CN108997252B - Green synthesis method of oxadiazole derivative - Google Patents
Green synthesis method of oxadiazole derivative Download PDFInfo
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- CN108997252B CN108997252B CN201810839267.8A CN201810839267A CN108997252B CN 108997252 B CN108997252 B CN 108997252B CN 201810839267 A CN201810839267 A CN 201810839267A CN 108997252 B CN108997252 B CN 108997252B
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- 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
- C07D271/07—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
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Abstract
The invention relates to the field of organic chemistry, overcomes the defects in the prior art when oxadiazole derivatives are synthesized, and provides a green synthesis method of the oxadiazole derivatives. The method comprises the following specific steps: (1) taking water as a solvent, taking N-hydroxybenzamidine or substituted N-hydroxybenzamidine as a raw material, adding an alkaline reagent, dropwise adding a carbonylation reagent, uniformly stirring, and carrying out reflux reaction at 100 ℃ for 1-5 hours; (2) and after the reaction is finished, cooling and standing, acidifying the reaction solution by using 1mol/L diluted HCl until the pH value is 3-4, performing suction filtration, collecting a filter cake, washing the filter cake by using clear water, and performing vacuum drying to finally obtain the oxadiazole derivative. N-hydroxybenzamidine or substituted N-hydroxybenzamidine and a carbonylation reagent are used as raw materials, the oxadiazole derivative is synthesized in one step in water under the action of an alkaline reagent, two steps of reactions of esterification and cyclization are simplified into one step, the reaction time is greatly shortened, the reaction yield is improved, and the method has the advantages of mild reaction conditions, convenience in separation and purification, environmental friendliness and the like.
Description
Technical Field
The invention belongs to the field of organic chemistry, and particularly relates to a green synthesis method of an oxadiazole derivative.
Background
The oxadiazole derivative has stronger biological activity and adsorption property, and is widely applied to the related fields of medicine, material science and the like. The compound with oxadiazole mother ring is an AT1 receptor subtype antagonist, is used as a new antihypertensive drug, and has wide prospect in the prevention and treatment of heart failure, kidney diseases and a plurality of heart and kidney vascular diseases; and it is also a COX inhibitor, which reduces prostaglandin synthesis by inhibiting COX, thus acting as an anti-inflammatory. Meanwhile, the compound with the oxadiazole mother ring is also a mixed control type acidic carbon steel corrosion inhibitor with excellent performance, and the compound has stronger adsorption performance on the metal surface and can effectively inhibit the corrosion of acid on the metal. Therefore, the research on the synthesis method of oxadiazole derivatives has been an important issue in the organic chemistry.
The method for synthesizing the oxadiazole derivative by taking the N-hydroxybenzamidine or the substituted N-hydroxybenzamidine as the raw material is simple and economic. The common method is to synthesize oxadiazole derivatives (journal of chemical and engineering Date,1987,32,127-128) by using o-chlorobenzaldehyde oxime and potassium cyanate as raw materials, but the method uses potassium cyanate, and the potassium cyanate is contacted with acid to generate extremely toxic cyanide gas, which is unsafe to produce, transport and use and has great harm to human bodies. Another method is to prepare the oxadiazole derivative by using 3-methylbenzylamine oxime and diketene under the action of sodium hydride (Chemical & Pharmaceutical Bulletin,1982,30, 336-class 340), and the reaction of the method needs to use lachrymator diketene and sodium hydride reagent with poor stability, both of which belong to dangerous Chemical raw materials, increase the production danger in use and are not beneficial to industrial safety.
Therefore, the development of a synthesis method of oxadiazole derivatives, which has mild reaction conditions, simple and safe operation and wide substrate applicability, is still one of the important tasks of organic chemistry workers.
Disclosure of Invention
The method overcomes the defects in the prior art, and has the advantages of short route, green and environment-friendly solvent, simple and convenient separation and purification, high product yield, wide substrate applicability range and the like. The oxadiazole derivative is synthesized by using water as a solvent, N-hydroxybenzamidine or substituted N-hydroxybenzamidine and a carbonylation reagent as raw materials and reacting in one step under the action of an alkaline reagent.
