CN118307537A - Preparation method of praziquantel impurity RRT0.76 - Google Patents
Preparation method of praziquantel impurity RRT0.76 Download PDFInfo
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- CN118307537A CN118307537A CN202410425679.2A CN202410425679A CN118307537A CN 118307537 A CN118307537 A CN 118307537A CN 202410425679 A CN202410425679 A CN 202410425679A CN 118307537 A CN118307537 A CN 118307537A
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- praziquantel
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- heat preservation
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- FSVJFNAIGNNGKK-UHFFFAOYSA-N 2-[cyclohexyl(oxo)methyl]-3,6,7,11b-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4-one Chemical compound C1C(C2=CC=CC=C2CC2)N2C(=O)CN1C(=O)C1CCCCC1 FSVJFNAIGNNGKK-UHFFFAOYSA-N 0.000 title claims abstract description 73
- 229960002957 praziquantel Drugs 0.000 title claims abstract description 73
- 239000012535 impurity Substances 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 62
- 238000004321 preservation Methods 0.000 claims abstract description 31
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 5
- 239000001301 oxygen Substances 0.000 claims abstract description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 28
- 238000002425 crystallisation Methods 0.000 claims description 23
- 230000008025 crystallization Effects 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 14
- 230000035484 reaction time Effects 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 11
- 238000001914 filtration Methods 0.000 claims description 11
- 239000003960 organic solvent Substances 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 125000000532 dioxanyl group Chemical group 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- 239000000126 substance Substances 0.000 description 14
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- 238000001228 spectrum Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 208000030852 Parasitic disease Diseases 0.000 description 2
- 239000003096 antiparasitic agent Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 238000005502 peroxidation Methods 0.000 description 2
- 201000004409 schistosomiasis Diseases 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 1
- 150000001491 aromatic compounds Chemical class 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000005416 organic matter Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Abstract
The invention discloses a preparation method of praziquantel impurity RRT0.76, which comprises the following steps: and (3) pre-reacting praziquantel with oxygen under the condition of ultraviolet irradiation, and removing the ultraviolet irradiation after the pre-reaction is finished, and carrying out heat preservation reaction. The preparation method of the praziquantel impurity RRT0.76 is simple, efficient and short in time consumption, and the purity and the yield of the prepared praziquantel impurity RRT0.76 are high.
Description
Technical Field
The invention relates to the technical field of organic matter synthesis, in particular to a preparation method of praziquantel impurity RRT 0.76.
Background
Praziquantel is a broad-spectrum antiparasitic drug, is very effective on main schistosomiasis of human body, and is the first drug for treating schistosomiasis and various parasitic diseases in the world soon after coming into the market in Germany since 1980. The advent of praziquantel is a major breakthrough in the treatment of parasitic diseases, and at present, praziquantel has become the most widely used antiparasitic drug in the world. The impurity RRT0.76 is an impurity formed by peroxidation of praziquantel in the production process of praziquantel, has a structure shown in formula I, and can be used for providing a control sample for praziquantel detection and quality control of praziquantel. CN101511784a provides a method for oxidizing alkylaromatic compounds to the corresponding hydroperoxide using a catalyst, but the method described in this technical scheme is only applicable to alkylaromatic compounds, and is not applicable to peroxidation of aromatic compounds containing heterocyclic rings, such as praziquantel. Due to the lack of a method for preparing the impurity RRT0.76 at present, the invention aims to provide a preparation method for synthesizing praziquantel impurity RRT0.76, which is simple and takes less time.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a preparation method of praziquantel impurity RRT0.76, which has the advantages of simple preparation method, short time consumption and high purity and yield of products.
In order to achieve the above purpose, the invention is realized by the following technical scheme:
a preparation method of praziquantel impurity RRT0.76, which comprises the following steps: and (3) pre-reacting praziquantel with oxygen under the condition of ultraviolet irradiation, and removing the ultraviolet irradiation after the pre-reaction is finished, and carrying out heat preservation reaction.
Further, praziquantel is dissolved in an organic solvent to perform a pre-reaction.
Further, the organic solvent is dioxane or acetone.
Further, the mass ratio of praziquantel to the organic solvent is 1: (15-25).
Further, the wavelength of the ultraviolet light is 254-365 nm.
Further, the wavelength of the ultraviolet light was 365nm.
Further, the pre-reaction temperature is 20-50 ℃, and the pre-reaction time is 36-48 h.
Further, the temperature of the heat preservation reaction is between 35 and 50 ℃, and the time of the heat preservation reaction is between 2 and 12 hours.
