CN104557902B - A kind of method for preparing thiabendazole - Google Patents
A kind of method for preparing thiabendazole Download PDFInfo
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- CN104557902B CN104557902B CN201510020379.7A CN201510020379A CN104557902B CN 104557902 B CN104557902 B CN 104557902B CN 201510020379 A CN201510020379 A CN 201510020379A CN 104557902 B CN104557902 B CN 104557902B
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The present invention relates to a kind of new method for synthesizing thiabendazole, monochloroacetone is synthesized as initiation material using acetone and chlorine, it directly can react to obtain the methylthiazol of 2 amino 4 with thiocarbamide without isolation, again 4 methylthiazols are obtained by diazo-reaction, the oxidation generation formic acid of thiazole 4, the last formic acid of thiazole 4 react to obtain target product thiabendazole with o-phenylenediamine.The thiabendazole of this product is a wide spectrum antihelmintic, has expeling effect to ascarid, hook, whip, pinworm, excrement strongylid and trichinzation, is also highly effective bactericide with broad spectrum, domestic nearly ten years to be widely used as fruit antistaling agent and the biocide mildewcide of multiple fields.
Description
Technical field
The present invention relates to a kind of pharmaceutical synthesis method, more particularly to general entitled thiabendazole (Thiabendazole)
The new synthetic method of compound, belongs to chemical industry synthesis field.
Background technology
Thiabendazole is also referred to as probenazole, Apl-Luster, abbreviation TBZ, is a kind of excellent anti-mould fresh keeping agent.It is mainly used in water
Fruit vegetable is fresh-keeping, and food antiseptic and daily necessities such as grain, cloth, ornament materials etc. are mould proof, it have efficiently, wide spectrum, low toxicity,
The features such as remaining less, thus in the food additives standard of countries in the world approved its be used for the anti-mildew fresh-keeping of fruits and vegetables.
There are many document patents also to disclose the synthetic method for reporting thiabendazole at present, as shown in following synthetic routes：
It is initiation material with lactic acid and o-phenylenediamine, first generates 2- ethoxys benzimidazole (compound 1), compound 1 is by potassium permanganate
MIBK (compound 2) is oxidized to, compound 2 obtains dibromo MIBK (compound 3) by bromo-reaction, and compound 3 is last
Thiabendazole (compound 4) is obtained with phosphorus pentasulfide, formamide.The processing step is simple, but waste water is more, and
Need to use phosphorus pentasulfide, very big pollution is caused to environment, is unfavorable for large-scale industrial production.
As obtained bromo acetone acid through bromo-reaction with pyruvic acid in CN1121516A, then by bromine in tetrahydrofuran solution
Prephenic acid carries out cyclization and obtains 4- carboxylic acid thiazoles, then in the presence of condensing agent polyphosphoric acids (PPA), at 220-230 DEG C
Under the conditions of through condensation reaction obtain thiabendazole (synthetic route is as follows)；Though the route step is simple but raw materials used pyruvic acid and bromine
Price it is higher, be not suitable for industrialized production, and phosphorus pentasulfide need to be used, be unfavorable for environmental protection.
As CN1042150A be it is a kind of by tartaric acid produce thiabendazole technique, form i.e. (1) winestone by five steps
Pyruvic acid is made in acid cleavage；(2) pyruvic acid bromo generation bromo acetone acid；(3) prepared by phosphorus pentasulfide and formamide
Thioformamide；(4) bromo acetone acid and thioformamide reaction generation thiazole carboxylic acid's hydrobromate；(5) thiazole carboxylic acid's hydrogen bromine
Hydrochlorate and o-phenylenediamine reaction generation thiabendazole (synthetic route is as follows)；Though the technique raw material is cheap and easy to get, the first step is anti-
Answer temperature very relatively low in high yield, it is economically uneconomical, and be also required to use thioformamide below, it is unfavorable for environmental protection.
Therefore one simple economy of necessary searching, environment-friendly synthesis technique produce thiophene benzene miaow on a large scale
Azoles.
The content of the invention
It is an object of the invention to provide a kind of raw material is cheap and easy to get, synthesis technique is simple, it is green, suitable for industrialization
The thiabendazole new preparation process of production.
The technical scheme that the present invention solves above-mentioned technical problem is as follows：A kind of synthetic method of thiabendazole, including it is following
Step：
1) monochloroacetone is generated through chlorination reaction as initiation material using acetone and chlorine；
2) monochloroacetone by step 1) generation reacts to obtain 2- amino -4- methylthiazols with thiocarbamide；
3) the 2- amino -4- methylthiazols of step 2) are obtained into 4- methylthiazols by diazo-reaction；
4) the 4- methylthiazols oxidation generation 4-thiazolecarboxylic acid of step 3)；
5) 4-thiazolecarboxylic acid of step 4) reacts to obtain product thiabendazole with o-phenylenediamine；
Synthetic route is as follows：
Further, step 1) is：According to mass ratio it is (18~20) by acetone, calcium carbonate and water:(2~3):1 is added to
In four-hole bottle, rectifying column is connect, post is suitable for reading to connect chlorination reactor, condenser；Backflow is started to warm up, leads to chlorine, it is warming up to 100~
110 DEG C stop logical chlorine, terminate reaction and obtain monochloroacetone reaction solution.
Or step 1) can also be：It is 1 by mass ratio:The acetone and water of (0.05~0.08) are added in four-hole bottle, are risen
The logical chlorine of temperature backflow, sodium hydrate aqueous solution is slowly added into reaction bulb, makes material liquid pH=3~4, temperature rises to 100~110
DEG C stop logical chlorine, terminate reaction and obtain monochloroacetone reaction solution.
