CN103896974A

CN103896974A - Method for preparing 2-hydroxyphenylboronic acid

Info

Publication number: CN103896974A
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: 2014-07-02
Anticipated expiration: 2034-04-11
Also published as: CN103896974B

Abstract

The invention discloses a method for preparing a 2-hydroxyphenylboronic acid. The method comprises the following steps: S1, adding a hydroxyl protecting agent to a mixed solution of phenol/organic solvent, and forming a mixed solution containing phenol intermediates after reaction; S2, controlling the mixed solution containing the phenol intermediates to be at a first temperature, adding n-butyllithium to the mixed solution containing the phenol intermediates with the first temperature, and forming a pre-reaction solution after reaction; S3, controlling the pre-reaction solution to be at a second temperature, adding borate to the pre-reaction solution with the second temperature and forming a to-be-hydrolyzed solution after reaction; S4, carrying out hydrolysis reaction on the to-be-hydrolyzed solution, extracting and then concentrating the extracting solution to obtain a 2-hydroxyphenylboronic acid crude product, wherein the first temperature is smaller than or equal to 0 DEG C and the second temperature and the second temperature are the same or different. The hydroxyl protecting agent is adopted in the method and the reaction temperatures are controlled, so that the yield of the 2-hydroxyphenylboronic acid is improved. Meanwhile, the phenol is taken as the raw material, so that the production cost of the 2-hydroxyphenylboronic acid is reduced.

Description

The preparation method of 2-hydroxybenzene boric acid

Technical field

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

Background technology

Suzuki-Miyaura linked reaction (SMC) is the important reaction that builds all kinds of C-C singly-bounds, and its main raw material is organic boronic compound.Wherein, 2-hydroxybenzene boric acid is a kind of compound important in organic boronic compound, all has important using value in organic synthesis and field of medicine and chemical technology.At present, its preparation method has following several:

(1) Bean, take phenylo boric acid as raw material, is hydrolyzed and obtains 2-hydroxybenzene boric acid through nitrated, shortening, diazotization, and reaction principle is as follows:

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

(2) to adopt bromo (adjacent, to) phenol be raw material to Gilman, reacts, then react with boric acid ester and be hydrolyzed and obtain hydroxybenzene boric acid product with two equivalent butyllithiums.This synthetic method route is short, but yield is lower, and take bromophenol as raw material, cost is higher, is unfavorable for scale operation.

(3) Chao builds equality by after the protection of the phenolic hydroxyl group of bromophenol silicon ethers protecting group, makes Grignard reagent, then reacts with boric acid ester and be hydrolyzed.Total separation yield of this method is still lower, only have below 30%, and adopt bromophenol be raw material, production cost is higher.

(4) to adopt adjacent bromophenol be raw material to Takeo, reacts, then react with boric acid ester and be hydrolyzed and obtain hydroxybenzene boric acid product with two equivalent butyllithiums.Reaction principle is as follows:

This method is also take o-bromophenol as raw material, and cost is higher, and need to add the n-Butyl Lithium reaction of two equivalents, is unfavorable for scale operation.

Generally speaking, all there is the defect that cost is high, operational path is long in the preparation method of 2-hydroxybenzene boric acid at present.Based on this, be necessary to design the short preparation method of a kind of low cost, operational path in order to synthetic 2-hydroxybenzene boric acid.

Summary of the invention

The present invention aims to provide a kind of preparation method of 2-hydroxybenzene boric acid, to solve the higher problem of preparation cost of 2-hydroxybenzene boric acid in prior art.

To achieve these goals, according to an aspect of the present invention, the preparation method that a kind of 2-hydroxybenzene boric acid is provided, it comprises the following steps: S1, in phenol/organic solvent mixing solutions, add hydroxyl protection reagent, form the mixing solutions that contains phenol intermediate after reaction; S2, make the mixing solutions that contains phenol intermediate in the first temperature, and add n-Butyl Lithium to having in the mixing solutions that contains phenol intermediate of the first temperature, after reaction, form pre-reaction solution; S3, make pre-reaction solution in the second temperature, and add boric acid ester to having in the pre-reaction solution of the second temperature, after reaction, form and treat hydrating solution; S4, will treat the hydrating solution reaction that is hydrolyzed, after extraction, concentrated extract obtains the thick product of 2-hydroxybenzene boric acid; Wherein, the first temperature≤0 ℃, the second temperature and the first temperature are identical or different.

Further, in above-mentioned steps S2, first adjust the first temperature to≤-30 ℃, then in the mixing solutions that contains phenol intermediate, add n-Butyl Lithium, insulation reaction 15～30min, then be warming up to 0～30 ℃, insulation reaction 0.5～2h, obtains pre-reaction solution; Preferably first adjust the first temperature to-70～-30 ℃.

Further, in above-mentioned steps S2, be that 1～2:1 adds n-Butyl Lithium according to the mol ratio of n-Butyl Lithium and phenol intermediate, preferably the mol ratio of n-Butyl Lithium and phenol intermediate is 1～1.3:1, preferably adds n-Butyl Lithium with the speed of dripping of 0.01～0.03g/min.

Further, in above-mentioned steps S3, adding after the step of boric acid ester reaction ...～... min, obtains treating hydrating solution.

Further, in above-mentioned steps S3, first adjust the second temperature to≤0 ℃, then in pre-reaction solution, add boric acid ester, insulation reaction 15～30min, then be warming up to 0～30 ℃, insulation reaction 0.5～2h, obtains treating hydrating solution; Preferably first adjust the second temperature to≤-30 ℃, more preferably to-70～-30 ℃.

Further, in above-mentioned steps S1, form the step of mixing solutions that contains phenol intermediate and comprise: S11, phenol is dissolved in to the first organic solvent, adds wherein hydroxyl protection reagent, by concentrated the reaction solution obtaining after the reaction phenol intermediate that obtains; S12, phenol intermediate is dissolved in to the second organic solvent, forms the mixing solutions that contains phenol intermediate, the first organic solvent and described the second organic solvent are identical or different.

Further, in above-mentioned steps S11, phenol is dissolved in the first organic solvent, add wherein catalyzer and be cooled to after 0～5 ℃, adding wherein hydroxyl protection reagent, being then warming up to 10～30 ℃, carry out insulation reaction 0.5～15h, obtain reaction solution, the concentrated phenol intermediate that obtains; Wherein, catalyzer is solid acid catalyst or triethylamine, preferred catalyst is thionamic acid, storng-acid cation exchange resin, ferric chloride (FeCl36H2O), stannic chloride pentahydrate, 12 ferric sulfate hydrate ammoniums, titanium sulfate, Sodium Bisulfate Monohydrate, tosic acid or triethylamine, more preferably thionamic acid, tosic acid or triethylamine.

Further, in above-mentioned steps S11, also comprise: in the reaction solution that obtains after reaction, add aqueous sodium hydroxide solution, stir, the pH that makes reaction solution is 8～14, and separatory obtains the first water and the first organic phase; In the first organic phase, add aqueous sodium hydroxide solution, after stirring, separatory obtains the second water and Second Organic Phase; Merge the first water and the second water, use the first organic solvent extraction, separatory obtains the 3rd organic phase; Merge Second Organic Phase and the 3rd organic phase, adopt after desiccant dryness, filter, after concentrating, obtain described phenol intermediate.

Further, in above-mentioned steps S11, be that 1～1.2:1 adds hydroxyl protection reagent according to hydroxyl protection reagent and phenol mol ratio, in the first organic solvent, add phenol according to 2.12～3mol/L, and add catalyzer according to 4.2～5 × 10-3mol/L to the first organic solvent; In step S12, according to 0.8～5.6mol/L to the second organic solvent is added to phenol intermediate.