Further, after the completion of the heat-insulating reaction, the post-treatment operations of concentration, crystallization, filtration, washing and drying are performed.
Further, the mixture was concentrated under reduced pressure.
Further, the crystallization temperature is 0-5 ℃, and the crystallization time is 4-8 h.
Further, the crystallization time was 4h.
Further, the solvent for crystallization is acetone or ethanol.
The technical scheme has the following advantages or beneficial effects:
In the preparation method of the praziquantel impurity RRT0.76, the preparation method is simple, short in time consumption, high in efficiency and high in product purity and yield, wherein oxygen is used as an oxidant, the pre-reaction catalysis is carried out by ultraviolet irradiation, and the thermal insulation reaction is carried out, so that the high-efficiency preparation of the praziquantel impurity RRT0.76 is realized.
Drawings
Fig. 1 is a liquid-phase spectrum of praziquantel impurity RRT0.76 prepared in example one of the present invention.
Fig. 2 is an H-NMR spectrum of praziquantel impurity RRT0.76 prepared in example one of the present invention.
Fig. 3 is an MS spectrum of praziquantel impurity RRT0.76 prepared in example one of the present invention.
Detailed Description
The invention is further described below with reference to the drawings and examples.
An embodiment of the present invention provides a method for preparing praziquantel impurity RRT0.76, comprising the steps of: and (3) pre-reacting praziquantel with oxygen under the condition of ultraviolet irradiation, and removing the ultraviolet irradiation after the pre-reaction is finished, and carrying out heat preservation reaction.
Specifically, praziquantel is dissolved in an organic solvent to perform a pre-reaction.
Specifically, the organic solvent is dioxane or acetone.
Specifically, the mass ratio of praziquantel to the organic solvent is 1: (15-25), such as 1: 15. 1: 16. 1: 17. 1: 18. 1: 19. 1: 20. 1: 21. 1: 22. 1: 23. 1: 24. 1:25 or any value therebetween.
Specifically, the wavelength of the ultraviolet light is 254-365 nm.
Specifically, the wavelength of ultraviolet light is 365nm.
Specifically, the pre-reaction temperature is 20 ℃ to 50 ℃, such as 20 ℃, 25 ℃,30 ℃, 35 ℃,40 ℃, 45 ℃, 50 ℃ or any value therebetween, and the pre-reaction time is 36h to 48h, such as 36h, 38h, 40h, 43h, 45h, 48h or any value therebetween.
Specifically, the temperature of the incubation reaction is 35-50 ℃, such as 35 ℃,38 ℃, 40 ℃, 42 ℃, 45 ℃, 47 ℃, 50 ℃ or any value therebetween, and the incubation reaction time is 2-12 hours, such as 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours or any value therebetween.
Specifically, after the completion of the heat-insulating reaction, the post-treatment operations of concentration, crystallization, filtration, washing and drying are performed.
Specifically, the concentration is reduced pressure concentration.
Specifically, the crystallization temperature is 0 to 5 ℃, such as 0 ℃,1 ℃,2 ℃,3 ℃,4 ℃, 5 ℃ or any value therebetween, and the crystallization time is 4 to 8 hours, such as 4 hours, 5 hours, 6 hours, 7 hours, 8 hours or any value therebetween.
Specifically, the crystallization time was 4h.
Specifically, the solvent for crystallization is acetone or ethanol.
The yield calculation formula in each of the following examples is: the amount of discharged ∈ product relative molecular mass x assay purity ∈ amount of praziquantel dosed = pure yield of product.
Example 1
10G (0.032 mol) praziquantel and 150g dioxane are added into a 500ml reaction bottle, stirring is started, after praziquantel is completely dissolved, pure oxygen is introduced, meanwhile, ultraviolet light with the wavelength of 254nm is used for irradiation, after the pre-reaction is carried out for 36 hours, the ultraviolet light irradiation is removed, the heat preservation reaction is carried out, the heat preservation reaction temperature is 35 ℃, and the heat preservation reaction time is 12 hours. After the reaction is finished, concentrating under reduced pressure at 70 ℃ to obtain reddish sticky substance, adding acetone with the mass which is 0.3 times that of the sticky substance for dissolving, cooling to 0 ℃ for crystallization for 4 hours, filtering, rinsing and drying to obtain praziquantel impurity RRT0.76 white powder 6.8g with the purity of 99.0% and the yield of 61.08%.
