94-62-2

Basic information

• Product Name: Piperine
• Synonyms: PIPERINE;N-PIPEROYLPIPERIDIN;(E,E)-1-[5-(1,3-Benzodioxol-5-yl)-1-oxo-2,4-pentadienyl]-piperidine;FEMA 2909;5-BENZO[1,3]DIOXOL-5-YL-1-PIPERIDIN-1-YL-PENTA-2,4-DIEN-1-ONE;1-PIPERONYLPIPERIDINE;1-PIPEROYLPIPERIDINE;1-PIPERYLPIPERIDINE
• CAS NO: 94-62-2
• Molecular Formula: C₁₇H₁₉NO₃
• Molecular Weight: 285.34
• EINECS: 202-348-0
• Product Categories: Alkaloids;Biochemistry;Pyridine Alkaloids;Aromatics;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals;Plant extract;chemical reagent;pharmaceutical intermediate;phytochemical;reference standards from Chinese medicinal herbs (TCM).;standardized herbal extract;LOXAPINE;natural product;Inhibitors
• Mol File: 94-62-2.mol

Chemical Properties

• Melting Point: 131-135 °C(lit.)
• Boiling Point: 427.77°C (rough estimate)
• Flash Point: 255.3 °C
• Appearance: Off-white to tan or yellow-tan/Crystalline Powder
• Density: 1.0864 (rough estimate)
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.5400 (estimate)
• Storage Temp.: Refrigerator
• Solubility: 0.04g/l
• PKA: 12.22(at 18℃)
• Water Solubility: 40 mg/L (18 ºC)
• Stability: Stable. Incompatible with strong oxidizing agents.
• Merck: 14,7472
• BRN: 90741
• CAS DataBase Reference: Piperine(CAS DataBase Reference)
• NIST Chemistry Reference: Piperine(94-62-2)
• EPA Substance Registry System: Piperine(94-62-2)

Safety Data

• Hazard Codes: Xn,Xi,N
• Statements: 22-21/22-20/21/22-51/53
• Safety Statements: 22-24/25-36/37-36-61
• RIDADR: UN 3077 9 / PGIII
• WGK Germany: 3
• RTECS: TN2321500
• TSCA: Yes
• Hazardous Substances Data: 94-62-2(Hazardous Substances Data)

Usage

Uses

Used in Pest Control:
Piperine is used in granular formulations as a pesticide against small animals such as dogs, cats, skunks, raccoons, and squirrels. Piperine pesticides are nontoxic and operate as a repellant when animals smell or taste them.
Used in Insecticides:
Piperine is also incorporated with other compounds to make insecticides. It is effective against houseflies, lice, and various other pests.
Used in Medicine:
Piperine has been used medicinally for thousands of years and continues to be used today. It is used to treat asthma and chronic bronchitis. It also has putative analgesic and anti-inflammatory properties that stem from its antioxidant properties. Research is examining the use of piperine in treating malaria.
Used in Epilepsy Treatment:
Antiepilepsirine, a derivative of piperine, is used to treat different types of epilepsy, especially in China.
Used in Enhancing Bioavailability:
A current area of interest is the efficacy of piperine in increasing the bioavailability of certain nutrients and drugs. It is thought to possibly aid digestion and increase the absorption in the digestive tract of numerous drugs used as cancer treatments, antihistamines, steroidal inflammation reducers, and antibiotics.
Used in the Food Industry:
As an organic insecticide, Piperine is used to protect crops from pests, ensuring the quality and safety of food products.
Used in Pharmaceutical Research:
Piperine is used as a TRPV1 activator in black pepper extract, which has potential applications in the development of new drugs and therapies.

History

Hans Christian Oersted (1777 1851) isolated piperine from black pepper in 1819 and published his findings in 1820. Oersted extracted a resin from pepper plants with alcohol, formed a soluble saltby adding hydrochloric acid with alcohol, and then separated piperine from solution by precipitation and distillation. In 1882, Leopold Rügheimer (1850 1917) synthesized piperine from piperinic acid chloride and piperidine. The complete synthesis of piperine was reported in 1894 by Albert Ladenburg (1842 1911) and M. Scholtz. Ladenburg and Scholtz used piperonal (C8H6O3) and acetaldehyde (CH3CHO) to produce piperinic acid (C12H10O4), which was then reacted with thionyl chloride (COCl2) and piperidine (C5H11N) to produce piperine.

Preparation

From piperoyl chloride and piperidine.

Safety Profile

Poison by ingestion and intraperitoneal routes. An experimental teratogen. Experimental reproductive effects. When heated to decomposition it emits toxic fumes of NOx.

Purification Methods

Piperine crystallises as light yellow crystals from EtOH or EtOAc (m 132o), aqueous EtOH (m 128-129o), Et2O (m129o), or*benzene/ligroin. [Beilstein 20 H 79, 20 I 23, 20 II 53, 20 III/IV 1341, 20/3 V 469.]

