CN104710372B - Metconazole and preparation method thereof - Google Patents
Metconazole and preparation method thereof Download PDFInfo
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- CN104710372B CN104710372B CN201310686927.0A CN201310686927A CN104710372B CN 104710372 B CN104710372 B CN 104710372B CN 201310686927 A CN201310686927 A CN 201310686927A CN 104710372 B CN104710372 B CN 104710372B
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- 0 CCC(C)=C[C@](*CCCC(C)(C)CCC(*CC*1(C)C)[C@@]1(C1)*1=C)*1*C1 Chemical compound CCC(C)=C[C@](*CCCC(C)(C)CCC(*CC*1(C)C)[C@@]1(C1)*1=C)*1*C1 0.000 description 10
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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
Abstract
The invention discloses a kind of high-purity metconazole and preparation method thereof；Its preparation is as follows：Cyclopentanone and 4-chloro-benzaldehyde obtain exocyclic double bond α, beta unsaturated ketone (II) after condensation reaction occurs；Then react to obtain α ', the double methyl substituted exocyclic double bond α of α ', beta unsaturated ketone (III) with methylating reagent；Then react to obtain double bond is reduced 2,2 dimethyl 5 (4 chlorobenzyl) cyclopentanone (IV) with hydrogen under catalyst action；The reduzate (IV) occurs Johnson Corey Chaykovsky and reacts to obtain propylene oxide compound (V)；The finally propylene oxide compound (V) and 1,2,4 triazoles react and high-purity metconazole (I) are obtained after recrystallization.The advantages of preparation method raw material of the invention is cheap and easy to get, route is short, selectivity is good, gross production rate is high, Atom economy is good, is especially suitable for industrialized production.
Description
Technical field
The invention belongs to agricultural chemicals and chemical field, and in particular to a kind of high-purity metconazole and preparation method thereof.
Background technology
Metconazole (common name Metconazole), developed by Japanese Wu Yu (Kureha) chemical industrial company within 1986, and
With American Cyanamid Company's (being now BASF) joint development after the triazole bactericidal agent listed in 1994.Its sterling is cis and anti-
Formula mixture, white, crystalline solid, heat endurance and hydrolytic stability are good, and Cis activity is high.
Metconazole is (thin by the C-14 demethylations enzyme of the biochemical synthesis of the mycoderm component ergosterol for suppressing phytopathogen
Born of the same parents cytochrome p 450 14DM) and play a role, compared with other triazole bactericidal agents, activity profile difference is larger.Two kinds of isomers are equal
There is bactericidal activity, but it is cis higher than trans.Be mainly used in cereal crops prevent and treat short shape rust, leaf rust, yellow rust, crown rust,
Disease caused by powdery mildew, glume blight and septoria musiva, fringe sickle-like bacteria etc..It is relatively low to other animal toxicities.Rat acute
The percutaneous LD50 of LD50 661mg/kg rat acutes>2000mg/kg；Rat acute suction LC50 (4h)>5.6mg/L.To rabbit skin
It is non-stimulated, there are minimal irritation, no phenomena of cutaneous irritation to lagophthalmos.Salmonella reversion test is negative.The acute oral LD50 of Bobwhite
790mg/kg.Rainbow trout LC50 (96h) 2.2~4.0mg/L；Common carp 3.99mg/L is nontoxic to sweet peak.Water flea LC50
(48h) 3.6~4.4mg/L.Oral LDsq (24h) 97mg/L.It is nontoxic to earthworm.
The synthetic method of metconazole has multiple patent reports so far.It is substantially with 1- (4- chlorobenzyls) -2- hydroxyls -2-
Methylol -3,3- dimethylcyclopentanes or 2,2- dimethyl -5- (4- chlorobenzyls) cyclopentanone are as key intermediate.
1st, by the synthetic route of 1- (4- chlorobenzyls) -2- hydroxyl -2- methylol -3,3- dimethylcyclopentanes
For the synthesis of 1- (4- chlorobenzyls) -2- hydroxyl -2- methylol -3,3- dimethylcyclopentanes, there is documents below public
Open：
1.1 synthetic route using 5,5- dimethyl-hydroresorcinol as raw material
Nineteen ninety, Japanese Wu Yu companies are made public for the first time with 5,5- dimethyl -1, and hydroresorcinol is raw material, by 1-
The synthetic route (US5142061) of (4- chlorobenzyls) -2- hydroxyl -2- methylol -3,3- dimethylcyclopentanes：
1.2 synthetic route using 4,4- dimethyl -2- cyclonenes as raw material
1991, Shell Co. Ltd of the U.S. was disclosed with 4,4- dimethyl -2- cyclonenes as raw material, by 1- (4- benzyl chlorides
Base) -2- hydroxyl -2- methylol -3,3- dimethylcyclopentanes synthetic route (EP0474303, US5151550)：
1.3 using adipate ester as raw material
2011, BASF AG was disclosed using adipate ester as raw material, by 1- (4- chlorobenzyls) -2- hydroxyl -2- hydroxyl first
The synthetic route (WO2012041871) of base -3,3- dimethylcyclopentanes：
It is above-mentioned generally to be deposited by the synthetic route of 1- (4- chlorobenzyls) -2- hydroxyl -2- methylol -3,3- dimethylcyclopentanes
Route length (such as 1.1 need 9 steps, 1,2 need 7 steps, 1.3 need 8 steps) the shortcomings that, so not possessing industrial applications value.
