of 3 '-connection, 5,5 '-ethyl diacetate base - 3,3 '-connection -1,2,4- oxadiazole structural formulas are as follows：
With diaminourea glyoxime and chloroformyl ethyl acetate as raw material, it is characterised in that comprise the following steps：
Under the conditions of (1) 25 DEG C, glycol dimethyl ether and pyridine are added sequentially in reaction bulb, it is to be mixed it is uniform after, in batches plus Enter diaminourea glyoxime, stir to being completely dissolved；Chloroformyl ethyl acetate is added dropwise in resulting solution, it is anti-under the conditions of 30～50 DEG C Answer 20～40min；The molal volume ratio of diaminourea glyoxime, chloroformyl ethyl acetate, pyridine and glycol dimethyl ether is： 10mmol：10～40mmol：5～30mmol：25～50ml；
(2) step (1) gained reactant liquor is warming up into 80～120 DEG C, continues to react after 1～3h, reactant liquor is poured into water, Jing The steps such as chloroform extraction, drying and vacuum distillation obtain 5,5 '-ethyl diacetate base -3,3 '-connection -1,2,4- oxadiazoles.
2. according to claim 15,5 '-ethyl diacetate base -3, the synthetic method of -1,2,4- oxadiazoles of 3 '-connection, its It is characterised by the molal volume ratio of diaminourea glyoxime, chloroformyl ethyl acetate, pyridine and glycol dimethyl ether in step (1) For 10mmol：25mmol：25mmol：30ml, reaction temperature is 40 DEG C, and the reaction time is 30min；The reaction temperature of step (2) For 100 DEG C, the reaction time is 2h.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101591307A (en) * 2009-06-26 2009-12-02 南开大学 Connection 1,2,3-thiadiazoles-5-formic acid and its production and use
WO2012040258A2 (en) * 2010-09-22 2012-03-29 Helicon Therapeutics, Inc. Therapeutic piperazines
CN103965125A (en) * 2014-05-06 2014-08-06 西安近代化学研究所 Synthetic method of 3,3'-binitro-5,5'-di-1,2,4-triazole

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101591307A (en) * 2009-06-26 2009-12-02 南开大学 Connection 1,2,3-thiadiazoles-5-formic acid and its production and use
WO2012040258A2 (en) * 2010-09-22 2012-03-29 Helicon Therapeutics, Inc. Therapeutic piperazines
CN103965125A (en) * 2014-05-06 2014-08-06 西安近代化学研究所 Synthetic method of 3,3'-binitro-5,5'-di-1,2,4-triazole

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
V. V. KISELEVA ET AL.: ""Synthesis of C-Azolylacetic acid esters based on carbethoxyethylacetimidate"", 《RUSS CHEM BULL》 *
王子俊 等: ""1,1’-二(硝氧甲基)-3,3’-二硝基-5,5’-联-1,2,4-三唑的合成及性能"", 《火炸药学报》 *

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