CN114671783B - Preparation method of 4,4' -dinitro diphenyl urea - Google Patents
Preparation method of 4,4' -dinitro diphenyl urea Download PDFInfo
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- CN114671783B CN114671783B CN202210277148.4A CN202210277148A CN114671783B CN 114671783 B CN114671783 B CN 114671783B CN 202210277148 A CN202210277148 A CN 202210277148A CN 114671783 B CN114671783 B CN 114671783B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
- C07C273/1809—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas with formation of the N-C(O)-N moiety
- C07C273/1818—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas with formation of the N-C(O)-N moiety from -N=C=O and XNR'R"
- C07C273/1827—X being H
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Abstract
The invention discloses a preparation method of 4,4 '-dinitro diphenyl urea, which comprises the steps of adding paranitroaniline and paranitroisocyanate into a ball milling tank, adding a trace amount of solvent and a ball milling medium, sealing the ball milling tank, placing the ball milling tank into a ball mill, performing mechanical ball milling reaction at a ball milling frequency of 15-30 Hz, and purifying after ball milling is finished to obtain the 4,4' -dinitro diphenyl urea. The invention adopts a mechanical grinding mode to prepare the 4,4' -dinitro diphenyl urea, avoids using a large amount of solvents, triethylamine and toxic raw materials, reduces the emission of three wastes, has the advantages of better yield, short reaction time, simple and convenient operation, less environmental pollution and the like, and has the yield of more than 90 percent and the purity of more than 99 percent.
Description
Technical Field
The invention belongs to the technical field of preparation of drug intermediates, and mainly relates to a preparation method of a drug nicarbazin intermediate 4,4' -dinitrodiphenyl urea for treating chicken coccidiosis.
Background
4,4' -dinitro diphenyl urea (CAS number: 587-90-6), DNC for short, has a structure shown in formula (I), and is an important intermediate for medicines, pesticides and dyes, and is a yellow-green solid. DNC and 2-hydroxy-4, 6-dimethylpyrimidine (HDP) are equimolar compounded to form nicarbazin, and the nicarbazin is an efficient, nontoxic, stable in performance and small in drug resistance, is an ideal anticoccidial feed additive, and has good control effects on various Eimeria of chickens. For coccidiosis caused by cecum coccidiosis, namely eimeria tenella, the independent DNC has only weak anticoccidial effect, and after the DNC is combined with HDP to form a pharmaceutical co-crystal, the anticoccidial effect is improved by about 10 times, and the DNC is compounded with the DNC to mainly help improve the absorption effect of the DNC in organisms.
（Ⅰ）
The preparation methods of DNC disclosed at home and abroad can be roughly classified into the following categories: (1) DNC is synthesized by taking paranitroaniline and phosgene as raw materials, and the related patents are PL123410 and CN 1075139A. (2) UK2443892 uses paranitroaniline and isocyanate as raw materials to synthesize DNC, and the method uses excessive triethylamine and a large amount of organic solvent. (3) DNC is synthesized by taking paranitroaniline and urea as raw materials, and related patents are CS124613, PL126634, CN101914042A, CN1033179A and the like. (4) DNC is synthesized by taking paranitroaniline and bis (trichloromethyl) carbonate (BTC) as raw materials, and the related patent is CN1463965A. Although the method has higher yield, the generated triethylamine hydrochloride wastewater is difficult to treat, the time consumption is longer, and the reaction is incomplete. Based on the above problems, it is particularly important to develop a process for preparing 4,4' -dinitrodiphenyl urea which is efficient and easy to operate.
Disclosure of Invention
In view of the above problems in the prior art, an object of the present invention is to provide a method for preparing 4,4' -dinitrodiphenyl urea (DNC), which uses paranitroaniline and paranitroisocyanate as raw materials and directly synthesizes DNC by mechanochemical technology. The method has the advantages of better yield, no need of triethylamine, effective reduction of the use of organic solvents, shortened reaction time, less environmental pollution and suitability for popularization and application.
