CN108129351A - A kind of preparation method of 4 '-bromomethyl -2- cyanobiphenyls - Google Patents
A kind of preparation method of 4 '-bromomethyl -2- cyanobiphenyls Download PDFInfo
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- CN108129351A CN108129351A CN201711444264.6A CN201711444264A CN108129351A CN 108129351 A CN108129351 A CN 108129351A CN 201711444264 A CN201711444264 A CN 201711444264A CN 108129351 A CN108129351 A CN 108129351A
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- cyanobiphenyls
- reaction
- bromomethyl
- bromide
- preparation
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- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 52
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 46
- XTEGARKTQYYJKE-UHFFFAOYSA-M Chlorate Chemical compound [O-]Cl(=O)=O XTEGARKTQYYJKE-UHFFFAOYSA-M 0.000 claims abstract description 20
- 239000002904 solvent Substances 0.000 claims abstract description 18
- SXDBWCPKPHAZSM-UHFFFAOYSA-N bromic acid Chemical compound OBr(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-N 0.000 claims abstract description 17
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims abstract description 16
- SXDBWCPKPHAZSM-UHFFFAOYSA-M bromate Inorganic materials [O-]Br(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-M 0.000 claims abstract description 16
- 239000012043 crude product Substances 0.000 claims abstract description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000003960 organic solvent Substances 0.000 claims abstract description 9
- 238000001514 detection method Methods 0.000 claims abstract description 8
- 239000012044 organic layer Substances 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 claims description 14
- XUXNAKZDHHEHPC-UHFFFAOYSA-M sodium bromate Chemical compound [Na+].[O-]Br(=O)=O XUXNAKZDHHEHPC-UHFFFAOYSA-M 0.000 claims description 12
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical group [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 claims description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 9
- 238000005893 bromination reaction Methods 0.000 claims description 8
- LFFIEVAMVPCZNA-UHFFFAOYSA-N 2-[4-(bromomethyl)phenyl]benzonitrile Chemical group C1=CC(CBr)=CC=C1C1=CC=CC=C1C#N LFFIEVAMVPCZNA-UHFFFAOYSA-N 0.000 claims description 7
- BZSXEZOLBIJVQK-UHFFFAOYSA-N 2-methylsulfonylbenzoic acid Chemical compound CS(=O)(=O)C1=CC=CC=C1C(O)=O BZSXEZOLBIJVQK-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 6
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 claims description 6
- 235000019396 potassium bromate Nutrition 0.000 claims description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 6
- XWNSFEAWWGGSKJ-UHFFFAOYSA-N 4-acetyl-4-methylheptanedinitrile Chemical compound N#CCCC(C)(C(=O)C)CCC#N XWNSFEAWWGGSKJ-UHFFFAOYSA-N 0.000 claims description 5
- 239000004153 Potassium bromate Substances 0.000 claims description 5
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 5
- 229940094037 potassium bromate Drugs 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 125000003944 tolyl group Chemical group 0.000 claims description 5
- VKJKEPKFPUWCAS-UHFFFAOYSA-M potassium chlorate Chemical compound [K+].[O-]Cl(=O)=O VKJKEPKFPUWCAS-UHFFFAOYSA-M 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical class CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 3
- WCLKSQYCWXZMGX-UHFFFAOYSA-N 1,2,3,4-tetrabromo-5,6-dimethoxybenzene Chemical compound COC1=C(Br)C(Br)=C(Br)C(Br)=C1OC WCLKSQYCWXZMGX-UHFFFAOYSA-N 0.000 claims description 3
- CBQMKYHLDADRLN-UHFFFAOYSA-N 7-methylhypoxanthine Chemical compound N1C=NC(=O)C2=C1N=CN2C CBQMKYHLDADRLN-UHFFFAOYSA-N 0.000 claims description 3
- 239000004154 Calcium bromate Substances 0.000 claims description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 3
- 230000031709 bromination Effects 0.000 claims description 3
- 235000019397 calcium bromate Nutrition 0.000 claims description 3
- 229910001622 calcium bromide Inorganic materials 0.000 claims description 3
- YALMXYPQBUJUME-UHFFFAOYSA-L calcium chlorate Chemical compound [Ca+2].[O-]Cl(=O)=O.[O-]Cl(=O)=O YALMXYPQBUJUME-UHFFFAOYSA-L 0.000 claims description 3
- WGEFECGEFUFIQW-UHFFFAOYSA-L calcium dibromide Chemical compound [Ca+2].[Br-].[Br-] WGEFECGEFUFIQW-UHFFFAOYSA-L 0.000 claims description 3
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 3
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 3