Example two
10G (0.032 mol) praziquantel and 200g dioxane are added into a 500ml reaction bottle, stirring is started, after praziquantel is completely dissolved, pure oxygen is introduced, meanwhile, ultraviolet light with the wavelength of 254nm is used for irradiation, after pre-reaction is carried out for 44 hours, the ultraviolet light irradiation is removed, the heat preservation reaction is carried out, the heat preservation reaction temperature is 45 ℃, and the heat preservation reaction time is 7 hours. After the reaction is finished, concentrating under reduced pressure at 70 ℃ to obtain reddish sticky substance, adding acetone with the mass which is 0.3 times that of the sticky substance for dissolving, cooling to 0 ℃ for crystallization for 4 hours, filtering, rinsing and drying to obtain 7.0g of praziquantel impurity RRT0.76 white powder with the purity of 99.1% and the yield of 62.94%.
Example III
10G (0.032 mol) praziquantel and 200g acetone are added into a 500ml reaction bottle, stirring is started, after praziquantel is completely dissolved, the temperature is kept at 20 ℃, pure oxygen is introduced, meanwhile, ultraviolet light with the wavelength of 365nm is used for irradiation, after pre-reaction is carried out for 40 hours, the ultraviolet light irradiation is removed, the heat preservation reaction is carried out, the heat preservation reaction temperature is 50 ℃, and the heat preservation reaction time is 2 hours. After the reaction is finished, concentrating under reduced pressure at 70 ℃ to obtain reddish sticky substance, adding acetone with the mass which is 0.3 times that of the sticky substance for dissolving, cooling to 5 ℃ for crystallization for 4 hours, filtering, rinsing and drying to obtain praziquantel impurity RRT0.76 white powder 6.9g with the purity of 99% and the yield of 62.10%.
Example IV
10G (0.032 mol) praziquantel and 200g dioxane are added into a 500ml reaction bottle, stirring is started, after praziquantel is completely dissolved, pure oxygen is introduced, meanwhile, ultraviolet light with the wavelength of 310nm is used for irradiation, after pre-reaction is carried out for 40 hours, the ultraviolet light irradiation is removed, the heat preservation reaction is carried out, the heat preservation reaction temperature is 35 ℃, and the heat preservation reaction time is 10 hours. After the reaction is finished, concentrating under reduced pressure at 70 ℃ to obtain reddish sticky matters, adding ethanol with the mass which is 0.3 times that of the sticky matters for dissolving, cooling to 3 ℃ for crystallization for 6 hours, filtering, rinsing and drying to obtain praziquantel impurity RRT0.76 white powder 6.3g with the purity of 99.3% and the yield of 56.76%.
Example five
10G (0.032 mol) praziquantel and 200g dioxane are added into a 500ml reaction bottle, stirring is started, after praziquantel is completely dissolved, pure oxygen is introduced, meanwhile, ultraviolet light with the wavelength of 365nm is used for irradiation, after pre-reaction is carried out for 48 hours, the ultraviolet light irradiation is removed, the heat preservation reaction is carried out, the heat preservation reaction temperature is 40 ℃, and the heat preservation reaction time is 8 hours. After the reaction is finished, concentrating under reduced pressure at 70 ℃ to obtain reddish sticky substance, adding acetone with the mass which is 0.3 times that of the sticky substance for dissolving, cooling to 0 ℃ for crystallization for 8 hours, filtering, rinsing and drying to obtain praziquantel impurity RRT0.76 white powder 6.8g with the purity of 99.2% and the yield of 61.21%.
Example six
10G (0.032 mol) praziquantel and 200g dioxane are added into a 500ml reaction bottle, stirring is started, after praziquantel is completely dissolved, pure oxygen is introduced, meanwhile, ultraviolet light with the wavelength of 365nm is used for irradiation, after pre-reaction is carried out for 48 hours, the ultraviolet light irradiation is removed, the heat preservation reaction is carried out, the heat preservation reaction temperature is 35 ℃, and the heat preservation reaction time is 10 hours. After the reaction is finished, concentrating under reduced pressure at 70 ℃ to obtain reddish sticky substance, adding acetone with the mass which is 0.3 times that of the sticky substance for dissolving, cooling to 0 ℃ for crystallization for 4 hours, filtering, rinsing and drying to obtain 7.8g of praziquantel impurity RRT0.76 white powder with the purity of 99.2% and the yield of 70.21%.
