130929-57-6

Basic information

• Product Name: Entacapone
• Synonyms: (E)-2-Cyano-3-(3，4-dihydroxy-5-nitrophenyl)-N，N-diethyl-2-pmpenamide;Entacapone (150 mg);(2E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethylprop-2-enaMide;2-PropenaMide,2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-, (2E)-;(E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethylacrylamide;Entacapone (isomer E);(E)-2-cyano-3-(5-(dihydroxyamino)-3,4-dioxocyclohexa-1,5-dienyl)-N,N-diethylacrylamide;ENTACAPONE
• CAS NO: 130929-57-6
• Molecular Formula: C₁₄H₁₅N₃O₅
• Molecular Weight: 305.29
• Product Categories: Intermediates & Fine Chemicals;Pharmaceuticals;Histone Methyltransf
• Mol File: 130929-57-6.mol

Chemical Properties

• Melting Point: 162-1630C
• Boiling Point: 526.6 °C at 760 mmHg
• Flash Point: 272.3 °C
• Appearance: white to light brown/
• Density: 1.392 g/cm³
• Vapor Pressure: 1.05E-11mmHg at 25°C
• Refractive Index: 1.641
• Storage Temp.: -20°C Freezer
• Solubility: DMSO: soluble20mg/mL, clear
• PKA: pKa ~4.5(at 25℃)
• Stability: Stable for 1 year from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20°C for up to 1 month.
• CAS DataBase Reference: Entacapone(CAS DataBase Reference)
• NIST Chemistry Reference: Entacapone(130929-57-6)
• EPA Substance Registry System: Entacapone(130929-57-6)

Safety Data

• WGK Germany: 3
• Hazardous Substances Data: 130929-57-6(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Entacapone is used as a COMT inhibitor for the treatment of Parkinson's disease. It acts as a peripherally acting inhibitor of catechol-O-methyl transferase (COMT), an enzyme involved in the metabolism of catecholamine neurotransmitters and related drugs. By inhibiting the metabolism of L-dopa when given as an adjuvant in patients with Parkinson's disease, Entacapone markedly prolongs the effects of L-dopa and improves its bioavailability. Results from clinical studies showed that 200mg/day Entacapone coadministered with L-dopa lowered the dose of the latter required to reduce fluctuations in motor performance.
Entacapone is also used as an adjunct to levodopa/carbidopa in the symptomatic treatment of patients with idiopathic Parkinson's Disease who experience the signs and symptoms of end-of-dose wearing off. It belongs to the cinnamic acid amides, which are amides of cinnamic acids.
Chemical Properties:
Entacapone is a yellow crystalline solid.
Brand Names:
Comtan (Orion), Comtess.

Anti-Parkinson's disease drugs

Entacapone is an anti-Parkinson's disease drug which is successfully developed by Orion Pharma company in Swedish. It is a highly selective potent catechol-O-methyltransferase (COMT) inhibitor, rarely penetrating the blood-brain barrier, and primarily acting in the intestinal tract. It is dose-dependent to decrease levels of 3-OMD in serum and the brain, increasing levodopa, dopamine and DOPAC levels in the brain and significantly reducing the dose which is required to increase dopamine concentration in striatal. Levodopa and carbidopa combining with COMTI can significantly increase the bioavailability of levodopa (3-4 times). Activity of COMTI in red blood cell is reversible. When in 800mg dose, the maximum inhibitory activity is up to 82%, so Entacapone combines with levodopa and carbidopa, which can be used for adjuvant therapy of idiopathic Parkinson's disease.

