CN111302973A - Preparation method of normal-temperature brominated sartanbiphenyl based on bromine - Google Patents
Preparation method of normal-temperature brominated sartanbiphenyl based on bromine Download PDFInfo
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- CN111302973A CN111302973A CN202010224627.0A CN202010224627A CN111302973A CN 111302973 A CN111302973 A CN 111302973A CN 202010224627 A CN202010224627 A CN 202010224627A CN 111302973 A CN111302973 A CN 111302973A
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- bromine
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 title claims abstract description 54
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 title claims abstract description 53
- 229910052794 bromium Inorganic materials 0.000 title claims abstract description 53
- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- 238000006243 chemical reaction Methods 0.000 claims abstract description 46
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 32
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 27
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 23
- 239000002904 solvent Substances 0.000 claims abstract description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 20
- 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 abstract description 16
- 238000005286 illumination Methods 0.000 claims abstract description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000002994 raw material Substances 0.000 claims abstract description 13
- 239000003208 petroleum Substances 0.000 claims abstract description 10
- 238000005893 bromination reaction Methods 0.000 claims abstract description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 6
- 230000031709 bromination Effects 0.000 claims abstract 3
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 42
- 239000000243 solution Substances 0.000 claims description 24
- 235000010290 biphenyl Nutrition 0.000 claims description 21
- 239000004305 biphenyl Substances 0.000 claims description 21
- 239000007788 liquid Substances 0.000 claims description 21
- 125000001246 bromo group Chemical group Br* 0.000 claims description 19
- ZGQVZLSNEBEHFN-UHFFFAOYSA-N 2-(4-methylphenyl)benzonitrile Chemical group C1=CC(C)=CC=C1C1=CC=CC=C1C#N ZGQVZLSNEBEHFN-UHFFFAOYSA-N 0.000 claims description 17
- 238000001953 recrystallisation Methods 0.000 claims description 16
- 238000000967 suction filtration Methods 0.000 claims description 14
- 238000001035 drying Methods 0.000 claims description 13
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical group CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 12
- 239000012065 filter cake Substances 0.000 claims description 12
- 238000010791 quenching Methods 0.000 claims description 12
- 230000000171 quenching effect Effects 0.000 claims description 12
- 238000000926 separation method Methods 0.000 claims description 5
- 239000011259 mixed solution Substances 0.000 claims description 4
- 238000004401 flow injection analysis Methods 0.000 claims description 3
- 239000003638 chemical reducing agent Substances 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 11
- 239000000126 substance Substances 0.000 abstract description 5
- 238000010924 continuous production Methods 0.000 abstract description 4
- 239000000203 mixture Substances 0.000 abstract description 3
- 231100000053 low toxicity Toxicity 0.000 abstract description 2
- 230000008569 process Effects 0.000 abstract description 2
- ALLIZEAXNXSFGD-UHFFFAOYSA-N 1-methyl-2-phenylbenzene Chemical group CC1=CC=CC=C1C1=CC=CC=C1 ALLIZEAXNXSFGD-UHFFFAOYSA-N 0.000 abstract 1
- 238000002347 injection Methods 0.000 abstract 1
- 239000007924 injection Substances 0.000 abstract 1
- 239000000047 product Substances 0.000 description 27
- QMSDNBJQBPHACW-UHFFFAOYSA-N 5-methyl-2-phenylbenzonitrile Chemical group N#CC1=CC(C)=CC=C1C1=CC=CC=C1 QMSDNBJQBPHACW-UHFFFAOYSA-N 0.000 description 10
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 10
- YUCRNASRVPZKNQ-UHFFFAOYSA-N 2-chlorobenzoyl cyanide Chemical group ClC1=CC=CC=C1C(=O)C#N YUCRNASRVPZKNQ-UHFFFAOYSA-N 0.000 description 9
- 239000003999 initiator Substances 0.000 description 9
- 239000007800 oxidant agent Substances 0.000 description 9
- 150000003254 radicals Chemical class 0.000 description 8
- 238000001704 evaporation Methods 0.000 description 7
- 230000001590 oxidative effect Effects 0.000 description 7
- 229940079593 drug Drugs 0.000 description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 4
- 239000007806 chemical reaction intermediate Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 206010020772 Hypertension Diseases 0.000 description 3
- 239000002220 antihypertensive agent Substances 0.000 description 3
- 229940127088 antihypertensive drug Drugs 0.000 description 3
- 238000005265 energy consumption Methods 0.000 description 3
