CN106749057B - A kind of synthetic method of midbody compound and prothioconazoles - Google Patents
A kind of synthetic method of midbody compound and prothioconazoles Download PDFInfo
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- CN106749057B CN106749057B CN201611264830.0A CN201611264830A CN106749057B CN 106749057 B CN106749057 B CN 106749057B CN 201611264830 A CN201611264830 A CN 201611264830A CN 106749057 B CN106749057 B CN 106749057B
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- 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 invention discloses the synthetic methods of a kind of midbody compound and prothioconazoles, wherein method includes, by 5,5 '-disulfide groups-bis- (1,2,4- triazoles) with 2- (1- chlorine cyclopropyl) the chloro- 1- of -3- (2- chlorphenyl) -2- propyl alcohol occur substitution reaction obtain key intermediate compound；Then target product prothioconazoles are obtained through reduction.Synthesis technology conversion ratio of the present invention and selectivity are high, and synthesis material is cheap and easily-available, reduces production cost.Also, the mild reaction condition that the present invention uses is easily-controllable, easy to operate, and product purification is easy, and can directly be recrystallized to give product.Wherein, each to walk intermediate body controlling means simply, accurately, product yield is higher, and Atom economy is preferable, avoids cumbersome post-processing, has very big competitive advantage and industrial production utility value.Meanwhile avoiding using raw materials such as highly basic, the three wastes are extremely low, meet the theory of Green Chemistry.
Description
Technical field
The invention belongs to organic synthesis fields, and in particular to the synthesis side of a kind of midbody compound and prothioconazoles
Method.
Background technique
Prothioconazoles are a kind of demethylation inhibitors (DMIs), and the mechanism of action is the precursor-for inhibiting sterol in fungi
L4- demethylation reactions of lanosterol.Prothioconazoles not only have good systemic activity, excellent protection, treatment and shovel
Except activity, and the lasting period is long.A large amount of field control effectiveness test result shows that prothioconazoles not only have good safety to crop
Property, preventing disease theraping effect is good, and increases production obviously, and compared with triazole bactericidal agent, prothioconazoles are lived with broader spectrum of sterilization
Property.
Prothioconazoles are currently used primarily in prevention and treatment cereal crop such as wheat, barley, rape, peanut, rice and beans and make
Numerous diseases such as object.Prothioconazoles almost have good control efficiency to all wheat diseases, such as the white powder of wheat and barley
Disease, banded sclerotial blight, wilt disease, leaf spot, rust, sclerotiniose, net blotch, moire disease etc..Prothioconazoles can also prevent and treat rape and flower
Raw soil-borne disease, such as sclerotiniose and main foliage disease, such as gray mold, black spot, brown spot, balck shank and rust.
Different according to the source of sulphur atom, the preparation strategy of prothioconazoles can be divided into two major classes.The first kind prepares rosickyite bacterium
The strategy of azoles is to obtain prothioconazoles (US4913727) with sulfur reaction using hydroxyl triazole compounds as key intermediate.Sulphur exists
Source in this kind of reaction as prothioconazoles compound sulphur atom.The key intermediate of this method can be with chloride
(US4913727) or epoxide (US5146001) is that starting material and triazole are substituted reaction and are made.This substitution reaction
Considerable amount of region isomer can be generated simultaneously, needed to remove by purification, caused yield not good enough (51~53%).It is crucial intermediate
Body can also be reacted by raw material and triazole of chloro ketone, then be made with Grignard Reagent reaction, and the method equally exists regional choice
Property problem.
United States Patent (USP) US5789430 discloses the method for preparing prothioconazoles with compound and sulphur directly reaction.This is anti-
Prothioconazoles, yield 20% should be reacted 44 hours to obtain at 200 DEG C using N- N-methyl 2-pyrrolidone N as solvent.US5789430 is simultaneously
Also disclose the improved method that prothioconazoles are prepared with compound and sulfur reaction.The improved method is that compound is molten in THF
Hydrogen first is pulled out with n-BuLi in agent, then is greatly improved (93%) with sulfur reaction, the yield of gained prothioconazoles, but the technical solution
Anhydrous and oxygen-free and ultralow temperature consersion unit and condition are needed, while needing to try using the n-BuLi for the high risk for being greater than two equivalents
Agent keeps the technical solution at high cost, and operation is dangerous, is unfavorable for industrialized production.
