CN104311448B - A kind of preparation method of dinitolmide - Google Patents
A kind of preparation method of dinitolmide Download PDFInfo
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- CN104311448B CN104311448B CN201410481428.2A CN201410481428A CN104311448B CN 104311448 B CN104311448 B CN 104311448B CN 201410481428 A CN201410481428 A CN 201410481428A CN 104311448 B CN104311448 B CN 104311448B
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Abstract
The preparation method that the present invention relates to a kind of compound, more particularly to the preparation method of a kind of dinitolmide. Described method is with ortho-methyl benzoic acid for raw material, dichloroethanes is solvent, and concentrated nitric acid is nitrating agent, and thionyl chloride is chloride reagent, DMF is the catalyst of acyl chloride reaction, adopt the dichloroethane solution that one kettle way is nitrated, chloride obtains intermediate 3,5-dinitros-ortho-methyl Benzenecarbonyl chloride., then through ammonia ammonification, recycling solvent, ammonia obtain the aqueous solution of dinitolmide, described aqueous solution is cooled down, precipitates out crystal, to obtain target product dinitolmide through filtering, wash and drying. The inventive method adopts one kettle way to carry out nitrated, acyl chloride reaction, simplifies technological process, with short production cycle, decreases three waste discharge; Ammonification is disposable recycling design and ammonia after completing, and preparation technology is simple, and cost is low, pollution-free, and yield is high, is a kind of environmental friendliness, the synthetic method of the dinitolmide of green high-efficient.
Description
Technical field
The preparation method that the present invention relates to a kind of compound, more particularly to the preparation method of a kind of dinitolmide.
Background technology
Dinitolmide (3,5-dinitro-2-ar-Toluic acid amine), for wide spectrum, efficiently, safety, noresidue anticoccidial drug, for feedstuff can promote the growth of chicken. Multiple eimeria tenella to chicken, as tender, murder by poisoning, Bu Shi, heap shape, the eimeria tenella such as huge and turkey coccidiosis etc. effectively. Particularly that Eimeria Tenella and murder by poisoning eimeria tenella is effective, mainly suppress to embrace without the fragmentation bud of sexual cycle. This product is applied not only to prevention, and may be used for treatment, application for the treatment of amount to the growth of chicken, grow, the incubation rate laid eggs all has no adverse effects, and the coccidiosis of rabbit is also had good preventive and therapeutic effect.
The traditional synthesis of dinitolmide is: 1) with ortho-methyl benzoic acid for raw material, obtains intermediate 3,5-dinitros-ortho-methyl benzoic acid through nitrated-washing-dry; 2) intermediate 3,5-dinitros-ortho-methyl benzoic acid obtains intermediate 3,5-dinitros-ortho-methyl Benzenecarbonyl chloride. through chloride-distillating recovering solvent; 3) intermediate 3,5-dinitros-ortho-methyl Benzenecarbonyl chloride. obtains target product dinitolmide through ammonification-washing-dry. The shortcoming of this technique is in that technological process is more complicated, and the production cycle is long, and production cost is higher, and the three wastes are many, is unfavorable for environmental conservation.
Summary of the invention
It is an object of the invention to solve the deficiencies in the prior art, it is provided that the preparation method of a kind of coccidiostat dinitolmide, present invention process flow process is simple, with short production cycle, operability is high, environmental friendliness, yield high, is suitable for large-scale production.
The technical solution adopted for the present invention to solve the technical problems is:
A kind of preparation method of dinitolmide, described method is with ortho-methyl benzoic acid for raw material, dichloroethanes is solvent, concentrated nitric acid is nitrating agent, thionyl chloride is chloride reagent, DMF is the catalyst of acyl chloride reaction, employing one kettle way is nitrated, chloride obtains intermediate 3, the dichloroethane solution of 5-dinitro-ortho-methyl Benzenecarbonyl chloride., then through ammonia ammonification, recycling solvent, ammonia obtain the aqueous solution of dinitolmide, are cooled down by described aqueous solution, precipitate out crystal, to obtain target product dinitolmide through filtering, wash and drying.
As preferably, described method specifically carries out as follows:
1) preparation of intermediate 3,5-dinitros-ortho-methyl Benzenecarbonyl chloride.:
Ortho-methyl benzoic acid is dissolved in the dichloroethanes of 3-4 times of its quality, slowly dripping content in 40��60 DEG C is the nitric acid of 98%, the mol ratio of ortho-methyl benzoic acid and nitric acid is 1:2.25, dropwise back flow reaction 1��2h, TLC monitors, after reaction terminates, obtain 3, 5-dinitro-benzoic dichloroethane solution of ortho-methyl, the DMF adding substrate mole 3 �� mol in above-mentioned solution makees catalyst, 40��60 DEG C slowly drip thionyl chloride, 3, mol ratio=the 1:1.5 of 5-dinitro-ortho-methyl benzoic acid and thionyl chloride, back flow reaction 1��3h, TLC monitors, after reaction terminates, obtain 3, the dichloroethane solution of 5-dinitro-ortho-methyl Benzenecarbonyl chloride.,
2) preparation of dinitolmide:
Proper ammonia is added in another reactor, ammonia and the benzoic mol ratio=4:1 of ortho-methyl, it is cooled to 15��20 DEG C, less than 30 DEG C slowly drip above-mentioned 3, the dichloroethane solution of 5-dinitro-ortho-methyl Benzenecarbonyl chloride., dropwise stirring 20��30min, after ammonification completes, it is warming up to 83��85 DEG C and reclaims dichloroethanes, the ammonia of tail gas absorbs through water simultaneously, the two applies mechanically next time respectively, treat solvent, Ammonia recovery is complete, remaining dinitolmide aqueous solution is cooled to 30 DEG C, filter, tap water, 105 DEG C dry, obtain target product dinitolmide, its purity (HPLC): >=98%, M.P:183��185 DEG C.
