CN108929207A - A kind of synthetic method of penta ring azoles intermediate - Google Patents
A kind of synthetic method of penta ring azoles intermediate Download PDFInfo
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- B01J29/06—Crystalline aluminosilicate zeolites; Isomorphous compounds thereof
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Abstract
The invention discloses a kind of synthetic method of penta ring azoles intermediate, synthetic method, the bromo- 1- of 2- (2, the 4- dichlorophenyl) synthetic method of ethyl ketone and the synthetic methods of ketal of predominantly 2,4- dichloroacetophenone.It is an advantage of the invention that：Penta succeeding in developing for cyclozocine type fungicide has filled up domestic blank, and the study on the synthesis of like derivatives based on this will be in the ascendant, succeed in developing and the industrialized implementation of various new type bactericides, and the present invention is a kind of penta novel ring azoles synthetic method.
Description
Technical field
The present invention relates to penta ring azoles field, specially a kind of synthetic method of penta ring azoles intermediate.
Background technique
Penta ring azoles (azaconazole), structural formula are, it is a kind of
Novel fungicide.The present invention studies the synthesis of penta ring azoles with a variety of Research on Methods.Simultaneously as zeolite catalyst has uniqueness
Structure and excellent performance, be also used in the wherein synthesis of mesosome bromo ketal.
Firstly, we are catalyst respectively in benzene using p-methyl benzenesulfonic acid, benzene+butanol, toluene is produced in the solvent of dimethylbenzene
The intermediate bromo ketal and chloro ketal of penta ring azoles.We have found that no matter in what solvent the yield of bromo ketal is always big
In the yield of chloro ketal.And in various solvents, reaction yield either bromo ketal or chloro ketal, with benzene+
Reaction yield highest in butanol.
Unique structure and excellent performance possessed by zeolite catalyst make it be widely used in petrochemical industry
Huge economic benefit is brought to the mankind in field.In organic synthesis, the synthesis of especially fine organic products, related zeolite
The basic research of catalyst application obtained it is some satisfactory as a result, the organic synthesis of zeolite catalysis research by
Gradually form a new field.The present invention has carried out in detail with regard to zeolite catalyst in the ketal reaction for synthesizing penta ring azoles intermediate
Thin research.
Firstly, we are prepared for a variety of HY zeolites and have carried out physicochemical properties characterization, then in benzene, benzene+butanol and
In toluene solvant, respectively with Y3, Y4, Y6 and Y9 zeolite is catalyst preparation bromo ketal, is found in various solvents, in benzene
Yield in+butanol is highest, this be the same by the resulting conclusion of catalyst of p-methyl benzenesulfonic acid.And in various HY zeolites
The yield sequence of gained ketal is Y3 in catalyst<Y4<Y6<Y9. this is sequentially identical as the Lewis acidity sequence of zeolite,
And it is opposite with the acidity in the acid site Bronsted sequence.Play main make in this explanation acid site Lewis in this ketal reaction
With.
Make catalyst there is corrosion equipment with p-methyl benzenesulfonic acid, pollute environment, it is troublesome in poeration the problems such as, and made with zeolite
The above problem is not only not present in catalyst, but also catalyst can repeated multiple times regeneration use；Also, product yield with to toluene
Sulfonic acid is close.Therefore, in ketal reaction, we can substitute p-methyl benzenesulfonic acid with zeolite catalyst completely.Especially Y9 effect
Fruit is best.
Meanwhile we are also according to the alkylation of regiospecific 1,2,4- triazole, have studied with the chloro- 1- (2,4- of 2-
Dichlorophenyl) ethyl ketone and 4- amino -4H-1,2,4- triazoles are the synthesis of penta ring azoles of raw material, and achieve satisfactory results.
Penta ring azoles its common name is azaconazole, trade name Rodewod, Safetray, other titles R28644,
Its chemical name is 1- [[2- (2,4 dichloro benzene base) -1,3- dioxolanes -2- base] methyl] -1H-1,2,4- triazoles.Its structure
Formula is：
Penta ring azoles category azoles fungicide, is sterol demethylation inhibitors.It is special that it has house fungus and Sapstain fungi
Activity.Meanwhile can be used for wood preservation, it is used for animal and human body, can effectively kill pathogenic microorganisms, guarantees animal and people
Health.Penta ring azoles is mould to the powder resisted on different plants to have very strong activity.Such as：Standing grain powdery mildew, erysiphe polygoni, two spores are white
Powder, apple mildew handle coccus, Sphaerothecapannosa, gooseberry monofilament shell bacterium, uncinula necator snag shell bacterium and some other true
Bacterium, such as：Venturia inaequalis, Kidney bean hair disc spore, fusarium oxysporum, grape raw rod method, the long compacted spore of standing grain, refer to colon fundamental series pearl root fungus
Shape mould etc..It can also be used in mushroom-cultivating and makees disinfectant in the container of fruit and vegetable, can also mix and answer with imazalil
For trees, as Wound healing agent.In short, succeeding in developing for penta ring azoles fungicide, all has agricultural production and human health
It is of great importance.
Penta ring azoles(I), it can be easy to by 1H-1, the metal of 2,4- triazoles (II)
Salt with(III) reaction obtains.Wherein Y is halogen, especially best with bromine.1H-1,2,4- triazole
(II) metal salt can especially be produced by (II) and alkali alcoholate with sodium methoxide best.(II) and the reaction of (III) is suitable
When the inert polar organic solvent of chemical reaction in carry out, such as：N, dinethylformamide (DMF) etc..Meanwhile reaction exists
It is carried out under reflux temperature.
Final product (I) can be isolated by the separation method crystallized.
Preceding method can be expressed from the next for：
Compound obtained like this is alkali formula, can be changed to its corresponding salt by the way that sour such as nitric acid, sulfuric acid appropriate is added.
The salt has certain therapeutic effect.These salt are successively converted to corresponding alkali formula with sodium hydroxide or potassium hydroxide reaction.
Compound (III) can be by(IV) it is made with ethylene glycol (V) through ketal reaction.
Both reactants flow back several hours in solvent appropriate, and water is removed in the form of azeotropic mixture.Reaction need to be added suitable
Catalyst, p-methyl benzenesulfonic acid or zeolite.Its reaction equation is as follows：
Document report is had no using zeolite as catalyst.
Penta ring azoles (I) also can be used the regiospecific alkylation of 1,2,4- triazole to be made.1,2,4- triazole is direct
Alkylation usually provides the mixtures of 1 and 4 substitutions, ratio according to alkylating reagent property and reaction condition it is different without
Together, but its range is generally 70:30‐90:Between 10.4- amino -4H-1,2,4- triazoles are active shielded triazoles, can
It is directly made by the derivative of hydrazine and formic acid.With 4- amino -4H-1,2,4- triazoles are alkylated the resulting triazolium salt of reaction,
Then amino is removed under micro- excessive nitrous acid effect, 1 substituent is mainly obtained, when halogenated alkane is
Its product in the solvent of 1- amylalcohol and dimethylbenzene, is with p-methyl benzenesulfonic acid again
Catalyst and ethylene glycol carry out ketal reaction and obtain penta ring azoles fungicide.
Its reaction equation is：
When RX=When, reaction equation is：
Penta ring azoles is synthesized in this way has no document report.
