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The development of multikilogram scale green and economical synthetic route of enantiomerically pure cis-4-amino-3-fluoro-1-methylpiperidine 1 is described. The synthesis features a highly regio-, ...

A Cu-catalyzed enantioselective aminoboration of E-vinylarenes with pivZPhos as a ligand is reported. Enantioenriched aminoborates are prepared with excellent regio- and enantioselectivities up to >99:1 er under the optimized conditions. The utility of the current method was further established by rapid conversion of an adduct to a chiral benzo[f][1,4]oxazepine. A model for the stereochemistry of the asymmetric aminoboration process, which agrees with the experimental outcomes, was generated by computational analysis of the systems.

Process development for a scalable and green synthesis of chiral tert-butanesulfinamide (TBSA) on a multikilogram scale is reported. The process is based on the identification of a chiral sulfinyl transfer agent, benzo[1,3]oxathiozin-2-one, that contains active and differentiated S–N and S–O bonds, allowing the synthesis to proceed under mild reaction conditions. This method is practical and overcomes the disadvantages of earlier methods deploying harsh reaction conditions and hazardous and toxic reagents.

Metal-catalyzed cross-coupling reactions are extensively employed in both academia and industry for the synthesis of biaryl derivatives for applications to both medicine and material science. Application of these methods to prepare tetra-ortho-substituted biaryls leads to chiral atropisomeric products that introduces the opportunity to use catalyst-control to develop asymmetric cross-coupling procedures to access these important compounds. Asymmetric Pd-catalyzed Suzuki-Miyaura and Negishi cross-coupling reactions to form tetra-ortho-substituted biaryls were studied employing a collection of P-chiral dihydrobenzooxaphosphole (BOP) and dihydrobenzoazaphosphole (BAP) ligands. Enantioselectivities of up to 95:5 and 85:15 er were identified for the Suzuki-Miyaura and Negishi cross-coupling reactions, respectively. Unique ligands for the Suzuki-Miyaura reaction vs the Negishi reaction were identified. A computational study on these Suzuki-Miyaura and Negishi cross-coupling reactions enabled an understanding in the differences between the enantiodiscriminating events between these two cross-coupling reactions. These results support that enantioselectivity in the Negishi reaction results from the reductive elimination step, whereas all steps in the Suzuki-Miyaura catalytic cycle contribute to the overall enantioselection with transmetalation and reductive elimination providing the most contribution to the observed selectivities.

The Pd-catalyzed 3-arylation of 2-oxindoles with aryl bromides, chlorides and triflates is found to proceed using i-Pr-BI-DIME and Me2-BI-DIME ligands. The mono-arylation of 3-unsubstituted oxindoles is accomplished using a Pd2(dba)3/i-Pr-BI-DIME catalyst system, and gives good yields of 3-aryloxindoles from aryl bromides and chlorides. The arylation of 3-substituted oxindoles is also possible using this catalyst/ligand system. The asymmetric arylation of 3-substituted oxindoles is accomplished using Me2-BI-DIME to furnish oxindoles bearing a quaternary C-3 stereocenter in enantiomeric ratios of up to 93:7.

A new family of dihydrobenzoazaphosphosphole ligands was prepared and shown to enable modification of the phosphine electronic character by variation of the N-substituent. This new family of phosphines was shown to be highly active in the Pd-catalyzed Suzuki–Miyaura cross-coupling reaction with hindered coupling partners.

A chromatography-free, asymmetric synthesis of the C2-symmetric P-chiral diphosphine t-Bu-SMS-Phos was developed using a chiral auxiliary-based approach in five steps from the chiral auxiliary in 36% overall yield. Separtion and recovery of the auxiliary were achieved with good yield (97%) to enable recycling of the chiral auxiliary. An air-stable crystalline form of the final ligand was identified to enable isolation of the final ligand by crystallization to avoid chromatography. This synthetic route was applied to prepare up to 4 kg of the final ligand. The utility of this material was demonstrated in the asymmetric hydrogenation of trifluoromethyl vinyl acetate at 0.1 mol % Rh loading to access a surrogate for the pharmaceutically relavent chiral trifluoroisopropanol fragment in excellent yield and enantiomeric excess (98.6%).

A new class of tunable heterophosphole dimeric ligands have been designed and synthesized. These ligands have enabled the first examples of Cu-catalyzed hydrogenation of 2-substituted-1-tetralones and related heteroaryl ketones via dynamic kinetic resolution, simultaneously creating two contiguous stereogenic centers with up to >99 : 1 dr and 98 : 2 er. The ligand-Cu complexes were isolated and characterized by single crystal X-ray, and DFT calculations revealed a novel heteroligated dimeric copper hydride transition state.

