22065-85-6

Basic information

• Product Name: N-Benzylpiperidine-4-carboxaldehyde
• Synonyms: 1-(Phenylmethyl)-4-piperidinecarbaldehyde;1-Benzyl-4-piperidinecarboxaldehyde,1-Benzyl-4-formylpiperidine;N-Benzylpiperidine-4-carboxyaldehyde;N-Benzy-4-Piperidine Carboxaldehyde;1-Benzyl-4-formylpiperidine, [(4-Formylpiperidin-1-yl)methyl]benzene;1-Benzylisonipecotaldehyde;N-Benzylpiperidine-4-carboxaldehyde 95%;N-BENZYLPIPERIDINE-4-CARBOXALDEHYDE
• CAS NO: 22065-85-6
• Molecular Formula: C₁₃H₁₇NO
• Molecular Weight: 203.28
• EINECS: 244-757-7
• Product Categories: Heterocycles;Building Blocks;Heterocyclic Building Blocks;Piperidines;pharmacetical;Alcohol Aldehyde & acid series;Piperidine;(intermediate of donepezil);Aromatics
• Mol File: 22065-85-6.mol
• Article Data: 31

Chemical Properties

• Melting Point: 315
• Boiling Point: 315.4 °C 760 mm Hg
• Flash Point: >230 °F
• Appearance: Clear colorless to pale yellow/Liquid
• Density: 1.026 g/mL at 25 °C
• Vapor Pressure: 0.00119mmHg at 25°C
• Refractive Index: n20/D 1.537
• Storage Temp.: Inert atmosphere,Store in freezer, under -20°C
• Solubility: Acetone (Slightly), Chloroform (Slightly), Dichloromethane (Slightly), DMSO (Sli
• PKA: 8.04±0.10(Predicted)
• Sensitive: Air Sensitive
• CAS DataBase Reference: N-Benzylpiperidine-4-carboxaldehyde(CAS DataBase Reference)
• NIST Chemistry Reference: N-Benzylpiperidine-4-carboxaldehyde(22065-85-6)
• EPA Substance Registry System: N-Benzylpiperidine-4-carboxaldehyde(22065-85-6)

Safety Data

• Hazard Codes: T
• Statements: 25-41
• Safety Statements: 26-28-36/37/39
• RIDADR: UN 2810 6.1/PG 3
• WGK Germany: 3
• HazardClass: IRRITANT
• PackingGroup: Ⅲ
• Hazardous Substances Data: 22065-85-6(Hazardous Substances Data)

Usage

Synthesis

A round bottom flask was charged with oxalyl chloride (16.2 g, 0.12 mol), dichloromethane (150 mL) and anhydrous dimethyl sulfoxide (20 mL). Stir the reaction mixture mass in a cryo bath at -70 °C for 15 min. The resulting mixture is charged dropwise with N-benzyl piperidine alcohol 3 (20 g, 0.097 mol), along with triethylamine (24.6 g, 0.24 mol) and continued stirring for the next 15 min. After that, the mass is allowed to attain room temperature overnight, then diluted with dichloromethane (100 mL) and quenched with cold water. The organic layer was washed subsequently with 5 % HCl solution, brine solution, 5 % sodium bicarbonate solution and dried over sodium sulfate. Toluene was removed in vacuo to afford N-Benzylpiperidine-4-carboxaldehyde (19.2 g, 96 %).

Chemical Properties

Colorless Oil

Uses

Reactant for:Stereospecific allylic alkylationReactions of Grignard reagents with carbonyl compoundsFluorodenitrations and nitrodehalogenations for labeled PET ligands and fluoropharmaceuticalsSelective α1 receptor antagonistsReactant for synthesis of:DonepezilMCH-R1 antagonists

InChI:InChI=1/C13H17NO/c15-11-13-6-8-14(9-7-13)10-12-4-2-1-3-5-12/h1-5,11,13H,6-10H2

Synthetic route

1-benzylpiperidine-4-carbonitrile (62718-31-4) → 1-benzyl-4-formylpiperidine (22065-85-6)

Conditions	Yield
Stage #1: 1-benzylpiperidine-4-carbonitrile With diisobutylaluminium hydride In toluene at 0℃; for 1h; Stage #2: With water; sodium hydroxide In methanol; toluene for 0.5h; pH=8; Temperature;	97.5%

