The synthesize method of Avatrombopag
Dec 22,2023
Description
Avatrombopag (Doptelet®) is an orally administered second-generation TPO-RA approved in the USA and the EU for the treatment of primary chronic ITP in adult patients who are refractory to (EU) or have had insufficient response to (USA) other treatments the drug is also approved in the USA for the treatment of thrombocytopenia in adult patients with CLD who are scheduled to undergo a procedure, and in the EU for the treatment of severe thrombocytopenia in adult patients with CLD who are scheduled to undergo an invasive procedure[1].
Development
It is a thrombopoietin receptor agonist indicated for the treatment of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure. The USFDA first approved it in May 2018 and subsequently approved by the European Medicine Agency (EMA) in June 2019. Initially developed by Astellas, avatrombopag's development rights have been transferred between several firms, most recently Dova Pharmaceuticals (an affiliate of PBM Capital). In March 2018, Dova entered into an agreement (through AkaRx) to grant Shanghai Fosun Pharma the drug's exclusive development and distribution rights in mainland China and Hong Kong.
Synthesize method
A large-scale synthetic route to avatrombopag and crystalline form protocols have been reported in a series of patents from Astellas[2]. As shown above, bromination of 1-(4-chlorothiophen-2-yl)ethenone (124) gave bromide 125. Condensation with thiourea produced thiazolamine 126 in 46% yield over two steps. Thiazolamine 126 was brominated with N-bromosuccinimide (NBS) in DMF, allowing nucleophilic aromatic substitution with 1-cyclohexylpiperazine (127) to provide 128 in 34% overall yield. Amide bond formation with 5,6-dichloro nicotinic acid (129) was accomplished by activation with phosphorus oxychloride to give nicotinamide 130 in 83% yield. A second nucleophilic aromatic substitution with ethyl isonipecotate 131, followed by hydrolysis, provided avatrombopag (132). Salt formation was demonstrated on 20 kg scale using maleic acid in a mixture of DMSO/acetone/water (2:2:1) to obtain avatrombopag maleate in 85% yield.
References
[1] Markham, Anthony. “Avatrombopag: A Review in Thrombocytopenia.” Drugs (2021): 1905–1913.
[2] Andrew C. Flick. “Synthetic Approaches to New Drugs Approved during 2018.” Journal of Medicinal Chemistry 63 19 (2020): 10652–10704.
- Related articles
- Related Qustion
- Avatrombopag: Pharmacodynamic Properties, Therapeutic Efficacy, Dosage and Administration Apr 1, 2024
Avatrombopag, a thrombopoietin receptor agonist, boosts platelet production without affecting function, offering potential treatment for ITP and CLD-associated thrombocytopenia.
- Avatrombopag: mechanism of action, pharmacokinetics and clinical applications Sep 26, 2023
Avatrombopag is a medication that treats thrombocytopenia by mimicking thrombopoietin, increasing platelet count through receptor activation and signal pathways.
- General Introduction of Avatrombopag Dec 1, 2021
Avatrombopag is used to treat thrombocytopenia (a low number of platelets [type of blood cell needed for blood clotting]) in people with chronic (ongoing) liver disease who are scheduled to have a medical or dental procedure to help prevent
Carbon tetrafluoride(CF4) is non-flammable gas and is used as a refrigerant in various industries. It is very stable due to the strength of its carbon-fluorine bond. The stable properties are determined by its structure.....
Dec 22,2023Chemical ReagentsCH3Cl is the chemical formula for the organic compound chloromethane, also known as methyl chloride. It is used as an extractant for oil and resins, a propellant in foam production, etc.....
Dec 22,2023Organic ChemistryAvatrombopag
570406-98-3You may like
- Avatrombopag (AKR-501)
-
- $0.00 / 10mg
- 2024-08-28
- CAS:570406-98-3
- Min. Order: 10mg
- Purity: 0.98
- Supply Ability: 10g
- Avatrombopag Base,Avatrombopag
-
- $0.00 / 25kg
- 2024-07-17
- CAS:570406-98-3
- Min. Order: 1kg
- Purity: >99% by HPLC
- Supply Ability: 5kg/Month
- Avatrombopag
-
- $0.00 / 1kg
- 2023-04-11
- CAS:570406-98-3
- Min. Order: 1kg
- Purity: 99%
- Supply Ability: 100kg