CN102285878B - Method for preparing 2-halo-4,5-dimethoxy benzoic acid - Google Patents
Method for preparing 2-halo-4,5-dimethoxy benzoic acid Download PDFInfo
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Abstract
The invention discloses a method for preparing 2-halo-4,5-dimethoxy benzoic acid. The method comprises: performing targeted halogenation of odimethoxy benzene serving as a raw material by using sulfuric acid, hydrogen peroxide and metal halide to obtain 3,4-dimethoxy halogenated benzene; and performing targeted cholromethylation of 3,4-dimethoxy halogenated benzene by using paraformaldehyde and hydrochloric acid to obtain 2-halo-4,5-dimethoxy benzyl chloride; and preparing the 2-halo-4,5-dimethoxy benzyl chloride by potassium permanganate oxidation in presence of tetrabutyl ammonium bromide serving as a catalyst. In the invention, the raw material is cheap and readily available, the product yield is high, the technical process is novel and environment-friendly, the reaction conditions are mild, the operation is simple, and the method is very suitable for industrial large-scale production.
Description
Technical field
The present invention relates to the field of chemical synthesis, particularly a kind of 2-halogen-4 of preparing, the method for 5-dimethoxybenzoic acid.
Background technology
2-halogen-4,5-dimethoxybenzoic acid, structure is suc as formula shown in I, can be used as a kind of intermediate pharmaceutically, for synthesizing of the class medicines such as various flavones, flavanone, isoflavones and mountain ketone, as patent CN201110004591.6 is just usingd it as preparing one of key intermediate raw material of mango aglycone.
Formula I
At present, domestic and foreign literature is to 2-halogen-4, the rare report of the preparation method of 5-dimethoxybenzoic acid, and according to the method for making of the 2-BROMO-4,5-DIMETHOXYBENZOIC ACID of only a small amount of bibliographical information, its main technique route and method have two kinds below:
First method---3,4-dimethoxy benzaldehyde method: with 3,4-dimethoxy benzaldehyde is raw material, in acetic acid, make 2-bromo-4 with bromine generation bromo-reaction, 5-dimethoxy benzaldehyde, then make 2-BROMO-4,5-DIMETHOXYBENZOIC ACID (reference: Collection of Czechoslovak Chemical Communications through oxidation, 53 (12), 3184-92; 1988; Piatak, Flynn, Yim, and Roosenberg.Observations on Bromine Rearrangement during Demethylation of Bromomethoxybenzoic Acids.J.Org.Chem., Vol.42, No.6,1977,1068-1070; Chai-Lin Kao and Ji-Wang Chern.A Novel Strategy for the Synthesis of Benzofuran Skeleton Neolignans:Application to Ailanthoidol, XH-14, and Obovaten.J.Org.Chem.2002,67,6772-6787), its operational path is as follows:
The subject matter that the method exists is as follows:
1) yield is low.The first step yield 65%, second step yield 74%, two step total recovery only has 48%.
2) bromo-reaction difficulty is large, long reaction time, poor selectivity.The first step is to 3, when 4-dimethoxy benzaldehyde carries out halo, owing to being subject to the joint effect of aldehyde radical steric hindrance and electronic effect, halo difficulty is larger, need long-time reaction, and the directional selectivity of halo is poor, occurring when C-6 position replaces to be also attended by C-2, the generation that C-5 position replaces, so reactant complicated component, after finishing, reaction also needs to adopt column chromatography, the means such as recrystallization could realize the separation of principal product, not only yield is low, and time-consuming, high (the document: Chai-Lin Kao and Ji-Wang Chern.A Novel Strategy for the Synthesis of Benzofuran Skeleton Neolignans:Application to Ailanthoidol of production cost, XH-14, and Obovaten.J.Org.Chem.2002, 67, 6772-6787).
3) when the first step is carried out bromo to Veratraldehyde, use the high bromine of toxicity, large to environment and hazard to person, and bromine is volatile gases, character is active, transportation, stores and operation is used all inconvenient.
Second method---3,4-dimethoxybenzoic acid method: directly with 3,4-dimethoxybenzoic acid is raw material, in acetic acid with bromine generation bromo-reaction, one step makes 2-BROMO-4,5-DIMETHOXYBENZOIC ACID (document: PCT Int.Appl., 2007103260,13Sep 2007), its operational path is as follows:
The problem that the method exists is:
1) raw material 3, and 4-dimethoxybenzoic acid price is high, and apparent availability is little, cannot meet batch production needs on a large scale;
2) be faced with equally the height poison of bromine, high harm and transportation, store and use the problems such as inconvenience;
3) compare with first method, because the impact of carboxyl steric hindrance and electronic effect is larger than aldehyde radical, bromo-reaction difficulty is larger, and the reaction times is longer, and selectivity is poorer, although only have single step reaction, actual recovery is less than 50%.Therefore, the method is substantially without actual application value.
