CN113480475A - Synthesis method of 4- (2-pyridyl) benzonitrile - Google Patents
Synthesis method of 4- (2-pyridyl) benzonitrile Download PDFInfo
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- CN113480475A CN113480475A CN202110961679.0A CN202110961679A CN113480475A CN 113480475 A CN113480475 A CN 113480475A CN 202110961679 A CN202110961679 A CN 202110961679A CN 113480475 A CN113480475 A CN 113480475A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/57—Nitriles
Abstract
The invention relates to a method for synthesizing 4- (2-pyridyl) benzonitrile, and belongs to the technical field of synthesis of drug intermediates. In order to solve the problems of large pollution and low yield in the prior art, the method for synthesizing the 4- (2-pyridyl) benzonitrile is characterized by comprising the step of reacting 2-halopyridine with p-cyanobenzene boronic acid in an ether solvent in the presence of inorganic base under the catalysis of ferric acetylacetonate to obtain the corresponding product, namely the 4- (2-pyridyl) benzonitrile. The method has the advantages of high product yield and purity, high product yield of over 80 percent, capability of effectively avoiding the problem of poor reaction selectivity caused by the adoption of a Grignard reagent or a lithium reagent, and environmental friendliness.
Description
Technical Field
The invention relates to a method for synthesizing 4- (2-pyridyl) benzonitrile, and belongs to the technical field of synthesis of drug intermediates.
Background
Atazanavir (trade name Reyataz, rituximab) is a second generation azapolypeptide HIV protease inhibitor, developed by behmere precious (BMS). It was first marketed in the united states by FDA approval on day 6, month 20 in 2003. The drug can selectively inhibit virus-specific Gap and Gap-Pol polyprotein, thereby preventing the formation of mature viral particles. In vitro tests show that the medicine has antagonistic action on drugs such as nevirapine, abacavir and the like, has addition effect when being used together with other protease inhibitors, didanosine, lamivudine and the like, and does not increase cytotoxicity. The atazanavir and other anti-reverse transcriptase medicaments are used together for treatment, the tolerance is better, and common adverse reactions are mild to moderate nausea, headache, diarrhea, rash and the like.
The intermediate 4- (2-pyridyl) benzonitrile is used as a main intermediate of atazanavir, 2-chloropyridine and p-cyanobenzene boronic acid are adopted to react under the catalysis of noble metals such as palladium, nickel and the like in the prior art, or under the catalysis of special ligands such as phosphine ligands or NHC ligands and the like, but the noble metals such as palladium and the like have better product yield and quality requirements, but are expensive and not beneficial to industrial production, and the nickel catalysis has the problem of high toxicity, has influence on human health and is not beneficial to safe production; the reaction is carried out by using a Grignard reagent or a lithium reagent, but the reaction has poor selectivity, low product yield and great environmental pollution.
Disclosure of Invention
The invention provides a method for synthesizing 4- (2-pyridyl) benzonitrile, aiming at solving the problems in the prior art, and how to reduce pollution and improve product yield.
The invention aims to realize the following technical scheme, and the method for synthesizing the 4- (2-pyridyl) benzonitrile is characterized by comprising the following steps of:
in the presence of inorganic base, under the catalysis of iron acetylacetonate, enabling 2-halopyridine of a compound shown in a formula II to react with p-cyanobenzene boronic acid of a compound shown in a formula III in an ether solvent to obtain a corresponding product, namely 4- (2-pyridyl) benzonitrile of a compound shown in a formula I;
wherein, in the formula II, X is halogen.
By adopting ferric acetylacetonate for catalysis in an ether solvent, the ferric acetylacetonate can be effectively combined with halogen in the raw material 2-halogenated pyridine to form an active intermediate state, then the 2-halogenated pyridine attacks a boric acid group of p-cyanobenzene boronic acid for reaction, and other ligands are not needed for assistance, so that the reaction selectivity is very high, and a product is effectively formed, and the advantages of high specific product yield and purity are achieved, and the product yield is over 80%; meanwhile, by adopting ferric acetylacetonate for catalysis, the problem of high cost caused by adopting palladium and other catalysis in the prior art can be effectively solved, the problem of poor reaction selectivity caused by adopting a Grignard reagent or a lithium reagent can be effectively avoided, and the adopted ferric acetylacetonate also has the advantages of no toxicity and no pollution, is environment-friendly and reduces the pollution to the environment.
In the above method for synthesizing 4- (2-pyridyl) benzonitrile, the halogen is preferably chlorine, bromine or iodine. Has the advantages of easily obtained raw materials, is more favorable for forming an active intermediate state with the ferric acetylacetonate, improves the reaction efficiency, and preferably adopts bromine as halogen.