The synthetic route of the invention is as follows:
the specific operation steps are as follows:
(1) taking water as a solvent, taking N-hydroxybenzamidine or substituted N-hydroxybenzamidine as a raw material, adding an alkaline reagent, dropwise adding a carbonylation reagent for reaction, uniformly stirring, and carrying out reflux reaction at 100 ℃ for 1-5 hours;
(2) and after the reaction is finished, cooling and standing, acidifying the reaction solution by using 1mol/L diluted HCl until the pH value is 3-4, performing suction filtration, collecting a filter cake, washing the filter cake by using clear water, and performing vacuum drying to finally obtain the oxadiazole derivative.
Wherein the structural formula of the substituted N-hydroxybenzamidine in the step (1) is
Wherein the substituent R1Is an alkyl group of 1 to 6 carbon atomsOne of alkoxy with 1 to 6 carbon atoms, halogen atom, cyano, trifluoromethyl or nitro; wherein the substituent R1At the ortho, meta or para position of the N-hydroxybenzamidine;
wherein the carbonylation reagent in the step (1) is one of methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, tert-butyl chloroformate and phenyl chloroformate.
Wherein the alkaline reagent in the step (1) is an inorganic base: NaOH, KOH, Ca (OH)2、Na2CO3、NaHCO3、K2CO3、KHCO3Or Cs2CO3(ii) a Or an organic base: NaOMe, Et3N, DMAP, DBU, DBN, DIPEA, DABCO or pyridine.
Further, the molar ratio of the N-hydroxybenzamidine or substituted N-hydroxybenzamidine to the carbonylation reagent in the step (1) is 1: 1-4; the molar ratio of the alkaline reagent to the N-hydroxybenzamidine or the substituted N-hydroxybenzamidine is 1-5: 1.
Preferably, the molar ratio of the N-hydroxybenzamidine or substituted N-hydroxybenzamidine to the carbonylation reagent in step (1) is 1: 1.5; the molar ratio of the alkaline reagent to the N-hydroxybenzamidine or the substituted N-hydroxybenzamidine is 2: 1.
The invention has the beneficial effects that: the invention adopts water as a solvent, N-hydroxybenzamidine or substituted N-hydroxybenzamidine and a carbonylation reagent as raw materials, and the oxadiazole derivative is synthesized by the one-step reaction under the action of an alkaline reagent, so that the synthesis steps and the manufacturing cost are greatly reduced, and the invention has the advantages of mild reaction conditions, convenient separation and purification, environmental protection, wide substrate applicability range and the like.
Detailed Description
The present invention will be described in detail with reference to examples, but the present invention is not limited to these examples.
Example 1
Adding N-hydroxybenzamidine (1mmol), 10mL of water and an alkaline reagent DMAP (2mmol) into a 25mL two-neck flask, dropwise adding phenyl chloroformate (1.5mmol) into the flask while stirring, heating to 100 ℃, refluxing and reacting for 2 hours, after the reaction is finished, stirring and cooling to room temperature, adjusting the pH of a reaction system to be 3-4 by using 1mol/L diluted HCl, separating out a solid, performing suction filtration, washing a filter cake by using clear water (15mL multiplied by 3), and performing vacuum drying to obtain the oxadiazole derivative, wherein the yield is 85%.
A white solid; mp:197 ℃ and 199 ℃;1H NMR(300MHz,DMSO-d6):δ＝12.97(s,1H,NH),7.83-7.81(m,2H,ArH),7.63-7.55(m,3H,ArH).13C NMR(75MHz DMSO-d6):δ＝160.4,157.8,132.7,129.8,126.5,123.8.
example 2
Referring to the method of example 1, isopropyl chloride was reacted as a raw material, and the yield of the oxadiazole derivative was 82%.
Example 3
Referring to the method of example 1, tert-butyl chloroformate was used as a starting material in the reaction, and the yield of the oxadiazole derivative was 83%.
Example 4
Referring to the method of example 1, the molar ratio of N-hydroxybenzamidine to phenyl chloroformate in the reaction was 1:1, and the yield of oxadiazole derivative was 76%.
Example 5
Referring to the method of example 1, the molar ratio of N-hydroxybenzamidine to phenyl chloroformate in the reaction was 1:4, and the yield of oxadiazole derivative was 83%.
