First-Generation Route

3 was followed for the first large-scale preparation of 1, the discovery route to prepare 2a utilized a relatively difficult-to-prepare chiral auxiliary which required enhrely new chemistry to be employed even for the prepara lion of several hundred grams of drug [3], 

A method to prepare 2a based on the work of a related analog [4] was employed for the first mulh-kilogram campaign. In this approach, 2a was prepared from lactam 5, which is derived from an optically enriched P-hydroxy acid. This method requires introduction of the amino group as an 0-benzylhydroxylamine, which we hoped would sufficiently protect the amino group of 2b during amide formation with triazole 3. 

The reachon condihons were successfully engineered to allow for operahon in a safe fashion on a mulh-kilogram scale. The reaction was carried out in a 35 wt% aqueous soluhon of hydrazine under rigorously controlled condihons to prevent any thermal events. ) Rather than isolate 7, it was simply extracted at the end of reachon and carried into the next step which involved trifluoroacetylahon with 

2) Information about hydrazine and its safe use can be obtained at www.hydrazine.com. 

3) Calorimetry studies of the reaction of hydrazine with 6 reveal a strong exotherm at temperatures above 85 °C. 

---

The examination of the total reagent usage in the two processes (last row in Table 8.3) clearly shows that the new enzymatic route (with recycling of 4) utilizes 7 times less input of chemicals. This includes 12 times less input of solvents as compared to the first-generation route. Moreover, in the optimized process, every chemical reaction is run in water with minimal solvents used for work-up. Some of the process water can be sent directly to the wastewater treatment plant, and the solvent from the hydrolysis/decarboxylation process is recovered. Further improvements from pilot plant and production scale runs have been demonstrated and will be implemented in the future. 

Elimination of all operational hazards encountered in first-generation route including sodium cyanide, dimethyl titanocene, and gaseons ammonia... 

Cefazolin is a first-generation cephalosporin with antibacterial activity similar to that of penicillin G but it is -lactamase-resistant. It is poorly absorbed from the gastrointestinal tract and, thus, it is primarily administered parenterally. It is widely used for ticatment of mastitis in lactating cows, sheep, and goats and for treatment at drying off by the intramammary route. 

Oxolinic acid, a first-generation quinolone, has been authorized for use in fin fish, calves, swine, and poultry by the oral route. It may be given with the feed, the drinking water, or as a bolus. In 1991, 11.4 tons of oxolinic acid in addition to 5.7 tons of flumequine were used by the Norwegian aquaculture industry (187). 

---