CN112159338A - Preparation of triphenyldiamidine impurity - Google Patents
Preparation of triphenyldiamidine impurity Download PDFInfo
- Publication number
- CN112159338A CN112159338A CN202011103519.4A CN202011103519A CN112159338A CN 112159338 A CN112159338 A CN 112159338A CN 202011103519 A CN202011103519 A CN 202011103519A CN 112159338 A CN112159338 A CN 112159338A
- Authority
- CN
- China
- Prior art keywords
- filter cake
- filtrate
- preparation
- triphenyldiamidine
- filtering
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 239000012535 impurity Substances 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 35
- 239000012065 filter cake Substances 0.000 claims abstract description 27
- 238000001914 filtration Methods 0.000 claims abstract description 26
- 239000000706 filtrate Substances 0.000 claims abstract description 24
- 238000002425 crystallisation Methods 0.000 claims abstract description 14
- 230000008025 crystallization Effects 0.000 claims abstract description 14
- 238000001816 cooling Methods 0.000 claims abstract description 13
- KUCOHFSKRZZVRO-UHFFFAOYSA-N terephthalaldehyde Chemical compound O=CC1=CC=C(C=O)C=C1 KUCOHFSKRZZVRO-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000003756 stirring Methods 0.000 claims abstract description 9
- 239000012043 crude product Substances 0.000 claims abstract description 8
- 238000010992 reflux Methods 0.000 claims abstract description 8
- 239000000047 product Substances 0.000 claims abstract description 7
- 238000001035 drying Methods 0.000 claims abstract description 6
- 238000007670 refining Methods 0.000 claims abstract description 6
- 238000005406 washing Methods 0.000 claims abstract description 6
- 238000000967 suction filtration Methods 0.000 claims abstract description 5
- 238000002156 mixing Methods 0.000 claims abstract description 3
- 150000001409 amidines Chemical class 0.000 claims abstract 2
- -1 amine amidine Chemical class 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 208000006968 Helminthiasis Diseases 0.000 description 1
- QXAITBQSYVNQDR-ZIOPAAQOSA-N amitraz Chemical compound C=1C=C(C)C=C(C)C=1/N=C/N(C)\C=N\C1=CC=C(C)C=C1C QXAITBQSYVNQDR-ZIOPAAQOSA-N 0.000 description 1
- 229960002587 amitraz Drugs 0.000 description 1
- IZALUMVGBVKPJD-UHFFFAOYSA-N benzene-1,3-dicarbaldehyde Chemical compound O=CC1=CC=CC(C=O)=C1 IZALUMVGBVKPJD-UHFFFAOYSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 208000014837 parasitic helminthiasis infectious disease Diseases 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
- C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
- C07C257/14—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to acyclic carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of a triphenyldiamidine impurity, which comprises the following steps: (1) and (3) crude product preparation: reacting terephthalaldehyde with N' - (4-aminophenyl) -N, N-dimethylacetamide, cooling, filtering, stirring filtrate for crystallization, and filtering to obtain a filter cake; concentrating the filtrate under reduced pressure, and filtering to obtain filter cake; (2) refining: mixing the filter cakes obtained in the two steps, adding ether for refluxing, carrying out hot filtration, cooling for crystallization, and carrying out suction filtration to obtain a filter cake, and washing the filter cake with a small amount of ether; drying to obtain a single amidine finished product, wherein the content is more than or equal to 95 percent; the invention has the following advantages: the operation is simple, scientific and reasonable.
Description
Technical Field
The invention relates to a method for synthesizing and refining N' - (4- ((4-formyl benzylidene) amino) phenyl) -N, N-dimethylacetamide (hereinafter referred to as monoamidine) as an impurity in triphenyldiamidine. Belongs to the technical field of compound preparation.
Background
Tribenzamidine, a broad spectrum anti-insect agent, has been approved by the Chinese authorities for its use as a treatment for soil-borne helminthiasis due to its good safety. At present, benzene dicarboxaldehyde is mainly reacted with N' - (4-aminophenyl) -N, N-dimethylacetamide (hereinafter referred to as amine amidine) to synthesize triphenyldiamidine in production. However, due to the complexity of the organic reaction, impurities are always generated regardless of the formulation ratio of terephthalaldehyde to amitraz. For better production, we studied the impurities in the product, and found that the impurities are monoamidine (shown in the following formula), and obtained a purification method of the impurities.
