RESUMO
The design, stereoselective synthesis and inâ vivo antiallodynic activity of four novel paroxetine analogs, named 3-hydroxy paroxetines (3HPXs), is reported herein. Among the novel synthesized compounds, three showed an antiallodynic effect, while (R,R)-3HPX was found to be 2.5 times more bioactive than (-)-paroxetine itself in neuropathic rats. Consequently, the current investigation not only discloses a novel promising analgesic drug, but also reveals that functionalization at the C3 position of paroxetine could be as effective as the common functionalization at either C4 or within the sesamol group.
Assuntos
Analgésicos/farmacologia , Dor/tratamento farmacológico , Paroxetina/farmacologia , Analgésicos/síntese química , Analgésicos/química , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Hidroxilação , Estrutura Molecular , Paroxetina/síntese química , Paroxetina/química , Ratos , Ratos Wistar , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A highly enantioselective tandem Michael/ring-closure reaction of α,ß-unsaturated pyrazoleamides and amidomalonates has been accomplished in the presence of a chiral N,N'-dioxide-Yb(OTf)3 complex (Tf: trifluoromethanesulfonyl) to give various substituted chiral glutarimides with high yields and diastereo- and enantioselectivities. Moreover, this methodology could be used for gram-scale manipulation and was successfully applied to the synthesis of (-)-paroxetine. Further nonlinear and HRMS studies revealed that the real catalytically active species was a monomeric L-PMe2 -Yb3+ complex. A plausible transition state was proposed to explain the origin of the asymmetric induction.
Assuntos
Paroxetina/síntese química , Pirazóis/química , Catálise , Paroxetina/química , EstereoisomerismoRESUMO
We have developed a novel approach for the synthesis of enantioenriched 3-boryl-tetrahydropyridines via the Cu(I)-catalyzed regio-, diastereo-, and enantioselective protoborylation of 1,2-dihydropyridines, which were obtained by the partial reduction of the pyridine derivatives. This dearomatization/enantioselective borylation stepwise strategy provides facile access to chiral piperidines together with the stereospecific transformation of a stereogenic C-B bond from readily available starting materials. Furthermore, the utility of this method is demonstrated for the concise synthesis of the antidepressant drug (-)-paroxetine. A theoretical study of the reaction mechanism is also described.
Assuntos
Antidepressivos/síntese química , Paroxetina/síntese química , Piperidinas/síntese química , Piridinas/química , Antidepressivos/química , Antidepressivos/farmacologia , Catálise , Di-Hidropiridinas/química , Estrutura Molecular , Paroxetina/química , Paroxetina/farmacologia , Piperidinas/química , EstereoisomerismoRESUMO
Non-aromatic nitrogen- and oxygen-containing heterocycles such as piperidines and pyrans are prevalent components of natural products and pharmaceutical drugs. Although it has been a workhorse as a synthetic method for assembling unsaturated sp(2)-hybridized substrates, transition metal-catalysed cross-coupling chemistry is traditionally not a suitable approach to prepare chiral non-aromatic heterocycles. Several mechanistic issues hamper the coupling of stereogenic secondary sp(3)-hybridized carbon-metal centres. Moreover, use of unsymmetrical allylic boronates in the Suzuki Miyaura cross-coupling is further complicated by the possibility of forming two regioisomeric products. Here we address this two-pronged problem and demonstrate that chiral enantiomerically enriched heterocyclic allylic boronates can be coupled with high stereochemical retention with a wide variety of aryl and alkenyl halides to independently afford both regioisomeric 2- and 4-substituted dihydropyrans and dehydropiperidines in high selectivity. A divergent mechanism is proposed where regiochemistry is governed by the nature of the ligands on the palladium catalyst. This scalable method is applied to the efficient preparation of the neuroactive alkaloid anabasine and the antidepressant drug paroxetine.
