CN101798290B - Method for synthesizing chiral cyproconazole - Google Patents
Method for synthesizing chiral cyproconazole Download PDFInfo
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- CN101798290B CN101798290B CN2010101380527A CN201010138052A CN101798290B CN 101798290 B CN101798290 B CN 101798290B CN 2010101380527 A CN2010101380527 A CN 2010101380527A CN 201010138052 A CN201010138052 A CN 201010138052A CN 101798290 B CN101798290 B CN 101798290B
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- UFNOUKDBUJZYDE-UHFFFAOYSA-N 2-(4-chlorophenyl)-3-cyclopropyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol Chemical compound C1=NC=NN1CC(O)(C=1C=CC(Cl)=CC=1)C(C)C1CC1 UFNOUKDBUJZYDE-UHFFFAOYSA-N 0.000 title claims abstract description 40
- 239000005757 Cyproconazole Substances 0.000 title claims abstract description 40
- 238000000034 method Methods 0.000 title claims abstract description 21
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 47
- 238000006735 epoxidation reaction Methods 0.000 claims abstract description 35
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000003054 catalyst Substances 0.000 claims abstract description 14
- XYDYWTJEGDZLTH-UHFFFAOYSA-N methylenetriphenylphosphorane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=C)C1=CC=CC=C1 XYDYWTJEGDZLTH-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000002994 raw material Substances 0.000 claims abstract description 12
- 229910052723 transition metal Inorganic materials 0.000 claims abstract description 12
- 150000003624 transition metals Chemical class 0.000 claims abstract description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 10
- SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical compound N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 claims description 12
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- -1 tertbutanol peroxide Chemical class 0.000 claims description 11
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- 238000010792 warming Methods 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 6
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- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
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- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical group OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 4
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 claims description 4
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- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 3
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- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 3
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- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical group CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 claims description 3
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- 241000723346 Cinnamomum camphora Species 0.000 description 1
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- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- DNVPQKQSNYMLRS-NXVQYWJNSA-N Ergosterol Natural products CC(C)[C@@H](C)C=C[C@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@@H]3CC[C@]12C DNVPQKQSNYMLRS-NXVQYWJNSA-N 0.000 description 1
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- ZBIKORITPGTTGI-UHFFFAOYSA-N [acetyloxy(phenyl)-$l^{3}-iodanyl] acetate Chemical compound CC(=O)OI(OC(C)=O)C1=CC=CC=C1 ZBIKORITPGTTGI-UHFFFAOYSA-N 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
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- YIKMRTHKLRXOBU-UHFFFAOYSA-N bromomethane;triphenylphosphane Chemical compound BrC.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YIKMRTHKLRXOBU-UHFFFAOYSA-N 0.000 description 1
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- Epoxy Compounds (AREA)
Abstract
The invention provides a method for synthesizing chiral cyproconazole, which comprises the following steps: carrying out ylide reaction on 1-(4-chlorphenyl)-2-cyclopropyl-1-acetone used as the raw material and methylidene triphenyl phosphorane to generate 1-(4-chlorphenyl)-2-cyclopropyl-1-propylene; carrying out epoxidation reaction on the 1-(4-chlorphenyl)-2-cyclopropyl-1-propylene and an epoxidation reagent under the action of a transition metal catalyst to produce an epoxidation intermediate; and carrying out ring opening on the epoxidation intermediate and 1,2,4-triazole to obtain the target product chiral cyproconazole. The chiral cyproconazole synthesized by the method of the invention has the advantages of high optical purity (e.e% is greater than 80%) and high total reaction yield (greater than 75%), and is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of synthesis technique of agricultural chemicals cyproconazole, particularly a kind of novel method of synthesis of chiral cyproconazole.
Background technology
The optical activity agricultural chemicals is chemistry of pesticide one of active research field relatively in the world at present.According to recent statistics, have 28% to be chipal compounds in the commercial agrochemicals.Surplus commercial 170 in kind of the chirality agricultural chemicals; Annual sales amount surpass 100,000,000 dollars have 30 surplus kind; Surpass 2,500 ten thousand dollars have 60 surplus kind; The chirality agricultural chemicals sales volume that wherein contains high reactivity chiral isomer composition surpasses 10,000,000,000 dollars, and the chirality agricultural chemicals annual sales amount of pure optically active isomer is near 3,000,000,000 dollars, and the chirality agricultural chemicals accounts for 35% of global agricultural chemicals market.
