CN115385807A - Recovery method of dapoxetine hydrochloride acetonitrile and isopropanol mother liquor - Google Patents
Recovery method of dapoxetine hydrochloride acetonitrile and isopropanol mother liquor Download PDFInfo
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- CN115385807A CN115385807A CN202211025077.5A CN202211025077A CN115385807A CN 115385807 A CN115385807 A CN 115385807A CN 202211025077 A CN202211025077 A CN 202211025077A CN 115385807 A CN115385807 A CN 115385807A
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- C07C213/10—Separation; Purification; Stabilisation; Use of additives
Abstract
The invention provides a method for recovering dapoxetine acetonitrile hydrochloride and isopropanol mother liquor, and relates to the technical field of recovery of dapoxetine mother liquor. The method specifically comprises the following steps: (1) Mixing the dapoxetine acetonitrile hydrochloride mother liquor with the isopropanol mother liquor obtained in the refining step, and carrying out reduced pressure distillation to obtain a yellow solid; (2) Dissolving the solid in purified water, adding an organic solvent for extraction, standing, and separating liquid; (3) Adding alkali into the water phase to adjust the pH = 8-9, adding an organic solvent for extraction, adding acid into the organic phase, stirring, and adjusting the pH = 2-3; (4) And (3) evaporating the obtained organic phase to dryness under reduced pressure, adding a crystallization solvent, heating to dissolve, cooling, stirring to crystallize, and filtering to obtain the dapoxetine hydrochloride. The method can effectively reduce the content of water-soluble impurities, organic impurities and inorganic impurities in the acetonitrile and isopropanol mother liquor, extracts and purifies the raw materials at a lower preparation temperature and with safety and no toxicity, and recovers the obtained dapoxetine hydrochloride with high purity and high yield, thereby having good economic benefit.
Description
Technical Field
The invention belongs to the technical field of recovery of dapoxetine hydrochloride mother liquor, and particularly relates to a recovery method of dapoxetine hydrochloride acetonitrile and isopropanol mother liquor.
Background
Dapoxetine hydrochloride (dapoxetine hydrochloride) has the chemical name of (S) -N, N-dimethyl-3- (naphthyl-1-oxy) -phenprobamate hydrochloride and the molecular formula: c 21 H 23 Hcl, a selective 5-hydroxytryptamine uptake inhibitor (SSRI), developed by american gift pharmaceutical company (Eli Lilly) marketed in europe in 2009 under the trade name Priligy for the treatment of male Premature Ejaculation (PE). The medicine has short half-life, small adverse reaction and obvious effect, and is the first oral administration prescription approved for treating PE in the world. The structural formula is shown as the following formula:
currently, there is still a large space for refining dapoxetine hydrochloride, for example, chinese patent CN109369424A discloses a refining method of crude dapoxetine hydrochloride, wherein the crude dapoxetine hydrochloride is dissolved in ethyl acetate, mechanical impurities are removed by filtration, then activated carbon or molecular sieve is added to adsorb inorganic substances, after concentration at 80 ℃, methanol and ethyl acetate are added in a volume ratio of 1:15, recrystallizing, filtering, leaching and drying the mixed solution to obtain the product. The purification method has a good effect on the purification of dapoxetine hydrochloride sold in the market or with high purity, but is not efficient under the conditions of low purity, complex organic impurities and inorganic impurities such as crude mother liquor and refined mother liquor in production.
At present, few technical schemes for recovering dapoxetine hydrochloride mother liquor are provided, and the recovered dapoxetine hydrochloride has low yield or unsatisfactory purity, so that the purposes of high yield and high purity cannot be achieved at the same time.
Therefore, the development of a mother liquor recovery scheme which is simple to operate and can obtain high-quality and high-yield dapoxetine hydrochloride is an urgent problem to be solved by those skilled in the art.
Disclosure of Invention
The invention aims to provide a method for recovering dapoxetine hydrochloride acetonitrile and isopropanol mother liquor.
The method effectively reduces the content of water-soluble impurities, organic impurities and inorganic impurities, can extract and purify the safe and nontoxic raw materials at a lower preparation temperature, recovers the obtained dapoxetine hydrochloride with high purity and high yield, and has good economic benefit.
