CN113979877A - Refining method for improving purity of 4-chloro-2-trifluoroacetylaniline mother liquor - Google Patents
Refining method for improving purity of 4-chloro-2-trifluoroacetylaniline mother liquor Download PDFInfo
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- CN113979877A CN113979877A CN202111259268.3A CN202111259268A CN113979877A CN 113979877 A CN113979877 A CN 113979877A CN 202111259268 A CN202111259268 A CN 202111259268A CN 113979877 A CN113979877 A CN 113979877A
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Abstract
The invention discloses a refining method for improving the purity of 4-chloro-2-trifluoroacetylaniline mother liquor, which takes the refined 4-chloro-2-trifluoroacetylaniline mother liquor as a raw material and obtains the 4-chloro-2-trifluoroacetylaniline with the same quality as the original batch through decompression concentration, hydrochloric acid salt formation, refined hydrochloride refined product, dissociation and refining. The refining method for improving the purity of the 4-chloro-2-trifluoroacetylaniline mother liquor has the advantages of simple process, changing waste into valuable, being beneficial to improving the comprehensive yield of products, increasing the income, reducing the generation of solid waste and being suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a refining method for improving the purity of an efavirenz intermediate 4-chloro-2-trifluoroacetylaniline mother liquor.
Background
Efavirenz, chemical name: (S) -6-chloro-4- (cyclopropylethynyl) -1, 4-hydro-4- (trifluoromethyl) -2H-3, 1-oxazaprinin-2-one having the structure shown below:
efavirenz tablets, developed by merck corporation of america, are currently the first-line anti-HIV drugs of choice, belong to selective non-nucleoside reverse transcriptase inhibitors of human immunodeficiency virus-type 1 (HIV-1), prevent viral transcription and replication by noncompetitive binding and inhibiting HIV-1 Reverse Transcriptase (RT) activity, and are suitable for use in combination with other antiviral drugs in the treatment of HIV-1 infected adults, adolescents and children.
The synthetic process route of the efavirenz intermediate 4-chloro-2-trifluoroacetylaniline is long, the production period is long, the yield is low, the cost is high, and the purity of 4-chloro-2-trifluoroacetylaniline in the refined mother liquor is about 85 percent and the content of 4-chloro-2-trifluoroacetylaniline is about 2 percent through detection and analysis, so a refining method for improving the purity of the 4-chloro-2-trifluoroacetylaniline mother liquor needs to be developed.
Disclosure of Invention
The invention aims to provide a refining method for improving the purity of 4-chloro-2-trifluoroacetylaniline mother liquor, which has the advantages of simple process, changing waste into valuable, being beneficial to improving the comprehensive yield of products, increasing the income, reducing the generation of solid waste and being suitable for industrial production.
In order to achieve the above purpose, the solution of the invention is:
a refining method for improving the purity of 4-chloro-2-trifluoroacetylaniline mother liquor is characterized in that 4-chloro-2-trifluoroacetylaniline refined mother liquor is used as a raw material, and the 4-chloro-2-trifluoroacetylaniline with the same quality as a main batch is obtained through reduced pressure concentration, hydrochloric acid salt formation, refined hydrochloride refined product, dissociation and refining.
Preferably, the decompression concentration temperature of the refined mother liquor of the 4-chloro-2-trifluoroacetylaniline is 30-70 ℃, the vacuum degree is controlled to be-0.08 MPa-0.09 MPa, and the salt is formed after the concentration and the drying.
Preferably, concentrated hydrochloric acid is selected as a salifying reagent, a salifying solvent is used for dissolving the concentrated and dried salified salt, the temperature is reduced to 0-10 ℃ after dissolution, concentrated hydrochloric acid is dripped, finally, the temperature is kept at 20-25 ℃ and stirred for 1 hour, and the concentrated hydrochloric acid is subjected to suction filtration, leaching and drying by the salifying solvent to obtain hydrochloride.
Preferably, the salt-forming solvent is isopropyl acetate, ethyl acetate or tert-butyl acetate.
Preferably, the refined solvent is adopted for reflux pulping for 2-4 hours, then the temperature is reduced to 10-15 ℃, the heat preservation and the stirring are carried out for 2-4 hours, the filtration is carried out, and the refined hydrochloride is obtained by leaching and draining the refined solvent.
Preferably, the refining solvent is ethanol, isopropanol or tert-butanol.
Preferably, the specific process of liberation is: and dissolving the refined hydrochloride product with methyl tert-butyl ether, controlling the internal temperature to be 20-30 ℃ after the hydrochloride product is dissolved, dropwise adding liquid caustic soda to adjust the pH of the system to 7-8, standing to separate out a water phase and an organic phase after the reaction is finished, washing the organic phase with saturated saline water, drying the organic phase with anhydrous sodium sulfate, and carrying out suction filtration and concentration until the organic phase is dried to obtain a mother liquor crude product.
Preferably, refining the mother liquor crude product obtained by dissociation, adding a solvent into the mother liquor crude product, heating to 50-60 ℃, keeping the temperature and stirring for 2-4 hours, then cooling to 10-20 ℃, keeping the temperature and stirring for 1-2 hours, performing suction filtration, leaching and draining, and drying to obtain the efavirenz intermediate 4-chloro-2-trifluoroacetylaniline with the same quality as the original batch.
