CN105439901A - Preparation method of 2-cyano-4'-methyl biphenyl - Google Patents
Preparation method of 2-cyano-4'-methyl biphenyl Download PDFInfo
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- CN105439901A CN105439901A CN201510776200.0A CN201510776200A CN105439901A CN 105439901 A CN105439901 A CN 105439901A CN 201510776200 A CN201510776200 A CN 201510776200A CN 105439901 A CN105439901 A CN 105439901A
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- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
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Abstract
The invention discloses a preparation method of 2-cyano-4'-methyl biphenyl. In the existence of a reaction solvent and a catalyst, the Suzuki coupling reaction of chlorobenzonitrile and methylbenzeneboronic acid is performed, the catalyst is polystyrene-triphenylphosphine supported palladium, the reaction solvent is EtOH/H2O, and the volume ratio of EtOH/H2O is (4 to 1) to (1 to 4). The preparation method sequentially comprises the following steps: (1) adding chlorobenzonitrile, methylbenzeneboronic acid and alkali into the reaction solvent, heating until the refluxing, adding the catalyst, and performing the reaction under the refluxing condition; (2) detecting by using TLC in the reaction process, and after the reaction is ended, performing the suction filtration to respectively obtain filtrate and a filter cake; and adding water into the filtrate, washing an obtained organic phase with a saturated saline solution, drying with anhydrous sodium sulfate, and carrying out the column chromatography isolation to obtain 2-cyano-4'-methyl biphenyl.
Description
Technical field
The invention belongs to the synthesis technique of husky smooth class antihypertensive drug intermediates, relate to a kind of synthetic method of 2-Cyano-4 '-methylbiphenyl.
Background technology
2-Cyano-4 '-methylbiphenyl, have another name called sartanbiphenyl, English name: 2-Cyano-4 '-methylbiphenyl, structural formula:
2-Cyano-4 '-methylbiphenyl is the key intermediate preparing husky smooth class antihypertensive drug, and at present the general method of synthesis 2-Cyano-4 '-methylbiphenyl is o-chloro benzonitrile and to the Suzuki linked reaction between methyl-boron-dihydroxide.This reaction has reaction conditions gentleness, productive rate high and raw material economics and the advantage such as to be easy to get, and has purposes widely in multiple fields such as chemical industry, medicine, agricultural chemicals.
Most of catalyst system of Suzuki linked reaction have all used part, these part major parts are to air and water sensitive, reaction medium toxicity used is large (as 1, 4-dioxane, toluene etc.), temperature of reaction is higher, and these catalyst system can not recycle, what be unfavorable for Green Chemistry advocates (DavidE.Bergbreiter, PhilipL.Osburn, AllanWilson, ErinM.Sink.J.Am.Chem.Soc.2000, 122, 9058-9064.MasatoNishimura, MasatoUeda, NorioMiyaura.Tetrahedron, 2002, 58, 5779-5787).
In recent years, document reports again does not need part, can be used for the catalyst system of Suzuki coupling, good catalytic activity is also achieved to the linked reaction of o-chloro benzonitrile and aryl boric acid, but it is large that this catalyst system is still faced with reaction medium toxicity, shortcoming (the Yu-LongZhao such as temperature of reaction is high and can not recycle, YouLi, Shui-MingLi, etal.Adv.Synth.Catal.2011,353,1543-1550.Yong-BoZhou, Zhen-XingXi, Wan-ZhiChen, Da-QiWang.Organometallics, 2008,27,5911-5920).