From the biological activity angle, the drug effect of optical activity agricultural chemicals and raceme preparation differs greatly, and the drug effect that has differs hundreds of times; From the environmental protection type agricultural angle, use the optical activity agricultural chemicals, can reduce dosage, alleviate toxicity and improve security, satisfied the new demand that social development proposes agricultural chemicals; See that from the economic benefit angle exploitation optical activity agricultural chemicals can conservation, reduces cost.
Cyproconazole is the triazole bactericidal agent of Switzerland mountain pass scholar company (Sandoz AG) exploitation; It is ergosterol demethylation suppressor factor; Have the effect of prevention and treatment, all effective to the Erysiphe on cereal crop, coffee, beet, fruit tree and the grape, Uredinales, the mould Pseudomonas of spore, Rhynchosporium spp, Septoria, Venturia germ, can prevent and treat cereal and coffee rust; Cereal, fruit tree and uncinula necator; Peanut, beet leaves pinta, scab of apple and peanut white rot can also be used with other sterilant.Cyproconazole 1989 is at first released as the sterilant of wheat class foliage-spray in France, afterwards as seed treatment agent, is widely used in the seed treatment of the winter wheat and the cotton of West Europe, the U.S..
Cyproconazole is the triazole bactericidal agent that contains a chiral centre, adopts the carbonyl epoxy method at present, with 1; 2; 4-triazole ring opening synthesis, the cyproconazole that obtains is a racemic modification, and is as shown in Figure 1; Also mainly with the sold-in and the use of raceme,, research obviously is superior to racemic modification on the market yet showing the drug effect of the single optical isomer of cyproconazole.But, the method for the synthesis of chiral cyproconazole of having reported at present, route is complicated, and condition is harsh, and is with high costs, is not suitable for large-scale commercial prodn.
The synthesis of chiral medicine has chiral separation and the synthetic two kinds of means of asymmetry catalysis after the chemosynthesis usually.The former need consume the chiral separation agent of equivalent when synthetic drugs, in the medicine with several chiral centres is synthetic, its consumption will be doubled and redoubled.The latter only needs a spot of chiral catalyst, just can synthesize a large amount of chiral drugs, and pollutes for a short time, is that the green of compliance with environmental protection requirements is synthesized.Over nearly more than 30 years, along with the fast development of Organometallic Chemistry, chiral catalyst and asymmetric catalysis constantly make progress, and fine chemical products such as many chiral medicinals, agricultural chemicals and spices form scale prodn gradually.Because asymmetry catalysis is synthetic to have efficient, highly selective, by product is few, environmentally friendly and characteristics such as Atom economy, might become the main means of production of chirality agricultural chemicals future.
Summary of the invention
The novel method that the purpose of this invention is to provide a kind of synthesis of chiral cyproconazole, this method be on existing technology basis through transition metal-catalyzed down, the asymmetric Epoxidation of alkene is realized.
The asymmetric epoxidation reaction of transition metal-catalyzed two keys has very consequence in chiral drug synthetic, and epoxidation reaction is the essential step of the suitability for industrialized production of cyproconazole sterilant.
In order to realize the object of the invention, the present invention provides a kind of synthesizing chiral cyproconazole, and it comprises the steps:
1) be that raw material (compound 3) generates 1-(4-chloro-phenyl-)-2-cyclopropyl-1-propylene A with the reaction of methylene tri phenyl phosphorus ylide with 1-(4-chloro-phenyl-)-2-cyclopropyl-1-acetone;
2) 1-(4-chloro-phenyl-)-2-cyclopropyl-1-propylene A and epoxidation reagent are produced the epoxidation intermediate B in the effect initial ring oxidizing reaction of transition-metal catalyst;
3) epoxidation intermediate B and 1,2, the open loop of 4-triazole obtains the title product cyproconazole.
The building-up reactions formula of chiral cyproconazole of the present invention is as shown in Figure 2.
Wherein, the mol ratio of 1-(4-chloro-phenyl-)-2-cyclopropyl-1-acetone and methylene tri phenyl phosphorus ylide is 1 in the step 1): (1-3);
In reaction process, earlier 1-(4-chloro-phenyl-)-2-cyclopropyl-1-acetone is dissolved in organic solvent, maintain the temperature at-20-0 ℃, add methylene tri phenyl phosphorus ylide then, after finishing, be warmed up to room temperature, stirred 4-12 hour under the room temperature.
Can in system, add entry after reaction finishes and carry out the cancellation reaction.
The mol ratio of 1-(4-chloro-phenyl-)-2-cyclopropyl-1-acetone and water is 1: (6-12).