- 230000007613 environmental effect Effects 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 2
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- 238000009776 industrial production Methods 0.000 description 2
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- OZAIFHULBGXAKX-UHFFFAOYSA-N 2,2'-azo-bis-isobutyronitrile Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- PFHOSZAOXCYAGJ-UHFFFAOYSA-N 2-[(2-cyano-4-methoxy-4-methylpentan-2-yl)diazenyl]-4-methoxy-2,4-dimethylpentanenitrile Chemical compound COC(C)(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)(C)OC PFHOSZAOXCYAGJ-UHFFFAOYSA-N 0.000 description 1
- CFMZSMGAMPBRBE-UHFFFAOYSA-N 2-hydroxyisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(O)C(=O)C2=C1 CFMZSMGAMPBRBE-UHFFFAOYSA-N 0.000 description 1
- RCEJCSULJQNRQQ-UHFFFAOYSA-N 2-methylbutanenitrile Chemical compound CCC(C)C#N RCEJCSULJQNRQQ-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 206010024769 Local reaction Diseases 0.000 description 1
- 206010031127 Orthostatic hypotension Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- -1 azo radical Chemical class 0.000 description 1
- 235000019400 benzoyl peroxide Nutrition 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 229940109239 creatinine Drugs 0.000 description 1
- LSXWFXONGKSEMY-UHFFFAOYSA-N di-tert-butyl peroxide Chemical compound CC(C)(C)OOC(C)(C)C LSXWFXONGKSEMY-UHFFFAOYSA-N 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 208000017574 dry cough Diseases 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 208000021822 hypotensive Diseases 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000013021 overheating Methods 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 201000001474 proteinuria Diseases 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- XUXNAKZDHHEHPC-UHFFFAOYSA-M sodium bromate Chemical compound [Na+].[O-]Br(=O)=O XUXNAKZDHHEHPC-UHFFFAOYSA-M 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000004065 wastewater treatment Methods 0.000 description 1
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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 invention discloses a preparation method of normal-temperature bromosartanbiphenyl based on bromine, and belongs to the technical field of pharmaceutical chemicals. The method comprises the steps of taking methyl biphenyl as a raw material, bromine as a bromination reagent, acetone, dichloromethane, petroleum ether or acetonitrile as a solvent, mixing the raw material and the bromination reagent with the solvent respectively, then flowing the mixture into a pipeline through an injection pipe, mixing the mixture in a mixer, then entering a constant-temperature water bath reactor, and carrying out reaction through illumination. The 2-cyano-4' -bromomethyl biphenyl synthesized by the method has the advantages of good purity, high yield, simple reaction system and low toxicity, is suitable for industrial application in the field of biological medicine, can be suitable for an automatic continuous production process, and accords with the development concepts of green chemical industry, high efficiency and economy.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a preparation method of normal-temperature bromo-sartanbiphenyl based on bromine.
Background
The sartan drug is a first-line treatment drug for hypertension resistance, has a brand-new blood pressure reduction mechanism, and has the advantages of stable blood pressure reduction, good curative effect, long action time and good tolerance of patients. Angiotensin II receptor Antagonists (ARB) antihypertensive drugs ("sartan drugs") have been known for more than 20 years, and have been one of the most common antihypertensive drugs in clinical use because of their remarkable antihypertensive effects and good tolerance, especially clinical trial data indicating that they have unique therapeutic effects and protective effects on cardiovascular diseases. The medicine has low incidence of adverse reactions such as dry cough, rebound of medicine stopping, postural hypotension, elevation of blood potassium and blood creatinine and the like caused by long-term application, and is recommended to be a first-line hypotensive medicine for hypertension patients with cardiovascular diseases and proteinuria by multiple treatment guidelines of WHO. The sartan drugs are clinically used for treating hypertension, and also have wide application prospects in the prevention and treatment of heart failure, myocardial infarction, nephropathy, diabetes and other cardiovascular and cerebrovascular diseases.
At present, the most important intermediate in the synthetic route of sartan bulk drugs is 2-cyano-4' -bromomethylbiphenyl, which is used as the core structure of most sartan drugs. A large number of documents have been reported on the synthetic routes.
