CN101125816B

CN101125816B - Alkyl 2,3,5,6-tetrafluoro-4-hydroxymethylbenzoate

Info

Publication number: CN101125816B
Application number: CN 200710079703
Authority: CN
Inventors: 王东朝; 姜友法
Original assignee: Jiangsu Yangnong Chemical Co Ltd
Current assignee: Jiangsu Yangnong Chemical Co Ltd
Priority date: 2003-12-26
Filing date: 2003-12-26
Publication date: 2011-03-16
Anticipated expiration: 2023-12-26
Also published as: CN101125816A

Abstract

The invention relates to a compound of 2, 3, 5, 6-tetrafluoro-4-methylolbenzoic-acid alkyl ester, which is applicable to synthesis of polydifluorophenyl alcohol 2, 3, 5, 6- tetrafluoro-p-benzodiol and which is an important intermediate for the preparation of pyrethroid, and is halogenated, hydrogenated and esterified to acquire tefluthrin.

Description

A kind of 2,3,5,6-tetrafluoro-4-hydroxymethyl-benzoic acid alkyl ester

The application is dividing an application of patent application on December 26 in 2003 " a kind of pyrethroid compound intermediates preparation ".

The application number of former patent application " a kind of pyrethroid compound intermediates preparation " is 200310122496.1; The applying date is on December 26th, 2003.

Technical field

The present invention relates to a kind of compound 2,3,5,6-tetrafluoro-4-hydroxymethyl-benzoic acid alkyl ester, this compound is applied to synthetic phenyl polyfluoride base alcohol 2,3,5, the 6-tetrafluoro is to Benzenediol, and it is the important intermediate of preparation pyrethroid, obtains tefluthrin through halo, hydrogenation, esterification.

Background technology

Cis-3-haloalkenyl group-2,2-dimethyl cyclopropane carboxylic acid and 4-methyl-2,3,5, the ester that 6-tetrafluoro phenyl alcohol forms, particularly tefluthrin [2,3,5,6-tetrafluoro-4-phenmethyl-cis-((Z)-2-chloro-3,3,3-three fluoro-third-1-thiazolinyl)-2,2-dimethyl cyclopropane carboxylic acid ester], be important sterilant and kill the mite product.Therefore need a kind of technology capable of being industrialized, effective to prepare and necessary resemble 2,3,5, the 6-tetrafluoro is to the such intermediate of Benzenediol.

Known preparation 2,3,5, the 6-tetrafluoro is to technology existing description in some patent of Benzenediol.In order further to improve yield and quality, require 2,3,5 of a kind of more high quality of invention and yield, the 6-tetrafluoro is to the industrial preparation process of Benzenediol.

Summary of the invention

The applicant has found a kind of preparation 2,3,5, and the 6-tetrafluoro can satisfy above-mentioned requirements to the method for Benzenediol, and safer with respect to existing this process of technology, is easy to control.This handicraft product uses simple solvent, does not need more processing step, and by-product is few, and the three wastes are handled simple, the product yield height, and purity reaches more than 97%.

Therefore, proposed below to be reduced into 2,3,5 by tetrafluoro dialkyl benzene carboxylicesters in the presence of reductive agent and solvent, the 6-tetrafluoro is to the technology of Benzenediol.

The R that mentions among the present invention ₁Or R ₂The straight or branched alkyl of identical or different 1-6 the carbon atom that is respectively is preferably methyl, ethyl, n-propyl, normal-butyl, n-pentyl, n-hexyl, sec.-propyl, isobutyl-, the tertiary butyl or neo-pentyl.More preferably R ₁And R ₂Be identical, methyl particularly.Be R ₁And R ₂It all is the tetrafluoro dimethyl terephthalate (DMT) of methyl.

Intermediate (II) can separate, purify with using it for anything else or continuing to be reacted to target product (III).Structural formula (II) intermediate is a new discovery, also is another aspect of the present invention.