Said organic solvent is preferably toluene, YLENE, benzene, THF, dioxane or ether.
Said methylene tri phenyl phosphorus ylide is prepared according to ordinary method by triphenylphosphine monobromomethane and n-Butyl Lithium.
The mol ratio of 1-(4-chloro-phenyl-) step 2)-2-cyclopropyl-1-propylene, transition-metal catalyst and epoxidation reagent is 1: (0.001-0.01): (1.5-3).
Earlier 1-(4-chloro-phenyl-)-2-cyclopropyl-1-propylene and transition-metal catalyst are dissolved in organic solvent, keep 0-10 ℃ of temperature, add epoxidation reagent then, be warming up to 30-80 ℃, reacted 4-12 hour.
Said organic solvent is preferably toluene, YLENE, benzene, THF (THF), dioxane, ether, N (DMF) or acetonitrile.
Said transition-metal catalyst is Cu, Fe, Ni, Co, Mn, Cr, Ti class catalyzer, can be its metal-salt, and complex compound or inner complex are preferably ferrocene, titanous chloride, cadmium trichloride, tetraisopropoxy titanium or salen-Mn complex compound.
Described epoxidation reagent is a superoxide.
Described superoxide is preferably metachloroperbenzoic acid (mCPBA), tertbutanol peroxide or ozone.
Epoxidation midbody and 1,2 in the step 3), the mol ratio of 4-triazole are 1: (2-5).
In reaction process, epoxidation midbody elder generation and solid alkali and 1,2, the 4-triazole is dissolved in organic solvent, adds phase-transfer catalyst then, and control reaction temperature is at 60-120 ℃.
Mol ratio between epoxidation midbody, solid alkali, the phase-transfer catalyst is 1: (01-1.5): (0.005-0.05).
Said organic solvent is preferably DMF, DMSO 99.8MIN. (DMSO) or N-Methyl pyrrolidone.
Said solid alkali comprises sodium hydroxide, Pottasium Hydroxide, salt of wormwood or sodium methylate.
Said phase-transfer catalyst comprises Tetrabutyl amonium bromide, benzyltriethylammoinium chloride or polyoxyethylene glycol.
Specifically, preparation method of the present invention comprises the steps:
1) 1-(4-chloro-phenyl-)-2-cyclopropyl-1-propylene A
With 1-(4-chloro-phenyl-)-2-cyclopropyl-1-acetone is that raw material ( compound 3,1 equivalents) is dissolved in organic solvent, maintains the temperature at-20-0 ℃; In system, drip methylene tri phenyl phosphorus ylide (1-3 equivalent); After dropwising, slowly be warmed up to room temperature, stirred 4-12 hour under the room temperature; After reaction finished, underpressure distillation got 1-(4-chloro-phenyl-)-2-cyclopropyl-1-propylene A;
2) epoxidation intermediate B
The transition-metal catalyst (0.001-0.01 equivalent) of 1-(4-chloro-phenyl-)-2-cyclopropyl-1-propylene A (1 equivalent) and catalytic amount is dissolved in organic solvent, keeps 0-10 ℃ of temperature, in system, add epoxidation reagent (1.5-3 equivalent); Be warming up to 30-80 ℃; Reacted 4-12 hour, reaction adds water stratification and washs neutrality after finishing; Organic phase reclaim under reduced pressure, residuum be not purified directly to be used for next step reaction;
3) cyproconazole is synthetic
Get epoxidation midbody (1 equivalent), solid alkali (0.1-1.5 equivalent) and 1,2; 4-triazole (2-5 equivalent) is dissolved in organic solvent, in system, adds phase-transfer catalyst (0.005-0.05 equivalent), and control reaction temperature is at 60-120 ℃; Gas chromatographic analysis epoxy intermediate B content finishes less than reaction in 1% o'clock, obtains the bullion of cyproconazole, and recrystallization obtains the pure article of cyproconazole; HPLC purity＞95%, e.e%＞80%.
Described recrystallization solvent comprises toluene, YLENE, methylene dichloride, chloroform, sherwood oil.
For increasing the chiral selectivity of reaction; Can also be in step 2) in system, add chiral ligand; Described chiral ligand comprises tartrate, DAIB (isocamphol), camphor sulfonamide and verivate thereof, BINOL (1-dinaphthol), 2 part or porphyrin.Its consumption is identical with the consumption of transition-metal catalyst.