In addition, carrying out carbonyl-protection with the method for forming acetal or dithioacetals is one in many organic synthesis
The important technology of item, and the stability due to acetal (ketone) under alkaline or neutral conditions, so that acetal (ketone) changes reaction and exists
Using quite extensively in industry, for example synthetic perfume, prepare radical protection in reaction intermediate and reaction process etc..Synthesis
The method of acetal (ketone) classics is to make dehydration catalyst with anhydrous HCl, and aldehyde (ketone) is reacted in anhydrous conditions with alcohol.But by
In after reaction, the separation process of product and reactant and catalyst is more complicated, and the HCl that reaction uses can be to ring
Border pollutes.When making catalyst with p-methyl benzenesulfonic acid, similarly there is these problems.Therefore, for many years some scientific researches
Worker is attempting always other synthetic methods：With Louis its acid, ion exchange resin, the complex of rhodium, and with load
Transition metal on active carbon, such as：The various method catalysis such as Rh, Ir, Pd, Pt carry out acetal (ketone) and change.Tooks et al. uses road
Lewis acid makees catalyst with ethylene oxide ketal.But these methods are not easy to operate or expensive.
Recent Petney makees catalyst 1,2- benzene dimethanol with montmorillonite KSF and sulphonated charcoal and protects carbonyls,
This method is mainly the absorption property for utilizing the surface of solids.This mentions the catalyst that zeolite makees acetal (ketone) change reaction for us
A thinking is supplied.
In view of application value of the zeolite in organic synthesis and industry, we are quasi- to prepare penta ring azoles with zeolites as catalysts
Intermediate bromo ketal, and achieve good experiment effect.Penta succeeding in developing for cyclozocine type fungicide has filled up the country
The study on the synthesis of blank, like derivatives based on this will be in the ascendant, various new type bactericides succeed in developing and
Industrialized implementation will generate far-reaching influence to the development of national economy.
Summary of the invention
The purpose of the present invention is to provide a kind of synthetic methods of penta ring azoles fungicide, which is the conjunction of penta ring azoles
At new method.
The technical solution adopted by the present invention is as follows：A kind of synthetic method of penta ring azoles intermediate, predominantly 2,4-dichloro-benzenes
The bromo- 1- of the synthetic method of ethyl ketone, 2- (2,4 dichloro benzene base) synthetic method of ethyl ketone and the synthetic method of ketal.
The synthetic method of 2,4-dichloroacetophenones, the specific steps are：
（1）In 250ml three-necked bottle, middle port installs blender, and two side ports fill dropping funel and condenser pipe respectively, in condenser pipe
Upper end fills monochlor(in)ate calcium drying tube, and even monochlor(in)ate hydrogen absorption plant；
（2）Aluminum trichloride (anhydrous) powder 20g (0.15 mol) quickly is weighed, is put into three-necked bottle, adds dichloro between 30 ml
Benzene instills 6 ml (0.06 mol) acetic anhydride under stiring, drips off within about 20 minutes；
（3）Then slightly boiled half an hour is kept in heating mantle, until without hydrogen chloride gas evolution；
（4）Three-necked bottle is dipped in cold bath, is instilled in the mixed liquor of 50ml concentrated hydrochloric acid and 50ml ice water under stiring, when in bottle
After solids is completely dissolved, oil reservoir is separated, water layer is extracted twice with 15ml m-dichlorobenzene every time；
（5）Merge oil reservoir, successively with 5% sodium hydroxide solution, each 20ml washing of water, oil reservoir anhydrous magnesium sulfate drying；
（6）It is evaporated under reduced pressure after crude product is dry, collects b22.132-135 DEG C of fraction, obtain product 54.712g, yield
55.46%, mp.33.1 DEG C.
The synthetic method of the bromo- 1- of 2- (2,4- dichlorophenyl) ethyl ketone, the specific steps are：
（1）Separatory funnel is being housed, in the drying three-neck flask of mechanical stirring and reflux condenser, is being placed by 19.0g
(99.42%, 0.1 mol) 2,4 dichloro benzene ethyl ketone is dissolved in the pure anhydrous ether of 50ml and is formed by solution；
（2）Solution is placed on cooling in ice bath, 0.2gAlCl3 one side is imported and stirs, be gradually added on one side from separatory funnel
16.0g (0.1mol) bromine, the speed of addition are about 1ml per minute；When ending close to reaction, solution becomes pink；
（3）After bromine adds, at once under reduced pressure by slight air stream to remove ether and hydrogen bromide, the bromo- 1- of 2- (2,
4- dichlorophenyl) ethyl ketone leaves end in solid fraction tan crystals, can be shaken with the mixture that 5ml water and 5ml petroleum ether form with
Remove color；
（4）Crystal is filtered with suction filtration, washs to obtain product 22.325g with methanol 20ml, yield 83.36%, mp.57-58 DEG C.
The synthetic method of ketal, the specific steps are：
(1) 13.39g (0.05mol) 2- bromo- 1- (2,4- dichlorophenyl) ethyl ketone is dissolved in 30ml butanol, adds 0.5g
P-methyl benzenesulfonic acid and 70ml benzene；Under stirring, 4.65g (0.075ml) ethylene glycol is added dropwise, is heated to reflux 6 hours, uses separator
Separate the moisture content that reaction generates；End of reaction is cooled to room temperature reaction mixture, after then being neutralized with 5% KOH solution, then
It is washed with deionized twice；Solvent is removed under reduced pressure after organic phase Na2SO4 drying in liquid separation, and raffinate crystallization, gained crystal is certainly
It recrystallizes primary in methanol, can obtain product 14.430g, yield 92.54%, mp.76-77 DEG C.Products obtained therefrom is 2- bromomethyl-
2- (2,4 dichloro benzene base) -1,3- dioxolanes（Bromo ketal）；
(2) it is placed in 19.0g (99.42%, 0.01mol) 2,4- dichloroacetophenone in the three-necked flask of 250ml, and is added
45ml butanol；At room temperature, 5.4ml (99.5%, 0.105 mol) bromine is added dropwise in one hour；Then at room temperature again
Stirring one hour is added 9.31g (95%, 0.15 mol) ethylene glycol, and 100ml anhydrous benzene and 1g is added to toluene sulphur
Acid, entire mixed liquor are stirred and are heated to reflux 4 hours, the water generated with separator separation；Stop reaction, reaction mixture
It is cooled to room temperature, after being neutralized with dilute KOH solution, then is washed with deionized twice, with separatory funnel liquid separation, oil mutually uses Na2SO4
Solvent is removed under reduced pressure after drying, Residual oil is added in methanol, and product crystallization is precipitated；Filtering, gained crude product are tied again in methyl alcohol again
It is brilliant primary, and washed once with methanol, it filters, dry, obtain product 25.953g, yield 83.22%, mp.77.0-77.5 DEG C,
Products obtained therefrom is bromo ketal；
(3) solvent benzol+butanol is changed to the experiment that benzene, toluene or dimethylbenzene repeat (2) by constant of the amount of other reagents；
(4) 19.0g (99.42%, 0.10 mol) 2,4 dichloro benzene ethyl ketone is changed into 22.51g (99.28%, 0.10 mol)
Solvent benzol+butanol is changed into the experiment that benzene,toluene,xylene repeats (2) by the chloro- 1- of 2- (2,4- dichlorophenyl) ethyl ketone；Gained produces
Product are 2- chloromethyl -2- (2,4 dichloro benzene base) -1,3- dioxolanes (chloro ketal)；
(5) 19.0g (99.42%, 0.10 mol) 2,4-dichloroacetophenones are dissolved in the molten of 45 ml butanol and 100 ml benzene
In liquid, 1g p-methyl benzenesulfonic acid and 9.31g (95%, 0.15 mol) ethylene glycol are added, stirs, is heated to reflux 6 hours, is flowed back
Temperature is 86-87 DEG C；Separator separates the moisture content of generation, is cooled to room temperature after completion of the reaction, is added dropwise 5.4 in one hour
Ml (99.5%, 0.105 mol) bromine, is then stirred for one hour；To reaction mixture with 5%KOH solution neutralize, spend from
Sub- water washing, and use Na2SO4After drying, decompression boils off solvent；Methanol is poured into Liquid Residue, crystal is therefrom precipitated, washing is dried
Product 18.932g is obtained afterwards, and yield 60.70%, mp. 76-77 DEG C, products obtained therefrom is bromo ketal.