In addition, the technical solution simultaneously also by the puzzlement of itself chemical regions selectivity, such as: (1) in key intermediate
If controlling the improper generation that will lead to regional isomerism impurity 11 during pulling out hydrogen with n-BuLi；(2) when preparing key intermediate
If it is clean that region isomer is not completely segregated purification, the generation of regional isomerism impurity will lead to.The separation of these high requests
Purification not only generates a large amount of three wastes, while greatly increasing cost.
US2013005985 disclose it is a kind of using Grignard Reagent such as i-PrMgCl replace n-BuLi compound is pulled out
Vulcanize the method for preparing prothioconazoles after hydrogen again.This method solve use n-BuLi reagent dangerous problem, but the technical side
Case still needs anhydrous and oxygen-free and ultralow temperature consersion unit and condition, while needing using the Grignard Reagent for being greater than two equivalents, and
And yield declines to a great extent and (drops to 68% from the 93% of n-BuLi).
Summary of the invention
The purpose of this section is to summarize some aspects of the embodiment of the present invention and briefly introduce some preferable implementations
Example.It may do a little simplified or be omitted to avoid our department is made in this section and the description of the application and the title of the invention
Point, the purpose of abstract of description and denomination of invention it is fuzzy, and this simplification or omit and cannot be used for limiting the scope of the invention.
In view of the technological gap of above-mentioned and/or existing synthesis prothioconazoles, the present invention is proposed.
Therefore, the one of purpose of the present invention is to provide a kind of midbody compound, which can use
In the synthesis of prothioconazoles.
In order to solve the above technical problems, the present invention provides the following technical scheme that a kind of midbody compound, chemistry knot
Structure formula are as follows:
The present invention another purpose therein is to solve the deficiency of prothioconazoles synthetic method in the prior art, is improved each
The conversion ratio of step reduces by-product, simplifies reaction condition, reduces energy consumption, shortens the reaction time, improves atom utilization, reduces
The three wastes.
In order to solve the above technical problems, the present invention provides the following technical scheme that a kind of synthetic method of prothioconazoles, packet
It includes, is that raw material aoxidizes to obtain sulfydryl -1,2,4- triazole through sulphur with 1,2,4- triazole；Sulfydryl -1,2,4- triazole is through aoxidizing
It is bis- (1,2,4- triazole) to form 5,5 '-disulfide groups-；It is sent out with 2- (1- chlorine cyclopropyl) the chloro- 1- of -3- (2- chlorphenyl) -2- propyl alcohol
Raw substitution reaction obtains midbody compound as described in claim 1；Target product prothioconazoles are obtained through reduction.
A kind of preferred embodiment of synthetic method as prothioconazoles of the present invention, in which: described with 1,2,4- tri- nitrogen
Azoles, which is raw material, aoxidizes to obtain sulfydryl -1,2 through sulphur, 4- triazole, including, 1,2,4- triazole is dissolved in organic solvent, is added
The sulphur for being 1:3~1:6 with 1,2,4- triazole molar ratios is heated to 100~180 DEG C, reacts 2~8h, is cooled to room temperature, mistake
Filter, filtrate are washed with saturated sodium-chloride, are extracted through ethyl acetate, and organic phase is separated, dry, and ethyl acetate is evaporated off and obtains sulfydryl -1,
2,4- triazoles；Wherein, organic solvent is one or more in DMF or toluene or DMSO；Wherein, dry to use solid drier
For one or more of anhydrous magnesium sulfate, anhydrous calcium chloride, anhydrous sodium sulfate, dead plaster or activated alumina.
A kind of preferred embodiment of synthetic method as prothioconazoles of the present invention, in which: it is described be heated to 100~
180 DEG C, temperature is preferably 110~160 DEG C.
A kind of preferred embodiment of synthetic method as prothioconazoles of the present invention, in which: 2~8h of the reaction,
Reaction time is preferably 3~6h.