References

Oersred., Schweigger's Journal, 29, 80 (1819) Fliickiger, Hanbury., Pharmacographica, 584 London (1879) Stenhouse., Pharm. J., 14,363 (1855) Cazeneuve, Caillot., Bull. Soc. Chim. Fr., 27,291 (1877) Riigheimer., Ber., 15, 1391 (1882) Peinemann., Arch. Pharm., 234, 245 (1896) Newman., Chem. Products, 16,379 (1953)

InChI:InChI=1/C17H19NO3/c19-17(18-10-4-1-5-11-18)7-3-2-6-14-8-9-15-16(12-14)21-13-20-15/h2-3,6-9,12H,1,4-5,10-11,13H2/b6-2-,7-3+

Synthetic route

1-crotonoylpiperidine (50838-22-7) + piperonal (120-57-0) → Piperine (94-62-2)

Conditions	Yield
With Aliquat 336; potassium carbonate In toluene at 90℃; for 10h;	95%
With potassium hydroxide; N-benzyl-N,N,N-triethylammonium chloride In dimethyl sulfoxide 1) 15 min, 25 deg C 2) 2 h, 60-65 deg C;	88%
Stage #1: piperonal With sodium hydroxide In water; dimethyl sulfoxide for 0.5h; Stage #2: 1-crotonoylpiperidine In water; dimethyl sulfoxide at 20℃;	75.3%
With potassium hydroxide; N-benzyl-N,N,N-triethylammonium chloride In dimethyl sulfoxide at 60 - 65℃; for 2h; Product distribution; various solvents;
With N-benzyl-N,N,N-triethylammonium chloride; sodium hydroxide In water; dimethyl sulfoxide at 25 - 30℃;	89 g

piperidine (110-89-4) + piperic acid (136-72-1) → Piperine (94-62-2)

Conditions	Yield
Stage #1: piperic acid With thionyl chloride In dichloromethane at 20℃; Schlenk technique; Stage #2: piperidine In dichloromethane at 20℃; for 1h; Schlenk technique; Inert atmosphere; stereoselective reaction;	95%
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 8h;	93%
With N,N-bis[2-oxo-3-oxazolidinyl]phosphorodiamidic chloride; triethylamine In dichloromethane at 20 - 25℃; for 1h;	90%
With dmap; dicyclohexyl-carbodiimide Amidation;	72%
With dmap; dicyclohexyl-carbodiimide In dichloromethane for 18h; Inert atmosphere;	71%

piperidine (110-89-4) + Bestmann ylide (73818-55-0, 15596-07-3) + (E)-3,4-methylenedioxycinnamaldehyde (58095-77-5, 14756-00-4) → Piperine (94-62-2)

Conditions	Yield
In tetrahydrofuran for 24h; Heating;	90%

piperidine (110-89-4) + (2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)penta-2,4-dienamide → Piperine (94-62-2)

Conditions	Yield
With dipotassium peroxodisulfate In water at 100℃; for 0.166667h; Microwave irradiation; Green chemistry;	83%

1-[(E)-3,4-(methylenedioxy)cinnamylsulfonyl]acetyl-piperidine (736947-76-5) → Piperine (94-62-2)

Conditions	Yield
With aluminum oxide; potassium hydroxide; dibromodifluoromethane In dichloromethane at 20℃; for 1h;	82%

N-acrylpiperidine (10043-37-5) + 3,4-methylenedioxy-trans-cinnamic acid (2373-80-0) → Piperine (94-62-2)

Conditions	Yield
Stage #1: 3,4-methylenedioxy-trans-cinnamic acid With N-Bromosuccinimide; tetrabutylammonium trifluoroacetate In 1,2-dichloro-ethane at 20℃; for 4h; Decarboxylation; bromination; Hunsdiecker reaction; Stage #2: N-acrylpiperidine With palladium diacetate; triphenylantimony; triethylamine In 1,2-dichloro-ethane for 20h; Heck reaction;	51%

N-acrylpiperidine (10043-37-5) + (E)-β-iodo-3,4-methylenedioxystyrene (202998-56-9) → Piperine (94-62-2)

Conditions	Yield
With palladium diacetate; triethylamine; triphenylphosphine; lithium chloride In acetonitrile at 70 - 80℃; for 18h;	38%

(E)-5-(3-bromoprop-1-en-1-yl)benzo[d][1,3]dioxole (67911-75-5) + N-<1-oxo-2-(3,6-diisopropyl-2-pyrazinylsulfinyl)ethyl>piperidine (136055-33-9) → Piperine (94-62-2)

Conditions	Yield
With potassium diisopropylamide 1.) THF, hexane, RT, 1 h, 2.) THF, hexane, reflux; Yield given. Multistep reaction;

1'-hydroxysafrole (5208-87-7) + 1-p-Tolylsulfanylethynyl-piperidine (80880-59-7) → Piperine (94-62-2)

Conditions	Yield
1.) BF3OEt2 in refluxing toluene; 2.) oxidation (m-chloroperbenzoic acid, CH2Cl2,-78 grad C); 3.) reflux in toluene; Yield given. Multistep reaction;

Acetic acid 1-(benzenesulfonyl-benzo[1,3]dioxol-5-yl-methyl)-4-oxo-4-piperidin-1-yl-butyl ester (104683-09-2) → piperine (94-62-2) + Piperine (94-62-2)

Conditions	Yield
With potassium tert-butylate In tert-butyl alcohol for 12h; Ambient temperature; Yield given. Yields of byproduct given;

piperidine (110-89-4) + piperic acid chloride (4711-72-2) → Piperine (94-62-2)

