Tuesday, March 24, 2015


Common name: Tolcapone; Ro-40-7592; Tasmar
Trademarks: Tasmar
Molecular Formula: C14H11NO5
CAS Registry Number: 134308-13-7
CAS Name: (3,4-dihydroxy-5-nitrophenyl)(4-methylphenyl)methanone
Molecular Weight: 273.241
SMILES: CC1=CC=C(C=C1)C(=O)C1=CC(=C(O)C(O)=C1)[N+]([O-])=O
InChI: InChI=1S/C14H11NO5/c1-8-2-4-9(5-3-8)13(17)10-6-11(15(19)20)14(18)12(16)7-10/h2-7,16,18H,1H3
Activity:  Treatment of Parkinson's Disease; COMT Inhibitors; Antiparkinsonian Drugs
Status: Launched 1997; Withdrawn 1998; Re-launched 2009
Originator: Chugai; Roche/Bristol-Myers Squibb

Tolcapone synthesis: Helv Chim Acta 1989, 72, 952-968 (Also Ref. 2, 3)

Raw Materials:
Lithium; 4-Benzyloxy-3-methoxybenzaldehyde; 4-Bromotoluene; Hydrogen bromide; Nitric acid


Step a: 143.8 ml of n-butyllithium solution (1.53M in hexane) are added dropwise at -70° within 30 minutes to 35.0 g of 4-bromotoluene (dissolved in 600 ml of tetrahydrofuran), After stirring at -70° for 60 minutes 48.5 g of 3-methoxy-4-benzyloxybenzaldehyde (dissolved in 450 ml of tetrahydrofuran) are added dropwise thereto during 30 minutes. The reaction mixture is stirred at -70° for 2 hours and at 0° for 30 minutes, poured into a mixture of ice and 150 ml of 2N sulfuric acid and extracted three times with 500 ml of ether. The combined ether phases are washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. There is obtained 4-(benzyloxy)-3-methoxy-4'-methylbenzhydrol as a yellowish oil which can be used directly in the subsequent reaction step.

Step b: 69.8 g of 4-(benzyloxy)-3-methoxy-4'-methylbenzhydrol (dissolved in 600 ml of methylene chloride) are treated within 30 minutes at 20° with 45.3 g of pyridinium chlorochromate and stirred at 20° for 3 hours. The precipitate formed is subsequently filtered and washed with methylene chloride. The filtrate is evaporated and the residue is filtered on 100 g of silica gel with ether. After recrystallization from ether, there is obtained 4-(benzyloxy)-3-methoxy-4'-methylbenzophenone.

Step c: 170 ml of 33 percent hydrobromic acid in glacial acetic acid are added at 20°-25° within 20 minutes to 42.4 g of 4-(benzyloxy)-3-methoxy-4'-methylbenzophenone (dissolved in 450 ml of methylene chloride). After stirring at 20° for 1.5 hours, the reaction mixture is poured into 750 ml of ice-water; the methylene chloride phase is separated and the aqueous phase is extracted twice more with 200 ml of methylene chloride. The combined methylene chloride phases are washed with 1200 ml of water, dried over sodium sulfate and evaporated. In order to remove the resulting benzyl bromide, the oily residue is treated with hexane and decanted off. There is obtained 4-hydroxy-3-methoxy-4'-methylbenzophenone as a yellowish oil which can be used directly in the subsequent reaction step.

Step d: 7.8 ml of 65 percent nitric acid are added dropwise at 20° within 20 minutes to 29.4 g of 4-hydroxy-3-methoxy-4'-methylbenzophenone (dissolved in 450 ml of acetic acid). After stirring for 1.5 hours, the reaction mixture is poured into 2 l of ice-water and the precipitate formed is filtered off, washed with water and dissolved in methylene chloride. The methylene chloride solution is washed with water, dried over sodium sulfate and evaporated. The residue is recrystallized from methanol. There is obtained 4-hydroxy-3-methoxy-4'-methyl-5-nitrobenzo-phenone of m.p. 137°-139° (from methylene chloride/ether).

Step e: 24.8 g of 4-hydroxy-3-methoxy-4'-methyl-5-nitrobenzo-phenone (dissolved in 120 ml of glacial acetic acid, 100 ml of 33 percent hydrobromic acid in glacial acetic acid and 68 ml of 48 percent aqueous hydrobromic acid) are boiled under reflux for 4 hours. The reaction mixture is subsequently evaporated under reduced pressure and the residue is distilled with toluene. The residue is dissolved in methylene chloride, washed with water, dried over sodium sulfate, filtered and evaporated. The product is crystallized from methylene chloride/low-boiling petroleum ether. There is obtained  3,4-dihydroxy-4'-methyl-5-nitrobenzophenone  (Tolcapone, Ro 40-7592) of m.p. 146°-148° (from methylene chloride).

Side-effect: TASMAR (tolcapone) should ordinarily be used in patients with Parkinson's disease on L-dopa/carbidopa who are experiencing symptom fluctuations and are not responding satisfactorily to or are not appropriate candidates for other adjunctive therapies. TASMAR should be discontinued if SGPT/ALT or SGOT/AST levels exceed 2 times the upper limit of normal or if clinical signs and symptoms suggest the onset of hepatic dysfunction (persistent nausea, fatigue, lethargy, anorexia, jaundice, dark urine, pruritus, and right upper quadrant tenderness).

1. Borgulya, J.; et. al. Catechol-O-methyltransferase-inhibiting pyrocatechol derivatives: Synthesis and structure-activity studies. Helv Chim Acta 1989, 72, 952-968.
2. Bernauer, K.; et. al. Catechol derivatives. US5476875
3. Bernauer, K.; et. al. 3,5-Disubstituierte Pyrocatecholderivate. EP0237929B1