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

Highlights from the Literature pubs.acs.org/OPRD

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

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EXPLORING THE LINKAGE BETWEEN CELL CULTURE PROCESS PARAMETERS AND DOWNSTREAM PROCESSING UTILIZING A PLACKETT−BURMAN DESIGN FOR A MODEL MONOCLONAL ANTIBODY

IMPACT OF BILE SALTS ON THE SOLUTION CRYSTAL GROWTH RATE AND RESIDUAL SUPERSATURATION OF AN ACTIVE PHARMACEUTICAL INGREDIENT Controlling nucleation and growth in crystallization using additives is an old technology, with relatively limited use due to the regulatory limitations imposed on such additives. The use of additives that are considered safe because of their biorelevance is a creative improvement of this technology. Bile salts are an example of endogenous surfactants present in the gastrointestinal tract and in biorelevant dissolution media. An example of the use of certain bile salts for the crystallization control of telaprevir (hepatitis C drug codeveloped by Vertex and Johnson & Johnson) was reported by a team from Purdue University, Merck & Co. and the University of Sheffield (Lu, J., et al. Cryst. Growth Des. 2017, 17, 3528). The crystallization impact of bile salts was investigated both in their monomeric as well as in their micellar form. The motivation for this work was crystallization control for supersaturated formulations needed for low solubility API’s (active pharmaceutical ingredients). Among others, it was found that monomeric sodium taurochendeoxycholate was effective in inhibiting secondary nucleation of telaprevir in highly supersaturated solutions. API concentration in the solution was monitored with a UV−vis spectrometer. To better mimic the in vivo conditions, the team decided to use a “common history” seeding method, producing the seeds in situ, rather than adding seeds previously prepared. A mechanistic insight into the interaction between the API and the bile salts was provided by zeta potential measurements. This paper has 49 references.

FDA’s support for Quality by Design (QbD) is expressed in various forms, one being reporting on US FDA regulatory research which employs QbD methodology. Such research work implicitlyyet unofficiallydescribes some of the expectations that US FDA officers might have when reviewing regulatory submissions. A recent paper from the Office of Biotechnology Products and colleagues from the US FDA discusses the use of statistical design of experiments (DoE) for proper bioprocess development (Agarabi, C. D., et al. Biotechnol. Prog. 2017, 33, 163). This study focuses on the careful linkage investigation between upstream process parameters and downstream critical quality attributes. This work is a continuation of the DoE data analysis reported earlier (Agarabi, C. D., et al. J. Pharm. Sci. 2015, 104, 1919) when 11 process parameters were investigated in a Plackett−Burman DoE matrix. The original study found that most of the parameters included in the DoE were statistically significant with respect to the process results analyzed. For the additional quality attributes included in the recent study, new process parameters were identified as statistically significant. Future work might include additional DoE matrixes aiming at quantifying any factor interactions that may exist and possibly attempt process optimization.

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INSIGHT INTO THE ROLE OF ADDITIVES IN CONTROLLING POLYMORPHIC OUTCOME: A CO2-ANTISOLVENT CRYSTALLIZATION PROCESS OF CARBAMAZEPINE A creative technology for polymorph control employing CO2antisolvent crystallization in the presence of additives was recently published by a group at the University of Limerick (Padrela, L., et al. Cryst. Growth. Des. 2017, 10.1021/ acs.cgd.7b00163). The model compound employed in this investigation was carbamazepine, a popular model in crystallization studies due, among others, to its four possible polymorphs: forms I, II, III, and IV, form III being the most stable form at ambient conditions. Carbamazepine is a generic drug used to treat epilepsy and other central nervous system diseases. Traditional crystallization methods, while capable to control the polymorphic outcome, are slower than CO2antisolvent crystallizations and also require two additional unit operations, filtration and drying, not needed with CO2antisolvent crystallizations. Fifteen additives were assessed for their polymorphic control capabilities, from five different classes of compounds: anionic and nonionic surfactants, and anionic and nonionic polymers. The team found that, when using sodium

FLOW SYNTHESIS OF CYCLOBUTANONES VIA [2 + 2] CYCLOADDITION OF KETENEIMINIUM SALTS AND ETHYLENE GAS

A continuous process for the [2 + 2] cycloaddition of keteneiminium salts to ethylene to produce a variety of 2monosubstituted cyclobutanones is described in a paper from the University of Cambridge and Syngenta Crop Protection AG (Battilocchio, C., et al. React. Chem. Eng. 2017, 2, 295). The reaction was conducted using a tube-in-tube reactor based on a semipermeable polymer membrane that allows controlled transfer of the gas into the liquid flow. Screening experiments identified residence time, temperature, and pressure as important process parameters, and an optimization investigation was conducted. As outlined before by Prof. Ley’s group, the processes described in this work contain both continuous and batch elements. Furthermore, to accommodate workup, specialized equipment (a static mixer and a membrane-based liquid−liquid separator) was used. The reactions depicted were executed at small scale (approximately 31 g/h) with future work possibly considering the process scalability. The Supporting Information has 36 pages, describing experimental protocols and detailed analytical results. © 2017 American Chemical Society

Published: September 11, 2017 1196

DOI: 10.1021/acs.oprd.7b00286 Org. Process Res. Dev. 2017, 21, 1196−1208

Organic Process Research & Development

Highlights from the Literature

and generally good. However, other nucleophiles may give lower

stearate or Eudragit L-100 needles of form II were obtained, whereas in the presence of Kolidon VA64 (a nonionic surfactant), sodium dodecyl sulfate, ethyl cellulose, and maltitol (a nonionic surfactant) pure form III, “blocky” crystals were obtained. The amount of additive used was approximately 5% w/ w. The investigation looked also at the possibility of using the same additives when solvent evaporation crystallization processes were practiced, to find that the latter led to polymorphic mixtures. Mechanistic insights are provided based on a careful molecular level analysis together with density functional theory calculations. Detailed solid-state characterization was executed using XRPD, Raman spectroscopy, and scanning electron microscopy. A rare exception to the Ostwald rule of stages was identified in one of the cases investigated.

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yields, and addition may occur at the 4-position instead.