P-Stereogenic chiral phosphine BI-BOP is employed for the first time as ligand to promote catalytic enantioselective synthesis of phosphoryl-substituted atropisomeric vinylarenes through a palladium−carbene pathway. This strategy utilizes 10 mol% palladium(II) acetate, 10 mol% phosphine ligand as well as a variety of N-tosylhydrazones and phosphoryl-substituted aryl bromides as the reaction partners. The desired axially chiral vinylarenes were isolated with up to 80% yield and 96:4 er, and can be further converted effectively and stereoselectively into dialkylphosphoryl-substituted atropisomeric arenes through a Grignard reaction. This protocol offers a general approach to synthesize phosphoryl-substituted atropisomeric vinylarenes with high enantiomeric purities.

A practical and efficient synthesis of the FLAP inhibitor 1 was developed addressing multiple scale-up and safety concerns posed by the established synthesis and utilized a resolution strategy (replacing supercritical fluid chromatography (SFC) separation) for expedient access to the key structural component of 1: the challenging chiral quaternary center. Also highlighted are in situ IR monitoring, condensation to form the 1,2,4-oxadiazole ring, and an efficient Suzuki-Miyaura coupling.

A general and efficient method for the synthesis of bulky and structurally diverse P-stereogenic chiral secondary phosphine oxides (SPOs) by using readily available chiral amino alcohol templates is described. These chiral SPOs could be used as chiral building blocks for the synthesis of difficult-to-access bulky P-stereogenic phosphine compounds or ligands for organic catalysis.

A convergent, robust, and concise synthesis of a developmental CCR1 antagonist is described using continuous flow technology. In the first approach, following an expeditious SNAr sequence for cyclopropane introduction, a safe, continuous flow Curtius rearrangement was developed for the synthesis of a p-methoxybenzyl (PMB) carbamate. Based on kinetic studies, a highly efficient and green process comprising three chemical transformations (azide formation, rearrangement, and isocyanate trapping) was developed with a relatively short residence time and high material throughput (0.8 kg h−1, complete E-factor = ∼9) and was successfully executed on 40 kg scale. Moreover, mechanistic studies enabled the execution of a semi-continuous, tandem Curtius rearrangement and acid–isocyanate coupling to directly afford the final drug candidate in a single, protecting group-free operation. The resulting API synthesis is further determined to be extremely green (RPG = 166%) relative to the industrial average for molecules of similar complexity.

The application of a Buchwald's third generation palladacycle containing a dihydrobenzooxaphosphole-based ligand (e.g., BIDIME) was reported in the Suzuki cross-coupling reaction. Using flow technology, high yield and reproducible Suzuki cross-coupling reaction for one of our key intermediates was achieved with Pd loadings as low as 0.5 mol %. This continuous flow approach overcomes catalyst deactivation and scale dependence issues that can be a problem in some traditional batch-mode operations and responds to the challenge of improving process greenness.

Through a computer-guided approach, new series of monophosphine ligands were designed and developed for asymmetric Suzuki–Miyaura couplings of challenging heterocyclic substrates. Computer modeling pointed to a tunable, yet unexplored quadrant in BI-DIME, leading to the discovery of the 3′,5′-dimethyl-substituted ligand which improved the atropisomeric selectivity of the Suzuki–Miyaura reaction from the previously reported 5:1 dr to 15:1 dr for the synthesis of a challenging HIV integrase intermediate, and up to 24:1 dr with various other quinoline substrates.

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 5, 6, and 7 in 99:1 er, providing a novel, concise synthetic route to this family of chiral piperidine-containing compounds.

An efficient continuous flow iron-catalyzed Kumada cross-coupling was developed for the coupling of 2-chloropyrazine and various aryl Grignard reagents in presence of low catalyst loadings (0.5 mol-%). Compared to batch mode, the continuous flow approach overcomes the exothermicity which enabled longer catalyst lifetime, facilitated scale-up and significantly improved the yield. To the best of our knowledge, this is the first example of flow iron-catalyzed Kumada cross-coupling reactions which addresses scale dependence issues which often plague Kumada reactions carried out in the traditional batch mode.

The direct arylation of pyridine substrates using non-precious catalysts is underdeveloped but highly desirable due to its efficiency to access important motifs while being extremely cost-effective. The first nickel-catalyzed C-3 direct arylation of pyridine derivatives to provide a new approach to valuable 1-azafluorene pharmacophore frameworks was developed. This transformation is accomplished using air-stable nickel catalyst precursors combined with phenanthroline ligands and tolerates a variety of substituents. Computational studies suggest facile oxidative addition via the pyridinium form, deprotonation, and a subsequent carbo-nickelation cyclization. Nickel homolysis/recombination permits isomerization to the stereochemical array needed for the final elimination.

