CN103896974B

CN103896974B - The preparation method of 2-hydroxy benzenes boric acid

Info

Publication number: CN103896974B
Application number: CN201410145635.0A
Authority: CN
Inventors: 谷杰; 陈文霆; 孟祥钊; 刘玉洁; 张海涛
Original assignee: BEIJING LAVIANA PHARMATECH Co Ltd
Current assignee: Lewei Pharmaceutical (Tianjin) Co., Ltd.
Priority date: 2014-04-11
Filing date: 2014-04-11
Publication date: 2017-01-04
Anticipated expiration: 2034-04-11
Also published as: CN103896974A

Abstract

The invention discloses the preparation method of a kind of 2 hydroxy benzenes boric acid, it includes S1, adds hydroxy protecting agent in phenol/organic solvent mixed solution, forms the mixed solution containing phenol intermediate after reaction；S2, make the mixed solution containing phenol intermediate be in the first temperature, and in the mixed solution containing phenol intermediate with the first temperature, add n-BuLi, after reaction, form pre-reaction solution；S3, make pre-reaction solution be in the second temperature, and in the pre-reaction solution have the second temperature, add borate, formed after reaction and treat hydrating solution；S4, will treat that hydrating solution is hydrolyzed reaction, after extraction, concentrated extract obtains the 2 thick products of hydroxy benzenes boric acid；Wherein, the first temperature≤0 DEG C, the second temperature and the first temperature are identical or different.The method uses hydroxy protecting agent, and controls reaction temperature, makes the productivity of 2 hydroxy benzenes boric acid improve.Meanwhile, with phenol as raw material, 2 hydroxy benzenes boric acid production costs are made to reduce.

Description

The preparation method of 2-hydroxy benzenes boric acid

Technical field

The present invention relates to organic synthesis field, in particular to the preparation method of a kind of 2-hydroxy benzenes boric acid.

Background technology

Suzuki-Miyaura coupling reaction (SMC) is to build the important reaction of all kinds of C--C single bond, and its primary raw material is organic boron Acid compound.Wherein, 2-hydroxy benzenes boric acid is a kind of compound important in organic boric acid compounds, in organic synthesis and medicineization Work field is respectively provided with important using value.At present, its preparation method has following several:

(1) Bean is with phenylboric acid as raw material, hydrolyzes through nitrification, catalytic hydrogenation, diazotising again and obtains 2-hydroxy benzenes boric acid, instead Answer principle as follows:

The defect of this synthetic method is that route is longer, and cost is high, and reaction selectivity is poor.

(2) Gilman uses bromo (adjacent, to) phenol to be raw material, reacts with two equivalent butyl lithiums, more anti-with borate And should hydrolyze and obtain hydroxy benzenes boric acid product.This synthetic method route is short, but yield is relatively low, and with bromophenol as raw material, Relatively costly, it is unfavorable for large-scale production.

(3) Chao builds after the phenolic hydroxyl group silicon ethers protection group of bromophenol protected by equality, makes Grignard reagent, then with borate React and hydrolyze.Total separation yield of this method is the most relatively low, and only less than 30%, and also being also adopted by bromophenol is raw material, Production cost is higher.

(4) Takeo uses adjacent bromophenol to be raw material, reacts with two equivalent butyl lithiums, then reacts with borate and hydrolyze and obtain Hydroxy benzenes boric acid product.Reaction principle is as follows:

This method is also with o-bromophenol as raw material, relatively costly, and needs to add the n-BuLi reaction of two equivalents, is unfavorable for Large-scale production.

Sum it up, all there is cost height, the defect of process route length in the preparation method of 2-hydroxy benzenes boric acid at present.Based on this, It is necessary to design the short preparation method of a kind of low cost, process route in order to synthesize 2-hydroxy benzenes boric acid.

Summary of the invention

It is desirable to provide the preparation method of a kind of 2-hydroxy benzenes boric acid, to solve the preparation of 2-hydroxy benzenes boric acid in prior art Relatively costly problem.

To achieve these goals, according to an aspect of the invention, it is provided the preparation method of a kind of 2-hydroxy benzenes boric acid, its Comprise the following steps: S1, addition hydroxy protecting agent in phenol/organic solvent mixed solution, formed after reaction containing in phenol The mixed solution of mesosome；S2, the mixed solution containing phenol intermediate is made to be in the first temperature, and to having containing of the first temperature There is addition n-BuLi in the mixed solution of phenol intermediate, after reaction, form pre-reaction solution；S3, pre-reaction solution is made to be in Second temperature, and in the pre-reaction solution have the second temperature, add borate, formed after reaction and treat hydrating solution；S4, general Treating that hydrating solution is hydrolyzed reaction, after extraction, concentrated extract obtains the 2-thick product of hydroxy benzenes boric acid；Wherein, the first temperature≤0 DEG C, Second temperature and the first temperature are identical or different.

Further, in above-mentioned steps S2, first adjust the first temperature to≤-30 DEG C, then molten to the mixing containing phenol intermediate Liquid adds n-BuLi, insulation reaction 15～30min, then is warming up to 0～30 DEG C, insulation reaction 0.5～2h, obtain pre-reaction molten Liquid；The most first adjust the first temperature to-70～-30 DEG C.

Further, in above-mentioned steps S2, it is 1～2:1 addition n-BuLi according to the mol ratio of n-BuLi Yu phenol intermediate, Preferably n-BuLi is 1～1.3:1 with the mol ratio of phenol intermediate, preferably adds n-BuLi with the speed of dripping of 0.01～0.03g/min.

Further, in above-mentioned steps S3, after the step adding borate, reaction ...～... min, obtain treating hydrating solution.

Further, in above-mentioned steps S3, first adjust the second temperature extremely≤0 DEG C, in pre-reaction solution, then add borate, Insulation reaction 15～30min, then it is warming up to 0～30 DEG C, insulation reaction 0.5～2h, obtain treating hydrating solution；The most first adjust second Temperature is to≤-30 DEG C, more preferably to-70～-30 DEG C.

Further, in above-mentioned steps S1, form the step of mixed solution containing phenol intermediate and include: S11, by phenol It is dissolved in the first organic solvent, is added thereto to hydroxy protecting agent, the reactant liquor obtained after reaction is concentrated to give phenol intermediate； S12, phenol intermediate is dissolved in the second organic solvent, forms the mixed solution containing phenol intermediate, the first organic solvent and institute State the second organic solvent identical or different.

Further, in above-mentioned steps S11, phenol is dissolved in the first organic solvent, is added thereto to catalyst and is cooled to After 0～5 DEG C, it is added thereto to hydroxy protecting agent, then heats to 10～30 DEG C, carry out insulation reaction 0.5～15h, reacted Liquid, is concentrated to give phenol intermediate；Wherein, catalyst is solid acid catalyst or triethylamine, preferred catalyst be sulfamic acid, Storng-acid cation exchange resin, ferric chloride (FeCl36H2O), stannic chloride pentahydrate, Ammonium ferric sulfate dodecahyrate, titanium sulfate, a water Sodium bisulfate, p-methyl benzenesulfonic acid or triethylamine, more preferably sulfamic acid, p-methyl benzenesulfonic acid or triethylamine.

Further, above-mentioned steps S11 also includes: the reactant liquor obtained after reaction adds sodium hydrate aqueous solution, stirs Mixing, the pH making reactant liquor is 8～14, and separatory obtains the first aqueous phase and the first organic facies；Hydroxide is added in the first organic facies Sodium water solution, after stirring, separatory obtains the second aqueous phase and Second Organic Phase；Merge the first aqueous phase and the second aqueous phase, have with first Machine solvent extraction, separatory obtains the 3rd organic facies；Merge Second Organic Phase and the 3rd organic facies, after using desiccant dryness, mistake Filter, obtains described phenol intermediate after concentration.