The synthetic method that prior art is used, exists raw material to be difficult for obtaining more, and yield is low, pollute greatly, and high in cost of production problem, thereby can only meet small-scale laboratory study needs, and be worth without practical application in industry.Therefore, need to find a kind of economical and practical and preparation 2-halogen-4 that gained productive rate is high, the method for 5-dimethoxybenzoic acid.
Summary of the invention
The technical problem to be solved in the present invention is that 5-dimethoxybenzoic acid is prepared the shortcoming that productive rate is low for 2-halogen-4 in prior art, provides a kind of high yield to prepare 2-halogen-4, the method for 5-dimethoxybenzoic acid.
The technological step that the present invention takes is, 1) veratrole and sulfuric acid, hydrogen peroxide and metal halide are that 30～60 ℃, molar feed ratio are to react under 1.0: 0.5～0.8: 1.0～1.2: 1.0～1.2 condition in temperature, obtain 3,4-dimethoxy halogeno-benzene; 2) 3,4-dimethoxy halogeno-benzene and paraformaldehyde, aqueous hydrochloric acid are that 40～90 ℃, molar feed ratio are to react under 1.0: 1.0～1.1: 1.5～2.5 condition in temperature, obtain 2-halogen-4,5-dimethoxy benzyl chlorine; 3) 2-halogen-4,5-dimethoxy benzyl chlorine is that 50～90 ℃, molar feed ratio are to react under 1.0: 3.0～3.5: 0.02～0.10 condition in temperature in the aqueous solution of potassium permanganate and Tetrabutyl amonium bromide, obtains 2-halogen-4,5-dimethoxybenzoic acid.
Particular content of the present invention is:
The first step: veratrole is under the effect of sulfuric acid, hydrogen peroxide and metal halide, and stirring reaction is 2～4 hours at 30～60 ℃, obtains 3,4-dimethoxy halogeno-benzene:
Wherein, described metal halide is sodium-chlor or Sodium Bromide, Repone K, Potassium Bromide, and the reasonable molar feed ratio of veratrole, sulfuric acid, hydrogen peroxide and metal bromide is 1.0: 0.5～0.8: 1.0～1.2: 1.0～1.2.
The feed ratio of each material and temperature of reaction are the most critical factors that affects this step reaction.Comparative example 5-8 has enumerated the contrast reaction outside reasonable molar feed ratio and temperature range.By comparative example, can be found out, the reaction outside reasonable molar feed ratio and temperature range, its by product increases, and principal product productive rate reduces.
As preferably, the molar feed ratio of veratrole, sulfuric acid, hydrogen peroxide and metal bromide is 1.0: 0.5～0.8: 1.0～1.2: 1.0～1.2.
As preferably, temperature of reaction is 30～60 ℃.
Can realize in C-4 position so directed halo obtain very single 3,4-dimethoxy halogeno-benzene.If temperature of reaction is too high or feed ratio is unreasonable, the directional property of reaction and unicity variation, occur that two replacements, trisubstituted possibility strengthen, and cause product component complicated, principal product separation difficulty.Otherwise temperature of reaction is too low, will cause the reaction times long.
This step reaction is reacted and can be completed for 2～4 hours under 30～60 ℃ of conditions.After having reacted, add in 0.5M aqueous solution of sodium bisulfite and superfluous hydrogen peroxide, by the ethyl acetate of 1～2 times of volume, extract at twice, extraction liquid merges, and steams except ethyl acetate, obtains 3,4-dimethoxy halogeno-benzene, and purity is greater than 95%, yield approximately 97%.
Second step: at 40～90 ℃ of 3,4-dimethoxy halogeno-benzene and paraformaldehyde, aqueous hydrochloric acids, stirring reaction is 4～6 hours, obtains 2-halogen-4,5-dimethoxy benzyl chlorine.
The feed ratio of each material and temperature of reaction are the most critical factors that affects this step reaction.Comparative example 11-13 has enumerated the contrast reaction outside reasonable molar feed ratio and temperature range.By comparative example, can be found out, the reaction outside reasonable molar feed ratio and temperature range, its by product increases, and principal product productive rate reduces.
As preferably, the molar feed ratio of this reaction 3,4-dimethoxy halogeno-benzene and paraformaldehyde, hydrochloric acid is 1.0: 1.0～1.1: 1.5～2.5.
As preferably, temperature of reaction is controlled at 40～90 ℃.
