RESUMO
Relebactam, a potent ß-lactamase inhibitor, in combination with Primaxin is an FDA-approved (Recarbrio) treatment for serious and antibiotic-resistant bacterial infections. An efficient synthesis of key chiral piperidine intermediate 1 suitable for large-scale preparation of relebactam is described. The key steps include a unique highly diastereoselective FeCl3·6H2O/NaBH4 reduction of a chiral oxime ether and chemoselective amidation of the resulting unprotected pipecolic acid. Nuclear magnetic resonance studies and density functional theory calculations were carried out on the substrate-Fe(III) complexes, which shed light on diastereoselective reduction.
Assuntos
Compostos Azabicíclicos/síntese química , Compostos Azabicíclicos/farmacologia , Boroidretos/química , Cloretos/química , Compostos Férricos/química , Oximas/química , Inibidores de beta-Lactamases/síntese química , Inibidores de beta-Lactamases/farmacologia , Compostos Azabicíclicos/química , Éteres/química , Estrutura Molecular , Oxirredução , Análise Espectral/métodos , Estereoisomerismo , Água/químicaRESUMO
Described here is an efficient stereoselective synthesis of vibegron enabled by an enzymatic dynamic kinetic reduction that proceeds in a high-pH environment. To overcome enzyme performance limitations under these conditions, a ketoreductase was evolved by a computationally and structurally aided strategy to increase cofactor stability through tighter binding.
Assuntos
Agonistas de Receptores Adrenérgicos beta 3/síntese química , Pirimidinonas/síntese química , Pirrolidinas/síntese química , Biocatálise , Concentração de Íons de Hidrogênio , Cinética , Modelos Moleculares , Oxirredução , Oxirredutases/química , EstereoisomerismoRESUMO
A highly efficient asymmetric synthesis of the key tetrahydropyranol intermediate of DPP-4 inhibitor omarigliptin (1) is described. The successful development of a protecting-group- and precious-metal-free synthesis was achieved via the discovery of a practical asymmetric Henry reaction and the application of a one-pot nitro-Michael-lactolization-dehydration through-process. Other features of the synthesis include a highly efficient MsCl-mediated dehydration and a crystallization-induced dynamic resolution for exceptional ee and dr upgrade. The synthesis of this complex intermediate utilizes simple starting materials and proceeds in four linear steps.
Assuntos
Inibidores da Dipeptidil Peptidase IV/síntese química , Compostos Heterocíclicos com 2 Anéis/síntese química , Piranos/síntese química , Inibidores da Dipeptidil Peptidase IV/química , Compostos Heterocíclicos com 2 Anéis/química , Estrutura Molecular , Piranos/químicaRESUMO
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.
Assuntos
Indóis/síntese química , Catálise , Indóis/química , Estrutura Molecular , EstereoisomerismoRESUMO
An efficient, new, and scalable semisynthesis of glucan synthase inhibitors 1 and 2 from the fermentation product enfumafungin 3 is described. The highlights of the synthesis include a high-yielding ether bond-forming reaction between a bulky sulfamidate 17 and alcohol 4 and a remarkably chemoselective, improved palladium(II)-mediated Corey-Yu allylic oxidation at the highly congested C-12 position of the enfumafungin core. Multi-hundred gram quantities of the target drug candidates 1 and 2 were prepared, in 12 linear steps with 25% isolated yield and 13 linear steps with 22% isolated yield, respectively.
Assuntos
Álcoois/química , Antifúngicos/síntese química , Antifúngicos/farmacologia , Crisenos/química , Crisenos/síntese química , Equinocandinas/química , Glucosiltransferases/antagonistas & inibidores , Glicosídeos/química , Paládio/química , Triterpenos/química , Catálise , Estrutura Molecular , EstereoisomerismoRESUMO
An efficient route to the HCV antiviral agent uprifosbuvir was developed in 5 steps from readily available uridine in 50% overall yield. This concise synthesis was achieved by development of several synthetic methods: (1) complexation-driven selective acyl migration/oxidation; (2) BSA-mediated cyclization to anhydrouridine; (3) hydrochlorination using FeCl3/TMDSO; (4) dynamic stereoselective phosphoramidation using a chiral nucleophilic catalyst. The new route improves the yield of uprifosbuvir 50-fold over the previous manufacturing process and expands the tool set available for synthesis of antiviral nucleotides.