2nd, by the synthetic route of 2,2- dimethyl -5- (4- chlorobenzyls) cyclopentanone
For the synthesis of 2,2- dimethyl -5- (4- chlorobenzyls) cyclopentanone, there is documents below to disclose：
The 2.1 synthetic route A using adipate ester as raw material
1987, Japanese Wu Yu companies made public for the first time metconazole bactericide and its first using adipate ester as raw material,
By 2,2- dimethyl -5- (4- chlorobenzyls) cyclopentanone synthetic route (EP0267778, US4938792, US5124345,
US5681979)：
The 2.2 synthetic route B using adipate ester as raw material
1996, Japanese Wu Yu companies were disclosed using adipate ester as raw material, by 2,2- dimethyl -5- (4- chlorobenzyls)
The synthetic route (US5519160, US5663447) of cyclopentanone：
The 2.3 synthetic route C using adipate ester as raw material
2000, Japanese Wu Yu companies were disclosed using adipate ester as raw material, by 2,2- dimethyl -5- (4- chlorobenzyls)
Another synthetic route (WO0112580, US7166750) of cyclopentanone：
There is the above-mentioned synthetic route by 2,2- dimethyl -5- (4- chlorobenzyls) cyclopentanone raw material to be easy to get (hexanedioic acid ester
It is dirt cheap and is easy to get) the advantages of, but there are still route relatively long (such as 2.2 need 8 steps, and 2,3 need 8 steps) or alkylation
Step, which has poor selectivity, causes lacking for target product low yield (all 2.1,2.1,2.3 three routes have this)
Point.The present invention is based on the studies above background, in order to solve the defects of above-mentioned route is longer, have developed one it is brand-new with honest and clean
The cyclopentanone that valency is easy to get is raw material, by the synthetic route of 2,2- dimethyl -5- (4- chlorobenzyls) cyclopentanone.The route has original
Expect cheap and easy to get, route short (total only needs 5 steps), the advantages of selectivity is good, gross production rate is high, Atom economy is good, fit very much
Close industrialized production.
In addition, studies have shown that metconazole has cis-trans-isomer, and cis-configuration therein has higher drug effect.
But metconazole product is produced and used in the form of cis-trans-isomer mixture up to now.
The content of the invention
It is an object of the invention to route existing for the synthesis technique for above-mentioned existing high-purity metconazole it is longer,
A kind of the shortcomings that raw material is not easy to obtain, yield is relatively low and economy is poor, there is provided high-purity metconazole and preparation method thereof.This
Invention provide one it is brand-new using cyclopentanone cheap and easy to get as raw material, by 2,2- dimethyl -5- (4- chlorobenzyls) ring
The synthetic route of pentanone；The route has that raw material is cheap and easy to get, route short (total only need 5 steps), the good, gross production rate of selectivity
High, the advantages of Atom economy is good, it is especially suitable for industrialized production.Also, the present invention is on the basis of said synthesis route exploitation
On also achieve the preparation of high-purity metconazole (cis-content reaches more than 99.5%, and trans content reaches less than 0.15%).
The purpose of the present invention is achieved through the following technical solutions：
The present invention relates to a kind of preparation method of high-purity metconazole, methods described comprises the following steps：
A, condensation reaction occurs for cyclopentanone and 4-chloro-benzaldehyde, obtains exocyclic double bond α, alpha, beta-unsaturated ketone (II)
Methylation reaction occurs for B, the exocyclic double bond α, alpha, beta-unsaturated ketone (II) and methylating reagent, obtains α ', α '-bis-
Methyl substituted exocyclic double bond alpha, beta-unsaturated ketone (III)
C, the α ', α '-bis- methyl substituted exocyclic double bond alpha, beta-unsaturated ketones (III) catalyst b effect under and hydrogen
Solid/liquid/gas reactions obtain 2,2- dimethyl -5- (4- chlorobenzyls) cyclopentanone (IV) that double bond is reduced；
D, Johnson-Corey-Chaykovsky occurs for 2,2- dimethyl -5- (4- chlorobenzyls) cyclopentanone (IV)
(in Johnson-section-tchaikovsky) reaction, obtain propylene oxide compound (V)；
E, the propylene oxide compound (V) and 1,2,4- triazoles are reacted, and the high-purity leaf bacterium is obtained after recrystallization
Azoles.Syntheti c route is as shown in Figure 1.