- XQHAGELNRSUUGU-UHFFFAOYSA-M lithium chlorate Chemical compound [Li+].[O-]Cl(=O)=O XQHAGELNRSUUGU-UHFFFAOYSA-M 0.000 claims description 3
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 claims description 3
- 229910001623 magnesium bromide Inorganic materials 0.000 claims description 3
- RNUHOKZSYYKPPI-UHFFFAOYSA-L magnesium;dibromate Chemical compound [Mg+2].[O-]Br(=O)=O.[O-]Br(=O)=O RNUHOKZSYYKPPI-UHFFFAOYSA-L 0.000 claims description 3
- NNNSKJSUQWKSAM-UHFFFAOYSA-L magnesium;dichlorate Chemical compound [Mg+2].[O-]Cl(=O)=O.[O-]Cl(=O)=O NNNSKJSUQWKSAM-UHFFFAOYSA-L 0.000 claims description 3
- KXKVLQRXCPHEJC-UHFFFAOYSA-N methyl acetate Chemical class COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 3
- 239000003208 petroleum Substances 0.000 claims description 3
- 239000000463 material Substances 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 abstract description 7
- 239000000047 product Substances 0.000 abstract description 7
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 5
- 239000006227 byproduct Substances 0.000 abstract description 4
- 125000001246 bromo group Chemical group Br* 0.000 abstract description 3
- 230000007797 corrosion Effects 0.000 abstract description 3
- 238000005260 corrosion Methods 0.000 abstract description 3
- 230000007613 environmental effect Effects 0.000 abstract description 3
- 230000007812 deficiency Effects 0.000 abstract description 2
- WLPATYNQCGVFFH-UHFFFAOYSA-N 2-phenylbenzonitrile Chemical group N#CC1=CC=CC=C1C1=CC=CC=C1 WLPATYNQCGVFFH-UHFFFAOYSA-N 0.000 abstract 3
- 125000005997 bromomethyl group Chemical group 0.000 abstract 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract 1
- 238000000034 method Methods 0.000 description 7
- 239000000376 reactant Substances 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 239000003651 drinking water Substances 0.000 description 4
- 235000020188 drinking water Nutrition 0.000 description 4
- CUILPNURFADTPE-UHFFFAOYSA-N hypobromous acid Chemical compound BrO CUILPNURFADTPE-UHFFFAOYSA-N 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 3
- 238000007792 addition Methods 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000000400 angiotensin II type 1 receptor blocker Substances 0.000 description 2
- XTEGARKTQYYJKE-UHFFFAOYSA-N chloric acid Chemical compound OCl(=O)=O XTEGARKTQYYJKE-UHFFFAOYSA-N 0.000 description 2
- 229940005991 chloric acid Drugs 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000036632 reaction speed Effects 0.000 description 2
- 208000001953 Hypotension Diseases 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 description 1
- SULWMEGSVQCTSK-UHFFFAOYSA-N diethyl hydrogen phosphite Chemical class CCOP(O)OCC SULWMEGSVQCTSK-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 208000021822 hypotensive Diseases 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- OCATYIAKPYKMPG-UHFFFAOYSA-M potassium bromate Chemical class [K+].[O-]Br(=O)=O OCATYIAKPYKMPG-UHFFFAOYSA-M 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 231100000004 severe toxicity Toxicity 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
Abstract
The present invention relates to pharmaceutical chemistry technical fields, specifically disclose a kind of preparation method of 4 ' bromomethyl, 2 cyanobiphenyl, include the following steps：2 cyanobiphenyl of organic solvent, water and 4 ' methyl is sequentially added into reaction bulb, then add in Bromide, bromate or chlorate, it is stirred at room temperature uniformly, controlling reaction temperature is at 15~25 DEG C, hydrochloric acid solution is added dropwise, time for adding is 5~20 hours, and drop finishes, controlling 15~45 DEG C of temperature, the reaction was continued 1 hour, TLC detection reaction ends；Reaction terminates layering, and organic layer is concentrated to dryness, and obtains crude product；Crude product is dissolved in solvent and is recrystallized, obtains 4 ' bromomethyl, 2 cyanobiphenyl sterling.The present invention overcomes the deficiencies in the prior art, and reaction condition is mild, and reaction selectivity is high, and by-product is few, and equipment corrosion is small, easy to operate, at low cost, environmental protection pressure is small, and product can be easily separated, bromide reagent is easy to operate safely, and bromine atoms utilization rate is high, is easy to industrialized production, and product purity is high.
