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ChemicalBook CAS DataBase List Adefovir dipivoxil
142340-99-6

Adefovir dipivoxil synthesis

8synthesis methods
Adefovir dipivoxil (trade names Preveon and Hepsera) is an antiviral acyclic nucleoside phosphonate (ANP) analog. It is a dipivoxil formulation of adefovir, a nucleoside reverse transcriptase inhibitor analog of adenosine with activity against hepatitis B virus (HBV), herpes virus, and human immunodeficiency virus (HIV). It is an orally-administered acyclic nucleotide analog reverse transcriptase inhibitor (ntRTI) that works by blocking reverse transcriptase for the treatment of hepatitis B. Adefovir dipivoxil is not effective against HIV-1.
Synthetic Routes
  • ROUTE 1

    • 202112071099005604.jpg

    Roux, Loic; Priet, Stephane; Payrot, Nadine; Weck, Clement; Fournier, Maelenn; Zoulim, Fabien; Balzarini, Jan; Canard, Bruno; Alvarez, Karine. Ester prodrugs of acyclic nucleoside thiophosphonates compared to phosphonates: Synthesis, antiviral activity and decomposition study. European Journal of Medicinal Chemistry. Volume 63. Pages 869-881. 2013.

  • ROUTE 2

    • 202112077633634585.jpg

    Yu, Richard H.; Schultze, Lisa M.; Rohloff, John C.; Dudzinski, Pawel W.; Kelly, Daphne E. Process Optimization in the Synthesis of 9-[2-(Diethylphosphonomethoxy)ethyl]adenine: Replacement of Sodium Hydride with Sodium tert-Butoxide as the Base for Oxygen Alkylation. Organic Process Research & Development. Volume 3. Issue 1. Pages 53-55. 1999.

  • ROUTE 3

    • 202112074928879970.jpg

    Wang, Xiao-qin; He, Ming-hua; Wang, Qin. Synthesis of 1,1'-[[[[2-(6-amino-9H-purin-9-yl)ethoxy]methyl]phosphinylidene]bis(oxymethylene)] ester (adefovir dipivoxil). Zhongguo Xinyao Zazhi. Volume 17. Issue 22. Pages 1937-1939. 2008.

  • ROUTE 4

    • 202112070908750304.jpg

    Liu, Ying; Wang, Decai. Synthesis of adefovir dipivoxil. Huagong Shikan. Volume 19. Issue 5. Pages 37-39.2005.

  • ROUTE 5

    • 202112072988756301.jpg

    Zhang, Yong; Li, Xin; Gong, Ping; Wang, Yumei. Synthesis of 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) and its oral prodrug adefovir dipivoxil. Shenyang Yaoke Daxue Xuebao. Volume 18. Issue 2. Pages 95-97. 2001.

  • ROUTE 6

    • 202112079908895643.jpg

    Zhang, Sha; Li, Xiao-hong; Li, Yong-shu. Improvement on the synthesis of adefovir dipivoxil. Zhejiang Huagong. Volume 44. Issue 7. Pages 7-9. 2013.

  • ROUTE 7

    • 202112076186866864.jpg

    Arimilli, Murty N.; Kelly, Daphne E.; Lee, Thomas T. K.; Manes, Lawrence V.; Munger, John D.; Prisbe, Ernest J.; Schultze, Lisa M. Crystalline forms of adefovir dipivoxil. Assignee Gilead Sciences, Inc., USA. 2002.

  • ROUTE 8

    • 202112076375646258.jpg

    Lu, Min; Li, Zhongjing; Yuan, Hongyu; Lu, Xiulian; Du, Zhenxin. A preparation method of adefovir dipivoxil crystal substance. Assignee Cisen Pharmaceutical Co., Ltd., 2017.

  • ROUTE 9

    • 202112073090761477.jpg

    Hu, Xiaoxia; Chen, Tieqian. Method for synthesizing Adefovir Dipivoxil as anti-hepatitis B virus medicament. 2005.

