CN109369549A - A kind of preparation method of prothioconazoles - Google Patents
A kind of preparation method of prothioconazoles Download PDFInfo
- Publication number
- CN109369549A CN109369549A CN201811639143.1A CN201811639143A CN109369549A CN 109369549 A CN109369549 A CN 109369549A CN 201811639143 A CN201811639143 A CN 201811639143A CN 109369549 A CN109369549 A CN 109369549A
- Authority
- CN
- China
- Prior art keywords
- formula
- compound shown
- reaction
- compound
- added
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D249/12—Oxygen or sulfur atoms
Abstract
The present invention provides a kind of preparation methods of prothioconazoles, comprising the following steps: A) compound shown in formula I reacts through chlorization cyclization, obtain compound shown in formula II；B) compound shown in formula II and compound shown in formula III, carry out Claisen condensation reaction, obtain compound shown in formula IV；C) compound shown in formula IV carries out epoxidation reaction, obtains compound shown in formula V；D) compound shown in formula V is reacted with hydrazine hydrate, obtains compound shown in formula VI；E) compound shown in formula VI is reacted with formaldehyde, rhodanate, obtains compound shown in formula VII；F) compound shown in formula VII is aoxidized, and obtains prothioconazoles shown in formula VIII.For total recovery up to 56%, raw material are cheap and easily-available, and whole process processing is convenient, yield with higher, have certain meaning to industrialized production.
Description
Technical field
The present invention relates to chemosynthesis technical field more particularly to a kind of preparation methods of prothioconazoles.
Background technique
Prothioconazoles chemical name is (RS) -2- [2- (1- chlorine cyclopropyl) -3- (2- chlorphenyl) -2- hydroxypropyl] -2,
4- dihydro -1,2,4- triazole -3- thioketones, the entitled Prothioconazole of English, chemical structural formula are as follows:
Prothioconazoles are wide spectrum triazole thioketone fungicide, are a kind of wide-spectrum bactericides of Beyer Co., Ltd's production and exploitation,
It possesses unique triazolinthione structure, and the mechanism of action is the precursor-lanosterol or 2 for inhibiting sterol in fungi, 4- methylene
Demethylation effect on base lanostenol 14, i.e. demethylation inhibitors (DMIS).In prothioconazoles not only have
Activity, the also activity with excellent protection, treatment, elimination are inhaled, and effect of increasing production is obvious.Compared with triazole bactericidal agent,
Prothioconazoles have broader spectrum of bactericidal activity.Prothioconazoles toxicity is low, no teratogenesis, mutagenicity, to embryo nontoxicity, to people
And Environmental security.It is mainly used for preventing and treating the numerous diseases of crops such as cereal, wheat, beans, almost has very to all diseases of wheat
Good preventive effect, such as powdery mildew, banded sclerotial blight, wilt disease, leaf spot, rust, sclerotiniose, net blotch, moire disease.
It is domestic at present less to the patent document of the study on the synthesis of prothioconazoles raw medicine.Beyer Co., Ltd's patent report it is main
There are two lines, and all inevitably used grignard reagent and grignard reaction in its patent route, the reaction is in industry
There is higher security risks in production, and yield is lower.
At patent document (WO9919307A1), a kind of method for preparing herbicide prothioconazoles is disclosed, this method is with α-
Acetyl group-gamma-butyrolacton is starting material, through superchlorination open loop, cyclisation, chlorination, formatting, is then coupled with triazole, then
Prothioconazoles are obtained by vulcanization reaction with sulphur, reaction formula is as follows:
This method needs to use more dangerous grignard reagent and grignard reaction, and yield is lower and generates more coupling pair
Product；In addition the toxic higher desulfurization prothioconazoles by-product of meeting generates in the route, generates shadow to the quality of later product
It rings.
At patent document (WO9918087A1), a kind of method for preparing herbicide prothioconazoles is disclosed, this method is with α-
Acetyl group-gamma-butyrolacton be starting material, through superchlorination open loop, cyclisation, chlorination, formatting, then with hydrazine hydrate substitution reaction,
Ring closure reaction, oxidation reaction finally obtain prothioconazoles, and reaction formula is as follows:
This method not can avoid the use of grignard reagent still, and there are biggish security risk, yields for industrial production
Lower, higher cost.
Summary of the invention
In view of this, the technical problem to be solved in the present invention is that provide a kind of preparation method of prothioconazoles, have compared with
High yield, and without using grignard reagent.
In order to solve the above technical problems, the present invention provides a kind of preparation methods of prothioconazoles, comprising the following steps:
A) compound shown in formula I is reacted through chlorization cyclization, obtains compound shown in formula II；
B) compound shown in formula II and compound shown in formula III, carry out Claisen condensation reaction, obtain IV shownization of formula
Close object；
C) compound shown in formula IV carries out epoxidation reaction, obtains compound shown in formula V；
D) compound shown in formula V is reacted with hydrazine hydrate, obtains compound shown in formula VI；
E) compound shown in formula VI is reacted with formaldehyde, rhodanate, obtains compound shown in formula VII；
F) compound shown in formula VII is aoxidized, and obtains prothioconazoles shown in formula VIII；
The reaction route of above-mentioned preparation method is as follows:
Preferably, above-mentioned steps A) specifically:
A1) compound shown in formula I is mixed in organic solvent with chlorination reagent, carries out chlorination；
A2 methanol, sulfonic acid chloride) is added, is reacted, after the reaction was completed, removes organic solvent, phase transfer is then added and urges
Agent and inorganic alkaline compound, reaction obtain compound shown in formula II.
It is currently preferred, the temperature that compound shown in the formula I and chlorination reagent mix in organic solvent preferably-
10~150 DEG C.
The organic solvent be preferably acetonitrile, tetrahydrofuran, dioxane, dichloroethanes, carbon trichloride, carbon tetrachloride,
Any one or a few in toluene, methanol and ethyl alcohol.
The molar ratio of compound shown in the formula I and chlorination reagent is preferably 1:(2~3).