Description
Technical field
The present invention relates to pharmaceutical chemistry technical fields, particularly belong to a kind of preparation side of 4 '-bromomethyl -2- cyanobiphenyls
Method.
Background technology
Sartans are antihypertensive first-line treatment medications, have completely new Hypotensive Mechanism, decompression is steady, curative effect
Well, long action time, patient tolerability are good.Most of sartans are all needed through intermediate 4 '-bromomethyl -2- cyanobiphenyls
To prepare.Presently disclosed synthetic method has following several：
US5621134 describes 4 '-methyl -2- cyanobiphenyls in the presence of free radical causes reagent, passes through cheap bromine
Element prepares 4 '-bromomethyl -2- cyanobiphenyls.But this method generates a large amount of hydrogen bromides during the reaction, the by-product
It can inhibit the progress of bromination reaction, reduce bromination reaction speed or even reaction is incomplete, therefore is not suitable for commercially producing.
CN101200455A discloses 4 '-methyl -2- cyanobiphenyls and product is obtained by the reaction with bromating agent under illumination condition,
But in large-scale production process, luminous energy is difficult to be introduced into inside reactor and bottom, is not suitable for industrialized production.
CN101597243A is reported using diethyl phosphite, and the dibromide in bromination reaction is converted into monobromination
Object.The method use a large amount of diethyl phosphites, increase production cost, are not suitable for commercially producing.
US6214999 is disclosed synthesizes 4 '-bromomethyl -2- cyanobiphenyls by the method for oxybromination.It uses respectively
HBr/NaBrO3, Br2/NaBrO3 oxybromination system, wherein HBr and Br2 belong to the high-risk reagent of strong corrosive and severe toxicity, right
Equipment is corroded, and operating process is dangerous, and this method industrial application value is not high.
For WO2011073703 by NaBrO3/NaHSO3 oxybromination systems, NaBrO3 dosages are three times of amount of substrate, are used
Amount is big, of high cost, is not suitable for commercially producing.
To sum up, preparation 4 '-bromomethyl -2- cyanobiphenyls are slow there are reaction speed, and industrial application value is small, production cost
Height corrodes equipment, and operation is dangerous, of high cost, is not suitable for industrialized production.It is insufficient.
Invention content
The object of the present invention is to provide a kind of preparation methods of 4 '-bromomethyl -2- cyanobiphenyls, overcome the prior art
Deficiency, reaction condition is mild, and reaction selectivity is high, and by-product is few, and equipment corrosion is small, easy to operate, at low cost, environmental protection pressure
Power is small, and product can be easily separated, and bromide reagent is easy to operate safely, and bromine atoms utilization rate is high, is easy to industrialized production, product purity
It is high.
To solve the above problems, the technical solution used in the present invention is as follows：
A kind of preparation method of 4 '-bromomethyl -2- cyanobiphenyls, it is characterised in that：Include the following steps：
Step 1 sequentially adds organic solvent, water and 4 '-methyl -2- cyanobiphenyls into reaction bulb, then adds in bromination
Salt, bromate or chlorate are stirred at room temperature uniformly, and hydrochloric acid solution, time for adding is added dropwise at 15~25 DEG C in controlling reaction temperature
It it is 5~20 hours, drop finishes, and the reaction was continued 1 hour for 15~45 DEG C of temperature of control, TLC detection reaction ends；
Step 2, reaction terminate layering, and organic layer is concentrated to dryness, and obtains crude product；
Crude product is dissolved in solvent and recrystallized by step 3, obtains 4 '-bromomethyl -2- cyanobiphenyl sterlings；
During the addition hydrochloric acid, control system temperature is no more than 30 DEG C.
The concentration of hydrochloric acid is 15~30%.
Further, the hydrochloric acid time for adding is 10~15 hours.
Further, the recrystallization solvent for use is toluene or ethyl acetate or t-butyl methyl ether or water.
Further, the recrystallization solvent for use is toluene.
Further, the Bromide is sodium bromide or potassium bromide or lithium bromide or magnesium bromide or calcium bromide.
Further, the Bromide is sodium bromide or potassium bromide.
Further, the bromate is sodium bromate or potassium bromate or lithium bromate or magnesium bromate or calcium bromate or sodium chlorate or chlorine
Sour potassium or lithium chlorate or magron or calcium chlorate.
Further, the bromate is sodium bromate or potassium bromate or sodium chlorate or potassium chlorate.