Compare with existing compound method, the present invention has following advantage:
1) synthetic chiral cyproconazole optical purity of products of the present invention is high, HPLC purity＞95%, e.e%＞80%;
2) do not change the existing route of producing, only need on the basis of existing production technique and equipment, simply adjust, total recovery height＞75% is fit to industrial production;
3) the used transition-metal catalyst of the present invention can reclaim, the recovery＞95%;
4) production cost is slightly higher than the production cost of racemize cyproconazole, but anti-microbial activity obviously is superior to the racemize cyproconazole, and the unit drug effect improves 40-50% than similar racemic modification.
Description of drawings
Fig. 1 is the synthesis technique of existing racemize cyproconazole;
Fig. 2 is the building-up reactions formula of chiral cyproconazole according to the invention.
Embodiment
Following examples are used to explain the present invention, but are not used for limiting scope of the present invention.
1) 1-(4-chloro-phenyl-)-2-cyclopropyl-1-propylene A
(20.8g 100mmol) is dissolved in the pre-dried toluene, maintains the temperature at-20 ℃ with 1-(4-chloro-phenyl-)-2-cyclopropyl-1-acetone; (41.5g in the toluene solution of the methylene tri phenyl phosphorus ylide that dropping prepares in advance in system; 150mmol, 1mol/L), after dropwising; Slowly be warmed up to room temperature; Stirred under the room temperature 6 hours, gas chromatographic analysis raw material 1-(4-chloro-phenyl-)-2-cyclopropyl-1-acetone content finishes less than reaction in 1% o'clock, the shrend that in reaction system, the adds 0.6mol reaction of going out.Underpressure distillation gets 1-(4-chloro-phenyl-)-2-cyclopropyl-1-propylene 19.5g, yield 95%.
2) the epoxidation intermediate B is synthetic
(20.6g is 100mmol) with the tetraisopropoxy titanium (5 * 10 of catalytic amount with 1-(4-chloro-phenyl-)-2-cyclopropyl-1-propylene A
-4Mol) be dissolved in DMF, keep 10 ℃ of temperature, in system, add tertbutanol peroxide (13.5g; 150mmol), be warming up to 40 ℃, reacted 6 hours; After gas chromatographic analysis raw material 1-(4-chloro-phenyl-)-2-cyclopropyl-1-propylene A disappears; Add water stratification and wash neutrality, the organic phase reclaim under reduced pressure, residuum is not purified directly to be used for next step reaction.
3) cyproconazole is synthetic
(22.2g, 100mmol), (0.8g, 20mmol) with 1,2, (13.8g 200mmol) is dissolved in DMF to the 4-triazole to sodium hydroxide, in system, adds 5 * 10 to get the epoxidation midbody
-4The Tetrabutyl amonium bromide of mole, control reaction temperature are at 60 ℃, and gas chromatographic analysis epoxy intermediate B content finishes less than reaction in 1% o'clock; Obtain the bullion of cyproconazole, the toluene recrystallization obtains the pure article of cyproconazole, yield 80%; HPLC purity 95.5%, e.e%:84%.
1) 1-(4-chloro-phenyl-)-2-cyclopropyl-1-propylene A's is synthetic
(20.8g 100mmol) is dissolved in the pre-dried dioxane, maintains the temperature at-10 ℃ with 1-(4-chloro-phenyl-)-2-cyclopropyl-1-acetone; (55.3g in the dioxane solution of the methylene tri phenyl phosphorus ylide that dropping prepares in advance in system; 200mmol, 1mol/L), after dropwising; Slowly be warmed up to room temperature; Stirred under the room temperature 8 hours, gas chromatographic analysis raw material 1-(4-chloro-phenyl-)-2-cyclopropyl-1-acetone content is less than 1%, and reaction finishes the back adds 1mol in reaction system the shrend reaction of going out.Underpressure distillation gets 1-(4-chloro-phenyl-)-2-cyclopropyl-1-propylene 19.2g, yield 93.1%.
2) the epoxidation intermediate B is synthetic
(20.6g is 100mmol) with the salen-Mn (1 * 10 of catalytic amount with 1-(4-chloro-phenyl-)-2-cyclopropyl-1-propylene A
-4Mol) be dissolved in toluene, keep 0 ℃ of temperature, in system, add mCPBA (25.9g; 150mmol), be warming up to 50 ℃, reacted 8 hours; After gas chromatographic analysis raw material 1-(4-chloro-phenyl-)-2-cyclopropyl-1-propylene A disappears; Add water stratification and wash neutrality, the organic phase reclaim under reduced pressure, residuum is not purified directly to be used for next step reaction.
