ASYMMETRIC METHOD FOR PRODUCING THIENO-INDOLE DERIVATIVES Russian patent published in 2020 - IPC C07D495/04 

FIELD: chemistry.

SUBSTANCE: invention relates to novel methods of producing thieno-indole derivatives corresponding to formula (Ia) or (Ib), using asymmetric synthesis, to prepare key intermediate compounds

,

where: R1 is hydrogen or linear or branched C₁-C₆ alkyl; R2 is a leaving group selected from halogen or sulphonate groups; BM is a DNA-binding fragment, corresponding to formula (II-1) or (II-2)

W1 is a self-splitting system corresponding to formula (III)

,

where n is 0 or 1; Z1 is a linker, corresponding to formula (IV-1) or (IV-2)

,

where p is number from 0 to 1, and R3 is a polyoxyethylene chain corresponding to formula (V)

,

where m is number from 0 to 5; and RM is a fragment, corresponding to formula (VI)

,

where m is as described above. Synthesis starts with N-alkylation of 5-amino-4-halo-3-alkyl-1-benzothiophen-7-ol derivatives with enantiopure glycidyl 3-nosylate, and subsequent intramolecular 6-endo-tet cyclization using alkyl Grignard reagents; Mitsunobu secondary alcohol activation promotes intramolecular spirocyclization, giving 4,4a,5,6-tetrahydro-8H-cyclopropa[c]thieno[3,2-e]indol-8-one derivatives; stereoelectronic control of regioselective cyclopropane opening enables to obtain key enantiomerically pure 8-(halomethyl)-1-alkyl-7,8-dihydro-6H-thieno[3,2-e]indole-4-ol intermediate compounds, from which final thieno-indole derivatives corresponding to formula (Ia) or (Ib) can then be obtained.

EFFECT: disclosed is an asymmetric method for producing thieno-indole derivatives.

14 cl, 3 ex