1-benzyl-4-piperidinecarboxylic acid methyl ester (10315-06-7) → 1-benzyl-4-formylpiperidine (22065-85-6)

Conditions	Yield
With red-aluminum/morpholine complex In toluene at -5 - 0℃; for 0.5h; Reagent/catalyst; Solvent; Inert atmosphere; Large scale;	96.5%
Multi-step reaction with 2 steps 1: 69.5 percent / LiAlH4 / tetrahydrofuran / 0.5 h / 50 °C 2: 94.3 percent / oxalyl chloride; dimethyl sulfoxide; Et3N / CH2Cl2 / 0.25 h / -55 °C View Scheme
Multi-step reaction with 4 steps 1.1: water; methanol; sodium hydroxide / 2 h / Reflux 2.1: thionyl chloride / 2 h / Reflux 2.2: 0.5 h / Cooling with ice 3.1: thionyl chloride / 5 h / Reflux 4.1: diisobutylaluminium hydride / toluene / 1 h / 0 °C 4.2: 0.5 h / pH 8 View Scheme

1-benzyl-4-piperidinemethanol (67686-01-5) → 1-benzyl-4-formylpiperidine (22065-85-6)

Conditions	Yield
With oxalyl dichloride; dimethyl sulfoxide; triethylamine In dichloromethane at -70 - 20℃; Swern Oxidation;	96%
With oxalyl dichloride; dimethyl sulfoxide; triethylamine In dichloromethane at -55℃; for 0.25h; Swern oxidation;	94.3%
Stage #1: 1-benzyl-4-piperidinemethanol With dimethylsulfide; triethylamine In toluene at -15 - -10℃; Inert atmosphere; Stage #2: With N-chloro-succinimide In toluene	85%

N-benzyl isonipecotic acid ethyl ester (24228-40-8) → 1-benzyl-4-formylpiperidine (22065-85-6)

Conditions	Yield
With diisobutylaluminium hydride In hexane; toluene at -78℃; for 2.5h; Flow reactor;	96%
With Red-ALP-KTB In various solvent(s) at 10℃;	95%
Stage #1: N-benzyl isonipecotic acid ethyl ester With morpholine; diisobutylaluminium hydride In tetrahydrofuran; hexane at 0℃; for 3.16667h; Inert atmosphere; Stage #2: With lithium diisobutylmethoxy aluminum hydride In tetrahydrofuran; hexane at 0℃; for 0.166667h; Inert atmosphere;	94%

pyrrolidine (123-75-1) + N-benzyl isonipecotic acid ethyl ester (24228-40-8) → 1-benzyl-4-formylpiperidine (22065-85-6) + 1-benzyl-4-piperidinemethanol (67686-01-5) + N-benzyl-4-(pyrrolidin-1-ylmethyl)piperidine + N-benzyl-4-(pyrrolidin-1-ylcarbonyl)piperidine

Conditions	Yield
With Red-ALP In various solvent(s) at 20℃; for 2h;	A 95% B n/a C n/a D n/a

1-benzyl-1,2,3,6-tetrahydropyridine-4-carbaldehyde (503544-95-4) → 1-benzyl-4-formylpiperidine (22065-85-6)

Conditions	Yield
With hydrogen; palladium on activated charcoal In methanol at 20℃; for 3h;	90%

1-benzyl-N,N-dimethylpiperidine-4-carboxamide → 1-benzyl-4-formylpiperidine (22065-85-6)

Conditions	Yield
With sodium hydride; sodium iodide In tetrahydrofuran at 60℃; chemoselective reaction;	75%

1-benzyl-4-vinyl-piperidine (42790-44-3) → 1-benzyl-4-formylpiperidine (22065-85-6)

Conditions	Yield
With PYRIMIDINE; sodium periodate; osmium(VIII) oxide In 1,4-dioxane; 2-methyl-propan-1-ol; water at 20℃; for 7h;	74%

C14H16NO3(1-)*Na(1+) → 1-benzyl-4-formylpiperidine (22065-85-6)

Conditions	Yield
Stage #1: C14H16NO3(1-)*Na(1+) With hydrogenchloride; water at 90℃; for 1.5 - 2h; Heating / reflux; Stage #2: With ammonia In water at 15℃; pH=8.5 - 9.0; Product distribution / selectivity;	68%

