SYNTHESIS OF (S)-6-HYDROXYTRYPTOPHANE AND ITS DERIVATIVES Russian patent published in 2023 - IPC C07D209/20 C07K7/64 A61K31/197 A61K31/475 A61P35/00 

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to methods of the synthesis of (S)-6-hydroxytryptophan derivatives, to compounds for the synthesis of amanitin derivatives or drug conjugates, to intermediate compounds for use in the synthesis of amanitin derivatives and drug-amatoxin conjugates, and to the use of specific catalysts suitable for promoting the above synthesis routes. A method of synthesizing (S)-6-acetyloxy-N-tert-butoxycarbonyltryptophan includes at least one step of enantioselective hydrogenation of an olefin precursor compound by using at least one chiral catalyst, wherein the said olefin precursor compound is selected from a benzyl ester [6-benzyloxy-1H-(benzyloxycarbonyl)-3-indole]-2-(tert-butoxycarbonylamino)acrylic acid (compound HDP 30.2824)

and 3-[6-benzyloxy-1H-(1-tert-butoxycarbonyl)-3-indole]-2-(benzyloxycarbonylamino)acrylic acid methyl ester (compound HDP 30.2739)

The chiral catalyst is a compound selected from the group consisting of cyclooctadiene-1,5-[(R,R)-DIPAMP]rhodium tetrafluoroborate (HDP 30.2758), (COD)Rh(I)(R,R)-Et-DuPhos (BF₄^-), (COD)Rh(I)(R,R)-DuPhos-ferrocene (BF₄^-), (COD)Rh(I)(R,R)-DuPhos-ferrocene-Et₂ (BF₄^-), (COD)Rh(I)(R,R)-DuPhos-alkyl(CF₃SO₃^-) and (COD)Rh(I)(R,R)-phenyl-DuPhos-alkyl(BF₄^-).

EFFECT: provision of an effective, simple and reproducible method of the synthesis of (S)-6-hydroxytryptophan, its derivatives and its structural elements, as well as provision of an effective method of the synthesis of (S)-6-acetyloxy-M-tert-butoxycarbonyltryptophan with a sufficiently high enantiomeric cleanliness.

14 cl, 7 dwg, 1 tbl, 22 ex