Recent advances in the synthesis of piperidones and piperidines

Weintraub, Philip M.; Sabol, Jeffrey S.; Kane, John M.; Borcherding, David R.

doi:10.1016/s0040-4020(03)00295-3

Cited by 447 publications

(97 citation statements)

References 391 publications

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“…of compounds synthesized was confirmed by physicochemical investigations.1 Н NMR spectra of piperidinones IIIа-IIIk contain a single set of doublets of atom Н 5 in the region 4.40-5.08 ppm with the coupling constant 3.0-3 6. Hz and a multiplet of atom Н 4 in the region 3.55-4.33 ppm indicating their axial-equatorial location and proving the diastereoselective character of the arylsulfanyllactamization.…”

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confidence: 65%

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Intramolecular electrophilic cyclization of functional derivatives of unsaturated Compounds: I. Synthesis of 5-arylsulfanyl-6-phenylpiperidin-2-ones from cinnamylacetamides and arylsulfenyl chlorides

et al. 2011

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Sterically nonhindered N-alkyl(aryl)amides of cinnamylacetic acid in the reaction with phenyl(4-tolyl)sulfenyl chlorides in acetic acid in the presence of lithium perchlorate undergo a selective cyclization into 5-arylsulfanyl-6-phenylpiperidin-2-ones. Under similar conditions the reaction with arylsulfenyl chlorides of amides containing bulky substituents at the nitrogen atom resulted in 5-arylsulfanyl-6-phenyltetrahydropyran-2-iminium perchlorates, which by treatment with aqueous ethanol were converted into the corresponding derivatives of pyran-2-ones.Piperidin-2-ones are compounds with unique biological characteristics [1][2][3]. They underlie the preparation of piperidine systems included into the composition of many alkaloids and physiologically active substances [4][5][6]. Therefore nowadays new substituted piperidones are synthesized [7][8][9][10][11].The introduction of sulfanyl groups in the piperidone ring can essentially modify the chemical and biological characteristics. In particular, among the sulfanyl derivatives of piperidin-2-oneов (δ-lactams) compounds were found capable to inhibit the activation of p38MAP-kinase [12], a very important quality both for prophylactic and treatment of infl ammation and autoimmune diseases, rheumatoid arthritis, infectious diseases, atherosclerosis, and pancreatitis.Although there are well developed approaches to nonfunctional piperidones, the methods of the synthesis of 5-alkyl(aryl)sulfanyl-substituted piperidones [12][13][14] are multistage and apply diffi cultly accessible and toxic reagents.Considering the synthetic potential of the reaction of electrophilic cyclization of unsaturated amides [15] and aiming at the development of the synthesis of 5-arylsulfanylpiperidin-2-ones we examined in detail the arylsulfenylation of cinnamylacetamides Iа-Ig. These compounds react with arylsulfenyl chlorides IIа-IIc at room temperature in acetic acid in the presence of an equimolar amount of LiClO 4 as "dopping-additive" [16,17] forming cyclization products whose structure is controlled mainly by the steric parameters of the substituent at the nitrogen atom of the nucleophilic substrate and the electronic characteristics of the electrophilic reagent.Amide with sterically nonhindered aliphatic (Ib, Ic) or aromatic (If, Ig) substituents react with phenyl-or 4-tolylsulfenyl chlorides (IIа, IIb) giving 5-arylsulfanyl-6-phenylpiperidones IIIb-IIIg, IIIi, IIIj (path а) in 81-95% yield (Scheme 1). In event of 4-nitrophenylsulfenyl chloride a decreased selectivity of reaction is observed due to the nucleophilic involvement of the oxygen atom of the iniial amides (path b), and as a result forms a mixture of compounds III and IV in the ratio 5 : 1 from amide If and 4 : 1 from amide Ig.In the reaction of unsubstituted amide Ia with 4-tolylsulfenyl chloride (IIb) lactam IIIa was isolated.