Preferably, the step 1) sodium hydrate aqueous solution is 20wt% sodium hydrate aqueous solution.
Further, step 2) is：Thiocarbamide is added into the monochloroacetone reaction solution of previous step makes monochloroacetone and thiocarbamide
Mol ratio be 1：(1.1~1.2), suspension is stirred into, heating water bath 5~6h of backflow, reaction solution is poured into frozen water after backflow
Cooled down in mixture, then stirring is lower adds sodium hydroxide, there is yellow solid precipitation；Oil reservoir, water layer acetic acid are separated after placement
Ethyl ester is extracted, and extract is dried after merging with oil reservoir, filtering, after normal pressure boils off ethyl acetate, is evaporated under reduced pressure, is collected 117
~120 DEG C of cut, it is 2- amino -4- methylthiazols that faint yellow solid is obtained after placement.
Preferably, the condition being evaporated under reduced pressure in step 2) is 1.05~1.1kPa.
Further, step 3) is：2- amino -4- methylthiazols are taken in there-necked flask, then add the mixed of water and the concentrated sulfuric acid
Close solution and obtain reaction mixture；Reaction mixture is cooled to -10~-15 DEG C, keeps the temperature to instill nitrous in 2~2.5h
The aqueous solution of sour sodium, the mol ratio of natrium nitrosum and 2- amino -4- methylthiazols is (1~1.1):1, after charging, keep
The temperature continues 1~1.5h of stirring, obtains diazol；Then the aqueous solution of sodium hypophosphite, secondary phosphorus is added dropwise at -5~-10 DEG C again
The mol ratio of sour sodium and 2- amino -4- methylthiazols is (1~1.2):1, after dripping, kept for -5~-10 DEG C and continue stirring 5
~6h, pH=9~10 are adjusted with alkali lye afterwards, then extracted with dichloromethane solution, merge organic phase, anhydrous sodium sulfate drying；
Distillation first steams dichloromethane in 30~40 DEG C of low temperature distillations, then raises the cut of 133~135 DEG C of temperature collection, obtains yellow liquid
Body obtains 4- methylthiazols.
Preferably, the concentration of aqueous solution of natrium nitrosum described in step 3) is 20~25wt%；The water of the sodium hypophosphite
Solution concentration is 15~20wt%.
It is furthermore preferred that the aqueous solution mass fraction of natrium nitrosum described in step 3) is 22wt%；The sodium hypophosphite
Aqueous solution mass fraction is 17.5~19.3wt%.
Preferably, step 3) reclaimed water and the volume ratio of the concentrated sulfuric acid 2:(1~1.2).
Preferably, mass fraction is used to adjust pH=9~10 for 45% sodium hydroxide solution in step 3).
Further, step 4) is：By 4- methylthiazols, potassium permanganate and water in reaction vessel, 4- methylthiazols and height
The mol ratio of potassium manganate is 1:(4.5~5.5), it is then that reaction solution is cold that agitating and heating is warming up to 50~55 DEG C of 22~24h of reaction
But, filter, with 40~50 DEG C of hot water wash filter cakes (manganese dioxide), filtrate adjusts pH=3 with watery hydrochloric acid, there is solid precipitation, filters, filter
Slag drying obtains thiazole 4- formic acid products.
Preferably, the mol ratio of 4- methylthiazols and potassium permanganate is 1 in step 4):(5.0~5.5).
Further, step 4) can also be：4- methylthiazols and salpeter solution are added to absorption nitrogen dioxide dress
In the autoclave put, the mol ratio of 4- methylthiazols and nitric acid is 1:(5-5.5)；Slow heating, finally at 105~115 DEG C, pressure
4~5h is reacted under 0.2~0.3MPa of power；Stop reaction, be cooled to normal temperature discharging, filtered after being diluted with water, filter cake with 10~
12wt% sodium bicarbonate solutions dissolve, then filter；Filtrate adjusts pH=3 with watery hydrochloric acid, filters, and filter cake drying obtains thiazole 4- formic acid
Product.
Preferably, the mass fraction of salpeter solution described in step 4) is 30~35%.
Preferably, the mol ratio of 4- methylthiazols and nitric acid is 1 in step 4):(5~5.3).
