SCRAM catalyst

Following an initial resolution step with 0.5 mol equivalents (R)-mandelic acid in TBME, the crystalline product was filtered and tlie waste isomers in the mother liquors (39% ee) were washed with base and then subjected to racemization with the SCRAM catalyst. Upon completion, the catalyst precipitated and was screened, fresh racemic amine was added, and the whole was resolved a second time. The process was repeated several times, giving the results summarized in Table 13.2. 

In the patent literature, processes are described for the epimerization of the benzyhc chiral center at the 4-posihon using an alkoxide base [28] and for reagent-based dehydrogenation, then rehydrogenation, of the amine [29]. We envisaged racemization of the chiral amine center using the SCRAM catalyst and the tertiary carbon center using an alkoxide base (Scheme 13.10). 

Recently, it has been reported that a SCRAM catalyst can dehydrogenate a wrong (lR,4R)-enantiomer of sertraline to the imine, which depending upon the reaction conditions, is then reduced back to the amine [22]. The whole process for epimerisation of the wrong enantiomer of sertraline is presented in Scheme 7.6. 

The use of highly enantiomerically enriched (S)-phenylethylamine resulted in formamide generation in 93% yield and 75% ee (Scheme 12.26). Scrambling of the stereocentre may occur by reversible formation of the imine by the SCRAM catalyst. 

The practical difficulty with carrying out a crystalhzation DTR process is the need to operate under conditions that allow selective crystalhzation of the least soluble diastereomer while permitting the racemization to take place. Amine racemization catalysts, such as SCRAM , Shvo, Pd/C, and Adam s, are more active at higher temperatures, which runs counter to the conditions required for crystaUization. A solution to this problem is to separate the diastereomeric resolution and racemization steps but couple them with a flow engineering design. In this way each reaction can be operated under optimal conditions for example, temperature, concentration and solvent, via an intermediary solvent exchange unit Since the racemization catalyst itself may affect the crystalhzation (or indeed the crystalhzation may affect the catalyst), it is preferred to keep them separate. This can be achieved by having the catalyst or product either permanently or temporarily in a different phase by immobilization, extraction, precipitation, distil-... 

Screening several amine racemization catalysts, we found that the SCRAM and the Shvo catalyst would both racemize the (S)-enantiomer at temperatures above 11() G. Interestingly, no dimeric products were found. The best racemization conditions were found to be using toluene or TBME at 150°C in a pressure vessel with 1 mol% SCRAM or 5 mol% Shvo catalyst over 24 h, providing quantitative conversion. In the presence of (R, R)-dibenzoyltartaric acid the racemization slowed, possibly because of unfavorable coordination of the alkylammonium substrate or acid quenching of the iridium hydride catalyst intermediate. 

The two mechanisms may result in substantial and characteristic differences in deuterium distribution. The metal hydride addition-elimination mechanism usually leads to a complex mixture of labeled isomers.195 198 208-210 Hydride exchange between the catalyst and the solvent may further complicate deuterium distribution. Simple repeated intramolecular 1,3 shifts, in contrast, result in deuterium scram-bling in allylic positions when the ir-allyl mechanism is operative. ... 

It is important to note the delicate nature of SCRAM-type catalysts. When an analogous complex with the chloride anion as the ligand was used, 120-fold... 

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