Metolachlor process

Cost of the catalyst. The transition metals used, such as rhodium, ruthenium, iridium or palladium, are extremely expensive. The same holds for complicated chiral ligands that often take six to ten synthetic steps for their production. An excellent way to beat these costs is to develop a highly active catalyst. A substrate catalyst ratio (SCR) of 1000 is often quoted as a minimum requirement. In the celebrated Metolachlor process, a SCR of over 100000 is possible. Factors determining the rate of reaction are numerous and often poorly understood. Deactivation of the catalyst also has a profound effect on the overall rate of the reaction. 

Until now, only a small number of industrial applications has been reported. The metolachlor process was originally was developed in the Central Research Laboratories of Ciba-Geigy (now Solvias), but is now operated by Syngenta. With a volume of >10 000 ty it is the largest known enantioselective catalytic production process [24—26]. 

Another good example is the Metolachlor process, see H.-U. Blaser, Adv. Synth. Cafa/,344, 17 (2002). 

Figure 3.36 a The original Josiphos ligand b the Ir-xyliphos complex used in the Ciba-Geigy metolachlor process. 

Fig. 2.6 World-record holder in asymmetric catalysis. With 10 000 t or more being produced per annum at an unsurpassed catalytic efficiency and effectiveness, the metolachlor process is unique.

As a rule, the asymmetric catalytic reaction is part of a more extensive multi-step synthesis. This is particularly pronounced for the cases where the active substance is the goal of the development work (categories A and D), but also for the more simple intermediates described in B and C. This means that the catalytic step has to be integrated into the overall synthesis and therefore, the route selection is a very important phase of process development. Very detailed discussions of this aspect can be found, e.g., in the contributions of Wirz et al. (p. 385, 399), Netscher et al. (p. 71) or Caille et al. (p. 349). It is important to realize that the effectiveness of the catalytic step is only one, albeit often an important, factor but that it is the cost of the overall synthesis which is decisive for the final choice as to which route will be chosen. The comparison of competing routes is not always easy and different approaches can be found in the contributions of Blaser et al. (p. 91), Pes-ti and Anzalone (p. 365), or Singh et al. (p. 335). In some cases, the overall synthesis is actually designed around an effective enantioselective transformation as for example described for the metolachlor process by Blaser et al. (p. 55). This situation will become rarer when more catalysts with well described scope and limitations will be commercially accessible. 

In comparison to Rh and Ru catalysis, Ir-catalyzed hydrogenation developed much later and still is used much less in industry. The discovery by a Ciba-Geigy team [107] that Ir catalysts are superior to Rh and Ru for the hydrogenation of N-aryl imines, culminating in the development of the (5)-metolachlor process (see below) gave Ir catalysis a strong boost. 

The substrate/catalyst ratio is 75,000, and one million turnovers are achieved in six hours, giving a product with an ee of 80%. A higher ee can be obtained, at lower substrate/catalyst ratios, but are not actually necessary for this product. This process will be used to produce several thousands tons per annum of (S)-metolachlor, to replace the previously marketed racemic metolaclor. 

Enantiomerically pure amines are extremely important building blocks for biologically active molecules, and whilst numerous methods are available for their preparation, the catalytic enantioselective hydrogenation of a C=N bond potentially offers a cheap and industrially viable process. The multi-ton synthesis of (S)-metolachlor fully demonstrates this [108]. Although phospholane-based ligands have not proven to be the ligands of choice for this substrate class, several examples of their effective use have been reported. 

The formation of dimers and trimers is a major issue in hydrogenations with iridium catalysts. In the context of developing an industrial process to produce (S)-metolachlor via an enantioselective imine hydrogenation (see Chapters 34 and 37), Blaser et al. investigated the causes of catalyst deactivation in the iri-dium/bisphosphine-catalyzed hydrogenation of DMA imine (Scheme 44.11) [84]. 

Metolachlor is the active ingredient of Dual , one of the most important grass herbicides for use in maize and a number of other crops. In 1997, after years of intensive research. Dual Magnum, with a content of approximately 90% (I S)-diastereomers and with the same biological effect at about 65% of the use rate, was introduced into the market. This chiral switch was made possible by the new technical process that is briefly described below. The key step of this new synthesis is the enantioselective hydrogenation of the isolated MEA imine, as depicted in Figure 1.3. 

Togni and Spindler introduced non-C2-symmetric ferrocene-based Josiphos-type ligands [47], which are effective for rhodium-catalyzed hydrogenation of a-(acetami-do)cinnamate, dimethyl itaconate, and / -keto esters. The Josiphos-type hgands have been applied as the stereodefming step in a number of industrial processes, as exemplified the use of PPF- Bu2 for the commercial synthesis of (-i-)-biotin [48], and Xyli-Phos for the preparation of the herbicide (S)-metolachlor [49]. 

An even more impressive example of catalytic efficiency is the manufacture of the optically active herbicide, (S)-metolachlor. The process, developed by Novartis [129], involves asymmetric hydrogenation of a prochiral imine, catalysed... 

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