The asymmetric sulfoxidation of an aryl ethyl sulfide in high enantioselectivity was required as part of a manufacturing route to a candidate drug (ZD3638) within AstraZeneca Pharmaceuticals. The initial discovery process provided small quantities of the required material to satisfy early toxicological work. The optimisation of this sulfoxidation process was required to improve enantioselectivity and therefore yield, and also to improve robustness for manufacturing routinely. Previous studies had indicated that asymmetric sulfoxidation of an aryl ethyl sulfide proceeded with moderate enantioselectivity. Initially, Sharpless conditions which are used for the oxidation of allylic alcohols were employed to effect sulfoxidation in 60% ee; this system was then studied extensively to provide new conditions in 80% ee. Finally, the use of factorial experimental design to explore key parameters in the catalyst formation for these conditions was then studied. This showed the equivalents of the titanium (IV) isopropoxide (0.95 equiv) and (-)-D-diethyl-D-tartrate (1.45 equiv) to be essential factors in controlling enantioselectivity; this has resulted in a viable process with 92% ee in solution, which is improved to greater than 99% ee in the subsequent work-up.
The development of a commercial manufacturing process for fulvestrant (the active ingredient in 'Faslodex') is described. Key steps in the synthesis are stereoselective 1,6-addition of an organocuprate to a steroidal dienone followed by copper-mediated aromatisation of the A-ring. The strategy for dealing with noncrystalline intermediates is outlined. The production of drug substance of acceptable quality is critically dependent on limiting the formation of key impurities. The origin of these impurities is discussed, and measures to prevent or control their formation are described.
Key steps in the synthesis of ZM549865 (a 5-HT receptor antagonist) are the palladium-catalysed amination of ethyl 8-bromo-6-fluoro-4-oxo-4H-2-chromenecarboxylate and subsequent hydrolysis of the ester group. The development of a simple, robust process capable of making multikilogram amounts of the required intermediate is described. Performing the amination step at 125 °C instead of 80 °C and optimising the hydrolysis conditions led to an increase in overall yield from 44% to about 70% as well as reducing the reaction time from days to hours. The chromone ring was initially constructed by reaction of 2-bromo-4-fluorophenol with dimethyl acetylenedicarboxylate followed by cyclisation. A potentially cheaper route was developed that involved formation of a substituted acetophenone via the Fries rearrangement, followed by condensation with diethyl oxalate and cyclisation.
An efficient manufacturing route to a novel farnesyl transferase inhibitor is described. The target molecule is a pro-drug, and its synthesis is complicated by the presence of labile functionality. The Medicinal Chemistry synthesis required trityl mercaptan to introduce a thiol group stereospecifically. An important objective of a new route was avoidance of such an atom-inefficient protecting group, and this was achieved by use of a bicyclic thiolactone. Reduction of the thiolactone with DIBAL afforded a masked aldehyde which participated cleanly in the key reductive amination step without loss of stereochemical integrity. The reported procedure for making the thiolactone was found to give inconsistent results. Development work resulted in a telescoped process that was operated successfully and reproducibly on the large scale. Removal of an N-Boc protecting group in the final step of the drug synthesis required careful choice of conditions to avoid cleaving other ester groups in the molecule. An impurity formed in the deprotection step was identified as the S-tert-butyl analogue arising from attack of the tert-butyl cation on the methionine residue; its identity was confirmed by independent synthesis.
YO1 5 D D U.V. irradiation of a variety of substituted chlorobenzenes in benzene gives the corresponding biphenyls, accompanied in some cases by products of reductive dechlorination. rn-Chlorofluorobenzene and p-bromochlorobenzene react with selective replacement of the heavier halogen. Isomer ratios have been measured for the photochemical phenylation of anisole with chloro-, bromo-, and iodo-benzenes. The excited singlet state of the chloro-compound is implicated in the mechanism of these reactions. Chloronitrobenzenes, which are photostable in benzene, are slowly reduced to nitrobenzene on irradiation in ethanol.AROMATIC chloro-compounds have been described as photochemically unreactive,l in contrast to bromoand iodo-compounds, by virtue of the greater strength of the carbon-chlorine bond. There are indeed numerous examples in the literature in which an aromatic chlorine substituent survives unchanged some other photochemical transformation in a substrate molecule,2 and other reports contrasting the photostability of aromatic chloro-compounds with the reactions undergone by the corresponding bromo-and iodo-compounds on irradiation under the same condition^.^ Most remarkable is the use of chlorobenzene as solvent for photochemical reactions of iodobenzene and its derivatives with organic ph~sphines.~ However, recent work has shown that all types of photochemical reaction known for bromo-aromatic
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