Preferably, cis-content more than 99.5% in the high-purity metconazole, trans content is below 0.15%.
Preferably, the step A is specially：Cyclopentanone is anti-at 0 DEG C~189 DEG C after being mixed with 4-chloro-benzaldehyde, catalyst a
Answer 1~12 hour；The cyclopentanone, 4-chloro-benzaldehyde, the mol ratio of catalyst are 1:(0.8~1.2):(0.01~0.5).
It is furthermore preferred that the back flow reaction is carried out under the conditions of existing for organic solvent a or in the presence of solvent-free；Institute
State organic solvent a for dichloromethane, acetone, methanol, tetrahydrofuran, ethyl acetate, ethanol, isopropanol, dioxane, toluene,
One or more of mixing in chlorobenzene, dimethyl sulfoxide, N,N-dimethylformamide.
It is furthermore preferred that the catalyst a is pyrrolidines, piperidines, morpholine, methanesulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, hydrogen
Sodium oxide molybdena or potassium hydroxide.
Preferably, the step B is specially：Alkali and first are sequentially added in batches in exocyclic double bond alpha, beta-unsaturated ketone (II)
Base reagent, under the conditions of existing for organic solvent b, reacted 1~12 hour at 0 DEG C~189 DEG C；The exocyclic double bond α, β-no
Saturated ketone (II), alkali, the mol ratio of methylating reagent are 1:(2.0~4.0):(2.5~5.0).
It is furthermore preferred that the alkali be sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, sodium tert-butoxide,
Potassium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate or butyl lithium.
It is furthermore preferred that the methylating reagent is iodomethane, dimethyl suflfate or dimethyl carbonate.
It is furthermore preferred that the organic solvent b be dichloromethane, it is acetone, methanol, tetrahydrofuran, ethyl acetate, ethanol, different
One or more of mixing in propyl alcohol, dioxane, toluene, chlorobenzene, dimethyl sulfoxide, N,N-dimethylformamide.
Preferably, the step C is specially：Under the conditions of existing for organic solvent c, mol ratio 1:(0.0001~
0.05) α ', α '-bis- methyl substituted exocyclic double bond alpha, beta-unsaturated ketones (III) are with catalyst b in 1~100atm hydrogen pressures
Reacted at room temperature 1~12 hour under power.
It is furthermore preferred that the catalyst b is palladium carbon or Raney nickel.
It is furthermore preferred that the organic solvent c be dichloromethane, it is acetone, methanol, tetrahydrofuran, ethyl acetate, ethanol, different
One or more of mixing in propyl alcohol, dioxane, toluene, chlorobenzene, dimethyl sulfoxide, N,N-dimethylformamide.
Preferably, the recrystallization process is specially：Obtained metconazole cis-trans-isomer mixture will be reacted at 40 DEG C
Organic solvent d is dissolved at~189 DEG C, is then cooled to 0~30 DEG C, the crystal of precipitation is done after being washed with cold recrystallization solvent
It is dry to obtain high-purity metconazole.
It is furthermore preferred that the organic solvent d be dichloromethane, it is acetone, methanol, tetrahydrofuran, ethyl acetate, ethanol, different
One or more of mixtures in propyl alcohol, dioxane, toluene, chlorobenzene, dimethyl sulfoxide, N,N-dimethylformamide.
The present invention first passes through three step simple reactions for raw material by cyclopentanone and synthesizes 2,2- dimethyl -5- (4- chlorobenzyls) ring penta
Ketone, then metconazole is obtained via epoxidation and open loop substitution two-step reaction, finally by being recrystallized to give the cis leaf bacterium of high-purity
Azoles.Compared with prior art, the present invention has following beneficial effect：
Overall process of the present invention has route short (amounting to only 5 steps, be metconazole synthetic route most short up to now), yield
High, the advantages of Atom economy is good, obtained product purity is high, and (cis-content reaches more than 99.5%, and trans content exists
Less than 0.15%), thus it is especially suitable for industrialized production.
Brief description of the drawings
The detailed description made by reading with reference to the following drawings to non-limiting example, further feature of the invention,
Objects and advantages will become more apparent upon：
Fig. 1 is the syntheti c route figure of high-purity metconazole；
Fig. 2 is the canonical plotting of the cis metconazole of fitting；
Fig. 3 is the canonical plotting of the trans metconazole of fitting.
Embodiment
With reference to specific embodiment, the present invention is described in detail.Following examples will be helpful to the technology of this area
Personnel further understand the present invention, but the invention is not limited in any way.It should be pointed out that the ordinary skill to this area
For personnel, without departing from the inventive concept of the premise, various modifications and improvements can be made.These belong to the present invention
Protection domain.
