PAT Application in the Expedited Development of a Three-Step, One-Stage Synthesis of the Dipeptide Intermediate of HCV Protease Inhibitor Faldaprevir

A concise scalable synthesis of a chiral dipeptide acid, key substructure of the HCV protease inhibitor faldaprevir, has been developed. A green process with an E-factor of 9.2 was achieved utilizing process analytical technology (PAT) to allow effective processing of multiple-steps in a one-stage operation. Mixed anhydride/oxazolone formation, peptide coupling, saponification, and then crystallization of the desired dipeptide acid were completed within 10 h. MultiMaxIR was used to detect the formation and consumption rates of key intermediates and to provide initial safety data which was subsequently confirmed by more comprehensive process safety testing. Further kinetic analysis was performed to determine the range of operability space to ensure conditions for a robust process

Copper-Catalyzed Asymmetric Propargylation of Cyclic Aldimines

The copper-catalyzed asymmetric propargylation of cyclic aldimines is reported. The influence of the imine trimer to inhibit the reaction was identified, and equilibrium constants between the monomer and trimer were determined for general classes of imines. Asymmetric propargylation of a diverse series of <i>N</i>-alkyl and <i>N</i>-aryl aldimines was achieved with good to high asymmetric induction. The utility was demonstrated by a titanium catalyzed hydroamination and reduction to generate the chiral indolizidines (−)-crispine A and (−)-harmicine

Copper-Catalyzed Asymmetric Propargylation of Cyclic Aldimines

The copper-catalyzed asymmetric propargylation of cyclic aldimines is reported. The influence of the imine trimer to inhibit the reaction was identified, and equilibrium constants between the monomer and trimer were determined for general classes of imines. Asymmetric propargylation of a diverse series of <i>N</i>-alkyl and <i>N</i>-aryl aldimines was achieved with good to high asymmetric induction. The utility was demonstrated by a titanium catalyzed hydroamination and reduction to generate the chiral indolizidines (−)-crispine A and (−)-harmicine

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

A Scalable and Regioselective Synthesis of 2‑Difluoromethyl Pyridines from Commodity Chemicals

A scalable <i>de novo</i> synthesis of difluoromethyl pyridines from inexpensive materials is reported. The pyridyl subunit is built around the difluoromethyl group rather than a late stage introduction of this moiety. This user-friendly approach allows access to a diverse range of substitution patterns on all positions on the ring system and on the difluoromethyl group

Synthesis of Enantioenriched 2‑Alkyl Piperidine Derivatives through Asymmetric Reduction of Pyridinium Salts

An Ir-catalyzed enantioselective hydrogenation of 2-alkyl-pyridines has been developed using ligand MeO-BoQPhos. High levels of enantioselectivities up to 93:7 er were obtained. The resulting enantioenriched piperidines can be readily converted into biologically interesting molecules such as the fused tricyclic structures <b>5</b>, <b>6</b>, and <b>7</b> in 99:1 er, providing a novel, concise synthetic route to this family of chiral piperidine-containing compounds

Development of a Large Scale Asymmetric Synthesis of the Glucocorticoid Agonist BI 653048 BS H₃PO₄

The development of a large scale synthesis of the glucocorticoid agonist BI 653048 BS H₃PO₄ (<b>1·H</b>_<b>3</b><b>PO</b>_<b>4</b>) is presented. A key trifluoromethyl ketone intermediate <b>22</b> containing an <i>N</i>-(4-methoxyphenyl)­ethyl amide was prepared by an enolization/bromine–magnesium exchange/electrophile trapping reaction. A nonselective propargylation of trifluoromethyl ketone <b>22</b> gave the desired diastereomer in 32% yield and with dr = 98:2 from a 1:1 diastereomeric mixture after crystallization. Subsequently, an asymmetric propargylation was developed which provided the desired diastereomer in 4:1 diastereoselectivity and 75% yield with dr = 99:1 after crystallization. The azaindole moiety was efficiently installed by a one-pot cross coupling/indolization reaction. An efficient deprotection of the 4-methoxyphenethyl group was developed using H₃PO₄/anisole to produce the anisole solvate of the API in high yield and purity. The final form, a phosphoric acid cocrystal, was produced in high yield and purity and with consistent control of particle size

Development of a Large Scale Asymmetric Synthesis of the Glucocorticoid Agonist BI 653048 BS H₃PO₄

The development of a large scale synthesis of the glucocorticoid agonist BI 653048 BS H₃PO₄ (<b>1·H</b>_<b>3</b><b>PO</b>_<b>4</b>) is presented. A key trifluoromethyl ketone intermediate <b>22</b> containing an <i>N</i>-(4-methoxyphenyl)­ethyl amide was prepared by an enolization/bromine–magnesium exchange/electrophile trapping reaction. A nonselective propargylation of trifluoromethyl ketone <b>22</b> gave the desired diastereomer in 32% yield and with dr = 98:2 from a 1:1 diastereomeric mixture after crystallization. Subsequently, an asymmetric propargylation was developed which provided the desired diastereomer in 4:1 diastereoselectivity and 75% yield with dr = 99:1 after crystallization. The azaindole moiety was efficiently installed by a one-pot cross coupling/indolization reaction. An efficient deprotection of the 4-methoxyphenethyl group was developed using H₃PO₄/anisole to produce the anisole solvate of the API in high yield and purity. The final form, a phosphoric acid cocrystal, was produced in high yield and purity and with consistent control of particle size

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