Assuntos
Anabasina/síntese química , Paládio/química , Paroxetina/síntese química , Anabasina/química , Catálise , Ligantes , Estrutura Molecular , Paroxetina/química , EstereoisomerismoRESUMO
The HKR of racemic anti- or syn-3-substituted epoxy esters catalyzed by a Co(III)salen complex provides ready access to the corresponding enantioenriched 3,4-disubstituted γ-butyrolactones and 3-substituted epoxy esters. This strategy has been successfully employed in the formal synthesis of biologically active 3,4-disubstituted piperidine derivatives, (-)-paroxetine and Ro 67-8867 and a natural product, (+)-eldanolide.
Assuntos
4-Butirolactona/química , Alcadienos/síntese química , Compostos de Epóxi/química , Ésteres/química , Paroxetina/síntese química , Piperidinas/síntese química , 4-Butirolactona/análogos & derivados , Alcadienos/química , Catálise , Hidrólise , Cinética , Estrutura Molecular , Fenômenos Ópticos , Compostos Organometálicos/química , Paroxetina/química , Piperidinas/química , EstereoisomerismoRESUMO
A new enantioselective synthetic method of (-)-paroxetine is reported. (-)-Paroxetine could be obtained in 15 steps (95% ee and 9.1% overall yield) from N,N-bis(p-methoxyphenyl)malonamide tert-butyl ester via the enantioselective phase-transfer catalytic alkylation and the diastereoselective Michael addition as the key steps.
Assuntos
Malonatos/química , Paroxetina/síntese química , Alquilação , Catálise , Ésteres , Estrutura Molecular , Paroxetina/química , EstereoisomerismoRESUMO
When combined with an appropriate nucleophilic component, 1,2- and 1,3-cyclic sulfamidates function as versatile precursors to a range of substituted and enantiopure heterocyclic classes. Functionalised enolates provide a direct entry to C-3 functionalised lactams, as exemplified by total syntheses of (-)-aphanorphine, (+)-laccarin and (-)-paroxetine. Heteroatom nucleophiles, such as thiol esters, amino esters and bromo phenols, provide concise access to a range of enantiomerically pure thiomorpholine, piperazine and benzofused heterocyclic scaffolds. The latter methodology enables a facile synthesis of the antibacteriocidal agent levofloxacin.
Assuntos
Lactamas/síntese química , Antibacterianos/síntese química , Hidrocarbonetos Aromáticos com Pontes/síntese química , Ciclização , Levofloxacino , Ofloxacino/síntese química , Paroxetina/síntese química , Pirróis/síntese química , Sulfonamidas/síntese químicaRESUMO
An efficient enantioselective total synthesis of (R)-rolipram and an efficient enantioselective formal synthesis of (3S,4R)-paroxetine has been achieved using the highly enantioselective Michael addition of malonate nucleophiles as key steps in both cases.
Assuntos
Paroxetina/síntese química , Rolipram/síntese química , Catálise , Malonatos/química , Estrutura Molecular , Paroxetina/química , Rolipram/química , EstereoisomerismoRESUMO
Short and efficient enantioselective syntheses of (-)-paroxetine and (+)-laccarin are described based on the highly stereospecific cleavage of C(3)-substituted 1,3-cyclic sulfamidates.
Assuntos
Indóis/síntese química , Paroxetina/síntese química , Piperidinas/síntese química , Estereoisomerismo , Ácidos Sulfônicos/químicaRESUMO
[reaction: see text] The Heck arylation of acyclic- and cyclic-substituted acrylates using several arenediazonium tetrafluoroborates was investigated. Arylations were carried out under aerobic, ligand-free conditions to provide the corresponding substituted acrylates in moderate to high isolated yields. Heck arylations were usually completed in less than 2 h in refluxing methanol. The aza-endocyclic acrylate derivative 11a was converted into the antidepressant drug (+/-)-paroxetine in a concise new route in good overall yield.