A kind of preparation method for applying the catalyst zeolite in the synthetic method of penta ring azoles fungicide, it is characterised in that：
(1) NaY zeolite is suspended in the NH of 3M4NO3(10 ml/g) is stirred at room temperature 24 hours in solution；
(2) it is filtered, washed zeolite, repeats exchange process in (1)；
(3) calcination 3 hours at 550 DEG C in muffle furnace；
(4) (1) (2) operation is repeated；
(5) NH will be obtained4Y sample is placed in the atmosphere that relative humidity is about 35%；It is allowed to saturation water suction about 16
Hour；
(6) by sample 550 DEG C progress hydro-thermal process 3 hours, the part dealuminzation of deamination and zeolite skeleton can be realized；It is obtained
HY zeolite, which is placed in vacuum desiccator, to be saved backup, and HY measurement knows that its Si/Al ratio is about 3, referred to as Y3.
The step（6）In, or by sample 660 DEG C progress hydro-thermal process 3 hours, its Si/Al is known in HY obtained measurement
Than being about 4, referred to as Y4.
The step（6）In, or by sample 760 DEG C progress hydro-thermal process 3 hours, its Si/Al is known in HY obtained measurement
Than being about 6, referred to as Y6.
The step（6）In, or by sample 810 DEG C progress hydro-thermal process 3 hours, its Si/Al is known in HY obtained measurement
Than being about 9, referred to as Y9.
A kind of synthetic method of the ketal using zeolite as catalyst, it is characterised in that method and step is：
(1) 19.0g (99.42%, 0.1mol) 2,4 dichloro benzene ethyl ketone is put into the 250ml three-necked flask for filling 45ml butanol
In, it is stirred for one hour after instilling 5.4ml (0.105mol) bromine at room temperature；9.31g (95%, 0.15mol) second two is added
Alcohol, and 100ml anhydrous benzene and 4gY3 zeolite is added, entire reaction solution is heated to reflux 6 hours, and reaction temperature is 88-99 DEG C, cold
But to room temperature, zeolite is filtered out, filtrate decompression boils off crystallisation by cooling after solvent；It is primary to gained crystal recrystallizing methanol, then
It is washed twice with methanol；Crystal obtains product 19.820g after drying, and zeolite catalyst must produce after Soxhlet extractor methanol extraction
Product 0.898g, products obtained therefrom add up to 20.718g, and yield 66.43%, 76.5-77.0 DEG C of mp., products obtained therefrom is bromo contracting
Ketone；
（2）Other conditions are constant, and Y3 zeolite is only changed into the experimentation that Y4, Y6 or Y9 zeolite repeat (1) respectively；
(3) 19.0g (99.42%, 0.1mol) 2,4 dichloro benzene ethyl ketone is put into the 250ml three-necked flask for filling 45ml benzene
In, it is stirred for one hour, is added 9.31g (95%, 0.15mol) after instilling 5.4ml (0.105mol) bromine at room temperature
Ethylene glycol, and add 100ml anhydrous benzene and 4g Y3 zeolite；Reaction solution is heated to reflux 4 hours, and separator separation generates
Water, reaction temperature be 88-89 DEG C；After completion of the reaction, reaction mixture is cooled to room temperature, gas chromatography analysis for sampling inspection
Survey its conversion ratio；
(4) other conditions are constant, and Y3 zeolite is only changed into the experimentation that Y4, Y6 or Y9 zeolite repeat (1)；
(5) other conditions are constant, repeat the experimentation of (3) with Y3, Y4, Y6 or Y9 zeolite respectively in toluene.
The results such as the conversion ratio (mol%) experiment (1)-(5) are included in table 6
| Y3 | Y4 | Y6 | Y9 | Fusing point (DEG C) | Reaction temperature (DEG C) | |
| Benzene | 85.75 | 98.97 | 99.23 | 99.65 | 83–84 | |
| Toluene | 94.90 | 98.47 | 98.22 | 98.34 | 114–115 | |
| Benzene+butanol * | 55.23 | 59.83 | 66.43 | 77.07 | 76–78 | 88–89 |
It * is the actual recovery (mol%) after gained bromo ketal separating-purifying
A kind of method that bromo ketal reacts penta ring azoles fungicide of synthesis with 1H-1,2,4- triazole；The specific steps are：
（1）1.15g sodium (0.05mol) is put into the 250ml three-necked flask for filling 60ml methanol, after its fully reacting, is added
Enter 3.45g (0.05 mol) 1H-1, after being stirred at room temperature 30 minutes, 75ml N, N- dimethyl formyl is added in 2,4- triazoles
Amine, methanol removed by evaporation under normal pressure, until temperature reaches 130 DEG C in bottle；
（2）12.5g (0.04 mol) 2- bromomethyl -2- (2,4 dichloro benzene base) -1,3- dioxolanes is added（Bromo ketal）With
1g KI；After reaction mixture is stirred at reflux 3 hours, it is cooled to room temperature and is poured into water；
（3）Reaction product Precipitation, filtering, and 1- [[2- (2,4- dichlorophenyl) -1,3- bis- is obtained with crystallizing from diisopropylether
Butyl oxide link -2- base] methyl] -1H-1,2,4- triazole（Penta ring azoles）7.198g, yield 59.98%, mp. 108.8-109.9 DEG C；
(4) it is different to be dissolved in two for 6g1- [[2- (2,4 dichloro benzene base) -1,3- dioxolanes -2- base] methyl] -1H-1,2,4- triazole
In propyl ether, nitric acid is added；
（5）After cooling, its nitrate is filtered out, then is crystallized from isopropanol and obtains 1- [[2- (2,4-dichlorophenyl)-twice
1,3- dioxolanes-2- base] methyl]-1H-1,2,4- triazole nitrate 3.0g, mp.172.5-173 DEG C；
(6) it is different to be dissolved in two for 6g 1- [[2- (2,4 dichloro benzene base) -1,3- dioxolanes -2- base] methyl] -1H-1,2,4- triazole
In propyl ether, sulfuric acid is added, forms sulfate；
（7）It is filtered out, then crystallize from isopropanol it is primary, after product is filtered out, then recrystallize from ethyl alcohol it is primary,
1- [[2- (2,4 dichloro benzene base) -1,3- dioxolanes -2- base] methyl] -1H-1,2,4- 4-triazole Sulfate is dried to obtain in filtering
6.4g, mp. 207–208℃。
One kind is using the chloro- 1- of 2- (2,4 dichloro benzene base) ethyl ketone and 4- amino -4H-1,2,4- triazole as base stock synthesis penta
Ring azoles method, it is characterised in that：Including
Step 1, raw materialPreparation；
Step 2, the synthesis of 1- (2,4- dichlorophenyl) -2- (1H -1,2,4- triazol-1-yls) ethyl ketone；
Step 3, the synthesis of penta ring azoles.