1-phenylmethyl-4-piperidone (3612-20-2) + diazomethyl-trimethyl-silane (18107-18-1) → 1-benzyl-4-formylpiperidine (22065-85-6)

Conditions	Yield
Stage #1: diazomethyl-trimethyl-silane With n-butyllithium; diisopropylamine In tetrahydrofuran at -78℃; for 1.25h; Stage #2: 1-phenylmethyl-4-piperidone In tetrahydrofuran at -78 - 20℃; for 4h; Heating / reflux;	55%
With N-ethyl-N,N-diisopropylamine; lithium diisopropyl amide

1-benzyl-4-methoxymethyl-piperidine (101775-64-8) → 1-benzyl-4-formylpiperidine (22065-85-6)

Conditions	Yield
Stage #1: 1-benzyl-4-methoxymethyl-piperidine With hydrogenchloride; methanol; water for 3h; Heating / reflux; Stage #2: With sodium hydroxide In water pH=12;	54%

1-Benzyl-4-(methoxymethylidene)-piperidine (120014-33-7) → 1-benzyl-4-formylpiperidine (22065-85-6)

Conditions	Yield
Stage #1: 1-Benzyl-4-(methoxymethylidene)-piperidine With hydrogenchloride In methanol; water for 3h; Heating / reflux; Stage #2: With sodium hydroxide In water pH=12;	54%
With hydrogenchloride; potassium carbonate In tetrahydrofuran
With formic acid In water at 35℃; for 3h; Inert atmosphere; Large scale;	57.7 kg

N-benzyl-1-oxa-6-azaspiro[2,5]-octane (19867-34-6) → 1-benzyl-4-formylpiperidine (22065-85-6)

Conditions	Yield
With magnesium bromide ethyl etherate In benzene at 40℃; for 0.333333h;	17.5 g

1-phenylmethyl-4-piperidone (3612-20-2) → 1-benzyl-4-formylpiperidine (22065-85-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: tetrabutylammonium bromide; NaOH / toluene; H2O / 4 h / 80 °C 2: 17.5 g / magnesium bromide etherate / benzene / 0.33 h / 40 °C View Scheme
Multi-step reaction with 2 steps 1.1: sodium t-butanolate / tetrahydrofuran / 1.5 h / 0 - 5 °C / Inert atmosphere; Large scale 1.2: 1 h / 5 °C / Large scale 2.1: formic acid / water / 3 h / 35 °C / Inert atmosphere; Large scale View Scheme

N-benzyl-2-(4-methylphenylsulfonyl)acetamide (330173-08-5) → 1-benzyl-4-formylpiperidine (22065-85-6)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: NaH / tetrahydrofuran / 0.25 h / 20 °C 1.2: 95 percent / tetrahydrofuran / 5 h / Heating 2.1: 90 percent / AlCl3; LiAlH4 / tetrahydrofuran / 3 h / 20 °C 3.1: 90 percent / HCl / acetone; H2O / 24 h / Heating 4.1: 90 percent / H2 / Pd/C / methanol / 3 h / 20 °C View Scheme

1-benzyl-3-(4-methylphenylsulfonyl)-4-dimethoxymethylpiperidine-2,6-dione → 1-benzyl-4-formylpiperidine (22065-85-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: 90 percent / AlCl3; LiAlH4 / tetrahydrofuran / 3 h / 20 °C 2: 90 percent / HCl / acetone; H2O / 24 h / Heating 3: 90 percent / H2 / Pd/C / methanol / 3 h / 20 °C View Scheme

1-benzyl-4-(dimethoxymethyl)-3-(p-tolylsulfonyl)piperidine → 1-benzyl-4-formylpiperidine (22065-85-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: 90 percent / HCl / acetone; H2O / 24 h / Heating 2: 90 percent / H2 / Pd/C / methanol / 3 h / 20 °C View Scheme

