CN105820128B - A kind of preparation method of cyproconazole - Google Patents
A kind of preparation method of cyproconazole Download PDFInfo
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- CN105820128B CN105820128B CN201510001628.8A CN201510001628A CN105820128B CN 105820128 B CN105820128 B CN 105820128B CN 201510001628 A CN201510001628 A CN 201510001628A CN 105820128 B CN105820128 B CN 105820128B
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Abstract
The present invention relates to the preparation method of the cyproconazole shown in chemical structural formula I：4 chlorobenzaldehydes are selected as raw material, react to obtain the propyl alcohol of key intermediate 1 (4 chlorphenyl) 2 cyclopropyl 1 through Grignard；Cyproconazole is made in the oxidized reaction of 1 (4 chlorphenyl) 2 cyclopropyl, 1 propyl alcohol, sulfur ylide reaction and ring-opening reaction；It is as follows to prepare reaction：Wherein, oxidant is selected from：N halogen succimide, the DMH of 1,3 dihalo- 5,5 or ketone aluminum alkoxide；Sulfur ylide reagent is by (CH3)2S and (CH3)2SO4React and be made in isobutanol under KOH effects；DBU is the alkene of 1,8 diazabicyclos [5.4.0] 11 carbon 7；NMP is N methyl pyrrolidones.
Description
Technical field
The present invention relates to the preparation method of the novel preparation method of agricultural chemicals, specifically cyproconazole.
Background technology
Cyproconazole (1984, Novartis Co., Ltd) is triazole bactericide, is ergosterol demethylation inhibitors, is had pre-
Anti- and treatment effect, to the Erysiphe on cereal crop, coffee, beet fruit tree and grape, Uredinales：Spore mould category,
Beak genuss, Septoria, Venturia germ are effective.
There are as below methods for the preparation method report of cyproconazole：
(1) the classical method [CN101798290B, 2012.3.7] for preparing cyproconazole：
(2) through Grignard reactions and C- methylate etc. reaction prepare cyproconazole method [CN101857576B,
2012.7.25]：
(3) through Grignard reaction and anti-Markovnikov addition reaction prepare cyproconazole method [CN101857576B,
2012.7.25]：
(4) method [CN101798290B, 2012.3.7] of diastereoisomer cyproconazole is prepared through Wittig reactions：
(5) prepare the method for cyproconazole through Darzens reactions and Friedel-Crafts acylations [Zhang Yu, Heilungkiang are big
Master's thesis, 2008]：
The preparation method of wherein key intermediate 1- (4- chlorphenyls) -2- cyclopropyl -1- acetone has：
(1) classical approach prepare 1- (4- chlorphenyls) -2- cyclopropyl -1- acetone [modern, 2004, (4)：195]：
(2) 1- (4- chlorphenyls) -2- cyclopropyl -1- acetone is prepared through Friedel-Crafts acylation reactions
[CN103044230B, 2014.10.8]：
(3) through alkylated reaction prepare 1- (4- chlorphenyls) -2- cyclopropyl -1- acetone [CN103044230B,
2014.10.8]：
(4) through condensation and oxidation reaction prepare 1- (4- chlorphenyls) -2- cyclopropyl -1- acetone [CN102675074A,
2012.9.19]：
Chinese invention patent [CN101786948B, 2013.1.30] selects magnesium metal reduction 2- (4- chlorphenyls) -3- rings third
Base butene nitrile obtains 2- (4- chlorphenyls) -3- cyclopropyl butyronitrile.
(5) 1- (4- chlorphenyls) -2- cyclopropyl -1- acetone is prepared through Wittig reactions and anti-Markovnikov addition
[CN102249882B, 2013.8.7]：
(6) " one pot " Darzens reactions prepare 1- (4- chlorphenyls) -2- cyclopropyl -1- acetone [CN102603508B,
2014.3.12]：
(7) sulfur ylide reaction prepare 1- (4- chlorphenyls) -2- cyclopropyl -1- acetone [CN102584558B,
2013.10.30]：
The content of the invention
It is an object of the invention to provide a kind of preparation method of the cyproconazole shown in chemical structural formula I, it is characterised in that
It is raw material to select 4- chlorobenzaldehydes, reacts to obtain key intermediate 1- (4- chlorphenyls) -2- cyclopropyl -1- third through Grignard
Alcohol；Cyproconazole is made in the oxidized reaction of 1- (4- chlorphenyls) -2- cyclopropyl -1- propyl alcohol, sulfur ylide reaction and ring-opening reaction；
It is as follows to prepare reaction：
Wherein, oxidant is selected from：N- halogen succimide, 1,3- dihalo- -5,5- DMHs or ketone-aluminum alkoxide；
Sulfur ylide reagent is by (CH3)2S and (CH3)2SO4React and be made in isobutanol under KOH effects；DBU is that 1,8- diazas are double
Carbon -7- the alkene of ring [5.4.0] 11；NMP is 1-METHYLPYRROLIDONE.
