CN103936678B - The chloro-2-cyano group of a kind of 4--N, the synthetic method of N-dimethyl-5-(4 '-aminomethyl phenyl)-1H-imidazoles-1-sulphonamide - Google Patents
The chloro-2-cyano group of a kind of 4--N, the synthetic method of N-dimethyl-5-(4 '-aminomethyl phenyl)-1H-imidazoles-1-sulphonamide Download PDFInfo
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- CN103936678B CN103936678B CN201410165615.XA CN201410165615A CN103936678B CN 103936678 B CN103936678 B CN 103936678B CN 201410165615 A CN201410165615 A CN 201410165615A CN 103936678 B CN103936678 B CN 103936678B
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- C—CHEMISTRY; METALLURGY
- 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
- C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Abstract
The invention discloses the chloro-2-cyano group of a kind of 4--N, the synthetic method of N-dimethyl-5-(4 '-aminomethyl phenyl)-1H-imidazoles-1-sulphonamide (cyazofamid), the method take p-methyl aceto phenone as raw material, intermediate 2-carbonyl-2-is prepared to phenmethyl acetaldehyde with tin anhydride oxidation, then adopt DMF etc. to make solvent, thionyl chloride makes chlorizating agent and reductive agent to prepare intermediate, this intermediate again with N, N-dimethyl sulfonamide chlorine Reactive Synthesis cyazofamid.The present invention compared with prior art, shortens reaction time, simplifies aftertreatment technology, is applicable to bulk industrial and produces.
Description
Technical field
The present invention relates to the chloro-2-cyano group of a kind of 4--N, the synthetic method of N-dimethyl-5-(4 '-aminomethyl phenyl)-1H-imidazoles-1-sulphonamide (cyazofamid).
Background technology
The chloro-2-cyano group of 4--N, N-dimethyl-5-(4 '-aminomethyl phenyl)-1H-imidazoles-1-sulphonamide (cyazofamid) is developed by Japanese Ishihara Sangyo Kaisha, Ltd., with the imidazoles sterilant of new generation of BASF joint development, be mainly used in the disease of preventing and treating the generation of Oomycete pathogenic bacteria, 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 is with the chloro-4 '-methyl acetophenone of 2,2-bis-for raw material, and first with azanol, oxalic dialdehyde cyclisation, then through thionyl chloride, sulfur subchloride dehydration reduction, last sulfonylation synthesizes cyazofamid.Because the method uses sulfur subchloride, and in reaction, heat release is violent, long reaction time, and cause aftertreatment technology complicated, 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, there is provided that a kind of reaction time is short, aftertreatment is simple, be applicable to bulk industrial and produce the chloro-2-cyano group of 4--N, the method for N-dimethyl-5-(4 '-aminomethyl phenyl)-1H-imidazoles-1-sulphonamide.The present invention is raw material with p-methyl aceto phenone, comprises the following steps:
1) tin anhydride, water and dioxane are added three mouthfuls of reaction flasks, being heated to 50 ~ 70 DEG C makes tin anhydride dissolve, and adds p-methyl aceto phenone, is warming up to 90 ~ 120 DEG C, react 4 ~ 6 hours, be cooled to room temperature, the elemental selenium that removed by filtration generates, concentrating under reduced pressure removes solvent, add sherwood oil making beating, obtain crude product 2-carbonyl-2-to phenmethyl acetaldehyde, carry out recrystallization with the mixed solvent of sherwood oil and ethyl acetate, obtain the 2-carbonyl-2-of purity more than 98% to phenmethyl acetaldehyde.Wherein, the mol ratio of p-methyl aceto phenone, tin anhydride, water and dioxane is 3:3 ~ 6:5.6:9 ~ 30, and the volume ratio of sherwood oil and ethyl acetate is 10 ~ 15:1.
2) 2-carbonyl-2-is joined in reaction flask to the mixed solvent (volume ratio of methyl alcohol and water is 2 ~ 10) of phenmethyl acetaldehyde, first alcohol and water, the inorganic salt of azanol, 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 (5)-hydroxyl-5 (4)-(4 '-aminomethyl phenyl)-2-oximido methyne imidazoles-3-oxygen.Wherein, 2-carbonyl-2-to the inorganic salt of phenmethyl acetaldehyde, azanol and oxalic dialdehyde mol ratio be 1:3 ~ 8:1 ~ 2.