We report the synthesis of enantiomerically enriched 1,4-benzodioxanes containing alkyl, aryl, heteroaryl, and/or carbonyl substituents at the 2-position. The starting 1,4-benzodioxines were readily synthesized via ring closing metathesis using an efficient nitro-Grela catalyst at ppm levels. Excellent enantioselectivities of up to 99:1 er were obtained by using the versatile catalyst system [Ir(cod)Cl]2/BIDIME-dimer in the asymmetric hydrogenation of 2-substituted 1,4-benzodioxines. Furthermore, DFT calculations reveal that the selectivity of the process is controlled by the protonation step; and coordinating groups on the substrate may alter the interaction with the catalyst, resulting in a change in the facial selectivity.

Metal-catalyzed cross-coupling reactions are extensively employed in both academia and industry for the synthesis of biaryl derivatives for applications to both medicine and material science. Application of these methods to prepare tetra-ortho-substituted biaryls leads to chiral atropisomeric products that introduces the opportunity to use catalyst-control to develop asymmetric cross-coupling procedures to access these important compounds. Asymmetric Pd-catalyzed Suzuki-Miyaura and Negishi cross-coupling reactions to form tetra-ortho-substituted biaryls were studied employing a collection of P-chiral dihydrobenzooxaphosphole (BOP) and dihydrobenzoazaphosphole (BAP) ligands. Enantioselectivities of up to 95:5 and 85:15 er were identified for the Suzuki-Miyaura and Negishi cross-coupling reactions, respectively. Unique ligands for the Suzuki-Miyaura reaction vs the Negishi reaction were identified. A computational study on these Suzuki-Miyaura and Negishi cross-coupling reactions enabled an understanding in the differences between the enantiodiscriminating events between these two cross-coupling reactions. These results support that enantioselectivity in the Negishi reaction results from the reductive elimination step, whereas all steps in the Suzuki-Miyaura catalytic cycle contribute to the overall enantioselection with transmetalation and reductive elimination providing the most contribution to the observed selectivities.

Novel bidentate phosphine ligands BABIPhos featuring a biaryl bis-dihydrobenzooxaphosphole core are presented. Their synthesis was achieved via Pd-catalyzed reductive homocoupling of dihydrobenzooxaphosphole aryl triflates. An efficient route toward various analogues was also established, giving access to phosphines with different electronic and steric properties. The newly obtained ligands demonstrated high efficiency and selectivity in Rh-catalyzed asymmetric hydrogenation of di- and trisubstituted enamides. This new class of ligands is complementary to previously described bidentate benzooxaphosphole ligands BIBOP.

Enantioselective synthesis of α-aryl and α-heteroaryl piperidines is reported. The key step is an iridium-catalyzed asymmetric hydrogenation of substituted N-benzyl pyridinium salts. High levels of enantioselectivity up to 99.3:0.7 er were obtained for a range of α-heteroaryl piperidines. DFT calculations support an outer-sphere dissociative mechanism for the pyridinium reduction. Notably, initial protonation of the final enamine intermediate determines the stereochemical outcome of the transformation rather than hydride reduction of the resultant iminium intermediate.

A chromatography-free, asymmetric synthesis of the C2-symmetric P-chiral diphosphine t-Bu-SMS-Phos was developed using a chiral auxiliary-based approach in five steps from the chiral auxiliary in 36% overall yield. Separtion and recovery of the auxiliary were achieved with good yield (97%) to enable recycling of the chiral auxiliary. An air-stable crystalline form of the final ligand was identified to enable isolation of the final ligand by crystallization to avoid chromatography. This synthetic route was applied to prepare up to 4 kg of the final ligand. The utility of this material was demonstrated in the asymmetric hydrogenation of trifluoromethyl vinyl acetate at 0.1 mol % Rh loading to access a surrogate for the pharmaceutically relavent chiral trifluoroisopropanol fragment in excellent yield and enantiomeric excess (98.6%).

A practical and cost-effective synthesis of (2-aminopyrimidin-5-yl) boronic acid 1b has been developed. Key features of the synthesis include the inexpensive in situ protection of the amine via bis-silylation using TMSCl followed by metal–halogen exchange using n-BuLi and trapping with B(Oi-Pr)3. The water-soluble boronic acid is isolated by a well-designed acid–base sequence providing the target in 80% yield and high purity for the two-step process. The large-scale (15 kg) implementation of a Suzuki–Miyaura borylation to form the pinacol boronic ester is also described.

