CN112409213A - Method for crystallizing triphendiamidine - Google Patents
Method for crystallizing triphendiamidine Download PDFInfo
- Publication number
- CN112409213A CN112409213A CN202011304293.4A CN202011304293A CN112409213A CN 112409213 A CN112409213 A CN 112409213A CN 202011304293 A CN202011304293 A CN 202011304293A CN 112409213 A CN112409213 A CN 112409213A
- Authority
- CN
- China
- Prior art keywords
- triphenyldiamidine
- crystallizing
- triphendiamidine
- heating
- dichloromethane
- 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
Links
- 238000000034 method Methods 0.000 title claims abstract description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 42
- 239000013078 crystal Substances 0.000 claims abstract description 18
- 238000010438 heat treatment Methods 0.000 claims abstract description 16
- 238000001035 drying Methods 0.000 claims abstract description 10
- 238000001704 evaporation Methods 0.000 claims abstract description 8
- 238000001914 filtration Methods 0.000 claims abstract description 6
- 230000008020 evaporation Effects 0.000 claims abstract description 5
- 239000012043 crude product Substances 0.000 claims abstract description 3
- 238000002425 crystallisation Methods 0.000 claims description 12
- 230000008025 crystallization Effects 0.000 claims description 8
- 239000002245 particle Substances 0.000 claims description 2
- 239000000047 product Substances 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 239000013557 residual solvent Substances 0.000 abstract description 3
- 239000002904 solvent Substances 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- 208000006968 Helminthiasis Diseases 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 208000014837 parasitic helminthiasis infectious disease Diseases 0.000 description 2
- 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
- 150000001875 compounds Chemical class 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000000077 insect repellent Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000003071 parasitic effect Effects 0.000 description 1
- ZWLUXSQADUDCSB-UHFFFAOYSA-N phthalaldehyde Chemical compound O=CC1=CC=CC=C1C=O ZWLUXSQADUDCSB-UHFFFAOYSA-N 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- -1 triphenyl diamidine Chemical compound 0.000 description 1
- 201000008827 tuberculosis Diseases 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a method for crystallizing triphendiamidine, which comprises the following steps: (1) dissolving the crude product of the triphenyldiamidine in dichloromethane, heating and concentrating to a slightly supersaturated state; (2) adding seed crystal, continuously heating for evaporation, filtering and drying to obtain the product; the crystal of the triphenyldiamidine obtained by the method can reduce the content of residual solvent in the triphenyldiamidine, the residual solvent is less than 230ppm and far lower than the national standard requirement, and the method is simple, scientific and reasonable to operate and can improve the labor production efficiency.
Description
Technical Field
The invention belongs to the technical field of material refining and purification, and particularly relates to a method for crystallizing triphendiamidine.
Background
Over a billion people in tropical and subtropical regions are infected with parasitic intestinal worms. Soil-borne public health organizations believe that worms have an effect equal to or greater than malaria or tuberculosis. Currently only a few drugs are available to combat soil-borne helminth infections. Tribenzamidine, a broad-spectrum insect repellent associated with amitriptan, was marketed in China since the mid-1980 s. Due to its good safety, this compound has been approved by the chinese authorities for use as a treatment for soil-borne helminthiasis. At present, benzene dicarbaldehyde is mainly reacted with amitraz to synthesize triphenyldiamidine in production. However, the solvent remaining in the produced triphenyldiamidine is difficult to remove, and therefore, it is important to find an effective method for reducing the solvent remaining in the triphenyldiamidine.
Disclosure of Invention
The invention provides a method for crystallizing triphendiamidine, which is characterized by comprising the following steps of:
(1) dissolving the crude product of the triphenyldiamidine in dichloromethane, heating and concentrating to a slightly supersaturated state;
(2) adding seed crystal, heating for evaporation, filtering, and drying.
The heating temperature in the step (1) is 40-42 ℃;
the heating evaporation temperature in the step (2) is 40-42 ℃;
the seed crystal added in the step (2) is triphenyldiamidine crystal, and the particle size d (0.9) of the seed crystal is less than or equal to 1.6 um;
in the step (2), the drying temperature is 100-120 ℃, and the drying time is 6-10 hours.
The invention aims to reduce the content of residual solvent in the triphenyldiamidine by changing the crystal form of the triphenyldiamidine.
The crystallization solvent of the triphenyldiamidine can be one of chloroform, dichloromethane, dichloroethane, DMF, DMSO and other solvents, and the triphenyldiamidine is unstable at high temperature due to the overhigh boiling point of the DMF, DMSO and other solvents; chloroform and dichloroethane are highly toxic, and dichloromethane is preferred as the crystallization solvent.