The specific method of step 1 is：
（1）Equipped with high-efficiency water cooling condenser 1 liter of round-bottomed flask in place 148g (2mol) Ethyl formate (52-53 DEG C of boiling point) and
150 milliliter of 95% ethyl alcohol；85% hydrazine hydrate of 120g (2mol) is added in solution, while being shaken 10 minutes；
（2）After habituation, solution is heated to reflux 18 hours, most of water and alcohol are evaporated under reduced pressure, until being remained in bottle
Lower 150 milliliters or so；Resulting syrup (thick formylhydrazine) heats 3 hours under normal pressure, during this period of time bath temperature by
150 DEG C are raised to 200 DEG C；
（3）After being as cold as 100 DEG C or so, syrup is dissolved in 50 ml, 95% ethyl alcohol, 5g active carbon is added, then filter
Liquid is diluted with 75 milliliters of ether and is placed in refrigerator cooling；
（4）Crystallized product is filtered, with 50ml 1:The washing of 2 alcohol-ether mixed solvents, filtering and drying, obtain aminotriazole(ATA)
57.125g yield 68%；
（5）Need purer product that washed crude product is recrystallized again, every gram of product 95% hot ethanol of 2ml, then plus
Enter 2.5ml ether, and cooling, purer product, mp. 81-82 DEG C can be obtained；
（6）Remaining amine is salted out in filtrate with hydrochloric acid, and the solution heating evaporation after merging, 50 ml concentrated hydrochloric acids are added,
Continue heating 2 hours；After cooling, slurry solution crystallization；
（7）It is smashed to pieces together with 50ml ethyl alcohol again, filters out 4- amino -4H-1,2,4- triazole hydrochlorides are washed with a small amount of ethyl alcohol
It washs, and dry；
（8）The yield of hydrochloride is 15.0g (the 12.4% of theoretical yield), and 147-148 DEG C of the salt fusing point, which adds alkali neutralization i.e.
Obtain 4- amino -4H-1,2,4- triazole.
The specific method of step 2 is：
（1）The synthesis of alkylation process 1- (2,4 dichloro benzene base) -2- (4- amino -4H-1,2,4- triazolyl) ethyl ketone chlorine；
The 2- of 4.41g (0.0525 mol) 4- amino -4H-1,2,4- triazole and 11.26g (99.28%, 0.05 mol)
Chloro- 1- (2,4- dichlorophenyl) ethyl ketone is placed in 250ml three-necked flask, and 100 ml isopropanols are added and stir together, is heated
Reflux 4 hours；I.e. crystallization is precipitated product at a reflux temperature, and reaction mixture is cooling, filters, and is washed with isopropanol, dries
Product 11.073g (72%) is obtained afterwards, mp. 214-215 DEG C；
（2）The formation of deammoniation process 1- (2,4 dichloro benzene base) -2- (1H-1,2,4- triazol-1-yl) ethyl ketone；
6.42g (0.021 mol) 1- (2,4 dichloro benzene base) -2- (4- amino -4H-1,2,4- triazolyl) ethyl ketone chlorine and
50ml water mixes in 250ml three-necked flask, and the hydrochloric acid of 3.60g (0.042 mol, 11.6M) is added, stirring；Work as mixing
When object is cooled to 0-5 DEG C, saturation sodium nitrite (1.52g, 0.022 mol) solution is instilled；There is gas to release；Reaction
NH is used after mixture heat to environment temperature4OH solution is neutralized to neutrality, and product, which is filtered out, to be come, and is washed with water, is dried to obtain product
5.171g, yield 96.2%, mp. 115-116 DEG C.
（3）The synthesis of single step reaction process 1- (2,4 dichloro benzene base) -2- (1H-1,2,4- triazol-1-yl) ethyl ketone；
The 2- of 4.41g (0.0525 mol) 4- amino -4H-1,2,4- triazole and 11.26g (99.28%, 0.05 mol)
Chloro- 1- (2,4- dichlorophenyl) ethyl ketone is placed in 250ml three-necked flask, and 100ml isopropanol is added and stirs together, is heated to reflux 4
Hour；After reaction mixture distillation removal isopropanol, 100ml water is added, and be cooled to 5 DEG C, is added 9.1ml (0.11mol)
Then concentrated hydrochloric acid is added dropwise to saturation sodium nitrite solution 15ml (0.055mol)；Reaction mixture is cooled to environment temperature, and
It is neutralized with solution of potassium carbonate, filtering, and product 11.35g, yield 89%, mp. 113.5-115.5 DEG C is washed with water to obtain.
The specific method of step 3 is：
（1）5.118g (0.02mol) 1- (2,4- dichlorophenyl) -2- (1H-1,2,4- triazol-1-yls) ethyl ketone, 2.48g
(95%, 0.04mol) ethylene glycol and 4.0g p-methyl benzenesulfonic acid are placed in 250ml three-necked flask；
（2）Then 14g1- amylalcohol and 130g dimethylbenzene are added, is stirred, is heated to reflux 20 hours, separates generation with water segregator
Water；
（3）Stop reaction, be cooled to room temperature, then, is neutralized with dilute potassium hydroxide solution, then be washed with deionized to neutrality,
It is dry with sodium sulphate, solvent is removed under reduced pressure, raffinate pours into the mixture of n,N-Dimethylformamide and water；
（4）Product therefrom crystallizes precipitation, is filtered, washed, dries to obtain product 3.402g, yield 56.7%, mp.107.0-109.8
℃。
It is an advantage of the invention that：First is that the p-methyl benzenesulfonic acid that ketal reaction used catalyst is not traditional, with one
The Y type zeolite of series, compared with p-methyl benzenesulfonic acid, yield is not low.Especially zeolite catalyst can repeat to recycle,
Do not pollute the environment, do not corrode equipment, it is easy to operate the advantages that, be the good substitute of Catalyzed by p-Toluenesulfonic Acid agent.Boiling
The application of stone catalyst not only has important scientific value and application value, but also with good economic efficiency and important
Environmental benefit；Second is that it is a kind of new that the regiospecific alkylation of the synthesis of penta ring azoles 1,2,4- triazole, which synthesizes penta ring azoles,
Method.
Specific embodiment
The present invention be such to implement, a kind of synthetic method of penta ring azoles intermediate, predominantly 2,4-dichloroacetophenones
Synthetic method, the bromo- 1- of 2- (2,4 dichloro benzene base) synthetic method of ethyl ketone and the synthetic method of ketal.