RESUMO
A mild, high-yielding procedure for the preparation of beta-ketophosphonates is described. The condensation is general with respect to the ester and phosphonate, and the products are obtained in high yields within minutes at 0 degrees C. The reaction procedure is operationally simple and amenable to large-scale preparations.
Assuntos
Organofosfonatos/síntese química , Estrutura Molecular , Organofosfonatos/química , EstereoisomerismoRESUMO
The reactions of chiral benzyl carbocations bearing alpha-phenyl substituents with N-sulfonylated indoles afford 1,1,2-triarylalkanes with anti-selectivities. This outcome is a reversal of facial diastereoselectivity relative to Bach's alpha-alkyl-bearing benzyl cations. The reactions are promoted by either a Brønsted acid (TFA) or Lewis acid (BF3.OEt2), offering differential diastereoselectivities and reactivities. The electronic properties of both reacting partners strongly influence the reaction rates and the product diastereoselectivities and appear to operate under kinetic control. This chemistry provides an efficient access to sterically congested tetrasubstituted ethanes.
Assuntos
Alcanos/síntese química , Indóis/química , Alcanos/química , Alquilação , Derivados de Benzeno/química , Catálise , Técnicas de Química Combinatória , Estrutura Molecular , EstereoisomerismoRESUMO
In this review the development of a viable large-scale synthesis of a p38 kinase inhibitor is discussed. Multiple strategies have been explored in devising syntheses to the intermediates containing the p38 kinase inhibitor's naphthyridinone core to allow the appendage of difluorophenyl and 4-N-tert-butylpiperidine fragments. A novel Heck lactamization reaction was discovered upon reacting 2,6-dichloroacrylanilide with a trihalo-substituted pyridine leading to the rapid synthesis of the naphthyridinone core. Investigations led to the development of two syntheses of 4-N-tert-butyl-chloropiperidine, including a novel methyl Grignard addition to an acetone iminium intermediate to build the tert-butyl group. The chemoselective addition of a 4-N-tertbutyl-chloropiperidine Grignard reagent to a pyridine oxide intermediate followed by re-aromatization using isobutylchloroformate and pyridine as solvent completed the synthesis of this potentially important p38 kinase inhibitor.
Assuntos
Inibidores Enzimáticos/síntese química , Naftiridinas/síntese química , Farmacologia Clínica/métodos , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Modelos Químicos , Estrutura Molecular , Naftiridinas/química , Naftiridinas/farmacologia , Farmacologia Clínica/tendências , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismoRESUMO
An asymmetric synthesis of a silicon-containing proline surrogate, N-Boc-(R)-silaproline (1), is described. Starting from N-Boc-dehydroalanine ester, deprotonation, followed by N-alkylation with chloromethyldimethylsilane under flow conditions, afforded the N-alkylated product 8 in 91% yield. An unprecedented enantioselective (NBD)2RhBF4/Josiphos 404-1 catalyzed 5-endo-trig hydrosilylation afforded the silaproline ester in 85-90% yield and >95% ee. Subsequent saponification and salt formation upgraded 1 to >99% ee.
Assuntos
Alanina/análogos & derivados , Compostos de Organossilício/síntese química , Prolina/análogos & derivados , Alanina/química , Alquilação , Catálise , Ciclização , Compostos de Organossilício/química , Prolina/síntese química , Prolina/químicaRESUMO
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.
Assuntos
Antagonistas dos Receptores de Orexina , Piperidinas/síntese química , Piperidinas/farmacologia , Pirimidinas/química , Pirimidinas/síntese química , Pirimidinas/farmacologia , Catálise , Estrutura Molecular , Piperidinas/químicaRESUMO
A practical, enantioselective synthesis of cis-2,5-disubstituted pyrrolidine is described. Application of an enzymatic DKR reduction of a keto ester, which is easily accessed through a novel intramolecular NâC benzoyl migration, yields syn-1,2-amino alcohol in >99% ee and >99:1 dr. Subsequent hydrogenation of cyclic imine affords the cis-pyrrolidine in high diastereoselectivity. By integrating biotechnology into organic synthesis and isolating only three intermediates over 11 steps, the core scaffold of ß3-AR agonists is synthesized in 38% overall yield.