Two potent glucocorticoid receptor agonists were prepared labeled with carbon-14 and with stable isotopes to perform drug metabolism, pharmacokinetics, and bioanalytical studies. Carbon-14 labeled (1) was obtained from an enantiopure alkyne (5) via a Sonogashira coupling to a previously reported 5-amino-4-iodo-[2-(14)C]pyrimidine [(14)C]-(6), followed by a base-mediated cyclization (1) in 72% overall radiochemical yield. Carbon-14 labeled (2) was prepared in five steps employing a key benzoic acid intermediate [(14)C]-(13), which was synthesized in one pot from enolization of trifluoromethylketone (12), followed by bromine-magnesium exchange and then electrophile trapping reaction with [(14)C]-carbon dioxide. A chiral auxiliary (S)-1-(4-methoxyphenyl)ethylamine was then coupled to this acid to give [(14)C]-(15). Propargylation and separation of diastereoisomers by crystallizations gave the desired diastereomer [(14)C]-(17) in 34% yield. Sonogashira coupling to iodopyridine (10) followed by cyclization to the azaindole [(14)C]-(18) and finally removal of the chiral auxiliary gave [(14)C]-(2) in 7% overall yield. For stable isotope syntheses, [(13)C6]-(1) was obtained in three steps using [(13)C4]-(6) and trimethylsilylacetylene-[(13)C2] in 26% yield, while [(2)H5]-(2) was obtained by first preparing the iodopyridine [(2)H5]-(10) in five steps. Then, Sonogashira coupling to chiral alkyne (24) and cyclization gave [(2)H5]-(2) in 42% overall yield.

The use of chiral phosphinamides is relatively unexplored because of the lack of a general method for the synthesis. Reported herein is the development of a general, efficient, and highly enantioselective method for the synthesis of structurally diverse P-stereogenic phosphinamides. The method relies on nucleophilic substitution of a chiral phosphinate derived from the versatile chiral phosphinyl transfer agent 1,3,2-benzoxazaphosphinine-2-oxide. These chiral phosphinamides were utilized for the first synthesis of readily tunable P-stereogenic Lewis base organocatalysts, which were used successfully for highly enantioselective catalysis.

The development of enantioselective carbon-carbon bond couplings catalyzed by non-precious metals is highly desirable in terms of cost-efficiency and sustainability. The first nickel-catalyzed enantioselective Mizoroki-Heck coupling is reported. This transformation is accomplished via mild reaction conditions, leveraging on QuinoxP* as a chiral ligand to afford oxindoles containing quaternary stereocenters. Good reactivity and selectivity are observed in the presence of various functional groups. Computational studies suggest that the oxidative addition assembles an atropisomeric intermediate responsible for the facial selectivity of the insertion step.

Air-stable P-chiral dihydrobenzooxaphosphole oxazoline ligands were designed and synthesized. When they were used in the iridium-catalyzed asymmetric hydrogenation of unfunctionalized 1-aryl-3,4-dihydronaphthalenes under one atmosphere pressure of H2 , up to 99:1 e.r. was obtained. High enantioselectivities were also observed in the reduction of the exocyclic imine derivatives of 1-tetralones.

Empagliflozin, (2S,3R,4R,5S,6R)-2-[4-chloro-3-[[4-[(3S)-oxolan-3-yl]oxyphenyl]methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol was recently approved by the FDA for the treatment of chronic type 2 diabetes mellitus. Herein, we report the synthesis of carbon-13 and carbon-14 labeled empagliflozin. Carbon-13 labeled empagliflozin was prepared in five steps and in 34% overall chemical yield starting from the commercially available α-D-glucose-[(13)C6]. For the radiosynthesis, the carbon-14 atom was introduced in three different positions of the molecule. In the first synthesis, Carbon-14 D-(+)-gluconic acid δ-lactone was used to prepare specifically labeled empagliflozin in carbon-1 of the sugar moiety in four steps and in 19% overall radiochemical yield. Carbon-14 labeled empagliflozin with the radioactive atom in the benzylic position was obtained in eight steps and in 7% overall radiochemical yield. In the last synthesis carbon-14 uniformly labeled phenol was used to give [(14)C]empagliflozin in eight steps and in 18% overall radiochemical yield. In all these radiosyntheses, the specific activities of the final compounds were higher than 53 mCi/mmol, and the radiochemical purities were above 98.5%.

An enantioselective copper-catalyzed asymmetric conjugate addition of Me2Zn to (Z)-nitroalkenes led to the formation of all-carbon quaternary stereogenic centers with high stereoselectivity. The key features of the new method are the unprecedented use of [(MeCN)4Cu]PF6 in conjunction with the Hoveyda ligand L1 and the use of (Z)-nitroalkene substrates so that undesired nitroalkene isomerization is minimized and enantioselectivity is enhanced dramatically. We also describe a novel, practical, and highly (Z)-selective nitroalkene synthesis.

A practical noncryogenic process for the Aggarwal stereospecific boronate rearrangement with chiral secondary benzylic carbamates has been developed. The use of LDA instead of sec-BuLi combined with an in situ trapping of the unstable lithiated carbamate was critical to success. Furthermore, this new process increased the substrate scope to include the versatile aryl iodide and bromide substrates. The methodology was applied to a diverse array of substrates and was demonstrated on multikilogram scale.

An efficient enantioselective synthesis of the chiral polycyclic cholesteryl ester transfer protein (CETP) inhibitor 1 has been developed. The synthesis was rendered practical for large scale via the development of a modified Hantzsch-type reaction to prepare the sterically hindered pyridine ring, enantioselective hydrogenation of hindered ketone 6 utilizing novel BIBOP-amino-pyridine derived Ru complex, efficient ICl promoted lactone formation, and a BF3 mediated hydrogenation process for diastereoselective lactol reduction. This efficient route was successfully scaled to produce multikilogram quantities of challenging CETP drug candidate 1.

A highly enantioselective enamide hydrogenation route to the title amine was developed. Highlights of the synthesis include an efficient two-step synthesis of a 2-sulfonyl 4-pyridyl ethyl ketone, a simple enamide synthesis by direct condensation of propionamide with a ketone, catalytic asymmetric enamide hydrogenation employing the in-house-developed ligand MeO-BIBOP, and a mild epimerization-free deprotection of a propionamide using Koenig’s procedure.

The rate limiting aromatization within the condensation approach toward pyrimidines utilizing amidines and activated olefins was addressed to provide for a general and rapid process. A strong solvent effect was elucidated to affect the rate for the initial alkoxide elimination from the intermediate Michael adduct wherein polar aprotic solvents demonstrate an addition controlled aromatization. Spectroscopic studies support a solvent dependent equilibrium between the amidine and alkoxide base wherein the rate for aromatization is optimal when the equilibrium toward the amidine anion was strongly favored.

Synthesis of the electron-rich 2-substituted-6-(phenylsulfonyl)pyridines is presented. A series of air-stable, tunable, P-chiral pyridyl-dihydrobenzooxaphosphole ligands were designed and synthesized by a diastereoselective S(N)Ar substitution of the corresponding sulfonyl pyridines. The ligands were successfully applied in the Ir-catalyzed asymmetric hydrogenation of unfunctionalized alkenes with good enantioselectivities.

A practical process was developed for the synthesis of 2-difluoromethylpyridines via a Cu-mediated Reductive Coupling-Hydrolysis-Decarboxylation sequence. The process employed 2-bromopyridines with a variety of functional groups on the pyridine as substrates and used readily available and inexpensive starting materials. For operational safety DMSO shall not be considered as solvent and the use of DMF is recommended.

During phase 1 and phase 2 drug development (early stage drug development), it is normal to continuously improve a manufacturing process, with changes made to the synthetic pathway, reagents, reaction conditions, crystallization parameters, drying conditions, or manufacturing equipment or scale or site. These manufacturing process changes (“process changes” used thereafter) may or may not affect quality attributes such as impurities, and quality attribute changes may or may not affect drug substance (DS) stability. But a common misconception is that almost all process changes and/or quality attribute changes affect DS stability, and a new (or repeat) stability study is conducted for the DS batch produced after process changes. This misconception is clearly refuted by our many years of DS stability experience. To understand how process changes might affect DS stability, we compiled and analyzed manufacturing processes, quality test results, and stability data for 48 batches from seven drug substances in recent development. Of these 48 batches, the seven first DS clinical batches were used as references against which the other respective 41 batches, which were produced after process changes, were compared for changes in manufacturing processes, quality test results, and stability data. This comparison showed that the chemical and physical stability of 36 (of the 41) batches was not affected by process changes, and the chemical or physical stability of the other 5 batches was affected by residual inorganic impurities, significant amounts of water or residual solvents, or significant changes in DS particle size distribution or surface area. These quality attributes that affect stability are called stability-related quality attributes (SRQAs). A new (or repeat) stability study is warranted only if process changes significantly affect SRQAs. We have established a procedure to systematically assess changes in manufacturing process and quality attributes (particularly impurity profiles), to identify SRQAs (risk assessment), and to make science- and risk-based stability testing decisions on whether and how stability testing for new DS batches should be conducted (risk management).