ChemicalBook > Product Catalog > Pharmaceutical intermediates > Heterocyclic compound > Pyran compounds > TRIOXSALEN
TRIOXSALEN Chemical Properties
- Melting point:229-231 °C(lit.)
- Boiling point:310.05°C (rough estimate)
- Density 1.2196 (rough estimate)
- refractive index 1.5557 (estimate)
- storage temp. 2-8°C
- solubility DMSO: soluble
- form powder
- color white
- Merck 14,9735
- BRN 221723
- CAS DataBase Reference3902-71-4
- IARC3 (Vol. 40, Sup 7) 1987
- EPA Substance Registry System7H-Furo[3,2-g]benzopyran-7-one, 2,5,9-trimethyl- (3902-71-4)
TRIOXSALEN Usage And Synthesis
- Chemical PropertiesWhite to slightly beige crystalline powder
- Usesmelanizing agent, antipsoriatic
- DefinitionChEBI: 7H-Furo[3,2-g]chromen-7-one in which positions 2, 5, and 9 are substituted by methyl groups. Like other psoralens, trioxsalen causes photosensitization of the skin. It is administered orally in conjunction with UV-A for phot therapy treatment of vitiligo. After photoactivation it creates interstrand cross-links in DNA, inhibiting DNA synthesis and cell division, and can lead to cell injury; recovery from the cell injury may be followed by increased melanisation of the epidermi .
- IndicationsTrioxsalen (Trisoralen) followed by UVA exposure is used to repigment vitiliginous areas and in photochemotherapy.
- Manufacturing Process(A) Preparation of 7-Hydroxy-4,8-Dimethylcoumarin: Chilled ethyl
acetoacetate (157 ml, 1.20 mols) followed by 2-methyl-resorcinol (130 g,
1.04 mols) was dissolved in well-stirred concentrated sulfuric acid (600 ml) at
such a rate as to keep the temperature below 10°C (ice bath). The stirred
solution was allowed to warm gradually and after 3 hours was added to water
(ca 8 liters) with mechanical stirring. The product was collected, washed twice
with water, and dried at 70° to 80°C until the first sign of darkening. Yield
191.3 g (95.4%). Recrystallization from aqueous ethanol gave 7-hydroxy-4,8-
dimethylcoumarin as colorless needles, MP 260.5° to 261°C. In dilute sodium
hydroxide, the compound gives a yellow solution which exhibits blue
fluorescence. (B) Preparation of 7-Allyloxy-4,8-Dimethylcoumarin: 7-Hydroxy-4,8-
dimethylcoumarin (191.3 g, 1.01 mols), anhydrous potassium carbonate (604
g, 4.37 mols), and allyl bromide (578 ml, 6.22 mols) were refluxed overnight
in acetone (ca 3 liters) with mechanical stirring. The reaction mixture was
concentrated nearly to dryness on a steam bath under reduced pressure,
water (ca 8 liters) was added, and the product was collected by filtration. It
was washed with 5% NaOH and water (ca 1.5-liter portions) and was dried in
a vacuum desiccator. The dry solid was washed with petroleum ether (30° to
60°C) to remove excess allyl bromide. Removal of the petroleum ether under
reduced pressure left 210.0 g (90.7% yield) of product. The 7-allyloxy-4,8-
dimethylcoumarin was crystallized from aqueous ethanol as colorless needles,
MP 108° to 109°C.
(C) Preparation of 6-Allyl-7-Hydroxy-4,8-Dimethylcoumarin: 7-Allyloxy-4,8- dimethylcoumarin (195.0 g, 0.84 mol) was heated (oil bath) to 2154°C (reaction mixture temperature) for 3 hours and was then poured into absolute alcohol (ca 1.5 liters). Activated carbon (Norite) (19.5 g) was added, and the solution was heated to boiling, filtered, and diluted with excess water (ca 12 liters). The product was collected by filtration and partially dried at 70°C for 6 hours. 6-Allyl-7-hydroxy-4,8-dimethylcoumarin was obtained as pale yellow microcrystalline prisms, MP 166° to 168°C, by two recrystallizations from aqueous ethanol of a portion of the partially dried solid. The remaining partially dried solid was used in the next step.
(D) Preparation of 7-Acetoxy-6-Allyl-4,8-Dimethylcoumarin: A solution of the partially dried 6-allyl-7-hydroxy-4,8-dimethylcoumarin obtained in the previous step, acetic anhydride (915 ml, 9.7 mols) and fused sodium acetate (2 g) was refluxed for 4 hours and added to water (ca 8 liters) with mechanical stirring. After excess acetic anhydride had decomposed, the 7- acetoxy-6-allyl-4,8-dimethylcoumarin was collected by filtration, dried, and recrystallized from absolute alcohol, MP 144.5° to 145.5°C. Yield 145.4 g (63.8%, based on 7-allyloxy-4,8-dimethylcoumarin).