4-carbethoxypiperidine (1126-09-6) → 1-benzyl-4-formylpiperidine (22065-85-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: 93 percent / NaHCO3 / ethanol; H2O / 2 h / 80 °C 2: 95 percent / Red-ALP-KTB / various solvent(s) / 10 °C View Scheme
Multi-step reaction with 3 steps 1: 76 percent / K2CO3 / ethanol / 72 h / Ambient temperature 2: 61 percent / LiAlH4 / tetrahydrofuran / 18 h / Heating 3: 1.) DMSO, (COCl)2, 2.) Et3N / 1.) CH2Cl2, from -65 deg C to -60 deg C, 15 min, 2.) CH2Cl2, from -78 deg C to RT, 6 h View Scheme
Multi-step reaction with 3 steps 1.1: triethylamine / toluene / 10 - 75 °C / Large scale 2.1: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 15 - 30 °C / Large scale 3.1: oxalyl dichloride; dimethyl sulfoxide / dichloromethane / -65 - -45 °C / Large scale 3.2: 0.5 h / -50 - -45 °C / Large scale View Scheme

benzyl chloride (100-44-7) + Fmoc-(S)-leucine bound to Wang resin → 1-benzyl-4-formylpiperidine (22065-85-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: 93 percent / NaHCO3 / ethanol; H2O / 2 h / 80 °C 2: 95 percent / Red-ALP-KTB / various solvent(s) / 10 °C View Scheme

isonipecotic acid (498-94-2) + paraformaldehyde → 1-benzyl-4-formylpiperidine (22065-85-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: 84 percent / SOCl2 / 20 h / 20 °C 2: 79.7 percent / Et3N / CH2Cl2 / 20 °C 3: 69.5 percent / LiAlH4 / tetrahydrofuran / 0.5 h / 50 °C 4: 94.3 percent / oxalyl chloride; dimethyl sulfoxide; Et3N / CH2Cl2 / 0.25 h / -55 °C View Scheme

methyl piperidine-4-carboxylate hydrochloride (7462-86-4) → 1-benzyl-4-formylpiperidine (22065-85-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: 79.7 percent / Et3N / CH2Cl2 / 20 °C 2: 69.5 percent / LiAlH4 / tetrahydrofuran / 0.5 h / 50 °C 3: 94.3 percent / oxalyl chloride; dimethyl sulfoxide; Et3N / CH2Cl2 / 0.25 h / -55 °C View Scheme
Multi-step reaction with 5 steps 1.1: triethylamine / methanol / 6 h / Reflux 2.1: water; methanol; sodium hydroxide / 2 h / Reflux 3.1: thionyl chloride / 2 h / Reflux 3.2: 0.5 h / Cooling with ice 4.1: thionyl chloride / 5 h / Reflux 5.1: diisobutylaluminium hydride / toluene / 1 h / 0 °C 5.2: 0.5 h / pH 8 View Scheme

benzyl bromide (100-39-0) + t-BuOCOCH2-X → 1-benzyl-4-formylpiperidine (22065-85-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: 79.7 percent / Et3N / CH2Cl2 / 20 °C 2: 69.5 percent / LiAlH4 / tetrahydrofuran / 0.5 h / 50 °C 3: 94.3 percent / oxalyl chloride; dimethyl sulfoxide; Et3N / CH2Cl2 / 0.25 h / -55 °C View Scheme

benzyl chloride (100-44-7) + metal → 1-benzyl-4-formylpiperidine (22065-85-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: 76 percent / K2CO3 / ethanol / 72 h / Ambient temperature 2: 61 percent / LiAlH4 / tetrahydrofuran / 18 h / Heating 3: 1.) DMSO, (COCl)2, 2.) Et3N / 1.) CH2Cl2, from -65 deg C to -60 deg C, 15 min, 2.) CH2Cl2, from -78 deg C to RT, 6 h View Scheme

1-phenylmethyl-4-piperidone (3612-20-2) + (methoxymethyl)triphenylphosphonium chloride (4009-98-7) → 1-benzyl-4-formylpiperidine (22065-85-6)

