24228-40-8

Basic information

• Product Name: Ethyl 1-benzylpiperidine-4-carboxylate
• Synonyms: RARECHEM AH CK 0037;AKOS 225-01;1-BENZYLPIPERIDINE-4-CARBOXYLIC ACID ETHYL ESTER;ETHYL 1-BENZYL-4-PIPERIDINECARBOXYLATE;ETHYL 1-BENZYLPIPERIDINE-4-CARBOXYLATE;BUTTPARK 33\04-91;Benzylpiperidinecarboxylicacidethylester;N-Benzyl-4-cabethoxypiperidine
• CAS NO: 24228-40-8
• Molecular Formula: C₁₅H₂₁NO₂
• Molecular Weight: 247.33
• EINECS: 246-094-9
• Product Categories: Piperidine;Heterocyclic Compounds;Aromatics;Heterocycles
• Mol File: 24228-40-8.mol

Chemical Properties

• Melting Point: 120-119℃
• Boiling Point: 122°C (0.5 mmHg)
• Flash Point: >110℃
• Appearance: colourless oil
• Density: 1.037 g/mL at 25 °C
• Vapor Pressure: 0.000208mmHg at 25°C
• Refractive Index: 1.5120-1.5160
• Storage Temp.: Inert atmosphere,Room Temperature
• PKA: 7.93±0.10(Predicted)
• CAS DataBase Reference: Ethyl 1-benzylpiperidine-4-carboxylate(CAS DataBase Reference)
• NIST Chemistry Reference: Ethyl 1-benzylpiperidine-4-carboxylate(24228-40-8)
• EPA Substance Registry System: Ethyl 1-benzylpiperidine-4-carboxylate(24228-40-8)

Safety Data

• Hazard Codes: Xi,T
• Statements: 36/37/38-25
• Safety Statements: 24/25-45
• RIDADR: UN 2810 6.1 / PGIII
• Hazardous Substances Data: 24228-40-8(Hazardous Substances Data)

Usage

Synthesis

Ethyl isonipecotate (50 g, 0.31 mol) was dissolved in toluene (150 mL) in a round bottom flask, charged with potassium carbonate (60 g, 0.43 mol) and stirred for 15 min. Benzyl chloride (42 g, 0.31 mol) was charged and the reaction mass was refluxed for 4 h at 100 °C. Upon completion of the reaction as marked by TLC (hexane:ethyl acetate; 2:1), the reaction mass was cooled to room temperature and quenched with water (100 mL), stirred and the organic phase was separated. The aqueous phase was again extracted with toluene (100 mL). Combined organic phase was washed twice with saturated brine solution (50 mL). Remove toluene in vacuo to obtain Ethyl N-benzylpiperidine-4-carboxylate ( 6.97 g, 91 %) as a yellow liquid.

Chemical Properties

Colourless Oil

InChI:InChI=1/C15H21NO2/c1-2-18-15(17)14-8-10-16(11-9-14)12-13-6-4-3-5-7-13/h3-7,14H,2,8-12H2,1H3

Upstream product

• 100-44-7 benzyl chloride 
• 100-39-0 benzyl bromide 
• 136081-74-8 ethyl 1-benzoyl-4-piperidine-carboxylate 
• 1126-09-6 4-carbethoxypiperidine 
• 100-51-6 benzyl alcohol 
• 23019-61-6 1-benzyl-4-(ethoxycarbonyl)pyridin-1-ium bromide 
• 100-52-7 benzaldehyde 

Downstream Products

• 40117-97-3 8-benzyl-8-aza-2-oxaspiro<4.5>decan-1-one 
• 67686-01-5 1-benzyl-4-piperidinemethanol 
• 74045-91-3 1-benzyl-piperidine-4-carboxylic acid hydrazide 
• 111627-25-9 α,α-bis-(4-fluorophenyl)-1-(phenylmethyl)-4-piperidinemethanol 
• 10315-07-8 N-benzylpiperidine-4-carboxylic acid 
• 857680-62-7 rac-8-benzyl-4-phenyl-2,8-diazaspiro[4.5]decan-1-one 
• 857680-61-6 rac-4-(2-amino-1-phenylethyl)-1-benzylpiperidine-4-carboxylic acid ethyl ester 
• 79139-61-0 1-phenyl-3,8-diazaspiro<4,5>decanone-4 
• 139228-33-4 4-((2-cyano-2-phenyl)acetyl)-N-benzylpiperidine 
• 1133285-98-9 ethyl 1-benzyl-4-(4-methoxybenzyl)piperidine-4-carboxylate 
• 76876-70-5 N-benzyl-4-(2-hydroxyethyl)piperidine 
• 857680-60-5 rac-1-benzyl-4-(2-nitro-1-phenylethyl)piperidine-4-carboxylic acid ethyl ester 
• 22065-85-6 N-benzyl-4-formylpiperidine 
• 136709-51-8 ethyl 1-benzyl-4-hydrazino>piperidine-4-carboxylate 