The synthesis of embodiment 1,2- (4- chlorine benzal) cyclopentanone (II)
In dry 150mL single port bottles, pyrrolidines (1mL, 0.0078mol, 0.1eq) is added, adds tetrahydrofuran
(70mL), cyclopentanone (6.9mL, 0.078mol, 1.0eq), 4-chloro-benzaldehyde (11.0g, 0.078mol, 1.0eq), 25 DEG C of stirrings
6 hours.Add ethyl acetate extraction, liquid separation.Target product, yield 68% are obtained after being spin-dried for.
1H NMR(400MHz,CDCl3):δ7.45-7.47(d,2H),7.37-7.39(d,2H),7.32-7.33(t,1H),
2.93-2.97(td,2H),2.39-2.43(t,2H),2.01-2.08(p,2H).
The synthesis of embodiment 2,2- (4- chlorine benzal) cyclopentanone (II)
In dry 250mL single port bottles, KOH (2.2g, 0.039mol, 0.5eq) is added, adds water (95mL), stirring is molten
Solution, add dichloromethane (70mL), cyclopentanone (6.9mL, 0.078mol, 1.0eq), 4-chloro-benzaldehyde (13.2g, 0.094mol,
1.2eq), 25 DEG C are stirred 12 hours.Add ethyl acetate extraction, liquid separation.Target product, yield 85% are obtained after being spin-dried for.
The synthesis of embodiment 3,2- (4- chlorine benzal) cyclopentanone (II)
In dry 150ml single port bottles, methanesulfonic acid (50 μ L, 0.00078mol, 0.01eq) is added, adds dimethyl sulfoxide
(70mL), cyclopentanone (6.9mL, 0.078mol, 1.0eq), 4-chloro-benzaldehyde (8.8g, 0.062mol, 0.8eq), backflow (189
DEG C) stir 1 hour.Add ethyl acetate extraction, liquid separation.Target product, yield 83% are obtained after being spin-dried for.
The synthesis of embodiment 4,2- (4- chlorine benzal) cyclopentanone (II)
In dry 50mL single port bottles, pyrrolidines (1.0mL, 0.0078mol, 0.1eq) is added, adds cyclopentanone
(6.9mL, 0.078mol, 1.0eq), 4-chloro-benzaldehyde (11.0g, 0.078mol, 1.0eq), 0 DEG C is stirred 6 hours.Add acetic acid
Ethyl ester extraction, liquid separation.Target product, yield 91% are obtained after being spin-dried for.
The synthesis of embodiment 5,2,2- dimethyl -5- (4- chlorine benzal) cyclopentanone (III)
Under nitrogen protection, dry in 10mL two-mouth bottles, addition 2- (4- chlorine benzal) cyclopentanone (0.1g, 0.484mmol,
1.0eq), potassium tert-butoxide (0.22g, 1.94mmol, 4.0eq), THF (5mL), 25 DEG C stirring 0.5 hour after iodomethane is added dropwise
(0.15mL, 2.43mmol, 5.0eq), drop finish, and 25 DEG C are reacted 6 hours.After reaction terminates, add water and ethyl acetate liquid separation, it is organic
Layer washing, is dried.Rotation obtains target product, yield 64% after removing solvent.
1H NMR(400MHz,CDCl3):δ7.55-7.57(d,2H),7.43-7.45(d,2H),7.34(s,1H),2.92-
2.96(td,2H),1.92-1.96(t,2H),1.21(s,6H).
The synthesis of embodiment 6,2,2- dimethyl -5- (4- chlorine benzal) cyclopentanone (III)
Under nitrogen protection, dry in 10mL two-mouth bottles, addition 2- (4- chlorine benzal) cyclopentanone (0.1g, 0.484mmol,
1.0eq), sodium hydride (60%) (58mg, 1.46mmol, 3.0eq), dioxane (5mL), 25 DEG C stirring 0.5 hour after be added dropwise
Dimethyl suflfate (0.184mL, 1.94mmol, 4.0eq), drop finish, and 0 DEG C is reacted 1 hour.After reaction terminates, add water and acetic acid second
Ester liquid separation, organic layer washing, is dried.Rotation obtains target product, yield 79% after removing solvent.
The synthesis of embodiment 7,2,2- dimethyl -5- (4- chlorine benzal) cyclopentanone (III)
Under nitrogen protection, dry in 10mL two-mouth bottles, addition 2- (4- chlorine benzal) cyclopentanone (0.1g, 0.484mmol,
1.0eq), cesium carbonate (0.32g, 0.97mmol, 2.0eq), dimethyl sulfoxide (5mL), 25 DEG C stirring 0.5 hour after be added dropwise carbonic acid two
Methyl esters (0.102mL, 1.21mmol, 2.5eq), drop finish, and flow back (189 DEG C) and react 12 hours.After reaction terminates, add water and acetic acid
Ethyl ester liquid separation, organic layer washing, is dried.Rotation obtains target product, yield 75% after removing solvent.