The patent CN 102746193A for preparing 2-cyano-4 ' -bromomethyl biphenyl uses 2,2 ' -azobis (4-methoxy-2, 4-dimethyl valeronitrile), 2 ' -azobisisobutyronitrile, 2 ' -azobis (2-methylbutyronitrile), dibenzoyl peroxide and di-tert-butyl peroxide as radical initiators, sodium bromate as oxidant, and halogenated alkanes such as methylene chloride and the like as solvents, so that the 2-cyano-4 ' -methyl biphenyl and bromine are subjected to benzyl bromination reaction. However, the above bromination reaction requires azo radical initiators, which remain in the waste liquid after the reaction, and thus the post-treatment of the waste liquid is extremely difficult.
The preparation method of 2-cyano-4 ' -bromomethyl biphenyl represented by the preparation method of the important intermediate 2-cyano-4 ' -bromomethyl biphenyl of the sartan antihypertensive drug CN 109776355A is characterized in that 2-cyano-4 ' -methyl biphenyl is used as a raw material, bromine is used as a bromine source, hydrogen peroxide is used as an oxidant, the raw material and the oxidant are uniformly mixed in an organic solvent under the action of a free radical initiator, then the mixture is added into water for sealing and reacts under the illumination condition, so that the use of azo compounds is avoided, and the preparation method is environment-friendly. However, the above preparation method still requires hydrogen peroxide as an oxidant and N-hydroxyphthalimide and the like as a radical initiator, so that the excessively high raw material cost is not favorable for industrial popularization, and particularly, the use of water seal increases the pressure of wastewater treatment after reaction, and is not suitable for practical production and application.
In particular, the preparation method of the 2-cyano-4' -bromomethyl biphenyl uses the auxiliary agents such as the oxidant, the free radical initiator and the like, increases the preparation cost and increases the environmental protection treatment pressure, and the preparation period of the method is long, the feeding proportion is large, and the method cannot be applied to the technical revolution trend of continuous and semi-continuous automatic production lines in actual industrial production.
Therefore, the development of a method for preparing 2-cyano-4' -bromomethylbiphenyl, which does not require an oxidizing agent and a radical initiator and can be applied to an automated continuous production line, is a problem to be solved by those skilled in the art.
Disclosure of Invention
In view of the above, the present invention aims to provide a method for preparing 2-cyano-4' -bromomethyl biphenyl, which does not require an oxidizing agent and a radical initiator and can be applied to an automated continuous production line, in view of the problems in the prior art.
In order to achieve the purpose, the invention adopts the following technical scheme:
a normal-temperature bromo-sartan biphenyl preparation method based on bromine is characterized in that 2-cyano-4 '-methyl biphenyl is used as a raw material, bromine is used as a bromo reagent, acetone, dichloromethane, petroleum ether or acetonitrile is used as a solvent, and a flow photochemical method is used for carrying out a constant-temperature reaction to generate the 2-cyano-4' -bromo-methyl biphenyl.
It should be noted that, unlike the prior art in which an oxidant, a radical initiator, and other additives are used, the reaction equation of the present invention is shown in fig. 1, and the reaction does not require the use of additives, and utilizes a photochemical reaction to realize a benzyl bromination reaction between 2-cyano-4' -methylbiphenyl and bromine, and controls the pressure, temperature, and feeding ratio of raw materials to avoid the inhibition of the reaction by hydrogen bromide generated by the reaction. Compared with the current industrial bromine used as a bromization reagent, the method uses a flow chemical method to prepare the product 2-cyano-4' -bromomethyl biphenyl with high purity, good yield and excellent atom economy in a new system, and the method can effectively shorten the reaction time and reduce the potential safety hazard.
Preferably, the isothermal reaction temperature is 20 ℃ to 60 ℃.
