CN103483166B - Method for preparing m-anisaldehyde - Google Patents
Method for preparing m-anisaldehyde Download PDFInfo
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- GVUMZPWBUAGJBP-UHFFFAOYSA-N CC(Oc1cc(C=O)ccc1)=O Chemical compound CC(Oc1cc(C=O)ccc1)=O GVUMZPWBUAGJBP-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/64—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of functional groups containing oxygen only in singly bound form
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/42—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by hydrolysis
- C07C45/43—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by hydrolysis of >CX2 groups, X being halogen
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
- C07C67/287—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
- C07C67/29—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by introduction of oxygen-containing functional groups
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Abstract
The invention relates to and provides a method for preparing m-anisaldehyde, and belongs to the technical field of medical chemical synthesis. The method comprises the following steps that the acetylation reaction is carried out on m-cresol and acetic anhydride under the condition of backflow, and 3-Diacetoxytoluene is obtained; under the action of a radical initiator, the 3-Diacetoxytoluene acts with chlorine so as to obtain mixed chloride of monochloride and dichloride, an alcohol solution containing water is added to neutralize urotropine, the Sommelet reaction is carried out, a compound in the formula IV is generated, and after the Sommelet reaction is finished, the solution is removed and Sommelet reaction fluid is obtained; a phase transfer catalyst and dimethyl sulfate are added to carry out the methylation reaction, the pH value is made to range from 7.5 to 10, and then methylation reaction fluid is obtained; an acidity reagent is added so that hydrolysis reaction can be carried out under the acidic condition, and then the m-anisaldehyde is obtained. The method has the advantages that raw materials are easy to obtain, cost is low, and the yield and purity of the finished m-anisaldehyde are high.
Description
Technical field
The present invention relates to a kind of preparation method of NSC 43794, belong to medication chemistry synthesis technical field.
Background technology
Return fragrant aldehyde between NSC 43794 is also called, its molecular structural formula is as follows:
Because NSC 43794 has lasting mountain quarrel fragrance, be widely used in the spices of preparation floral type; It is also a kind of organic synthesis intermediate, is widely used in the synthesis of food, medicine and daily chemical industry related products.As for the synthesis of have anti-cancer function 4H-chromene compounds, for the synthesis of having crying of a child beautiful jade compound etc. that is anticancer, anti-platelet function.Therefore, NSC 43794 has good using value.
At present, in prior art about the synthetic method of NSC 43794 report less, main adopt the synthesis of following several method:
Reacted under potassium hydroxide catalysed by 3-hydroxy benzaldehyde and methyl-sulfate, by the synthesis that methylates, its synthetic route is as follows:
Or adopt 3-bromoanisole and formaldehyde to synthesize under the effect of the catalyzer such as palladium, its synthetic route is as follows:
Or adopt 3-hydroxy benzaldehyde to make catalyzer at salt of wormwood, obtain NSC 43794 with iodomethane reaction under acetone solvent reflux conditions, this reaction scheme is as follows:
Although above-mentioned building-up reactions route is comparatively simple, the raw material 3-hydroxy benzaldehyde related to and the production cost of 3-bromobenzaldehyde high, and raw material is difficult to obtain.
Summary of the invention
The present invention is directed to above problems of the prior art, a kind of preparation method of NSC 43794 is provided, realize providing a kind of newly take meta-cresol as the preparation method of raw material, there is raw material be easy to get, easy handling and the low effect of cost, solve because hydroxyl in meta-cresol exists the problem causing radical initiation reaction cancellation.
The object of the invention is to be achieved by the following technical programs, a kind of preparation method of NSC 43794, the method comprises the following steps:
A, acetylization reaction: make meta-cresol and aceticanhydride under reflux conditions carry out acetylization reaction, obtain type I compound 3-acetoxyl group toluene;
B, chlorination reaction: under the effect of radical initiator, make benzyl position methyl and the chlorine generation chlorination reaction of type I compound 3-acetoxyl group toluene, obtains the mixing chloro-product of formula II compound one chlorine product and formula III compound dichloro product;
C, Suo Mulai react: the mixing chloro-product obtained by above-mentioned steps B adds in moisture alcoholic solvent, add urotropine again, make the formula II compound one chlorine product in mixing chloro-product carry out Suo Mulai and react production IV compound, after reaction terminates, except desolventizing, obtain the Suo Mulai reaction solution containing formula IV compound and formula III compound dichloro product;
D, methylation reaction: in above-mentioned Suo Mulai reaction solution, add phase-transfer catalyst and methyl-sulfate carries out methylation reaction, in described methylation reaction process, the pH value of reaction system is 7.5 ~ 10, after methylation reaction terminates, obtain the methylation reaction liquid containing NSC 43794 and formula V compound;
E, hydrolysis reaction: add acid reagent to obtained above containing in the methylation reaction liquid of NSC 43794 and formula V compound, formula V compound is hydrolyzed reaction in acid condition, after hydrolysis reaction terminates, carry out aftertreatment, obtain product NSC 43794.
The preparation method of NSC 43794 of the present invention, take meta-cresol as raw material, carries out acetylization reaction prior to aceticanhydride, can ensure that follow-up chlorination reaction and Suo Mulai reaction carry out smoothly.If when phenolic hydroxyl group exists, chlorination reaction is crossed after free radical in kind causes and can, very soon by phenolic hydroxyl group cancellation, be caused chlorination reaction not carry out.Therefore, by first protecting phenolic hydroxyl group, the generation of side reaction can either be reduced, efficiency and the yield of reaction can be improved again.Then, under the effect of radical initiator, chlorination reaction can be made to carry out smoothly, in chlorination process, to prepare intermediate product formula II compound one chlorine product and formula III compound dichloro product, also at a small amount of trichlorine product in chlorination reaction process, those skilled in the art can carry out adjusting the generation controlling trichlorine product according to the molar equivalent ratio of the raw material of routine, can improve transformation efficiency and the yield of intermediate product raw material.As preferably, the content controlling trichlorine product is no more than 0.5%.On the other hand, because intermediate product formula II compound one chlorine product does not become aldehyde by hydrolysis reaction, therefore, first intermediate product formula II compound one chlorine product is made to carry out reacting to urotropine and generate corresponding aldehyde by Suo Mulai reaction (Sommelet reaction), then, after again the Suo Mulai reaction solution containing formula IV compound and formula III compound dichloro product obtained and methyl-sulfate being carried out methylation reaction, then the reaction that is hydrolyzed, obtain corresponding product NSC 43794.The inventive method technological operation is simple, safety, and raw materials used being easy to obtains, and cost is low, is suitable for industrial application.
In the preparation method of above-mentioned NSC 43794, as preferably, the mol ratio of meta-cresol described in steps A and aceticanhydride is 1:1.0 ~ 2.0.Higher reaction conversion ratio can either be ensured, again can the cost of conservation.As further preferred, the mol ratio of meta-cresol described in steps A and aceticanhydride is 1:1.15 ~ 1.50.This step yield can be made further to reach about 99%.
