RESUMO
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.
Assuntos
Crowdsourcing , Estrutura Molecular , Bases de Dados de Compostos Químicos , Humanos , Modelos Químicos , Relação Quantitativa Estrutura-Atividade , EstereoisomerismoRESUMO
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.
Assuntos
Carbolinas/farmacologia , Descoberta de Drogas , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Carbolinas/síntese química , Carbolinas/química , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Oxazolidinonas/síntese química , Rutênio/química , Catálise , Estrutura Molecular , Oxazolidinonas/química , Solventes/química , EstereoisomerismoRESUMO
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.
Assuntos
Cresóis/química , Ciclopropanos/antagonistas & inibidores , Ciclopropanos/síntese química , Ciclopropanos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Piperidinas/química , Piridinas/antagonistas & inibidores , Piridinas/síntese química , Piridinas/farmacologia , Renina/antagonistas & inibidores , Catálise , Ciclopropanos/química , Inibidores Enzimáticos/química , Hidrogenação , Hipertensão/tratamento farmacológico , Estrutura Molecular , Piridinas/química , Renina/química , EstereoisomerismoRESUMO
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.
Assuntos
Química Farmacêutica/economia , Receptores de Prostaglandina E/antagonistas & inibidores , Acilação , Antagonistas Adrenérgicos , Temperatura Baixa , Ciclopropanos/química , Ciclopropanos/farmacologia , Cetonas/química , Cetonas/farmacologia , Receptores de Prostaglandina E Subtipo EP4 , Estereoisomerismo , Temperatura , Tiofenos/química , Tiofenos/farmacologiaRESUMO
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).
Assuntos
Benzenossulfonatos/síntese química , Benzopiranos/síntese química , Inibidores de Lipoxigenase , Inibidores de Lipoxigenase/síntese química , Oxidiazóis/síntese química , Araquidonato 5-Lipoxigenase/química , Benzenossulfonatos/química , Benzopiranos/química , Inibidores de Lipoxigenase/química , Estrutura Molecular , Oxidiazóis/química , EstereoisomerismoRESUMO
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.
Assuntos
Iminas/síntese química , Hidrogenação , Iminas/química , EstereoisomerismoRESUMO
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.
Assuntos
Compostos de Bifenilo/síntese química , Catepsinas/antagonistas & inibidores , Hidrocarbonetos Fluorados/química , Inibidores de Proteases/síntese química , Álcoois/química , Compostos de Bifenilo/química , Catepsina K , Ésteres/química , Hidrólise , Inibidores de Proteases/química , Estereoisomerismo , Especificidade por SubstratoRESUMO
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.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Oxirredutases Intramoleculares/química , Ciclização , Estrutura Molecular , Prostaglandina-E SintasesRESUMO
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.
Assuntos
Amidas/síntese química , Antagonistas de Receptor B1 da Bradicinina , Piridinas/síntese química , Amidas/química , Amidas/farmacologia , Aminas/síntese química , Aminas/química , Azóis/síntese química , Azóis/química , Ácidos Borônicos/síntese química , Ácidos Borônicos/química , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/química , Hidrogenação , Metilação , Piridinas/química , Piridinas/farmacologia , EstereoisomerismoRESUMO
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.
Assuntos
Química Orgânica/métodos , Química Farmacêutica/métodos , Ciclopropanos/síntese química , Compostos Heterocíclicos com 3 Anéis/síntese química , Receptores de Prostaglandina E/antagonistas & inibidores , Succinimidas/química , Ácidos Carboxílicos/química , Química Orgânica/instrumentação , Química Farmacêutica/instrumentação , Cristalização , Ciclopropanos/química , Desenho de Fármacos , Eletrônica , Compostos Heterocíclicos com 3 Anéis/química , Modelos Químicos , Estrutura Molecular , Receptores de Prostaglandina E Subtipo EP4 , Estereoisomerismo , Sulfonamidas/química , Tecnologia FarmacêuticaRESUMO
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.
RESUMO
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.
RESUMO
[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.
Assuntos
Aminas/química , Hidrogênio/química , Iminas/química , Nitrogênio/química , Catálise , Hidrogênio/metabolismo , Ligação de Hidrogênio , Nitrogênio/metabolismo , Oxirredução , EstereoisomerismoRESUMO
[reaction: see text] A base-induced ring opening/imine isomerization/diastereoselective organometallic addition sequence on 4-substituted 2-perfluoroalkyl-1,3-oxazolidines has been developed for the asymmetric synthesis of aryl alpha-perfluoroalkylamine derivatives. This practical method provides chiral amino alcohols in 60-95% yield with uniformely high diastereoselectivities ranging from 35:1 to >100:1.
RESUMO
[reaction: see text] Activation of substituted 1,1-diarylmethanols as their corresponding toluenesulfonates and subsequent displacement with a range of carbon, nitrogen, oxygen, and sulfur nucleophiles proceeds in 81-96% yield. Enantiomerically enriched diarylmethanols 8a-c were activated and displaced with pyridine acetate enolate with complete stereochemical inversion at carbon to yield 1,1-diarylalkyl derivatives 10a-c without loss of optical purity.
RESUMO
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.
Assuntos
Compostos Azo/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Renina/antagonistas & inibidores , Tolueno/análogos & derivados , Compostos Azo/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Cristalografia por Raios X , Ciclização , Conformação Molecular , Estrutura Molecular , Inibidores de Proteases/química , Estereoisomerismo , Tolueno/síntese química , Tolueno/química , Tolueno/farmacologiaRESUMO
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.
Assuntos
Cetonas/química , Elementos de Transição/química , Catálise , Cromatografia Líquida de Alta Pressão , Hidrocarbonetos Bromados/síntese química , Espectroscopia de Ressonância Magnética , Metais/química , Propano/análogos & derivados , Propano/síntese química , Solventes , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
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.