CN103936678A - Synthesis method of 4-chloro-2-cyano-N,N-dimethyl-5-(4-methylphenyl)-1H-imidazole-1-sulfonamide - Google Patents
Synthesis method of 4-chloro-2-cyano-N,N-dimethyl-5-(4-methylphenyl)-1H-imidazole-1-sulfonamide Download PDFInfo
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- CN103936678A CN103936678A CN201410165615.XA CN201410165615A CN103936678A CN 103936678 A CN103936678 A CN 103936678A CN 201410165615 A CN201410165615 A CN 201410165615A CN 103936678 A CN103936678 A CN 103936678A
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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
- C07D233/66—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 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
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Abstract
The invention discloses a synthesis method of 4-chloro-2-cyano-N,N-dimethyl-5-(4-methylphenyl)-1H-imidazole-1-sulfonamide (cyazofamid). According to the synthesis method, methylacetophenone is taken as a raw material, selenium dioxide is used for oxidation to prepare an intermediate, namely 2-carbonyl-2-p-benzyl aldehyde, then N,N-dimethylformamide and the like are taken as solvents, thionyl chloride is taken as a chlorinating agent and reducing agent for preparing the intermediate, and then intermediate further reacts with N,N-dimethyl sulfonamide chloride to synthesize the cyazofamid. Compared with the prior art, the synthesis method has the advantages that the reaction period is shortened, the post-treatment process is simplified and the synthesis method is suitable for mass industrial production.
Description
Technical field
The present invention relates to the chloro-2-cyano group-N of a kind of 4-, the synthetic method of N-dimethyl-5-(4-aminomethyl phenyl)-1H-imidazoles-1-sulphonamide (cyazofamid).
Background technology
The chloro-2-cyano group-N of 4-, N-dimethyl-5-(4-aminomethyl phenyl)-1H-imidazoles-1-sulphonamide (cyazofamid) is to be developed by Japanese Ishihara Sangyo Kaisha, Ltd., imidazoles sterilant of new generation with BASF joint development, be mainly used in preventing and treating the disease that Oomycete pathogenic bacteria produces, as: the late blight of potato, tomato late blight, downy mildew of garpe, cucumber downy mildew etc.Have good prolection, residual effect is long, and resistance of rainwater washing against.Both can carry out soil treatment, and also can use by foliar spray, and there is very low toxicity and good environment compatibility.European patent EP 0705823A1 discloses a kind of preparation method of cyazofamid, and the method,, first with azanol, oxalic dialdehyde cyclisation then is reduced through thionyl chloride, sulfur subchloride dehydration for raw material with the chloro-4 '-methyl acetophenone of 2,2-bis-, the synthetic cyazofamid of last sulfonylation.Because the method uses sulfur subchloride, and in reaction, heat release is violent, and long reaction time, causes aftertreatment technology complexity, and the batch production cycle is long.
Summary of the invention
The object of the invention is to solve deficiency of the prior art and defect, provide that a kind of reaction time is short, aftertreatment is simple, be applicable to the chloro-2-cyano group-N of suitability for industrialized production 4-in batches, the method for N-dimethyl-5-(4-aminomethyl phenyl)-1H-imidazoles-1-sulphonamide.
The synthetic route that provides of the present invention is as follows:
The present invention, taking p-methyl aceto phenone as raw material, comprises the following steps:
1) tin anhydride, water and dioxane are added to three mouthfuls of reaction flasks, be heated to 50～70 DEG C tin anhydride is dissolved, add p-methyl aceto phenone, be warming up to 90～120 DEG C, react 4～6 hours, be cooled to room temperature, cross the simple substance selenium that filters out generation, concentrating under reduced pressure is removed solvent, add sherwood oil making beating, obtain crude product 2-carbonyl-2-p-phenmethyl acetaldehyde, carry out recrystallization with the mixed solvent of sherwood oil and ethyl acetate, obtain the more than 98% 2-carbonyl-2-p-phenmethyl acetaldehyde of purity.Wherein, the mol ratio of p-methyl aceto phenone, tin anhydride, water and dioxane is 1:1～2:0.1～0.5:3～10, and the volume ratio of sherwood oil and ethyl acetate is 10～15:1.