In order to realize the purpose, the invention provides a recovery method of dapoxetine acetonitrile hydrochloride and isopropanol mother liquor, which specifically comprises the following steps:
(1) Mixing the dapoxetine acetonitrile hydrochloride mother liquor with the isopropanol mother liquor in the refining step, and distilling under reduced pressure to obtain a yellow solid;
(2) Dissolving the solid obtained in the step (1) in purified water, adding an organic solvent for extraction, standing and separating liquid;
(3) Adding alkali into the water phase obtained in the step (2) to adjust the pH = 8-9, adding an organic solvent for extraction, adding acid into the organic phase, stirring, and adjusting the pH = 2-3;
(4) And (4) after the organic phase obtained in the step (3) is decompressed and evaporated to dryness, adding a crystallization solvent, heating to dissolve, cooling, stirring to crystallize, and filtering to obtain dapoxetine hydrochloride.
In a preferred embodiment, in step (1), the dapoxetine hydrochloride acetonitrile mother liquor and the isopropanol mother liquor of the refining step are obtained by the following steps:
adding the crude dapoxetine hydrochloride into acetonitrile, heating, refluxing, dissolving, cooling to 20-25 ℃, stirring for 2-4 h, and carrying out suction filtration to obtain a filtrate, namely a dapoxetine hydrochloride acetonitrile mother solution; adding the obtained solid into isopropanol, heating to 70-75 ℃ for dissolution, cooling to 0-5 ℃, stirring for 1-2 h, carrying out suction filtration, wherein the filtrate is isopropanol mother liquor in the refining step, and drying the obtained solid to obtain refined dapoxetine hydrochloride;
and combining the acetonitrile mother liquor and the isopropanol mother liquor to obtain the mother liquor to be recovered by the dapoxetine hydrochloride.
In a preferred embodiment, in the step (1), the mass ratio of the crude dapoxetine hydrochloride, acetonitrile and isopropanol is 1: (1-5): (1-10).
In a preferred embodiment, in the step (1), the reduced pressure distillation temperature is 40 to 60 ℃.
In a preferred embodiment, in the step (2), the mass ratio of the solid to the purified water is 1: (2-4).
In a preferred embodiment, in the step (2), the organic solvent is selected from one or more of ethyl acetate, toluene and dichloromethane, and the mass ratio of the organic solvent to the purified water is 1: (2-4).
In a preferred embodiment, in the step (3), the base is selected from one or more of sodium carbonate, potassium carbonate, triethylamine and ammonia water, the acid is hydrochloric acid with a mass fraction of 36-38%, and the stirring time after the acid is added is 0.5-1 h.
In a preferred embodiment, in the step (3), the organic solvent is selected from one or more of toluene, dichloromethane and ethyl acetate, and the mass ratio of the organic solvent to the water phase is 1: (2-4).
In a preferred embodiment, in the step (4), the reduced pressure evaporation temperature is 50 to 60 ℃, and the crystallization solvent is isopropanol.
In a preferred embodiment, in the step (4), the crystallization temperature is-5 to 5 ℃, and the stirring crystallization time is 2 to 4 hours.
Compared with the prior art, the technical scheme of the invention has the following advantages:
the invention provides a method for recovering mother liquor by taking dapoxetine acetonitrile hydrochloride and isopropanol mother liquor as raw materials, the overall preparation method is simple and mild, the raw materials are high in safety, toxic and harmful substances are not generated, the impurity removal effect is good, and the recovery effect of the dapoxetine hydrochloride mother liquor with high yield and high quality is considered.
Drawings
These and/or other aspects and advantages of the present invention will become more apparent and more readily appreciated from the following detailed description of the embodiments of the invention, taken in conjunction with the accompanying drawings of which:
FIG. 1 is a chromatogram of recovery of dapoxetine hydrochloride in example 1 of the present invention;
FIG. 2 is a chromatogram of recovered dapoxetine hydrochloride in example 2 of the present invention;
FIG. 3 is a chromatogram of recovery of dapoxetine hydrochloride in example 3 of the present invention.
Detailed Description
For a better understanding of the present invention for those skilled in the art, the present invention will be described in further detail with reference to the accompanying drawings and specific embodiments, but it should be understood that the scope of the present invention is not limited to the specific embodiments.
