Opicapone Chemical Properties

Boiling point:

701.1±70.0 °C(Predicted)

Density 

1.80±0.1 g/cm3(Predicted)

solubility 

DMSO : 100 mg/mL (242.03 mM; Need ultrasonic)H2O : < 0.1 mg/mL (insoluble)

form 

Powder

pka

4.67±0.38(Predicted)

color 

Light yellow to yellow

InChI

InChI=1S/C15H10Cl2N4O6/c1-5-10(13(17)20(24)6(2)11(5)16)14-18-15(27-19-14)7-3-8(21(25)26)12(23)9(22)4-7/h3-4,22-23H,1-2H3

InChIKey

ASOADIZOVZTJSR-UHFFFAOYSA-N

SMILES

C1(O)=CC(C2ON=C(C3C(C)=C(Cl)C(C)=[N+]([O-])C=3Cl)N=2)=CC([N+]([O-])=O)=C1O

Opicapone Usage And Synthesis

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.

Definition

ChEBI: Opicapone is a ring assembly and an oxadiazole.

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.

storage

Store at -20°C