CN106883266A - A kind of 1(4 chlorphenyls)The Preparation Method And Their Intermediate of the acetone of 2 cyclopropyl 1 - Google Patents
A kind of 1(4 chlorphenyls)The Preparation Method And Their Intermediate of the acetone of 2 cyclopropyl 1 Download PDFInfo
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- CN106883266A CN106883266A CN201710049273.9A CN201710049273A CN106883266A CN 106883266 A CN106883266 A CN 106883266A CN 201710049273 A CN201710049273 A CN 201710049273A CN 106883266 A CN106883266 A CN 106883266A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/6552—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/56—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds
- C07C45/57—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom
- C07C45/60—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom in six-membered rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members 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
- C07D309/10—Oxygen atoms
- C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
Abstract
The present invention relates to a kind of 1(4 chlorphenyls)The preparation method of the acetone of 2 cyclopropyl 1, the method is with the α hydroxyl p-chlorobenzyl phosphonate esters and 3 shown in Formulas I, 42HDihydropyran is raw material, and the compound shown in Formula II is prepared under catalyst existence condition;Compound and cyclopropyl methyl ketone shown in Formula II carry out reacting the compound prepared shown in formula III in the presence of alkali and solvent;Hydrolysis prepares 1 to compound shown in formula III in acid condition(4 chlorphenyls)The acetone of 2 cyclopropyl 1.The present invention 1(4 chlorphenyls)The preparation of the acetone of 2 cyclopropyl 1 is with the α hydroxyl p-chlorobenzyl phosphonate esters and 3,4 2 shown in Formulas IHDihydropyran is raw material, and raw material is cheap and easy to get, and step is simple, and with low cost, three-waste pollution is few, environmental protection, is suitable to industrialized production, 1 for finally preparing(4 chlorphenyls)The acetone purity of 2 cyclopropyl 1 is high, content more than 96%, high income, yield is more than 83%.
Description
Technical field
The present invention relates to the preparation method of bactericide cyproconazole intermediate, more particularly to 1- (4- chlorphenyls) -2- cyclopropyl -
The preparation method of 1- acetone and its intermediate.
Background technology
Cyproconazole (cyproconazole) is the triazole bactericidal agent of Shan De companies of Switzerland (Sandoz AG) exploitation, is one
Kind of systemic fungicide, with protectiveness, therapeutic and roots out virus function, is widely used in West Europe and North America.1- (4- chlorobenzenes
Base) -2- cyclopropyl -1- acetone be synthesize cyproconazole key intermediate.At present, reported it is various on 1- (4- chlorphenyls)-
The preparation method of 2- cyclopropyl -1- acetone, such as Chinese patent CN201110432969 discloses a kind of 1- (4- chlorphenyls) -2- rings third
The preparation method of base -1- acetone, the reaction equation of the method is as follows:
The method preparation technology is complicated, and step is various.
US4973767 discloses a kind of side of grignard reagent method synthesis 1- (4- chlorphenyls) -2- cyclopropyl -1- acetone synthesis
Method.It obtains 4- (4- chlorphenyls) -1- butylene -4- after using chloropropene and magnesium generation grignard reagent with 4-chloro-benzaldehyde reaction
Alcohol, the latter obtains 1- (4- chlorphenyls) -2- cyclopropyl-ethanols under zinc, stannous chloride effect with methylene bromide cyclization, then in grass
4- chlorophenylcyclopromethyl methyl ketones are oxidized under the effect such as acyl chlorides, triethylamine, 4- chlorophenylcyclopromethyl methyl ketones are in tetrahydrofuran
In solvent target is obtained with sodium hydride and iodomethane reaction.It is required that grignard reagent and sodium hydride are used, to the aqueous of reaction system
Rate requirement is high, is not suitable for industrialized production.