Further, above-mentioned the first organic solvent is polar organic solvent, preferably the first organic solvent is methylene dichloride, propyl carbinol, propyl alcohol, tetrahydrofuran (THF), acetic acid, acetone, pyridine, dimethyl formamide, methyl alcohol, ethylene glycol or dimethyl sulfoxide (DMSO), and more preferably described the first organic solvent is methylene dichloride or tetrahydrofuran (THF); The second organic solvent is polar ether kind solvent or non-polar organic solvent, preferably polar ether kind solvent is ether, propyl ether, isopropyl ether, tetrahydrofuran (THF), propylene oxide or methyl tertiary butyl ether, and more preferably polar ether kind solvent is tetrahydrofuran (THF) or methyl tertiary butyl ether; Preferably non-polar organic solvent is benzene, normal hexane, pentamethylene, heptane, toluene, tetracol phenixin, and preferably non-polar organic solvent is normal hexane or toluene.

Further, in above-mentioned steps S4, hydrolysis reaction step comprises: to temperature be-30～20 ℃ treat in hydrating solution, add hydrochloric acid, make to treat that the pH of hydrating solution is 1～2, after stirring, separatory obtains the 4th water and the 4th organic phase; After adding ethyl acetate to extract in the 4th water, separatory obtains the 5th organic phase, merges the 4th organic phase and the 5th organic phase, adopts after desiccant dryness, filters and concentrate to obtain the thick product of 2-hydroxybenzene boric acid.

Further, above-mentioned steps S4 also comprises the step that the thick product of 2-hydroxybenzene boric acid is carried out to aftertreatment; The step of aftertreatment comprises: the thick product of 2-hydroxybenzene boric acid is added in normal hexane and pulled an oar, filter and obtain filter cake; Filter cake is carried out to filtering and washing with normal hexane, at 30～80 ℃, dry 2～4h, obtains 2-hydroxybenzene boric acid.

Further, above-mentioned hydroxyl protection reagent is methoxychlor methane, Benzoyl chloride, iso-butylene, triphenylmethyl chloride, 3, and 4-dihydropyrane or TERT-BUTYL DIMETHYL CHLORO SILANE, be preferably 3,4-dihydropyrane or TERT-BUTYL DIMETHYL CHLORO SILANE.

Further, above-mentioned boric acid ester is trimethyl borate, triethyl borate, tripropoxy-boron, triisopropyl borate ester, tributyl borate or triamyl borate; Be preferably triisopropyl borate ester, trimethyl borate or triethyl borate.

Apply the preparation method of 2-hydroxybenzene boric acid of the present invention; by adopting hydroxyl protection reagent; and control the state of temperature of reaction system in each step; be conducive to improve the replacement rate of ortho-hydrogens atom in boric acid ester Pyrogentisinic Acid; reduce the growing amount of by product in reaction process, and then improve the productive rate of object product.Meanwhile, in aforesaid method, take the lower phenol of price as raw material, can reduce the production cost of 2-hydroxybenzene boric acid.In addition, prepare the method for 2-hydroxybenzene boric acid compared to adjacent bromophenol, the above-mentioned method of the present invention is directly prepared 2-hydroxybenzene boric acid take phenol as raw material, and it is environmental protection more, and operational path is shorter, is more suitable for large-scale industrialization and produces.

Embodiment

It should be noted that, in the situation that not conflicting, the feature in embodiment and embodiment in the application can combine mutually.Describe the present invention in detail below in conjunction with embodiment.

Introducing as background technology part, there is the problem that cost is higher in the preparation method of 2-hydroxybenzene boric acid.In order to address this problem, inventor provides a kind of preparation method of 2-hydroxybenzene boric acid, it comprises the following steps: S1, in phenol/organic solvent mixing solutions, add hydroxyl protection reagent, form the mixing solutions that contains phenol intermediate after reaction; S2, make the mixing solutions that contains phenol intermediate in the first temperature, and add n-Butyl Lithium to having in the mixing solutions that contains phenol intermediate of the first temperature, after reaction, form pre-reaction solution; S3, make pre-reaction solution in the second temperature, and add boric acid ester to having in the pre-reaction solution of the second temperature, after reaction, form and treat hydrating solution; S4, will treat the hydrating solution reaction that is hydrolyzed, after extraction, concentrated extract obtains the thick product of 2-hydroxybenzene boric acid; Wherein, the first temperature≤0 ℃, the second temperature and the first temperature are identical or different.

In the above-mentioned method of the present invention, prepare 2-hydroxybenzene boric acid take phenol as raw material.In phenol, the hydrogen atom of different positions has different activity.Wherein, the hydrogen atom activity in phenolic hydroxyl group is higher than the hydrogen atom activity of phenol ortho.Based on this, in the time that n-Butyl Lithium carries out the hydrogen atom substitution reaction of phenol, what it preferentially replaced is the hydrogen atom of phenolic hydroxyl group in phenol.And use hydroxyl protection reagent, and the phenolic hydroxyl group in phenol can be protected, form phenol intermediate.Thereby be conducive to impel n-Butyl Lithium to carry out the substitution reaction of phenol ortho hydrogen atom, and then be conducive to reduce the consumption of n-Butyl Lithium.The consumption of n-Butyl Lithium reduces, and is conducive to reduce on the one hand the preparation cost of 2-hydroxybenzene boric acid, is conducive on the other hand improve the safety and stability of reaction.

Meanwhile, at the temperature that is equal to or less than 0 ℃, the activity of the ortho-hydrogens atom of phenol is relatively high, and the hydrogen atom activity of a position and contraposition is relatively low.Based on this; the mixing solutions that contains phenol intermediate is set to be less than at the temperature of-30 ℃; add after n-Butyl Lithium to it; be conducive to impel more n-Butyl Lithium to carry out the substitution reaction of the hydrogen atom of phenol ortho; form the phenol intermediate that ortho position replaces; its structure is suc as formula shown in I, and wherein P is that hydroxyl protection reagent carries out the blocking group forming after protective reaction:

In addition, make n-Butyl Lithium, under the lesser temps that is equal to or less than 0 ℃, substitution reaction occur, be conducive to improve the security of reaction.After previous reaction, form the pre-reaction solution that contains above-mentioned ortho position fortified phenol intermediate.In this pre-reaction solution, add boric acid ester, can make boric acid ester to the lithium atom generation substitution reaction in the fortified phenol intermediate of ortho position, form the thick product of target product 2-hydroxybenzene boric acid.

To, after hydrating solution hydrolysis, can obtain the thick product of object product 2-hydroxybenzene boric acid.Generally speaking; in above-mentioned reaction process, adopt hydroxyl protection reagent, and control the state of temperature of reaction system in each step, be conducive to improve the replacement rate of ortho-hydrogens atom in boric acid ester Pyrogentisinic Acid; reduce the growing amount of by product in reaction process, and then improve the productive rate of object product.Meanwhile, in aforesaid method, take the lower phenol of price as raw material, can reduce the production cost of 2-hydroxybenzene boric acid.In addition, prepare the method for 2-hydroxybenzene boric acid compared to adjacent bromophenol, the above-mentioned method of the present invention is directly prepared 2-hydroxybenzene boric acid take phenol as raw material, and it is environmental protection more, and operational path is shorter, is more suitable for large-scale industrialization and produces.