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PHOSPHONIUM SALTS AS PSEUDOHALIDES: REGIOSELECTIVE NICKEL-CATALYZED CROSS-COUPLING OF COMPLEX PYRIDINES AND DIAZINES

A BIFUNCTIONAL REAGENT DESIGNED FOR THE MILD, NUCLEOPHILIC FUNCTIONALIZATION OF PYRIDINES

Last year, McNally and co-workers at the University of Colorado disclosed conditions for the selective functionalization of azaarenes via phosphonium salt formation followed by phosphorus displacement by various nucleophiles (J. Am. Chem. Soc. 2016, 138, 13806). Now, a new publication from the same group significantly expands the usefulness of the triphenylphosphonium salt intermediates by demonstrating that they can also function as pseudohalides in nickel-catalyzed cross-coupling

A recent paper from Fier at Merck & Co., Inc. describes the use of α-chloro-O-methanesulfonyl aldoximes as activating agents for the direct functionalization of pyridines with various nucleophiles (J. Am. Chem. Soc. 2017, 139, 9499). By simply heating pyridines with these reagents in the presence of sodium triflate, activated pyridinium salts are formed. Subsequent treatment of these intermediate species with various nucleophiles under basic conditions then results in addition to the pyridine ring, leading to rearomatization via the collapse of the activating group, expelling a nitrile and the functionalized heterocycle. In this initial communication, the addition of cyanide is the main focus, but preliminary results show that a number of common carbon nucleophiles such as Grignards, dialkylzincs, and malonates can be used, as can some oxygen nucleophiles such as methoxide. The chloroxime reagent itself is a crystalline bench-stable solid that is readily prepared on a large scale from acetaldehyde oxime using common and inexpensive reagents. The ability to functionalize pyridines directly without recourse to classic pyridine N-oxide chemistry for instance, which can have serious practical limitations, is clearly valuable. In the case of cyanide, the reaction is efficient, and the regioselectivity of the addition to the pyridine 2-position (or isoquinoline 1-position) is predictable,

reactions with boronic acids to form pharmaceutically relevant heterobiaryls (Angew. Chem., Int. Ed. 2017, 56, 9833). This reaction is noteworthy because phosphonium salt formation is extremely selective for the 4-position of pyridines, whereas there is no general way to directly halogenate this position, especially in complex systems. Furthermore, the intermediate phosphonium salts are invariably solids that can be isolated directly by crystallization, often without the need for additional purification. In cases where the 4-position is blocked, either by a substituent or a nitrogen atomas in pyrazinesthe reaction instead occurs at the 2-position in comparable efficiency. The sequence is demonstrated on a number of drug-like molecules, but the use of triflic anhydride as an activating agent, and the requirement for up to 10 mol % of an expensive NHC ligand may limit the applicability of the reaction in a process setting. 1197



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A PRACTICAL AND CATALYST-FREE TRIFLUOROETHYLATION REACTION OF AMINES USING TRIFLUOROACETIC ACID


VISIBLE-LIGHT-DRIVEN CARBOXYLATION OF ARYL HALIDES BY THE COMBINED USE OF PALLADIUM AND PHOTOREDOX CATALYSTS

A report from Iwasawa and co-workers describes mild conditions for the carboxylation of aryl bromides and chlorides through the A recent communication from the Denton group describes the remarkable trifluoroethylation of primary and secondary amines

merger of palladium and photoredox catalysis (J. Am. Chem. Soc.

using trifluoroacetic acid as the trifluoroethyl source (Nat.

2017, 139, 9467). Although a number of different palladium,

Commun. 2017, 8, 15613). Under the optimized reaction

nickel, and copper systems have been reported to effect this

conditions, simply heating a secondary amine with a small

transformation, a general feature of these reactions has been the

excess of trifluoroacetic acid in the presence of phenylsilane in THF forms the alkylated products in good yields. Furthermore, a

use of a superstoichiometric organometallic or zerovalent metal

three-component variant is also reported, where a primary amine is used and an aldehyde is also added before the trifluoroacetic

as the reducing agent. An advantage of Iwasawa’s method is the

acid, leading to the double reductive alkylation of the starting

use of an inexpensive and benign amineHunig’s basein this

amine. Interestingly, the operation of two competitive

role, allowing for a homogeneous reaction system. A heteroleptic

mechanismstrifluoroethylation and amide formationis observed under the reaction conditions. For trifluoroacetic

iridium photocatalyst is used to shuttle electrons from the amine

acid, the alkylation pathway is strongly favored, but as the pKa of

reductant to a palladium−Xphos system that is responsible for

the acid increases, the amidation pathway becomes dominant. the carboxylation. Yields are generally high, and the reaction

Thus, for trichloro- and difluoroacetic acid, the alkylation products still predominate, albeit in lower yields; however, all

appears to be fairly insensitive to steric hindrance around the site

other acids examined favor amide formation and do not produce

of coupling. The ability to use both aryl bromides and aryl

useful amounts of the alkylated products. Clearly, the use of trifluoroacetic acid in place of expensive and difficult to handle

chlorides is a definite advantage over many previously reported

reagents such as trifluoroethyl trifluoromethanesulfonate and

systems, although the reaction was only demonstrated on simple

trifluoroacetaldehyde will be an advantage when the synthesis of substrates.

trifluoroethylamine-containing molecules is required, although the reaction does not work well for anilines. 1198



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DECARBOXYLATIVE ALKYNYLATION


THE MERGER OF TRANSITION METAL AND PHOTOCATALYSIS

A number of paradigms exist for modulating and enhancing the reactivity of transition metal complexes to allow useful crosscoupling reactions to occur. Perhaps best explored is the area of ligand design, but other modalities such as energy transfer and redox changes can be equally powerful. Research into the latter two mechanisms has recently blossomed, thanks to the advent of photoredox catalysts that can work in concert with traditional transition metal catalysts in so-called metallaphotocatalysis coupling reactions. Furthermore, the ability of photoredox catalysts to generate reactive radical species from seemingly innocuous functional groups such as carboxylic acids has enabled the use of several nontraditional nucleophiles as coupling partners in these dual catalytic systems. A review of the field over the past decade by MacMillan and co-workers (Nat. Rev. Chem. 2017, 1, 52) provides a clear mechanistic explanation of how the unique properties of metallaphotoredox systems have allowed classical challenges in transition metal and crosscoupling chemistry to be overcome. Although the case studies in the reviewlike the field it encapsulatespredominantly employ nickel-based systems, recent developments in the use of palladium, gold, copper, and other metals in this context are also discussed. This review contains 183 references.

A recent publication from the Baran group and their collaborators at Asymchem and Bristol−Myers Squibb describes the decarboxylative alkynylation of activated esters (Angew. Chem., Int. Ed. 2017, 10.1002/anie.201705107). The reaction

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builds on the group’s previously reported redox-active ester technology, using a nickel or iron catalyst to cross-couple hydroxyphthalimide esters with various alkynylmetal reagents.