CN101786948 is disclosed with cyclopropyl methyl ketone, p-chlorobenzyl cyanide and sodium hydride as raw material, through being condensed, being hydrogenated with,
The method that oxidation obtains 1- (4- chlorphenyls) -2- cyclopropyl -1- acetone, the method also needs to use sodium hydride, to reaction system
Water content requirement is strict, there is unsafe factor in magnesium powder restoring operation, and the easy autohemagglutination of p-chlorobenzyl cyanide is not suitable for industrializing big rule
Mould is produced.
The preparation method on 1- (4- chlorphenyls) -2- cyclopropyl -1- acetone reported also has:For example
CN102603508, CN101125807A, CN101857576A, CN102942465 etc..But the above method exist production cost it is high,
It is difficult to control using hazardous chemical, reaction condition, there is potential safety hazard, is not met environment protection requirement etc. and be unfavorable for industry
The problem that metaplasia is produced.
The content of the invention
The technical problems to be solved by the invention are to overcome the deficiencies in the prior art, there is provided a kind of economy, environmental protection
1- (4- the chlorphenyls) -2- cyclopropyl -1- acetone for being suitable for industrialized production preparation method.
It is another object of the present invention to provide a kind of 1- (4- chlorphenyls) -2- cyclopropyl -1- acetone intermediate and
Its preparation method.
To solve above technical problem, the present invention is adopted the following technical scheme that:
A kind of intermediate of 1- (4- chlorphenyls) -2- cyclopropyl -1- acetone, the intermediate is the compound shown in II,Wherein, R is the alkyl that carbon number is 1~5,
Or the intermediate is the alkoxypropan ene derivative shown in formula III,
Another technical scheme that the present invention takes is:A kind of intermediate of 1- (4- chlorphenyls) -2- cyclopropyl -1- acetone
Preparation method, shown method comprises the following steps:
(1) Alpha-hydroxy p-chlorobenzyl phosphonate ester and 3,4-2H- dihydropyran shown in Formulas I are made in catalyst, solvent and 20
DEG C~120 DEG C under conditions of carry out reacting the compound obtained shown in Formula II,
Wherein, R is alkyl that carbon number is 1~5, it is preferable that R is methyl or ethyl.
(2) compound and cyclopropyl methyl ketone shown in the Formula II that step (1) prepares are made in alkali, solvent and -78 DEG C
Horner-Wadsworth-Emmons is carried out under conditions of~120 DEG C and reacts the compound obtained shown in formula III, it is as described
Intermediate,
Further, in step (1), the Alpha-hydroxy p-chlorobenzyl phosphonate ester, 3,4-2H- dihydropyran and catalyst
Molar ratio is 1:1.0~3:0.01~1.
It is further preferred that the Alpha-hydroxy p-chlorobenzyl phosphonate ester, 3,4-2H- dihydropyran and feeding intake for catalyst are rubbed
You are than being 1:1.0~2.5:0.01~0.50.
Further, in step (1), the catalyst is p-methyl benzenesulfonic acid.
Further, in step (1), the solvent is toluene, tetrahydrofuran, chloroform, 1,2- dichloroethanes, Isosorbide-5-Nitrae-dioxy
One or more in six rings of combination.
It is further preferred that in step (1), the solvent be one kind in toluene, tetrahydrofuran, 1,2- dichloroethanes or
Several combinations.
Further, in step (1), the reaction is carried out at 30 DEG C~110 DEG C.
It is further preferred that the reaction is carried out at 30 DEG C~60 DEG C.
Further, the specific embodiment of step (1) is as follows:The Alpha-hydroxy p-chlorobenzyl phosphonate ester is dissolved in molten
In agent, 3, the 4-2H- dihydropyran and catalyst are then sequentially added, 1~12 is reacted under conditions of 30 DEG C~60 DEG C small
When.
Further, the step of preparation method is post-processed after also terminating including the reaction in step (1), specifically
Implement as follows:Will react terminate after reaction solution with sodium hydroxide solution wash layering after, organic phase dry concentrate after obtain institute
The compound shown in Formula II is stated, the compound shown in the Formula II is further purified or be directly used in next step.
