CN101643456A - Synthesis method of symmetric 1, 3, 4-oxadiazole - Google Patents
Synthesis method of symmetric 1, 3, 4-oxadiazole Download PDFInfo
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- CN101643456A CN101643456A CN200910067476A CN200910067476A CN101643456A CN 101643456 A CN101643456 A CN 101643456A CN 200910067476 A CN200910067476 A CN 200910067476A CN 200910067476 A CN200910067476 A CN 200910067476A CN 101643456 A CN101643456 A CN 101643456A
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Abstract
The invention provides a synthesis method of symmetric 1, 3, 4-oxadiazole, which comprises the following steps: obtaining symmetric hydrazide by one-step reaction with hydrazine hydrate after acylating carboxylic acid; refluxing the symmetric hydrazide in a POC1<3> solvent for 10 hours; after the reaction system is cooled to room temperature, slowly and dropwisely adding the solution in ice water;after the reaction solution adding, keeping static until all the while solid precipitates; carrying out the suction filtration, and washing with water to obtain the pure objective product. The symmetric hydrazide can be directly obtained by the method; the cyclization reaction is directly carried out; the obtained substance is treated with water so as to obtain the pure objective product, namelysymmetric 1, 3, 4-oxadiazole. The method has few steps; the solvent used in the purifying process of the product is water, rather than an organic solvent; the yield of every step of the whole synthesis procedure is very high; and therefore, the chemical reaction is economical and protects the environment.
Description
Technical field:
The present invention discloses a kind of symmetrical 1,3, and the synthetic method of 4-oxadiazole for a kind of new organic compound synthetic method, belongs to the organic chemistry synthesis technical field.
Background technology:
Publish thesis from M.S.Gibson in 1962 and to have developed 1,3, (Tetrahedron, 1962, V (18): 1377-1380) since the reaction mechanism of 4-oxadiazole cyclization, people constantly adopt novel method synthetic 1,3,4-oxadiazole derivative, wherein synthetic have 1 of a symmetrical structure, 3, the main method of 4-oxadiazole derivative has:
1) thiosemicarbazide and aromatic carboxylic acid---see 1. (chemical reagent of formula, 1997,19 (6): 373-381.), perhaps Urea,amino-and aromatic carboxylic acid---see 2. (Synth.Commun. of formula, 2002,32 (21): 3339-3345.), under the effect of polyphosphoric acid (PPA), carry out cyclization and make symmetric 1,3,4-oxadiazole compound;
2) the bishydrazide cyclization make symmetric 1,3,4-oxadiazole compound.
With carboxylic acid and the synthetic ester of alcohol reaction, ester and hydrazine hydrate reaction generate hydrazides, and hydrazides and acyl chloride reaction generate symmetric bishydrazide---see that formula is 1..Perhaps hydrazides and carboxylic acid react and generate symmetric bishydrazide---see that formula is 2..It is symmetric 1,3 that the bishydrazide cyclization makes, 4-oxadiazole compound.
3) tetrazole and acylate rearrangement reaction obtain 1,3,4-oxadiazole compound.(J.org.chem.，2001，66：4062-4064.)
All exist some shortcoming and defect in the above-mentioned existing synthetic technology:
Method 1) does the dewatering agent reaction at polyphosphoric acid and synthesize 1,3, during the 4-oxadiazole, easily cause side reactions such as coking or degraded because of temperature control is improper.
Method 2) with the synthetic ester of carboxylic acid and alcohol reaction, ester and hydrazine hydrate reaction generate hydrazides, and hydrazides and generate the symmetric double hydrazides with acyl chloride reaction sees that formula 1..Perhaps, hydrazides and carboxylic acid react and generate symmetric hydrazides, see that formula 2..Carry out cyclization at last and obtain 1,3, the 4-oxadiazole.Each step productive rate of this method all is far smaller than 90%, and the final product that obtains needs column chromatography to purify.
Method 3) carboxylic acid is obtained acyl chlorides through after the acidylate, obtain acylate with corresponding tetrazole reaction then, then carrying out cyclization again obtains 1,3, the 4-oxadiazole.Desired raw material in this method---tetrazole is synthetic very complicated, and resulting final product need be purified through column chromatography.
In sum, existing technology: the first, side reactions such as coking or degraded easily take place when making dewatering agent with polyphosphoric acid.The second, the route complexity---need at least through four steps, and the productive rate of each step product all is far smaller than 90%, just can obtains target product, involve great expense.The 3rd, resulting material demand is purified with a large amount of organic solvents, causes the expense of entire synthesis process to raise like this, causes serious environmental to pollute simultaneously.
