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The ability of maleate half-ester salts to serve as electrophilic partners in 1,4-conjugate addition reactions with control of regioselectivity has previously been explored in only a limited context with soft nucleophiles. We have demonstrated that benzylic anions of picolines, as well as enolates of ketones, esters, and nitriles, react with lithium 4-(tert-butoxy)-4-oxobutenoate in a completely regioselective manner. This new method was applied to an expedient two-step process for preparing a key azaindanone intermediate for the clinical-candidate drug MK-8666.

An asymmetric synthesis of HCV NS5B nucleoside polymerase inhibitor (1) is described. This novel route features several remarkably diastereoselective and high-yielding transformations, including construction of the all-carbon quaternary stereogenic center at C-2 via a thermodynamic aldol reaction. A subsequent glycosylation reaction with activated uracil via C-1 phosphate and installation of the cyclic phosphate group using an achiral phosphorus(III) reagent followed by oxidation provides 1.

Previous methods to prepare a bicyclic N-hydroxyl urea intermediate in the synthesis of the potent β-lactamase inhibitor relebactam were effective, but deemed unsuitable for long-term use. Therefore, we developed an in situ protection protocol during hydrogenolysis and a robust deprotection/isolation sequence of this unstable intermediate employing a reactive crystallization. During the hydrogenation studies, we discovered a significant rate enhancement of O-benzyl ether hydrogenolysis in the presence of organic amine bases, especially DABCO. The broader utility of the application of organic bases on the hydrogenolysis of a range of O- and N-benzyl-containing substrates was demonstrated.

The development of a scalable asymmetric route to a new calcitonin gene-related peptide (CGRP) receptor antagonist is described. The synthesis of the two key fragments was redefined, and the intermediates were accessed through novel chemistry. Chiral lactam 2 was prepared by an enzyme mediated dynamic kinetic transamination which simultaneously set two stereocenters. Enzyme evolution resulted in an optimized transaminase providing the desired configuration in >60:1 syn/anti. The final chiral center was set via a crystallization induced diastereomeric transformation. The asymmetric spirocyclization to form the second fragment, chiral spiro acid intermediate 3, was catalyzed by a novel doubly quaternized phase transfer catalyst and provided optically pure material on isolation. With the two fragments in hand, development of their final union by amide bond formation and subsequent direct isolation is described. The described chemistry has been used to deliver over 100 kg of our desired target, ubrogepant.

A model for the stereoselectivity of intramolecular alkylations by N,N'-disubstituted cinchona alkaloids reported by Xiang et al. was established using density functional theory (DFT) calculations. The stereocontrol is based on the minimal distortion of the transition state (TS) and catalyst required to achieve favorable electrostatic interactions in the favored TS. Counterions must be included in computational modeling of ion-paired catalysis in order to reproduce experimental enantioselectivity.

Retro-Brook rearrangements refer to the intramolecular migration of a silyl group from oxygen to carbon. In this study, we report a novel propargylic retro-Brook rearrangement observed in terminal alkynes bearing a silyl ether moiety. Retro-Brook rearrangements involving [1,2]-, [1,4]-, and [1,5]-migrations are described, affording propargylsilanes in reasonable yield. The reaction mechanism was investigated experimentally by deuterium quenching and rationalized by density functional theory calculations. The terminal alkyne and the subsequent propargyl/allenyl dianion were shown to be crucial for the reaction favoring the retro-Brook rearrangement product over the Brook rearrangement. The second deprotonation at the propargylic position was determined to be the rate-limiting step. In addition, a gas-phase Brook-type rearrangement of the propargylsilanes was observed under GC-MS conditions. This observation was also further confirmed by DFT calculations.

A low level of lead in zinc dust was identified as the causative agent responsible for inhibiting selective reduction of a dibromoimidazole derivative via metal agglomeration and lead deposition on the zinc surface.

A scalable and efficient synthesis of the GPR40 agonist MK-8666 was developed from a simple pyridine building block. The key step to set the stereochemistry at two centers relied on an enzymatic dynamic kinetic reduction of an unactivated ketone. Directed evolution was leveraged to generate an optimized ketoreductase that provided the desired trans alcohol in >30:1 dr and >99% ee. Further, it was demonstrated that all four diastereomers of this hydroxy-ester could be prepared in high yield and selectivity. Subsequently, a challenging intramolecular displacement was carried out to form the cyclopropane ring system with perfect control of endo/exo selectivity. The endgame coupling strategy relied on a Pd-catalyzed C–O coupling to join the headpiece chloropyridine with the benzylic alcohol tailpiece.