Further, step 5) is：O-phenylenediamine and polyphosphoric acids are added in reaction bulb, lead to nitrogen protection, stirs lower oil
Bath is brought rapidly up to 150~155 DEG C, then adds 4-thiazolecarboxylic acid, then is warming up to 220~230 DEG C, and insulation reaction 2~
2.5h, the mol ratio of o-phenylenediamine, polyphosphoric acids and 4-thiazolecarboxylic acid is (1-1.2):(0.62-0.65):1；Stop reaction
Afterwards, reaction product is poured into mixture of ice and water, mixture is changed into dark brown liquid；Again pH=5~6 are neutralized to alkali lye
When, there is purplish grey Precipitation, filter out solid, purplish grey solid i.e. thiabendazole crude product is washed with water to obtain；Crude product is dissolved in 10~
In the water of 12 times of quality, pH=1~2 are adjusted with watery hydrochloric acid, add activated carbon backflow to decolourize, filtering, filtrate uses unsaturated carbonate hydrogen while hot
Sodium water solution be adjusted to pH=7~8 then filtering drying to obtain white crystalline solid be thiabendazole.
Preferably, alkali lye described in step 5) is 40wt% sodium hydroxide solution.
Preferably, step 5) can also be：By o-phenylenediamine, 4-thiazolecarboxylic acid, niter cake, potassium acid sulfate and phosphoric acid
Add in reaction vessel, o-phenylenediamine, 4-thiazolecarboxylic acid, niter cake, the mol ratio of potassium acid sulfate and phosphoric acid are (1-1.2):
1:(1-1.2):(1-1.2):(2-2.5), mixture react 4~5h at 170~180 DEG C；Stop reaction, reaction product is fallen
Enter in mixture of ice and water, mixture is changed into dark brown liquid；When being neutralized to pH=5-6 with alkali lye again, there is purplish grey Precipitation,
Solid is filtered out, purplish grey solid i.e. thiabendazole crude product is washed with water to obtain；Crude product is dissolved in the water of 10~12 times of quality, with dilute salt
Acid adjusts pH=1-2, adds activated carbon backflow to decolourize, filtering, filtrate is adjusted to pH=7-8 with saturated sodium bicarbonate aqueous solution while hot, so
It is thiabendazole that filtering drying, which obtains white crystalline solid, afterwards.
Preferably, alkali lye described in step 5) is 40wt% sodium hydroxide solution.
On the basis of above-mentioned technical proposal, synthetic method of the invention can also do following improvement.
Further, step 2) is to react to obtain 2- mercaptos by the monochloroacetone of previous step generation and two thiocarbamate amine
Base -4- methylthiazols；Step 3) is by the 2- sulfydryl -4- methylthiazols oxidation generation 4- methylthiazols of previous step generation；Contain
Its synthetic route of the synthetic method of above-mentioned two step is as follows：
Preferably, abovementioned steps 2) be：Monochloroacetone is mixed with water, and pH=2-3 is adjusted with watery hydrochloric acid, mixed liquor is cooled to
40-45 DEG C, then adding in the solution of ammonium dithiocarbamate and water, reaction mixture stirs 4-5h at 40~45 DEG C, and one
The mol ratio of chlroacetone and ammonium dithiocarbamate is 1: (1.5-1.6)；Stop adjusting pH=8-9 with alkaline matter after reacting,
It is extracted with ethyl acetate, merges organic phase, it is 2- sulfydryl -4- methylthiazols to dry and be concentrated to give colorless oil.
More excellent, alkaline matter described in step 2) is sodium hydrate solid.
More excellent, monochloroacetone mixes with the water of 2.5~3 times of quality in step 2)；Ammonium dithiocarbamate and water
In solution, both mass ratioes are 2.5~3:1.
More excellent, monochloroacetone mixes with the water of 2.7 times of quality in step 2)；The solution of ammonium dithiocarbamate and water
In, both mass ratioes are 2.35~2.6:1.
Preferably, abovementioned steps 3) be：2- sulfydryl -4- methylthiazols are taken to be suspended in the mixed solution of water and concentrated hydrochloric acid,
Hydrogenperoxide steam generator is slowly added dropwise under agitation, wherein, the mol ratio of 2- sulfydryl -4- methylthiazols, concentrated hydrochloric acid and hydrogen peroxide
For 1:(0.3~0.4):(3-3.5), the quality of water is 9~10 times of amounts of 2- sulfydryl -4- methylthiazol quality；Dropwise addition process temperature
Degree maintains 45~50 DEG C, is incubated 1~1.5h after being added dropwise at this temperature；After being cooled to room temperature, with lye pH adjustment=9-10, then
Extracted with dichloromethane, distilled after merging organic phase, first steam dichloromethane in 30-40 DEG C of low temperature, then raise temperature collection 133
~135 DEG C of cut obtains 4- methylthiazols.
Preferably, abovementioned steps 3) described in alkali lye be 40wt% sodium hydroxide solution.
Preferably, abovementioned steps 3) described in hydrogenperoxide steam generator be 30wt% aqueous hydrogen peroxide solution.
Preferably, abovementioned steps 3) in 2- sulfydryl -4- methylthiazols, concentrated hydrochloric acid and hydrogen peroxide mol ratio be 1:
(0.36-0.4):3.3；The quality of water is 9.5 times of amounts of 2- sulfydryl -4- methylthiazol quality.