Summary of the invention:
The present invention discloses a kind of symmetrical 1,3, and the synthetic method of 4-oxadiazole has overcome the synthetic method operational path complexity of existing such compound, and synthetic product yields poorly, and environmental pollution seriously waits shortcoming.
Synthetic route of the present invention is as follows:
Concrete synthetic method is as follows:
The carboxylic acid that takes by weighing 5-10mol places flask, adds the SOCl of 5-10mL
2Refluxed 10 hours down at 78 ℃, cool to room temperature, decompression steams unnecessary SOCl
2, airtight being placed in the frozen water of flask stirred 5 minutes.Slowly drip the hydrazine hydrate of 2-5mL80% then, dropping to does not have white smoke to generate.At room temperature stirred after dropwising 10 minutes, and added 20-30mL water then in flask, stirred 30 minutes, suction filtration obtains white solid matter on filter paper.Its drying is placed in the flask, and then adds the POCl of 10-15mL
3, refluxing 10 hours down at 100 ℃, cool to room temperature is added drop-wise to (stirring) in the frozen water to its settled solution, after dropwising, leaves standstill to solid complete
Portion separates out, and suction filtration washes with water 3-4 time then, obtains white solid on filter paper, after the drying promptly.
The advantage of synthesis technique of the present invention is as follows: each the step purification process in the building-up process only need wash with water and get final product, synthetic route is short, do not need to purify with column chromatography, save a large amount of organic solvents, and the productive rate of each step gained target product surpasses 90%, building-up process cheap, the safety and environmental protection of cost economy simple to operate, synthetic.
Description of drawings
Fig. 1 is the H-NMR figure of embodiment 1;
Fig. 2 is the X-single crystal diffraction unit cell figure of embodiment 1;
Fig. 3 is the IR figure of embodiment 1.
Fig. 4 is the H-NMR figure of embodiment 2;
Fig. 5 is the X-single crystal diffraction unit cell figure of embodiment 2;
Fig. 6 is the IR figure of embodiment 2.
Fig. 7 is the H-NMR figure of embodiment 3;
Fig. 8 is the IR figure of embodiment 3.
Fig. 9 is the H-NMR figure of embodiment 4;
Figure 10 is the IR figure of embodiment 4.
Embodiment
Further describe this synthetic method in following embodiment, described embodiment only is used for illustration purpose, and is not intended to the use range of restriction present method.
Embodiment 1:
2,5-two (2-methoxyl group) phenyl-1,3,4-oxadiazole synthetic.
With 1.52g (10mmol) o-methoxybenzoic acid, 5mL SOCl
2, join in the 50mL flask.At 78 ℃ of following reflux 10 hours, cool to room temperature, decompression steams unnecessary SOCl
2, airtight flask, be placed in the frozen water and stirred 5 minutes.Open wide flask, slowly drip the hydrazine hydrate of 2mL 80%, at room temperature stirred after dropwising 10 minutes, add 20mL water then in flask, stirred 30 minutes, suction filtration obtains white solid matter on filter paper.Its drying is placed in the flask, adds the POCl of 10mL again
3, 100 ℃ of following reflux 10 hours, cool to room temperature, its settled solution slowly is added drop-wise to (stirring) in the frozen water, after dropwising, leave standstill to solid and all separate out suction filtration, wash with water 3-4 time, on filter paper, obtain white solid, promptly get after the drying purified 2,5-two (2-methoxyl group) phenyl-1,3, the 4-oxadiazole.Synthetic route is as follows:
The gained material characterizes as follows through nuclear-magnetism (H-NMR), X-monocrystal diffraction, infrared spectra (IR): H-NMR figure sees Fig. 1; X-single crystal diffraction unit cell figure sees Fig. 2; IR figure sees Fig. 3.
Embodiment 2
2,5-two (2-thienyl)-1,3,4-oxadiazole synthetic.
With 1.28g (10mmol) 2-thiophenic acid, 5mL SOCl
2, join in the 50mL flask.At 78 ℃ of following reflux 10 hours, cool to room temperature, decompression steams unnecessary SOCl
2, airtight flask, be placed in the frozen water and stirred 5 minutes.Open wide flask, slowly drip the hydrazine hydrate of 2mL 80%, at room temperature stirred after dropwising 10 minutes, add 20mL water in flask, stirred 30 minutes, suction filtration obtains white solid matter on filter paper.Its drying is placed in the flask, adds the POCl of 10mL again
3, 100 ℃ of following reflux 10 hours, cool to room temperature, its settled solution slowly is added drop-wise to (stirring) in the frozen water, after dropwising, leave standstill to solid and all separate out suction filtration, wash with water 3-4 time, on filter paper, obtain white solid, promptly get after the drying purified 2,5-two (2-thienyl)-1,3, the 4-oxadiazole.Synthetic route is as follows:
The gained material characterizes as follows through nuclear-magnetism (H-NMR), X-monocrystal diffraction, infrared spectra (IR):
H-NMR figure sees Fig. 4.X-single crystal diffraction unit cell figure sees Fig. 5.IR figure sees Fig. 6.