Asymmetric phase transfer catalysis has been recognized as an approach that is greener and more sustainable than synthetic alternatives and has evolved into one of the most practical methods in challenging enantioselective synthesis. An overview of the current status of asymmetric phase transfer catalysis in industry is presented by summarizing research progress from both journal publications and patent applications.

MK-8970 is an acetal carbonate prodrug of raltegravir (Isentress). This work presents the Merck team’s investigations into the polymorphism of MK-8970, the thermodynamic relationship between the discovered crystalline forms, and implementation of that knowledge toward solving key processing challenges. MK-8970 was found to exist in two enantiotropic polymorphs, with a crossover temperature of approximately 117 °C, as determined from solubility data. Form 2 of MK-8970, the stable form at ambient temperature, was confirmed to be a true racemic crystal form and not a conglomerate on the basis of single-crystal X-ray structure data. In preparation for scale-up of MK-8970, form control was established by mapping out solubility curves for the relevant crystalline forms in ethyl acetate as a function of temperature. Lastly an investigation of the relative solubilities of MK-8970 and a troublesome imidate impurity identified improved solvent systems for maximizing rejection of this impurity while avoiding signifi...

A highly efficient TMSI-mediated deprotection and direct isolation method to obtain zwitterionic compounds from the corresponding N-Boc derivatives has been developed. This method has been demonstrated in the final deprotection/isolation of the β-lactamase inhibitor MK-7655 as a part of its manufacturing process. Further application of this process toward other zwitterionic compounds, such as dipeptides and tripeptides, has been successfully developed. Furthermore, a catalytic version of this transformation has been demonstrated in the presence of BSA or BSTFA.

A general and efficient asymmetric synthesis of cyclic indoline aminals was developed with a high level of 1,3-stereoinduction through a dynamic crystallization-driven condensation. Dehydrogenation of the indoline aminals with potassium permanganate produced the corresponding cyclic indole aminals in high yields and excellent enantioselectivities. This general methodology was successfully applied to the synthesis of a wide variety of chiral cyclic indoline aminals and indole aminals with aromatic and aliphatic functional groups.

We report the discovery of novel N,N′-disubstituted cinchona alkaloids as efficient phase-transfer catalysts for the assembly of stereogenic quaternary centers. In comparison to traditional cinchona-alkaloid-based phase-transfer catalysts, these new catalysts afford substantial improvements in enantioselectivity and reaction rate for intramolecular spirocyclization reactions with catalyst loadings as low as 0.3 mol % under mild conditions.

Compound 1, a potent and irreversible inhibitor of β-lactamases, is in clinical trials with β-lactam antibiotics for the treatment of serious and antibiotic-resistant bacterial infections. A short, scalable, and cost-effective route for the production of this densely functionalized polycyclic molecule is described.

Process safety is an important consideration not only when conducting reactions on manufacturing scale, but also on lab and kilo lab scale. This contribution presents a discussion of Merck’s Reaction Review policy, originally specific to Process Chemistry and now applied broadly across the whole chemistry organization. Details of the policy and case studies are included.

The development of a practical, asymmetric synthesis of the hepatitis C virus (HCV) protease inhibitor MK-5172 (1), an 18-membered macrocycle, is described.

This article reviews antiviral therapies that have been approved for human use during the last decade, with a focus on the process chemistry that enabled access to these important drugs. In particular, process chemistry highlights from the practical syntheses of the HCV drugs sofosbuvir (Gilead), grazoprevir (Merck), and elbasvir (Merck), the HIV therapy darunavir (Tibotec) and the influenza treatment peramivir (BioCryst) are presented.

A six-step route starting from a readily available vinyl boronate was identified to produce an enantioenriched cyclopropanol in an overall 16% yield. Key steps involve the use of lithium acetylide-ethylene diamine complex 5 and an enzymatic resolution of a racemic cyclopropanol acetate. Process safety considerations surrounding the use of 5 were examined, and an improved procedure is described which was safely demonstrated at multikilogram scale.