The synthesis of embodiment 8,2,2- dimethyl -5- (4- chlorobenzyls) cyclopentanone (IV)
Dry 50mL reactors, addition 2,2- dimethyl -5- (4- chlorine benzal) cyclopentanone (200mg, 0.85mmol,
1.0eq), Pd/C (5%) (18mg, 0.0085mmol, 0.01eq), vacuumizes, changes H2Two arrive three times, H25mL methanol is added under atmosphere
Solvent, it is filled with H2To 1atm, stir 6 hours at room temperature.Rotation obtains target product, yield 87% after removing solvent.
1H NMR(400MHz,CDCl3):δ7.22-7.24(d,2H),7.07-7.09(d,2H),3.04-3.08(dd,
1H),2.59-2.64(q,2H),2.39-2.47(m,1H),1.91-1.98(m,1H),1.71-1.77(m,1H),1.47-1.66
(m,2H),1.08(s,3H),0.86(s,3H).
The synthesis of embodiment 9,2,2- dimethyl -5- (4- chlorobenzyls) cyclopentanone (IV)
Dry 300mL reactors, addition 2,2- dimethyl -5- (4- chlorine benzal) cyclopentanone (2.0g, 8.5mmol,
1.0eq), Raney's nickel (25.0mg, 0.425mmol, 0.05eq), is vacuumized, and changes H2Two arrive three times, H250mL ethanol is added under atmosphere
Solvent, it is filled with H2To 10atm, stir 12 hours at room temperature.Rotation obtains target product, yield 83% after removing solvent.
The synthesis of embodiment 10,2,2- dimethyl -5- (4- chlorobenzyls) cyclopentanone (IV)
Dry 300mL reactors, addition 2,2- dimethyl -5- (4- chlorine benzal) cyclopentanone (20g, 85mmol,
1.0eq), Raney's nickel (0.5mg, 0.0085mmol, 0.0001eq), is vacuumized, and changes H2Two arrive three times, H2100mL second is added under atmosphere
Acetoacetic ester solvent, is filled with H2To 100atm, stir 1 hour at room temperature.Rotation obtains target product, yield 74% after removing solvent.
The synthesis of embodiment 11,4,4- dimethyl -7- (4- chlorobenzyls) -1- oxos-spiral shell [2,4] heptane (V)
Under nitrogen protection, in dry 25mL two-mouth bottles, potassium tert-butoxide (0.257g, 2.32mmol, 1.1eq), iodine are added
Change front three sulfoxide (0.52g, 2.32mmol, 1.1eq), inject 2.5mL dimethyl sulfoxides, 0 DEG C reaction 1 hour after, inject dissolved with
The dimethyl sulfoxide 2.5mL of 2,2- dimethyl -5- (4- chlorobenzyls) cyclopentanone (0.5g, 2.11mmol, 1.0eq), 25 DEG C of stirrings are anti-
Answer 6 hours.React after terminating, add water and ethyl acetate to extract liquid separation, organic layer washing, dry, rotation obtains target production after removing solvent
Thing, yield 75%.
1H NMR(400MHz,CDCl3):δ7.25-7.27(d,2H),7.11-7.13(d,2H),2.60-2.72(dd,
2H),2.47-2.56(m,2H),2.34-2.41(m,1H),1.65-1.81(m,2H),1.47-1.56(m,2H),1.00(s,
3H),0.88(s,3H).
The synthesis of embodiment 12,4,4- dimethyl -7- (4- chlorobenzyls) -1- oxos-spiral shell [2,4] heptane (V)
Under nitrogen protection, in dry 25mL two-mouth bottles, addition sodium hydride (60%) (0.101g, 2.53mmol,
1.2eq), iodate front three sulfoxide (0.56g, 2.53mmol, 1.2eq), 2.5mL dioxane is injected, after 0 DEG C of 1 hour of reaction,
Inject the dioxane 2.5mL dissolved with 2,2- dimethyl -5- (4- chlorobenzyls) cyclopentanone (0.5g, 2.11mmol, 1.0eq), 0 DEG C
Stirring reaction 12 hours.React after terminating, add water and ethyl acetate to extract liquid separation, organic layer washing, dry, rotation obtains after removing solvent
Target product, yield 67%.
The synthesis of embodiment 13,4,4- dimethyl -7- (4- chlorobenzyls) -1- oxos-spiral shell [2,4] heptane (V)
Under nitrogen protection, in dry 25mL two-mouth bottles, addition butyl lithium (1M) (2.11mL, 2.11mmol, 1.0eq),
Iodate trimethyl sulphur (0.47g, 2.11mmol, 1.0eq), 2.5mL tetrahydrofurans are injected, after 0 DEG C of 1 hour of reaction, injection is molten
There are the tetrahydrofuran 2.5mL of 2,2- dimethyl -5- (4- chlorobenzyls) cyclopentanone (0.5g, 2.11mmol, 1.0eq), backflow (66
DEG C) stirring reaction 1 hour.After reaction terminates, add water and ethyl acetate to extract liquid separation, organic layer washing, dry, after solvent is removed in rotation
Obtain target product, yield 72%.
