Medicinal Chemistry Route

Even though there are a few drawbacks, as mentioned above, we felt that the Medicinal Chemistry route was straightforward and we should be able to use the original synthetic scheme for a first delivery with modifications as follows ... 

At the beginning of the project, we had studied the introduction of the pMB group to 4 as a nitrogen protecting group, as used in the Medicinal Chemistry route. There was a classical regioselectivity problem, O- versus N-alkylation. Under the Medicinal Chemistry conditions, the desired N-alkylated product 5 was mainly formed, but around 10-12% of the corresponding O-alkylated product 16 was also... 

Scheme 1.14 Original Medicinal Chemistry route for Efavirenz (1).

The original Medicinal Chemistry route was straightforward but, from a process chemistry point of view [20], several problems were identified at the beginning of the project and some of them were quite similar to those for the previous development candidate ... 

All three previously mentioned issues associated with the Medicinal Chemistry route were rooted in cyclopropylacetylide (37) addition to the ketone 36. Other steps in the Medicinal route are suitable for large scale preparation. Thus, our effort for this process development focused on asymmetric addition to ketone 36 with close to 1 equiv of 37 [21],... 

Synthesis of pyrazole 3 by the Medicinal Chemistry route was straightforward from N-Boc isonipecotic acid (45), so we utilized the route after some optimizations, as summarized in Table 2.4. The key 1,3-diketone intermediate 48 was prepared from 45 without issues. A minor problem in the original route was the exothermic nature of the Claisen condensation between methyl ketone 47 and methyl phenylacetate. Slow addition of l.lequiv of methyl phenylacetate to a mixture of 47, 0.2equiv of MeOH, and 2.5equiv of NaH in THF at room temperature solved this exothermic issue and reduced the amount of self-condensation of... 

The Second Generation Candidates 3.1.2.1 The Medicinal Chemistry Route... 

Though the medicinal chemistry route allowed for the preparation of rizatriptan (1) in a straightforward manner, it suffered from several shortcomings that prohibited implementation of the synthesis on a kilogram scale ... 

Perhaps the advantage of the medicinal chemistry route lies in the flexibility of introducing different alkyl groups on the primary amine through reductive amination on 2-aminoethyl indole 10 and hence allows access to various N, N-dialkyl tryptamine derivatives for structure-activity relationship (SAR) studies. 

While the Medicinal Chemistry route was adequate for the initial discovery stage of drug development, viewed against the need to make multiple kilograms or much larger quantities of compound 1 efficiently, the original route suffered from a few obvious shortcomings. 

In our retro-synthetic analysis, we envisioned the pyrrolidinylethanol side chain could be installed via the Ullmann ether formation or the analogous reachons from the aryl-iodide functional group. The key intermediate 9 (cis) in the Medicinal Chemistry route was not stable under strongly acidic or basic conditions since it was easily isomerized to the thermodynamically more stable trans-isomer 9a via... 

After careful scrutiny of the Medicinal Chemistry route, we evaluated the advantages and shortcomings for the synthesis of 1 ... 

In the original Medicinal Chemistry route, protection of the phenolic OH with a benzoate was carried out prior to N-methylation. In order to simplify the process, the direct N-methylation of hydroxypyrimidinone 3 was investigated. To our delight, methylation of 3 gave a mixture of the desired N-methyl product 31 and the undesired O-methyl by-product 32 as a 70 30 mixture (Scheme 6.7 path b). Surprisingly, methyl ethers 28-30 were not observed at all (Scheme 6.7 path a). 

The Medicinal Chemistry route introduced the oxadiazole fragment prior to installation of the 4-FBA (Scheme 6.1). The overall yield for these two steps was only 37%. The oxadiazole required a two-step synthesis and was a much more expensive reagent than 4-FBA. In order to improve the chemical yield, reduce cost and improve the overall process robustness, we investigated the amidation with 4-FBA prior to installing the oxadiazole moiety. 

With consideration of the shortcomings and advantages of the Medicinal Chemistry route discussed above, a retrosynthesis of 1 was designed to incorporate the convergent coupling of hydroxypyridine 9 and fluoroarene 11 as the key step (Scheme 8.2). Enantioselective preparation of the a-arylpyrrolidine 12 was identified as the key challenge. 

In this chapter the development of the synthesis of taranabant will be presented. In Section 9.1, we focus on evaluation and optimization of the Medicinal Chemistry route, and development of an asymmetric version of this initial route. In Section 9.2 the discovery and implementation of a new asymmetric route will be discussed, and extensions of the utility of this chemistry will also be discussed. Finally, the factors involved in selecting a route as a potential manufacturing approach for taranabant are presented. 

The initial medicinal chemistry route to the azabicyclo[3.3.0]octane-3-carboxylic acid produced the azabicyclo system in a diastereoselective but racemic manner, and required a classical resolution to achieve enantioenriched material (Teetz et al., 1984a, b 1988). Reaction of (R)-methyl 2-acetamido-3-chloropropanoate (43) and 1-cyclopentenylpyrrolidine (44) in DMF followed by an aqueous acidic work-up provided racemic keto ester 45 in 84% yield (Scheme 10.11). Cyclization of 45 in refluxing aqueous hydrochloric acid provided the bicyclic imine, which was immediately reduced under acidic hydrogenation conditions. The desired cis-endo product 46 was obtained upon recrystaUization. The acid was protected as the benzyl ester using thionyl chloride and benzyl alcohol, providing subunit 47 as the racemate. Resolution of 47 was accomplished by crystallization with benzyloxy-carbonyl-L-phenylalanine or L-dibenzoyl-tartaric acid. 

The initial medicinal chemistry route for the early syntheses of sildenafil required -1540 kg solvent/kg API. After four years of development, a modified chemical route and process led to a 93.9% reduction in the total amount of solvent used. The continued optimization of the sildenafil process as it went into commercial production further reduced the amount of solvent used from 94 to 19 kg solvent/kg API. Several highly hazardous solvents were also eliminated from the production scheme including DCM, methanol, and diethyl ether. Upon implementation of solvent recovery, the total amount of solvent required was only 5 kg solvent/kg API produced [17, 20]. The final commercial route used only 0.32% of the total solvent used for the initial synthesis. 

Manufacturing process, route from medicinal chemistry to multi-kilos for clinical study supplies A highly optimized and concise large-scale synthesis of a purine bronchodilator was developed by the Astra Production Chemical company from Sweden. Supplies for the initial biological studies were generated by the medicinal chemistry route shown in Scheme 5. The overall yield was about 14%, which was improved in the environmentally friendly manufacturing process to about 51% (Schemes 6 and 7). 

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