The synthetic method of 2,4-dichloroacetophenones, the specific steps are：
（1）In 250ml three-necked bottle, middle port installs blender, and two side ports fill dropping funel and condenser pipe respectively, in condenser pipe
Upper end fills monochlor(in)ate calcium drying tube, and even monochlor(in)ate hydrogen absorption plant；
（2）Aluminum trichloride (anhydrous) powder 20g (0.15 mol) quickly is weighed, is put into three-necked bottle, adds dichloro between 30 ml
Benzene instills 6 ml (0.06 mol) acetic anhydride under stiring, drips off within about 20 minutes；
（3）Then slightly boiled half an hour is kept in heating mantle, until without hydrogen chloride gas evolution；
（4）Three-necked bottle is dipped in cold bath, is instilled in the mixed liquor of 50ml concentrated hydrochloric acid and 50ml ice water under stiring, when in bottle
After solids is completely dissolved, oil reservoir is separated, water layer is extracted twice with 15ml m-dichlorobenzene every time；
（5）Merge oil reservoir, successively with 5% sodium hydroxide solution, each 20ml washing of water, oil reservoir anhydrous magnesium sulfate drying；
（6）It is evaporated under reduced pressure after crude product is dry, collects b22.132-135 DEG C of fraction, obtain product 54.712g, yield
55.46%, mp.33.1 DEG C.
The synthetic method of the bromo- 1- of 2- (2,4- dichlorophenyl) ethyl ketone, the specific steps are：
（1）Separatory funnel is being housed, in the drying three-neck flask of mechanical stirring and reflux condenser, is being placed by 19.0g
(99.42%, 0.1 mol) 2,4 dichloro benzene ethyl ketone is dissolved in the pure anhydrous ether of 50ml and is formed by solution；
（2）Solution is placed on cooling in ice bath, 0.2gAlCl3 one side is imported and stirs, be gradually added on one side from separatory funnel
16.0g (0.1mol) bromine, the speed of addition are about 1ml per minute；When ending close to reaction, solution becomes pink；
（3）After bromine adds, at once under reduced pressure by slight air stream to remove ether and hydrogen bromide, the bromo- 1- of 2- (2,
4- dichlorophenyl) ethyl ketone leaves end in solid fraction tan crystals, can be shaken with the mixture that 5ml water and 5ml petroleum ether form with
Remove color；
（4）Crystal is filtered with suction filtration, washs to obtain product 22.325g with methanol 20ml, yield 83.36%, mp.57-58 DEG C.
The synthetic method of ketal, the specific steps are：
(1) 13.39g (0.05mol) 2- bromo- 1- (2,4- dichlorophenyl) ethyl ketone is dissolved in 30ml butanol, adds 0.5g
P-methyl benzenesulfonic acid and 70ml benzene；Under stirring, 4.65g (0.075ml) ethylene glycol is added dropwise, is heated to reflux 6 hours, uses separator
Separate the moisture content that reaction generates；End of reaction is cooled to room temperature reaction mixture, after then being neutralized with 5% KOH solution, then
It is washed with deionized twice；Solvent is removed under reduced pressure after organic phase Na2SO4 drying in liquid separation, and raffinate crystallization, gained crystal is certainly
It recrystallizes primary in methanol, can obtain product 14.430g, yield 92.54%, mp.76-77 DEG C.Products obtained therefrom is 2- bromomethyl-
2- (2,4 dichloro benzene base) -1,3- dioxolanes（Bromo ketal）.
(2) it is placed in 19.0g (99.42%, 0.01mol) 2,4- dichloroacetophenone in the three-necked flask of 250ml, and adds
Enter 45ml butanol；At room temperature, 5.4ml (99.5%, 0.105 mol) bromine is added dropwise in one hour；Then at room temperature
It is stirred for one hour, 9.31g (95%, 0.15 mol) ethylene glycol is added, and 100ml anhydrous benzene and 1g is added to toluene sulphur
Acid, entire mixed liquor are stirred and are heated to reflux 4 hours, the water generated with separator separation；Stop reaction, reaction mixture
It is cooled to room temperature, after being neutralized with dilute KOH solution, then is washed with deionized twice, with separatory funnel liquid separation, oil mutually uses Na2SO4
Solvent is removed under reduced pressure after drying, Residual oil is added in methanol, and product crystallization is precipitated；Filtering, gained crude product are tied again in methyl alcohol again
It is brilliant primary, and washed once with methanol, it filters, dry, obtain product 25.953g, yield 83.22%, 77.0-77.5 DEG C of mp.,
Products obtained therefrom is bromo ketal；
(3) solvent benzol+butanol is changed to the experiment that benzene, toluene or dimethylbenzene repeat (2) by constant of the amount of other reagents；
（4）19.0g (99.42%, 0.10 mol) 2,4 dichloro benzene ethyl ketone is changed into 22.51g (99.28%, 0.10 mol)
Solvent benzol+butanol is changed into the experiment that benzene,toluene,xylene repeats (2) by the chloro- 1- of 2- (2,4- dichlorophenyl) ethyl ketone；Gained produces
Product are 2- chloromethyl -2- (2,4 dichloro benzene base) -1,3- dioxolanes (chloro ketal)；
The experimental result of (2), (3), (4) is listed as follows：
Table 1：2,4 dichloro benzene ethyl ketone (0.10mol) and 5.4ml bromine (0.105mol), ethylene glycol (0.15mol) are with 1g to first
Benzene sulfonic acid is the reaction yield (mol%) of catalyst
Note：Yield is all the actual recovery after products therefrom separating-purifying.
Table 2：The chloro- 1- of 2- (2,4 dichloro benzene base) ethyl ketone (0.10 mol) and ethylene glycol (0.15 mol) are with 1g to toluene
Sulfonic acid is the reaction yield (mol%) of catalyst
Note：Yield is all the actual recovery after products therefrom separating-purifying.
(5) 19.0g (99.42%, 0.10 mol) 2,4-dichloroacetophenones are dissolved in 45ml butanol and 100 ml benzene
Solution in, add 1g p-methyl benzenesulfonic acid and 9.31g (95%, 0.15 mol) ethylene glycol, stir, be heated to reflux 6 hours,
Reflux temperature is 86-87 DEG C；Separator separates the moisture content of generation, is cooled to room temperature after completion of the reaction, is added dropwise in one hour
5.4 ml (99.5%, 0.105 mol) bromine, is then stirred for one hour；Reaction mixture 5%KOH solution is neutralized, is used
Deionized water washing, and use Na2SO4 After drying, decompression boils off solvent；Methanol is poured into Liquid Residue, crystal is therefrom precipitated, wash
It washs and obtains product 18.932g after drying, yield 60.70%, mp. 76-77 DEG C, products obtained therefrom is bromo ketal.
A kind of preparation method for applying the catalyst zeolite in the synthetic method of penta ring azoles fungicide, it is characterised in that：
(1) NaY zeolite is suspended in the NH of 3M4NO3(10 ml/g) is stirred at room temperature 24 hours in solution；
(2) it is filtered, washed zeolite, repeats exchange process in (1)；
(3) calcination 3 hours at 550 DEG C in muffle furnace；
(4) (1) (2) operation is repeated；
(5) NH will be obtained4Y sample is placed in the atmosphere that relative humidity is about 35%；It is allowed to saturation water suction about 16
Hour；
(6) by sample 550 DEG C progress hydro-thermal process 3 hours, the part dealuminzation of deamination and zeolite skeleton can be realized；It is obtained
HY zeolite, which is placed in vacuum desiccator, to be saved backup, and HY measurement knows that its Si/Al ratio is about 3, referred to as Y3.