Conditions	Yield
In diethyl ether
In diethyl ether 1.) -60 deg C to 10 deg C, 2.) 10 deg C, 1 h; Yield given;
In tetrahydrofuran at 20℃;
In dichloromethane at 60℃;

piperidine (110-89-4) + chavicinoyl chloride → Piperine (94-62-2)

piperidine (110-89-4) + piperinic acid chloride → Piperine (94-62-2)

Conditions	Yield
With benzene

piperidine (110-89-4) + trityl thiosemicarbazide resin → Piperine (94-62-2)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: 100 percent / acetone / 20 °C 2.1: KOH / methanol / 0.17 h / 0 °C 2.2: 85 percent / methanol / 1 h / 0 °C 3.1: 92 percent / oxone / methanol; H2O / 0 °C 4.1: 82 percent / KOH; Al2O3; CBr2F2 / CH2Cl2 / 1 h / 20 °C View Scheme

thioacetic acid S-(3-benzo[1,3]dioxol-5-yl-allyl) ester (736947-15-2) → Piperine (94-62-2)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: KOH / methanol / 0.17 h / 0 °C 1.2: 85 percent / methanol / 1 h / 0 °C 2.1: 92 percent / oxone / methanol; H2O / 0 °C 3.1: 82 percent / KOH; Al2O3; CBr2F2 / CH2Cl2 / 1 h / 20 °C View Scheme

1-[(E)-3,4-(methylenedioxy)cinnamylthio]acetyl-piperidine (736947-38-9) → Piperine (94-62-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: 92 percent / oxone / methanol; H2O / 0 °C 2: 82 percent / KOH; Al2O3; CBr2F2 / CH2Cl2 / 1 h / 20 °C View Scheme

1-chloroacetyl-piperidine (1440-60-4) → Piperine (94-62-2)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: KOH / methanol / 0.17 h / 0 °C 1.2: 85 percent / methanol / 1 h / 0 °C 2.1: 92 percent / oxone / methanol; H2O / 0 °C 3.1: 82 percent / KOH; Al2O3; CBr2F2 / CH2Cl2 / 1 h / 20 °C View Scheme

piperonal (120-57-0) + rhodaninoic acid → Piperine (94-62-2)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: benzene / 4 h / Heating 2.1: LiAlH4; AlCl3 / tetrahydrofuran / 1 h / 0 °C 3.1: 83 percent / DIAD; Ph3P / benzene / 1 h / 20 °C 4.1: KOH / methanol / 0.17 h / 0 °C 4.2: 85 percent / methanol / 1 h / 0 °C 5.1: 92 percent / oxone / methanol; H2O / 0 °C 6.1: 82 percent / KOH; Al2O3; CBr2F2 / CH2Cl2 / 1 h / 20 °C View Scheme

(E)-3-(benzo[d][1,3]dioxol-5-yl)prop-2-en-1-ol (58095-76-4) → Piperine (94-62-2)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: 83 percent / DIAD; Ph3P / benzene / 1 h / 20 °C 2.1: KOH / methanol / 0.17 h / 0 °C 2.2: 85 percent / methanol / 1 h / 0 °C 3.1: 92 percent / oxone / methanol; H2O / 0 °C 4.1: 82 percent / KOH; Al2O3; CBr2F2 / CH2Cl2 / 1 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: 55 percent / PDC / CH2Cl2 / 20 °C 2: 90 percent / tetrahydrofuran / 24 h / Heating View Scheme
Multi-step reaction with 2 steps 1: PBr3 / CH2Cl2 / 0.5 h / -5 °C 2: 1.) potassium diisopropylamide (KDA) / 1.) THF, hexane, RT, 1 h, 2.) THF, hexane, reflux View Scheme

ethyl (E)-3-(benzo[d][1,3]dioxol-5-yl)acrylate (24393-66-6) → Piperine (94-62-2)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: LiAlH4; AlCl3 / tetrahydrofuran / 1 h / 0 °C 2.1: 83 percent / DIAD; Ph3P / benzene / 1 h / 20 °C 3.1: KOH / methanol / 0.17 h / 0 °C 3.2: 85 percent / methanol / 1 h / 0 °C 4.1: 92 percent / oxone / methanol; H2O / 0 °C 5.1: 82 percent / KOH; Al2O3; CBr2F2 / CH2Cl2 / 1 h / 20 °C View Scheme

piperonal (120-57-0) → Piperine (94-62-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: 94 percent / benzene / 24 h / Heating 2: 87 percent / DIBAL-H / tetrahydrofuran; hexane / 6 h / -10 - 20 °C 3: 55 percent / PDC / CH2Cl2 / 20 °C 4: 90 percent / tetrahydrofuran / 24 h / Heating View Scheme
Multi-step reaction with 4 steps 2: 1) alkali, 2) acid 3: oxalyl chloride / benzene 4: diethyl ether View Scheme
Multi-step reaction with 2 steps 1: 71 percent 2: 1.) BF3OEt2 in refluxing toluene; 2.) oxidation (m-chloroperbenzoic acid, CH2Cl2,-78 grad C); 3.) reflux in toluene View Scheme
Multi-step reaction with 3 steps 1: lithium hydroxide / tetrahydrofuran / 4 h / Reflux 2: sodium hydroxide / methanol / 8 h / 20 °C 3: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 8 h / 20 °C View Scheme

