11-[N-ethoxycarbonyl-4-piperidylidene]-8-chloro-6,11-dihydro-5H-benzo-[5,6]-cyclohepta-[1,2- b]-pyridine (C₂₂H₂₃ClN₂O₂) is a non-sedative antihistamine, known as Loratadine and marketed as Claritin™. The preparation of the active pharmaceutical ingredient (API) is described in U.S. 4,282,233 (to Schering). The patent describes reacting 16.2g of 11-[N-methyl-4- piperidylidene]-8-chloro-6,11-dihydro-5H-benzo-[5,6]-cyclohepta-[1,2-b]-pyridine (C₂₀H₂₁ClN₂) in 200ml of benzene with 10.9g of ethylchloroformate (C₃H₅ClO₂₎ for 18 hours. The mixture is cooled, poured into ice water and separated into aqueous and organic phases. The organic layer is washed with water and evaporated to dryness. The residue is triturated (ground to a fine powder) with petroleum ether and recrystallized from isopropyl ether.

(a). What is the reaction by-product?

(b). The reaction appears to be carried out under conditions that maximize both selectivity and conversion (long time at low temperature), as might be expected given the cost of the raw material. If the conversion is 99.9% and the selectivity for the desired ethoxycarbonyl substituted compound is 100%, how much excess ethylchloroformate remains at the end of the reaction? 

(c). What fraction of the ethylchloroformate feed is lost to waste products? 

(d). Assuming that the volumes of water and isopropyl ether used in the quenching, washing and recrystallization steps are the same as the initial solvent volume, and that none of these materials are re-used in the process, estimate the total mass of waste material produced per kg of the API.

(e). If the recovery (plant yield) of the API from the washing and recrystallization steps is 92%, estimate the feed flow rates of 11-[N-methyl-4-piperidylidene]-8-chloro-6,11-dihydro-5Hbenzo-[5,6]-cyclohepta-[1,2-b]-pyridine and ethylchloroformate required to produce a batch of 10kg of the API.  

(f). How much API could be produced per batch in a 3.8m3 (1000 US gal) reactor? 

(g). What would be the advantages and disadvantages of carrying out the other process steps n the same vessel?