Unsymmetrical hydrogen migration synthesizing method for (R, R)-formoterol

Abstract

The invention relates to an asymmetric hydrogen transfer synthesis method for (R,R)-formoterol, and relates to a novel method for synthesizing an optical pure beta 2-adrenoreceptor excitant, namely formoterol. The method comprises: firstly, taking 4-hydroxyl-3 nitroacetophenone as a raw material, using benzyl groups to protect phenolic hydroxyl groups, and obtaining alpha-bromo keto after bromination; secondly, taking (S,S)-Rh-PEG-BsDPEN as a catalyst and formic acid and derivatives of the formic acid as hydrogen sources, and synthesizing chiral alcohol intermediate by an asymmetric hydrogen transfer method; thirdly, using (R)-alpha-methyl phenylethylamine and methoxyl phenylacetone to generate imine compounds, and obtaining chiral amine intermediate through hydrogenation reduction under the catalysis of Pt / C; and fourthly, reacting and coupling the chiral alcohol intermediate and the chiral amine intermediate, removing protective groups, and obtaining the (R,R)-formoterol. The invention uses the asymmetric hydrogen transfer method and a chiral auxiliary reagent to synthesize the (R,R)-formoterol, and has high yield and good ee value. Compared with a method for synthesizing chiral formoterol through chemical splitting, the method has the advantages of high total yield, mild reaction conditions, low cost and so on, and is favorable for industrial production.

Description

technical field [0001] The asymmetric hydrogen transfer synthesis method of (R, R)-formoterol relates to a new method for synthesizing optically pure β2-adrenoceptor agonist formoterol, which belongs to the technical field of chiral β2-adrenoreceptor agonist synthesis . Background technique [0002] The invention relates to the synthesis of (R, R) formoterol, a long-acting anti-asthma drug with significant curative effect. The structure is as follows: [0003] [0004] Formoterol, chemical name 3-formamido-4-hydroxy-α-(N-(1-methyl-2-(p-methoxyphenyl)ethyl)aminomethyl) Benzyl alcohol is a long-acting β2-adrenergic receptor agonist with high pharmacological activity, rapid onset of action, long acting time, and obvious anti-inflammatory effect. It is used for the treatment of chronic bronchial asthma and glucocorticoids Used in combination for the treatment of severe asthma. The formoterol molecule has two chiral centers, and there are four isomeric forms (R, R), (S, S)...

AI Technical Summary

Problems solved by technology

[0006] 1. The synthetic method of chiral alcohol intermediate: (1) the method for diastereomer resolution, representative document has: AngelGuerrero et al.Tetrahedron: Asymmetry, 2000,11,2705-2717 (with vinyl acetate ester kinetic resolution); (2) use chiral amino alcohol and borane to generate chiral oxazoborane as catalyst, asymmetric reduction of α-bromo ketone to obtain chiral alcohol intermediate, representative documents include: Robert Hett et al.Org.Process Res.Dev.1998, 2, 96-99. In these two synthetic methods, the operation of the diastereoisomer resolution process is complicated, and 50% of the invalid enantiomers are produced simultaneously, Raw material utilization rate is low, which increases the cost of production

The chiral oxazolborane catalyst used in the second synthetic method is expensive, complex to synthesize, and the consumption is also relatively large (10% mol), and borane is highly toxic, volatile, and harsh in reaction conditions, so it is difficult to realize industrialization

This method finally generates half of the invalid enantiomers (S, S configuration), resulting in a lot of waste of raw materials, which is not in line with atom economy

Images