Temperature of reaction is too low, and reaction time consumption is long; Otherwise temperature of reaction surpasses 90 ℃, by product increases, and causes principal product yield to decline, aftertreatment difficulty.
After reaction finishes, reaction solution is down to room temperature, and with the dichloromethane extraction twice of 1～2 times of volume, extraction liquid merges, wash with water to nearly neutrality, by appropriate anhydrous magnesium sulfate or dried over sodium sulfate, vacuum reclaims dichloromethane solvent, drains as far as possible, obtain 2-halogen-4,5-dimethoxy benzyl chlorine, purity is greater than 93%, and yield is greater than 97%.
The 3rd step: 2-halogen-4,5-dimethoxy benzyl chlorine in the aqueous solution of potassium permanganate and Tetrabutyl amonium bromide at 50～90 ℃ stirring reaction 5～9 hours, obtain 2-halogen-4,5-dimethoxybenzoic acid.
The feed ratio of each material and temperature of reaction are the most critical factors that affects this step reaction.Comparative example 16-19 has enumerated the contrast reaction outside reasonable molar feed ratio and temperature range.By comparative example, can be found out, the reaction outside reasonable molar feed ratio and temperature range, its by product increases, and principal product productive rate reduces.
As preferably, these step reaction 2-halogen-4, the molar feed ratio of 5-dimethoxy benzyl chlorine and potassium permanganate, Tetrabutyl amonium bromide is 1.0: 3.0～3.5: 0.02～0.10.
As preferably, temperature of reaction is 50～90 ℃.
In this step reaction, temperature of reaction is very large on yield impact, need strictly control.Temperature of reaction is too low, and reaction is difficult to thoroughly carry out, and yield is low; Otherwise temperature of reaction is too high, by product increases, and causes equally principal product yield to decline.
After reaction finishes, reaction solution is taken advantage of heat filtering, and filtrate is used salt acid for adjusting pH to 4, and adularescent Precipitation more than standing 3h, filters, and filtrate is drying to obtain 2-halogen-4,5-dimethoxybenzoic acid.Product purity is greater than 94%, and yield is more than 95%.
Major advantage of the present invention is:
1) the present invention compared with prior art, 2-halogen-4, the productive rate of 5-dimethoxybenzoic acid is greater than 88%, compared with the total recovery of prior art 48～50%, is significantly increased;
2) compared with prior art, raw material veratrole is existing large-scale industrial production at home in the present invention, and the source of goods is stable, and price is well below raw materials used price in bibliographical information;
3) compared with prior art, the raw material veratrole that the present invention selects is when carrying out halogenating reaction, the steric hindrance that it suffers and the impact of electronic effect are far beyond 3,4-dimethoxy benzaldehyde and 3,4-dimethoxybenzoic acid is little, so halogenating reaction easily carries out, and directional selectivity is high, product is single, without carrying out loaded down with trivial details post excessively and recrystallization operation;
4) the present invention compared with prior art, with H
2sO
4/ H
2o
2/ NaX (or KX) system (X=Cl, Br) replaces Br of the prior art
2/ AcOH system is carried out halogenating reaction, has avoided the use of the volatile halogen of poisonous and harmful, friendly to environment and the person, is convenient to transportation, storage and operation and uses.
Embodiment
The invention discloses a kind of 2-of preparation halogen-4, the method for 5-dimethoxybenzoic acid, those skilled in the art can use for reference content herein, suitably improve processing parameter and realize.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the artly, they are all deemed to be included in the present invention.Method of the present invention and application are described by preferred embodiment, related personnel obviously can change methods and applications as herein described or suitably change and combination within not departing from content of the present invention, spirit and scope, realizes and apply the technology of the present invention.
The technological step that the present invention takes is, 1) veratrole and sulfuric acid, hydrogen peroxide and metal halide are that 30～60 ℃, molar feed ratio are to react under 1.0: 0.5～0.8: 1.0～1.2: 1.0～1.2 condition in temperature, obtain 3,4-dimethoxy halogeno-benzene; 2) 3,4-dimethoxy halogeno-benzene and paraformaldehyde, aqueous hydrochloric acid are that 40～90 ℃, molar feed ratio are to react under 1.0: 1.0～1.1: 1.5～2.5 condition in temperature, obtain 2-halogen-4,5-dimethoxy benzyl chlorine; 3) 2-halogen-4,5-dimethoxy benzyl chlorine is that 50～90 ℃, molar feed ratio are to react under 1.0: 3.0～3.5: 0.02～0.10 condition in temperature in the aqueous solution of potassium permanganate and Tetrabutyl amonium bromide, obtains 2-halogen-4,5-dimethoxybenzoic acid.