The embodiment of the invention provides a recovery method of dapoxetine acetonitrile hydrochloride and isopropanol mother liquor, and solves the problem that no effective recovery scheme exists for acetonitrile and isopropanol mother liquor in the prior art.
In order to solve the problems, the technical scheme of the invention has the following general idea:
a recovery method of dapoxetine hydrochloride acetonitrile and isopropanol mother liquor comprises the following steps:
(1) Mixing the dapoxetine acetonitrile hydrochloride mother liquor with the isopropanol mother liquor in the refining step, and distilling under reduced pressure to obtain a yellow solid;
(2) Dissolving the solid obtained in the step (1) in purified water, adding an organic solvent for extraction, standing and separating liquid;
(3) Adding alkali into the water phase obtained in the step (2) to adjust the pH to be 8-9, adding an organic solvent for extraction, adding acid into the organic phase for stirring, and adjusting the pH to be 2-3;
(4) And (4) after the organic phase obtained in the step (3) is evaporated to dryness under reduced pressure, adding a crystallization solvent, heating to dissolve, cooling, stirring to crystallize, and filtering to obtain the dapoxetine hydrochloride.
In a preferred embodiment, in the step (1), the dapoxetine acetonitrile hydrochloride mother liquor and the isopropanol mother liquor of the refining step are obtained by the following steps:
adding the crude dapoxetine hydrochloride into acetonitrile, heating, refluxing, dissolving to clear, cooling to 20-25 ℃, stirring for 2-4 h, and performing suction filtration to obtain a filtrate, namely a dapoxetine hydrochloride acetonitrile mother solution; adding the obtained solid into isopropanol, heating to 70-75 ℃ for dissolution, cooling to 0-5 ℃, stirring for 1-2 h, carrying out suction filtration, wherein the filtrate is isopropanol mother liquor in the refining step, and drying the obtained solid to obtain refined dapoxetine hydrochloride;
and combining the acetonitrile mother liquor and the isopropanol mother liquor to obtain the mother liquor to be recovered by the dapoxetine hydrochloride.
In a preferred embodiment, in the step (1), the mass ratio of the crude dapoxetine hydrochloride, acetonitrile and isopropanol is 1: (1-5): (1-10).
The method takes the dapoxetine acetonitrile hydrochloride and the isopropanol mother liquor as raw materials, and due to the synthesis process, the impurities in the dapoxetine acetonitrile hydrochloride and the isopropanol mother liquor are various, and the impurities include organic impurities, inorganic impurities, water-soluble impurities and water-insoluble impurities, so that the method can effectively remove the related impurities from the acetonitrile and the isopropanol mother liquor and also has higher yield, and is more difficult compared with the mother liquor of other solvents. Therefore, the invention designs the treatment steps, and the recovered dapoxetine hydrochloride has high yield and high purity.
In a preferred embodiment, in the step (1), the reduced pressure distillation temperature is 40 to 60 ℃.
The distillation temperature used by the invention is lower, and impurities generated by removing methyl from dapoxetine hydrochloride are avoided.
In a preferred embodiment, in the step (2), the mass ratio of the solid to the purified water is 1: (2-4).
In a preferred embodiment, in the step (2), the organic solvent is selected from one or more of ethyl acetate, toluene and dichloromethane, and the mass ratio of the organic solvent to the purified water is 1: (2-4).
In the invention, after the mother liquor is distilled under reduced pressure, a hydrochloride solid is obtained, and is extracted by using an organic solvent after being dissolved in water, so that organic impurities in the raw materials can be effectively removed.
In a preferred embodiment, in the step (3), the base is selected from one or more of sodium carbonate, potassium carbonate, triethylamine and ammonia water, the acid is hydrochloric acid with a mass fraction of 36% to 38%, the stirring time after the acid is added is 0.5 to 1 hour, and preferably, the stirring speed is 100 to 300rpm.
In a preferred embodiment, in step (3), the organic solvent is selected from one or more of toluene, dichloromethane and ethyl acetate, and the mass ratio of the organic solvent to the aqueous phase is 1: (2-4).