Pharmacokinetics

This product is rapid oral absorption, the bioavailability is a dose-dependent with the range of 30% to 45%. In the range of 5~800 mg, pharmacokinetics of Entacapone (abbreviation: Ent) is linear, peak plasma concentration is related to AUC and dose. Food does not affect the absorption of this product, 98% Ent combines with plasma albumin, rarely distributing in tissues. In patients with Parkinson disease (abbreviated: PD), and is required to take levodopa/carbidopa, the peak concentration of Ent arrives within 1~2h. The rate of Ent through the blood-brain barrier is low, the plasma elimination half-life is 1.5~3.5h. After oral administration, Ent (E-configuration) is metabolized to Z-isomer in the blood and is present in plasma and red blood cells. Z-isomer has little impact on the clinical efficacy. Its drug-time curve is similar to Ent. Z-Ent accounts for about 5% of the total AUC. Ent and Z-Ent are acidified by glucose in the liver. After metabolism of Ent: 10% excreted in the urine, 90% of Ent excreted in the feces, only 0.2% excreted in the urine in phony drugs. While taking levodopa in PD patients, and oral Ent 200 mg after elimination half-life of about 1 h, the body has no savings. Pharmacokinetic study shows that in healthy persons and patients with PD, Ent can increase the bioavailability of levodopa. In the short-term PD patients taking Ent, AUC of levodopa increase 25%, while the long-term taking Ent can increase 50%. AUC of 3-OMD relatively reduces 60%. In these studies, they found that plasma peak time of levodopa will be extended. Single dose of Entacapone (while not taking levodopa/carbidopa), in patients with liver disease, the patient's AUC and Cmax is 2 times of the patients with normal liver function. We should adjust the dosage of the patient. In patients with mild to moderate kidney disease, it is not necessary to adjust the dosage. Kidney patients receiving dialysis can extend dosing interval. The above information is edited by the lookchem of Liu Yujie.

Chemical property

Crystals, melting point 162--163 ℃.

Production method

1.83 g 3,4-dihydroxy-5-nitrobenzaldehyde and 1.5g N, N-diethyl-cyanoacetamide and a catalytic amount of piperidine acetate are dissolved in 40ml of dry ethanol , followed by stirring overnight , 2.23 g crude product is obtained, yield 73%, melting point 153~156 ℃. Heated at 90 ℃, the 3.0 kg crude product is dissolved in 8.0kg acetic acid (or formic acid) containing 80 g HBr (or 40gHCl).It is slowly cooled to 20 ℃, and stirred at this temperature for 20h, then at 15 ℃ stirred for 6h. The precipitated crystals were collected by filtration, carefully washed with cool (4 ℃) 1L toluene-acetic acid (1: l v/v) mixed solution, and washed with 1L cold toluene. It is dried at 45 ℃under vacuum and 2.4kg crystalline pure Entacapone is obtained, yield 80%, melting point 162-163 ℃.

Originator

Orion Pharma (Finland)

Therapeutic Function

Antiparkinsonian

Biochem/physiol Actions

Entacapone is a catechol-O-methyl transferase (COMT) inhibitor. Used in treatment of Parkinson′s disease, entacapone is administered with L-DOPA to inihibit COMT from converting L-DOPA into a compound that cannot cross the blood brain barrier.

Clinical Use

#N/A

Drug interactions

Potentially hazardous interactions with other drugs Anticoagulants: enhances anticoagulant effect of warfarinAntidepressants: use with caution in combination with moclobemide, tricyclics and venlafaxine; avoid with MAOIs. Dopaminergics: possibly enhances effects of apomorphine; possibly reduces concentration of rasagiline; max dose of selegiline is 10 mg in combination.

Metabolism

Entacapone undergoes extensive first-pass metabolism to form glucuronide metabolites.It is eliminated mainly in the faeces with about 10-20% being excreted in the urine, mainly as glucuronide conjugates

References

1) Forsberg?et al.?(2003),?Pharmacokinetics and pharmacodynamics of entacapone and tolcapone after acute and repeated administration: a comparative study in the rat; J. Pharmacol. Exp. Ther.,?304?498 2) Merello?et al. (1994),?Effect of entacapone, a peripherally acting catechol-O-methyltransferase inhibitor, on the motor response to acute treatment with levodopa in patients with Parkinson’s disease; J. Neurol. Neurosurg. Psychiatry,?57?186 3) Giovanni?et al. (2010),?Entacapone and tolcapone, two catechol O-methyltransferase inhibitors, block fibril formation of alpha-synuclein and beta amyloid and protect against amyloid-induced toxicity; J. Biol. Chem.,?285?14941 4) Chen?et al. (2016),?Entacapone is an Antioxident More Potent than Vitamin C and Vitamin E for Scavenging of Hypochlorous Acid and Peroxynitrite, and the Inhibition of Oxidative Stress-induced Cell Death; Med. Sci. Monit.,?22?687

InChI:InChI=1/C14H15N3O5/c1-3-16(4-2)14(20)10(8-15)5-9-6-11(17(21)22)13(19)12(18)7-9/h5-7,18-19H,3-4H2,1-2H3/b10-5+