isosafrole (120-58-1) → Piperine (94-62-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: 65 percent / SeO2 / dioxane / 16 h / Heating 2: 90 percent / tetrahydrofuran / 24 h / Heating View Scheme

methyl (2E)-3-(1,3-benzodioxol-5-yl)acrylate (40918-96-5) → Piperine (94-62-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: 87 percent / DIBAL-H / tetrahydrofuran; hexane / 6 h / -10 - 20 °C 2: 55 percent / PDC / CH2Cl2 / 20 °C 3: 90 percent / tetrahydrofuran / 24 h / Heating View Scheme

piperidine (110-89-4) + 3.) methyl halide → Piperine (94-62-2)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: Et3N; hydroquinone / benzene / 5 h / 20 °C 2.1: N-bromosuccinimide; tetrabutylammonium trifluoroacetate / 1,2-dichloro-ethane / 4 h / 20 °C 2.2: 51 percent / Pd(OAc)2; Ph3Sb; Et3N / 1,2-dichloro-ethane / 20 h View Scheme

furfural (98-01-1) + ArgoGel-Rink resin bound NH2COCH2NH2 → Piperine (94-62-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: methanol / 15 h / 20 °C 2: 80 percent / tetrahydrofuran / 2 h / 20 °C 3: 75 percent / NaClO2; NaH2PO4 / 2-methyl-propan-2-ol 4: 72 percent / DCC; DMAP View Scheme

furfural tosylhydrazone (18708-18-4) → Piperine (94-62-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: 80 percent / tetrahydrofuran / 2 h / 20 °C 2: 75 percent / NaClO2; NaH2PO4 / 2-methyl-propan-2-ol 3: 72 percent / DCC; DMAP View Scheme

(2E,4E)-5-(3,4-methylenedioxyphenyl)-2,4-pentadienal (54976-52-2, 83047-59-0) → Piperine (94-62-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: 75 percent / NaClO2; NaH2PO4 / 2-methyl-propan-2-ol 2: 72 percent / DCC; DMAP View Scheme

3,4-methylenedioxy-trans-cinnamic acid (2373-80-0) → Piperine (94-62-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: 73 percent / N-iodosuccinimide, tetrabutylammonium trifluoroacetate / 1,2-dichloro-ethane / Ambient temperature 2: 38 percent / palladium acetate, triphenylphosphine, lithium chloride, triethylamine / acetonitrile / 18 h / 70 - 80 °C View Scheme

piperic acid (136-72-1) → Piperine (94-62-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: (COCl)2 / CH2Cl2 / 3 h / Ambient temperature 2: diethyl ether / 1.) -60 deg C to 10 deg C, 2.) 10 deg C, 1 h View Scheme
Multi-step reaction with 2 steps 1: oxalyl chloride / benzene 2: diethyl ether View Scheme
Multi-step reaction with 2 steps 1: thionyl chloride / dichloromethane / 2 h / Inert atmosphere; Cooling with ice 2: dichloromethane / 60 °C View Scheme

Piperine (94-62-2) → tetrahydropiperine (23434-88-0)

Conditions	Yield
With zinc copper In methanol for 3h; Heating;	98%
With 5% Pd/C; hydrogen under 2068.65 Torr; for 4h;	98.5%
With 5% Pd(II)/C(eggshell); hydrogen In dichloromethane for 12h;	97%

Piperine (94-62-2) → piperic acid (136-72-1)

Conditions	Yield
With water; potassium hydroxide In ethanol for 18h; Reflux;	96.4%
With potassium hydroxide In methanol at 150℃; for 24h;	94%
Stage #1: Piperine With potassium hydroxide In ethanol for 20h; Reflux; Stage #2: With hydrogenchloride In water pH=3;	94.5%

Piperine (94-62-2) → (E)-5-(benzo[1,3]dioxol-5-yl)-1-(piperidin-1-yl)pent-3-en-1-one (23512-55-2)

Conditions	Yield
With methanol; magnesium at 20℃; for 2h; Reduction;	96%
With methanol; magnesium at 20℃; for 2h;	95%

Piperine (94-62-2) → (E)-5-(benzo[1,3]dioxol-5-yl)-1-(piperidin-1-yl)pent-3-en-1-one (23512-55-2) + cis-5-benzo[1,3]dioxol-5-yl-1-piperidin-1-yl-pent-3-en-1-one

Conditions	Yield
With acetic acid; zinc for 2h; Ambient temperature;	A 95% B n/a
With ethylene dibromide; sodium iodide; (2,2'-bipyridine)nickel(II) dibromide In water; N,N-dimethyl-formamide Electrochemical reaction;	A 80 % Chromat. B 20 % Chromat.

