Crystallization process synthesis costs

The three most interesting routes identified between 1990 and 1995 are compared in Table 12.2 in terms of manufacturing costs, investment, environmental impact, and complexity. Although chiral chromatography is relatively complex compared to diastereomeric salt crystallization or synthesis from a chiral precursor, these figures are clearly in favor of the MCC process, mainly because of manufacturing costs and environmental impact. 

The effectiveness of the experimental design applied to the zeohte synthesis has been successfully tested. The advantages of the experimental design are the following reducing the number of experiments results in a decrease in the investigation time and the reduction of its costs. Moreover, it is possible to separate the individual effects from the interaction of the same. There is also a possibility to determine the direction of the crystallization process due to expression of all effects in terms of numerical values. 

At present, the resolution of racemates via dassical diastereomer crystallization as a method of chiral target production is somewhat hampered by a rapid development of other methods, mainly asymmetric synthesis, including biocatalysis [9] and enantioselective chromatography [11], Diastereomer crystallization remains, however, an important technique because of its two fundamental advantages, especially attradive for industry. First, process development (practical know-how and accessibility to wide libraries of the resolving agents) is usually fast and easy. Second, the cost is often low compared to other methods. 

Finally, the strategy should be of interest because it only requires two reactions steps. This is possible because ketimine isolation is not required, and while rarely discussed can be time consuming, may provide mediocre yield, and unnecessarily lengthens the synthesis of amines. Furthermore, all the reagents are already in use by the pharmaceutical industry, a broad range of ketone substrates are suitable (even aliphatic ketones), either enantiomeric form of the a-chiral amine product can be produced, and the process has been demonstrated on a 20 g scale. The method is compatible with acetonides, ethers, silyl ethers, bulky esters, secondary amides, tertiary amides, carbamates, urethanes, etc. With these beneficial qualities noted, the method suffers when non-branched 2-alkanones are used (product des <75%). In these cases, HCl salt formation allows further enrichment via crystallization, alternatively stoichiometric Yb(OAc)3 can be used during the reductive amination to allow enhanced de. Both of these solutions require additional processing time and/or cost and require consideration before scale-up. 

---