CN107417501B - Preparation method of pinaverium bromide intermediate 2-bromo-4, 5-dimethoxy benzyl bromide - Google Patents
Preparation method of pinaverium bromide intermediate 2-bromo-4, 5-dimethoxy benzyl bromide Download PDFInfo
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- PAJNRELOTRXFAQ-UHFFFAOYSA-N 1-bromo-2-(bromomethyl)-4,5-dimethoxybenzene Chemical compound COC1=CC(Br)=C(CBr)C=C1OC PAJNRELOTRXFAQ-UHFFFAOYSA-N 0.000 title claims abstract description 33
- IKGXLCMLVINENI-QOXGANSBSA-M [Br-].COc1cc(Br)c(C[N+]2(CCOCC[C@@H]3CC[C@H]4C[C@@H]3C4(C)C)CCOCC2)cc1OC Chemical compound [Br-].COc1cc(Br)c(C[N+]2(CCOCC[C@@H]3CC[C@H]4C[C@@H]3C4(C)C)CCOCC2)cc1OC IKGXLCMLVINENI-QOXGANSBSA-M 0.000 title claims abstract description 9
- 229960002088 pinaverium bromide Drugs 0.000 title claims abstract description 9
- 238000002360 preparation method Methods 0.000 title claims abstract description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 139
- GYPMBQZAVBFUIZ-UHFFFAOYSA-N 1,2-dimethoxy-4-methylbenzene Chemical compound COC1=CC=C(C)C=C1OC GYPMBQZAVBFUIZ-UHFFFAOYSA-N 0.000 claims abstract description 71
- 238000006243 chemical reaction Methods 0.000 claims abstract description 55
- 238000005893 bromination reaction Methods 0.000 claims abstract description 45
- 239000003999 initiator Substances 0.000 claims abstract description 43
- 238000000034 method Methods 0.000 claims abstract description 25
- 239000012454 non-polar solvent Substances 0.000 claims abstract description 21
- 150000003254 radicals Chemical class 0.000 claims abstract description 20
- SXDBWCPKPHAZSM-UHFFFAOYSA-N bromic acid Chemical compound OBr(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-N 0.000 claims abstract description 19
- SXDBWCPKPHAZSM-UHFFFAOYSA-M bromate Inorganic materials [O-]Br(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-M 0.000 claims abstract description 18
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims abstract description 17
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 16
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 12
- 238000006479 redox reaction Methods 0.000 claims abstract description 4
- 230000009471 action Effects 0.000 claims abstract description 3
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical group ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 50
- 238000010992 reflux Methods 0.000 claims description 35
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 28
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical group [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 claims description 26
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 14
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 14
- 125000003118 aryl group Chemical group 0.000 claims description 13
- XUXNAKZDHHEHPC-UHFFFAOYSA-M sodium bromate Chemical group [Na+].[O-]Br(=O)=O XUXNAKZDHHEHPC-UHFFFAOYSA-M 0.000 claims description 13
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 12
- 239000012043 crude product Substances 0.000 claims description 12
- 239000012074 organic phase Substances 0.000 claims description 12
- 239000000706 filtrate Substances 0.000 claims description 11
- 238000001953 recrystallisation Methods 0.000 claims description 11
- -1 2-bromo-4, 5-dimethoxybromobenzyl Chemical group 0.000 claims description 10
- 230000031709 bromination Effects 0.000 claims description 10
- 238000004440 column chromatography Methods 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 238000012544 monitoring process Methods 0.000 claims description 4
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- 235000019400 benzoyl peroxide Nutrition 0.000 claims description 3
- 239000012295 chemical reaction liquid Substances 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- XWNSFEAWWGGSKJ-UHFFFAOYSA-N 4-acetyl-4-methylheptanedinitrile Chemical compound N#CCCC(C)(C(=O)C)CCC#N XWNSFEAWWGGSKJ-UHFFFAOYSA-N 0.000 claims description 2
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims description 2
- 239000004153 Potassium bromate Substances 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 235000019396 potassium bromate Nutrition 0.000 claims description 2
- 229940094037 potassium bromate Drugs 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 11
- 238000005580 one pot reaction Methods 0.000 abstract description 8
- 239000002994 raw material Substances 0.000 abstract description 8
- 238000009776 industrial production Methods 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- 239000000047 product Substances 0.000 description 19
- 239000006227 byproduct Substances 0.000 description 13
- 239000003208 petroleum Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 238000004817 gas chromatography Methods 0.000 description 11