ENANTIOSELECTIVE CHEMO- AND BIOCATALYSIS: PARTNERS IN RETROSYNTHESIS

This review by Turner, Carreira, and co-workers (Angew. Chem., Int. Ed. 2017, 56, 8942) considers the impact of the ascendant field of biocatalysis on synthetic planning and aims to provide a guide to the use of biocatalytic transformations in chemical synthesis, with a particular focus on new retrosynthetic considerations. As the arsenal of available and synthetically useful biocatalysts continues to grow, it is important that enzymatic transformations are considered alongside chemocatalysts when designing synthetic routes. The rapidly expanding availability of new enzymes, along with the falling cost of genome sequencing, DNA synthesis, and directed evolution, has made enzymatic steps an increasingly common feature in drug synthesis, and it behooves (and benefits) process chemists to be knowledgeable in this area. At present, many enantioselective transformations are possible or practical using only chemocatalytic or only biocatalytic methods, making it important for synthetic chemists to be aware of the complementary capabilities and limitations of both approaches. The authors compare and contrast recent developments in biocatalysis with the latest chemocatalytic options, highlighting the differences in scope and practicality. It is divided into sections on C−C and C−N bond formation, hydrolysis and condensation reactions, redox reactions, and sequential transformations and cascades. This review contains 270 references.

The coupling is demonstrated on primary and secondary esters, which can be formed in situ from the corresponding carboxylic acids, using protected or unprotected acetylides. To install terminal alkyne groups, an alkynylzinc nucleophileformed by transmetalation of the Grignard with zinc chloridealong with a nickel catalyst is required. However, couplings of nonterminal alkynes can utilize the Grignard reagents directly, with a ligandless iron catalyst instead of nickel. The reaction is demonstrated to be amenable to scale-up and is used to prepare a valuable alkynyl amino acid derivative on a 1 mol (>600 g) scale. This transformation may offer an alternative to the introduction of terminal alkynes in place of classic methods such as the Corey−Fuchs and Seyforth−Gilbert-type reactions that are unappealing on scale. However, the relatively dilute conditions, the high cost of the 4−4′-dimethoxy-2−2′-bipyridine ligand required for the nickel system, and the need for a large excess of the organometallic may be drawbacks in a process setting. 1199



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PRACTICAL SINGLY AND DOUBLY ELECTROPHILIC AMINATING AGENTS: A NEW, MORE SUSTAINABLE PLATFORM FOR CARBON−NITROGEN BOND FORMATION

to prepare aziridines, carbazoles, and medium-sized N-heterocycles.

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A NEW SHORT AND STEREOCONTROLLED SYNTHESIS OF C2-SYMMETRIC 1,2-DIAMINES

C2-symmetric 1,2-diamines represent an important class of ligands in both catalytic and enantioselective synthesis as exemplified by the extensive reported applications of both 1,2diphenyl-1,2-aminoethane (DPEN) and trans-1,2-diaminocyclohexane (DAC). With the initial aim to prepare derivatives of DPEN with significantly diminished electron density at nitrogen, Corey and co-workers have developed a versatile diastereoselective synthesis to this class of diamines (Org. Lett. 2017, 19, 3883). Key to the success of the approach was the intermediacy of the previously unknown cyclic bis-imine, which is accessed in high yields through the condensation of aqueous glyoxal trimer, cyclohexanone, NH4OAc in THF/anhydrous NH3. This compound can be stored indefinitely in the freezer, and the addition at low temperature in excess of two equivalents of either organolithium or Grignard reagents in the presence of BF3·OEt2 led to the complete formation of the trans-cyclic amine with none of the corresponding meso compound being detected. The desired diamine could be subsequently obtained after acidic hydrolysis of the cyclohexylidene diamine followed by extractive workup and purification. Acyclic/cyclic alkyl, (hetero)aryl, allyl, and propargylic nucleophiles were all successful substrates, and subsequent functional group manipulation of several systems allowed the synthetically useful bis-pyrrolidines and bis-isoindolines to be prepared. In addition, the separation of the racemic products was demonstrated by both chiral chromatography and classical resolution techniques. The use of one equivalent of the organometallic reagent allowed the monoamines to also be obtained. The pKa of the 1,2-pentafluoroethyl-1,2-aminoethane (PFEEN) was measured as 2.45 (9:1 water−ethanol) making it the least basic 1,2-disubstituted ethylenediamine known.

Although there are numerous synthetic approaches to aromatic and heteroaromatic amines, many of these either involve transition metal catalysts/ligands and/or forcing reaction conditions thus entailing a significant amount of reaction optimization to access this highly biologically relevant class of compounds. Kürti, Ess, Li, and co-workers have reported a reagent-based approach exploiting single and double umpolung of nitrogen to enable flexible disconnections for the formation of both unsymmetrical and symmetrical secondary amines (J. Am. Chem. Soc. 2017, 139, 11184). Electrophilic nitrogen sources have been reported previously though often suffer from drawbacks such as heat/light sensitivity, significant side reactions, or severe limitations in scope. The current report describes two bench-stable reagents with the first being a doubly N-electrophilic iminomalonate featuring a sulfonate leaving group on the nitrogen. Key to the success of this reagent is the nature of the ester with increased steric bulk both enhancing stability and promoting reaction at N as opposed to C. Treatment of this reagent with either alkyl or aryl metal reagents at depressed temperature led to a double electrophilic amination taking place, thus leading to the protected symmetrical amines. Attempts to intercept the reaction after a single amination failed, but the problem to synthesize unsymmetrical diamines was addressed through the development of the analogous stable, crystalline ketomalonate hydrate. The initial generation of the imine through addition of the imine proceeded smoothly leading to a singly N-electrophilic iminomalonate, which in turn could undergo electrophilic amination with a distinct Grignard reagent to generate the unsymmetrical protected diamine. The dialkylmalonyl protecting group on the amine could be easily removed either under mildly basic conditions or through treatment by a base and a mild oxidant such as NCS with the latter conditions proving to be far more general. The versatility of the approach is further enhanced with methodologies presented 1200