3) 4 (5)-hydroxyl-5 (4)-(4 '-aminomethyl phenyl)-2-oximido methyne imidazoles-3-oxygen and organic solvent are joined in three mouthfuls of reaction flasks, thionyl chloride is dripped under room temperature, backflow is warming up to after dropwising, react 3 ~ 6 hours, be cooled to room temperature, add water to stir, leave standstill separatory, removing aqueous phase, 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 (5)-hydroxyl-5 (4)-(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-is to the synthesis of phenmethyl acetaldehyde
36.6g (0.33mol) tin anhydride is added in the 250ml four-hole boiling flask that thermometer, agitator and reflux condensing tube are housed, 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, cross and filter filter residue, by dense for filtrate decompression dry, add the making beating of 80ml sherwood oil, filter to obtain red brown solid, with sherwood oil: ethyl acetate=10 (volume ratio) recrystallization, obtains purity 98.5%, yield 82.3%.
2) synthesis of 4 (5)-hydroxyl-5 (4)-(4 '-aminomethyl phenyl)-2-oximido methyne imidazoles-3-oxygen
44.4g (0.3mol) 2-carbonyl-2-is added to phenmethyl acetaldehyde, 104.3g (1.50mol) oxammonium hydrochloride, 200ml methyl alcohol and 100ml water in the 500ml four-hole boiling flask that thermometer, agitator and reflux condensing tube are housed, be warming up to backflow, react 2 hours, then 47.9g (0.33mol) 40% glyoxal water solution is added, back flow reaction 2 hours, be cooled to room temperature, filter, dry 62.0g (0.30mol) white solid, yield 89.8%, purity 95.3%.
3) synthesis of 4 (5)-chloro-2-cyano group-5 (4)-(4 '-aminomethyl phenyl) imidazoles
24.5g (0.1mol) 4 (5)-hydroxyl-5 (4)-(4 '-aminomethyl phenyl)-2-oximido methyne imidazoles-3-oxygen is added in the 250ml four-hole boiling flask that thermometer, agitator and reflux condensing tube are housed, 150ml ethyl acetate, control temperature is at 25 ± 5 DEG C, slow dropping 23.8g (0.2mol) sulfur oxychloride, backflow is warming up to after dropwising, react 3 hours, be down to room temperature, add 100ml water, separatory, steams organic phase except ethyl acetate, product with methylalcohol recrystallization, yield 75%, purity 96.4%.
4) synthesis of the chloro-2-cyano group of 4--N, N-dimethyl-5-(4 '-aminomethyl phenyl)-1H-imidazoles-1-sulphonamide
23.6g (0.1mol) 4 (5)-chloro-2-cyano group-5 (4)-(4 '-aminomethyl phenyl) imidazoles, 80ml ethyl acetate is added in the 250ml four-hole boiling flask that reflux condensing tube, agitator and thermometer are housed, 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, add 40ml water to stir, 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%.
In p-methyl aceto phenone synthesis cyazofamid total recovery for 48%, purity is 98.1%.
Structural Identification:
IR (KBr, cm
-1): 1180,1392 (sulfoamido stretching vibration) 1447,1474,1497,1556 (phenyl ring skeletal vibration), 2242 (C ≡ N stretching vibrations)
1HNMR(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 confirms that the compound that the method obtains is the chloro-2-cyano group of 4--N, N-dimethyl-5-(4 '-aminomethyl phenyl)-1H-imidazoles-1-sulphonamide.
Embodiment 2
1) 2-carbonyl-2-is to the synthesis of phenmethyl acetaldehyde
50.0g (0.45mol) tin anhydride is added in the 250ml four-hole boiling flask that thermometer, agitator and reflux condensing tube are housed, 150ml dioxane, 10ml distilled water, 50 DEG C are warming up under vigorous stirring, 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, cross the selenium filtering generation, by dense for filtrate decompression dry, add the making beating of 80ml sherwood oil, filter to obtain red brown solid, with sherwood oil: ethyl acetate=10 (volume ratio) recrystallization, obtains purity 98.5%, yield 83.2%.
2) synthesis of 4 (5)-hydroxyl-5 (4)-(4 '-aminomethyl phenyl)-2-oximido methyne imidazoles-3-oxygen
44.4g (0.3mol) 2-carbonyl-2-is added to phenmethyl acetaldehyde, 104.3g (1.50mol) oxammonium sulfate, 200ml methyl alcohol and 100ml water in the 500ml four-hole boiling flask that thermometer, agitator and reflux condensing tube are housed, 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, dry white solid, yield 93%, purity 94.8%.
