Preparation method of eluxadoline intermediate compound

Abstract

The invention provides a preparation method of an eluxadoline intermediate compound, and concretely discloses a method for preparing (S)-2-tertbutyloxycarbonyl amino-3-(4-carbamyl-2,6-dimethyl phenyl) propanoic acid shown by a formula 11. The method comprises the following steps of Step I, obtaining a compound shown by a formula 4 through a compound shown by a formula 1; Step II, obtaining a compound shown by a formula 5 by the compound shown by the formula 4; Step III, obtaining a compound shown by a formula 6 by the compound shown by the formula 5; Step IV, protecting amino groups in the compound shown by the formula 6 to obtain a compound shown by a formula 9; Step V, performing selective hydrolysis on the compound shown by the formula 9 to obtain a compound shown by a formula 10; then, performing ammonolysis to obtain the compound shown by the formula 11. The process routes of the method use the fire-new design; intermediate compounds obtained by the reaction in each step are all synthesized for the first time; a method of firstly performing carbonylation and then performing asymmetrical reduction is used in the process routes; the asymmetrical reduction is realized in the later stage; the catalyst consumption is favorably reduced; the cost is reduced. The formulas are shown as the accompanying drawing.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to the preparation of an esadoline intermediate (S)-2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethylphenyl)propionic acid method. Background technique [0002] Eluxadoline is a new active ingredient that triggers nervous system receptors, approved by the US FDA on May 27, 2015 as a mu opioid receptor agonist, a delta receptor antagonist, and a kappa receptor agonist The agent is approved for marketing. The drug was developed by Furiex, a unit of Forest Lab, for the treatment of diarrhea caused by irritable bowel syndrome in adults. Its structure is as follows: [0003] [0004] In the synthesis of Exadoline, a key intermediate - tyrosine derivative (S)-2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl Phenyl) propionic acid, its structure is as follows: [0005] [0006] So far, a variety of synthetic key intermediates have been reported, the tyrosine derivativ...

AI Technical Summary

Problems solved by technology

[0017] This synthetic route uses the expensive palladium catalyzed reaction twice, and the reaction conditions are harsh in anhydrous and oxygen-free environment, and the chiral intermediate N-(tert-butoxycarbonyl)-3-iodo-L-alanine methyl ester is extremely insoluble. Stable, easy to eliminate side effects

This all greatly increases the difficulty of industrialization of this synthetic route

[0018] Obviously, in the known synthetic routes, there are following disadvantages: the use of expensive catalysts and expensive and difficult to obtain raw materials with chiral centers; the reaction conditions involved are harsh (such as asymmetric reduction) or difficult to control (such as Heck reaction); and cumbersome post-processing (such as through multiple column chromatography purification), etc.

These deficiencies make it difficult for the above-mentioned synthetic route to be applied in large-scale industrialization, and then there are many problems in the industrialized production of exadoline

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