2) mixed solvent (volume ratio of methyl alcohol and water is 2～10) of 2-carbonyl-2-p-phenmethyl acetaldehyde, first alcohol and water, the inorganic salt of azanol are joined in reaction flask, back flow reaction 1～6 hour, be cooled to room temperature, add glyoxal water solution, continue back flow reaction 1～6 hour, be cooled to room temperature, filter to obtain 4-hydroxyl-4 (5)-(4-aminomethyl phenyl)-2-oximido methyne imidazoles-3-oxygen.Wherein, the inorganic salt of azanol, 2-carbonyl-2-p-phenmethyl acetaldehyde and oxalic dialdehyde mol ratio be 1:3～8:1～2.
3) 4-hydroxyl-4 (5)-(4-aminomethyl phenyl)-2-oximido methyne imidazoles-3-oxygen and organic solvent are joined in three mouthfuls of reaction flasks, under room temperature, drip thionyl chloride, after dropwising, be warming up to backflow, react 3～6 hours, be cooled to room temperature, add water to stir, leave standstill separatory, remove water, organic phase is steamed and is desolventized, by recrystallizing methanol, obtain 4 (5)-chloro-2-cyano group-5 (4)-(4-aminomethyl phenyl) imidazoles.Wherein, described organic solvent is ethyl acetate, ethylene dichloride, chloroform, N, one or more in dinethylformamide, wherein, the mol ratio of 4-hydroxyl-4 (5)-(4-aminomethyl phenyl)-2-oximido methyne imidazoles-3-oxygen and sulfur oxychloride is 1:2～4.
4) by 4 (5)-chloro-2-cyano group-5 (4)-(4-aminomethyl phenyl) imidazoles, Anhydrous potassium carbonate, N, N dimethylamine base SULPHURYL CHLORIDE and ethyl acetate join in reaction flask, back flow reaction 3～8 hours, be cooled to room temperature, add water to stir, filter to obtain cyazofamid crude product, by re-crystallizing in ethyl acetate, obtain cyazofamid.Wherein, 4 (5)-chloro-2-cyano group-5 (4)-(4-aminomethyl phenyl) imidazoles, N, the mol ratio of N dimethylamine base SULPHURYL CHLORIDE and Anhydrous potassium carbonate is 1:1～2:1～3.
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail.
Embodiment 1
1) 2-carbonyl-2-p-phenmethyl acetaldehyde is synthetic
In the 250ml four-hole boiling flask that thermometer, agitator and reflux condensing tube are housed, add 36.6g (0.33mol) tin anhydride, 150ml dioxane, 10ml distilled water, stirring is warming up to 50 DEG C, add 40.4g (0.3mol) p-methyl aceto phenone, be warming up to 110 DEG C of reactions 5 hours, be down to room temperature, remove by filter filter residue, by dense filtrate decompression dry, add the making beating of 80ml sherwood oil, filter to obtain sorrel solid, with sherwood oil: ethyl acetate=10 (volume ratio) recrystallization, obtains purity 98.5%, yield 82.3%.
2) synthesizing of 4-hydroxyl-4 (5)-(4-aminomethyl phenyl)-2-oximido methyne imidazoles-3-oxygen
In the 500ml four-hole boiling flask that thermometer, agitator and reflux condensing tube are housed, add 44.4g (0.3mol) 2-carbonyl-2-p-phenmethyl acetaldehyde, 104.3g (1.50mol) oxammonium hydrochloride, 200ml methyl alcohol and 100ml water, be warming up to backflow, react 2 hours, then add 47.9g (0.33mol) 40% glyoxal water solution, back flow reaction 2 hours, be cooled to room temperature, filter, be dried to obtain 62.0g (0.30mol) white solid, yield 89.8%, purity 95.3%.
