CN110938075B - Ganciclovir preparation method - Google Patents
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- CN110938075B CN110938075B CN201911357346.6A CN201911357346A CN110938075B CN 110938075 B CN110938075 B CN 110938075B CN 201911357346 A CN201911357346 A CN 201911357346A CN 110938075 B CN110938075 B CN 110938075B
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Abstract
The invention provides a preparation method of ganciclovir, which comprises the following steps: step 1, taking glyceraldehyde acetal ester and diacetyl guanine as raw materials, taking dioxane as a solvent, carrying out condensation reaction under the action of trifluoroacetic acid, and carrying out post-treatment to obtain triacetyl ganciclovir; step 2, hydrolyzing the triacetyl ganciclovir obtained in the step 1 to obtain a ganciclovir crude product; and 3, refining the ganciclovir crude product obtained in the step 2 to obtain a ganciclovir finished product. The method is calculated by diacetylguanine, and the total yield reaches 35 to 40 percent; the quality of the prepared bulk drug product is greatly improved, the impurity C and the impurity F (guanine) are controlled to be below 0.05 percent, the total impurity is 0.06 percent to 0.10 percent, and the product purity is more than 99.9 percent.
Description
Technical Field
The invention relates to the technical field of substance synthesis, in particular to a preparation method of ganciclovir.
Background
Ganciclovir is the 2 nd generation nucleoside antiviral drug, is mainly used for the treatment and prevention of cytomegalovirus infection in clinic, and is suitable for patients with cytomegalovirus retinitis, AIDS, organ transplantation, malignant tumor and the like caused by serious immunologic hypofunction, and patients infected with pneumonia, gastroenteritis, liver and CMV in the central nervous system.
Regarding the preparation method of ganciclovir, original research Syntex company in the United states uses 1, 3-dibenzyloxy-2-propoxyl acetate to condense with diacetyl guanine, separates isomers, and obtains ganciclovir by palladium-carbon catalytic hydrogenolysis debenzylation. There are disadvantages: the total yield is only 6.8 to 26.8 percent calculated by diacetyl guanine; the finished product ganciclovir has low quality, the EP impurity F (guanine) can be controlled to be about 0.5%, and the main purity can only reach about 99.0%. Therefore, in summary, the existing production process of triacetyl ganciclovir mainly has the problems of low yield and quality of triacetyl ganciclovir products. Therefore, it is difficult to improve the product yield and control the product purity in the industrial production.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provides a preparation method of ganciclovir, which is prepared by synthesizing glycerol acetal ester and diacetyl guanine serving as main raw materials, wherein the total yield is 35-40% by calculation of the diacetyl guanine; the quality of the prepared bulk drug product is greatly improved, the impurity C and the impurity F (guanine) are controlled to be below 0.05 percent, the total impurity is 0.06 percent to 0.10 percent, and the product purity is more than 99.9 percent.
The invention is realized by the following steps:
the invention provides a preparation method of ganciclovir, which comprises the following steps:
step 1, taking glyceraldehyde acetal ester and diacetyl guanine as raw materials, taking dioxane as a solvent, carrying out condensation reaction under the action of trifluoroacetic acid, and carrying out post-treatment to obtain triacetyl ganciclovir;
step 2, hydrolyzing the triacetyl ganciclovir obtained in the step 1 to obtain a ganciclovir crude product;
and 3, refining the ganciclovir crude product obtained in the step 2 to obtain a ganciclovir finished product.
Preferably, the mass ratio of the glycerol acetal ester to the diacetylguanine in the step 1 is 2.0-2.5: 1. the volume ratio of the mass of the diacetylguanine to the mass of trifluoroacetic acid is 10-15: 1, the mass-volume ratio of the diacetylguanine to the dioxane is 1: 3-5; the unit of the mass-to-volume ratio is g/ml. The condensation reaction in the step 1 is carried out at the temperature of 80-85 ℃ for 45-50 hours.
Preferably, the post-processing step in step 1 comprises: after the condensation reaction is finished, cooling and filtering, washing the obtained filter cake with dioxane, adding the filter cake into methanol, heating, stirring to dissolve the filter cake, filtering to obtain a first filtrate, cooling the filtrate, crystallizing, filtering to obtain a second filtrate and a crude product I of the filter cake di-triacetyl ganciclovir, concentrating the second filtrate under reduced pressure to dryness, and adding the remainder into a mixture of methanol, ethyl acetate which is 1: 4, cooling and crystallizing the mixed solvent to obtain a crude product II of triacetyl ganciclovir; and combining the crude product I of the triacetyl ganciclovir and the crude product II of the triacetyl ganciclovir, and recrystallizing the mixture by absolute ethyl alcohol to obtain a pure product of the triacetyl ganciclovir.