Above-mentioned improved synthetic method, it is that monochloroacetone is synthesized as initiation material using acetone and chlorine, without isolation can be straight
Connect and react to obtain 2- sulfydryl -4- methylthiazols with two thiocarbamate amine, initial oxidation generation 4- methylthiazols, reoxidize as thiophene
Azoles -4- formic acid, last 4-thiazolecarboxylic acid react to obtain target product thiabendazole with o-phenylenediamine.
The invention also discloses application of the foregoing new synthetic method in thiabendazole preparation.
The advantages of invention novel synthesis, is as follows：The present invention solves existing thiabendazole synthetic method and is unsuitable for advising
The problem of mould is produced in batches, thiabendazole is prepared using cheap commercially available industrial chemicals and synthesis technique easy to operate,
Produce thiabendazole with being easy to economy of large scale, and the atom utilization of process chemistry reaction is high, more conducively greenization
Development.
Brief description of the drawings
Fig. 1 is the synthetic route chart of process route one of the present invention；
Fig. 2 is the synthetic route chart of process route two of the present invention.
Embodiment
The principles and features of the present invention are described below, and the given examples are served only to explain the present invention, is not intended to limit
Determine the scope of the present invention.
Embodiment 1
1.1) preparation of monochloroacetone
200g acetone, 20g calcium carbonate and 10mL water are added in 500mL four-hole bottle, connect rectifying column, post is suitable for reading to connect chlorine
Change reactor, condenser；Backflow is started to warm up, leads to chlorine, 100 DEG C is warming up to and stops logical chlorine, terminate reaction.Reactant gas phase is examined
Survey contains acetone 1.8%, monochloroacetone 95.4%, 1,1- dichloroacetones 1.2%, other impurity 1.6%.
1.2) synthesis of 2- amino -4- methylthiazols
113.88g (1.50mol) sulphur is directly added into monochloroacetone reaction solution (125g containing monochloroacetone, 1.36mol)
Urea, stir into suspension, heating water bath backflow 5h.Reaction solution is poured into the beaker for filling 500g mixture of ice and water, in low temperature
Cooled down in pump, then stirring is lower adds 200g sodium hydroxides, there is yellow solid precipitation.Oil reservoir is separated after placement, water layer is with right amount
Ethyl acetate extracts three times, drying after extract merges with oil reservoir, filters, and normal pressure boils off ethyl acetate, after subtract under 1.06kPa
Pressure distillation, collects 117-120 DEG C of cut, after placement faint yellow solid is 2- amino -4- methylthiazol 68.4g, yield
60%, it is 98.2% through HPLC detection purity, fusing point is 44-46 DEG C.
1.3) synthesis of 4- methylthiazols
68.4g (0.6mol) 2- amino -4- methylthiazols are taken in 2L there-necked flasks, then 150mL water is added and 75mL is dense
The mixed solution of sulfuric acid, reaction mixture is cooled to -10~-15 DEG C, keeps the temperature to instill the water-soluble of natrium nitrosum in 2h
Liquid (41.4g, 0.6mol natrium nitrosum are dissolved in 150mL water).After charging, the temperature is kept to continue to stir 1h, now
Diazol.Then again at -5~-10 DEG C be added dropwise sodium hypophosphite the aqueous solution (63.6g, 0.6mol sodium hypophosphite are dissolved in 300mL
Water).After dripping, continue to stir 5h at -5 DEG C.Afterwards with mass fraction be 45% sodium hydroxide solution adjust pH=9~
10.Then with the extraction of 105mL dichloromethane solutions three times, organic phase, anhydrous sodium sulfate drying are merged.Distill first low temperature (30~
40 DEG C) dichloromethane is steamed, then the cut of 133~135 DEG C of temperature collection is raised, obtain yellow liquid 42g, yield 70%.
1.4) synthesis of thiazole 4- formic acid
4- methylthiazols (19.8g, 0.2mol), 200mL water and potassium permanganate (158g, 1.0mol) are put into 500mL tri-
In mouth reaction bulb, agitating and heating is warming up to 50 DEG C of reaction 24h.Then reaction solution is cooled down, then filtered, with 40 DEG C of hot water filter washes
Cake (manganese dioxide), filtrate adjust pH=3 with watery hydrochloric acid, there is solid precipitation, filter, and filter cake is washed with a small amount, and dries to obtain product
17.6g, yield 68.2%, 196-198 DEG C of fusing point.
1.5) synthesis of thiabendazole
O-phenylenediamine (10.8g, 0.1mol) and polyphosphoric acids (21g, 0.062mol) are added in reaction bulb, leads to nitrogen and protects
Shield, stir lower oil bath and be brought rapidly up to 150 DEG C, then add 4-thiazolecarboxylic acid (12.9g, 0.1mol), then be warming up to 230
DEG C, insulation reaction 2h.Stop reaction, poured into while hot in 200g mixture of ice and water after somewhat cooling down, mixture is changed into dark-brown liquid
Body.When being neutralized to pH=5-6 with 40% sodium hydroxide solution again, there are a large amount of purplish grey Precipitations, filter out solid, use
20mL*4 washes to obtain purplish grey solid i.e. thiabendazole crude product, crude product is dissolved in the water of 10 times of quality, and pH=is adjusted with watery hydrochloric acid
1-2, activated carbon backflow is added to decolourize, filtering, filtrate is adjusted to alkalescent (pH=7-8) with saturated sodium bicarbonate aqueous solution while hot, so
Filtering drying obtains white crystalline solid 17.7g, yield 88%, 304-306 DEG C of fusing point afterwards.
