Method for preparing microsomal prostaglandin E2 synthase-1 inhibitor

Abstract

The invention discloses a method for preparing a microsomal prostaglandin E2 synthase-1 inhibitor. The method comprises the following three steps: 1) preparing N-substituted amide from 5-iodoisatoic anhydride and 4-(3-chlorophenyl)benzylamine hydrochloride; 2) reacting N-substituted amide with crotonyl alcohol to produce 3-[(3'-chloro[1,1'-diphenyl]-4-yl)methyl]-2-propyl-6-iodoquinazolinone; and 3) subjecting a reaction product of the previous step and the o-chlorobenzamide to a Goldberg amination reaction to obtain the target product. The preparation method is simple in steps, avoids the useof alkali and toxic chemical reagents such as triphenyl phosphite, uses cheap and readily-available crotonyl alcohol as a raw material, realizes automatic transferring of hydrogen, does not use alkaliduring the reaction, achieves one-pot reaction, only by-produces water, has high atom economy in the reaction, meets the requirements of green chemistry and shows good development prospects.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a method for preparing microsomal prostaglandin E2 synthase-1 inhibitor. Background technique [0002] Traditional antipyretic and analgesic anti-inflammatory drugs mainly target cyclooxygenase-2 (COX-2), and have a huge market worldwide. Although they have been improved several times, there are still many side effects, and there has been no good effect. substitute. Since the discovery of microsomal prostaglandin synthase-1 (mPGES-1) in 1999, researchers have realized that it may be a new target for antipyretic, analgesic and anti-inflammatory drugs. In the past 10 years since then, a lot of research has been done on its biochemical and pathophysiological properties. However, its pharmaceutical research is still in its infancy, [0003] [0004] Prostaglandin E2 synthase-1, as a class of inhibitors of human microsomal prostaglandin synthase 1, has sh...

AI Technical Summary

Problems solved by technology

The original synthesis method requires 4-step reaction, and the atom economy of the reaction is low, resulting in a very low yield of the reaction

And in the first step reaction, the reaction needs to add an excessive amount of highly toxic triphenyl phosphite, and the reaction will inevitably generate a large amount of by-products (J.Med.Chem.2012,55,3792-3803)

Images