Preferably, in the step 2, the triacetyl ganciclovir is hydrolyzed under the catalysis of 40% methylamine water solution, and the mass-to-volume ratio of the triacetyl ganciclovir pure product to 40% methylamine water solution is 5-6: 1; the unit of the mass-to-volume ratio is g/ml. The temperature of the hydrolysis reaction is 60-80 ℃, and the reaction time is 1-2 hours. The synthesis of the ganciclovir crude product adopts methylamine hydrolysis, and the reaction difficulty and the risk coefficient are greatly reduced.
Preferably, in the step 3, the ganciclovir crude product is refined by 80% ethanol water solution and activated carbon, and is dried to obtain ganciclovir refined product. More preferably, the volume-to-weight ratio of the ethanol aqueous solution to the ganciclovir crude product is 75-85: 1; the unit of the volume-mass ratio is ml/g; the weight of the activated carbon is 2.5-5% of the weight of the ganciclovir crude product.
The invention has the beneficial effects that:
the preparation method of ganciclovir provided by the invention adopts glycerol acetal ester and diacetyl guanine as main raw materials for synthesis preparation, and the total yield reaches 35-40% by calculation of diacetyl guanine; the quality of the prepared bulk drug product is greatly improved, the impurity C and the impurity F (guanine) are controlled to be below 0.05 percent, the total impurity is 0.06 percent to 0.10 percent, and the product purity is more than 99.9 percent;
the raw material of the glyceraldehyde acetal ester is simple and easy to obtain, has low price and no toxicity and danger, and the inventor finds that the total yield is very high and the production cost is lower than that of other raw materials by simultaneously selecting the glyceraldehyde acetal ester and the diacetyl guanine through experiments.
The post-treatment of the condensation reaction adopts simple refining purification to replace column chromatography, thereby simplifying the operation and improving the productivity; the production cost is reduced, and the method is favorable for industrial mass production.
Drawings
FIG. 1 is a chromatogram of a system-adapted solution;
FIG. 2 is a profile of the relevant substance profile of the crude ganciclovir (before purification);
FIG. 3 is a profile of the relevant substances of ganciclovir for injection (before purification);
FIG. 4 is a chart of ganciclovir (after refining) with reference to the substance;
fig. 5 is a check map of related substances of ganciclovir for injection (after purification).
Detailed Description
The technical solution of the present invention will be described in detail with reference to examples. The following examples are merely illustrative of the present invention and should not be construed as limiting thereof. The specific techniques or conditions not mentioned in the examples are all performed according to the literature in the field or the conventional technical means in the field.
Example 1
Embodiment 1 of the present invention provides a method for preparing ganciclovir, comprising the following steps:
step 1: synthesis of triacetylganciclovir
In a 500ml three-necked flask, 30.0g of diacetylguanine, 120ml of dioxane, 61.0g of glycerol acetal ester and 2.3ml of trifluoroacetic acid were charged, and the mixture was heated to 80 ℃ in an oil bath with stirring, followed by TLC [ developing agent: and (3) chloroform and methanol are 85 to 15 ℃, the mixture is cooled to 20 ℃ after the reaction is finished, the mixture is filtered, a filter cake is washed by 20ml of dioxane and added into the methanol (50ml), the mixture is heated to 60 ℃, the mixture is stirred to be dissolved and filtered, the filtrate is cooled to 0 ℃, then crystallization is carried out for 30min, the filtration is carried out, and the filter cake is dried for 5h at the temperature of 60-80 ℃ to obtain 14.0g of light yellow crude triacetyl ganciclovir I. The filtrate was concentrated to dryness under reduced pressure, and the residue was added to a mixture of methanol: ethyl acetate ═ 1: 4, heating to 60 ℃, dissolving, cooling to 5-10 ℃ for 12 hours, crystallizing, filtering, leaching the filter cake with 95% ethanol for 3 times, each time washing with 20ml, and drying at 60-80 ℃ for 5 hours to obtain 12.8g of light yellow triacetyl ganciclovir crude product II. Crude I and II were combined to give 26.8g (55.1% yield), and recrystallized from 135g of absolute ethanol to give 24.6g of pure white triacetyl ganciclovir.