It is worth to be noted that, in consideration of the distribution and fluidity requirements of the mobile chemical reaction on the raw materials, products, reaction intermediates and byproducts in the system, the invention selects acetone, dichloromethane, petroleum ether or acetonitrile with similar polarity to the raw materials, products, reaction intermediates and byproducts as the solvent. In addition, in consideration of the factors of preparation energy consumption, industrial cost, environmental consumption and the like, the temperature of the constant-temperature water bath reaction is 20-60 ℃, so that the energy consumption is reduced, the production safety risk is reduced, and meanwhile, the raw materials, the products, the reaction intermediates and the byproducts are fully dissolved and uniformly distributed in a solvent system of acetone, dichloromethane, petroleum ether or acetonitrile, so that the raw materials, the products, the reaction intermediates and the byproducts have good fluidity, and the blockage of a reaction pipeline is prevented.
Further preferably, the constant-temperature light reaction comprises the following steps:
s1, preparing a 2-cyano-4' -methyl biphenyl solution and a bromine solution respectively;
s2, respectively placing the 2-cyano-4' -methyl biphenyl solution and the bromine solution in the step S1 in a pressure propulsion system;
s3, pushing the 2-cyano-4' -methyl biphenyl solution and the bromine solution into a mixer by using a pressure propulsion system to form a mixed solution;
s4, pushing the mixed solution obtained in the step S3 into a flow pipeline for reaction, and collecting the generated solution after the reaction is finished.
Still more preferably, the flow tube in step S4 is placed in a constant temperature water bath reactor for light irradiation reaction.
More preferably, the illumination conditions of the illumination reaction are 4000K LED lamps of 365nm, 385nm, 405nm, 475nm and 610 nm.
Still further preferably, the pressure boosting system in step S3 includes a syringe and a flow syringe pump.
It is worth mentioning that the injector is mounted on the flow injection pump and passes through the flow injection pump
Still more preferably, the flow rates of the 2-cyano-4' -methylbiphenyl solution and the bromine solution in the step S3 are 1.5 mL/min.
Most preferably, the concentration of the 2-cyano-4' -methyl biphenyl solution is 0.05mol/L, and the concentration of the bromine solution is 0.525 mol/L.
Preferably, the preparation method further comprises:
and S5, adding a reducing agent into the generated liquid for quenching, then sequentially carrying out liquid separation and suction filtration on the generated liquid, adding a recrystallization solvent for recrystallization, carrying out secondary suction filtration, and finally drying the filter cake to obtain the pure 2-cyano-4' -bromomethyl biphenyl.
Further preferably, the recrystallization solvent is isopropyl ether.
Compared with the prior art, the invention has the advantages that:
the method takes 2-cyano-4 '-methyl biphenyl as a raw material, bromine as a bromization reagent, acetone, dichloromethane, petroleum ether or acetonitrile as a solvent, and performs a constant-temperature illumination reaction to generate the 2-cyano-4' -methyl biphenyl, a free radical initiator or an oxidant is not needed, so that the difficulty in post-treatment of waste liquid is reduced, and the method has the advantages of simplicity, mildness, safety, environmental protection, rapidness, high efficiency and the like, and is suitable for continuous industrial production; the synthesized 2-cyano-4' -bromomethyl biphenyl has good purity, high yield, simple reaction system and low toxicity, and is suitable for industrial application in the field of biological medicine.
Meanwhile, compared with the traditional kettle-type discontinuous preparation process, the flow photochemical reaction adopted by the invention has the advantages that the tubular flow reaction device is utilized, the preparation energy consumption is reduced, the reaction units are decomposed, the reaction equivalent of each reaction unit is reduced, the safety production risk of local reaction overspeed or local overheating is avoided, the safety performance of reaction equipment is improved, the reaction period is shortened, the reaction charge ratio is reduced, the method is suitable for the automatic continuous production process, and the development concept of green chemical industry, high efficiency and economy is met.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the provided drawings without creative efforts.
FIG. 1 shows the reaction equation of the present invention.
FIG. 2 is the nuclear magnetic spectrum of the structure of the product of example 1.
FIG. 3 is a liquid chromatogram of a 2-cyano-4' -bromomethylbiphenyl standard.
FIG. 4 is a liquid chromatogram of the product of example 1.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The present invention will be further specifically illustrated by the following examples for better understanding, but the present invention is not to be construed as being limited thereto, and certain insubstantial modifications and adaptations of the invention by those skilled in the art based on the foregoing disclosure are intended to be included within the scope of the invention.