3) synthesizing of 4 (5)-chloro-2-cyano group-5 (4)-(4-aminomethyl phenyl) imidazoles
In the 250ml four-hole boiling flask that thermometer, agitator and reflux condensing tube are housed, add 24.5g (0.1mol) 4-hydroxyl-4 (5)-(4-aminomethyl phenyl)-2-oximido methyne imidazoles-3-oxygen, 150ml ethyl acetate, control temperature at 25 ± 5 DEG C, slowly drip 23.8g (0.2mol) sulfur oxychloride, after dropwising, be warming up to backflow, react 3 hours, be down to room temperature, add 100ml water, separatory, steams organic phase except ethyl acetate product recrystallizing methanol, yield 75%, purity 96.4%.
4) the chloro-2-cyano group-N of 4-, N-dimethyl-5-(4-aminomethyl phenyl)-1H-imidazoles-1-sulphonamide synthetic
In the 250ml four-hole boiling flask that reflux condensing tube, agitator and thermometer are housed, add 23.6g (0.1mol) 4 (5)-chloro-2-cyano group-5 (4)-(4-aminomethyl phenyl) imidazoles, 80ml ethyl acetate, 16.7g (0.12mol) Anhydrous potassium carbonate, 16.7g (0.12mol) N, N dimethylamine base SULPHURYL CHLORIDE, back flow reaction 3 hours, be cooled to room temperature, adding 40ml water stirs, filter, filter cake re-crystallizing in ethyl acetate, obtain white solid, fusing point: 150.4 DEG C～151.7 DEG C, purity 98.8%, yield 96.2%.
Taking the synthetic cyazofamid total recovery of p-methyl aceto phenone as 48%, purity is 98.1%.
Structural Identification:
IR (KBr, cm
-1): 1180,1392 (sulfoamido stretching vibrations) 1447,1474,1497,1556 (phenyl ring skeletal vibration), 2242 (C ≡ N stretching vibrations)
1H?NMR(500MHz，CDCl
3，δppm)：2.424(s，9H，CH
3)，7.378-7.394(d，2H，ph-H)，7.444-7.460(d，2H，ph-H)
Ultimate analysis (%): theoretical value: C48.03, H4.00, N17.00; Measured value: C48.00, H3.95, N16.97
Said structure appraising datum has confirmed that the compound that the method obtains is the chloro-2-cyano group-N of 4-, N-dimethyl-5-(4-aminomethyl phenyl)-1H-imidazoles-1-sulphonamide.
Embodiment 2
1) 2-carbonyl-2-p-phenmethyl acetaldehyde is synthetic
In the 250ml four-hole boiling flask that thermometer, agitator and reflux condensing tube are housed, add 50.0g (0.45mol) tin anhydride, 150ml dioxane, 10ml distilled water, under vigorous stirring, be warming up to 50 DEG C, add 40.4g (0.3mol) p-methyl aceto phenone, be warming up to 110 DEG C of reactions 5 hours, then reaction solution is down to room temperature, remove by filter the selenium of generation, by dense filtrate decompression dry, add the making beating of 80ml sherwood oil, filter to obtain sorrel solid, with sherwood oil: ethyl acetate=10 (volume ratio) recrystallization, obtains purity 98.5%, yield 83.2%.
2) synthesizing of 4-hydroxyl-4 (5)-(4-aminomethyl phenyl)-2-oximido methyne imidazoles-3-oxygen
In the 500ml four-hole boiling flask that thermometer, agitator and reflux condensing tube are housed, add 44.4g (0.3mol) 2-carbonyl-2-p-phenmethyl acetaldehyde, 104.3g (1.50mol) oxammonium sulfate, 200ml methyl alcohol and 100ml water, be warming up to backflow, react 2 hours, then add 47.9g (0.33mol) 40% glyoxal water solution, back flow reaction 2 hours, is cooled to room temperature, filter, be dried to obtain white solid, yield 93%, purity 94.8%.
