A survey of solvent usage for papers published in Organic Process Research & Development has been carried out for the years 1997–2012. Three solvent categories were studied: (i) solvents of concern, (ii) dipolar aprotic solvents, and (iii) neoteric solvents. In the analysis of dipolar aprotic solvent use it was found that nearly 50% of DMF/DMAc/NMP/DMSO usage is attributed to nucleophilic substitution reactions (mostly SNAr and SN2 reactions). Ideas on how to minimise the use of these four solvents in nucleophilic substitution reactions are presented, and it is hoped that these ideas will be adopted by chemists looking at SN type reactions at all stages of development. The only neoteric solvent showing any significant use is 2-methyltetrahydrofuran; usage of this solvent grew rapidly during the survey period.

The development of a second-generation process for the synthesis of eletriptan via a Fischer indole cyclisation is described. The finalised process offers several potential advantages over the current route of manufacture including cost, throughput, and safety.Eletriptan (R)-7 belongs to the class of drugs known as triptans and was approved in the United States in December 2002. It is a potent and selective 5-HT agonist and is marketed as Relpax for the treatment of migraine. It is currently a low volume product; however, at the time the research was started, the development of novel formulations and drug delivery systems could have significantly increased bulk demand for the drug. The current manufacturing route 1 to eletriptan 7 is well developed and robust, but does suffer some limitations (scheme 1). The key starting material 5 is extremely expensive and contributes approximately 50% of the total cost of manufacture. It uses the costly, unnatural isomer of proline as well as the highly noxious and sensitizing reagent phenyl vinyl sulfone. The synthesis also incorporates a lithium aluminium hydride reduction, generating large waste aqueous streams. Thus an alternative route of manufacture was sought that would be able to deliver this increase in bulk demand.During the assessment of alternative routes to eletriptan, the Fischer indole synthesis was highlighted as a particularly attractive way to build up the molecule. It had the potential to deliver a convergent, highly efficient synthesis (scheme 2), as well as being a well understood and reliable transformation. The Fischer indole reaction was discovered in 1883 by Hermann Emil Fischer, 2 and despite its age, is still one of the most commonly used methods to synthesise indole containing molecules. Indeed several other members of the Triptan family of drugs are manufactured via this method. 3 If this approach were successful, then many of the issues associated with the current route of manufacture could be avoided.The Fischer reaction proceeds via condensation of an aryl hydrazine with a carbonyl compound, followed by a 1,3-sigmatropic rearrangement and subsequent elimination of ammonia. 4 In order to prove that the Fischer reaction was viable for the preparation of eletriptan (R)-7, the synthesis of either aldehyde 8 or a suitably protected form would be required, together with the hydrazine 10. Formation of 8 or 9 and indeed 10 however, proved to be quite challenging. The first successful synthesis (scheme 3) of 9 was via lithiation of N-methylpyrolle 5 11 and subsequent alkylation with 2-(2-bromoethyl)-1,3-dioxolane, followed by hydrogenation of the pyrrole to yield the racemic pyrrolidine 9a.This synthesis was not amenable to further scale up, due to the low yields, cryogenic reaction conditions and chromatography. However sufficient material was isolated to validate the use of 9a in the Fischer indole reaction by condensation with commercially available 4-bromophenyl hydrazine. This delivered rac-5, a racemic form of an intermediate in the original synth...

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An efficient and practical synthesis is presented of the pharmaceutically active MMP-3 inhibitor UK-370,106 (1) via an olefination/catalytic asymmetric hydrogenation sequence. Commercially available 5-bromo-2-iodotoluene was converted in two steps to the biarylpropanal equivalent (11), which was reacted with the phosphonosuccinate (10) to selectively afford the transβ-substituted itaconate (12). Catalytic asymmetric hydrogenation of the itaconate (12) was achieved in good conversion and with 86-96% enantiomeric excess with a range of phosphinemodified rhodium and ruthenium cationic complexes. The resulting enantiomerically enriched 2-alkyl succinate (2) was elaborated to the desired drug substance (1) in two steps. The synthesis benefits from several crystalline intermediates, allowing control of process impurities, and can be operated safely within parameters readily achievable on scale. Investigations into the polymorphic forms of (1) have shown that the compound crystallizes in planar sheets, based on a backbone of hydrogen-bonding amide and acid functionalities, with large hydrophobic pockets formed by the biarylpropyl groups. An understanding of this crystal-packing arrangement has aided the development of crystallization processes allowing complete control over solid form.

The development and scale-up of a potential manufacturing route to the endothelin antagonists UK-350,926 1 and UK-349,862 2 are described. A key synthetic challenge in designing an efficient route to these molecules was the optical lability of the stereogenic centre during the construction of the acylsulfonamide functionality. In the discovery synthesis of UK-350,926 the chiral centre was introduced by classical resolution and the acylsulfonamide functionality synthesized by construction of the N-sulfonyl bond. An alternative more efficient process route was developed involving the preparation of racemic UK-350,926 and final step dynamic resolution with (S)-(−)-1-phenylethylamine as the key step. The process route prepared the acylsulfonamide by construction of the N-carbonyl bond, eliminates a cryogenic reaction and a hazardous intermediate from the synthesis, improves the overall process yield, and allows access to both endothelin antagonists from common intermediates without the need for purification by chromatography. Full experimental details of the new five-step process to prepare UK-349,862 from commercially available starting materials are given for the first time.