Solid-phase synthesis of aromatic phosphinic acid derivatives

摘要

A process for preparing aromatic phosphinic acid derivatives of formula Y-R1-P(O)(R2)-OR3 (I)), comprises: (a) reacting an adduct of formula resin-linker-Z-E1-S1n (II) with a phosphinate of formula A1O-P(O)(H)-A* (III) in the presence of a Pd catalyst to form a resin-bound compound of formula resin-linker-Z-E1-P(O)(H)-OA1n (IV); (b) optionally converting E1 to a derivatised group (E1)' in one or more reaction steps to form a resin-bound compound of formula resin-linker-Z-(E1)'-P(O)(H)-OA1n (IV'); (c) optionally hydrolysing (IV) or (IV') to form a resin-bound compound of formula resin-linker-Z-E1-P(O)(H)-OHn (V) or resin-linker-Z-(E1)'-P(O)(H)-OHn (V'); (d) optionally converting (V) or (V') to a compound of formula resin-linker-Z-E1-P(O)(H)-OR3n (VI) or resin-linker-Z-(E1)'-P(O)(H)-OR3n (VI'), where R3 is as defined above but not H; (e) optionally converting (IV), (V), (VI), (IV'), (V') or (VI') to a compound of formula resin-linker-Z-E1-P(O)(R2)-OA4n (VII), resin-linker-Z-(E1)'-P(O)(R2)-OA4n (VII'), resin-linker-Z-E1-P(O)(E2)-OA4n (VIII) or resin-linker-Z-(E1)'-P(O)(E2)-OA4n (VIII'), (f) modifying E1, (E1)', E2 and A4, if necessary, to obtain a compound of formula resin-linker-Z-R1-P(O)(R2)-OR3n (IX); and (g) cleaving (IX) to obtain (I). R1 = optionally substituted aryl or heteroaryl; R2 = H or an organic group optionally bonded through a heteroatom; R3 = H or a C-bonded organic group; Y = a functional group remaining after cleaving (I) from a resin resin = an n-valent polymer residue; n = 1 or more; linker = an organic linker; Z = a functional group or bond from which Y is formed when the compound is cleaved from the resin-linker residue; E1 = R1 or a precursor of R1; S1 = a functional group suitable for Pd-catalysed substitutions analogous to the Heck reaction; A1 = H or an organic group; A* = a hydrolytically removable group or a group removable after an intermediate reaction; (E1)' is not further defined; E2 = a group that can be derivatised to form E2; A4 = A1, H or R3.