The volume ratio of compound shown in the formula I and organic solvent is preferably 1:(2~10).
The molar ratio of compound shown in the formula I and methanol is preferably 1:(1.2~2.5).
The molar ratio of compound shown in the formula I and sulfonic acid chloride is preferably 1:(1.1~3.0).
The molar ratio of compound shown in the formula I and inorganic alkaline compound is preferably 1:(1~3).
The molar ratio of compound shown in the formula I and phase transfer catalyst is preferably 1.0:(0.001~0.02).
The phase transfer catalyst is preferably tetrabutylammonium bromide, in tetrabutylammonium chloride and benzyl triethyl ammonium bromide
Any one or more.
The inorganic alkaline compound is preferably sodium hydroxide, potassium hydroxide, sodium carbonate, in potassium carbonate and lithium hydroxide
Any one or more.
It is currently preferred, the step a1) after reaction, post-processing step includes:
Water washing is added in system, organic phase is separated after standing, adjusts pH to neutrality, after dry, remove organic solvent, obtain
To chlorizate.
The present invention is to the method for removing organic solvent and is not particularly limited, and can be well known to those skilled in the art
Method such as rotates.
The chlorination reagent is preferably chlorine or liquid chlorine.
When the chlorination reagent is selected from chlorine, above-mentioned steps a) is preferred specifically:
Compound shown in formula I is dissolved in organic solvent, at reflux, is passed through chlorine, is then cooled at room temperature
Stirring, the extra chlorine of vacuum removal.
It is described at reflux, the time for being passed through chlorine is preferably 1~15h.
The time stirred at room temperature is preferably 0.5~8h.
Currently preferred, the reaction system is provided with the device for absorbing chlorine tail gas, such as lye absorption plant.
Then methanol is added and sulfonic acid chloride is reacted.
Currently preferred, the adding manner of the sulfonic acid chloride is to be added dropwise.Preferably, during dropwise addition, using inertia
Gas is protected.The temperature that sulfonic acid chloride is added dropwise is preferably 0~5 DEG C.
After dropwise addition, reacted.The temperature of the reaction is preferably 50~60 DEG C, and the reaction time is preferably 6~8h.
After reaction, currently preferred, add water quenching reaction.After organic solvent extraction, pH is adjusted to neutrality, is done
After dry, removing organic solvent, product 2,4- dichloro-butyric acid methyl esters are obtained.
Then phase transfer catalyst and inorganic alkaline compound is added, reaction obtains compound shown in formula II.
The temperature of the reaction is preferably 80~90 DEG C, and the reaction time is preferably 1~5h.
In some embodiments of the invention, the step A) specifically:
At -10 DEG C~150 DEG C, chemical compounds I is uniformly mixed with organic solvent, 100 DEG C are heated to, what is be heated to reflux
It is slowly introducing chlorine under state, is then cooled under room temperature and stirs, after methanol is added, sulphonyl is added dropwise in the extra chlorine of vacuum removal
Chlorine continues back flow reaction, after fully reacting, sloughs organic solvent, phase transfer catalyst and inorganic base is added, it is anti-to be further continued for reflux
It answers, after fully reacting, cooling washing after sloughing organic solvent, obtains compound ii.
It is currently preferred, the step B) specifically:
B1) compound shown in formula II is uniformly mixed in organic solvent with compound shown in formula III, highly basic, in reflux shape
It is reacted under state；
B2) end of reaction is added dropwise diluted acid quenching reaction, obtains compound shown in formula IV.
The temperature preferably -10 that compound shown in the formula II mixes in organic solvent with compound shown in formula III~
150℃。
The time reacted at reflux is preferably 1~15h.
The organic solvent be preferably acetonitrile, tetrahydrofuran, dioxane, dichloroethanes, carbon trichloride, carbon tetrachloride,
Any one or more in toluene, methanol and ethyl alcohol.
The highly basic is preferably sodium methoxide, sodium tert-butoxide, sodium ethoxide, sodium hydride, potassium methoxide, in potassium ethoxide and potassium tert-butoxide
Any one or more.
The diluted acid is preferably hydrochloric acid, sulfuric acid or acetic acid.
The concentration of the diluted acid is preferably 1%~15%, more preferably 10% or 15%.The concentration refers to mass percent
Concentration.
The molar ratio of compound shown in compound shown in the formula II and formula III is preferably 1.0~4.0:1.0~4.0.
The volume ratio of compound shown in the formula II and organic solvent is preferably 1:(2~10).
The molar ratio of compound shown in the formula II and highly basic is preferably 1:(1.2~2.5).
In some embodiments of the invention, the step B) specifically:
At -10 DEG C~150 DEG C, compound ii and compound III are uniformly mixed with organic solvent, highly basic heating is added
To reflux, end of reaction, cooling is added dropwise 10% diluted acid and is quenched, and separates organic phase, sloughs organic solvent and obtain compounds Ⅳ.
It is currently preferred, the step C) specifically:
Compound shown in formula IV is reacted in organic solvent with dimethyl sulphide and dimethyl suflfate, is obtained shown in formula V
Compound.
The temperature of the reaction is preferably -10~150 DEG C, and the time of the reaction is preferably 1~15h.
The organic solvent be preferably acetonitrile, tetrahydrofuran, dioxane, dichloroethanes, carbon trichloride, carbon tetrachloride,
Any one or more in toluene, methanol and ethyl alcohol.
The molar ratio of compound, dimethyl sulphide and dimethyl suflfate shown in the formula IV is preferably 1:(1~5): (1~4).
The volume ratio of compound shown in the formula IV and organic solvent is preferably 1:(2~10).
After reaction, inorganic base aqueous solution quenching reaction is added dropwise, obtains compound shown in formula V.
The inorganic base is preferably sodium methoxide, sodium tert-butoxide, sodium ethoxide, any one in sodium hydroxide and potassium hydroxide
Or it is a variety of.
In some embodiments of the invention, the step C) specifically:
At -10 DEG C~160 DEG C, compounds Ⅳ is uniformly mixed with organic solvent, dimethyl sulphide and dimethyl sulfate is added
Ester, end of reaction, cooling are added dropwise certain density inorganic base aqueous solution and are quenched, separate organic phase, slough organic solvent
Close object V.