Relevant articles and documents

First synthesis of racemic trans propargylamino-donepezil, a pleiotrope agent able to both inhibit AChE and MAO-B, with potential interest against Alzheimer’s disease

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease towards which pleiotropic approach using Multi-Target Directed Ligands is nowadays recognized as probably convenient. Among the numerous targets which are today validated against AD, acetylcholinesterase (ACh) and Monoamine Oxidase-B (MAO-B) appear as particularly convincing, especially if displayed by a sole agent such as ladostigil, currently in clinical trial in AD. Considering these results, we wanted to take benefit of the structural analogy lying in donepezil (DPZ) and rasagiline, two indane derivatives marketed as AChE and MAO-B inhibitors, respectively, and to propose the synthesis and the preliminary in vitro biological characterization of a structural compromise between these two compounds, we called propargylaminodonepezil (PADPZ). The synthesis of racemic trans PADPZ was achieved and its biological evaluation established its inhibitory activities towards both (h)AChE (IC50 = 0.4 μM) and (h)MAO-B (IC50 = 6.4 μM).

Novel 1,2,4-oxadiazole derivatives as selective butyrylcholinesterase inhibitors: Design, synthesis, and biological evaluation

Alzheimer’s disease (AD) is a progressive mental disorder that brings a huge economic burden to the healthcare systems. During this illness, acetylcholine levels in the cholinergic systems gradually diminish, which results in severe memory loss and cognitive impairments. Moreover, Butyrylcholinesterase (BuChE) enzyme participates in cholinergic neurotransmission regulation by playing a prominent role in the latter phase of AD. In this study, based on donepezil, which is an effective acetylcholinesterase (AChE) inhibitor, a series of 1,2,4-oxadiazole compounds were designed, synthesized and their inhibitory activities towards AChE and BuChE enzymes were evaluated. Some structures exhibited a higher selectivity rate towards BuChE in comparison to donepezil. Notably, compound 6n with an IC50 value of 5.07 μM and an SI ratio greater than 19.72 showed the highest potency and selectivity towards BuChE enzyme. The docking result revealed that compound 6n properly fitted the active site pocket of BuChE enzyme, and formed desirable lipophilic interactions and hydrogen bonds. Moreover, according to in silico ADME studies, these compounds have proper potential for being developed as new oral anti-Alzheimer’s agents.

Basic Anion-Exchange Resin-Catalyzed Aldol Condensation of Aromatic Ketones with Aldehydes in Continuous Flow

A general method for the aldol condensation of aromatic ketones with aldehydes was developed under continuous-flow conditions using a commercially available, strongly basic anion-exchange resin (A26) as catalyst. This procedure, in addition to exhibiting a wide substrate scope, promoted carbon-carbon bond formation under mild conditions using a quasi-stoichiometric ratio of starting reagents with good to excellent yields, thereby forming a limited amount of waste and allowing the process to be applied to sequential-flow systems. A proof of concept was developed in the first fully heterogeneously catalyzed two-step flow synthesis of donepezil, which is a blockbuster commercial anti-Alzheimer's drug.

Fast continuous alcohol amination employing a hydrogen borrowing protocol

A continuous flow method for the direct conversion of alcohols to amines via a hydrogen borrowing approach is reported. The method utilises a low loading (0.5%) of a commercial catalyst system ([Ru(p-cymene)Cl2]2 and DPEPhos), reagent grade solvent and is selective for primary alcohols. Successful methylation of amines using methanol and the direct dimethylamination of alcohols using commercial dimethylamine solution are reported. The synthesis of two pharmaceutical agents Piribedil (5) and Buspirone (25) were accomplished in good yields employing these new methods.

Novel N-benzylpiperidine carboxamide derivatives as potential cholinesterase inhibitors for the treatment of Alzheimer's disease

A series of fifteen acetylcholinesterase inhibitors were designed and synthesised based upon the previously identified lead compound 5,6-dimethoxy-1-oxo-2,3-dihydro-1H-inden-2-yl 1-benzylpiperidine-4-carboxylate (5) which showed good inhibitory activity (IC50 0.03 ± 0.07 μM) against acetylcholinesterase. A series of compounds were prepared wherein the ester linker in the original lead compound was exchanged for a more metabolically stable amide linker and the indanone moiety was exchanged for a range of aryl and aromatic heterocycles. The two most active analogues 1-benzyl-N-(5,6-dimethoxy-8H-indeno[1,2-d]thiazol-2-yl)piperidine-4-carboxamide (28) and 1-benzyl-N-(1-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) piperidine-4-carboxamide (20) afforded in vitro IC50 values of 0.41 ± 1.25 and 5.94 ± 1.08 μM, respectively. In silico screening predicts that 20 will be a blood brain-barrier permeant, and molecular dynamic simulations are indicative of a close correlation between the binding of 20 and the Food and Drug Administration-approved cholinesterase inhibitor donepezil (1).