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fluorine through bromine, the corresponding approach to alkyl iodides is challenging due to both unfavorable energetics as well as the ease of cleavage of the carbon−iodine bond formed. Several approaches have been reported using strongly electrophilic radicals though all of these have limitations either with a poor substrate scope (ineffective for benzylic substrates), or harsh reaction conditions/unstable reagents being required. Schreiner, Gandelman, and co-workers have developed the easy to prepare reagent 1-iodo-3,5,5-trimethylhydantoin (1-ITMH), which functions both as a powerful radical initiator and an iodine donor and is capable of efficiently iodinating a range of hydrocarbons (J. Org. Chem. 2017, 82, 7093) though in the cases of unsymmetrical systems leads to mixtures of the iodinated products. 1-ITMH displays both good thermal stability as well as good solubility in nonpolar solvents with reaction optimization studies indicating that neat conditions are the most effective with irradiation of the reaction mixture (white LED light) crucial for success. The addition of a cosolvent or the presence of water also led to a dramatic attrition in yield. The reaction conditions were also shown to be effective for a range of benzylic substrates thus providing the missing iodine version of the Wohl−Ziegler reaction with in situ derivatization to the corresponding benzoates carried out to facilitate purification. The use of flash vacuum pyrolysis enabled the five-membered radial derived from 1-ITMH to be characterized by IR with its stabilization hypothesized to be due to hyperconjugative interactions of the unpaired spin with adjacent C−C bonds that compensate for the potentially destabilizing effect of the adjacent carbonyl groups.

INVERTING CONVENTIONAL CHEMOSELECTIVITY IN PALLADIUM-CATALYZED AMINE ARYLATIONS WITH MULTIPLY HALOGENATED PYRIDINES

Site- and chemoselective cross-coupling reactions offer a rapid means of accessing diversity with site selectivity in heteroarenes being dictated by the most electrophilic position (in the case of identical halogens) or by the bond-dissociation energies (in the cases of nonidentical halogens). Sigman, Tan, and co-workers have reported on an intriguing study in which orthogonal halogen reactivity in a system is controlled through precise tuning of the catalyst−substrate system (J. Am. Chem. Soc. 2017, 139, 10613). Utilizing 2-chloro-5-bromo-pyridine as a model substrate in a Buchwald−Hartwig amination with aniline, a screen of 75 phosphine-based ligands was carried out which initially indicated that both a degree of conformational flexibility as well as bidentate coordination was necessary to promote selective C−Cl oxidative addition. The solvent was also shown to be an important variable with dioxane providing an enhancement in both yield and selectivity when compared to results obtained with toluene. Correlating the selectivity results obtained with a series of molecular descriptors suggested that the trans-influence, and therefore the σ-donor ability of the ligand is important for the selective coupling of the C−Cl bond. The fact that electronic as opposed to steric properties was instrumental in governing selectivity was further confirmed through a comparison of the measured 31P NMR shifts and the cone angles of a series of truncated ligands with the observed selectivity. Given that 1,1′ferrocenyl diphosphines appeared uniquely able to provide both synthetically viable yields and selectivities and that increased σdonation increased selectivity for the oxidative addition of the C−Cl bond, the authors investigated a series of tunable bis(dialkylamino)phosphines in this series and found that the commercially available (though under-utilized) ligand DMAPF provided the best results. With the optimized conditions in hand, a series of substrates were evaluated with selectivity for the 2-Cl position maintained even in cases when the 2-position was either electronically deactivated or sterically encumbered compared to the bromide.

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A DIRECT SYNTHESIS OF HIGHLY SUBSTITUTED Π-RICH AROMATIC HETEROCYCLES FROM OXETANES

ALIPHATIC C−H BOND IODINATION BY A N-IODOAMIDE AND ISOLATION OF AN ELUSIVE N-AMIDYL RADICAL

The most direct access to synthetically valuable alkyl halides is through direct C−H functionalization of unactivated hydrocarbons, and though this transformation is well-established for 1201




The Paal−Knorr synthesis of pyrroles and furans represents a well-established reliable method to access these classes of heterocycles though the synthesis of the 1,4-dicarbonyl precursors can present challenges, particularly in cases in which highly substituted compounds are desired. Vanderwal and coworkers have provided an operationally simple approach utilizing easily accessible oxetane-containing 1,4-dioxygenated intermediates as precursors to the heterocycles (Angew. Chem., Int. Ed. 2017, 56, 10525). The model precursors were accessed from readily available and cheap 3-oxetanone through routine Wittig or Aldol chemistries, and it was found that rearrangement to the requisite furans could be induced cleanly by a variety of Lewis and Brønsted acids with catalyst loadings as low as 0.1%. Despite the ease of the rearrangement, the precursors are stable and can be stored indefinitely, while the synthetic versatility of the products is also highlighted. To evaluate substrate scope, several general reaction conditions were defined (typically BF3.OEt2/ DCM or TFA/DCM), and using the TFA-based conditions, it was shown to be possible to convert the Aldol-adducts directly to the furans through the ring-opening, dehydration, and aromatization sequence. The addition of 2 equiv of a primary amine in the presence of molecular sieves to the reaction system led to the corresponding pyrroles, though longer reaction times were required to minimize the amount of the corresponding 1,4addition product. Finally, the utility and generality of the methodology were demonstrated in the preparation of benzofurans and indoles.

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were developed indicating that C−N boron migration can be avoided in these systems, and complete epimerization to the trans-systems can be achieved through treatment with a weak base such as TEA. Furthermore, conditions were developed to remove the nosyl-protecting group while leaving the MIDA− boronate system intact. Switching the base to Hunig’s base and reacting the borylketenimine with salicylaldehyde derivatives enabled the formation of a series of boryliminocoumarins, and these were further shown to be capable of being incorporated into more complex systems through Suzuki−Miyaura coupling. This approach was demonstrated to have potential utility in the fluorescent labeling of peptides. Finally, the borylketenimines were shown to react with diisopropylamine, water, and 1,4benzoquinone to generate α-borylamidines, σ-borylamides, and σ-boryliminooxetanes, respectively.