Step 2: synthesis of crude ganciclovir
Putting 24.6g of triacetyl ganciclovir pure product and 125ml of 40% methylamine water solution into a three-mouth bottle, stirring for 1h, slowly heating to 70 ℃ for reaction for 1.5h, and tracking the reaction by TLC (developing agent: and (2) adding 2-3 drops of triethylamine into chloroform and methanol at a ratio of 85: 15, concentrating under reduced pressure after the reaction is finished, adding water (50ml) into residues, concentrating under reduced pressure, adding water (400ml), heating and refluxing for 1h, adding 0.5g of activated carbon, stirring and refluxing for 30min, filtering while hot, washing a filter cake with 10ml of hot water, combining filtrate and washing liquor, cooling to 0-5 ℃ for crystallization for 1h, filtering, and drying the filter cake at 60-80 ℃ for 5h to obtain 13.9g of a white crystalline powder ganciclovir crude product.
Performing related substance inspection (HPLC) on the prepared ganciclovir crude product and the refined ganciclovir by using a related substance inspection method under the quality standard item of ganciclovir recorded by EP; chromatographic conditions and systematic testing: strongly acidic cation exchange group bonded silica gel is used as a filling agent; acetonitrile-0.05% trifluoroacetic acid water solution (50:50) is used as a mobile phase; the detection wavelength is 254 nm; the flow rate is 1.5 ml/min; the column temperature was 40 ℃. The number of theoretical plates is not less than 5000 calculated according to ganciclovir peak. The chromatogram of the system adaptive solution is shown in figure 1, and the inspection spectrum of related substances of the ganciclovir crude product (before refining) is shown in figure 2;
and step 3: ganciclovir purification
Adding 13.9g of ganciclovir crude product into 1050ml of 80% ethanol, heating to 78-80 ℃, heating and refluxing for 2h after the solid is completely dissolved, adding 0.5g of activated carbon, continuously refluxing for 30min, filtering while hot, cooling the filtrate to 5-10 ℃, crystallizing for 1h, filtering, and drying the filter cake for 5h at 75 ℃ to obtain 11.9g of white crystalline powder ganciclovir finished product.
The ganciclovir (after refining) related substance inspection map is shown in figure 4; the results of fig. 2 and 4 are summarized in table 1.
TABLE 1
As can be seen from Table 1, in the ganciclovir prepared by the method provided by the invention, the impurity C and the impurity F (guanine) are both controlled below 0.05%, the total impurity content is 0.06% -0.10%, and the product purity is more than 99.9%.
Calculated as diacetylguanine, the total yield is: 36.5 percent and the content of High Performance Liquid Chromatography (HPLC) is 99.95 percent.
Example 2
Embodiment 4 of the present invention provides a method for preparing ganciclovir, which comprises the steps of, except that in step 3, "the volume-to-weight ratio of the aqueous ethanol solution to the crude ganciclovir is 75: 1; the unit of the volume-mass ratio is ml/g; the weight of the activated carbon is 2.5% of the weight of the crude ganciclovir product, and the rest is the same as that of the activated carbon in the embodiment 1.
Example 3
Embodiment 4 of the present invention provides a method for preparing ganciclovir, which comprises the steps of, except that in step 3, "the volume-to-weight ratio of the aqueous ethanol solution to the crude ganciclovir is 85: 1; the unit of the volume-mass ratio is ml/g; the weight of the activated carbon is 5% of the weight of the crude ganciclovir product, and the rest is the same as that of the activated carbon in the example 1.
Comparative example 1
The comparative example is the same as example 1 except that step 3 is changed to "no 80% ethanol aqueous solution, only activated carbon is used for refining".
Comparative example 2
The comparative example is the same as example 1 except that step 3 is changed to 'only 80% ethanol aqueous solution without activated carbon refining'.
Comparative example 3
In the comparative example, except for step 3, the volume-to-weight ratio of the ethanol aqueous solution to the ganciclovir crude product is changed to 70: 1; the unit of the volume-mass ratio is ml/g; the weight of the activated carbon is 2% of the weight of the crude ganciclovir product, and the rest is the same as that of the activated carbon in the example 1.
Comparative example 4
In the comparative example, except for step 3, the volume-to-weight ratio of the ethanol aqueous solution to the ganciclovir crude product is changed to 90: 1; the unit of the volume-mass ratio is ml/g; the weight of the activated carbon is 5% of the weight of the crude ganciclovir product, and the rest is the same as that of the activated carbon in the example 1.
Comparative example 5
The comparative example selects 1, 3-dibenzyloxy-2-propoxyethyl acetate to be condensed with diacetyl guanine, separates isomers, and obtains ganciclovir by palladium-carbon catalytic hydrogenolysis debenzylation.
Experimental example 1
The comparison of the yield and quality of example 1 and comparative example 5 is shown in Table 1.
TABLE 1
As can be seen from Table 1, the yield and quality of the final product obtained by using the glycerol acetal ester as the main raw material are much higher than those obtained by using other main raw materials.