Synthetic route

(E)-2-cyano-N,N-diethyl-3-(3-pivaloyloxy-4-hydroxy-5-nitrophenyl)propenamide (345317-61-5) → entacapone (130929-57-6)

Conditions	Yield
With phosphate buffer at 37℃; pH=7.4; Kinetics;	100%

(E)-2-cyano-N,N-diethyl-3-[3-t-butyloxycarbonyloxy-4-hydroxy-5-nitrophenyl]propenamide (404860-98-6) → entacapone (130929-57-6)

Conditions	Yield
With phosphate buffer at 37℃; pH=7.4; Kinetics;	100%

(2E)-2-cyano-3-(3-methoxy-4-hydroxy-5-nitro-phenyl)-N,Ndiethylprop-2-enamide (857629-78-8) → entacapone (130929-57-6)

Conditions	Yield
Stage #1: (2E)-2-cyano-3-(3-methoxy-4-hydroxy-5-nitro-phenyl)-N,Ndiethylprop-2-enamide With aluminum (III) chloride; triethylamine In dichloromethane at 0 - 5℃; for 3 - 4h; Heating / reflux; Stage #2: With hydrogenchloride In dichloromethane at 0 - 20℃; for 0.5h;	98%
With aluminum (III) chloride; triethylamine In dichloromethane	98%
Stage #1: (2E)-2-cyano-3-(3-methoxy-4-hydroxy-5-nitro-phenyl)-N,Ndiethylprop-2-enamide With aluminum (III) chloride; triethylamine In tetrahydrofuran at 0℃; Reflux; Stage #2: With hydrogenchloride In tetrahydrofuran; water for 6h; Solvent; Temperature; Time; Cooling;	92%

2-cyano-N,N-diethyl-3-(4-hydroxy-3-methoxy-5-nitrophenyl)prop-2-enamide (146698-91-1) → entacapone (130929-57-6)

Conditions	Yield
With pyridine; aluminum (III) chloride In dichloromethane at 0 - 45℃; for 2.5h;	94.1%

3,4-dimethoxy entacapone (1067233-93-5) → entacapone (130929-57-6)

Conditions	Yield
Stage #1: 3,4-dimethoxy entacapone With aluminum (III) chloride In N,N-dimethyl-formamide at 5 - 80℃; for 15h; Stage #2: With hydrogenchloride; water In N,N-dimethyl-formamide at 5 - 30℃; for 2.5h; Product distribution / selectivity;	92%
Stage #1: 3,4-dimethoxy entacapone With pyridine; aluminum (III) chloride In N,N-dimethyl-formamide at 5 - 80℃; for 15h; Stage #2: With hydrogenchloride; water In N,N-dimethyl-formamide at 5 - 30℃; for 2h; Product distribution / selectivity;	80%
Stage #1: 3,4-dimethoxy entacapone With boron tribromide In dichloromethane at -15 - 20℃; Stage #2: With water In dichloromethane for 0.5h; Product distribution / selectivity;	74%
With aluminum (III) chloride In pyridine at 80℃;

entacapone; piperidine salt (1047659-01-7) → entacapone (130929-57-6)

Conditions	Yield
With hydrogenchloride In water; isopropyl alcohol at 20 - 30℃;	91.1%

N,N-diethyl-2-cyano-3-(3-ethoxy-4-hydroxy-5-nitrophenyl)acrylamide → entacapone (130929-57-6)

Conditions	Yield
With pyridine; aluminum (III) chloride In dichloromethane at 0 - 45℃; for 50h;	87.3%

C15H16N3O5(1-)*C4H12N(1+) → entacapone (130929-57-6)

Conditions	Yield
With pyridine; aluminum (III) chloride In chloroform at 0℃; for 0.5h; Reflux;	81.1%

2-cyano-N,N-diethylacetamide (26391-06-0) + 3,4-dihydroxy-5-nitrobenzaldehyde (116313-85-0) → entacapone (130929-57-6)

Conditions	Yield
Stage #1: 2-cyano-N,N-diethylacetamide; 3,4-dihydroxy-5-nitrobenzaldehyde With piperidine In 1,2-dimethoxyethane; n-heptane for 15 - 25h; Heating / reflux; Stage #2: In dichloromethane at 25 - 35℃; for 24h; Product distribution / selectivity;	75%
With piperidine In isopropyl alcohol for 12 - 15h; Heating / reflux;	75.5%
Stage #1: 2-cyano-N,N-diethylacetamide; 3,4-dihydroxy-5-nitrobenzaldehyde With acetic acid; diethylamine In toluene Knoevenagel Condensation; Stage #2: With hydrogen bromide In acetic acid; toluene at 20℃;	73.8%