In the above method for synthesizing 4- (2-pyridyl) benzonitrile, the reaction temperature is preferably 45 to 65 ℃. By adopting the catalyst to carry out catalytic reaction, the reaction can be carried out at a milder temperature, the production operation is more facilitated, the generation of impurities is reduced, and the purity and quality of the product are improved.
In the above method for synthesizing 4- (2-pyridyl) benzonitrile, preferably, the ether solvent is one or more selected from the group consisting of ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, and methyl tertiary butyl ether. The reaction can be carried out mildly, and the recovery is easy. The ether solvent can better promote the reaction and improve the conversion rate and the product yield.
In the above method for synthesizing 4- (2-pyridyl) benzonitrile, the presence of an inorganic base can promote the reaction, can avoid the effect of the steric hindrance of the raw materials on the reaction, and can make the reaction proceed efficiently, wherein the inorganic base can be an alkali metal salt or an alkali metal hydroxide, such as sodium hydroxide, potassium hydroxide, etc.; or weakly alkaline substances such as sodium carbonate or potassium carbonate which are slightly less alkaline than the alkali. Preferably, the inorganic base is selected from sodium carbonate or potassium carbonate. The production of byproducts can be better reduced, and the purity and quality requirements of the product can be better ensured.
In the above method for synthesizing 4- (2-pyridyl) benzonitrile, the molar ratio of the 2-halopyridine of the compound of formula II to the p-cyanophenylboronic acid of the compound of formula III is 1: 1.0 to 1.1. The raw materials are reacted under the condition of the dosage of the basic molar equivalent, so that the raw materials can be more fully utilized, and the waste of the raw materials and the generation of impurities are reduced.
In the above method for synthesizing 4- (2-pyridyl) benzonitrile, preferably, the molar ratio of the compound of formula ii, 2-halopyridine, iron acetylacetonate, and inorganic base is 1: 0.05-0.15: 2.0 to 2.5.
In the above method for synthesizing 4- (2-pyridyl) benzonitrile, preferably, the method further comprises a post-treatment after the reaction is finished, wherein the post-treatment comprises distilling the reaction solution to remove the solvent to obtain a corresponding concentrate, adding water and a water-insoluble solvent to the concentrate, stirring, standing, layering, collecting an organic layer, and crystallizing to obtain the corresponding compound 4- (2-pyridyl) benzonitrile of formula I. The product can be effectively separated, and impurities such as inorganic salt can be effectively removed by adding water and a water-insoluble solvent, so that the purity and quality of the product are better improved. The water and the water-insoluble organic solvent are added according to the requirement, and the adding amount of the water is preferably 3-5 times of the mass of the compound of the formula II; the dosage of the water-insoluble organic solvent is 4-8 times of the mass of the compound of the formula II. As a further preference, the water-insoluble solvent is selected from one or more of ethyl acetate, dichloromethane and chloroform.
The synthesis method of the 4- (2-pyridyl) benzonitrile can be represented by the following chemical reaction equation:
here, BIron acetylacetonate (Fe (acac)3) The structure of (a) is as follows:
in summary, compared with the prior art, the invention has the following advantages:
1. the method has the advantages of high reaction selectivity, effective formation of products, high specific product yield and purity, and high product yield of over 80 percent.
2, the problem of high cost caused by the existing catalysis of palladium and the like can be effectively solved by adopting ferric acetylacetonate for catalysis, the problem of poor reaction selectivity caused by the adoption of a Grignard reagent or a lithium reagent can be effectively avoided, and the method has the advantage of being environment-friendly.
Detailed Description
The technical solution of the present invention is further specifically described below by way of specific examples, but the present invention is not limited to these examples.
Example 1
15.8g (0.1mol) of 2-bromopyridine, 16.17g (0.11mol) of p-cyanobenzene boronic acid, 5.29g (0.015mol) of ferric acetylacetonate, 27.6g (0.2mol) of potassium carbonate and 100g of ethylene glycol monomethyl ether as a solvent are added into a 250ml three-neck flask, then heating to 55 ℃ under stirring for heat preservation reaction for 4.5h, controlling the temperature at 45 ℃ after the reaction is finished, carrying out reduced pressure distillation to remove the solvent until the solvent is evaporated to dryness, then adding 50ml water and 100ml ethyl acetate, stirring for 10min, standing, separating, collecting organic phase, extracting water layer with 20ml ethyl acetate, combining collected organic phases, drying with 5g magnesium sulfate for 30min, filtering, collecting filtrate, adding 400ml of normal hexane into the filtrate for full crystallization, filtering, and drying the obtained solid wet product to obtain 14.5g of the product 4- (2-pyridyl) benzonitrile, wherein the yield is 80.7%, and the purity is more than 98%.