Preferably, the solvent added to the crude mother liquor is n-hexane or n-heptane.
The main impurities in the refined mother liquor of the 4-chloro-2-trifluoroacetylaniline are N-pivaloyl parachloroaniline (RRT is 0.3-0.4), degradation impurities (RRT is 0.7-0.8), RRT is 1.5-1.6 and RRT is 1.8-2.1, the main impurities are directly dissolved by a benign solvent, the effect of removing the degradation impurities (RRT is 0.7-0.8) by dropwise adding the non-benign solvent for crystallization is poor, so that the 4-chloro-2-trifluoroacetylaniline is considered to be changed into hydrochloride thereof, the hydrochloride thereof is refined, and then the finished product of the 4-chloro-2-trifluoroacetylaniline is obtained by dissociating, concentrating and refining.
After the scheme is adopted, the refined mother liquor of the 4-chloro-2-trifluoroacetylaniline is used as a raw material, the raw material is firstly concentrated under reduced pressure, then a salifying reagent is selected for leaching and pumping to obtain hydrochloride, a refined hydrochloride is obtained after refining, and the efavirenz intermediate 4-chloro-2-trifluoroacetylaniline with the purity of more than or equal to 99.0% is obtained after dissociating and drying. The refining method has simple process, good refining effect and good quality of the obtained product, and is suitable for industrial production; in addition, the refining method provided by the invention can change waste into valuable, improve the comprehensive yield of products, reduce the generation of solid wastes, reduce the production cost, increase the income and realize clean production.
Detailed Description
The technical solution and the advantages of the present invention will be described in detail with reference to the following embodiments.
The invention provides a refining method for improving the purity of 4-chloro-2-trifluoroacetylaniline mother liquor, which comprises the following steps:
step 1, using refined mother liquor of 4-chloro-2-trifluoroacetylaniline as a raw material, and concentrating and drying the raw material at the temperature of between 30 and 70 ℃ and the vacuum degree of between-0.08 and-0.09 Mpa to form salt;
step 2, selecting concentrated hydrochloric acid as a salifying reagent, selecting solvents such as isopropyl acetate, ethyl acetate and tert-butyl acetate as a salifying system, dissolving the concentrated and dried materials, cooling to 0-10 ℃ after dissolution, dropwise adding concentrated hydrochloric acid, finally keeping the temperature at 20-25 ℃ and stirring for 1 hour, performing suction filtration, leaching with the salifying solvent, and drying to obtain hydrochloride;
step 3, refining the hydrochloride by using ethanol, isopropanol, tert-butanol and the like as solvents, wherein the dosage of the solvents is 3-8 times of the mass of the hydrochloride, the refining method comprises the steps of refluxing and pulping for 2-4 hours, cooling to 10-15 ℃, preserving heat, stirring for 2-4 hours, carrying out suction filtration, leaching by using the refined solvents, and carrying out suction drying to obtain a refined hydrochloride product;
step 4, dissolving the refined hydrochloride product with methyl tert-butyl ether, controlling the internal temperature to be 20-30 ℃ after the hydrochloride product is dissolved, dropwise adding liquid caustic soda to adjust the pH of the system to 7-8, standing and separating out a water phase and an organic phase after the reaction is finished, washing the organic phase with saturated brine, drying the organic phase with anhydrous sodium sulfate, and carrying out suction filtration and concentration until the organic phase is dried to obtain a mother liquor crude product;
and 5, adding a certain amount of solvent (such as n-hexane, n-heptane and the like) into the crude product of the mother liquor, heating to 50-60 ℃, keeping the temperature and stirring for 2-4 hours, cooling to 10-20 ℃, keeping the temperature and stirring for 1-2 hours, performing suction filtration, leaching and draining, and drying to obtain the efavirenz intermediate 4-chloro-2-trifluoroacetylaniline (the purity is more than or equal to 99.0%) with the same quality as the raw batch.