3) synthesizing of 4 (5)-chloro-2-cyano group-5 (4)-(4-aminomethyl phenyl) imidazoles
In the 250ml four-hole boiling flask that thermometer, agitator and reflux condensing tube are housed, add 24.5g (0.1mol) 4-hydroxyl-4 (5)-(4-aminomethyl phenyl)-2-oximido methyne imidazoles-3-oxygen, 150ml ethyl acetate and 10mlN, dinethylformamide, control temperature at 25 ± 5 DEG C, slowly drip 23.8g (0.2mol) sulfur oxychloride, after dropwising, be warming up to backflow, react 3 hours, be down to room temperature, add 100ml water, separatory, organic phase is steamed except ethyl acetate, product recrystallizing methanol, yield 76.3%, purity 95.7%.
4) the chloro-2-cyano group-N of 4-, N-dimethyl-5-(4-aminomethyl phenyl)-1H-imidazoles-1-sulphonamide synthetic
In the 250ml four-hole boiling flask that reflux condensing tube, agitator and thermometer are housed, add 23.6g (0.1mol) 4 (5)-chloro-2-cyano group-5 (4)-(4-aminomethyl phenyl) imidazoles, 80ml ethyl acetate, 27.8g (0.20mol) Anhydrous potassium carbonate, 16.7g (0.12mol) N, N dimethylamine base SULPHURYL CHLORIDE, back flow reaction 3 hours, be cooled to room temperature, adding 40ml water stirs, filter, filter cake re-crystallizing in ethyl acetate, obtain white solid, purity 98%, yield 89.2%.
Taking the synthetic cyazofamid total recovery of p-methyl aceto phenone as 46.1%, purity is 89.2%.
Embodiment 3
Method is substantially the same manner as Example 2, and difference is step 3) in solvent be changed to ethylene dichloride and DMF.Taking the synthetic cyazofamid total recovery of p-methyl aceto phenone as 45.7%, purity is 89.2%.
Embodiment 4
Method is substantially the same manner as Example 2, and difference is step 4) in Anhydrous potassium carbonate be 0.12mol.Taking the synthetic cyazofamid total recovery of p-methyl aceto phenone as 46.6%, purity is 98.2%.
Embodiment 5
Method is substantially the same manner as Example 2, and difference is due to step 3) with step 4) employing solvent be ethyl acetate, so this two-step reaction can be linked up and operates.Taking the synthetic cyazofamid total recovery of p-methyl aceto phenone as 48.3%, purity is 98.1%.
Table 1
| Cyazofamid | Production cycle | Aftertreatment | Yield |
| Prior art | 36h | Desulfurization | 53.7％ |
| Embodiment 5 | 21h | Do not need | 48％ |
As can be seen from the above table, compared with prior art, product yield is substantially suitable in the present invention, but reaction process of the present invention is without desulfurization, has simplified aftertreatment technology, and has almost shortened half compared with the original production cycle, is conducive to industrial applications.
Claims (2)
1. the chloro-2-cyano group-N of 4-, the synthetic method of N-dimethyl-5-(4-aminomethyl phenyl)-1H-imidazoles-1-sulphonamide, is characterized in that, taking p-methyl aceto phenone as raw material, comprising the following steps:
1) by tin anhydride, water and dioxane add three mouthfuls of reaction flasks, being heated to 50～70 DEG C dissolves tin anhydride, add p-methyl aceto phenone, be warming up to 90～120 DEG C, react 4～6 hours, be cooled to room temperature, remove by filter filter residue, concentrating under reduced pressure is removed solvent, add sherwood oil making beating, carry out recrystallization with the mixed solvent of sherwood oil and ethyl acetate, obtain 2-carbonyl-2-p-phenmethyl acetaldehyde, wherein, p-methyl aceto phenone, tin anhydride, the mol ratio of water and dioxane is 1:1～2:0.1～0.5:3～10, the volume ratio of sherwood oil and ethyl acetate is 10～15:1,
