A method for preparing acyclovir impurity R
By protecting acyclovir with N-acetyl and hydrolyzing it, a high-purity acyclovir impurity R was prepared, which solved the problem of insufficient preparation methods in the existing technology and achieved the synthesis of impurity R with high efficiency and high yield.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- GUANGZHOU CATO RES CHEM INC
- Filing Date
- 2026-02-13
- Publication Date
- 2026-06-09
AI Technical Summary
The lack of efficient methods for preparing high-purity acyclovir impurity R in the existing technology affects the quality control of acyclovir raw materials and related drugs.
Using acyclovir as a raw material, compound 1 was generated through an N-acetyl protection reaction. Then, it was reacted with formaldehyde aqueous solution under acid catalysis to generate compound 2, and compound 3 was generated through deN-acetyl protection. Finally, hydrolysis was carried out to obtain acyclovir impurity R.
The reaction selectivity and yield were improved, and high-purity acyclovir impurity R was obtained with a yield of up to 12.1%, and intermediate compound 1 had better solubility.
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Abstract
Description
Technical Field
[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for preparing acyclovir impurity R. Background Technology
[0002] Acyclovir is a broad-spectrum, highly effective, and low-toxicity antiviral drug primarily used to treat various infections caused by herpes simplex virus (HSV). It can be used for primary or recurrent skin, mucous membrane, and external genital infections, as well as HSV infections in immunocompromised individuals.
[0003] Impurity reference standards are standard substances used for the qualitative identification, quantitative detection, and purity control of impurities in pharmaceuticals, active pharmaceutical ingredients, or related preparations. They are a core component of the pharmaceutical quality research and quality control system and must possess characteristics such as well-defined structure, high purity, and good stability.
[0004] Acyclovir Impurity R is a critical process / degradation-related impurity of acyclovir listed in the European Pharmacopoeia (EP). It is a dimer derivative of acyclovir, chemically named 1,1'-methylenebis(2-amino-9-((2-hydroxyethoxy)methyl)-1,9-dihydro-6H-purine-6-one), with the molecular formula... With a molecular weight of 462.42, it is one of the core reference standards for the quality control and registration of acyclovir. Currently, the production process of acyclovir is relatively mature, but there are few reports on the synthesis methods of acyclovir impurity R. To better control the quality of acyclovir active pharmaceutical ingredient and related drugs, developing an efficient synthetic method for preparing high-purity acyclovir impurity R and providing a high-quality impurity reference standard is of great significance for the quality control of acyclovir active pharmaceutical ingredient production.
[0005] Summary of the Invention
[0006] The purpose of this invention is to provide a method for preparing acyclovir impurity R, so as to solve the problem that there is no efficient method for preparing high-purity acyclovir impurity R in the prior art.
[0007] To achieve the above objectives, the present invention adopts the following technical solution: A method for preparing acyclovir impurity R, the process includes: (1) Compound 1 is generated by N-acetyl-protected amino reaction using acyclovir as a raw material; (2) Compound 1 reacts with an aqueous formaldehyde solution to form compound 2 under acid catalysis; (3) Compound 2 was de-N-acetyl protected and purified to obtain compound 3, which is the acyclovir impurity R; The structural formula of compound 1 is: ; The structural formula of compound 2 is: ; The structural formula of compound 3 is: .
[0008] Furthermore, in step (1), acyclovir and acetyl chloride / acetic anhydride are used as raw materials to carry out an acetylation reaction at room temperature to generate compound 1.
[0009] Further, the detailed process of step (1) is as follows: In the reaction vessel, 15.0 g of acyclovir, 220.0-330.0 mL of 0.2-0.3 M pyridine, and 24.0-35.0 mL of trimethylchlorosilane are added dropwise. The mixture is stirred for 40-50 min until the reaction solution is semi-transparent. Then, 6.0-6.5 mL of acetyl chloride and 7.5-9.0 mL of acetic anhydride are slowly added. After the addition is complete, the mixture is reacted at room temperature and purified to obtain compound 1.
[0010] Further, the detailed process of step (2) is as follows: In the reaction vessel, add 7.0~12.0 g of compound 1, add 90.0~130.0 mL of 38% formaldehyde aqueous solution to replace nitrogen gas, add 18.0~30.0 mL of acetic acid, react at room temperature overnight, add dichloromethane and water to the reaction solution, add sodium bicarbonate solid in batches, adjust pH=7, and purify to obtain compound 2.
