CN108191765A - A kind of preparation method of enilconazole - Google Patents
A kind of preparation method of enilconazole Download PDFInfo
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- CN108191765A CN108191765A CN201711427596.3A CN201711427596A CN108191765A CN 108191765 A CN108191765 A CN 108191765A CN 201711427596 A CN201711427596 A CN 201711427596A CN 108191765 A CN108191765 A CN 108191765A
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- enilconazole
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D233/60—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to ring nitrogen atoms
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Abstract
The invention discloses a kind of preparation method of enilconazole, step includes：By 2,4 dichloro, 2 ' chloroacetophenone, reducing agent, organic base, catalyst adds in temperature control in reaction vessel and reacts 8 10h in 65 75 DEG C, sodium hydroxide, dimethylacetylamide are added in after concentration, imidazoles reacts 4~6h in 95~105 DEG C, allyl chloride is added dropwise after cooling, 5~7h is reacted at 100~110 DEG C, elutriation filters, and obtains enilconazole crude product；Crude product dries to obtain enilconazole dry product using ethyl alcohol recrystallization；The reducing agent is formic acid or isopropanol, and the catalyst is RuCl2(pph3)3.This method uses catalyst and mild reducing agent, and the sodium borohydride than generally using is high with yield, and impurity is few, reacts the advantages of mild, there is the potentiality of industrialized production.
Description
Technical field
The present invention relates to chemosynthesis technical fields, and in particular to a kind of novel processing step of enilconazole.
Background technology
Enilconazole (C14H14Cl2N2O) also known as imazalil, entitled 1- [2- (2,4- dichlorophenyl) -2- (2- allyl oxygen of chemistry
Base) ethyl] -1H- imidazoles, it is a kind of absorbability benzimidazole germicide developed by janssenpharmaceutica, it is right
The fungal disease of the plants such as water fruits and vegetables has prophylactic-therapeutic effect, and especially common penicilliosis, green mould effect are protruded.Because of it
There is high-efficiency broad spectrum and low toxicity, be widely used in the anti-corrosive fresh-keeping of fruits and vegetables, had a extensive future.Enilconazole
Molecular weight is 297.2, and structural formula is：
The synthetic method for the enilconazole reported at present is generally using bis- chloro- 2 '-chloroacetophenones of 2,4- as raw material or intermediate production
Object with sodium borohydride by carbonyl reduction into hydroxyl, then does substitution reaction with imidazoles and allyl chloride successively and ultimately generates product.It should
Technique faces that impurity is more in reduction step, the relatively low difficulty of yield, and is needed using sodium borohydride reduction charging process
Low temperature is added portionwise, and generates large quantity of exhaust gas, condition is more harsh, and manipulation strength is big, there is certain risk.Therefore, to recovery step
Suddenly it is notable to do new development significance.
Invention content
The technical problems to be solved by the invention are insufficient for the above-mentioned prior art or existing for product and provide a kind of
The novel processing step of enilconazole, this method mild condition is easy to operate, and yield, product purity are higher, post processing mode
Simply, it is easy to accomplish large-scale production.
The present invention provides a kind of preparation method of enilconazole, step includes：
By 2,4-, bis- chloro- 2 '-chloroacetophenones, reducing agent, organic base, catalyst adds in reaction vessel temperature control in 65-
75 DEG C of reaction 8-10h, add in sodium hydroxide, dimethylacetylamide, imidazoles reacts 4~6h in 95~105 DEG C, after cooling after concentration
Allyl chloride is added dropwise, reacts 5~7h at 100~110 DEG C, obtains enilconazole after purification；The reducing agent be formic acid or isopropanol,
The catalyst is RuCl2(pph3)3。
The beneficial effects of the invention are as follows：The present invention uses mild reducing agent and new catalyst RuCl2(pph3)3Collocation,
It realizes and hydrogen is provided by organic hydrogen source to restore substrate, reaction purpose is reached in a manner of hydrogen migration, adopted compared to conventional
It being restored with sodium borohydride, reaction condition is milder, and reaction is more prone to carry out, and the impurity of generation is few and easily removes,
Operation difficulty substantially reduces, and product yield is up to more than 60% and purity is up to more than 98%, suitable for industrialized production, before
Scape is wide.
Description of the drawings
Fig. 1 is 1 gained enilconazole fine work of embodiment1H NMR spectras.