- 238000010521 absorption reaction Methods 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 239000000758 substrate Substances 0.000 description 10
- OEGPRYNGFWGMMV-UHFFFAOYSA-N (3,4-dimethoxyphenyl)methanol Chemical compound COC1=CC=C(CO)C=C1OC OEGPRYNGFWGMMV-UHFFFAOYSA-N 0.000 description 8
- 239000012156 elution solvent Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- WJUFSDZVCOTFON-UHFFFAOYSA-N veratraldehyde Chemical compound COC1=CC=C(C=O)C=C1OC WJUFSDZVCOTFON-UHFFFAOYSA-N 0.000 description 6
- FBWLFLLMKHARDG-UHFFFAOYSA-N 3-bromo-1,2-dimethoxy-4-methylbenzene Chemical compound COC1=CC=C(C)C(Br)=C1OC FBWLFLLMKHARDG-UHFFFAOYSA-N 0.000 description 5
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000003912 environmental pollution Methods 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- BJRJHJZVSWZXIP-UHFFFAOYSA-N 5-chloro-2-methoxy-4-methylbenzenesulfonyl chloride Chemical compound COC1=CC(C)=C(Cl)C=C1S(Cl)(=O)=O BJRJHJZVSWZXIP-UHFFFAOYSA-N 0.000 description 2
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000008901 benefit Effects 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
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000007039 two-step reaction Methods 0.000 description 2
- BMKDZUISNHGIBY-ZETCQYMHSA-N (+)-dexrazoxane Chemical compound C([C@H](C)N1CC(=O)NC(=O)C1)N1CC(=O)NC(=O)C1 BMKDZUISNHGIBY-ZETCQYMHSA-N 0.000 description 1
- KVLMMRAXLYFCNY-UHFFFAOYSA-N 1-bromo-4,5-dimethoxy-2-methylbenzene Chemical compound COC1=CC(C)=C(Br)C=C1OC KVLMMRAXLYFCNY-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 229960000605 dexrazoxane Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 238000007347 radical substitution reaction Methods 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 230000002048 spasmolytic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/22—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of halogens; by substitution of halogen atoms by other halogen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of an pinaverium bromide intermediate 2-bromo-4, 5-dimethoxy benzyl bromide, which comprises the following steps: in a non-polar solvent, as a bromate,Bromine released by oxidation reduction reaction of bromide under the action of sulfuric acid is a bromine source, electrophilic bromination reaction of an aromatic ring C-H bond is carried out on the bromine and 3, 4-dimethoxytoluene shown in a formula (1), after the reaction is completed, an initiator and sulfuric acid are added, free radical bromination reaction of a benzyl methyl C-H bond is carried out, and 2-bromine-4, 5-dimethoxybromobenzyl shown in a formula (8) is prepared; the reaction formula is shown below. The method is carried out by adopting a one-pot method, has cheap and easily obtained raw materials, is simple, convenient and safe to operate, reduces the production cost, obviously improves the yield of the 2-bromo-4, 5-dimethoxy benzyl bromide (8), has the yield up to 85 percent, and is very suitable for industrial production.
Description
The technical field is as follows:
the invention relates to the field of organic chemistry, and relates to a preparation method of 2-bromo-4, 5-dimethoxy benzyl bromide.
Background art:
pinaverium bromide, also known as dexrazoxane and known in the English name of pinaverium bromide, is a calcium antagonist drug with highly selective spasmolytic effect on gastrointestinal tracts, is marketed in 1975, is sold in more than 50 countries, and has extremely wide market prospect. 2-bromo-4, 5-dimethoxy benzyl bromide is a key intermediate for synthesizing pinaverium bromide. In the prior art, 3, 4-dimethoxybenzyl alcohol is generally adopted to react with liquid bromine, and the 2-bromo-4, 5-dimethoxybenzyl bromide [ J.org.chem.,1987,52,704-706 is synthesized by a one-pot method; j.org.chem.,2000,65, 6398-6411; CN102060807 ]; or reacting 3, 4-dimethoxybenzyl alcohol with liquid bromine to obtain 2-bromo-4, 5-dimethoxybenzyl alcohol, and reacting 2-bromo-4, 5-dimethoxybenzyl alcohol with phosphorus tribromide to obtain 2-bromo-4, 5-dimethoxybenzyl bromide. There are also reports in the literature of a method for synthesizing 2-bromo-4, 5-dimethoxybromobenzyl by three-step reactions, i.e., bromination of liquid bromine on an aromatic ring, reduction of carbonyl by sodium borohydride, bromination of benzyl tribromide and the like, using 3, 4-dimethoxybenzaldehyde as a base material [ eur.j.med.chem.,2012,55, 125-136; org, Lett.,2014,16,484-487 ]. The Liu Tan column subject group reported a one-pot synthesis method of 2-bromo-4, 5-dimethoxybromobenzyl using 3, 4-dimethoxytoluene as a base material and N-bromosuccinimide (NBS) as a brominating reagent [ Chin. chem. Lett.,2003,14,371-374 ], but the yield was only 38.6%.