As long as according to above-mentioned method, just can obtain the thick product of 2-hydroxybenzene boric acid that product content is higher.One preferred embodiment in, in above-mentioned steps S2, first adjust the first temperature to≤-30 ℃, then in the mixing solutions that contains phenol intermediate, add n-Butyl Lithium, insulation reaction 15～30min, then be warming up to 0～30 ℃, insulation reaction 0.5～2h, obtains pre-reaction solution.

As long as the first temperature is less than or equal to 0 ℃, just can impel the ortho-hydrogens atom generation substitution reaction of n-Butyl Lithium and phenol intermediate.Preferably the first temperature is-30 ℃, while carrying out the substitution reaction of n-Butyl Lithium, is more conducive to make the directionally ortho-hydrogens atom in fortified phenol intermediate of n-Butyl Lithium at-30 ℃ of temperature, thereby is conducive to further improve purity and the output of object product.More preferably, first adjust the first temperature to-70～-30 ℃.Under this temperature condition, when being conducive to make the ortho-hydrogens atom of n-Butyl Lithium and phenol intermediate to react, make it have higher speed of reaction.In addition, also help and reduce in reaction process because low temperature maintains the energy expenditure of bringing.

In addition, carry out insulation reaction for the first time adding after the step of n-Butyl Lithium, be conducive to make n-Butyl Lithium at a lower temperature optionally with the ortho-hydrogens atom generation substitution reaction of phenol intermediate, reduce the generation of by product.This is just conducive to improve the content of fortified phenol intermediate in ortho position in pre-reaction solution, and then improves the product content of ultimate aim product.While being warming up to 0～30 ℃ after insulation reaction, temperature-rise period is that nature heats up.When this can make n-Butyl Lithium fully locate, accelerate the speed of reaction of n-Butyl Lithium and phenol intermediate ortho-hydrogens atom, and then Reaction time shorten, pre-reaction solution obtained., the mixing solutions after insulation reaction is heated up, the location that also helps ortho-hydrogens atom in further raising n-Butyl Lithium Pyrogentisinic Acid intermediate replaces, and makes to form in system more ortho position fortified phenol intermediate meanwhile.

In above-mentioned method, the add-on of n-Butyl Lithium can be adjusted according to the theoretical ratio of reaction.One preferred embodiment in, in above-mentioned steps S2, be that 1～2:1 adds n-Butyl Lithium according to the mol ratio of n-Butyl Lithium and phenol intermediate, preferably the mol ratio of n-Butyl Lithium and phenol intermediate is 1～1.3:1.Add n-Butyl Lithium according to aforementioned proportion, be conducive to make phenol intermediate ortho-hydrogens atom to be replaced completely, and then be conducive to improve the output of target product.More preferably add n-Butyl Lithium with the speed of dripping of 0.01～0.03g/min.Drip n-Butyl Lithium with above-mentioned speed, be conducive to make substitution reaction more stably to be carried out, and then improve the security of reaction.

In aforesaid method, adding after the step of boric acid ester, the concrete reaction times can be adjusted according to number and the concrete speed of reaction of reaction raw materials.Preferably, react after adding the step of boric acid ester ...～... min, obtains treating hydrating solution., as long as boric acid ester is reacted according to step S3 with ortho position fortified phenol intermediate in pre-reaction solution, reacted mixing solutions is hydrolyzed meanwhile, just can obtains the thick product of 2-hydroxybenzene boric acid that product content is higher.One more preferred embodiment in, first adjust the second temperature to≤0 ℃, then in pre-reaction solution, add boric acid ester, insulation reaction 15～30min, then be warming up to 0～30 ℃, insulation reaction 0.5～2h, obtains treating hydrating solution.

The temperature setting of pre-reaction solution is set to and is equal to or less than 0 ℃, can reduce the activity of other hydrogen atom in the fortified phenol intermediate of ortho position.Thereby be conducive to reduce the probability that boric acid ester and other hydrogen atom react, reduce the growing amount of by product, impel later stage boric acid ester and ortho position fortified phenol intermediate to carry out lithium atom substitution reaction, hydrating solution is treated in formation.Simultaneously, because the hydrogen atom of other position on the lithium atom in the fortified phenol intermediate of ortho position and phenyl ring still has certain reactive behavior, before adding boric acid ester, pre-reaction solution is lowered the temperature, be conducive to prevent that in the fortified phenol intermediate of ortho position, lithium atom substitution reaction occurs in other site of phenyl ring, thereby form the intermediate of many lithiumations or the substitution product in other site of phenyl ring.Generally speaking, pre-reaction solution is lowered the temperature, be conducive to suppress the formation of by product, thereby improve the productive rate of target product.

In the process of real reaction, as long as the second temperature is less than or equal to 0 ℃, just can reduce the probability that other hydrogen atoms in boric acid ester and ortho position fortified phenol intermediate react, also can reduce by two ortho positions and all have the intermediate of lithium atom simultaneously, thereby reduce the quantity of by product, and impel boric acid ester and above-mentioned lithium atom generation substitution reaction.Preferably the second temperature≤-30 ℃, more preferably to-70～-30 ℃.Under this temperature condition, be conducive to further reduce the quantity of the by product forming because of lithium atom and other atomic reaction of hydrogen, what be conducive to make boric acid ester and ortho position lithium atom in the fortified phenol intermediate of ortho position reacts the relatively high speed of maintenance simultaneously.In addition,, in above-mentioned method, the add-on of boric acid ester can be adjusted according to the theoretical ratio of reaction.One preferred embodiment in, in above-mentioned steps S3, be that 1～2:1 adds boric acid ester according to the mol ratio of boric acid ester and phenol intermediate, the mol ratio of preferred boric acid ester and phenol intermediate is 1.1～1.5:1.Add boric acid ester according to aforementioned proportion, be conducive to make the ortho position lithium atom of ortho position fortified phenol intermediate to be replaced completely, and then be conducive to improve the output of target product.Preferably add boric acid ester with the speed of dripping of 0.1～0.3g/min.Drip boric acid ester with above-mentioned speed, be conducive to make stable reaction to be carried out, and then improve the security of reaction.

In above-mentioned method; after the mixing solutions that contains phenol intermediate forming after protective reaction; directly in this system, carry out n-Butyl Lithium substitution reaction, boric acid ester substitution reaction and the hydrolysis reaction of " cooking-pot type ", just can prepare target product 2-hydroxybenzene boric acid.One preferred embodiment in, the solution after protective reaction can also be carried out to concentration, obtain, after phenol intermediate, further phenol intermediate being dissolved in to the substitution reaction of carrying out the later stage in organic solvent.Particularly, above-mentioned steps S1 comprises the following steps: S11, phenol is dissolved in to the first organic solvent, adds wherein hydroxyl protection reagent, by concentrated the reaction solution obtaining after the reaction phenol intermediate that obtains; S12, phenol intermediate is dissolved in to the second organic solvent, forms the mixing solutions that contains phenol intermediate, the first organic solvent and the second organic solvent are identical or different.In this step, the substitution reaction of the hydroxyl protection reaction of phenol and phenol intermediate, respectively independently carrying out in system, is conducive to the impurity in minimizing system, is conducive to improve stability and the security of reaction simultaneously.