Fig. 2 is the gas-chromatography spectrogram of 1 gained enilconazole fine work of embodiment.
Specific embodiment
The present invention provides a kind of preparation method of enilconazole, step includes：
By 2,4-, bis- chloro- 2 '-chloroacetophenones, reducing agent, organic base, catalyst adds in reaction vessel temperature control in 65-
75 DEG C of reaction 8-10h, add in sodium hydroxide, dimethylacetylamide, imidazoles reacts 4~6h in 95~105 DEG C, after cooling after concentration
Allyl chloride is added dropwise, reacts 5~7h at 100~110 DEG C, obtains enilconazole after purification；The reducing agent be formic acid or isopropanol,
The catalyst is RuCl2(pph3)3。
The reaction equation of above-mentioned reaction is as follows：
Preferably, described 2,2 ', 4 '-trichloroacetophenone, reducing agent, organic base, catalyst, sodium hydroxide, dimethyl second
Amide, imidazoles, allyl chloride mol ratio are 1:18~22:0.4~0.6:0.03~0.07:1.5~2.5:9~11:1.5~
1.7:1.5~1.7.
It is more preferred, in one embodiment of the invention, described 2, it is 2 ', 4 '-trichloroacetophenone, reducing agent, organic
Alkali, catalyst, sodium hydroxide, dimethylacetylamide, imidazoles, allyl chloride mol ratio are 1:20:0.5:0.05:2:10:
1.6:1.6。
Preferably, after substrate is reduced, sodium hydroxide, dimethylacetylamide are added in, imidazoles reacts 5h, cooling in 100 DEG C
After allyl chloride is added dropwise, react 6h at 105 DEG C.
Preferably, the organic base is triethylamine or DIPEA.
Preferably, the purification step includes：It cools down after reaction, adds in the water of twice reaction system volume, stir
5~15min is mixed, suction filtration obtains enilconazole crude product, and enilconazole crude product obtains enilconazole product with ethyl alcohol recrystallization.
Preferably, described to be cooled to be cooled to room temperature, the room temperature is generally 15~30 DEG C.
A kind of preparation method of enilconazole provided by the invention is further described below in conjunction with specific embodiment.
The embodiments described below is exemplary, and is only used for explaining the present invention, and is not considered as limiting the invention.
Experimental method in following embodiments is conventional method unless otherwise specified.It is real used in following embodiments
It tests material unless otherwise specified, is that market is commercially available.
Embodiment one
A kind of preparation method of enilconazole is present embodiments provided, step includes：
Under stiring, successively by isopropanol 120g (2.0mol), 2,4- bis- chloro- 2 '-chloroacetophenone 22.3g
(0.1mol), DIPEA6.5g (0.05mol), RuCl2(pph3)3In 4.8g (0.005mol) input 250ml three-necked flasks, rise
65 DEG C of insulation reaction 10h of temperature.Reaction, which finishes, is cooled to 50 DEG C, and negative pressure, which is steamed to no liquid, drips, and is down to room temperature.Add in DMA 87g
(1.0mol), sodium hydroxide 8g (0.2mol), imidazoles 10.9g (0.16mol) are warming up to 100 DEG C of insulation reaction 5h, are down to room
Temperature is added dropwise allyl chloride 12g (0.16mol), is warming up to 105 DEG C of insulation reaction 6h.Reaction, which finishes, is down to room temperature, adds in 160ml
Water, suction filtration obtain enilconazole crude product, and crude product adds in 45ml ethyl alcohol, and temperature rising reflux 1h is down to room temperature suction filtration, obtains enilconazole fine work
13.5g, yield 60.54%, liquid phase analysis purity >=98%, 50.8~52.1 DEG C of fusing point.
Gained enilconazole fine work is carried out1H NMR characterize, acquired results as shown in Figure 1,1HNMR (400MHz,
CDCl3)：3.72~3.94 (m, 2H ,=CH2)；3.95~4.21 (m, 2H, CH2)；4.92~5.14 (m, 2H, OCH2)；5.15
~5.19 (m, 1H, CHO)；5.70~5.80 (m, 1H ,=CH)；6.93 (s, 1H, Het)；7.01 (s, 1H, Het)；7.24~
7.30 (m, 2H, Ar)；7.30~7.44 (m, 2H, Ar+Het).
Gained enilconazole fine work is subjected to gas-chromatography characterization, acquired results are as shown in attached drawing 2 and table 1.