In the prior art, 3, 4-dimethoxybenzyl alcohol or 3, 4-dimethoxybenzaldehyde is used as a basic raw material, the price is high, the production cost is high, toxic liquid bromine or phosphorus tribromide is used as a brominating reagent, the operation is dangerous, and the environmental pollution is large; although 3, 4-dimethoxytoluene is used as a basic raw material, the raw material is cheap and easy to obtain, NBS is used as a brominating agent, the price of the NBS is high, the content of effective bromine is low, the required dosage is large, and the yield of the product is only 38.6 percent, so the technology has higher production cost and is not suitable for industrialization. Since the market price of the 3, 4-dimethoxytoluene is much lower than that of the 3, 4-dimethoxybenzyl alcohol or the 3, 4-dimethoxybenzaldehyde, if a bromination method which is simple and safe to operate, low in production cost, small in environmental pollution and easy for industrial production can be found, the production cost of the 2-bromo-4, 5-dimethoxybenzyl bromide is greatly reduced, and thus the production cost of the pinaverium bromide is reduced.
In the prior art, 3, 4-dimethoxytoluene and a brominating reagent react to synthesize 2-bromo-4, 5-dimethoxybromobenzyl, and the reaction comprises two steps of electrophilic bromination of an aromatic ring C-H bond and radical bromination of a benzyl methyl C-H bond (as shown in the following reaction formula):
the first step is as follows: electrophilic bromination of C-H bonds of aromatic rings
The second step is that: radical bromination of benzylic methyl C-H bond
Because the methoxyl is an ortho-para positioning group and has strong activation effect on electrophilic bromination reaction of aromatic ring C-H bonds, six products (2) to (7) can be formed when raw material 3, 4-dimethoxytoluene (1) and a bromination reagent are subjected to electrophilic bromination reaction of aromatic ring C-H bonds, and only (2) is used as a raw material for synthesizing a target product 2-bromo-4, 5-dimethoxybromobenzyl (8), so how to improve the selectivity of the first step reaction is a key factor for improving the yield of the 2-bromo-4, 5-dimethoxybromobenzyl (8).
Disclosure of Invention
The technical problems to be solved by the invention are mainly three:
firstly, improving the selectivity and yield of the intermediate 2-bromo-3, 4-dimethoxytoluene (2) generated from the raw material 3, 4-dimethoxytoluene (1);
secondly, the selectivity and the yield of a target product 2-bromo-4, 5-dimethoxybromobenzyl (8) synthesized by 2-bromo-3, 4-dimethoxytoluene (2) are improved;
and in order to realize the aim of industrialization, the selected method has the characteristics of simple and safe operation, low production cost, small environmental pollution, easy control of reaction, easy amplification and the like, and preferably can realize two-step reaction and one-pot reaction, thereby reducing the operation steps of separation, simplifying the production process and reducing the production cost.
In order to solve the technical problems, the invention adopts the technical scheme that:
a preparation method of an pinaverium bromide intermediate 2-bromo-4, 5-dimethoxy benzyl bromide comprises the following steps:
in a nonpolar solvent, bromine released by oxidation reduction reaction of bromate and bromide under the action of sulfuric acid is taken as a bromine source, electrophilic bromination reaction of an aromatic ring C-H bond is carried out on the bromine and 3, 4-dimethoxytoluene shown as a formula (1), after the reaction is completed, an initiator and sulfuric acid are added, free radical bromination reaction of a benzyl methyl C-H bond is carried out, and 2-bromine-4, 5-dimethoxybromobenzyl shown as a formula (8) is prepared
The specific reaction equation is as follows:
in the invention, 3, 4-dimethoxytoluene shown in formula (1) is subjected to electrophilic bromination reaction of aromatic ring C-H bond to obtain 2-bromo-4, 5-dimethoxytoluene intermediate shown in formula (2), but the intermediate is not separated, and the subsequent second step of radical bromination reaction of benzyl methyl C-H bond is directly carried out by a one-pot method.
The non-polar solvent is preferably carbon tetrachloride.
Further, the method of the invention comprises the following steps:
adding 3, 4-dimethoxytoluene shown in formula (1), bromate and bromide solid into a nonpolar solvent, heating to reflux, slowly dropwise adding sulfuric acid, carrying out electrophilic bromination reaction of aromatic ring C-H bonds, tracking and monitoring until the 3, 4-dimethoxytoluene is completely reacted, adding an initiator and sulfuric acid, carrying out free radical bromination reaction of benzyl methyl C-H bonds, and after the reaction is completely finished, carrying out post-treatment on the reaction solution to obtain the 2-bromo-4, 5-dimethoxybenzyl bromide shown in formula (8).
The mass ratio of the bromate to the bromide is 1:2, and the mass ratio of the 3, 4-dimethoxytoluene represented by the formula (1) to the bromate is 1: 0.8-0.9.