Example 2
15.8g (0.1mol) of 2-bromopyridine, 15.43g (0.105mol) of p-cyanoborobenzene, 4.59g (0.013mol) of ferric acetylacetonate, 30.36g (0.22mol) of potassium carbonate and 120g of ethylene glycol monomethyl ether as a solvent are put into a 250ml three-necked flask, then heating to 60 ℃ under stirring for heat preservation reaction for 5h, controlling the temperature at 45 ℃ after the reaction is finished, carrying out reduced pressure distillation to remove the solvent until the solvent is evaporated to dryness, then adding 75ml water and 150ml ethyl acetate, stirring for 15min, standing, separating, collecting organic phase, extracting water layer with 30ml ethyl acetate, combining collected organic phases, drying with 7.5g magnesium sulfate for 30min, filtering, collecting filtrate, adding 600ml of normal hexane into the filtrate for full crystallization, filtering, and drying the obtained solid wet product to obtain 14.62g of the product 4- (2-pyridyl) benzonitrile, wherein the yield is 81.2 percent, and the purity is 98.2 percent.
Example 3
15.8g (0.1mol) of 2-bromopyridine, 16.17g (0.11mol) of p-cyanoborobenzene, 3.53g (0.01mol) of ferric acetylacetonate, 26.5g (0.25mol) of sodium carbonate and 130g of glycol dimethyl ether as a solvent are added into a 250ml three-neck flask, then heating to 50 ℃ under stirring for heat preservation reaction for 5h, controlling the temperature at 45 ℃ after the reaction is finished, carrying out reduced pressure distillation to remove the solvent until the solvent is evaporated to dryness, then 75ml of water and 150ml of dichloromethane were added, stirred for 15min, allowed to stand, separated, the organic phase was collected, the aqueous layer was extracted with 30ml of dichloromethane, the collected organic phases were combined, dried over 7.5g of magnesium sulfate for 30min, filtering, collecting filtrate, adding 600ml of normal hexane into the filtrate for full crystallization, filtering, and drying the obtained solid wet product to obtain 14.52g of the product 4- (2-pyridyl) benzonitrile, wherein the yield is 80.8 percent, and the purity reaches 98.1 percent.
Example 4
Adding 15.8g (0.1mol) of 2-bromopyridine, 15.43g (0.105mol) of p-cyanobenzoic acid, 4.24g (0.012mol) of ferric acetylacetonate, 24.4g (0.23mol) of sodium carbonate and 110g of methyl tert-butyl ether solvent into a 250ml three-necked flask, heating to 45 ℃ under stirring for carrying out heat preservation reaction for 6h, controlling the temperature to 45 ℃ after the reaction is finished, carrying out reduced pressure distillation to remove the solvent until the solvent is evaporated to dryness, adding 75ml of water and 150ml of ethyl acetate, stirring for 15min, standing, carrying out liquid separation, collecting an organic phase, extracting a water layer by using 30ml of ethyl acetate, combining the collected organic phases, drying for 30min by using 7.5g of magnesium sulfate, filtering, collecting a filtrate, adding 600ml of n-hexane into the filtrate for full crystallization, filtering to obtain a solid wet product, drying to obtain 14.78g of the product 4- (2-pyridyl) benzonitrile, wherein the yield is 82.1%, and the purity is 98.25%.
Example 5
Adding 15.8g (0.1mol) of 2-bromopyridine, 16.17g (0.11mol) of p-cyanobenzoic acid, 4.59g (0.013mol) of ferric acetylacetonate, 30.36g (0.22mol) of potassium carbonate and 120g of methyl tert-butyl ether solvent into a 250ml three-necked flask, heating to 65 ℃ under stirring for carrying out heat preservation reaction for 4h, controlling the temperature to be 45 ℃ after the reaction is finished, carrying out reduced pressure distillation to remove the solvent until the solvent is evaporated to dryness, then adding 80ml of water and 150ml of dichloromethane, stirring for 15min, standing, carrying out liquid separation, collecting an organic phase, extracting a water layer by using 30ml of dichloromethane, combining the collected organic phases, drying for 30min by using 8g of magnesium sulfate, filtering, collecting a filtrate, adding 600ml of n-hexane into the filtrate for full crystallization, filtering to obtain a solid wet product, drying to obtain 14.8g of the product 4- (2-pyridyl) benzonitrile, wherein the yield is 82%, and the purity is 98.5%.