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SYNTHESIS OF 6-AZASPIRO[4.3]ALKANES AND 1-SUBSTITUTED 2-AZASPIRO[3.3]HEPTANES: INNOVATIVE SCAFFOLDS FOR DRUG DISCOVERY

AMPHOTERIC BORYLKETENIMINES: VERSATILE INTERMEDIATES IN THE SYNTHESIS OF BORYLATED HETEROCYCLES

There is a current drive within modern drug discovery to increase the amount or fraction of sp3-character (Fsp3) within novel biologically active molecules, and the most facile way to achieve this is through the incorporation of novel three-dimensionally shaped building blocks. Mykhailiuk and co-workers have published two reports on different series of azaspiroalkanes, which fulfill many of the criteria of such series of building blocks such as being readily accessible on multigram scale as well as being in appropriate ADME property space. 1-Substituted-2azaspiro[3.3]heptanes were accessed through the Staudinger reaction of ketenes generated from cyclobutanecarboxylic acid and N-TMS imines to generate the intermediate spirocyclic azetidinone derivative, which could be reduced (Angew. Chem., Int. Ed. 2017, 139, 8865). Alkyl, aryl, and heteroaryl substituents were all tolerated in the 2-position derived from the imine, and a range of functional group transformations carried out to further demonstrate the utility of these molecular frameworks. ADME property space was similar to the related 2-substituted piperidines, and the replacement of the latter molecule motif in approved anesthetic Bupivacaine with the spirocyclic analogue led to both a faster onset of action as well as less systemic toxicity. For the synthesis of 6-azaspiro[4.3]alkanes, the key reaction involves the [3 + 2] cycloaddition between azomethine ylides and electron-deficient alkenes derived from cyclobutanone derivatives (Eur. J. Org. Chem. 2017, 31, 4530). Two sets of conditions for the cycloaddition were demonstrated to be

The use of boron-containing compounds as both building blocks as well as biologically active entities continues to grow within medicinal chemistry. Given that the propensity for boron to form reversible covalent interactions with nucleophiles makes the synthesis of such compounds challenging particularly in heteroatom-rich environments, there exists a need for new strategies to access boron-containing molecules. Yudin and coworkers have reported on a new methodology utilizing in situ generated borylketenimine as linchpin reagents for the synthesis of a variety of different boron-containing heterocycles (Chem. Eur. J. 2017, 23, 9711). In the model system, the ketenimine is generated through the reaction of commercially available ethynyl MIDA (N-methyliminodiacetic acid) boronate with tosyl (or nosyl) azide under copper catalysis (CuI) with the base and trapped to form a four-membered borylazetidinimine by the presence of a preformed imine. The optimization of the reaction conditions demonstrated NMM to be the best base, while the solubility of the MIDA species led to DMF and MeCN being the best solvents, with the latter selected for scope studies owing to operational convenience. A wide range of borylazetidinimines were accessed in a trans-selective fashion with an increase in rate and yield observed for alkyl-substituted imines. Stereoretentive deuterodeboronation conditions for the borylazetidinimines 1202



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effective with a wide variety of substrates prepared with either two or three points of diversity being accessible depending on the cyclic ketone derivative employed. In addition, various functional group manipulations of the electron-withdrawing group derived


ENANTIOSELECTIVE SYNTHESIS OF ANTI-1,2-OXABORINANE-3-ENES FROM ALDEHYDES AND 1,1-DI(BORYL)ALK-3-ENES USING RUTHENIUM AND CHIRAL PHOSPHORIC ACID CATALYSTS

from the alkene were also demonstrated. In this case, the building blocks obtained were also optically active, and although the synthesis described is racemic, the separation of the enantiomers through chiral chromatography, enzymatic resolution, or use of an external chiral auxiliary is described. Again, the ADME properties were measured and shown to be in a similar space to the analogous benzyl-protected piperidines or morpholines.

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DIRECTED C−H AMINATION OF ALCOHOLS VIA RADICAL RELAY CHAPERONES Murakami and co-workers at Kyoto University have expanded upon their recently described Pd-catalyzed double bond transposition of 1,1-di(boryl)alk-3-enes for asymmetric aldehyde allylation, by discovering a Ru-catalyzed double bond transposition that provides the Z-vinylboronate moiety, opposed to the E-vinyl boronate produced with Pd-catalysis (J. Am. Chem.

Nagib and co-workers at Ohio State University have described a

Soc. 2017, 139, 10903). This elegant strategy provides anti-

radical relay chaperone strategy to convert alcohols to valuable β-

homoallylic alcohols in high enantioselectivities using the well-

amino alcohols employing 1,5-hydrogen atom transfer (J. Am. Chem. Soc. 2017, 139, 10204). The alcohol is first converted to a

known TRIP−phosphoric acid catalyst by first isomerizing 1,1-

tunable imidate (trichloroacetimidates for phenylethanol

di(boryl)alk-3-enes to 1,1-di(boryl)alk-2-enes, which are useful

derivates and benzimidates for alkyl alcohols) that not only can

allylboron reagents. The 1,1-di(boryl)alk-3-enes are easily made

easily generate an N-centered radical but also provide a two-atom

by alkylation of commercially available bis(pinacolatoboryl)-

linker that sets up a selective 1,5-hydrogen atom transfer. Using −

conditions developed by the same group to generate I3 in situ

methane. In both the ruthenium and palladium chemistry, the Z-

from NaI, PhI(OAc)2, and visible light, a N-centered radical is

vinyl boron product is initially formed, but in this case, the

generated, which forms the oxazoline (1,5-hydrogen atom transfer, iodine trap, and iodine displacement). A variety of

ruthenium catalyst does not isomerize the Z-vinyl boron product

compounds can then be accessed from the oxazoline by different

to the more thermodynamically favored E-vinyl boron product.

workup conditions. Simple HCl mediated hydrolysis affords the unprotected β-amino alcohols, while treatment with DDQ can

Interestingly, the initial double bond transposition occurs much

further oxidize the oxazoline to the oxazole. Phenylethanol

more rapidly and selectively with the Ru-catalyst than the Pd-

derivates are most easily oxidized due to the lower benzylic C−H

catalyst. The Z-isomer of the anti-homoallylic alcohols cyclize to

bond energy, but impressively, alcohols with stronger C−H the 1,2-oxaborinan-3-enes upon workup, which are stable

bonds can also be used as substrates, requiring alcohol conversion to benzimidates, which contain a more reactive N-

compounds and can be purified by column chromatography. A

centered radical as well as a more nucleophilic nitrogen. It is

variety of useful transformations of the products are shown,

important to note that NaI must be sufficiently dry for optimum including Suzuki couplings, Chan−Lam couplings, bromination,

reaction, and PhI(OAc)2, if wet, can be treated with base to remove traces of acetic acid that is detrimental to the reaction.

oxidation, and hydrogenation. 1203



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IN SITU METHYLENE CAPPING: A GENERAL STRATEGY FOR THE EFFICIENT STEREORETENTIVE CATALYTIC OLEFIN METATHESIS. THE CONCEPT, METHODOLOGICAL IMPLICATIONS, AND APPLICATIONS TO THE SYNTHESIS OF BIOLOGICALLY ACTIVE COMPOUNDS

in excellent selectivity. Additionally, several examples of MRCM to generate 14- to 21-membered rings are shown.