3) cyproconazole is synthetic
Get the epoxidation midbody (22.2g, 100mmol), Pottasium Hydroxide (5.6g 100mmol) and 1,2; (27.6g 400mmol) is dissolved in DMSO to the 4-triazole, in system, adds 0.001 mole benzyltriethylammoinium chloride, and control reaction temperature is at 100 ℃; Gas chromatographic analysis epoxy intermediate B content finishes less than reaction in 1% o'clock, obtains the bullion of cyproconazole, and the methylene dichloride recrystallization obtains the pure article of cyproconazole; Yield 87%, HPLC purity 97%, e.e%:83%.
1) 1-(4-chloro-phenyl-)-2-cyclopropyl-1-propylene A's is synthetic
(20.8g 100mmol) is dissolved among the pre-dried THF, maintains the temperature at 0 ℃ with 1-(4-chloro-phenyl-)-2-cyclopropyl-1-acetone; In the THF solution of the methylene tri phenyl phosphorus ylide that dropping prepares in advance in system (82.8g, 300mmol, 1mol/L); After dropwising, slowly be warmed up to room temperature, stirred 4 hours under the room temperature; Gas chromatographic analysis raw material 1-(4-chloro-phenyl-)-2-cyclopropyl-1-acetone content is less than 1%, and reaction finishes the back adds 1.2mol in reaction system the shrend reaction of going out.Underpressure distillation gets 1-(4-chloro-phenyl-)-2-cyclopropyl-1-propylene A 20g, yield 97.2%.
2) the epoxidation intermediate B is synthetic
With 1-(4-chloro-phenyl-)-2-cyclopropyl-1-propylene A (20.6g, 100mmol), the titanous chloride (5 * 10 of catalytic amount
-4Mol) and 2 part (5 * 10
-4Mol) be dissolved in the dioxane, keep 5 ℃ of temperature, in system, feed ozone; Be warming up to 80 ℃; Reacted 12 hours, gas chromatographic analysis raw material 1-(4-chloro-phenyl-)-2-cyclopropyl-1-propylene A adds water stratification and washs neutrality after disappearing; Organic phase reclaim under reduced pressure, residuum be not purified directly to be used for next step reaction.
3) cyproconazole is synthetic
Get the epoxidation midbody (22.2g, 100mmol), (6.9g is 50mmol) with 1 for salt of wormwood; 2, (34.5g 500mmol) is dissolved in N-Methyl pyrrolidone to the 4-triazole, in system, adds 0.003 mole polyoxyethylene glycol; Control reaction temperature is at 120 ℃, and gas chromatographic analysis epoxy intermediate B content finishes less than reaction in 1% o'clock, obtains the bullion of cyproconazole, and the YLENE recrystallization obtains the pure article of cyproconazole; Yield 85%, HPLC purity 98.5%, e.e%:89%.
1) 1-(4-chloro-phenyl-)-2-cyclopropyl-1-propylene A's is synthetic
(20.8g 10mmol) is dissolved in the pre-dried ether, maintains the temperature at-20 ℃ with 1-(4-chloro-phenyl-)-2-cyclopropyl-1-acetone; (27.6g in the diethyl ether solution of the methylene tri phenyl phosphorus ylide that dropping prepares in advance in system; 10mmol, 1mol/L), after dropwising; Slowly be warmed up to room temperature; Stirred under the room temperature 12 hours, gas chromatographic analysis raw material 1-(4-chloro-phenyl-)-2-cyclopropyl-1-acetone content is less than 1%, and reaction finishes the back adds 60mmol in reaction system the shrend reaction of going out.Underpressure distillation gets 1-(4-chloro-phenyl-)-2-cyclopropyl-1-propylene A 19.8g, yield 96%.
2) the epoxidation intermediate B is synthetic
With 1-(4-chloro-phenyl-)-2-cyclopropyl-1-propylene A (20.6g, 100mmol), the cadmium trichloride (5 * 10 of catalytic amount
-4Mol) and porphyrin (5 * 10
-4Mol) be dissolved in acetonitrile, keep 4 ℃ of temperature, in system, add tertbutanol peroxide (13.5g; 150mmol), be warming up to 30 ℃, reacted 4 hours; After gas chromatographic analysis raw material 1-(4-chloro-phenyl-)-2-cyclopropyl-1-propylene A disappears; Add water stratification and wash neutrality, the organic phase reclaim under reduced pressure, residuum is not purified directly to be used for next step reaction.