(E) Preparation of 7-Acetoxy-6-(2',3'-Dibromopropyl)-4,8-Dimethylcoumarin: 7-Acetoxy-6-allyl-4,8-dimethylcoumarin (145.4 g, 0.534 mol) was dissolved in chloroform (ca 800 ml). The stirred solution was cooled in an ice bath and bromine (85.2 g, 0.534 mol) in chloroform (200 ml) was added at such a rate as to keep the temperature below 25°C. Evaporation of chloroform on the steam bath left an off-white residue of the crude dibromide. Yield 230.6 g (quantitative). 7-Acetoxy-6-(2',3'-dibromopropyl)-4,8-dimethylcoumarin was crystallized from ethanol as colorless prisms, MP 141.5° to 142.5°C. (F) Preparation of 2',4,8-Trimethylpsoralen: Crude 7-acetoxy-6-(2',3'- dibromopropyl)-4,8-dimethylcoumarin (245.7 g, 0.57 mol) was refluxed for 1 1/2 hours with a stirred solution of sodium (65.4 g, 2.85 mols) in a magnesium-dried ethanol (2.1 liters). After standing at room temperature for 15 minutes, the reaction mixture was poured into a stirred mixture of ice (8,000 g) and a 3.5% HCl (8 liters). Twelve hours later, the precipitate had coagulated and was collected by filtration; it was thoroughly washed with successive 3-liter portions of 5% NaOH, water, 0.5% HCl, and water. After partial drying at 60°C for 5 hours, the crude trimethylpsoralen material was thoroughly dried in a vacuum desiccator. Yield 110.1 g (85%). Fractional crystallization, using activated carbon (Norite) (30.8 g), from mixtures of chloroform and petroleum ether (30° to 60°C) and finally from chloroform alone gave colorless prisms of 2',4,8-trimethylpsoralen, MP 234.5° to 235°C. Yield 61.8 g (48%)
- brand nameTrisoralen (Valeant).
- Therapeutic FunctionDermal pigmentation enhancer
- Purification MethodsPurify trioxsalen by recrystallisation from CHCl3. If too impure, it is fractionally crystallised from CHCl3/pet ether (b 30-60o) using Norit and finally crystallised from CHCl3 alone to give colourless prisms, m 234.5-235o. It is a photosensitiser so it should be stored in the dark. [UV: Kaufmann J Org Chem 26 117 1961, Baeme et al. J Chem Soc 2976 1949, Beilstein 19/4 V 472.]
TRIOXSALEN Preparation Products And Raw materials
- 3-(HYDROXYMETHYL)-2,5,9-TRIMETHYL-7H-FURO[3,2-G]BENZOPYRAN-7-ONE Psoralen 1-(O-B-D-GALACTOPYRANOSYL)*METHYL TRIOXSALEN TRIOXSALEN(RG) 1-(O-BETA-D)-GALACTOPYRANOSYL)METHYL TRIOXSALEN 1-(O-?-D)-GALACTOPYRANOSYL)METHYL TRIOXSALEN 1,15-bis(4'-trioxsalen)-2,6,10,14-tetramethyl-2,6,10,14-tetrazapentadecane 3-(2-HYDROXY-ETHOXYMETHYL)-2,5,9-TRIMETHYL-FURO[3,2-G]CHROMEN-7-ONE TRIOXSALEN 3-CHLOROMETHYL-2,5,9-TRIMETHYL-7H-FURO[3,2-G]BENZOPYRAN-7-ONE PSORALEN-C 2 CEP 3-(6-HYDROXYHEXYL)METHYL-2,5,9-TRIMETHYL-7H-FURO[3,2-G]-BENZOPYRAN-7-ONE TRIOXSALEN, 4'-AMINOMETHYL-, HYDROCHLORIDE TRIOXSALEN, 4'-HYDROXYMETHYL- Trioxsalen, 4-Aminomethyl-, HCl 3-(2-AMINOOXY-ETHOXYMETHYL)-2,5,9-TRIMETHYL-FURO[3,2-G]CHROMEN-7-ONE PSORALEN-C 6 CEP 3-(2-AMINO-ETHOXYMETHYL)-2,5,9-TRIMETHYL-FURO[3,2-G]CHROMEN-7-ONE
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