Further, the method of the present invention is preferably carried out by the following steps:
adding 3, 4-dimethoxytoluene shown in formula (1), bromate and bromide solid into a nonpolar solvent A, heating to reflux, slowly dropwise adding sulfuric acid A to perform electrophilic bromination reaction of aromatic ring C-H bonds, tracking and monitoring until the 3, 4-dimethoxytoluene is completely reacted, adding 30-40% of the total volume of an initiator solution, dissolving the initiator solution into a nonpolar solvent B in advance to prepare the initiator solution, slowly dropwise adding sulfuric acid B and the rest of the initiator solution to perform free radical bromination reaction of benzyl methyl C-H bonds, and after the reaction is completely completed, performing aftertreatment on a reaction solution to prepare 2-bromo-4, 5-dimethoxybenzyl bromide shown in formula (8).
The bromate is sodium bromate or potassium bromate, and sodium bromate is preferred; the bromide is sodium bromide or potassium bromide, preferably sodium bromide;
a, B in nonpolar solvent A and nonpolar solvent B is used to designate nonpolar solvents that distinguish different uses, nonpolar solvent A is used to dissolve 3, 4-dimethoxytoluene, nonpolar solvent B is used to dissolve the initiator, A, B has no chemical significance.
A, B in sulfuric acid A and sulfuric acid B is used to distinguish the sulfuric acids added in the different steps, sulfuric acid A is added in electrophilic bromination reaction of C-H bonds of aromatic rings, and sulfuric acid B is added in radical bromination reaction of C-H bonds of methyl groups at benzyl position, A, B has no chemical meaning.
Further, the nonpolar solvents a and B are preferably carbon tetrachloride; the volume of the nonpolar solvent A is generally 0.1-1 mL/mmol, preferably 0.16-0.76 mL/mmol, and more preferably 0.36-0.76 mL/mmol, based on the amount of 3, 4-dimethoxytoluene.
The volume dosage of the non-polar solvent B is generally 5-50 mL/g, preferably 6.2-30.4 mL/g based on the mass of the initiator.
The initiator is one or a mixture of more than two of Azodiisoheptanonitrile (ABVN), Azodiisobutyronitrile (AIBN) and dibenzoyl peroxide (BPO), and preferably the Azodiisoheptanonitrile (ABVN);
the mass usage amount of the initiator is 3-24 g/mol, preferably 4.6-22.4 g/mol, more preferably 10-22.4 g/mol, and more preferably 17-22.4 g/mol based on the mass of the 3, 4-dimethoxytoluene.
In the invention, sulfuric acid is respectively added in two steps of electrophilic bromination reaction of C-H bonds of an aromatic ring and radical bromination reaction of C-H bonds of a benzyl methyl, and the total amount of the sulfuric acid, namely the total amount of sulfuric acid A and sulfuric acid B is 50-55% of the sum of the total amount of bromate and bromide.
Further, the sulfuric acid A added in electrophilic bromination reaction of the C-H bond of the aromatic ring is half volume of the total amount of sulfuric acid, and the sulfuric acid B added in radical bromination reaction of the C-H bond of the benzyl position is half volume of the total amount of sulfuric acid.
The amount and concentration of the sulfuric acid A or the sulfuric acid B are the same and are 6.5-18.4 mol/L, preferably 8-12 mol/L, and more preferably 11-12 mol/L.
Further, the dropping speed of the sulfuric acid A added during the electrophilic bromination reaction of the C-H bond of the aromatic ring is preferably 0.01 to 0.1mL/min, more preferably 0.02 to 0.06 mL/min.
Further, the dropping speed of the sulfuric acid B added during the radical bromination reaction of the benzylic methyl C-H bond is preferably 0.01 to 0.1mL/min, more preferably 0.02 to 0.05 mL/min.
When the rest of the initiator solution is dripped, the dripping speed is preferably 0.01-0.1 mL/min, and more preferably 0.02-0.05 mL/min.
In the present invention, the reaction system is always heated to reflux.
The post-treatment method of the reaction liquid comprises the following steps: cooling the reaction liquid to room temperature, filtering, adding a sodium bicarbonate solution into the filtrate for washing, standing, separating liquid, drying an organic phase by using anhydrous sodium sulfate, filtering, concentrating, and purifying a crude product by column chromatography or recrystallization to obtain the 2-bromo-4, 5-dimethoxy benzyl bromide shown in the formula (8).
The washing is generally performed by using a sodium bicarbonate solution, and the mass concentration of the sodium bicarbonate solution is 3-10%.
The elution solvent for the column chromatography is preferably a mixture of ethyl acetate and petroleum ether.
The recrystallization is generally carried out by taking a mixed solvent of ethyl acetate and petroleum ether as a solvent.
In the present invention, the progress of the reaction can be monitored by gas chromatography.