[0011] Further, in step (3), compound 2, a methanol solution of ammonia and methanol are hydrolyzed to remove N-acetyl groups, and the resulting solid is successively slurried with formic acid water and dichloromethane. Solid-liquid separation yields compound 3, which is acyclovir impurity R.
[0012] Further, the detailed process of step (3) is as follows: 6.0~7.0 g of compound 2, 9.5~22.0 mL of 7.0 M ammonia methanol solution and 23.5~50.0 mL of 0.5 M methanol are added to the reaction vessel and refluxed at 50 °C for 1~2 days. The resulting solid is then slurried with 30.0~35.0 mL of 0.1% formic acid water and 3.0~5.0 mL of dichloromethane. Solid-liquid separation yields white solid compound 3, which is acyclovir impurity R.
[0013] The advantages of this invention are that the obtained intermediate (such as compound 1) has better solubility than acyclovir. Furthermore, compared to the acetalization reaction pathway using acyclovir as a starting material, the reaction selectivity of this invention is improved, effectively increasing the reaction yield, with the yield of acyclovir impurity R reaching as high as 12.1%. Attached Figure Description
[0014] The accompanying drawings, which are included to provide a further understanding of the invention and form part of this application, do not constitute an undue limitation of the invention. In the drawings: Figure 1 This is the NMR spectrum of compound 1 in this invention; Figure 2 This is the NMR spectrum of compound 2 in this invention; Figure 3 This is the NMR spectrum of compound 3 in this invention; Figure 4 This is the mass spectrum of compound 3 in this invention; Figure 5 This is the synthetic route diagram for compound 3 of the present invention. Detailed Implementation
[0015] The present invention will now be described in detail with reference to the accompanying drawings and specific embodiments. The illustrative embodiments and descriptions of the present invention are used to explain the present invention, but are not intended to limit the present invention. Example 1
[0016] Synthesis of Compound 1 In a 500 mL single-necked flask, acyclovir (15.0 g, 66.0 mmol, 1.0 eq) was added sequentially, followed by pyridine (330.0 mL, 0.2 M), and then trimethylchlorosilane (33.9 mL, 4.0 eq). The mixture was stirred for 45 min until it became translucent. Acetyl chloride (6.3 mL, 1.3 eq) was then slowly added until the addition was complete, and the reaction was allowed to proceed at room temperature. TLC monitoring (DCM:MeOH = 5:1) showed complete consumption of the reactants. The reaction mixture was concentrated to obtain a pale yellow solid-liquid mixture, which was dissolved in 120 mL of pure water. The aqueous phase was washed with dichloromethane (200 mL × 3), and a solid precipitated from the aqueous phase. Filtering yielded 7.8 g of white solid compound 1. The filtrate was purified by reversed-phase column chromatography (water / methanol = 25 / 75) to obtain 3.0 g of white solid compound 1. A total of 10.8 g of compound 1 was purified, with a reaction yield of 61.3%. The NMR spectrum of compound 1 is shown below. Figure 1 As shown.
[0017] Synthesis of Compound 2 Compound 1 (7.8 g, 29.2 mmol) was added to a 500 mL three-necked flask, followed by 94.5 mL of 38% formaldehyde aqueous solution. The mixture was purged with nitrogen three times, and then 19.5 mL of acetic acid was added. The reaction mixture was allowed to react overnight at room temperature. 150 mL each of dichloromethane and water were added to the reaction solution, and sodium bicarbonate was added in portions to adjust the pH to 7. The mixture was extracted with dichloromethane (100 mL × 5). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation under reduced pressure. The crude product was purified by column chromatography (DCM:MeOH = 40:1) to give 6.8 g of white solid compound 2, with a yield of 71.1%. The NMR spectrum of compound 2 is shown below. Figure 2 As shown.