Piperine (94-62-2) → (2E,4E)-5-(1,3-benzodioxol-5-yl)-1-(piperidin-1-yl)-2,4-pentadien-1-thione (1313741-02-4)

Conditions	Yield
With Lawessons reagent In tetrahydrofuran at 20℃; for 20h;	85%

Piperine (94-62-2) → chabamide

Conditions	Yield
With silica gel In neat (no solvent, solid phase) at 200℃; for 3h; Reagent/catalyst; Solvent; Temperature; Time; Diels-Alder Cycloaddition; regioselective reaction;	82%

Piperine (94-62-2) → (E)-3-[(1S,2S,5R,6S)-5,6-Bis-benzo[1,3]dioxol-5-yl-2-(piperidine-1-carbonyl)-cyclohex-3-enyl]-1-piperidin-1-yl-propenone + nigramide B + chabamide + (E)-3-(2,6-bis(benzo[d][1,3]dioxol-5-yl)-5-(piperidine-1-carbonyl)cyclohex-3-en-1-yl)-1-(piperidin-1-yl)prop-2-en-1-one

Conditions	Yield
With 1,1'-bis-(diphenylphosphino)ferrocene; rac-3-octanol; cobalt(II) chloride at 170℃; for 72h; Diels-Alder reaction; Further byproducts given;	A 2% B 12% C 81% D 4%

Piperine (94-62-2) → (3E,5E)-6-(benzo[d][1,3]dioxol-5-yl)-2-(piperidin-1-yl)hexa-3,5-dienenitrile

Conditions	Yield
Stage #1: Piperine With bis(triphenylphosphine)iridium(I) carbonyl chloride In toluene at 20℃; for 0.0833333h; Stage #2: With 1,1,3,3-Tetramethyldisiloxane In toluene at 20℃; for 0.0833333h; Stage #3: With trimethylsilyl cyanide In toluene at 20℃; for 0.5h;	81%

diethyl 2-chloromalonate (14064-10-9) + Piperine (94-62-2) → (3R,6S)-3-Benzo[1,3]dioxol-5-yl-6-(piperidine-1-carbonyl)-3,6-dihydro-thiopyran-2,2-dicarboxylic acid diethyl ester (139059-84-0)

Conditions	Yield
With caesium carbonate; sulfur In acetonitrile Heating;	80%

Piperine (94-62-2) → SCT-63

Conditions	Yield
With diisobutylaluminium hydride In toluene at -10℃; for 0.5h;	80%
With lithium aluminium tetrahydride In tetrahydrofuran for 72h; Inert atmosphere;	34%
With sodium tetrahydroborate; iodine In tetrahydrofuran at 0℃; for 48h;	13%
With lithium aluminium tetrahydride In diethyl ether for 24h; Reduction; Heating;
With sodium tetrahydroborate; iodine In tetrahydrofuran at 0℃; for 48h; Inert atmosphere;

Piperine (94-62-2) → (2E,4E)-5-(3,4-dihydroxyphenyl)-1-(piperidin-1-yl)penta-2,4-dien-1-one

Conditions	Yield
With boron tribromide In dichloromethane at 20℃; for 48h;	76.2%
With boron tribromide In dichloromethane at -15 - 20℃; for 24h;	53%
With boron tribromide In dichloromethane at 0 - 20℃; for 16h;	50%

Piperine (94-62-2) → 4,5-(trans)-2,3-epoxy piperylpiperidine

Conditions	Yield
With dihydrogen peroxide at 37℃; for 18h; Horseradish peroxidase, 0,1M sodium phosphate buffer, pH 6,5;	75%

Piperine (94-62-2) → (E)-5-(benzo[d][1,3]dioxol-5-yl)-1-(piperidin-1-yl)pent-4-en-1-one

Conditions	Yield
With sodium tetrahydroborate; iodine In tetrahydrofuran at 0℃; for 0.333333h;	74%

Piperine (94-62-2) → nigramide B + chabamide + (E)-3-(2,6-bis(benzo[d][1,3]dioxol-5-yl)-5-(piperidine-1-carbonyl)cyclohex-3-en-1-yl)-1-(piperidin-1-yl)prop-2-en-1-one + [(1S,5R,6R)-5-Benzo[1,3]dioxol-5-yl-6-((E)-2-benzo[1,3]dioxol-5-yl-vinyl)-2-(piperidine-1-carbonyl)-cyclohex-2-enyl]-piperidin-1-yl-methanone

Conditions	Yield
With rac-3-octanol; triphenylphosphine; cobalt(II) chloride at 170℃; for 72h; Diels-Alder reaction; Further byproducts given;	A 11% B 74% C 9% D 4%
With rac-3-octanol; cobalt(II) chloride at 170℃; for 72h; Diels-Alder reaction;	A 15% B 41% C 3% D 41%
With cobalt(II) chloride In various solvent(s) at 177℃; for 72h; Diels-Alder reaction;	A 4.2% B 11.5% C 1% D 11.5%

Piperine (94-62-2) → sodium piperonyl pentadienoate (161196-18-5)

Conditions	Yield
With sodium hydroxide In ethanol at 86.5℃; for 24h; Concentration; Temperature; Time;	70.03%
Multi-step reaction with 3 steps 1: potassium hydroxide / ethanol / Reflux 2: sulfuric acid / water 3: sodium hydroxide / ethanol / 1 h / 80.5 °C View Scheme

diethyl 2-chloromalonate (14064-10-9) + Piperine (94-62-2) → 1,1,2,2-tetracarboethoxy-ethylene (6174-95-4) + (3R,6S)-3-Benzo[1,3]dioxol-5-yl-6-(piperidine-1-carbonyl)-3,6-dihydro-selenopyran-2,2-dicarboxylic acid diethyl ester (139059-85-1)