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“…They underlie the preparation of piperidine systems included into the composition of many alkaloids and physiologically active substances [4][5][6]. Therefore nowadays new substituted piperidones are synthesized [7][8][9][10][11].…”

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confidence: 99%

Intramolecular electrophilic cyclization of functional derivatives of unsaturated Compounds: I. Synthesis of 5-arylsulfanyl-6-phenylpiperidin-2-ones from cinnamylacetamides and arylsulfenyl chlorides

et al. 2011

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“…4,5 Alkylation of 2-bromo-5-(hydroxymethyl)phenol 14 with 15 proceeded efficiently in N-methyl pyrrolidone with powdered potassium carbonate as a base. When 1-chloro-2-methoxyethane was used instead of the bromide, the reaction did not complete.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

A Second Generation Synthesis of Benzyl Piperidine Derivatives: A Key Intermediate for the Preparation of SERT/5-HT_1A Dual Inhibitor

Ueno

Terauchi

et al. 2015

Org. Process Res. Dev.

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A second generation process for benzyl piperidine 10 is described. By the use of a Horner−Wadsworth−Emmons reaction and selective hydrogenation with Pt/C in ethyl acetate, 2-bromo-5-(hydroxymethyl) phenol 14 was efficiently converted to the compound 10 on a 5 kg scale. A small amount of water was found to be critical to complete the selective hydrogenation with low levels of debrominated byproduct 15. Impurities of the compound 10 were controlled by limiting the quality of 2-bromo-5-(hydroxymethyl) phenol 14 and 1-bromo-2-methoxyethane 15. ■ INTRODUCTIONIncreasing numbers of patients are affected by neuropsychiatric disorders such as schizophrenia, bipolar disorder, and depression. Selective serotonin reuptake inhibitors (SSRIs) such as escitalopram and paroxetine are commonly used for the treatment of depressions. However, the slow onset of the action is an issue. It has been reported that the combination of SSRIs with 5-HT 1A antagonists can accelerate the onset action of SSRIs, 1 so we have started a program to explore such new drug candidates. We were therefore pleased to find that the novel benzyl piperidine compound connected to a chromone core (1, Scheme 1) was a promising candidate as it is both a dual serotonin transport inhibitor and a 5-HT 1A inhibitor. 2 In the early stages of the clinical development, the intermediate 2 was manufactured by the route shown in Scheme 2. Nucleophilic addition of 2-methoxyethanol to 4-bromo-3-fluorobenzoic acid 4 gave 5 in 87% yield. A diborane reduction of the carboxylic acid 5 gave the benzyl alcohol 6, which was sufficiently pure for the next step. Bromination with 47% aqueous HBr/toluene system, followed by treatment with triphenyl phosphine, precipitated the phosphonium salt 8 in 78% yield over 3 steps. A Wittig reaction of 8 with N-Boc piperidone in 2-propanol in the presence of K 2 CO 3 gave a clean conversion to 9, which was hydrogenated with Rh/C in ethyl acetate to give 10, together with the debrominated 18. Refluxing 10 in 2-propanol with concentrated hydrochloric acid removed the Boc group, and after recrystallization, the hydrochloride of 2 was obtained in 87% yield over three steps. The overall yield of the hydrochloride of 2 from 4-bromo-3-fluorobenzoic acid 4 was 58%.The route was successfully scaled up to supply 40 kg of API for early clinical trials. However, the route needed to be improved for future material supply due to the following three problems:i. In the first step, hydrogen fluoride is formed at acidic workup. ii. After the Wittig reaction, silica gel column chromatography was needed to remove phosphine oxide.iii. At the hydrogenation step, 40 wt % (vs starting material 9) of expensive 10% Rh/C (50% wet) was needed for full conversion. ■ RESULTS AND DISCUSSIONTo address these problems, new routes were investigated. A potential second generation synthesis was found as shown in Scheme 3. We were delighted to find that the selective decarbonylative Heck reaction 3 of the acid chloride 11 and the methylene piperidine 12 gave 13, which was then hy...