Further, the organic solvent is dichloromethane or dichloroethanes or carbon tetrachloride or chlorobenzene or hexane or heptane
Or hexamethylene or petroleum ether or methyl acetate or ethyl acetate or Ethyl formate.
Further, the organic solvent is dichloromethane.
Further, the reaction mass molar ratio is 4 '-methyl -2- cyanobiphenyls：Bromide：Bromate or chlorate：
Hydrochloric acid is 1：0.6~1.2：0.3~0.8：1.0~2.0.
Further, the reaction mass molar ratio is 4 '-methyl -2- cyanobiphenyls：Bromide：Bromate or chlorate：
Hydrochloric acid is 1：0.6~0.7：0.3~0.4：1.0~1.2.
Further, reactant quality is than 4 '-methyl -2- cyanobiphenyls：Solvent：Water is 1：2~6：2~6.
Further, reactant quality is than 4 '-methyl -2- cyanobiphenyls：Solvent：Water is 1：3~4：3~4.
Preparation principle：In acid condition, Bromide and bromate or chloric acid reactant salt generate hypobromous acid, and hypobromous acid is again
Bromination reaction occurs with 4 '-methyl -2- cyanobiphenyls and synthesizes 4 '-bromomethyl -2- cyanobiphenyls, chemical equation is as follows：
2NaBr+NaBrO3+3HCl→3BrOH+3NaCl
Or 3NaBr+NaClO3+3HCl→3BrOH+4NaCl
Compared with prior art, implementation result of the invention is as follows by the present invention：
A kind of preparation method of 4 '-bromomethyl -2- cyanobiphenyls of the present invention, reaction condition is mild, reaction selectivity
Height, by-product is few, and equipment corrosion is small, easy to operate, at low cost, and environmental protection pressure is small, and product can be easily separated, bromide reagent safety
Easy to operate, bromine atoms utilization rate is high, is easy to industrialized production, and product purity is high.
Specific embodiment
With reference to embodiment, the invention will be further described, but the present invention is not limited to these instances, and is being de-
Under the premise of from present inventive concept, carried out by it is any improvement be within the scope of the present invention.
Embodiment 1
A kind of preparation method of 4 '-bromomethyl -2- cyanobiphenyls of the present invention, it is characterised in that：Include the following steps：
Step 1 sequentially adds organic solvent, water and 4 '-methyl -2- cyanobiphenyls into reaction bulb, then adds in bromination
Salt, bromate or chlorate are stirred at room temperature uniformly, and hydrochloric acid solution is added dropwise at 15~25 DEG C in controlling reaction temperature, and time for adding is
5~20 hours, drop finished, and the reaction was continued 1 hour for 15~45 DEG C of temperature of control, TLC detection reaction ends；
Step 2, reaction terminate layering, and organic layer is concentrated to dryness, and obtains crude product；
Crude product is dissolved in solvent and recrystallized by step 3, obtains 4 '-bromomethyl -2- cyanobiphenyl sterlings；
During the addition hydrochloric acid, control system temperature is no more than 30 DEG C.
The concentration of hydrochloric acid is 15~30%.
Further, the hydrochloric acid time for adding is 10~15 hours.
Further, the recrystallization solvent for use is toluene or ethyl acetate or t-butyl methyl ether or water.
Further, the recrystallization solvent for use is toluene.
Further, the Bromide is sodium bromide or potassium bromide or lithium bromide or magnesium bromide or calcium bromide.
Further, the Bromide is sodium bromide or potassium bromide.
Further, the bromate is sodium bromate or potassium bromate or lithium bromate or magnesium bromate or calcium bromate or sodium chlorate or chlorine
Sour potassium or lithium chlorate or magron or calcium chlorate.
Further, the bromate is sodium bromate or potassium bromate or sodium chlorate or potassium chlorate.
Further, the organic solvent is dichloromethane or dichloroethanes or carbon tetrachloride or chlorobenzene or hexane or heptane
Or hexamethylene or petroleum ether or methyl acetate or ethyl acetate or Ethyl formate.
Further, the organic solvent is dichloromethane.
Further, the reaction mass molar ratio is 4 '-methyl -2- cyanobiphenyls：Bromide：Bromate or chlorate：
Hydrochloric acid is 1：0.6~1.2：0.3~0.8：1.0~2.0.
Further, the reaction mass molar ratio is 4 '-methyl -2- cyanobiphenyls：Bromide：Bromate or chlorate：
Hydrochloric acid is 1：0.6~0.7：0.3~0.4：1.0~1.2.