A kind of preferred embodiment of synthetic method as prothioconazoles of the present invention, in which: the sulfydryl -1,2,4- tri-
Nitrogen azoles is bis- (1,2,4- triazole) through oxidation formation 5,5 '-disulfide groups -, including, by sulfydryl -1,2,4- triazole is dissolved in DCM,
Pyridine is added, controlled at -2 DEG C~6 DEG C, benzene sulfonyl chloride is added in stirring, and DCM is removed after reaction, and water and second is added in residue
Acetoacetic ester is filtered after reaction, and is washed with water and ethyl acetate, and the solid product being obtained by filtration is dry, obtains solid chemical combination
Object (V) i.e. 5,5 '-disulfide groups-bis- (1,2,4- triazole)；Wherein, dry to use solid drier for anhydrous magnesium sulfate, anhydrous
One or more of calcium chloride, anhydrous sodium sulfate, dead plaster or activated alumina.
A kind of preferred embodiment of synthetic method as prothioconazoles of the present invention, in which: the reaction temperature is preferred
It is 0 DEG C~4 DEG C.
A kind of preferred embodiment of synthetic method as prothioconazoles of the present invention, in which: described and 2- (1- chlorine cyclopropyl
Base) substitution reaction occurs for the chloro- 1- of -3- (2- chlorphenyl) -2- propyl alcohol, including, by the solid chemical compound (V) and organic solvent,
Potassium carbonate is stirred, and is heated to 20 DEG C~100 DEG C, and 2- (1- chlorine cyclopropyl) the chloro- 1- of -3- (2- chlorphenyl) -2- propyl alcohol is added
Midbody compound is cooled to room temperature after reaction, is filtered, filtrate saturated common salt water washing, and ethyl acetate extraction, organic phase is used
Saturated common salt water washing separates organic phase, dry, and revolving obtains compound (VI)；Wherein, organic solvent be methanol, it is ethyl alcohol, different
One or more of propyl alcohol, acetonitrile, acetone or DMF；Wherein, solid chemical compound (V) is 1:2~1:4 with potassium carbonate molar ratio；
Wherein, solid chemical compound (V) same to 2- (1- chlorine cyclopropyl) the chloro- 1- of -3- (2- chlorphenyl) -2- propanol compounds (II) molar ratio is
1:2~1:5；Wherein, drying uses solid drier for anhydrous magnesium sulfate, anhydrous calcium chloride, anhydrous sodium sulfate, dead plaster
Or one or more of activated alumina.
A kind of preferred embodiment of synthetic method as prothioconazoles of the present invention, in which: the solid drier, it is excellent
It is selected as anhydrous sodium sulfate.
A kind of preferred embodiment of synthetic method as prothioconazoles of the present invention, in which: it is described be heated to 20 DEG C~
100 DEG C, preferably 40 DEG C~80 DEG C.
A kind of preferred embodiment of synthetic method as prothioconazoles of the present invention, in which: the organic solvent is, excellent
It is selected as DMF.
A kind of preferred embodiment of synthetic method as prothioconazoles of the present invention, in which: described to obtain mesh through reduction
Product prothioconazoles are marked, including, compound (VI) is dissolved in organic solvent, reducing agent, 20 DEG C of -60 DEG C of items of reaction temperature are added
After being stirred to react under part, recrystallization precipitates crystal and filters to obtain target compound prothioconazoles.Wherein, organic solvent is methanol, second
It is alcohol, isopropanol, acetonitrile, one or more in acetone；Wherein, reducing agent TCEP, DTT, Zn, sodium borohydride, in lithium aluminium hydride reduction
One or more.
A kind of preferred embodiment of synthetic method as prothioconazoles of the present invention, in which: the organic solvent, preferably
For methanol.
A kind of preferred embodiment of synthetic method as prothioconazoles of the present invention, in which: the reaction temperature, preferably
It is 30 DEG C~50 DEG C.
A kind of preferred embodiment of synthetic method as prothioconazoles of the present invention, in which: the reducing agent, preferably
Metal Zn.
Beneficial effects of the present invention:
(1) synthesis technology conversion ratio of the present invention and selectivity are high, and synthesis material is cheap and easily-available, reduces production cost.