Conditions	Yield
With selenium; caesium carbonate In acetonitrile Heating;	A 70% B 24%

Piperine (94-62-2) → [(1S,2R,5S,6R)-2-Benzo[1,3]dioxol-5-yl-6-((E)-2-benzo[1,3]dioxol-5-yl-vinyl)-5-(piperidine-1-carbonyl)-cyclohex-3-enyl]-piperidin-1-yl-methanone + (E)-3-[(1S,2S,5R,6S)-5,6-Bis-benzo[1,3]dioxol-5-yl-2-(piperidine-1-carbonyl)-cyclohex-3-enyl]-1-piperidin-1-yl-propenone + (E)-3-[(1R,2S,5R,6S)-2,6-Bis-benzo[1,3]dioxol-5-yl-5-(piperidine-1-carbonyl)-cyclohex-3-enyl]-1-piperidin-1-yl-propenone + chabamide

Conditions	Yield
With rac-3-octanol; triphenylphosphine; cobalt(II) chloride at 170℃; for 72h; Diels-Alder reaction; Further byproducts given;	A 2% B 3% C 2% D 62%

Piperine (94-62-2) → tetrahydropiperine (23434-88-0) + (E)-5-(benzo[d][1,3]dioxol-5-yl)-1-(piperidin-1-yl)pent-4-en-1-one

Conditions	Yield
With sodium tetrahydroborate; iodine In tetrahydrofuran at 0℃; for 0.333333h;	A 58% B 14%

N-benzyl C-(trifluoromethyl)nitrone + Piperine (94-62-2) → 5-(((E)-2-(benzo[d][1,3]dioxol-5-yl)vinyl)-2-benzyl-3-(trifluoromethyl)isoxazolidin-4-yl)(piperidin-1-yl)methanone

Conditions	Yield
In toluene at 70 - 80℃; chemoselective reaction;	58%

N-t-butyltrifluoromethylnitrone (2344-50-5) + Piperine (94-62-2) → 5-(((E)-2-(benzo[d][1,3]dioxol-5-yl)vinyl)-tert-butyl-3-(trifluoromethyl)isoxazolidin-4-yl)(piperidin-1-yl)methanone

Conditions	Yield
In toluene at 70 - 80℃; chemoselective reaction;	49%

Piperine (94-62-2) → (2Z,4Z)-3,5-diamino-5-(benzo[d][1,3]dioxol-5-yl)-1-(piperidin-1-yl)penta-2,4-dien-1-one

Conditions	Yield
Stage #1: Piperine With sulfur In dimethyl sulfoxide at 20℃; Sealed tube; Stage #2: With ammonium carbonate In dimethyl sulfoxide at 80℃; for 12h; Sealed tube;	48%

Piperine (94-62-2) → 4R,5R-dihydroxypiperine

Conditions	Yield
Stage #1: Piperine With potassium osmate(VI) dihydrate; (DHQ)2PHAL; potassium carbonate; potassium hexacyanoferrate(III) In water; tert-butyl alcohol at 20℃; for 24h; Stage #2: With sodium sulfite In water; tert-butyl alcohol at 20℃; for 12h;	44.5%
With potassium osmate(VI) dihydrate; potassium carbonate; hydroquinidein 1,4-phthalazinediyl diether; potassium hexacyanoferrate(III) In water; tert-butyl alcohol at 20℃; for 24h;	44.5%

Piperine (94-62-2) → 4S,5S-dihydroxypiperine

Conditions	Yield
Stage #1: Piperine With potassium osmate(VI) dihydrate; (DHQD)2PHAL; potassium carbonate; potassium hexacyanoferrate(III) In water; tert-butyl alcohol at 20℃; for 24h; Stage #2: With sodium sulfite In water; tert-butyl alcohol at 20℃; for 12h;	44.4%
With potassium osmate(VI) dihydrate; potassium carbonate; hydroquinidein 1,4-phthalazinediyl diether; potassium hexacyanoferrate(III) In water; tert-butyl alcohol at 20℃; for 24h;	44.4%

Piperine (94-62-2) → nigramide B + chabamide + (E)-3-(2,6-bis(benzo[d][1,3]dioxol-5-yl)-5-(piperidine-1-carbonyl)cyclohex-3-en-1-yl)-1-(piperidin-1-yl)prop-2-en-1-one

Conditions	Yield
at 130℃; for 72h; Diels-Alder reaction;	A 9.7% B 41% C 6.3%

Upstream product

• 104683-09-2 Acetic acid 1-(benzenesulfonyl-benzo[1,3]dioxol-5-yl-methyl)-4-oxo-4-piperidin-1-yl-butyl ester 
• 110-89-4 piperidine 
• 41193-98-0 1-(4-oxo-butyryl)-piperidine 
• 67911-75-5 (E)-5-(3-bromoprop-1-en-1-yl)benzo[d][1,3]dioxole 
• 136055-33-9 N-<1-oxo-2-(3,6-diisopropyl-2-pyrazinylsulfinyl)ethyl>piperidine 
• 336108-26-0 (E)-5-(1,3-benzodioxol-5-yl)-2-pentenal 
• 139-85-5 3,4-dihydroxybenzaldehyde 
• 22980-23-0 2-oxa-3-oxobicyclo[2.2.0]hex-5-ene 
• 504-31-4 pyran-2-one 
• 1796-25-4 1-(2-bromoacetyl)piperidine 
• 58095-77-5 (E)-3,4-methylenedioxycinnamaldehyde 
• 82895-48-5 1,2-methylenedioxy-4-(phenylsulfonylmethyl)benzene 
• 86452-60-0 4-hydroxy-1-(piperidin-1-yl)butan-1-one 
• 495-76-1 piperonol 