Experimental example 2
The percentage reduction of impurity C and impurity F (guanine) before and after refining the ganciclovir crude product in examples 1-3 and comparative examples 1-4 is shown in table 2.
TABLE 2
| Group of | Percent reduction of impurity C | Percent reduction of impurity F | Percent reduction of total impurities |
| Example 1 | 0.078％ | 0.099％ | 0.177％ |
| Example 2 | 0.082％ | 0.097％ | 0.179％ |
| Example 3 | 0.075％ | 0.102％ | 0.177％ |
| Comparative example 1 | 0.079％ | 0.101％ | 0.180％ |
| Comparative example 2 | 0.011％ | 0.015％ | 0.026％ |
| Comparative example 3 | 0.023％ | 0.022％ | 0.045％ |
| Comparative example 4 | 0.033％ | 0.040％ | 0.073％ |
As is clear from Table 2, the impurity content was lower in examples 1 to 3 of the present invention. The method adopts simple purification (the ganciclovir crude product is purified by 80 percent ethanol water solution and active carbon in the step 3) to replace column chromatography, and can reduce the content of impurities. And the volume-weight ratio of the 80% ethanol-ethanol aqueous solution to the ganciclovir crude product is 75-85 (ml): 1 (g); when the weight of the activated carbon is 2.5-5% of the weight of the ganciclovir crude product, the impurity removal effect is the best.
Experimental example 3
The final ganciclovir product prepared in example 1 was prepared into ganciclovir for injection, and the prepared crude ganciclovir product and refined ganciclovir were subjected to substance testing (HPLC) using the substance testing method under the quality standard of ganciclovir recorded in EP, and the results are shown in table 3.
TABLE 3
As can be seen from Table 3, in the ganciclovir prepared by the preparation method of ganciclovir provided by the invention, the impurity C and the impurity F (guanine) in the ganciclovir for injection are controlled to be below 0.05%, the total impurity is 0.06% -0.10%, and the product purity is more than 99.9%.
The invention is not to be considered as limited to the particular embodiments shown, but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (4)
1. A preparation method of ganciclovir is characterized by comprising the following steps:
step 1, taking glyceraldehyde acetal ester and diacetyl guanine as raw materials, taking dioxane as a solvent, carrying out condensation reaction under the action of trifluoroacetic acid, and carrying out post-treatment to obtain triacetyl ganciclovir; the volume ratio of the mass of the diacetylguanine to the trifluoroacetic acid is 10-15: 1, the mass ratio of the glycerol acetal ester to the diacetylguanine is 2.0-2.5: 1, the mass-volume ratio of the diacetylguanine to the dioxane is 1: 3-5; the unit of the mass-to-volume ratio is g/ml; the post-processing step comprises: after the condensation reaction is finished, cooling and filtering, washing the obtained filter cake with dioxane, adding the filter cake into methanol, heating, stirring to dissolve the filter cake, filtering to obtain a first filtrate, cooling the filtrate, crystallizing, filtering to obtain a second filtrate and a crude product I of the filter cake di-triacetyl ganciclovir, concentrating the second filtrate under reduced pressure to dryness, and adding the remainder into a mixture of methanol, ethyl acetate = 1: 4, cooling and crystallizing the mixed solvent to obtain a crude product II of triacetyl ganciclovir; combining the triacetyl ganciclovir crude product I and the triacetyl ganciclovir crude product II, and recrystallizing with absolute ethyl alcohol to obtain a triacetyl ganciclovir pure product;
step 2, hydrolyzing the triacetyl ganciclovir obtained in the step 1 to obtain a ganciclovir crude product;
step 3, refining the ganciclovir crude product obtained in the step 2 to obtain a ganciclovir finished product; refining the ganciclovir crude product by using 80% ethanol water solution and active carbon, and drying to obtain ganciclovir refined product; the volume-weight ratio of the ethanol aqueous solution to the ganciclovir crude product is 75-85: 1; the unit of the volume-mass ratio is ml/g; the weight of the activated carbon is 2.5-5% of the weight of the ganciclovir crude product.
2. The preparation method of ganciclovir according to claim 1, wherein the condensation reaction in step 1 is carried out at 80-85 ℃ for 45-50 h.
3. The preparation method of ganciclovir according to claim 1, wherein in the step 2, the triacetyl ganciclovir is hydrolyzed under the catalysis of 40% methylamine water solution, and the mass-volume ratio of the triacetyl ganciclovir pure product to 40% methylamine water solution is 5-6: 1; the unit of the mass-to-volume ratio is g/ml.
4. The method for preparing ganciclovir according to claim 1, wherein the temperature of the hydrolysis reaction in the step 2 is 60-80 ℃ and the reaction time is 1-2 hours.
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