The invention discloses a preparation method of 4,4' -dinitro diphenyl urea, which is characterized in that paranitroaniline and paranitroisocyanate are added into a ball milling tank, a trace amount of solvent and a ball milling medium are added, the ball milling tank is sealed and then is placed into a ball mill, the ball milling tank is subjected to mechanical ball milling reaction at a ball milling frequency of 15-30 Hz, and after ball milling, 4' -dinitro diphenyl urea is purified to obtain the 4,4' -dinitro diphenyl urea, wherein the ball milling frequency of the invention is preferably 30Hz;
the chemical equation is as follows:
。
further, the invention also defines that the solvent is one of methanol, ethanol, water, ethyl acetate, toluene or benzene.
Further, the present invention also defines that the addition of the trace amount of the solvent is 0.15 to 0.5. Mu.L/mg based on the total amount of the raw materials.
Further, the invention also defines that the ball milling medium is stainless steel ball milling beads or polytetrafluoroethylene ball milling beads; the ball milling media has a diameter of at least one of 7mm, 10mm, 12mm or 14 mm.
Furthermore, the invention also limits the mechanical ball milling reaction to 20-60 min.
Further, the invention also defines the purification process as follows: pulping the product with absolute ethanol and toluene, filtering, and drying to obtain yellow-green solid 4,4' -dinitrodiphenyl urea.
The invention uses mechanochemical method to react p-nitroaniline and p-nitroisocyanate in the presence of trace solvent to obtain the product 4,4' -dinitrodiphenyl urea, which avoids using a large amount of solvent, triethylamine and toxic raw materials, reduces three-waste discharge, has the advantages of better yield, short reaction time, less environmental pollution and the like, and is suitable for industrialized popularization and application.
Detailed Description
How the invention may be carried out will now be further illustrated by means of specific examples.
Example 1
430.2mg of paranitroaniline and 493.5mg of paranitroisocyanate are placed in a 50mL stainless steel ball milling tank, methanol is measured according to the ratio of 0.15 mu L/mg and is added into the ball milling tank, 2 stainless steel balls with the diameter of 14mm are added into the ball milling tank, the ball milling tank is sealed, the ball milling frequency is set to be 30Hz, the ball milling time is 35min, 6mL toluene and 6mL absolute ethyl alcohol are sequentially adopted for pulping the ball milled products, 4' -dinitrodiphenyl urea is obtained after filtering and drying (80 ℃), the yield is 88.03%, and the HPLC content is 98.84%.
Example 2
430.2mg of paranitroaniline and 493.5mg of paranitroisocyanate are placed in a 50mL stainless steel ball milling tank, ethyl acetate is measured according to the ratio of 0.2 mu L/mg and is added into the ball milling tank, stainless steel balls with the diameter of 14mm multiplied by 2 are added into the ball milling tank to mill balls, the ball milling tank is subjected to sealing treatment, the ball milling frequency is set to be 30Hz, the ball milling time is 55min, 6mL toluene and 6mL absolute ethyl alcohol are sequentially adopted to pulp the ball milled product, 4' -dinitrodiphenyl urea is obtained after filtering and drying (80 ℃), the yield is 90.57%, and the HPLC content is 99.01%.
Example 3
430.2mg of paranitroaniline and 493.5mg of paranitroisocyanate are placed in a 50mL stainless steel ball milling tank, toluene is measured according to the ratio of 0.25 mu L/mg and is added into the ball milling tank, stainless steel balls with the diameter of 14mm multiplied by 2 are added into the ball milling tank to mill beads, the ball milling tank is subjected to sealing treatment, the ball milling frequency is set to be 15Hz, the ball milling time is 20 min, 6mL toluene and 6mL absolute ethyl alcohol are sequentially adopted for pulping the ball milled products, 4' -dinitrodiphenyl urea is obtained after filtering and drying (80 ℃), the yield is 76.32%, and the HPLC content is 98.69%.
