CN102311364B - Preparation method of o(p)-hydroxybenzonitrile - Google Patents
Preparation method of o(p)-hydroxybenzonitrile Download PDFInfo
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Abstract
The invention provides a preparation method of o(p)-hydroxybenzonitrile which is an important fine chemical intermediate applied in medical and pesticide fields. The method comprises the steps of: reacting the raw material of o(p)-halogenated benzonitrile with an anhydrous alcohol solution of alkali metal alkoxide at a concentration of 5-50% for 1-24h in a mol ratio of 1:2-5, at a temperature of 100-250DEG C and under a pressure of 0.5-6MPa, then conducting temperature falling, cooling, reduced pressure distillation and exsolution, and adding hydrochloric acid for acidification, thus obtaining an o(p)-hydroxybenzonitrile solid. The method provided in the invention has cheap raw material, short reaction step, safe operation, high yield and less by-product, thus being suitable for business production.
Description
Technical field
The present invention relates to a kind of chemical synthesis process, relate in particular to a kind of be widely used in medicine and the important fine-chemical intermediate neighbour of pesticide field (to) preparation method of hydroxy-phenylformonitrile.
Background technology
Adjacent (to) hydroxy-phenylformonitrile belongs to important fine-chemical intermediate.Salicylonitrile (claiming again salicylonitrile) can be used for producing Betriol (Boehringer,Ing.), and this medicine belongs to beta-receptor blocade.Be mainly used in atrial fibrillation; The irregular pulse such as supraventricular tachycardia; Stenocardia and hypertensive treatment.P-HBN can be used for producing the benzene cyano group agricultural chemicals such as " cynock ", " S-4087 ", " bromoxynil ", " chloroxynil ", " white bacterium is clear ", and p-HBN also can be used for liquid crystal material and field of perfumery simultaneously.
At present in the world the neighbour of exploitation (to) preparation method of hydroxy-phenylformonitrile mainly contains hydroxy benzaldehyde method, hydroxy-benzoic acid method, hydroxybenzamide method and halogeno-benzene formonitrile HCN method.
1, hydroxy benzaldehyde method by adjacent (to) hydroxy benzaldehyde react with oxammonium hydrochloride make neighbour (to) hydroxy-phenylformonitrile.The technological process of wherein preparing salicylonitrile is: in aqueous sodium hydroxide solution, add salicylaldhyde (salicylic aldehyde), oxammonium hydrochloride, mixture is heated on boiling water bath 3 hours, generate salicylaldoxime, after 2.5 hours, obtain salicylonitrile through aftertreatment with diacetyl oxide reflux again.The technological process of preparing p-HBN is: p-Hydroxybenzaldehyde, oxammonium hydrochloride, formic acid are refluxed 30 minutes, then with diluted sodium hydroxide solution neutralization, obtain p-HBN after aftertreatment.(" meticulous Organic Chemicals and intermediate handbook ", Chemical Industry Press, 1998) its reaction formula is as follows:
R1, R2 in above-claimed cpd represent respectively following group:
In the time of R1=OH, R2=H;
In the time of R2=OH, R1=H.
The shortcoming of the method be raw material neighbour (to) hydroxy benzaldehyde price is higher, compared with the raw material of additive method, lacks cost advantage.
2, hydroxy-benzoic acid method by adjacent (to) hydroxy-benzoic acid ammonification make neighbour (to) hydroxy-phenylformonitrile.In Degussa patent US2007265462A1, salicylic acid and ammonia are under phosphate-containing catalyzer existence condition, and temperature is reacted and obtained salicylonitrile at 250-500 DEG C.In " meticulous Organic Chemicals and intermediate handbook " (the same), P-hydroxybenzoic acid, under phosphorus oxychloride existence condition, passes into ammonia, at 250 DEG C, is incubated 1 hour, obtains p-HBN.Its reaction formula is as follows:
R1, R2 definition in above-claimed cpd is the same.
The shortcoming of the method is to need phosphoric acid salt or phosphorus oxychloride as catalyzer, and phosphate catalyst is introduced and needed phosphoric acid, boric acid, zinc sulfate to prepare according to certain method according to US2007265462A1, makes operating process become complicated, has also increased raw materials cost.And phosphorus oxychloride is a kind of severe poisonous chemicals, there is pungent odour.In damp atmosphere, be acutely fuming, increased the danger of operation.