The step（6）In, or by sample 660 DEG C progress hydro-thermal process 3 hours, its Si/Al is known in HY obtained measurement
Than being about 4, referred to as Y4.
The step（6）In, or by sample 760 DEG C progress hydro-thermal process 3 hours, its Si/Al is known in HY obtained measurement
Than being about 6, referred to as Y6.
The step（6）In, or by sample 810 DEG C progress hydro-thermal process 3 hours, its Si/Al is known in HY obtained measurement
Than being about 9, referred to as Y9.
The characterization of HY
(1) the obtained zeolite of confirmation of being confirmed as of crystal structure is Y type zeolite, i.e., its skeleton structure is not during processing
There is change, has done X ray powder diffraction (XRD) by taking Y9 as an example to verify：
The XRD data of 3 raw material NaY zeolite of table
The XRD data of 4 brand-new Y9 zeolite of table
By the comparison of above two table it is found that Y9 and the diffraction pattern of NaY are substantially similar, only the 2 θ values of Y9 slightly increase (or brilliant
Interplanar distance slightly reduces), peak intensity is declined slightly, this illustrates the skeleton structure of zeolite, and there is no great changes.
(2) estimation of skeleton Si/Al ratio, hydro-thermal process cause interplanar distance reduction to be because zeolite skeleton part is de-
The reason of aluminium-plus silicon.
Since Si-O key (≈ 1.6) is stronger and short than Al-O key (≈ 1.7), therefore the crystalline substance of HY zeolite that hydro-thermal process obtains
Born of the same parents' size and its spacing reduce.In fact, it has been discovered that the unit cell dimension a () of Y type zeolite and its skeleton Si/Al are than it
Between monotone decreasing empirical function：
The skeleton Si/Al ratio of various Y zeolites herein is to calculate to obtain a by XRD data (interplanar distance D).
Then it is obtained again with 1. estimating.
Again by theoretical formula：NAlZeolite unit cell composition can be obtained in=192/ (1+Si/Al) and Nsi=192-NAl.
(3) property of HY zeolite；We used the acid zeolites of four kinds of different structures：Y3, Y4, Y6 and Y9,
Its physical property is listed in table 5.
The property of 5 zeolite catalyst of table
The catalytic action of zeolite is its catalytic center, and what acid zeolite played catalytic action is its acid centre.Its just from
Son (mainly H+) be filled in the zeolite skeleton being made of oxygen-octahedron and aluminum-oxygen tetrahedron, these H+It is regarded as
The acid site Bronsted (Bronsted acid sites, BAS) of zeolite.In addition, there is also de- in the duct of zeolite
The acid site Lewis (Lewis acid sites, LAS) of the non-framework aluminum formed after aluminium, zeolite is considered non-by these
What framework aluminum generated.LAS and BAS are usually simultaneous in acid zeolite.
The Bronsted acidity order for these four acid zeolites that we use is：
Y3≈Y4>Y6>Y9
Its Lewis acidity is then just opposite：
Y3<Y4<Y6<Y9
And strongest acid site is LAS rather than BAS in Y type zeolite.
A kind of synthetic method of the ketal using zeolite as catalyst, it is characterised in that method and step is：
(1) 19.0g (99.42%, 0.1mol) 2,4 dichloro benzene ethyl ketone is put into the 250ml three-necked flask for filling 45ml butanol
In, it is stirred for one hour after instilling 5.4ml (0.105mol) bromine at room temperature；9.31g (95%, 0.15mol) second two is added
Alcohol, and 100ml anhydrous benzene and 4gY3 zeolite is added, entire reaction solution is heated to reflux 6 hours, and reaction temperature is 88-99 DEG C, cold
But to room temperature, zeolite is filtered out, filtrate decompression boils off crystallisation by cooling after solvent；It is primary to gained crystal recrystallizing methanol, then
It is washed twice with methanol；Crystal obtains product 19.820g after drying, and zeolite catalyst must produce after Soxhlet extractor methanol extraction
Product 0.898g, products obtained therefrom add up to 20.718g, and yield 66.43%, 76.5-77.0 DEG C of mp., products obtained therefrom is bromo contracting
Ketone；
（2）Other conditions are constant, and Y3 zeolite is only changed into the experimentation that Y4, Y6 or Y9 zeolite repeat (1) respectively；
(3) 19.0g (99.42%, 0.1mol) 2,4 dichloro benzene ethyl ketone is put into the 250ml three-necked flask for filling 45ml benzene
In, it is stirred for one hour, is added 9.31g (95%, 0.15mol) after instilling 5.4ml (0.105mol) bromine at room temperature
Ethylene glycol, and add 100ml anhydrous benzene and 4g Y3 zeolite；Reaction solution is heated to reflux 4 hours, and separator separation generates
Water, reaction temperature be 88-89 DEG C；After completion of the reaction, reaction mixture is cooled to room temperature, gas chromatography analysis for sampling inspection
Survey its conversion ratio；
(4) other conditions are constant, and Y3 zeolite is only changed into the experimentation that Y4, Y6 or Y9 zeolite repeat (1)；
(5) other conditions are constant, repeat the experimentation of (3) with Y3, Y4, Y6 or Y9 zeolite respectively in toluene.
The results such as the conversion ratio (mol%) experiment (1)-(5) are included in table 6
It * is the actual recovery (mol%) after gained bromo ketal separating-purifying
A kind of method that bromo ketal reacts penta ring azoles fungicide of synthesis with 1H-1,2,4- triazole；The specific steps are：
（1）1.15g sodium (0.05mol) is put into the 250ml three-necked flask for filling 60ml methanol, after its fully reacting, is added
Enter 3.45g (0.05 mol) 1H-1, after being stirred at room temperature 30 minutes, 75ml N, N- dimethyl formyl is added in 2,4- triazoles
Amine, methanol removed by evaporation under normal pressure, until temperature reaches 130 DEG C in bottle；
（2）12.5g (0.04 mol) 2- bromomethyl -2- (2,4 dichloro benzene base) -1,3- dioxolanes is added（Bromo ketal）With
1g KI；After reaction mixture is stirred at reflux 3 hours, it is cooled to room temperature and is poured into water；
（3）Reaction product Precipitation, filtering, and 1- [[2- (2,4- dichlorophenyl) -1,3- bis- is obtained with crystallizing from diisopropylether
Butyl oxide link -2- base] methyl] -1H-1,2,4- triazole（Penta ring azoles）7.198g, yield 59.98%, mp. 108.8-109.9 DEG C；
(4) it is different to be dissolved in two for 6g1- [[2- (2,4 dichloro benzene base) -1,3- dioxolanes -2- base] methyl] -1H-1,2,4- triazole
In propyl ether, nitric acid is added；
（5）After cooling, its nitrate is filtered out, then is crystallized from isopropanol and obtains 1- [[2- (2,4-dichlorophenyl)-twice
1,3- dioxolanes-2- base] methyl]-1H-1,2,4- triazole nitrate 3.0g, mp.172.5-173.0 DEG C；
(6) it is different to be dissolved in two for 6g 1- [[2- (2,4 dichloro benzene base) -1,3- dioxolanes -2- base] methyl] -1H-1,2,4- triazole
In propyl ether, sulfuric acid is added, forms sulfate；
（7）It is filtered out, then crystallize from isopropanol it is primary, after product is filtered out, then recrystallize from ethyl alcohol it is primary,
1- [[2- (2,4 dichloro benzene base) -1,3- dioxolanes -2- base] methyl] -1H-1,2,4- 4-triazole Sulfate is dried to obtain in filtering
6.4g, mp. 207–208℃。
One kind is using the chloro- 1- of 2- (2,4 dichloro benzene base) ethyl ketone and 4- amino -4H-1,2,4- triazole as base stock synthesis penta
Ring azoles method, it is characterised in that：Including
Step 1, raw materialPreparation；
Step 2, the synthesis of 1- (2,4- dichlorophenyl) -2- (1H -1,2,4- triazol-1-yls) ethyl ketone；
Step 3, the synthesis of penta ring azoles.