The method of the invention is characterized in that:
firstly, a redox system consisting of bromate, bromide and sulfuric acid is used as a brominating agent. Its advantage has three aspects: 1) under the condition of no sulfuric acid, the bromate and the bromide do not have redox reaction, so that the generation speed of bromine can be regulated and controlled by controlling the addition of the sulfuric acid, the electrophilic bromination reaction speed of the C-H bond of the aromatic ring is regulated and controlled, and the selectivity of the first-step reaction is improved; 2) the bromate and the bromide are solid substances, the purity of industrial products is stable, the dosage can be accurately calculated, and a polybrominated product formed by excessive bromine can be avoided; 3) the bromate and the bromide are non-volatile substances, and the operation is simple and safe.
Secondly, a nonpolar solvent carbon tetrachloride is used as a solvent for reaction, and the effects are as follows: 1) the nonpolar solvent is not beneficial to electrophilic bromination reaction of the C-H bond of the aromatic ring, and the electrophilic bromination reaction rate of the C-H bond of the aromatic ring can be reduced, so that the selectivity of the first-step reaction is improved, and the formation of byproducts (3) to (7) is avoided; 2) the nonpolar carbon tetrachloride is not miscible with water, so that trace water in the sulfuric acid is not brought into the organic solvent, and the reaction can be carried out in the nonpolar organic solvent; 3) nonpolar carbon tetrachloride is used as a solvent, which is beneficial to the free radical bromination reaction of benzyl methyl C-H bond (the second step), and can realize two-step reaction in one pot.
And thirdly, in the free radical bromination reaction of the benzyl methyl C-H bond, an initiator is added to promote the free radical substitution reaction, so that the formation of a polysubstituted product on an aromatic ring is avoided.
The reaction is carried out in one pot, the control of the electrophilic bromination reaction rate and the control of the reaction end point are realized by controlling the dripping speed and the adding amount of the sulfuric acid, and the formation of other electrophilic byproducts is avoided; and after the first-step reaction is finished, adding an initiator and the rest sulfuric acid to carry out free radical bromination reaction of a benzylic methyl C-H bond (the second step), wherein the application of the initiator and a nonpolar reaction solvent can well promote the free radical bromination reaction and inhibit the electrophilic bromination reaction on an aromatic ring, so that the formation of polybrominated by-products on the aromatic ring is avoided, and the yield of the target product 2-bromo-4, 5-dimethoxy benzyl bromide (8) is improved.
The method is carried out by adopting a one-pot method, has cheap and easily obtained raw materials, is simple, convenient and safe to operate, simplifies the production process, reduces the production cost, obviously improves the yield of the 2-bromo-4, 5-dimethoxy benzyl bromide (8), reaches the yield of 85 percent, and is very suitable for industrial production.
Detailed Description
The substantial and significant advantages of the present invention are further illustrated below by the examples, without limiting the scope of the invention thereto.
Example 1
3, 4-dimethoxytoluene (7.6g,50mmol), sodium bromate (6.0g,40mmol), sodium bromide (8.2g,80mmol) and carbon tetrachloride (18mL) are added into a reaction bottle provided with a stirring device, a reflux condenser tube, a thermometer and a tail gas absorption device, heated to reflux, slowly dropwise added with 1/2 volume of sulfuric acid (60mmol of concentrated sulfuric acid is diluted with 4mL of water and is added within about 1.5h), tracked by gas chromatography, after a substrate completely participates in the reaction, rapidly added with 1/3 volume of initiator solution (0.25g of ABVN is dissolved in 7mL of carbon tetrachloride), after violent reflux of the system occurs, continuously and slowly dropwise added with the rest of sulfuric acid and initiator solution (added within about 4.5 h), continuously reacted until no product is formed or a byproduct is obviously increased (about 1.5h), cooled to room temperature, filtered, and the filtrate is washed by 10mL of sodium bicarbonate solution (5 percent), Standing to separateThe organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (elution solvent ethyl acetate: petroleum ether: 1:30 by volume) to give 8.16g of 2-bromo-4, 5-dimethoxybenzyl bromide in 53% yield. The product is a white solid; melting point 82.1-83.2 deg.C;1H NMR(400MHz,CDCl3)7.02(s,1H),6.93(s,1H),4.59(s,2H),3.88(s,3H),3.87(s,3H).
example 2
3, 4-dimethoxytoluene (7.6g,50mmol), sodium bromate (6.0g,40mmol), sodium bromide (8.2g,80mmol) and carbon tetrachloride (18mL) are added into a reaction bottle provided with a stirring device, a reflux condenser tube, a thermometer and a tail gas absorption device, heated to reflux, slowly dropwise added with 1/2 volume of sulfuric acid (60mmol of concentrated sulfuric acid is diluted with 4mL of water and is added within about 1.5h), tracked by gas chromatography, after a substrate completely participates in the reaction, rapidly added with 1/3 volume of initiator solution (0.16g of AIBN is dissolved in 7mL of carbon tetrachloride), after violent reflux of the system occurs, continuously dropwise added with the rest of sulfuric acid and initiator solution (added within about 4.5 h), continuously reacted until no product is formed or a byproduct is obviously increased (about 1.5h), cooled to room temperature, filtered, and the filtrate is washed by 10mL of sodium bicarbonate solution (5 percent), The organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (elution solvent was ethyl acetate: petroleum ether: 1:30 by volume) to give 4.15g of 2-bromo-4, 5-dimethoxybenzyl bromide, yield 27%.
