Amplification preparation method of ganciclovir
A four-step synthesis of Ganciclovir using glycerol and benzeneboronic acid with paraformaldehyde and N-acetylguanine addresses safety concerns by providing a safer and more efficient production method with improved yield and simplified purification.
Patent Information
- Application Number
- CN202510588354.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-05-08
- Publication Date
- 2025-07-15
AI Technical Summary
The existing ganciclovir preparation process has problems such as difficult raw materials, complex operation, low yield and safety risks caused by the use of co-solvents.
Glycerol, phenylboric acid, paraformaldehyde and N-acetylguanine are used as raw materials to synthesize ganciclovir through four-step reactions, including the formation of intermediates 1 and 2 in an organic solvent, and then react with N-acetylguanine to form intermediate 3, and finally ganciclovir is generated under the action of alkali and hydrogen peroxide.
It provides a synthesis pathway with simple operation, stable, short steps and high yield, which reduces raw material costs and avoids the risk of use of cosolvents and improves the overall yield.
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Figure CN120309613A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of organic synthesis, and particularly relates to a method for the large-scale preparation of ganciclovir. Background Art
[0002] Ganciclovir, English name: Ganciclovir, chemical name: 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine, as an antiviral drug, was synthesized by Syntex Research in 1980. It has strong anti-cytomegalovirus, HSV-I, HSV-II, varicella-zoster virus (VZV), Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6) activities in vitro and in vivo. Among them, the inhibitory activities against cytomegalovirus and EBV are 10-20 times stronger than acyclovir and 15-19 times stronger than foscarnet. Ganciclovir and its salts can inhibit the synthesis of cytomegalovirus DNA, slow down the extension of viral DNA and inhibit the replication of cytomegalovirus to achieve antiviral activity.
[0003] At present, ganciclovir and ganciclovir sodium are on the market at home and abroad. Compared with ganciclovir, ganciclovir sodium has better water solubility and also has great advantages in dosage form selection. Querying the database of the National Center for Drug Evaluation shows that at present, more than 80% of ganciclovir in China is injection, and most of the preparation processes of this product are to dissolve ganciclovir with a cosolvent and then perform lyophilization. The use of cosolvent has certain risks to the product quality and product safety. Using ganciclovir sodium as the raw material can avoid the use of other excipients, thus avoiding the safety problems caused by factors such as cosolvents.
[0004] Therefore, it is necessary to develop a synthesis method with easily available raw materials, convenient operation, easy reaction control and appropriate overall yield. Summary of the Invention
[0005] The purpose of the present invention is to provide a preparation method for producing ganciclovir with easily available raw materials, convenient operation, easy reaction control and appropriate overall yield. The process is carried out in four steps. The first step is that glycerol and phenylboronic acid react in an organic solvent to generate intermediate 1. The second step is that intermediate 1, paraformaldehyde and anhydrous magnesium sulfate react in an organic solvent under the action of hydrogen chloride to generate intermediate 2. The third step is that intermediate 2 reacts with N-acetylguanine under the action of a base to generate intermediate 3. The fourth step is that intermediate 3 reacts in an organic solvent under the action of a base and hydrogen peroxide to generate ganciclovir. The technical solution of the present invention is simple and stable in operation, has shorter steps, the products of each step are easy to separate, and has high yield, providing a new synthetic route for this compound.
[0006] The synthetic route of the preparation method of ganciclovir of the present invention is as follows:
[0007]
[0008] In the first step, glycerol and phenylboronic acid react in an organic solvent to form intermediate 1.
[0009] Further, in the above technical solution, the molar ratio of glycerol to phenylboronic acid is 1-1.5:1.
[0010] Further, in the above technical solution, the organic solvent is selected from toluene, benzene or n-butanol.
[0011] In the second step, intermediate 1, paraformaldehyde and anhydrous magnesium sulfate react in an organic solvent under the action of hydrogen chloride to form intermediate 2.