(2) reaction condition is mildly easily-controllable, easy to operate, and product purification is easy, and can directly be recrystallized to give product.
(3) each to walk intermediate body controlling means simply, accurately, product yield is higher, and Atom economy is preferable, avoids cumbersome
Post-processing has very big competitive advantage and industrial production utility value.
(4) it avoids using raw materials such as highly basic, the three wastes are extremely low, meet the theory of Green Chemistry.
Detailed description of the invention
In order to illustrate the technical solution of the embodiments of the present invention more clearly, required use in being described below to embodiment
Attached drawing be briefly described, it should be apparent that, drawings in the following description are only some embodiments of the invention, for this
For the those of ordinary skill of field, without any creative labor, it can also be obtained according to these attached drawings other
Attached drawing.Wherein:
Fig. 1 is the MS map of compounds Ⅳ；
Fig. 2 is the MS map of compound V；
Fig. 3 is the MS map of compound VI；
Fig. 4 is the MS map of compound VII；
Fig. 5 is compound VII1H-NMR map, wherein1H NMR (400MHz, Chloroform-d) δ 11.92 (s,
1H), 7.85 (s, 1H), 7.59-7.50 (m, 1H), 7.40-7.33 (m, 1H), 7.21 (tt, J=7.3,5.3Hz, 2H), 4.79
(d, J=14.6Hz, 1H), 4.50 (d, J=14.6Hz, 1H), 4.27 (s, 1H), 3.62 (d, J=14.0Hz, 1H), 3.17 (d,
J=14.0Hz, 1H), 1.02-0.85 (m, 2H), 0.85-0.73 (m, 2H).
Specific embodiment
In order to make the foregoing objectives, features and advantages of the present invention clearer and more comprehensible, right combined with specific embodiments below
A specific embodiment of the invention is described in detail.
In the following description, numerous specific details are set forth in order to facilitate a full understanding of the present invention, but the present invention can be with
Implemented using other than the one described here other way, those skilled in the art can be without prejudice to intension of the present invention
In the case of do similar popularization, therefore the present invention is not limited by the specific embodiments disclosed below.
Secondly, " one embodiment " or " embodiment " referred to herein, which refers to, may be included at least one realization side of the invention
A particular feature, structure, or characteristic in formula." in one embodiment " that different places occur in the present specification not refers both to
The same embodiment, nor the individual or selective embodiment mutually exclusive with other embodiments.
In order to describe convenience of the invention, the conventional and unconventional abbreviation of various reagents is used.These abbreviations are this fields
Known to technical staff, but in order to clearly be listed below:
THF: tetrahydrofuran
DMF:N, dinethylformamide
DMSO: dimethyl sulfoxide
DCM: methylene chloride
TCEP: three (2- carboxyethyl) phosphines
DTT: dithiothreitol (DTT)
Embodiment 1:
The synthesis of 2- (1- chlorine cyclopropyl) the chloro- 1- of -3- (2- chlorphenyl) -2- propyl alcohol
In the case where there is the 250mL flask with three necks,round bottom device of constant pressure titration funnel and condenser pipe, carries out anhydrous and oxygen-free and operate nitrogen
Under the conditions of gas shielded, 10g (0.062mol) 2- chlorobenzyl chloride is mixed with 50mLTHF solution and is placed in constant pressure funnel, three
The THF solution and a small amount of iodine of 1.8g (0.074mol) magnesium chips and 10ml are added in mouth flask, instills the THF of 2ml 2- chlorobenzyl chloride
Solution, low-grade fever cause, and place a device into ice bath and (drop/3s) is slowly added dropwise until dripping off, 1h is reacted after dripping off again, by above-mentioned lattice
THF (30mL) solution that family name's reactant slowly instills the chloro- 1- chloracetyl cyclopropane of 9.0g (0.058mol) 1- is slowly added dropwise
(drop/3s) until drip off, the 1h that drips off that the reaction was continued, device is consistently placed in ice bath.Finally slowly reaction solution is slowly added into
Quenching reaction in the NH4Cl ice water solution of saturation stirs 1h, separates organic phase with separatory funnel, it is dry that anhydrous sodium sulfate is added
Afterwards, THF is evaporated off to obtain, obtains 14.45g compound (II) pale yellowish oil liquid, yield 89%.
