Hydrophosphination of Bicyclo[1.1.0]butane-1-carbonitriles

Hydrophosphination of bicyclo[1.1.0]­butyl nitriles with phosphine boranes and phosphites provided novel cyclobutyl-P derivatives. The reaction generally favors the <i>syn</i>-diastereomer, and the nitrile can be reduced and converted to other functional groups, thus enabling the preparation of bidentate ligands that access new conformational space by virtue of their attachment to the torsionally malleable but sterically restrictive cyclobutane scaffold. The enantioselective hydrogenation of dehydrophenylalanine using a bidentate phosphine–phosphite ligand illustrates the synthetic utility of the newly prepared scaffold

Carbamoyl Anion Addition to Nitrones

The addition of carbamoyl anions derived from <i>N</i>,<i>N</i>-disubstituted formamides and LDA to <i>N</i>-<i>tert</i>-butyl nitrones is described. The reaction was demonstrated with a variety of formamides and nitrones and provided a direct route to α-(<i>N</i>-hydroxy)­amino amides. The use of a <i>tert</i>-leucinol derived chiral auxiliary on the nitrone provided products in good diastereoselectivity. Derivatization of the products by <i>tert</i>-butyl deprotection or <i>N</i>-deoxygenation was demonstrated

The Reaction of Grignard Reagents with Bunte Salts: A Thiol-Free Synthesis of Sulfides

S-Alkyl, S-aryl, and S-vinyl thiosulfate sodium salts (Bunte salts) react with Grignard reagents to give sulfides in good yields. The S-alkyl Bunte salts are prepared from odorless sodium thiosulfate by an S_N2 reaction with alkyl halides. A Cu-catalyzed coupling of sodium thiosulfate with aryl and vinyl halides was developed to access S-aryl and S-vinyl Bunte salts. The reaction is amenable to a broad structural array of Bunte salts and Grignard reagents. Importantly, this route to sulfides avoids the use of malodorous thiol starting materials or byproducts

Part 2: Designation and Justification of API Starting Materials: Current Practices across Member Companies of the IQ Consortium

Designation and justification of active pharmaceutical ingredient starting material (API SM) is a standard part of the drug development and commercialization process. However, knowledge of current practices used within the industry varies, depending on the individual company interpretation of regulatory guidelines. In 2011, the API and Analytical Leadership Groups within the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ Consortium or IQ), established a Working Group on API SMs to determine current practices within the pharmaceutical industry on this topic. A survey composed of four key areas, representing (1) drug substance (DS) attributes, (2) API SM attributes, (3) control strategy, and (4) regulatory practices and strategy, was developed and distributed to IQ member companies. Data representing a total of 50 API SMs (used to prepare 24 late stage clinical or marketed DSs) were obtained. This data was used to gain a better understanding of approaches utilized by pharmaceutical companies to define API SMs. The data gathered was anonymous, and the key information obtained is summarized in this manuscript. While no single approach to justifying API SMs emerged from the survey data, key trends were evident that will provide valuable insight for the reader on this important topic

Part 2: Designation and Justification of API Starting Materials: Current Practices across Member Companies of the IQ Consortium

Designation and justification of active pharmaceutical ingredient starting material (API SM) is a standard part of the drug development and commercialization process. However, knowledge of current practices used within the industry varies, depending on the individual company interpretation of regulatory guidelines. In 2011, the API and Analytical Leadership Groups within the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ Consortium or IQ), established a Working Group on API SMs to determine current practices within the pharmaceutical industry on this topic. A survey composed of four key areas, representing (1) drug substance (DS) attributes, (2) API SM attributes, (3) control strategy, and (4) regulatory practices and strategy, was developed and distributed to IQ member companies. Data representing a total of 50 API SMs (used to prepare 24 late stage clinical or marketed DSs) were obtained. This data was used to gain a better understanding of approaches utilized by pharmaceutical companies to define API SMs. The data gathered was anonymous, and the key information obtained is summarized in this manuscript. While no single approach to justifying API SMs emerged from the survey data, key trends were evident that will provide valuable insight for the reader on this important topic

Copper-Catalyst-Controlled Site-Selective Allenylation of Ketones and Aldehydes with Propargyl Boronates

A practical and highly site-selective copper-PhBPE-catalyst-controlled allenylation with propargyl boronates has been developed. The methodology has shown to be tolerant of diverse ketones and aldehydes providing the allenyl adducts in high selectivity. The BPE ligand and boronate substituents were shown to direct the site selectivity for which either propargyl or allenyl adducts can be acquired in high selectivity. A model is proposed that explains the origin of the site selectivity

A Computational Investigation of the Ligand-Controlled Cu-Catalyzed Site-Selective Propargylation and Allenylation of Carbonyl Compounds

A copper-catalyzed site-selective propargylation/allenylation reaction toward carbonyl compounds has been mechanistically investigated using a computational approach. Different reaction pathways and catalytic cycles were investigated. Control of the site selectivity arises from a destabilizing interaction introduced by the phenyl-substituted ligand

Synthesis of Phosphaguanidines by Hydrophosphination of Carbodiimides with Phosphine Boranes

The direct addition of anionic secondary phosphine boranes to carbodiimides yields both chiral and achiral phosphaguanidine boranes under ambient temperature conditions. An analogous preparation of menthol-derived phosphinite boranes is also described. These products can be deborinated to give the corresponding phosphines, and subsequently oxidized to give phosphine oxides. The robustness of this method was further demonstrated in the synthesis of structurally novel cyclic phosphaguanidines

Process Development and Pilot-Plant Synthesis of (<i>S</i>)-<i>tert</i>-Butyl 1-Oxo-1-(1-(pyridin-2-yl)cyclopropylamino)propan-2-ylcarbamate: Studies on the Scale-Up of Kulinkovich–Szymoniak Cyclopropanation

A practical and scalable synthesis of (<i>S</i>)-<i>tert</i>-butyl 1-oxo-1-(1-(pyridin-2-yl)­cyclopropylamino)­propan-2-ylcarbamate, an intermediate in the manufacture of a lymphocyte function-associated antigen 1 inhibitor, is described. The titled compound is prepared via an efficient one-pot, two-step telescoped sequence starting from readily available materials. A modified Kulinkovich–Szymoniak cyclopropanation of a nitrile followed by in situ amide formation with an activated carboxylic acid derivative afforded the target product in about 50% overall isolated yield and >97% purity

Process Development and Pilot-Plant Synthesis of (<i>S</i>)-<i>tert</i>-Butyl 1-Oxo-1-(1-(pyridin-2-yl)cyclopropylamino)propan-2-ylcarbamate: Studies on the Scale-Up of Kulinkovich–Szymoniak Cyclopropanation

A practical and scalable synthesis of (<i>S</i>)-<i>tert</i>-butyl 1-oxo-1-(1-(pyridin-2-yl)­cyclopropylamino)­propan-2-ylcarbamate, an intermediate in the manufacture of a lymphocyte function-associated antigen 1 inhibitor, is described. The titled compound is prepared via an efficient one-pot, two-step telescoped sequence starting from readily available materials. A modified Kulinkovich–Szymoniak cyclopropanation of a nitrile followed by in situ amide formation with an activated carboxylic acid derivative afforded the target product in about 50% overall isolated yield and >97% purity