ABSTRACT
We report that selective N-phosphorylation of aminoimidazoles results in a key steering element that controls isomeric selectivity in the condensation of ß-ethoxy acrylamides and aminoimidazoles to furnish imidazo[1,2-a]pyrimidines. We identified conditions that provide highly selective (99:1) phosphorylation at the endo- or exocyclic nitrogen. Either the 2-amino or 4-amino isomer of the (benzo)imidazo[1,2-a]pyrimidine products could be isolated in 64-95% yield. Mass spectrometric analysis and computational studies give insight into the mechanism of this exceptionally selective transformation.
ABSTRACT
This paper brings together the concepts of molecular complexity and crowdsourcing. An exercise was done at Merck where 386 chemists voted on the molecular complexity (on a scale of 1-5) of 2681 molecules taken from various sources: public, licensed, and in-house. The meanComplexity of a molecule is the average over all votes for that molecule. As long as enough votes are cast per molecule, we find meanComplexity is quite easy to model with QSAR methods using only a handful of physical descriptors (e.g., number of chiral centers, number of unique topological torsions, a Wiener index, etc.). The high level of self-consistency of the model (cross-validated R(2) â¼0.88) is remarkable given that our chemists do not agree with each other strongly about the complexity of any given molecule. Thus, the power of crowdsourcing is clearly demonstrated in this case. The meanComplexity appears to be correlated with at least one metric of synthetic complexity from the literature derived in a different way and is correlated with values of process mass intensity (PMI) from the literature and from in-house studies. Complexity can be used to differentiate between in-house programs and to follow a program over time.
Subject(s)
Crowdsourcing , Molecular Structure , Databases, Chemical , Humans , Models, Chemical , Quantitative Structure-Activity Relationship , StereoisomerismABSTRACT
In this paper, we report the development of different synthetic routes to MK-7246 (1) designed by the Process Chemistry group. The syntheses were initially designed as an enabling tool for Medicinal Chemistry colleagues in order to rapidly explore structure-activity relationships (SAR) and to procure the first milligrams of diverse target molecules for in vitro evaluation. The initial aziridine opening/cyclodehydration strategy was also directly amenable to the first GMP deliveries of MK-7246 (1), streamlining the transition from milligram to kilogram-scale production needed to support early preclinical and clinical evaluation of this compound. Subsequently a more scalable and cost-effective manufacturing route to MK-7246 (1) was engineered. Highlights of the manufacturing route include an Ir-catalyzed intramolecular N-H insertion of sulfoxonium ylide 41 and conversion of ketone 32 to amine 31 in a single step with excellent enantioselectivity through a transaminase process. Reactions such as these illustrate the enabling impact and efficiency gains that innovative developments in chemo- and biocatalysis can have on the synthesis of pharmaceutically relevant target molecules.
Subject(s)
Carbolines/pharmacology , Drug Discovery , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Carbolines/chemical synthesis , Carbolines/chemistry , Molecular Structure , Stereoisomerism , Structure-Activity RelationshipABSTRACT
In this report, we disclose our findings regarding the remarkable effect of a low-level impurity found in the solvent used for a ruthenium-catalyzed direct arylation reaction. This discovery allowed for the development of a robust and high-yield arylation protocol that was demonstrated on a multikilogram scale using carboxylate as the cocatalyst. Finally, a practical, scalable, and chromatography-free synthesis of the biaryl core of Anacetrapib is described.
Subject(s)
Oxazolidinones/chemical synthesis , Ruthenium/chemistry , Catalysis , Molecular Structure , Oxazolidinones/chemistry , Solvents/chemistry , StereoisomerismABSTRACT
A practical enantioselective synthesis of renin inhibitor MK-1597 (ACT-178882), a potential new treatment for hypertension, is described. The synthetic route provided MK-1597 in nine steps and 29% overall yield from commercially available p-cresol (7). The key features of this sequence include a catalytic asymmetric hydrogenation of a tetrasubstituted ene-ester, a highly efficient epimerization/saponification sequence of 4 which sets both stereocenters of the molecule, and a short synthesis of amine fragment 2.
