N-[4-(3,4-Dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine, sertraline imine (3), is an intermediate for the synthesis of Zoloft, sertraline hydrochloride (1). A cleaner, simpler, and more efficient alternative to the Schiff base-mediated formation of sertraline imine has been developed and is presented in this paper. The condensation reaction between 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalone, sertraline tetralone (2), and monomethylamine was carried out in ethanol, without the need for classical dehydrating agent, such as TiCl4, or more novel approaches, such as molecular sieves, both of which produce hazardous byproducts and solid wastes. The low solubility of the imine 3 in this type of solvent is exploited, such that the reaction equilibrium favorably enhances the imine formation. Furthermore, an improved and highly selective catalytic reduction of 3 with Pd/CaCO3 catalyst in ethanol as the reaction solvent, followed by the resolution of the racemic cis isomer (6) with d-(−)-mandelic acid results in a more efficient telescoped commercial process to (1S-cis)-4-(3,4-dichlorophenol)-1,2,3,4-tetrahydro-N-methyl-1-naphthalen-amine mandelate, sertraline mandelate (4). This new process has been implemented commercially and eliminates the use of hazardous material such as TiCl4, significantly reduces undesirable byproducts, reduces the number of intermediate isolations, and improves the overall process yield and productivity on industrial scale.

The heat of reaction is an important parameter in the safe, successful scale-up of chemical processes. Reaction heat data is used to calculate the potential adiabatic temperature rise of the desired reaction, providing a worst-case scenario for rapid reaction of the entire batch with no heat loss to the surroundings. The data is used in parallel with information regarding the thermal stability of reaction mixtures/components and an intimate knowledge of the process to analyze the risk associated with running it on-scale. If the level of risk is judged to be unacceptable, the analysis can be used to make rational process changes in order to reduce the risk to an acceptable level. The Pfizer global process safety network provides a heat of reaction for all processes run in our kilo laboratories, pilot plant, and manufacturing facilities. In general, there are two methods used to determine reaction heats: (1) experimental measurement using some form of calorimetry, or (2) estimation techniques. Since experimental measurement is not always practical, accurate, or necessary, we set out to show that estimation techniques could be used reliably and efficiently to provide heat of reaction data for a wide range of chemistry. To gain confidence in our ability to accurately predict reaction heats, we carried out a comparative study of measured versus estimated values. The results of this study will be discussed in detail, including rationalization of any significant disparity through further analysis to more fully understand the limitations/advantages of both techniques. To help ensure consistent application of measurement/ estimation across the Pfizer global process safety network, we developed a decision tree to determine whether estimation or measurement should be considered for a particular reaction. In order to maximize the efficiency gain and to ensure accuracy in our estimations, we have created a heat estimation database that allows for (1) rapid archival/retrieval of model compounds, (2) calculation of reaction heat and adiabatic temperature rise, and (3) reporting/documentation of the results.

An on-line near-infrared (NIR) spectroscopic method has been developed to determine in situ the endpoint of a bulk pharmaceutical hydrogenation reaction in a loop hydrogenator. This hydrogenation employs a 5% palladium-on-carbon catalyst with tetrahydrofuran (THF) as the reaction solvent. The traditional test for monitoring the endpoint of the hydrogenation is a gas chromatographic procedure that requires an estimated 60 min from the time a sample is taken to the point where the analysis results become available. The use of NIR spectroscopy in an on-line mode of operation allows spectra to be collected every 2 min and thereby significantly improves response time and result availability. The need for obtaining results in “real time” stems from the creation of undesired side products if the reaction is allowed to continue past the optimal endpoint. If the reaction is not stopped before these side products reach a level of approximately 0.8% (wt/wt), the batch requires additional purification at considerable time and cost. A partial least-squares model was constructed, validated, and successfully used to determine the endpoint of subsequent batches.