Example 3
3, 4-dimethoxytoluene (7.6g,50mmol), sodium bromate (6.0g,40mmol), sodium bromide (8.2g,80mmol) and carbon tetrachloride (38mL) are added into a reaction bottle provided with a stirring device, a reflux condenser tube, a thermometer and a tail gas absorption device, heated to reflux, slowly dropwise added with 1/2 volume of sulfuric acid (60mmol of concentrated sulfuric acid is diluted with 4mL of water and is added within about 1 hour), tracked by gas chromatography, after a substrate completely participates in the reaction, rapidly added with 1/3 volume of initiator solution (0.25g of azodiisoheptonitrile is dissolved in 7mL of carbon tetrachloride), after violent reflux of the system occurs, continuously dropwise added with the rest of sulfuric acid and initiator solution (is added within about 4.5 hours), continuously reacted until a product is not formed or a byproduct is obviously increased (about 1.5 hours), cooled to room temperature, filtered, and the filtrate is washed by 10mL of sodium bicarbonate solution (5 percent), The organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (elution solvent was ethyl acetate: petroleum ether: 1:30 by volume) to give 6.9g of 2-bromo-4, 5-dimethoxybenzyl bromide with a yield of 45%.
Example 4
3, 4-dimethoxytoluene (7.6g,50mmol), sodium bromate (6.0g,40mmol), sodium bromide (8.2g,80mmol) and carbon tetrachloride (18mL) are added into a reaction bottle provided with a stirring device, a reflux condenser tube, a thermometer and a tail gas absorption device, heated to reflux, slowly dropwise added with 1/2 volume of sulfuric acid (60mmol of concentrated sulfuric acid is diluted with 2mL of water and is added within about 1 hour), tracked by gas chromatography, after a substrate completely participates in the reaction, rapidly added with 1/3 volume of initiator solution (0.25g of ABVN is dissolved in 7mL of carbon tetrachloride), after violent reflux of the system occurs, continuously and slowly dropwise added with the rest of sulfuric acid and initiator solution (added within about 4.5 hours), and continuously reacted until no product is formed or a byproduct is obviously increased (about 1.5 hours), cooled to room temperature and filtered, and the filtrate is washed with 10mL of sodium bicarbonate solution (5 percent), The organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (elution solvent was ethyl acetate: petroleum ether: 1:30 by volume) to give 10.4g of 2-bromo-4, 5-dimethoxybenzyl bromide, in 68% yield.
Example 5
3, 4-dimethoxytoluene (7.6g,50mmol), sodium bromate (6.0g,40mmol), sodium bromide (8.2g,80mmol) and carbon tetrachloride (18mL) are added into a reaction bottle provided with a stirring device, a reflux condenser tube, a thermometer and a tail gas absorption device, heated to reflux, slowly dropwise added with 1/2 volume of sulfuric acid (60mmol of concentrated sulfuric acid is diluted with 2mL of water and is added within about 1.5h), tracked by gas chromatography, after a substrate completely participates in the reaction, rapidly added with 1/3 volume of initiator solution (0.62g of ABVN is dissolved in 7mL of carbon tetrachloride), after violent reflux of the system occurs, continuously and slowly dropwise added with the rest of sulfuric acid and initiator solution (added within about 4.5 h), continuously reacted until no product is formed or a byproduct is obviously increased (about 1.5h), cooled to room temperature, filtered, and the filtrate is washed by 10mL of sodium bicarbonate solution (5 percent), The organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (elution solvent was ethyl acetate: petroleum ether: 1:30 by volume) to give 11.8g of 2-bromo-4, 5-dimethoxybenzyl bromide, 77% yield.