2-cyano-N,N-diethylacetamide (26391-06-0) + 3,4-dihydroxy-5-nitrobenzaldehyde (116313-85-0) → entacapone (130929-57-6) + (2Z)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide (145195-63-7)

Conditions	Yield
Stage #1: 2-cyano-N,N-diethylacetamide; 3,4-dihydroxy-5-nitrobenzaldehyde With piperidine In isopropyl alcohol for 12 - 15h; Heating / reflux; Stage #2: With acetic acid In isopropyl alcohol at 20℃;	A 75.5% B n/a
piperidine; methylamine hydrochloride In butan-1-ol at 82℃; for 4 - 5h; Product distribution / selectivity;
piperidine; methylamine hydrochloride In i-Amyl alcohol at 89 - 90℃; for 3h; Product distribution / selectivity;

2-cyano-3-(3-hydroxy-4-methoxy-5-nitrophenyl)prop-2-eneamide → entacapone (130929-57-6)

Conditions	Yield
Stage #1: 2-cyano-3-(3-hydroxy-4-methoxy-5-nitrophenyl)prop-2-eneamide With triethylamine In ethanol at 70 - 75℃; for 14h; Stage #2: With hydrogenchloride In water Time;	55%

(E)-2-cyano-N,N-diethyl-3-[3,4-bis(pivaloyloxymethoxy)-5-nitrophenyl]propenamide (404860-97-5) → entacapone (130929-57-6)

Conditions	Yield
With phosphate buffer at 37℃; for 4h; pH=7.4; Kinetics;	20%

(2Z)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide (145195-63-7) → entacapone (130929-57-6)

Conditions	Yield
With hydrogenchloride In water; toluene at 7 - 20℃; for 4h; Heating / reflux;	14%

entacapone (686349-59-7) → entacapone (130929-57-6)

Conditions	Yield
iodine In ethyl acetate for 10 - 12h; Product distribution / selectivity; Heating / reflux; Isomerisation;
With hydrogen bromide; acetic acid In water at 15 - 90℃; for 23 - 26h;
With hydrogen bromide; acetic acid at 90℃;

N,N-Hydrochloric diethylcyanoacetamide + 3,4-dihydroxy-5-nitrobenzaldehyde (116313-85-0) → entacapone (130929-57-6)

Conditions	Yield
	2.23 g (73%)

2-cyano-N,N-diethyl-3-(4-hydroxy-3-methoxy-5-nitrophenyl)prop-2-enamide (146698-91-1) → entacapone (130929-57-6) + (2Z)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide (145195-63-7)

Conditions	Yield
With pyridine; aluminum (III) chloride In dichloromethane at 0 - 55℃; for 3.08333 - 4.25h;

isonitrovanillin (6635-20-7) → entacapone (130929-57-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogen bromide / water / 4 h / Reflux 2: 1-methyl-piperazine / methanol / 20 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: piperidine; acetic acid / ethanol / 3 h / Reflux 2.1: N,N-dimethyl-formamide; bis(trichloromethyl) carbonate / chloroform / 2 h / Reflux 2.2: 2 h 3.1: aluminum (III) chloride; pyridine / chloroform / 0.5 h / 0 °C / Reflux View Scheme
Multi-step reaction with 4 steps 1: piperidine; acetic acid / ethanol / 3 h / Reflux 2: thionyl chloride / Reflux 3: ethyl acetate / Cooling with ice 4: aluminum (III) chloride; pyridine / chloroform / 0.5 h / 0 °C / Reflux View Scheme

vanillin (121-33-5) → entacapone (130929-57-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: nitric acid; acetic acid / 0 - 20 °C 2: hydrogen bromide / water / 4 h / Reflux 3: 1-methyl-piperazine / methanol / 20 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1: acetic acid; diethylamine / toluene / Reflux 2: nitric acid 3: aluminum (III) chloride / N,N-dimethyl-formamide / 100 °C View Scheme
Multi-step reaction with 3 steps 1.1: acetic acid; diethylamine / cyclohexane / Reflux 2.1: sodium nitrite; nitric acid / dichloromethane / 2 h / 20 °C 3.1: aluminum (III) chloride; triethylamine / tetrahydrofuran / 0 °C / Reflux 3.2: 6 h / Cooling View Scheme
Multi-step reaction with 3 steps 1.1: acetic acid; nitric acid / water / 4 h / 15 - 30 °C 2.1: tetrabutylammomium bromide; aluminum (III) chloride / dichloromethane / 0.5 h / 0 - 10 °C / Reflux 2.2: 25 h / 0 - 10 °C / Reflux 3.1: piperidine / isopropyl alcohol / 23 h / Reflux View Scheme