Disclosure of Invention
The invention provides a preparation method of triphenyldiamidine impurity, wherein N' - (4- ((4-formylbenzylidene) amino) phenyl) -N, N-dimethylacetamide (hereinafter referred to as monoamidine) in the triphenyldiamidine impurity comprises the following steps:
(1) and (3) crude product preparation: reacting terephthalaldehyde with N' - (4-aminophenyl) -N, N-dimethylacetamide (hereinafter referred to as amine amidine), cooling and filtering, stirring and crystallizing filtrate, and filtering to obtain a filter cake; concentrating the filtrate under reduced pressure, and filtering to obtain filter cake;
(2) refining: mixing the filter cakes obtained in the two steps, adding ether for refluxing, carrying out hot filtration, cooling for crystallization, and carrying out suction filtration to obtain a filter cake, and washing the filter cake with a small amount of ether; drying to obtain the monoamidine finished product with the content more than or equal to 95 percent.
The reaction temperature of terephthalaldehyde and amine amidine in the preparation of the impurities in the triphenyldiamidine in the step (1) is 50 ℃, and the reaction time is 5-10 minutes;
in the step (1) of preparing the impurities in the triphenyldiamidine, the temperature of reaction between terephthalaldehyde and amine amidine is reduced, the reaction is finished, the temperature is reduced, the filtration is carried out, and the crystallization temperature of filtrate is 20-25 ℃; the crystallization time is 10-60 minutes;
in the step (1) of preparing the impurities in the triphenyldiamidine, the vacuum degree of filtrate is reduced and concentrated to be 0.09MPa-0.1MPa, the temperature is controlled to be 20-25 ℃, and the volume of the filtrate is concentrated to be 1/4-1/3 of the original volume;
in the step (2) of refining operation, diethyl ether is added for refluxing for 10 minutes, the temperature is controlled to be 20-23 ℃ when the temperature is reduced for crystallization, and the crystallization time is 30-60 minutes.
The invention aims to obtain an effective method for synthesizing and purifying impurities in triphenyldiamidine through research on the impurities in the triphenyldiamidine.
The invention has the following advantages:
the method is simple, scientific and reasonable in operation.
The content of the impurity monoamidine obtained by the method is more than or equal to 95 percent.
Detailed Description
Example 1
Adding 20g of terephthalaldehyde and 200mL of ethyl acetate into a dry and clean reaction bottle, heating to 50 ℃, adding 20g of amine amidine, reacting for 10 minutes, cooling to 20 ℃, filtering, stirring and crystallizing filtrate at 20 ℃, stirring and crystallizing for 10 minutes, performing suction filtration to obtain a filter cake, concentrating the filtrate under reduced pressure, keeping the vacuum degree at 0.09MPa, keeping the temperature at 20 ℃, concentrating the filtrate to 1/3 of the original volume, and performing suction filtration to obtain the filter cake. The two filter cakes were combined and had a monoamidine content of 87%.
And taking 6g of the combined crude product, adding 150mL of diethyl ether, heating and refluxing for 10 minutes, carrying out hot filtration, cooling the filtrate to 20 ℃, keeping the temperature for crystallization for 30 minutes, filtering, washing a filter cake with a small amount of diethyl ether, and drying to obtain a finished monoamidine product with the content of 95%.
Example 2
Adding 20g of terephthalaldehyde and 200mL of ethyl acetate into a dry and clean reaction bottle, heating to 50 ℃, adding 20g of amine amidine, reacting for 10 minutes, cooling to 23 ℃, filtering, stirring and crystallizing filtrate at 23 ℃, stirring and crystallizing for 30 minutes, filtering to obtain a filter cake, concentrating the filtrate under reduced pressure, keeping the vacuum degree at 0.095MPa, keeping the temperature at 23 ℃, concentrating the filtrate to 1/4 of the original volume, and filtering to obtain a filter cake; the two filter cakes were combined to give a monoamidine content of 88%.
And taking 6g of the combined crude product, adding 150mL of diethyl ether, heating and refluxing for 10 minutes, carrying out hot filtration, cooling the filtrate to 23 ℃, keeping the temperature for crystallization for 45 minutes, filtering, washing a filter cake with a small amount of diethyl ether, and drying to obtain a monoamidine finished product with the content of 96%.