2) 2-carbonyl-2-p-phenmethyl acetaldehyde, the mixed solvent of first alcohol and water, the inorganic salt of azanol are added to reaction flask, back flow reaction 1～6 hour, be cooled to room temperature, add glyoxal water solution, continue back flow reaction 1～6 hour, be cooled to room temperature, filter to obtain 4-hydroxyl-4 (5)-(4-aminomethyl phenyl)-2-oximido methyne imidazoles-3-oxygen, wherein, the volume ratio of methyl alcohol and water is 2～10:1, inorganic salt, 2-carbonyl-2-p-phenmethyl acetaldehyde and the oxalic dialdehyde of azanol mol ratio be 1:3～8:1～2;
3) 4-hydroxyl-4 (5)-(4-aminomethyl phenyl)-2-oximido methyne imidazoles-3-oxygen and organic solvent are joined in three mouthfuls of reaction flasks, under room temperature, drip thionyl chloride, 65～85 DEG C are reacted 3～6 hours, be cooled to room temperature, stirring adds water, leave standstill separatory, remove water, organic phase is steamed and is desolventized, by recrystallizing methanol, obtain 4 (5)-chloro-2-cyano group-5 (4)-(4-aminomethyl phenyl) imidazoles, wherein, described organic solvent is ethyl acetate, ethylene dichloride, chloroform, N, one or more in dinethylformamide, the mol ratio of 4-hydroxyl-4 (5)-(4-aminomethyl phenyl)-2-oximido methyne imidazoles-3-oxygen and sulfur oxychloride is 1:2～4,
4) by 4 (5)-chloro-2-cyano group-5 (4)-(4-aminomethyl phenyl) imidazoles, Anhydrous potassium carbonate, N, N dimethylamine base SULPHURYL CHLORIDE and ethyl acetate join in reaction flask, back flow reaction 3～8 hours, be cooled to room temperature, stirring adds water, filter, by re-crystallizing in ethyl acetate, obtain target product, wherein, 4 (5)-chloro-2-cyano group-5 (4)-(4-aminomethyl phenyl) imidazoles, N, the mol ratio of N dimethylamine base SULPHURYL CHLORIDE and Anhydrous potassium carbonate is 1:1～2:1～3.
2. synthetic method according to claim 1, is characterized in that: step 2) described in add before oxalic dialdehyde reflux time 1～3 hour, add after oxalic dialdehyde reflux time 1～3 hour.
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| CN104292166A (en) * | 2014-10-14 | 2015-01-21 | 西安近代化学研究所 | Method for synthesizing 4-chloro-2-cyano-N,N-dimethyl-5-p-methylphenylimidazole-1-sulfamide |
| CN105130904A (en) * | 2015-08-24 | 2015-12-09 | 如东众意化工有限公司 | Synthetic method for 2-cyano-4-chloro-5-(4-methylphenyl)imidazole |
| CN106187820A (en) * | 2016-07-02 | 2016-12-07 | 深圳市康立生生物科技有限公司 | A kind of preparation method of bambuterol impurity B |
| CN106986830A (en) * | 2017-05-11 | 2017-07-28 | 蚌埠中实化学技术有限公司 | The synthetic method of 4 chlorine, 2 cyano group 1 dimethylamino-sulfonyl 5 (4 aminomethyl phenyl) imidazoles |
| CN107417622A (en) * | 2017-09-20 | 2017-12-01 | 西安近代化学研究所 | A kind of process for purification of 4 (5) chlorine 2 cyano group 5 (4) (4 ' aminomethyl phenyl) imidazoles |
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| CN105130904A (en) * | 2015-08-24 | 2015-12-09 | 如东众意化工有限公司 | Synthetic method for 2-cyano-4-chloro-5-(4-methylphenyl)imidazole |
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| JP2020508324A (en) * | 2017-02-23 | 2020-03-19 | アダマ・マクテシム・リミテッド | Method for preparing 2-cyanoimidazole compound |
| CN110337434B (en) * | 2017-02-23 | 2022-11-22 | 安道麦马克西姆有限公司 | Process for preparing 2-cyanoimidazole compounds |
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| CN106986830A (en) * | 2017-05-11 | 2017-07-28 | 蚌埠中实化学技术有限公司 | The synthetic method of 4 chlorine, 2 cyano group 1 dimethylamino-sulfonyl 5 (4 aminomethyl phenyl) imidazoles |
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| CN107417622B (en) * | 2017-09-20 | 2020-05-05 | 西安近代化学研究所 | A refining method of 4(5) -chloro-2-cyano-5 (4) - (4' -methylphenyl) imidazole |
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