Parent material (I) can be very simply by tetrafluoro terephthalic acid and alkyl alcohol preferably the lower alkyl alcohol esterification make.The tetrafluoro terephthalic acid is a kind of intermediate for preparing sterilant, makes easily by the hydrolysis of tetrafluoro terephthalonitrile, and the yield height.The tetrafluoro terephthalonitrile can be made through fluoridizing easily by tetrachloro-p-phenylene's dintrile, and initial substance tetrachloro-p-phenylene dintrile is a kind of obtainable industrial goods.

The used appropriate reductant of this technology is a metal hydride, as the hydroborate of lithium, sodium, potassium or calcium, as POTASSIUM BOROHYDRIDE, sodium borohydride; A kind of aluminum hydride metal such as potassium hydride KH aluminium, lithium aluminium hydride; Alkoxyl group aluminum hydride metal such as MAlHx (OR) y, wherein, M---basic metal, R---alkanes, x, y can be independently 1,2,3, and x+y=4; The hydride of aluminium, boride; Hydrogen; A kind of hydrogen give body, as Virahol, ammonium formate, trialkyl ammonium formate or tetrahydrobenzene.

Using under the reduction reaction situation of metal hydride, the usage quantity of metal hydride all depends on the character of reductive agent itself except hydroborate, generally and the mol ratio of diester (I) at 1-3: 1, be preferably in 1-1.5: 1.For alkoxyl group aluminum hydride metal, with respect to the mol ratio of diester (I) at 4-12: 1, be preferably in 4-8: 1.Prepare the change of the intermediate of structure (II) if desired, the consumption of reductive agent generally reduces by half.

The solvent that reduction reaction is suitable has: alcohols; Glycols; Ethers; Gylcol ether; Second two ethers; Poly-second two ethers, polyether class, the mixture of a kind of lower alcohol (as methyl alcohol, ethanol), a kind of two-phase solvent mix 1.Prepare the change of the intermediate of structure (II) if desired, the consumption of reductive agent generally reduces by half.

The solvent that reduction reaction is suitable has: alcohols; Glycols; Ethers; Gylcol ether; Second two ethers; Poly-second two ethers, polyether class, the mixture of a kind of lower alcohol (as methyl alcohol, ethanol), a kind of two-phase solvent mixture; Polar aprotic solvent; Organic acid; Ester; Water; Ether; The mixture of rudimentary anion surfactant.

Do with hydroborate in the reduction reaction of reductive agent, suitable solvent has alcohols, as: methyl alcohol, ethanol, Virahol; Glycols is as ethylene glycol or polyoxyethylene glycol; Also can be ethers, as: methyl ether ， diox, tetrahydrofuran (THF); Gylcol ether, as 1, the 2-glycol dimethyl ether; Second two ethers are as diglyme; The polyether class; A kind of lower alkyl alcohol such as methyl alcohol, alcoholic acid mixture.Improve reaction yield and transformation efficiency for making reaction carry out to add a kind of auxiliary agent or catalyzer fully, or be used for reducing the usage quantity of hydroborate.Proper auxiliary agent is sex change metal-salt or boride.Best sex change metal-salt is aluminium, zinc, titanium salt such as aluminum chloride, zinc chloride, titanium tetrachloride etc.Boride such as boron trifluoride or alkyl boride.When using sodium borohydride, POTASSIUM BOROHYDRIDE, then can make auxiliary agent with lithiumation thing such as lithium chloride or lithiumbromide.General and the reductive agent mol ratio of amount of auxiliary is at 0.05-1: 1, and the best is 0.1-0.5: 1.Appropriate catalyst has salt, as tetraalkylammonium salt, phosphonate, open chain or the cyclic polyethers.Catalyst consumption is generally the 0.01-0.1 moles/mole of reductive agent.

When making reductive agent with hydroborate, also can use a kind of two-phase solvent mixture as solvent, by water and water-soluble or water-insoluble solvent such as aromatic hydrocarbon, particularly toluene is formed.In this case, generally need to add a kind of catalyzer and improve speed of reaction.Suitable catalyzer has cationic salts, as tetraalkylammonium salt, phosphonate, polyethylene glycol ether open chain or cyclic polyethers such as end closure, crown ether etc.