Downstream Products

• 110-89-4 piperidine 
• 136-72-1 piperic acid 
• 1239492-96-6 (S)-methyl 2-((2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)penta-2,4-dienamido)-3-phenylpropanoate 
• 1263201-32-6 (S)-methyl 2-((2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)penta-2,4-dienamido)-2-phenylacetate 
• 1263201-33-7 (R)-methyl 2-((2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)penta-2,4-dienamido)-3-phenylpropanoate 
• 1263201-34-8 (R)-methyl 2-((2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)penta-2,4-dienamido)-3-(4-hydroxyphenyl)propanoate 
• 1263201-35-9 (R)-methyl 2-((2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)penta-2,4-dienamido)-3-(2,4-dihydroxyphenyl)propanoate 
• 94-62-2 piperine 
• 1228296-71-6 5-(3',4'-methylenedioxy-phenyl)-2E,4E-pentadienoic acid 4-chlorophenyl amide 
• 1239493-05-0 2-[[(2E, 4E)-5-(1,3-benzodioxol-5-yl)penta-2,4-dienoyl]amino]-3-phenyl-propanoic acid 
• 30511-77-4 Isochavicine 
• 30511-76-3 Isopeperine 
• 209-22-3 1,8-naphthalenedisulfide 

Relevant articles and documents

The development of novel cytochrome P450 2J2 (CYP2J2) inhibitor and the underlying interaction between inhibitor and CYP2J2

Human Cytochrome P450 2J2 (CYP2J2) as an important metabolic enzyme, plays a crucial role in metabolism of polyunsaturated fatty acids (PUFAs). Elevated levels of CYP2J2 have been associated with various types of cancer, and therefore it serves as a potential drug target. Herein, using a high-throughput screening approach based on enzymic activity of CYP2J2, we rapidly and effectively identified a novel natural inhibitor (Piperine, 9a) with IC50 value of 0.44 μM from 108 common herbal medicines. Next, a series of its derivatives were designed and synthesised based on the underlying interactions of Piperine with CYP2J2. As expected, the much stronger inhibitors 9k and 9l were developed and their inhibition activities increased about 10 folds than Piperine with the IC50 values of 40 and 50 nM, respectively. Additionally, the inhibition kinetics illustrated the competitive inhibition types of 9k and 9l towards CYP2J2, and K i were calculated to be 0.11 and 0.074 μM, respectively. Furthermore, the detailed interaction mechanism towards CYP2J2 was explicated by docking and molecular dynamics, and our results revealed the residue Thr114 and Thr 315 of CYP2J2 were the critical sites of action, moreover the spatial distance between the carbon atom of ligand methylene and Fe atom of iron porphyrin coenzyme was the vital interaction factor towards human CYP2J2.

Piperine derivative as well as preparation method and application thereof

The invention provides a piperine derivative as well as a preparation method and an application thereof. The piperine derivative is a compound shown as a formula (I), or a salt thereof, or a stereoisomer thereof, or a hydrate thereof. The compound provided by the invention can effectively protect nerve cells and improve the survival rate of the nerve cells, so that the compound provided by the invention can effectively treat neurodegenerative diseases and can be used for preparing medicines for treating the neurodegenerative diseases.

Identification and optimization of piperine analogues as neuroprotective agents for the treatment of Parkinson's disease via the activation of Nrf2/keap1 pathway

Parkinson's disease (PD) is a slowly progressive and complex neurodegenerative disorder. Up to date, there are no approved drugs that could slow or reverse the neurodegenerative process of PD. Here, we reported the synthesis of series of piperine analogues and the evaluation of their neuroprotective effects against hydrogen peroxide (H2O2) induced damage in the neuron-like PC12 cells. Among these analogues, 3b exhibited the most potent protection effect and its underlying mechanism was further investigated. Further results indicated that the ROS scavenging and cytoprotection effect of 3b might be related to the Nrf2 activation and upregulation of related phase II antioxidant enzymes, such as HO-1 and NQO1. In in vivo study, oral administration (100 mg/kg) of 3b significantly attenuated PD-associated behavioral deficits in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD and protected tyrosine hydroxylase-immunopositive dopaminergic neurons. Our results provided evidence that 3b might be a promising candidate for Parkinson's disease treatment.

Vicinal difluorination as a C=C surrogate: An analog of piperine with enhanced solubility, photostability, and acetylcholinesterase inhibitory activity

Piperine, a natural product derived from peppercorns, has a variety of biological activities that make it an attractive lead compound for medicinal chemistry. However, piperine has some problematic physicochemical properties including poor aqueous solubility and a susceptibility to UV-induced degradation. In this work, we designed an analog of piperine in which the central conjugated hydrocarbon chain is replaced with a vicinal difluoroalkane moiety. We show that this fluorinated analog of piperine has superior physicochemical properties, and it also has higher potency and selectivity towards one particular drug target, acetylcholinesterase. This work highlights the potential usefulness of the threo-difluoroalkane motif as a surrogate for E-alkenes in medicinal chemistry.