Example 6
3, 4-dimethoxytoluene (7.6g,50mmol), sodium bromate (6.0g,40mmol), sodium bromide (8.2g,80mmol) and carbon tetrachloride (18mL) are added into a reaction bottle provided with a stirring device, a reflux condenser tube, a thermometer and a tail gas absorption device, heated to reflux, slowly dropwise added with 1/2 volume of sulfuric acid (60mmol of concentrated sulfuric acid is diluted with 2mL of water and is added within about 1.5h), tracked by gas chromatography, after a substrate completely participates in the reaction, rapidly added with 1/3 volume of initiator solution (0.87g of ABVN is dissolved in 7mL of carbon tetrachloride), after violent reflux of the system occurs, continuously and dropwise added with the rest of sulfuric acid and initiator solution (added within about 4.5 h), continuously reacted until no product is formed or a byproduct is obviously increased (about 1.5h), cooled to room temperature, filtered, and the filtrate is washed by 10mL of sodium bicarbonate solution (5 percent), The organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (elution solvent was ethyl acetate: petroleum ether: 1:30 by volume) to give 12.6g of 2-bromo-4, 5-dimethoxybenzyl bromide, in 82% yield.
Example 7
3, 4-dimethoxytoluene (7.6g,50mmol), sodium bromate (6.0g,40mmol), sodium bromide (8.2g,80mmol) and carbon tetrachloride (18mL) are added into a reaction bottle provided with a stirring device, a reflux condenser tube, a thermometer and a tail gas absorption device, heated to reflux, slowly dropwise added with 1/2 volume of sulfuric acid (60mmol of concentrated sulfuric acid is diluted with 2mL of water and is added within about 1.5h), tracked by gas chromatography, after a substrate completely participates in the reaction, rapidly added with 1/3 volume of initiator solution (0.87g of ABVN is dissolved in 7mL of carbon tetrachloride), after violent reflux of the system occurs, continuously and dropwise added with the rest of sulfuric acid and initiator solution (added within about 4.5 h), continuously reacted until no product is formed or a byproduct is obviously increased (about 1.5h), cooled to room temperature, filtered, and the filtrate is washed by 10mL of sodium bicarbonate solution (5 percent), The organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by recrystallization (recrystallization solvent ethyl acetate: petroleum ether: 1:13 by volume) to obtain 12.3g of 2-bromo-4, 5-dimethoxybenzyl bromide with a yield of 80%.
Example 8
3, 4-dimethoxytoluene (7.6g,50mmol), sodium bromate (6.0g,40mmol), sodium bromide (8.2g,80mmol) and carbon tetrachloride (18mL) are added into a reaction bottle provided with a stirring device, a reflux condenser tube, a thermometer and a tail gas absorption device, heated to reflux, 1/2 volume of sulfuric acid (60mmol of concentrated sulfuric acid is diluted by 2mL of water and is added within about 1.5h), tracked by gas chromatography, after a substrate completely participates in the reaction (about 1h), 1/3 volume of initiator solution (1.12g of ABVN is dissolved in 7 mL) is rapidly added, after violent reflux of the system occurs, the rest of sulfuric acid and initiator solution are continuously and dropwise added within about 4.5 h), the reaction is continued until no product is formed or a byproduct is obviously increased (about 1.5h), the reaction is carried out at room temperature and filtered, and the filtrate is washed by 10mL of sodium bicarbonate solution (5 percent), The organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by recrystallization (recrystallization solvent ethyl acetate: petroleum ether: 1:13 by volume) to give 13.08g of 2-bromo-4, 5-dimethoxybenzyl bromide in 85% yield.
Example 9
3, 4-dimethoxytoluene (7.6g,50mmol), sodium bromate (6.29g,41.7mmol), sodium bromide (8.58g,83.3mmol) and carbon tetrachloride (18mL) are added into a reaction bottle provided with a stirring device, a reflux condenser tube, a thermometer and a tail gas absorption device, the reaction bottle is heated to reflux, 1/2 volume of sulfuric acid (62.5mmol of concentrated sulfuric acid is diluted by 2mL of water and is added within about 1.5h), the reaction bottle is tracked by gas chromatography, after a substrate completely participates in the reaction, 1/3 volume of initiator solution (1.12g of ABVN is dissolved in 7mL of carbon tetrachloride) is rapidly added, after violent reflux of the system occurs, the rest of sulfuric acid and initiator solution (added within about 4.5 h) are continuously added, the reaction is continued until a product is not formed or a byproduct is obviously increased (about 2h), the reaction bottle is cooled to room temperature and filtered, and a filtrate is washed by 10mL of sodium bicarbonate solution (5 percent), The organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by recrystallization (recrystallization solvent ethyl acetate: petroleum ether: 1:13 by volume) to obtain 13.01g of 2-bromo-4, 5-dimethoxybenzyl bromide in 84% yield.
