CN113149987B - Preparation method of injection-grade ganciclovir - Google Patents
Preparation method of injection-grade ganciclovir Download PDFInfo
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- CN113149987B CN113149987B CN202110434509.7A CN202110434509A CN113149987B CN 113149987 B CN113149987 B CN 113149987B CN 202110434509 A CN202110434509 A CN 202110434509A CN 113149987 B CN113149987 B CN 113149987B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
Abstract
The invention discloses a preparation method of injection-grade ganciclovir. Dissolving ganciclovir crude product in DMF water solution by regulating pH, then adding acetone, ethyl acetate or low carbon chain monohydric alcohol or dihydric alcohol, cooling, crystallizing, filtering to obtain ganciclovir sodium, dissolving sodium salt in warm water, adding proper amount of DMF, regulating pH to meta-acidity, cooling, crystallizing, filtering, washing, vacuum drying. The invention reduces related substances in ganciclovir, the single impurity is less than five parts per million, the total impurity is not more than one thousandth, and other indexes meet the requirement of injection-grade raw materials.
Description
Technical Field
The invention relates to the technical field of chemical refining, in particular to a refining method of injection-grade ganciclovir.
Background
Ganciclovir is a commonly used antiviral drug. Is mainly used for treating retina diseases, such as retinitis, related pathological changes caused by cytomegalovirus infection, cytomegalovirus retinitis and the like. Is mainly used for treating cytomegalovirus infection diseases caused by immune function injury. Such as treatment of human immunodeficiency patients with cytomegalovirus retinitis; also for preventing cytomegalovirus infection in organ transplant recipients; and preventing and treating late AIDS infection, cytomegalovirus infection, etc. The variety is pushed out by Syntex in the United states, the solid preparation is marketed in the United states in 1988, the injection is marketed in the United states in 6 months of 1989, and the related single impurity in the related substances is required to be less than 0.1% because the injection has higher requirements on the aspects of related substances, microorganisms, bacterial endotoxin and the like of the raw materials, so that the quality of the injection is consistent with that of the original injection, a refining method for improving the quality of ganciclovir raw materials is sought, the curative effect of clinical application is ensured, and the side effect is reduced.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention provides a preparation method of injection-grade ganciclovir, which adopts mixed organic solvent and low-temperature operation to facilitate the removal of impurities generated in synthesis (namely impurities in a ganciclovir crude product) and reduce the generation amount of degraded impurities. The invention effectively removes synthesis byproducts and degradation products, and simultaneously effectively reduces new degradation products generated in the refining process, and the refining method is an industrial production method.
In order to achieve the above purpose, the technical scheme adopted by the invention comprises the following steps:
the preparation method of the injection-grade ganciclovir comprises the following steps:
(1) Dissolving ganciclovir crude product in water solution containing DMF, regulating pH to 11.5-12.5 with alkaline solution, adding active carbon, stirring, and filtering to obtain filtrate;
(2) Adding an organic solvent into the filtrate obtained in the step (1), reducing the temperature to-10 to-25 ℃ to generate white precipitate, filtering and washing a filter cake; the organic solvent is one or more of acetone, ethyl acetate, ethyl formate, methyl acetate, ethanol, methanol, isopropanol and ethylene glycol;
(3) Dissolving the filter cake, adding a proper amount of DMF, controlling the temperature not to exceed 30 ℃, adding acid to adjust the pH value to 6-7, cooling to below-5 ℃ (preferably-15 to-20 ℃), stirring, filtering, washing the filter cake, and drying under reduced pressure to obtain the injection-grade ganciclovir.
Preferably, the organic solvent is one or more of acetone, ethyl acetate, ethyl formate, methyl acetate, ethanol, methanol, isopropanol and ethylene glycol, and the volume ratio of DMF added in the step (1) to the organic solvent in the step (2) is 1:5 to 1:10. in the step (1), the mass-volume ratio of the ganciclovir crude product to water is 1:2-4 kg/L.
Preferably, the preparation method specifically comprises the following steps:
(1) Adding ganciclovir crude product into water solution containing DMF, adjusting pH to 11.5-12.5 with alkaline solution to obtain mixed solution (mixed solution comprises water, ganciclovir crude product, DMF and alkaline solution), adding 1.5-2.5% active carbon into the mixed solution, stirring, and filtering to obtain filtrate; the step is carried out at 20-30 ℃;1.5-2.5% means: the mass of the activated carbon is 1.5-2.5% of the mass of the ganciclovir crude product.