As preferably, step 2) used by the content of ammonia be 20%.
Reaction equation of the present invention is:
The invention has the beneficial effects as follows: the inventive method adopts one kettle way to carry out nitrated, acyl chloride reaction, simplifies technological process, with short production cycle, decreases three waste discharge; Ammonification is disposable recycling design and ammonia after completing, and preparation technology is simple, and cost is low, pollution-free, and yield is high, is a kind of environmental friendliness, the synthetic method of the dinitolmide of green high-efficient.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is described further, but protection scope of the present invention is not limited to that, in embodiment, agents useful for same is all commercial conventional reagent.
Embodiment 1:
A kind of preparation method of dinitolmide, described preparation method carries out as follows:
1) preparation of intermediate 3,5-dinitros-ortho-methyl Benzenecarbonyl chloride.:
By ortho-methyl benzoic acid 20g(0.148mol in there-necked flask) it is dissolved in 60g dichloroethanes, 40��45 DEG C slowly drip the nitric acid 21g(0.333mol that content is 98%), dropwise back flow reaction 1.5h, TLC monitors, after reaction terminates, obtain 3, 5-dinitro-benzoic dichloroethane solution of ortho-methyl, in above-mentioned solution add 0.2g(3 �� mol) DMF make catalyst, 40��60 DEG C slowly drip thionyl chloride 26.6g, back flow reaction 1.5h, TLC monitors, after reaction terminates, obtain 3, the dichloroethane solution of 5-dinitro-ortho-methyl Benzenecarbonyl chloride.,
2) preparation of dinitolmide
The ammonia 140g that content is 20% is added in another four-hole bottle, it is cooled to 15 DEG C, less than 30 DEG C slowly drip above-mentioned 3, the dichloroethane solution of 5-dinitro-ortho-methyl Benzenecarbonyl chloride., dropwise stirring at normal temperature 25min, after ammonification completes, it is warming up to 83��85 DEG C and reclaims dichloroethanes, tail gas (ammonia) absorbs through water simultaneously, and the two applies mechanically next time respectively, treats that solvent, Ammonia recovery are complete, remaining dinitolmide aqueous solution is cooled to 30 DEG C, filtration, tap water, 105 DEG C dry, obtain target product dinitolmide 32.35g;Total recovery=96.01%, purity (HPLC)=98.89%, M.P:183��185 DEG C.
Comparative example:
Implement traditionally
1) the benzoic preparation of intermediate 3,5-dinitros-ortho-methyl
Equipped with, in the 250mL there-necked flask of thermometer, adding benzoic 7.5 times amount of concentrated sulphuric acid 150g(ortho-methyl), ortho-methyl benzoic acid 20g(0.148mol), open stirring and be warming up to 40 DEG C of insulation 10min, make it be completely dissolved, drip in 98% nitric acid 21g, 1h in 50��65 DEG C and add. 90��100 DEG C of reaction 1h, place 3h, above-mentioned reactant is added drop-wise in 1337g cold water, precipitates out crystal, filter, filter cake clear water washs, 100 DEG C of drying, it is thus achieved that described intermediate 3,5-dinitros-ortho-methyl benzoic acid 34.72g, its content of liquid chromatogram measuring is 92.55% (calculating with external standard method), yield 96.01%;
2) preparation of intermediate 3,5-dinitros-ortho-methyl Benzenecarbonyl chloride.:
The mix homogeneously in 200ml there-necked flask by 22.51g3,5-dinitro-ortho-methyl benzoic acid and 23.2g phosphorus pentachloride, loads onto condenser and absorbs the conduit of HCL gas, slowly heating in oil bath, and the HCL water that reaction is released absorbs. Heating (reacting very violent) is stopped when heating is to 30min, backflow 1.2h is reheated after 10min, decompression is distilled off by-product phosphorus oxychloride, cooling, obtain residue that is 3,5-dinitro-ortho-methyl Benzenecarbonyl chloride. 22.52g, its content of liquid chromatogram measuring is 93.63% (calculating with external standard method), yield 85.71%.