The development of heterogeneous catalysis technology improves more greatly the shortcoming of traditional catalyst, (the ValericaPandarus such as Pagliaro, RosariaCiriminna, MarioPagliaro, etal.Org.Process.Res.Dev.2013,17,1492-1497) then utilize the organic silica loaded palladium catalyst catalysis o-chloro benzonitrile of diphenylphosphine ligand functional groups and the Suzuki linked reaction to methylphenylboronic acid, prepared 2-Cyano-4 '-methylbiphenyl compound, and this catalyzer can recycle 4 times.But aforesaid method solvent for use is ethanol, alkali used is salt of wormwood, and the preparation of its catalyzer is complicated, and use cost is high, and recycling is poor, and therefore application is in the industry restricted.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of preparation method of with low cost, 2-Cyano-4 '-methylbiphenyl that yield is higher.
In order to solve the problems of the technologies described above, the invention provides a kind of preparation method of 2-Cyano-4 '-methylbiphenyl, under reaction solvent and catalyzer existent condition, carry out o-chloro benzonitrile and the Suzuki linked reaction to methylphenylboronic acid, described catalyzer is polystyrene-triphenylphosphine supported palladium, and described reaction solvent is EtOH/H
2o, described EtOH/H
2the volume ratio of O is 4:1 ~ 1:4; Carry out following steps successively:
1), in reaction solvent, add o-chloro benzonitrile, to methylphenylboronic acid and alkali, after being heated to backflow, then adding catalyzer and react under reflux conditions;
Described o-chloro benzonitrile be 1:1.25 to the mol ratio of methylphenylboronic acid, the mol ratio of described o-chloro benzonitrile and alkali is 1:2; The catalyzer of every 10mmol o-chloro benzonitrile adapted 41.4mg;
2), reaction process TLC detects, and after reaction terminates (disappearances of TLC detection reaction liquid o-chloro benzonitrile), suction filtration, respectively must filtrate and filter cake; Add water in filtrate, gained organic phase uses anhydrous sodium sulfate drying with after saturated common salt water washing, and column chromatography for separation, obtains 2-Cyano-4 '-methylbiphenyl.
Remarks illustrate: the reaction solvent of every 10mmol o-chloro benzonitrile adapted 100 ~ 150mL.
Improvement as the preparation method of 2-Cyano-4 '-methylbiphenyl of the present invention: filter cake is through ethyl acetate, reaction solvent washing, dry under room temperature, reclaims the polystyrene-triphenylphosphine supported palladium obtained as catalyzer.
Further improvement as the preparation method of 2-Cyano-4 '-methylbiphenyl of the present invention: described alkali is salt of wormwood, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate or cesium carbonate.Optimum is sodium carbonate.
Further improvement as the preparation method of 2-Cyano-4 '-methylbiphenyl of the present invention: reaction solvent preferred volume ratio is the EtOH/H of 1:1
2o (v/v, 1/1).
Technical scheme of the present invention is specific as follows: under solvent and catalyzer existent condition, by o-chloro benzonitrile and the method being prepared by the Suzuki linked reaction of methylphenylboronic acid to 2-Cyano-4 '-methylbiphenyl, in atmosphere, successively by 100mL solvent EtOH/H
2o, the o-chloro benzonitrile of 10mmol, 12.5mmol joins in 250mL there-necked flask to the alkali of methylphenylboronic acid and 20mmol, be heated to backflow, add 41.4mg polystyrene-triphenylphosphine loaded palladium catalyst, reaction process TLC detects, after reaction terminates, suction filtration, 3 × 20mL ethyl acetate is washed, 2 × 4mLEtOH/H
2o (v/v, 1/1) washs, dry under room temperature, reclaims and obtains polystyrene-triphenylphosphine loaded palladium catalyst.Filtrate adds the extraction of 40mL water, organic phase 20mL saturated common salt water washing, and organic phase anhydrous sodium sulfate drying filters, and filtrate concentrates, and column chromatography for separation, obtains 2-Cyano-4 '-methylbiphenyl.The catalyzer reclaimed can recycle.
The preparation method of 2-Cyano-4 '-methylbiphenyl provided by the invention does not use part, does not need protection of inert gas, reaction medium is environmentally friendly, reaction conditions is gentle, catalyzer can catalysis Suzuki linked reaction and can recycling efficiently, all has a wide range of applications in multiple fields such as chemical industry, medicine, agricultural chemicals.