3, hydroxybenzamide method by adjacent (to) hydroxybenzamide Dehydration obtain adjacent (to) hydroxy-phenylformonitrile.Mai, Khuong; Patil, Ghanshyam is in Tetrahedron Letters, 1986, vol.27, in #20p.2203-2206 taking adjacent (to) hydroxybenzamide is as raw material, trichloromethylchloroformate is dewatering agent, synthesize high yield (94%) neighbour (to) hydroxy-phenylformonitrile.Its reaction formula is as follows:
R1, R2 definition in above-claimed cpd is the same.
Although the method yield is higher, the raw material neighbour of the method (to) hydroxybenzamide price is also higher, the trichloromethylchloroformate of employing is a kind of asphyxiant, character is unstable, therefore exists the unsafe shortcoming of technique.
4, halogeno-benzene formonitrile HCN method by adjacent (to) halogeno-benzene formonitrile HCN react with alkali-metal oxyhydroxide make neighbour (to) hydroxy-phenylformonitrile.The people such as Gallon are at Angewandte Chemie, International Edition; Vol.46; Nb.38; (2007); P.7251-7254 in, react with potassium hydroxide with adjacent bromobenzylcyanide, and added palladium catalyst, make salicylonitrile.The people such as Tlili are at Angewandte Chemie, International Edition; Vol.48; Nb.46; (2009); P.8725-8728 in, taking to bromobenzylcyanide or to iodobenzene formonitrile HCN as raw material, CuI is catalyzer, reacts and obtains cyano group cyanobenzene with a hydronium(ion) oxidation caesium.Its reaction formula is as follows:
R1, R2 in above-claimed cpd; R1 ', R2 ' represent respectively following group:
In the time of R1=Br, R2=H, R1 '=OH, R2 '=H;
In the time of R2=Br, I, R1=H, R2 '=OH, R1 '=H.
The shortcoming of the method, for having adopted expensive CuI or palladium nanoparticle catalyst, causes the problem of raw materials cost raising.Simultaneously, through our experimental study, under catalyst-free condition, adjacent (to) halogeno-benzene formonitrile HCN and alkali-metal oxyhydroxide effect make neighbour (to) cyan-hydrolysis of halogeno-benzene formonitrile HCN generate neighbour (to) hydroxy-benzoic acid, but not adjacency pair hydroxy-phenylformonitrile.
In addition, in Degussa patent US2006173207A1, introduced adjacent (to) cyano group methyl-phenoxide react with the alcoholic solution of alkali metal alcoholates make neighbour (to) hydroxy-phenylformonitrile.Its raw material neighbour (to) cyano group methyl-phenoxide by adjacent (to) methylanisole and ammonia, oxygen generation ammonia oxidation make.Its reaction formula is as follows:
R1, R2 in above-claimed cpd represent respectively following group:
In the time of R1=CN, R2=H;
In the time of R2=CN, R1=H.
The shortcoming of the method be raw material be no matter adjacent (to) cyano group methyl-phenoxide or neighbour (to) methylanisole, on market, be all difficult to obtain, be unsuitable for scale operation.
Summary of the invention
Object of the present invention is intended to overcome the shortcoming existing in above-mentioned prior art, provides a kind of cost of material cheap, and reactions steps is short, operational safety, and by product is few, neighbour that yield is high (to) preparation method of hydroxy-phenylformonitrile.
The present invention introduced a kind of neighbour (to) preparation method of hydroxy-phenylformonitrile, taking adjacent (to) halogeno-benzene formonitrile HCN (general formula I) is as raw material, anhydrous alcohol solution with the strength of solution alkali metal alcoholates that is 5～50%, be 1: 2～5 in both reaction mol ratios, temperature of reaction is 100～250 DEG C, reaction pressure is under 0.5～6MPa condition, react 1～24 hour, through cooling down, underpressure distillation precipitation, hcl acidifying, obtain neighbour (to) hydroxy-phenylformonitrile solid (general formula I I).