According to instruction of the present invention, those skilled in the art have the ability to be selected from the preparation technology of concrete phenol intermediate, to obtain the phenol intermediate that content is higher.One preferred embodiment in; in above-mentioned steps S11; phenol is dissolved in the first organic solvent; add wherein catalyzer and be cooled to after 0～5 ℃; add wherein hydroxyl protection reagent; after being warming up to 10～30 ℃, insulation reaction 0.5～15h, obtains reaction solution, the concentrated phenol intermediate that obtains.Reacting between hydroxyl protection reagent and phenol is thermopositive reaction, before adding hydroxyl protection reagent, system temperature is down to 0～5 ℃, is conducive to prevent the bumping of excess Temperature initiator system after exothermic heat of reaction.Add and temperature is controlled to 10～30 ℃ after hydroxyl protection reagent and is also conducive to make reacting balance to carry out.Add catalyzer to be conducive to improve speed of reaction, optional catalyzer includes but not limited to solid acid catalyst.Under the katalysis of the acid active site of solid catalyst surface, the hydrogen atom in phenol phenolic hydroxyl group can be replaced by the blocking group in hydroxyl protection reagent quickly, forms comparatively stable group.Preferred above-mentioned solid acid catalyst includes but not limited to that the acid active centre in thionamic acid, storng-acid cation exchange resin, ferric chloride (FeCl36H2O), stannic chloride pentahydrate, 12 ferric sulfate hydrate ammoniums, titanium sulfate, Sodium Bisulfate Monohydrate, these catalyzer of tosic acid is more; and acidity is stronger, can further impel the hydrogen atom in blocking group fortified phenol phenolic hydroxyl group.More preferably, adopt thionamic acid or tosic acid as catalyzer, its catalytic efficiency is higher.Optional catalyzer can also be selected basic catalyst triethylamine, and it also can promote that in hydroxyl protection reagent and phenol, phenolic hydroxyl group reacts, and forms comparatively stable blocking group.

In above-mentioned method, utilize hydroxyl protection reagent the hydroxyl in phenol can be protected, obtain the reaction solution that contains phenol intermediate.This reaction solution is concentrated, just can obtain the phenol intermediate that content is higher.One preferred embodiment in, the reaction solution that carries out hydroxyl protection reaction is carried out to purification processes.Concrete working method is as follows: in the reaction solution that obtains after reaction, add aqueous sodium hydroxide solution, stir, the pH that makes reaction solution is 8～14, and separatory obtains the first water and the first organic phase; In the first organic phase, add aqueous sodium hydroxide solution, after stirring, separatory obtains the second water and Second Organic Phase; Merge the first water and the second water, use the first organic solvent extraction, separatory obtains the 3rd organic phase; Merge Second Organic Phase and the 3rd organic phase, dry, the concentrated phenol intermediate that obtains.In reaction solution or the first organic phase, add aqueous sodium hydroxide solution, can make unreacted phenol salify and be dissolved in the water to be removed, the catalyzer in system and some water miscible impurity can be extracted and remove simultaneously.Obtain comparatively pure phenol intermediate.Utilize the first organic solvent to extract water, phenol intermediate a small amount of in water can be reclaimed.After final merging organic phase, carry out concentrate drying, can obtain phenol intermediate comparatively pure, that content is higher.

In above-mentioned method, hydroxyl protection reagent can be adjusted according to concrete reaction theory ratio with the add-on of catalyzer.One preferred embodiment in, in above-mentioned steps S11, be that 1～1.2:1 adds hydroxyl protection reagent according to hydroxyl protection reagent and phenol mol ratio, in the first organic solvent, add phenol according to 2.12～3mol/L, and according to 4.2～5 × 10 ^-3mol/L adds catalyzer to the first organic solvent; In step S12, according to 0.8～5.6mol/L to the second organic solvent is added to phenol intermediate.Add reactant, solvent and catalyzer according to above-mentioned ratio, be conducive to make reaction fully reaction in the system of homogeneous comparatively.

It in above-mentioned method, the first solvent and the second solvent is not had to particular requirement, as long as can provide the comparatively reaction system of homogeneous.One preferred embodiment in, above-mentioned the first organic solvent is polar organic solvent, and it includes but not limited to methylene dichloride, propyl carbinol, propyl alcohol, tetrahydrofuran (THF), acetic acid, acetone, pyridine, dimethyl formamide, methyl alcohol, ethylene glycol or dimethyl sulfoxide (DMSO).Phenol all has higher solubleness in these solvents, thereby is conducive to provide the more reaction system of homogeneous phase, and phenol is reacted more fully with hydroxyl protection reagent.More preferably this first organic solvent is methylene dichloride or tetrahydrofuran (THF).Above-mentioned the second organic solvent is polar ether kind solvent or non-polar organic solvent.Wherein polar ether kind solvent includes but not limited to ether, propyl ether, isopropyl ether, tetrahydrofuran (THF), propylene oxide or methyl tertiary butyl ether, more preferably tetrahydrofuran (THF) or methyl tertiary butyl ether; Wherein non-polar organic solvent includes but not limited to benzene, normal hexane, pentamethylene, heptane, toluene, tetracol phenixin, is preferably normal hexane or toluene.The substitution reaction that these solvents all can make phenol intermediate is carried out in the system of homogeneous comparatively, thereby is conducive to improve the output of object product 2-hydroxybenzene boric acid.

In above-mentioned method, as long as will treat the hydrating solution reaction that is hydrolyzed, just can obtain object product 2-hydroxybenzene boric acid.One preferred embodiment in, in above-mentioned steps S4, hydrolysis reaction step comprises: to temperature be-30～20 ℃ treat in hydrating solution, add hydrochloric acid, make to treat that the pH of hydrating solution is 1～2, after stirring, separatory obtains the 4th water and the 4th organic phase; After adding ethyl acetate to extract in the 4th water, separatory obtains the 5th organic phase, merges the 4th organic phase and the 5th organic phase, adopts after desiccant dryness, filters and concentrate to obtain the thick product of 2-hydroxybenzene boric acid.Adjustment treats that the pH of hydrating solution is 1～2, is conducive to make its hydrolysis to generate target product 2-hydroxybenzene boric acid.Add ethyl acetate to be conducive to a small amount of product extraction in water to be reclaimed.In addition, can adopt conventional siccative for the siccative of dry organic phase, as anhydrous sodium sulphate, anhydrous cupric sulfate etc.

As long as according to above-mentioned method, just can obtain the thick product of 2-hydroxybenzene boric acid that content is higher.One preferred embodiment in, step S4 also comprises the step that the thick product of 2-hydroxybenzene boric acid is carried out to aftertreatment; The step of aftertreatment comprises: the thick product of 2-hydroxybenzene boric acid is added in normal hexane and pulled an oar, filter and obtain filter cake; By normal hexane washing leaching cake filtering and washing, at 30～80 ℃, dry 2～4h, obtains 2-hydroxybenzene boric acid.Thick product is carried out to aftertreatment, be conducive to remove the impurity component in product, obtain comparatively pure target product.