Embodiment 2:
The synthesis of prothioconazoles
The synthesis of compound (IV)
1,2,4- triazole of 5g (0.072mol) is dissolved in the DMF of 15ml, 6.9g (0.216mol) sublimed sulfur is added, adds
Heat after reacting 3.5h, is cooled to room temperature to 140 DEG C, is filtered, and filtrate is washed with saturated sodium-chloride, and ethyl acetate extraction has separated
Machine phase, it is dry with anhydrous sodium sulfate, ethyl acetate is evaporated off and obtains solid chemical compound (IV) 6.95g, yield 95%.
The synthesis of compound (V)
3.03g (30mmol) compound (IV) is dissolved in 30mLDCM, 2.37g (30mmol) is added and steams pyridine again.Ice bath
Under stirring condition, 2.64g (15mmol) benzene sulfonyl chloride is added dropwise, 1h or so is added dropwise.Ice-water bath is removed, stirs 5h at room temperature.
DCM is boiled off, 15mL water and 10mL ethyl acetate is added in residue, reacts 1h, filtering, and washed with suitable water and ethyl acetate
It washs.The solid product being obtained by filtration is drained in vacuum oven, obtains solid chemical compound (V) 2.88g, yield 96%.
The synthesis of compound (VI)
4g (20mmol) compound (V) and 20ml DMF, 5.52g (40mmol) potassium carbonate are stirred, are heated to 50
℃.Compound (II) 11.74g (42mmol) is added dropwise, 2h is added dropwise, the reaction was continued h, stops reaction, is cooled to room temperature.It takes out
Filter, filtrate saturated common salt water washing, ethyl acetate extraction, organic phase three times, separate organic phase, nothing with saturated common salt water washing
Aqueous sodium persulfate is dry, the product of revolving.Obtain compound (VI) 11.4g, yield 83%.
The synthesis of target compound (VII) prothioconazoles
It takes 5g (0.0072mol) compound (VI) to be dissolved in the methanol of 30ml, 0.97g (0.015mol) metal Zn is added,
30 DEG C are stirred to react 3h, stop reaction, directly recrystallize, precipitate crystal and filter to obtain target compound (VII) prothioconazoles 4.3g,
Yield is 86%.
The present invention redesigns synthetic route to reduce production cost, improves each step in above-described embodiment mode
Conversion ratio is that raw material aoxidizes to obtain sulfydryl -1,2 through sulphur with 1,2,4- triazole, and 4- triazole forms two sulphur using oxidation
Key, then with it is chloro- through 2- made from grignard reaction (1- chlorcyclopropane) -3- with 2- chlorobenzyl chloride as the chloro- 1- chloracetyl cyclopropane of 1-
Substitution reaction occurs for 1- (2- chlorphenyl) -2- propyl alcohol, then through restoring
Comparative example 1:
The synthesis of prothioconazoles
The synthesis of compound (IV)
1,2,4- triazole of 5g (0.072mol) is dissolved in the DMSO of 15ml, 11.52g (0.36mol) sublimed sulfur is added,
180 DEG C are heated to, after reacting 5h, is cooled to room temperature, is filtered, filtrate is washed with saturated sodium-chloride, and ethyl acetate extraction has separated
Machine phase, it is dry with anhydrous sodium sulfate, ethyl acetate is evaporated off and obtains solid chemical compound (IV) 5.89g, yield 81%.
The synthesis of compound (V)
3.03g (30mmol) compound (IV) is dissolved in 30mLDCM, 3.16g (40mmol) is added and steams pyridine again.6℃
Under stirring condition, 3.53g (20mmol) benzene sulfonyl chloride is added dropwise, 1h or so is added dropwise.4h is stirred at room temperature.DCM is boiled off, it is remaining
20mL water and 20mL ethyl acetate is added in object, reacts 1h, filtering, and washed with suitable water and ethyl acetate.It will be obtained by filtration
Solid product drained in vacuum oven, obtain solid chemical compound (V) 2.49g, yield 83%.