Example 1
A normal temperature bromo sartan biphenyl preparation method based on bromine, dissolve 11g 2-cyano-4-methyl biphenyl in 30mL acetone, pack into syringe A tube; 5mL of bromine was dissolved in 30mL of acetone and loaded into syringe B. A, B two syringes were mounted on the flow syringe pump, assembled, set A, B and the flow rates of both tubes were 1.5 mL/min. And (3) opening the constant-temperature water bath device, heating to 55 ℃, keeping the temperature, opening the 4000K LED lamp with the wavelength of 365nm for illumination for 30 minutes, and simultaneously opening the flow reactor. After the reaction is finished, adding 15g of sodium bisulfite into the received product, quenching, separating liquid, rotationally evaporating an organic phase to remove a solvent, adding isopropyl ether for recrystallization, performing suction filtration, and drying a filter cake in an oven to obtain a pure product, namely the 2-cyano-4-bromomethyl biphenyl, wherein the purity is 90 percent, and the yield is 92 percent.
Example 2
A normal temperature bromo sartan biphenyl preparation method based on bromine, dissolve 11g 2-cyano-4-methyl biphenyl in 30mL acetone, pack into syringe A tube; 5mL of bromine was dissolved in 30mL of acetone and loaded into syringe B. A, B two syringes were mounted on the flow syringe pump, assembled, set A, B and the flow rates of both tubes were 1.5 mL/min. Turning on the constant temperature water bath device, heating to 30 deg.C, maintaining the temperature, turning on the 4000K LED lamp at 385nm for 30min, and turning on the flow reactor. After the reaction is finished, adding 15g of sodium bisulfite into the received product, quenching, separating liquid, rotationally evaporating an organic phase to remove a solvent, adding isopropyl ether for recrystallization, performing suction filtration, and drying a filter cake in an oven to obtain a pure product, namely the 2-cyano-4-bromomethyl biphenyl, wherein the purity is 91 percent, and the yield is 92 percent.
Example 3
A normal temperature bromo sartan biphenyl preparation method based on bromine, dissolve 11g 2-cyano-4-methyl biphenyl in 30mL acetone, pack into syringe A tube; 5mL of bromine was dissolved in 30mL of acetone and loaded into syringe B. A, B two syringes were mounted on the flow syringe pump, assembled, set A, B and the flow rates of both tubes were 1.5 mL/min. And (3) opening the constant-temperature water bath device, heating to 60 ℃, keeping the temperature, opening a 4000K LED lamp with the wavelength of 405nm for illumination for 30 minutes, and simultaneously opening the flow reactor. After the reaction is finished, adding 15g of sodium bisulfite into the received product, quenching, separating liquid, rotationally evaporating an organic phase to remove a solvent, adding isopropyl ether for recrystallization, performing suction filtration, and drying a filter cake in an oven to obtain a pure product, namely the 2-cyano-4-bromomethyl biphenyl, wherein the purity is 93 percent, and the yield is 92 percent.
Example 4
A normal temperature bromo sartan biphenyl preparation method based on bromine, dissolve 11g 2-cyano-4-methyl biphenyl in 30mL acetone, pack into syringe A tube; 5mL of bromine was dissolved in 30mL of acetone and loaded into syringe B. A, B two syringes were mounted on the flow syringe pump, assembled, set A, B and the flow rates of both tubes were 1.5 mL/min. The thermostatic water bath device is started, the temperature is heated to 45 ℃, the temperature is maintained, 4000K LED lamp light with the wavelength of 475nm is turned on for 30 minutes, and meanwhile, the flow reactor is turned on. After the reaction is finished, adding 15g of sodium bisulfite into the received product, quenching, separating liquid, rotationally evaporating an organic phase to remove a solvent, adding isopropyl ether for recrystallization, performing suction filtration, and drying a filter cake in an oven to obtain a pure product, namely the 2-cyano-4-bromomethyl biphenyl, wherein the purity is 92% and the yield is 90%.
