CN106431969A - Method for preparing 2-methyl-4-formaldoxime methyl benzoate - Google Patents

Method for preparing 2-methyl-4-formaldoxime methyl benzoate Download PDF

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Publication number
CN106431969A
CN106431969A CN201610857038.XA CN201610857038A CN106431969A CN 106431969 A CN106431969 A CN 106431969A CN 201610857038 A CN201610857038 A CN 201610857038A CN 106431969 A CN106431969 A CN 106431969A
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methyl
formaldoxime
benzoic acid
method preparing
institute
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CN106431969B (en
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王勇
李立威
黄道友
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Jingchu University of Technology
Jingmen Pharmaceutical Industry Technology Research Institute
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Jingchu University of Technology
Jingmen Pharmaceutical Industry Technology Research Institute
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C249/04—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/14—Preparation of carboxylic acid nitriles by reaction of cyanides with halogen-containing compounds with replacement of halogen atoms by cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds

Abstract

The invention discloses a method for preparing 2-methyl-4-formaldoxime methyl benzoate. The method comprises the following steps: performing acylating chlorination on 2-methyl-4-bromobenzoic acid, carrying out methanol esterification and cyano substitution, and then performing nucleophilic addition elimination with hydroxylamine hydrochloride under alkaline conditions to obtain a target product. The method has the advantages that the process route is simple; reaction conditions are mild; the product yield is high; the total yield reaches 61 percent; the product quality is high; the appearance is white solid; the purity reaches 99.2 percent.