It in the above-mentioned method of the present invention, boric acid ester is not had to special requirement, as long as can replace the ortho position lithium atom in the fortified phenol intermediate of ortho position formation boric acid ester group.Preferably, this boric acid ester includes but not limited to trimethyl borate, triethyl borate, tripropoxy-boron, triisopropyl borate ester, tributyl borate or triamyl borate.The ortho position lithium atom of these boric acid esters in all can fortified phenol intermediate, through later stage hydrolysis, can obtain target product 2-hydroxybenzene boric acid.Preferred boric acid ester is triisopropyl borate ester, trimethyl borate or triethyl borate, and these several boric acid ester viscositys are less, is more soluble in the second organic solvent, thereby is conducive to improve the replacement speed of boric acid ester compared with other boric acid esters.Meanwhile, as long as the phenolic hydroxyl group of the hydroxyl protection reagent of employing in can phenol protected, form stable group.Preferably this hydroxyl protection reagent includes but not limited to methoxychlor methane, Benzoyl chloride, iso-butylene, triphenylmethyl chloride, 3,4-dihydropyrane or TERT-BUTYL DIMETHYL CHLORO SILANE.This several hydroxyl protection reagent all can with phenol in phenolic hydroxyl group react, form comparatively stable group.And in the hydrolysis reaction in later stage, all can there is hydrolysis and form phenolic hydroxyl group in these groups.Preferably, above-mentioned hydroxyl protection reagent is 3,4-dihydropyrane or TERT-BUTYL DIMETHYL CHLORO SILANE.When these two kinds of hydroxyl protection reagent react with phenolic hydroxyl group, reaction conditions is comparatively gentle, and the blocking group forming can comparatively sufficient deprotection in the hydrolytic process in later stage.Thereby be conducive to improve the production rate of target product.More preferably; in the reaction that in hydroxyl protection reagent Pyrogentisinic Acid, phenolic hydroxyl group is protected; with 3; 4-dihydropyrane when reagent, adopts the solid acid catalysts such as thionamic acid, storng-acid cation exchange resin, ferric chloride (FeCl36H2O), stannic chloride pentahydrate, 12 ferric sulfate hydrate ammoniums, titanium sulfate, Sodium Bisulfate Monohydrate, tosic acid can impel protective reaction to carry out quickly as protection.During using TERT-BUTYL DIMETHYL CHLORO SILANE as protection reagent, adopt basic catalyst triethylamine can make protective reaction carry out quickly.

Below in conjunction with specific embodiment, the present invention is described in further detail, these embodiment can not be interpreted as restriction the present invention scope required for protection.

Embodiment 1

5g phenol is dissolved in 25mL THF, according to 4.2 × 10 ^-3mol/L adds wherein tosic acid and is cooled to after 5 ℃, drips wherein 5.4g3,4-dihydropyrane, and making the mol ratio of itself and phenol is 1.2:1.Naturally be warming up to after 20 ℃, insulation reaction 5.5h, obtains the mixing solutions that contains phenol intermediate;

With N ₂by after the above-mentioned mixing solutions displacement that contains phenol intermediate three times, add n-Butyl Lithium with the speed of dripping of 0.01g/min to the above-mentioned mixing solutions that contains phenol intermediate of the temperature of-70 ℃, and the mol ratio of n-Butyl Lithium and phenol is 1.35:1.Drip and finish rear insulation reaction 15min, naturally rise to 20 ℃, insulation reaction 1h, obtains pre-reaction solution;

The speed of dripping with 0.1g/min adds triisopropyl borate ester to the above-mentioned pre-reaction solution of the temperature of-70 ℃, and the mol ratio of triisopropyl borate ester and phenol intermediate is 1:1.Drip and finish rear insulation reaction 1h, obtain treating hydrating solution;

Treat to add in hydrating solution the hydrochloric acid of 2mol/L to its pH=2 to above-mentioned, stir 1h, separatory, water is extracted with ethyl acetate three times, merges organic phase, and with after 20g anhydrous magnesium sulfate drying 20min, filtration drying agent, obtains the thick product of 2-hydroxybenzene boric acid after concentrating;

By after above-mentioned thick product underpressure distillation, add normal hexane to pull an oar, filter and obtain filter cake, with after normal hexane washing leaching cake, at 30 ℃, dry 4h, obtains 2-hydroxybenzene boric acid.

Embodiment 2 to 9

65.8g phenol is dissolved in 330ml methylene dichloride, according to 4.2 × 10 ^-3mol/L adds wherein tosic acid and is cooled to after 5 ℃, drips wherein 70.5g3,4-dihydropyrane, and making the mol ratio of itself and phenol is 1.2:1.Naturally be warming up to after 20 ℃, insulation reaction 1h, obtains reaction solution.To the aqueous sodium hydroxide solution that adds 180ml1mol/L in reaction solution, make its pH=14, stir separatory after 30min, obtain the first water and the first organic phase.To the aqueous sodium hydroxide solution that adds 180ml1mol/L in the first organic phase, stir separatory after 30min, obtain the second water and Second Organic Phase.Merge the first water and the second water, extract with 80ml methylene dichloride, separatory obtains the 3rd organic phase.Merge Second Organic Phase and the 3rd organic phase, with after the water washing of 80ml saturated common salt, concentrating under reduced pressure obtains phenol intermediate, stand-by.

Be below the subsequent preparation process of embodiment 2 to 9:

Embodiment 2

According to 1.12mol/L, above-mentioned 2g phenol intermediate is added in tetrahydrofuran solvent, obtain the mixing solutions that contains phenol intermediate;

With N ₂by after the above-mentioned mixing solutions displacement that contains phenol intermediate three times, add n-Butyl Lithium with the speed of dripping of 0.03g/min to the above-mentioned mixing solutions that contains phenol intermediate of the temperature of-70 ℃, and the mol ratio of n-Butyl Lithium and phenol is 1.1:1.Drip and finish rear insulation reaction 20min, naturally rise to 20 ℃, insulation reaction 2h, obtains pre-reaction solution;

The speed of dripping with 0.1g/min adds triisopropyl borate ester to the above-mentioned pre-reaction solution of the temperature of-70 ℃, and the mol ratio of triisopropyl borate ester and phenol intermediate is 1.1:1.Drip and finish rear insulation reaction 20min, naturally rise to 20 ℃, insulation reaction 1h, obtains treating hydrating solution;

Treat that by above-mentioned hydrating solution is cooled to 10 ℃, add wherein the hydrochloric acid of 2mol/L to its pH=1, stir 2h, separatory, obtains the 4th water and the 4th organic phase.The 4th water is extracted with ethyl acetate three times, and separatory obtains the 5th organic phase.Merge the 4th organic phase and the 5th organic phase, with after 10g anhydrous magnesium sulfate drying 20min, filtration drying agent, obtains the thick product of 2-hydroxybenzene boric acid after concentrating;

By after above-mentioned thick product underpressure distillation, add normal hexane to pull an oar, filter and obtain filter cake, with after normal hexane washing leaching cake, at 80 ℃, dry 2h, obtains 2-hydroxybenzene boric acid.

Embodiment 3

With N ₂by after the above-mentioned mixing solutions displacement that contains phenol intermediate three times, add n-Butyl Lithium with the speed of dripping of 0.02g/min to the above-mentioned mixing solutions that contains phenol intermediate of the temperature of-70 ℃, and the mol ratio of n-Butyl Lithium and phenol is 1.1:1.Drip and finish rear insulation reaction 20min, naturally rise to 20 ℃, insulation reaction 2h, obtains pre-reaction solution;

The speed of dripping with 0.2g/min adds triisopropyl borate ester to the above-mentioned pre-reaction solution of the temperature of-30 ℃, and the mol ratio of triisopropyl borate ester and phenol intermediate is 1.1:1.Drip and finish rear insulation reaction 20min, naturally rise to 20 ℃, insulation reaction 1h, obtains treating hydrating solution;

By after above-mentioned thick product underpressure distillation, add normal hexane to pull an oar, filter and obtain filter cake, with after normal hexane washing leaching cake, at 60 ℃, dry 2h, obtains 2-hydroxybenzene boric acid.

