Method for synthesizing AMG837

A technology for compounds and intermediates, applied in the field of synthetic compounds, can solve the problems of expensive metal catalysts, long routes, low yields, etc., and achieve the effects of shortening the synthesis route, good repeatability, and mild reaction conditions

Active Publication Date: 2019-12-20
SOUTH UNIVERSITY OF SCIENCE AND TECHNOLOGY OF CHINA
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  • Abstract
  • Description
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Problems solved by technology

[0005] Currently, there are several routes for the synthesis of AMG-837, such as Chem.Asian J.2011,6,1778–1790., Org.Process Res.Dev.2011,15,570–580., Tetrahedron 66(2010)4730e4737. , Angew.Chem.Int.Ed.2013,52,7532–7535. reports, but these methods have problems such as long routes, low yields, chiral resolution or the use of expensive metal catalysts. Therefore, exploring AMG- A new synthetic route for 837 is necessary

Method used

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  • Method for synthesizing AMG837
  • Method for synthesizing AMG837
  • Method for synthesizing AMG837

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Embodiment

[0053] The synthetic route of AMG837 is as follows

[0054]

[0055] The specific steps are:

[0056] (1) Synthesis of Intermediate C

[0057] According to the method reported in the literature: B.M.Trost, J.T.Masters, B.R.Taft, J.-P.Lumb, Asymmetric synthesis of chiralβ-alkynyl carbonyl and sulfonyl derivatives viasequential palladium and copper catalyst. Chem.Sci.7,6217-6231(2016) .)

[0058] Pd(dppf)Cl was charged to an oven-dried 100 mL round bottom flask equipped with a stir bar 2 (365.9 mg, 0.50 mmol, 5 mol%) and 3-hydroxymethylphenylboronic acid (1.90 g, 12.5 mmol, 1.25 equiv). The flask was sealed with a septum and the gas was displaced with Ar, then DME (20 mL) was added. Add Na under argon flow 2 CO 3 (2.12 g, 20.0 mmol, 2.0 equiv), then 4-bromobenzotrifluoride (1.40 mL, 10.0 mmol, 1.0 equiv) was added via syringe. The vessel was heated to 80°C, then sealed with a yellow plastic cap, and the reaction mixture was stirred for 18 hours. The container was cool...

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Abstract

The invention relates to a method for synthesizing a compound, in particular to a method for synthesizing AMG837. The method comprises the following steps: a step of preparing an intermediate D by a reaction of an intermediate E with propyne; a step of deprotecting the intermediate D to prepare an intermediate B; a step of preparing an intermediate A by a reaction of the intermediate B with an intermediate C; and a step of hydrolyzing the intermediate A. According to the method, a chiral C-C bond of the AMG837 is constructed by taking a Sonogashira C(sp)-C(sp<3>) asymmetric cross coupling reaction as a key step, so that the synthesis route is obviously shortened, and the total yield can reach 10%. The reaction condition is mild, repeatability is good, industrial expansion synthesis is easy, and the application prospect is good.

Description

technical field [0001] The invention relates to a method for synthesizing compounds, in particular to a method for synthesizing AMG837. Background technique [0002] In today's world, with the rapid economic development and the acceleration of industrialization, the threat of non-communicable diseases to human health is increasing day by day, among which diabetes and the accompanying complications are ruthless killers that endanger health. According to the statistics of the International Diabetes Federation, there were 151 million diabetic patients in the world in 2000, and currently there are 285 million diabetic patients in the world. If the current growth rate is maintained, it is estimated that by 2030, nearly 500 million people worldwide will suffer from diabetes. [0003] Type 2 diabetes is a progressive disease. With the progress of type 2 diabetes, blood sugar tends to rise gradually, and the intensity of treatment to control hyperglycemia should also be strengthened...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D453/04C07B53/00
CPCC07B53/00C07B2200/07C07D453/04
Inventor 刘心元董晓阳
Owner SOUTH UNIVERSITY OF SCIENCE AND TECHNOLOGY OF CHINA
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