Pilot processing

Oxamide is produced commercially by Ube Industries, Ltd. (Japan) and a pilot process is being operated by Enichem (Italy). It is not produced domestically as a commercial fertilizer, although it was the subject of much research and development activity by the Tennessee Valley Authority s (TVA) National Fertilizer Research and Development Center. It is made in small quantities for industrial use by AUied Chemical, Hummel Chemical Co., and United Guardian, Inc. Oxamide has appHcation as a controlled release nitrogen source for the turf and specialty agricultural markets. 

Pilot process before putting into operation. 

Simple mixing of raw materials and intermediates may present special problems when processing significantly larger quantities in comparison to the pilot process or laboratory bench amounts. All aspects of the toll should be considered while performing the PHA to identify potential problems caused by the scale-up. 

Merck has developed a pilot process for the hydrogenation of an intermediate 20 for MK-0431 (Fig. 34.13) and carried out the reduction on a >50-kg scale with ee-values up to 98%, albeit with low to medium TONs and TOFs [84]. Takasago has developed a reductive animation version where the corresponding />-keto ester is hydrogenated in the presence of amines, giving directly the corresponding /5-ami-no ester, though as yet no details are available of this process [83]. 

Pilot processes are technically on a similar level especially with regard to catalyst performance they have been carried out on multi kilogram to tonne scale, but have not (yet) been applied on a regular basis. 

Rh / Me-DuPhos no details available pilot processes, Dow Chirotech [36]... 

The hydrogenation of enamides and enol acetates without acid function is often more demanding, and at present is not applied widely. Besides a bench-scale application by Roche with a Ru-biphep catalyst [55], two examples are of interest a pilot process for a cyclic enol acetate by Roche [55], and a feasibility study by Bristol-Myers Squibb [56], both using Rh-DuPhos catalysts (Fig. 37.11). In the latter case, despite very good ee-values, a chiral pool route was finally chosen. Chiral Quests Rh-f-KetalPhos (see Fig. 37.9) has been shown to hydrogenate a variety of substituted aryl enamide model substrates at r.t., 1 bar, with very promising catalyst performance (ee 98-99%, TON 10000) [47]. 

Further hydrogenations of a variety of C=C substrates depicted in Figure 37.22 range from a pilot process to several feasibility studies. Of special interest are PhanePhos, originally reported by Merck, an unsymmetrically substituted phos-pholane developed by Pfizer, and the rare case of an Ir-diphosphine complex active for the hydrogenation of a C=C bond. Nevertheless, the catalyst performances of most processes summarized in Figure 37.22 are probably not (yet) sufficient for manufacturing purposes. Indeed, several of the reports explicitly mention that further development was stopped, either because another route proved to be superior or because the compound was abandoned. 

The hydrogenation of a-amino ketones was also a key step for the synthesis of three more pharma actives (Fig. 37.25). Roche [95] divulged a pilot process involving the hydrogenation/dynamic kinetic resolution of a cyclic a-amino ketone using an optimized MeO-biphep ligand. The Ru-catalyzed reaction was carried out on a 9-kg scale with excellent enantio- and diastereoselectivities, and very... 

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