7-Step Flow Synthesis of the HIV Integrase Inhibitor Dolutegravir.

Dolutegravir (DTG), an important active pharmaceutical ingredient (API) used in combination therapy for the treatment of HIV, has been synthesized in continuous flow. By adapting the reported GlaxoSmithKline process chemistry batch route for Cabotegravir, DTG was produced in 4.5 h in sequential flow operations from commercially available materials. Key features of the synthesis include rapid manufacturing time for pyridone formation, one-step direct amidation of a functionalized pyridone, and telescoping of multiple steps to avoid isolation of intermediates and enable for greater throughput.

Facile synthesis of 1,3-thiazolidin-4-ones as antitubercular agents.

We have developed, highly efficient, one-pot, solvent-free, [Et3NH][HSO4] catalyzed multicomponent reaction protocol for the synthesis of 1,3-thiazolidin-4-ones in excellent yields. For the first time, the 1,3-thiazolidin-4-ones were evaluated in vitro for their antimycobacterial activity against Mycobacterium tuberculosis dormant MTB H37Ra and Mycobacterium bovis BCG strains. Among the synthesized basic 1,3-thiazolidin-4-ones, particularly the compounds 4c, 4d, 4e, 4f, 4h, 4i and 4j displays promising antitubercular activity along with no significant cytotoxicity against the cell lines MCF-7, A549 and HCT-116.

Efficient and novel one-pot synthesis of polycycles bearing cyclols by FeCl3-promoted [2 + 2] cycloaddition: application to cannabicyclol, cannabicyclovarin, and ranhuadujuanine A.

Simple and facile synthetic routes for the preparation of biologically interesting cyclol bearing polycycles were developed using FeCl3-promoted [2 + 2] cycloaddition from readily available benzopyrans possessing a variety of substituents. As examples of this methodology, one-step syntheses of cannabicyclol, cannabicyclovarin, and ranhuadujuanine A were accomplished in good yield.

A multicomponent synthetic strategy for two-carbon-tethered 1,3-oxathiole-indole pairs.

An efficient methodology for the multicomponent synthesis of new and highly functionalized heterocycles containing 1,3-oxathiole and indole units which are connected through an sp(2)-C(2) bridge has been developed. This domino reaction enables successful assembly of three new sigma bonds including a C-S bond and a C-O bond in a one-pot operation. Features of this strategy include mild conditions, convenient one-pot operation, and high stereo- and regioselectivity.

A rapid and facile method for the general synthesis of 3-aryl substituted 4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyrazines and their ring fused analogues.

We report a general and facile method that provides rapid entry into 3-aryl substituted 4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyrazines and their ring fused analogues in one-pot under palladium-copper catalysis. The methodology utilises simple and easily available substrates of broad range. The applicability of this reaction for the synthesis of optically active products has been demonstrated. A plausible reaction mechanism has also been proposed.

Solid-phase synthesis of PEGylated lipopeptides using click chemistry.

A versatile methodology for efficient synthesis of PEGylated lipopeptides via CuAAC "Click" conjugation between alkyne-bearing solid-supported lipopeptides and azido-functionalized PEGs is described. This new and very robust method offers a unique platform for synthesizing PEGylated lipopeptides with a high level of complexity. These molecules, obtained in a single purification step, are ideally suited for functionalization of solid-supported lipid bilayers and liposomal drug delivery systems and are particularly valuable in enzyme activation strategies.

An improved method for the synthesis of gamma-DDB.

A mild and efficient method for the synthesis gamma-DDB has been developed through anhydride-linker assisted intramolecular Ullmann reaction. Highly regioselective bromination of differentially protected gallate was realized by virtue of the introduction of NBS.

Dynamic combinatorial chemistry with hydrazones: cholate-based building blocks and libraries.

We describe an efficient and general strategy for the synthesis of dimethyl acetal functionalised steroidal hydrazides based on the cholic acid skeleton with the aim of using these compounds as building blocks for dynamic combinatorial chemistry. Deprotection of the acetal protected building blocks with TFA leads to formation of libraries containing macrocyclic N-acyl hydrazone oligomers. The isolation of several of these, and their characterisation using NMR is described. The effects on the equilibrium library distribution by varying the substituents at C-7 and C-12, extending the side-chain with glycine, and inverting the configuration at C-3 are discussed. Finally, we report the exchange properties of these macrocycles and demonstrate new examples of proof-reading and self-sorting in dynamic combinatorial libraries.

One-pot, pseudo four-component synthesis of a spiro[diindeno[1,2-b:2',1'-e]pyridine-11,3'-indoline]-trione library.