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NICKEL-CATALYZED β,γ-DICARBOFUNCTIONALIZATION OF ALKENYL CARBONYL COMPOUNDS VIA CONJUNCTIVE CROSS-COUPLING

1,2-Dicarbofunctionalization of alkenes is a powerful way to rapidly build molecular complexity. Engle and co-workers at Scripps Research Institute have developed a highly regioselective, three-component conjunctive Ni-catalyzed cross coupling between organozinc nucleophiles, aryl electrophiles, and β,γalkenyl amides (J. Am. Chem. Soc. 2017, 139, 10657). The Ni(0)catalyzed reaction is selective due to the use of an amide directing group [Daugulis’ 8-aminoquinoline (AQ)] that directs the nickel to form a 5-membered AQ-chelated intermediate after a selective 1,2-aryl-insertion. Electron-rich, electron-deficient, and heteroaryl iodides are efficient substrates. Except for cyclohexenyl iodide, alkenyl iodides are not suitable reaction partners. Common organozinc reagents, such as diphenylzinc, dimethylzinc, and diethylzinc, serve as the nucleophile. Secondary organozinc reagents are not tolerated, except for dicyclopropylzinc. The use of dioxane was instrumental in suppressing diarylation, and importantly, NiCl2·glyme was also a suitable catalyst. The AQ-directing group could be efficiently removed with sodium hydroxide in refluxing EtOH.

Despite the incredible advancements made in olefin catalysis, several challenges still exist. One in particular is Z-selective cross metathesis with terminal alkenes that also contain several useful functional groups, such as aldehydes, allylic alcohols, or carboxylic acids. The Ru-catalysts that are compatible with the largest range of functional groups, unfortunately form methylidene species that are unstable after reaction with terminal alkenes. Hoveyda and co-workers at Boston College have developed an in situ methylene capping strategy using Z-butene to bypass the unstable methylidine species, and carry out exceptionally Z-selective cross metathesis and macrocyclic ring closing cross metathesis (MRCM) with a broad range of substrates (J. Am. Chem. Soc. 2017, 139, 10919). This strategy utilizes a ruthenium catechothiolate catalyst that was developed in the same lab, that has been proven to promote transformations with a variety of substrates, but struggles with terminal alkenes. Methylene capping incorporates a third alkene that will participate in cross metathesis faster than homocoupling, or cross metathesis of terminal olefins which would generate the unstable methylidine complex. The resulting Ru-carbene can then react with a similarly capped Ru-carbene to generate the final product. Z-Butene was identified as the perfect balance of steric size, large enough to ensure minimal methylidene formation and small enough to compete effectively with a terminal alkene for reaction. The substrates are first reacted with catalyst and 20 equiv of commercially available, unpurified Zbutene for 1 h, then concentrated, and additional catalyst is added and placed under 100 Torr vacuum to remove unproductive olefins. Transformations with a ∼ 70:30 Z:E butene mixture that is more readily available, are equally effective. Terminal alkyl and aryl alkenes with unprotected indoles, alcohols, aldehydes, carboxylic acids, and β-substitution perform

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CATALYTIC INTERMOLECULAR CARBOAMINATION OF UNACTIVATED ALKENES VIA DIRECTED AMINOPALLADATION

Engle and co-workers from Scripps Research Institute added to the utility of the same β,γ-alkenyl amide scaffold as above, developing a regioselective 1,2-carboamination using Pd(OAc)2 as catalyst. Instead of organozinc reagents as nucleophiles with the Ni-chemistry from above, protected nitrogen nucleophiles (which can be used as ammonia surrogates) are utilized (J. Am. Chem. Soc. 2017, 139, 11261). The Pd-catalyst, bound to the directing group, activates the alkene, allowing nitrogen addition to the γ-position. The generated five-membered palladacycle does not undergo β-hydride elimination due to the stability imparted by the AQ-directing group, instead is intercepted by an aryl or alkenyl iodide to generate Pd(IV), followed by reductive 1204




requires the reactants to be readily available; each functional group subset combinations should have differential masses and very minimal interactions between the substituents to the corresponding functional group. Furthermore, the team ran 75 000 reactions within a few days and analyzed the data via GCMS and MS Excel macros. The SD protocol disclosed may find applications in wide range of reaction protocols with a diverse functional group for the rapid identification of reaction conditions.

elimination to provide the product. A variety of nitrogen nucleophiles containing electron-withdrawing groups are competent, including five- and six-membered cyclic imides, tosyl- and nosyl-protected amines, 1,2,4-triazole, benzimidazole, and carbazole. Styrenyl iodides are the most reactive coupling partners, while aryl iodides require excessive equivalents to achieve moderate yields. HFIP, along with four or more equivalents of electrophile, is required to obtain useful yields. Extensive reaction kinetics and DFT work was used to shed light on the Pd(II)−Pd(IV) reaction mechanism.

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REDOX ACTIVITY OF OXO-BRIDGED IRIDIUM DIMERS IN AN N,O-DONOR ENVIRONMENT: CHARACTERIZATION OF REMARKABLY STABLE Ir(IV,V) COMPLEXES

EXPLOITING CARBONYL GROUPS TO CONTROL INTERMOLECULAR RHODIUM-CATALYZED ALKENE AND ALKYNE HYDROACYLATION

Willis and co-workers at the University of Oxford have reported the use of simple carbonyl groups such as esters, ketones, and amides as an effective chelating group to prepare a wide range of synthetically useful 1,3-dicarbonyl compounds in excellent yields and selectivities (J. Am. Chem. Soc. 2017, 139, 10142). The team obtained optimal conditions for the formation of the linear isomer using Rh-bis(dicyclohexylphosphino)ethane (Rh-dcpe) derived catalyst, which tolerated a variety of alkynes containing functional groups such as nitriles, silanes, and alcohols. Interestingly, the team accessed the corresponding branched isomers by simply changing the reaction conditions. The simplified protocol reported extends the metal-catalyzed chelation-controlled functionalization of C−H bonds.