In specific embodiment, embodiment 1-4 has set forth the first step reaction of the inventive method when temperature condition is 30～60 ℃.Under such temperature condition, reaction can realize in C-4 position directed halo obtain very single 3,4-dimethoxy halogeno-benzene.If temperature of reaction is too high or feed ratio is unreasonable, the directional property of reaction and unicity variation, occur that two replacements, trisubstituted possibility strengthen, and cause product component complicated, principal product separation difficulty.Otherwise temperature of reaction is too low, will cause the reaction times long.
In specific embodiment, embodiment 9-11 has set forth the second step reaction of the inventive method when temperature condition is 40～90 ℃.If temperature of reaction is too low, reaction time consumption is long; Otherwise temperature of reaction surpasses 90 ℃, by product increases, and causes principal product yield to decline, aftertreatment difficulty.
In specific embodiment, embodiment 14-15 has set forth the three-step reaction of the inventive method when temperature condition is 50～90 ℃.In this step reaction, temperature of reaction is very large on yield impact, need strictly control.Temperature of reaction is too low, and reaction is difficult to thoroughly carry out, and yield is low; Otherwise temperature of reaction is too high, by product increases, and causes equally principal product yield to decline.
In order to make those skilled in the art understand better technical scheme of the present invention, below in conjunction with specific embodiment, the present invention is described in further detail.
Embodiment 1:3,4-dimethoxy chlorobenzene synthetic
Take 15.0g (0.11mol) veratrole and put in 250ml reaction flask, add 6.0g (0.06mol) vitriol oil, 14ml 30% hydrogen peroxide (to be roughly equal to 0.13mol H
2o
2) and 100ml water, under stirring, add 7.0g (0.12mol) sodium-chlor, in 50 ℃ of stirring reactions 3.5 hours, after TLC detects the disappearance of raw material point, add in 0.5M aqueous solution of sodium bisulfite and superfluous hydrogen peroxide, by about 200ml ethyl acetate, extract at twice (2 * 100ml), extraction liquid merges, and with the anhydrous magnesium sulfate drying of about 8g, vacuum reclaims ethyl acetate, drain as far as possible, obtain 3,4-dimethoxy chlorobenzene 18.3g, yield 98%, be light yellow oil, through HPLC, detect purity and reach 95.7%.
1HNMR(CDCl
3)δ3.86(s，3H)，3.88(s，3H)，6.75-6.91(m，3H)；
13CNMR(CDCl
3)δ56.0，56.1，112.0，112.1，120.3，125.7，149.6。
Embodiment 2:3,4-dimethoxy chlorobenzene synthetic
Take 36.0g (0.26mol) veratrole and put in 500ml reaction flask, add 18.0g (0.18mol) vitriol oil, 33ml 30% hydrogen peroxide (to be roughly equal to 0.29mol H
2o
2) and 200ml water, under stirring, add 21.0g (0.28mol) Repone K, in 45 ℃ of stirring reactions 4 hours, after TLC detects the disappearance of raw material point, add in 0.5M aqueous solution of sodium bisulfite and superfluous hydrogen peroxide, by about 300ml ethyl acetate, extract at twice (2 * 150ml), extraction liquid merges, and with the anhydrous magnesium sulfate drying of about 8g, vacuum reclaims ethyl acetate, drain as far as possible, obtain 3,4-dimethoxy chlorobenzene 43.6g, yield 97.2%, be light yellow oil, through HPLC, detect purity and reach 96.3%.
1HNMR(CDCl
3)δ3.86(s，3H)，3.88(s，3H)，6.75-6.91(m，3H)；
13CNMR(CDCl
3)δ56.0，56.1，112.0，112.1，120.3，125.7，149.6。
Embodiment 3:3,4-dimethoxy bromobenzene synthetic
Take 28.0g (0.20mol) veratrole and put in 500ml reaction flask, add 12.0g (0.12mol) vitriol oil, 24ml 30% hydrogen peroxide (to be roughly equal to 0.21mol H
2o
2) and 150ml water, under stirring, add 22.0g (0.21mol) Sodium Bromide, in 60 ℃ of stirring reactions 3 hours, after TLC detects the disappearance of raw material point, add in 0.5M aqueous solution of sodium bisulfite and superfluous hydrogen peroxide, by about 200ml ethyl acetate, extract at twice (2 * 100ml), extraction liquid merges, and with the anhydrous magnesium sulfate drying of about 8g, vacuum reclaims ethyl acetate, drain as far as possible, obtain 3,4-dimethoxy bromobenzene 42.8g, yield 97.3%, be light yellow oil, through HPLC, detect purity and reach 95.5%.