Example 4
430.2mg of paranitroaniline and 493.5mg of paranitroisocyanate are placed in a 50mL stainless steel ball mill, water is taken according to the ratio of 0.3 mu L/mg and added into the ball mill, polytetrafluoroethylene ball milling beads with the diameter of 14mm multiplied by 2 are added, the ball mill is subjected to sealing treatment, the ball milling frequency is set to be 30Hz, the ball milling time is 25min, 6mL toluene and 6mL absolute ethyl alcohol are sequentially adopted for pulping the ball milled products, 4' -dinitrodiphenyl urea is obtained after filtering and drying (80 ℃), the yield is 88.64%, and the HPLC is 98.84%.
Example 5
Placing 430.2mg of paranitroaniline and 493.5mg of paranitroisocyanate into a 50mL stainless steel ball milling tank, measuring methanol according to the ratio of 0.4 mu L/mg, adding the methanol into the ball milling tank, adding stainless steel balls with the diameter of 10mm multiplied by 2, milling beads, sealing the ball milling tank, setting the ball milling frequency at 30Hz, milling for 45min, pulping the ball-milled product by adopting 6mL toluene and 6mL absolute ethyl alcohol in sequence, filtering, and drying (80 ℃) to obtain 4,4' -dinitrodiphenyl urea with the yield of 87.56 percent and the HPLC content of 98.75 percent.
Example 6
430.2mg of paranitroaniline and 493.5mg of paranitroisocyanate are placed in a 50mL stainless steel ball mill tank, ethanol is measured according to the ratio of 0.5 mu L/mg and is added into the ball mill tank, polytetrafluoroethylene ball milling beads with the diameter of 10mm multiplied by 2 are added into the ball mill tank, the ball mill tank is subjected to sealing treatment, the ball milling frequency is set to be 30Hz, the ball milling time is 35min, 6mL toluene and 6mL absolute ethyl alcohol are sequentially adopted for pulping the ball milled products, 4' -dinitrodiphenyl urea is obtained after filtering and drying (80 ℃), the yield is 83.71%, and the HPLC content is 99.04%.
Example 7
430.2mg of paranitroaniline and 493.5mg of paranitroisocyanate are placed in a 50mL stainless steel ball milling tank, ethyl acetate is measured according to the ratio of 0.25 mu L/mg and is added into the ball milling tank, stainless steel balls with the diameter of 12mm multiplied by 2 are added into the ball milling tank to mill balls, the ball milling tank is subjected to sealing treatment, the ball milling frequency is set to be 20Hz, the ball milling time is 55min, 6mL toluene and 6mL absolute ethyl alcohol are sequentially adopted to pulp the ball milled product, 4' -dinitrodiphenyl urea is obtained after filtering and drying (80 ℃), the yield is 79.95%, and the HPLC content is 98.63%.
Example 8
430.2mg of paranitroaniline and 493.5mg of paranitroisocyanate are placed in a 50mL stainless steel ball milling tank, toluene is measured according to the ratio of 0.25 mu L/mg and is added into the ball milling tank, stainless steel ball milling balls with the diameter of 12mm multiplied by 2 are added into the ball milling tank, the ball milling tank is subjected to sealing treatment, the ball milling frequency is set to be 25Hz, the ball milling time is 50min, 6mL toluene and 6mL absolute ethyl alcohol are sequentially adopted for pulping the ball milled products, 4' -dinitrodiphenyl urea is obtained after filtering and drying (80 ℃), the yield is 83.71%, and the HPLC content is 98.99%.
Example 9
Placing 430.2mg of paranitroaniline and 493.5mg of paranitroisocyanate into a 50mL stainless steel ball milling tank, measuring ethanol according to the ratio of 0.25 mu L/mg, adding stainless steel balls with the diameter of 12mm multiplied by 2 into the ball milling tank, milling beads, sealing the ball milling tank, setting the ball milling frequency to be 15Hz, milling for 30min, pulping the ball-milled product by adopting 6mL of toluene and 6mL of absolute ethanol in sequence, filtering, and drying (80 ℃) to obtain 4,4' -dinitrodiphenyl urea with the yield of 77.18 percent and the HPLC content of 98.54 percent.