Embodiment
Below will the present invention is further illustrated by embodiment.
The preparation method of embodiment 1, polystyrene-triphenylphosphine:
By phenylbenzene (4-ethenylphenyl) phosphine 2.0g (6.9mmol), vinylbenzene 2.9ml (27.6mmol), 3mL toluene adds in 10mL there-necked flask, dissolves, adds 78.0mgAIBN (Diisopropyl azodicarboxylate), N
2under protection, be heated with stirring to 70 DEG C of reaction 24h, TLC detection reaction liquid phenylbenzene (4-ethenylphenyl) phosphines and disappear; Concentrated except desolventizing, gained solid 6mLTHF (tetrahydrofuran (THF)) dissolves, drip (within about 5 minutes, dropwising) in the 60ml methyl alcohol of 0 DEG C, separate out white solid, suction filtration, obtain white powder polystyrene-triphenylphosphine compound (III) 4.73g, yield: 97%.
The preparation method of embodiment 2, polystyrene-triphenylphosphine loaded palladium catalyst:
1g compound (III), 10mlTHF are joined in 25ml reaction flask, is warming up to 50 DEG C, then add 84.0mg (0.375mmol) Pd (OAc)
2continue reaction 4h at 50 DEG C after, be cooled to 0 DEG C, this solution is dripped (within about 10 minutes, dropwising) in the 20ml hexane of 0 DEG C, stirred at ambient temperature 12h, suction filtration, filter cake 5ml methanol wash column, obtain 1.05g black solid polystyrene-triphenylphosphine supported palladium compound, yield: 97%.
The preparation method of embodiment 3,2-Cyano-4 '-methylbiphenyl:
O-chloro benzonitrile 1.376g (10mmol), joins methylphenylboronic acid 1.700g (12.5mmol) and anhydrous sodium carbonate 2.764g (20mmol) and fills 100mLEtOH/H
2in the there-necked flask of O (v/v, 1/1), reflux, add 41.4mg polystyrene-triphenylphosphine loaded palladium catalyst, continue reflux 1h, TLC detection reaction liquid o-chloro benzonitrile and disappear, suction filtration, filter cake 3 × 20ml ethyl acetate washing, 2 × 4mlEtOH/H
2o (v/v, 1/1) washs, and is dried to constant weight under room temperature, reclaims and obtains polystyrene-triphenylphosphine loaded palladium catalyst 40.2mg, the rate of recovery: 97%; The filtrate of suction filtration gained adds the extraction of 40ml water, organic phase (being positioned at upper strata) 20ml saturated common salt water washing, and the organic phase after washing is with 2.0g anhydrous sodium sulfate drying half an hour, concentrated, column chromatography for separation, obtains 2-Cyano-4 '-methylbiphenyl 1.78g, yield: 92%.White powder; Fusing point: 47.2-48.9 DEG C;
1hNMR (500MHz, CDCl
3) δ 7.75 (d, J=7.9Hz, 1H), 7.63 (d, J=7.9Hz, 1H), 7.50 (d, J=7.9Hz, 1H), 7.46 (m, 2H), 7.41 (m, 1H), 7.30 (d, J=7.9Hz, 2H), 2.42 (s, 3H) .HRMS (ESI): m/zcalcdforC
14h
11n [M+H]
+: 194.0970, found:194.0966.
Reclaiming by suction filtration the catalyzer obtained can recycle.
Described column chromatography for separation is specially: adopt in-built 40g200-300 object silica gel, using sherwood oil as elutriant, flow rate control is 3mL/min, collects the elutriant of 30min-50min; Then remove after desolventizing through Rotary Evaporators, obtain 2-Cyano-4 '-methylbiphenyl 1.78g, yield: 92%.
