Amines resolution

Around 70% of the pharmaceuticals on the market are chiral, and approximately one third of these are chiral amines [1], This represents a substantial number of achve drug substances that are typically manufactured at a scale of 1-100 l y . The three main manufacturing processes used to introduce these homochiral centers are from optically active starting materials (the so-called Chiral Pool approach), by asymmetric synthesis and by resolution. The last technique is widely practiced but results in waste of the undesired enantiomer. This chapter deals with developments in asymmetric transformations, that is to say methods for augmenting the yield of amine resolution processes to theory 100%, resulting in an alternative to asymmetric synthesis and a practical Green Chemistry solution to the synthesis of optically active amines. Figure 13.1 shows different approaches to the asymmetric transformation that will be discussed in the chapter. 

Three methods for chiral amine resolution are used in the manufacture of pharmaceuticals crystallization used most commonly enzymic resolution used occasionally chromatography used frequently during early phase and increasingly in commercial production. In each of these an isomer waste stream of at least 50% of the starting material is produced. 

Since platinum(IV) complexes are also kinetically inert, optical diastereomers of Pt(en)2(L-2,3-diaminopropionic acid)4+ have been prepared.1028 The first synthetic procedure involves the chlorine oxidation of PtCl2(L-2,3-diaminopropionic acid) followed by reaction with ethylenedi-amine. Resolution is achieved through the (+)-tartrate salt. Alternatively the resolved complex can be prepared directly from the reaction of L-2,3-diaminopropionic acid on optically active cis-[PtCl2(en)2]Cl2. (... 

EPON 8121 130 2,700-3,700 Very high reactivity when combined with aliphatic amines Resolution... 

Similarly, the DKR of chiral amines can, in principle, be achieved by combining the known amine resolution by lipase-catalyzed acylation [23] with metal-cat-... 

Another important difference between (dynamic) kinetic resolution of alcohols and amines is the ease with which the acylated product, an ester and an amide, respectively, is hydrolyzed. This is necessary in order to recover the substrate enantiomer which has undergone acylation. Ester hydrolysis is generally a facile process but amide hydrolysis, in contrast, is often not trivial. For example, in the BASF process [28] for amine resolution by lipase-catalyzed acylation the amide product is hydrolyzed using NaOH in aq. ethylene glycol at 150 °C (Fig. 9.18). In the case of phenethylamine this does not present a problem but it will obviously lead to problems with a variety of amines containing other functional groups. 

Fig. 9.22 CaLB for acylation and deacylation steps in amine resolution.

Rizzo RC, Jorgensen WL (1999) OPLS All-atom model for amines Resolution of the amine hydration problem. J Am Chem Soc 121 4827-4836... 

Yield is based on a half amount of the racemate. Enantiomeric excess is ofthe recovered amine. Resolution efficiency = yield x e.e. 

An enzymatic procedure for amine resolution, employing acylation by C. antarctica lipase B and deacylation by penicillin G acylase, has been demonstrated by Ismail et al. (Figure 14.14) [20]. The acylase catalyzed deacylation provides a greener process than the standard chemical deacylation as a result of the elimination of the salt waste stream typically generated by deacylating under strongly alkaline condi tions. It is also more amenable to sensitive functional groups that are not stable under basic conditions. A drawback of this approach is that the amide hydrolysis step is... 

Shin and Kim developed various methods aimed at increasing the product concentrations of transaminase catalyzed amine resolutions, through the contin uous removal of product ketone from the reactions (Figure 14.21). The application of an aqueous/organic two phase system to the co transaminase catalyzed resolution of racemic ( methylbenzylamine 1 was found to be superior to an aqueous only system in product concentration obtained [26, 27]. A drawback of the biphasic system was an increased enzyme deactivation rate compared to the aqueous only system due to the aqueous/organic emulsion. Another disadvantage was the... 

The product is, of course, racemic but, as it is an amine, resolution with an acid should be straightforward. Crystallization of its tartrate salt, for example, leads to the required single enantiomer in 99.9% ee. With such cheap starting materials, resolution is just about acceptable, even though it wastes half the material. It would be better to oxidize the indene enantio-selectively, and the solution here, as you saw in Chapter 41, is to use a Jacobsen epoxidation, which gives the epoxide in 79% yield and 84% ee. 

Synthesised commercially from glucose. Used in amine resolution and as a precursor in vitamin C synth. Inexpensive starting material for chiral syntheses. Antilipidaemic, low acute mammalian toxicity. Monohydrate. Mp 103° dec. Mg -21.6 (c, 2.28 in MeOH). Log P 0.34 (calc). 

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