The study of oxidation states in catalysis is a fundamental part in understanding reaction mechanism. There is tremendous benefit to be derived in understanding reaction mechanism, which could lead to better catalyst and ligand design, efficient reaction protocol, and so forth. Crabtree et al. have reported an unprecedented Ir(IV,V) dimer, which under ambient temperature exhibited remarkable stability (J. Am. Chem. Soc. 2017, 139, 9672). The charge delocalization across the iridium centers led to its stability and modest reduction potential. Furthermore, the oxidation of Ir(IV,V) complex resulted in a highly reactive Ir(V,V) μ-oxo species, and notably the 2-(2-pyridinyl)-2propanolate (pyalk) ligand does not oxidize in the process. The stability of these complexes enabled the detailed study and characterization of these species. In addition, X-ray crystallography, density functional theory (DFT) calculations, and so forth supported the electronic states and stability of these complexes. The study may help shed light on the mechanism of the allimportant water oxidation.

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DECODING THE MECHANISM OF INTRAMOLECULAR COPPER-DIRECTED HYDROXYLATION OF SP3C−H BONDS

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SNAP DECONVOLUTION: AN INFORMATICS APPROACH TO HIGH-THROUGHPUT DISCOVERY OF CATALYTIC REACTIONS High-throughput experimentation (HTE) has been a powerful tool in drug discovery and to a less extent in catalysis. However, its full potential has not been realized in synthetic chemistry due in part to the inadequate tools of monitoring a wide range of chemical transformations, without relying on the functional group to act as markers. Hartwig et al. have disclosed an automated method which involves running three sets of reactions with identical functional groups but with different substituents that differentiate their masses (Science 2017, 357, 175). As a result, differential masses are obtained and can be identified by mass spectrometry or gas chromatography. The team term the concept “snap deconvolution” (SD). To be effective, the SD

A collaboration between researchers at Southern Methodist University, The Scripps Research Institute, and Johns Hopkins University have led to the overhaul of the previously accepted mechanism of copper directed C−H oxidation (J. Org. Chem. 2017, 82, 7887). The team carried a comprehensive mechanistic study on the Cu-directed C−H oxidation. In addition, the team reported detailed structural, computational, and spectroscopic 1205




ably, dinitroarenes reacted selectively to afford monoarylation

characterization of the reaction intermediate and reaction kinetic analysis to propose the active mononuclear LCuII(OOR) species. An application of the new findings to previously reported protocols led to a cost-effective, predictable, and higher-yielding reactions. The reported protocol could help develop a new catalyst for other Cu-based C−H oxidations.

products. Mechanistic studies, including stoichiometric reactions of BrettPhos−Pd(0) with nitrobenzene and 1-nitronaphthalene, support the oxidative addition of the Ar−NO2 bond onto a Pd(0)

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center. DFT calculations of the proposed catalytic cycle suggest that a nitroarene−Pd π-complex is the catalyst resting state from

STEREOSELECTIVE SYNTHESIS OF TETRASUBSTITUTED OLEFINS Current methods for the stereoselective synthesis of substituted olefins still present operational limitations in a scale up setting. Building on fundamental understanding of the chemistry of lithium amides and lithium enolates, collaborators in academia and industry report a stereoselective synthesis of tetra substituted acyclic all-carbon olefins (Zhang, H.; Gosselin, F., et al. J. Am. Chem. Soc. 2017, 139, 10777). The two-step procedure combines the selective formation of an E-enol tosylate mediated by LiHMDS and Me2NEt with a high-yielding Suzuki−Miyaura coupling. Preliminary inspection of solvent effects upon the enolization and tosylation of 1,2-diphenylbutan-1-one revealed that commercially available metal HMDS amides or alkoxides afford neither practical yields nor E/Z selectivities in the strongly coordinating THF solvent. Remarkably, the use of mixtures containing 2.0 equiv of LiHMDS and Me2NEt in toluene resulted in high yields of pure E-isomer after quench with Ts2O in DCM. Subsequent Suzuki−Miyaura coupling with pinacol boronic esters in the presence of a Pd(OAc)2−RuPhos catalyst yielded the desired olefins. The overall sequence works well with a variety of substituents (both electronically and sterically diverse) and provides development scientists with the opportunity to advance reliable and scalable processes for the preparation of tetra substituted olefins.

which the oxidative addition of the Ar−NO2 bond occurs.

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OXIDATIVE [1,2]-BROOK REARRANGEMENTS

The group of Professor Amos B. Smith reports alkylations and arylations of radical species formed via oxidative, photoredoxcatalyzed, [1,2]-Brook rearrangements (J. Am. Chem. Soc. 2017, 139, 9487). Hypervalent silicon intermediates generated by deprotonation of an aryl(trialkylsilyl)methanol can generate αbenzyl silyl ether radicals capable of reacting with electrondeficient olefins or electron-deficient aromatic compounds. In the alkylation with olefins, the oxidation of the hypervalent silicon intermediate by an activated Ir photoredox catalyst would take place to form the silyl ether radical. For the arylation, an

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early single-electron transfer occurs between the activated Ir

THE SUZUKI−MIYAURA COUPLING OF NITROARENES Nitroarenes are primary intermediates in the chain of synthetic transformations that provide functionalized arenes. A consortium of scientists at Kyoto University and Tosoh Corporation describes the preparation of biaryls from nitroarenes as electrophilic reactants via a modified Suzuki−Myaura coupling (Sakaki, S.; Nakao, Y., et al. J. Am. Chem. Soc. 2017, 139, 9423). Careful screening of reagents and solvents led to the distinctive combination of Pd(acac)2, BrettPhos, 18-crown-6, and K3PO4· nH2O in 1,4-dioxane to enable the cleavage of Ar−NO2 bonds. Optimized conditions promoted the coupling of a wide range of nitroarenes and arylboronic acids and demonstrated an extraordinary tolerance to stereoelectronic diversity. Remark-

photoredox catalyst and the arene to afford an arene radical anion and an Ir(IV) species able to oxidize the hypervalent silicon intermediate. An examination of the radical donor and acceptor scopes demonstrated the wide applicability of the new methodology, with the exception of simple acrylates known to resist reduction of the intermediate α-carbonyl radicals. Control experiments demonstrated the need for base, light, and photocatalyst for the reaction to occur. Stoichiometric octanal is added to the arylation mixtures to quench the cyanide anion formed in the process. 1206




approach. The article points out that the lack of harmonized alignment around what is and is not acceptable provides a barrier to the adoption of continuous manufacturing as part of investment for drug launch decisions and supports the option of an ICH-sponsored guideline to help build a consensus. The article also points out the need for technologies that help to integrate drug substance and drug product manufacture as part of the end-to-end manufacture of a pharmaceutical product. The authors of the white paper are drawn from industry, academia, and FDA.