Be the aprotic, polar inert solvent than The suitable solvent when making reductive agent, as aromatic hydrocarbon, as toluene, methyl-phenoxide or ethers, as: diox, tetrahydrofuran (THF), glycol dimethyl ether or relevant oligo-ether with the hydrogen aluminide.

Reduction reaction can be carried out in the temperature range of solvent boiling point at-20 ℃, and generally at 30-120 ℃, better temperature range is 40-80 ℃, and the reaction times is depended on the activity of reductive agent, generally at 1-20 hour.This method prepares compound (III), and reaction is preferably uninterrupted continuously, and the content of guaranteeing compound (II) preferably is controlled in 1% less than 5%.

Another kind method is given body such as Virahol, ammonium formate, trialkyl ammonium formate or tetrahydrobenzene reduction diester with hydrogen or hydrogen, carries out under the effect of metal, metal oxide, mixed metal oxide, metal-salt or metal composite catalyst, diester is reduced to 2,3,5, the 6-tetrafluoro is to Benzenediol.If master metal group VIII metal as palladium, platinum, rhodium, rhenium, nickel, optionally is equipped with inert support, this carrier can be carbon, aluminum oxide, alkaline earth metal carbonate.Metal oxide has cupric oxide, chromic oxide.Mixed oxide such as copper chromium platform gold.Catalyzer 0.01-5mol% is preferably in 0.01-1mol%.The metal oxide of non-group VIII metal and mixed oxide are the 0.1-10wt% of reductive agent as catalyst consumption, are preferably in 0.1-1wt%.After reaction finishes, can reclaim catalyzer by routine techniques, as filtering, be adsorbed onto on the inert material or precipitation, in addition recovery set is used.If use hydrogen, pressure generally needs 1-200atm, preferably 10-50atm.Temperature is controlled at 50-200 ℃, is preferably in 50-120 ℃.If give body with hydrogen, reaction is generally carried out under solvent natural pressure and certain temperature condition.

The solvent that the catalytic hydrogenating reduction reaction is suitable for has alcohols, as methyl alcohol, Virahol; Aromatic hydrocarbon such as toluene, dimethylbenzene; Ethers such as THF, 1, the 2-glycol dimethyl ether; Or organic acid, as acetate; Or ester, as ethyl acetate, methyl acetate etc.Best solvent is Virahol or Virahol and aromatic mixed solvent.If preparation compound (II), the consumption of hydrogen is in a half termination reaction.

After the reduction reaction, should be undertaken by following one or multinomial step subsequently:

1, filtering separation catalyzer and recovery

2, water or organic acid or inorganic acid aqueous solution termination reaction

3, distillating recovering solvent

4, add a kind of different solvent

5, with water soluble acid or alkali extraction, remove water miscible inorganics or disposable reaction solvent.

6, by conventional means such as crystallization or evaporation recovery product.

Product also can be retained in the solvent, directly enters next step reaction, can shorten reactions steps.

The applicant is simultaneously through the following steps with 2,3,5, and the 6-tetrafluoro is converted into tefluthrin to Benzenediol.

1) with 2,3,5, halogenation obtains 2,3,5 to the 6-tetrafluoro to Benzenediol, 6-tetrafluoro-4-monochloromethyl phenylcarbinol;

This halogenation process is normally used to be that haloid acid family materials such as hydrochloric acid or Hydrogen bromide can carry out stable reaction.Used solvent is inert or not miscible with water solvent, arene for example, and the optimal temperature of reaction is between 50 ℃-150 ℃, optimum temps is 75 ℃-100 ℃.