1HNMR(CDCl
3)δ3.81(s，3H)，3.82(s，3H)，6.69(d，J＝8.8Hz，1H，H6)，6.93-7.01(m，2H，H3、H5)。
Embodiment 4:3,4-dimethoxy bromobenzene synthetic
Take 40.0g (0.29mol) veratrole and put in 500ml reaction flask, add 17.0g (0.17mol) vitriol oil, 33ml 30% hydrogen peroxide (to be roughly equal to 0.29mol H
2o
2) and 250ml water, under stirring, add 36.0g (0.30mol) Potassium Bromide, in 50 ℃ of stirring reactions 4 hours, after TLC detects the disappearance of raw material point, add in 0.5M aqueous solution of sodium bisulfite and superfluous hydrogen peroxide, by about 300ml ethyl acetate, extract at twice (2 * 150ml), extraction liquid merges, and with the anhydrous sodium sulfate drying of about 10g, vacuum reclaims ethyl acetate, drain as far as possible, obtain 3,4-dimethoxy chlorobenzene 61.5g, yield 97.8%, be light yellow oil, through HPLC, detect purity and reach 95.9%.
1HNMR(CDCl
3)δ3.81(s，3H)，3.82?(s，3H)，6.69(d，J＝8.8Hz，1H，H6)，6.93-7.01(m，2H，H3、H5)。
Comparative example 5: the synthetic impact of molar feed ratio to 3,4-dimethoxy chlorobenzene
Take 15.0g (0.11mol) veratrole and put in 250ml reaction flask, add 4.0g (0.04mol) vitriol oil, 14ml 30% hydrogen peroxide (to be roughly equal to 0.13mol H
2o
2) and 100ml water, under stirring, add 7.0g (0.12mol) sodium-chlor, in 50 ℃ of stirring reactions 3.5 hours, after TLC detects the disappearance of raw material point, add in 0.5M aqueous solution of sodium bisulfite and superfluous hydrogen peroxide, by about 200ml ethyl acetate, extract at twice (2 * 100ml), extraction liquid merges, anhydrous magnesium sulfate drying with about 8g, vacuum reclaims ethyl acetate, drains as far as possible, obtains 3,4-dimethoxy chlorobenzene 12.6g, yield 67%.The molar feed ratio of this reaction sulfuric acid goes beyond the scope, so yield is lower.In Table 1
Comparative example 6: the synthetic impact of molar feed ratio to 3,4-dimethoxy chlorobenzene
Take 15.0g (0.11mol) veratrole and put in 250ml reaction flask, add 6.0g (0.06mol) vitriol oil, 14ml 30% hydrogen peroxide (to be roughly equal to 0.13mol H
2o
2) and 100ml water, under stirring, add 10.5g (0.18mol) sodium-chlor, in 50 ℃ of stirring reactions 3.5 hours, after TLC detects the disappearance of raw material point, add in 0.5M aqueous solution of sodium bisulfite and superfluous hydrogen peroxide, by about 200ml ethyl acetate, extract at twice (2 * 100ml), extraction liquid merges, anhydrous magnesium sulfate drying with about 8g, vacuum reclaims ethyl acetate, drains as far as possible, obtains 3,4-dimethoxy chlorobenzene 11.0g, yield 59%.The halid molar feed ratio of this reacting metal goes beyond the scope, so yield is lower.In Table 1
Comparative example 7: the synthetic impact of temperature to 3,4-dimethoxy chlorobenzene
Take 15.0g (0.11mol) veratrole and put in 250ml reaction flask, add 6.0g (0.06mol) vitriol oil, 14ml 30% hydrogen peroxide (to be roughly equal to 0.13mol H
2o
2) and 100ml water, under stirring, add 7.0g (0.12mol) sodium-chlor, in 80 ℃ of stirring reactions 3.5 hours, after TLC detects the disappearance of raw material point, add in 0.5M aqueous solution of sodium bisulfite and superfluous hydrogen peroxide, by about 200ml ethyl acetate, extract at twice (2 * 100ml), extraction liquid merges, anhydrous magnesium sulfate drying with about 8g, vacuum reclaims ethyl acetate, drains as far as possible, obtains 3,4-dimethoxy chlorobenzene 14.6g, yield 78%.This temperature of reaction is higher, causes by product to increase, and principal product yield reduces.In Table 1
Comparative example 8: the synthetic impact of temperature to 3,4-dimethoxy chlorobenzene