Further, in above-mentioned steps S11, it is 1～1.2:1 addition hydroxyl protection examination according to hydroxy protecting agent and phenol mol ratio Agent, adds phenol according to 2.12～3mol/L in the first organic solvent, and according to 4.2～5 × 10-3mol/L to the first organic solvent Add catalyst；In step S12, add phenol intermediate according to 0.8～5.6mol/L to by the second organic solvent.

Further, above-mentioned first organic solvent is polar organic solvent, the preferably first organic solvent be dichloromethane, n-butyl alcohol, Propanol, oxolane, acetic acid, acetone, pyridine, dimethylformamide, methanol, ethylene glycol or dimethyl sulfoxide, more excellent Selecting described first organic solvent is dichloromethane or oxolane；Second organic solvent is polar ether kind solvent or nonpolar organic molten Agent, preferably polar ether kind solvent are ether, propyl ether, diisopropyl ether, oxolane, expoxy propane or methyl tertiary butyl ether(MTBE), more Preferably polar ether kind solvent is oxolane or methyl tertiary butyl ether(MTBE)；Preferably non-polar organic solvent be benzene, normal hexane, Pentamethylene., Heptane, toluene, carbon tetrachloride, preferably non-polar organic solvent are normal hexane or toluene.

Further, in above-mentioned steps S4, hydrolysis step includes: to temperature be-30～20 DEG C treat in hydrating solution add Hydrochloric acid, making the pH treating hydrating solution is 1～2, and after stirring, separatory obtains the 4th aqueous phase and the 4th organic facies；In the 4th aqueous phase After addition ethyl acetate extracts, separatory obtains the 5th organic facies, merges the 4th organic facies and the 5th organic facies, uses and is dried Agent is dried, filters and be concentrated to give the 2-thick product of hydroxy benzenes boric acid.

Further, above-mentioned steps S4 also includes the step that the 2-thick product of hydroxy benzenes boric acid carries out post processing；The step of post processing Including: add to the 2-thick product of hydroxy benzenes boric acid normal hexane is pulled an oar, be filtrated to get filter cake；With normal hexane, filter cake is carried out sucking filtration Washing, is dried 2～4h at 30～80 DEG C, obtains 2-hydroxy benzenes boric acid.

Further, above-mentioned hydroxy protecting agent be methoxyl group chloromethanes, Benzenecarbonyl chloride., isobutene., triphenylchloromethane, 3,4- Dihydropyran or tert-butyl chloro-silicane, preferably 3,4-dihydropyran or tert-butyl chloro-silicane.

Further, above-mentioned borate is methyl borate., triethyl borate, triproylborate, triisopropyl borate ester, boric acid Tributyl or triamylborate；It is preferably triisopropyl borate ester, methyl borate. or triethyl borate.

The preparation method of the 2-hydroxy benzenes boric acid of the application present invention, by using hydroxy protecting agent, and controls to react in each step The state of temperature of system, is conducive to improving the Replacement rate of ortho-hydrogens atom in borate Pyrogentisinic Acid, reduces by-product in course of reaction Growing amount, and then improve purpose product productivity.Meanwhile, with the relatively low phenol of price as raw material in said method, it is possible to fall The production cost of low 2-hydroxy benzenes boric acid.Additionally, prepare the method for 2-hydroxy benzenes boric acid compared to adjacent bromophenol for, this Bright above-mentioned method directly prepares 2-hydroxy benzenes boric acid with phenol for raw material, and it is more environmentally-friendly, and process route is shorter, is more suitable for Industrialization large-scale production.

Detailed description of the invention

It should be noted that in the case of not conflicting, the embodiment in the application and the feature in embodiment can be mutually combined. The present invention is described in detail below in conjunction with embodiment.

As background section is introduced, there is relatively costly problem in the preparation method of 2-hydroxy benzenes boric acid.In order to solve this One problem, inventor provides the preparation method of a kind of 2-hydroxy benzenes boric acid, and it comprises the following steps: S1, to phenol/ Organic solvent mixed solution adds hydroxy protecting agent, after reaction, forms the mixed solution containing phenol intermediate；S2, make to contain The mixed solution having phenol intermediate is in the first temperature, and in the mixed solution containing phenol intermediate with the first temperature Add n-BuLi, after reaction, form pre-reaction solution；S3, pre-reaction solution is made to be in the second temperature, and to having the second temperature The pre-reaction solution of degree adds borate, is formed after reaction and treat hydrating solution；S4, will treat that hydrating solution is hydrolyzed reaction, After extraction, concentrated extract obtains the 2-thick product of hydroxy benzenes boric acid；Wherein, the first temperature≤0 DEG C, the second temperature and the first temperature phase Same or different.

In the method that the present invention is above-mentioned, prepare 2-hydroxy benzenes boric acid with phenol for raw material.In phenol, the hydrogen atom of diverse location There is different activity.Wherein, the hydrogen atom activity in phenolic hydroxyl group is higher than the hydrogen atom activity of phenol ortho.Based on this, just When butyl lithium carries out the hydrogen atom substitution reaction of phenol, it is the most substituted is the hydrogen atom of phenolic hydroxyl group in phenol.And use hydroxyl Protection reagent, it is possible to protected by the phenolic hydroxyl group in phenol, forms phenol intermediate.Thus be conducive to promoting n-BuLi to enter The substitution reaction of row phenol ortho hydrogen atom, and then advantageously reduce the consumption of n-BuLi.The consumption of n-BuLi reduces, and one Aspect advantageously reduces the preparation cost of 2-hydroxy benzenes boric acid, is on the other hand conducive to improving the safety and stability of reaction.

Meanwhile, at a temperature of equal to or less than 0 DEG C, the activity of the ortho-hydrogens atom of phenol is of a relatively high, and meta and para-position Hydrogen atom activity is relatively low.Based on this, the mixed solution containing phenol intermediate is set smaller than at a temperature of-30 DEG C, to It adds after n-BuLi, is conducive to promoting the substitution reaction of the hydrogen atom that more n-BuLi carries out phenol ortho, forms neighbour The substituted phenol intermediate in position, its structure is as shown in formula I, and wherein P is the guarantor formed after hydroxy protecting agent carries out protection reaction Protect group:

Additionally, make n-BuLi that substitution reaction to occur under the lower temperature equal to or less than 0 DEG C, be conducive to improving the safety of reaction Property.After previous reaction, form the pre-reaction solution containing above-mentioned ortho position fortified phenol intermediate.In this pre-reaction solution Add borate, it is possible to make borate to the lithium atom generation substitution reaction in the fortified phenol intermediate of ortho position, form target product The thick product of 2-hydroxy benzenes boric acid.

Will be after hydrating solution hydrolyzes, it is possible to obtain the thick product of purpose product 2-hydroxy benzenes boric acid.Sum it up, above-mentioned reaction During use hydroxy protecting agent, and control the state of temperature of reaction system in each step, be conducive to improving borate Pyrogentisinic Acid The Replacement rate of middle ortho-hydrogens atom, reduces the growing amount of by-product in course of reaction, and then improves the productivity of purpose product.Meanwhile, With the relatively low phenol of price as raw material in said method, it is possible to reduce the production cost of 2-hydroxy benzenes boric acid.Additionally, compared to neighbour For bromophenol prepares the method for 2-hydroxy benzenes boric acid, the above-mentioned method of the present invention directly prepares 2-hydroxy benzenes with phenol for raw material Boric acid, it is more environmentally-friendly, and process route is shorter, is more suitable for industrialization large-scale production.