Compound shown in formula V is reacted with hydrazine hydrate, obtains compound shown in formula VI.
In the reaction process, it is preferably added to alkali compounds.
The alkali compounds is preferably potassium carbonate, sodium hydroxide or sodium carbonate.
The solvent of the reaction is preferably methanol, ethyl alcohol, acetonitrile or tetrahydrofuran.
After reaction, reaction dissolvent is removed, extracts, after dry, precipitation, obtains compound shown in product formula VI.
Compound shown in formula VI is reacted with formaldehyde, rhodanate, obtains compound shown in formula VII.
The rhodanate is preferably sodium sulfocyanate or potassium rhodanide.
The solvent of the reaction is preferably acetonitrile, acetone.
Compound shown in formula VII is aoxidized, and prothioconazoles shown in formula VIII can be obtained.
The oxidant that the oxidation uses is preferably ferric trichloride.
The present invention is using butyrolactone compound shown in formula I as starting material, by the reactions such as chlorination alcoholysis and cyclization synthesis
Mesosome II, using with compound III be condensed synthesis compounds Ⅳ, then by epoxidation reaction synthesis compound V, then with
It is hydrated hydrazine reaction and synthesizes compound VI, compound VII is then synthesized with rhodanate, then obtains rosickyite bacterium through peroxidization
Azoles.For total recovery up to 56%, raw material are cheap and easily-available, and whole process processing is convenient, yield with higher, to industrial metaplasia
Producing has certain meaning.
Specific embodiment
In order to further illustrate the present invention, below with reference to embodiment to the preparation methods of prothioconazoles provided by the invention into
Row detailed description.
Embodiment 1
(1) synthesis of compound ii
It weighs gamma-butyrolacton 120g (1.36mol), puts into reaction flask, be warming up to 120~130 DEG C, start slowly logical chlorine
Gas (1.63mol), lye absorb tail gas, lead to chlorine about 6h, after leading to chlorine, in 120~130 DEG C of stirring 1h.It is cooled to 20~25
DEG C, 200mL water washing is added, stands, separates lower layer's organic phase, adjusts PH=6~7, stirring with saturated sodium bicarbonate aqueous solution
It after 0.5h, stands, separates lower layer's organic phase, anhydrous sodium sulfate is dry, obtains object yellow oil 195g, yield is
89.0%.
Previous step yellow oil 100g (0.74mol), methanol 300mL are weighed, is put into reaction flask, nitrogen protection, drop
Sulfonic acid chloride 150g (1.11mol) is slowly added dropwise to 0~5 DEG C in temperature, after being added dropwise, is warming up to 55 DEG C, keeps the temperature 6h.Heat preservation terminates
Afterwards, it is cooled to -5~0 DEG C, water quenching is added to go out, methylene chloride extraction stands, separates lower layer's organic phase, molten with saturated sodium bicarbonate water
Liquid adjusts PH=6-7, stands, separates lower layer's organic phase, dry, and precipitation obtains the faint yellow oily 2 of object, 4- dichloro-butyric acid
Methyl esters 115g, yield 95.0%.
150mL water is added in there-necked flask, piece alkali 26g (0.64mol), tetrabutylammonium bromide 3g (9.3mmol) is added, stirs
It mixes uniformly, is warming up to 70 DEG C, 2,4- dichloro-butyric acid methyl esters 100g (0.56mol) is slowly added dropwise, after being added dropwise, be warming up to 80 DEG C
10min is kept the temperature, gas phase tracks to 98% or more feed stock conversion, is continuously heating to 95 DEG C or more, and collection steams organic phase, obtains
The chloro- 1- methyl formate of 1--cyclopropane 59g (compound ii), yield 96%.
(2) synthesis of compounds Ⅳ
Weigh o-chlorobenzene acetic acid methyl esters (III) 66.5g (0.36mol), tetrahydrofuran 80mL, sodium hydride 8.9g
(0.37mol), stirring and dissolving after sodium hydride is completely dissolved, are slowly added to the chloro- 1- methyl formate-cyclopropane 50g of 1-
(0.36mol) is warming up to reflux, keeps the temperature 4h, and gas phase tracks chloro- 99% or more the 1- methyl formate-cyclopropane conversion ratio of 1-, cooling
To 20~25 DEG C, 10% dilute hydrochloric acid solution 60mL quenching reaction liquid is added, is added tetrabutylammonium bromide 3.2g (0.1mol), heating
Reflux keeps the temperature 5h, is down to 20~25 DEG C, stands, and separates organic phase, water phase (50mLx2), and aqueous phase extracted merges organic phase, takes off
It is molten to obtain compound IV, it is weak yellow liquid 68g, yield 96%.
(3) synthesis of compound V
It weighs in toluene 200g, dimethyl sulphide 60.2g (1.0mol) investment reaction flask, is warming up to 35~40 DEG C, sulphur is added dropwise
Dimethyl phthalate 81.9g (0.65mol), after dripping off, in 35~40 DEG C of stirring 4h.10~15 DEG C are cooled to, compounds Ⅳ is added
Potassium hydroxide is added portionwise after stirring 0.5h in 130.7g (0.5mol), 93.3g (1.50mol) is added altogether, interior temperature control system is 10
~15 DEG C, 2h is stirred, 150g water is added, is stirred, stands, separates lower layer's salt water, organic phase is washed to neutrality, and negative pressure is evaporated off molten
Agent obtains object V, yellow oil 127.1g, yield 88.0%.