Further, reactant quality is than 4 '-methyl -2- cyanobiphenyls：Solvent：Water is 1：2~6：2~6.
Embodiment 2
600g dichloromethane, 600g drinking water, 193g sartanbiphenyls (1eq) are sequentially added into 3L reaction bulbs, is then added
Enter 69g sodium bromides (0.67eq), 50g sodium bromates (0.33eq), be stirred at room temperature uniformly, 15~25 DEG C of controlling reaction temperature is added dropwise
200g hydrochloric acid solutions (concentration 20%, 1.1eq), time for adding about 12 hours, drop finish, and the reaction was continued 1 for 35~45 DEG C of temperature of control
Hour, TLC detection reaction ends.Organic phase is separated, solvent evaporated obtains crude product 280g.Crude product is dissolved in into weight in about 500 g toluene
Crystallization, obtains 4 '-bromomethyl -2- cyanobiphenyl sterling 237g, yield 87%.
Embodiment 3
600g dichloromethane, 600g drinking water, 193g sartanbiphenyls (1eq) are sequentially added into 3L reaction bulbs, is then added
Enter 79g potassium bromide (0.67eq), 56g potassium bromates (0.33eq), be stirred at room temperature uniformly, 15~25 DEG C of controlling reaction temperature is added dropwise
200g hydrochloric acid solutions (concentration 20%, 1.1eq), time for adding about 12 hours, drop finish, and the reaction was continued 1 for 35~45 DEG C of temperature of control
Hour, TLC detection reaction ends.Organic phase is separated, solvent evaporated obtains crude product 285g.Crude product is dissolved in into weight in about 500 g toluene
Crystallization, obtains 4 '-bromomethyl -2- cyanobiphenyl sterling 245g, yield 90%.
Embodiment 4
600g dichloromethane, 600g drinking water, 193g sartanbiphenyls (1eq) are sequentially added into 3L reaction bulbs, is then added
Enter 103g sodium bromides (1eq), 35g sodium chlorate (0.33eq), be stirred at room temperature uniformly, 15~25 DEG C of controlling reaction temperature is added dropwise
200g hydrochloric acid solutions (concentration 20%, 1.1eq), time for adding about 12 hours, drop finish, and the reaction was continued 1 for 35~45 DEG C of temperature of control
Hour, TLC detection reaction ends.Organic phase is separated, solvent evaporated obtains crude product 278g.Crude product is dissolved in into weight in about 500 g toluene
Crystallization, obtains 4 '-bromomethyl -2- cyanobiphenyl sterling 223g, yield 82%.
Embodiment 5
600g dichloromethane, 600g drinking water, 193g sartanbiphenyls (1eq) are sequentially added into 3L reaction bulbs, is then added
Enter 103g potassium bromide (1eq), 41g potassium chlorate (0.33eq), be stirred at room temperature uniformly, 15~25 DEG C of controlling reaction temperature is added dropwise
200g hydrochloric acid solutions (concentration 20%, 1.1eq), time for adding about 12 hours, drop finish, and the reaction was continued 1 for 35~45 DEG C of temperature of control
Hour, TLC detection reaction ends.Organic phase is separated, solvent evaporated obtains crude product 282g.Crude product is dissolved in into weight in about 500 g toluene
Crystallization, obtains 4 '-bromomethyl -2- cyanobiphenyl sterling 234g, yield 86%
A kind of preparation method of 4 '-bromomethyl -2- cyanobiphenyls of the present invention, preparation principle：In acid condition, bromine
Salt dissolving and bromate or chloric acid reactant salt, generate hypobromous acid, and with 4 '-methyl -2- cyanobiphenyls bromination reaction occurs for hypobromous acid again
4 '-bromomethyl -2- cyanobiphenyls are synthesized, chemical equation is as follows：
2NaBr+NaBrO3+3HCl→3BrOH+3NaCl
Or 3NaBr+NaClO3+3HCl→3BrOH+4NaCl
Above content is only to present inventive concept example and explanation, affiliated those skilled in the art couple
Described specific embodiment does various modifications or additions or substitutes in a similar way, without departing from invention
Conceive or surmount range defined in the claims, be within the scope of protection of the invention.
