Chiral 4-halogenated tryptophan derivative and synthesis method thereof

Abstract

The invention discloses a chiral 4-halogenated tryptophan derivative and a synthetic method thereof, and the synthetic method comprises the following steps: S1, sequentially adding an N-acylglycine derivative, anhydride and carboxylate into a compound 1, and carrying out a condensation reaction to obtain a compound 2; S2, mixing the compound 2 with alcohols and metal alkoxy compounds, and carryingout alcoholysis ring opening to obtain a compound 3; and S3, mixing the compound 3 with a complex formed by a catalyst and a ligand, hydrogen and an alcohol solvent, and carrying out an asymmetric hydrogenation reaction to obtain a compound 4, namely the chiral 4-halotryptophan derivative. According to the synthetic method, the chiral 4-halotryptophan derivative 4 is prepared with the effects ofhigh yield and high enantioselectivity, and the synthetic method is simple to operate, low in cost, green, economical and suitable for large-scale synthesis.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a chiral 4-halogenated tryptophan derivative and a synthesis method thereof Background technique [0002] Compounds containing indole ring structural units usually have significant biological activity and are widely used in the treatment of tumors, cardiovascular and cerebrovascular diseases and other diseases. At the same time, such compounds can also be used as important organic chemical raw materials and intermediates in the fields of pesticides, spices, dyes and other fine chemicals. Tryptophan derivatives are important structural components of indole alkaloid natural products, and often participate in the biosynthesis of natural products as building blocks. Among them, chiral 4-halogenated tryptophan derivatives are widely used in the asymmetric synthesis of drugs lysergic acid and other complex indole alkaloids such as indolactam V, clavicipiticacid, communesin F, etc. At...

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Problems solved by technology

[0005] 3) Glycine Schiff's base-nickel complexes derived from 4-halotropine quaternary ammonium salts and chiral proline are prepared by alkylation reaction, and the proline derivatives in the complex act as Chiral auxiliaries (Zlatopolskiy, B.D.; Zischler, J.; D.; Urusova, E.A.; Guliyev, M.; Bannykh, O.; Endepols, H.; Neumaier, B.J.Med.Chem.2018, 61, 189-206); Chirality reduces the economy of this reaction

[0006] 4) The dehydration reaction of 4-haloindole and serine under the condition of acetic anhydride / acetic acid produces 4-halo-N-acetyl tryptophan racemate, which is prepared by kinetic resolution under the action of acyltransferase Chiral 4-halogenated tryptophan derivatives (Yokoyama, Y.; Osanai, K.; Mitsuhashi, M.; Kondo, K.; Murakami, Y. Heterocycles 2001, 55, 653–659); the synthesis route of this method is simple, The design is ingenious; but there are many impurities in the first step reaction, and the total yield of resolution is not high

[0007] 5) 4-halogenated indole and α-methylene glycine derivatives were prepared by palladium-mediated oxidative coupling to the corresponding indole enamine precursors, and further synthesized chiral 4-halogenated amines by catalytic asymmetric hydrogenation reaction Amino acid derivatives (following formula); the synthetic route is simple, but the shortcoming is that a stoichiometric metal palladium needs to be used in the first step coupling reaction; in addition, for the asymmetric hydrogenation reaction of such enamine substrates, most ligands gives only moderate enantioselectivities, when the ligand is (S,S)-1,2-bis[(2-methoxyphenyl)phenylphosphino]ethane [abbreviated DIPAMP], ee values Up to 94% (Yokoyama, Y.; Matsumoto, T.; Murakami, Y.J.Org. Chem. 1995, 60, 1486-1487)

[0009] Each of the above routes has its own characteristics, and at the same time has its own defects.

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