Embodiment 4

With N ₂by after the above-mentioned mixing solutions displacement that contains phenol intermediate three times, add n-Butyl Lithium with the speed of dripping of 0.01g/min to the above-mentioned mixing solutions that contains phenol intermediate of the temperature of-70 ℃, and the mol ratio of n-Butyl Lithium and phenol is 1.1:1.Drip and finish rear insulation reaction 20min, naturally rise to 20 ℃, insulation reaction 2h, obtains pre-reaction solution;

The speed of dripping with 0.1g/min adds triisopropyl borate ester to the above-mentioned pre-reaction solution of the temperature of 0 ℃, and the mol ratio of triisopropyl borate ester and phenol intermediate is 1.1:1.Drip and finish rear insulation reaction 20min, naturally rise to 20 ℃, insulation reaction 1h, obtains treating hydrating solution;

Embodiment 5

With N ₂by after the above-mentioned mixing solutions displacement that contains phenol intermediate three times, add n-Butyl Lithium with the speed of dripping of 0.02g/min to the above-mentioned mixing solutions that contains phenol intermediate of the temperature of-30 ℃, and the mol ratio of n-Butyl Lithium and phenol is 1.1:1.Drip and finish rear insulation reaction 20min, naturally rise to 20 ℃, insulation reaction 2h, obtains pre-reaction solution;

By after above-mentioned thick product underpressure distillation, add normal hexane to pull an oar, filter and obtain filter cake, with after normal hexane washing leaching cake, at 60 ℃, dry 3h, obtains 2-hydroxybenzene boric acid.

Embodiment 6

With N ₂by after the above-mentioned mixing solutions displacement that contains phenol intermediate three times, add n-Butyl Lithium with the speed of dripping of 0.03g/min to the above-mentioned mixing solutions that contains phenol intermediate of the temperature of-30 ℃, and the mol ratio of n-Butyl Lithium and phenol is 1.0:1.Drip and finish rear insulation reaction 20min, naturally rise to 20 ℃, insulation reaction 1.5h, obtains pre-reaction solution;

The speed of dripping with 0.1g/min adds triisopropyl borate ester to the above-mentioned pre-reaction solution of the temperature of-30 ℃, and the mol ratio of triisopropyl borate ester and phenol intermediate is 1.1:1.Drip and finish rear insulation reaction 20min, naturally rise to 20 ℃, insulation reaction 1h, obtains treating hydrating solution;

Treat that by above-mentioned hydrating solution is cooled to 15 ℃, add wherein the hydrochloric acid of 2mol/L to its pH=2, stir 2h, separatory, obtains the 4th water and the 4th organic phase.The 4th water is extracted with ethyl acetate three times, and separatory obtains the 5th organic phase.Merge the 4th organic phase and the 5th organic phase, with after 10g anhydrous magnesium sulfate drying 20min, filtration drying agent, obtains the thick product of 2-hydroxybenzene boric acid after concentrating;

Embodiment 7

With N ₂by after the above-mentioned mixing solutions displacement that contains phenol intermediate three times, add n-Butyl Lithium with the speed of dripping of 0.02g/min to the above-mentioned mixing solutions that contains phenol intermediate of the temperature of-30 ℃, and the mol ratio of n-Butyl Lithium and phenol is 1.1:1.Drip and finish rear insulation reaction 20min, naturally rise to 20 ℃, insulation reaction 1.5h, obtains pre-reaction solution;

Embodiment 8

With N ₂by after the above-mentioned mixing solutions displacement that contains phenol intermediate three times, add n-Butyl Lithium with the speed of dripping of 0.02g/min to the above-mentioned mixing solutions that contains phenol intermediate of the temperature of-30 ℃, and the mol ratio of n-Butyl Lithium and phenol is 1.3:1.Drip and finish rear insulation reaction 20min, naturally rise to 20 ℃, insulation reaction 1.5h, obtains pre-reaction solution;

Embodiment 9

With N ₂by after the above-mentioned mixing solutions displacement that contains phenol intermediate three times, add n-Butyl Lithium with the speed of dripping of 0.02g/min to the above-mentioned mixing solutions that contains phenol intermediate of the temperature of-30 ℃, and the mol ratio of n-Butyl Lithium and phenol is 2.0:1.Drip and finish rear insulation reaction 20min, naturally rise to 20 ℃, insulation reaction 1.5h, obtains pre-reaction solution;

Embodiment 10～22

65.8g phenol is dissolved in 330ml methylene dichloride, according to 5 × 10 ^-3mol/L adds wherein tosic acid and is cooled to after 0 ℃, drips wherein 64.1g3,4-dihydropyrane, and making the mol ratio of itself and phenol is 1.1:1.Naturally be warming up to after 30 ℃, insulation reaction 0.5h, obtains reaction solution.To the aqueous sodium hydroxide solution that adds 150ml1mol/L in reaction solution, make its pH=8, stir separatory after 30min, obtain the first water and the first organic phase.To the aqueous sodium hydroxide solution that adds 150ml1mol/L in the first organic phase, stir separatory after 30min, obtain the second water and Second Organic Phase.Merge the first water and the second water, extract with 80ml methylene dichloride, separatory obtains the 3rd organic phase.Merge Second Organic Phase and the 3rd organic phase, with after the water washing of 80ml saturated common salt, concentrating under reduced pressure obtains phenol intermediate, stand-by.

Be below the subsequent preparation process of embodiment 10 to 22:

Embodiment 10

The speed of dripping with 0.2g/min adds triisopropyl borate ester to the above-mentioned pre-reaction solution of the temperature of-30 ℃, and the mol ratio of triisopropyl borate ester and phenol intermediate is 1.3:1.Drip and finish rear insulation reaction 20min, naturally rise to 20 ℃, insulation reaction 1h, obtains treating hydrating solution;

Embodiment 11

The speed of dripping with 0.2g/min adds triisopropyl borate ester to the above-mentioned pre-reaction solution of the temperature of-30 ℃, and the mol ratio of triisopropyl borate ester and phenol intermediate is 1.5:1.Drip and finish rear insulation reaction 20min, naturally rise to 20 ℃, insulation reaction 1h, obtains treating hydrating solution;

Embodiment 12

The speed of dripping with 0.2g/min adds triisopropyl borate ester to the above-mentioned pre-reaction solution of the temperature of-30 ℃, and the mol ratio of triisopropyl borate ester and phenol intermediate is 1.6:1.Drip and finish rear insulation reaction 20min, naturally rise to 20 ℃, insulation reaction 1h, obtains treating hydrating solution;

Embodiment 13

The speed of dripping with 0.2g/min adds triisopropyl borate ester to the above-mentioned pre-reaction solution of the temperature of-30 ℃, and the mol ratio of triisopropyl borate ester and phenol intermediate is 2.0:1.Drip and finish rear insulation reaction 20min, naturally rise to 20 ℃, insulation reaction 1h, obtains treating hydrating solution;

Embodiment 14

According to 1.12mol/L, above-mentioned 2g phenol intermediate is added in tetrahydrofuran solvent, obtain the mixing solutions that contains phenol intermediate; With N ₂by after the above-mentioned mixing solutions displacement that contains phenol intermediate three times, add n-Butyl Lithium with the speed of dripping of 0.02g/min to the above-mentioned mixing solutions that contains phenol intermediate of the temperature of-70 ℃, and the mol ratio of n-Butyl Lithium and phenol is 1.5:1.Drip and finish rear insulation reaction 20min, naturally rise to 20 ℃, insulation reaction 1.5h, obtains pre-reaction solution;

The speed of dripping with 0.2g/min adds triisopropyl borate ester to the above-mentioned pre-reaction solution of the temperature of-70 ℃, and the mol ratio of triisopropyl borate ester and phenol intermediate is 2.5:1.Drip and finish rear insulation reaction 20min, naturally rise to 20 ℃, insulation reaction 1h, obtains treating hydrating solution;

Embodiment 15

According to 5.6mol/L, above-mentioned 2g phenol intermediate is added in tetrahydrofuran solvent, obtain the mixing solutions that contains phenol intermediate;