(2) Adding 1.7-5 times of first organic solvent (namely, the volume of the first organic solvent is 1.7-5 times of that of the filtrate) into the filtrate at 20-30 ℃, reducing the temperature to minus 10-minus 25 ℃ to generate white precipitate (namely, ganciclovir sodium), stirring, filtering, and washing a filter cake with a second organic solvent; the second organic solvent may be the same as or different from the first organic solvent;
(3) Dissolving the filter cake at room temperature (dissolving by adding water), adding a proper amount of DMF, controlling the temperature not to exceed 30 ℃ (specifically controlling the temperature to be between 20 and 30 ℃), slowly adding hydrochloric acid solution, adjusting the pH to be 6 to 7, cooling to below-15 ℃), stirring, filtering, repeatedly washing the filter cake, and drying under reduced pressure to obtain ganciclovir meeting the injection-grade requirement.
More specifically, the refining method specifically comprises the following steps:
(1) Adding the ganciclovir crude product into an aqueous solution containing DMF (DMF), stirring at 20-30 ℃ (stirring to enable the ganciclovir crude product to be fully dissolved in the aqueous solution containing DMF), adjusting the pH to 11.5-12.5 by using an alkaline solution, adding 1.5-2.5% of active carbon, stirring for 15-30 minutes, and filtering;
(2) Adding 1.7-5 times of first organic solvent into the filtrate at 20-30 ℃, reducing the temperature to-10 to-25 ℃ under stirring (namely, fully mixing the filtrate with the first organic solvent by stirring), generating white precipitate, stirring for 20 minutes, filtering, and washing a filter cake by using a second organic solvent.
(3) Dissolving the filter cake at room temperature, adding a proper amount of DMF (3-8% of the water for dissolving the filter cake, namely, the volume ratio of the added DMF to the water for dissolving the filter cake is 3-8:1), controlling the temperature to be not more than 30 ℃, slowly adding hydrochloric acid solution, adjusting the pH value to be 6-7, cooling to below-5 ℃, stirring for one hour, filtering, repeatedly washing the filter cake with water, and drying under reduced pressure to obtain ganciclovir with high purity meeting the requirement of injection grade.
The first and second organic solvents are one or more of acetone, ethyl acetate, ethyl formate, methyl acetate, ethanol, methanol, isopropanol and ethylene glycol.
Preferably, the alkaline solution is a sodium hydroxide solution, more preferably, the sodium hydroxide solution is a 2-3N sodium hydroxide solution. The volume ratio of DMF added in step (1) to the first organic solvent added in step (2) is 1:5 to 1:10.
preferably, in step (1), the volume ratio of DMF to water is 1:1 to 1:3.
the step (1) is carried out at 20-30 ℃, and the temperature of DMF, water, alkaline solution and filtrate is 20-30 ℃; preferably, the temperature for precipitating ganciclovir sodium in the step (2) is between-15 ℃ and-20 ℃ (namely, the temperature is reduced to between-15 ℃ and-20 ℃); preferably, in the step (3), after the filter cake is dissolved, DMF is added in an amount of 3 to 8% of the amount of dissolved water.
Compared with the prior art, the method adopts the mixed organic solvent (DMF and first organic solvent) to separate out ganciclovir sodium salt, effectively removes related impurities generated in the drug synthesis process, and simultaneously reduces the amount of guanine and other impurities generated by degradation in the refining process due to the low-temperature operation, wherein the guanine which is a main degradation product can be reduced by at least 0.05 percent.
Detailed Description
The present invention will be described in detail with reference to examples, but the present invention is not limited to the following specific examples.
Example 1
According to the post-treatment process of ganciclovir Wei Changgui (the synthesis process and the conventional post-treatment process of ganciclovir are implemented in a certain organic solvent or a mixed solvent of more than two solvents, and recrystallization treatment is implemented), the total related substances in the obtained ganciclovir are 0.8%, and the maximum single impurity guanine is 0.4%, and the limit of the related substances meets the standard requirements of solid preparations.