The crystallization method of the triphenyldiamidine is one of cooling crystallization and concentration crystallization, and because the boiling point of dichloromethane is low, the cooling crystallization is not suitable for selection; the preferred crystallization mode is concentrated crystallization.
Adding seed crystals in the process of crystallizing the triphenyldiamidine, adopting a concentration crystallization method, paying attention to the state of the solution when the seed crystals are added, controlling the evaporation amount when a dichloromethane solution is evaporated, and adding the seed crystals when the dichloromethane solution is evaporated to a slightly supersaturated state; the crystal seed is qualified triphenyl diamidine crystal with solvent residue after being crushed.
The invention has the following advantages: (1) the crystallization method is simple to operate, scientific and reasonable, and can improve the labor production efficiency; (2) the triphenyldiamidine product obtained by the crystallization method has the solvent residue less than 230ppm, which is far lower than the national standard requirement.
Detailed Description
Example 1
Dissolving 10g of crude triphenyldiamidine into 100mL of dichloromethane, heating to 40 ℃, concentrating the solution to a slightly supersaturated state, adding a certain amount of crushed triphenyldiamidine crystals with qualified solvent residues, and then continuously heating and evaporating to the required concentration. Filtering, drying at 100 deg.C for 10 hr to obtain final product of triphenyldiamidine, wherein the dichloromethane solvent residue is 210ppm, which is less than national standard.
Example 2
Dissolving 10g of crude triphenyldiamidine into 100mL of dichloromethane, heating to 41 ℃, concentrating the solution to a slightly supersaturated state, adding a certain amount of crushed crystal seeds with qualified solvent residues, and continuously heating and evaporating to the required concentration. And (3) filtering, and drying at 110 ℃ for 8 hours to obtain the finished product of the triphenyldiamidine, wherein the dichloromethane solvent residue is 210ppm and is less than the national standard.
Example 3
Dissolving 10g of crude triphenyldiamidine into 100mL of dichloromethane, heating to 42 ℃, concentrating the solution to a slightly supersaturated state, adding a certain amount of crushed crystal seeds with qualified solvent residues, and continuously heating and evaporating to the required concentration. And (4) filtering, and drying at 120 ℃ for 6 hours to obtain the finished product of the triphenyldiamidine, wherein the dichloromethane solvent residue is 210ppm and is less than the national standard.
As described above. The invention is not limited to the specific embodiments, and any person skilled in the art can substitute or change the technical solution of the invention within the technical scope of the invention, and the technical solution of the invention should be covered by the protection scope of the invention.
Claims (5)
1. A method for crystallizing triphendiamidine is characterized by comprising the following steps:
(1) dissolving the crude product of the triphenyldiamidine in dichloromethane, heating and concentrating to a slightly supersaturated state;
(2) adding seed crystal, heating for evaporation, filtering, and drying.
2. The method for crystallizing triphendiamidine according to claim 1, wherein the heating temperature in step (1) is 40 to 42 ℃.
3. The method for crystallizing triphendiamidine according to claim 1, wherein the heating temperature in step (2) is 40 to 42 ℃.
4. The method for the crystallization of triphenyldiamidine according to claim 1, wherein the seed crystals added in the step (2) are triphenyldiamidine crystals having a particle size d (0.9) of 1.6 μm or less.
5. The method for crystallizing triphendiamidine according to claim 1, wherein the drying temperature in step (2) is 100 to 120 ℃ and the drying time is 6 to 10 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011304293.4A CN112409213A (en) | 2020-11-19 | 2020-11-19 | Method for crystallizing triphendiamidine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011304293.4A CN112409213A (en) | 2020-11-19 | 2020-11-19 | Method for crystallizing triphendiamidine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN112409213A true CN112409213A (en) | 2021-02-26 |
Family
ID=74773575
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011304293.4A Pending CN112409213A (en) | 2020-11-19 | 2020-11-19 | Method for crystallizing triphendiamidine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112409213A (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1165814A (en) * | 1996-05-16 | 1997-11-26 | 中国预防医学科学院寄生虫病研究所 | Amino benzene carbon amidine derivative and its use |
-
2020
- 2020-11-19 CN CN202011304293.4A patent/CN112409213A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1165814A (en) * | 1996-05-16 | 1997-11-26 | 中国预防医学科学院寄生虫病研究所 | Amino benzene carbon amidine derivative and its use |
Non-Patent Citations (3)
| Title |
|---|
| 姚润华等: "驱肠虫新药三苯双脒的研究简报", 《科研简讯》 * |
| 朱葆佺: "《新编药物合成反应路线图设计与制备工艺新技术实务全书》", 31 March 2005, 天津电子出版社 * |
| 肖树华等: "三苯双脒———一种新的广谱抗肠道蠕虫新药", 《中国寄生虫学与寄生虫病杂志》 * |
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| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20210226 |