As long as according to above-mentioned method, it becomes possible to obtain the 2-thick product of hydroxy benzenes boric acid that product content is higher.Preferred in one In embodiment, in above-mentioned steps S2, first adjust the first temperature to≤-30 DEG C, then to the mixed solution containing phenol intermediate Middle addition n-BuLi, insulation reaction 15～30min, then it is warming up to 0～30 DEG C, and insulation reaction 0.5～2h, obtain pre-reaction solution.

As long as the first temperature is less than or equal to 0 DEG C, it becomes possible to promote n-BuLi to replace with the ortho-hydrogens atom of phenol intermediate Reaction.Preferably first temperature is-30 DEG C, when carrying out the substitution reaction of n-BuLi at a temperature of-30 DEG C, is more beneficial for making positive fourth Ortho-hydrogens atom in base lithium directionally fortified phenol intermediate, thus be conducive to improving further purity and the yield of purpose product. It is further preferable that first adjust the first temperature to-70～-30 DEG C.Under this temperature conditions, be conducive to making in the middle of n-BuLi and phenol While the ortho-hydrogens atom of body reacts so that it is there is higher reaction rate.Additionally, also help reduction course of reaction In maintain the energy expenditure brought due to low temperature.

Additionally, carry out insulation reaction for the first time after the step adding n-BuLi, be conducive to making n-BuLi at a lower temperature Optionally with the ortho-hydrogens atom generation substitution reaction of phenol intermediate, reduce the generation of by-product.This is advantageous for improving in advance The content of ortho position fortified phenol intermediate in reaction solution, and then improve the product content of final goal product.Rise after insulation reaction When temperature is to 0～30 DEG C, temperature-rise period is that nature heats up.While this can make n-BuLi fully position, accelerate n-BuLi with The reaction rate of phenol intermediate ortho-hydrogens atom, and then shorten the response time, obtain pre-reaction solution.Meanwhile, by anti-for insulation Mixed solution after should heats up, and also helps and improves the location of ortho-hydrogens atom in n-BuLi Pyrogentisinic Acid's intermediate further Replace, make system is formed more ortho position fortified phenol intermediate.

In above-mentioned method, the addition of n-BuLi can be adjusted according to the theoretical proportions of reaction.The most real in one Execute in mode, in above-mentioned steps S2, be 1～2:1 addition n-BuLi according to the mol ratio of n-BuLi Yu phenol intermediate, excellent Selecting n-BuLi is 1～1.3:1 with the mol ratio of phenol intermediate.Add n-BuLi according to aforementioned proportion, be conducive to making in phenol Mesosome ortho-hydrogens atom is fully substituted, and then is conducive to improving the yield of target product.More preferably with 0.01～0.03g/min drip Speed adds n-BuLi.Drip n-BuLi with above-mentioned speed, be conducive to making substitution reaction more stably carry out, and then improve anti- The safety answered.

In said method, add borate step after, the concrete response time can according to reaction raw materials number and concrete Reaction rate be adjusted.Preferably, react after adding the step of borate ...～... min, obtain treating hydrating solution.Meanwhile, As long as making borate react with ortho position fortified phenol intermediate in pre-reaction solution, by molten for reacted mixing according to step S3 Liquid is hydrolyzed, and just can obtain the 2-thick product of hydroxy benzenes boric acid that product content is higher.At a kind of embodiment being more highly preferred to In, first adjust the second temperature extremely≤0 DEG C, in pre-reaction solution, then add borate, insulation reaction 15～30min, then heat up To 0～30 DEG C, insulation reaction 0.5～2h, obtain treating hydrating solution.

The temperature of pre-reaction solution is equal to or less than 0 DEG C, it is possible to reduce other hydrogen atom in the fortified phenol intermediate of ortho position Activity.Thus advantageously reduce the probability that borate reacts with other hydrogen atom, reduce the growing amount of by-product, promote Later stage borate and ortho position fortified phenol intermediate carry out lithium atom substitution reaction, are formed and treat hydrating solution.Simultaneously as ortho position On lithium atom in fortified phenol intermediate and phenyl ring, the hydrogen atom of other position still has certain reactivity, is adding boric acid Being lowered the temperature by pre-reaction solution before ester, other site desirably preventing phenyl ring in the fortified phenol intermediate of ortho position occurs lithium former Sub-substitution reaction, thus form intermediate or the substitution product in other site of phenyl ring of many lithiumations.Sum it up, pre-reaction is molten Liquid is lowered the temperature, and is conducive to suppressing the formation of by-product, thus improves the productivity of target product.

During real reaction, as long as the second temperature is less than or equal to 0 DEG C, it becomes possible to reduce borate and ortho position fortified phenol The probability that other hydrogen atoms in intermediate react, also can reduce by two ortho positions all has the intermediate of lithium atom simultaneously, thus Reduce the quantity of by-product, and promote borate and above-mentioned lithium atom generation substitution reaction.Preferably second temperature≤-30 DEG C, more excellent Choosing is to-70～-30 DEG C.Under this temperature conditions, be conducive to reducing the by-product formed with other atomic reaction of hydrogen because of lithium atom further The quantity of thing, is conducive to making borate keep of a relatively high with the reaction of ortho position lithium atom in the fortified phenol intermediate of ortho position simultaneously Speed.Additionally, in above-mentioned method, the addition of borate can be adjusted according to the theoretical proportions of reaction.Excellent in one In the embodiment of choosing, in above-mentioned steps S3, it is 1～2:1 addition borate according to the mol ratio of borate Yu phenol intermediate, Preferred boric acid ester is 1.1～1.5:1 with the mol ratio of phenol intermediate.Add borate according to aforementioned proportion, be conducive to making ortho position take The ortho position lithium atom of substituting phenol intermediate is fully substituted, and then is conducive to improving the yield of target product.Preferably with The speed of dripping of 0.1～0.3g/min adds borate.Drip borate with above-mentioned speed, be conducive to making stable reaction carry out, and then improve The safety of reaction.

In above-mentioned method, after the mixed solution containing phenol intermediate formed after protection reaction, directly enter in this system The row n-BuLi substitution reaction of " cooking-pot type ", borate substitution reaction and hydrolysis, it becomes possible to prepare target product 2-hydroxyl Base phenylboric acid.In a preferred embodiment, it is also possible to reacted for protection solution is carried out concentration, obtains phenol After intermediate, further phenol intermediate is dissolved in organic solvent the substitution reaction carrying out the later stage.Specifically, above-mentioned steps S1 Comprise the following steps: S11, phenol is dissolved in the first organic solvent, be added thereto to hydroxy protecting agent, will obtain after reaction Reactant liquor is concentrated to give phenol intermediate；S12, phenol intermediate is dissolved in the second organic solvent, is formed containing phenol intermediate Mixed solution, the first organic solvent and the second organic solvent are identical or different.In this step, the hydroxyl protection of phenol is reacted with The substitution reaction of phenol intermediate is carried out respectively in independent system, advantageously reduces the impurity in system, is conducive to carrying simultaneously The stability of high reaction and safety.