Synthesis, bioactivity and molecular modeling studies on potential anti-Alzheimer piperidinehydrazide-hydrazones

A group of N-benzylpiperidine-3/4-carbohydrazide-hydrazones were designed, synthesized and evaluated for acetylcholinesterase (AChE), butyrylcholinesterase (BuChE)activities, Aβ42 self-aggregation inhibitory potentials, and antioxidant capacities, in vitro. All of the compounds displayed eeAChE and huAChE inhibitory activity in a range of IC50 = 5.68–11.35 μM and IC50 = 8.80–74.40 μM, respectively and most of the compounds exhibited good to moderate inhibitory activity on BuChE enzyme. Kinetic analysis and molecular modeling studies were also performed for the most potent compounds (1g and 1j). Not only the molecular modeling studies but also the kinetic analysis suggested that these compounds might be able to interact with the catalytic active site (CAS)and the peripheral anionic site (PAS)of the enzymes. In the light of the results, compound 1g and compound 1j may be suggested as lead compounds for multifunctional therapy of AD.

Direct Reductive Amination of Carbonyl Compounds with H2 Using Heterogeneous Catalysts in Continuous Flow as an Alternative to N-Alkylation with Alkyl Halides

A general continuous-flow procedure for direct reductive amination of secondary and primary amines with aromatic and aliphatic aldehydes as well as ketones is reported. The use of hydrogen gas and commercially available Pt/C as a heterogeneous catalyst is a key. In addition to exhibiting an excellent functional group tolerance, this method allows the fast formation of C?N bonds without production of any hazardous chemical waste. Applications to the synthesis of key intermediates toward active pharmaceutical ingredients (Donepezil and Arformoterol/Tamsulosin) are also described. (Figure presented.).

4,5-dimethoxy-2-nitrobenzohydrazides and 1-(1-benzylpiperidin-4-yl)ethan-1-ones as potential antioxidant/cholinergic endowed small molecule leads

The objective of this research is to generate leads for developing our ultimate poly-active molecules with utility in central nervous system (CNS) diseases. Indeed, poly-active molecules capable of mitigating brain free radical damage while enhancing acetylcholine signaling (via cholinesterase inhibition) are still being sought for combating Alzheimer’s disease (AD). We differentiate “poly-active” agents from “multi-target” ones by defining them as single molecular entities designed to target only specific contributory synergistic pharmacologies in a disease. For instance, in AD, free radicals either initiate or act in synergy with other pharmacologies, leading to disease worsening. For this preliminary report, a total of 14 (i.e., 4,5-dimethoxy-2-nitrobenzohydrazide plus 1-(1-benzylpiperidin-4-yl)ethan-1-one) derivatives were synthesized and screened, in silico and in vitro, for their ability to scavenge free radicals and inhibit acetylcholinesterase (AChE)/butyrylcholinesterase (BuChE) enzymes. Overall, six derivatives (4a, 4d, 4e, 4f, 4g, 9b) exhibited potent (>30%) antioxidant properties in the oxygen radical absorbance capacity (ORAC) assay. The antioxidant values were either comparable or more potent than the comparator molecules (ascorbic acid, resveratrol, and trolox). Only three compounds (4d, 9a, 9c) yielded modest AChE/BuChE inhibitions (>10%). Please note that a SciFinder substance data base search confirmed that most of the compounds reported herein are new, except 9a and 9c which are also commercially available.

NOVEL MODULATORS OF THE 5-HYDROXYTRYPTAMINE RECEPTOR 7 AND THEIR METHOD OF USE

Pharmaceutical compositions of the invention comprise functionalized lactone derivatives having a disease-modifying action in the treatment of diseases associated with dysregulation of 5-hydroxytryptamine receptor 7 activity.

Mitsunobu Reaction Using Basic Amines as Pronucleophiles

A novel protocol for extending the scope of the Mitsunobu reaction to include amine nucleophiles to form C-N bonds through the utilization of N-heterocyclic phosphine-butane (NHP-butane) has been developed. Both aliphatic alcohols and benzyl alcohols are suitable substrates for C-N bond construction. Various acidic nucleophiles such as benzoic acids, phenols, thiophenol, and secondary sulfonamide also provide the desired products of esters, ethers, thioether, and tertiary sulfonamide with 43-93% yields. Importantly, C-N bond-containing pharmaceuticals, Piribedil and Cinnarizine, have been synthesized in one step from the commercial amines under this Mitsunobu reaction system.