Merck ketone reduction

L-699,392, Merck s drug for the treatment of chronic asthma, is an example of asymmetric amplification on an industrial scale (see Figure 13.19). The ketone reduction can be carried out stoichiometrically with a borane-(-)-a-pinene reagent. The terpene natural products are often mixtures of isomers and enantiomers. A reagent prepared from 98% optically pure (-)-a-pinene gives a product e.e. of 97%, but a reagent prepared from less expensive 70% optically pure (-)-a-pinene yields a product e.e. of 95%, which can be pushed to >99.5% by using an excess [30]. 

This topically active carbonic anhydrase inhibitor is a powerful controller of the elevated intraocular pressure associated with glaucoma, and has been prepared by Merck in > 32% yield in a multistep synthesis starting from (R)-3-hydroxybutyrate [49]. Although the key ketone reduction step has been recently improved by researchers at Zeneca by replacing a chemical process with a biological one [50], the Merck synthesis well illustrates the potentialities of the approach to enantiomerically pure drugs based on the use of chiral non-racemic substrates. 

In Figure 13.19 we have shown a route to L-699,392 published by Merck involving three steps based on homogeneous catalysts, viz. two Heck reactions and one asymmetric hydrogen transfer reaction, making first an alcohol and subsequently a sulphide [21], Stoichiometric reductions for the ketone function have been reported as well [22] and the Heck reaction on the left-hand side can be replaced by a classic condensation reaction. L-699,392 is used in the treatment of asthma and related diseases. 

Tellers et from Merck optimized this catalyst system for the reduction of an a-substituted ketone that was needed as an intermediate for a drug development candidate. They obtained the best result (93 % ee) with ligand (L) in a method using 90psi hydrogen pressure that was suitable for use at large scale (Figure 1.26). 

Reduction of ketones. Merck chemists3 have used oxazaborolidine-catalyzed reduction of a ketone for introduction of chirality in a synthesis of MK-927 (4), a carbonic anhydrase inhibitor. They found that even traces of water decreases the enantioselectivity in reductions of 2. Highest enantioselectivity (98 2) is obtained by... 

An excellent application of the Narasaka reduction is a diastereoselective synthesis by Merck scientists of 7, a structurally novel analog of the natural product compactin (8)7, which is a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase8 (Scheme 4.1e). The key step in the construction of the P-hydroxy-8-lactone moiety in 7 is the highly diastereoselective reduction of the P-hydroxy ketone 9 using a triethyl borane/sodium borohydride system. The yyn-diol 10 was obtained in high yield and with a remarkably high level of diastereoselectivity. 

The Merck Research Laboratories described one of the rare approaches to use immobilized alcohol dehydrogenase (ADH) - in this case for the enan-tioselective reduction of ketone 16, a key intermediate for the production of the... 

Indene Oxide (ChiRex). The epoxidation of indene is an attractive route to cis l-amino-2-indanol, an intermediate in the Crixivan synthesis (HIV protease inhibitor of Merck) and ligand for BH3 reductions of ketones (60a,61). 

Ru-Cataiyzed Transfer Hydrogenation of Ketones (Merck, Lanxess). Two Ru-catalyzed transfer hydrogenations have been developed and applied on a multi-10-kg scale. Two variants are applied, one based on Ru/amino alcohol complexes with iPrOH/base and the other based on Ru/Ts-dpen complexes with HCOOH/NEta as a reducing system, respectively. Generally, good enantioselectivities have been obtained for several aryl ketones but with lower activities than for comparable hydrogenation reactions described above (see, eg, the results for 3,5-bis-trifluoromethyl-acetophenone described above (72)). Merck (77) has developed a process for the reduction of 3,5-bis-trifluoromethyl-acetophenone, and Lanxess has applied Noyori s Ru/Ts-dpen system to reduction of aryl y3-keto esters on up to a ton scale (78). 

The route via racemic carbinol 7 requires its derivatization into a mixture of dia-stereomers, their separation by crystallization and final removal of the derivatizing agent [16]. Moreover, the wrong enantiomer of ferf-alcohol 7 cannot be racemized via oxidation-reduction, a process that was successfully applied in the S5mthetic approach to sertraline, as presented in Chap. 7. At Merck Research Laboratories, the enantioselective alkynylation of trifluoromethyl ketone 5 by cyclopropylacety-lene 6 was therefore studied as the key step in the asymmetric s5mthesis of enan-tiopure efavirenz (5)-l (Scheme 13.2) [16]. The observation that the Li-acetylide of... 

In 2006, the group from Merck reported an interesting utilization of various commercially available ketoreductases (KREDs) for the reduction of a.p-unsaturated ketones 12 and 13 for the synthesis of chiral allylic alcohols 14 and IS [19]. This enzymatic reduction combined with a dynamic kinetic racemization proved to be a very powerful method for the production of optically pure product in excellent yield starting from a racemic ketone, as shown in Scheme 12.7. 

Another relevant example is provided by the enzymatic s)mthesis of the antidiabetic, sitagliptin, which was codeveloped by Merck and Codexis workers [67] to replace a rhodium-catalyzed, high-pressure, as5mimetric hydrogenation of an enamine. If involves an overall enantioselective reductive amination of a ketone using an (R)-transaminase-catalyzed reaction with isopropylamine (Figure 1.5). The starting point was an (R)-selective transaminase, which showed no activity with the ketone substrate. In silico studies were employed to identify whaf was needed to be able to fif fhe... 

An example of Ellman s methodology as applied to a chiral reduction has been described in a drug discovery programme undertaken by Merck to develop selective non-steroidal glucocorticoid receptor agonists such as 243. Ketone 238 was converted to ketimine 239 by reaction with (i )-(-l-)-tert-butanesulfinamide and titanium tetraethoxide. Asymmetric reduction was effected by treatment with sodium borohydride followed by deprotection under acidic conditions to afford amine 242. The chiral product was subsequently converted to glucocorticoid receptor agonist 243 (Scheme 14.80). 

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