Conditions	Yield
Stage #1: (methoxymethyl)triphenylphosphonium chloride With n-butyllithium In diethyl ether; hexane at 0 - 20℃; for 0.5h; Stage #2: 1-phenylmethyl-4-piperidone In diethyl ether; hexane at 20℃; for 3h; Stage #3: With hydrogenchloride; sodium hydroxide more than 3 stages;

benzyl chloride (100-44-7) → 1-benzyl-4-formylpiperidine (22065-85-6)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: triethylamine / toluene / 10 - 75 °C / Large scale 2.1: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 15 - 30 °C / Large scale 3.1: oxalyl dichloride; dimethyl sulfoxide / dichloromethane / -65 - -45 °C / Large scale 3.2: 0.5 h / -50 - -45 °C / Large scale View Scheme
Multi-step reaction with 3 steps 1.1: toluene / 2 h / 10 - 15 °C 1.2: 6 h / 70 °C 2.1: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 0.25 h / 15 - 30 °C 3.1: oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 0.5 h / -55 - -48 °C 3.2: 1.08 h / -55 - -20 °C View Scheme
Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / ethanol / 3 h / Reflux; Large scale 2: red-aluminum/morpholine complex / toluene / 0.5 h / -5 - 0 °C / Inert atmosphere; Large scale View Scheme
Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / ethanol / 3 h / Reflux 2: red-aluminum/morpholine complex / cyclohexane / 3 h / 0 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1.1: potassium carbonate / toluene / 0.25 h 1.2: 4 h / 100 °C 2.1: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 2 h / 20 °C / Inert atmosphere 3.1: dimethyl sulfoxide; oxalyl dichloride; triethylamine / dichloromethane / -70 - 20 °C View Scheme

4-piperidinecarboxylic acid methyl ester hydrochloride → 1-benzyl-4-formylpiperidine (22065-85-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / ethanol / 3 h / Reflux; Large scale 2: red-aluminum/morpholine complex / toluene / 0.5 h / -5 - 0 °C / Inert atmosphere; Large scale View Scheme

benzaldehyde (100-52-7) → 1-benzyl-4-formylpiperidine (22065-85-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogen; platinum on activated charcoal / toluene / 80 °C / Flow reactor 2: diisobutylaluminium hydride / toluene; hexane / 2.5 h / -78 °C / Flow reactor View Scheme

1-benzyl-piperidine-4-carboxylic acid amide (62992-68-1) → 1-benzyl-4-formylpiperidine (22065-85-6)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: thionyl chloride / 5 h / Reflux 2.1: diisobutylaluminium hydride / toluene / 1 h / 0 °C 2.2: 0.5 h / pH 8 View Scheme

isonipecotic acid (498-94-2) → 1-benzyl-4-formylpiperidine (22065-85-6)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: thionyl chloride / 2 h / Reflux 2.1: triethylamine / methanol / 6 h / Reflux 3.1: water; methanol; sodium hydroxide / 2 h / Reflux 4.1: thionyl chloride / 2 h / Reflux 4.2: 0.5 h / Cooling with ice 5.1: thionyl chloride / 5 h / Reflux 6.1: diisobutylaluminium hydride / toluene / 1 h / 0 °C 6.2: 0.5 h / pH 8 View Scheme

5,6-dimethoxy-1-indanone (2107-69-9) + 1-benzyl-4-formylpiperidine (22065-85-6) → 1-benzyl-4-<(5,6-dimethoxy-1-oxoindan-2-ylidenyl)methyl>piperidine (120014-07-5)

Conditions	Yield
With potassium hydroxide; N-benzyl-N,N,N-triethylammonium chloride In water; toluene at 20℃; Product distribution / selectivity; Inert atmosphere; Reflux;	100%
With sodium methylate In methanol; ethanol at 79℃; for 1.58333h; Product distribution / selectivity; Heating / reflux;	93.4%
With sodium methylate In methanol at 66℃; for 1h; Product distribution / selectivity; Heating / reflux;	93.9%

1-benzyl-4-formylpiperidine (22065-85-6) + tris-iso-propylsilyl acetylene (89343-06-6) → (R)-(-)-1-(N-benzyl-4-piperidinyl)-3-triisopropylsilyl-2-propyn-1-ol

Conditions	Yield
With (αR,2S)-(-)-1-(2-diphenylphosphinobenzyl)-α-(2,2-dimethylpropynyl)-2-pyrrolidinemethanol; copper (I) tert-butoxide In tert-butyl alcohol at 25℃; for 72h; Inert atmosphere; enantioselective reaction;	99%