IR(KBr)/cm-1:3108,3064,2945,2806,2673,1630,1584,1500,1426, 1375,1315,
1286,1241,1208,1104,998,892,836,756.
1H NMR,δ:3.05(s,1H),8.07(s,5H),8.86(s,1H).
Embodiment 2
2.1) preparation of monochloroacetone
200g acetone and 10mL water are added in 500mL four-hole bottle, temperature rising reflux leads to chlorine, is slowly added into reaction bulb
20% sodium hydrate aqueous solution, make material liquid pH=3~4, temperature rises to 100 DEG C and stops logical chlorine, terminates reaction.Reactant gas phase
Detection contains acetone 2.0%, monochloroacetone 94.2%, 1,1- dichloroacetones 1.5%, other impurity 2.3%.
2.2) synthesis of 2- sulfydryls -4- methylthiazols
Monochloroacetone (74.0g, 0.8mol) is mixed with 200mL water, and pH=2 is adjusted with watery hydrochloric acid, mixed liquor is cooled to 40
DEG C, then add ammonium dithiocarbamate (132g, 1.2mol) and in the solution of 50mL water, reaction mixture is in 40 DEG C of stirrings
5h, stop adjusting pH=9 with sodium hydroxide after reacting, extracted with 3*100mL ethyl acetate, merge organic phase, drying is concentrated to give nothing
Color grease 86.0g, yield 82%.Aqueous phase recovery is in next group.
2.3) synthesis of 4- methylthiazols
2- sulfydryl -4- methylthiazols (78.6g, 0.6mol) are taken to be suspended in the mixed solution of 750mL water and 18mL concentrated hydrochloric acids
In, w (H are slowly added dropwise under agitation2O2The hydrogenperoxide steam generator 225g of)=30%, process temperature is added dropwise and maintains 45 DEG C, is added dropwise
After be incubated 1.5h at such a temperature.After being cooled to room temperature, pH=9-10 is adjusted with w (NaOH)=40% aqueous solution, then use 3*
180mL dichloromethane extraction, distills after merging organic phase, and first low temperature (30-40 DEG C) steams dichloromethane, then raises temperature receipts
133-135 DEG C of cut of collection is 4- methylthiazols, is yellow liquid 46.5g, yield 78%.
2.4) synthesis of thiazole 4- formic acid
By 4- methylthiazols (19.8g, 0.2mol) and 180mL30%HNO3(1.06mol) is added to absorption dioxy
In the 250mL autoclaves for changing nitrogen device, slow heating, finally 4h is reacted under 115 DEG C, pressure 0.2MPa.Stop reaction, it is cold
But discharge, filtered after being diluted with water, filter cake is dissolved with 10% sodium bicarbonate solution, then is filtered to normal temperature.Filtrate is adjusted with watery hydrochloric acid
PH=3, filter drying product 16.5g, yield 64%, 195-197 DEG C of fusing point.
2.5) synthesis of thiabendazole
By o-phenylenediamine (10.8g, 0.1mol), 4-thiazolecarboxylic acid (12.9g, 0.1mol), niter cake (12.0g,
0.1mol), potassium acid sulfate (13.6g, 0.1mol) and phosphoric acid (0.2mol) are added in reaction bulb, and mixture reacts 4h at 180 DEG C.
Stop reaction, poured into while hot in 200g mixture of ice and water after somewhat cooling down, mixture is changed into dark brown liquid.Again with 40%
When sodium hydroxide solution is neutralized to pH=5-6, there are a large amount of purplish grey Precipitations, filter out solid, purple ash is washed to obtain with 20mL*4
Color solid is thiabendazole crude product, crude product is dissolved in the water of 10 times of quality, adjusts pH=1-2 with watery hydrochloric acid, adds activated carbon to flow back
Decolourize, filtering, filtrate is adjusted to alkalescent (pH=7-8) with saturated sodium bicarbonate aqueous solution while hot, and then filtering drying obtains white
Crystalline solid 15.3g, yield 76%, 304-306 DEG C of fusing point.
IR(KBr)/cm-1:3108,3064,2945,2806,2673,1630,1584,1500,1426, 1375,1315,
1286,1241,1208,1104,998,892,836,756.
1H NMR,δ:3.05(s,1H),8.07(s,5H),8.86(s,1H).
Embodiment 3
3.1) preparation of monochloroacetone
180g acetone, 30g calcium carbonate and 10mL water are added in 500mL four-hole bottle, connect rectifying column, post is suitable for reading to connect chlorine
Change reactor, condenser；Backflow is started to warm up, leads to chlorine, 110 DEG C is warming up to and stops logical chlorine, terminate reaction.Reactant gas phase is examined
Survey contains acetone 2.1%, monochloroacetone 95.6%, 1,1- dichloroacetones 1.4%, other impurity 0.9%.