Example 5
A normal temperature bromo sartan biphenyl preparation method based on bromine, dissolve 11g 2-cyano-4-methyl biphenyl in 30mL acetone, pack into syringe A tube; 5mL of bromine was dissolved in 30mL of acetone and loaded into syringe B. A, B two syringes were mounted on the flow syringe pump, assembled, set A, B and the flow rates of both tubes were 1.5 mL/min. And (3) opening the constant-temperature water bath device, heating to 20 ℃, keeping the temperature, and opening a 610nm 4000K LED lamp for illumination for 30 minutes, and simultaneously opening the flow reactor. After the reaction is finished, adding 15g of sodium bisulfite into the received product, quenching, separating liquid, rotationally evaporating an organic phase to remove a solvent, adding isopropyl ether for recrystallization, performing suction filtration, and drying a filter cake in an oven to obtain a pure product, namely the 2-cyano-4-bromomethyl biphenyl, wherein the purity is 90 percent, and the yield is 92 percent.
Example 6
A normal temperature bromo sartan biphenyl preparation method based on bromine, dissolve 11g 2-cyano-4-methyl biphenyl in 30mL dichloromethane, pack into syringe A tube; 7mL of bromine was dissolved in 30mL of dichloromethane and loaded into syringe B tube. A, B two syringes were mounted on the flow syringe pump, assembled, set A, B and the flow rates of both tubes were 1.5 mL/min. The thermostatic waterbath device is started, the temperature is heated to 50 ℃, the temperature is kept, 4000K LED lamp light with the light of 475nm is turned on for 30 minutes, and the flow reactor is simultaneously turned on. After the reaction is finished, adding 15g of sodium bisulfite into the received product, quenching, separating liquid, rotationally evaporating an organic phase to remove a solvent, adding isopropyl ether for recrystallization, performing suction filtration, and drying a filter cake in an oven to obtain a pure product, namely the 2-cyano-4-bromomethyl biphenyl, wherein the purity is 93 percent, and the yield is 91 percent.
Example 7
A normal temperature bromo sartan biphenyl preparation method based on bromine, dissolve 10g 2-cyano-4-methyl biphenyl in 30mL acetonitrile, pack into syringe A tube; 7mL of bromine was dissolved in 30mL of acetonitrile and loaded into syringe B. A, B two syringes were mounted on the flow syringe pump, assembled, set A, B and the flow rates of both tubes were 1.5 mL/min. The thermostatic water bath device is turned on, heated to 55 ℃, the temperature is maintained, a 4000KLED lamp at 610nm is turned on for illumination for 30 minutes, and the flow reactor is turned on simultaneously. After the reaction is finished, 16g of sodium bisulfite is added into the received product for quenching, liquid separation is carried out, the organic phase is rotated and evaporated to remove the solvent, isopropyl ether is added for recrystallization, suction filtration is carried out, and the filter cake is put into a drying oven for drying to obtain the pure product 2-cyano-4-bromomethyl biphenyl, wherein the purity is 90 percent, and the yield is 93 percent.
Example 8
A normal temperature bromo sartan biphenyl preparation method based on bromine, dissolve 10g 2-cyano-4-methyl biphenyl in 30mL petroleum ether, pack into syringe A tube; 7mL of bromine was dissolved in 30mL of petroleum ether and loaded into syringe B. A, B two syringes were mounted on the flow syringe pump, assembled, set A, B and the flow rates of both tubes were 1.5 mL/min. The thermostatic water bath device is turned on, heated to 60 ℃, the temperature is maintained, a 4000KLED lamp at 475nm is turned on for illumination for 30 minutes, and the flow reactor is turned on simultaneously. After the reaction is finished, 16g of sodium bisulfite is added into the received product for quenching, liquid separation is carried out, the organic phase is rotated and evaporated to remove the solvent, isopropyl ether is added for recrystallization, suction filtration is carried out, and the filter cake is put into an oven for drying to obtain the pure product 2-cyano-4-bromomethyl biphenyl with the purity of 91 percent and the yield of 92 percent.
Example 9
A normal temperature bromo sartan biphenyl preparation method based on bromine, dissolve 10g 2-cyano-4-methyl biphenyl in 30mL petroleum ether, pack into syringe A tube; 7mL of bromine was dissolved in 30mL of petroleum ether and loaded into syringe B. A, B two syringes were mounted on the flow syringe pump, assembled, set A, B and the flow rates of both tubes were 1.5 mL/min. The thermostatic water bath device is turned on, heated to 20 ℃, the temperature is maintained, a 4000KLED lamp at 475nm is turned on for illumination for 30 minutes, and the flow reactor is turned on simultaneously. After the reaction is finished, 16g of sodium bisulfite is added into the received product for quenching, liquid separation is carried out, the organic phase is rotated and evaporated to remove the solvent, isopropyl ether is added for recrystallization, suction filtration is carried out, and the filter cake is put into an oven for drying to obtain the pure product 2-cyano-4-bromomethyl biphenyl, wherein the purity is 92 percent, and the yield is 91 percent.