According to the teachings of the present invention, those skilled in the art have the ability selected from the preparation technology of concrete phenol intermediate, to obtain The phenol intermediate that content is higher.In a preferred embodiment, in above-mentioned steps S11, phenol is dissolved in first organic In solvent, after being added thereto to catalyst and being cooled to 0～5 DEG C, it is added thereto to hydroxy protecting agent, after being warming up to 10～30 DEG C Insulation reaction 0.5～15h, obtains reactant liquor, is concentrated to give phenol intermediate.Reaction between hydroxy protecting agent and phenol is for putting Thermal response, was down to 0～5 DEG C by system temperature before adding hydroxy protecting agent, and after desirably preventing exothermic heat of reaction, temperature is too high draws The bumping of the system of sending out.Control also to be conducive to making reacting balance carry out at 10～30 DEG C by temperature after adding hydroxy protecting agent.Addition is urged Agent is conducive to improving reaction rate, and optional catalyst includes but not limited to solid acid catalyst.In solid catalyst surface Under the catalytic action of acid active site, the hydrogen atom in phenol phenolic hydroxyl group can be quickly by the blocking group in hydroxy protecting agent Replaced, formed relatively stable group.The most above-mentioned solid acid catalyst include but not limited to sulfamic acid, highly acid sun from Sub-exchange resin, ferric chloride (FeCl36H2O), stannic chloride pentahydrate, Ammonium ferric sulfate dodecahyrate, titanium sulfate, Sodium Bisulfate Monohydrate, Acid active center in these catalyst of p-methyl benzenesulfonic acid is more, and acidity is stronger, it is possible to promote blocking group to replace further Hydrogen atom in phenol phenolic hydroxyl group.It is highly preferred that use sulfamic acid or p-methyl benzenesulfonic acid as catalyst, its catalytic efficiency is more High.Optional catalyst can also select base catalyst triethylamine, and it also is able to promote hydroxy protecting agent and phenol hydroxyl in phenol Base reacts, and forms relatively stable blocking group.

In above-mentioned method, utilize hydroxy protecting agent to be protected by the hydroxyl in phenol, obtain containing phenol intermediate Reactant liquor.This reactant liquor is concentrated, just can obtain the phenol intermediate that content is higher.In a preferred embodiment, The reactant liquor carrying out hydroxyl protection reaction is carried out purification processes.Concrete operational approach is as follows: the reactant liquor obtained after reaction Middle addition sodium hydrate aqueous solution, stirring, the pH making reactant liquor is 8～14, and separatory obtains the first aqueous phase and the first organic facies； Adding sodium hydrate aqueous solution in the first organic facies, after stirring, separatory obtains the second aqueous phase and Second Organic Phase；Merge first Aqueous phase and the second aqueous phase, with the first organic solvent extraction, separatory obtains the 3rd organic facies；Merge Second Organic Phase and the 3rd organic Phase, is dried, is concentrated to give phenol intermediate.Sodium hydrate aqueous solution is added, it is possible to make not in reactant liquor or the first organic facies The phenol of reaction becomes salt being dissolved in the water to be removed, simultaneously can be by the catalyst in system and some water miscible impurity extraction And remove.Obtain the purest phenol intermediate.Utilize the first organic solvent that aqueous phase is extracted, it is possible to by few in aqueous phase The phenol intermediate of amount reclaims.Final merge organic facies after carry out concentrate drying, it is possible to obtain the purest, content relatively High phenol intermediate.

In above-mentioned method, hydroxy protecting agent can be adjusted according to concrete reaction theory ratio with the addition of catalyst. In a preferred embodiment, in above-mentioned steps S11, it is 1～1.2:1 addition according to hydroxy protecting agent and phenol mol ratio Hydroxy protecting agent, adds phenol according to 2.12～3mol/L in the first organic solvent, and according to 4.2～5 × 10^-3Mol/L is to One organic solvent adds catalyst；In step S12, add phenol intermediate according to 0.8～5.6mol/L to by the second organic solvent. Add reactant, solvent and catalyst according to above-mentioned ratio, be conducive to making reaction fully react in the most homogeneous system.

In above-mentioned method, the first solvent and the second solvent do not had particular/special requirement, as long as it can provide the most homogeneous reaction System.In a preferred embodiment, above-mentioned first organic solvent is polar organic solvent, and it includes but not limited to Dichloromethane, n-butyl alcohol, propanol, oxolane, acetic acid, acetone, pyridine, dimethylformamide, methanol, ethylene glycol, Or dimethyl sulfoxide.Phenol is respectively provided with higher dissolubility in these solvents, thus is conducive to provide the most homogeneous reactant System, makes phenol react more fully with hydroxy protecting agent.More preferably this first organic solvent is dichloromethane or oxolane. Above-mentioned second organic solvent is polar ether kind solvent or non-polar organic solvent.Wherein polar ether kind solvent include but not limited to ether, Propyl ether, diisopropyl ether, oxolane, expoxy propane or methyl tertiary butyl ether(MTBE), more preferably oxolane or methyl tertiary butyl ether(MTBE)； Wherein non-polar organic solvent includes but not limited to benzene, normal hexane, Pentamethylene., heptane, toluene, carbon tetrachloride, is just being preferably Hexane or toluene.These solvents all can make the substitution reaction of phenol intermediate carry out in the most homogeneous system, thus favorably In the yield improving purpose product 2-hydroxy benzenes boric acid.

In above-mentioned method, as long as will treat that hydrating solution is hydrolyzed reaction, just can obtain purpose product 2-hydroxy benzenes boric acid. In a preferred embodiment, in above-mentioned steps S4, hydrolysis step includes: to temperature be-30～20 DEG C wait hydrolyze Adding hydrochloric acid in solution, making the pH treating hydrating solution is 1～2, and after stirring, separatory obtains the 4th aqueous phase and the 4th organic facies；To After in 4th aqueous phase, addition ethyl acetate extracts, separatory obtains the 5th organic facies, merges the 4th organic facies and the 5th organic facies, After using desiccant dryness, filter and be concentrated to give the 2-thick product of hydroxy benzenes boric acid.Adjust and treat that the pH of hydrating solution is 1～2, have It is beneficial to make it hydrolyze generation target product 2-hydroxy benzenes boric acid.Add ethyl acetate to be conducive to extracting back a small amount of product in aqueous phase Receive.Additionally, the desiccant of routine can be used for being dried the desiccant of organic facies, such as anhydrous sodium sulfate, anhydrous cupric sulfate etc..

As long as according to above-mentioned method, it becomes possible to obtain the 2-thick product of hydroxy benzenes boric acid that content is higher.Preferably implement in one In mode, step S4 also includes the step that the 2-thick product of hydroxy benzenes boric acid carries out post processing；The step of post processing includes: by 2- The thick product of hydroxy benzenes boric acid adds to pull an oar in normal hexane, is filtrated to get filter cake；Filter cake filtering and washing is washed, at 30～80 DEG C with normal hexane Under be dried 2～4h, obtain 2-hydroxy benzenes boric acid.Thick product is carried out post processing, is conducive to removing the impurity component in product, To the purest target product.

In the method that the present invention is above-mentioned, borate be there is no special requirement, as long as it can be by the fortified phenol intermediate of ortho position Ortho position lithium atom carry out replace formed borate group.Preferably, this borate include but not limited to methyl borate., Triethyl borate, triproylborate, triisopropyl borate ester, butyl borate or triamylborate.These borates all can take Ortho position lithium atom in substituting phenol intermediate, hydrolyzes through the later stage, i.e. can get target product 2-hydroxy benzenes boric acid.Preferred boric acid Ester is triisopropyl borate ester, methyl borate. or triethyl borate, and these several borate viscositys are less, and relatively other borates are more easy to It is dissolved in the second organic solvent, thus is conducive to improving the replacement speed of borate.Meanwhile, if the hydroxy protecting agent of employing Can protect by phenolic hydroxyl group in phenol, form stable group.Preferably this hydroxy protecting agent includes but not limited to first Epoxide chloromethanes, Benzenecarbonyl chloride., isobutene., triphenylchloromethane, 3,4-dihydropyran or tert-butyl chloro-silicane.These are several Plant hydroxy protecting agent all to react with the phenolic hydroxyl group in phenol, form relatively stable group.And in the hydrolysis in later stage In reaction, these groups all can hydrolyze to form phenolic hydroxyl group.Preferably, above-mentioned hydroxy protecting agent is 3,4-dihydropyran or Tert-butyl chloro-silicane.When both hydroxy protecting agent and phenolic hydroxyl group react, reaction condition is the gentleest, and shape The blocking group become can more sufficient deprotection in the hydrolytic process in later stage.Thus be conducive to improving the generation of target product Rate.It is highly preferred that in so that in hydroxy protecting agent Pyrogentisinic Acid, phenolic hydroxyl group carries out the reaction protected, with 3,4-dihydropyran is as protection During reagent, use sulfamic acid, storng-acid cation exchange resin, ferric chloride (FeCl36H2O), stannic chloride pentahydrate, 12 hydrations The solid acid catalysts such as ammonium ferric sulfate, titanium sulfate, Sodium Bisulfate Monohydrate, p-methyl benzenesulfonic acid can promote protection reaction to enter quickly OK.During using tert-butyl chloro-silicane as protection reagent, use base catalyst triethylamine that protection can be made to react quickly Carry out.