3.2) synthesis of 2- amino -4- methylthiazols
113.88g (1.50mol) sulphur is directly added into monochloroacetone reaction solution (115g containing monochloroacetone, 1.25mol)
Urea, stir into suspension, heating water bath backflow 6h.Reaction solution is poured into the beaker for filling 480g mixture of ice and water, in low temperature
Cooled down in pump, then stirring is lower adds 180g sodium hydroxides, there is yellow solid precipitation.Oil reservoir is separated after placement, water layer is with right amount
Ethyl acetate extracts three times, drying after extract merges with oil reservoir, filters, and normal pressure boils off ethyl acetate, after subtract under 1.1kPa
Pressure distillation, collects 117-120 DEG C of cut, after placement faint yellow solid is 2- amino -4- methylthiazol 66.1g, yield
58%, it is 98.6% through HPLC detection purity, fusing point is 44-46 DEG C.
3.3) synthesis of 4- methylthiazols
68.4g (0.6mol) 2- amino -4- methylthiazols are taken in 2L there-necked flasks, then 150mL water is added and 90mL is dense
The mixed solution of sulfuric acid, reaction mixture is cooled to -10~-15 DEG C, keeps the temperature to instill the water of natrium nitrosum in 2.5h
Solution (45.5g, 0.66mol natrium nitrosum are dissolved in 160mL water).After charging, the temperature is kept to continue to stir 1.5h,
Now obtain diazol.Then the aqueous solution (76.3g, 0.72mo) sodium hypophosphite that sodium hypophosphite is added dropwise at -5~-10 DEG C again is molten
In 320mL water).After dripping, continue to stir 6h at such a temperature.Afterwards with the sodium hydroxide solution that mass fraction is 45%
Adjust pH=9~10.Then with the extraction of 110mL dichloromethane solutions three times, organic phase, anhydrous sodium sulfate drying are merged.Distillation
First 30-40 DEG C of low temperature steams dichloromethane, then raises the cut of 133~135 DEG C of temperature collection, obtains yellow liquid 43.2g, receives
Rate 72%.
3.4) synthesis of thiazole 4- formic acid
4- methylthiazols (19.8g, 0.2mol), 200mL water and potassium permanganate (173.8g, 1.1mol) are put into 500mL
In three mouthfuls of reaction bulbs, agitating and heating is warming up to 55 DEG C of reaction 22h.Then reaction solution is cooled down, then filtered, with 50 DEG C of hot water wash
Filter cake (manganese dioxide), filtrate adjust pH=3 with watery hydrochloric acid, there is solid precipitation, filter, and filter cake is washed with a small amount, and drying to produce
Product 18.1g, yield 70.2%, 196-198 DEG C of fusing point.
3.5) synthesis of thiabendazole
O-phenylenediamine (12.96g, 0.12mol) and polyphosphoric acids (22g, 0.065mol) are added in reaction bulb, lead to nitrogen
Protection, stir lower oil bath and be brought rapidly up to 155 DEG C, then add 4-thiazolecarboxylic acid (12.9g, 0.1mol), then be warming up to 220
DEG C, insulation reaction 2.5h.Stop reaction, poured into while hot in 210g mixture of ice and water after somewhat cooling down, mixture is changed into dark-brown
Liquid.When being neutralized to pH=5-6 with 40% sodium hydroxide solution again, there are a large amount of purplish grey Precipitations, filter out solid, use
20mL*4 washes to obtain purplish grey solid i.e. thiabendazole crude product, crude product is dissolved in the water of 12 times of quality, and pH=is adjusted with watery hydrochloric acid
1-2, activated carbon backflow is added to decolourize, filtering, filtrate is adjusted to alkalescent (pH=7-8) with saturated sodium bicarbonate aqueous solution while hot, so
Filtering drying obtains white crystalline solid 17.1g, yield 85%, 304-306 DEG C of fusing point afterwards.
IR(KBr)/cm-1:3108,3064,2945,2806,2673,1630,1584,1500,1426, 1375,1315,
1286,1241,1208,1104,998,892,836,756.
1H NMR,δ:3.05(s,1H),8.07(s,5H),8.86(s,1H).
Embodiment 4
4.1) preparation of monochloroacetone
200g acetone and 15mL water are added in 500mL four-hole bottle, temperature rising reflux leads to chlorine, is slowly added into reaction bulb
20% sodium hydrate aqueous solution, make material liquid pH=3~4, temperature rises to 110 DEG C and stops logical chlorine, terminates reaction.Reactant gas phase
Detection contains acetone 1.7%, monochloroacetone 94.7%, 1,1- dichloroacetones 1.6%, other impurity 2.0%.
4.2) synthesis of 2- sulfydryls -4- methylthiazols
Monochloroacetone (74.0g, 0.8mol) is mixed with 200mL water, and pH=2 is adjusted with watery hydrochloric acid, mixed liquor is cooled to 45
DEG C, then add ammonium dithiocarbamate (141g, 1.28mol) and in the solution of 60mL water, reaction mixture stirs at 45 DEG C
4h is mixed, stops adjusting pH=8 with sodium hydroxide after reacting, is extracted with 3*100mL ethyl acetate, merge organic phase, drying is concentrated to give
Colorless oil 90.2g, yield 86%.Aqueous phase recovery is in next group.
