The Process Research Synthesis

The synthesis of losartan potassium (1) by the process research chemists at Merck is outlined in the following (Griffiths et ak, 1999 Larsen et al., 1994). Phenyltetrazole (8) is protected as the trityl phenyltetrazole 9 (Scheme 9.3). Ortho-lithiation of 9 followed by quenching with triisopropyl borate afforded boronic acid 10 after treatment with aqueous ammonium chloride. Reaction of glycine (11) with methyl pentanimidate (12) in a methanol/water mixture yielded (pentanimidoylamino) acetic acid (13), which underwent a Vilsmeier reaction with phosphorous oxychloride in DMF followed by hydrolysis to give imidazole-4-carbaldehyde 14 in moderate yield. 

We thank Lun Teh Yuen for technical expertise in the synthesis work. Louis D. Scampavia also contributed in the organic synthetic work. ESCA analyses were carried out by Dr. C. L. Kibby. We thank the Process Research Department of Chevron Research Company for support over the course of this study. 

An example of a typical validation scheme for a chemical synthesis in process research is given in Fig. 1. In this example the process research chemist sets up a number of experiments. The most important question presented by the chemist to the analytical department is Is the variability of the analytical process small compared to the variation performed in the process validation [1, 2],... 

The original manufacturing formula (HV) and five variations are performed in the first step of the synthesis. Six samples are analysed. The results of these six analyses are used to assess the validation of this process step. In this case validation of the analytical method is a prerequisite for any decision that is made about the validity of the process. This information is needed before the process research chemist can start variations of the process otherwise it is possible that the data received cannot be assessed. The difficulty of assessing the data of the process validation results from the fact that the data is influenced by the analytical method and the uncertainty of the chemical process. If the uncertainty of the analytical method is larger or in the same range as the variations of the chemical process, assessment of the data is not possible. 

In the prenomination phase, the polymorphism screen will be limited due to the amount of compound available, and strategies must therefore be employed to reflect this situation. Initially, the Medicinal Chemistry batches should be analyzed to gain preliminary evidence for the propensity of the compound to show variations in the solid-state form of the compound. It is possible that the Process Research and Development department will also be working on the synthesis and crystallization of the compound. Therefore, a useful starting place for searching for polymorphs is to screen the material produced by the process chemists as they attempt to optimize the crystallization conditions. Work can also be undertaken by the Pharmaceutical and Analytical departments, in parallel, to use some of the above methods to generate polymorphs. However, these initial studies will probably have to be carried out on a micro- or semi-microscale. 

With sufficient material in hand from the feared benzyne-osmium sequence to support immediate drug development activities, our process research efforts turned to establishing a preferred commercial synthetic route to varenicline (1). Given the extensive and highly successful development of the discovery synthesis from 6 to varenicline in early scale-up campaigns, and the supportive studies by the safety laboratory, the process research task therefore became clear— to establish a reliable supply of benzazepine 6. 

The first enantioselective route to 1 offered several advantages over the existing route many more crystalline intermediates, early introduction of asymmetry, no oxime reduction, convergency, and no chromatography. There were still some problems that needed fixing, in particular the extra BOC group manipulations and only moderate selectivity on the CBS reduction. Section 6 describes the process research that addressed these issues, culminating in the second enantioselective synthesis of 1. Section 5 describes a key result that helped us get there. 

The synthetic 21-amino acid polypeptide KL4 [(KL4)4K] was developed as a pulmonary surfactant to be used in treatment of respiratory distress syndrome (RDS) in infants (IRDS) and in adults (ARDS). KL4 is designed to contain intermittent hydrophobic (Leucine) and hydrophilic (Lysine) regions to mimic the structure of the natural surfactant protein B (SP-B). The solution phase synthesis of KL4 is a challenging task. The protection and deprotection patterns, the possibility of diastereomer formation in every coupling step, the solubility (or lack of it) of the different fragments and the isolation of intermediates are among the potential problems that face such a synthesis. The process research work resulted in a successful and efficient large scale synthesis of KL4 which will be discussed. 

The Discovery synthesis shown in Scheme 3 was linear by design and, therefore, less efficient for larger scale manufacture. As is always the case, however, the Process Research and Development group benefitted greatly from this previous work. The synthesis of the quinazolinone core 2 will be described in more detail later. The major issues widi the Discovery route from a scale-up perspective were the preparation and isolation of the dialdehyde 3 and the subsequent aldol addition/elimination to form 1, which had the potential for "dimer" formation by the reaction of 1 with a second molecule of 2. Finally, a reductive amination of 1 with diethyl amine provided CP-392,110 (racemic CP-465,022), albeit with variable yields. 

There has been considerable research into the production of substitute natural gas (SNG) from fractions of cmde oil, coal, or biomass (see Euels SYNTHETIC, Euels frombiomass Euels fromwaste). The process involves partial oxidation of the feedstock to produce a synthesis gas containing carbon... 

The first demonstration of catalytic conversion of synthesis gas to hydrocarbons was accompHshed ia 1902 usiag a nickel catalyst (42). The fundamental research and process development on the catalytic reduction of carbon monoxide was carried out by Fischer, Tropsch, and Pichler (43). Whereas the chemistry of the Fischer-Tropsch synthesis is complex, generalized stoichiometric relationships are often used to represent the fundamental aspects ... 

In the words of a recent paper on MSE education (Flemings and Cahn 2000), chemistry departments have historically been interested in individual atoms and molecules, but increasingly they are turning to condensed phases . A report by the National Research Council (of the USA) in 1985 highlighted the opportunities for chemists in the materials field, and this was complemented by the NRC s later analysis (MSE 1989) which, inter alia, called for much increased emphasis on materials synthesis and processing. As a direct consequence of this recommendation, the National Science Foundation (of the USA) soon afterwards issued a formal call for research proposals in materials synthesis and processing (Lapporte 1995), and by that time it can be said that materials chemistry had well and truly arrived, in the... 

During the chemistry forming (synthesis) stage for product/ process research and development to focus on the chemistry and process (refer to Section 4.2). 

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