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“…The imine moieties are important intermediates and versatile starting materials for the synthesis of chiral amines [23,24], pyrimidine derivatives [25], phenylhydrazones [26,27], Mannich bases [28], indoles [29], quinoxalines [30], imidazoles [31], amino triphenylmethanes [32], Michael adducts [33], allyl products [34], optically active α-alkyl aldehydes [35,36] by hydrogenation [37], nucleophilic addition with organometallics [38] and cycloaddition reaction [39]. Many reagents have been used for the synthesis of optically active imines such as solid super acids, K-10 montmorillonite [40,41], Tandam catalysts [42], MnO 2 [43], CaO [44], ZnCl 2 [23,24], MgSO 4 -PPTS [26,27], alumina [45], Ti(OR) 4 [46], CuCl [47], MCM-41-SO 3 nanocatalyst [48], P 2 O 5 -SiO 2 [49] promoted by microwave irradiation [43], Cinchona alkaloid-thiourea [50], Infrared [51,52] and ultrasound radiation [53].…”

Section: Introductionmentioning

confidence: 99%

Solvent-Free Synthesis and Spectral Linearity of Some (E)-2-(substituted benzylideneamino)-N-(3-chloro-4-fluorophenyl)-hexahydro-2<i>H</i>-cyclopenta[b]thiophene-3-carboxamides

Thirunarayanan

Sekar²

2013

ILCPA

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Some(E)-2-(substituted benzylideneamino)-N-(3-chloro-4-fluorophenyl)-hexahydro-2H-cyclopenta [b]thiophene-3-carboxamide derivatives have been synthesized by SiO 2 :H 3 PO 4 catalyzed solventfree condensation of 2-amino-N-(3-chloro-4-fluorophenyl)-hexahydro-2H-cyclopenta [b]thiophene-3-carboxamide and various substituted benzaldehydes in microwave irradiation. The yield of the iminecarboximido derivatives has been found to be more than 85 %. The purity of all imine-carboximido derivatives has been checked using their physical constants and spectral data. The spectral data of the iminecarboximido derivatives such as infrared ν (cm -1 ) of CO, NH, C-N, C-Cl, C-F, C=N, and the NMR chemical shifts (δ, ppm) of NH, CH, CO and C=N have been correlated with Hammett substituent constants, F and R parameters. From the results of statistical analysis, the effects of substituent on the above spectral group absorptions have been discussed.

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Recent advances in the synthesis of piperidones and piperidines

Cited by 447 publications

References 391 publications

Intramolecular electrophilic cyclization of functional derivatives of unsaturated Compounds: I. Synthesis of 5-arylsulfanyl-6-phenylpiperidin-2-ones from cinnamylacetamides and arylsulfenyl chlorides

Intramolecular electrophilic cyclization of functional derivatives of unsaturated Compounds: I. Synthesis of 5-arylsulfanyl-6-phenylpiperidin-2-ones from cinnamylacetamides and arylsulfenyl chlorides

A Second Generation Synthesis of Benzyl Piperidine Derivatives: A Key Intermediate for the Preparation of SERT/5-HT_1A Dual Inhibitor

Solvent-Free Synthesis and Spectral Linearity of Some (E)-2-(substituted benzylideneamino)-N-(3-chloro-4-fluorophenyl)-hexahydro-2<i>H</i>-cyclopenta[b]thiophene-3-carboxamides

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Recent advances in the synthesis of piperidones and piperidines

Cited by 447 publications

References 391 publications

Intramolecular electrophilic cyclization of functional derivatives of unsaturated Compounds: I. Synthesis of 5-arylsulfanyl-6-phenylpiperidin-2-ones from cinnamylacetamides and arylsulfenyl chlorides

Intramolecular electrophilic cyclization of functional derivatives of unsaturated Compounds: I. Synthesis of 5-arylsulfanyl-6-phenylpiperidin-2-ones from cinnamylacetamides and arylsulfenyl chlorides

A Second Generation Synthesis of Benzyl Piperidine Derivatives: A Key Intermediate for the Preparation of SERT/5-HT1A Dual Inhibitor

Solvent-Free Synthesis and Spectral Linearity of Some (E)-2-(substituted benzylideneamino)-N-(3-chloro-4-fluorophenyl)-hexahydro-2<i>H</i>-cyclopenta[b]thiophene-3-carboxamides

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A Second Generation Synthesis of Benzyl Piperidine Derivatives: A Key Intermediate for the Preparation of SERT/5-HT_1A Dual Inhibitor