Drug synthesis, generalized scheme

The search for a general synthesis of enantio-merically pure non-biaryl atropisomers has been given added impetus by the discovery [26, 27] that the absolute configuration of some atropiso-meric amides affects their biological activity. The enantiomeric atropisomers 21 and 22 (Scheme 13) differed in activity at the tachykinin NK, receptor by a factor of 6-13, with 21 being the more active. Atroposelectivity must now be an important new consideration in drug synthesis. 

A generalized scheme for the synthesis of a drug substance is shown in Figure 1. Every reactant, reagent, solvent, intermediate, and by-product can be considered a potential impurity and should be addressed. Not all byproducts are known when development begins, so efforts to discover and identify them must be included in the investigation of impurities. 

There are several methods of preparation of antibacterial quinolones, drugs widely used in the therapy of various bacterial diseases. The most general method is based on the nucleophilic cyclization of 2-halobenzoyl derivatives 402, leading to the key intermediates 403. The methodology is exemplified in Scheme 63 by the synthesis of a broad-spectrum drug ciprofloxacin... 

There is another good reason not to aim too high in the physicochemical studies of the first sample of drug substance. In most cases the synthesis is only a first scheme in later scale-up it will be refined, and in general the first small samples contain some small amounts of impurities, which may influence the precision of the determined constants. But it is necessary... 

Multiatomic [6] as well as cationic [7] rhodium catalysts also display a high preference for linear hydroformylation products. However, a catalyst system which generally yields branched hydroformylation products has not yet been found. Vinylarenes, such as styrene (16), form preferentially the (.vo-aldehyde 20 and not the n-aldehydes. The possibility to form a relatively stable Rh- -allyl complex 18 is most likely the decisive factor for this result [8]. Subsequent oxidation of 20 leads to 2-arylpropionic acids 21, of which some derivatives like 22-24 are of great importance as non-steroidal inflammatory drugs (NSID) (Scheme 3) [9]. For their synthesis by the hydroformylation of styrenes, not only a regioselective but also an enantioselective reaction process is... 

Besides the more common reactions such as hydrogenation, isomerization, alkylation, and the Diels-Alder reaction. Sharpless epoxidation and dihydroxylation by asymmetrical catalysis are rapidly emerging as reactions with immense industrial potential. Table 9.7 lists some important syntheses based on asymmetric catalysis. These include processes for the pharmaceutical drugs (S)-naproxen, (S)-ibuprofen, (,S)-propranolol, L-dopa, and cilastatin, a fragrance chemical, L-menthol, and an insecticide (/ )-disparlure. Deltamethrin, an insecticide, is another very good example of industrial asymmetric synthesis. The total synthetic scheme is also given for each product. In general, the asymmetric step is the key step in the total synthesis, but this is not always so, as in the production of ibuprofen. Many of the processes listed in the table are in industrial production. 

Nitrosonium tetrafluorobprate was used later as oxidant for convertion of dithiolanthione 150 to dication 151. This technique was found to be general for oxidation of number of thiocarbonyl compounds (Scheme 56). Application of free halogens such as Br2, ICl, IBr, I2 is also useful for synthesis of these dications. Interaction of the drug methimazole 152 with I2 gives dication disulfide 153 and monocation 154 depending on acidity of reaction media (Scheme 57). ... 

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