A convergent and enantioselective route to the hNK-1 receptor antagonist (1) is described, which sets all six stereogenic centers with high diastereoselectivity and delivers 1 in only 11 steps and 23% overall yield. The process was enabled by the development of the enantioselective enzymatic reduction of 3-functionalized cyclopentenones and stereospecific Pd-catalyzed etherification coupling of fragments 6 and 7.

The hNK-1 antagonist candidate 3 is synthetically one of most challenging antagonist candidates at Merck, having six chiral centers. The ether bond was formed via π-allyl palladium chemistry with the zinc alkoxide of the chiral alcohol and chiral 2-cyclopenten-1-ol, prepared via enzymatic reduction of the corresponding ketone, to set two chiral centers. 4-Fluorophenyl group was introduced to the cyclopentene ring via 1,4-addition in a stereospecific manner. The δ-lactam having the quaternary chiral amine function was embedded onto the cyclopentane ring using Seebach’s chiral oxazolidinone. In this article, scalable synthesis of 3 is described in a chronological order.

The development of practical and efficient syntheses of the potent non-nucleoside reverse transcriptase inhibitors 1 and 2 is described. The preparation of 1 proceeded in four synthetic steps and in 48% overall yield from 3. The long-term synthesis of 2 proceeded in nine synthetic steps and in 47% overall yield from commercially available 2,6-diflurorpyridine. The route to 2 was highlighted by the three-step synthesis of intermediate 22 and the high yielding coupling between 18 and phenol 8. The overall sequence required no chromatography and has successfully been utilized for the manufacture of 2 on large scale.

A concise and practical synthesis of a 1,4-diaryl-5-methyl-1,2,3-triazole is described. A mGluR1 antagonist 1 was prepared with one-pot operation by the Negishi coupling reaction between two building blocks, 5-bromophthalimidine (2) and 1-aryl-5-methyl-4-triazolylzinc (3-Zn). Bromide 2 was synthesized via N-selective cyclization of o-hydroxymethylbenzamide 8 easily prepared from phthalide 4. Zinc species 3-Zn was generated in situ by transmetalation of 1-aryl-4-magnesio-5-methyltriazole (3-Mg), which in turn was generated by the regioselective click chemistry between 2,4-difluorophenylazide (5) and propynylmagnesium bromide. The risk assessment of potentially explosive arylazides is also mentioned.

A general and efficient synthetic method for the synthesis of biologically important series of 3,6-disubstituted-1H-pyrazolo[3,4-b]pyridines was discovered. 2,6-Difluoropyridine was deprotonated using 1.1 equiv of n-BuLi in THF at

The synthesis of compound 1 by deprotection of the THP, tert-butyl protected amino-pyrazolopyridine (2), is described. The original conditions for this transformation were conducted in a one-pot procedure and necessitated the use of large quantities of either TsOH or benzenesulfonic acid (5 equiv) and trifluoroacetic acid (10−25 equiv) and produced 1 in moderate yield (50−65%). A series of high-throughput screens of Bronstead acids, Lewis acids, and solvents was rapidly performed with the goal of identifying improved efficiency and reaction yield. Through these screens, sulfuric acid was discovered to be a suitable replacement; however, yields of 1 were still unacceptable. A decoupling of the two deprotection steps revealed that the THP byproduct resulting from removal of the THP protecting group was problematic in the subsequent removal of the tert-butyl group. Consequently, a two-step deprotection protocol was developed which, in combination with design of experiment (DOE) optimization, improved the ove...

Investigation of one anhydrous and four hydrated forms of a pharmaceutical compound (1) using both single-crystal and high-resolution powder X-ray diffraction methods revealed a two-dimensional framework which, upon exposure to moisture, absorbed water between the layers, causing the lattice to expand by as much as 20% of the axial length along a. The single-crystal structure was solved and refined for the pentahydrate form in space group C2 with unit cell parameters a = 36.961(5) A, b = 7.458(2) A, c = 20.691(4) A, β = 99.461(1)°, and V = 5626(4) A3. In the single-crystal structure the water layers were parallel to the bc plane and sandwiched by the crystalline compound 1 framework. Upon a change of relative humidity, water goes in and out of the interlayer space with the retention of the layer structure of the development compound. Starting from the anhydrous form, each additional water of hydration increased the interlayer spacing of the pharmaceutical solid by ∼1.3 A, half the size of a water molecule...