The synthesis of embodiment 14, metconazole (I)
Under nitrogen protection, in dry 50mL two-mouth bottles, addition 1,2,4- triazoles (200mg, 2.9mmol, 1.45eq),
Sodium hydride (60%) (120mg, 3.0mmol, 1.5eq), 10mL n-hexanes are injected, after being stirred at room temperature 15 minutes, inject 10mL N,
Dinethylformamide, after 50 DEG C are stirred 1 hour.Injection is dissolved with 4,4- dimethyl -7- (4- chlorobenzyls) -1- oxos-spiral shell [2,4]
The DMF solution 10mL of heptane (0.5g, 2.0mmol, 1.0eq), 60~80 DEG C are reacted 2~4 hours, TLC inspections
To survey, after reaction terminates, addition water and ethyl acetate extraction liquid separation, organic layer washing, dry, rotation obtains target product after removing solvent,
Thick product yield 76%.
1H NMR(400MHz,CDCl3):δ8.15(s,1H)7.98(s,1H)7.21-7.23(d,2H),7.05-7.07(d,
2H),4.16-4.29(q,2H),3.63(s,1H),2.30-2.50(m,3H),1.66-1.81(m,2H),1.29-1.48(m,
2H),1.02(s,3H),0.61(s,3H).
The synthesis of embodiment 15, metconazole (I)
Under nitrogen protection, in dry 50mL two-mouth bottles, addition 1,2,4- triazoles (140mg, 2.0mmol, 1.0eq),
Potassium tert-butoxide (220mg, 2.0mmol, 1.0eq), 10mL dimethyl sulfoxides are injected, after 0 DEG C is stirred 2 hours.Injection is dissolved with 4,4- bis-
The dimethyl sulfoxide solution 10mL of methyl -7- (4- chlorobenzyls) -1- oxos-spiral shell [2,4] heptane (0.5g, 2.0mmol, 1.0eq), 0
DEG C reaction 12 hours, TLC detections, after reaction terminates, adds water and ethyl acetate extraction liquid separation, organic layer washing, dries, rotation goes
Target product, thick product yield 64% are obtained after solvent.
The synthesis of embodiment 16, metconazole (I)
Under nitrogen protection, in dry 50mL two-mouth bottles, addition 1,2,4- triazoles (170mg, 2.4mmol, 1.2eq),
Potassium tert-butoxide (260mg, 2.4mmol, 1.2eq), 10mL dioxane is injected, after 25 DEG C are stirred 1.5 hours.Injection is dissolved with 4,4-
The dioxane solution 10mL of dimethyl -7- (4- chlorobenzyls) -1- oxos-spiral shell [2,4] heptane (0.5g, 2.0mmol, 1.0eq),
25 DEG C are reacted 6 hours, TLC detections, after reaction terminates, are added water and ethyl acetate extraction liquid separation, organic layer washing, are dried, rotation
Target product, thick product yield 82% are obtained after removing solvent.
Embodiment 17, recrystallization high-purity metconazole
In dry single port bottle, dichloromethane 2mL is added, thick finished product (along 83.69%, anti-11.74%) 1g, stirring, adds
Heat be warming up to backflow (40 DEG C) make sample all dissolving after, be put into rapidly in 0 DEG C of frozen water and cool, stand still for crystals.Filter, with 0 DEG C
Isopropanol washes one to twice.Vacuum drying, yield 86%, sample is through high performance liquid chromatography detection, cis-content 97.71%,
Trans content is 2.02%.
Embodiment 18, recrystallization high-purity metconazole
In dry single port bottle, acetonitrile 2mL is added, (along 83.69%, anti-11.74%) 1g, stirring, heating rises thick finished product
After temperature makes sample all dissolve to backflow (82 DEG C), it is put into rapidly in 20 DEG C of water and cools, stand still for crystals.Filter, with 20 DEG C of acetonitriles
One is washed to twice.Vacuum drying, yield 82%, sample are trans to contain through high performance liquid chromatography detection, cis-content 98.03%
Measure as 1.43%.
Embodiment 19, recrystallization high-purity metconazole
In dry single port bottle, dimethyl sulfoxide 2mL is added, thick finished product (along 83.69%, anti-11.74%) 1g, stirring, adds
Heat be warming up to backflow (189 DEG C) make sample all dissolving after, be put into rapidly in 30 DEG C of water and cool, stand still for crystals.Filter, with 30 DEG C
Toluene washes one to twice.Vacuum drying, yield 87%, sample is through high performance liquid chromatography detection, cis-content 97.18%, instead
Formula content is 2.15%.