Assuntos
Antidepressivos/síntese química , Boratos/química , Compostos de Diazônio/química , Paroxetina/síntese química , Antidepressivos/farmacologia , Catálise , Estrutura Molecular , Paroxetina/farmacologia , EstereoisomerismoAssuntos
Aldeídos/química , Lactamas/síntese química , Lactonas/síntese química , Malonatos/química , Paroxetina/síntese química , Antidepressivos/química , Catálise , Cristalografia por Raios X , Lactamas/química , Lactonas/química , Modelos Moleculares , Estrutura Molecular , Paroxetina/química , Solventes , EstereoisomerismoRESUMO
[reaction: see text] An intermolecular aza-double Michael reaction leading to functionalized piperidin-2-ones from simple starting materials has been developed. The method allows alpha,beta-unsaturated amides to be used as a synthon of the piperidine nucleus. In addition, the utility of this methodology is demonstrated by its application to a formal synthesis of the indolo[2,3-a]quinolizidine alkaloids, (+/-)-deplancheine, (+/-)-tacamonine, and the antidepressant paroxetine.
Assuntos
Amidas/química , Alcaloides Indólicos/síntese química , Paroxetina/síntese química , Antidepressivos de Segunda Geração/síntese química , Alcaloides Indólicos/química , Paroxetina/química , Piperidinas/síntese química , EstereoisomerismoRESUMO
The synthesis of optically active substituted piperidines has been achieved by using four different methodologies. The first one is an intramolecular nucleophilic displacement of activated alcohol moieties that was used to build up the piperidine ring of (-)-prosophylline and (-)-slaframine, and the second one is a ring-closing metathesis of unsaturated amines which was employed in the synthesis of (+)-sedamine and 4a,5-dihydrostreptazoline. The third methodology is the alpha-functionalization of N-Boc piperidines which was particularly useful in the synthesis of argatroban, and the fourth one is a ring expansion of prolinols to 3-chloropiperidines or 3-hydroxypiperidines which was utilized to synthesize (-)-paroxetine, (-)-pseudoconhydrine, the piperidine ring of (-)-velbanamine and (+)-zamifenacin.
Assuntos
Piperidinas/síntese química , Alcaloides/síntese química , Alcaloides/química , Arginina/análogos & derivados , Química/métodos , Dioxóis/síntese química , Dioxóis/química , Paroxetina/síntese química , Paroxetina/química , Ácidos Pipecólicos/síntese química , Ácidos Pipecólicos/química , Piperidinas/química , Pirrolidinas/síntese química , Pirrolidinas/química , SulfonamidasRESUMO
The structural requirements for high affinity at the serotonin transporter (5-HTT) have been investigated through the preparation of rigid paroxetine analogs. Tropane-derived analogs (4a-i) of paroxetine (2) were designed and synthesized as potential inhibitors of serotonin reuptake based on the structural and biological similarity between the two compound classes. Overall, the affinity of tropane-derived analogs at the 5-HTT was found to be at least an order of magnitude lower than that of paroxetine and ranged from 2-400nM. The reduced affinity at the 5-HTT may be attributed to the inability of the rigid tropane-derived analogs to adopt conformations favored by the 5-HTT. Within the series of tropane analogs, the 2beta,3beta- and 2beta,3alpha-isomers, 4a and 4d, were the most potent at the DAT and NET and are also significantly more potent than paroxetine (2) suggesting that their reduced conformational flexibility maximizes residence time in conformations favored by these transporters. Examination of the previously published preparation and structural assignment of 4a by additional NMR and X-ray crystallographic data has established that nucleophilic addition to the intermediate 2beta-methanesulfonyloxymethyl-3beta-(4-fluorophenyl)tropane unexpectedly provided the aza-bicyclo[3.2.2]nonane derivative 10a.