Take 15.0g (0.11mol) veratrole and put in 250ml reaction flask, add 6.0g (0.06mol) vitriol oil, 14ml 30% hydrogen peroxide (to be roughly equal to 0.13mol H
2o
2) and 100ml water, under stirring, add 7.0g (0.12mol) sodium-chlor, in 20 ℃ of stirring reactions 6 hours, through TLC, detect, still have part material point existence.Continuation stirring reaction 2 hours under 20 ℃ of conditions, TLC detects, and still has a small amount of raw material point to exist, and illustrates to react still thoroughly not complete.Add in 0.5M aqueous solution of sodium bisulfite and superfluous hydrogen peroxide, by about 200ml ethyl acetate, extract at twice (2 * 100ml), extraction liquid merges, anhydrous magnesium sulfate drying with about 8g, vacuum reclaims ethyl acetate, drains as far as possible, obtains 3,4-dimethoxy chlorobenzene 16.5g, yield approximately 88%.This temperature of reaction is too low, and reaction time consumption is long.In Table 1
The impact on reaction of table 1. molar feed ratio and temperature
Embodiment 9:2-is chloro-4,5-dimethoxy benzyl chlorine synthetic
Take 8.6g (0.05mol) 3,4-dimethoxy chlorobenzene is put in 250ml reaction flask, adds 10ml (about 0.11mol) concentrated hydrochloric acid, 1.5g (0.05mol) paraformaldehyde and 100ml water, and at 60 ℃, stirring reaction is 5 hours.After reaction finishes, reaction solution is down to room temperature, and with twice of dichloromethane extraction of 200ml (2 * 100ml), extraction liquid merges, wash with water to nearly neutrality, with about 10g anhydrous magnesium sulfate drying, vacuum reclaims dichloromethane solvent, drains as far as possible, obtain 2-chloro-4,5-dimethoxy benzyl chlorine 10.7g, yield 97.3%, detects purity through HPLC and reaches 93.8%.White powder,
1hNMR (CDCl
3) δ 3.86 (3H, s), 3.88 (3H, s), 4.61 (2H, s), 6.91 (1H, s) 7.02 (1H, s).
Synthesizing of embodiment 10:2-bromo-4,5-dimethoxy benzyl chlorine
Take 26.0g (0.12mol) 3,4-dimethoxy bromobenzene is put in 500ml reaction flask, adds 20ml (about 0.22mol) concentrated hydrochloric acid, 3.9g (0.13mol) paraformaldehyde and 200ml water, and at 70 ℃, stirring reaction is 4.5 hours.After reaction finishes, reaction solution is down to room temperature, and with twice of dichloromethane extraction of 300ml (2 * 150ml), extraction liquid merges, wash with water to nearly neutrality, with about 10g anhydrous sodium sulfate drying, vacuum reclaims dichloromethane solvent, drains as far as possible, obtain 2-bromo-4,5-dimethoxy benzyl chlorine 31.0g, yield 97.6%, detects purity through HPLC and reaches 95.1%.White powder, mp60-61 ℃,
1hNMR (CDCl
3) δ 3.81 (3H, s), 3.82 (3H, s), 4.60 (2H, s), 6.85 (1H, s) 6.97 (1H, s);
13cNMR (CDCl
3) δ 46.3,55.8,55.9,113.0,114.3,115.3,128.3,148.3,148.5; FTIR (KBr, cm
-1): 1440 (CH
2).
Comparative example 11: the synthetic impact of molar feed ratio on 2-bromo-4,5-dimethoxy benzyl chlorine
Take 26.0g (0.12mol) 3,4-dimethoxy bromobenzene is put in 500ml reaction flask, adds 12ml (about 0.13mol) concentrated hydrochloric acid, 3.9g (0.13mol) paraformaldehyde and 200ml water, and at 70 ℃, stirring reaction is 4.5 hours.Reaction solution is down to room temperature, and with twice of dichloromethane extraction of 300ml (2 * 150ml), extraction liquid merges, and washes with water to nearly neutrality, with about 10g anhydrous sodium sulfate drying, vacuum reclaims dichloromethane solvent, drains as far as possible, obtain 2-bromo-4,5-dimethoxy benzyl chlorine 21.4g, yield 67.4%.The molar feed ratio of this reaction hydrochloric acid is too low, so the yield of product is lower.In Table 2