Example 1
Preparation of hydrochloride
Taking 2000g of refined 4-chloro-2-trifluoroacetylaniline mother liquor (the purity is about 85 percent) and concentrating under reduced pressure under the conditions of water bath temperature of 30-70 ℃ and vacuum pressure of-0.08 MPa to-0.09 MPa until no liquid flows out to obtain 46.32g of mother liquor material to be recovered;
dissolving 150mL of isopropyl acetate, cooling to 0-10 ℃ after dissolving, slowly dripping 31.94g of concentrated hydrochloric acid, keeping the temperature at 20-25 ℃ after dripping, stirring for 1 hour, performing suction filtration, leaching with a dissolving solvent, and drying to obtain 64.66g of a wet crude hydrochloride product (the purity is more than or equal to 95.0%);
adding 300mL of isopropanol into the wet hydrochloride crude product, heating to reflux and pulping for 2-4 hours, cooling to 10-15 ℃, preserving heat and stirring for 2-4 hours, performing suction filtration, leaching with a refined solvent, draining, and drying to obtain 51.19g of a refined hydrochloride product (the purity is more than or equal to 99.0%);
(di) hydrochloride salt free
Dissolving 51.19g of fine hydrochloride by using 130mL of methyl tert-butyl ether, dropwise adding liquid caustic soda at the internal temperature of 20-30 ℃ after the fine hydrochloride is dissolved to adjust the pH value of the system to 7-8, standing and separating out a water phase and an organic phase after the reaction is finished, washing the organic phase by using saturated brine, drying the organic phase by using anhydrous sodium sulfate, and carrying out suction filtration and concentration until the organic phase is dried to obtain 43.56g of crude mother liquor;
(III) refining the crude product of the mother liquor
Adding 40mL of n-heptane into 43.56g of the crude mother liquor material, heating to 50-60 ℃, keeping the temperature, stirring for 2-4 hours, cooling to 10-20 ℃, keeping the temperature, stirring for 1-2 hours, performing suction filtration, leaching, draining, and drying to obtain 41.82g of efavirenz intermediate 4-chloro-2-trifluoroacetylaniline (the purity is more than or equal to 99.5%).
Comparative example 1
As in table 1 below.
TABLE 1 comparison before and after refining
The above embodiments are only for illustrating the technical idea of the present invention, and the protection scope of the present invention is not limited thereby, and any modifications made on the basis of the technical scheme according to the technical idea of the present invention fall within the protection scope of the present invention.
Claims (9)
1. A refining method for improving the purity of 4-chloro-2-trifluoroacetylaniline mother liquor is characterized by comprising the following steps: the refined mother liquor of the 4-chloro-2-trifluoroacetylaniline is used as a raw material, and the 4-chloro-2-trifluoroacetylaniline with the same quality as the original batch is obtained through decompression concentration, hydrochloric acid salt formation, refined hydrochloride fine product, dissociation and refinement.
2. The refining process of claim 1, wherein: the refined mother liquor of 4-chloro-2-trifluoroacetylaniline is concentrated under reduced pressure at 30-70 deg.C and vacuum degree controlled at-0.08-0.09 Mpa, and is dried to form salt.
3. The refining process of claim 1, wherein: selecting concentrated hydrochloric acid as a salifying reagent, dissolving the concentrated and dried salified solution by using a salifying solvent, cooling to 0-10 ℃ after dissolving, dropwise adding the concentrated hydrochloric acid, finally keeping the temperature at 20-25 ℃ and stirring for 1 hour, performing suction filtration, leaching by using the salifying solvent, and drying to obtain the hydrochloride.
4. The refining process of claim 3, wherein: the salifying solvent adopts isopropyl acetate, ethyl acetate or tert-butyl acetate.
5. The refining process of claim 3, wherein: and (3) refluxing and pulping for 2-4 hours by using a refined solvent, cooling to 10-15 ℃, preserving heat, stirring for 2-4 hours, performing suction filtration, leaching by using the refined solvent, and performing suction drying to obtain a refined hydrochloride product.
6. The refining process of claim 5, wherein: the refined solvent adopts ethanol, isopropanol or tert-butanol.
7. The refining process of claim 1, wherein: the specific process of dissociation is as follows: and dissolving the refined hydrochloride product with methyl tert-butyl ether, controlling the internal temperature to be 20-30 ℃ after the hydrochloride product is dissolved, dropwise adding liquid caustic soda to adjust the pH of the system to 7-8, standing to separate out a water phase and an organic phase after the reaction is finished, washing the organic phase with saturated saline water, drying the organic phase with anhydrous sodium sulfate, and carrying out suction filtration and concentration until the organic phase is dried to obtain a mother liquor crude product.
8. The refining process of claim 7, wherein: refining the mother liquor crude product obtained by dissociation, adding a solvent into the mother liquor crude product, heating to 50-60 ℃, keeping the temperature and stirring for 2-4 hours, then cooling to 10-20 ℃, keeping the temperature and stirring for 1-2 hours, carrying out suction filtration, leaching and draining, and drying to obtain the efavirenz intermediate 4-chloro-2-trifluoroacetylaniline with the same quality as the original batch.
9. The refining process of claim 8, wherein: the solvent added into the crude mother liquor is n-hexane or n-heptane.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115073310A (en) * | 2022-07-05 | 2022-09-20 | 盐城迪赛诺制药有限公司 | Method for reducing specific impurities in efavirenz key intermediate mother liquor |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108947855A (en) * | 2018-08-10 | 2018-12-07 | 江苏沙星化工有限公司 | A kind of synthetic method of efavirenz key intermediate |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108947855A (en) * | 2018-08-10 | 2018-12-07 | 江苏沙星化工有限公司 | A kind of synthetic method of efavirenz key intermediate |
Non-Patent Citations (1)
| Title |
|---|
| 胡争朋: "依非韦伦关键中间体的合成研究", 《中国优秀硕士学位论文全文数据库（电子期刊） 工程科技I辑》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115073310A (en) * | 2022-07-05 | 2022-09-20 | 盐城迪赛诺制药有限公司 | Method for reducing specific impurities in efavirenz key intermediate mother liquor |
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Application publication date: 20220128 |