Embodiment 3
2,5-phenylbenzene-1,3,4-oxadiazole synthetic.
With 1.22g (10mmol) phenylformic acid, 5mL SOCl
2, join in the 50mL flask.At 78 ℃ of following reflux 10 hours, cool to room temperature, decompression steams unnecessary SOCl
2, airtight flask, in frozen water, stirred 5 minutes.Open wide flask, slowly drip the hydrazine hydrate of 2mL 80%, at room temperature stirred after dropwising 10 minutes, add 20mL water in flask, stirred 30 minutes, suction filtration obtains white solid matter on filter paper.Its drying is placed in the flask, adds the POCl of 10mL again
3, 100 ℃ of following reflux 10 hours, cool to room temperature, its settled solution slowly is added drop-wise to (stirring) in the frozen water, after dropwising, leave standstill to solid and all separate out suction filtration, wash with water 3-4 time, on filter paper, obtain white solid, promptly get after the drying purified 2,5-phenylbenzene-1,3, the 4-oxadiazole.Synthetic route is as follows:
The gained material characterizes as follows through nuclear-magnetism (H-NMR), infrared spectra (IR): H-NMR figure sees Fig. 7, and IR figure sees Fig. 8.
2,5-two (4-methyl) phenyl-1,3,4-oxadiazole synthetic.
With 1.36g (10mmol) p-methylbenzoic acid, 5mL SOCl
2, join in the 50mL flask.At 78 ℃ of following reflux 10 hours, cool to room temperature, decompression steams unnecessary SOCl
2, airtight flask, in frozen water, stirred 5 minutes.Open wide flask, slowly drip the hydrazine hydrate of 2mL 80%, at room temperature stirred after dropwising 10 minutes, add 20mL water in flask, stirred 30 minutes, suction filtration obtains white solid matter on filter paper.Its drying is placed in the flask, adds the POCl of 10mL again
3, 100 ℃ of following reflux 10 hours, cool to room temperature, its settled solution slowly is added drop-wise to (stirring) in the frozen water, after dropwising, leave standstill to solid and all separate out suction filtration, wash with water 3-4 time, on filter paper, obtain white solid, promptly get after the drying purified 2,5-two (4-methyl) phenyl-1,3, the 4-oxadiazole.Synthetic route is as follows:
The gained material characterizes as follows through nuclear-magnetism (H-NMR), infrared spectra (IR): H-NMR figure sees Fig. 9, and IR figure sees Figure 10.
Claims (6)
1, a kind of synthetic method of symmetrical 1.3.4-oxadiazole may further comprise the steps:
1) will can obtain symmetric hydrazides with the hydrazine hydrate single step reaction after the carboxylic acid acidylate;
2) symmetrical hydrazides is at POCl
3Refluxed 10 hours in the solvent;
3) behind the reaction system cool to room temperature, solution is added drop-wise in the frozen water lentamente, after reaction soln dropwises, should leaves standstill to white solid matter and all separate out, carry out suction filtration again, wash with water, promptly.
2, the synthetic method of the described symmetrical 1.3.4-oxadiazole of claim is characterized in that: the SOCl that adds 5-10mL in the carboxylic acid of 5-10mol
2, 78 ℃ were refluxed 10 hours down, cool to room temperature, and decompression steams unnecessary SOCl
2, airtight being placed in the frozen water stirred 5 minutes; Slowly drip the hydrazine hydrate of 2-5mL 80% then, dropping to does not have white smoke dirt to become; At room temperature stirred after dropwising 10 minutes, and added 20-30mL water then in flask, stirred 30 minutes, suction filtration obtains white solid matter on filter paper; Drying is placed in the flask, adds the POCl of 10-15mL again
3, refluxing 10 hours down at 100 ℃, cool to room temperature is added drop-wise to (stirring) in the frozen water to its settled solution, after dropwising, leave standstill to solid and all separate out, suction filtration washes with water 3-4 time then, on filter paper, obtain white solid, promptly get 1,3 after the drying, the 4-oxadiazole.