3,4-dimethoxy-5-nitrobenzoyl chloride (134610-30-3) → entacapone (130929-57-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium hydride / tetrahydrofuran / -5 °C 2: sodium tris(acetoxy)borohydride / 45 °C 3: aluminum (III) chloride / pyridine / 80 °C View Scheme

(2E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)prop-2-enoic acid (160391-70-8) → entacapone (130929-57-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: thionyl chloride / 25 - 80 °C 2: diethylamine / dichloromethane / 2.33 h / -5 - 0 °C View Scheme

(2E)-2-cyano-3-(3-methoxy-4-hydroxy-phenyl)-N,N-diethylprop-2-enamide (893419-47-1) → entacapone (130929-57-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: nitric acid 2: aluminum (III) chloride / N,N-dimethyl-formamide / 100 °C View Scheme

2-cyano-3-(3,4-dimethoxy-5-nitrophenyl)-3-hydroxy-N,N-diethyl-prop-2-enamide → entacapone (130929-57-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium tris(acetoxy)borohydride / 45 °C 2: aluminum (III) chloride / pyridine / 80 °C View Scheme

(2E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-2-propenoyl chloride (1291066-63-1) → entacapone (130929-57-6)

Conditions	Yield
With diethylamine In dichloromethane at -5 - 0℃; for 2.33333h;

2-cyano-N,N-diethylacetamide (26391-06-0) → entacapone (130929-57-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: acetic acid; diethylamine / toluene / Reflux 2: nitric acid 3: aluminum (III) chloride / N,N-dimethyl-formamide / 100 °C View Scheme
Multi-step reaction with 3 steps 1.1: acetic acid; diethylamine / cyclohexane / Reflux 2.1: sodium nitrite; nitric acid / dichloromethane / 2 h / 20 °C 3.1: aluminum (III) chloride; triethylamine / tetrahydrofuran / 0 °C / Reflux 3.2: 6 h / Cooling View Scheme

3,4-dihydroxy-5-nitrobenzaldehyde (116313-85-0) → entacapone (130929-57-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: piperidine; acetic acid / ethanol / 4 h / 80 °C 2: thionyl chloride / 25 - 80 °C 3: diethylamine / dichloromethane / 2.33 h / -5 - 0 °C View Scheme

4,5-Dimethoxy-3-nitrobenzoic acid (91004-48-7) → entacapone (130929-57-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: thionyl chloride / toluene / 60 °C 2: sodium hydride / tetrahydrofuran / -5 °C 3: sodium tris(acetoxy)borohydride / 45 °C 4: aluminum (III) chloride / pyridine / 80 °C View Scheme

2-methoxy-4-iodophenol (203861-62-5) → entacapone (130929-57-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: triethylamine; tetrakis(triphenylphosphine) palladium(0); triphenylphosphine / N,N-dimethyl-formamide / 5 h / 95 - 100 °C / Inert atmosphere 2: nitric acid; acetic acid / 15 °C 3: pyridine; aluminum (III) chloride / dichloromethane / 0 - 45 °C View Scheme

2-cyano-N,N-diethylacrylamide (53793-77-4) → entacapone (130929-57-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: triethylamine; tetrakis(triphenylphosphine) palladium(0); triphenylphosphine / N,N-dimethyl-formamide / 5 h / 95 - 100 °C / Inert atmosphere 2: nitric acid; acetic acid / 15 °C 3: pyridine; aluminum (III) chloride / dichloromethane / 0 - 45 °C View Scheme

isonitrovanillin (6635-20-7) + 2-cyano-N,N-diethylacetamide (26391-06-0) → entacapone (130929-57-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: IRA 96 resin / toluene / Reflux 2: triethylamine; ethanol / 12 h / 70 - 75 °C View Scheme

butyryl chloride (141-75-3) + entacapone (130929-57-6) → (E)-2-cyano-N,N-diethyl-3-[3,4-dibutyryloxy-5-nitrophenyl]propenamide