[0012] Further, in the above technical solution, the molar ratio of intermediate 1 to paraformaldehyde is 1:1-1.5.
[0013] Further, in the above technical solution, the organic solvent is selected from dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran or dioxane.
[0014] In the third step, intermediate 2 reacts with N-acetylguanine under the action of a base to form intermediate 3.
[0015] Further, in the above technical solution, the molar ratio of intermediate 2, N-acetylguanine and the base is 1:1-1.5:1.1-3.
[0016] Further, in the above technical solution, the organic solvent is selected from tetrahydrofuran, acetonitrile, 2-methyltetrahydrofuran or dioxane.
[0017] In the fourth step, intermediate 3 reacts in an organic solvent under the action of a base and hydrogen peroxide to form ganciclovir.
[0018] Further, in the above technical solution, the base is selected from sodium hydroxide, potassium hydroxide or lithium hydroxide.
[0019] Further, in the above technical solution, the organic solvent is selected from methanol, ethanol or water.
[0020] Compared with the prior art, the present invention has the following remarkable advantages:
[0021] A. The overall production yield of the present invention is higher than that of the currently known processes, and the synthesis process is more competitive in the market. The technical solution of the present invention is simple and stable in operation, has shorter steps, and the products of each step are easy to separate, providing a new synthesis route for this compound.
[0022] B. Using glycerol, benzaldehyde, paraformaldehyde and N-acetylguanine as raw materials, the raw materials are cheap and easily available, reducing the raw material cost. Description of the Drawings
[0023] Figure 1 It is the infrared spectrum of ganciclovir obtained in Example 1;
[0024] Figure 2 It is the HPLC spectrum of ganciclovir obtained in Example 1. Detailed Description of the Invention
[0025] The present invention will be further described below in conjunction with specific embodiments. These embodiments should be understood as being only for illustrative purposes of the present invention and not for limiting the protection scope of the present invention. After reading the content recorded in the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent changes and modifications also fall within the scope defined by the claims of the present invention.
[0026] Example 1
[0027] The first step:
[0028] Add phenylboronic acid (10.97 g, 0.090 mol, 1.1 eq) and glycerol (7.55 g, 0.082 mol, 1 eq) to benzene (100 ml) as the solvent. The reaction solution is refluxed and separated for 15 hours. After the reaction is completed, the reaction solution is cooled to room temperature, and then water and ethyl acetate are added for extraction to obtain crude intermediate 1 (13.87 g, yield: 95%).
[0029] The second step:
[0030] Add intermediate 1 (13 g, 0.073 mol, 1 eq), paraformaldehyde (2.4 g, 0.08 mol, 1.1 eq) and anhydrous magnesium sulfate (9.63 g, 0.08 mol, 1.1 eq) to tetrahydrofuran (130 ml). The reaction solution is cooled to 0 °C. Hydrogen chloride gas is introduced into the reaction system, and the mixture is stirred for 1 hour. After the reaction is completed, the reaction mixture is extracted with water and dichloromethane, filtered and then concentrated by rotary evaporation to obtain intermediate 2 (15.18 g, yield: 92%).
[0031] The third step:
[0032] At 0 °C, 60% sodium hydride (2.92 g, 0.073 mol, 1.1 eq) is added in batches to a solution of N-acetylguanine (12.74 g, 0.066 mol, 1 eq) in tetrahydrofuran (70 ml). After the reaction solution is stirred at room temperature for 1 hour, it is cooled to 0 °C, and then intermediate 2 (15 g, 0.066 mol, 1 eq) is added in batches to the above reaction solution. Stir at room temperature until the reaction is completed. After adding water to the reaction solution, it is extracted with ethyl acetate. The organic layer is dried with anhydrous sodium sulfate and then concentrated by rotary evaporation and purified by column chromatography to obtain intermediate 3 (23.26 g, yield: 92%).