To further verify the excellent effects of the present invention, the inventors also carried out the following experimental comparisons:
comparative example 1
A normal temperature bromo sartan biphenyl preparation method based on bromine is provided, which comprises dissolving 5Kg 2-cyano-4-methyl biphenyl and 4L liquid bromine in 30L solvent, loading into a reaction kettle, and reacting for 4 h. After the reaction is finished, adding sodium bisulfite into the received product for quenching, separating liquid, rotationally evaporating an organic phase to remove a solvent, adding isopropyl ether for recrystallization, performing suction filtration, and drying a filter cake in an oven to obtain a pure product, namely the 2-cyano-4' -bromomethyl biphenyl, wherein the purity is 85 percent, and the yield is 84 percent.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (10)
1. The preparation method of normal-temperature bromo sartan biphenyl based on bromine is characterized in that 2-cyano-4 '-methyl biphenyl is used as a raw material, bromine is used as a bromination reagent, acetone, dichloromethane, petroleum ether or acetonitrile is used as a solvent, and a flowing photochemical method is used for carrying out a constant-temperature reaction to generate the 2-cyano-4' -bromo methyl biphenyl.
2. The bromine-based normal-temperature bromo sartan biphenyl preparation method according to claim 1, wherein the temperature of the isothermal reaction is 20 ℃ to 60 ℃.
3. The bromine-based normal-temperature bromo sartan biphenyl preparation method according to claim 2, wherein the flowing photochemical method constant-temperature reaction comprises the following steps:
s1, preparing a 2-cyano-4' -methyl biphenyl solution and a bromine solution respectively;
s2, respectively placing the 2-cyano-4' -methyl biphenyl solution and the bromine solution in the step S1 in a pressure propulsion system;
s3, pushing the 2-cyano-4' -methyl biphenyl solution and the bromine solution into a mixer by using a pressure propulsion system to form a mixed solution;
s4, pushing the mixed solution obtained in the step S3 into a flow pipeline for reaction, and collecting the generated solution after the reaction is finished.
4. The method for preparing normal-temperature bromo-sartan biphenyl based on bromine according to claim 3, wherein the flow pipeline in the step S4 is placed in a constant-temperature water bath reactor for illumination reaction.
5. The method for preparing normal-temperature bromo-sartan biphenyl based on bromine according to claim 3, wherein the illumination conditions of the illumination reaction are that 4000K LED lamps of 365nm, 385nm, 405nm, 475nm and 610nm are used for illuminating for 30 min.
6. The method for preparing normal-temperature bromo sartan biphenyl based on bromine according to claim 3, wherein the pressure propulsion system in step S3 comprises an injector and a flow injection pump.
7. The method for preparing normal-temperature bromo sartan biphenyl based on bromine according to claim 3, wherein the flow rate of the 2-cyano-4' -methyl biphenyl solution and the bromine solution in step S3 is 1.5 mL/min.
8. The method for preparing normal-temperature bromo sartan biphenyl based on bromine according to claim 7, wherein the concentration of the 2-cyano-4' -methyl biphenyl solution is 0.05mol/L, and the concentration of the bromine solution is 0.525 mol/L.
9. The preparation method of normal-temperature bromo sartan biphenyl based on bromine according to any one of claims 2 to 8, characterized in that the preparation method further comprises:
and S5, adding a reducing agent into the generated liquid for quenching, then sequentially carrying out liquid separation and suction filtration on the generated liquid, adding a recrystallization solvent for recrystallization, carrying out secondary suction filtration, and finally drying the filter cake to obtain the pure 2-cyano-4' -bromomethyl biphenyl.
10. The method for preparing normal-temperature bromo sartan biphenyl based on bromine according to claim 9, wherein the recrystallization solvent is isopropyl ether.
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| CN113105327A (en) * | 2021-03-30 | 2021-07-13 | 湖北宇阳药业有限公司 | Synthetic method of 4-bromomethyl-2-methyl formate biphenyl |
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