  • ROUTE 10

    • 202112077332258053.jpg

    Hwang, Seong Gwan; Lee, Su Jin. Method for preparation of adefovir dipivoxil and its intermediate. Assignee Mirae Fine Chem Co., Ltd., S. Korea. 2010

202112071099005604.jpg

Roux, Loic; Priet, Stephane; Payrot, Nadine; Weck, Clement; Fournier, Maelenn; Zoulim, Fabien; Balzarini, Jan; Canard, Bruno; Alvarez, Karine. Ester prodrugs of acyclic nucleoside thiophosphonates compared to phosphonates: Synthesis, antiviral activity and decomposition study. European Journal of Medicinal Chemistry. Volume 63. Pages 869-881. 2013.

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Yield:142340-99-6 78.1%

Reaction Conditions:

with triethylamine in 1-methyl-pyrrolidin-2-one at 50 - 55;Inert atmosphere;Large scale;Solvent;Reagent/catalyst;Temperature;

Steps:

1; 2; 3; 1
Adding N-methylpyrrolidone to a 50 L reactor and adding 1.70 kg of compound 2 with stirring.Triethylamine 2.52kg (4eq),Compound 3 5.62kg (6eq), protected with nitrogen, heated to 50 ~ 55 ° C,Incubate for 5-7 hours, HPLC monitor compound 4>74%; reaction solution is cooled to 25±5°C;The reaction solution was transferred to a 100 L swing drum and 34 kg (20 w/w) of ethyl acetate was added.Stir at 25 ± 5 ° C for 0.5 h; press filter, filter cake washed with 8.50 kg of ethyl acetate (5 w / w),The organic phase was combined to a 200 L kettle; the organic phase was added with 17.00 kg of purified water (10 w/w).Stir for 0.5 h, separate the liquid; transfer the aqueous phase to a 200 L kettle, add 17.00 kg of ethyl acetate (10 w/w), stir for 0.5 h, and separate the liquid; add the organic phase, add 17.00 kg of purified water (10 w / w), stir 0.5h, liquid separation; add 17.00kg purified water (10w / w) to the organic phase, stir for 0.5h, liquid separation; organic phase added 17.00kg saline (10w / w), stirred for 0.5h, liquid separation; organic addition 17.00kg saline solution (10w / w), stirred for 0.5h, liquid separation; organic phase added 17.00kg brine (10w / w), stirred for 0.5h, liquid separation; organic phase added 3.40kg (2w / w) anhydrous sulfuric acid Sodium, 170g (0.1w / w) activated carbon, stirred at 25 ± 5 ° C for 1h; filter press, filter cake washed with 3.40kg (2w / w) ethyl acetate; filtrate transferred to 200L kettle, 40 ± 5 ° C decompression Concentrate to about 8.5L (5v / w); add 15.30kg of methyl tert-butyl ether (9w / w), warmed to 43 ± 3 ° C, stirred for 0.5h; cooled to 5 ± 5 ° C, crystallization for 12h; centrifugation, The filter cake was washed with 1.70 kg of methyl tert-butyl ether (1 w/w); the filter cake was dried under vacuum at 40 ± 5 ° C to give compound 4 white 1.66 kg, yield 53.2%.Add 2.50 kg (2w/w) of acetone to a 10L four-necked flask, add 1.25kg of compound 4 with stirring, and raise the temperature to 40-45 °C; slowly add 2.50kg (2w/w) of methyl tert-butyl ether and heat up to 40 ~45 ° C, heat stirring for 0.5h; heat filtration to 20L glass crystallization kettle, heating to 40 ~ 45 ° C, heat preservation 0.5h; slow cooling; 38 ± 1 ° C added 0.3% seed crystal; slow cooling to 30 ~ 35 °C, keep warm crystal for 6h; slowly cool down to 5±5°C, heat crystallization for 12h; centrifugation, filter cake washed with 1.25kg (1w/w) of methyl tert-butyl ether; filter cake dried under vacuum at 40±5°C The compound 5 white crystalline powder was 1.00 kg, and the yield was 78.1%.

References:

Beijing Ji Mei Tang Pharmaceutical Co., Ltd.;Li Pei;He Jie;Jiang Aibin;Wang Hui CN110143983, 2019, A Location in patent:Paragraph 0020; 0051; 0054; 0055; 0057; 0060; 0061

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