Subject(s)
Cresols/chemistry , Cyclopropanes/antagonists & inhibitors , Cyclopropanes/chemical synthesis , Cyclopropanes/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Piperidines/chemistry , Pyridines/antagonists & inhibitors , Pyridines/chemical synthesis , Pyridines/pharmacology , Renin/antagonists & inhibitors , Catalysis , Cyclopropanes/chemistry , Enzyme Inhibitors/chemistry , Hydrogenation , Hypertension/drug therapy , Molecular Structure , Pyridines/chemistry , Renin/chemistry , StereoisomerismABSTRACT
A scalable synthesis of a potent renin inhibitor (1) is described. The absolute stereochemistry is set via an unprecedented diastereoselective Dieckmann cyclization directed by a remote chiral protecting group. This transformation enables preparation of chiral 1,3-[3.3.1]-diazabicyclononenes by desymmetrization of alkyl-esters, with selectivities ranging from 4 to 17:1.
Subject(s)
Azo Compounds/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Renin/antagonists & inhibitors , Toluene/analogs & derivatives , Azo Compounds/chemistry , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Crystallography, X-Ray , Cyclization , Molecular Conformation , Molecular Structure , Protease Inhibitors/chemistry , Stereoisomerism , Toluene/chemical synthesis , Toluene/chemistry , Toluene/pharmacologyABSTRACT
Practical, chromatography-free syntheses of 5-lipoxygenase inhibitor MK-0633 p-toluenesulfonate (1) are described. The first route used an asymmetric zincate addition to ethyl 2,2,2-trifluoropyruvate followed by 1,3,4-oxadiazole formation and reductive amination as key steps. An improved second route features an inexpensive diastereomeric salt resolution of vinyl hydroxy-acid 22 followed by a robust end-game featuring a through-process hydrazide acylation/1,3,4-oxadiazole ring closure/salt formation sequence to afford MK-0633 p-toluenesulfonate (1).
Subject(s)
Benzenesulfonates/chemical synthesis , Benzopyrans/chemical synthesis , Lipoxygenase Inhibitors , Lipoxygenase Inhibitors/chemical synthesis , Oxadiazoles/chemical synthesis , Arachidonate 5-Lipoxygenase/chemistry , Benzenesulfonates/chemistry , Benzopyrans/chemistry , Lipoxygenase Inhibitors/chemistry , Molecular Structure , Oxadiazoles/chemistry , StereoisomerismABSTRACT
The evolution of scalable, economically viable synthetic approaches to the potent and selective prostaglandin EP4 antagonist 1 is presented. The chromatography-free synthesis of multikilogram quantities of 1 using a seven-step sequence (six in the longest linear sequence) is described. This approach has been further modified in an effort to identify a long-term manufacturing route. Our final synthesis involves no step requiring cryogenic (< -25 degrees C) conditions; comprises a total of four steps, only three of which are in the longest linear synthesis; and features the use of two consecutive iron-catalyzed Friedel-Crafts substitutions.
Subject(s)
Chemistry, Pharmaceutical/economics , Receptors, Prostaglandin E/antagonists & inhibitors , Acylation , Adrenergic Antagonists , Cold Temperature , Cyclopropanes/chemistry , Cyclopropanes/pharmacology , Ketones/chemistry , Ketones/pharmacology , Receptors, Prostaglandin E, EP4 Subtype , Stereoisomerism , Temperature , Thiophenes/chemistry , Thiophenes/pharmacologyABSTRACT
A practical, kilogram-scale chromatography-free synthesis of mPGE synthase I inhibitor MK-7285 is described. The route features a convergent assembly of the core phenanthrene unit via amide-directed ortho-metalation and proximity-induced anionic cyclization, followed by imidazole synthesis and late-stage cyanation.