In a three-step sequence starting from readily available starting materials, 2,3-carbon disubstituted furo[2,3-b]pyridines can be accessed in good yields and purity. Furo[2,3-b]pyridines bearing ester, amide and ketone groups at the 2-position can be prepared with a variety of aryl and alkyl groups at the 3-position.

An efficient and practical method for the preparation of benzyloxyacetic acids is described. The procedure involves the reaction of readily available chloroacetic acid with benzyl alcohol in the presence of powdered KOH providing a safer alternative to the known literature procedures, which completely eliminates the use of pyrophoric bases such as sodium hydride and sodium metal.

Asymmetric phase transfer catalysis has been recognized as an approach that is greener and more sustainable than synthetic alternatives and has evolved into one of the most practical methods in challenging enantioselective synthesis. An overview of the current status of asymmetric phase transfer catalysis in industry is presented by summarizing research progress from both journal publications and patent applications.

4-Hydroxyquinolinone esters are a common motif for many medicinal agents. Several methods exist for preparation of these compounds, generally involving the use of sodium hydride, which raises significant safety issues and limits their application to large-scale synthesis. In this note a practical, safe, and general method that employs a combination of diisopropylethylamine and sodium tert-butoxide is described. This allows for the synthesis of 4-hydroxyquinolinone esters and amides in good yields.

Several derivatives of 4-aryl-l,5-disubstituted 1,2,3-triazole were synthesized in good yields via 1,3-dipolar cycloaddition followed by Negishi reaction under new conditions.

Cyclic indole aminals are efficiently prepared through a highly stereoselective, dynamic crystallization-driven cyclocondensation followed by dehydrogenation of the primary indoline aminals.

Hydrogenation of (E)-2-nitropyrrolidinostyrene in the presence of the doped rhodium catalyst is safe, scalable, and highly effective for the preparation of 6-benzyloxyindole. Reaction kinetics with/without additives also were examined using in situ IR for the first time. Results showed that the additives decelerate the hydrogenolysis of benzyl ethers, while simultaneously accelerating the de-oxygenation of N-oxy-intermediates.

A highly effective and mild deprotection method was developed for benzyl thioethers using dibutylmagnesium in the presence of a catalytic amount of titanocene dichloride. This methodology is applicable to both aromatic and aliphatic benzyl thioethers.

[Chemical reaction: See text] A Et3Al mediated intramolecular epoxide opening, cyclopropanation reaction is described. The transformation provided highly functionalized bicyclo[3.1.0]hexane systems in high efficiency and with perfect H or F endo selectivity. Application of this reaction to the synthesis of mGluR2/3 agonist 1 (43% overall yield) and a few intermediates suitable for the synthesis of other bicyclo[3.1.0]hexane mGluR2/3 agonists is discussed.

An enantioselective synthesis of substituted 2-methyl chromans was accomplished in four steps using four sequential Pd-catalyzed reactions. A study of the key palladium-catalyzed regioselective aryl ether ring formation of two different substrates was also carried out to better understand the factors which affect the selectivity of the reaction.

The asymmetric synthesis of a Merck anti-HIV drug candidate is described. The target molecule contains four stereogenic centers, three of which are located in a highly functionalized cyclopentane unit. The convergent synthesis involves the preparation of two key advanced intermediates: the cyclopentane unit and a substituted pyrazole unit. The cyclopentane unit was prepared via two different procedures; a highly diastereoselective Diels-Alder reaction with a chiral oxazolidinone auxiliary and a sequence that incorporated a molybdenum-catalyzed asymmetric allylic alkylation reaction to set the stereocenters. The other key step was a highly diastereoselective hydroxyl-directed reductive amination. The overall yield for the 16-step synthesis was 10%.

A practical preparation of an αvβ3 antagonist is reported. The antagonist consists of three key components, a tetrahydronaphthyridine moiety, a β-alanine moiety, and a central imidazolidone moiety. The tetrahydronaphthyridine component was prepared using two different methods, both of which relied on variations of the Friedlander reaction to establish the desired regiochemistry. The β-alanine component was prepared using Davies' asymmetric 1,4-addition methodology as the key stereo-defining step. The central imidazolidone portion was created from these two components using an effective three-step cyclization protocol. Thus, a highly convergent process for the drug candidate was defined.

Novel N,N′-dibenzylated cinchona alkaloid-based phase-transfer catalysts are designed to provide improved enantioselectivity for the intramolecular spirocyclization of substrates of type (I), (III), and (V) compared to traditional cinchona alkaloid catalysts.