Example 10
Adding 3, 4-dimethoxytoluene (7.6g,50mmol), sodium bromate (6.54g,43.3mmol), sodium bromide (8.93g,86.7mmol) and carbon tetrachloride (18mL) into a reaction bottle provided with a stirring device, a reflux condenser tube, a thermometer and a tail gas absorption device, heating to reflux, slowly dropwise adding 1/2 volume of sulfuric acid (65.5mmol of concentrated sulfuric acid is diluted with 2mL of water and is added within about 1 hour), tracking by using gas chromatography, quickly adding 1/3 volume of initiator solution (1.12g of ABVN is dissolved in 7 mL) after a substrate completely participates in the reaction, after violent reflux of the system, continuously dropwise adding the rest sulfuric acid and the initiator solution (is added within about 4.5 hours), continuously reacting until no more products or byproducts are obviously increased (about 1.5 hours), cooling to room temperature, filtering, washing carbon tetrachloride with 10mL of sodium bicarbonate solution (5%), filtering, The organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by recrystallization (recrystallization solvent ethyl acetate: petroleum ether: 1:13 by volume) to obtain 12.93g of 2-bromo-4, 5-dimethoxybenzyl bromide with a yield of 84%.
Claims (10)
1. A preparation method of an pinaverium bromide intermediate 2-bromo-4, 5-dimethoxy benzyl bromide is characterized by comprising the following steps:
in a nonpolar solvent, bromine released by oxidation reduction reaction of bromate and bromide under the action of sulfuric acid is taken as a bromine source, the bromine and 3, 4-dimethoxytoluene shown in a formula (1) are subjected to electrophilic bromination reaction of aromatic ring C-H bonds, after the reaction is completed, an initiator and sulfuric acid are added, and free radical bromination reaction of benzyl methyl C-H bonds is carried out, so that 2-bromo-4, 5-dimethoxybromobenzyl shown in a formula (8) is prepared; the reaction formula is shown as follows:
2. the method of claim 1, wherein the method is: adding 3, 4-dimethoxytoluene shown in formula (1), bromate and bromide solid into a nonpolar solvent, heating to reflux, slowly dropwise adding sulfuric acid, carrying out electrophilic bromination reaction of aromatic ring C-H bonds, tracking and monitoring until the 3, 4-dimethoxytoluene is completely reacted, adding an initiator and sulfuric acid, carrying out free radical bromination reaction of benzyl methyl C-H bonds, and after the reaction is completely finished, carrying out post-treatment on the reaction solution to obtain the 2-bromo-4, 5-dimethoxybenzyl bromide shown in formula (8).
3. The method according to claim 1, wherein the mass ratio of bromate to bromide is 1:2, and the mass ratio of 3, 4-dimethoxytoluene to bromate represented by the formula (1) is 1:0.8 to 0.9.
4. The method of claim 1, wherein the bromate salt is sodium bromate or potassium bromate; the bromide is sodium bromide or potassium bromide.
5. The method of claim 1 wherein the initiator is one or a mixture of two or more of azobisisoheptonitrile, azobisisobutyronitrile, and dibenzoyl peroxide.
6. The method of claim 1, wherein the non-polar solvent is carbon tetrachloride.
7. A method according to any one of claims 1 to 6, characterized in that it is carried out by the following steps:
adding 3, 4-dimethoxytoluene shown in formula (1), bromate and bromide solid into a nonpolar solvent A, heating to reflux, slowly dropwise adding sulfuric acid A to perform electrophilic bromination reaction of aromatic ring C-H bonds, tracking and monitoring until the 3, 4-dimethoxytoluene is completely reacted, adding 30-40% of the total volume of an initiator solution, dissolving the initiator solution into a nonpolar solvent B in advance to prepare the initiator solution, slowly dropwise adding sulfuric acid B and the rest of the initiator solution to perform free radical bromination reaction of benzyl methyl C-H bonds, and after the reaction is completely completed, performing aftertreatment on a reaction solution to prepare 2-bromo-4, 5-dimethoxybenzyl bromide shown in formula (8).
8. The method according to claim 7, wherein the mass amount of the initiator is 3 to 24g/mol based on the mass amount of 3, 4-dimethoxytoluene.
9. The method according to claim 7, wherein the total amount of sulfuric acid A and sulfuric acid B is 50 to 55% of the sum of the total amount of bromate and bromide; the mass concentration of the sulfuric acid A or the sulfuric acid B is the same and is 6.5-18.4 mol/L; the added sulfuric acid A is half volume of the total amount of sulfuric acid used in electrophilic bromination of C-H bonds of aromatic rings, and the added sulfuric acid B is half volume of the total amount of sulfuric acid used in radical bromination of C-H bonds of benzyl methyl groups.
10. The method according to claim 7, wherein the post-treatment method of the reaction solution comprises: cooling the reaction liquid to room temperature, filtering, adding a sodium bicarbonate solution into the filtrate for washing, standing, separating liquid, drying an organic phase by using anhydrous sodium sulfate, filtering, concentrating, and purifying a crude product by column chromatography or recrystallization to obtain the 2-bromo-4, 5-dimethoxy benzyl bromide shown in the formula (8).
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