923287-50-7

Basic information

• Product Name: Opicapone
• Synonyms: Opicapone;Opicapone (BIA 9-1067);5-[3-(2,5-Dichloro-4,6-dimethyl-1-oxido-3-pyridinyl)-1,2,4-oxadiazol-5-yl]-3-nitro-1,2-benzenediol;BIA 9-1067;1,2-Benzenediol, 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxido-3-pyridinyl)-1,2,4-oxadiazol-5-yl]-3-nitro-;2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide
• CAS NO: 923287-50-7
• Molecular Formula: C15H11Cl2N4O6-
• Molecular Weight: 414.17704
• Mol File: 923287-50-7.mol
• Article Data: 6

Chemical Properties

• Boiling Point: 701.1±70.0 °C(Predicted)
• Appearance: /
• Density: 1.80±0.1 g/cm3(Predicted)
• PKA: 4.67±0.38(Predicted)
• CAS DataBase Reference: Opicapone(CAS DataBase Reference)
• NIST Chemistry Reference: Opicapone(923287-50-7)
• EPA Substance Registry System: Opicapone(923287-50-7)

Safety Data

• Hazardous Substances Data: 923287-50-7(Hazardous Substances Data)

Usage

Description

Opicapone is a selective and reversible catechol O-methyltransferase (COMT) inhibitor that was developed by the Portuguese pharmaceutical firm Bial and sold to Neurocrine Biosciences. The drug was approved by the USFDA as adjunctive treatment to levodopa (L-Dopa)/ dopa-decarboxylase inhibitor (DDCI) therapy in adults with Parkinson’s disease (PD) and end-of-dose motor fluctuations that cannot be stabilized on those combinations. In 14- to 15- week double-blind multinational trials and in one-year openlabel extension studies in this patient population, opicapone was an effective and generally well-tolerated adjunctive therapy to L-Dopa plus a DDCI and other PD therapies. During the double-blind phase, adjunctive opicapone (50 mg once daily) provided significantly greater improvements in motor fluctuations than placebo, and no new unexpected safety concerns were identified after treatment with opicapone over a 1.4 year period. Furthermore, no serious cases of hepatotoxicity were reported in clinical trials, which represents a significant safety profile improvement over existing standard-of-care COMT inhibitors enticapone, tolcapone, and nebicapone.

Uses

Opicapone, is used for the synthesis of novel nitrocatechol-substituted heterocycles, having the ability to inhibit catechol-O-methyltransferase (COMT), used for the treatment of Parkinson`s diseases.

Synthesis

Although several synthetic approaches to opicapone or opicapone subunits have been disclosed, a synthetic approach described by Bial was exemplified on a scale capable of producing 14.4 kg of the active pharmaceutical ingredient (API). Commercial 2,4-pentanedione (114) was condensed with cyanoacetamide in warm methanol to give rise to cyanopyridone 115 in excellent yield. Chlorination with sulfuryl chloride in chilled acetonitrile followed by treatment with phosphorus oxychloride resulted in dichloropyridine 117. Next, treatment with hydroxylamine in aqueous methanol converted nitrile 117 to the corresponding Nhydroxyamidine 118, and this was followed by exposure to pyridine and acid chloride 119. These operations facilitated a cyclization reaction, which furnished the key oxadiazole 120 in good yield. Subjection of 120 to urea hydrogen peroxide (UHP) in dichloromethane to establish the pyridine N-oxide functionality within opicapone preceded methyl ether cleavage through the use of aluminum trichloride in warm pyridine to furnish opicapone (X) in 53% yield for the two-step sequence. The preparation of acid chloride 119 involved the nitration of commercially available benzoic acid 121 followed by thionyl chloride-mediated conversion of the resulting nitrobenzoic acid 122 to acid chloride 119. Interestingly, although the nitration step is low-yielding and involves nitric acid, the authors report an operationally simple isolation method that has been exemplified on multiple kilogram scale. No yield was reported for the conversion of 122 to 119.

Upstream product

• 22027-96-9 5-nitroveratral 
• 91004-48-7 4,5-Dimethoxy-3-nitrobenzoic acid 
• 923288-55-5 3,4-bis(benzyloxy)-5-nitrobenzoic acid 
• 91591-63-8 2,5-dichloro-4,6-dimethylpyridine-3-carbonitrile 
• 15785-54-3 5-nitrovanillic acid 
• 923288-59-9 2,5-dichloro-N'-hydroxy-4,6-dimethylnicotinimidamide 
• 1391712-50-7 5-[3-(2,5-dichloro-4,6-dimethyl-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-2-hydroxy-3-methoxy-1-nitrobenzene 
• 42590-00-1 4-hydroxy-3-methoxy-5-nitrobenzoic acid methyl ester 
• 3943-74-6 4-hydroxy-3-methoxybenzoic acid methyl ester 
• 121-34-6 3-methoxy-4-hydroxybenzoic acid 
• 896125-90-9 (Z)-2,5-dichloro-N'-hydroxy-4,6-dimethylnicotinimidamide 
• 1402714-41-3 5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-2-hydroxy-3-methoxy-1-nitrobenzene 
• 23819-92-3 5-chloro-4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile 
• 769-28-8 3-Cyano-4,6-dimethyl-2(1H)-pyridon 

Relevant articles and documents

PROCESS FOR THE PREPARATION OF OPICAPONE AND INTERMEDIATES THEREOF

The present invention i s relates to a process for the preparation of opicapone and a process to prepare intermediates to be used therein.

CHEMICAL COMPOUND USEFUL AS INTERMEDIATE FOR PREPARING A CATECHOL-O-METHYLTRANSFERASE INHIBITOR

There is disclosed a methylated intermediate which may be demethylated to provide an inhibitor of catechol-O-methyltransferase useful in the treatment of Parkinson's disease. Also disclosed are methods of making and using said intermediate.

DOSAGE REGIMEN FOR COMT INHIBITORS

The invention relates to the use of an oxodiazolyl compound (I) for the preparation of a medicament for the prevention or treatment of central and peripheral nervous system associated disorders, wherein said medicament is administered according to a dosing regimen having a dosing periodicity ranging from about twice a day to about once every other day.