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12 Holton, R.A., Somoza, C., Kim, H.-B., Liang, F., Biediger, R.J., Boatman, P.D., Shindo, M., Smith, C.C., Kim, S., Nadizadeh, H., Suzuki, Y., Tao, C., Vu, P., Tang, S., Zhang, P., Murthi, K.K., Gentile, L.N., and Liu, J.H. (1994) J. Am. Chem. Soc., 116, 1597-1598 and 1599-1600. 13 US Patent 5,136,060-issued August 4, 1992. 14 Denis, J.N., Greene, A.E., Guenard, D., Gueritte-Voegelein, F., Mangatal, L., and Potier, P. (1988) J. Am. Chem. Soc., 110, 5917-5919. 15 Tabata, H. (2004) Adv. Biochem....

Crystallization Induced Diastereomer Transformation

CIDT is a hybrid process involving selective crystallization of desired diastereomer and in situ epimerization of undesired diastereomer. Figure 9.6 illustrates the system, in which two solid diastereomers, A- and B- can equilibrate with each other via their dissolved counterparts A- and B- The solubility products of A and B are given by LA A- and LB Bj , and the equilibrium constant for A and B in solution is given by K B AJ. For LAK > LB ata temperature below their melting points, the...

Cooh

We assumed, if details were not known, that solvents would be recycled by distillation and that this would involve a 10 loss. However, the organic chemist' s penchant for using different solvents for the various steps in multistep syntheses makes recycling difficult owing to cross contamination. A benchmarking exercise performed by the GCI Pharmaceutical Roundtable (see above) revealed that solvents were a major contributor to the E factors of pharmaceutical manufacturing processes. Indeed, it...

Greenness Assessment of Pharmaceutical Processes and Technology

In the past decade, several methods have been developed which focus on assessing pharmaceutical processes based on ecological, economic, and efficiency criteria. Heinzl 25 proposed a method to assess pharmaceutical processes as they progress from R& D to manufacturing based on three indices mass loss, environmental impact, and economics. This method begins with the definition of process development goals after which the mass loss indices (MLIs) are calculated. MLIs are calculated for by-...

Dynamic Resolution Processes

The integration of a catalyzed kinetic enantiomer resolution and concurrent racemization is known as a dynamic kinetic resolution (DKR). This asymmetric transformation can provide a theoretical 100 yield without any requirement for enantiomer separation. Enzymes have been used most commonly as the resolving catalysts and precious metals as the racemizing catalysts. Most examples involve racemic secondary alcohols, but an increasing number of chiral amine enzyme DKRs are being reported. Reetz,...

Dcc

I n recent years, increasing numbers of crystallizable compounds have been developed as amorphous APIs as a means of improving their pharmaceutical delivery 10 . In addition to these, some ' difficult-to-crystallize' substances, such as peptide-like drugs, also need to be developed as amorphous APIs. The manufacturing process of such compounds has to provide high-quality amorphous powders without crystallization at the final step. One of the possible purification methods is extraction using...

Integrated Pollution Control

In most parts of the world the local or national regulator(s) responsible for the environment also have powers to limit the amount of material that may be released from a manufacturing process into the atmosphere or local watercourses. In some cases, where the factory effluent is discharged into a sewerage system, this control may be exerted indirectly via limits on the eventual release by the sewerage system operator. In the United States a comprehensive document has been published by the EPA...

Sertraline

Sertraline is the active pharmaceutical ingredient API in Pfizer's antidepressant Zoloft 25 . The developed commercial process employs an SMB chromatographic resolution of tetralone Scheme 13.10 in gt 99 ee followed by diastereose-lective reductive amination to give 95 sertraline cis-isomer and 5 trans-isomer the 4R -tetralone can be racemized with an alkoxide base 8 . Asymmetric processes to sertraline have been described 26 . Our studies started with the original patented process involving...

Sitagliptin through Diastereoselective Hydrogenation of an Enamine The PGA Enamine Ester Route

The first-generation route to sitagliptin was used to prepare over 100 kg ofmaterial for early clinical studies. Many aspects of this route made it a viable one for the large-scale manufacture and commercialization of sitagliptin. Two high-value intermediates, P-amino acid and triazole, are coupled together close to the end of the synthesis, rendering it highly convergent, short and efficient. The overall yield for the process was 45 for the longest linear sequence of nine steps, which...