(4) synthesis of compound VI
Compound 100g (0.36mol) shown in ethyl alcohol 300mL, Formula V is sequentially added in four-hole bottle, stirring is cooled to 15-20
DEG C, it throws sodium hydroxide 12g (0.29mol), stirs evenly, be added hydrazine hydrate 45g (0.72mol), after adding, be to slowly warm up to 60
DEG C, keep the temperature 4 hours.Liquid phase tracking, 99% or more conversion ratio is qualified, after residual is qualified, is cooled to 20~25 DEG C, 50mL is added
Water, negative pressure slough ethyl alcohol, are cooled to 40~50 DEG C, and 200mL toluene, 100mL water is added, and stir 10min, stand, separate organic
Phase, water phase toluene (50mLx2) are extracted twice, and combining methylbenzene phase washed once with saturated sodium-chloride water solution, are stood, have been separated
Machine phase, negative pressure precipitation obtain target product VI pale tan oil 80g, yield 90%.
(5) synthesis of compound VII
Compound 60g (0.23mol) shown in acetonitrile 200mL, Formula IV is sequentially added in four-hole bottle, is cooled to 15~25 DEG C,
It is added dropwise formaldehyde 18g (0.24mol), after being added dropwise, stirs 30min, be added sodium sulfocyanate 20.3g (0.25), stir 10min,
It 10~15 DEG C of temperature control, being added sulfuric acid 33g (0.28mol), keeps the temperature 2 hours, liquid chromatogram tracks to 99% or more feed stock conversion,
Water 60mL is added, is warming up to 30~35 DEG C, stirs 30min, decompression filters.100mL water is added in filter cake, is warming up to 30~35 DEG C,
30min is stirred, decompression filters, and obtains target product VII, pale solid 76g, yield 98%.
(6) synthesis of prothioconazoles
Water 125g, Iron(III) chloride hexahydrate 113g (0.42mol) are weighed, stirring and dissolving is cooled to 50~60 DEG C, and formula is added
Compound 75g shown in VII (0.21mol) keeps temperature to 50~60 DEG C of stirring 2h, and liquid chromatogram tracks to feed stock conversion
99.5% or more, 10 DEG C are cooled to hereinafter, decompression suction filtration, obtains VIII white solid 72g, yield 97%.
Prothioconazoles total recovery 56%, product purity 98% (HPLC).
Structure detection is carried out to the prothioconazoles of preparation, hydrogen spectrum and mass spectrometric data are as follows:
1H NMR(300MHz,CDCl3): δ=0.78-0.97 (m, 4H, CH2CH2), 3.19 (d, J=14Hz, 1H, CH2),
3.64 (d, J=14Hz, 1H, CH2), 4.50 (d, J=14Hz, 1H, CH2), 4.81 (d, J=14Hz, 1H, N-CH2),7.30-
7.56 (m, 4H, ArH), 7.88 (s, 1H, Triazole-H)
MS-EI (m/z, %): 344 (M+,1).
Embodiment 2
(1) synthesis of compound ii
It weighs gamma-butyrolacton 100g (1.13mol), puts into reaction flask, be warming up to 120~125 DEG C, start slowly logical chlorine
Gas (1.35mol), lye absorb tail gas, lead to chlorine about 6h, after leading to chlorine, in 110~120 DEG C of stirring 1h.It is cooled to 20~25
DEG C, 180mL water washing is added, stands, separates lower layer's organic phase, adjusts PH=6~7, stirring with saturated sodium bicarbonate aqueous solution
It after 1h, stands, separates lower layer's organic phase, anhydrous sodium sulfate is dry, obtains object yellow oil 160g, yield is
88.0%.
Previous step yellow oil 80g (0.59mol), methanol 260mL are weighed, is put into reaction flask, nitrogen protection, cooling
To 0~5 DEG C, sulfonic acid chloride 120g (1.11mol) is slowly added dropwise, after being added dropwise, is warming up to 60 DEG C, keeps the temperature 5h.After heat preservation,
It is cooled to -5~0 DEG C, water quenching is added to go out, dichloroethanes extraction stands, separates lower layer's organic phase, use saturated sodium bicarbonate aqueous solution
PH=6-7 is adjusted, stands, separates lower layer's organic phase, dry, precipitation obtains the faint yellow oily 2 of object, 4- dichloro-butyric acid first
Ester 90g, yield 93.0%.
150mL water is added in there-necked flask, piece alkali 20g (0.52mol), tetrabutylammonium bromide 2.4g (7.4mmol) is added,
It stirs evenly, is warming up to 65 DEG C, 2,4- dichloro-butyric acid methyl esters 80g (0.45mol) is slowly added dropwise, after being added dropwise, is warming up to 90
DEG C heat preservation 30min, gas phase tracks to 98% or more feed stock conversion, is continuously heating to 95 DEG C or more, and collection steams organic phase, obtains
To the chloro- 1- methyl formate of 1--cyclopropane 47g (compound ii), yield 95%.
(2) synthesis of compounds Ⅳ
O-chlorobenzene acetic acid methyl esters (III) 60g (0.32mol), toluene 90mL, sodium methoxide 17.8g (0.33mol) are weighed, is stirred
Dissolution, after sodium methoxide is completely dissolved, is slowly added to the chloro- 1- methyl formate of 1--cyclopropane 45g (0.32mol), is warming up to reflux,
3h is kept the temperature, gas phase tracks chloro- 99% or more the 1- methyl formate-cyclopropane conversion ratio of 1-, is cooled to 20~25 DEG C, and it is dilute to be added 10%
Hydrochloric acid solution 54mL quenching reaction liquid is added tetrabutylammonium bromide 2.9g (0.09mol), temperature rising reflux, keeps the temperature 5h, it is down to 20~
It 25 DEG C, stands, separates organic phase, water phase (80mLx2), aqueous phase extracted merges organic phase, and precipitation obtains compound IV, is faint yellow
Liquid 62g, yield 95%.
(3) synthesis of compound V
It weighs in dichloroethanes 200g, dimethyl sulphide 72.2g (1.2mol) investment reaction flask, is warming up to 35~40 DEG C, drop
Add dimethyl suflfate 73.7g (0.78mol), after dripping off, in 35~40 DEG C of stirring 4h.10~15 DEG C are cooled to, compound is added
Sodium hydroxide is added portionwise after stirring 1h in IV156.8g (0.6mol), 72g (1.8mol) is added altogether, interior temperature control system is 10~15
DEG C, 1.5h is stirred, 200g water is added, is stirred, stands, separates lower layer's salt water, organic phase is washed to neutrality, and solvent is evaporated off in negative pressure,
Obtain object V yellow oil 150g, yield 89.0%.