4.3) synthesis of 4- methylthiazols
2- sulfydryl -4- methylthiazols (78.6g, 0.6mol) are taken to be suspended in the mixed solution of 750mL water and 20mL concentrated hydrochloric acids
In, w (H are slowly added dropwise under agitation2O2The hydrogenperoxide steam generator 238g of)=30%, process temperature is added dropwise and maintains 50 DEG C, is added dropwise
After be incubated 1h at such a temperature.After being cooled to room temperature, pH=9-10 is adjusted with w (NaOH)=40% aqueous solution, then use 3*
180mL dichloromethane extraction, distills after merging organic phase, and first low temperature (30-40 DEG C) steams dichloromethane, then raises temperature receipts
133-135 DEG C of cut of collection is 4- methylthiazols, is yellow liquid 45.3g, yield 76%.
4.4) synthesis of thiazole 4- formic acid
By 4- methylthiazols (19.8g, 0.2mol) and 180mL 35%HNO3(1.0mol) is added to absorption dioxy
In the 250mL autoclaves for changing nitrogen device, slow heating, finally 5h is reacted under 105 DEG C, pressure 0.3MPa.Stop reaction, cooling
Discharge, filtered after being diluted with water, filter cake is dissolved with 12% sodium bicarbonate solution, then is filtered to normal temperature.Filtrate adjusts pH with watery hydrochloric acid
=3, filter drying product 17.3g, yield 67%, 195-197 DEG C of fusing point.
2.5) synthesis of thiabendazole
By o-phenylenediamine (12.96g, 0.12mol), 4-thiazolecarboxylic acid (12.9g, 0.1mol), niter cake (14.4g,
0.12mol), potassium acid sulfate (16.32g, 0.12mol) and phosphoric acid (0.25mol) are added in reaction bulb, and mixture is anti-at 170 DEG C
Answer 5h.Stop reaction, poured into while hot in 200g mixture of ice and water after somewhat cooling down, mixture is changed into dark brown liquid.Use again
When 40% sodium hydroxide solution is neutralized to pH=5-6, there are a large amount of purplish grey Precipitations, filter out solid, washed with 20mL*4
It is thiabendazole crude product to obtain purplish grey solid, crude product is dissolved in the water of 12 times of quality, adjusts pH=1-2 with watery hydrochloric acid, adds activity
Charcoal backflow is decolourized, and filtering, filtrate is adjusted to alkalescent (pH=7-8) with saturated sodium bicarbonate aqueous solution while hot, then filtering drying
Obtain white crystalline solid 14.9g, yield 74%, 304-306 DEG C of fusing point.
IR(KBr)/cm-1:3108,3064,2945,2806,2673,1630,1584,1500,1426, 1375,1315,
1286,1241,1208,1104,998,892,836,756。
1H NMR,δ:3.05(s,1H),8.07(s,5H),8.86(s,1H)。
The foregoing is only presently preferred embodiments of the present invention, be not intended to limit the invention, it is all the present invention spirit and
Within principle, any modification, equivalent substitution and improvements made etc., it should be included in the scope of the protection.
Claims (6)
1. a kind of synthetic method of thiabendazole, comprises the following steps：
1) monochloroacetone is generated through chlorination reaction as initiation material using acetone and chlorine；
2) monochloroacetone by step 1) generation reacts to obtain 2- amino -4- methylthiazols with thiocarbamide；
3) the 2- amino -4- methylthiazols of step 2) are obtained into 4- methylthiazols by diazo-reaction；
4) the 4- methylthiazols oxidation generation 4-thiazolecarboxylic acid of step 3)；
5) 4-thiazolecarboxylic acid of step 4) reacts to obtain thiabendazole product with o-phenylenediamine；
Synthetic route is as follows：
Wherein, step 5) is that o-phenylenediamine, 4-thiazolecarboxylic acid, niter cake, potassium acid sulfate and phosphoric acid are added into reaction vessel
In, o-phenylenediamine, 4-thiazolecarboxylic acid, niter cake, the mol ratio of potassium acid sulfate and phosphoric acid are (1-1.2):1:(1-1.2):
(1-1.2):(2-2.5), mixture react 4~5h at 170~180 DEG C；Stop reaction, reaction product is poured into mixture of ice and water
In, mixture is changed into dark brown liquid；When being neutralized to pH=5-6 with alkali lye again, there is purplish grey Precipitation, filter out solid, use
Wash to obtain purplish grey solid i.e. thiabendazole crude product；Crude product is dissolved in the water of 10~12 times of quality, pH=1- is adjusted with watery hydrochloric acid
2, add activated carbon backflow to decolourize, filtering, filtrate is adjusted to pH=7-8 with saturated sodium bicarbonate aqueous solution while hot, then filtering drying
It is thiabendazole to obtain white crystalline solid.
