Medicinal Route

Medicinal chemists at Merck prepared 2 in eight linear steps with an overall yield of 12%. Their starting material, 4-chloro-3-cyanoanline (3), was reacted with 

Several limitations of the original method were identified at the beginning of the project as follows  

1) When we started this project, the starting material 3 was not commercially available on a large scale (currently, large amounts of 3 are available for around 1000 per kg). 

3) Chiral separation of the racemic product required silica gel separation of bis-camphanyl derivatives. 

4) Furthermore, camphanyl chloride is quite expensive ( 113.5 per 5g from Aldrich) and resolving a racemic mixture at the final step of the preparation is not an efficient method for large scale synthesis. 

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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],... 

The major issue for the large scale preparation of our target 1 was the preparation of the cyclopentanone 2. With the exception of 2, we felt the original Medicinal route was suitable for the large scale preparation with standard development optimization. Thus, the outline of this section is ... 

Scheme 7.1 Medicinal route for the preparation of the cyclopentane core 10.

Keywords Drug delivery systems Targeted drug delivery Nanoparticles Nanobiotechnology Personalized medicine Routes of drug administration Drug delivery devices Controlled release Protein/peptide delivery Drug formulations... 

The starting point for the design of any practical synthesis in a process group is the medicinal chemistry route. Most often the tatter is designed for versatility not efficiency. However, it is always a good source for excellent ideas for designing a practical route, and it is an excellent source for information on the characteristics of key intermediates. The medicinal route to 1 (Figure 2) built up the key 2-hydroxymethyl carbapenem from the commercially available protected... 

When presented with the medicinal route (figure 2) several issues immediately stood out number of linear steps, chromatography, low temperature reactions, low to moderate yields, distillation for purification and use of expensive reagents. Since the presentation of a compound to our group carried with it the expectation of near immediate supply of API for advanced in vitro and in vivo testing, foremost in our thoughts was to develop a route, to set the final synthetic steps and produce 100+g quantities quickly. 

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