Patent ID: 8273862
Filing Date: 2012-09-25
Classification: A61P,C07C,C07D,C07H

Abstract:
1. A process to prepare compounds of Formula (I): wherein: Z is selected from the group consisting of Alk Sp Z Ar is 1,2-, 1,3-, or 1,4-phenylene optionally substituted with one, two, or three groups independently selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 5 carbon atoms, thioalkoxy of 1 to 4 carbon atoms, halogen, nitro, —COOR′, —CONHR′, —O(CH n is an integer from 0 to 5; R′ is a straight or branched alkyl of 1 to 5 carbon atoms optionally substituted by one or two groups of —OH, alkoxy of 1 to 4 carbon atoms, thioalkoxy of 1 to 4 carbon atoms; Sp is a straight or branched-chain divalent or trivalent alkyl radical of 1 to 18 carbon atoms, divalent or trivalent aryl or heteroaryl radical, divalent or trivalent cycloalkyl of 3 to 18 carbon atoms or heterocycloalkyl radical, divalent or trivalent aryl- or heteroaryl-alkyl (C W′ is R or CH 3 ; R 2 is or H; R or H; R 4 is or H; R R R X is an iodine or bromine atom; R Q is selected from the group consisting of —NNHCO—, —NNHCS—, —NNHCONH—, —NNHCSNH—, and —NO—; comprising the steps of: a. reacting a carboxylic acid of the formula with a mercapto compound of the formula in an alcohol solvent in the presence of an alkyl carboxylic acid, alk b. isolating the bilinker-carboxylic acid of step (a); c. reacting the isolated bilinker-carboxylic acid of step (b) with an at least a 3 fold molar excess of N-hydroxysuccinimide, 2,3,5,6-tetrafluorophenol, pentafluorophenol, 4-nitrophenol, 2,4-dinitrophenol, or N-hydroxysulfosuccinimide in the presence of 1,3-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), or N,N′-disuccinimdyl carbonate in an inert solvent containing 0-50% N,N-dimethylformamide (DMF) to generate a trilinker-activated ester of the formula where Z is hereinbefore defined; d. reacting the trilinker-activated ester formed in step c in the presence of a base or an organic base with a methyltrithio antitumor antibiotic CH e. isolating the activated ester of step (d) and purifying to yield antitumor antibiotics of Formula (I)