[0018] Synthesis of acyclovir impurity R (compound 3) Compound 2 (6.6 g, 23.7 mmol, 1.0 eq), a methanol solution of ammonia (7.0 M, 20.3 mL, 6.0 eq), and 47.4 mL of methanol (0.5 M) were added to a 25 mL single-necked flask and refluxed at 50 °C for 1.5 days. After the reaction was complete, the solid obtained by concentration under reduced pressure was slurried with 0.1% formic acid solution (30 mL), and the resulting solid was slurried with dichloromethane (3.0 mL). Solid-liquid separation yielded 1.32 g of white solid compound 3, which was acyclovir impurity R, with a yield of 12.1%. HPLC analysis showed a purity of 95.3%. The NMR spectrum of compound 3 is shown below. Figure 3 As shown, the mass spectrometry is as follows Figure 4 As shown. The synthesis route is as follows. Figure 5 As shown. Example 2
[0019] Synthesis of Compound 1 In a 500 mL single-necked flask, acyclovir (15.0 g, 66.0 mmol, 1.0 eq) was added sequentially, followed by pyridine (330.0 mL, 0.2 M), and then trimethylchlorosilane (33.9 mL, 4.0 eq). The mixture was stirred for 45 min until it became translucent. Acetic anhydride (8.1 mL, 1.3 eq) was then slowly added until the addition was complete, and the reaction was allowed to proceed at room temperature. TLC monitoring (DCM:MeOH = 5:1) showed that the starting materials were completely consumed. The reaction solution was concentrated to obtain a pale yellow oil, which was dissolved in 120 mL of pure water. The aqueous phase was washed with dichloromethane (200 mL × 3), and a solid precipitated in the aqueous phase. Filtering yielded 7.0 g of white solid compound 1. The filtrate was purified by reversed-phase column chromatography (water / methanol = 25 / 75) to obtain 2.8 g of white solid compound 1. A total of 9.8 g of compound 1 was obtained after purification, with a reaction yield of 55.7%.
[0020] Synthesis of Compound 2 Compound 1 (9.8 g, 36.6 mmol) was added to a 500 mL three-necked flask, followed by 118.7 mL of 38% formaldehyde aqueous solution. The mixture was purged with nitrogen three times, and then 24.5 mL of acetic acid was added. The reaction mixture was allowed to react overnight at room temperature. 200 mL each of dichloromethane and water were added to the reaction solution, and sodium bicarbonate was added in portions to adjust the pH to 7. The mixture was extracted with dichloromethane (150 mL × 5). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation under reduced pressure. The crude product was purified by column chromatography (DCM:MeOH = 40:1) to give 6.8 g of white solid compound 2, with a yield of 70.8%.
[0021] Synthesis of acyclovir impurity R (compound 3) Compound 2 (6.8 g, 24.5 mmol, 1.0 eq), a methanol solution of ammonia (7.0 M, 21.0 mL, 6.0 eq), and 49.0 mL of methanol (0.5 M) were added to a 25 mL single-necked flask and refluxed at 50 °C for 1.5 days. After the reaction was completed, the solid obtained by concentration under reduced pressure was slurried with 0.1% formic acid water (30 mL), and the solid obtained by filtration was slurried with dichloromethane (3.0 mL). Solid-liquid separation yielded 1.3 g of white solid compound 3, which was acyclovir impurity R, with a yield of 11.5% and a purity of 94.8% according to HPLC analysis. Example 3
[0022] Synthesis of Compound 1 In a 500 mL single-necked flask, acyclovir (15.0 g, 66.0 mmol, 1.0 eq) was added sequentially, followed by pyridine (220.0 mL, 0.3 M), and then trimethylchlorosilane (33.9 mL, 4.0 eq). The mixture was stirred for 45 min until it became translucent. Acetyl chloride (6.3 mL, 1.3 eq) was then slowly added until the addition was complete, and the reaction was allowed to proceed at room temperature. TLC monitoring (DCM:MeOH = 5:1) showed that the starting materials were completely consumed. The reaction mixture was concentrated to obtain a pale yellow solid-liquid mixture, which was dissolved in 120 mL of pure water. The aqueous phase was washed with dichloromethane (200 mL × 3), and a solid precipitated from the aqueous phase. Filtering yielded 6.5 g of white solid compound 1. The filtrate was purified by reversed-phase column chromatography (water / methanol = 25 / 75) to obtain 2.4 g of white solid compound 1. A total of 8.9 g of compound 1 was purified, with a reaction yield of 50.5%.
[0023] Synthesis of Compound 2 Compound 1 (8.9 g, 33.3 mmol) was added to a 500 mL three-necked flask, followed by 107.8 mL of 38% formaldehyde aqueous solution. The mixture was purged with nitrogen three times, and then 22.2 mL of acetic acid was added. The reaction mixture was allowed to react overnight at room temperature. 150 mL each of dichloromethane and water were added to the reaction solution, and sodium bicarbonate was added in portions to adjust the pH to 7. The mixture was extracted with dichloromethane (100 mL × 5). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation under reduced pressure. The crude product was purified by column chromatography (DCM:MeOH = 40:1) to give 6.5 g of white solid compound 2, with a yield of 71.0%.