The synthesis of compound (VI)
By 4g (20mmol) compound (V) and 40ml acetonitrile, 8., 28g (60mmol) potassium carbonate are stirred, are heated to
80℃.Compound (II) 21.24g (80mmol) is added dropwise, 2h is added dropwise, the reaction was continued 4h, stops reaction, is cooled to room temperature.
It filtering, filtrate saturated common salt water washing, ethyl acetate extraction, organic phase three times, separates organic phase with saturated common salt water washing,
Anhydrous sodium sulfate is dry, the product of revolving.Obtain compound (VI) 10.7g, yield 78%.
The synthesis of target compound (VII) prothioconazoles
Take 5g (0.0072mol) compound (VI) to be dissolved in the ethyl alcohol of 30ml, be added 1.98g (0.0079mol) TCEP, 50
It DEG C is stirred to react 3h, stops reaction, is directly recrystallized, is precipitated crystal and filter to obtain target compound (VII) prothioconazoles 4.1g, receipts
Rate is 82%.
Comparative example 2:
The synthesis of prothioconazoles
The synthesis of compound (IV)
1,2,4- triazole of 5g (0.072mol) is dissolved in the toluene of 20ml, 9.22g (0.288mol) sublimed sulfur is added,
100 DEG C are heated to, after reacting 10h, is cooled to room temperature, is filtered, filtrate is washed with saturated sodium-chloride, and ethyl acetate extraction separates
Organic phase, it is dry with anhydrous sodium sulfate, ethyl acetate is evaporated off and obtains solid chemical compound (IV) 4.07g, yield 56%.
The synthesis of compound (V)
3.03g (30mmol) compound (IV) is dissolved in 30mLDCM, 3.16g (40mmol) is added and steams pyridine again.-2℃
Under stirring condition, 3.53g (20mmol) benzene sulfonyl chloride is added dropwise, 1h or so is added dropwise.5h is stirred at room temperature.DCM is boiled off, it is remaining
20mL water and 20mL ethyl acetate is added in object, reacts 1h, filtering, and washed with suitable water and ethyl acetate.It will be obtained by filtration
Solid product drained in vacuum oven, obtain solid chemical compound (V) 2.1g, yield 70%.
The synthesis of compound (VI)
By 4g (20mmol) compound (V) and 40ml acetone, 11.04g (80mmol) potassium carbonate is stirred, is heated to
30℃.Compound (II) 21.24g (60mmol) is added dropwise, 2h is added dropwise, the reaction was continued 4h, stops reaction, is cooled to room temperature.
It filtering, filtrate saturated common salt water washing, ethyl acetate extraction, organic phase three times, separates organic phase with saturated common salt water washing,
Anhydrous sodium sulfate is dry, the product of revolving.Obtain compound (VI) 7.0g, yield 51%.
The synthesis of target compound (VII) prothioconazoles
It takes 5g (0.0072mol) compound (VI) to be dissolved in the acetone of 30ml, 0.55g (0.0144mol) hydroboration is added
Sodium, 20 DEG C are stirred to react 5h, stop reaction, directly recrystallize, precipitate crystal and filter to obtain target compound (VII) prothioconazoles
2.72g, yield 55%.
Embodiment 3
The synthesis of compound (VI)
6g (30mmol) compound (V) and 30ml DMF, 12.42g (90mmol) potassium carbonate are stirred, are heated to
60℃.Compound (II) 17.61g (63mmol) is added dropwise, 2h is added dropwise, and the reaction was continued, stops reaction, is cooled to room temperature.It takes out
Filter, filtrate saturated common salt water washing, ethyl acetate extraction, organic phase three times, separate organic phase, nothing with saturated common salt water washing
Aqueous sodium persulfate is dry, the product of revolving.Obtain compound (VI) 17.31g, yield 84%.
The synthesis of target compound (VII) prothioconazoles
It takes 6.25g (0.009mol) compound (VI) to be dissolved in the methanol of 30ml, 1.21g (0.019mol) metal is added
Zn, 40 DEG C are stirred to react 3h, stop reaction, directly recrystallize, precipitate crystal and filter to obtain target compound (VII) prothioconazoles
5.5g, yield 88%.