It is an object of the invention to provide cyproconazole preparation method, it is characterised in that oxidant is selected from N- halogen succinyl
During imines, oxidation reaction is as follows：
Wherein, X is selected from：Chlorine, bromine or iodine.
It is an object of the invention to provide cyproconazole preparation method, it is characterised in that oxidant be selected from 1,3- dihalo-s-
During 5,5- DMH, oxidation reaction is as follows：
Wherein, X is selected from：Chlorine, bromine or iodine.
It is an object of the invention to provide cyproconazole preparation method, it is characterised in that oxidant is selected from ketone-alkoxy
During aluminium, oxidation reaction is as follows：
Wherein, Y is selected from：Methyl, phenyl, or Y2Selected from (CH2)5；R is selected from：Isopropyl or the tert-butyl group；Ketone is oxidant,
It is solvent；Aluminum alkoxide is catalyst.
The present invention has the following advantages that compared with prior art：
(1) present invention is the new technology for preparing cyproconazole；Key innovation is to use 4- chlorobenzaldehydes and 1- cyclopropyl chlorine
Ethane is raw material, reacts to obtain key intermediate 1- (4- chlorphenyls) -2- cyclopropyl -1- propyl alcohol through Grignard.
1- cyclopropyl chloroethanes is by the He of embodiment 1 described in Chinese invention patent [CN103044230B, 2014.10.8]
The method of embodiment 2 is prepared.
(2) N- halogen succimide, 1,3- dihalo- -5,5- DMHs or ketone-aluminum alkoxide oxidation 1- (4- chlorine are selected
Phenyl) obtained 1- (4- the chlorphenyls) -2- cyclopropyl -1- acetone of -2- cyclopropyl -1- propyl alcohol.
Wherein, X is selected from：Chlorine, bromine or iodine；Y is selected from：Methyl, phenyl or (CH2)5；R is selected from：Isopropyl or the tert-butyl group.Ketone is
Oxidant, and solvent；Aluminum alkoxide is catalyst.
Embodiment
With reference to embodiment, the present invention is described in further detail, rather than limitation of the invention further.
Embodiment 1
The preparation of 1- (4- chlorphenyls) -2- cyclopropyl -1- propyl alcohol
12.0mmol 1- cyclopropyl chloroethanes be dissolved in 20.0mL absolute ethers 1- cyclopropyl chloroethanes absolute ethers are molten
Liquid；2.0mL1- cyclopropyl chloroethanes anhydrous ether solution is taken to add the mixture of 12.0mmol magnesium chips and 10mL absolute ethers
In, low-grade fever initiation reaction to flowing back, by the diethyl ether solution of remaining 1- cyclopropyl chloroethanes instill 12.0mmol magnesium chips and 10mL without
In the mixture of water ether, flowed back 30min, and reaction is finished, is cooled to room temperature, obtains 1- cyclopropyl chloroethanes RMgBrs, standby.
10.0mmol 4- chlorobenzaldehydes are dissolved in 20.0mL absolute ethers, and ice bath is cooled to 0 DEG C, obtain 4- chlorobenzaldehydes
Anhydrous ether solution；The 1- cyclopropyl chloroethanes RMgBrs prepared are slowly added dropwise in 4- chlorobenzaldehyde anhydrous ether solutions
In, drop finishes, and reaction solution is warmed to room temperature stirring 1.0h.Reaction is finished, and adds saturated aqueous ammonium chloride, then with ether aqueous phase extracted,
Merge organic phase.Saturated common salt water washing organic phase, anhydrous sodium sulphate are dried, and are fractionated to obtain 1- (4- chlorphenyls) -2- cyclopropyl -1-
Propyl alcohol, yield 95.0%.