Conditions	Yield
With triethylamine In tetrahydrofuran at 20℃; for 15h;	93%

diethylamine (109-89-7) + entacapone (130929-57-6) → C14H15N3O5*C4H11N

Conditions	Yield
In ethanol at 25 - 30℃;	92%

entacapone (130929-57-6) + (2Z)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide (145195-63-7) → entacapone; sodium salt (1047659-02-8)

Conditions	Yield
With sodium hydroxide In ethanol; water at 20℃;	87.1%

(pivaloyloxy)acetic acid (89941-82-2) + entacapone (130929-57-6) → (E)-2-cyano-N,N-diethyl-3-[3,4-bis(pivaloyloxyacetyloxy)-5-nitrophenyl]propenamide

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In ethyl acetate at 20℃;	85%

N-ethyl-N,N-diisopropylamine (7087-68-5) + entacapone (130929-57-6) → C14H15N3O5*C8H19N

Conditions	Yield
In ethanol at 25 - 30℃;	80%

triethylamine (121-44-8) + entacapone (130929-57-6) → C14H15N3O5*C6H15N

Conditions	Yield
In ethanol at 25 - 30℃;	78%

piperidine (110-89-4) + entacapone (130929-57-6) → entacapone; piperidine salt (1047659-01-7)

Conditions	Yield
In ethanol at 25 - 30℃;	77%
In ethanol

morpholine (110-91-8) + entacapone (130929-57-6) → C14H15N3O5*C4H9NO

Conditions	Yield
In ethanol at 25 - 30℃;	76%

acetic anhydride (108-24-7) + entacapone (130929-57-6) → (E)-2-cyano-N,N-diethyl-3-(3,4-diacetyloxy-5-nitrophenyl)propenamide

Conditions	Yield
With sulfuric acid In ethyl acetate at 50℃; for 2h;	74%

di-tert-butyl dicarbonate (24424-99-5) + entacapone (130929-57-6) → (E)-2-cyano-N,N-diethyl-3-[3-t-butyloxycarbonyloxy-4-hydroxy-5-nitrophenyl]propenamide (404860-98-6)

Conditions	Yield
With 15-crown-5; sodium carbonate In tetrahydrofuran at 50℃; for 12h;	64%

iodomethyl pivaloate (53064-79-2) + entacapone (130929-57-6) → (E)-2-cyano-N,N-diethyl-3-[3,4-bis(pivaloyloxymethoxy)-5-nitrophenyl]propenamide (404860-97-5)

Conditions	Yield
With potassium carbonate In acetone at 20℃;	56%

entacapone (130929-57-6) + (valeroyloxy)acetic acid → (E)-2-cyano-N,N-diethyl-3-[3,4-bis(valeryloxyacetyloxy)-5-nitrophenyl]propenamide

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In tetrahydrofuran at 20℃;	52%

2,2-dimethylpropanoic anhydride (1538-75-6) + entacapone (130929-57-6) → (E)-2-cyano-N,N-diethyl-3-(3-pivaloyloxy-4-hydroxy-5-nitrophenyl)propenamide (345317-61-5)

Conditions	Yield
With sulfuric acid at 50℃; for 2h;	48%

entacapone (130929-57-6) → 2-cyano-N,N-diethyl-3-(2-hydroxy-7-nitro-2-oxo-2λ5-benzo[1,3,2]dioxaphosphol-5-yl)-acrylamide + C14H13N3O8P(3-)*3Na(1+)

Conditions	Yield
Stage #1: entacapone With pyridine; trichlorophosphate at 0 - 20℃; for 2h; phosphorylation; Stage #2: With sodium hydroxide In methanol Hydrolysis;	A n/a B 45%

pivaloyl chloride (3282-30-2) + entacapone (130929-57-6) → (E)-2-cyano-N,N-diethyl-3-[3,4-dipivaloyloxy-5-nitrophenyl]propenamide

Conditions	Yield
With pyridine; dmap at 20℃; for 15h;	45%

entacapone (130929-57-6) + Acetoxyacetyl chloride (13831-31-7) → (E)-2-cyano-N,N-diethyl-3-[3,4-bis(acetoxyacetyloxy)-5-nitrophenyl]propenamide