Being described in further detail the present invention below in conjunction with specific embodiment, these embodiments are it is not intended that limit institute of the present invention Claimed scope.

Embodiment 1

5g phenol is dissolved in 25mL THF, according to 4.2 × 10^-3After mol/L is added thereto to p-methyl benzenesulfonic acid and is cooled to 5 DEG C, Drip 5.4g3,4-dihydropyran wherein so that it is be 1.2:1 with the mol ratio of phenol.After warming naturally to 20 DEG C, insulation reaction 5.5h, obtains the mixed solution containing phenol intermediate；

With N₂The above-mentioned mixed solution containing phenol intermediate is replaced after three times, drips, with 0.01g/min, the temperature that speed is to-70 DEG C Above-mentioned mixed solution containing phenol intermediate add n-BuLi, and the mol ratio of n-BuLi and phenol is 1.35:1.Drip and finish Rear insulation reaction 15min, rises to 20 DEG C naturally, and insulation reaction 1h obtains pre-reaction solution；

Triisopropyl borate ester, and triisopropyl borate ester is added to the above-mentioned pre-reaction solution of the temperature of-70 DEG C with the speed of dripping of 0.1g/min It is 1:1 with the mol ratio of phenol intermediate.Drip insulation reaction 1h after finishing, obtain treating hydrating solution；

Treating that the hydrochloric acid adding 2mol/L in hydrating solution, to its pH=2, stirs 1h to above-mentioned, separatory, aqueous phase ethyl acetate extracts Take three times, merge organic facies, after being dried 20min with 20g anhydrous magnesium sulfate, filtration drying agent, after concentration, obtain 2-hydroxy benzenes The thick product of boric acid；

After the decompression distillation of above-mentioned thick product, add normal hexane and pull an oar, be filtrated to get filter cake, after normal hexane washing filter cake, At 30 DEG C, it is dried 4h, obtains 2-hydroxy benzenes boric acid.

Embodiment 2 to 9

65.8g phenol is dissolved in 330ml dichloromethane, according to 4.2 × 10^-3Mol/L is added thereto to p-methyl benzenesulfonic acid and lowers the temperature After 5 DEG C, drip 70.5g3,4-dihydropyran wherein so that it is be 1.2:1 with the mol ratio of phenol.After warming naturally to 20 DEG C, Insulation reaction 1h, obtains reactant liquor.The sodium hydrate aqueous solution of 180ml1mol/L is added so that it is pH=14 in reactant liquor, Separatory after stirring 30min, obtains the first aqueous phase and the first organic facies.The hydrogen-oxygen of 180ml1mol/L is added in the first organic facies Change sodium water solution, separatory after stirring 30min, obtain the second aqueous phase and Second Organic Phase.Merge the first aqueous phase and the second aqueous phase, Extracting with 80ml dichloromethane, separatory obtains the 3rd organic facies.Merge Second Organic Phase and the 3rd organic facies, use 80ml After saturated aqueous common salt washing, it is concentrated under reduced pressure to give phenol intermediate, stand-by.

It is below the subsequent preparation process of embodiment 2 to 9:

Embodiment 2

According to 1.12mol/L, above-mentioned for 2g phenol intermediate is added in tetrahydrofuran solvent, obtain the mixing containing phenol intermediate Solution；

With N₂The above-mentioned mixed solution containing phenol intermediate is replaced after three times, drips, with 0.03g/min, the temperature that speed is to-70 DEG C Above-mentioned mixed solution containing phenol intermediate add n-BuLi, and the mol ratio of n-BuLi and phenol is 1.1:1.Drip and finish Rear insulation reaction 20min, rises to 20 DEG C naturally, and insulation reaction 2h obtains pre-reaction solution；

Triisopropyl borate ester, and triisopropyl borate ester is added to the above-mentioned pre-reaction solution of the temperature of-70 DEG C with the speed of dripping of 0.1g/min It is 1.1:1 with the mol ratio of phenol intermediate.Drip insulation reaction 20min after finishing, naturally rise to 20 DEG C, insulation reaction 1h, obtain Treat hydrating solution；

Treat that hydrating solution is cooled to 10 DEG C by above-mentioned, be added thereto to the hydrochloric acid of 2mol/L to its pH=1, stir 2h, separatory, Obtain the 4th aqueous phase and the 4th organic facies.Being extracted with ethyl acetate three times by 4th aqueous phase, separatory obtains the 5th organic facies.Merge 4th organic facies and the 5th organic facies, after being dried 20min with 10g anhydrous magnesium sulfate, filtration drying agent, obtain 2-hydroxyl after concentration The thick product of base phenylboric acid；

After the decompression distillation of above-mentioned thick product, add normal hexane and pull an oar, be filtrated to get filter cake, after normal hexane washing filter cake, At 80 DEG C, it is dried 2h, obtains 2-hydroxy benzenes boric acid.

Embodiment 3

With N₂The above-mentioned mixed solution containing phenol intermediate is replaced after three times, drips, with 0.02g/min, the temperature that speed is to-70 DEG C Above-mentioned mixed solution containing phenol intermediate add n-BuLi, and the mol ratio of n-BuLi and phenol is 1.1:1.Drip and finish Rear insulation reaction 20min, rises to 20 DEG C naturally, and insulation reaction 2h obtains pre-reaction solution；

Triisopropyl borate ester, and triisopropyl borate ester is added to the above-mentioned pre-reaction solution of the temperature of-30 DEG C with the speed of dripping of 0.2g/min It is 1.1:1 with the mol ratio of phenol intermediate.Drip insulation reaction 20min after finishing, naturally rise to 20 DEG C, insulation reaction 1h, obtain Treat hydrating solution；

After the decompression distillation of above-mentioned thick product, add normal hexane and pull an oar, be filtrated to get filter cake, after normal hexane washing filter cake, At 60 DEG C, it is dried 2h, obtains 2-hydroxy benzenes boric acid.

Embodiment 4

With N₂The above-mentioned mixed solution containing phenol intermediate is replaced after three times, drips, with 0.01g/min, the temperature that speed is to-70 DEG C Above-mentioned mixed solution containing phenol intermediate add n-BuLi, and the mol ratio of n-BuLi and phenol is 1.1:1.Drip and finish Rear insulation reaction 20min, rises to 20 DEG C naturally, and insulation reaction 2h obtains pre-reaction solution；

Add triisopropyl borate ester with the speed of dripping of 0.1g/min to the above-mentioned pre-reaction solution of the temperature of 0 DEG C, and triisopropyl borate ester with The mol ratio of phenol intermediate is 1.1:1.Drip insulation reaction 20min after finishing, naturally rise to 20 DEG C, insulation reaction 1h, treated Hydrating solution；

Embodiment 5

With N₂The above-mentioned mixed solution containing phenol intermediate is replaced after three times, drips, with 0.02g/min, the temperature that speed is to-30 DEG C Above-mentioned mixed solution containing phenol intermediate add n-BuLi, and the mol ratio of n-BuLi and phenol is 1.1:1.Drip and finish Rear insulation reaction 20min, rises to 20 DEG C naturally, and insulation reaction 2h obtains pre-reaction solution；

After the decompression distillation of above-mentioned thick product, add normal hexane and pull an oar, be filtrated to get filter cake, after normal hexane washing filter cake, At 60 DEG C, it is dried 3h, obtains 2-hydroxy benzenes boric acid.