Embodiment 2
The preparation of 1- (4- chlorphenyls) -2- cyclopropyl -1- acetone
0.012mol N- chlorosuccinamides and 60mL dichloromethane, heating stirring are slowly added to 0.10mol to dissolving
1- (4- chlorphenyls) -2- cyclopropyl -1- propyl alcohol and 30mL dichloromethane mixed liquors, drop finish, and continue to stir 2h, reaction is finished, filtering
Succimide is reclaimed, filtrate is with 100mL water washings, anhydrous Na2SO4Dry, be fractionated to obtain 1- (4- chlorphenyls) -2- cyclopropyl -1-
Acetone, yield 93.1%；
Embodiment 3
The preparation of 1- (4- chlorphenyls) -2- cyclopropyl -1- acetone
Chloro- 5, the 5- DMHs of 0.06mol 1,3- bis- and 60mL chloroforms, heating stirring are slowly added to dissolving
0.10mol 1- (4- chlorphenyls) -2- cyclopropyl -1- propyl alcohol and 30mL chloroform mixed liquors, drop finish, and continue to stir 2h, reaction
Finish, be recovered by filtration 5,5- DMHs, filtrate is with 100mL water washings, anhydrous Na2SO4Dry, be fractionated to obtain 1- (4- chlorobenzenes
Base) -2- cyclopropyl -1- acetone, yield 92.6%；
Embodiment 4
The preparation of 1- (4- chlorphenyls) -2- cyclopropyl -1- acetone
0.1mol 1- (4- chlorphenyls) -2- cyclopropyl -1- propyl alcohol, 0.050mol aluminium isopropoxides, 100mL acetone, are stirred back
Flow 5.0h.It is acidified with hydrochloric acid, is washed to neutrality, anhydrous Na2SO4Dry, revolving recovery organic solvent；It is fractionated to obtain 1- (4- chlorobenzenes
Base) -2- cyclopropyl -1- acetone, yield 94.5%.
Embodiment 5
The preparation of 2- (4- chlorphenyls) -3- cyclopropyl -1,2- epoxy butanes
2- (4- chlorphenyls) -3- cyclopropyl -1,2- epoxy butane by Chinese invention patent [CN101565406B,
2010.11.10] in embodiment 2 describe method prepare.
Embodiment 6
The preparation of cyproconazole
Cyproconazole is pressed the method that embodiment 5 describes in Chinese invention patent [CN102382068B, 2013.11.27] and prepared.
Claims (1)
1. the preparation method of the cyproconazole shown in a kind of chemical structural formula I, it is characterised in that selection 4- chlorobenzaldehydes are raw material, warp
Grignard reacts to obtain key intermediate 1- (4- chlorphenyls) -2- cyclopropyl -1- propyl alcohol；1- (4- chlorphenyls) -2- cyclopropyl -
Cyproconazole is made in the oxidized reaction of 1- propyl alcohol, sulfur ylide reaction and ring-opening reaction；It is as follows to prepare reaction：
Wherein, sulfur ylide reagent is by (CH3)2S and (CH3)2SO4React and be made in isobutanol under KOH effects；DBU is 1,
Carbon -7- the alkene of 8- diazabicyclos [5.4.0] 11；NMP is 1-METHYLPYRROLIDONE；Oxidant is selected from ketone-aluminum alkoxide, oxidation
Reaction is as follows：
Wherein, Y is selected from：Methyl, phenyl, or Y2Selected from (CH2)5；R is selected from：Isopropyl or the tert-butyl group；Ketone is oxidant, Ye Shirong
Agent；Aluminum alkoxide is catalyst.
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Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106588793B (en) * | 2017-01-22 | 2019-09-20 | 江西华士药业有限公司 | A kind of preparation method of cyproconazole |
| MX2020009041A (en) * | 2018-03-06 | 2020-10-14 | Upl Ltd | A process for preparation of fungicidally active triazole compounds. |
| CN109553583B (en) * | 2018-12-04 | 2022-03-22 | 淮安国瑞化工有限公司 | Method for preparing cyproconazole by using 2, 4' -dichloroacetophenone as raw material |
| WO2021048210A1 (en) | 2019-09-12 | 2021-03-18 | Saltigo Gmbh | Improved process for preparing cyclopropyl compounds from alkenes |
| 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 |
| CN111718239A (en) * | 2020-07-16 | 2020-09-29 | 福建师范大学福清分校 | Method for separating dimethyl sulfide and methanol aqueous solution by continuous extractive distillation |
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Effective date of registration: 20171220 Address after: 330700 Ningbo avenue of Fengxin County Industrial Park, Yichun, Jiangxi Applicant after: Jiangxi Huashi Pharmaceutical Co., Ltd. Address before: Yuelu District City, Hunan province 410082 Changsha Lushan Road No. 1 Applicant before: Hunan University |
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