Further, in step (2), the molar ratio of compound, cyclopropyl methyl ketone and alkali shown in the Formula II
It is 1:1.0~2:1.0~2.
It is further preferred that the molar ratio of the compound, cyclopropyl methyl ketone and alkali shown in the Formula II is 1:1.1
~1.8:1.1~1.8.
Further, in step (2), the alkali is n-BuLi, lithium diisopropylamine, sodium hydride, Sodamide, tertiary fourth
One or more in sodium alkoxide, potassium tert-butoxide of combination.
Further, in step (2), the Horner-Wadsworth-Emmons reactions are entered at -78 DEG C~100 DEG C
OK.
It is further preferred that in step (2), the Horner-Wadsworth-Emmons reactions are at -78 DEG C~50 DEG C
Carry out.
Further, in step (2), the solvent be toluene, tetrahydrofuran, dimethyl sulfoxide, DMF,
The combination of one or more in 1-METHYLPYRROLIDONE, n-butanol, isobutanol, the tert-butyl alcohol.
It is further preferred that in step (2), the solvent is toluene, tetrahydrofuran, dimethyl sulfoxide, N, N- dimethyl methyls
The combination of one or more in acid amides, the tert-butyl alcohol.
Further, the specific embodiment of step (2) is as follows:By the compound obtained in step (1) shown in Formula II and
Cyclopropyl methyl ketone dissolves in a solvent, after then adding described alkali, charging to finish under -78 DEG C~15 DEG C temperature conditionss,
Reacted 2~16 hours under the conditions of 15 DEG C~120 DEG C.
Further, the step of preparation method is post-processed after also terminating including the reaction in step (2), specifically
Implement as follows:After the Horner-Wadsworth-Emmons reactions terminate, the extraction that adds water is concentrated to give shown in formula III after going out
Crude compound.
It is further preferred that the crude compound shown in the formula III can be directly used for 1- (4- chlorphenyls) -2- rings third
The preparation of base -1- acetone.
The another technical scheme that uses of the present invention for:A kind of preparation side of 1- (4- chlorphenyls) -2- cyclopropyl -1- acetone
Method, the described method comprises the following steps:
The compound of (a) according to above method formula III;
B () makes the reaction that is hydrolyzed in acid condition of the compound shown in the formula III that step (a) is prepared obtain formula
Compound shown in IV, as described 1- (4- chlorphenyls) -2- cyclopropyl -1- acetone,
Further, in step (b), the acid that the acid condition is selected is in acetic acid, hydrochloric acid, p-methyl benzenesulfonic acid, sulfuric acid
The combination of one or more.
Further, in step (b), the hydrolysis is carried out under the conditions of 0~80 DEG C.
It is further preferred that the hydrolysis is carried out under the conditions of 10 DEG C~60 DEG C.
Further, in step (b), the solvent be water, methyl alcohol, ethanol, isopropanol, the tert-butyl alcohol, Isosorbide-5-Nitrae-dioxane,
In tetrahydrofuran, toluene, dichloromethane, 1,2- dichloroethanes, N,N-dimethylformamide, dimethyl sulfoxide one or more
Combination.
It is further preferred that in step (b), the solvent be one kind in water, methyl alcohol, ethanol, tetrahydrofuran, toluene or
Several combinations.
Further, the specific embodiment of step (b) is:By the compound dissolving obtained in step (a) shown in formula III
In solvent, acid is added dropwise, is reacted 0.5~3 hour under the conditions of 0~80 DEG C after completion of dropping.
Further, the preparation method of 1- (4- the chlorphenyls) -2- cyclopropyl -1- acetone is also reacted including step (b)
The step of being post-processed after end, is embodied as follows:After reaction terminates, separating-purifying after reaction solution is concentrated obtains institute
State 1- (4- chlorphenyls) -2- cyclopropyl -1- acetone.