The specific method of step 1 is：
（1）Equipped with high-efficiency water cooling condenser 1 liter of round-bottomed flask in place 148g (2mol) Ethyl formate (52-53 DEG C of boiling point) and
150 milliliter of 95% ethyl alcohol；85% hydrazine hydrate of 120g (2mol) is added in solution, while being shaken 10 minutes；
（2）After habituation, solution is heated to reflux 18 hours, most of water and alcohol are evaporated under reduced pressure, until being remained in bottle
Lower 150 milliliters or so；Resulting syrup (thick formylhydrazine) heats 3 hours under normal pressure, during this period of time bath temperature by
150 DEG C are raised to 200 DEG C；
（3）After being as cold as 100 DEG C or so, syrup is dissolved in 50 ml, 95% ethyl alcohol, 5g active carbon is added, then filter
Liquid is diluted with 75 milliliters of ether and is placed in refrigerator cooling；
（4）Crystallized product is filtered, with 50ml 1:The washing of 2 alcohol-ether mixed solvents filters and dry, obtains aminotriazole(ATA)
57.125g yield 68%；
（5）Need purer product that washed crude product is recrystallized again, every gram of product 95% hot ethanol of 2ml, then plus
Enter 2.5ml ether, and cooling, purer product, mp. 81-82 DEG C can be obtained；
（6）Remaining amine is salted out in filtrate with hydrochloric acid, and the solution heating evaporation after merging, 50 ml concentrated hydrochloric acids are added,
Continue heating 2 hours；After cooling, slurry solution crystallization；
（7）It is smashed to pieces together with 50ml ethyl alcohol again, filters out 4- amino -4H-1,2,4- triazole hydrochlorides are washed with a small amount of ethyl alcohol
It washs, and dry；
（8）The yield of hydrochloride is 15.0g (the 12.4% of theoretical yield), and 147-148 DEG C of the salt fusing point, which adds alkali neutralization i.e.
Obtain 4- amino -4H-1,2,4- triazole.
The specific method of step 2 is：
（1）The synthesis of alkylation process 1- (2,4 dichloro benzene base) -2- (4- amino -4H-1,2,4- triazolyl) ethyl ketone chlorine；
The 2- of 4.41g (0.0525 mol) 4- amino -4H-1,2,4- triazole and 11.26g (99.28%, 0.05 mol)
Chloro- 1- (2,4- dichlorophenyl) ethyl ketone is placed in 250ml three-necked flask, and 100 ml isopropanols are added and stir together, is heated
Reflux 4 hours；I.e. crystallization is precipitated product at a reflux temperature, and reaction mixture is cooling, filters, and is washed with isopropanol, dries
Product 11.073g (72%) is obtained afterwards, mp. 214-215 DEG C；
（2）The formation of deammoniation process 1- (2,4 dichloro benzene base) -2- (1H-1,2,4- triazol-1-yl) ethyl ketone；
6.42g (0.021 mol) 1- (2,4 dichloro benzene base) -2- (4- amino -4H-1,2,4- triazolyl) ethyl ketone chlorine and
50ml water mixes in 250ml three-necked flask, and the hydrochloric acid of 3.60g (0.042 mol, 11.6M) is added, stirring；Work as mixing
When object is cooled to 0-5 DEG C, saturation sodium nitrite (1.52 g, 0.022 mol) solution is instilled；There is gas to release；Anti-
It is neutralized with NH4OH solution to neutrality after answering mixture heat to environment temperature, product, which is filtered out, to be come, and is washed with water, and dries to produce
5.171 g of product, yield 96.2%, mp. 115-116 DEG C.
（3）The synthesis of single step reaction process 1- (2,4 dichloro benzene base) -2- (1H-1,2,4- triazol-1-yl) ethyl ketone；
The 2- of 4.41g (0.0525 mol) 4- amino -4H-1,2,4- triazole and 11.26g (99.28%, 0.05 mol)
Chloro- 1- (2,4- dichlorophenyl) ethyl ketone is placed in 250ml three-necked flask, and 100ml isopropanol is added and stirs together, is heated to reflux 4
Hour；After reaction mixture distillation removal isopropanol, 100ml water is added, and be cooled to 5 DEG C, is added 9.1ml (0.11mol)
Then concentrated hydrochloric acid is added dropwise to saturation sodium nitrite solution 15ml (0.055mol)；Reaction mixture is cooled to environment temperature, and
It is neutralized with solution of potassium carbonate, filtering, and product 11.35g, yield 89%, mp. 113.5-115.5 DEG C is washed with water to obtain.
The specific method of step 3 is：
（1）5.118g (0.02mol) 1- (2,4- dichlorophenyl) -2- (1H-1,2,4- triazol-1-yls) ethyl ketone, 2.48g
(95%, 0.04mol) ethylene glycol and 4.0g p-methyl benzenesulfonic acid are placed in 250ml three-necked flask；
（2）Then 14g1- amylalcohol and 130g dimethylbenzene are added, is stirred, is heated to reflux 20 hours, separates generation with water segregator
Water；
（3）Stop reaction, be cooled to room temperature, then, is neutralized with dilute potassium hydroxide solution, then be washed with deionized to neutrality,
It is dry with sodium sulphate, solvent is removed under reduced pressure, raffinate pours into the mixture of n,N-Dimethylformamide and water；
（4）Product therefrom crystallizes precipitation, is filtered, washed, dries to obtain product 3.402g, yield 56.7%, mp.107.0-109.8
℃。
Claims (3)
1. a kind of synthetic method of penta ring azoles intermediate, the bromo- 1- (2,4- of the synthetic method of predominantly 2,4- dichloroacetophenone, 2-
Dichlorophenyl) synthetic method of ethyl ketone and the synthetic method of ketal.