Be below the control experiment of embodiment 3 under different condition:
Comparative example 3-1, make anhydrous sodium carbonate into Anhydrous potassium carbonate, molar weight is constant, and all the other are with embodiment 3, obtains 2-Cyano-4 '-methylbiphenyl 1.58g, yield: 82%.
Comparative example 3-2, make anhydrous sodium carbonate into sodium hydroxide, molar weight is constant, and all the other are with embodiment 3, obtains 2-Cyano-4 '-methylbiphenyl 1.23g, yield: 64%.
Comparative example 3-3, make anhydrous sodium carbonate into potassium hydroxide, molar weight is constant, and all the other are with embodiment 3, obtains 2-Cyano-4 '-methylbiphenyl 0.98g, yield: 51%.
Comparative example 3-4, make anhydrous sodium carbonate into sodium bicarbonate, molar weight is constant, and all the other are with embodiment 3, obtains 2-Cyano-4 '-methylbiphenyl 1.56g, yield: 81%.
Comparative example 3-5, make anhydrous sodium carbonate into cesium carbonate, molar weight is constant, and all the other are with embodiment 3, obtains 2-Cyano-4 '-methylbiphenyl 0.79g, yield: 41%.
Comparative example 3-6, by EtOH/H
2o (v/v, 1/1) makes EtOH/H into
2o (v/v, 4/1), cumulative volume is constant, and all the other are with embodiment 3, obtains 2-Cyano-4 '-methylbiphenyl 1.33g, yield: 69%.
Comparative example 3-7, by EtOH/H
2o (v/v, 1/1) makes EtOH/H into
2o (v/v, 1/4), cumulative volume is constant, and all the other are with embodiment 3, obtains 2-Cyano-4 '-methylbiphenyl 1.08g, yield: 56%.
Comparative example 3-8, make polystyrene-triphenylphosphine loaded palladium catalyst into PPh
3, molar weight is constant, and all the other, with embodiment 3, do not obtain product.
Comparative example 3-9, make polystyrene-triphenylphosphine loaded palladium catalyst into Pd (OAc)
2, molar weight is constant, and all the other, with embodiment 3, do not obtain product.
Comparative example 3-10, make polystyrene-triphenylphosphine loaded palladium catalyst into Pd (PPh
3)
4, molar weight is constant, and all the other are with embodiment 3, obtains 2-Cyano-4 '-methylbiphenyl 0.71g, yield: 37%.
Be below the recycling test of polystyrene-triphenylphosphine loaded palladium catalyst:
Comparative example 3-11, made into reclaim the catalyzer obtained in embodiment 3 by the polystyrene in embodiment 3-triphenylphosphine loaded palladium catalyst, molar weight is constant, and all the other are with embodiment 3, obtains 2-Cyano-4 '-methylbiphenyl 1.78g, yield: 92%.Recovery obtains polystyrene-triphenylphosphine loaded palladium catalyst 40.0mg, the rate of recovery 97%.
Comparative example 3-12, made into reclaim the catalyzer obtained in comparative example 3-11 by the polystyrene in embodiment 3-triphenylphosphine loaded palladium catalyst, molar weight is constant, and all the other are with embodiment 3, obtains 2-Cyano-4 '-methylbiphenyl 1.78g, yield: 92%.Recovery obtains polystyrene-triphenylphosphine loaded palladium catalyst 40.0mg, the rate of recovery 97%.
Comparative example 3-13, made into reclaim the catalyzer obtained in comparative example 3-12 by the polystyrene in embodiment 3-triphenylphosphine loaded palladium catalyst, molar weight is constant, and all the other are with embodiment 3, obtains 2-Cyano-4 '-methylbiphenyl 1.76g, yield: 91%.Recovery obtains polystyrene-triphenylphosphine loaded palladium catalyst 38.7mg, the rate of recovery 93%.