(4) synthesis of compound VI
Compound 120g (0.43mol) shown in acetonitrile 300mL, Formula V is sequentially added in four-hole bottle, stirring is cooled to 15-20
DEG C, it throws sodium carbonate 40g (0.37mol), stirs evenly, be added hydrazine hydrate 54g (0.86mol), after being added dropwise, be to slowly warm up to
50 DEG C, keep the temperature 2 hours.Liquid phase tracking, 99% or more conversion ratio is qualified, after residual is qualified, is cooled to 20~25 DEG C, 50mL is added
Water, negative pressure slough acetonitrile, are cooled to 40~50 DEG C, and 200mL toluene, 100mL water is added, and stir 10min, stand, separate organic
Phase, water phase toluene (50mLx2) are extracted twice, and combining methylbenzene phase washed once with saturated sodium-chloride water solution, are stood, have been separated
Machine phase, negative pressure precipitation obtain target product VI pale tan oil 95g, yield 89%.
(5) synthesis of compound VII
Compound 72g (0.27mol) shown in acetone 240mL, Formula IV is sequentially added in four-hole bottle, is cooled to 10~15 DEG C,
It is added dropwise formaldehyde 21.6g (0.28mol), after being added dropwise, stirs 30min, be added sodium sulfocyanate 24.3g (0.30), stirring
30min 10~15 DEG C of temperature control, is added sulfuric acid 40g (0.33mol), keeps the temperature 2 hours, liquid chromatogram tracks to feed stock conversion
99% or more, water 100mL is added, is warming up to 30~35 DEG C, stirs 40min, decompression filters.100mL water is added in filter cake, is warming up to
30~35 DEG C, 30min is stirred, decompression filters, and obtains target product VII, white solid 91g, yield 97%.
(6) synthesis of prothioconazoles
Water 180g, anhydrous ferric trichloride 102.5g (0.63mol) are weighed, stirring and dissolving is warming up to 50~60 DEG C, and formula is added
Compound 112g shown in VII (0.32mol) keeps temperature to 50~60 DEG C of stirring 2h, and liquid chromatogram tracks to feed stock conversion
99.5% or more, 10 DEG C are cooled to hereinafter, decompression suction filtration, obtains VIII white solid 108g, yield 96%.
Prothioconazoles total recovery 54%, product purity 98% (HPLC).
Structure detection is carried out to the prothioconazoles of preparation, hydrogen spectrum and mass spectrometric data are as follows:
1H NMR(300MHz,CDCl3): δ=0.78-0.97 (m, 4H, CH2CH2), 3.19 (d, J=14Hz, 1H, CH2),
3.64 (d, J=14Hz, 1H, CH2), 4.50 (d, J=14Hz, 1H, CH2), 4.81 (d, J=14Hz, 1H, N-CH2),7.30-
7.56 (m, 4H, ArH), 7.88 (s, 1H, Triazole-H)
MS-EI (m/z, %): 344 (M+,1).
Embodiment 3
(1) synthesis of compound ii
It weighs gamma-butyrolacton 180g (2.04mol), puts into reaction flask, be warming up to 120~130 DEG C, start slowly logical chlorine
Gas (2.45mol), lye absorb tail gas, lead to chlorine about 8h, after leading to chlorine, in 120~130 DEG C of stirring 2h.It is cooled to 20~25
DEG C, 300mL water washing is added, stands, separates lower layer's organic phase, adjusts PH=6~7, stirring with saturated sodium bicarbonate aqueous solution
It after 2h, stands, separates lower layer's organic phase, anhydrous sodium sulfate is dry, obtains object yellow oil 292g, yield is
91.0%.
Previous step yellow oil 200g (1.48mol), methanol 400mL are weighed, is put into reaction flask, nitrogen protection, drop
Sulfonic acid chloride 300g (2.2mol) is slowly added dropwise to 0~5 DEG C in temperature, after being added dropwise, is warming up to 58 DEG C, keeps the temperature 8h.Heat preservation terminates
Afterwards, -5~5 DEG C are cooled to, water quenching is added to go out, dichloroethanes extraction stands, separates lower layer's organic phase, molten with saturated sodium bicarbonate water
Liquid adjusts PH=6-7, stands, separates lower layer's organic phase, dry, and precipitation obtains the faint yellow oily 2 of object, 4- dichloro-butyric acid
Methyl esters 225g, yield 93.0%.
300mL water is added in there-necked flask, piece alkali 52g (1.28mol), tetrabutylammonium bromide 6g (18.6mmol) is added,
It stirs evenly, is warming up to 70 DEG C, 2,4- dichloro-butyric acid methyl esters 200g (1.02mol) is slowly added dropwise, after being added dropwise, is warming up to 70
DEG C heat preservation 40min, gas phase tracks to 98% or more feed stock conversion, is continuously heating to 95 DEG C or more, and collection steams organic phase, obtains
To the chloro- 1- methyl formate of 1--cyclopropane 120g (compound ii), yield 95%.
(2) synthesis of compounds Ⅳ
Weigh o-chlorobenzene acetic acid methyl esters (III) 133g (0.72mol), tetrahydrofuran 180mL, sodium hydroxide 30g
(0.74mol) is slowly added to the chloro- 1- methyl formate of 1--cyclopropane 50g (0.36mol), is warming up to reflux after mixing evenly, protects
Warm 5h, gas phase track chloro- 99% or more the 1- methyl formate-cyclopropane conversion ratio of 1-, are cooled to 20~25 DEG C, and 10% dilute salt is added
Acid solution 150mL quenching reaction liquid is added tetrabutylammonium bromide 6.4g (0.2mol), temperature rising reflux, keeps the temperature 6h, is down to 20~25
DEG C, it stands, separates organic phase, water phase (200mLx2), aqueous phase extracted merges organic phase, and precipitation obtains compound IV, is faint yellow
Liquid 135g, yield 95%.