And (3) adding weak base such as sodium carbonate, potassium carbonate, triethylamine and ammonia water into the extracted water phase to free the dapoxetine hydrochloride, and extracting with an organic solvent again to remove water-soluble impurities. While treatment with strong bases such as sodium hydroxide produces degradation impurities, the purity of the resulting product is reduced after the same treatment steps. Adding commercially available concentrated hydrochloric acid with the mass fraction of 36-38% into the raw materials after impurity removal, stirring for reaction to promote the dapoxetine free base to form hydrochloride, and recrystallizing to finish the recovery process.
In a preferred embodiment, in step (3), the organic solvent may be extracted repeatedly 2 to 3 times to increase the extraction effect.
In a preferred embodiment, in the step (4), the reduced-pressure evaporation temperature is 50 to 60 ℃ to a constant weight of an evaporated material, the crystallization solvent is isopropanol, and preferably, the mass ratio of the crystallization solvent to the evaporated material is (4 to 6): 1.
in a preferred embodiment, in the step (4), the temperature-raising dissolution temperature is 70 to 75 ℃.
In a preferred embodiment, in the step (4), the crystallization temperature is-5 to 5 ℃, and the stirring crystallization time is 2 to 4 hours.
In a preferred embodiment, in the step (4), after the crystallization and the filtration, rinsing with pre-cooled isopropanol at 5 ℃ for 2 to 4 times, and drying at 50 to 60 ℃ for 2 to 3 hours.
The dapoxetine hydrochloride is indissolvable in isopropanol at normal temperature, the dapoxetine hydrochloride can be dissolved at high temperature, the product yield loss is small when the dapoxetine hydrochloride is used as a refining solvent to ensure cooling crystallization, and meanwhile, the isopropanol can dissolve most organic impurities and can remove some polar impurities due to hydroxyl carried by the isopropanol, so that the refining effect is better. However, dapoxetine hydrochloride is easily dissolved in ethanol and methanol, so the solvent is not suitable for being used as a refined solvent.
The technical scheme of the application is explained in detail by the following specific embodiments:
the technical means used in the present invention are conventional means well known to those skilled in the art, and various raw materials, reagents, instruments, equipment and the like used in the present invention can be commercially available or can be prepared by existing methods, if not specifically indicated.
The mother liquor used in the embodiments 1-3 of the invention is prepared by the following method:
adding 25kg of crude dapoxetine hydrochloride into 75kg of acetonitrile, heating, refluxing, dissolving, cooling to 20-25 ℃, stirring for 4h, performing suction filtration, adding the obtained solid into 125kg of isopropanol, heating to 70-75 ℃, dissolving, cooling to 0-5 ℃, stirring for 2h, performing suction filtration, and drying to obtain dapoxetine hydrochloride, and combining acetonitrile mother liquor and isopropanol mother liquor to obtain the mother liquor to be recovered by the dapoxetine hydrochloride in the embodiment of the invention.
Example 1
(1) Mixing crude acetonitrile mother liquor of dapoxetine hydrochloride and isopropanol mother liquor obtained in the refining step, heating 500g of the mixture to 50-60 ℃, and distilling the mixture under reduced pressure to obtain 20g of yellow solid;
(2) Adding the yellow solid obtained in the step (1) into 60g of purified water, stirring to dissolve the solid, extracting once with 20g of ethyl acetate, standing, and separating liquid;
(3) Adding ammonia water into the obtained water phase to adjust the pH to be between 8 and 9, then adding toluene for extraction twice, adding 20g of toluene each time, adding hydrochloric acid with the mass fraction of 35% into the obtained organic toluene phase to adjust the pH to be between 2 and 3, stirring for 1 hour, and separating liquid;
(4) And (3) evaporating the obtained toluene phase at 50-60 ℃ under reduced pressure, adding 80g of isopropanol, heating to 70-75 ℃ for dissolving, cooling to 0-5 ℃ for crystallizing for 2h, filtering, leaching and drying to obtain dapoxetine hydrochloride.
By detection, 12.5g of dapoxetine hydrochloride is recovered, and the yield is 62.5%. As shown in fig. 1, the HPLC assay purity was: 99.934%, maximum single hetero 0.035%.