Description

A kind of method preparing 2-methyl-4-formaldoxime yl benzoic acid methyl esters
Technical field
The present invention relates to pharmaceutical intermediate preparation field, specifically, be to prepare 2-methyl-4-formaldehyde oximido with regard to one The method of methyl benzoate.
Background technology
The research and development of novel pesticide for prevention and administer animal husbandry pest resistance to insecticide and control its harm have very heavy The effect wanted.Compound fluralaner is a kind of novel, high to mammalian safe, insecticidal activity and broad spectrum activity different Oxazolines insecticide, as being respectively provided with good insecticidal activity to insects such as tick mesh, Siphonaptera, Anoplura, Semiptera and Dipteras.At present Fluralaner starts selling and promotes in countries such as Europe and the U.S. as veterinary drug, but in China also in Primary Study It in the stage, is also formed without commercially producing.2-methyl-4-formaldoxime yl benzoic acid methyl esters is synthesis isoxazolines compound The important intermediate of fluralaner, external mainly with reference to following process route at present（WO2008122375A2）Close Become：
This route is with 2-methyl-4-bromobenzoic acid as raw material, adds through Vilsmeier-Haack reaction, esterification, nucleophilic The multistep reactions such as elimination are become to obtain target product 2-methyl-4-formaldoxime yl benzoic acid methyl esters.In this route first step In Vilsmeier-Haack reaction, n-BuLi to be used is in-78oUnder C react, this industrially reaction condition more harsh, And use n-BuLi to there is bigger security risk, and the raw material examination using in second step esterification reaction process in a large number Agent species is more, and post-reaction treatment is complicated, thus result in that raw materials for production are relatively costly, impurity in products is more and yield is relatively low.
Content of the invention
It is an object of the invention to for the deficiencies in the prior art, provide a kind of simple to operate, yield is high, low cost, suitable The method closing industrialization large-scale production 2-methyl-4-formaldoxime yl benzoic acid methyl esters.
It is an object of the invention to be accomplished by：
A kind of method preparing 2-methyl-4-formaldoxime yl benzoic acid methyl esters, comprises the following steps：
（1）2-methyl-4-bromobenzoic acid is dissolved in methyl alcohol, is then added thereto to chloride reagent, in 20-80oC reacts 1- 10 hours, cooling, add it to after the aqueous wash medium of saturated sodium carbonate washs, be extracted with ethyl acetate, organic phase is used successively Water and saturated nacl aqueous solution washing, reduced pressure concentration, obtain henna 2-methyl-4-methyl-bromobenzoate；
（2）It after upper step product is dissolved in DMF solvent, is added thereto to cyanylation agent, at 40-180oAfter C reaction 5-72 hour, being cooled to room temperature, adding it in saturated sodium carbonate solution, filter, filtrate is extracted by ethyl acetate Take, concentrate, crystallization, filter, obtain white solid 2-methyl-4-cyano-benzoic acid methyl ester；
（3）2-methyl-4-cyano-benzoic acid methyl ester alcohols solvent is dissolved, adds hydroxylamine hydrochloride, alkali and water, 20-130oC Reaction 2-12 hour, reduced pressure concentration, filter, obtain white solid crude product, then with ethyl acetate and petroleum ether mixed solvent weight Crystallization, obtains 2-methyl-4-carboxaldehyde radicals methyl benzoate white solid.
Described chloride reagent is thionyl chloride, phosphorus trichloride, phosphorus pentachloride or oxalyl chloride.
Described cyanylation agent is cuprous cyanide, zinc cyanide, potassium ferrocyanide, Cymag, potassium cyanide or trimethyl cyanogen Base silane.
Described alcohols solvent is methyl alcohol, ethanol, propyl alcohol or butanol, and each solvent corresponding reaction temperature respectively is followed successively by 20-80oC、20-100oC、20-110oC、20-130oC, each solvent corresponding reaction time respectively is 2-12 h, 2-10h, 2- 8h、2-6h.
The alkali adding together with hydroxylamine hydrochloride is sodium carbonate, potassium carbonate, ammonium carbonate, sodium acid carbonate, saleratus, bicarbonate Any one in ammonium, NaOH, potassium hydroxide, ammoniacal liquor, triethylamine, pyridine or piperidines.
6. the method preparing 2-methyl-4-formaldoxime yl benzoic acid methyl esters according to claim 1, its feature exists In：Described chloride reagent addition is 1.0-2.0 with the mol ratio of 2-methyl-4-bromobenzoic acid:1；Cyanylation agent adds The mol ratio entering amount with 2-methyl-4-bromobenzoic acid is 2.0-10.0:1；The addition of hydroxylamine hydrochloride and alkali respectively with 2-methyl- The mol ratio of 4-bromobenzoic acid is 1.0-1.8:1 and 2.0-3.6:1.
Compared with prior art, the beneficial effects of the present invention is：
It is long that the present invention solves process route in former technique, operation complexity, severe reaction conditions, and production safety risk is relatively big, receives The shortcomings such as rate is low, and quantity of three wastes is big and not disposable.Synthetic route of the present invention is shorter, and technological operation is simple, reaction condition milder, The raw material being used are cheap and easily-available, and the solvent of use and the equal recoverable of accessory substance, production cost is lower, more meets industry Change production requirement.
The present invention, with 2-methyl-4-bromobenzoic acid as initiation material, replaces through chloride, esterification, cyano group, last and hydrochloric acid Azanol one-step method oximate obtains target product.Its advantage is that process route is short, and method is simple to operate, and product yield is high, total recovery To 61%, good product quality, purity reach 99.2% and outward appearance for white.
Synthetic route of the present invention is as follows：
Detailed description of the invention
Below by example, the present invention is described, but the present invention is not limited to these examples.
Synthetic route of the present invention is as follows：
Embodiment 1
（1）The preparation of 2-methyl-4-methyl-bromobenzoate：2-methyl-4-bromobenzoic acid 1,5 g is dissolved in 30 ml methyl alcohol, Xiang Qi Middle addition 2 ml thionyl chlorides, in 70oC back flow reaction 6 hours, solution is cooled to room temperature, adds 30 ml saturated sodium carbonates molten Liquid, is sufficiently stirred for, and is extracted with ethyl acetate 15 ml twice, and organic layer washes 10 ml with water twice successively, and saturated aqueous common salt 10 Ml washs, and anhydrous magnesium sulfate is dried, and filters, reduced pressure concentration, obtains henna 2-methyl-4-methyl-bromobenzoate 2,5.17 G, yield 97%.
（2）The preparation of 2-methyl-4-cyano-benzoic acid methyl ester：By step（1）Gained 2-methyl-4-methyl-bromobenzoate 2, 5.17g adds 20 ml DMF dissolve after, add 10.2 g cuprous cyanides, stirring, solid matter quickly dissolves, solution in Clarification look, is heated to 160oC reacts 12 hours, is cooled to room temperature, reaction solution is poured into 100 ml saturated sodium carbonate solutions In, there is yellow solid to separate out, filter, filtrate is extracted with ethyl acetate 25 ml tri-times, and organic layer washes 15 ml two successively with water Secondary, and saturated aqueous common salt 15 ml washing, anhydrous magnesium sulfate is dried, and filters, reduced pressure concentration, crystallisation by cooling, filters, obtains white Solid 2-methyl-4-cyano-benzoic acid methyl ester（3,2.86 g）, yield 72%.
（3）The preparation of 2-methyl-4-formaldoxime yl benzoic acid methyl esters：By step（2）Gained 2-methyl-4-cyanobenzoic acid Methyl esters 3, adds 20 ml methyl alcohol to dissolve, adds 1.15 g azanol hydrochloric acid and 1.73g natrium carbonicum calcinatum, finally add in 2.86 g Enter 20 ml distilled water, in 70oC back flow reaction 8 hours, is cooled to room temperature, reduced pressure concentration, obtains crude product.Use ethyl acetate With petroleum ether mixed solvent, crude product is recrystallized, obtain pure target product 2-methyl-4-formaldoxime yl benzoic acid first Ester 4,2.53 g, yield 87%.Product appearance is white crystals, content 99.2%HPLC.[flowing phase：Water:Methyl alcohol 5:2；Detection ripple Long：240 nm；Flow velocity：1 ml/min；Solution is prepared：Take sample 0.01g flowing phase dilution to 25 ml；Sample size 5.