In the preparation method of above-mentioned NSC 43794, as preferably, the temperature of chlorination reaction described in step B is 60 DEG C ~ 75 DEG C.Chlorination reaction can be made to carry out fast, raise the efficiency, can ensure again not produce too much trichlorine product, improve yield.
In the preparation method of above-mentioned NSC 43794, as preferably, the mol ratio of the acetoxyl group toluene of type I compound 3-described in step B and chlorine is 1:1.05 ~ 2.08.As further preferred, the mol ratio of described type I compound 3-acetoxyl group toluene and chlorine is 1:1.50 ~ 1.85.Generation more formula III compound dichloro product dichloro product can be made, reduce the consumption that Suo Mulai reacts Raw, further improve reaction efficiency and reduce raw materials cost.
In the preparation method of above-mentioned NSC 43794, as preferably, the consumption of radical initiator described in step B is 2.0% ~ 5.0% of the consumption of type I compound 3-acetoxyl group toluene.Free radical reaction can be caused faster.As further preferred, the consumption of described radical initiator is 2.5% ~ 3.5% of the consumption of type I compound 3-acetoxyl group toluene.
In the preparation method of above-mentioned NSC 43794, as preferably, radical initiator described in step B is selected from the one in azo-initiator, peroxide initiator or redox initiator.As further preferred, described azo-initiator is selected from Diisopropyl azodicarboxylate, 2,2'-Azobis(2,4-dimethylvaleronitrile) or azo-bis-iso-dimethyl; Described peroxide initiator is selected from organic peroxide evocating agent or inorganic peroxide initiator; Described organic peroxide evocating agent is selected from benzoyl peroxide, lauroyl peroxide, isopropyl benzene hydroperoxide, peroxidized t-butyl perbenzoate, peroxidized t-butyl perbenzoate; Described inorganic peroxide initiator is selected from persulfuric acid salt, as Potassium Persulphate, Sodium Persulfate, ammonium persulphate etc.Described redox initiator is selected from tertbutyl peroxide/Sodium Pyrosulfite initiator, benzoyl peroxide/DMA initiator or benzoyl peroxide/N, N-Diethyl Aniline initiator.Most preferably, described radical initiator is selected from Diisopropyl azodicarboxylate.
In the preparation method of above-mentioned NSC 43794, as preferably, chlorination reaction described in step B is carried out in halogenated alkane solvents or halogenated aryl hydrocarbon solvent.Adopt above-mentioned solvent reaction mild condition, easy handling.As further preferred, described halogenated alkane solvents is selected from methylene dichloride, trichloromethane, tetracol phenixin, monochloroethane or ethylene dichloride etc.; Described halogenated aryl hydrocarbon solvent is selected from chlorobenzene, dichlorobenzene etc.Can adjust according to the consumption of routine for solvent load used in chlorination reaction, be not particularly limited.As preferably, the consumption of described halogenated alkane solvents or halogenated aryl hydrocarbon solvent and the consumption (wt) of formula II compound are than being 1:4 ~ 6.
In the preparation method of above-mentioned NSC 43794, as preferably, Suo Mulai reaction described in step C is specially:
The mixing chloro-product obtained by above-mentioned steps B adds in moisture alcoholic solvent, add urotropine again, then, react 1.5 ~ 3.0 hours at ambient temperature, then be warming up to backflow and carry out reaction 3.0 ~ 5.0 hours, after desolventizing, add water again to react at ambient temperature, after reaction terminates, layering, removing aqueous phase, obtains the Suo Mulai reaction solution containing formula IV compound and formula III compound dichloro product.Formula II compound one chlorine product conversion can be made to be corresponding aldehyde by Suo Mulai reaction, formula III compound dichloro product can not be made again to participate in reaction, ensure content and the yield of product, wherein urotropine can adjust according to the content of mixing chloro-product Chinese style II compound one chlorine product.As further preferred, the mol ratio of described formula II compound one chlorine product and urotropine is 1:1.05 ~ 1.20.
In the preparation method of above-mentioned NSC 43794, as preferably, described in step C, alcoholic solvent is selected from C
1~ C
4alcoholic solvent.As further preferred, described alcoholic solvent is selected from ethanol, methyl alcohol or Virahol.As preferably, above-mentioned moisture alcoholic solvent to be volume content be 60% ~ 80% the alcoholic solvent aqueous solution.
In the preparation method of above-mentioned NSC 43794, as preferably, phase-transfer catalyst described in step D is quaternary ammonium salt.Because methylation reaction reacts in nonhomogeneous system, the yield of speed of reaction and product effectively can be improved by adding phase-transfer catalyst.As further preferred, described quaternary ammonium salt is selected from the one in bromogeramine (dodecyl dimethyl benzyl ammonium bromide), benzyltriethylammoinium chloride, Tetrabutyl amonium bromide, tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate, tri-n-octyl methyl ammonium chloride, Dodecyl trimethyl ammonium chloride and tetradecyl trimethyl ammonium chloride.As most preferably, described quaternary ammonium salt is bromogeramine.As further preferred, the consumption of phase-transfer catalyst described in step D is 3% ~ 10% of the quality of 3-acetoxyl group toluene.Further preferably, the consumption of described phase-transfer catalyst is 5% ~ 8% of the quality of 3-acetoxyl group toluene.
In the preparation method of above-mentioned NSC 43794, as preferably, the mol ratio of methyl-sulfate described in step D and 3-acetoxyl group toluene is 1.5 ~ 3.0:1.Further preferably, the mol ratio of described methyl-sulfate and 3-acetoxyl group toluene is 2.0 ~ 2.2:1.
In the preparation method of above-mentioned NSC 43794, in methylation reaction process described in step D, the pH value of reaction system controls the aqueous solution adjustment by adopting alkaline reagents.Described alkaline reagents is as sodium hydroxide, potassium hydroxide, sodium carbonate etc.As preferably, in methylation reaction process described in step D, the pH value of reaction system is 8.0 ~ 8.5.More effectively can prevent dimethyl sulfate Ester hydrolysis, improve raw material availability, ensure yield.
In the preparation method of above-mentioned NSC 43794, as preferably, described methylation reaction carries out in alcoholic solvent, and described alcoholic solvent is selected from C
1~ C
4alcoholic solvent; As methyl alcohol, ethanol, Virahol etc.
In the preparation method of above-mentioned NSC 43794, hydrolysis reaction object described in step e formula V compound is hydrolyzed react generation final product.As preferably, described acid reagent is selected from hydrochloric acid or sulfuric acid etc.
In the preparation method of above-mentioned NSC 43794, as preferably, aftertreatment described in step e comprise washing, extraction, except desolventizing and distillation.Adopt the working method of this area routine.Water and alkaline reagents such as sodium carbonate or sodium bicarbonate is adopted to carry out washing and neutralizing treatment as washed; Adopt the water-insoluble such as ethylene dichloride or chloroform solvent to extract as extracted.Lower boiling cut and high boiling cut can be removed by distillation or fractionation, improve purity.As further preferably, in described washing process, add phase-transfer catalyst.Can more effective removing by product, improve product purity.
