Process Mass Intensity (PMI) for (a) process in organic solvents, (b) process in water with surfactants.

A novel Green Chemistry Process Scorecard was developed to assess the environmental impact of chemical production processes to manufacture the Active Pharmaceutical Ingredients (API) within our portfolio. These new metrics not only cover the resource consumption from the overall chemical synthesis, but also consider the use of Substances of Concern and the number of chemical transformations. The Process Mass Intensity (PMI), i.e. the ratio of accumulated kilogram quantities of materials per kilogram of API, is used to quantify the resource consumption. An 'eco-label' for specific APIs is used to visualize the environmental impact from their chemical synthesis. For an overview of the environmental impact of a complete product portfolio, a diagram of PMI or total waste quantity vs. the number of synthetic steps can also be used as a visualization tool to identify chemical syntheses with a high need for process improvements. Implementation of this process led to a dramatic change of mindset within the organization. It now supports and drives the decision making at Chemical and Analytical Development, and helps to trigger new projects more readily for sustainability reasons.

The formation of hydrazoic acid HN 3 is inherent to many azide processes due to the presence of small amounts of protic components in the reaction mixtures. Hydrazoic acid is an unstable component which may decompose violently. To ensure safe working conditions during the development or the production of azides, the lower decomposition limit (LDL) of this substance in a nitrogen atmosphere was determined using a 5-L explosion sphere. No decomposition could be observed for HN 3 concentrations below 10%. Moreover, the influence of solvent vapors was investigated to demonstrate that they can be used to inhibit the decomposition reaction of hydrazoic acid.

With the redesign of three chemical steps, the throughput of the valsartan manufacturing process could be significantly increased, and with the substitution of chlorobenzene with cyclohexane in the bromination of 4′-methyl-biphenyl-2-carbonitrile (6) to 4′bromomethyl-biphenyl-2-carbonitrile (5), halogenated solvents are no longer used in the whole valsartan production process. The alkylation of (S)-2-amino-3-methyl-butyric acid benzyl ester (8) with 4′-bromomethyl-biphenyl-2-carbonitrile (5), and the acylation of (S)-2-[(2′-cyano-biphenyl-4-ylmethyl)-amino]-3-methyl-butyric acid benzyl ester (4) to (S)-2-[(2′-cyano-biphenyl-4-ylmethyl)pentanoyl-amino]-3-methyl-butyric acid benzyl ester (3) were thoroughly modified. In the acylation of 4 to 3, N-ethyldiisopropylamine was replaced by aqueous sodium hydroxide by using the conditions of the Schotten-Baumann reaction, leading to a better quality of intermediate 3. In the alkylation of 8 with 5, N-ethyldiisopropylamine was indirectly replaced by aqueous sodium hydroxide. The reaction runs under homogenous conditions with (S)-2-amino-3-methyl-butyric acid benzyl ester (8) acting as acceptor for hydrobromic acid; recycling of 8 is performed by extraction with aqueous sodium hydroxide.

Hydrazoic acid (HN 3 ) is formed during the synthesis of tributyltin azide and in the following cycloaddition to prepare a tetrazole ring compound. The formation of this substance is inherent to many azide processes because small amounts of protic components cannot be avoided. Hydrazoic acid is a very toxic volatile compound, which has highly explosive properties. Under certain conditions (presence of impurities in the reaction mixture), the gas concentration can come close to the decomposition limit. Therefore, online monitoring of this gas concentration is essential to ensure the process safety. FT-IR and FT-NIR experiments were performed in the laboratory scale to calibrate the spectrometers. Due to the possibility of using quartz light fiber cables, a FT-NIR spectrometer was installed to monitor the hydrazoic acid concentration in the industrial scale. * To whom correspondence should be addressed: Building WSJ-145.11.54, Scheme 1. Synthesis of tri-n-butyltin azide Scheme 2. Cycloaddition of tri-n-butyltin azide to a nitrile to form a tetrazole ring compound Scheme 3. Postulated mechanism of the formation of hydrazoic acid in presence of protic components 2 HN 3 f H 2 + 3 N 2