[0033] Step 4:
[0034] Intermediate 3 (23 g, 0.06 mol) was added to a mixed solvent of methanol (25 ml) and water (25 ml), and the temperature was lowered to 0 °C. Lithium hydroxide (10%, 43 ml, 0.18 mol, 3 eq) was added to the above reaction mixture, and hydrogen peroxide (10%, 62 ml, 0.18 mol, 3 eq) was slowly added dropwise to the above reaction mixture. The mixture was stirred at room temperature for 1 hour, and then the reaction mixture was cooled to 0 °C. Sodium sulfite (22.69 g, 0.18 mol, 3 eq) was slowly added to the above reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with brine and dried over anhydrous sodium sulfate. The obtained crude product was purified by column chromatography to obtain ganciclovir (13.16 g, yield: 86%).
[0035] Example 2
[0036] Step 1:
[0037] Phenylboronic acid (122.05 g, 1 mol, 1 eq) and glycerol (92 g, 1 mol, 1 eq) were added to the solvent toluene (900 ml), and the reaction solution was refluxed and separated for 15 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and then water and ethyl acetate were added for extraction to obtain crude Intermediate 1 (174 g, yield: 99%).
[0038] Step 2:
[0039] Intermediate 1 (160.27 g, 0.9 mol, 1 eq), paraformaldehyde (40.54 g, 1.35 mol, 1.5 eq) and anhydrous magnesium sulfate (108.33 g, 0.9 mol, 1 eq) were added to dichloromethane (1600 ml), and the reaction solution was cooled to 0 °C. Hydrogen chloride gas was introduced into the reaction system, and the mixture was stirred for 1 hour. After the reaction was completed, the reaction mixture was extracted with water and dichloromethane, and after filtration, the solvent was evaporated to obtain Intermediate 2 (187.17 g, yield: 92%).
[0040] Step 3:
[0041] At 0 °C, 60% sodium hydride (35.2 g, 0.88 mol, 1.1 eq) was added in batches to an acetonitrile solution of N-acetylguanine (154.45 g, 0.8 mol, 1 eq). After the reaction solution was stirred at room temperature for 1 hour, it was cooled to 0 °C, and then Intermediate 2 (180.84 g, 0.8 mol, 1 eq) was added in batches to the above reaction solution. The mixture was stirred at room temperature until the reaction was completed. After the reaction solution was added with water, it was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then the solvent was evaporated and purified by column chromatography to obtain Intermediate 3 (281.99 g, yield: 92%).
[0042] Step 4:
[0043] The intermediate 3 (268.20 g, 0.7 mol) was added to a mixed solvent of ethanol (300 ml) and water (300 ml), and the temperature was lowered to 0 °C. Sodium hydroxide (10%, 840 ml, 2.1 mol, 3 eq) was added to the above reaction mixture, and hydrogen peroxide (10%, 714 ml, 2.1 mol, 3 eq) was slowly added dropwise to the above reaction mixture. The mixture was stirred at room temperature for 1 hour, and then the reaction mixture was cooled to 0 °C. Sodium sulfite (264.68 g, 2.1 mol, 3 eq) was slowly added to the above reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with brine and then dried over anhydrous sodium sulfate. The solvent was evaporated to obtain a crude product, which was purified by column chromatography to obtain ganciclovir (155.35 g, yield: 87%).
[0044] Example 3
[0045] First step:
[0046] Phenylboronic acid (300 g, 2.46 mol, 1 eq) and glycerol (92 g, 3.20 mol, 1.3 eq) were added to the solvent n-butanol (3000 ml). The reaction solution was refluxed and separated for 15 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and then water and ethyl acetate were added for extraction to obtain the crude intermediate 1 (438.08 g, yield: 97%).