Due to the implementation of above-mentioned technical proposal, the present invention has the following advantages that compared with prior art:
The preparation of 1- (4- chlorphenyls) -2- cyclopropyl -1- acetone of the present invention is with the Alpha-hydroxy p-chlorobenzyl phosphonic acids shown in Formulas I
Ester and 3,4-2H- dihydropyran are raw material, and raw material is cheap and easy to get, and step is simple, and with low cost, three-waste pollution is few, environmental protection,
Be suitable to industrialized production, 1- (4- the chlorphenyls) -2- cyclopropyl -1- acetone purity for finally preparing is high, content 96% with
On, high income, yield is more than 83%.
Specific embodiment
The present invention is described in further details below in conjunction with specific embodiment.It should be understood that these embodiments are for saying
The bright basic principles, principal features and advantages of the present invention, and the present invention is not limited by the following examples.Used in embodiment
Implementation condition can do further adjustment according to specific requirement, and unreceipted implementation condition is usually the condition in normal experiment.
Embodiment one
The present embodiment provides a kind of preparation method of 1- (4- chlorphenyls) -2- cyclopropyl -1- acetone, and the method includes following
Step:
(1) by Alpha-hydroxy p-chlorobenzyl dimethyl phosphonate (with 4-chloro-benzaldehyde and dimethylphosphite as raw material, reference
J.Organomet.Chem.2016,804,59-65;Phosphorus,Sulfur Silicon Relat.Elem.2014,
It is prepared by method described in 189,812-818 or J.Org.Chem.2014,79,6172-6178) (2.51g, 10.0mmol) be dissolved in
In toluene (50mL), be subsequently added 3,4-2H- dihydropyran (841mg, 10.0mmol) and p-methyl benzenesulfonic acid (190mg,
1.0mmol).Reaction solution is stirred 5 hours at 50 DEG C.After reaction terminates, reaction solution is washed point with sodium hydroxide solution (20mL)
Layer, organic layer is concentrated under reduced pressure to slough toluene.Gained crude product purifies (petroleum ether through column chromatography:Ethyl acetate=3:1) obtain colourless
Compound (R is methyl) (3.05g) shown in oily Formula II, content 95%, yield 91%.
1H NMR(400MHz,CDCl3)δ(ppm)7.43(1H,dd,J1=1.6Hz, J2=8.4Hz), 7.38 (1H, dd, J1
=1.6Hz, J2=8.4Hz), 7.32 (2H, d, J=8.4Hz), 5.11 (0.46H, s), 5.06 (0.65H, d, J=17.2Hz),
4.97 (0.47H, d, J=12.0Hz), 4.49 (0.65H, s), 3.96-4.17 (6H, m), 3.13-3.55 (1H, m), 3.33-
3.38(1H,m),1.40-1.85(6H,m).
(2) compound (1.67g, 5.0mmol) shown in Formula II resulting in step (1) is dissolved in N, N- dimethyl
In formamide (5.0mL), then sequentially add cyclopropyl methyl ketone (505mg, 6.0mmol) and Sodamide (234mg,
6.0mmol).Reaction solution is stirred 3 hours at 40 DEG C.After reaction terminates, to addition water (10mL), resulting mixture in reaction
It is extracted with ethyl acetate (extraction three times, each 10mL).Gained organic phase is merged, is concentrated after being dried with sodium sulphate, obtained and slightly produce
Compound (1.51g) shown in product formula III, content 80.1%, yield 83%.
1H NMR(400MHz,CDCl3) δ (ppm) 7.44 (2H, d, J=6.0Hz), 7.20 (2H, d, J=6.0Hz), 4.88
(1H, t, J=4.8Hz), 3.72-3.76 (1H, m), 3.63-3.66 (1H, m), 1.96-2.01 (1H, m), 1.71-1.77 (2H,
m),1.66(3H,s),1.55-1.65(3H,m),1.19-1.27(1H,m),0.47-0.56(2H,m),0.25-0.31(2H,
m).