Formula I
Formula II
R1, R2 in above-claimed cpd; R1 ', R2 ' represent respectively following group:
In the time that R1 is F, Cl or Br, R2=H, R1 '=OH, R2 '=H;
In the time that R2 is F, Cl or Br, R1=H, R2 '=OH, R1 '=H.
Further,
The anhydrous alcohol solution of described alkali metal alcoholates is the absolute methanol solution of sodium methylate, or one in the ethanol solution of sodium ethylate.
The anhydrous alcohol solution concentration of described alkali metal alcoholates preferably 20～30%.
Described neighbour (to) anhydrous alcohol solution of halogeno-benzene formonitrile HCN and alkali metal alcoholates react mol ratio preferably 1: 2～3.
Described neighbour (to) preferably 100～200 DEG C of the temperature of reaction of the anhydrous alcohol solution of halogeno-benzene formonitrile HCN and alkali metal alcoholates, reaction pressure is 1～3MPa preferably.
Described underpressure distillation precipitation, the alcohol of sloughing is recyclable applying mechanically also.
In reaction formula of the present invention, (see Fig. 1), the anhydrous alcohol solution that A is alkali metal alcoholates, B is hydrochloric acid, compared with existing reaction process, has following clear superiority:
1. adopted wide material sources, low-cost neighbour (to) halogeno-benzene formonitrile HCN is as raw material.
2. without adding catalyzer, just do not deposit the operation unsafe problems that causes in the prior art production process with hypertoxic catalyzer yet, significantly reduced production cost simultaneously yet.
3. technological process is simple, is easy to suitability for industrialized production.
4. by product is few, no coupling product neighbour (to) generation of hydroxy-benzoic acid, in the inventive method with raw material neighbour (to) halogeno-benzene formonitrile HCN reacts is the anhydrous alcohol solution of alkali metal alcoholates, have a small amount of sodium hydroxide generation owing to there being water to exist, make neighbour (to) cyan-hydrolysis of halogeno-benzene formonitrile HCN become neighbour (to) hydroxy-benzoic acid, cause the generation of by product, therefore do not have the alkali-metal anhydrous alcohol solution of water just can not cause the generation of this by product.
5. yield is high, and product yield exceedes 95% (product purity > 99.0%).
Brief description of the drawings
Fig. 1 is reaction formula figure of the present invention.
With way of example, the invention will be further described more below, provides implementation detail of the present invention, but be not to be intended to limit protection scope of the present invention.
Embodiment
Embodiment 1
In 1000ml autoclave pressure, adding strength of solution is 20.7% methanol solution of sodium methylate 250g, o-Cyanochlorobenzene 60g, with after nitrogen replacement autoclave pressure air, be warming up to 160 DEG C, still voltage rise is to 2.5Mpa, under this state, react 6～9 hours, finish reaction, be cooled to below 50 DEG C, reclaim under reduced pressure methyl alcohol (can apply mechanically), add cold-water solution bottom product, filter after insolubles, be that 36% hydrochloric acid carries out acidifying by concentration, separate out white product salicylonitrile, content > 99.0% after drying, quality 50.5g, yield 96.4%.
Embodiment 2
In 1000ml autoclave pressure, adding strength of solution is 28.5% methanol solution of sodium methylate 258g, p-Cyanochlorobenzene 75g, with after nitrogen replacement autoclave pressure air, be warming up to 200 DEG C, still voltage rise is to 2.8Mpa, under this state, react 5～7 hours, finish reaction, be cooled to below 50 DEG C, reclaim under reduced pressure methyl alcohol (can apply mechanically), adds cold-water solution bottom product, filters after insolubles, carry out acidifying with 36% hydrochloric acid, separate out white product p-HBN, content > 99.0% after drying, quality 62.8g.Yield 95.9%.
Embodiment 3
In 1000ml autoclave pressure, adding strength of solution is the ethanolic soln 244g of 25.7% sodium ethylate, adjacent bromobenzylcyanide 70g, with after nitrogen replacement autoclave pressure air, be warming up to 200 DEG C, still voltage rise is to 3.0Mpa, under this state, react 5～7 hours, finish reaction, be cooled to below 50 DEG C, decompression recycling ethanol (can apply mechanically), adds cold-water solution bottom product, filters after insolubles, carry out acidifying with 36% hydrochloric acid, separate out white product salicylonitrile, content > 99.0% after drying, quality 43.5g.Yield 96.1%.
