RESUMO
A novel method for the oxidation of indolines to indoles is described. The method uses a Cu(I) catalyst and an organic percarbonate as the stoichiometric oxidant. The procedure was successfully applied at 0.5 kg scale in the production of a key intermediate in the synthesis of Elbasvir, which is a novel therapy for the treatment of hepatitis C virus infection.
Assuntos
Cobre/química , Indóis/química , Catálise , Oxirredução , Análise Espectral/métodosRESUMO
Development of a practical synthesis of MK-7009, a 20-membered [corrected] macrocycle, is described. A variety of ring-closing strategies were evaluated, including ring-closing metathesis, intermolecular palladium-catalyzed cross-couplings, and macrolactamization. Ring closure via macrolactamization was found to give the highest yields under relatively high reaction concentrations. Optimization of the ring formation step and the synthesis of key intermediates en route to MK-7009 are reported.
Assuntos
Técnicas de Química Sintética/métodos , Indóis/química , Indóis/síntese química , Lactamas/química , Compostos Macrocíclicos/química , Catálise , Ciclização , Ciclopropanos , Hidrogenação , Isoindóis , Lactamas Macrocíclicas , Leucina/análogos & derivados , Paládio/química , Prolina/análogos & derivados , SulfonamidasRESUMO
A practical asymmetric synthesis of a novel aminopiperidine-fused imidazopyridine dipeptidyl peptidase IV (DPP-4) inhibitor 1 has been developed. Application of a unique three-component cascade coupling with chiral nitro diester 7, which is easily accessed via a highly enantioselective Michael addition of dimethyl malonate to a nitrostyrene, allows for the assembly of the functionalized piperidinone skeleton in one pot. Through a base-catalyzed, dynamic crystallization-driven process, the cis-piperidionone 16a is epimerized to the desired trans isomer 16b, which is directly crystallized from the crude reaction stream in high yield and purity. Isomerization of the allylamide 16b in the presence of RhCl(3) is achieved without any epimerization of the acid/base labile stereogenic center adjacent to the nitro group on the piperidinone ring, while the undesired enamine intermediate is consumed to <0.5% by utilizing a trace amount of HCl generated from RhCl(3). The amino lactam 4, obtained through hydrogenation and hydrolysis, is isolated as its crystalline pTSA salt from the reaction solution directly, as such intramolecular transamidation has been dramatically suppressed via kinetic control. Finally, a Cu(I) catalyzed coupling-cyclization allows for the formation of the tricyclic structure of the potent DPP-4 inhibitor 1. The synthesis, which is suitable for large scale preparation, is accomplished in 23% overall yield.
Assuntos
Inibidores da Dipeptidil Peptidase IV/síntese química , Compostos Heterocíclicos com 3 Anéis/síntese química , Piperidonas/síntese química , Catálise , Cromatografia em Gel , Cristalografia por Raios X , Inibidores da Dipeptidil Peptidase IV/química , Compostos Heterocíclicos com 3 Anéis/química , Isomerismo , Espectroscopia de Ressonância Magnética , Conformação Molecular , Estrutura Molecular , Piperidonas/químicaRESUMO
A stereoselective nine-step synthesis of the potent HIV nucleoside reverse transcriptase translocation inhibitor (NRTTI) islatravir (EfdA, MK-8591) from 2-deoxyribose is described. Key findings include a diastereodivergent addition of an acetylide nucleophile to an enolizable ketone, a chemoselective ozonolysis of a terminal olefin and a biocatalytic glycosylation cascade that uses a unique strategy of byproduct precipitation to drive an otherwise-reversible transformation forward.
Assuntos
Desoxiadenosinas/síntese química , Desoxirribose/química , Alcinos/química , Inibidores da Transcriptase Reversa/síntese química , Silanos/química , EstereoisomerismoRESUMO
The synthesis of the potent anti-HIV investigational treatment islatravir is described. The key step in this synthesis is a highly enantioselective catalytic asymmetric alkynylation of a ketone. This reaction is a rare example of the asymmetric addition of an alkyne nucleophile to a ketone through ligand-accelerated catalysis that was performed on a greater than 100 g scale. By leveraging a multienzyme cascade, a highly diastereoselective aldol-glycosylation was used to complete the target in eight steps.