Assuntos
Agonistas de Receptores Adrenérgicos beta 3/síntese química , Pirrolidinas/síntese química , Agonistas de Receptores Adrenérgicos beta 3/química , Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Amino Álcoois/química , Catálise , Hidrogenação , Iminas/química , Estrutura Molecular , Oxirredução , Pirrolidinas/química , Pirrolidinas/farmacologia , EstereoisomerismoRESUMO
The Heck coupling of acrylanilides with 4-bromo-2-chloro-3-iodo-pyridine using palladium acetate can produce bis-Heck products or undergo an unusual tandem Heck-lactamization ring formation to generate 5-chloro-1-aryl-1,6-naphthyridin-2(1H)-ones.
Assuntos
Anilidas/química , Halogênios/química , Lactamas/química , Naftiridinas/química , Piridinas/química , Ciclização , Halogênios/metabolismo , Estrutura Molecular , Paládio/química , Piridinas/metabolismoRESUMO
Compound 1 is a p38 MAP kinase inhibitor potentially useful for the treatment of rheumatoid arthritis and psoriasis. A novel six-step synthesis suitable for large-scale preparation was developed in support of a drug development program at Merck Research Laboratories. The key steps include a tandem Heck-lactamization, N-oxidation, and a highly chemoselective Grignard addition of 4-(N-tert-butylpiperidinyl)magnesium chloride to a naphthyridone N-oxide. The N-oxide exerted complete chemoselectivity via chelation in directing the Grignard addition to the alpha position as opposed to 1,4-addition on the ene-lactam. The dihydropyridyl adduct was in situ aromatized with isobutylchloroformate followed by heating in pyridine. Syntheses of Grignard precursor, N-tert-butyl-4-chloro-piperidine, were accomplished via transamination with a quaternary ammonium piperidone or via addition of methylmagnesium chloride to an iminium ion. Utilizing this chemistry, multi-kilogram preparation of compound 1 was successfully demonstrated.
Assuntos
Inibidores Enzimáticos/síntese química , Naftiridinas/química , Naftiridinas/síntese química , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Óxidos N-Cíclicos/química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Estrutura Molecular , Naftiridinas/farmacologiaRESUMO
[reaction: see text] A practical asymmetric synthesis of N-tert-butyl disubstituted pyrrolidines via a nitrile anion cyclization strategy is described. The five-step chromatography-free synthesis of (3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylic acid (2) from 2-chloro-1-(2,4-difluorophenyl)-ethanone achieved a 71% overall yield. The cyclization substrate was prepared via a catalytic CBS asymmetric reduction, t-butylamine displacement of the chlorohydrin, and a conjugate addition of the hindered secondary amine to acrylonitrile. The key nitrile anion 5-exo-tet cyclization concomitantly formed the pyrrolidine ring with clean inversion of the C-4 center to afford 1,3,4-trisubstituted chiral pyrrolidine in >95% yield and 94-99% ee. Diethyl chlorophosphate and lithium hexamethyldisilazide were shown to be the respective optimum activating group and base in this cyclization. The trans-cis mixture of the pyrrolidine nitrile undergoes a kinetically controlled epimerization/ saponification to afford the pure trans-pyrrolidine carboxylic acid target compound in >99.9% chemical and optical purity. This chemistry was also shown to be applicable to both electronically neutral and rich substituted phenyl substrates.