The process flow routes of the preparation method of NSC 43794 of the present invention is as follows:
In sum, the present invention compared with prior art, has the following advantages:
1. the preparation method of NSC 43794 of the present invention, be that raw material provides a kind of brand-new synthetic method with meta-cresol, solve existing employing 3-hydroxy benzaldehyde or the cost existing for 3-bromobenzaldehyde high, and raw material used is difficult to the problem for preparing, and the present invention adopts meta-cresol to have raw material is easy to get, the advantage that cost is low.
2. the preparation method of NSC 43794 of the present invention; first by protecting phenolic hydroxyl group; what follow-up chlorination reaction and Suo Mulai can be made to react carries out smoothly; with adopt radical initiator inseparable especially in chlorination reaction process; by protecting phenolic hydroxyl group; thus the free radical in chlorination reaction process can be made to cause smoothly, the problem of cancellation after free radical will being caused to cause because of the existence of phenolic hydroxyl group.
3. the preparation method of NSC 43794 of the present invention, a chlorine product without the need to chlorination reaction being obtained is separated with dichloro product, after directly the chloro-product of mixing being carried out Suo Mulai reaction and methylation reaction and hydrolysis reaction, just can it be directly made all to be converted into final product, improve the transformation efficiency of raw material, also make operation easier, be conducive to suitability for industrialized production.
4. the preparation method of NSC 43794 of the present invention, the total recovery of the product NSC 43794 finally obtained can reach about 70%, and purity is also higher.
Embodiment
Below by specific embodiment, technical scheme of the present invention is described in further detail, but the present invention is not limited to these embodiments.
Embodiment 1
Acetylization reaction
Meta-cresol 32.4g(0.30mol is added in the there-necked flask of 250mL) and aceticanhydride 35.2g(0.345mol); under stirring; slowly be warming up to backflow (about 140 DEG C); carry out acetylization reaction 3 ~ 4 hours; reaction end can adopt vapor-phase chromatography detection raw material meta-cresol to react completely and be as the criterion; after reaction terminates; adopt Rotary Evaporators to carry out underpressure distillation and slowly steam acetic acid and the unreacted aceticanhydride of part; steam to the greatest extent; be cooled to room temperature; obtain acetylization reaction product formula II compound 3-acetoxyl group toluene 43g, molar yield is 95%.
Chlorination reaction
Get clean 250mL reaction flask, chlorine hydride tail gas absorber is installed, described hydrogen chloride absorption device is as adopted water to absorb or adopting the chlorine hydride tail gas absorber of the routines such as alkali liquor absorption, then, 3-acetoxyl group toluene 21.5g(0.15mol is added in the reaction flask of cleaning) and tetracol phenixin 85g, when being slowly warmed up to 60 DEG C ~ 70 DEG C, add Diisopropyl azodicarboxylate 0.6g again, then, control temperature passes into chlorine and carries out chlorination reaction under the condition of 70 DEG C ~ 75 DEG C, pass into chlorine process to be specially and to start first slowly to pass into chlorine, when producing etc. there being a large amount of hydrogen chloride gas, suitable increasing passes into chlorine flowrate and constant, temperature controls at about 75 DEG C, when question response liquid color slightly turns yellow, reduce logical chlorine flowrate to being about first the first half, gas chromatographic detection can be adopted, control reaction end, be less than 0.5% with intermediate raw material 3-acetoxyl group toluene to be as the criterion, after chlorination reaction terminates, underpressure distillation removing carbon tetrachloride solvent, obtain mixing chloro-product 33g, described mixing chloro-product Chinese style II compound one chloro thing is 32.9%, III compound dichloro product is 64.0%, the three chloro things that also content is a small amount of are 2.8%.
In above-mentioned mixing chloro-product, the content detection of each composition specifically adopts GC-9790II type gas chromatograph (FTD detector), Zhejiang Fu Li Analytical Instrument Co., Ltd;
Chromatographic condition: OV-101 capillary column (20m × 0.25mm (ID) × 0.25 μm), column temperature (temperature programming: 180 DEG C keep 5min, 250 DEG C are warming up to again with 30 DEG C/min, keep 35min), vaporization temperature 260 DEG C, detected temperatures 260 DEG C, nitrogen output pressure is 0.24MP, air-output pressure is 0.06MP, and hydrogen output pressure is 0.1MP, splitting ratio 50:1.Described NSC 43794 appearance time is about 6.8min, 3-acetoxyl group toluene appearance time is about 3.5min, meta-cresol appearance time is about 2.8min, and the appearance time of a chloro thing, dichloro-thing and three chloro things is about 9.0min, 18.2min and 39.3min respectively.
Suo Mulai reacts
The chloro-product 15g getting mixing obtained above joins in the reaction flask of 250mL, add urotropine 4.5g(0.032mol again) and solution (mL/mL) 50mL of 60% ethanol, the amount of described urotropine can do corresponding adjustment according to the difference of the content of a chloro thing in mixing chloro-product, then stirring reaction after 2 hours at ambient temperature, slowly be warming up to back flow reaction 3.5 hours again, after reaction terminates, underpressure distillation removing alcohol solvent, after being cooled to room temperature again, add water 20g, stir 30 minutes, then half an hour is left standstill, layering removing aqueous phase, obtain Suo Mulai reaction solution 12g, containing formula IV compound and formula III compound dichloro product in described Suo Mulai reaction solution.
Methylation reaction
In order to raise the efficiency, methylation reaction is carried out again after the Suo Mulai reaction solution several batches adopting aforesaid method to obtain can being merged, directly singly can certainly criticize and carry out methylation reaction, the present embodiment preferably adopts the amount after repeatedly merging to implement, and is specially:
Getting the Suo Mulai reaction solution 100g utilizing aforesaid method to obtain joins in reaction flask, add phase-transfer catalyst bromogeramine 5g and methanol solvate 400g again, then, slowly drip the pH value to 10 of the sodium hydroxide solution adjustment reaction system of 40% at ambient temperature, stir 15min, then control temperature slowly drips methyl-sulfate 150g and carries out methylation reaction under the condition of 20 DEG C ~ 25 DEG C, in described methylation reaction process, the pH of the hierarchy of control is not less than 7.5, preferably control 7.5 ~ 8.0, after dropping terminates, stir under the condition of 20 DEG C again and carry out methylation reaction 2h, reaction terminates, obtain the methylation reaction liquid containing NSC 43794 and formula V compound,
Hydrolysis reaction
The HCl solution 100g that acid reagent mass content is 20% is added to obtained above containing in the methylation reaction liquid of NSC 43794 and formula V compound, stir hydrolysis reaction 2 hours, after hydrolysis reaction terminates, hydrolysis reaction liquid is proceeded in 3000mL reaction flask, add water about 1200mL, stir 30min, then add ethylene dichloride to extract, each 200g ethylene dichloride extraction, extract three times, merge the organic extractant phase liquid collected, water 100g is added again in organic phase, again about sodium bicarbonate adjust ph to 7.0, in order to better remove by product m-methoxybenzoic acid, a small amount of phase-transfer catalyst bromogeramine can be added, by the mode of phase transition, to make in m-methoxybenzoic acid and after m-methoxybenzoic acid sodium, more easily be removed, mix up rear stratification, divide phase of anhydrating, collect organic phase, first pressure reducing and steaming solvent, upper prop underpressure distillation again, control pressure is below 4kpa, and tower top temperature controls below 125 DEG C, by rectifying (fractionation), removing low boiling point solvent and high-boiling-point impurity, obtain faint yellow finishing room methoxybenzaldehyde 52g, yield 67.4%, purity reaches more than 99.5%.