3, a kind of 2,5-two (2-methoxyl group) phenyl-1,3, the synthetic method of 4-oxadiazole, its feature is as follows:
1.52g (10mmol) o-methoxybenzoic acid is added 5mL SOCl
2, 78 ℃ of following reflux 10 hours, cool to room temperature, decompression steams unnecessary SOCl
2, airtight being placed in the frozen water stirred 5 minutes; Slowly drip the hydrazine hydrate of 2mL 80%, at room temperature stirred after dropwising 10 minutes, add 20mL water then, stirred 30 minutes, suction filtration obtains white solid matter on filter paper; Drying is placed in the flask, adds the POCl of 10mL again
3, 100 ℃ of following reflux 10 hours, cool to room temperature, its settled solution slowly is added drop-wise to (stirring) in the frozen water, after dropwising, leave standstill to solid and all separate out suction filtration, wash with water 3-4 time, on filter paper, obtain white solid, promptly get 2 after the drying, 5-two (2-methoxyl group) phenyl-1,3, the 4-oxadiazole.
4, a kind of 2,5-two (2-thienyl)-1,3, the synthetic method of 4-oxadiazole, its feature is as follows:
1.28g (10mmol) 2-thiophenic acid is added 5mL SOCl2, and at 78 ℃ of following reflux 10 hours, cool to room temperature, decompression steams unnecessary SOCl
2, airtight being placed in the frozen water stirred 5 minutes, slowly dripped the hydrazine hydrate of 2mL 80%, at room temperature stirred after dropwising 10 minutes, added 20mL water, stirred 30 minutes, and suction filtration obtains white solid matter on filter paper; Drying is placed in the flask, adds the POCl of 10mL again
3, 100 ℃ of following reflux 10 hours, cool to room temperature, its settled solution slowly is added drop-wise to (stirring) in the frozen water, after dropwising, leave standstill to solid and all separate out suction filtration, wash with water 3-4 time, on filter paper, obtain white solid, promptly get 2 after the drying, 5-two (2-thienyl)-1,3, the 4-oxadiazole.
5, a kind of 2,5-phenylbenzene-1,3, the synthetic method of 4-oxadiazole, its feature is as follows:
1.22g (10mmol) phenylformic acid is added 5mL SOCl2,78 ℃ of following reflux 10 hours, cool to room temperature, decompression steams unnecessary SOCl2, is enclosed in the frozen water to stir 5 minutes, slowly drip the hydrazine hydrate of 2mL 80%, at room temperature stirred after dropwising 10 minutes, and added 20mL water, stirred 30 minutes, suction filtration obtains white solid matter on filter paper; Drying is placed in the flask, adds the POCl3 of 10mL again, 100 ℃ of following reflux 10 hours, cool to room temperature slowly is added drop-wise to (stirring) in the frozen water to its settled solution, after dropwising, leave standstill to solid and all separate out, suction filtration washes with water 3-4 time, obtains white solid on filter paper, promptly get 2 after the drying, 5-phenylbenzene-1,3, the 4-oxadiazole.
6, a kind of 2,5-two (4-methyl) phenyl-1,3, the synthetic method of 4-oxadiazole, its feature is as follows:
1.36g (10mmol) p-methylbenzoic acid is added 5mL SOCl2,78 ℃ of following reflux 10 hours, cool to room temperature, decompression steams unnecessary SOCl2, is enclosed in the frozen water to stir 5 minutes, slowly drip the hydrazine hydrate of 2mL 80%, at room temperature stirred after dropwising 10 minutes, and in flask, added 20mL water, stirred 30 minutes, suction filtration obtains white solid matter on filter paper; Drying is placed in the flask, adds the POCl3 of 10mL again, 100 ℃ of following reflux 10 hours, cool to room temperature slowly is added drop-wise to (stirring) in the frozen water to its settled solution, after dropwising, leave standstill to solid and all separate out, suction filtration washes with water 3-4 time, obtains white solid on filter paper, promptly get 2 after the drying, 5-two (4-methyl) phenyl-1,3, the 4-oxadiazole.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104628668A (en) * | 2015-02-12 | 2015-05-20 | 尹磊 | Synthesis method of pharmaceutical intermediate oxadiazole compound |
| CN108084109A (en) * | 2017-12-21 | 2018-05-29 | 南京工业大学 | One kind 2,5- bis- substitutes the synthetic method of -1.3.4- oxadiazoles |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104628668A (en) * | 2015-02-12 | 2015-05-20 | 尹磊 | Synthesis method of pharmaceutical intermediate oxadiazole compound |
| CN108084109A (en) * | 2017-12-21 | 2018-05-29 | 南京工业大学 | One kind 2,5- bis- substitutes the synthetic method of -1.3.4- oxadiazoles |
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