1-benzyl-4-formylpiperidine (22065-85-6) + nitromethane (75-52-5) → C14H20N2O3

Conditions	Yield
With potassium fluoride In isopropyl alcohol at 20℃;	96%

1-benzyl-4-formylpiperidine (22065-85-6) + 3-methoxyphenyl bromide (2398-37-0) → N-benzyl-4-[hydroxy(3-methoxyphenyl)methyl]piperidine (255723-94-5)

Conditions	Yield
Stage #1: 3-methoxyphenyl bromide With magnesium In tetrahydrofuran for 0.5h; Grignard reaction; Heating; Stage #2: N-benzyl-4-formylpiperidine In tetrahydrofuran at 20℃; for 2h; Addition;	94.3%

5,6-dimethoxy-1-indanone (2107-69-9) + 1-benzyl-4-formylpiperidine (22065-85-6) → (E)-2-((1-benzylpiperidine-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one

Conditions	Yield
With potassium tert-butylate In tert-butyl alcohol at 0 - 25℃; for 1.25h; Product distribution / selectivity;	92.2%
With sodium methylate In isopropyl alcohol at 0 - 25℃; for 3.25h; Product distribution / selectivity;	92.5%
With tetrabutylammomium bromide; potassium hydroxide In dichloromethane; water at 38℃; for 1.5h;	90%

1-benzyl-4-formylpiperidine (22065-85-6) + diethyl cyanophosphonate (2942-58-7) + lithium cyanide (2408-36-8) → (1-benzylpiperidin-4-yl)cyanomethyl diethylphosphate

Conditions	Yield
In tetrahydrofuran at 20℃; for 0.5h;	92%

5,6-dimethoxy-1-indanone (2107-69-9) + 1-benzyl-4-formylpiperidine (22065-85-6) → 1-benzyl-4-<(5,6-dimethoxy-1-oxoindan-2-ylidenyl)methyl>piperidine hydrochloride

Conditions	Yield
Stage #1: 5,6-dimethoxy-1-indanone; N-benzyl-4-formylpiperidine In dichloromethane at 25 - 30℃; Stage #2: With potassium hydroxide In methanol; dichloromethane at 0 - 30℃;	91.3%

2-methylbenzothiazol-5-yl methyl ketone (20077-92-3) + 1-benzyl-4-formylpiperidine (22065-85-6) → 3-(1-benzylpiperidin-4-yl)-3-hydroxy-1-(2-methylbenzothiazol-6-yl)propan-1-one

Conditions	Yield
With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.75h;	90%

1-benzyl-4-formylpiperidine (22065-85-6) + (4-chlorphenyl)magnesium bromide (873-77-8) → (1-benzylpiperidin-4-yl)(4-chlorophenyl)methanol (1226878-35-8)

Conditions	Yield
In tetrahydrofuran at 20℃; for 0.55h; Grignard reaction; Inert atmosphere;	90%

Diethyl (2-oxopropyl)phosphonate (1067-71-6) + 1-benzyl-4-formylpiperidine (22065-85-6) → (E)-4-(1-benzylpiperidin-4-yl)but-3-en-2-one (1335032-58-0)

Conditions	Yield
Stage #1: Diethyl (2-oxopropyl)phosphonate With potassium carbonate In tetrahydrofuran at 20℃; for 0.583333h; Reflux; Stage #2: N-benzyl-4-formylpiperidine In tetrahydrofuran for 3h; Wittig reaction; Reflux;	90%

1-benzyl-4-formylpiperidine (22065-85-6) + 5,6-Diethoxy-1-indanone (137013-02-6) → 1-benzyl-4-[(5,6-diethoxy-1-indanon)-2-ylidene]methylpiperidine

Conditions	Yield
With sodium methylate In tetrahydrofuran; methanol; water for 2h;	89%

1-benzyl-4-formylpiperidine (22065-85-6) + 3-chloro-1-(3,4-dimethoxyphenyl)propan-1-one (4693-38-3) → 1-benzyl-4-<(5,6-dimethoxy-1-oxoindan-2-ylidenyl)methyl>piperidine (120014-07-5)

Conditions	Yield
With triethylammonium tetrachloroaluminate at 55 - 175℃; for 11h; Temperature; Reagent/catalyst; Concentration; Inert atmosphere;	89%

5,6-dimethoxy-1-indanone (2107-69-9) + 1-benzyl-4-formylpiperidine (22065-85-6) → donepezil (120014-06-4)