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Intramolecular Oxidoreductases/chemistry , Cyclization , Molecular Structure , Prostaglandin-E SynthasesABSTRACT
A practical large-scale chromatography-free synthesis of EP4 antagonist MF-310, a potential new treatment for chronic inflammation, is presented. The synthetic route provided MF-310 as its sodium salt in 10 steps and 17% overall yield from commercially available pyridine dicarboxylate 7. The key features of this sequence include a unique regioselective reduction of succinimide 2 controlled by the electronic properties of a remote pyridine ring, preparation of cyclopropane carboxylic acid 3 via a Corey-Chaykovsky cyclopropanation, and a short synthesis of sulfonamide 5.
Subject(s)
Chemistry, Organic/methods , Chemistry, Pharmaceutical/methods , Cyclopropanes/chemical synthesis , Heterocyclic Compounds, 3-Ring/chemical synthesis , Receptors, Prostaglandin E/antagonists & inhibitors , Succinimides/chemistry , Carboxylic Acids/chemistry , Chemistry, Organic/instrumentation , Chemistry, Pharmaceutical/instrumentation , Crystallization , Cyclopropanes/chemistry , Drug Design , Electronics , Heterocyclic Compounds, 3-Ring/chemistry , Models, Chemical , Molecular Structure , Receptors, Prostaglandin E, EP4 Subtype , Stereoisomerism , Sulfonamides/chemistry , Technology, PharmaceuticalABSTRACT
N-H ketoimines 3a-3v are readily prepared in high yield via organometallic addition to nitriles and isolated as corresponding bench-stable hydrochloride salts. Homogeneous asymmetric hydrogenation of unprotected N-H ketoimines 3a-3v using Ir-(S,S)-f-binaphane as catalyst provides chiral amines 4a-4v in 90-95% yield with enantioselectivities up to 95% ee.
Subject(s)
Imines/chemical synthesis , Hydrogenation , Imines/chemistry , StereoisomerismABSTRACT
A practical and efficient synthesis of bradykinin B(1) antagonist 1 is described. A convergent strategy was utilized which involved synthesis of three fragments: 3, 6, and 7. Cross coupling of fragments 6 and 7 followed by amidation with 3 enabled efficient synthesis of 1 in 19 steps total, a 35% overall yield from commercially available pyridine 10. The key to the success of the synthesis was the development of a fluorodenitration step to install the fluorine in pyridine 7 and a catalytic enantioselective hydrogenation of N-acyl enamide 9 to set the stereochemistry.
Subject(s)
Amides/chemical synthesis , Bradykinin B1 Receptor Antagonists , Pyridines/chemical synthesis , Amides/chemistry , Amides/pharmacology , Amines/chemical synthesis , Amines/chemistry , Azoles/chemical synthesis , Azoles/chemistry , Boronic Acids/chemical synthesis , Boronic Acids/chemistry , Hydrocarbons, Fluorinated/chemical synthesis , Hydrocarbons, Fluorinated/chemistry , Hydrogenation , Methylation , Pyridines/chemistry , Pyridines/pharmacology , StereoisomerismABSTRACT
An enantioselective synthesis of the Cathepsin K inhibitor odanacatib (MK-0822) 1 is described. The key step involves the novel stereospecific S(N)2 triflate displacement of a chiral alpha-trifluoromethylbenzyl triflate 9a with (S)-gamma-fluoroleucine ethyl ester 3 to generate the required alpha-trifluoromethylbenzyl amino stereocenter. The triflate displacement is achieved in high yield (95%) and minimal loss of stereochemistry. The overall synthesis of 1 is completed in 6 steps in 61% overall yield.
Subject(s)
Biphenyl Compounds/chemical synthesis , Cathepsins/antagonists & inhibitors , Hydrocarbons, Fluorinated/chemistry , Protease Inhibitors/chemical synthesis , Alcohols/chemistry , Biphenyl Compounds/chemistry , Cathepsin K , Esters/chemistry , Hydrolysis , Protease Inhibitors/chemistry , Stereoisomerism , Substrate SpecificityABSTRACT
Electron-rich aryl bromides are rapidly converted to the corresponding lithium triarylmagnesiates with (n-Bu)3MgLi, which undergo efficient nickel-catalyzed Kumada-Corriu cross-coupling reactions with a variety of aryl and alkenyl bromides, chlorides, tosylates, and triflates.