Example 6
With reference to the procedure of example 1, Na was added during the reaction2CO3The reaction was carried out using an alkaline reagent, and the yield of the oxadiazole derivative was 73%.
Example 7
Referring to the procedure of example 1, the molar ratio of DMAP to N-hydroxybenzamidine in the reaction was 1:1, and the yield of the oxadiazole derivative was 65%.
Example 8
Referring to the procedure of example 1, the molar ratio of DMAP to N-hydroxybenzamidine in the reaction was 2.5:1, and the yield of the oxadiazole derivative was 84%.
Example 9
This example refers to the method of example 1, and the substrate compatibility of substituted N-hydroxybenzamidines was examined. The results are shown in Table 1.
TABLE 1 substituted N-hydroxybenzamidine substrate Adaptation Studies
Claims (6)
1. A green synthesis method of oxadiazole derivatives is characterized by comprising the following steps:
(1) taking water as a solvent, taking N-hydroxybenzamidine or substituted N-hydroxybenzamidine as a raw material, adding an alkaline reagent, dropwise adding a carbonylation reagent for reaction, uniformly stirring, and carrying out reflux reaction at 100 ℃ for 1-5 hours;
(2) after the reaction is finished, cooling and standing, acidifying the reaction solution by using 1mol/L diluted HCl until the pH value is 3-4, carrying out suction filtration, collecting a filter cake, washing the filter cake by using clear water, and carrying out vacuum drying to finally obtain the oxadiazole derivative;
the structural formula of the substituted N-hydroxybenzamidine is shown as
Wherein the substituent R1Is one of alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms, halogen atom, cyano, trifluoromethyl and nitro; wherein the substituent R1In the ortho, meta or para position of the N-hydroxybenzamidine.
2. The green synthesis method of oxadiazole derivatives according to claim 1, wherein: the carbonylation reagent is one of methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, tert-butyl chloroformate and phenyl chloroformate.
3. The green synthesis method of oxadiazole derivatives according to claim 1, wherein: the alkaline reagent is inorganic alkali or organic alkali.
4. The green synthesis method of oxadiazole derivatives according to claim 1, wherein: the molar ratio of the N-hydroxybenzamidine or substituted N-hydroxybenzamidine to the carbonylation reagent is 1: 1-4.
5. The green synthesis method of oxadiazole derivatives according to claim 1, wherein: the molar ratio of the alkaline reagent to the N-hydroxybenzamidine or the substituted N-hydroxybenzamidine is 1-5: 1.
6. The green synthesis method of oxadiazole derivatives according to claim 3, wherein: wherein the inorganic base is NaOH, KOH, Ca (OH)2、Na2CO3、NaHCO3、K2CO3、KHCO3Or Cs2CO3(ii) a The organic base is NaOMe and Et3N, DMAP, DBU, DBN, DIPEA, DABCO or pyridine.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102766138A (en) * | 2012-07-23 | 2012-11-07 | 上海凯谱林医药开发有限公司 | Preparation method of azilsartan |
| CN105431416A (en) * | 2013-06-12 | 2016-03-23 | 科研制药株式会社 | 4-alkynyl imidazole derivative and medicine comprising same as active ingredient |
| CN107207483A (en) * | 2014-08-29 | 2017-09-26 | Tes制药有限责任公司 | α amino β carboxymuconate semialdehyde decarboxylase inhibitors |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102766138A (en) * | 2012-07-23 | 2012-11-07 | 上海凯谱林医药开发有限公司 | Preparation method of azilsartan |
| CN105431416A (en) * | 2013-06-12 | 2016-03-23 | 科研制药株式会社 | 4-alkynyl imidazole derivative and medicine comprising same as active ingredient |
| CN107207483A (en) * | 2014-08-29 | 2017-09-26 | Tes制药有限责任公司 | α amino β carboxymuconate semialdehyde decarboxylase inhibitors |
Non-Patent Citations (1)
| Title |
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| A novel bifunctional chelating agent based on bis(hydroxamamide) for 99mTc labeling of polypeptides;Masahiro Ono et al.;《J. Label Compd. Radiopharm》;20111212;第55卷;第71-79页 * |
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