The gas-chromatography characterization result of 1 embodiment of table, 1 gained enilconazole fine work
| Retention time | Area | Area percentage | Peak height | Peak height percentage |
| 5.383 | 103706 | 0.07 | 105180 | 0.25 |
| 5.485 | 642 | 0.00 | 1233 | 0.00 |
| 5.963 | 92352 | 0.07 | 46078 | 0.11 |
| 6.437 | 211633 | 0.15 | 134356 | 0.32 |
| 6.595 | 138509481 | 99.00 | 40819978 | 98.20 |
| 6.969 | 66672 | 0.05 | 51320 | 0.12 |
| 7.283 | 521198 | 0.37 | 306618 | 0.74 |
| 10.318 | 399203 | 0.29 | 101872 | 0.25 |
| It amounts to | 139904887 | 100 | 41566635 | 100.00 |
Embodiment two
A kind of preparation method of enilconazole is present embodiments provided, step includes：Under stiring, successively by formic acid 92g
(2.0mol), 2,4- bis- chloro- 2 '-chloroacetophenone 22.5g (0.1mol), triethylamine 5g (0.05mol), RuCl2(pph3)3
In 4.8g (0.005mol) input 250ml three-necked flasks, heat up 75 DEG C of insulation reaction 8h.Reaction, which finishes, is cooled to 50 DEG C, negative pressure
It steams to no liquid and drips, be down to room temperature.Add in DMA 87g (1.0mol), sodium hydroxide 8g (0.2mol), imidazoles 10.9g
(0.16mol) is warming up to 100 DEG C of insulation reaction 5h, is down to room temperature, and allyl chloride 12g (0.16mol) is added dropwise, is warming up to 105 DEG C
Insulation reaction 6h.Reaction, which finishes, is down to room temperature, adds in 150ml water, and suction filtration obtains enilconazole crude product, and crude product adds in 46ml ethyl alcohol,
Temperature rising reflux 1h is down to room temperature suction filtration, obtains enilconazole fine work 14.1g, yield 64.23%, and liquid phase analysis purity >=98% melts
51.0~52.1 DEG C of point.
Embodiment three
A kind of preparation method of enilconazole is present embodiments provided, step includes：Under stiring, successively by formic acid 185g
(4.0mol), 2,4- bis- chloro- 2 '-chloroacetophenone 45.1g (0.2mol), triethylamine 10g (0.1mol), RuCl2(pph3)3
In 9.5g (0.01mol) input 500ml three-necked flasks, heat up 70 DEG C of insulation reaction 9h.Reaction, which finishes, is cooled to 50 DEG C, and negative pressure is steamed
It is dripped to no liquid, is down to room temperature.Add in DMA 175g (2.0mol), sodium hydroxide 16g (0.4mol), imidazoles 22g
(0.32mol) is warming up to 100 DEG C of insulation reaction 5h, is down to room temperature, and allyl chloride 24g (0.32mol) is added dropwise, is warming up to 105 DEG C
Insulation reaction 6h.Reaction, which finishes, is down to room temperature, adds in 320ml water, and suction filtration obtains enilconazole crude product, and crude product adds in 100ml ethyl alcohol,
Temperature rising reflux 1h is down to room temperature suction filtration, obtains enilconazole fine work 28.7g, yield 64.4%, and liquid phase analysis purity >=98% melts
50.9~52.0 DEG C of point.
The foregoing is merely presently preferred embodiments of the present invention, is not intended to limit the invention, it is all the present invention spirit and
Within principle, any modification, equivalent replacement, improvement and so on should all be included in the protection scope of the present invention.
Claims (7)
1. a kind of preparation method of enilconazole, it is characterised in that：Step includes：
By 2,4-, bis- chloro- 2 '-chloroacetophenones, reducing agent, organic base, catalyst adds in reaction vessel temperature control in 65-75 DEG C
8-10h is reacted, sodium hydroxide, dimethylacetylamide are added in after concentration, imidazoles reacts 4~6h in 95~105 DEG C, is added dropwise after cooling
Allyl chloride reacts 5~7h at 100~110 DEG C, obtains enilconazole after purification；The reducing agent be formic acid or isopropanol, it is described
Catalyst is RuCl2(pph3)3。
2. the preparation method of enilconazole as described in claim 1, it is characterised in that：2,2 ', the 4 '-trichloroacetophenone is gone back
Former agent, organic base, catalyst, sodium hydroxide, dimethylacetylamide, imidazoles, allyl chloride mol ratio are 1:18~22:0.4
~0.6:0.03~0.07:1.5~2.5:9~11:1.5~1.7:1.5~1.7.