(3) compound (1.51g) shown in formula III resulting in step (2) is dissolved in tetrahydrofuran (5.0mL),
Then to addition hydrochloric acid solution (6N, 1.5mL) in the solution.Reaction solution is stirred 30 minutes at 25 DEG C.After reaction terminates, decompression
Boil off solvent.Gained crude product purifies (petroleum ether through column chromatography:Ethyl acetate=20:1) colorless oil compound 1- (4- chlorine is obtained
Phenyl) -2- cyclopropyl -1- acetone (0.86g), content 98%, yield 83%.
Embodiment two
The present embodiment provides a kind of preparation method of 1- (4- chlorphenyls) -2- cyclopropyl -1- acetone, and the method includes following
Step:
(1) by Alpha-hydroxy p-chlorobenzyl diethyl phosphonate (with 4-chloro-benzaldehyde and diethyl phosphite as raw material, reference
Tetrahedron Lett.2004,45,9233-9236;Phosphorus,Sulfur Silicon Relat.Elem.1996,
117,37-54;It is prepared by method described in Tetrahedron 2008,64,4295-4303) (2.79g, 10.0mmol) be dissolved in first
In benzene (50mL), be subsequently added 3,4-2H- dihydropyran (841mg, 10.0mmol) and p-methyl benzenesulfonic acid (190mg,
1.0mmol).Reaction solution is stirred 5 hours at 50 DEG C.After reaction terminates, reaction solution is washed point with sodium hydroxide solution (20mL)
Layer, organic layer is concentrated under reduced pressure to slough toluene.Gained crude product purifies (petroleum ether through column chromatography:Ethyl acetate=3:1) obtain colourless
Compound (R is ethyl) (3.30g) shown in oily Formula II, content 95%, yield 91%.
1H NMR(400MHz,CDCl3)δ(ppm)7.43(1H,dd,J1=1.6Hz, J2=8.4Hz), 7.38 (1H, dd, J1
=1.6Hz, J2=8.4Hz), 7.32 (2H, d, J=8.4Hz), 5.10 (0.46H, s), 5.05 (0.65H, d, J=17.2Hz),
4.96 (0.47H, d, J=12.0Hz), 4.48 (0.66H, s), 3.96-4.17 (4.3H, m), 3.53-3.55 (0.69H, m),
3.33-3.38(1H,m),1.40-1.85(6H,m),1.22-1.30(6H,m).
(2) compound (1.81g, 5.0mmol) shown in Formula II resulting in step (1) is dissolved in N, N- dimethyl
In formamide (5.0mL), then sequentially add cyclopropyl methyl ketone (505mg, 6.0mmol) and Sodamide (234mg,
6.0mmol).Reaction solution is stirred 3 hours at 40 DEG C.After reaction terminates, to addition water (10mL), resulting mixture in reaction
It is extracted with ethyl acetate (extraction three times, each 10mL).Gained organic phase is merged, is concentrated after being dried with sodium sulphate, obtained and slightly produce
Compound (1.55g) shown in product formula III, content 82%, yield 87%.
(3) compound (1.55g) shown in formula III resulting in step (2) is dissolved in tetrahydrofuran (5.0mL),
Then to addition hydrochloric acid solution (6N, 1.5mL) in the solution.Reaction solution is stirred 30 minutes at 25 DEG C.After reaction terminates, decompression
Boil off solvent.Gained crude product purifies (petroleum ether through column chromatography:Ethyl acetate=20:1) colorless oil compound 1- (4- chlorine is obtained
Phenyl) -2- cyclopropyl -1- acetone (0.90g), content 97%, yield 87%.
Embodiment three
The present embodiment provides a kind of preparation method of 1- (4- chlorphenyls) -2- cyclopropyl -1- acetone, and the method includes following
Step:
(1) -78 DEG C will be cooled to dissolved with tetrahydrofuran (10.0mL) solution of diisopropylamine (0.51g, 5.0mmol), with
N-BuLi (3.1mL, 1.6M) is instilled in the backward solution, resulting solution is cooled to -40 DEG C again after being stirred 30 minutes at 0 DEG C.