Adding 2.5 kg of ganciclovir crude product into 6 liters of water, slowly adding 4 liters of 2.5N sodium hydroxide solution (stirring at the same time), measuring the pH to be 11.9, adding 5 liters of DMF, adding 45 g of active carbon, stirring for 30 minutes, and filtering to remove the active carbon to obtain filtrate (all the operations are carried out at room temperature); the filtrate was stirred, acetone 30L was added, then cooled to-20℃to precipitate a white material, and after stirring continued for 20 minutes, the filtrate was filtered and the solid (i.e., filter cake) was washed twice with a small amount of acetone. Dissolving the solid in 20 liters of water again, stirring and dissolving, adding 1 liter of DMF, controlling the temperature not to exceed 30 ℃, slowly adding 2N hydrochloric acid solution, adjusting the pH to 6.5, cooling to-15 ℃, stirring for 1 hour, filtering, repeatedly washing the filter cake with water, and drying under reduced pressure to obtain 2.15 kilograms of ganciclovir with high purity meeting the injection-level requirement. The related substances are detected, guanine is 0.04%, total impurities are lower than 0.1%, and the yield is 84.6%.
Example 2
2.5 kg of ganciclovir crude product is added into 6 liters of water, 4 liters of 2.5N sodium hydroxide solution is slowly added, the pH value is measured to be 12.0, 6 liters of DMF is added, 50 g of active carbon is added, stirring is carried out for 30 minutes, active carbon is removed by filtration, the filtrate is stirred, 30L of ethyl acetate is added, then the temperature is reduced to minus 20 ℃, white substances are separated out, stirring is continued for 20 minutes, filtration is carried out, and the solid is washed twice by a small amount of ethyl acetate. Dissolving the solid in 20L of water again, stirring to dissolve, adding 0.6L of DMF, controlling the temperature not to exceed 30 ℃, slowly adding 2N hydrochloric acid solution, adjusting the pH to 6, cooling to-18 ℃, stirring for 1 hour, filtering, repeatedly washing the filter cake with water, and drying under reduced pressure to obtain 2.18 kg of ganciclovir. The related substances are detected, the guanine is 0.05%, the total impurity is lower than 0.1%, and the yield is 87.2%.
Example 3
5 kg of ganciclovir crude product is added into 15 liters of water, 4 liters of 3.0N sodium hydroxide solution is slowly added, the pH value is measured to be 12.5, 8 liters of DMF is added, 80 g of active carbon is added, stirring is carried out for 30 minutes, the active carbon is removed by filtration, the filtrate is stirred, 80L of ethanol is added, then the temperature is reduced to minus 20 ℃, white substances are separated out, stirring is continued for 20 minutes, filtration is carried out, and the solid is washed twice by a small amount of ethanol. Dissolving the solid in 25 liters of water again, stirring and dissolving, adding 2 liters of DMF, controlling the temperature not to exceed 30 ℃, slowly adding 3N hydrochloric acid solution, adjusting the pH to 6, cooling to-18 ℃, stirring for 1 hour, filtering, repeatedly washing the filter cake with water, and drying under reduced pressure to obtain 4.28 kg of ganciclovir. The related substances are detected, guanine is 0.04%, total impurities are lower than 0.1%, and the yield is 85.6%.
Example 4
2.5 kg of ganciclovir crude product is added into 6 liters of water, 4 liters of 2.5N sodium hydroxide solution is slowly added, the pH value is measured to be 12.1, 6 liters of DMF is added, 50 g of active carbon is added, stirring is carried out for 30 minutes, active carbon is removed by filtration, 35L of methanol is added under the stirring of filtrate, then the temperature is reduced to minus 10 ℃, white substances are separated out, stirring is continued for 20 minutes, filtration is carried out, and the solid is washed twice by a small amount of methanol. Dissolving the solid in 20L of water again, stirring to dissolve, adding 1L of DMF, controlling the temperature to be not more than 30 ℃, slowly adding 2.5N hydrochloric acid solution, adjusting the pH to 6, cooling to-20 ℃, stirring for 1 hour, filtering, repeatedly washing the filter cake with water, and drying under reduced pressure to obtain 2.1 kg of ganciclovir. The related substances are detected, the guanine is 0.06%, the total impurity is lower than 0.1%, and the yield is 84.0%.