Embodiment 2
Acetylization reaction
Meta-cresol 32.4g(0.30mol is added in the there-necked flask of 250mL) and aceticanhydride 45.9g(0.45mol), under stirring, slowly be warming up to backflow (about 140 DEG C), carry out acetylization reaction 4 hours, the vapor-phase chromatography that can adopt reaction end detects raw material meta-cresol and reacts completely to be as the criterion and follow the tracks of, suitably the reaction times can be increased if do not reacted completely, after acetylization reaction terminates, adopt Rotary Evaporators to carry out underpressure distillation and slowly steam acetic acid and the unreacted aceticanhydride of part, steam to the greatest extent, be cooled to room temperature, obtain acetylization reaction product formula II compound 3-acetoxyl group toluene 44g, molar yield is 97%.
Chlorination reaction
Get clean 250mL reaction flask, chlorine hydride tail gas absorber is installed, described hydrogen chloride absorption device is as adopted water to absorb or adopting the chlorine hydride tail gas absorber of the routines such as alkali liquor absorption, then, 3-acetoxyl group toluene 21.5g(0.15mol is added in the reaction flask of above-mentioned cleaning) and methylene dichloride 129g, when being slowly warmed up to 70 DEG C, add 2,2'-Azobis(2,4-dimethylvaleronitrile) 1.0g again, heat up again after can certainly first adding 2,2'-Azobis(2,4-dimethylvaleronitrile), then, control temperature passes into chlorine and carries out chlorination reaction under the condition of 70 DEG C ~ 75 DEG C, pass into chlorine process to be specially and to start first slowly to pass into chlorine, when producing etc. there being a large amount of hydrogen chloride gas, suitable increasing passes into chlorine flowrate and constant, temperature controls at about 75 DEG C, when question response liquid color slightly turns yellow, reduce logical chlorine flowrate to being about first the first half, gas chromatographic detection can be adopted, control reaction end, be less than 0.5% with intermediate raw material 3-acetoxyl group toluene to be as the criterion, in whole chlorination reaction process, the mol ratio of 3-acetoxyl group toluene and chlorine is 1:1.51, after chlorination reaction terminates, underpressure distillation removing dichloromethane solvent, obtain mixing chloro-product 32g, described mixing chloro-product Chinese style II compound one chloro thing is 39.1%, III compound dichloro product is 59.1%, the three chloro things that also content is a small amount of are 1.3%.Concrete detection method, according to the method in embodiment 1, repeats no more here.
Suo Mulai reacts
The chloro-product 15g getting mixing obtained above joins in the reaction flask of 250mL, add urotropine 5.0g(0.036mol again) and solution (mL/mL) 50mL of 80% ethanol, then stirring reaction after 2 hours at ambient temperature, slowly be warming up to back flow reaction 4.5 hours again, after reaction terminates, underpressure distillation removing alcohol solvent, after being cooled to room temperature again, add water 20g, stir 30 minutes, then half an hour is left standstill, layering removing aqueous phase, obtain Suo Mulai reaction solution 13g, containing formula IV compound and formula III compound dichloro product in described Suo Mulai reaction solution.
Methylation reaction
In order to raise the efficiency, methylation reaction is carried out again after the Suo Mulai reaction solution several batches adopting aforesaid method to obtain can being merged, directly singly can certainly criticize and carry out methylation reaction, the present embodiment preferably adopts the amount after repeatedly merging to implement, and is specially:
Getting the Suo Mulai reaction solution 100g utilizing aforesaid method to obtain joins in reaction flask, add phase-transfer catalyst benzyltriethylammoinium chloride 6g and alcohol solvent 400g again, then, slowly drip the pH value to 9.0 of the sodium hydroxide solution adjustment reaction system of 40% at ambient temperature, stir 15min, then control temperature slowly drips methyl-sulfate 155g and carries out methylation reaction under the condition of 20 DEG C ~ 25 DEG C, in described methylation reaction process, the pH of the hierarchy of control is not less than 7.5, preferably control 7.5 ~ 8.0, after dropping terminates, stir under the condition of 20 DEG C again and carry out methylation reaction 3.0h, reaction terminates, obtain the methylation reaction liquid containing NSC 43794 and formula V compound,
Hydrolysis reaction
The HCl solution 110g that acid reagent mass content is 20% is added to obtained above containing in the methylation reaction liquid of NSC 43794 and formula V compound, stir hydrolysis reaction 2 hours, after hydrolysis reaction terminates, hydrolysis reaction liquid is proceeded in 3000mL reaction flask, add water about 1200mL, stir 30min, then add trichloromethane to extract, each 200g chloroform extraction, extract three times, merge the organic extractant phase liquid collected, water 100g is added again in organic phase, about adding sodium carbonate adjust ph to 7.0 again, in order to better remove by product m-methoxybenzoic acid, a small amount of phase-transfer catalyst benzyltriethylammoinium chloride can be added, by the mode of phase transition, to make in m-methoxybenzoic acid and after m-methoxybenzoic acid sodium, more easily be removed, mix up rear stratification, divide phase of anhydrating, collect organic phase, by the first pressure reducing and steaming solvent of organic phase obtained, upper prop underpressure distillation again, control pressure is below 4kpa, tower top temperature controls below 125 DEG C, by rectifying (fractionation), removing low boiling point solvent and high-boiling-point impurity, obtain faint yellow finishing room methoxybenzaldehyde 53g, purity reaches more than 99.5%.
Embodiment 3
Acetylization reaction
Meta-cresol 32.4g(0.30mol is added in the there-necked flask of 250mL) and aceticanhydride 61g(0.6mol), under stirring, slowly be warming up to backflow (about 140 DEG C), carry out acetylization reaction 3.5 hours, the vapor-phase chromatography that can adopt reaction end detects raw material meta-cresol and reacts completely to be as the criterion and follow the tracks of, suitably the reaction times can be increased if do not reacted completely, after acetylization reaction terminates, adopt Rotary Evaporators to carry out underpressure distillation and slowly steam acetic acid and the unreacted aceticanhydride of part, steam to the greatest extent, be cooled to room temperature, obtain acetylization reaction product formula II compound 3-acetoxyl group toluene 43.5g.