Embodiment 20, recrystallization high-purity metconazole
In dry single port bottle, dioxane 2mL is added, thick finished product (along 83.69%, anti-11.74%) 1g, stirring, adds
Heat be warming up to backflow (101 DEG C) make sample all dissolving after, be put into rapidly in 0 DEG C of frozen water and cool, stand still for crystals.Filter, with 0 DEG C
Dioxane washes one to twice.Vacuum drying, yield 72%, sample are through high performance liquid chromatography detection, cis-content
98.03%, trans content 1.22%.
Embodiment 21, recrystallization high-purity metconazole
In dry single port bottle, isopropanol 2mL is added, thick finished product (along 83.69%, anti-11.74%) 1g, stirs, heating
Be warming up to backflow (82 DEG C) make sample all dissolving after, be placed in 25 DEG C of coolings, stand still for crystals.Filter, one to two are washed with isopropanol
It is secondary.Vacuum drying, yield 80%.Sample is through high performance liquid chromatography detection, cis-content 99.62%, trans content
0.12%.
The efficient liquid phase characterizing method of metconazole purity is as follows in above example 17~21：
According to standard sample data first, percentage composition are ordinate, and area is abscissa, are fitted to corresponding curve point
Not as shown in Figure 2,3, A is cis in wherein Fig. 2, and B is trans in Fig. 3, and each area is the average value of 3 data；Then 3 times
Measurement sample tries to achieve A, B area average, and the standard curve for being substituted into the cis and trans sample of above-mentioned fitting obtains purity
Data；A%=2.86525 × 10 in Fig. 2-5B%=2.84758 × 10 in area, Fig. 3-5area。
The specific embodiment of the present invention is described above.It is to be appreciated that the invention is not limited in above-mentioned
Particular implementation, those skilled in the art can make various deformations or amendments within the scope of the claims, this not shadow
Ring the substantive content of the present invention.
Claims (7)
1. a kind of preparation method of metconazole, it is characterised in that methods described comprises the following steps：
A, condensation reaction occurs for cyclopentanone and 4-chloro-benzaldehyde, obtains exocyclic double bond α, alpha, beta-unsaturated ketone (II)
Methylation reaction occurs for B, the exocyclic double bond α, alpha, beta-unsaturated ketone (II) and methylating reagent, obtains α ', α '-bis- methyl
Substituted exocyclic double bond alpha, beta-unsaturated ketone (III)
C, the α ', α '-bis- methyl substituted exocyclic double bond alpha, beta-unsaturated ketones (III) are under catalyst b effects and hydrogen is anti-
2,2- dimethyl -5- (4- chlorobenzyls) cyclopentanone (IV) that double bond is reduced should be obtained
D, Johnson-Corey-Chaykovsky reactions occur for 2,2- dimethyl -5- (4- chlorobenzyls) cyclopentanone (IV),
Obtain propylene oxide compound (V)
E, the propylene oxide compound (V) and 1,2,4- triazoles are reacted, and the metconazole is obtained after recrystallization；
The step A is specially：Cyclopentanone is small in 0 DEG C~189 DEG C reactions 1~12 after being mixed with 4-chloro-benzaldehyde, catalyst a
When；The cyclopentanone, 4-chloro-benzaldehyde, catalyst a mol ratio are 1:(0.8~1.2):(0.01~0.5)；The reaction is
Carried out under the conditions of existing for organic solvent a or in the presence of solvent-free；The organic solvent a is dichloromethane, acetone, first
Alcohol, tetrahydrofuran, ethyl acetate, ethanol, isopropanol, dioxane, toluene, chlorobenzene, dimethyl sulfoxide, N,N-dimethylformamide
In one or more of mixing；
The step B is specially：Alkali and methylating reagent are sequentially added in batches in exocyclic double bond α, alpha, beta-unsaturated ketone (II),
Under the conditions of organic solvent b is existing, reacted 1~12 hour at 0 DEG C~189 DEG C；The exocyclic double bond alpha, beta-unsaturated ketone (II),
Alkali, the mol ratio of methylating reagent are 1:(2.0~4.0):(2.5~5.0)；
The step C is specially：Under the conditions of existing for organic solvent c, mol ratio 1:The α ' of (0.0001~0.05), α '-
Double methyl substituted exocyclic double bond alpha, beta-unsaturated ketones (III) react at room temperature 1 with catalyst b under 1~100atm Hydrogen Vapor Pressures
~12 hours；
In the step D, Johnson-Corey-Chaykovsky reactions are：