Claims (10)
1. a kind of preparation method of 4 '-bromomethyl -2- cyanobiphenyls, it is characterised in that：Include the following steps：
Step 1 sequentially adds organic solvent, water and 4 '-methyl -2- cyanobiphenyls into reaction bulb, then add in Bromide,
Bromate or chlorate are stirred at room temperature uniformly, and hydrochloric acid solution is added dropwise at 15~25 DEG C in controlling reaction temperature, time for adding for 5~
20 hours, drop finished, and the reaction was continued 1 hour for 15~45 DEG C of temperature of control, TLC detection reaction ends；
Step 2, reaction terminate layering, and organic layer is concentrated to dryness, and obtains crude product；
Crude product is dissolved in solvent and recrystallized by step 3, obtains 4 '-bromomethyl -2- cyanobiphenyl sterlings；
During the addition hydrochloric acid, control system temperature is no more than 30 DEG C；
The concentration of hydrochloric acid is 15~30%.
2. a kind of preparation method of 4 '-bromomethyl -2- cyanobiphenyls according to claim 1, it is characterised in that：The hydrochloric acid
Time for adding is 10~15 hours.
3. a kind of preparation method of 4 '-bromomethyl -2- cyanobiphenyls according to claim 1, it is characterised in that：The heavy knot
Brilliant solvent for use is toluene or ethyl acetate or t-butyl methyl ether or water.
4. a kind of preparation method of 4 '-bromomethyl -2- cyanobiphenyls according to claim 1, it is characterised in that：The bromination
Salt is sodium bromide or potassium bromide or lithium bromide or magnesium bromide or calcium bromide.
5. a kind of preparation method of 4 '-bromomethyl -2- cyanobiphenyls according to claim 1, it is characterised in that：The bromic acid
Salt for sodium bromate or potassium bromate or lithium bromate or magnesium bromate or calcium bromate or sodium chlorate or potassium chlorate or lithium chlorate or magron or
Calcium chlorate.
6. a kind of preparation method of 4 '-bromomethyl -2- cyanobiphenyls according to claim 1, it is characterised in that：It is described organic
Solvent is dichloromethane or dichloroethanes or carbon tetrachloride or chlorobenzene or hexane or heptane or hexamethylene or petroleum ether or acetic acid
Methyl esters or ethyl acetate or Ethyl formate.
7. a kind of preparation method of 4 '-bromomethyl -2- cyanobiphenyls according to claim 1, it is characterised in that：The reaction
Molar ratio of material 4 '-methyl -2- cyanobiphenyls：Bromide：Bromate or chlorate：Hydrochloric acid is 1：0.6~1.2：0.3~0.8：
1.0~2.0.
8. a kind of preparation method of 4 '-bromomethyl -2- cyanobiphenyls according to claim 1, it is characterised in that：The reaction
Molar ratio of material 4 '-methyl -2- cyanobiphenyls：Bromide：Bromate or chlorate：Hydrochloric acid is 1：0.6~0.7：0.3~0.4：
1.0~1.2.
9. a kind of preparation method of 4 '-bromomethyl -2- cyanobiphenyls according to claim 1, it is characterised in that：The reaction
Amount of substance is than 4 '-methyl -2- cyanobiphenyls：Solvent：Water is 1：2~6：2~6.
10. a kind of preparation method of 4 '-bromomethyl -2- cyanobiphenyls according to claim 1, it is characterised in that：It is described anti-
Amount of substance is answered than 4 '-methyl -2- cyanobiphenyls：Solvent：Water is 1：3~4：3~4.
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| CN108947870A (en) * | 2018-07-23 | 2018-12-07 | 湖北宇阳药业有限公司 | A kind of preparation method of bromo sartanbiphenyl |
| CN109438230A (en) * | 2018-11-26 | 2019-03-08 | 深圳市第二人民医院 | The synthetic method of the bromo- 2- naphthoate of Adapalene intermediate 6- |
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| CN1894180A (en) * | 2003-12-15 | 2007-01-10 | 科学与工业研究会 | Ecology-friendly bromo-benzene synthesizing method |
| CN102333758A (en) * | 2009-02-25 | 2012-01-25 | 科学与工业研究委员会 | A process for the eco-friendly preparation of 3, 5-dibromo-4-hydroxybenzonitrile |
| CN104744303A (en) * | 2015-02-15 | 2015-07-01 | 北京欣奕华科技有限公司 | 2-R-4'-bromomethyl biphenyl and preparation method thereof |
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| CN1405356A (en) * | 2001-08-02 | 2003-03-26 | 罗姆和哈斯公司 | Method for treating water-contained system |
| CN1894180A (en) * | 2003-12-15 | 2007-01-10 | 科学与工业研究会 | Ecology-friendly bromo-benzene synthesizing method |
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