Conditions	Yield
With aluminum oxide; Pt/Al2O3 In tetrahydrofuran; ethanol; water; isopropyl alcohol at 45 - 55℃; for 7h; Temperature; Solvent; Reagent/catalyst; Aldol Condensation;	88%
Multi-step reaction with 2 steps 1: sodium methylate / tetrahydrofuran 2: palladium 10% on activated carbon; hydrogenchloride / ethanol; water View Scheme

1-benzyl-4-formylpiperidine (22065-85-6) + (4-iodo-5-methoxypyrrolo[2,3-b]pyridin-1-yl)triisopropylsilane → (1-benzyl-4-piperidyl)-(5-methoxy-1-triisopropylsilylpyrrolo[2,3-b]pyridin-4-yl)methanol

Conditions	Yield
Stage #1: (4-iodo-5-methoxypyrrolo[2,3-b]pyridin-1-yl)triisopropylsilane With isopropylmagnesium chloride In tetrahydrofuran at 0℃; for 0.666667h; Stage #2: N-benzyl-4-formylpiperidine In tetrahydrofuran at 0℃; for 1h;	84.8%

1-benzyl-4-formylpiperidine (22065-85-6) + diethyl ((6-((2-methyl-1-oxo-1-(phenylamino)propan-2-yl)oxy)quinolin-2-yl)methyl)phosphonate → (E)-2-((3-(2-(1-benzylpiperidin-4-yl)vinyl)isoquinolin-7-yl)oxy)-2-methyl-N-phenylpropanamide

Conditions	Yield
Stage #1: diethyl ((6-((2-methyl-1-oxo-1-(phenylamino)propan-2-yl)oxy)quinolin-2-yl)methyl)phosphonate With n-butyllithium In tetrahydrofuran at 0℃; for 0.166667h; Inert atmosphere; Stage #2: N-benzyl-4-formylpiperidine In tetrahydrofuran at 0 - 20℃; Inert atmosphere;	84%

1-benzyl-4-formylpiperidine (22065-85-6) + diethyl cyanomethyl phosphonate (50586-62-4) → (2E)-3-(1-benzylpiperidin-4-yl)prop-2-enenitrile (151097-69-7)

Conditions	Yield
Stage #1: diethyl cyanomethyl phosphonate With potassium carbonate In tetrahydrofuran at 20℃; for 0.5h; Reflux; Stage #2: N-benzyl-4-formylpiperidine In tetrahydrofuran for 12h; Reflux;	83%

5,6-dimethoxy-1-indanone (2107-69-9) + 1-benzyl-4-formylpiperidine (22065-85-6) → 2-((1-benzyl-piperidin-4-yl)-hydroxymethyl)-5,6-dimethoxyindan-1-one (197010-20-1)

Conditions	Yield
With N-benzyl-N,N,N-triethylammonium chloride; potassium carbonate In water; toluene for 4h; Reflux; Large scale;	81.29%

picolinic acid hydrazide (1452-63-7) + 1-benzyl-4-formylpiperidine (22065-85-6) → (E)-N'-((1-benzylpiperidin-4-yl)methylene)picolinohydrazide

Conditions	Yield
In methanol at 100℃; for 0.5h; Microwave irradiation;	80%

1-benzyl-4-formylpiperidine (22065-85-6) + 2,2,2-trifluorodiazoethane (371-67-5) + N-butylamine (109-73-9) → 1-benzyl-4-(1-butyl-4-(trifluoromethyl)-4,5-dihydro-1H-1,2,3-triazol-5-yl)piperidine

Conditions	Yield
With silver carbonate In toluene at 25℃; for 8h; diastereoselective reaction;	79%

1-benzyl-4-formylpiperidine (22065-85-6) + (3-fluorobenzyl)(triphenyl)phosphonium bromide (89302-81-8) → (E)-1-benzyl-4-(3-fluorostyryl)piperidine

Conditions	Yield
With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; Cooling with ice;	78.1%

1-benzyl-4-formylpiperidine (22065-85-6) + 2-bromo-5,6-dimethoxy-1-indanone (2747-08-2) → (E)-2-((1-benzylpiperidine-4-yl)methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one