Embodiment 6

With N₂The above-mentioned mixed solution containing phenol intermediate is replaced after three times, drips, with 0.03g/min, the temperature that speed is to-30 DEG C Above-mentioned mixed solution containing phenol intermediate add n-BuLi, and the mol ratio of n-BuLi and phenol is 1.0:1.Drip and finish Rear insulation reaction 20min, rises to 20 DEG C naturally, and insulation reaction 1.5h obtains pre-reaction solution；

Triisopropyl borate ester, and triisopropyl borate ester is added to the above-mentioned pre-reaction solution of the temperature of-30 DEG C with the speed of dripping of 0.1g/min It is 1.1:1 with the mol ratio of phenol intermediate.Drip insulation reaction 20min after finishing, naturally rise to 20 DEG C, insulation reaction 1h, obtain Treat hydrating solution；

Treat that hydrating solution is cooled to 15 DEG C by above-mentioned, be added thereto to the hydrochloric acid of 2mol/L to its pH=2, stir 2h, separatory, Obtain the 4th aqueous phase and the 4th organic facies.Being extracted with ethyl acetate three times by 4th aqueous phase, separatory obtains the 5th organic facies.Merge 4th organic facies and the 5th organic facies, after being dried 20min with 10g anhydrous magnesium sulfate, filtration drying agent, obtain 2-hydroxyl after concentration The thick product of base phenylboric acid；

Embodiment 7

With N₂The above-mentioned mixed solution containing phenol intermediate is replaced after three times, drips, with 0.02g/min, the temperature that speed is to-30 DEG C Above-mentioned mixed solution containing phenol intermediate add n-BuLi, and the mol ratio of n-BuLi and phenol is 1.1:1.Drip and finish Rear insulation reaction 20min, rises to 20 DEG C naturally, and insulation reaction 1.5h obtains pre-reaction solution；

Embodiment 8

With N₂The above-mentioned mixed solution containing phenol intermediate is replaced after three times, drips, with 0.02g/min, the temperature that speed is to-30 DEG C Above-mentioned mixed solution containing phenol intermediate add n-BuLi, and the mol ratio of n-BuLi and phenol is 1.3:1.Drip and finish Rear insulation reaction 20min, rises to 20 DEG C naturally, and insulation reaction 1.5h obtains pre-reaction solution；

Embodiment 9

With N₂The above-mentioned mixed solution containing phenol intermediate is replaced after three times, drips, with 0.02g/min, the temperature that speed is to-30 DEG C Above-mentioned mixed solution containing phenol intermediate add n-BuLi, and the mol ratio of n-BuLi and phenol is 2.0:1.Drip and finish Rear insulation reaction 20min, rises to 20 DEG C naturally, and insulation reaction 1.5h obtains pre-reaction solution；

Embodiment 10～22

65.8g phenol is dissolved in 330ml dichloromethane, according to 5 × 10^-3Mol/L is added thereto to p-methyl benzenesulfonic acid and is cooled to After 0 DEG C, drip 64.1g3,4-dihydropyran wherein so that it is be 1.1:1 with the mol ratio of phenol.After warming naturally to 30 DEG C, Insulation reaction 0.5h, obtains reactant liquor.The sodium hydrate aqueous solution of 150ml1mol/L is added so that it is pH=8 in reactant liquor, Separatory after stirring 30min, obtains the first aqueous phase and the first organic facies.The hydrogen-oxygen of 150ml1mol/L is added in the first organic facies Change sodium water solution, separatory after stirring 30min, obtain the second aqueous phase and Second Organic Phase.Merge the first aqueous phase and the second aqueous phase, Extracting with 80ml dichloromethane, separatory obtains the 3rd organic facies.Merge Second Organic Phase and the 3rd organic facies, use 80ml After saturated aqueous common salt washing, it is concentrated under reduced pressure to give phenol intermediate, stand-by.

It is below the subsequent preparation process of embodiment 10 to 22:

Embodiment 10

Triisopropyl borate ester, and triisopropyl borate ester is added to the above-mentioned pre-reaction solution of the temperature of-30 DEG C with the speed of dripping of 0.2g/min It is 1.3:1 with the mol ratio of phenol intermediate.Drip insulation reaction 20min after finishing, naturally rise to 20 DEG C, insulation reaction 1h, obtain Treat hydrating solution；

Embodiment 11

Triisopropyl borate ester, and triisopropyl borate ester is added to the above-mentioned pre-reaction solution of the temperature of-30 DEG C with the speed of dripping of 0.2g/min It is 1.5:1 with the mol ratio of phenol intermediate.Drip insulation reaction 20min after finishing, naturally rise to 20 DEG C, insulation reaction 1h, obtain Treat hydrating solution；

Embodiment 12

Triisopropyl borate ester, and triisopropyl borate ester is added to the above-mentioned pre-reaction solution of the temperature of-30 DEG C with the speed of dripping of 0.2g/min It is 1.6:1 with the mol ratio of phenol intermediate.Drip insulation reaction 20min after finishing, naturally rise to 20 DEG C, insulation reaction 1h, obtain Treat hydrating solution；

Embodiment 13

Triisopropyl borate ester, and triisopropyl borate ester is added to the above-mentioned pre-reaction solution of the temperature of-30 DEG C with the speed of dripping of 0.2g/min It is 2.0:1 with the mol ratio of phenol intermediate.Drip insulation reaction 20min after finishing, naturally rise to 20 DEG C, insulation reaction 1h, obtain Treat hydrating solution；

Embodiment 14

According to 1.12mol/L, above-mentioned for 2g phenol intermediate is added in tetrahydrofuran solvent, obtain the mixing containing phenol intermediate Solution；With N₂The above-mentioned mixed solution containing phenol intermediate is replaced after three times, drips, with 0.02g/min, the temperature that speed is to-70 DEG C The above-mentioned mixed solution containing phenol intermediate of degree adds n-BuLi, and the mol ratio of n-BuLi and phenol is 1.5:1.Drip Insulation reaction 20min after finishing, rises to 20 DEG C naturally, and insulation reaction 1.5h obtains pre-reaction solution；

Triisopropyl borate ester, and triisopropyl borate ester is added to the above-mentioned pre-reaction solution of the temperature of-70 DEG C with the speed of dripping of 0.2g/min It is 2.5:1 with the mol ratio of phenol intermediate.Drip insulation reaction 20min after finishing, naturally rise to 20 DEG C, insulation reaction 1h, obtain Treat hydrating solution；

Embodiment 15

According to 5.6mol/L, above-mentioned for 2g phenol intermediate is added in tetrahydrofuran solvent, obtain the mixing containing phenol intermediate molten Liquid；

Embodiment 16

According to 2.8mol/L, above-mentioned for 2g phenol intermediate is added in tetrahydrofuran solvent, obtain the mixing containing phenol intermediate molten Liquid；