3) cyproconazole is synthetic
Get the epoxidation midbody (22.2g, 100mmol), (8.1g is 150mmol) with 1 for sodium methylate; 2, (17.3g 250mmol) is dissolved in DMF to the 4-triazole, in system, adds 0.005 mole Tetrabutyl amonium bromide; Control reaction temperature is at 100 ℃, and gas chromatographic analysis epoxy intermediate B content finishes less than reaction in 1% o'clock, obtains the bullion of cyproconazole, and the chloroform recrystallization obtains the pure article of cyproconazole; Yield 83%, HPLC purity 97.5%, e.e%:87%.
Though, the present invention has been done detailed description in the preceding text with general explanation and specific embodiments, on basis of the present invention, can to some modifications of do or improvement, this will be apparent to those skilled in the art.Therefore, these modifications or the improvement on the basis of not departing from spirit of the present invention, made all belong to the scope that requirement of the present invention is protected.
Claims (9)
1. a synthesizing chiral cyproconazole is characterized in that it comprises the steps:
1) be that raw material and the reaction of methylene tri phenyl phosphorus ylide generate 1-(4-chloro-phenyl-)-2-cyclopropyl-1-propylene with 1-(4-chloro-phenyl-)-2-cyclopropyl-1-acetone;
2) 1-(4-chloro-phenyl-)-2-cyclopropyl-1-propylene and epoxidation reagent are in the effect initial ring oxidizing reaction of transition-metal catalyst; Produce the epoxidation midbody; Said transition-metal catalyst is tetraisopropoxy titanium, titanous chloride, cadmium trichloride or salen-Mn complex compound, and described epoxidation reagent is metachloroperbenzoic acid, tertbutanol peroxide or ozone;
3) epoxidation midbody and 1,2, the open loop of 4-triazole obtains chiral cyproconazole.
2. method according to claim 1 is characterized in that, the mol ratio of 1-in the step 1) (4-chloro-phenyl-)-2-cyclopropyl-1-acetone and methylene tri phenyl phosphorus ylide is 1: (1-3).
3. method according to claim 1 and 2; It is characterized in that, adopt in the step 1) earlier 1-(4-chloro-phenyl-)-2-cyclopropyl-1-acetone to be dissolved in organic solvent, maintain the temperature at-20-0 ℃; Add methylene tri phenyl phosphorus ylide then; After finishing, be warmed up to room temperature, stirred 4-12 hour under the room temperature.
4. method according to claim 3 is characterized in that, in system, adds entry after reaction finishes in the step 1) and carries out the cancellation reaction, and the mol ratio of 1-(4-chloro-phenyl-)-2-cyclopropyl-1-acetone and water is 1: (6-12).
5. according to the said method of claim 1, it is characterized in that step 2) in the mol ratio of 1-(4-chloro-phenyl-)-2-cyclopropyl-1-propylene, transition-metal catalyst and epoxidation reagent be 1: (0.001-0.01): (1.5-3).
6. method according to claim 5 is characterized in that step 2) in earlier 1-(4-chloro-phenyl-)-2-cyclopropyl-1-propylene and transition-metal catalyst are dissolved in organic solvent; Keep 0-10 ℃ of temperature; Add epoxidation reagent then, be warming up to 30-80 ℃, reacted 4-12 hour.
7. method according to claim 1 is characterized in that, epoxidation midbody and 1,2 in the step 3), and the mol ratio of 4-triazole is 1: (2-5).
8. method according to claim 7 is characterized in that, in the step 3) in reaction process, the epoxidation midbody earlier with solid alkali and 1,2, the 4-triazole is dissolved in organic solvent, adds phase-transfer catalyst then, control reaction temperature is at 60-120 ℃.
9. method according to claim 8 is characterized in that said solid alkali is selected from sodium hydroxide, Pottasium Hydroxide, salt of wormwood or sodium methylate; Said phase-transfer catalyst comprises Tetrabutyl amonium bromide, benzyltriethylammoinium chloride or polyoxyethylene glycol.
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| CN101357906A (en) * | 2008-09-09 | 2009-02-04 | 中国人民解放军第二军医大学 | Novel triazolols antifungal compound, preparation method and application thereof |
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| CN101357906A (en) * | 2008-09-09 | 2009-02-04 | 中国人民解放军第二军医大学 | Novel triazolols antifungal compound, preparation method and application thereof |
| CN101565406A (en) * | 2009-04-29 | 2009-10-28 | 江苏七洲绿色化工股份有限公司 | Preparation process for cyproconazole |
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