Assuntos
Alcanos/química , Compostos Aza/química , Compostos Bicíclicos com Pontes/química , Paroxetina/química , Paroxetina/síntese química , Tropanos/química , Alcanos/síntese química , Compostos Aza/síntese química , Compostos Bicíclicos com Pontes/síntese química , Cristalografia por Raios X , Ligantes , Espectroscopia de Ressonância Magnética , Glicoproteínas de Membrana/antagonistas & inibidores , Moduladores de Transporte de Membrana , Proteínas de Membrana Transportadoras/antagonistas & inibidores , Modelos Moleculares , Conformação Molecular , Proteínas do Tecido Nervoso/antagonistas & inibidores , Paroxetina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Serotonina , Relação Estrutura-Atividade , Tropanos/síntese química , Tropanos/farmacologiaRESUMO
Paroxetine is a well-known antidepressant, used worldwide in therapeutics. In comparison with other selective serotonin reuptake inhibitors, it exhibits the highest activity in serotonin reuptake inhibition. Paroxetine metabolism initially involves its demethylenation to the catechol intermediate, which is then O-methylated at positions C3 or C4. Herein, the chemistry resulting in the syntheses of these metabolites (3S,4R)-4-(4-fluorophenyl)-3-(hydroxymethyl)piperidine and (3S,4R)-4-(4-fluorophenyl)-3-(4-hydroxy-3-methoxyphenoxymethyl)piperidine is described starting from the common intermediate (3S,4R)-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine. Additionally, the common intermediate was used to synthesize paroxetine, which had the same structure and stereochemistry as commercial paroxetine, thereby confirming our synthetic route.
Assuntos
Antidepressivos de Segunda Geração/metabolismo , Paroxetina/síntese química , Paroxetina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/metabolismo , Animais , Humanos , Paroxetina/química , Ratos , EstereoisomerismoRESUMO
A new chemoenzymatic method for the preparation of an intermediate of (-)-Paroxetine is reported. Cyclic anhydrides are used as acylating agents in the lipase-catalyzed esterification of trans-4-(4'-fluorophenyl)-3-hydroxymethyl-N-phenyloxycarbonylpiperidine in organic solvents. The best enantioselectivities are obtained with two different lipases from Candida antarctica. These two lipases show opposite stereochemical preference in these processes, so that both enantiomers can be obtained in their optically pure forms. The (3S,4R) isomer is an intermediate for the synthesis of (-)-Paroxetine.
Assuntos
Anidridos/metabolismo , Candida/enzimologia , Lipase/metabolismo , Paroxetina/síntese química , Acetilação , Anidridos/química , Catálise , Esterificação , Indicadores e Reagentes , Paroxetina/análogos & derivados , Piperidinas/química , Solventes , EstereoisomerismoRESUMO
A dramatic acceleration of the enantioselective copper-catalyzed conjugate reduction of alpha,beta-unsaturated lactones, lactams, and esters is reported upon addition of alcohol additives. Good to excellent yields and enantioselectivities were realized using a catalyst generated in situ from CuCl(2).H(2)O, t-BuONa, p-tol-BINAP, and PMHS, and this methodology was applied to the synthesis of (-)-Paroxetine.
Assuntos
Lactamas/química , Lactonas/química , Paroxetina/química , Paroxetina/síntese química , Álcoois/química , Catálise , Conformação Molecular , Estrutura Molecular , OxirreduçãoRESUMO
Two-fold crystallization of trans-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine enriched in (+)-enantiomer 3b (65.2-79.4% ee) yielded the racemate that crystallized out of solution and the mother liquor highly enriched in 3b (95.4-97.6% ee). Differences in infrared spectra of the racemate and enantiomer proved that the racemate consists of a racemic compound. Furthermore, solution NMR spectra of enriched 3b showed differentiation of some resonances (self-induced non-equivalence), which indicated strong diastereomeric interactions between solutes in apolar solvent. The enantiomeric composition of products was determined by NMR spectroscopy in the presence of R-Mosher acid.