2. a kind of synthetic method of penta ring azoles intermediate according to claim 1, it is characterised in that：2,4- dichloroacetophenones
Synthetic method, the specific steps are：
（1）In 250ml three-necked bottle, middle port installs blender, and two side ports fill dropping funel and condenser pipe respectively, in condenser pipe
Upper end fills monochlor(in)ate calcium drying tube, and even monochlor(in)ate hydrogen absorption plant；
（2）Aluminum trichloride (anhydrous) powder 20g (0.15 mol) quickly is weighed, is put into three-necked bottle, adds dichloro between 30 ml
Benzene instills 6 ml (0.06 mol) acetic anhydride under stiring, drips off within about 20 minutes；
（3）Then slightly boiled half an hour is kept in heating mantle, until without hydrogen chloride gas evolution；
（4）Three-necked bottle is dipped in cold bath, is instilled in the mixed liquor of 50ml concentrated hydrochloric acid and 50ml ice water under stiring, when in bottle
After solids is completely dissolved, oil reservoir is separated, water layer is extracted twice with 15ml m-dichlorobenzene every time；
（5）Merge oil reservoir, successively with 5% sodium hydroxide solution, each 20ml washing of water, oil reservoir anhydrous magnesium sulfate drying；
（6）It is evaporated under reduced pressure after crude product is dry, collects b22.132-135 DEG C of fraction, obtain product 54.712g, yield
55.46%, mp.33.1 DEG C；
A kind of synthetic method of penta ring azoles intermediate according to claim 1, it is characterised in that：2- bromo- 1- (2,4- dichloro
Phenyl) ethyl ketone synthetic method, the specific steps are：
（1）Separatory funnel is being housed, in the drying three-neck flask of mechanical stirring and reflux condenser, is being placed by 19.0g
(99.42%, 0.1 mol) 2,4 dichloro benzene ethyl ketone is dissolved in the pure anhydrous ether of 50ml and is formed by solution；
（2）Solution is placed on cooling in ice bath, 0.2gAlCl3 one side is imported and stirs, be gradually added on one side from separatory funnel
16.0g (0.1mol) bromine, the speed of addition are about 1ml per minute；When ending close to reaction, solution becomes pink；
（3）After bromine adds, at once under reduced pressure by slight air stream to remove ether and hydrogen bromide, the bromo- 1- of 2- (2,
4- dichlorophenyl) ethyl ketone leaves end in solid fraction tan crystals, can be shaken with the mixture that 5ml water and 5ml petroleum ether form with
Remove color；
（4）Crystal is filtered with suction filtration, washs to obtain product 22.325g with methanol 20ml, yield 83.36%, mp.57-58 DEG C.
3. a kind of synthetic method of penta ring azoles intermediate according to claim 1, it is characterised in that：The synthesis side of ketal
Method, the specific steps are：
(1) 13.39g (0.05mol) 2- bromo- 1- (2,4- dichlorophenyl) ethyl ketone is dissolved in 30ml butanol, adds 0.5g
P-methyl benzenesulfonic acid and 70ml benzene；Under stirring, 4.65g (0.075ml) ethylene glycol is added dropwise, is heated to reflux 6 hours, uses separator
Separate the moisture content that reaction generates；End of reaction is cooled to room temperature reaction mixture, after then being neutralized with 5% KOH solution, then
It is washed with deionized twice；Liquid separation, organic phase Na2SO4It is removed under reduced pressure solvent after drying, raffinate crystallization, gained crystal is from first
It is recrystallized once in alcohol, product 14.430g can be obtained, yield 92.54%, mp.76-77 DEG C, products obtained therefrom is 2- bromomethyl-2-
(2,4 dichloro benzene base) -1,3- dioxolanes（Bromo ketal）；
(2) it is placed in 19.0g (99.42%, 0.01mol) 2,4- dichloroacetophenone in the three-necked flask of 250ml, and is added
45ml butanol；At room temperature, 5.4ml (99.5%, 0.105 mol) bromine is added dropwise in one hour；Then at room temperature again
Stirring one hour is added 9.31g (95%, 0.15 mol) ethylene glycol, and 100ml anhydrous benzene and 1g is added to toluene sulphur
Acid, entire mixed liquor are stirred and are heated to reflux 4 hours, the water generated with separator separation；Stop reaction, reaction mixture
It is cooled to room temperature, after being neutralized with dilute KOH solution, then is washed with deionized twice, with separatory funnel liquid separation, oil mutually uses Na2SO4
Solvent is removed under reduced pressure after drying, Residual oil is added in methanol, and product crystallization is precipitated；Filtering, gained crude product are tied again in methyl alcohol again
It is brilliant primary, and washed once with methanol, it filters, dry, obtain product 25.953g, yield 83.22%, 77.0-77.5 DEG C of mp.,
Products obtained therefrom is bromo ketal；
(3) solvent benzol+butanol is changed to the experiment that benzene, toluene or dimethylbenzene repeat (2) by constant of the amount of other reagents；
（4）19.0g (99.42%, 0.10 mol) 2,4 dichloro benzene ethyl ketone is changed into 22.51g (99.28%, 0.10 mol)
Solvent benzol+butanol is changed into the experiment that benzene,toluene,xylene repeats (2) by the chloro- 1- of 2- (2,4- dichlorophenyl) ethyl ketone；To gained
Product is 2- chloromethyl -2- (2,4 dichloro benzene base) -1,3- dioxolanes (chloro ketal)；
(5) 19.0g (99.42%, 0.10 mol) 2,4-dichloroacetophenones are dissolved in 45 ml butanol and 100 ml benzene
In solution, 1g p-methyl benzenesulfonic acid and 9.31g (95%, 0.15 mol) ethylene glycol are added, stirs, is heated to reflux 6 hours, is returned
Flowing temperature is 86-87 DEG C；Separator separates the moisture content of generation, is cooled to room temperature after completion of the reaction, is added dropwise 5.4 in one hour
Ml (99.5%, 0.105 mol) bromine, is then stirred for one hour；To reaction mixture with 5%KOH solution neutralize, spend from
Sub- water washing, and use Na2SO4After drying, decompression boils off solvent；Methanol is poured into Liquid Residue, crystal is therefrom precipitated, washing is dried
Product 18.932g is obtained afterwards, and yield 60.70%, mp. 76-77 DEG C, products obtained therefrom is bromo ketal.
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| CN109251137A (en) * | 2018-09-14 | 2019-01-22 | 新昌县泰如科技有限公司 | The synthetic method of one kind 2,4- dichloroacetophenone |
| CN109721480A (en) * | 2018-11-14 | 2019-05-07 | 新昌县泰如科技有限公司 | The synthetic method of one kind 2,4- dichloroacetophenone |
| CN115611870A (en) * | 2022-12-05 | 2023-01-17 | 南京桦冠生物技术有限公司 | Preparation method of isavuconazole intermediate V |
| CN116041309A (en) * | 2023-01-17 | 2023-05-02 | 浙江宇龙生物科技股份有限公司 | Continuous extraction synthesis method of substituted ketal |
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| CN115611870A (en) * | 2022-12-05 | 2023-01-17 | 南京桦冠生物技术有限公司 | Preparation method of isavuconazole intermediate V |
| CN116041309A (en) * | 2023-01-17 | 2023-05-02 | 浙江宇龙生物科技股份有限公司 | Continuous extraction synthesis method of substituted ketal |
| CN116041309B (en) * | 2023-01-17 | 2023-11-14 | 浙江宇龙生物科技股份有限公司 | Continuous extraction synthesis method of substituted ketal |
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