Embodiment 16

According to 2.8mol/L, above-mentioned 2g phenol intermediate is added in tetrahydrofuran solvent, obtain the mixing solutions that contains phenol intermediate;

With N ₂by after the above-mentioned mixing solutions displacement that contains phenol intermediate three times, add n-Butyl Lithium with the speed of dripping of 0.02g/min to the above-mentioned mixing solutions that contains phenol intermediate of the temperature of-70 ℃, and the mol ratio of n-Butyl Lithium and phenol is 1.1:1.Drip and finish rear insulation reaction 20min, naturally rise to 20 ℃, insulation reaction 1.5h, obtains pre-reaction solution;

The speed of dripping with 0.2g/min adds triisopropyl borate ester to the above-mentioned pre-reaction solution of the temperature of-70 ℃, and the mol ratio of triisopropyl borate ester and phenol intermediate is 1.1:1.Drip and finish rear insulation reaction 20min, naturally rise to 20 ℃, insulation reaction 1h, obtains treating hydrating solution;

Embodiment 17

According to 1.86mol/L, above-mentioned 2g phenol intermediate is added in tetrahydrofuran solvent, obtain the mixing solutions that contains phenol intermediate;

Embodiment 18

According to 0.8mol/L, above-mentioned 2g phenol intermediate is added in tetrahydrofuran solvent, obtain the mixing solutions that contains phenol intermediate;

Embodiment 19

According to 1.12mol/L, above-mentioned 2g phenol intermediate is added in normal hexane solvent, obtain the mixing solutions that contains phenol intermediate;

Embodiment 20

According to 1.12mol/L, above-mentioned 2g phenol intermediate is added in toluene solvant, obtain the mixing solutions that contains phenol intermediate;

Embodiment 21

According to 1.12mol/L, above-mentioned 2g phenol intermediate is added in methyl tert-butyl ether solvent, obtain the mixing solutions that contains phenol intermediate;

Embodiment 22

The speed of dripping with 0.2g/min adds trimethyl borate to the above-mentioned pre-reaction solution of the temperature of-30 ℃, and the mol ratio of trimethyl borate and phenol intermediate is 1.1:1.Drip and finish rear insulation reaction 20min, naturally rise to 20 ℃, insulation reaction 1h, obtains treating hydrating solution;

Embodiment 23

50g phenol is dissolved in 230ml methylene dichloride, according to 4.2 × 10 ^-3mol/L adds triethylamine temperature control to 20 ℃ wherein, drips wherein TERT-BUTYL DIMETHYL CHLORO SILANE, and making the mol ratio of itself and phenol is 1.0:1.Insulation reaction 15h, obtains reaction solution.In reaction solution, add 100ml deionized water to wash, separatory obtains the first water and the first organic phase.By 100ml aqueous sodium hydroxide solution (concentration is 1mol/L) washing the first organic phase, separatory obtains the second water and Second Organic Phase.With 50g anhydrous sodium sulfate drying Second Organic Phase, after filtration drying agent, concentrating under reduced pressure obtains phenol intermediate;

Above-mentioned 110.6g phenol intermediate is added in 770ml tetrahydrofuran solvent, obtain the mixing solutions that contains phenol intermediate;

With N ₂by after the above-mentioned mixing solutions displacement that contains phenol intermediate three times, add n-Butyl Lithium with the speed of dripping of 0.02g/min to the above-mentioned mixing solutions that contains phenol intermediate of the temperature of-78 ℃, and the mol ratio of n-Butyl Lithium and phenol is 1.1:1.Drip and finish rear insulation reaction 15min, naturally rise to 20 ℃, insulation reaction 1.5h, obtains pre-reaction solution;

The speed of dripping with 0.2g/min adds triisopropyl borate ester to the above-mentioned pre-reaction solution of the temperature of-78 ℃, and the mol ratio of triisopropyl borate ester and phenol intermediate is 1.1:1.Drip and finish rear insulation reaction 20min, naturally rise to 20 ℃, insulation reaction 1h, obtains treating hydrating solution;

Treat that by above-mentioned hydrating solution is cooled to 10 ℃, add wherein the hydrochloric acid of 2mol/L to its pH=1, stir 1h, separatory, obtains the 4th water and the 4th organic phase.The 4th water is extracted with ethyl acetate three times, and separatory obtains the 5th organic phase.Merge the 4th organic phase and the 5th organic phase, with 150g anhydrous sodium sulfate drying 20min, filtration drying agent obtains the thick product of 2-hydroxybenzene boric acid after also concentrating;

Embodiment 24

65.8g phenol is dissolved in 330ml methylene dichloride, according to 5 × 10 ^-3mol/L adds wherein tosic acid and is cooled to after 0 ℃, drips wherein 64.1g3,4-dihydropyrane, and making the mol ratio of itself and phenol is 1.1:1.Naturally be warming up to after 30 ℃, insulation reaction 0.5h, obtains reaction solution.To the aqueous sodium hydroxide solution that adds 150ml1mol/L in reaction solution, make its pH=8, stir separatory after 30min, obtain the first water and the first organic phase.To the aqueous sodium hydroxide solution that adds 150ml1mol/L in the first organic phase, stir separatory after 30min, obtain the second water and Second Organic Phase.Merge the first water and the second water, extract with 80ml methylene dichloride, separatory obtains the 3rd organic phase.Merge Second Organic Phase and the 3rd organic phase, with after the water washing of 80ml saturated common salt, concentrating under reduced pressure obtains phenol intermediate;

With N ₂by after the above-mentioned mixing solutions displacement that contains phenol intermediate three times, add n-Butyl Lithium with the speed of dripping of 0.02g/min to the above-mentioned mixing solutions that contains phenol intermediate of the temperature of 0 ℃, and the mol ratio of n-Butyl Lithium and phenol is 1.1:1.Drip and finish rear insulation reaction 3.5h, obtain pre-reaction solution;

Testing method:

1) product content: adopt the HPLC chromatographic instrument of Agilent 1100 series of Beijing Lewei Taike Medical Technology Co., Ltd. to test the thick product of 2-hydroxybenzene boric acid, calculate and deduct the product content after solvent in thick product with peak area normalization method; Chromatographic condition is as follows: chromatographic condition: instrument numbering: LAVI YS0052; Post type: Agilent-ZORBAX SB-C18; Post specification: 1.8 μ m, 4.6 × 50mm; Moving phase type: 10% (acetonitrile+0.05%TFA): 90% (water+0.05%TFA); Sample size 5 μ L; Detector: UV-DAD; Temperature: 40oC;

2) transformation efficiency: according to the chromatogram content of the thick product Raw of 2-hydroxybenzene boric acid, calculate the transformation efficiency of raw material.Test result is as shown in table 1:

Table 1

?	Product content (%)	Transformation efficiency (%)	?	Product content (%)	Transformation efficiency (%)
						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, can find out, adopt the method in the above embodiment of the present invention, prepared 2-hydroxybenzene boric acid has higher transformation efficiency and product content.Especially, when in embodiment, adopt in the present invention preferred processing condition time, as being-70～-30 ℃ by the first temperature and the second Temperature Setting, the mol ratio of n-Butyl Lithium and phenol is set as at 1.1～1.3 o'clock, prepared 2-hydroxybenzene boric acid has higher transformation efficiency and product content.

The foregoing is only the preferred embodiments of the present invention, be not limited to the present invention, for a person skilled in the art, the present invention can have various modifications and variations.Within the spirit and principles in the present invention all, any modification of doing, be equal to replacement, improvement etc., within all should being included in protection scope of the present invention.

