Enantioselective synthesis metolachlor

The chiral switch of the metolachlor was achieved in 1997. It was put on the market with a content of approximately 90% of the Sc active diastereomers. The key step of the large-scale enantioselective synthesis is the catalytic hydrogenation of the MEA imine shown in Figure 17. A mixture of [IrCl(l,5-cyclooctadiene)]2, the chiral diphosphine (i ,5)-xylyphos, iodide (as tetrabutylammonium or sodium salts) and acetic (30%) or sulfuric (at low... 

When it became clear that the two IS-enantiomers of metolachlor were responsible fijr most of the biological activity (see Fig. 1), there was the obvious challenge of finding a chemically and economically feasible production process for the active stereoisomers. Many methods allow the enantioselective synthesis of chiral molecules (that is the preferential formation of one enantiomer instead of the usual racemate). However, the selective preparation of S-metolachlor was a formidable task, due to the very special structure and properties of this molecule and also because of the extremely efficient production process for the racemic product as described above. During the course of the development efforts, the following minimal requirements evolved for a technically viable catalytic system ee S80%, substrate to catalyst ratio (s/c) >50 000 and turnover fi-equency (tof) >10 000 h" . 

During the search for a reasonable enantioselective synthesis route toward the herbicide metolachlor (3), it was tried to immobilize functionahzed Josiphos hgands (Scheme 2) [38]. Silica gel- and polystyrene-bound versions... 

Chiral amines are important intermediates for biologically active eompounds, and enantioseleetive hydrogenation of C=N is an attractive route for their synthesis. Metolachlor is an A-chloroacetylated, alkoxyalkylated ortho-disubstituted aniline, which is the active ingredient of Dual , a herbieide used for maize and other grass crops. The original synthetic route gave a racemic mixture, but 95% of the herbicidal activity arises from the stereoisomer with (S) stereochemistry at the chiral carbon. An enantioselective route to (A)-metolaehlor has now been commereia-... 

Nowadays enantioselective synthesis of the herbicide (5)-metolachlor (Dual Magnum) is, to our knowledge, one of the most successful commercial applications of asymmetric C=N bond hydrogenation. Developed by Blaser and Spindler as a key step in the technical synthesis of (5)-metolachlor, the enantioselective hydrogenation of an imine intermediate 193 proceeds in the presence of an iridium ferrocenyl-diphosphine catalyst bearing a Solvias Josiphos-type chiral ligand (/ )-Xyliphos to give... 

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. 

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. 

Enantioselective Hydrogenation of A -Arylimines in the Synthesis of the Chiral Herbicide, ( S)-Metolachlor... 

Figure 2.54 Old industrial racemic process for the synthesis of metolachlor versus the new enantioselective process developed by Solvias/Novartis. Source adapted from Blaser et al. [312].

Figure 2.55 Preparation and structure of ferrocenyl diphosphine ligands for enantioselective Metolachlor synthesis and dependence of performance on the substituents in the ligand.

The first reported example of enantioselective reductive amination was that of Blaser et al. at Solvias (Scheme 7.7) [2]. At the time, 1999, they were still tweaking the industrial process for metolachlor, the active ingredient of the herbicide Dual , and examined its synthesis via the reductive amination of methoxyacetone with 2 methyl 5 ethyl aniline (MEA, limiting reagent). Working at the 100 mmol scale, they showed that a very low loading of an Ir xyhphos complex, under 80 bar (1160 psi) H2, neat, 50 °C, and 14 h, were optimal. By doing so, a 76% ee with full conversion was achieved. 

Scheme 7.1 The first enantioselective reductive amination synthesis of metolachlor.

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. 

Reductive alkylation using Ir ferrocenyl diphosphine catalysts. Because the synthesis, isolation, and purification of the MEA imine are cost factors, the most attractive method would be an enantioselective reductive alkylation, in analogy to the existing process for rac-metolachlor. At that time, enantioselective reduc-... 

Each year, Novartis manufactures wlOOOO tonnes of the the scheme below. The key to enantioselectivity is the first herbicide 5-Metolachlor, the synthesis of which is shown in step of asymmetric hydrogenation. 

A remarkable increase in catalyst efficiency in SCCO2 as compared to conventional solvents was observed for the Ir-catalyzed enantioselective hydrogenation of imines shown in Scheme 12.12 [34]. Imine hydrogenation is a key step in the commercial synthesis of (S)-metolachlor, a commercial herbicide produced by Novartis in Switzerland. The reaction is approximately zero-order with respect to substrate in CO2 whereas it slows down dramatically at higher conversion in the organic solvent (Fig. 12.8). Thus, the time required for quantitative conversion is reduced by a factor of 20 when changing from the conventional to the supercritical solvent ... 

Xyliphos/Ir-catalysed enantioselective hydrogenation of the imine derivative and synthesis of Metolachlor. 

This chapter summarizes some of the most characteristic results obtained with the use of mainly homogeneous metal complex eatalysts either in the industry or in processes recommended for practical use. These are large seale processes of asymmetric synthesis of the herbicide metolachlor, synthesis of optically pure menthol with the use of chiral iridium and rhodium phosphine complexes, consideration of the synthesis of ethyl 2-hydroxybutyrate as a monomer for the preparation of biodegradable polyesters with use of heterogeneous ehiral modified nickel catalyst, the manufacturing of (fJ)-pantolactone by means of a possible eata-IjTic systems for enantioselective hydrogenation of ketopantolactone, and catalytic systems for the preparation of other pharmaceuticals. 

In the area of asymmetric hydrogenation chiral dighosphines have played a center role since and many applications have been developed. Important new ligands that have been introduced comprise Noyori s BINAP [28], DuPhos (Burk) [29], Takaya s BINAPHOS [30], and Ci-symmetric ferrocene-based ligands introduced by Togni [31]. Industrial products, of which the synthesis uses enantioselective phosphine-derived metal-catalysts are for instance menthol, metolachlor, biotin, and several alcohols, e.g. (R)-1,2-propanedioI, For details about the applications the reader is referred to reviews and references therein [32, 33]. Substituents and backbones have an enormous influence on the performance of the ligands, but usually rationalizations are lacking. 

SCHEME 30 J7. Enantioselective hydrogenation of C=N bond in the synthesis of (5 -metolachlor. 

After taking up the challenge for the synthesis of (5)-metolachlor on an industrial scale, Blaser reported on the very first example of asymmetric reductive amination and succeeded to synthesize the desired (5)-enantiomer of metolachlor 77 up to 78% ee ° Blaser optimized the reaction condition where the 2-methyl-5-ethylaniline (MEA, 79) was treated with 1.2 equivalents of dry methoxyacetone (MOA, 78), 0.01 mol% Ir-xyliphos catalyst 81 in the presence of tetrabutylammonium iodide (TBAI), and a small amount of trifluoroacetic acid in cyclohexane as the solvent under 80 bar hydrogen pressure at 50 °C. Within 16 hours, almost complete conversion was reached furnishing the chiral amine 80 with 99% conversion and 78% ee. Upon chloroa-cetylization, 80 afforded the desired compound metolachlor 77 without any loss of enantioselectivity (Scheme 39.20). 

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