Example 2
(1) Mixing crude acetonitrile mother liquor of dapoxetine hydrochloride and isopropanol mother liquor obtained in the refining step, heating 500g of the mixture to 50-60 ℃, and distilling the mixture under reduced pressure to obtain 20g of yellow solid;
(2) Adding the yellow solid obtained in the step (1) into 60g of purified water, stirring to dissolve the solid, extracting with 20g of toluene once, standing, and separating liquid;
(3) Adding ammonia water into the obtained water phase to adjust the pH to be = 8-9, then adding toluene for extraction twice, adding 20g of toluene each time, adding hydrochloric acid with the mass fraction of 35% into the obtained organic toluene phase to adjust the pH to be = 2-3, stirring for 1 hour, and then separating liquid;
(4) And (3) evaporating the toluene phase at 50-60 ℃ under reduced pressure, adding 80g of isopropanol, heating to 70-75 ℃ for dissolving, cooling to 0-5 ℃ for crystallizing for 2h, filtering, leaching and drying to obtain dapoxetine hydrochloride.
By detection, 12.7g of the obtained dapoxetine hydrochloride is recovered, and the yield is 63.5%. As shown in fig. 2, the HPLC assay purity was: 99.470 percent and maximum single impurity of 0.22 percent.
Example 3
(1) Mixing crude acetonitrile mother liquor of dapoxetine hydrochloride and isopropanol mother liquor obtained in the refining step, heating 500g of the mixture to 50-60 ℃, and distilling the mixture under reduced pressure to obtain 20g of yellow solid;
(2) Adding the yellow solid obtained in the step (1) into 60g of purified water, stirring to dissolve the solid, extracting once with 20g of ethyl acetate, standing, and separating liquid;
(3) Adding ammonia water into the obtained water phase to adjust the pH to be = 8-9, then respectively adding ethyl acetate to extract twice, adding 20g of ethyl acetate each time, adding hydrochloric acid with the mass fraction of 35% into the obtained organic ethyl acetate phase to adjust the pH to be = 2-3, stirring for 1 hour, and then separating liquid;
(4) And (3) evaporating the ethyl acetate phase to dryness at 50-60 ℃ under reduced pressure, adding 80g of isopropanol, heating to 70-75 ℃ for dissolution, cooling to 0-5 ℃ for crystallization for 2h, filtering, leaching and drying to obtain the dapoxetine hydrochloride.
Detection shows that 10.2g of dapoxetine hydrochloride is recovered, and the yield is 51%. As shown in fig. 3, the HPLC assay purity was: 99.930%, maximum single impurity 0.033%.
The foregoing description of specific exemplary embodiments of the invention has been presented for the purposes of illustration and description. It is not intended to limit the invention to the precise form disclosed, and obviously many modifications and variations are possible in light of the above teaching. The exemplary embodiments were chosen and described in order to explain certain principles of the invention and its practical application to enable one skilled in the art to make and use various exemplary embodiments of the invention and various alternatives and modifications as are suited to the particular use contemplated. It is intended that the scope of the invention be defined by the claims and their equivalents.
Claims (10)
1. A recovery method of dapoxetine acetonitrile hydrochloride and isopropanol mother liquor is characterized by comprising the following steps:
(1) Mixing the dapoxetine acetonitrile hydrochloride mother liquor with the isopropanol mother liquor in the refining step, and distilling under reduced pressure to obtain a yellow solid;
(2) Dissolving the solid obtained in the step (1) in purified water, adding an organic solvent for extraction, standing and separating liquid;
(3) Adding alkali into the water phase obtained in the step (2) to adjust the pH = 8-9, adding an organic solvent for extraction, adding acid into the organic phase, stirring, and adjusting the pH = 2-3;
(4) And (4) after the organic phase obtained in the step (3) is evaporated to dryness under reduced pressure, adding a crystallization solvent, heating to dissolve, cooling, stirring to crystallize, and filtering to obtain the dapoxetine hydrochloride.