Conditions	Yield
With 1-phenylphospholane-1-oxide; diphenylsilane; N-ethyl-N,N-diisopropylamine In toluene at 100℃; for 24h; Wittig Olefination; Inert atmosphere;	76%

1-benzyl-4-formylpiperidine (22065-85-6) + diethyl (1-tritylimidazol-4-yl)methylphosphonate (473659-21-1) → (E)-1-benzyl-4-(1-triphenylmethylimidazol-4-ylethylene)piperidine

Conditions	Yield
With potassium tert-butylate In tetrahydrofuran for 2h; Horner-Wadsworth-Emmons reaction; Heating;	74%
With potassium tert-butylate In tetrahydrofuran for 2h; Heating / reflux;	74%

Upstream product

• 120014-33-7 1-Benzyl-4-(methoxymethylidene)-piperidine 
• 62992-68-1 1-benzyl-piperidine-4-carboxylic acid amide 
• 62718-31-4 1-benzylpiperidine-4-carbonitrile 
• 498-94-2 isonipecotic acid 
• 10315-07-8 N-benzylpiperidine-4-carboxylic acid 
• 67686-01-5 1-benzyl-4-piperidinemethanol 
• 100-39-0 benzyl bromide 
• 100-52-7 benzaldehyde 
• 100-44-7 benzyl chloride 
• 3612-20-2 1-phenylmethyl-4-piperidone 
• 4009-98-7 (methoxymethyl)triphenylphosphonium chloride 
• 42790-44-3 1-benzyl-4-vinyl-piperidine 
• 101775-64-8 1-benzyl-4-methoxymethyl-piperidine 
• 7462-86-4 methyl piperidine-4-carboxylate hydrochloride 

Downstream Products

• 137996-00-0 1-benzyl-4-(methoxyethenyl)piperidine 
• 137995-48-3 1-benzyl-4-<2-(4-fluorophenyl)-1-hydroxyethyl>piperidine 
• 163726-70-3 1-(2-methyl-6-benzothiazolyl)-3-(N-benzyl-4-piperidinyl)-2-propen-1-one 
• 163726-58-7 3-(1-benzylpiperidin-4-yl)-1-(2,3-dihydrobenzo<1,4>dioxin-6-yl)-3-hydroxypropan-1-one 
• 163726-69-0 1-(1-ethyl-2-methyl-5-benzimidazolyl)-3-(N-benzyl-4-piperidinyl)-2-propen-1-one 
• 120014-07-5 1-benzyl-4-<(5,6-dimethoxy-1-oxoindan-2-ylidenyl)methyl>piperidine 
• 255723-94-5 N-benzyl-4-[hydroxy(3-methoxyphenyl)methyl]piperidine 

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).

Synthesis method of N-benzyl-4-piperidine formaldehyde

The invention belongs to the technical field of medicine synthesis, and particularly relates to a synthesis method of N-benzyl-4-piperidine formaldehyde. According to the invention, 4-piperidinecarboxylic acid is used as a raw material; an esterification reaction is carried out to generate 4-methyl piperidinecarboxylate hydrochloride; an alkylation reaction is carried out on N-benzyl-4-methyl piperidinecarboxylate hydrochloride to generate N-benzyl-4-methyl piperidinecarboxylate; n-benzyl-4-methyl piperidinecarboxylate is hydrolyzed to obtain N-benzyl-4-piperidinecarboxylic acid, N-benzyl-4-piperidinecarboxylic acid is subjected to an acylation reaction to generate N-benzyl-4-piperidinecarboxamide, N-benzyl-4-piperidinecarboxamide is dehydrated to obtain 1-benzylpiperidine-4-nitrile, and 1-benzylpiperidine-4-nitrile is subjected to a reduction reaction to generate N-benzyl-4-piperidineformaldehyde. The method is mild in reaction condition, simple in aftertreatment and high in yield, N-benzyl-4-piperidinecarboxaldehyde can be obtained at the high yield at the temperature of 0 DEG C, column chromatography is not needed, and repeatability is high.

SMALL MOLECULE INHIBITORS OF THE BFRB:BFD INTERACTION

The present technology provides compounds of Formula I and related methods for treating a bacterial infection as well as methods for inhibiting interaction of a bacterioferritin and a bacterioferritin-associated ferredoxin.