2), obtain 4-methyl-2,3,5, the 6-tetrafluorobenzyl alcohol after 6-tetrafluoro-4-monochloromethyl phenylcarbinol hydrogenation with 2,3,5

Hydrogenation process in this step is used hydrogen and metal catalyst such as palladium, nickel, the hydrogen halide that cooperates alkaloids to emit in order to absorption reaction.Suitable alkaloids has alkali, alkaline earth metal oxide and carbonate.Alcohols, ester class and aromatic hydrocarbon are ideal solvents comparatively, and the optimal temperature of reaction is 0-60 ℃, and suitable pressure condition is that normal pressure is to 10atm.

3) with 4-methyl-2,3,5,6-tetrafluorobenzyl alcohol and cis-((Z)-2-chloro-3,3,3-three fluoro-third-1-thiazolinyl)-2,2-dimethylcyclopropane base acyl chlorides or cis-((Z)-2-chloro-3,3,3-three fluoro-third-1-thiazolinyl)-2, the synthetic tefluthrin that obtains of 2-dimethylcyclopropane yl carboxylic acid.

Just can obtain tefluthrin by esterification.The method of esterification process is: remove the HCl that produces by the physics method, catch up with as heating method or with inert blowing gas; Chemical process available bases such as pyridine neutralize.Esterification reacts completely if use the cyclopropane yl carboxylic acid can not use solvent or dewater to make under the strongly acidic catalyst effect with inert solvent such as toluene, dimethylbenzene or similar solvent.

Embodiment

With some concrete examples the present invention is described below, but the present invention not only is confined to following embodiment:

Embodiment 1, and 3,5, the 6-tetrafluoro is to the preparation method (1) of Benzenediol

In the four-hole boiling flask of a 2000ml, drop into methyl alcohol 500ml, sodium borohydride 37g, be warming up to 50 ℃, be incubated after 1 hour, drop into tetrafluoro diethyl terephthalate 294g, continue under 50 ℃ temperature, to react 5 hours, be cooled to room temperature, with 30% hydrochloric acid 300ml hydrolysis, use the 500ml carbon tetrachloride extraction again, the tetrafluoro terephthalyl alcohol 167.2g that obtains the title of white solid behind the tetracol phenixin is sloughed in decompression, content is 97.7%, and yield is 77.8%

Embodiment 22, and 3,5, the 6-tetrafluoro is to the preparation method (2) of Benzenediol

In the four-hole boiling flask of a 2000ml, drop into ethanol 500ml, POTASSIUM BOROHYDRIDE 54g, be warming up to 50 ℃, be incubated after 1 hour, drop into tetrafluoro dimethyl terephthalate (DMT) 266g, continue under 50 ℃ temperature, to react 5 hours, be cooled to room temperature, with 30% hydrochloric acid 300ml hydrolysis, use the 500ml carbon tetrachloride extraction again, after sloughing tetracol phenixin, decompression obtains tetrafluoro terephthalyl alcohol 176.4g, content is 98.1%, and yield is 82.4%.

Embodiment 32, and 3,5, the 6-tetrafluoro is to the preparation method (3) of Benzenediol

Process is as described in (example one), and methyl alcohol is thrown 370ml, and the content of tetrafluoro terephthalyl alcohol is 93.1%, and yield is 76%

Embodiment 42, and 3,5, the 6-tetrafluoro is to the preparation method (4) of Benzenediol

In the autoclave of a 1000ml, add tetrafluoro to toluene dioctyl phthalate propyl ester 161g, active palladium 1.61g, methyl alcohol 500ml, logical hydrogen hydrogenating reduction under 60～70 ℃ temperature condition, pressure condition is 3.5atm.After waiting not have tangible absorption, be cooled to room temperature, suction filtration elimination Pd/c then, filtrate negative pressure precipitation, white solid tetrafluoro terephthalyl alcohol 85.6g, content is 97.5%, yield is 79.5%.

