Enamine amides

This example covers very classical processes such as syntheses of a wide variety of compounds including imines, enamines, amides, oxazolines, hydrazones, etc. .. 

Researchers at Merck Co. [35] who, together with scientists from Solvias, had developed the enantioselective hydrogenation of unprotected enamine amides and esters [36], reported a more recent example of product inhibition. The product amine amide or ester was found to be an inhibitor of the catalyst, and indeed instances of catalyst poisoning by amines have been reported several times (see later). The authors also found an excellent solution to this problem the addition of BOC-anhydride to the hydrogenation reaction neatly reacts away all the amine to form the BOC-protected amine, whereas the enamine was left unreacted (Scheme 44.4). This addition resulted in a remarkable rate enhancement [35]. 

However, this approach required additional functional group manipulation steps since the chiral P-amino ester intermediate had to be hydrolyzed and activated to be converted to the desired amide. These steps could potentially be dirni-nated by introducing the triazole fragment much earlier in the synthesis and then introducing the chiral center on an enamine-amide instead of an enamine-ester (Route B on Scheme 5.8). 

Second-Ceneration Chiral Auxiliarf Route. The PC A Enamine-amide Route 115... 

Second-Ceneration Chiral Auxiliary Route. The PGA Enamine-amide Route... 

With the (S)-PGA enamine-amide route, sitagliptin was prepared in 65% overall yield from 2,4,5-trifluorophenylacetic acid (9) in 4 chemical steps [18]. Two addi-honal crystallization steps are required for enanhomeric purity upgrade and final salt formation. The (S)-PGA enamine-amide hydrogenahon approach eliminated the ester hydrolysis and amide formation steps of the (S)-PGA enamine-ester route by incorporating the newly developed Meldrum s acid chemistry, which enabled direct amidahon with triazole 3. 

I 5 Synthesis of Sitagliptin, the Active Ingredient in Januvia " and Janumet" Table 5.2 Asymmetric hydrogenation of unprotected enamine-amide 27. 

Carbon disulfide (1) reacts with enamines, amides and nitrogen heterocyclic compounds for example, aziridines (31) give products like (32) and (33) (Scheme 14). The relative amounts of the products (32) and (33) will be governed by the stereoelectronic nature of the groups R and R. ... 

Fig. 2.14 Rh-catalyzed enamine reductions in the absence of an N-acyl group (a) enamine ester substrate, (b) enamine amide substrate.

Others. When applying these under appropriately designed conditions (0.3 mol% catalyst, 50 °C, 5-6 bar H2) the direct hydrogenation of enamine esters and enamine amides has been successfully conducted in excellent yields and optical purities without the need for the addition of an acyl group (see Fig. 2.14) [73]. 

Enamines Amides Triazines Amides Carboxylic adds Either category... 

Fig. 4.3 Hydrogenation of enamine amide batches of 13, containing various amounts of ammonium chloride ( % conversion % e.e.) (reproduced from [27], with the permission of the American Chemical Society)...

The final improvement in the hydrogenation step was achieved before the large-scale process was set up, enabling production of 20,000 tons of sitagbptin by 2007 [22]. In Scheme 4.3, 0.3% of ammonium chloride is indicated as the promoter of asymmetric hydrogenation. A positive effect of the inorganic salt was observed when the significant variability in the e.e. and yield was traced to the content of this salt in the various batches of the (3-enamine amide 13 [27]. 

Clausen AM, Dziadul B, Cappuccio KL, Kaba M, Starbuck C, Hsiao Y, Dowling TM (2006) Identification of ammonium chloride as an effective promoter of the asymmetric hydrogenation of a, p-enamine amide. Org Proc Res Dev 10 723-726... 

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