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A mild, high-yielding, and practical protocol for the direct amidation of alkyl cyanoacetates using DBU is presented. This method eliminates the need for activation of cyanoacetic acid and/or high temperatures. It has been applied to the large-scale synthesis of CP-690,550-10 (1), a compound under development for the treatment of autoimmune diseases.

Isobutylene off-gas amounts liberated during the methanesulfonic acid-catalyzed deprotection of N-BOC-pyrrolidine in THF, methanol, ethanol, 2-propanol, toluene, and dichloromethane were measured using on-line gas-phase mass spectroscopy. While one full equivalent of isobutylene was released as an off-gas when THF was used as the reaction solvent, emissions were reduced by 65-95% in other solvents. In alcohol solvents, the corresponding alkyl tert-butyl ethers are formed as byproducts of the reaction as expected. In dichloromethane and toluene, oligomers of isobutylene can be formed under the reaction conditions. These results provided the basis for developing an effective acid/toluene scrubber for isobutylene that was successfully employed on the pilot plant scale.

No abstract

Mass spectrometry was used to monitor vacuum-drying endpoints in the laboratory and pilot plant to demonstrate feasibility of its application. The technique is relatively simple to interface to existing equipment at minimal cost, requires no direct sample contact, and is generally applicable to multiple dryer configurations. Results of the feasibility study showing the monitoring of multiple solvents, along with correlation of the mass spectrometric technique to conventional percent loss on drying (LOD) measurements, are discussed.