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MODELING IN THE QUALITY BY DESIGN ENVIRONMENT: REGULATORY REQUIREMENTS AND RECOMMENDATIONS FOR DESIGN SPACE AND CONTROL STRATEGY APPOINTMENT Djuris and Djuric from the University of Belgrade have provided a discussion of the use of modeling during development and the rest of the lifecycle of a pharmaceutical product (Int. J. Pharm. 2017, 10.1016/j.ijpharm.2017.05.070). An overview of good practice when it comes to the use of models as part of pharmaceutical development and postapproval lifecycle management of both drug substance and drug product is integrated into the discussion. Health Authority feedback, collated from publications and presentations, on how models should be used, verified on being applied at pilot or commercial scale and described in submissions is also provided. Emerging design space concepts (multiple-unit, dynamic, and adaptive) that are starting to appear in the lexicon of enhanced pharmaceutical development and methods for process uncertainty analysis are also discussed.

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PRACTICAL HIGH-THROUGHPUT EXPERIMENTATION FOR CHEMISTS Merck have summarized the utility to the process chemist of high throughput experimentation (Shevlin, M. ACS Med. Chem. Lett. 2017, 8, 601−607). While the technology is traditionally associated with screening reagents, adsorbents, polymorphs, and salts, the article points out that it has a number of other uses, including the elucidation of reaction mechanisms and solubility determinations. By running large arrays, multidimensional hypotheses can be examined, together with runs that assess reproducibility, null hypotheses and act as negative controls. The use of microgram quantities of material in each run means that overall material consumption can be minimal. As part of three case studies that are described, it is shown that through judicious prioritisation of the parameters or attributes under examination, plates with only 48 wells can still be used to solve complex problems. The author points out that ultrafast analytical techniques are required if the analysis of large data sets is to have a manageable impact on workflows. Tips on liquid handling and agitation are provided. The author points out that a flexible means of dispensing different solids to large arrays remains an unsolved problem.

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HOLISTIC APPROACH TO PRODUCTION CONTROL A control strategy working group of the International Society of Production Engineers (ISPE) has produced an article based on a presentation given at the Facilities of the Future conference held in November 2016 (Herwig et al. Pharmaceut. Eng. 2017, 44−49). In it they describe the opportunity presented to pharmaceutical manufacturing by cyber-physical systems and digitization. More specifically, the authors describe how this socalled “Pharma 4.0” could lead to a control strategy for the manufacture of pharmaceuticals that, instead of being a narrow set of elements that is frozen at the end of development, also encompasses the facilities, utilities, equipment, and productionspecific controls. All of these elements would then work synergistically and flex to ensure production is both flexible and reliable, while mitigating risks to the patient and a business. In other words, how the control strategy concept can evolve from “what is submitted (in a marketing submission)” to how a manufacturing process is actually implemented. The authors issue a clarion call for “data integrity by design”, which includes the use of integrated and retrievable data flows, as part of this paradigm shift.

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POINTS ARISING FROM THE 2ND INTERNATIONAL SYMPOSIUM ON THE CONTINUOUS MANUFACTURING OF PHARMACEUTICALS The meeting was held in September 2016, and the main points have been summarized in a white paper (J. Pharm. Sci. 2017, 10.1016/j.xphs.2017.06.015). Progress made since the inaugural meeting in May 2014 is provided in the areas of quality risk management, batch definition, control strategy, material traceability, controlling raw materials, process monitoring, material collection and diversion, real time release testing, data processing, and process validation. Regulatory interactions are reported as having been consistently supportive of the adoption of continuous manufacturing solutions while pointing out that regulators are also working out what constitutes an acceptable

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BIOCATALYSIS IN THE PHARMACEUTICAL INDUSTRY: THE NEED FOR SPEED Merck have provided a commentary on what it will take for the use of biocatalysis for API manufacture to become a more widely applied technology (Truppo, M. D. ACS Med. Chem. Lett. 2017, 8, 476). The article points out reasons why biocatalysis has not been used more widely to-date, focusing on the time associated with the optimization of performance of a biocatalyst using protein engineering. The author proposes that the current speed 1207




com; [email protected]; [email protected]; [email protected].

of protein engineering will need to accelerate by approximately an order of magnitude for the benefits of biocatalysis to be routinely realized. High-throughput methodologies that expedite the correlation of mutations to the various attributes that dictate biocatalyst utility are also requested. Likewise, the author identifies the need for a rapid, inexpensive, and general method for enzyme immobilization. The author points out that we are at the dawn of a new phase of biocatalytic development which could be considered to involve rational directed evolution and leverage computation (including in silico biocatalyst design), informatics, and high-throughput experimentation as part of the design− make−test cycle.

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DISTRIBUTION OF CATALYTIC SPECIES AS AN INDICATOR TO OVERCOME REPRODUCIBILITY PROBLEMS The Burés group at the University of Manchester have exploited the study of the relative amounts of the different species present in a catalytic cycle as a means of building process understanding (J. Am. Chem. Soc. 2017, 139, 8432). Where this distribution is sensitive to process parameter variation, such a study can be used as a tool for overcoming issues of irreproducibility in catalysis and moving to a more robust area of operating space. These points are illustrated with examples, albeit ones with comparatively simple catalytic cycles, of the conjugate addition of carbon nucleophiles to enals using iminium catalysis. While the authors use NMR for this study, they point out that any analytical method that indicates speciation can be used. The understanding gained from the study allowed the catalyst loading to be reduced from 10 mol % to 0.1 mol % in one example. Robert Ely Achaogen, Inc., 1 Tower Place, Suite 300, South San Francisco, California 94080, United States Paul Richardson Pfizer, Chemistry, 10578 Science Center Drive, San Diego, California 92121, United States Andrei Zlota The Zlota Company, LLC, 15 Fairbanks Road, Sharon, Massachusetts 02067-2858, United States Alan Steven AstraZeneca, Silk Road Business Park, Charter Way, Macclesfield SK10 2NA, U.K. Robert Kargbo Usona Institute, 277 Granada Drive, San Luis Obispo, California 93401, United States Christopher C. Nawrat Merck & Co., Rahway, New Jersey 07065, United States Antonio Ramirez Bristol-Myers Squibb, Chemical Development, One Squibb Drive, New Brunswick, New Jersey 08903, United States John Knight* JKonsult Ltd., Meadow View, Cross Keys, Hereford, HR1 3NT, U.K.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

E-mail: [email protected]; paul.f.richardson@pfizer.com; [email protected]; Alan.Steven@astrazeneca. 1208


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

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