Claims (6)

1. the method preparing 2-methyl-4-formaldoxime yl benzoic acid methyl esters, it is characterised in that the method comprises the following steps：
（1）2-methyl-4-bromobenzoic acid is dissolved in methyl alcohol, is then added thereto to chloride reagent, in 20-80oC reacts 1-10 Hour, cooling, add it to after the aqueous wash medium of saturated sodium carbonate washs, be extracted with ethyl acetate, organic phase washed with water With saturated nacl aqueous solution washing, reduced pressure concentration, obtain henna 2-methyl-4-methyl-bromobenzoate；
（2）It after upper step product is dissolved in DMF solvent, is added thereto to cyanylation agent, at 40-180oAfter C reaction 5-72 hour, being cooled to room temperature, adding it in saturated sodium carbonate solution, filter, filtrate is extracted by ethyl acetate Take, concentrate, crystallization, filter, obtain white solid 2-methyl-4-cyano-benzoic acid methyl ester；
（3）2-methyl-4-cyano-benzoic acid methyl ester alcohols solvent is dissolved, adds hydroxylamine hydrochloride, alkali and water, 20-130oC is anti- Answer 2-12 hour, reduced pressure concentration, filter, obtain white solid crude product, more heavily tied by ethyl acetate and petroleum ether mixed solvent Crystalline substance, obtains 2-methyl-4-carboxaldehyde radicals methyl benzoate white solid.
2. the method preparing 2-methyl-4-formaldoxime yl benzoic acid methyl esters according to claim 1, it is characterised in that：Institute The chloride reagent stated is thionyl chloride, phosphorus trichloride, phosphorus pentachloride or oxalyl chloride.
3. the method preparing 2-methyl-4-formaldoxime yl benzoic acid methyl esters according to claim 1, it is characterised in that：Institute The cyanylation agent stated is cuprous cyanide, zinc cyanide, potassium ferrocyanide, Cymag, potassium cyanide or trimethyl cyanoalkysilane.
4. the method preparing 2-methyl-4-formaldoxime yl benzoic acid methyl esters according to claim 1, it is characterised in that：Institute The alcohols solvent stated is methyl alcohol, ethanol, propyl alcohol or butanol, and each solvent corresponding reaction temperature respectively is followed successively by 20-80oC、20- 100oC、20-110oC、20-130oC, each solvent corresponding reaction time respectively is 2-12 h, 2-10h, 2-8h, 2-6h.
5. the method preparing 2-methyl-4-formaldoxime yl benzoic acid methyl esters according to claim 1, it is characterised in that：Institute The alkali adding together with hydroxylamine hydrochloride stated be sodium carbonate, potassium carbonate, ammonium carbonate, sodium acid carbonate, saleratus, ammonium hydrogen carbonate, Any one in NaOH, potassium hydroxide, ammoniacal liquor, triethylamine, pyridine or piperidines.
6. the method preparing 2-methyl-4-formaldoxime yl benzoic acid methyl esters according to claim 1, it is characterised in that：Institute The chloride reagent addition stated is 1.0-2.0 with the mol ratio of 2-methyl-4-bromobenzoic acid:1；Cyanylation agent addition with The mol ratio of 2-methyl-4-bromobenzoic acid is 2.0-10.0:1；The addition of hydroxylamine hydrochloride and alkali respectively with 2-methyl-4-bromobenzene The mol ratio of formic acid is 1.0-1.8:1 and 2.0-3.6:1.
CN201610857038.XA 2016-09-28 2016-09-28 A kind of method for preparing 2- methyl -4- formaldoxime yl benzoic acid methyl esters Active CN106431969B (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109503383A (en) * 2018-12-27 2019-03-22 西南大学 The electrochromic material of the double mutagens colors of high optical contrast
CN109553528A (en) * 2018-12-21 2019-04-02 荆门医药工业技术研究院 A kind of synthetic method of 2- methyl -4- acetylbenzoic acid methyl esters
CN109651146A (en) * 2019-01-28 2019-04-19 荆楚理工学院 A kind of preparation method and application of 3- methyl -4- formaldoxime yl benzoic acid ethyl ester
CN109912414A (en) * 2019-04-11 2019-06-21 荆门医药工业技术研究院 A kind of preparation method and application of 4- formaldoxime yl benzoic acid ethyl ester

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109553528A (en) * 2018-12-21 2019-04-02 荆门医药工业技术研究院 A kind of synthetic method of 2- methyl -4- acetylbenzoic acid methyl esters
CN109503383A (en) * 2018-12-27 2019-03-22 西南大学 The electrochromic material of the double mutagens colors of high optical contrast
CN109503383B (en) * 2018-12-27 2023-09-12 西南大学 High optical contrast bicolor electrochromic material
CN109651146A (en) * 2019-01-28 2019-04-19 荆楚理工学院 A kind of preparation method and application of 3- methyl -4- formaldoxime yl benzoic acid ethyl ester
CN109912414A (en) * 2019-04-11 2019-06-21 荆门医药工业技术研究院 A kind of preparation method and application of 4- formaldoxime yl benzoic acid ethyl ester

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