[0047] Second step:
[0048] The intermediate 1 (400 g, 2.25 mol, 1 eq), paraformaldehyde (81.08 g, 2.7 mol, 1.2 eq) and anhydrous magnesium sulfate (270.83 g, 2.25 mol, 1 eq) were added to 2-methyltetrahydrofuran (4000 ml). The reaction solution was cooled to 0 °C. Hydrogen chloride gas was introduced into the reaction system, and the mixture was stirred for 1 hour. After the reaction was completed, the reaction mixture was added with water and dichloromethane for extraction. After filtration, the solvent was evaporated to obtain the intermediate 2 (473.03 g, yield: 93%).
[0049] Third step:
[0050] At 0 °C, 60% sodium hydride (238.8 g, 5.97 mol, 3 eq) was added in portions to an acetonitrile solution of N-acetylguanine (577.25 g, 2.99 mol, 1.5 eq). After the reaction solution was stirred at room temperature for 1 hour, the temperature was lowered to 0 °C, and then the intermediate 2 (450 g, 1.99 mol, 1 eq) was added in portions to the above reaction solution. The mixture was stirred at room temperature until the reaction was completed. After adding water to the reaction solution, it was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then the solvent was evaporated and purified by column chromatography to obtain the intermediate 3 (716.7 g, yield: 94%).
[0051] Fourth step:
[0052] The intermediate 3 (700 g, 1.83 mol) was added to a mixed solvent of ethanol (700 ml) and water (700 ml), and the temperature was lowered to 0 °C. Potassium hydroxide (10%, 3080 ml, 5.49 mol, 3 eq) was added to the above reaction mixture. Hydrogen peroxide (10%, 1866.6 ml, 5.49 mol, 3 eq) was slowly added dropwise to the above reaction mixture, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to 0 °C. Sodium sulfite (691.96 g, 5.49 mol, 3 eq) was slowly added to the above reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with brine and dried over anhydrous sodium sulfate. The crude product obtained by rotary evaporation was purified by column chromatography to obtain the product (401.48 g, yield: 86%).
[0053] As described above, only the preferred specific embodiments of the present invention are provided, but the protection scope of the present invention is not limited thereto. Any person skilled in the art within the technical scope disclosed by the present invention, according to the technical solution and inventive concept of the present invention, making equivalent substitutions or changes, should be covered by the protection scope of the present invention.
Claims
1. A preparation method of ganciclovir, characterized in that, It includes the following steps: In the first step, glycerol and phenylboronic acid react in an organic solvent to form intermediate 1; In the second step, intermediate 1, paraformaldehyde and anhydrous magnesium sulfate react in an organic solvent under the action of hydrogen chloride to form intermediate 2; In the third step, intermediate 2 reacts with N-acetylguanine under the action of a base to form intermediate 3; In the fourth step, intermediate 3 reacts in an organic solvent under the action of a base and hydrogen peroxide to form ganciclovir.
2. The preparation method of ganciclovir according to claim 1, characterized in that: In the first step, the molar ratio of glycerol to phenylboronic acid is 1 to 1.5:
1.
3. The preparation method of ganciclovir according to claim 1, wherein: In the first step, the organic solvent is selected from toluene, benzene or n-butanol.
4. The preparation method of ganciclovir according to claim 1, characterized in that: In the second step, the molar ratio of intermediate 1 to paraformaldehyde is 1:1 to 1.
5.
5. The preparation method of ganciclovir according to claim 1, characterized in that: In the second step, the organic solvent is selected from dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran or dioxane.
6. The preparation method of ganciclovir according to claim 1, characterized in that: In the third step, the molar ratio of intermediate 2, N-acetylguanine and the base is 1:1 - 1.5:1.1 - 3.
7. The preparation method of ganciclovir according to claim 1, wherein: In the third step, the organic solvent is selected from tetrahydrofuran, acetonitrile, 2-methyltetrahydrofuran or dioxane.
8. The preparation method of ganciclovir according to claim 1, characterized in that: In the fourth step, the organic solvent is selected from methanol, ethanol or water.