Example 10
Placing 430.2mg of paranitroaniline and 493.5mg of paranitroisocyanate into a 50mL stainless steel ball milling tank, measuring methanol according to the ratio of 0.25 mu L/mg, adding the methanol into the ball milling tank, adding stainless steel balls with the diameter of 12mm multiplied by 2, milling beads, sealing the ball milling tank, setting the ball milling frequency at 30Hz, milling for 60min, pulping the ball-milled product by adopting 6mL toluene and 6mL absolute ethyl alcohol in sequence, filtering, and drying (80 ℃) to obtain 4,4' -dinitrodiphenyl urea with the yield of 86.03 percent and the HPLC content of 98.79 percent.
Claims (8)
1. A preparation method of 4,4 '-dinitro diphenyl urea is characterized in that paranitroaniline and paranitroisocyanate are added into a ball milling tank, then a trace amount of solvent and a ball milling medium are added, the ball milling tank is sealed and then is placed into a ball mill, mechanical ball milling reaction is carried out at the ball milling frequency of 15-30 Hz, 4' -dinitro diphenyl urea is obtained after the ball milling is finished,
the chemical equation is as follows:
。
2. the process for producing 4,4' -dinitrodiphenyl urea according to claim 1, wherein the solvent is one of methanol, ethanol, water, ethyl acetate, toluene and benzene.
3. The process for producing 4,4' -dinitrodiphenyl urea according to claim 1, wherein the addition of a trace amount of the solvent is 0.15 to 0.5. Mu.L/mg based on the total amount of the raw materials.
4. The method for producing 4,4' -dinitrodiphenyl urea according to claim 1, wherein the ball milling medium is stainless steel ball milling beads or polytetrafluoroethylene ball milling beads.
5. The process for the preparation of 4,4' -dinitrodiphenyl urea according to claim 4, wherein the ball milling medium has a diameter of at least one of 7mm, 10mm, 12mm or 14 mm.
6. The method for preparing 4,4' -dinitrodiphenyl urea according to claim 1, wherein the mechanical ball milling reaction is 20-60 min.
7. The process for the preparation of 4,4' -dinitrodiphenyl urea according to claim 1, characterized in that the purification process is: pulping the product with absolute ethanol and toluene, filtering, and drying to obtain yellow-green solid 4,4' -dinitrodiphenyl urea.
8. The process for the preparation of 4,4' -dinitrodiphenyl urea according to any of claims 1 to 7, characterized in that the ball milling frequency is 30Hz.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110256255A (en) * | 2019-07-11 | 2019-09-20 | 浙江工业大学 | A kind of Mechanochemical synthesis of bis- (4-nitrophenoxy) benzene of 1,4- |
| CN110498745A (en) * | 2019-08-27 | 2019-11-26 | 浙江工业大学 | A kind of method that ethylbenzene and its derivatives selectively oxidation prepare acetophenone and its derivative |
| CN113651787A (en) * | 2021-07-28 | 2021-11-16 | 浙江工业大学 | Solvent-free ball milling-amino acid coupling synthesis method of pyran-2-ketone compounds |
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- 2022-03-21 CN CN202210277148.4A patent/CN114671783B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110256255A (en) * | 2019-07-11 | 2019-09-20 | 浙江工业大学 | A kind of Mechanochemical synthesis of bis- (4-nitrophenoxy) benzene of 1,4- |
| CN110498745A (en) * | 2019-08-27 | 2019-11-26 | 浙江工业大学 | A kind of method that ethylbenzene and its derivatives selectively oxidation prepare acetophenone and its derivative |
| CN113651787A (en) * | 2021-07-28 | 2021-11-16 | 浙江工业大学 | Solvent-free ball milling-amino acid coupling synthesis method of pyran-2-ketone compounds |
Non-Patent Citations (1)
| Title |
|---|
| Perveen, Shahnaz 等.1,3-Disubstituted ureas as antiglycating agents.Journal of the Chemical Society of Pakistan.2013,第35卷(第6期),1605-1613. * |
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