Chlorination reaction
Get clean 1000mL reaction flask, chlorine hydride tail gas absorber is installed, described hydrogen chloride absorption device is as adopted water to absorb or adopting the chlorine hydride tail gas absorber of the routines such as alkali liquor absorption, then, 3-acetoxyl group toluene 96g(0.6mol is added in the reaction flask of above-mentioned cleaning) and ethylene dichloride 340g, when being slowly warmed up to 70 DEG C, add Diisopropyl azodicarboxylate 1.9g again, heat up again after can certainly first adding Diisopropyl azodicarboxylate, then, control temperature passes into chlorine and carries out chlorination reaction under the condition of 70 DEG C ~ 75 DEG C, pass into chlorine process to be specially and to start first slowly to pass into chlorine, when producing etc. there being a large amount of hydrogen chloride gas, suitable increasing passes into chlorine flowrate and constant, temperature controls at about 75 DEG C, when question response liquid color slightly turns yellow, reduce logical chlorine flowrate to being about first the first half, gas chromatographic detection can be adopted, control reaction end, be less than 0.5% with intermediate raw material 3-acetoxyl group toluene to be as the criterion, in whole chlorination reaction process, the mol ratio of 3-acetoxyl group toluene and chlorine is 1:1.65, after chlorination reaction terminates, underpressure distillation removing dichloroethane solvent, obtain mixing chloro-product 130g, 3-acetoxyl group toluene transforms substantially completely, described mixing chloro-product Chinese style II compound one chloro thing is 34%, III compound dichloro product is 62.5%, also containing three a small amount of chloro things is 2.3%.Concrete detection method, according to the method in embodiment 1, repeats no more here.
Suo Mulai reacts
Mixing chloro-product 130g obtained above is joined in the reaction flask of 1000mL, add urotropine 45g(0.32mol again) and solution (mL/mL) 200mL of 80% ethanol, then stirring reaction after 2 hours at ambient temperature, slowly be warming up to back flow reaction 4.5 hours again, after reaction terminates, underpressure distillation removing alcohol solvent, after being cooled to room temperature again, add water 170g, stir 30 minutes, then half an hour is left standstill, layering removing aqueous phase, obtain Suo Mulai reaction solution 104g, containing formula IV compound and formula III compound dichloro product in described Suo Mulai reaction solution.
Methylation reaction
Suo Mulai reaction solution 104g obtained above is joined in another reaction flask, add phase-transfer catalyst Dodecyl trimethyl ammonium chloride 6g and alcohol solvent 400g again, then, slowly drip the pH value to 9.0 of the sodium hydroxide solution adjustment reaction system of 40% at ambient temperature, stir 15min, then control temperature slowly drips methyl-sulfate 151g and carries out methylation reaction under the condition of 20 DEG C ~ 25 DEG C, in described methylation reaction process, the pH of the hierarchy of control is not less than 7.5, preferably control 7.5 ~ 8.0, after dropping terminates, stir under the condition of 20 DEG C again and carry out methylation reaction 3.0h, reaction terminates, obtain the methylation reaction liquid containing NSC 43794 and formula V compound,
Hydrolysis reaction
The HCl solution 110g that acid reagent mass content is 20% is added to obtained above containing in the methylation reaction liquid of NSC 43794 and formula V compound, stir hydrolysis reaction 2 hours, after hydrolysis reaction terminates, hydrolysis reaction liquid is proceeded in the reaction flask of 3000mL, add water about 1200mL, stir 30min, then add methylene dichloride to extract, each 200g dichloromethane extraction, extract three times, merge the organic extractant phase liquid collected, water 100g is added again in organic phase, about adding sodium carbonate adjust ph to 7.0 again, in order to better remove by product m-methoxybenzoic acid, a small amount of phase-transfer catalyst bromogeramine can be added, by the mode of phase transition, to make in m-methoxybenzoic acid and after m-methoxybenzoic acid sodium, more easily be removed, mix up rear stratification, divide phase of anhydrating, collect organic phase, by the first pressure reducing and steaming solvent of organic phase obtained, then upper prop underpressure distillation, removing low boiling point solvent and high-boiling-point impurity, obtain faint yellow finishing room methoxybenzaldehyde 56g, purity reaches more than 99.5%.
Embodiment 4
The synthesis of the 3-acetoxyl group toluene of the present embodiment adopts the method for embodiment 1 to carry out acetylization reaction, repeats no more here.
Chlorination reaction
Get clean 1000mL reaction flask, chlorine hydride tail gas absorber is installed, described hydrogen chloride absorption device is as adopted water to absorb or adopting the chlorine hydride tail gas absorber of the routines such as alkali liquor absorption, then, 3-acetoxyl group toluene 96g(0.6mol is added in the reaction flask of above-mentioned cleaning) and dichlorobenzene 576g, when being slowly warmed up to 70 DEG C, add benzoyl peroxide/N again, N-Diethyl Aniline initiator 4.8g, can certainly first add benzoyl peroxide/N, heat up again after N-Diethyl Aniline initiator, then, control temperature passes into chlorine and carries out chlorination reaction under the condition of 70 DEG C ~ 75 DEG C, pass into chlorine process to be specially and to start first slowly to pass into chlorine, when producing etc. there being a large amount of hydrogen chloride gas, suitable increasing passes into chlorine flowrate and constant, temperature controls at about 75 DEG C, when question response liquid color slightly turns yellow, reduce logical chlorine flowrate to being about first the first half, gas chromatographic detection can be adopted, control reaction end, be less than 0.5% with intermediate raw material 3-acetoxyl group toluene to be as the criterion, in whole chlorination reaction process, the mol ratio of 3-acetoxyl group toluene and chlorine is 1:2.08, after chlorination reaction terminates, underpressure distillation removing dichlorobenzene solvent, obtain mixing chloro-product 128g, described mixing chloro-product Chinese style II compound one chloro thing is 28.3%, III compound dichloro product is 66.2%, also containing three a small amount of chloro things is 4.5%.Concrete detection method, according to the method in embodiment 1, repeats no more here.
Suo Mulai reacts
The chloro-product 128g of mixing obtained above is joined the reaction vial of 1000mL, add urotropine 32g(0.23mol again) and solution (mL/mL) 250mL of 80% ethanol, then stirring reaction after 2 hours at ambient temperature, slowly be warming up to back flow reaction 4.5 hours again, after reaction terminates, underpressure distillation removing alcohol solvent, after being cooled to room temperature again, add water 180g, stir 30 minutes, then half an hour is left standstill, layering removing aqueous phase, obtain Suo Mulai reaction solution 106g, containing formula IV compound and formula III compound dichloro product in described Suo Mulai reaction solution.