RESUMO
[reaction: see text] An efficient five-step synthesis of 1,6-naphthyridone 3b, a p38 mitogen-activated protein (MAP) kinase inhibitor intermediate, in 32% overall yield starting from acetonedicarboxylate (ADC) is described. The synthesis began with a selective monoamidation of ADC dimethyl ester enolate 9. A novel concomitant enamine formation and an imide cyclization afforded the nitrogen differentially protected enamide imide 12. Treatment of 12 with KO(t)Bu and 3-ethoxyacrylate produced lactam 15 quantitatively, which was converted to tetrachloronaphthyridone 19 via a one-pot p-methoxybenzyl (PMB) deprotection and bischlorination. A highly regioselective Pd(OAc)2/IMes-catalyzed Suzuki coupling completed the synthesis.
Assuntos
Naftiridinas/síntese química , Acetona/química , Ácidos Dicarboxílicos/química , Cetonas/síntese químicaRESUMO
Two efficient routes to 1-tert-butyl-4-chloropiperidine are described. In the first route, the key thionyl chloride mediated chlorination reaction features the use of tetrabutylammonium chloride as an additive that effectively suppresses the formation of an elimination-derived side product. In the second route, a novel alternative synthesis of 1-tert-butyl-4-chloropiperidine was developed in which the tertiary butyl group on the nitrogen is efficiently generated through the addition of methylmagnesium chloride to a dimethyliminium salt in 71% overall yield.
Assuntos
Butanos/síntese química , Cloreto de Magnésio/química , Piperidinas/síntese química , Sais/química , Hidrólise , Indicadores e Reagentes/química , OxirreduçãoRESUMO
A practical synthesis of benzisoxazole 1 and its conversion to alpha-aryloxyisobutyric acid 2 using 1,1,1-trichloro-2-methyl-2-propanol (chloretone) was developed. Benzisoxazole 1 was formed in high yields by the action of either methanesulfonyl chloride/base upon intermediate oxime 8 or with thionyl chloride/base, which initially forms cyclic sulfite 10. A highly reactive, short-lived intermediate derived from chloretone was detected by ReacIR and its half-life determined to be approximately 5 min. Reaction conditions for the Bargellini reaction were developed that resulted in a 95% yield of 2 from the reaction of highly hindered phenol 1 with chloretone hemihydrate and powdered NaOH in acetone. Thus highly hindered alpha-aryloxyisobutyric acids can be made in a single step in high yield.
Assuntos
Butiratos/síntese química , Isoxazóis/síntese química , PPAR alfa/agonistas , PPAR gama/agonistas , Propionatos/síntese química , Butiratos/química , Isoxazóis/química , Estrutura Molecular , Propionatos/químicaRESUMO
[reaction: see text] A mild and transition-metal-free method for the alpha-arylation of aliphatic nitriles with activated heteroaryl halides was developed using NaHMDS or KHMDS as base at ambient temperature. The key to the success of this method is generation of the nitrile anion in the presence of the heteroaryl halide. The method is applicable to both primary and secondary carbonitriles and a wide range of heteroaryl halides. Selective monoarylation was observed with primary carbonitriles. The operational simplicity and the mild reaction conditions add to the value of this method as a practical alternative to the preparation of alpha-heteroaryl carbonitriles.
Assuntos
Hidrocarbonetos Halogenados/química , Nitrilas/síntese química , Alquilação , Estrutura Molecular , Nitrilas/química , EstereoisomerismoRESUMO
A six-step preparation of thrombin inhibitor drug candidate 1 from pyrazinone 7 in 47% overall yield is described. The problem of low reactivity between weak amine nucleophile 4 and poor electrophile 3-bromopyrazinone 17 was overcome with the use of pyridinylthioimidate 27 in the presence of ZnCl(2) to afford adduct 3 in high yield. Several zinc complexes were characterized by solution and solid-state NMR and X-ray crystallographic analyses, and provided insight into the reaction mechanism. Preparation of pyridine N-oxide amine 4 was accomplished via a selective oxidation of the corresponding pyridinylamine 6. Pyridinylthioimidate 27 was prepared from pyrazinone 7 via a two-step one-pot process in near quantitative yield. Chlorination of the pyrazinone ring in 3 followed by hydrolysis and amide coupling completed the synthesis of 1. This chromatography-free synthesis was used successfully to prepare multikilogram quantities of the drug with reproducibility and high purity.