(3) synthesis of compound V
It weighs in methanol 300g, dimethyl sulphide 120g (2.0mol) investment reaction flask, is warming up to 35~40 DEG C, sulfuric acid is added dropwise
Dimethyl ester 164g (1.30mol), after dripping off, in 35~40 DEG C of stirring 6h.10~15 DEG C are cooled to, compound IV261g is added
Potassium hydroxide is added portionwise after stirring 2h in (1.0mol), and 188g (3.0mol) is added altogether, and interior temperature control system is at 10~15 DEG C, stirring
400g water is added in 3h, stirs, and stands, separates lower layer's salt water, organic phase is washed to neutrality, and solvent is evaporated off in negative pressure, obtains object
V yellow oil 253g, yield 87.0%.
(4) synthesis of compound VI
Compound 200g (0.72mol) shown in tetrahydrofuran 500mL, Formula V is sequentially added in four-hole bottle, stirring is cooled to
It 15-20 DEG C, throws potassium carbonate 80g (0.58mol), stirs evenly, be added dropwise hydrazine hydrate 90g (1.44mol), after being added dropwise, slowly
70 DEG C are warming up to, keeps the temperature 5 hours.Liquid phase tracking, 99% or more conversion ratio is qualified, after residual is qualified, is cooled to 20~25 DEG C, adds
Enter 1500mL water, negative pressure sloughs tetrahydrofuran, is cooled to 40~50 DEG C, and 300mL ethyl acetate, 100mL water, stirring is added
30min stands, separates organic phase, and water phase ethyl acetate (50mLx2) is extracted twice, combined ethyl acetate phase, with saturation chlorination
Sodium water solution washed once, and stands, separates organic phase, negative pressure precipitation obtains target product VI pale tan oil 162g, yield
It is 91%.
(5) synthesis of compound VII
Compound 120g (0.46mol) shown in acetonitrile 300mL, Formula IV is sequentially added in four-hole bottle, is cooled to 15~25 DEG C,
It is added dropwise formaldehyde 36g (0.48mol), after being added dropwise, stirs 50min, be added sodium sulfocyanate 20.3g (0.25), stir 10min,
It 10~15 DEG C of temperature control, being added acetic acid 40g (0.56mol), keeps the temperature 3 hours, liquid chromatogram tracks to 99% or more feed stock conversion,
Water 150mL is added, is warming up to 30~35 DEG C, stirs 40min, decompression filters.200mL water is added in filter cake, is warming up to 30~35 DEG C,
50min is stirred, decompression filters, and obtains target product VII, pale solid 150g, yield 98%.
(6) synthesis of prothioconazoles
Isopropanol 252g, anhydrous ferric trichloride 120g (0.74mol) are weighed, stirring and dissolving is cooled to 50~60 DEG C, is added
Compound 132g shown in Formula VII (0.36mol) keeps temperature to 50~60 DEG C of stirring 3h, and liquid chromatogram tracks to raw material conversion
99.0% or more rate is cooled to 10 DEG C hereinafter, decompression suction filtration, obtains VIII white solid 125g, yield 96%.
Prothioconazoles total recovery 55%, product purity 98% (HPLC).
Structure detection is carried out to the prothioconazoles of preparation, hydrogen spectrum and mass spectrometric data are as follows:
1H NMR(300MHz,CDCl3): δ=0.78-0.97 (m, 4H, CH2CH2), 3.19 (d, J=14Hz, 1H, CH2),
3.64 (d, J=14Hz, 1H, CH2), 4.50 (d, J=14Hz, 1H, CH2), 4.81 (d, J=14Hz, 1H, N-CH2),7.30-
7.56 (m, 4H, ArH), 7.88 (s, 1H, Triazole-H)
MS-EI (m/z, %): 344 (M+,1).
As can be seen from the above embodiments, preparation method provided by the invention is not necessarily to grignard reagent, and obtains higher receipts
Rate.
The above description of the embodiment is only used to help understand the method for the present invention and its core ideas.It should be pointed out that pair
For those skilled in the art, without departing from the principle of the present invention, the present invention can also be carried out
Some improvements and modifications, these improvements and modifications also fall within the scope of protection of the claims of the present invention.
Claims (9)
1. a kind of preparation method of prothioconazoles, which comprises the following steps:
A) compound shown in formula I is reacted through chlorization cyclization, obtains compound shown in formula II；
B) compound shown in formula II and compound shown in formula III, carry out Claisen condensation reaction, obtain compound shown in formula IV；
C) compound shown in formula IV carries out epoxidation reaction, obtains compound shown in formula V；
D) compound shown in formula V is reacted with hydrazine hydrate, obtains compound shown in formula VI；
E) compound shown in formula VI is reacted with formaldehyde, rhodanate, obtains compound shown in formula VII；
F) compound shown in formula VII is aoxidized, and obtains prothioconazoles shown in formula VIII；
2. preparation method according to claim 1, which is characterized in that the step A) specifically:
A1) compound shown in formula I is mixed in organic solvent with chlorination reagent, carries out chlorination；
A2 methanol, sulfonic acid chloride) is added, is reacted, after the reaction was completed, removes organic solvent, phase transfer catalyst is then added
And inorganic alkaline compound, reaction obtain compound shown in formula II.
3. preparation method according to claim 2, which is characterized in that the chlorination reagent is chlorine or liquid chlorine；It is described to have
Solvent is in acetonitrile, tetrahydrofuran, dioxane, dichloroethanes, carbon trichloride, carbon tetrachloride, toluene, methanol and ethyl alcohol
Any one or a few；The phase transfer catalyst is tetrabutylammonium bromide, tetrabutylammonium chloride and benzyl triethyl ammonium bromide
In any one or more；The inorganic alkaline compound is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and hydrogen-oxygen
Change any one or more in lithium.