Claims

1. a preparation method for 2-hydroxybenzene boric acid, is characterized in that, comprises the following steps:

S1, in phenol/organic solvent mixing solutions, add hydroxyl protection reagent, after reaction, form the mixing solutions that contains phenol intermediate;

S2, contain phenol intermediate described in making mixing solutions in the first temperature, and to have described the first temperature described in contain phenol intermediate mixing solutions in add n-Butyl Lithium, after reaction, form pre-reaction solution;

S3, make described pre-reaction solution in the second temperature, and add boric acid ester to having in the described pre-reaction solution of described the second temperature, after reaction, form and treat hydrating solution;

S4, will described in treat the hydrating solution reaction that is hydrolyzed, extraction afterwards concentrated extract obtains the thick product of described 2-hydroxybenzene boric acid;

Wherein, described the first temperature≤0 ℃, described the second temperature and described the first temperature are identical or different.

2. method according to claim 1, it is characterized in that, in described step S2, first adjust described the first temperature to≤-30 ℃, then in the described mixing solutions that contains phenol intermediate, add described n-Butyl Lithium, insulation reaction 15～30min, then be warming up to 0～30 ℃, insulation reaction 0.5～2h, obtains described pre-reaction solution; Preferably first adjust described the first temperature to-70～-30 ℃.

3. method according to claim 1 and 2, it is characterized in that, in described step S2, be that 1～2:1 adds described n-Butyl Lithium according to the mol ratio of described n-Butyl Lithium and described phenol intermediate, the mol ratio of preferred described n-Butyl Lithium and described phenol intermediate is 1～1.3:1, preferably adds described n-Butyl Lithium with the speed of dripping of 0.01～0.03g/min.

4. method according to claim 1, is characterized in that, in described step S3, is adding after the step of described boric acid ester, and reaction 0.5～4min, treats hydrating solution described in obtaining.

5. method according to claim 4, it is characterized in that, in described step S3, first adjust described the second temperature to≤0 ℃, then in described pre-reaction solution, add described boric acid ester, insulation reaction 15～30min, then be warming up to 0～30 ℃, insulation reaction 0.5～2h, treats hydrating solution described in obtaining; Preferably first adjust described the second temperature to≤-30 ℃, more preferably to-70～-30 ℃.

6. according to the method described in claim 1,4 or 5, it is characterized in that, in described step S3, be that 1～2:1 adds described boric acid ester according to the mol ratio of described boric acid ester and described phenol intermediate, the mol ratio of preferred described boric acid ester and described phenol intermediate is 1.1～1.5:1, preferably adds described boric acid ester with the speed of dripping of 0.1～0.3g/min.

7. method according to claim 1, is characterized in that, in described step S1, the step that forms the mixing solutions that contains phenol intermediate comprises:

S11, phenol is dissolved in to the first organic solvent, adds wherein described hydroxyl protection reagent, by concentrated the reaction solution obtaining after the reaction phenol intermediate that obtains;

S12, described phenol intermediate is dissolved in to the second organic solvent, forms the mixing solutions that contains described phenol intermediate, described the first organic solvent and described the second organic solvent are identical or different.

8. method according to claim 7, is characterized in that, in described step S11,

Phenol is dissolved in described the first organic solvent, adds wherein catalyzer and be cooled to after 0～5 ℃, add wherein described hydroxyl protection reagent, then be warming up to 10～30 ℃, carry out insulation reaction 0.5～15h, obtain reaction solution, the concentrated phenol intermediate that obtains;

Wherein, described catalyzer is solid acid catalyst or triethylamine, preferred described catalyzer is thionamic acid, storng-acid cation exchange resin, ferric chloride (FeCl36H2O), stannic chloride pentahydrate, 12 ferric sulfate hydrate ammoniums, titanium sulfate, Sodium Bisulfate Monohydrate, tosic acid or triethylamine, more preferably thionamic acid, tosic acid or triethylamine.

9. according to the method described in claim 7 or 8, it is characterized in that, in described step S11, also comprise:

In the reaction solution that obtains after reaction, add aqueous sodium hydroxide solution, stir, the pH that makes described reaction solution is 8～14, and separatory obtains the first water and the first organic phase;

In described the first organic phase, add aqueous sodium hydroxide solution, after stirring, separatory obtains the second water and Second Organic Phase;

Merge described the first water and the second water, with described the first organic solvent extraction, separatory obtains the 3rd organic phase; Merge described Second Organic Phase and described the 3rd organic phase, adopt after desiccant dryness, filter, after concentrating, obtain described phenol intermediate.

10. method according to claim 8 or claim 9, is characterized in that,

In described step S11, be that 1～1.2:1 adds described hydroxyl protection reagent according to described hydroxyl protection reagent and described phenol mol ratio, in described the first organic solvent, add described phenol according to 2.12～3mol/L, and according to 4.2～5 × 10 ^-3mol/L adds described catalyzer to described the first organic solvent;

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

11. methods according to claim 7, is characterized in that,

Described the first organic solvent is polar organic solvent, preferably described the first organic solvent is methylene dichloride, propyl carbinol, propyl alcohol, tetrahydrofuran (THF), acetic acid, acetone, pyridine, dimethyl formamide, methyl alcohol, ethylene glycol or dimethyl sulfoxide (DMSO), and more preferably described the first organic solvent is methylene dichloride or tetrahydrofuran (THF);

Described the second organic solvent is polar ether kind solvent or non-polar organic solvent, preferred described polar ether kind solvent is ether, propyl ether, isopropyl ether, tetrahydrofuran (THF), propylene oxide or methyl tertiary butyl ether, and more preferably described polar ether kind solvent is tetrahydrofuran (THF) or methyl tertiary butyl ether; Preferred described non-polar organic solvent is benzene, normal hexane, pentamethylene, heptane, toluene, tetracol phenixin, and preferred described non-polar organic solvent is normal hexane or toluene.

12. methods according to claim 1, is characterized in that, in described step S4, described hydrolysis reaction step comprises:

To temperature be-30～20 ℃ described in treat to add hydrochloric acid in hydrating solution, described in making, treat that the pH of hydrating solution is 1～2, after stirring, separatory obtains the 4th water and the 4th organic phase;

After adding ethyl acetate to extract in described the 4th water, separatory obtains the 5th organic phase, merges described the 4th organic phase and described the 5th organic phase, adopts after desiccant dryness, filters and concentrate to obtain the thick product of described 2-hydroxybenzene boric acid.

13. methods according to claim 12, is characterized in that, described step S4 also comprises the step that the thick product of described 2-hydroxybenzene boric acid is carried out to aftertreatment; The step of described aftertreatment comprises: the thick product of described 2-hydroxybenzene boric acid is added in normal hexane and pulled an oar, filter and obtain filter cake; Described filter cake is carried out to filtering and washing with normal hexane, at 30～80 ℃, dry 2～4h, obtains described 2-hydroxybenzene boric acid.

14. according to the method described in any one in claim 1 to 13; it is characterized in that; described hydroxyl protection reagent is methoxychlor methane, Benzoyl chloride, iso-butylene, triphenylmethyl chloride, 3; 4-dihydropyrane or TERT-BUTYL DIMETHYL CHLORO SILANE; be preferably 3,4-dihydropyrane or TERT-BUTYL DIMETHYL CHLORO SILANE.

15. according to the method described in any one in claim 1 to 13, it is characterized in that, described boric acid ester is trimethyl borate, triethyl borate, tripropoxy-boron, triisopropyl borate ester, tributyl borate or triamyl borate; Be preferably triisopropyl borate ester, trimethyl borate or triethyl borate.