2. The method for recovering dapoxetine acetonitrile hydrochloride and isopropanol mother liquor in claim 1, wherein in step (1), the dapoxetine acetonitrile hydrochloride mother liquor and the isopropanol mother liquor in the refining step are obtained by the following steps:
adding the crude dapoxetine hydrochloride into acetonitrile, heating, refluxing, dissolving, cooling to 20-25 ℃, stirring for 2-4 h, and carrying out suction filtration to obtain a filtrate, namely a dapoxetine hydrochloride acetonitrile mother solution; adding the obtained solid into isopropanol, heating to 70-75 ℃ for dissolving, cooling to 0-5 ℃, stirring for 1-2 h for suction filtration, wherein the filtrate is isopropanol mother liquor in the refining step, and drying the obtained solid to obtain refined dapoxetine hydrochloride;
and combining the acetonitrile mother liquor and the isopropanol mother liquor to obtain the mother liquor to be recovered by the dapoxetine hydrochloride.
3. The method for recovering dapoxetine acetonitrile hydrochloride and isopropanol mother liquor according to claim 2, wherein in step (1), the mass ratio of the crude dapoxetine hydrochloride, acetonitrile and isopropanol is 1: (1-5): (1-10).
4. The method for recovering the dapoxetine acetonitrile hydrochloride and isopropanol mother liquor in claim 1, wherein in step (1), the reduced pressure distillation temperature is 40-60 ℃.
5. The method for recovering dapoxetine acetonitrile hydrochloride and isopropanol mother liquor according to claim 1, wherein in step (2), the mass ratio of the solid to the purified water is 1: (2-4).
6. The method for recovering dapoxetine acetonitrile hydrochloride and isopropanol mother liquor according to claim 1, wherein in step (2), the organic solvent is selected from one or more of ethyl acetate, toluene and dichloromethane, and the mass ratio of the organic solvent to purified water is 1: (2-4).
7. The method for recovering dapoxetine acetonitrile hydrochloride and isopropanol mother liquor according to claim 1, wherein in step (3), the base is one or more selected from sodium carbonate, potassium carbonate, triethylamine and ammonia water, the acid is hydrochloric acid with a mass fraction of 36% -38%, and the stirring time after the acid is added is 0.5-1 h.
8. The method for recovering dapoxetine acetonitrile hydrochloride and isopropanol mother liquor according to claim 1, wherein in step (3), the organic solvent is one or more selected from toluene, dichloromethane and ethyl acetate, and the mass ratio of the organic solvent to the aqueous phase is 1: (2-4).
9. The method for recovering the dapoxetine acetonitrile hydrochloride and the isopropanol mother liquor in claim 1, wherein in the step (4), the reduced pressure evaporation temperature is 50-60 ℃, and the crystallization solvent is isopropanol.
10. The method for recovering dapoxetine acetonitrile hydrochloride and isopropanol mother liquor according to claim 1, wherein in step (4), the crystallization temperature is-5 to 5 ℃, and the stirring crystallization time is 2 to 4 hours.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106748817A (en) * | 2016-12-06 | 2017-05-31 | 安徽省金楠医疗科技有限公司 | A kind of dapoxetine hydrochloride preparation method |
| CN106883133A (en) * | 2017-03-10 | 2017-06-23 | 南京斯贝源医药科技有限公司 | A kind of preparation method of dapoxetine hydrochloride |
| CN109369424A (en) * | 2018-07-09 | 2019-02-22 | 华控创新（北京）药物研究院有限公司 | A kind of purification process of dapoxetine hydrochloride |
| CN114621107A (en) * | 2022-04-01 | 2022-06-14 | 广药白云山化学制药(珠海)有限公司 | Method for recycling product from dapoxetine hydrochloride mother liquor |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106748817A (en) * | 2016-12-06 | 2017-05-31 | 安徽省金楠医疗科技有限公司 | A kind of dapoxetine hydrochloride preparation method |
| CN106883133A (en) * | 2017-03-10 | 2017-06-23 | 南京斯贝源医药科技有限公司 | A kind of preparation method of dapoxetine hydrochloride |
| CN109369424A (en) * | 2018-07-09 | 2019-02-22 | 华控创新（北京）药物研究院有限公司 | A kind of purification process of dapoxetine hydrochloride |
| CN114621107A (en) * | 2022-04-01 | 2022-06-14 | 广药白云山化学制药(珠海)有限公司 | Method for recycling product from dapoxetine hydrochloride mother liquor |
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