Patent ID: 8546549

Claim:
A method of preparing compounds of the following formula: wherein Z is selected from the group consisting of and wherein W′ is R 5 ′ is a hydrogen or the group RCO, wherein R is hydrogen, branched or unbranched alkyl of 1 to 10 carbon atoms, alkylene of 2 to 10 carbon atoms, aryl of 6 to 11 carbon atoms, a (C 6 -C 11 ) aryl-alkyl (C 1 -C 5 ) group, or a heteroaryl or heteroaryl-alkyl (C 1 -C 5 ) group wherein heteroaryl is defined as 2- or 3-furyl, 2- or 3-thienyl, 2- or 3-(N-methylpyrrolyl), 2-, 3-, or 4-pyridinyl, 2-, 4-, or 5-(N-methylimidazolyl), 2-, 4-, or 5-oxazolyl, 2-, 3-, 5-, or 6-pyrimidinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl, or 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolyl, all aryl and heteroaryl groups optionally substituted by one or more hydroxy, amino, carboxy, halo, nitro, (C 1 -C 3 ) alkoxy of 1 to 3 carbon atoms, or thioalkoxy of 1 to 5 carbon atoms; X is an iodine or bromine atom; 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 2 CO 2 H where alk 2 is 1 to 4 carbon atoms at about 20° to 70° C. for about 1 to 24 hours, to produce a bilinker-carboxylic acid of the following formula: b. isolating the bilinker-carboxylic acid of step (a); c. reacting the isolated bilinker-carboxylic acid of step (b) with 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: 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 3 —S—S—S—W′ in an inert organic solvent to generate an activated ester of the formula below and the temperature of the reaction is ≦5° C. and wherein the methyltrithio antitumor antibiotic CH 3 —S—S—S—W′ comprises N-acetyl-LL-E33288 γ 1 I : e. isolating the activated ester of step (d) and purifying to yield antitumor antibiotics of the formula: