Some Items of Interest to Process R&D Chemists ... - Groupe Charette

Highlights from the Literature pubs.acs.org/OPRD

Some Items of Interest to Process R&D Chemists and Engineers

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PLATFORM FOR RING-FLUORINATED BENZOHETEROLE DERIVATIVES: PALLADIUM-CATALYZED REGIOSELECTIVE 1,1-DIFLUOROALLYLATION AND HECK CYCLIZATION

Oxidative addition in transition-metal-catalyzed reactions has attracted intense interest and consequently has been widely studied. The broadly held view that the thermodynamics of addition of methane to trans-(PH3)2IrX complexes is generally favored by increased σ donation from ligand X was for the first time examined comprehensively. Krogh-Jespersen, Goldman, and co-workers (J. Am. Chem. Soc. 2016, 138, 149−163) found that contrary to the widely held view, strongly electron donating ligands do not favor the thermodynamics of C−H and N−H bond addition to Ir(I) complexes. The study reported a systematic approach based on density functional theory (DFT) calculations, which elucidated the electronic factors that influence the thermodynamics of the oxidative addition of these bonds to Ir(I) complexes. To validate the study, the rates of reductive elimination from a series of isoelectronic Ir(III) phenyl hydride complexes were experimentally determined and were found to be consistent to the computational analysis. This result could spawn more investigations and help in the rational design of highly active pincer−iridium complexes.

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The substitution of hydrogen atoms with fluorine substituents in organic molecules is of great importance not only in organic synthesis but also in pharmaceutical industries, agro-chemicals, and materials science. The high electronegativity of fluorine and its relatively small steric footprint impact a number of variables, such as acidity or basicity of neighboring groups, dipole moment, and properties such as bioavailability, metabolic stability, etc. Ichikawa and co-workers (Org. Lett. 2016, 18, 2248) have found a regioselective synthesis of 1,1-difluoroallylated compounds. The 1,1-difluoro intermediates successfully underwent Heck cyclization to produce difluorinated indolines and dihydrobenzofurans. In addition, the difluorinated compounds afforded 2-fluoroindolines and 2-fluorobenzofurans in high yields. The use of t-BuOK or NaH and the Pd catalyst was critical in switching the regioselectivity in the allylic substitution reaction. The disclosed protocol is complementary to other approaches for the synthesis of fluorine-containing benzoheterole derivatives.

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Many organic compounds contain “similar” C−H bonds, and their selective oxidation often poses a great challenge. This process is of vital importance not only in synthesis but also in large-scale industrial processes, academia, and industrial research. Schoenebeck and co-workers (J. Am. Chem. Soc. 2016, 138, 518−526) discovered a Cu-catalyzed tunable aerobic hydroxylation of tertiary α-C−H bonds and selective cleavage of C−C bonds in ketones. They investigated the underlying mechanisms that triggered the selectivity between the two reactivity modes via experiment, in situ IR spectroscopy, and computational studies.

ASSESSMENT OF THE ELECTRONIC FACTORS DETERMINING THE THERMODYNAMICS OF “OXIDATIVE ADDITION” OF C−H AND N−H BONDS TO IR(I) COMPLEXES

© XXXX American Chemical Society

FACTORS THAT CONTROL C−C BOND CLEAVAGE VERSUS C−H BOND HYDROXYLATION IN COPPER-CATALYZED OXIDATIONS OF KETONES WITH O2

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DOI: 10.1021/acs.oprd.6b00055 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Highlights from the Literature

solubility because the amorphous material is in metastable equilibrium with the solution. Amorphous solubility measurements can be challenging, especially for rapid “crystallizers” (i.e., substances that once in solution crystallize quickly), preventing reliable solubility measurements. A team from Lilly and Purdue University reported a new method for experimental measurement and theoretical calculation of such amorphous solubility (Almeida e Sousa, L.; et al. Mol. Pharmaceutics 2015, 12, 484). Previously developed concentration measurement methods (UV and fluorescence assays) were modified for the compounds investigated. The new experimental method developed enabled capture of the transient amorphous precipitate. The model compounds employed in the study were ibuprofen, phenylbutazone, diclofenac, tolnaftate, sorafenib, and griseofulvin. The solubility enhancements were, as expected, compound-dependent, and they were estimated using the supersaturation ratios between the amorphous and crystalline materials. The supersaturation ratio varied between 4 for ibuprofen and 54 for sorafenib. The theoretical calculations were based on the thermal properties of the crystalline and amorphous phases, the crystalline drug solubility, and the estimated concentration of water in the water-saturated amorphous phase. Excellent agreement between the calculated and measured amorphous solubilities was obtained for the six drugs studied.

The products of these reactions are a central motif in a wide range of natural products and biologically active molecules. Their findings could be of wider relevance for understanding enzymatic reactivities as well as the fate of peroxide species in metastatic cancer. In addition, they will help provide deeper mechanistic understanding and development of selective oxidative catalysis.

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COPPER-CATALYZED DIVERGENT ADDITION REACTIONS OF ENOLDIAZOACETAMIDES WITH NITRONES

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ON THE SCALE-UP OF MICROREACTORS FOR LIQUID−LIQUID REACTIONS When relatively small amounts of single-phase media are handled, the scale-up of continuous processes can be achieved by “scaling-out” or “numbering-up”, which means that instead of designing and building larger units (as in the case of batch processes) one can use several small-scale continuous reactors in parallel. When larger amounts of material are processed and/or when heterogeneous systems are present, larger units are needed. Just as for batch processes, the scale-up of such continuous processes requires the identification of a scale-up strategy, including the definition of a scale-up factor (a mixing process parameter that must be either kept constant or changed in a controlled way upon scale-up). Continuing their efforts on the scale-up of single-phase continuous processes, a team from Lonza and the University of Ottawa reported their findings on the scale-up of processes occurring in liquid−liquid systems (Plouffe, P.; et al. Chem. Eng. Sci. 2016, 143, 216). Scaling up at a constant rate of energy dissipation (ε) was proven to be an effective strategy for liquid−liquid systems as well. The test reaction employed was the alkaline (0.5 M NaOH in water) hydrolysis of 4-nitrophenyl acetate in n-butanol or toluene solvent. Sizing of the microreactor channels was done at constant ε based on a “3/7th approach” using the equation ε ∼ f(Q3/dh7), where f is a dimensionless friction factor, Q is the volumetric flow rate (m3/s), and dh is the hydraulic diameter (m). For the smallest practical microreactor with the hydraulic diameter of 286 mm, a 10-fold scale-up requires a microreactor with a hydraulic diameter of 103/7 × (286 mm) = 767 mm. The authors found a good correlation between the dimensionless drop diameter and the dimensionless Weber number (We = (ρv2l)/σ, where ρ is the density, v is the velocity, l is the characteristic length, and σ is the interfacial tension between the organic and the aqueous phase). Because of the known decrease in the heat transfer area-to-volume ratio upon scaleup, future work will address the heat transfer challenges

The first highly enantioselective base-copper-catalyzed vinyl carbene addition to nitrones was reported by Doyle and coworkers (J. Am. Chem. Soc. 2016, 138, 44−47). They used a copper(I) tetrafluoroborate/bisoxazoline complex as the catalyst and a [3 + 3] cycloaddition reaction that gave excellent yields and enantioselectivities under extremely mild conditions. When the catalyst was changed to copper(I) triflate, the Mannich addition products were obtained in high yields. In comparison with the group’s previously reported dirhodium-catalyzed cycloaddition of enoldiazoacetates (53−96% yield, 77−93% ee), the yields and enantioselectivities obtained in this report (90−96% yield, 93−98% ee) are generally superior. In addition, the use of copper salts provided versatile catalytic activities as well as ready availability, low cost, and environmentally benign conditions. Finally, on the basis of experiments and previous reports, they reported plausible pathways that explained the divergent addition reactions.

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ASSESSMENT OF THE NEW AMORPHOUS “SOLUBILITY” OF A GROUP OF DIVERSE DRUGS USING NEW EXPERIMENTAL AND THEORETICAL APPROACHES A common approach to enhance the aqueous solubility of novel active pharmaceutical ingredients (APIs) is to develop them as amorphous compounds. In such cases, it is useful to be able to estimate up front the increase in solubility for the amorphous forms compared with their crystalline analogues. Such amorphous “solubility” is not a true thermodynamic B




conducted with dehydroepiandrosterone (DHEA, 3β-hydroxyandrost-5-en-17-one). DHEA was first isolated in 1934, but in the 1990s, because of potentially new therapeutic indications, increased interest in the study of this drug substance led to the preparation and characterization of six polymorphs and four solvates. Using the cryotechnology developed, the team was able to detect a novel DHEA polymorph, form VII, as well as a new solvate (S5). By multiphase powder X-ray diffraction analysis, the authors determined the crystal structure of the novel form VII as well as that of form III, which had not been reported previously. One of the experimental challenges of this study was the fact that no single phase of the new forms could be isolated and that all of the samples analyzed changed composition over time. Theoretical calculations were also conducted to validate the crystal structures. Future work will focus on a methodology to quantify the various DHEA polymorphs during their solid-state transformations.

associated with the scale-up of such heterogeneous liquid−liquid processes.

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ROTIGOTINE: UNEXPECTED POLYMORPHISM WITH PREDICTABLE OVERALL MONOTROPIC BEHAVIOR After the ritonavir learning of 1999, the pharmaceutical industry became much more aware of polymorphs and the associated challenges for drug development. In spite of this increased awareness, a similar setback occurred nearly a decade later. Rotigotine (below) is a drug substance known since the 1980s, and in 2003 it was filed as the API for Neupro, a transdermal skin patch for the treatment of Parkinson’s disease. A polymorph screening was conducted, and no polymorphs were found. In 2008, “suddenly” a new form of rotigotine was identified (noticed first as “snowlike crystals” formed in the patch). The patch was withdrawn from the U.S. market until 2012, after reformulation. The new polymorph, form II, is the stable solid phase, with the previously known form I as the metastable polymorph. The two polymorphs differ in the position of the thiophene ring with respect to the tetrahydronaphthalenol plane. Several patents were granted for the novel form II and for the new formulations, but little additional information was available to explain the rotigotine phase behavior. Form II appeared to have a similar efficacy as form I, but the spontaneous crystallization of form II in the patch was unacceptable. A team from two Paris universities (Rietveld, I. B.; Ceólin, R. J. Pharm. Sci. 2015, 104 (12), 4117) used the calorimetric and crystallographic data published in the patents to develop a pressure−temperature phase diagram of the two polymorphs. This analysis confirme that form I is monotropic in relation to form II. To this day it is not entirely clear what triggered, after many years of handling, the conversion of form I to form II. There are two working hypotheses: one that an impurity and the other that an “event” triggered this transformation. It is believed that the formulation matrix effectively inhibited the polymorphic transformation.

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DEVELOPMENT OF A DIASTEREOSELECTIVE PHOSPHORYLATION OF A COMPLEX NUCLEOSIDE VIA DYNAMIC KINETIC RESOLUTION

Recently, phosphoramidate analogues of nucleosides have been investigated as potential antiviral therapeutics for the treatment of viral diseases (e.g., HBV1, HCV2, and influenza). The parent nucleosides can suffer from poor activity caused by rate-limiting in vivo monophosphorylation, a required step in the formation of the active nucleoside triphosphate. Preformation of the phosphoramidate acts as a prodrug strategy, releasing the monophosphate directly and aiding the formation of the active triphosphate. Introduction of the phosphoramidate creates additional synthetic complexity because stereocontrol of the phosphorus stereocenter is often challenging and limited methods exist to address this problem. Now Tran, Eastgate, and co-workers in the Chemical Development Group at BristolMyers Squibb report a novel approach for stereocontrol of the phosphorus stereocenter (J. Org. Chem. 2015, 80, 4994). A stable phosphoramidic acid derivative is coupled to the nucleoside in a process mediated by HATU and quinine to deliver the coupled product in high chemical yield with good diastereoselectivity. This unusual process was shown to proceed through dynamic kinetic resolution of a 1:1 mixture of activated phosphonate ester diastereoisomers. The optimized conditions afforded the product with a combined [S,S(P)] and [S,R(P)] assay yield of 89% and an [S,S(P):S,R(P)] diastereomeric ratio of ∼7:1. Isolation of the major isomer was achieved by single crystallization from anisole, where the product was isolated in 57% yield with excellent purity (>95%) and a high diastereomeric ratio (>50:1).

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NEW POLYMORPH OF DEHYDROEPIANDROSTERONE OBTAINED VIA CRYOMODIFICATION Conventional polymorph screening is conducted using one of at least 16 methods, such as slow cooling, fast evaporation, slurry handling, and capillary crystallization, among others. In certain instances, specialized, or “targeted” screening is conducted. A team from two Moscow universities and two research institutes developed a novel methodology for preparing drug substance nanoparticles (Chernyshev, V. V.; et al. Cryst. Growth Des. 2016, DOI: 10.1021/acs.cgd.5b01666), primarily for the goal of improved solubility. The method involves transfer of the drug substance into the gas phase by evaporation or sublimation in a gas flow, followed by contact with a cold surface. When this method was applied to a benzodiazepine compound, the team discovered a new polymorph, one with better anxiolytic activity and fewer side effects. This paper reports the results of a similar investigation C



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INTRAMOLECULAR sp3 FUNCTIONALIZATION OF CYCLOPROPYL α-AMINO ACID-DERIVED BENZAMIDES

palladium- and copper-catalyzed carbon−nitrogen bond formation have substantially impacted the design and synthesis of drug candidates. Despite the development of myriad methods for the coupling of alkyl- and arylamines, transformations involving the simplest amine nucleophile, ammonia, and yielding the corresponding monoarylamine (aniline) products are less common. This scarcity of metalcatalyzed amination processes that employ ammonia has been attributed to several challenges. For example, high concentrations of ammonia can displace supporting ligands from the metal, resulting in catalyst deactivation. An additional complication associated with these cross-coupling processes is the ability of the monoarylamine products to further react with equivalents of the electrophile to form undesired di- and triarylamine byproducts. Now a report from the Billingsley group (J. Org. Chem. 2016, 81, 330) describes the use of inexpensive and readily available valine amino acid as an “ammonia surrogate” for use in C−N cross-coupling processes. The developed conditions obviate the need for a special experimental setup or handling of ammonia reagents. This process, which is proposed to proceed via an amination− oxidation sequence, selectively promotes the transformation of a range of aryl and heteroaryl iodides as well as bromides to the corresponding monoarylamines. Lower catalyst loadings (90%) of the mononitrated products. In cases with meta substituents, separable mixtures of regioisomers were obtained after nitration, with reaction at the less hindered C−H occurring predominantly. The authors also disclosed a mild two-step method for removal of the pyrimidine ring through initial silane-mediated reduction followed by reaction with hydrazine. Initial mechanistic studies suggested that palladacycle formation is not a reversible step and that the reaction may involve a radical process.

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The class of controlled hydroacylation reactions that have enjoyed the most success typically rely on a chelating group, which either has to be removed or utilized in subsequent transformations. An alternative to this would be to utilize a functional group that would be desirable to have in the final product. Willis and co-workers have reported the Rh-catalyzed alkyne acylation of α-amino aldehydes (J. Am. Chem. Soc. 2016, DOI: 10.1021/jacs.5b11892). Key to the success of the reaction is the presence of both electron-withdrawing (Cbz, Ts) and methylthiomethyl (MTM) protecting groups on the nitrogen. After determination of the optimal conditions and scope using the aldehyde derived from glycine, the methodology was extended to enantiomerically pure substrates. After the development of robust conditions for their preparation through reduction of the Weinreb amide (ester reduction led to significant racemization), the Rh-catalyzed reaction was demonstrated for a range of alkynes with excellent functional group tolerance and no observable erosion of enantiopurity. However, both alkenes and allenes showed poor reactivity. The authors also demonstrated that it was possible to replace the MTM group with several other S-containing moieties and that orthogonal deprotections could be achieved through a judicious choice of the N-protecting groups. The utility of the methodology was demonstrated by concise enantio- and diastereoselective syntheses of sphingosine and a range of tagged derivatives.

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SYNTHESIS OF ENANTIOPURE PIPERAZINES VIA ASYMMETRIC LITHIATION−TRAPPING OF N-BOC PIPERAZINES: UNEXPECTED ROLE OF THE ELECTROPHILE AND DISTAL N-SUBSTITUENT

The synthesis of enantioenriched α-substituted N-heterocycles through asymmetric sparteine-mediated lithiation of the Bocprotected derivatives is well-established for both pyrrolidine and piperidine derivatives. However, the analogous reaction of piperazines is plagued with problems such as ring fragmentation and mediocre stereoselectivity. O’Brien and co-workers have carried out a systematic study of the reaction and provided both a mechanistic rationale and a viable solution to the typically encountered problems (J. Am. Chem. Soc. 2016, 138, 651). The study showed that not only the enantioselectivity but also the extent of ring fragmentation observed are dependent on the nature of the electrophile. However, it was demonstrated that increasing the steric bulk of the distal N-substituent was able to reduce the amount of ring fragmentation and thus increase the yields of the desired products, although surprisingly this was accompanied by a decrease in the rate of lithiation as measured by in situ IR spectroscopy. In an extension of this, the authors exploited the use of a chiral α-methylbenzyl N-alkyl group to potentially favor one diastereomer. In conjunction with the sparteine derivative, this creates a long-range match/mismatch effect that successfully allows a range of derivatives to be formed in good yield with a high diastereomeric ratio (dr). Several electrophiles still proved problematic. For example, in the case of benzophenone it was hypothesized that a single electron transfertype mechanism was also operative, leading to a tetrahydropyrazine byproduct as well as a depressed yield and dr. For methylbased electrophiles, two approaches were exploited, with the use of a more reactive electrophile and an in situ diamine switch of N,N,N′,N′-tetramethyl-1,2-ethylenediamine (TMEDA) for the sparteine derivative leading to improved yields and dr. Finally, the α-methylbenzyl group could be easily removed by a variety of approaches, and the utility of this methodology was demonstrated by the synthesis of an advanced intermediate

PALLADIUM(II)-CATALYZED, HETEROATOM-DIRECTED, REGIOSELECTIVE C−H NITRATION OF ANILINES USING PYRIMIDINE AS A REMOVABLE DIRECTING GROUP

Although nitration of aromatic systems represents a robust methodology, several issues still exist with the classical approaches, such as functional group compatibility, selectivity, and overnitration in the case of highly activated systems. Kapur and co-workers have reported Pd-mediated nitration of anilines utilizing pyrimidine as a removable directing group (Org. Lett. 2016, 18, 448). Model studies of the nitration of N-phenylpyrimidin-2-amine indicated that AgNO3 was the ideal nitro J




for the synthesis of indinavir as well as a series of 2,5- and 2,6trans-piperazines.

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Alan Steven Chemical Development, AstraZeneca, Cambridge CB4 0FZ, U.K.. E-mail: [email protected].

DIRECT TRANSFORMATION OF ETHYL ARENES INTO PRIMARY AROMATIC AMIDES WITH N-BROMOSUCCINIMIDE AND I2−AQUEOUS NH3

John Knight*

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JKonsult Ltd, Meadow View, Cross Keys, Hereford HR1 3NT, U.K.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected].

Togo and co-workers have described a simple one-pot methodology for the synthesis of primary aromatic amides starting from ethyl arenes (Org. Lett. 2016, DOI: 10.1021/ acs.orglett.6b00048). In an optimization study using ethylbenzene as the substrate, they found the solvent to be a key variable, with a 5:1 mixture of ethyl acetate and water being the best. A range of brominating reagents were effective in the first step, which was carried out at 80 °C, with the α-bromoacetophenone shown to be the intermediate product. Direct treatment of the intermediate with both I2 and NH3 at ambient temperature led to the isolation of the desired amide. A range of substrates were effectively converted, though thiophene-derived examples also were brominated on the ring and a boronic acid was converted to the corresponding bromide. Conditions were also developed for the transformation of electron-deficient and electron-rich substrates through optimization of the solvent system, reagent stoichiometry, reaction time, and temperature. In several cases for the electron-rich substrates, ring bromination was also observed. Also, in these cases a series of different intermediates were observed, which through a series of control experiments were all shown to lead to the desired amide, enabling a mechanistic hypothesis to be proposed.

Mark McLaughlin Department of Process Research, Merck Research Laboratories, Merck & Co., Inc., Rahway, New Jersey 07065, United States. E-mail: mark_mclaughlinmerck.com.

Robert Ely Onyx Pharmaceuticals, 249 East Grand Avenue, South San Francisco, California 94080, United States. E-mail: REly@ gmail.com.

Antonio Ramirez Bristol-Myers Squibb, Chemical Development, One Squibb Drive, New Brunswick, New Jersey 08903, United States. E-mail: [email protected].

Paul Richardson Pfizer, Chemistry, 10578 Science Center Drive, San Diego, California 09121, United States. E-mail: paul.f.richardson@ pfizer.com.

Andrei Zlota The Zlota Company, LLC, 15 Fairbanks Road, Sharon, Massachusetts 02067-2858, United States. E-mail: andrei. [email protected].

Robert Kargbo Department of Process Chemistry, AMRI, 26 Corporate Circle, Albany, New York 12212, United States. E-mail: [email protected]. K


Some Items of Interest to Process R&D Chemists ... - Groupe Charette

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