Methylation reaction
Getting Suo Mulai reaction solution 106g obtained above joins in reaction flask, add phase-transfer catalyst Dodecyl trimethyl ammonium chloride 10g and isopropanol solvent 400g again, then, slowly drip the pH value to 8.5 of the sodium hydroxide solution adjustment reaction system of 40% at ambient temperature, stir 15min, then control temperature slowly drips methyl-sulfate 227g (1.8mol) and carries out methylation reaction under the condition of 20 DEG C ~ 25 DEG C, in described methylation reaction process, the pH of the hierarchy of control is not less than 7.5, preferably control 7.5 ~ 8.0, after dropping terminates, stir under the condition of 20 DEG C again and carry out methylation reaction 3.0h again, reaction terminates, obtain the methylation reaction liquid containing NSC 43794 and formula V compound,
Hydrolysis reaction
The HCl solution 110g that acid reagent mass content is 20% is added to obtained above containing in the methylation reaction liquid of NSC 43794 and formula V compound, stir hydrolysis reaction 2 hours, after hydrolysis reaction terminates, hydrolysis reaction liquid is proceeded in the reaction flask of 3000mL, add water about 1200mL, stir 30min, then add methylene dichloride to extract, each 200g dichloromethane extraction, extract three times, merge the organic extractant phase liquid collected, water 2.0g is added again in organic phase, about adding sodium carbonate adjust ph to 7.0 again, in order to better remove by product m-methoxybenzoic acid, a small amount of phase-transfer catalyst bromogeramine can be added, by the mode of phase transition, to make in m-methoxybenzoic acid and after m-methoxybenzoic acid sodium, more easily be removed, mix up rear stratification, divide phase of anhydrating, collect organic phase, by the first pressure reducing and steaming solvent of organic phase obtained, then upper prop underpressure distillation, removing low boiling point solvent and high-boiling-point impurity, obtain faint yellow finishing room methoxybenzaldehyde 55g, purity reaches more than 99.5%.
Embodiment 5
The synthesis of the 3-acetoxyl group toluene of the present embodiment adopts the method for embodiment 3 to carry out acetylization reaction, repeats no more here.
Chlorination reaction
Get clean 1500mL reaction flask, chlorine hydride tail gas absorber is installed, described hydrogen chloride absorption device is as adopted water to absorb or adopting the chlorine hydride tail gas absorber of the routines such as alkali liquor absorption, then, 3-acetoxyl group toluene 96g(0.6mol is added in the reaction flask of above-mentioned cleaning) and ethylene dichloride 385g, when being slowly warmed up to 70 DEG C, add tertbutyl peroxide/Sodium Pyrosulfite initiator 2.0g again, heat up again after first can certainly adding tertbutyl peroxide/Sodium Pyrosulfite initiator, then, control temperature passes into chlorine and carries out chlorination reaction under the condition of 70 DEG C ~ 75 DEG C, pass into chlorine process to be specially and to start first slowly to pass into chlorine, when producing etc. there being a large amount of hydrogen chloride gas, suitable increasing passes into chlorine flowrate and constant, temperature controls at about 75 DEG C, when question response liquid color slightly turns yellow, reduce logical chlorine flowrate to being about first the first half, gas chromatographic detection can be adopted, control reaction end, be less than 0.5% with intermediate raw material 3-acetoxyl group toluene to be as the criterion, in whole chlorination reaction process, the mol ratio of 3-acetoxyl group toluene and chlorine is 1:1.85, after chlorination reaction terminates, underpressure distillation removing dichloroethane solvent, obtain mixing chloro-product 134g, described mixing chloro-product Chinese style II compound one chloro thing is 30%, III compound dichloro product is 68.2%, also containing three a small amount of chloro things is 1.3%.Concrete detection method, according to the method in embodiment 1, repeats no more here.
Suo Mulai reacts
The chloro-product 134g of mixing obtained above is joined the reaction vial of 1000mL, add urotropine 37g(0.26mol again) and 70% ethanol (mL/mL) 250mL, then stirring reaction after 3 hours at ambient temperature, slowly be warming up to back flow reaction 4.0 hours again, after reaction terminates, underpressure distillation removing alcohol solvent, after being cooled to room temperature again, add water 200g, stir 30 minutes, then half an hour is left standstill, layering removing aqueous phase, obtain Suo Mulai reaction solution 102g, containing formula IV compound and formula III compound dichloro product in described Suo Mulai reaction solution.
Methylation reaction
Suo Mulai reaction solution 102g obtained above is joined in another reaction flask, add phase-transfer catalyst Dodecyl trimethyl ammonium chloride 3g and propanol solvent 400g again, then, slowly drip the pH value to 8.5 of the sodium hydroxide solution adjustment reaction system of 30% at ambient temperature, stir 15min, then control temperature slowly drips methyl-sulfate 166g (1.32mol) and carries out methylation reaction under the condition of 20 DEG C ~ 25 DEG C, in described methylation reaction process, the pH of the hierarchy of control is not less than 7.5, preferably control 7.5 ~ 8.0, after dropping terminates, stir under the condition of 25 DEG C again and carry out methylation reaction 3.0h, reaction terminates, obtain the methylation reaction liquid containing NSC 43794 and formula V compound,
Hydrolysis reaction
The HCl solution 115g that acid reagent mass content is 20% is added to obtained above containing in the methylation reaction liquid of NSC 43794 and formula V compound, stir hydrolysis reaction 3 hours, after hydrolysis reaction terminates, hydrolysis reaction liquid is proceeded in the reaction flask of 3000mL, add water about 1200mL, stir 30min, then add methylene dichloride to extract, each 200g dichloromethane extraction, extract three times, merge the organic extractant phase liquid collected, water 2.0g is added again in organic phase, about adding sodium carbonate adjust ph to 7.0 again, in order to better remove by product m-methoxybenzoic acid, a small amount of phase-transfer catalyst Dodecyl trimethyl ammonium chloride can be added, by the mode of phase transition, to make in m-methoxybenzoic acid and after m-methoxybenzoic acid sodium, more easily be removed, mix up rear stratification, divide phase of anhydrating, collect organic phase, by the first pressure reducing and steaming solvent of organic phase obtained, then upper prop underpressure distillation, removing low boiling point solvent and high-boiling-point impurity, obtain faint yellow finishing room methoxybenzaldehyde 57g, purity reaches more than 99.5%.
Embodiment 6
The synthesis of the 3-acetoxyl group toluene of the present embodiment adopts the method for embodiment 3 to carry out acetylization reaction, repeats no more here.
