The Synthesis of Metolachlor

Indeed, the imine intermediate 142 in the synthesis of metolachlor has been reduced in 97% ee using an iridium complex of the phospholane-containing ligand 55 [80]. 

The synthesis of metolachlor (17) is described in detail elsewhere (Chapter 9). This compound is sold as an enantioenriched compound (—80% ee) rather than the pure enantiomer due to economic constraints. 

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].

Show reagents and experimental conditions for the synthesis of Metolachlor from these four organic starting materials. Your synthesis will most likely give a racemic mixture. The chiral catalyst used by Novartis for reduction in Step 2 gives 80% enantiomeric excess of the S enantiomer. 

Reductive amination is a well-known methodology in organic synthesis as is evident from the literature reviews. There are a large number of reports available in the literature that deal with the asymmetric imine reduction, but there are few reports available on asymmetric reductive amination. The asymmetric version of this brilliant methodology was introduced in 1999 when Blaser et al. reported on the first asymmetric reductive amination for the synthesis of metolachlor. ... 

An even more impressive example of catalytic efficiency has recently been disclosed by Novartis (Bader and Bla.ser, 1997). The key step in a proce.ss for the synthesis of the optically active herbicide, (S)-metolachlor involves asymmetric hydrogenation of a prochiral imine catalysed by an iridium-ferrocenyldipho-sphine complex (see Fig. 2.36). 

Kumada s use of a ferrocene moved away from the C2-symmetrical motive, as planar chirality can result from the two ferrocene rings having different substituents. The development of this class of ligand is well documented [5, 125-127]. The best-known uses of these ligands are for reductions of carbon-heteroatom multiple bonds, as in the synthesis of the herbicide, Metolachlor [128, 129]. 

The raw materials used in the commercial synthesis of metolachlor include 2-ethyl 6-methyl-aniline, which can be built up from... 

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

The synthesis of racemic metolachlor was accomplished by condensation of 2-methyl-6-ethyl-aniline (MEA) with methoxyacetone, followed by Pt/C reduction and chloroacetylation according to Figure 16. 

Scheme 9.20 illustrates the last key steps in the synthesis of (S)-metolachlor. Early on, researchers at Novartis turned their attention to creating conditions for an asymmetric, homogeneous, metal-catalyzed hydrogenation of imine 83 to... 

For a rendition of the story behind the research and development of the asymmetric hydrogenation in the synthesis of (S)-metolachlor, see H.-U. Blaser, Adv. Synth. Catal., 2002, 344, 17. 

The syntheses of ibuprofen, (S)-metolachlor, and (-)-menthol represent only three of the numerous uses of soluble transition metal complexes to catalyze, often stereoselectively, key steps in the production of biologically important compounds in the laboratory or on an industrial scale. Discussions in Chapter 12, especially with regard to asymmetric conditions, will explore more fully the use of these catalysts in the synthesis of other organic compounds. 

Scheme 7.1 The first enantioselective reductive amination synthesis of metolachlor.

Table 1. Comparison of possible routes for the synthesis of (S)-metolachlor...

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. 

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

In recent years an amazing number and variety of chiral ferrocene ligands have been used in asymmetric catalysis. A quite remarkable example of the great utility of chiral ferrocene hgands is the synthesis of a precursor of the herbicide (IX)-metolachlor by an Ir-Xyliphos-catalysed asymmetric imine hydrogenation reaction (Scheme 3.19). 

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. 

The preparation of Metolachlor proved to be the second example (after the synthesis of (-)-menthol) of using an asymmetric catalysis on a large scale 100,000 tons per year Metolachlor was produced in optically active form using this procedure. 

Following is a retrosynthetic analysis for the synthesis of the herbicide (S)-Metolachlor from 2-ethyl-6-methylaniline, chloroacetic acid, acetone, and methanol. 

Another commercial success, this time for Ciba-Geigy, now Novartis, has been the synthesis of the herbicide, (5)-metolachlor, from the imine shown below using an iridium catalyst. The key advantage of iridiumjs- the extremely impressive rate (>200,000 turnovers h ) and catalyst lifetime ( 10 turnovers) at the... 

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

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