3. the preparation method of enilconazole as claimed in claim 2, it is characterised in that：2,2 ', the 4 '-trichloroacetophenone is gone back
Former agent, organic base, catalyst, sodium hydroxide, dimethylacetylamide, imidazoles, allyl chloride mol ratio are 1:20:0.5:
0.05:2:10:1.6:1.6。
4. the preparation method of enilconazole as described in claim 1, it is characterised in that：Addition sodium hydroxide, dimethylacetylamide,
Imidazoles reacts 5h in 100 DEG C, and allyl chloride is added dropwise after cooling, reacts 6h at 105 DEG C.
5. the preparation method of the enilconazole as described in any one of Claims 1 to 4 claim, it is characterised in that：It is described organic
Alkali is triethylamine or DIPEA.
6. the preparation method of enilconazole as described in claim 1, it is characterised in that：The purification step includes：Reaction terminates
Postcooling adds in the water of twice reaction system volume, stirs 5~15min, and suction filtration obtains enilconazole crude product, enilconazole crude product
Enilconazole product is obtained with ethyl alcohol recrystallization.
7. the preparation method of enilconazole as described in claim 1, it is characterised in that：It is described to be cooled to be cooled to 15~30 DEG C.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110437154A (en) * | 2019-09-10 | 2019-11-12 | 武汉川泰科技有限公司 | A kind of preparation method of enilconazole bulk pharmaceutical chemicals |
| CN110845416A (en) * | 2019-11-19 | 2020-02-28 | 武汉回盛生物科技股份有限公司 | O-allylation method of α -diaryl substituted ethanol |
| CN111012740A (en) * | 2019-12-26 | 2020-04-17 | 武汉回盛生物科技股份有限公司 | Enconazole liquid preparation for external use and preparation method thereof |
| CN114409600A (en) * | 2022-01-19 | 2022-04-29 | 武汉回盛生物科技股份有限公司 | Synthetic method of enilconazole |
| CN116082245A (en) * | 2022-12-26 | 2023-05-09 | 武汉工程大学 | Enconazole crystal and preparation method and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101781294A (en) * | 2010-03-10 | 2010-07-21 | 天津药物研究院 | Imidazole derivative, and preparation method and application thereof |
-
2017
- 2017-12-26 CN CN201711427596.3A patent/CN108191765B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101781294A (en) * | 2010-03-10 | 2010-07-21 | 天津药物研究院 | Imidazole derivative, and preparation method and application thereof |
Non-Patent Citations (4)
| Title |
|---|
| BUI THE KHAI ET AL.: "Selective Reduction of Aldehydes by a Formic Acid-Trialkylamine-RuCl2(PPh3)3 System", 《TETRAHEDRON LETTERS》 * |
| FRANCIS CHEVREUIL ET AL.: "Synthesis of new isoxazoles and dihydroisoxazoles and in vitro evaluation of their antifungal activity", 《JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY》 * |
| RATAN L. CHOWDHURY ET AL.: "Efficient Ruthenium-catalysed Transfer Hydrogenation of Ketones by Propan-2-o1", 《JOURNAL OF THE CHEMICAL SOCIETY, CHEMICAL COMMUNICATION》 * |
| 季世春 等: "硝酸异康唑的合成新工艺", 《中国现代应用药学》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110437154A (en) * | 2019-09-10 | 2019-11-12 | 武汉川泰科技有限公司 | A kind of preparation method of enilconazole bulk pharmaceutical chemicals |
| CN110845416A (en) * | 2019-11-19 | 2020-02-28 | 武汉回盛生物科技股份有限公司 | O-allylation method of α -diaryl substituted ethanol |
| CN111012740A (en) * | 2019-12-26 | 2020-04-17 | 武汉回盛生物科技股份有限公司 | Enconazole liquid preparation for external use and preparation method thereof |
| CN114409600A (en) * | 2022-01-19 | 2022-04-29 | 武汉回盛生物科技股份有限公司 | Synthetic method of enilconazole |
| CN116082245A (en) * | 2022-12-26 | 2023-05-09 | 武汉工程大学 | Enconazole crystal and preparation method and application thereof |
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