Bulk Drugs 5-ht4r Partial Agonist, Sl-65.0155 Synthesis Process Optimization

Dementia disease, also known as "Alzheimer's disease",is a slow development of the disease, resulting in gradual loss of brain cells, eventually leading to memory, determines decision-making power, a sense of orientation, attention and language skills of the injury. The majority of them will die after suffering from such a disease for 5 to 10 years. Nearly a 10-year clinical research suggested that acetylcholinesterase (AChE) inhibitors have a therapeutic role to play in AD and have become a first-line therapy. However, recently, serotonin 5-HT4R agonists with a special effect have been accepted on the treatment of Alzheimer's disease, and proved to be a promising new agent for the treatment of dementia. AD drug SL-65.0155 (Sanofi-Aventis Pharma) which has entered Phase II clinical treatment is one of the representatives.The synthesis and pharmacological test of SL-65.0155 have frequently been patented. However, the known methods for preparing it have been limited to laboratory synthesis scale, which have obvious disadvantages for the application in industry. In the present dissertation, the efficient synthetic way toward SL-65.0155 for the sake of industrial application has been investigated. Thus, the key starting material benzodioxane amino acid (4) was prepared according to a precedent method with slight modifications. Subsequently, preparation of the key intermediate oxadiazole (8) was studied in detail by screening various protection and deprotection methods toward industrial processes. Improvements both in terms of yields and operation simplicity were achieved. Meanwhile, the hydroxylpiperidine derivative (19) as a new building block was synthesized using an alternative way, which afforded satisfactory yield.Finally, the target molecule SL-65.0155 was synthesized via a convergent strategy with much improved overall-yield.The present synthetic way carries several obvious advantages, such as low cost of the starting materials, operational simplicity, good yields along with other characters for industrial benign.