RESUMO
Efficient cascade couplings to synthesize functionalized piperidinones 1 and bispidines 2 and 3 have been developed. Simple modifications to the reaction conditions allow for the highly controlled and selective formation of each compound. In addition, the cis isomer of 1 can be selectively obtained under acidic conditions, while the preparation of the corresponding trans isomer can also be readily realized through a base-catalyzed, dynamic crystallization-driven process.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Piperidinas/síntese química , Cristalização , Indicadores e Reagentes , Conformação Molecular , Preparações Farmacêuticas/síntese química , EstereoisomerismoRESUMO
[reaction: see text] An expedient, atom-economical, asymmetric synthesis of 1-aryl-3-azabicyclo[3.1.0]hexanes, including (+)-Bicifadine and DOV21947, in a single-stage through process without isolation of any intermediates has been developed. The key of this synthesis is the in-depth mechanistic understanding of the complicated epoxy nitrile coupling at each reaction stage. Therefore, the desired trisubstituted cyclopropane can be prepared in high ee and yield by controlling the reaction pathway through manipulating the nitrile anion aggregation state.
Assuntos
Compostos Aza/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Ciclopropanos/síntese química , Compostos Aza/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Ciclopropanos/química , Estrutura Molecular , Nitrilas/química , EstereoisomerismoRESUMO
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.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Infecções por HIV/tratamento farmacológico , Hepatite C/tratamento farmacológico , Influenza Humana/tratamento farmacológico , Animais , Antivirais/química , Descoberta de Drogas , HIV/efeitos dos fármacos , Hepacivirus/efeitos dos fármacos , HumanosRESUMO
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.
RESUMO
The development of an efficient and robust process for the production of HIV NNRTI doravirine is described. The synthesis features a continuous aldol reaction as part of a de novo synthesis of the key pyridone fragment. Conditions for the continuous flow aldol reaction were derived using microbatch snapshots of the flow process.
Assuntos
Infecções por HIV/tratamento farmacológico , Transcriptase Reversa do HIV/antagonistas & inibidores , Piridonas/síntese química , Inibidores da Transcriptase Reversa/síntese química , Triazóis/síntese química , Aldeídos/química , Estrutura Molecular , Piridonas/química , Piridonas/farmacologia , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Triazóis/química , Triazóis/farmacologiaRESUMO
[reaction: see text]. In the copper salt catalyzed ether formation from aryl bromides or iodides and phenols, 2,2,6,6-tetramethylheptane-3,5-dione (TMHD) was found to greatly accelerate the ordinarily difficult reaction, making it occur under more moderate temperatures and reaction times. A series of aryl halides and phenols were shown to form ethers in NMP as the solvent, cesium carbonate as the base, and CuCl and TMHD as the catalysts. The reaction was shown to tolerate electron-rich aryl bromides and electron-neutral phenols.
Assuntos
Éteres/síntese química , Cetonas/síntese química , Catálise , Cobre , Indicadores e Reagentes , Cinética , Ligantes , Espectroscopia de Ressonância MagnéticaRESUMO
L-733,725, a new immunosuppressant drug candidate, was prepared by a highly chemoselective alkylation of the macrolide ascomycin at the C32 hydroxy position with the imidazolyl trichloroacetimidate 16. The trichloroacetimidate-activated side chain 16 was prepared by an efficient four-step sequence in 42% overall yield. The high chemoselectivity in the alkylation of the C32 hydroxy group of the unprotected ascomycin was the result of the synergetic effects of the electron-donating protecting group on the imidazole 16, the polar, moderately basic solvent, and the strong acid catalyst. N,N-Dimethylpivalamide mixed with acetonitrile was found to be the best solvent and trifluromethanesulfonic acid the best catalyst. This synthesis coupled with a resin column purification of L-733,725 followed by crystallization of its tartrate salt has been used to make multi-kilogram quantities of the bulk drug with consistent and high purity.