A Short, Efficient, and Stereoselective Synthesis of Piperine and its Analogues

A quantitative synthesis of piperine from commercially available starting material is presented. The synthesis relies on a stereoselective nucleophilic attack of an in situ generated cuprate onto a cyclobutene lactone. The so-formed aryl-substituted cyclobutene spontaneously undergoes a conrotatory 4π-electrocyclic ring opening to form the 4-aryl pentadienoic acid as a single diastereoisomer. The high-yielding synthesis can be easily modulated on the aryl and on the amide moiety for the synthesis of a wide range of piperine analogues.

Piperine synthesis method

The invention discloses a piperine synthesis method. According to the synthesis method, 5-(1,2-methylenedioxyphenyl)-2-pentenal is taken as the primary raw material; a palladium catalyst is used, oxygen is taken as the oxidizing agent, trifluoroacetic acid is taken as the additive, in a polar organic solvent, one-step oxidation-dehydrogenation is performed to obtain 5-(1,2-methylenedioxyphenyl)-2,4-dipentenal, then oxidation and amidation are carried out to obtain piperine, and the yield is high. The key step namely palladium is used to catalyze oxidation-dehydrogenation is realized, and piperine can be synthesized efficiently and concisely. Compared with a conventional method, the operation is simple, the reaction yield is higher, the method is environmentally friendly, the yield is high,and the atom utilization rate is high.

PROCESS FOR THE PREPARATION OF PIPERINE

The present application relates to a process for the preparation of piperine of high purity having low concentrations of isomeric impurities.

Synthesis, antimicrobial, antioxidant and nematicidal activity of (2E,4E)-5-(Benzo[d] [1,3]dioxol-5yl)penta-2,4-dienamides

The amides of piperic acid have been synthesized via the condensation of piperic acid with amines. The structural characterization was done by IR, 1H-NMR, EI-MS and elemental analysis. The amides 3a-3o were evaluated for their biological activity. It has been found that among others the newly synthesized compound 3f, 3k, 3m, and 3o have great potential against root-knot nematode Meloidogyne incognita that usually affect tomato crop. These compounds exhibited 92, 96, 82 and 95% mortality rate at lethal concentration (LC50) 4.4, 3.4, 4.5 and 3.5 mg/mL, respectively. Conventionally used nematicide furadan was taken as standard. Compound 3h, 3c and, 3j exhibited significant anti-oxidant activities against 1,1-diphenylpicrylhydrazil (DPPH) radical with 80, 70 and 72% inhibition (EC50 = 625, 937 and 937.5 μg/mL), respectively. Ascorbic acid was used as standard. When tested for antimicrobial activity 3m was found to be the most active one showing zone of inhibition in the range of 18-30 mm against all tested microbial strains. Good biological activities of synthetic amides indicate their ability to behave as a good antimicrobial and nematicidal agent.

A metal-free approach for transamidation of amides with amines in aqueous media

An efficient, environmentally benign and a mild protocol for transamidation of amides with a variety of amines in the presence of K2S2O8 using stoichiometric quantity in aqueous conditions has been established. This method works under conventional thermal conditions and in microwave irradiation as well. A series of amides have been prepared using this reaction and this is a greener protocol for transamidation, which offers a diverse kind of substrate scope with exclusive product formation (yields 90-98%).

Efficient modulation of γ-aminobutyric acid type a receptors by piperine derivatives

Piperine activates TRPV1 (transient receptor potential vanilloid type 1 receptor) receptors and modulates γ-aminobutyric acid type A receptors (GABAAR). We have synthesized a library of 76 piperine analogues and analyzed their effects on GABAAR by means of a two-microelectrode voltage-clamp technique. GABAAR were expressed in Xenopus laevis oocytes. Structure-activity relationships (SARs) were established to identify structural elements essential for efficiency and potency. Efficiency of piperine derivatives was significantly increased by exchanging the piperidine moiety with either N,N-dipropyl, N,N-diisopropyl, N,N-dibutyl, p-methylpiperidine, or N,N-bis(trifluoroethyl) groups. Potency was enhanced by replacing the piperidine moiety by N,N-dibutyl, N,N-diisobutyl, or N,N-bistrifluoroethyl groups. Linker modifications did not substantially enhance the effect on GABAAR. Compound 23 [(2E,4E)-5-(1,3-benzodioxol-5-yl)-N,N-dipropyl-2,4-pentadienamide] induced the strongest modulation of GABAA (maximal GABA-induced chloride current modulation (IGABA-max = 1673% ± 146%, EC 50 = 51.7 ± 9.5 μM), while 25 [(2E,4E)-5-(1,3-benzodioxol- 5-yl)-N,N-dibutyl-2,4-pentadienamide] displayed the highest potency (EC 50 = 13.8 ± 1.8 μM, IGABA-max = 760% ± 47%). Compound 23 induced significantly stronger anxiolysis in mice than piperine and thus may serve as a starting point for developing novel GABA AR modulators.