A one-pot, pseudo four-component method for the efficient and simple synthesis of spiro[diindeno[1,2-b:2',1'-e]pyridine-11,3'-indoline]-2',10,12-trione derivatives in refluxing acetonitrile is reported. The features of this procedure are mild reaction conditions, high yields of products, and operational simplicity.

Chromeno[2,3-d]pyrimidine-triones synthesis by a three-component coupling reaction.

A simple and one-pot synthesis of new chromeno[2,3-d]pyrimidine-triones by a three-component condensation reaction of barbituric acids, aldehydes and cyclohexane-1,3-diones in refluxing ethanol in the presence of p-toluenesulfonic acid (p-TSA) for 3-10 h is reported. Two cyclohexane-1,3-diones, four barbituric acids and six substituted aldehydes were chosen for the library validation. Prominent among the advantages of this new method are operational simplicity, good yields and easy work-up procedures employed.

Efficient and effective compound management to support lead optimization.

The introduction of lean thinking and Six Sigma methodologies into the drug discovery process has become an important approach for ensuring efficient workflows while containing costs. For the compound management department at Bristol-Myers Squibb, this has resulted in a partnership with the research community to evaluate and streamline processes to enable cost-disciplined science. The authors describe the results of Lean Six Sigma approaches in the automation and informatics environment that have been optimized to support parallel processing of compounds. This new platform facilitates the rapid and simultaneous data generation from structure activity and structure liability assays. As a result of these compound management improvements, reduction of timelines and quicker decision making has been achieved in the lead optimization process.

High-quality cost-effective compound management support for HTS.

Four years ago, the first acoustic droplet ejectors (ADEs) were launched on the market, providing a new generation of high-throughput noncontact liquid handlers that outclassed traditional contact instruments in almost every respect. This introduction of noncontact dispensing has triggered radical changes to the screening/compound management interface. Higher quality is achieved through greater accuracy and precision, whereas lower sample volumes can be used, and 1536 plate formats have become a reliable reality. Prior to the ADE instrument launch, 1536 assay-ready plate preparation was a high-effort enterprise requiring users to spend time developing liquid-handling methods along with daily fine-tuning of instruments to reach the desired level of performance. By overcoming the nanoliter dispensing hurdle and successfully transferring assays to high-density formats, a new dimension for cutting costs has emerged. Once the screening customer has adapted to this new world, the rules of supply can also change, with the traditional automated plate store no longer being necessary when the compound library can be stored in 1536 plates. Processing efficiency recently has been further supported by innovative new automation-friendly solutions such as plate desealers, prolonging the life span of working plate copies. Both cost and waste control have never had a higher profile, and noncontact dispensing contributes to these important areas. In some processes (e.g., when piercing septa), contact dispensing remains the best option, but cost control is still essential, and an innovative solution to minimize DMSO consumption from tip washing has had a big impact on consumable budget without compromising quality.

Modular synthesis of oxazolines and their derivatives.

A class of modular oxazolines and their derivatives 1-5 were synthesized with moderate to excellent yields using a simple one-pot method; 4 x 3 bis-oxazolines were obtained, as expected, from each of the three reactions of 1,4-dicyanobenzene, 1,3-dicyanobenzene, and 1,2-dicyanobenzene with optically active amino alcohols in chlorobenzene under dry, anaerobic conditions. ZnCl(2) was used as a Lewis acid catalyst. Direct condensation of 1, 2-bis(cyanomethyl) benzene or 2-cyanophenylacetonitrile did not yield the target products, but two series of novel compounds (4 and 5) were isolated and their structures were confirmed by X-Ray analysis. All products (1-5) were characterized by NMR, IR, and MS.

Efficient synthesis of trisubstituted pyrazoles and isoxazoles using a traceless "catch and release" solid-phase strategy.

An efficient three-component, two-step "catch and release" solid-phase synthesis of 3,4,5-trisubstituted pyrazoles and isoxazoles has been developed. The first step involves a base-promoted condensation of a 2-sulfonyl- or a 2-carbonyl-acetonitrile derivative (1 or 7) with an isothiocyanate 2 and in situ immobilization of the resulting thiolate anion on Merrifield resin. Reaction of the resin-bound sulfonyl intermediate 4 with hydrazine or hydroxylamine, followed by release from the resin and intramolecular cyclization, affords 3,5-diamino-4-(arylsulfonyl)-1H-pyrazoles 5 or isoxazoles 6, respectively. Reaction of the resin-bound carbonyl intermediate 9 with hydrazine, on the other hand, leads to 3-(arylamino)-5-aryl-1H-pyrazole-4-carbonitriles 10.