Conditions	Yield
With triethylamine In tetrahydrofuran at 20℃; for 15h;	28%

Upstream product

• 345317-61-5 (E)-2-cyano-N,N-diethyl-3-(3-pivaloyloxy-4-hydroxy-5-nitrophenyl)propenamide 
• 145195-63-7 (2Z)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide 
• 857629-78-8 (2E)-2-cyano-3-(3-methoxy-4-hydroxy-5-nitro-phenyl)-N,Ndiethylprop-2-enamide 
• 686349-59-7 entacapone 
• 116313-85-0 3,4-dihydroxy-5-nitrobenzaldehyde 
• 146698-91-1 2-cyano-N,N-diethyl-3-(4-hydroxy-3-methoxy-5-nitrophenyl)prop-2-enamide 
• 1047659-01-7 entacapone; piperidine salt 
• 1067233-93-5 3,4-dimethoxy entacapone 
• 6635-20-7 isonitrovanillin 
• 121-33-5 vanillin 
• 134610-30-3 3,4-dimethoxy-5-nitrobenzoyl chloride 
• 160391-70-8 (2E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)prop-2-enoic acid 
• 893419-47-1 (2E)-2-cyano-3-(3-methoxy-4-hydroxy-phenyl)-N,N-diethylprop-2-enamide 
• 1291066-63-1 (2E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-2-propenoyl chloride 

Downstream Products

• 404860-98-6 (E)-2-cyano-N,N-diethyl-3-[3-t-butyloxycarbonyloxy-4-hydroxy-5-nitrophenyl]propenamide 
• 404860-97-5 (E)-2-cyano-N,N-diethyl-3-[3,4-bis(pivaloyloxymethoxy)-5-nitrophenyl]propenamide 
• 404860-94-2 (E)-2-cyano-N,N-diethyl-3-[3,4-dibenzoyloxy-5-nitrophenyl]propenamide 
• 1047659-01-7 entacapone; piperidine salt 
• 1047659-02-8 entacapone; sodium salt 

Relevant articles and documents

Synthesis of entacapone by Pd-catalyzed heck coupling reaction

Synthesis of entacapone from 4-iodo-2-methoxy-phenol with 2-cyano-N,N-diethylacrylamide by palladium-catalyzed Heck reaction, as a key step, is described.

Method for producing entacapone

The present invention relates to an entacapone production method, which comprises a nitration reaction, a de-methylation reaction and a condensation reaction. The nitration reaction is completed by glacial acetic acid, vanillin and 65% nitric acid within 3-5 hours; the de-methylation reaction is completed by reaction among nitrovanillin, dichloromethane, tetrabutyl ammonium bromide, anhydrous aluminum chloride and pyridine; and the condensation reaction is completed by reaction among isopropanol, 3,4-dihydroxyl-5-nitro benzaldehyde, N,N-diethyl cyanoacetamide and piperidine. The entacapone production method provided by the invention is high in yield, high in purity and stable in quality.

Entacapone preparation method

The invention relates to an entacapone preparation method, which comprises: carrying out condensation on 3-alkoxy-4-hydroxybenzaldehyde and cyanoacetic acid to generate an intermediate 2-cyano-acrylicacid (III), carrying out a reaction on the compound (III) and a halogenating agent to generate an acyl halide (IV), carrying out a reaction on the acyl halide (IV) and diethylamine to generate the salt (V) of entacapone alkyl ether, and carrying out acidolysis demethylation on the salt (V) in a suitable solvent to generate entacapone (I). According to the present invention, the method has characteristics of convenient operation, mild reaction conditions and high in yield, and is suitable for large-scale industrial production. The formulas (I), (III), (IV) and (V) are defined in the specification.