Embodiment 4
In 1000ml autoclave pressure, adding strength of solution is ethanolic soln 334g, the p-Fluorophenyl cyanide 65g of 29.5% sodium ethylate, with after nitrogen replacement autoclave pressure air, be warming up to 200 DEG C, still voltage rise is to 2.5Mpa, under this state, react 6～8 hours, finish reaction, be cooled to below 50 DEG C, decompression recycling ethanol (can apply mechanically), adds cold-water solution bottom product, filters after insolubles, carry out acidifying with 36% hydrochloric acid, separate out white product p-HBN, content > 99.0% after drying, quality 61.3g.Yield 95.3%.
Claims (2)
- A neighbour (to) preparation method of hydroxy-phenylformonitrile, it is characterized in that: taking adjacent (to) halogeno-benzene formonitrile HCN (formula I) is as raw material, anhydrous alcohol solution with the strength of solution alkali metal alcoholates that is 20～30%, be 1:2～3 in both reaction mol ratios, temperature of reaction is 100～200 DEG C, and reaction pressure is under 1～3MPa condition, react 1～24 hour, through cooling down, underpressure distillation precipitation, hcl acidifying, obtain neighbour (to) hydroxy-phenylformonitrile (formula II) solid; The anhydrous alcohol solution of described alkali metal alcoholates is the methanol solution of sodium methylate, or one in the ethanolic soln of sodium ethylate;R1, R2 in above-claimed cpd; R1 ', R2 ' represent respectively following group:In the time that R1 is F, Cl or Br, R2=H, R1 '=OH, R2 '=H;In the time that R2 is F, Cl or Br, R1=H, R2 '=OH, R1 '=H.
- According to claim 1 a kind of adjacent (to) preparation method of hydroxy-phenylformonitrile, it is characterized in that: also recyclable applying mechanically of the alcoholic solution that described underpressure distillation precipitation is sloughed.
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| WO2014186981A1 (en) * | 2013-05-24 | 2014-11-27 | 江苏联化科技有限公司 | Method for preparing o(p)-hydroxybenzonitrile |
| CN103739518B (en) * | 2013-12-26 | 2016-03-30 | 安徽广信农化股份有限公司 | A kind of synthesis technique of salicylonitrile |
| CN105859577A (en) * | 2016-05-13 | 2016-08-17 | 安徽广信农化股份有限公司 | Synthesis method for 2-hydroxy-benzonitril |
| CN106083651B (en) * | 2016-06-03 | 2017-11-21 | 安徽广信农化股份有限公司 | The synthesis technique of salicylonitrile |
| CN110003052A (en) * | 2019-05-17 | 2019-07-12 | 常州工程职业技术学院 | A method of using micro passage reaction synthesizing o-hydroxy formonitrile HCN |
| CN114853577B (en) * | 2021-01-20 | 2024-08-09 | 三门峡环宇生化科技有限公司 | Method for preparing dimethyl ether and co-producing p-hydroxybenzonitrile |
| CN116987007B (en) * | 2023-08-10 | 2024-07-02 | 新泰市华宝化工科技有限公司 | Preparation process of p-hydroxybenzonitrile |
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| DE10222330A1 (en) * | 2002-05-17 | 2003-11-27 | Degussa | Non-catalytic production of alkoxybenzonitriles, useful as intermediates for the synthesis of agrochemicals and pharmaceuticals, comprises substitution of mono-halogenated starting compounds with an alcoholate |
| DE10242080A1 (en) * | 2002-09-11 | 2004-03-25 | Degussa Ag | Process for the catalyst-free production of cyanophenols comprises reaction of a substituted methoxybenzonitrile with an alkali metal alcoholate at a specified temperature |
| CN100351226C (en) * | 2006-06-09 | 2007-11-28 | 武汉大学 | Method for preparing 2,6- dialkoxy benzene nitrile |
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