[0024] Synthesis of acyclovir impurity R (compound 3) Compound 2 (6.5 g, 23.3 mmol, 1.0 eq), a methanol solution of ammonia (7.0 M, 20.0 mL, 6.0 eq), and 46.6 mL of methanol (0.5 M) were added to a 25 mL single-necked flask and refluxed at 50 °C for 1.5 days. After the reaction was completed, the solid obtained by concentration under reduced pressure was slurried with 0.1% formic acid water (35 mL), and the solid obtained by filtration was slurried with dichloromethane (5.0 mL). Solid-liquid separation yielded 1.28 g of white solid compound 3, which was acyclovir impurity R, with a yield of 11.9% and a purity of 95.0% according to HPLC analysis. Example 4
[0025] Synthesis of Compound 1 In a 500 mL single-necked flask, acyclovir (15.0 g, 66.0 mmol, 1.0 eq) was added sequentially, followed by pyridine (330.0 mL, 0.2 M), and then trimethylchlorosilane (25.4 mL, 3.0 eq). The mixture was stirred for 45 min until it became translucent. Acetyl chloride (6.3 mL, 1.3 eq) was then slowly added until the addition was complete, and the reaction was allowed to proceed at room temperature. TLC monitoring (DCM:MeOH = 5:1) showed that the reactants were completely consumed. The reaction mixture was concentrated to obtain a pale yellow solid-liquid mixture, which was dissolved in 120 mL of pure water. The aqueous phase was washed with dichloromethane (200 mL × 3), and a solid precipitated from the aqueous phase. Filtering yielded 7.5 g of white solid compound 1. The filtrate was purified by reversed-phase column chromatography (water / methanol = 25 / 75) to obtain 3.0 g of white solid compound 1. A total of 10.5 g of compound 1 was obtained after purification, with a reaction yield of 60.0%.
[0026] Synthesis of Compound 2 Compound 1 (10.5 g, 39.3 mmol) was added to a 500 mL three-necked flask, followed by 127.2 mL of 38% formaldehyde aqueous solution. The mixture was purged with nitrogen three times, and then 26.2 mL of acetic acid was added. The reaction mixture was allowed to react overnight at room temperature. 150 mL each of dichloromethane and water were added to the reaction solution, and sodium bicarbonate was added in portions to adjust the pH to 7. The mixture was extracted with dichloromethane (100 mL × 5). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation under reduced pressure. The crude product was purified by column chromatography (DCM:MeOH = 40:1) to give 6.5 g of white solid compound 2, with a yield of 59.5%.
[0027] Synthesis of acyclovir impurity R (compound 3) Compound 2 (6.5 g, 23.4 mmol, 1.0 eq), a methanol solution of ammonia (7.0 M, 20.1 mL, 6.0 eq), and 46.8 mL of methanol (0.5 M) were added to a 25 mL single-necked flask and refluxed at 50 °C for 1.5 days. After the reaction was completed, the solid obtained by concentration under reduced pressure was slurried with 0.1% formic acid water (30 mL), and the solid obtained by filtration was slurried with dichloromethane (3.0 mL). Solid-liquid separation yielded 1.31 g of white solid compound 3, which was acyclovir impurity R, with a yield of 13.3% and a purity of 95.5% according to HPLC analysis. Example 5
[0028] Synthesis of Compound 1 In a 500 mL single-necked flask, acyclovir (15.0 g, 66.0 mmol, 1.0 eq) was added sequentially, followed by pyridine (330.0 mL, 0.2 M), and then trimethylchlorosilane (33.9 mL, 4.0 eq). The mixture was stirred for 45 min until it became translucent. Acetyl chloride (6.3 mL, 1.3 eq) was then slowly added until the addition was complete, and the reaction was allowed to proceed at room temperature. TLC monitoring (DCM:MeOH = 5:1) showed that the reactants were completely consumed. The reaction mixture was concentrated to obtain a pale yellow solid-liquid mixture, which was dissolved in 120 mL of pure water. The aqueous phase was washed with dichloromethane (200 mL × 3), and a solid precipitated from the aqueous phase. Filtering yielded 7.8 g of white solid compound 1. The filtrate was purified by reversed-phase column chromatography (water / methanol = 25 / 75) to obtain 3.0 g of white solid compound 1. A total of 10.8 g of compound 1 was obtained after purification, with a reaction yield of 61.3%.