ABSTRACT
We report herein a simple, scalable, transition-metal-free approach to the synthesis of alpha-aryl methyl ketones from diazonium tetrafluoroborate salts under mild conditions. This methodology uses easily accessible and nontoxic starting material and was applied to the multi-kilogram-scale preparation of 1-(3-bromo-4-methylphenyl)propan-2-one.
Subject(s)
Ketones/chemistry , Transition Elements/chemistry , Catalysis , Chromatography, High Pressure Liquid , Hydrocarbons, Brominated/chemical synthesis , Magnetic Resonance Spectroscopy , Metals/chemistry , Propane/analogs & derivatives , Propane/chemical synthesis , Solvents , Spectrometry, Mass, Electrospray IonizationABSTRACT
A facile and general protocol for the preparation of 2-amino-1,3,4-oxadiazoles is reported. This method relies on a tosyl chloride/pyridine-mediated cyclization of a thiosemicarbazide, which is readily prepared by acylation of a given hydrazide with the appropriate isothiocyanate. Cyclization of the thiosemicarbazide consistently outperforms the analogous semicarbazide cyclization under these conditions, for 18 distinct examples. Utilizing this protocol, we have prepared 5-alkyl- and 5-aryl-2-amino-1,3,4-oxadiazoles in 78-99% yield.
Subject(s)
Oxazoles/chemical synthesis , Semicarbazides/chemistryABSTRACT
A practical, chromatography-free synthesis of potent cathepsin K inhibitor 1 is described. The addition of 4-bromophenyllithium to an alpha-trifluoromethylimine derived from commercially available (S)-leucinol was accomplished in a highly diastereoselective manner (97.6% de, 91% yield). Subsequent Suzuki cross-coupling afforded biaryl 7. Oxidation of the alcohol and sulfide functionalities led to the formation of carboxylic acid 8. Crystallization of 7 and acid 8 as its dicyclohexylamine salt gave excellent impurity rejection. The final amide coupling with commercially available aminoacetonitrile hydrochloride afforded 1 in excellent purity (99.6A% by HPLC, 100% de, <3 ppm Pd, W, Cr).
Subject(s)
Cathepsins/antagonists & inhibitors , Imines/chemistry , Lithium/chemistry , Cathepsin K , Molecular StructureABSTRACT
A practical, chromatography-free catalytic asymmetric synthesis of a potent and selective PDE4 inhibitor (L-869,298, 1) is described. Catalytic asymmetric hydrogenation of thiazole ketone 5a afforded the corresponding alcohol 3b in excellent enantioselectivity (up to 99.4% ee). Activation of alcohol 3b via formation of the corresponding p-toluenesulfonate followed by an unprecedented displacement with the lithium enolate of ethyl 3-pyridylacetate N-oxide 4a generated the required chiral trisubstituted methane. The displacement reaction proceeded with inversion of configuration and without loss of optical purity. Conversion of esters 2b to 1 was accomplished via a one-pot deprotection, saponification, and decarboxylation sequence in excellent overall yield.
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Combinatorial Chemistry Techniques , Cyclic N-Oxides/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Pyridines/chemical synthesis , Cyclic N-Oxides/pharmacology , Cyclic Nucleotide Phosphodiesterases, Type 4 , Enzyme Inhibitors/pharmacology , Magnetic Resonance Spectroscopy , Molecular Structure , Pyridines/pharmacology , StereoisomerismABSTRACT
[Reaction: see text] Addition of lithium bis(trimethylsilyl)amide to perfluorinated ketones 1a-j affords (E)-N-TMS-ketimines 2a-j that are reduced in situ to afford racemic perfluoromethylated amine hydrochloride salts 3a-j in 54-97% yields. Solvolysis of the N-Si bond in MeOH leads to formation of bench-stable, isolable N-H imine Z/E isomer mixtures along with a methanol adduct. Enantioselective reduction of these three-component mixtures provides the first catalytic asymmetric synthesis of trifluoromethylated amines in 72-95% yields and 75-98% ee.