Under nitrogen protection, in dry 25mL two-mouth bottles, 0.257g potassium tert-butoxides, 0.52g iodate front three sulfoxides, injection are added
2.5mL dimethyl sulfoxides, after 0 DEG C of 1 hour of reaction, inject dissolved with 0.5g 2, the two of 2- dimethyl -5- (4- chlorobenzyls) cyclopentanone
First sulfoxide 2.5mL, 25 DEG C of stirring reactions 6 hours；
Or under nitrogen protection, in dry 25mL two-mouth bottles, add 2.11mL 1M butyl lithiums, 0.47g iodate trimethyl sulphur, note
Enter 2.5mL tetrahydrofurans, after 0 DEG C of 1 hour of reaction, inject dissolved with 0.5g 2,2- dimethyl -5- (4- chlorobenzyls) cyclopentanone
Tetrahydrofuran 2.5mL, 66 DEG C of return stirrings react 1 hour；
In the step E, propylene oxide compound (V) and 1,2,4- triazoles, which react, is：
Under nitrogen protection, in dry 50mL two-mouth bottles, the triazoles of 200mg 1,2,4-, the sodium hydrides of 120mg 60%, note are added
Enter 10mL n-hexanes, after being stirred at room temperature 15 minutes, inject 10mL DMFs, after 50 DEG C are stirred 1 hour, injection
Dissolved with 0.5g 4, the DMF solution of 4- dimethyl -7- (4- chlorobenzyls) -1- oxos-spiral shell [2,4] heptane
10mL, 60~80 DEG C are reacted 2~4 hours, TLC detections；
Or under nitrogen protection, in dry 50mL two-mouth bottles, add the triazoles of 170mg 1,2,4-, 260mg potassium tert-butoxides, injection
10mL dioxane, after 25 DEG C are stirred 1.5 hours, inject dissolved with 0.5g 4,4- dimethyl -7- (4- chlorobenzyls) -1- oxos-spiral shell
The dioxane solution 10mL of [2,4] heptane, 25 DEG C are reacted 6 hours, TLC detections；
The recrystallization process is specially：It is molten at 40 DEG C~189 DEG C that obtained metconazole cis-trans-isomer mixture will be reacted
Then solution is cooled to 0~30 DEG C in organic solvent d, the crystal of precipitation is dried to obtain high-purity after being washed with cold recrystallization solvent
Spend metconazole；The organic solvent d is dichloromethane, acetone, methanol, tetrahydrofuran, ethyl acetate, acetonitrile, ethanol, isopropyl
One or more of mixtures in alcohol, dioxane, toluene, chlorobenzene, N,N-dimethylformamide.
2. the preparation method of metconazole as claimed in claim 1, it is characterised in that the catalyst a be pyrrolidines, piperidines,
Morpholine, methanesulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, sodium hydroxide or potassium hydroxide.
3. the preparation method of metconazole as claimed in claim 1, it is characterised in that the alkali is sodium hydride, sodium hydroxide, hydrogen
Potassium oxide, lithium hydroxide, cesium hydroxide, sodium tert-butoxide, potassium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate or butyl lithium.
4. the preparation method of metconazole as claimed in claim 1, it is characterised in that the methylating reagent is iodomethane, sulphur
Dimethyl phthalate or dimethyl carbonate.
5. the preparation method of metconazole as claimed in claim 1, it is characterised in that the organic solvent b is dichloromethane, third
Ketone, methanol, tetrahydrofuran, ethyl acetate, ethanol, isopropanol, dioxane, toluene, chlorobenzene, dimethyl sulfoxide, N, N- dimethyl
One or more of mixing in formamide.
6. the preparation method of metconazole as claimed in claim 1, it is characterised in that the catalyst b is palladium carbon or Raney's nickel.
7. the preparation method of metconazole as claimed in claim 1, it is characterised in that the organic solvent c is dichloromethane, third
Ketone, methanol, tetrahydrofuran, ethyl acetate, ethanol, isopropanol, dioxane, toluene, chlorobenzene, dimethyl sulfoxide, N, N- dimethyl
One or more of mixing in formamide.
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| CN106699559B (en) * | 2015-11-12 | 2021-04-06 | 浙江九洲药业股份有限公司 | Preparation process of loxoprofen sodium |
| CN106045830B (en) * | 2016-06-01 | 2021-07-09 | 上海试四赫维化工有限公司 | Preparation method of 2, 2-dimethyl-5- (4-chlorobenzyl) cyclopentanone |
| GB2581208B (en) * | 2019-02-11 | 2021-07-28 | Rotam Agrochem Int Co Ltd | A novel form of metconazole, a process for its preperation and use of the same |
| CN111718304A (en) * | 2020-05-30 | 2020-09-29 | 上海赫腾精细化工有限公司 | Synthetic method of triazole bactericide |
| CN113429273A (en) * | 2021-06-09 | 2021-09-24 | 江苏省农用激素工程技术研究中心有限公司 | Synthesis method of metconazole intermediate |
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