Then by the compound (1.81g, 5.0mmol) and cyclopropyl methyl ketone shown in Formula II resulting in the step of embodiment two (1)
(505mg, 6.0mmol) is instilled in reaction system successively, and reaction solution warms naturally to 0 DEG C, and stirs 3 hours at such a temperature.
After reaction terminates, reaction solution is cooled to 0 DEG C, instills saturated ammonium chloride solution (10mL) and reaction is quenched.It is extracted with ethyl acetate
(extraction three times, each 15mL).Gained organic phase is merged, is concentrated after being dried with sodium sulphate, obtain the change shown in crude product formula III
Compound (1.50g), content 86%, yield 88%.
(2) compound (1.50g) shown in formula III resulting in step (1) is dissolved in tetrahydrofuran (5.0mL),
Then to adding 30% dilution heat of sulfuric acid (1.0mL) in the solution.Reaction solution is stirred 30 minutes at 25 DEG C.After reaction terminates,
Decompression boils off solvent.Gained crude product purifies (petroleum ether through column chromatography:Ethyl acetate=20:1) colorless oil compound 1- is obtained
(4- chlorphenyls) -2- cyclopropyl -1- acetone (0.93g), content 96%, yield 89%.
Example IV
The present embodiment provides a kind of preparation method of 1- (4- chlorphenyls) -2- cyclopropyl -1- acetone, and the method includes following
Step:
(1) compound (1.81g, 5.0mmol) shown in Formula II resulting in the step of embodiment two (1) is dissolved in N, N-
In dimethylformamide (5.0mL), cyclopropyl methyl ketone (505mg, 6.0mmol) and potassium tert-butoxide are then sequentially added
(673mg,6.0mmol).Reaction solution is stirred 3 hours at 40 DEG C.It is resulting to water (10mL) is added in reaction after reaction terminates
Mixture be extracted with ethyl acetate (extraction three times, each 10mL).Gained organic phase is merged, it is dense after being dried with sodium sulphate
Contracting, obtains the compound (1.60g) shown in crude product formula III, content 80%, yield 88%.
(2) compound (1.60g) shown in formula III resulting in step (1) is dissolved in ethanol (5.0mL), then
To addition p-methyl benzenesulfonic acid (95.1mg, 0.5mmol) in the solution.Reaction solution is stirred 1 hour at 40 DEG C.After reaction terminates,
Decompression boils off solvent.Gained crude product purifies (petroleum ether through column chromatography:Ethyl acetate=20:1) colorless oil compound 1- is obtained
(4- chlorphenyls) -2- cyclopropyl -1- acetone (0.96g), content 96%, yield 92%.
The present invention is described in detail above, its object is to allow the personage for being familiar with this art to will appreciate that this
The content of invention is simultaneously carried out, and it is not intended to limit the scope of the present invention, and the invention is not restricted to above-mentioned implementation
Example, the equivalent change or modification that all Spirit Essences of the invention are made should all be included within the scope of the present invention.
Claims (10)
1. a kind of intermediate of 1- (4- chlorphenyls) -2- cyclopropyl -1- acetone, the intermediate is the compound shown in Formula II,
Wherein, R is the alkyl that carbon number is 1~5,
Or the intermediate is the alkoxypropan ene derivative shown in formula III,
2. a kind of preparation method of the intermediate of 1- (4- chlorphenyls) -2- cyclopropyl -1- acetone, it is characterised in that shown method
Comprise the following steps:
(1) make Alpha-hydroxy p-chlorobenzyl phosphonate ester and 3,4-2H- dihydropyran shown in Formulas I catalyst, solvent and 20 DEG C~
Carry out reacting the compound obtained shown in Formula II under conditions of 120 DEG C,
Wherein, R is alkyl that carbon number is 1~5;
(2) compound and cyclopropyl methyl ketone shown in the Formula II that step (1) prepares are made in alkali, solvent and -78 DEG C~120
Horner-Wadsworth-Emmons is carried out under conditions of DEG C and reacts the compound obtained shown in formula III, as described centre
Body,
3. the preparation method of the intermediate of 1- (4- chlorphenyls) -2- cyclopropyl -1- acetone according to claim 2, it is special
Levy and be:In step (1), the molar ratio of the Alpha-hydroxy p-chlorobenzyl phosphonate ester, 3,4-2H- dihydropyran and catalyst
It is 1:1.0~3:0.01~1.