A new synthesis of Entacapone and report on related studies

A new synthesis of the catechol-O-methyltransferase (COMT) inhibitor, entacapone (E-isomer) has been achieved under mild conditions by amine-mediated demethylation of the precursor 2-Cyano-3-(3- hydroxy-4-methoxy-5-nitrophenyl) prop-2-eneamide, wherein the methoxyl group adjacent to a nitro group gets demethylated under nucleophilic attack. Similar demethylation was achieved on ethyl 2-cyano-3-(3, 4-dimethoxy-5-nitrophenyl) prop-2-enoate, 2-cyano-3-(3,4-dimethoxy-5-nitrophenyl)-N,N-diethylprop-2-enamide, ethyl 2-cyano-3-(3-hydroxy-4-methoxy-5-nitrophenyl) prop-2-enoate and ethyl 2-cyano-3-(4-methoxy-3-nitrophenyl) prop-2-enoate. The scope of demethylation has been studied. Analogues of ethyl 2-cyano-3-(3, 4-dimethoxy-5-nitrophenyl) prop-2-enoate wherein a methoxyl group is not adjacent to a NO 2 group are unaffected and phenolic derivatives yield the amine salts. Entacapone has been converted to salts with organic bases. The crystal structure of the isomer of entacapone (Z-isomer), a significant human metabolite of E-isomer has been established. NMR methods for deriving E and Z geometry and other similar molecules have been successfully established, mainly by studying the proton coupled 13C spectra. Preliminary studies reveal in vitro activity for some compounds against tuberculosis (TB) and dengue. [Figure not available: see fulltext.]

Novel triethylamine mediated thermal reactions of 3-aryl-2-cyanoprop-2-enoic acid derivatives - Demethylation, reduction and vinylogation

3-Aryl-2-propenoic acid derivatives undergo interesting reactions with hot triethylamine. Substrates like 6 having a methoxyl with a nitro in the ortho and cyanoacrylic derivatives in the para positions give O-demethylated products, for example, entacapone 7. On the other hand compounds like 16 having the NO2 in the para and cyanoacrylic in the ortho position undergo reduction and vinylogation. The latter phenomenon is observed in the absence of the NO2 group also.

DENGUE AND WEST NILE VIRUS PROTEASE INHIBITORS

Compounds and methods of treating or preventing a Flavivirus infection in a subject are provided. The methods comprise administering to the subject a therapeutically effective amount of a compound as described herein. The methods are useful in treating and/or preventing Flavivirus infections such as, for example, West Nile Virus, Dengue Virus, and Japanese Encephalitis Virus. Methods of inhibiting a Flavivirus protease in a cell are also provided.

PROCESS FOR THE PREPARATION OF ENTACAPONE AND ITS INTERMEDIATE THEREOF

Provided herein are processes for preparing a compound of Formula (V), comprising nitrating a compound of Formula (IV), with a nitrating agent in the presence of a catalyst.

Efficient approach to pure entacapone and related compounds

A new and efficient process through a new intermediate, (2E)-2-cyano-3-(3,4-dihydroxy-5-nirtrophenyl)prop-2-enoic acid 15, has been described for preparing substantially pure entacapone 1. This new intermediate 15 was prepared by Knoevenagel condensation of 3,4-dihydroxy-5-nitrobenzaldehyde 2 with 2-cyanoacetic acid 14 and was further condensed with diethylamine to get pure entacapone 1. Some of the important process-related impurities of entacapone (17, 18, 19, and 20) were also prepared easily from this intermediate 15. Copyright Taylor & Francis Group, LLC.

Arylcyanoacrylamides as inhibitors of the Dengue and West Nile virus proteases

The 3-aryl-2-cyanoacrylamide scaffold was designed as core pharmacophore for inhibitors of the Dengue and West Nile virus serine proteases (NS2B-NS3). A total of 86 analogs was prepared to study the structure-activity relationships in detail. Thereby, it turned out that the electron density of the aryl moiety and the central double bond have a crucial influence on the activity of the compounds, whereas the influence of substituents of the amide residue is less relevant. The para-hydroxy substituted analog was found to be the most potent inhibitor in this series with a Ki-value of 35.7 μM at the Dengue and 44.6 μM at the West Nile virus protease. The aprotinin competition assay demonstrates a direct interaction of the inhibitor molecule with active centre of the Dengue virus protease. The target selectivity was studied in a counterscreen with thrombin and found to be 2.8:1 in favor of DEN protease and 2.3:1 in favor of WNV protease, respectively.

PROCESS FOR THE PREPARATION OF ENTACAPONE

The present invention relates to an improved process for the preparation of Entacapone of formula (I) comprising a step of, condensation of 3,4-dihydroxy-5-nitrobenzaldehyde of formula (II) with N,N-diethylcyanoacetamide of formula (III) in the presence of two component solvent system, a catalyst and optionally a phase transfer catalyst to give Entacapone of formula (I).