Example 5
2.5 kg of ganciclovir crude product is added into 6 liters of water, 4.1 liters of 2.5N sodium hydroxide solution is slowly added, the pH value is measured to be 12.1, 5 liters of DMF is added, 50 g of active carbon is added, stirring is carried out for 30 minutes, active carbon is removed by filtration, 35L of isopropanol is added under stirring of filtrate, then the temperature is reduced to-20 ℃ to precipitate white substances, stirring is continued for 20 minutes, filtration is carried out, and the solid is washed twice with a small amount of isopropanol. Dissolving the solid in 20L of water again, stirring to dissolve, adding 0.8L of DMF, controlling the temperature not to exceed 30 ℃, slowly adding 2.5N hydrochloric acid solution, adjusting the pH to 6, cooling to-20 ℃, stirring for 1 hour, filtering, repeatedly washing a filter cake with water, and drying under reduced pressure to obtain 2.2 kg of ganciclovir. The related substances are detected, the guanine is 0.03%, the total impurity is lower than 0.1%, and the yield is 88.0%.
Example 6
2.5 kg of ganciclovir crude product is added into 5L of water, 5L of 2.0N sodium hydroxide solution is slowly added, the pH value is measured to be 11.8, 5L of DMF is added, 45 g of active carbon is added, stirring is carried out for 30 minutes, active carbon is removed by filtration, 30L of ethylene glycol is added under the stirring of filtrate, then the temperature is reduced to minus 20 ℃, white substances are separated out, stirring is continued for 20 minutes, filtration is carried out, and the solid is washed twice by a small amount of ethylene glycol. Dissolving the solid in 20 liters of water again, stirring and dissolving, adding 1 liter of DMF, controlling the temperature not to exceed 30 ℃, slowly adding 2.0N hydrochloric acid solution, adjusting the pH to 6.5, cooling to-15 ℃, stirring for 1 hour, filtering, repeatedly washing a filter cake with water, and drying under reduced pressure to obtain 2.0 kg of ganciclovir. The related substances are detected, guanine is 0.04%, total impurities are lower than 0.1%, and the yield is 80.0%.
The above embodiments are only for illustrating the technical solution of the present invention, and not for limiting the same; 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 or all of the technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit of the invention. The above embodiments are merely preferred embodiments of the present invention, and any modifications and variations made according to the present invention should be included in the protection scope of the present invention.
Claims (6)
1. The preparation method of the injection-grade ganciclovir is characterized by comprising the following steps of:
(1) Adding ganciclovir crude product into a DMF-containing water solution, adjusting the pH to 11.5-12.5 by using an alkaline solution, adding 1.5-2.5% of active carbon, stirring, and filtering to obtain filtrate; the step is carried out at 20-30 ℃;
(2) Adding a first organic solvent with the volume of 1.7-5 times into the filtrate at 20-30 ℃, reducing the temperature to-10 to-25 ℃ to generate white precipitate, stirring, filtering, and washing a filter cake with a second organic solvent;
(3) Dissolving a filter cake at room temperature, adding a proper amount of DMF, controlling the temperature to be not more than 30 ℃, slowly adding hydrochloric acid solution, adjusting the pH to 6-7, cooling to below-15 ℃, stirring, filtering, repeatedly washing the filter cake, and drying under reduced pressure to obtain ganciclovir meeting the injection-grade requirement;
wherein, in the step (3), water is added to dissolve the filter cake, and the amount of DMF (dimethyl formamide) is 3-8% of the water amount for dissolving the filter cake;
the first and second organic solvents are one or more of acetone, ethyl acetate, ethyl formate, methyl acetate, ethanol, methanol, isopropanol and ethylene glycol.
2. The method for preparing injection-grade ganciclovir according to claim 1, wherein the alkaline solution is sodium hydroxide solution.
3. The method for preparing injection-grade ganciclovir according to claim 2, wherein the volume ratio of DMF added in step (1) to the first organic solvent added in step (2) is 1:5 to 1:10.
4. the method for preparing injection-grade ganciclovir according to claim 1 or 2, wherein in step (1), the volume ratio of DMF to water is 1:1 to 1:3.
5. a process for the preparation of injection grade ganciclovir according to claim 3, wherein the sodium hydroxide solution is 2-3N sodium hydroxide solution.
6. The preparation method of injection-grade ganciclovir according to claim 1, wherein the step (1) is carried out at 20-30 ℃, and the temperature of DMF, water, alkaline solution and filtrate is 20-30 ℃; the temperature for separating out ganciclovir sodium in the step (2) is-15 to-20 ℃.
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