Application of the modified Pictet-Spengler cyclization reaction for the preparation of an imidazopyrazine ring: synthesis of new pyrido- and pyrimido-imidazopyrazines.

An efficient and versatile method for the synthesis of imidazopyrazine ring using the modified Pictet-Spengler strategy has been reported. The two step strategy offers rapid assembly of druglike core templates pyridine or pyrimidine and imidazole into new annulated polycyclic skeletons: pyrido- and pyrimido-imidazopyrazines. The rate of endo cyclization of aryl/heteroaryl-amine substrates has been compared with traditionally used aliphatic amine substrates, and results have been discussed in the light of the pK(a) values of amines present in each substrate.

Practical synthesis of 5-aryl-3-alkylsulfonyl-phenol and 5-aryl-3-arylsulfonyl-phenol libraries.

A straightforward and cost-effective synthesis of 5-aryl-3-alkylsulfonyl-phenols by a sequential scaffold derivatization strategy has been developed. The procedure is suitable for parallel synthesis of small libraries around the biphenyl privileged core having an unusual 1,3,5-substitution pattern. The synthesis is exemplified by a pilot library of 30 compounds.

Traceless solid-phase synthesis of heteroannulated 1,3-oxazin-6-ones.

A microwave-assisted solid-phase synthesis of heteroannulated 1,3-oxazin-6-ones has been developed. Significant rate enhancement was observed for all steps carried out under microwave irradiation, and the overall reaction time was dramatically shortened when compared to the conventional procedures. A representative set of 20 bi- and tricyclic heteroannulated 1,3-oxazin-6-ones was prepared. Key steps in the synthesis are (i) five-member heterocycle formation, (ii) acylation of amine, and (iii) ring closure to give the heteroannulated 1,3-oxazin-6-one.

Efficient method for the synthesis of pyranoquinoline, thiopyranoquinoline, thienoquinoline, and naphtho[2,7]naphthyridine derivatives catalyzed by iodine.

A mild and efficient method for the synthesis of pyranoquinoline, thiopyranoquinoline, thienoquinoline, and naphtho[2,7]naphthyridine derivatives via three-component reaction of aromatic aldehyde, naphthalen-2-amine, and heterocycloketones, including tetrahydropyran-4-one, tetrahydrothiopyran-4-one, pyridinone, and thiophenone, is described using iodine as catalyst. The features of this procedure are mild reaction conditions, good to high yields, and operational simplicity.

Diversification of a thieno[2,3-d]pyrimidin-4-one scaffold via regioselective alkylation reactions.

The 2-aryl-2,3,5,6,7,8-hexahydro[1]benzothieno[2,3-d]pyrimidin-4(1H)-ones and 2-aryl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4(3H)-ones have been diversified by alkylation reactions, applying benzylchlorides and N-substituted 2-chloroacetamides as alkylating agents. Under the found uniform conditions the substitution direction does not depend on the structure of the alkylating agent and gives monoalkylated products in high yields with simple workup. The alkylation of the 2,3-dihydropyrimidin-4(1H)-one derivatives proceeds onto the N1-position; however, in the case of pyrimidin-4(3H)-ones the O-alkylated products are formed selectively. An alternative strategy for the synthesis of the N1-benzyl-2,3-dihydropyrimidin-4(1H)-one derivatives is also developed. It applies the redaction of N2-substituted Gewald's amides with aromatic aldehydes and allows simple introduction of various substituents in the final molecule.

Solid-phase synthesis of novel 7,8-functionalized pyrazolo[1,5-a][1,3,5]-2-oxo-4-thioxotriazine derivatives via cyclization reactions of dithiocarboxy resin bound pyrazoles.

A general method is described for the solid-phase synthesis of novel 7,8-functionalized pyrazolo[1,5-a][1,3,5]-2-oxo-4-thioxotriazine derivatives. The sequence developed for this purpose is based on cyclization reactions of resin-bound 3,4-functionalized-5-amino-1-dithiocarboxypyrazoles 4 and 5, promoted by reaction with various isocyanates. The resin-bound pyrazoles produced by cyclization reactions of cyanocarboimidates 8 or 3-ethoxyacrylonitriles 9 with Merrifield resin linked hydrazine dithiocarbazate 3, serve as key intermediates for subsequent bicyclic heterocycle diversification. Reactions of the resin-bound 5-amino-1-dithiocarboxy pyrazoles 4 and 5 with various aryl isocyanates produce the novel 7,8-functionalized pyrazolo[1,5-a][1,3,5]-2-oxo-4-thioxotriazine derivatives 6 and 7 in good yields and high purities.