Production method of Acyclovir

  • Acyclovir is a synthetic purine nucleoside analogue. It is mainly used for various infections caused by herpes simplex virus. It can be used for initial or recurrent skin, mucous membrane, external genital infections and HSV infections in people with immunodeficiency. It is the first choice for the treatment of HSV encephalitis, and it is better than arabinosine to reduce morbidity and mortality. It can also be used for herpes zoster, Epstein-Barr virus, and immunodeficiency patients with chickenpox and other infections. Topically applied to the skin only, acyclovir is less absorbed by the skin.


    Physical and chemical properties

    Appearance and properties: white to light yellow crystalline powder

    Density: 1.77

    Melting point: 256-257°C

    Boiling point: 595ºC at 760 mmHg

    Stability: stable, but incompatible with strong oxidants

    Storage conditions: The warehouse is ventilated, low temperature and dry, and stored separately from food materials


    production method


    Method 1: Preparation of N-7(or 9)-diacetylguanine with guanosine as the raw material. Add 283g of guanine nucleotide, 1.03L of 10mol of acetic anhydride, and 210mL of 2mol of acetic acid into a 5L three-necked flask, and heat to reflux. For 1h, add 0.2mol PTS17.2g, then reflux for 1h, recover acetic anhydride and acetic acid by distillation under reduced pressure, add 600mL ethyl acetate to the concentrate, reflux for 1.5h, and filter after cooling to obtain the product. Guanine nucleotide [acetic anhydride, acetic acid, PTS]→N-7-(or 9)-diacetylguanine N-acetyl-9-[(2-acetoxyethoxy)methyl]guanine Add 200g of N-7 (or 9)-diacetylguanine, 282g of 2-oxa-1,4-butanediol diacetate, 9g of PTSA, and 1.2L of toluene into a three-necked flask. After refluxing for 24h, cool quickly To 0°C, filter and dry to obtain the product. N-7(or 9)-Diacetylguanine [2-oxa-1,4-butanediol diacetate, PTSA, toluene]→N-acetyl-9-[(2-acetoxyethoxy Yl)methyl]guanine acyclovir, place 0.5mol of N-acetyl-9-[(2-acetoxyethoxy)methyl]guanine, 2.7L of 25% methylamine aqueous solution in three In a neck flask, react at 35-37°C for 0.5h with stirring, concentrate to dryness under reduced pressure, add 350ml of ethanol to dissolve, filter, wash the filter cake with ethanol, and dry to obtain a crude product. Recrystallized with 40 times water to obtain a fine product. N-acetyl-9-[(2-acetoxyethoxy)methyl]guanine[methylamine]→[35-37℃, 0.5h] acycloguanosine

    Method 2: Preparation of N,N-diacetylguanine with guanine as the raw material. Put 5g of guanine in a round bottom flask, add 81mL of acetic anhydride, stir and mix, add a small amount of acetic acid and zinc acetate, heat and reflux for 16h, cool , Recover the acetic acid under reduced pressure, filter it after cooling in an ice bath, wash with ethanol and water and then dry to obtain the product. Guanine [Acetic Anhydride, Acetic Acid, Zinc Acetate] → Preparation of N,N-Diacetylguanine 1,3-dioxolane After mixing 248g of ethylene glycol and 120g of paraformaldehyde, add concentrated sulfuric acid slowly while stirring 22.1g, reflux for 3h after the addition, cool the reaction solution to room temperature, transfer to a separatory funnel, add sodium chloride for saturated salting out, separate the organic phase, dry and distill, and collect the 74-76°C fraction as the product. Preparation of ethylene glycol [paraformaldehyde, concentrated sulfuric acid]→1,3-dioxolane N-acetyl-9-[(2-acetoxyethoxy)methyl]guanine 31g of acetic anhydride, acetic acid Mix 5g of p-toluenesulfonic acid with 2g, cool to below 10℃ under stirring, add 24g of dioxane, and keep the temperature no more than 40℃, cool to room temperature, add 78mL of toluene and 15g of N,N-diacetylguanine, stir Reflux for 1 h, cool to room temperature, add chloroform, filter, and dry to obtain the product. N,N-Diacetylguanine [1,3-dioxolane, PST, acetic anhydride, acetic acid, toluene]→N-acetyl-9-[(2-acetoxyethoxy)methyl]guanine Preparation of Purine Acycloguanosine Mix the N-acetyl-9-[(2-acetoxyethoxy)methyl]guanine obtained in the previous step with 120 mL of a 40% methylamine aqueous solution, and heat for 1 hour with stirring, and then cool down After filtration, the filtrate was concentrated under reduced pressure, washed with ethanol, and filtered to obtain a crude product, which was recrystallized with water to obtain a pure acyclovir. N-acetyl-9-[(2-acetoxyethoxy)methyl]guanine[methyl]→acycloguanosine. The 2-chloro-9-(2-hydroxyethoxymethyl) hypoxanthine obtained by the action of 2-chloro-9-(-2-hydroxyethoxymethyl) adenine with sodium nitrite (melting point> 310℃) Saturate with liquid ammonia and heat it at 125℃ for 5h to produce acyclic guanosine.


    Method 1: Use guanine as raw material. Mix guanine and acetic anhydride, add a small amount of acetic acid and zinc acetate, stir and reflux. The excess acetic anhydride was evaporated under reduced pressure, cooled to 0°C and filtered, the filter cake was washed with ethanol and water, and dried to obtain N,N`-diacetylguanine with a yield of 92.6%. Mix acetic anhydride, acetic acid and p-toluenesulfonic acid and cool to below 10°C. Add dioxolane while stirring, and control the internal temperature below 40°C. Cool to room temperature, add toluene and N,N'-diacetylguanine, stir and reflux. Cool to room temperature, add chloroform, and filter. The filter cake was washed with chloroform, dried and dissolved in a 40% methylamine aqueous solution, stirred and refluxed. After cooling and filtering, the filtrate was concentrated under reduced pressure to a slurry, and after cooling, it was washed with ethanol and filtered. The filter cake is recrystallized with water to obtain acyclovir with a yield of 75% and a melting point of 255-258°C. N,N'-Diacetylguanine can also be reacted with 2-oxa-1,4-butanediol diacetate in dimethyl sulfoxide and catalyzed by p-toluenesulfonic acid at 100°C. Chromatography is performed to obtain the diacetate of acyclovir, which is then hydrolyzed in a methanol solution of saturated ammonia gas to obtain acyclovir. The total yield based on guanine is 43%.


    Method 2: After guanine trimethylsilanization, and then react with 2-benzyloxyethoxymethyl chloride, then remove the benzyl group to obtain acyclovir with a yield of 24%.


    This product is a purine nucleoside derivative, which has an inhibitory effect on DNA synthesis. Its anti-herpes virus activity is 160 times stronger than arabinosine. It is clinically used for herpes simplex virus encephalitis, herpes virus keratitis and external genital infection, AIDS varicella-zoster virus infection and cytomegalovirus infection, chronic hepatitis B, etc.


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