Comparative example one
10G (0.032 mol) praziquantel and 150g dioxane are added into a 500ml reaction bottle, stirring is started, after praziquantel is completely dissolved, pure oxygen is introduced at 25 ℃, no ultraviolet irradiation is used for carrying out pre-reaction for 36 hours, the temperature is increased to 35 ℃ for carrying out heat preservation reaction, and the heat preservation reaction time is 12 hours. After the reaction is finished, concentrating under reduced pressure at 70 ℃ to obtain reddish sticky substance, adding acetone with the mass which is 0.3 times that of the sticky substance for dissolving, cooling to 0 ℃ for crystallization for 4 hours, filtering, rinsing and drying to obtain praziquantel impurity RRT0.76 white powder 6.1g with the purity of 67.5% and the yield of 37.36%.
Comparative example two
10G (0.032 mol) praziquantel and 150g (1.693 mol) dioxane are added into a 500ml reaction bottle, stirring is started, after praziquantel is completely dissolved, pure oxygen is introduced at 25 ℃, irradiation is carried out by using 254nm of ultraviolet wavelength, after pre-reaction is carried out for 36 hours, the temperature is raised to 35 ℃, irradiation is carried out by continuously using 254nm of ultraviolet wavelength, heat preservation reaction is carried out, and the heat preservation reaction time is 12 hours. After the reaction is finished, concentrating under reduced pressure at 70 ℃ to obtain reddish sticky substance, adding acetone with the mass which is 0.3 times of that of the sticky substance for dissolution, cooling to 0 ℃ for crystallization for 4 hours, filtering, rinsing and drying to obtain praziquantel impurity RRT0.76 white powder 6.5g with the purity of 87.2% and the yield of 51.43%.
In the present invention, fig. 1 is a liquid phase spectrum of praziquantel impurity RRT0.76 prepared in example one, fig. 2 is an H-NMR spectrum of praziquantel impurity RRT0.76 prepared in example one, and fig. 3 is an MS spectrum of praziquantel impurity RRT0.76 prepared in example one. As can be seen from fig. 1, the purity of the obtained praziquantel impurity RRT0.76 reaches 99%, and as can be seen from fig. 2 and 3, the obtained product is praziquantel impurity RRT0.76.
The embodiments are merely illustrative of the technical solution of the present invention, and not limiting thereof; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some of the technical features thereof can be replaced with equivalents; such modifications and substitutions do not depart from the spirit and scope of the technical solutions of the embodiments of the present invention, and therefore all other embodiments obtained by those skilled in the art without making creative efforts are intended to fall within the protection scope of the present invention.
Claims (10)
1. A method for preparing praziquantel impurity RRT0.76, which is characterized by comprising the following steps:
and (3) pre-reacting praziquantel with oxygen under the condition of ultraviolet irradiation, and removing the ultraviolet irradiation after the pre-reaction is finished, and carrying out heat preservation reaction.
2. The method for preparing praziquantel impurity RRT0.76 according to claim 1, wherein: praziquantel is dissolved in an organic solvent for pre-reaction;
preferably, the organic solvent is dioxane or acetone.
3. The method for preparing praziquantel impurity RRT0.76 according to claim 2, wherein: the mass ratio of praziquantel to the organic solvent is 1: (15-25).
4. The method for preparing praziquantel impurity RRT0.76 according to claim 1, wherein: the wavelength of the ultraviolet light is 254-365 nm;
Preferably, the wavelength of the ultraviolet light is 365nm.
5. The method for preparing praziquantel impurity RRT0.76 according to claim 1, wherein: the pre-reaction temperature is 20-50 ℃, and the pre-reaction time is 36-48 h.
6. The method for preparing praziquantel impurity RRT0.76 according to claim 1, wherein: the temperature of the heat preservation reaction is between 35 and 50 ℃, and the time of the heat preservation reaction is between 2 and 12 hours.
7. The method for preparing praziquantel impurity RRT0.76 according to claim 1, wherein: after the heat preservation reaction is completed, the post-treatment operations of concentration, crystallization, filtration, washing and drying are carried out.
8. The method for preparing praziquantel impurity RRT0.76 according to claim 7, wherein: the concentration is reduced pressure concentration.
9. The method for preparing praziquantel impurity RRT0.76 according to claim 7, wherein: the crystallization temperature is 0-5 ℃ and the crystallization time is 4-8 h;
Preferably, the crystallization time is 4h.
10. The method for preparing praziquantel impurity RRT0.76 according to claim 7, wherein: the solvent for crystallization is acetone or ethanol.
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| Publication Number | Publication Date |
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| CN118307537A true CN118307537A (en) | 2024-07-09 |
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