Discovery route synthesis

A comparative cost analysis showed that the classical resolution route (Scheme 8.2) was 12 times cheaper than the discovery route (Scheme 8.1). The classical resolution route was successfully scaled up and used to launch the product and provide the first year s market supply. However, using a final-stage resolution meant that by definition half of the synthetic materials were thrown away. When an E factor analysis [8] was performed on the pregabalin synthesis it was found that 86 kg of waste was being produced for every kilogram of the desired product, and this inspired a search for more efficient chemistries. 

With the key pyrrole 27 in hand, the team was in a position to complete the synthesis. Hydrolysis and decarboxylation of the tert-butyl ester was initially attempted using the conditions employed in the discovery route for the conversion of 14 to 15. While these reaction conditions effected the hydrolysis and decarboxylation of 27 to 28 in good yield, the formation of impurities resulting from dimerization of the pyrrole was also observed. After screening various acids, the team eventually found that side product formation could be completely suppressed using 1 M H2S04 in 3 1 Me0H/H20 at 65 °C to afford the pyrrole 28 in quantitative yield. 

Through their refinements to the synthesis of 1, the Astellas process group ultimately developed a multikilogram-scale process for the production of 1, which both decreased the cost and increased the safety of the synthesis relative to earlier discovery and process routes.34 The resulting process additionally provided conivaptan HCl (1) in 56% overall yield from cyanobenzazepinone 19, representing a four-fold increase in yield relative to the first-generation process synthesis and sixfold increase in yield relative to the initial discovery route. 

In addition to the discovery route,21 52 several alternate syntheses of rivastigmine have been reported. The discovery route involved synthesis of key intermediate phenol 39 by following Stedman s procedure,53 as shown in Scheme 7. This was then treated with N-ethyl-jV-methyl carbamoyl chloride (40) to afford racemic rivastigmine ( 2), which was resolved using di-p-toluoyl-D-tartrate (DTTA) to give (. -rivastigmine (2). 

Development usually starts with the discovery synthesis, a process designed to produce only small quantities, and often involving chemicals and procedures not amenable to a manufacturing process. Early development converts the discovery route to a synthetic route that does not have chemical, safety, environmental, or operational issues that would prevent it from being commercially viable. This must be done before the drug substance solid form and impurity profile become set by formulation development and toxicological studies. 

As evident above, the discovery route to varenicline is a linear, nine-step synthesis that takes advantage of symmetry. Notably, the first step of the route is the only one that involves carbon-carbon bond formation. Benzazepine 6, a key synthetic intermediate, was known in the literature, and its preparation is the primary subject of this chapter. The latter steps have proven robust and safe on scale, providing a six-step regulatory synthesis from 6 to varenicline delivered in the desired salt form. 

The discovery route utilized the pyridinium chlorochromate (PCC) oxidation of 2-cyclohexylethanol in CH2CI2 in presence of molecular sieves. It is a simple process, as the aldehyde is simply isolated by filtration of the reaction mixture through silica gel. However, this process was proven to be difficult to scale up due to difficulties of filtration of the chromium salts. Furthermore, the environmental issues created by the large amount of toxic chromium salts make this process unsuitable for large-scale synthesis. Two other processes (Scheme 6.7) were therefore developed and tested to prepare the required 2-cyclohexyl acetaldehyde at the pilot-plant scale ... 

Starting with bench scale equipment (up to 100 L in the so-called kilo lab) or pilot scale fermentors (up to 5000 L when titer is low), this early preparative work uses whatever synthetic method or fermentation conditions (the microorganism and the nutrients) are immediately available. In most cases of synthesis, the route may be a somewhat streamlined version of the discovery route or a temporary route that may or may not include parts of synthesis schemes being considered for eventual development. In most cases of biosynthesis, the microorganism is that from the discovery stage, but taken from whatever stage of microbial strain improvement is amenable to scale up from shake flasks or bench scale fermentors. 

Sridharan, N. S., Gelemter, H., Hart, A. J. Subgoal generation and synthesis search procedures in SYNCHEM, a computer program for the discovery of synthesis routes for organic molecules. In preparation. 

The only synthesis published to date by the medicinal chemists Cai et al. was not amenable to scale-up. The discovery route started with the 0-alkylation of 5-iodovanillin (230) with 2-iodoethanol in the presence of K2CO3 and 18-crown-6 ether in DMF to give compound 231 (Scheme 30.41). The Stetter reaction of 3,4,5-trimethoxyphenyl vinyl ketone (232) with aldehyde 231 in the presence of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride catalyst (233) and triethylamine in DMF gave the 1,4-dione (234). Reduction of 234 with sodium borohydride in a MeOH-THF mixture gave the corresponding 1,4-diol (235). Diol 235 was cyclized with 5% trifluoroacetic acid in CHCI3 to furnish a mixture of cis and trans isomers of 2,5-diaryl tetrahydrofurans. 

To provide an operationally and commercially feasible alternative process for 229, every operation of the discovery route was analyzed systematically and the key issues to be addressed and the problems found were attempted one by one. One of the first problems with this discovery synthesis was that it was linear and all the building blocks were added in a stepwise fashion. To provide a convergent synthesis, we planned the synthesis of the key intermediate (240) using the Stetter reaction of an enone (232) with an advanced cyanoal-dehyde (242) (Scheme 30.42). 

The initial discovery route to analogs of crizotinib is shown in Scheme 1, and was designed to vary the nature of the aromatic moiety at a late stage in the synthesis. Initial borohydride reduction of the acetophenone generates the racemic alcohol, which is coupled to 3-hydroxy-2-nitropyridine through a Mitsunobu reaction. Nitro reduction followed by bromination introduces the halogen to the 5-position. Boc protection of the amino function enables Pd-mediated borylation to be employed to introduce the... 

The discovery route varied little from the industrial synthesis. From bromopyridine 24, the boronic acid 30 was prepared in 88% yield via metal-halogen exchange and quenching the corresponding anion with BfOCHsls. Suzuki coupling with 2-bromopyridine 31 afforded the common intermediate 25. 

In one of the Vertex s process approaches, the original synthesis of ester 12 was improved where POCI3 was used to facilitate the Friedel-Crafts acylation. " The conditions to carry out the condensation between aniline and diethyl ethoxymethylene-malonate (10) were similar to those of the discovery route except with somewhat elevated temperature (150 °C vs 110 °C). The greater improvement was to carry out the Friedel-Crafts acylation in the presence of POCI3 and phosphoric acid at 70 °C. The overall yield for converting 10- 12 was 70%, more than doubled the yield for the discovery route. 

When 1 was selected for scale-up, we were required to prepare very rapidly a moderate amount of material for initial studies (ca. SOOg) by i t is commonly referred to as an expedient synthesis.[4] Given the limited time firame and file pressure on the process chemist to deliver quickly an initial batch of the drug candidate, this route is usually file discovery route after suitable adjustments, fiiat is, in our specific case, the introduction of a resolution step. At the same time, we sought to develop a scalable route, i.e. one that could eventually deliver quickly and cheaply large amounts of material that will be required later on. 

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