Development of a Safe and Economical Synthesis of Methyl 6‑Chloro-5-(trifluoromethyl)nicotinate: Trifluoromethylation on Kilogram Scale

Reported herein is a safe and economical synthesis of methyl 6-chloro-5-(trifluoromethyl)­nicotinate, an intermediate in the synthesis of novel anti-infective agents. The key to this process is the trifluoromethylation of an aryl iodide using an inexpensive methyl chlorodifluoroacetate (MCDFA)/KF/CuI system, with an emphasis on the development work which led to this effective process

Hydrophosphination of Propargylic Alcohols and Amines with Phosphine Boranes

The first uncatalyzed hydrophosphinations of propargylic amines and alcohols with phosphine– borane complexes are described. The reactions proceed at ambient temperature or below without the use of protecting groups or the need to handle pyrophoric secondary phosphines, furnishing air-stable phosphineborane–amines and alcohols in good yields. Utilization of chiral propargylic substrates and unsymmetrical secondary phosphineboranes leads to diastereomeric <i>P</i>-chiral products that can be separated by fractional crystallization or chromatography. Initial applications of these new P–X species to asymmetric catalysis are detailed

[2,3]-Sigmatropic Rearrangements of 2‑Phosphineborane 2‑Propen-1-ols: Rapid Access to Enantioenriched Diphosphine Monoxide Derivatives

Hydrophosphination of secondary propargylic alcohols generates phosphine-containing allylic alcohols that undergo facile [2,3]-sigmatropic rearrangements with chlorophosphines, furnishing highly enantioenriched, crystalline diphosphine monoxides. The configuration at the newly formed stereocenter is opposite to that expected based on prior studies, and an ab initio computational evaluation of the possible transition states was performed to help explain the stereochemical course of the reaction

Process Development of the BACE Inhibitors BI 1147560 BS and BI 1181181 MZ

The development of large-scale syntheses of two beta-site amyloid precursor protein cleaving enzyme (BACE) inhibitors is described. New methodologies were discovered to overcome safety and scalability problems with existing procedures. The sterically hindered quaternary, neopentyl stereocenter was formed in high diastereoselectivity by the addition of a carbamoyl anion to an N-sulfinyl ketimine. An aryl nitrile was installed by a palladium- and cyanide-free electrophilic cyanation affected by transnitrilation of an arylmagnesium derivative with dimethylmalononitrile. A safe route to an oxetanylmethylamine side chain was devised based on diethyl malonate and dibenzylamine starting materials. A mild enamine fluorination was developed for the synthesis of a fluoroisobutylamine side chain

Process Development of the BACE Inhibitors BI 1147560 BS and BI 1181181 MZ

The development of large-scale syntheses of two beta-site amyloid precursor protein cleaving enzyme (BACE) inhibitors is described. New methodologies were discovered to overcome safety and scalability problems with existing procedures. The sterically hindered quaternary, neopentyl stereocenter was formed in high diastereoselectivity by the addition of a carbamoyl anion to an N-sulfinyl ketimine. An aryl nitrile was installed by a palladium- and cyanide-free electrophilic cyanation affected by transnitrilation of an arylmagnesium derivative with dimethylmalononitrile. A safe route to an oxetanylmethylamine side chain was devised based on diethyl malonate and dibenzylamine starting materials. A mild enamine fluorination was developed for the synthesis of a fluoroisobutylamine side chain

Process Development of the BACE Inhibitors BI 1147560 BS and BI 1181181 MZ

The development of large-scale syntheses of two beta-site amyloid precursor protein cleaving enzyme (BACE) inhibitors is described. New methodologies were discovered to overcome safety and scalability problems with existing procedures. The sterically hindered quaternary, neopentyl stereocenter was formed in high diastereoselectivity by the addition of a carbamoyl anion to an N-sulfinyl ketimine. An aryl nitrile was installed by a palladium- and cyanide-free electrophilic cyanation affected by transnitrilation of an arylmagnesium derivative with dimethylmalononitrile. A safe route to an oxetanylmethylamine side chain was devised based on diethyl malonate and dibenzylamine starting materials. A mild enamine fluorination was developed for the synthesis of a fluoroisobutylamine side chain

Process Development of the BACE Inhibitors BI 1147560 BS and BI 1181181 MZ

The development of large-scale syntheses of two beta-site amyloid precursor protein cleaving enzyme (BACE) inhibitors is described. New methodologies were discovered to overcome safety and scalability problems with existing procedures. The sterically hindered quaternary, neopentyl stereocenter was formed in high diastereoselectivity by the addition of a carbamoyl anion to an N-sulfinyl ketimine. An aryl nitrile was installed by a palladium- and cyanide-free electrophilic cyanation affected by transnitrilation of an arylmagnesium derivative with dimethylmalononitrile. A safe route to an oxetanylmethylamine side chain was devised based on diethyl malonate and dibenzylamine starting materials. A mild enamine fluorination was developed for the synthesis of a fluoroisobutylamine side chain