Embodiment 4
The synthesis of compound (VI)
6g (30mmol) compound (V) and 30ml DMF, 12.42g (90mmol) potassium carbonate are stirred, are heated to
80℃.Compound (II) 17.61g (63mmol) is added dropwise, 2h is added dropwise, and the reaction was continued, stops reaction, is cooled to room temperature.It takes out
Filter, filtrate saturated common salt water washing, ethyl acetate extraction, organic phase three times, separate organic phase, nothing with saturated common salt water washing
Aqueous sodium persulfate is dry, the product of revolving.Obtain compound (VI) 16.49g, yield 80%.
The synthesis of target compound (VII) prothioconazoles
It takes 6.25g (0.009mol) compound (VI) to be dissolved in the methanol of 30ml, 0.97g (0.015mol) metal boron is added
Sodium hydride, 50 DEG C are stirred to react 3h, stop reaction, directly recrystallize, precipitate crystal and filter to obtain target compound (VII) rosickyite bacterium
Azoles 5.06g, yield 81%.
Embodiment 5
The synthesis of compound (VI)
6g (30mmol) compound (V) and 30ml DMF, 12.42g (90mmol) potassium carbonate are stirred, are heated to
100℃.Compound (II) 17.61g (63mmol) is added dropwise, 2h is added dropwise, and the reaction was continued, stops reaction, is cooled to room temperature.It takes out
Filter, filtrate saturated common salt water washing, ethyl acetate extraction, organic phase three times, separate organic phase, nothing with saturated common salt water washing
Aqueous sodium persulfate is dry, the product of revolving.Obtain compound (VI) 11.54g, yield 56%.
The synthesis of target compound (VII) prothioconazoles
It takes 6.25g (0.009mol) compound (VI) to be dissolved in the methanol of 30ml, 0.97g (0.015mol) metal is added
TECP, 20 DEG C are stirred to react 3h, stop reaction, directly recrystallize, precipitate crystal and filter to obtain target compound (VII) prothioconazoles
3.44g, yield 55%.
3~5 reaction principle of embodiment are as follows:
In above-described embodiment 1~5, the key intermediate compound of synthesising target compound, chemical structure are produced
Formula are as follows:
Provided data based on the above embodiment, it is known that the synthetic method of prothioconazoles provided by the invention can obtain
To more excellent yield.
In the particular embodiment, Examples 1 and 2 are all made of provided by the invention about organic solvent selection, temperature control
Range processed and the preferred embodiment of reducing agent selection, so the yield in each phase targets compound is more excellent.Compared to it
Under, comparative example 1 follows preferred embodiment substantially, and in synthetic route, not using this in the synthesis of individual target compound
The preferred embodiment of the temperature or reducing agent that provide is invented, corresponding yield is undesirable.In comparative example 2, each step targeted
With the synthesis of object, the preferred model not selected using the present invention about reaction time, reaction temperature, organic solvent and reducing agent
It encloses.
Wherein specific mechanism is as follows:
In terms of reaction temperature and reaction time angle, excessively high reaction temperature and too long reaction time, it may appear that reaction
When balancing objective product accounts for major portion, reaction is still continuing, and balance is pushed further into, so that by-product increases；Too low is anti-
Temperature and too short reaction time are answered, reaction can be made to be unable to fully carry out, preferable chemical balance can not be presented, then obtain
It obtains preferable target product and compares yield.The reaction that the present invention passes through design and the synthesis of each step target product to synthetic route
The matched design of temperature and reaction time provides preferred control range.
It should be noted that the above examples are only used to illustrate the technical scheme of the present invention and are not limiting, although referring to preferable
Embodiment describes the invention in detail, those skilled in the art should understand that, it can be to technology of the invention
Scheme is modified or replaced equivalently, and without departing from the spirit and scope of the technical solution of the present invention, should all be covered in this hair
In bright scope of the claims.