With N₂The above-mentioned mixed solution containing phenol intermediate is replaced after three times, drips, with 0.02g/min, the temperature that speed is to-70 DEG C Above-mentioned mixed solution containing phenol intermediate add n-BuLi, and the mol ratio of n-BuLi and phenol is 1.1:1.Drip and finish Rear insulation reaction 20min, rises to 20 DEG C naturally, and insulation reaction 1.5h obtains pre-reaction solution；

Triisopropyl borate ester, and triisopropyl borate ester is added to the above-mentioned pre-reaction solution of the temperature of-70 DEG C with the speed of dripping of 0.2g/min It is 1.1:1 with the mol ratio of phenol intermediate.Drip insulation reaction 20min after finishing, naturally rise to 20 DEG C, insulation reaction 1h, obtain Treat hydrating solution；

Embodiment 17

According to 1.86mol/L, above-mentioned for 2g phenol intermediate is added in tetrahydrofuran solvent, obtain the mixing containing phenol intermediate Solution；

Embodiment 18

According to 0.8mol/L, above-mentioned for 2g phenol intermediate is added in tetrahydrofuran solvent, obtain the mixing containing phenol intermediate molten Liquid；

Embodiment 19

Add to, in normal hexane solvent, obtain the mixing containing phenol intermediate molten by above-mentioned for 2g phenol intermediate according to 1.12mol/L Liquid；

Embodiment 20

According to 1.12mol/L, above-mentioned for 2g phenol intermediate is added in toluene solvant, obtain the mixed solution containing phenol intermediate；

Embodiment 21

Add to, in methyl tert-butyl ether solvent, obtain containing phenol intermediate by above-mentioned for 2g phenol intermediate according to 1.12mol/L Mixed solution；

Embodiment 22

Methyl borate. is added to the above-mentioned pre-reaction solution of the temperature of-30 DEG C with the speed of dripping of 0.2g/min, and methyl borate. and benzene The mol ratio of phenol intermediate is 1.1:1.Drip insulation reaction 20min after finishing, naturally rise to 20 DEG C, insulation reaction 1h, obtain treating water Solve solution；

Embodiment 23

50g phenol is dissolved in 230ml dichloromethane, according to 4.2 × 10^-3Mol/L is added thereto to triethylamine temperature control to 20 DEG C, Drip tert-butyl chloro-silicane wherein so that it is be 1.0:1 with the mol ratio of phenol.Insulation reaction 15h, obtains reactant liquor. Adding 100ml deionized water in reactant liquor to wash, separatory obtains the first aqueous phase and the first organic facies.Use 100ml hydrogen-oxygen Changing sodium water solution (concentration is 1mol/L) and wash the first organic facies, separatory obtains the second aqueous phase and Second Organic Phase.With 50g without Aqueous sodium persulfate is dried Second Organic Phase, is concentrated under reduced pressure to give phenol intermediate after filtration drying agent；

Add to, in 770ml tetrahydrofuran solvent, obtain the mixed solution containing phenol intermediate by above-mentioned for 110.6g phenol intermediate；

With N₂The above-mentioned mixed solution containing phenol intermediate is replaced after three times, drips, with 0.02g/min, the temperature that speed is to-78 DEG C Above-mentioned mixed solution containing phenol intermediate add n-BuLi, and the mol ratio of n-BuLi and phenol is 1.1:1.Drip and finish Rear insulation reaction 15min, rises to 20 DEG C naturally, and insulation reaction 1.5h obtains pre-reaction solution；

Triisopropyl borate ester, and triisopropyl borate ester is added to the above-mentioned pre-reaction solution of the temperature of-78 DEG C with the speed of dripping of 0.2g/min It is 1.1:1 with the mol ratio of phenol intermediate.Drip insulation reaction 20min after finishing, naturally rise to 20 DEG C, insulation reaction 1h, obtain Treat hydrating solution；

Treat that hydrating solution is cooled to 10 DEG C by above-mentioned, be added thereto to the hydrochloric acid of 2mol/L to its pH=1, stir 1h, separatory, Obtain the 4th aqueous phase and the 4th organic facies.Being extracted with ethyl acetate three times by 4th aqueous phase, separatory obtains the 5th organic facies.Merge 4th organic facies and the 5th organic facies, obtain 2-hydroxyl after being dried 20min, filtration drying agent concentration with 150g anhydrous sodium sulfate The thick product of phenylboric acid；

Embodiment 24

65.8g phenol is dissolved in 330ml dichloromethane, according to 5 × 10^-3Mol/L is added thereto to p-methyl benzenesulfonic acid and is cooled to After 0 DEG C, drip 64.1g3,4-dihydropyran wherein so that it is be 1.1:1 with the mol ratio of phenol.After warming naturally to 30 DEG C, Insulation reaction 0.5h, obtains reactant liquor.The sodium hydrate aqueous solution of 150ml1mol/L is added so that it is pH=8 in reactant liquor, Separatory after stirring 30min, obtains the first aqueous phase and the first organic facies.The hydrogen-oxygen of 150ml1mol/L is added in the first organic facies Change sodium water solution, separatory after stirring 30min, obtain the second aqueous phase and Second Organic Phase.Merge the first aqueous phase and the second aqueous phase, Extracting with 80ml dichloromethane, separatory obtains the 3rd organic facies.Merge Second Organic Phase and the 3rd organic facies, use 80ml After saturated aqueous common salt washing, it is concentrated under reduced pressure to give phenol intermediate；

With N₂The above-mentioned mixed solution containing phenol intermediate is replaced after three times, drips speed to the temperature of 0 DEG C with 0.02g/min The above-mentioned mixed solution containing phenol intermediate adds n-BuLi, and the mol ratio of n-BuLi and phenol is 1.1:1.Drip after finishing Insulation reaction 3.5h, obtains pre-reaction solution；

Method of testing:

1) product content: use the HPLC chromatogram instrument of Agilent 1100 series of Beijing Lewei Taike Medical Technology Co., Ltd. The 2-thick product of hydroxy benzenes boric acid is tested, calculates the product content after deducting solvent in thick product with peak area normalization method；Color Spectral condition is as follows: chromatographic condition: instrument is numbered: LAVI YS0052；Post type: Agilent-ZORBAX SB-C18；Post is advised Lattice: 1.8 μm, 4.6 × 50mm；Flowing facies type: 10% (acetonitrile+0.05%TFA): 90% (water+0.05%TFA)；Sample size 5 μ L； Detector: UV-DAD；Temperature: 40oC；

2) conversion ratio: according to the chromatographic content of raw material in the 2-thick product of hydroxy benzenes boric acid, calculate the conversion ratio of raw material.Test result As shown in table 1:

Table 1

	Product content (%)	Conversion ratio (%)		Product content (%)	Conversion ratio (%)
						Embodiment 1	82	100	Embodiment 13	83.4	86
Embodiment 2	84.5	100	Embodiment 14	63	95
						Embodiment 3	80	100	Embodiment 15	88.7	100
Embodiment 4	71	100	Embodiment 16	84	100
						Embodiment 5	87.6	100	Embodiment 17	87	100
Embodiment 6	87.4	100	Embodiment 18	56	100
						Embodiment 7	87.2	100	Embodiment 19	69.2	100
Embodiment 8	87.6	100	Embodiment 20	54.3	100
						Embodiment 9	80.3	100	Embodiment 21	70.5	100
Embodiment 10	87.2	99	Embodiment 22	56.4	100
						Embodiment 11	87.8	99	Embodiment 23	30.7	100
Embodiment 12	84.8	99	Embodiment 24	60	100

From above data, it can be seen that use the method in the above embodiment of the present invention, prepared 2-hydroxy benzenes boric acid There is higher conversion ratio and product content.Especially, when embodiment uses the preferred processing condition in the present invention, as incited somebody to action First temperature and the second temperature are set as-70～-30 DEG C, when the mol ratio of n-BuLi Yu phenol is set as 1.1～1.3, prepared 2-hydroxy benzenes boric acid there is higher conversion ratio and product content.