Chlorination reaction
Get clean 1000mL reaction flask, chlorine hydride tail gas absorber is installed, described hydrogen chloride absorption device is as adopted water to absorb or adopting the chlorine hydride tail gas absorber of the routines such as alkali liquor absorption, then, 3-acetoxyl group toluene 96g(0.6mol is added in the reaction flask of above-mentioned cleaning) and ethylene dichloride 480g, when being slowly warmed up to 70 DEG C, then add lauroyl peroxide initiator 4.5g, heat up again after can certainly first adding lauroyl peroxide initiator, then, control temperature passes into chlorine and carries out chlorination reaction under the condition of 70 DEG C ~ 75 DEG C, pass into chlorine process to be specially and to start first slowly to pass into chlorine, when producing etc. there being a large amount of hydrogen chloride gas, suitable increasing passes into chlorine flowrate and constant, temperature controls at about 75 DEG C, when question response liquid color slightly turns yellow, reduce logical chlorine flowrate to being about first the first half, gas chromatographic detection can be adopted, control reaction end, be less than 0.5% with intermediate raw material 3-acetoxyl group toluene to be as the criterion, in whole chlorination reaction process, the mol ratio of 3-acetoxyl group toluene and chlorine is 1:1.05, after chlorination reaction terminates, underpressure distillation removing dichloroethane solvent, obtain mixing chloro-product 132g, described mixing chloro-product Chinese style II compound one chloro thing is 30.4%, III compound dichloro product is 67.2%, also containing three a small amount of chloro things is 2.4%.Concrete detection method, according to the method in embodiment 1, repeats no more here.
Suo Mulai reacts
The chloro-product 132g of mixing obtained above is joined in the reaction flask of 1000mL, add urotropine 35g(0.25mol again) and solution (mL/mL) 300mL of 80% ethanol, then stirring reaction after 2.5 hours at ambient temperature, slowly be warming up to back flow reaction 3.0 hours again, after reaction terminates, underpressure distillation removing alcohol solvent, after being cooled to room temperature again, add water 170g, stir 30 minutes, then half an hour is left standstill, layering removing aqueous phase, obtain Suo Mulai reaction solution 105g, containing formula IV compound and formula III compound dichloro product in described Suo Mulai reaction solution.
Methylation reaction
Suo Mulai reaction solution 105g obtained above is joined in another reaction flask, add phase-transfer catalyst 4-butyl ammonium hydrogen sulfate 8g and alcohol solvent 400g again, then, slowly drip the pH value to 8.5 of the sodium hydroxide solution adjustment reaction system of 40% at ambient temperature, stir 15min, then control temperature slowly drips methyl-sulfate 189g and carries out methylation reaction under the condition of 20 DEG C ~ 25 DEG C, in described methylation reaction process, the pH of the hierarchy of control is not less than 7.5, preferably control 7.5 ~ 8.0, after dropping terminates, stir under the condition of 25 DEG C again and carry out methylation reaction 2.5h, reaction terminates, obtain the methylation reaction liquid containing NSC 43794 and formula V compound,
Hydrolysis reaction
The aqueous sulfuric acid 110g that acid reagent mass content is 10% is added to obtained above containing in the methylation reaction liquid of NSC 43794 and formula V compound, stir hydrolysis reaction 2 hours, after hydrolysis reaction terminates, hydrolysis reaction liquid is proceeded in the reaction flask of 3000mL, add water about 1200mL, stir 30min, then add methylene dichloride to extract, each 200g dichloromethane extraction, extract three times, merge the organic extractant phase liquid collected, water 2.0g is added again in organic phase, about adding sodium bicarbonate adjust ph to 7.0 again, in order to better remove by product m-methoxybenzoic acid, a small amount of phase-transfer catalyst 4-butyl ammonium hydrogen sulfate can be added, by the mode of phase transition, to make in m-methoxybenzoic acid and after m-methoxybenzoic acid sodium, more easily be removed, mix up rear stratification, divide phase of anhydrating, collect organic phase, by the first pressure reducing and steaming solvent of organic phase obtained, then upper prop underpressure distillation, removing low boiling point solvent and high-boiling-point impurity, obtain faint yellow finishing room methoxybenzaldehyde 56g, purity reaches more than 99.5%.
Embodiment 7
The synthesis of the 3-acetoxyl group toluene of the present embodiment adopts the method for embodiment 3 to carry out acetylization reaction, repeats no more here.
Chlorination reaction
Get clean 1000mL reaction flask, chlorine hydride tail gas absorber is installed, described hydrogen chloride absorption device is as adopted water to absorb or adopting the chlorine hydride tail gas absorber of the routines such as alkali liquor absorption, then, 3-acetoxyl group toluene 96g(0.6mol is added in the reaction flask of above-mentioned cleaning) and ethylene dichloride 400g, when being slowly warmed up to 60 DEG C, then add Potassium Persulphate 2.4g, heat up again after can certainly first adding Potassium Persulphate initiator, then, control temperature passes into chlorine and carries out chlorination reaction under the condition of 65 DEG C ~ 70 DEG C, pass into chlorine process to be specially and to start first slowly to pass into chlorine, when producing etc. there being a large amount of hydrogen chloride gas, suitable increasing passes into chlorine flowrate and constant, temperature controls at about 70 DEG C, when question response liquid color slightly turns yellow, reduce logical chlorine flowrate to being about first the first half, gas chromatographic detection can be adopted, control reaction end, be less than 0.5% with intermediate raw material 3-acetoxyl group toluene to be as the criterion, in whole chlorination reaction process, the mol ratio of 3-acetoxyl group toluene and chlorine is 1:1.7, after chlorination reaction terminates, underpressure distillation removing dichloroethane solvent, obtain mixing chloro-product 131g, described mixing chloro-product Chinese style II compound one chloro thing is 29.3%, III compound dichloro product is 67.8%, also containing three a small amount of chloro things is 2.4%.Concrete detection method, according to the method in embodiment 1, repeats no more here.
Suo Mulai reacts
The chloro-product 131g of mixing obtained above is joined in the reaction flask of 1000mL, add urotropine 32g(0.23mol again) and 80% aqueous ethanolic solution (mL/mL) 300mL, then stirring reaction after 2.5 hours at ambient temperature, slowly be warming up to back flow reaction 3.0 hours again, after reaction terminates, underpressure distillation removing alcohol solvent, after being cooled to room temperature again, add water 180g, stir 30 minutes, then half an hour is left standstill, layering removing aqueous phase, obtain Suo Mulai reaction solution 103g, containing formula IV compound and formula III compound dichloro product in described Suo Mulai reaction solution.