Example 6
Adding 11.3g (0.1mol) of 2-chloropyridine, 15.43g (0.105mol) of p-cyanobenzoic acid, 3.53g (0.01mol) of ferric acetylacetonate, 24.4g (0.23mol) of sodium carbonate and 110g of methyl tert-butyl ether solvent into a 250ml three-necked flask, heating to 50 ℃ under stirring for carrying out heat preservation reaction for 5h, controlling the temperature to be 45 ℃ after the reaction is finished, carrying out reduced pressure distillation to remove the solvent until the solvent is evaporated to dryness, then adding 75ml of water and 150ml of ethyl acetate, stirring for 15min, standing, carrying out liquid separation, collecting an organic phase, extracting a water layer by using 30ml of ethyl acetate, combining the collected organic phases, drying for 30min by using 8.0g of magnesium sulfate, filtering, collecting a filtrate, adding 600ml of n-hexane into the filtrate for full crystallization, filtering to obtain a solid wet product, drying to obtain 14.7g of the product 4- (2-pyridyl) benzonitrile, wherein the yield is 81.7%, and the purity is 98.4%.
The specific embodiments described herein are merely illustrative of the spirit of the invention. Various modifications or additions may be made to the described embodiments or alternatives may be employed by those skilled in the art without departing from the spirit or ambit of the invention as defined in the appended claims.
While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.
Claims (9)
1. A method for synthesizing 4- (2-pyridyl) benzonitrile, which is characterized by comprising the following steps:
in the presence of inorganic base, under the catalysis of iron acetylacetonate, enabling 2-halopyridine of a compound shown in a formula II to react with p-cyanobenzene boronic acid of a compound shown in a formula III in an ether solvent to obtain a corresponding product, namely 4- (2-pyridyl) benzonitrile of a compound shown in a formula I;
wherein, in the formula II, X is halogen.
2. The method for synthesizing 4- (2-pyridyl) benzonitrile according to claim 1, wherein the halogen is chlorine, bromine or iodine.
3. The method for synthesizing 4- (2-pyridyl) benzonitrile according to claim 2, wherein the temperature of the reaction is 45 ℃ to 65 ℃.
4. The method for synthesizing 4- (2-pyridyl) benzonitrile according to claim 1, 2, or 3, wherein the ether solvent is one or more selected from the group consisting of ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, and methyl tertiary butyl ether.
5. The method for synthesizing 4- (2-pyridyl) benzonitrile according to claim 1, 2 or 3, wherein the inorganic base is selected from sodium carbonate or potassium carbonate.
6. The method for synthesizing 4- (2-pyridyl) benzonitrile according to claim 1, 2 or 3, wherein the molar ratio of the 2-halopyridine of the compound of formula II to the p-cyanophenylboronic acid of the compound of formula III is 1: 1.0 to 1.1.
7. The method for synthesizing 4- (2-pyridyl) benzonitrile according to claim 1, 2 or 3, wherein the molar ratio of the compound of formula II, 2-halopyridine, iron acetylacetonate and inorganic base is 1: 0.05-0.15: 2.0 to 2.5.
8. The method for synthesizing 4- (2-pyridyl) benzonitrile according to claim 1, 2 or 3, wherein the method further comprises a post-treatment after the reaction is finished, wherein the post-treatment comprises distilling the reaction solution to remove the solvent to obtain a corresponding concentrate, adding water and a water-insoluble solvent to the concentrate, stirring, standing, layering, collecting an organic layer, and then crystallizing to obtain the corresponding compound, namely 4- (2-pyridyl) benzonitrile of formula I.
9. The method for synthesizing 4- (2-pyridyl) benzonitrile according to claim 8, wherein the water-insoluble solvent is one or more selected from the group consisting of ethyl acetate, dichloromethane and chloroform.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101638352A (en) * | 2009-08-14 | 2010-02-03 | 大连理工大学 | Aryl-replaced nitrogen heterocyclic compound preparation method |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101638352A (en) * | 2009-08-14 | 2010-02-03 | 大连理工大学 | Aryl-replaced nitrogen heterocyclic compound preparation method |
Non-Patent Citations (3)
| Title |
|---|
| DANIEL TRAWNY，等: "The Side Chain Makes the Difference: Investigation of the 2D Self-Assembly of 1,3,5-Tris[4-(4-pyridinyl)phenyl]benzene Derivatives by Scanning Tunneling Microscopy", 《EUR. J. ORG. CHEM.》 * |
| 何川: "过渡金属铜和银参与的碳-氮、碳-碳偶联反应及其机理研究", 《武汉大学博士学位论文》 * |
| 赵临襄, 中国医药科技出版社 * |
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