Recommendation for the Development and Synthesis Route of Brexpiprazole

Introduction

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Brexpiprazole tablets are an atypical antipsychotic medication primarily used for the treatment of psychiatric disorders such as schizophrenia and bipolar disorder. It works by modulating neurotransmitter balance in the brain to alleviate psychiatric symptoms and improve mood states in patients. Originally developed jointly by Denmark's Lundbeck Pharmaceuticals and Japan's Dainichi Pharma, brexpiprazole was approved by the FDA in 2015 for the treatment of schizophrenia and as adjunct therapy for major depressive disorder. In May 2023, the U.S. FDA expanded its indication to include agitation in Alzheimer's disease patients. On June 28,2024, brexpiprazole was approved in China for the treatment of schizophrenia.  

CAS number  913611-97-9

Molecular Formula  C₂₅H₂₇N₃O₂S

Molecular Weight  433.57

Chemical Name  7-(4-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)butoxy)quinolin-2(1H)-one.

 

Retrosynthetic Analysis ：

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Patent Status

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The core patent for brexiprazole in China (ZL200680011923.0) is set to expire in April 2026, and its market will face competition from generic drugs. Following the approval of brexiprazole for domestic marketing, leading pharmaceutical companies have already initiated targeted strategies to capture market share.

 

 

Synthetic Route

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（1）Nucleophilic substitution at the fluorine position

 

（2）Ethyl mercaptate and benzaldehyde react to form benzothiophene (with the mercapto group at the α-carbon attacking the aldehyde group).

 

（3）BocThe deacidification reaction catalyzed by monovalent copper, where acid removes the Boc group.

 

（4）Nucleophilic substitution (impurity control of compound 7 is critical)

 

（5）Nucleophilic substitution (Compound 5 may be selected as the starting material, meeting the ICH requirements for starting material selection).

 

 

References

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[1] Wu, C.; Chen, W.; Jiang, D.; Jiang, X.; Shen, J. An Improved Synthesis of 4-(1-Piperazinyl)benzo[b]thiophene Dihydrochloride. Org. Process Res. Dev. 2015, 19, 555−558.

[2] Goossen, L. J.; Manjolinho, F.; Khan, B. A.; Rodriguez, N. Microwave-assisted Cu-catalyzed Protodecarboxylation of Aromatic Carboxylic Acids. J. Org. Chem. 2009, 74, 2620−2623.

 

 

Contact Us

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Need a trusted partner for Brexpiprazole? Cosperpharm is ready to support your pharmaceutical manufacturing, quality control, or research program. Contact our team today for pricing, documentation, and technical support.

 

Phone: +86-18986204913

 

Tel: +86-027-83338163

 

E-Mail: info@cosperpharma.com