Comparative example 12: the synthetic impact of temperature on 2-bromo-4,5-dimethoxy benzyl chlorine
Take 26.0g (0.12mol) 3,4-dimethoxy bromobenzene is put in 500ml reaction flask, add 20ml (about 0.22mol) concentrated hydrochloric acid, 3.9g (0.13mol) paraformaldehyde and 200ml water, at 25 ℃, stirring reaction is 6 hours, through TLC, detect and still have part material point to exist, under 25 ℃ of conditions, continue stirring reaction 2 hours again, TLC detects, still have a small amount of raw material point to exist, illustrate that reaction does not still thoroughly complete.Twice of dichloromethane extraction of 300ml (2 * 150ml) for reaction solution, extraction liquid merges, and washes with water to nearly neutrality, with about 10g anhydrous sodium sulfate drying, vacuum reclaims dichloromethane solvent, drains as far as possible, obtain 2-bromo-4,5-dimethoxy benzyl chlorine 27.6g, yield 86.9%.This temperature of reaction is too low, and the reaction times is long.In Table 2
Comparative example 13: the synthetic impact of temperature on 2-bromo-4,5-dimethoxy benzyl chlorine
Take 26.0g (0.12mol) 3,4-dimethoxy bromobenzene is put in 500ml reaction flask, adds 20ml (about 0.22mol) concentrated hydrochloric acid, 3.9g (0.13mol) paraformaldehyde and 200ml water, and at 100 ℃, stirring reaction is 4.5 hours.After reaction finishes, reaction solution is down to room temperature, with twice of 300ml dichloromethane extraction (2 * 150ml), extraction liquid merges, and washes with water to nearly neutrality, with about 10g anhydrous sodium sulfate drying, vacuum reclaims dichloromethane solvent, drains as far as possible, obtains 2-bromo-4,5-dimethoxy benzyl chlorine 26.4g, yield 83%.This temperature of reaction is too high, and by product increases, and principal product productive rate reduces.In Table 2
The impact on reaction of table 2 molar feed ratio and temperature
Embodiment 14:2-is chloro-4,5-dimethoxybenzoic acid synthetic
Take 17.6g (0.08mol) 2-chloro-4,5-dimethoxy benzyl chlorine is put in 500ml reaction flask, after adding 200ml water, 1.3g (0.004mol) Tetrabutyl amonium bromide, reaction solution is heated to 70 ℃, under stirring, add 38.0g (0.24mol) potassium permanganate, react 7 hours, through TLC, detecting raw material point disappears, reaction solution is taken advantage of heat filtering, and filtrate is used salt acid for adjusting pH to 4, adularescent Precipitation, standing 3h, filter, it is chloro-4 that filtrate is drying to obtain 2-, 5-dimethoxybenzoic acid 16.5g, yield 95.5%, detects purity 94.8% through HPLC.Fusing point: 183-185 ℃,
1hNMR (CDCl
3): δ 7.59 (s, 1H), δ 7.21 (s, 1H), δ 3.95 (s, 3H), δ 3.93 (s, 3H).
Synthesizing of embodiment 15:2-bromo-4,5-dimethoxybenzoic acid
Claim 29.1g (0.11mol) 2-bromo-4,5-dimethoxy benzyl chlorine is put in 500ml reaction flask, after adding 300ml water, 2.6g (0.008mol) Tetrabutyl amonium bromide, reaction solution is heated to 85 ℃, under stirring, add 55.3g (0.35mol) potassium permanganate, react 5 hours, through TLC, detecting raw material point disappears, reaction solution is taken advantage of heat filtering, and filtrate is used salt acid for adjusting pH to 4, adularescent Precipitation, standing 5h, filter, filtrate is drying to obtain 2-BROMO-4,5-DIMETHOXYBENZOIC ACID 27.3g, yield 95.3%, detects purity 96.7% through HPLC.Fusing point 188-190 ℃;
1hNMR (CDCl
3): δ 7.58 (s, 1H), δ 7.14 (s, 1H), δ 3.94 (s, 3H), δ 3.92 (s, 3H);
13cNMR (CDCl
3) δ 56.1,56.4,114.7,115.5,117.3,121.2,147.8,152.8,170.7.