RESUMO
A practical synthesis of a highly functionalized tetrahydropyran DPP-4 inhibitor is described. The asymmetric synthesis relies on three back-to-back Ru-catalyzed reactions. A Ru-catalyzed dynamic kinetic resolution (DKR) reduction establishes two contiguous stereogenic centers in one operation. A unique dihydropyran ring is efficiently constructed through a preferred Ru-catalyzed cycloisomerization. Hydroboration followed by a Ru-catalyzed oxidation affords the desired functionalized pyranone core scaffold. Finally, stereoselective reductive amination and subsequent acidic deprotection afford the desired, potent DPP-4 inhibitor in 25% overall yield.
Assuntos
Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores da Dipeptidil Peptidase IV/farmacologia , Pironas/síntese química , Pironas/farmacologia , Aminação , Catálise , Inibidores da Dipeptidil Peptidase IV/química , Inibidores Enzimáticos , Glicina/análogos & derivados , Glicina/química , Hipoglicemiantes , Cinética , Estrutura Molecular , Oxirredução , Pironas/química , Rutênio/química , EstereoisomerismoRESUMO
A simple, one-pot preparation of cyclic amines via efficient chlorination of amino alcohols with use of SOCl(2) has been developed. This approach obviates the need for the classical N-protection/O-activation/cyclization/deprotection sequence commonly employed for this type of transformation. The reaction pathways and the general scope of this method have also been investigated.
Assuntos
Amino Álcoois/síntese química , Óxidos de Enxofre/química , Amino Álcoois/química , Ciclização , Desidratação , Halogenação , Estrutura Molecular , EstereoisomerismoRESUMO
A practical, efficient synthesis of 1, a hepatitis C virus RNA replication inhibitor, is described. Starting with the inexpensive diacetone glucose, the 12-step synthesis features a novel stereoselective rearrangement to prepare the key crystalline furanose diol intermediate. This is followed by a highly selective glycosidation to couple the C-2 branched furanose epoxide with deazapurine.
Assuntos
Antivirais/síntese química , Hepacivirus/genética , RNA Viral/biossíntese , Antivirais/farmacologia , Cromatografia Líquida de Alta Pressão , Espectroscopia de Ressonância MagnéticaRESUMO
An efficient asymmetric synthesis of a selective estrogen receptor modulator (SERM) that has a dihydrobenzoxathiin core structure bearing two stereogenic centers is reported. The stereogenic centers were established by an unprecedented chiral sulfoxide-directed stereospecific reduction of an alpha,beta-unsaturated sulfoxide to the saturated sulfide in one step. Studies to elucidate the mechanism for this reduction are reported. Highly efficient Cu(I)-mediated ether formation was used to install the ether side chain, and selective debenzylation conditions were developed to remove the benzyl protecting groups on the phenols.
Assuntos
Boranos/química , Moduladores de Receptor Estrogênico/síntese química , Safrol/análogos & derivados , Safrol/química , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Oxirredução , EstereoisomerismoRESUMO
A streamlined and high-yielding synthesis of aprepitant (1), a potent substance P (SP) receptor antagonist, is described. The enantiopure oxazinone 16 starting material was synthesized via a novel crystallization-induced dynamic resolution process. Conversion of 16 to the penultimate intermediate cis-sec-amine 9 features a highly stereoselective Lewis acid-catalyzed trans acetalization of chiral alcohol 3 with trichloroacetimidate 18 followed by inversion of the adjacent chiral center on the morpholine ring. The six-step process for the synthesis of 9 was accomplished in extremely high overall yield (81%) and with only two isolations.
RESUMO
An efficient stereoselective synthesis of the orally active NK(1) receptor antagonist Aprepitant is described. A direct condensation of N-benzyl ethanolamine with glyoxylic acid yielded a 2-hydroxy-1,4-oxazin-3-one which was activated as the corresponding trifluoroacetate. A Lewis acid mediated coupling with enantiopure (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol afforded a 1:1 mixture of acetal diastereomers which was converted into a single isomer via a novel crystallization-induced asymmetric transformation. The resulting 1,4-oxazin-3-one was converted via a unique and highly stereoselective one-pot process to the desired alpha-(fluorophenyl)morpholine derivative. Interesting and unexpected [1,2]-Wittig and [1,3]-sigmatropic rearrangements were identified during the optimization of these key steps. In the final step, a triazolinone side chain was appended to the morpholine core. The targeted clinical candidate was thus obtained in 55% overall yield over the longest linear sequence.