4. preparation method according to claim 2, which is characterized in that compound shown in the formula I and chlorination reagent rub
You are than being 1:(2~3)；The volume ratio of compound shown in the formula I and organic solvent is 1:(2~10)；Chemical combination shown in the formula I
The molar ratio of object and methanol is 1:(1.2~2.5)；The molar ratio of compound shown in the formula I and sulfonic acid chloride be 1:(1.1~
3.0)；The molar ratio of compound shown in the formula I and inorganic alkaline compound is 1:(1~3)；Compound shown in the formula I with
The molar ratio of phase transfer catalyst is 1.0:(0.001~0.02).
5. preparation method according to claim 1, which is characterized in that the step B) specifically:
B1) compound shown in formula II is mixed in organic solvent with compound shown in formula III, highly basic is added, at reflux
It is reacted；
B2) end of reaction is added dropwise diluted acid quenching reaction, obtains compound shown in formula IV.
6. preparation method according to claim 5, which is characterized in that the organic solvent is acetonitrile, tetrahydrofuran, dioxy
Any one or more in six rings, dichloroethanes, carbon trichloride, carbon tetrachloride, toluene, methanol and ethyl alcohol；The highly basic is
Sodium methoxide, sodium tert-butoxide, sodium ethoxide, sodium hydride, potassium methoxide, any one or more in potassium ethoxide and potassium tert-butoxide；It is described
Diluted acid is hydrochloric acid, sulfuric acid or acetic acid.
7. preparation method according to claim 5, which is characterized in that chemical combination shown in compound shown in the formula II and formula III
The molar ratio of object is 1.0~4.0:1.0~4.0；The volume ratio of compound shown in the formula II and organic solvent be 1:(2~
10)；The molar ratio of compound shown in the formula II and highly basic is 1:(1.2~2.5)；The time of the reaction is 1~15h；Institute
The concentration for stating diluted acid is 1%~15%.
8. preparation method according to claim 1, which is characterized in that the step C) specifically:
Compound shown in formula IV is reacted in organic solvent with dimethyl sulphide and dimethyl suflfate, obtains chemical combination shown in formula V
Object.
9. preparation method according to claim 8, which is characterized in that compound, dimethyl sulphide and sulphur shown in the formula IV
The molar ratio of dimethyl phthalate is 1:(1~5): (1~4)；The volume ratio of compound shown in the formula IV and organic solvent is 1:(2
~10)；The temperature of the reaction is -10~150 DEG C, and the time of the reaction is 1~15h.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811639143.1A CN109369549A (en) | 2018-12-29 | 2018-12-29 | A kind of preparation method of prothioconazoles |
| PCT/CN2019/100176 WO2020134104A1 (en) | 2018-12-29 | 2019-08-12 | Preparation method for prothioconazole |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811639143.1A CN109369549A (en) | 2018-12-29 | 2018-12-29 | A kind of preparation method of prothioconazoles |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109369549A true CN109369549A (en) | 2019-02-22 |
Family
ID=65372276
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811639143.1A Pending CN109369549A (en) | 2018-12-29 | 2018-12-29 | A kind of preparation method of prothioconazoles |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN109369549A (en) |
| WO (1) | WO2020134104A1 (en) |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110183389A (en) * | 2019-06-25 | 2019-08-30 | 芮城县斯普伦迪生物工程有限公司 | A kind of triazole thioketone derivative compound and preparation method |
| CN110218196A (en) * | 2019-05-20 | 2019-09-10 | 江苏蓝丰生物化工股份有限公司 | The preparation method of prothioconazoles intermediate triazole alkane derivatives |
| CN110218197A (en) * | 2019-06-25 | 2019-09-10 | 芮城县斯普伦迪生物工程有限公司 | Utilize the method and micro channel systems of micro passage reaction continuous production prothioconazoles |
| CN110627627A (en) * | 2019-09-20 | 2019-12-31 | 江苏澄扬作物科技有限公司 | Preparation method of 1- (1-chlorocyclopropyl) -2- (2-chlorphenyl) ethanone and intermediate thereof |
| WO2020134104A1 (en) * | 2018-12-29 | 2020-07-02 | 安徽久易农业股份有限公司 | Preparation method for prothioconazole |
| CN111675608A (en) * | 2020-05-26 | 2020-09-18 | 安徽久易农业股份有限公司 | Process for producing 1-chloro-1' -chloroacetyl-cyclopropane |
| CN111892547A (en) * | 2020-08-28 | 2020-11-06 | 安徽久易农业股份有限公司 | Synthesis method of prothioconazole intermediate |
| CN113666840A (en) * | 2021-10-22 | 2021-11-19 | 江苏七洲绿色科技研究院有限公司 | Preparation method of prothioconazole intermediate |
| CN114345259A (en) * | 2022-01-10 | 2022-04-15 | 江苏云帆化工有限公司 | Continuous synthesis device for chlorination reaction of prothioconazole |
| CN116162067A (en) * | 2023-04-21 | 2023-05-26 | 江苏七洲绿色科技研究院有限公司 | Preparation method of prothioconazole |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022107139A1 (en) * | 2020-11-19 | 2022-05-27 | Adama Makhteshim Ltd. | Process for the preparation of prothioconazole and intermediates thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5146001A (en) * | 1990-06-13 | 1992-09-08 | Bayer Aktiengesellschaft | Preparation of benzyl ketones and an oxirane |