Comparative example 16: the synthetic impact of molar feed ratio on 2-BROMO-4,5-DIMETHOXYBENZOIC ACID
Claim 29.1g (0.11mol) 2-bromo-4,5-dimethoxy benzyl chlorine to put in 500ml reaction flask, reaction solution is heated to 85 ℃ after adding 300ml water, 2.6g (0.008mol) Tetrabutyl amonium bromide, under stirring, add 24.9g (0.16mol) potassium permanganate, react 5 hours, reaction solution is taken advantage of heat filtering, filtrate is used salt acid for adjusting pH to 4, adularescent Precipitation, standing 5h, filters, filtrate is dry, obtain 2-BROMO-4,5-DIMETHOXYBENZOIC ACID 18.6g, yield 64.9%.This reaction potassium permanganate feed ratio is too low, so product yield is lower.In Table 3
Comparative example 17: the synthetic impact of molar feed ratio on 2-BROMO-4,5-DIMETHOXYBENZOIC ACID
Claim 29.1g (0.11mol) 2-bromo-4,5-dimethoxy benzyl chlorine to put in 500ml reaction flask, reaction solution is heated to 85 ℃ after adding 300ml water, 0.21g (0.00065mol) Tetrabutyl amonium bromide, under stirring, add 55.3g (0.35mol) potassium permanganate, react 5 hours, reaction solution is taken advantage of heat filtering, filtrate is used salt acid for adjusting pH to 4, adularescent Precipitation, standing 5h, filters, filtrate is dry, obtain 2-BROMO-4,5-DIMETHOXYBENZOIC ACID 16.4g, yield 57.2%.This reaction Tetrabutyl amonium bromide feed ratio is too low, so product yield is lower.In Table 3
Comparative example 18: the synthetic impact of temperature on 2-BROMO-4,5-DIMETHOXYBENZOIC ACID
Claim 29.1g (0.11mol) 2-bromo-4,5-dimethoxy benzyl chlorine is put in 500ml reaction flask, add after 300ml water, 2.6g (0.008mol) Tetrabutyl amonium bromide, under 25 ℃ of conditions, under stirring, add 55.3g (0.35mol) potassium permanganate, react 8 hours, through TLC, detect, raw material point still exists in a large number.Under 25 ℃ of conditions, continue stirring reaction 8 hours again, through TLC, detect and still have part material point to exist, reaction solution is taken advantage of heat filtering, and filtrate is used salt acid for adjusting pH to 4, adularescent Precipitation, standing 5h, filters, and filtrate is dry, obtain 2-BROMO-4,5-DIMETHOXYBENZOIC ACID 21.8g, yield 76.1%.This temperature of reaction is too low, and reaction is difficult to thoroughly carry out, length consuming time, and yield reduces.In Table 3
Comparative example 19: the synthetic impact of temperature on 2-BROMO-4,5-DIMETHOXYBENZOIC ACID
Claim 29.1g (0.11mol) 2-bromo-4,5-dimethoxy benzyl chlorine is put in 500ml reaction flask, after adding 300ml water, 2.6g (0.008mol) Tetrabutyl amonium bromide, reaction solution is heated to 98 ℃, under stirring, add 55.3g (0.35mol) potassium permanganate, react 5 hours, through TLC, detecting raw material point disappears, reaction solution is taken advantage of heat filtering, and filtrate is used salt acid for adjusting pH to 4, adularescent Precipitation, standing 5h, filter, filtrate is dry, obtains 2-bromo-4,5-dimethoxybenzoic acid 24.8g, yield 86.5%.This temperature of reaction is too high, and by product increases, and causes equally principal product yield to decline.In Table 3
The impact on reaction of table 3 molar feed ratio and temperature
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (10)
1. prepare 2-halogen-4 for one kind, the method for 5-dimethoxybenzoic acid, wherein halogen is bromine or chlorine, it is characterized in that, comprises the following steps:
1) veratrole and sulfuric acid, hydrogen peroxide and metal halide are to react under 30～60 ℃, the molar feed ratio condition that is 1.0:0.5～0.8:1.0～1.2:1.0～1.2 in temperature, obtain 3,4-dimethoxy halogeno-benzene; Described metal halide is sodium-chlor or Sodium Bromide, Repone K, Potassium Bromide;
2) 3,4-dimethoxy halogeno-benzene and paraformaldehyde, aqueous hydrochloric acid are to react under 40～90 ℃, the molar feed ratio condition that is 1.0:1.0～1.1:1.5～2.5 in temperature, obtain 2-halogen-4,5-dimethoxy benzyl chlorine;
3) 2-halogen-4,5-dimethoxy benzyl chlorine is to react under 50～90 ℃, the molar feed ratio condition that is 1.0:3.0～3.5:0.02～0.10 in temperature in the aqueous solution of potassium permanganate and Tetrabutyl amonium bromide, obtains 2-halogen-4,5-dimethoxybenzoic acid.
2. method according to claim 1, is characterized in that, molar feed ratio is 1.0:0.5～0.7:1.0～1.2:1.0～1.1 described in step 1).
3. method according to claim 1, is characterized in that, the step 1) reaction times is 1～8 hour.
4. method according to claim 3, is characterized in that, the step 1) reaction times is 2～4 hours.
5. method according to claim 1, is characterized in that step 2) described molar feed ratio is 1.0:1.0～1.1:1.8～2.1.
6. method according to claim 1, is characterized in that step 2) reaction times is 2～8 hours.
7. method according to claim 6, is characterized in that step 2) reaction times is 4～6 hours.
8. method according to claim 1, is characterized in that, molar feed ratio is 1.0:3.0～3.2:0.05～0.07 described in step 3).
9. method according to claim 1, is characterized in that, the step 3) reaction times is 2～10 hours.
10. method according to claim 9, is characterized in that, the step 3) reaction times is 5～9 hours.
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