Embodiment 52, and 3,5, the 6-tetrafluoro is to the preparation method (5) of Benzenediol

Process is as described in (example four), and catalyzer Raney's nickel 1.61g, the content of tetrafluoro terephthalyl alcohol are 97.8%, and yield is 80.7%

Embodiment six 4-methylols-2,3,5, the preparation method of 6-tetrafluorobenzoic aid ester

In the 100ml of dried and clean flask, drop into tetrahydrofuran (THF) 20ml, glycol dimethyl ether 10ml, sodium borohydride 54g, controlled temperature slowly adds tetrafluoro to toluene dioctyl phthalate methyl esters 4.0g at 35 ℃, is warming up to 70 ℃, stir, insulation 5hr, sampling is regularly carried out the gas spectrum and is detected.Reactant leaves standstill to shake after 48hr lowers the temperature again and is warming up to, and analyze to show that reaction is incomplete, so add another part glycol dimethyl ether 10ml, and continuation concussion reaction 5hr.The gas spectrum shows that diester disappears, and the mixture water 100ml of Compound I I and compound III handles, again with ethyl acetate 50ml extraction 3 times.Extract obtains sticking white solid after merging processing.The gas spectrum shows that mixture is glycol 63% and monoesters 37%.Can get 4-methylol-2,3,5,6-tetrafluorobenzoic aid ester by the column chromatography purification.

It detects data: fusing point: 65.6 ℃, and purity: 97.6%

Nuclear magnetic resonance data: D ₄In the methyl alcohol ¹⁹F-135.2 (polymorphic, 2F);-146.3 (polymorphic, 2F)

D ₄In the methyl alcohol ¹H 4.67 (singlet ,-CH2-, 2H); 3.90 (singlet, OCH3,3H)

Mass spectrum: molecular ion peak is at m/z238 (30%), and fragment ion peak is 207 (100%), and 187 (30%), 177 (25%), 159 (20%), 149 (22%), 131 (24%), 99 (24%), 81 (20%), 59 (17%)

Embodiment seven:

The preparation method (1) of tefluthrin [2,3,5,6-tetrafluoro-4-phenmethyl cis-((Z)-2-chloro-3,3,3-three fluoro-third-1-thiazolinyl)-2,2-dimethyl cyclopropane carboxylic acid ester]:

The first step: Synthetic 2,3,5,6-tetrafluoro-4-brooethyl phenylcarbinol

2,3,5, the 6-tetrafluoro joins in the 1L reactor the solution 80g of Benzenediol and methyl iso-butyl ketone (MIBK), and reactor is furnished with backflow and receiving device.Boil off solvent by distillation.Add toluene (303g) again, dewater by component distillation.Be heated to 60 ℃, keep 30min, add Silcolapse (0.2g) and 48% Hydrogen bromide (109.3g), be heated to 95 ℃, first backflow 30min is component distillation band water 5.5hr again.Add entry (150ml) and Hydrogen bromide (36.6g) then and cool to 55 ℃.Stir 15min at 55 ℃, separate water layer with 30min again.Oil reservoir washs layering with prefabricated solution (water 150ml+40% sodium acetate aqueous solution 36g), and toluene layer analyzes 2,3,5,6-tetrafluoro-4-brooethyl phenylcarbinol content, and yield is 96.2%

Second step: synthetic 4-methyl-2,3,5,6-tetrafluorobenzyl alcohol

Following process is carried out in the 1L glass autoclave (working volume 350-500mls) of a dispersion agitator of outfit (1000rpm), and the H2 charging is by inserting tube process Buchi Gas controller 6002 types.Heating and cooling control is bathed by Jelabo FP40 temperature.Methyl alcohol (362g), water (6g), 2,3,5,6-tetrafluoro-4-brooethyl phenylcarbinol (95.1g 100%wt.), MgO (18.1g), 5% palladium/carbon catalyst ((58 type) Johnson Matthey company provides) (0.8g 100%wt.) joins in the reactor, adds a cover, and displaces O2 (near 0) with N2, be pressurized to 2.5bar with H2, stir,, make the entire reaction temperature be controlled at 50 ℃ by the temperature bath by Buchi controller control pressure 2.5bar.The H2 consumption is by the control of Buchi controller.Reaction until H2 no longer consume till (general 60--90min), release, and with the N2 displacement, blowing is with small amount of methanol (30g) flushing autoclave.Filtered and recycled spent catalyst and inorganic salt, (2 * 30g) wash filter cake with small amount of methanol.Merging filtrate, analytical calculation gets 2,3,5,6-tetrafluoro-4-methylbenzyl alcohol 60.4g, yield 89.4%