| CN101456808A (en) * | 2009-01-06 | 2009-06-17 | 长沙理工大学 | Method for preparing ibuprofen |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19961603A1 (en) * | 1999-12-21 | 2001-06-28 | Bayer Ag | Production of 2-chlorocyclopropyl-1-chlorophenyl-triazolonyl-propanol derivative, useful as microbicide, from 2-chlorocyclopropyl-2-chlorobenzyl-oxirane |
| CN102249949B (en) * | 2011-05-13 | 2013-12-18 | 大连奇凯医药科技有限公司 | Preparation method of cyclopropyl fenpropathin derivative |
| CN106928041A (en) * | 2017-03-02 | 2017-07-07 | 芮城县斯普伦迪生物工程有限公司 | A kind of 2 chlorobenzyls（1 chlorine cyclopropyl）The preparation method of ketone |
| CN109369549A (en) * | 2018-12-29 | 2019-02-22 | 安徽久易农业股份有限公司 | A kind of preparation method of prothioconazoles |
-
2018
- 2018-12-29 CN CN201811639143.1A patent/CN109369549A/en active Pending
-
2019
- 2019-08-12 WO PCT/CN2019/100176 patent/WO2020134104A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5146001A (en) * | 1990-06-13 | 1992-09-08 | Bayer Aktiengesellschaft | Preparation of benzyl ketones and an oxirane |
| CN101456808A (en) * | 2009-01-06 | 2009-06-17 | 长沙理工大学 | Method for preparing ibuprofen |
Non-Patent Citations (3)
| Title |
|---|
| REPPE, WALTER ET AL.,: "Dehydrierung vonγ-Diolen und Reaktionen der γ-Lactone", 《ANNALEN DER CHEMIE, JUSTUS LIEBIGS》 * |
| 徐宁: "丙硫菌唑的工业化工艺的开发", 《应用技术》 * |
| 秦永其: "丙硫菌唑的工艺改进", 《农药》 * |
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020134104A1 (en) * | 2018-12-29 | 2020-07-02 | 安徽久易农业股份有限公司 | Preparation method for prothioconazole |
| CN110218196A (en) * | 2019-05-20 | 2019-09-10 | 江苏蓝丰生物化工股份有限公司 | The preparation method of prothioconazoles intermediate triazole alkane derivatives |
| CN110218197B (en) * | 2019-06-25 | 2022-10-21 | 芮城县斯普伦迪生物工程有限公司 | Method for continuously producing prothioconazole by using microchannel reactor and microchannel system |
| CN110218197A (en) * | 2019-06-25 | 2019-09-10 | 芮城县斯普伦迪生物工程有限公司 | Utilize the method and micro channel systems of micro passage reaction continuous production prothioconazoles |
| CN110183389A (en) * | 2019-06-25 | 2019-08-30 | 芮城县斯普伦迪生物工程有限公司 | A kind of triazole thioketone derivative compound and preparation method |
| CN110627627A (en) * | 2019-09-20 | 2019-12-31 | 江苏澄扬作物科技有限公司 | Preparation method of 1- (1-chlorocyclopropyl) -2- (2-chlorphenyl) ethanone and intermediate thereof |
| CN111675608A (en) * | 2020-05-26 | 2020-09-18 | 安徽久易农业股份有限公司 | Process for producing 1-chloro-1' -chloroacetyl-cyclopropane |
| CN111675608B (en) * | 2020-05-26 | 2023-12-15 | 安徽久易农业股份有限公司 | Process for producing 1-chloro-1' -chloroacetyl-cyclopropane |
| CN111892547A (en) * | 2020-08-28 | 2020-11-06 | 安徽久易农业股份有限公司 | Synthesis method of prothioconazole intermediate |
| CN113666840A (en) * | 2021-10-22 | 2021-11-19 | 江苏七洲绿色科技研究院有限公司 | Preparation method of prothioconazole intermediate |
| CN114345259A (en) * | 2022-01-10 | 2022-04-15 | 江苏云帆化工有限公司 | Continuous synthesis device for chlorination reaction of prothioconazole |
| CN116162067A (en) * | 2023-04-21 | 2023-05-26 | 江苏七洲绿色科技研究院有限公司 | Preparation method of prothioconazole |
| CN116162067B (en) * | 2023-04-21 | 2023-08-08 | 江苏七洲绿色科技研究院有限公司 | Preparation method of prothioconazole |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2020134104A1 (en) | 2020-07-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109369549A (en) | A kind of preparation method of prothioconazoles | |
| CN111393427B (en) | Synthetic method of sulfuryl pyraflufen | |
| CN103588730A (en) | Synthetic method for preparing triazole fungicide type (III) compound | |
| CN102190628A (en) | Preparation method of 5-fluoro-6-ethyl-4-hydroxypyrimidine intermediate and Voriconazole | |
| CN112707889B (en) | Synthesis method of lansoprazole | |
| CN109988132B (en) | Preparation method of amiodarone hydrochloride | |
| CN102001979B (en) | Preparation method of 2-(2', 2'-difluoroethoxyl)-6-trifluoromethyl phenyl propyl sulfide | |
| CN100522923C (en) | Preparation method of 2-bromo-2-nitro-1,3-propylene glycol | |
| AU2001284887A1 (en) | Processes for preparing cilostazol | |
| CN108530323B (en) | A kind of preparation method of 2- (2,2- difluoroethoxy) -6- trifluoromethyl benzene sulfonyl chloride | |
| US20130274501A1 (en) | Process for preparing bicalutamide | |
| CN107325091B (en) | A kind of preparation method of benzene pyrazoles humulone | |
| CN103145639B (en) | The preparation method of 2-methyl-4-(trifluoromethyl) thiazole-5-formic acid | |
| CN108863991A (en) | A kind of preparation method and application of 2- hydroxymethyl-oxetane derivative | |
| CN103204803A (en) | Method used for synthesizing etoricoxib | |
| CN112694403B (en) | Method for preparing (R) - (+) -2- (4-hydroxyphenoxy) methyl propionate | |
| CN108912043A (en) | A kind of synthetic method of 2,3,5- trichloropyridine | |
| CN105745191A (en) | Method for preparing silodosin and intermediate thereof | |
| Györyovő et al. | Thermal behaviour of zinc (II) 5-chlorosalicylate complex compounds | |
| CN104650036B (en) | 6 substituted-phenyl quianzolinones and application thereof | |
| CN107721941B (en) | Preparation method of 3-amino-5-methyl isoxazole | |
| CN109516935A (en) | A kind of naphthylthio carbonyl complex and its preparation method and application | |
| CN104961675A (en) | Preparation method of isavuconazole intermediate | |
| CN117327016A (en) | Preparation method of fenpyrad intermediate | |
| CN106432109A (en) | Preparation method of quizalofop-P-ethyl |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20190222 |