The foregoing is only the preferred embodiments of the present invention, be not limited to the present invention, for those skilled in the art For, the present invention can have various modifications and variations.All within the spirit and principles in the present invention, any amendment of being made, etc. With replacement, improvement etc., should be included within the scope of the present invention.

Claims

1. the preparation method of a 2-hydroxy benzenes boric acid, it is characterised in that comprise the following steps:

S1, in phenol/organic solvent mixed solution, add hydroxy protecting agent, formed containing phenol intermediate after reaction Mixed solution；

S2, the described mixed solution containing phenol intermediate is made to be in the first temperature, and to having the institute of described first temperature State addition n-BuLi in the mixed solution containing phenol intermediate, after reaction, form pre-reaction solution；

S3, described pre-reaction solution is made to be in the second temperature, and in the described pre-reaction solution with described second temperature Add borate, formed after reaction and treat hydrating solution；

S4, treating that hydrating solution is hydrolyzed reaction by described, after extraction, to obtain described 2-hydroxy benzenes boric acid thick for concentrated extract Product；

Wherein, described second temperature and described first temperature are identical or different；

In described step S2, first adjust described first temperature to≤-30 DEG C, then to the described mixing containing phenol intermediate Solution adds described n-BuLi, insulation reaction 15～30min, then is warming up to 0～30 DEG C, insulation reaction 0.5～2h, To described pre-reaction solution；

In described step S3, first adjust described second temperature extremely≤0 DEG C, then add described in described pre-reaction solution Borate, insulation reaction 15～30min, then be warming up to 0～30 DEG C, insulation reaction 0.5～2h, obtain described in treat hydrating solution.

Method the most according to claim 1, it is characterised in that in described step S2, first adjusts described first temperature extremely -70～-30 DEG C.

Method the most according to claim 1, it is characterised in that in described step S2, according to described n-BuLi and described benzene The mol ratio of phenol intermediate is the 1～2:1 described n-BuLi of addition.

In method the most according to claim 3, it is characterised in that in described step S2, described n-BuLi and described phenol The mol ratio of mesosome is 1～1.3:1.

Method the most according to claim 3, it is characterised in that in described step S2, adds with the speed of dripping of 0.01～0.03g/min Enter described n-BuLi.

Method the most according to claim 1, it is characterised in that in described step S3, first adjusts described second temperature to≤-30 DEG C.

Method the most according to claim 6, it is characterised in that in described step S3, first adjusts described second temperature extremely -70～-30 DEG C.

Method the most according to claim 1, it is characterised in that in described step S3, according to described borate and described phenol The mol ratio of intermediate is the 1～2:1 described borate of addition.

In the middle of method the most according to claim 8, it is characterised in that in described step S3, described borate and described phenol The mol ratio of body is 1.1～1.5:1.

Method the most according to claim 8, it is characterised in that in described step S3, adds with the speed of dripping of 0.1～0.3g/min Described borate.

11. methods according to claim 1, it is characterised in that in described step S1, form the mixing containing phenol intermediate The step of solution includes:

S11, phenol being dissolved in the first organic solvent, be added thereto to described hydroxy protecting agent, will obtain after reaction is anti- Liquid is answered to be concentrated to give phenol intermediate；

S12, described phenol intermediate is dissolved in the second organic solvent, forms the mixed solution containing described phenol intermediate, Described first organic solvent is identical or different with described second organic solvent.

12. methods according to claim 11, it is characterised in that in described step S11,

Phenol is dissolved in described first organic solvent, after being added thereto to catalyst and being cooled to 0～5 DEG C, is added thereto to Described hydroxy protecting agent, then heats to 10～30 DEG C, carries out insulation reaction 0.5～15h, obtains reactant liquor, be concentrated to give To phenol intermediate；

Wherein, described catalyst is solid acid catalyst or triethylamine.

13. methods according to claim 12, it is characterised in that described catalyst is sulfamic acid, highly acidic cation exchange Resin, ferric chloride (FeCl36H2O), stannic chloride pentahydrate, Ammonium ferric sulfate dodecahyrate, titanium sulfate, Sodium Bisulfate Monohydrate, right Toluenesulfonic acid or triethylamine.

14. methods according to claim 11, it is characterised in that also include in described step S11:

Adding sodium hydrate aqueous solution, stirring in the reactant liquor obtained after reaction, the pH making described reactant liquor is 8～14, Separatory obtains the first aqueous phase and the first organic facies；

Adding sodium hydrate aqueous solution in described first organic facies, after stirring, separatory obtains the second aqueous phase and Second Organic Phase；

Merging described first aqueous phase and the second aqueous phase, with described first organic solvent extraction, separatory obtains the 3rd organic facies；Close And described Second Organic Phase and described 3rd organic facies, after using desiccant dryness, filter, obtain after concentration in described phenol Mesosome.

15. methods according to claim 14, it is characterised in that

In described step S11, it is the 1～1.2:1 described hydroxyl of addition according to described hydroxy protecting agent and described phenol mol ratio Protection reagent, adds described phenol according to 2.12～3mol/L in described first organic solvent, and according to 4.2～5 × 10^-3Mol/L adds described catalyst to described first organic solvent；

In described step S12, to described, second organic solvent is added described phenol intermediate according to 0.8～5.6mol/L.

16. methods according to claim 11, it is characterised in that

Described first organic solvent is polar organic solvent；

Described second organic solvent is polar ether kind solvent or non-polar organic solvent.

17. methods according to claim 16, it is characterised in that described first organic solvent be dichloromethane, n-butyl alcohol, third Alcohol, oxolane, acetic acid, acetone, pyridine, dimethylformamide, methanol, ethylene glycol or dimethyl sulfoxide.

18. methods according to claim 16, it is characterised in that described polar ether kind solvent be ether, propyl ether, diisopropyl ether, Oxolane, expoxy propane or methyl tertiary butyl ether(MTBE).

19. methods according to claim 16, it is characterised in that described non-polar organic solvent be benzene, normal hexane, Pentamethylene., Heptane, toluene or carbon tetrachloride.

20. methods according to claim 1, it is characterised in that in described step S4, described hydrolysis step includes:

To temperature be treat described in-30～20 DEG C in hydrating solution add hydrochloric acid, make described in treat that the pH of hydrating solution is 1～2, After stirring, separatory obtains the 4th aqueous phase and the 4th organic facies；

After in described 4th aqueous phase, addition ethyl acetate extracts, separatory obtains the 5th organic facies, and merging the described 4th has Machine phase and described 5th organic facies, after using desiccant dryness, filter and be concentrated to give the described 2-thick product of hydroxy benzenes boric acid.

21. methods according to claim 20, it is characterised in that described step S4 also includes described 2-hydroxy benzenes boric acid thick Product carries out the step of post processing；The step of described post processing includes: added to by the described 2-thick product of hydroxy benzenes boric acid just own Alkane is pulled an oar, is filtrated to get filter cake；With normal hexane, described filter cake is carried out filtering and washing, at 30～80 DEG C, is dried 2～4h, Obtain described 2-hydroxy benzenes boric acid.

22. according to the method according to any one of claim 1 to 21, it is characterised in that described hydroxy protecting agent is methoxyl group chlorine Methane, Benzenecarbonyl chloride., isobutene., triphenylchloromethane, 3,4-dihydropyran or tert-butyl chloro-silicane.

23. according to the method according to any one of claim 1 to 21, it is characterised in that described borate is methyl borate., boron Triethylenetetraminehexaacetic acid ester, triproylborate, triisopropyl borate ester, butyl borate or triamylborate.