3) synthesis of 4 (5)-chloro-2-cyano group-5 (4)-(4 '-aminomethyl phenyl) imidazoles
Thermometer is being housed, 24.5g (0.1mol) 4 (5)-hydroxyl-5 (4)-(4 '-aminomethyl phenyl)-2-oximido methyne imidazoles-3-oxygen is added in the 250ml four-hole boiling flask of agitator and reflux condensing tube, 150ml ethyl acetate and 10mlN, dinethylformamide, control temperature is at 25 ± 5 DEG C, slow dropping 23.8g (0.2mol) sulfur oxychloride, backflow is warming up to after dropwising, react 3 hours, be down to room temperature, add 100ml water, separatory, organic phase is steamed except ethyl acetate, product with methylalcohol recrystallization, yield 76.3%, purity 95.7%.
4) synthesis of the chloro-2-cyano group of 4--N, N-dimethyl-5-(4 '-aminomethyl phenyl)-1H-imidazoles-1-sulphonamide
23.6g (0.1mol) 4 (5)-chloro-2-cyano group-5 (4)-(4 '-aminomethyl phenyl) imidazoles, 80ml ethyl acetate is added in the 250ml four-hole boiling flask that reflux condensing tube, agitator and thermometer are housed, 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, add 40ml water to stir, filter, filter cake re-crystallizing in ethyl acetate, obtain white solid, purity 98%, yield 89.2%.
In p-methyl aceto phenone synthesis cyazofamid total recovery for 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.In p-methyl aceto phenone synthesis cyazofamid total recovery for 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.In p-methyl aceto phenone synthesis cyazofamid total recovery for 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, operate so this two-step reaction can be linked up.In p-methyl aceto phenone synthesis cyazofamid total recovery for 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, but reaction process of the present invention is without the need to desulfurization, simplifies aftertreatment technology, and almost shortens half compared with the original production cycle, is conducive to industrial applications in the present invention.
Claims (2)
1. the synthetic method of the chloro-2-cyano group of a 4--N, N-dimethyl-5-(4 '-aminomethyl phenyl)-1H-imidazoles-1-sulphonamide, its synthetic route is as follows:
Concrete reactions steps is as follows:
1) by tin anhydride, water and dioxane add three mouthfuls of reaction flasks, being heated to 50 ~ 70 DEG C makes tin anhydride dissolve, add p-methyl aceto phenone, be warming up to 90 ~ 120 DEG C, react 4 ~ 6 hours, be cooled to room temperature, cross and filter filter residue, concentrating under reduced pressure removes solvent, add sherwood oil making beating, recrystallization is carried out with the mixed solvent of sherwood oil and ethyl acetate, obtain 2-carbonyl-2-p-tolyl acetaldehyde, wherein, p-methyl aceto phenone, tin anhydride, the mol ratio of water and dioxane is 3:3 ~ 6:5.6:9 ~ 30, the volume ratio of sherwood oil and ethyl acetate is 10 ~ 15:1,
2) 2-carbonyl-2-p-tolyl acetaldehyde, the mixed solvent of first alcohol and water, the inorganic salt of azanol are added 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 (5)-hydroxyl-5 (4)-(4 '-aminomethyl phenyl)-2-oximido methyne imidazoles-3-oxygen, wherein, the volume ratio of methyl alcohol and water is 2 ~ 10:1,2-carbonyl-2-p-tolyl acetaldehyde, the inorganic salt of azanol and oxalic dialdehyde mol ratio be 1:3 ~ 8:1 ~ 2;
3) 4 (5)-hydroxyl-5 (4)-(4 '-aminomethyl phenyl)-2-oximido methyne imidazoles-3-oxygen and organic solvent are joined in three mouthfuls of reaction flasks, thionyl chloride is dripped under room temperature, 65 ~ 85 DEG C are reacted 3 ~ 6 hours, be cooled to room temperature, add water stirring, leave standstill separatory, removing aqueous phase, 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 (5)-hydroxyl-5 (4)-(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 stirring, 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 oxalic dialdehyde before reflux time 1 ~ 3 hour, reflux time 1 ~ 3 hour after adding oxalic dialdehyde.
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| CN105130904B (en) * | 2015-08-24 | 2017-10-13 | 如东众意化工有限公司 | A kind of chlorine 5 of 2 cyano group 4（4 aminomethyl phenyls）The synthetic method of imidazoles |
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