Claims (2)
1. a kind of synthetic method of prothioconazoles, it is characterised in that: including,
5,5 '-disulfide groups-bis- (1,2,4- triazole) and 2-(1- chlorine cyclopropyl) the chloro- 1-(2- chlorphenyl of -3-) -2- propyl alcohol hair
Raw substitution reaction obtains following midbody compound:
Target product prothioconazoles are obtained through reduction；Wherein,
Before obtaining the midbody compound, further include,
It is that raw material aoxidizes to obtain sulfydryl -1,2,4- triazole through sulphur with 1,2,4- triazole；
Sulfydryl -1,2,4- triazole are bis- (1,2,4- triazole) through oxidation formation 5,5 '-disulfide groups -；
Described to be raw material with 1,2,4- triazole aoxidize to obtain sulfydryl -1,2 through sulphur, 4- triazole, including,
1,2,4- triazole is dissolved in organic solvent, the sulphur for being 1:3 ~ 1:6 with 1,2,4- triazole molar ratios is added, adds
Heat is reacted 2 ~ 8h, is cooled to room temperature to 100 ~ 180 DEG C, filters, and filtrate is washed with saturated sodium-chloride, extracted through ethyl acetate,
Organic phase is separated, it is dry, ethyl acetate is evaporated off and obtains sulfydryl -1,2,4- triazole；Wherein,
The organic solvent is one or more in DMF or toluene or DMSO；
The sulfydryl -1,2,4- triazole is bis- (1,2,4- triazole) through oxidation formation 5,5 '-disulfide groups -, including,
By sulfydryl -1,2,4- triazole is dissolved in DCM, and pyridine is added, and controlled at -2 DEG C ~ 6 DEG C, benzene sulphur is added in stirring
Acyl chlorides removes DCM after reaction, residue is added water and ethyl acetate, filters after reaction, and washed with water and ethyl acetate, will
The solid product being obtained by filtration is dry, and it is bis- (1,2,4- triazole) to obtain 5,5 '-disulfide groups-；
Described 5,5 '-disulfide groups-bis- (1,2,4- triazole) and 2-(1- chlorine cyclopropyl) the chloro- 1-(2- chlorphenyl of -3-) -2- third
Substitution reaction occurs for alcohol, including,
Described 5,5 '-disulfide groups-bis- (1,2,4- triazoles) and organic solvent, potassium carbonate are stirred,
20 DEG C ~ 100 DEG C are heated to, 2-(1- chlorine cyclopropyl is added) the chloro- 1-(2- chlorphenyl of -3-) -2- propyl alcohol, it is cooling after reaction
It to room temperature, filters, filtrate saturated common salt water washing, ethyl acetate extraction, organic phase saturated common salt water washing separates organic
Phase, dry, revolving obtains the midbody compound；Wherein,
The organic solvent is one or more of methanol, ethyl alcohol, isopropanol, acetonitrile, acetone or DMF；
5,5 '-disulfide groups-bis- (1,2,4- triazole) are 1:2 ~ 1:4 with potassium carbonate molar ratio；
5,5 '-disulfide groups-bis- (1,2,4- triazole) are with 2-(1- chlorine cyclopropyl) the chloro- 1-(2- chlorphenyl of -3-) -2- propyl alcohol rubs
You are than being 1:2 ~ 1:5；
The drying uses solid drier for anhydrous magnesium sulfate, anhydrous calcium chloride, anhydrous sodium sulfate, dead plaster or activity
One or more of aluminium oxide；
It is described to obtain target product prothioconazoles through reduction, including,
The midbody compound is dissolved in organic solvent, reducing agent is added, is stirred under the conditions of 20 DEG C ~ 60 DEG C of reaction temperature
After reaction, recrystallization precipitates crystal and filters to obtain target compound prothioconazoles；Wherein,
Organic solvent is methanol, ethyl alcohol, isopropanol, acetonitrile, one or more in acetone；
Reducing agent is one or more of TCEP, DTT, Zn, sodium borohydride, lithium aluminium hydride reduction.
2. the synthetic method of the prothioconazoles according to claim 1, it is characterised in that: sulfydryl -1,2,4- triazole is through oxygen
Changing and forming the reaction temperature of 5,5 '-disulfide groups-bis- (1,2,4- triazoles) is 0 DEG C ~ 4 DEG C.
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| CN113788797A (en) * | 2021-10-12 | 2021-12-14 | 京博农化科技有限公司 | Desulfurized prothioconazole impurity and synthetic method and application thereof |
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