Process design and development of drug candidates using cross-coupling reactions as key steps are discussed. In the anti-MRS carbapenem project, all drug candidates were prepared effectively in a few steps from the commercially available diazo intermediate by either Suzuki–Miyaura cross-coupling or Stille–Migita cross-coupling, demonstrating the versatility, effectiveness, functional group tolerability, and mild reaction conditions of cross-coupling methods.

Catalytic asymmetric alkylation reactions of branched racemic carbonates 1a and 1b with sodium dimethyl malonate, promoted by molybdenum and ligand 5, proceed by a kinetic resolution in toluene, THF, tetrahydropyran, i-PrOAc, 1,2-dichloroethane, and MeCN with k(rel) of 7-16. In THF, MeCN, tetrahydropyran, and i-PrOAc using the (S,S)-5 ligand, the fast reacting (S)-carbonate enantiomer provides the branched product with high ee (97-99.5%) and branched/linear selectivity, but the ee erodes as the reaction of the slow-reacting (R)-enantiomer takes place. This implies that the rate of equilibration of the oxidative addition complexes in these solvents is competitive with the subsequent malonate displacement step. In toluene and dichloroethane, the ee and branched/linear ratios diminish during the reaction of the slow-reacting (R)-isomer, but not nearly as much as in the other solvents. This is most likely due to either an increase in the rate of equilibration of the oxidative addition complexes relative to the malonate displacement step, or vice versa. Because of the minimal stereochemical memory effect in toluene and 1,2-dichloroethane, the reactions in these solvents can be carried to completion (dynamic kinetic asymmetric transformation) and still provide product with excellent ee (>95%). The anion of dimethyl methylmalonate also reacts via a kinetic resolution, although the ee's, rates, and k(rel) values differ from those of the reactions with dimethyl malonate.

An asymmetric synthesis of dual orexin receptor antagonist MK-6096 (1) is described. Key steps for the trans-2,5-disubstituted piperidinyl ether fragment include a biocatalytic transamination, a trans-selective Mukaiyama aldol, and a regioselective pyridyl SNAr process. The pyrimidyl benzoic acid was synthesized via a Negishi coupling and a nitrile hydrolysis. Coupling of the two fragments via a catalytic T3P-mediated amidation completed the synthesis. Unusual behaviors in the hydrolysis of pyrimidyl benzonitrile and the amide coupling of the pyrimidyl benzoic acid are also described.

An efficient protocol for the palladium-catalyzed Suzuki–Miyaura cross-coupling reaction of unprotected haloimidazoles is reported. The relatively mild reaction conditions allow for ready access to a wide array of functionalized imidazole derivatives in good to excellent yields. The synthetic utility of this method is demonstrated by the total synthesis of nortopsentin D.

Synthesis of 2-[3-aminopropyl]-5,6,7,8-tetrahydronaphthyridine was accomplished via a one-pot double Suzuki reaction followed by deprotection and a highly regioselective intramolecular Chichibabin cyclization. A variety of reactions conditions were screened for the Chichibabin cyclization including choice of base, solvent and reaction temperature.

Molybdenum-catalyzed asymmetric allylic alkylation reactions were carried out using the inexpensive, air-stable, and readily available Mo(CO)6 as precatalyst. In situ IR was used to determine the required activation time and temperature required to achieve the maximum concentration of the ‘‘active’’ catalyst from the molybdenum-precatalyst and chiral ligand. Results from comparison studies are consistent with the notion that the same active catalyst is generated regardless of molybdenum-precatalyst.

A simple and scalable method for the preparation of a potentially versatile organostannane, 1-aza-5-chloro-5-stannabicyclo[3.3.3]undecane ( 1 ), is described. Stannane 1 was prepared by the disproportionation of N(CH 2 CH 2 CH 2 SnBu 3 ) 3 and SnCl 4 at 70–100°C. This reaction requires the addition of water or an alcohol to proceed efficiently. Under typical conditions, 1 was isolated in 50–55% yield after a simple acid/base extraction sequence.

Crystalline 1beta-methyl-2-formyl carbapenem pNB esters were prepared by osmium-mediated oxidative cleavage of the corresponding 2-vinyl derivatives. Reduction of the 2-formyl compounds gave the corresponding 2-hydroxymethyl derivatives, which are key intermediates for the anti-MRS carbapenem candidate (1).