Example 3
Adding 20g of terephthalaldehyde and 200mL of ethyl acetate into a dry and clean reaction bottle, heating to 50 ℃, adding 20g of amine amidine, reacting for 10 minutes, cooling to 25 ℃, filtering, stirring filtrate for crystallization, stirring at 25 ℃ for 60 minutes, and filtering to obtain a filter cake; concentrating the filtrate under reduced pressure to obtain filter cake, maintaining the vacuum degree at 0.1MPa and the temperature at 25 deg.C, concentrating the filtrate to 1/4 of the original volume, and filtering; the filter cakes obtained in the two times are combined, and the content of the monoamidine is 90 percent.
And taking 6g of the combined crude product, adding 150mL of diethyl ether, heating and refluxing for 10 minutes, carrying out hot filtration, cooling the filtrate to 25 ℃, keeping the temperature for crystallization for 60 minutes, filtering, washing a filter cake with a small amount of diethyl ether, and drying to obtain a finished monoamidine product with the content of 96%.
The above description is only for the specific mode of the invention, but the scope of the invention is not limited thereto, and any person skilled in the art can substitute or change the technical solution of the invention within the technical scope shown in the present invention, and the technical solution of the invention should be covered by the scope of the invention.
Claims (5)
1. The preparation method of the triphenyldiamidine impurity is characterized by comprising the following steps:
(1) and (3) crude product preparation: reacting terephthalaldehyde with N' - (4-aminophenyl) -N, N-dimethylacetamide (hereinafter referred to as amine amidine), cooling and filtering, stirring and crystallizing filtrate, and filtering to obtain a filter cake; concentrating the filtrate under reduced pressure, and filtering to obtain filter cake;
(2) refining: mixing the filter cakes obtained in the two steps, adding ether for refluxing, carrying out hot filtration, cooling for crystallization, and carrying out suction filtration to obtain a filter cake, and washing the filter cake with a small amount of ether; drying to obtain the monoamidine finished product with the content more than or equal to 95 percent.
2. The method of claim 1, wherein the reaction of terephthalaldehyde with amidine in the step (1) is carried out at 50 ℃ for 5-10 minutes.
3. The preparation of triphenyldiamidine impurity according to claim 1, wherein the temperature of the reaction between terephthalaldehyde and amitramidine is reduced and filtered, and the temperature of filtrate crystallization is 20-25 ℃ in the crude product preparation in step (1); the crystallization time is 10-60 minutes.
4. The method for preparing the triphenyldiamidine impurity according to claim 1, wherein the vacuum degree of the filtrate in the crude product preparation in the step (1) is reduced to 0.09MPa-0.1MPa, the temperature is controlled to be 20-25 ℃, and the volume of the filtrate is concentrated to 1/4-1/3 of the original volume.
5. The preparation of triphenyldiamidine impurity according to claim 1, wherein the refining operation of step (2) is performed by adding ether under reflux for 10 min, cooling and crystallizing at 20-23 deg.C for 30-60 min.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011103519.4A CN112159338A (en) | 2020-10-15 | 2020-10-15 | Preparation of triphenyldiamidine impurity |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011103519.4A CN112159338A (en) | 2020-10-15 | 2020-10-15 | Preparation of triphenyldiamidine impurity |
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| Publication Number | Publication Date |
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| CN112159338A true CN112159338A (en) | 2021-01-01 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011103519.4A Pending CN112159338A (en) | 2020-10-15 | 2020-10-15 | Preparation of triphenyldiamidine impurity |
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| Country | Link |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1174030A (en) * | 1996-08-19 | 1998-02-25 | 中国预防医学科学院寄生虫病研究所 | Triphenyl diamidine enteric coated tablet as vermifuge |
| CN108785249A (en) * | 2017-04-27 | 2018-11-13 | 中国疾病预防控制中心寄生虫病预防控制所 | The dosage form of the nanometer superfine powder containing triphenyl diamidine |
-
2020
- 2020-10-15 CN CN202011103519.4A patent/CN112159338A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1174030A (en) * | 1996-08-19 | 1998-02-25 | 中国预防医学科学院寄生虫病研究所 | Triphenyl diamidine enteric coated tablet as vermifuge |
| CN108785249A (en) * | 2017-04-27 | 2018-11-13 | 中国疾病预防控制中心寄生虫病预防控制所 | The dosage form of the nanometer superfine powder containing triphenyl diamidine |
Non-Patent Citations (1)
| Title |
|---|
| ERMINIA FONTANA等: "Carbon-14 labelled Tribendimidine, a broad-spectrum anthelmintic drug", 《JOURNAL OF LABELLED COMPOUNDS RADIOPHARMACEUTICALS》, vol. 56, 31 May 2013 (2013-05-31), pages 471 * |
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