4. the preparation method of the intermediate of 1- (4- chlorphenyls) -2- cyclopropyl -1- acetone according to claim 2, it is special
Levy and be:In step (1), the catalyst is p-methyl benzenesulfonic acid.
5. the preparation method of the intermediate of 1- (4- chlorphenyls) -2- cyclopropyl -1- acetone according to claim 2, it is special
Levy and be, the specific embodiment of step (1) is as follows:The Alpha-hydroxy p-chlorobenzyl phosphonate ester is dissolved in solvent, then
3, the 4-2H- dihydropyran and catalyst are sequentially added, is reacted 1~12 hour under conditions of 30 DEG C~60 DEG C.
6. the preparation method of the intermediate of 1- (4- chlorphenyls) -2- cyclopropyl -1- acetone according to claim 2, it is special
Levy and be, in step (2), the molar ratio of compound, cyclopropyl methyl ketone and alkali shown in the Formula II is 1:1.0~2:
1.0~2.
7. the preparation method of the intermediate of 1- (4- chlorphenyls) -2- cyclopropyl -1- acetone according to claim 2, it is special
Levy and be, in step (2), the alkali is n-BuLi, lithium diisopropylamine, sodium hydride, Sodamide, sodium tert-butoxide, tertiary fourth
One or more in potassium alcoholate of combination.
8. a kind of preparation method of 1- (4- chlorphenyls) -2- cyclopropyl -1- acetone, it is characterised in that methods described includes following
Step:
Compound shown in the method formula III of (a) according to any one of claim 2~7 claim;
B () makes the reaction that is hydrolyzed in acid condition of the compound shown in the formula III that step (a) is prepared obtain formula IV institute
The compound for showing, as described 1- (4- chlorphenyls) -2- cyclopropyl -1- acetone,
9. the preparation method of 1- (4- chlorphenyls) -2- cyclopropyl -1- acetone according to claim 8, it is characterised in that step
Suddenly in (b), the acid that the acid condition is selected is the combination of one or more in acetic acid, hydrochloric acid, p-methyl benzenesulfonic acid, sulfuric acid.
10. the preparation method of 1- (4- chlorphenyls) -2- cyclopropyl -1- acetone according to claim 8, it is characterised in that
The specific embodiment of step (b) is:Compound obtained in step (a) shown in formula III is dissolved in solvent, acid is added dropwise,
Reacted 0.5~3 hour under the conditions of 0~80 DEG C after completion of dropping.
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CN201710049273.9A CN106883266B (en) | 2017-01-23 | 2017-01-23 | Preparation method of 1- (4-chlorphenyl) -2-cyclopropyl-1-acetone and intermediate thereof |
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CN110734364A (en) * | 2019-12-04 | 2020-01-31 | 上海生农生化制品股份有限公司 | Synthesis method of 1- (4-chlorphenyl) -2-cyclopropyl-1-acetone |
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CN113121322A (en) * | 2019-12-30 | 2021-07-16 | 辽宁众辉生物科技有限公司 | Synthesis method of 1- (4-chlorphenyl) -2-cyclopropyl-1-acetone |
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CN114195625A (en) * | 2021-11-30 | 2022-03-18 | 江苏剑牌农化股份有限公司 | Preparation method of 1- (4-chlorphenyl) -2-cyclopropyl-1-acetone |
CN114195625B (en) * | 2021-11-30 | 2023-12-01 | 江苏剑牌农化股份有限公司 | Preparation method of 1- (4-chlorophenyl) -2-cyclopropyl-1-acetone |
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