3) preparation of dinitolmide
In 200ml there-necked flask, add 800ml ammonia (content 28%), stirring, slowly drip melt 3 in 40 DEG C, 5-dinitro-ortho-methyl Benzenecarbonyl chloride. 22.5g, dropwises, and places 1.5h, sucking filtration, cold water washs, and 100 DEG C dry, obtain target product dinitolmide 21.40g(yield 92%); Total recovery=73%, purity (HPLC)=95.33%, M.P:183��185 DEG C.
Be can be seen that by the result of embodiment 1 with comparative example, the product yield of the preparation method of the present invention is high, product content is high, organic solvent is as reaction media, solvent recovery is conducive to apply mechanically, save cost, and avoided the problem producing a large amount of waste water in preparation process, be a kind of eco-friendly preparation method.
Embodiment described above is the one preferably scheme of the present invention, not the present invention is done any pro forma restriction, also has other variant and remodeling under the premise without departing from the technical scheme described in claim.
Claims (2)
1. the preparation method of a dinitolmide, it is characterized in that, described method is with ortho-methyl benzoic acid for raw material, dichloroethanes is solvent, concentrated nitric acid is nitrating agent, thionyl chloride is chloride reagent, DMF is the catalyst of acyl chloride reaction, adopt the dichloroethane solution that one kettle way is nitrated, chloride obtains intermediate 3,5-dinitros-ortho-methyl Benzenecarbonyl chloride., then through ammonia ammonification, recycling solvent, ammonia obtain the aqueous solution of dinitolmide, described aqueous solution is cooled down, precipitates out crystal, to obtain target product dinitolmide through filtering, wash and drying; Described method specifically carries out as follows:
1) preparation of intermediate 3,5-dinitros-ortho-methyl Benzenecarbonyl chloride.:
Ortho-methyl benzoic acid is dissolved in the dichloroethanes of 3-4 times of its quality, slowly dripping content in 40��60 DEG C is the nitric acid of 98%, the mol ratio of ortho-methyl benzoic acid and nitric acid is 1:2.25, dropwise back flow reaction 1��2h, TLC monitors, after reaction terminates, obtain 3, 5-dinitro-benzoic dichloroethane solution of ortho-methyl, the DMF adding substrate mole 3 �� mol in above-mentioned solution makees catalyst, 40��60 DEG C slowly drip thionyl chloride, 3, mol ratio=the 1:1.5 of 5-dinitro-ortho-methyl benzoic acid and thionyl chloride, back flow reaction 1��3h, TLC monitors, after reaction terminates, obtain 3, the dichloroethane solution of 5-dinitro-ortho-methyl Benzenecarbonyl chloride.,
2) preparation of dinitolmide:
Proper ammonia is added in another reactor, ammonia and the benzoic mol ratio=4:1 of ortho-methyl, it is cooled to 15��20 DEG C, less than 30 DEG C slowly drip above-mentioned 3, the dichloroethane solution of 5-dinitro-ortho-methyl Benzenecarbonyl chloride., dropwise stirring 20��30min, after ammonification completes, it is warming up to 83��85 DEG C and reclaims dichloroethanes, the ammonia of tail gas absorbs through water simultaneously, the two applies mechanically next time respectively, treat solvent, Ammonia recovery is complete, remaining dinitolmide aqueous solution is cooled to 30 DEG C, filter, tap water, 105 DEG C dry, obtain target product dinitolmide.
2. the preparation method of dinitolmide according to claim 1, it is characterised in that step 2) used by the content of ammonia be 20%.
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| CN105906523B (en) * | 2016-05-12 | 2018-01-02 | 浙江荣耀生物科技股份有限公司 | The synthetic method of one bulb dysentery spirit |
| CN107121515A (en) * | 2017-06-22 | 2017-09-01 | 扬州大学 | A kind of method for extracting dinitolmide and its metabolite residual simultaneously from chicken tissues |
| CN109721504B (en) * | 2019-01-29 | 2022-03-11 | 浙江工业大学 | Method for continuously preparing amide from carboxylic acid |
| CN112266326A (en) * | 2020-11-10 | 2021-01-26 | 杭州臻挚生物科技有限公司 | Preparation method of dichlorotoluene nitride intermediate |
| CN113149845B (en) * | 2021-03-11 | 2022-07-05 | 台州学院 | Preparation method of 3, 5-dinitro-2-methylbenzoic acid |
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Address after: Changan city Jiaxing town Zhejiang city of Haining province (314400 agricultural areas) Chunchao Road No. 3 Patentee after: ZHEJIANG ESIGMA BIOTECHNOLOGY CO., LTD. Address before: Changan city Jiaxing town Zhejiang city of Haining province (314400 agricultural areas) Chunchao Road No. 3 Patentee before: Zhejiang Huineng Animal Medicine Co., Ltd. |
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Denomination of invention: Preparation method of dinitolmide Effective date of registration: 20170303 Granted publication date: 20160608 Pledgee: The Bank of Nanjing Limited by Share Ltd of Hangzhou city Small and micro businesses franchise branch Pledgor: Gansu Huineng Biological Engineering Co. Ltd.|Zhejiang Huineng biological Limited by Share Ltd Registration number: 2017330000019 |
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