[0029] Synthesis of Compound 2 Compound 1 (7.8 g, 29.2 mmol) was added to a 500 mL three-necked flask, followed by 94.5 mL of 38% formaldehyde aqueous solution. Nitrogen gas was then introduced three times to purge the solution. 19.5 mL of acetic acid was added, and the mixture was allowed to react overnight at room temperature. 150 mL each of dichloromethane and water were added to the reaction mixture. Sodium bicarbonate was added in portions to adjust the pH to 7. The mixture was extracted with dichloromethane (100 mL × 5). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation under reduced pressure. The crude product was purified by column chromatography (DCM:MeOH = 40:1) to give 6.8 g of white solid compound 2, with a yield of 71.1%.
[0030] Synthesis of acyclovir impurity R (compound 3) Compound 2 (6.6 g, 23.7 mmol, 1.0 eq), a methanol solution of ammonia (7.0 M, 10.2 mL, 3.0 eq), and 47.4 mL of methanol (0.5 M) were added to a 25 mL single-necked flask and refluxed at 50 °C for 1.5 days. After the reaction was completed, the solid obtained by concentration under reduced pressure was slurried with 0.1% formic acid water (30 mL), and the solid obtained by filtration was slurried with dichloromethane (3.0 mL). Solid-liquid separation yielded 0.73 g of white solid compound 3, which was acyclovir impurity R, with a yield of 6.7% and a purity of 93.5% according to HPLC analysis.
[0031] The technical solutions provided by the embodiments of the present invention have been described in detail above. Specific examples have been used to illustrate the principles and implementation methods of the embodiments of the present invention. The descriptions of the embodiments above are only for helping to understand the principles of the embodiments of the present invention. At the same time, for those skilled in the art, there will be changes in the specific implementation methods and application scope based on the embodiments of the present invention. Therefore, the content of this specification should not be construed as a limitation of the present invention.
Claims
1. A method for preparing acyclovir impurity R, characterized in that the process... include: (1) Compound 1 is generated by N-acetyl-protected amino reaction using acyclovir as a raw material; (2) Compound 1 reacts with an aqueous formaldehyde solution to form compound 2 under acid catalysis; (3) Compound 2 was deprotected by N-acetyl group and purified to obtain compound 3, which is the acyclovir impurity R; the structural formula of compound 1 is: ； The structural formula of compound 2 is: The structural formula of compound 3 is: 。 2. The method for preparing acyclovir impurity R according to claim 1, characterized in that, In step (1), acyclovir and acetyl chloride / acetic anhydride are used as raw materials to carry out an acetylation reaction at room temperature to generate compound 1.
3. The method for preparing acyclovir impurity R according to claim 2, characterized in that, The detailed process of step (1) is as follows: In the reaction vessel, 15.0 g of acyclovir, 220.0-330.0 mL of 0.2-0.3 M pyridine, and 24.0-35.0 mL of trimethylchlorosilane are added dropwise. The mixture is stirred for 40-50 min until the reaction solution is semi-transparent. 6.0-6.5 mL of acetyl chloride and 7.5-9.0 mL of acetic anhydride are slowly added. After the addition is complete, the mixture is reacted at room temperature and purified to obtain compound 1.
4. The method for preparing acyclovir impurity R according to claim 1, characterized in that, The detailed process of step (2) is as follows: In the reaction vessel, add 7.0~12.0 g of compound 1, add 90.0~130.0 mL of 38% formaldehyde aqueous solution to replace nitrogen gas, add 18.0~30.0 mL of acetic acid, react at room temperature overnight, add dichloromethane and water to the reaction solution, add sodium bicarbonate solid in batches, adjust pH=7, and purify to obtain compound 2.
5. The method for preparing acyclovir impurity R according to claim 1, characterized in that, In step (3), compound 2, a methanol solution of ammonia and methanol are hydrolyzed to remove N-acetyl groups. The resulting solid is then slurried with formic acid water and dichloromethane. Solid-liquid separation yields compound 3, which is acyclovir impurity R.
6. The method for preparing acyclovir impurity R according to claim 1, characterized in that, The detailed process of step (3) is as follows: 6.0~7.0 g of compound 2, 9.5~22.0 mL of 7.0 M ammonia methanol solution and 23.5~50.0 mL of 0.5 M methanol are added to the reaction vessel and refluxed at 50 °C for 1~2 days. The resulting solid is then slurried with 30.0~35.0 mL of 0.1% formic acid water and 3.0~5.0 mL of dichloromethane. The solid-liquid separation yields white solid compound 3, which is acyclovir impurity R.