Comparative example 3-14, made into reclaim the catalyzer obtained in comparative example 3-13 by the polystyrene in embodiment 3-triphenylphosphine loaded palladium catalyst, molar weight is constant, and all the other are with embodiment 3, obtains 2-Cyano-4 '-methylbiphenyl 1.74g, yield: 90%.Recovery obtains polystyrene-triphenylphosphine loaded palladium catalyst 38.1mg, the rate of recovery 92%.
Comparative example 3-15, made into reclaim the catalyzer obtained in comparative example 3-14 by the polystyrene in embodiment 3-triphenylphosphine loaded palladium catalyst, molar weight is constant, and all the other are with embodiment 3, obtains 2-Cyano-4 '-methylbiphenyl 1.76g, yield: 89%.Recovery obtains polystyrene-triphenylphosphine loaded palladium catalyst 37.4mg, the rate of recovery 90%.
Finally, it is also to be noted that what enumerate above is only several specific embodiments of the present invention.Obviously, the invention is not restricted to above embodiment, many distortion can also be had.All distortion that those of ordinary skill in the art can directly derive from content disclosed by the invention or associate, all should think protection scope of the present invention.
Claims (4)
- The preparation method of 1.2-Cyano-4 '-methylbiphenyl, under reaction solvent and catalyzer existent condition, carry out o-chloro benzonitrile and the Suzuki linked reaction to methylphenylboronic acid, it is characterized in that: described catalyzer is polystyrene-triphenylphosphine supported palladium, and described reaction solvent is EtOH/H 2o, described EtOH/H 2the volume ratio of O is 4:1 ~ 1:4; Carry out following steps successively:1), in reaction solvent, add o-chloro benzonitrile, to methylphenylboronic acid and alkali, after being heated to backflow, then adding catalyzer and react under reflux conditions;Described o-chloro benzonitrile be 1:1.25 to the mol ratio of methylphenylboronic acid, the mol ratio of described o-chloro benzonitrile and alkali is 1:2; The catalyzer of every 10mmol o-chloro benzonitrile adapted 41.4mg;2), reaction process TLC detects, after reaction terminates, suction filtration, respectively filtrate and filter cake; Add water in filtrate, gained organic phase uses anhydrous sodium sulfate drying with after saturated common salt water washing, and column chromatography for separation, obtains 2-Cyano-4 '-methylbiphenyl.
- 2. the preparation method of 2-Cyano-4 '-methylbiphenyl according to claim 1, is characterized in that: filter cake is through ethyl acetate, reaction solvent washing, dry under room temperature, reclaims the polystyrene-triphenylphosphine supported palladium obtained as catalyzer.
- 3. the preparation method of 2-Cyano-4 '-methylbiphenyl according to claim 1 and 2, is characterized in that:Described alkali is salt of wormwood, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate or cesium carbonate.
- 4. the preparation method of the 2-Cyano-4 '-methylbiphenyl according to claim 1,2 or 3, is characterized in that: the EtOH/H of reaction solvent to be volume ratio be 1:1 2o.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112661666A (en) * | 2020-12-24 | 2021-04-16 | 南京工业大学 | Process for catalytically synthesizing 2-cyano-4' -methyl biphenyl |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104086456A (en) * | 2014-07-24 | 2014-10-08 | 宜春学院 | Synthesis method of sartanbiphenyl |
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| CN104086456A (en) * | 2014-07-24 | 2014-10-08 | 宜春学院 | Synthesis method of sartanbiphenyl |
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| 姚其正 等: "2-氰基2-4′-甲基联苯合成方法的研究", 《药学进展》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112661666A (en) * | 2020-12-24 | 2021-04-16 | 南京工业大学 | Process for catalytically synthesizing 2-cyano-4' -methyl biphenyl |
| CN112661666B (en) * | 2020-12-24 | 2023-04-21 | 南京工业大学 | Process for catalytic synthesis of 2-cyano-4' -methyl biphenyl |
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