The 3rd step: synthetic tefluthrin

Cis-((Z)-2-chloro-3,3,3-three fluoro-third-1-thiazolinyl)-2,2-dimethylcyclopropane base acyl chlorides (257g) joins one to be furnished with in the four-hole boiling flask that disperses agitator, adds toluene (257g), lysed 2,3,5, add an amount of pyridine (51g) in the 6-tetrafluoro 4-methylbenzyl alcohol (188.1g) and place dropping funnel together, the solution that drips alcohol is gone in the acyl chlorides, temperature maintenance is at 35-45 ℃, drip and finish, be warming up to 95 ℃, be incubated 2 hours, be cooled to 60 ℃, add and boil off solvent behind the water-soluble salt and get tefluthrin 410.3g, content is 95.5%, and yield is 96.5%.

Embodiment 8: the preparation method (2) of tefluthrin [2,3,5,6-tetrafluoro-4-phenmethyl cis-((Z)-2-chloro-3,3,3-three fluoro-third-1-thiazolinyl)-2,2-dimethyl cyclopropane carboxylic acid ester]:

In the enamel high pressure still of 1000ml, throw methyl alcohol 250ml, sodium borohydride 20g.Controlled temperature slowly adds tetrafluoro terephthalic acid methyl esters 133g at 50 ℃, stir insulation 5hr, sampling analysis, gas spectrum show when diester has disappeared, add 30% HCL20ml in the mixture, carbon tetrachloride extraction with 250ml, tetracol phenixin is sloughed in decompression, adds toluene 300ml, 48% Hydrogen bromide (122.3g), be heated to 95 ℃, collect the azeotrope of toluene and water 95-100 ℃ of backflow after 30 minutes.React and be cooled to about 55 ℃ after 5.5 hours, with the washing of 5% sodium acetate aqueous solution once, slough solvent toluene, add methyl alcohol (450g), water (7.5g), 5% palladium/carbon catalyst (1.2g100%wt) in the residuum, the good seal device, approaching zero to oxygen level with nitrogen replacement, pressurized with hydrogen is to 2.5bar, and temperature of reaction is controlled at about 50 ℃.Till H2 no longer absorbed, nitrogen replacement was used in release, crossed catalyzer and inorganic salt that elimination was lost efficacy, and filtrate boils off solvent.Add toluene 150ml, pyridine 28.8g in the residuum, be warming up to 35-45 ℃, splash into cis-((Z)-2-chloro-3,3,3-three fluoro-third-1-thiazolinyl)-2,2-dimethylcyclopropane base formyl chloride (85.8g) drips and finishes, be warming up to 75-90 ℃, be incubated 2 hours, be cooled to 60 ℃, add and boil off solvent behind the water-soluble salt and get tefluthrin 71.1g, content is 94.9%, is 64.1% to the total recovery of tetrafluoro terephthalic acid methyl esters.

The applicant has invented a kind of new preparation method of intermediate of pyrethroid compound, this intermediate 2,3,5,6-tetrafluoro terephthalyl alcohol, and then obtaining seven Flumethrins by halo, hydrogenation, esterification, this technology has the advantages that process route is simple, safe and reliable, mass yield is high, cost is low, is fit to very much suitability for industrialized production. The present invention has also found the compound of new intermediate simultaneously.

Claims

1. a compound (II) 2,3,5,6-tetrafluoro-4-hydroxymethyl-benzoic acid alkyl ester,

R wherein ₂Straight or branched alkyl for 1-6 carbon atom.

2. a kind of compound according to claim 1 (II) is characterized in that R ₂Be methyl.