Methylation reaction
Suo Mulai reaction solution 103g obtained above is joined in another reaction flask, add phase-transfer catalyst Tetrabutyl amonium bromide 3.1g and alcohol solvent 400g again, then, slowly drip the pH value to 8.5 of the sodium hydroxide solution adjustment reaction system of 40% at ambient temperature, stir 15min, then control temperature slowly drips methyl-sulfate 113g and carries out methylation reaction under the condition of 22 DEG C ~ 24 DEG C, in described methylation reaction process, the pH of the hierarchy of control is not less than 7.5, preferably control 7.5 ~ 8.0, after dropping terminates, stir under the condition of 24 DEG C again and carry out methylation reaction 3h, reaction terminates, obtain the methylation reaction liquid containing NSC 43794 and formula V compound,
Hydrolysis reaction
The aqueous sulfuric acid 110g that acid reagent mass content is 10% is added to obtained above containing in the methylation reaction liquid of NSC 43794 and formula V compound, stir hydrolysis reaction 1.5 hours, after hydrolysis reaction terminates, hydrolysis reaction liquid is proceeded in the reaction flask of 3000mL, add water about 1200mL, stir 30min, then add methylene dichloride to extract, each 200g dichloromethane extraction, extract three times, merge the organic extractant phase liquid collected, water 2.0g is added again in organic phase, about adding sodium bicarbonate adjust ph to 7.0 again, in order to better remove by product m-methoxybenzoic acid, a small amount of phase-transfer catalyst Tetrabutyl amonium bromide can be added, by the mode of phase transition, to make in m-methoxybenzoic acid and after m-methoxybenzoic acid sodium, more easily be removed, mix up rear stratification, divide phase of anhydrating, collect organic phase, by the first pressure reducing and steaming solvent of organic phase obtained, then upper prop underpressure distillation, removing low boiling point solvent and high-boiling-point impurity, obtain faint yellow finishing room methoxybenzaldehyde 53g, purity reaches more than 99.5%.
Embodiment 8
The embodiment of the present embodiment is consistent with embodiment 6, difference is only that described radical initiator is selected from the one in isopropyl benzene hydroperoxide, peroxidized t-butyl perbenzoate, peroxidized t-butyl perbenzoate, Sodium Persulfate, ammonium persulphate or azo-bis-iso-dimethyl, and the consumption of described radical initiator is 2.5% ~ 3.5% of the consumption of type I compound 3-acetoxyl group toluene.Implement one by one, repeat no more here.Adopt above-mentioned initiator, the total recovery of the final product NSC 43794 obtained all can reach more than 68%, and purity reaches more than 99.5%.
Embodiment 9
The concrete preparation method of the present embodiment is consistent with embodiment 4, difference is only that described phase-transfer catalyst is selected from tetradecyl trimethyl ammonium chloride, Tetrabutyl amonium bromide or tri-n-octyl methyl ammonium chloride, and the consumption of described phase-transfer catalyst is 5% ~ 8% of the quality of Suo Mulai elutriant, implement one by one, repeat no more here.The total recovery of the final product NSC 43794 obtained all can reach more than 68%, and purity reaches more than 99.5%.
Specific embodiment described in the present invention is only to the explanation for example of the present invention's spirit.Those skilled in the art can make various amendment or supplement or adopt similar mode to substitute to described specific embodiment, but can't depart from spirit of the present invention or surmount the scope that appended claims defines.
Although made a detailed description the present invention and quoted some specific embodiments as proof, to those skilled in the art, only otherwise it is obvious for leaving that the spirit and scope of the present invention can make various changes or revise.
Claims (9)
1. a preparation method for NSC 43794, is characterized in that, the method comprises the following steps:
A, acetylization reaction: make meta-cresol and aceticanhydride under reflux conditions carry out acetylization reaction, obtain type I compound 3-acetoxyl group toluene;
B, chlorination reaction: under the effect of radical initiator, make benzyl position methyl and the chlorine generation chlorination reaction of type I compound 3-acetoxyl group toluene, obtains the mixing chloro-product of formula II compound one chlorine product and formula III compound dichloro product;
C, Suo Mulai react: the mixing chloro-product obtained by above-mentioned steps B adds in moisture alcoholic solvent, add urotropine again, make the formula II compound one chlorine product in mixing chloro-product carry out Suo Mulai and react production IV compound, after reaction terminates, except desolventizing, obtain the Suo Mulai reaction solution containing formula IV compound and formula III compound dichloro product;
D, methylation reaction: in above-mentioned Suo Mulai reaction solution, add Phase-transfer catalyst quaternary ammonium salt and methyl-sulfate carries out methylation reaction, in described methylation reaction process, the pH value of reaction system is 7.5 ~ 10, after methylation reaction terminates, obtain the methylation reaction liquid containing NSC 43794 and formula V compound;
E, hydrolysis reaction: add acid reagent to obtained above containing in the methylation reaction liquid of NSC 43794 and formula V compound, formula V compound is hydrolyzed reaction in acid condition, after hydrolysis reaction terminates, carry out aftertreatment, obtain product NSC 43794.
2. the preparation method of NSC 43794 according to claim 1, it is characterized in that, the temperature of chlorination reaction described in step B is 60 DEG C ~ 75 DEG C; The mol ratio of described type I compound 3-acetoxyl group toluene and chlorine is 1:1.05 ~ 2.08.
3. the preparation method of NSC 43794 according to claim 1, it is characterized in that, the consumption of radical initiator described in step B is 2.0% ~ 5.0% of the consumption of type I compound 3-acetoxyl group toluene.
4. the preparation method of NSC 43794 according to claim 1, it is characterized in that, radical initiator described in step B is selected from the one in azo-initiator, peroxide initiator or redox initiator.
5. the preparation method of NSC 43794 according to claim 4, is characterized in that, described azo-initiator is selected from Diisopropyl azodicarboxylate, 2,2'-Azobis(2,4-dimethylvaleronitrile) or nitrogen two isopropylformic acid dimethyl ester; Described nitride initiator of crossing is selected from organic peroxide evocating agent or inorganic peroxide initiator; Described redox initiator is selected from tertbutyl peroxide/Sodium Pyrosulfite initiator, benzoyl peroxide/DMA initiator or benzoyl peroxide/N, N-Diethyl Aniline initiator.
6. the preparation method of NSC 43794 according to claim 1-5 any one, it is characterized in that, the chlorination reaction described in step B is carried out in halogenated alkane or halogenated aryl hydrocarbon.
7. the preparation method of NSC 43794 according to claim 1-5 any one, is characterized in that, Suo Mulai reaction described in step C is specially:
The mixing chloro-product obtained by above-mentioned steps B adds in moisture alcoholic solvent, add urotropine again, then, react 1.5 ~ 3.0 hours at ambient temperature, then be warming up to backflow and carry out reaction 3.0 ~ 5.0 hours, after desolventizing, add water again to react at ambient temperature, after reaction terminates, layering, removing aqueous phase, obtains the Suo Mulai reaction solution containing formula IV compound and formula III compound dichloro product.
8. the preparation method of NSC 43794 according to claim 1-5 any one, is characterized in that phase-transfer catalyst described in step D is 3% ~ 10% of the quality of Suo Mulai reaction solution.
9. the preparation method of NSC 43794 according to claim 1-5 any one, it is characterized in that, described quaternary ammonium salt is selected from the one in bromogeramine, benzyltriethylammoinium chloride, Tetrabutyl amonium bromide, tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate, tri-n-octyl methyl ammonium chloride, Dodecyl trimethyl ammonium chloride and tetradecyl trimethyl ammonium chloride.
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