Process Development For The Production Of Methyl 5-minopentanoate Hydrochloride And The Design And Synthesis Of Lanosterol Derived TGR5 Agonists

In the first part,a new preparation method of methyl 5-aminovalerate hydrochloride was described in details.As a versatile building block,methyl 5-aminovalerate hydrochloride is widely used to prepare a variety of bioactive molecules.Despite the simple structure,the high prices and limited suppliers become obstacle to further applications.Therefore,it is necessary to develop a low-cost,environmentfriendly and easily scale-up process.On the basis of literature investigation,we developed a robust process to prepare methyl 5-aminovalerate hydrochloride from the cheap and readily available 2-pyridinone.This process was successfully scaled up with several hundred grams per batch.We have applied for a Chinese invention patent regarding this process.The bile acids receptors mainly include membrane receptors and nuclear receptors,among which TGR5 is the best-studied membrane receptor.When activated by bile acids,TGR5 played vital roles in regulating a series of metabolic signaling pathways,and inflammatory response.Targeting TGR5 receptor has become a promising therapeutic approach for treating non-alcoholic hepatitis,type 2 diabetes,obesity,inflammatory bowel disease and other related chronic diseases.Based on lanosterol scaffold,our group utilized C3-OH configuration inversion strategy together with the construction of a carboxylic acid through double bond cleavage in the side chain to mimic the structure of bile acids and developed a series of potent TGR5 agonists.Based on representative compounds CZF530 and CZF544,a systematic structural modification at C24 position of lanosterol side chain was carried out.By enriching C24 substituents with amides,extending or shortening side chain to form amides,ureas,and carbamates,a series of lanosterol derived compounds were prepared and evaluated.Unfortunately,TGR5 activity of the new compounds was not improved.Docking analysis showed that introducing C7-OH might form hydrogen bond with Ser247 of h TGR5,which provided a basic reference for further structural modification.