Asymmetric synthesis method of (R,R)-formoterol tartrate

Abstract

The invention relates to an asymmetric synthesis method of (R,R)-formoterol tartrate, which comprises the following steps: by taking (S,S)-CsDPEN and transition metal complex as a catalyst, performing asymmetric hydrogen transfer reaction on alpha-bromoketone used as a raw material, thus obtaining a chiral alcohol intermediate compound; performing reaction steps of nitro-reduction, formylation, cyclization and the like, thus obtaining a key intermediate compound FM 1; by taking Pt / C as a catalyst and alpha-methylphenylethylamine as a chiral assistant, synthesizing an intermediate compound FM 2-3; performing tartaric acid salification, ionization and alpha-methylphenethyl removal, and reacting with benzaldehyde, thus preparing a chiral amine intermediate compound FM 2; reacting and coupling the two key intermediate compounds, and performing protective group removal to obtain (R,R)-formoterol FM 4; and performing tartaric acid salification on the FM 4, thus preparing the target product (R,R)-formoterol tartrate FM 5. According to the invention, the (R,R)-formoterol is synthesized through an asymmetric hydrogen transfer method by means of the chiral assistant, and high yield and favorable ee value are achieved. Compared with a chemical resolution method for synthesizing chiral formoterol, the method provided by the invention has the advantages of high overall yield, mild reaction conditions, low cost and the like, thereby being beneficial to industrial production.

Description

technical field [0001] Asymmetric hydrogen transfer synthesis method of (R, R)-formoterol tartrate, involving a new method for synthesizing optically pure β2-adrenoceptor agonist formoterol, belonging to the synthesis of chiral β2-adrenoceptor agonists technical field. Background technique [0002] The present invention relates to the synthesis of long-acting anti-asthma drug-(R, R) formoterol with remarkable curative effect. The structure is as follows: [0003] [0004] Formoterol, chemical name 3-carboxamido-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 duration of action, and significant anti-inflammatory effect. Combined use for the treatment of severe asthma. The formoterol molecule has two chiral centers and exists in four isomeric forms (R, R), (S, S), (S, R) or (R, S). Pharmacological studies have shown that the phar...

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

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