2. synthetic method according to claim 1, it is characterised in that step 1) is：By acetone, calcium carbonate and water according to matter
It is (18~20) to measure ratio:(2~3):1 is added in four-hole bottle, connects rectifying column, and post is suitable for reading to connect chlorination reactor, condenser；Start
Temperature rising reflux, lead to chlorine, be warming up to 100~110 DEG C and stop logical chlorine, terminate reaction and obtain monochloroacetone reaction solution；Or step
1) it is：It is 1 by mass ratio:The acetone and water of (0.05~0.08) are added in four-hole bottle, and temperature rising reflux leads to chlorine, into reaction bulb
Sodium hydrate aqueous solution is slowly added to, makes material liquid pH=3~4, temperature rises to 100~110 DEG C and stops logical chlorine, terminates reaction and obtain
Monochloroacetone reaction solution.
3. synthetic method according to claim 1, it is characterised in that step 2) is：It is anti-to the monochloroacetone of previous step
Addition thiocarbamide in liquid is answered to make the mol ratio of monochloroacetone and thiocarbamide be 1：(1.1~1.2), stir into suspension, and heating water bath returns
5~6h is flowed, reaction solution is poured into mixture of ice and water after backflow and cooled down, then stirring is lower adds sodium hydroxide, there is yellow solid
Separate out；Oil reservoir is separated after placement, aqueous layer with ethyl acetate is extracted, and extract is dried after merging with oil reservoir, and filtering, normal pressure steams
After removing ethyl acetate, it is evaporated under reduced pressure, collects 117~120 DEG C of cut, it is 2- amino -4- methyl that faint yellow solid is obtained after placement
Thiazole.
4. synthetic method according to claim 1, it is characterised in that step 3) is：2- amino -4- methylthiazols are taken in three
In mouth bottle, the mixed solution for then adding water and the concentrated sulfuric acid obtains reaction mixture；Reaction mixture is cooled to -10~-15 DEG C,
The temperature is kept to instill the aqueous solution of natrium nitrosum, the mol ratio of natrium nitrosum and 2- amino -4- methylthiazols in 2~2.5h
For (1~1.1):1, after charging, keep the temperature to continue 1~1.5h of stirring, obtain diazol；Then again -5~-10
The aqueous solution of sodium hypophosphite is added dropwise at DEG C, the mol ratio of sodium hypophosphite and 2- amino -4- methylthiazols is (1~1.2):1, it is added dropwise
After complete, kept for -5~-10 DEG C and continue 5~6h of stirring, adjust pH=9~10 with alkali lye afterwards, then extracted with dichloromethane solution,
Merge organic phase, anhydrous sodium sulfate drying；Distillation first steams dichloromethane in 30~40 DEG C of low temperature distillations, then raises temperature collection
133~135 DEG C of cut, obtain yellow liquid and obtain 4- methylthiazols.
5. synthetic method according to claim 1, it is characterised in that step 4) is：By 4- methylthiazols, potassium permanganate and
For water in reaction vessel, the mol ratio of 4- methylthiazols and potassium permanganate is 1:(4.5~5.5), agitating and heating is warming up to 50~
Then 55 DEG C of 22~24h of reaction cool down reaction solution, filter, and with 40~50 DEG C of hot water wash filter cakes, filtrate adjusts pH=with watery hydrochloric acid
3, there is solid precipitation, filter, filter residue drying obtains thiazole 4- formic acid；Or step 4) is：By 4- methylthiazols and salpeter solution
It is added to in the autoclave for absorbing nitrogen dioxide device, the mol ratio of 4- methylthiazols and nitric acid is 1:(5-5.5)；Slowly
Heating, 4~5h is finally reacted under 105~115 DEG C, 0.2~0.3MPa of pressure；Stop reaction, be cooled to normal temperature discharging, use water
Filtered after dilution, filter cake 10~12wt% sodium bicarbonate solutions dissolve, then filter；Filtrate adjusts pH=3 with watery hydrochloric acid, filters,
Filter cake drying obtains thiazole 4- formic acid.
6. application of the synthetic method in thiabendazole preparation described in claim 1-5 any claims.
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| CN1042150A (en) * | 1989-09-21 | 1990-05-16 | 青岛海洋大学 | A kind of technology of producing Top Form Wormer |
| CN101255102A (en) * | 2008-04-02 | 2008-09-03 | 陈灿银 | Method for preparing monochloroacetone |
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| CN1042150A (en) * | 1989-09-21 | 1990-05-16 | 青岛海洋大学 | A kind of technology of producing Top Form Wormer |
| CN101255102A (en) * | 2008-04-02 | 2008-09-03 | 陈灿银 | Method for preparing monochloroacetone |
Non-Patent Citations (3)
| Title |
|---|
| Arylation radicalaire du thiazole en phase liquide;Gaston Vernin，等;《Bullentin de la societe chimique de France》;19631231(第11期);第2504-2508页 * |
| Enzymatic Oxidation of methyl groups on aromatic heterocycles: A Versatile method for the preparation of heteroaromatic carboxylic acids;Andreas Kiener;《Angew. Chem. Int. Ed. Engl.》;19921231;第31卷;第774-775页 * |
| 肉香型香料4-甲基-5-噻唑乙醇的合成;李树安;《精细化工》;20050731;第22卷(第7期);第521-523页 * |
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