acetylmethadol Property

Boiling point:

456.0±45.0 °C(Predicted)

Density 

1.020±0.06 g/cm3(Predicted)

pka

9.40±0.50(Predicted)

Hazard and Precautionary Statements (GHS)

acetylmethadol Chemical Properties,Usage,Production

Originator

Acetylmethadol ,National Inst. for Drug Abuse

Uses

Analgesic (narcotic).

Definition

ChEBI: Acetylmethadol is a diarylmethane.

Manufacturing Process

Racemic 1-dimethylamino-2-propanol (100.0 g, 0.97 mol) was stirred with vinyl propionate (63.6 ml, 0.58 mol) at 40°C and Novozym 435 (5.0 g) was added. The reaction was stirred slowly for 75 h and after this time TLC (10% methanol/dichloromethane-visualize KMnO4 solution) indicated that the reaction had gone to at least 50% conversion. The enzyme was removed by filtration and the filtrate was distilled at reduced pressure. S-(+)-1- Dimethylamino-2-propanol was obtained as a colourless oil (31.6 g, 64%), boil point 35°C.
A solution of thionyl chloride (37 ml, 0.48 mol) in chloroform (20 ml) was added slowly, with stirring, to a cooled (ice/water) solution of S-(+)-1- dimethylamino-2-propanol (30.6 g, 0.32 mol) in chloroform (85 ml). When the addition was complete a precipitate formed. The mixture was allowed to warm to room temperature over 30 min and then heated to reflux for a further 30 min. The precipitate redissolved on heating but then the product crystallized out from the boiling solvent as it formed. More chloroform (20 ml) was needed to maintain the stirring. The cooled mixture was diluted with ether and filtered. The 45.0 g (96%) of crude product was isolated. This was recrystallised from 2-propanol as in the other series to give 30.9 g (65%) of R-(-)-1-dimethylamino-2-chloropropane, melting point 192°-193°C.
A 50% w/v solution of sodium hydroxide in water (12.5 ml, 0.32 mol) was added to a mechanically stirred suspension of diphenylacetonitrile (15.0 g,0.08 mol) and dibenzo-18-crown-6 (0.5 g, cat.) in dimethylsulphoxide (12.5 ml). The color rapidly deepened to an orange/brown. R-(-)-1-Dimethylamino- 2-chloropropane (30.0 g, 0.095 mol) was added in portions over 30 min, this caused the temperature to rise to 30°C. After the addition was complete the mixture was warmed to 45°-50°C (water bath) and stirred for a further hour. The reaction mixture was then allowed to cool to room temperature and was poured into ice/water (250 ml) and extracted with ethyl acetate (3 times 150 ml). The combined extracts were dried (MgSO4) and filtered and evaporated down to -100 ml. The product was extracted into 1N HCl (100 ml+50 ml) and this was back washed with ethyl acetate. The aqueous was basified with 2 M sodium hydroxide and extracted into ethyl acetate (3 times 100 ml). The extracts were washed with brine (70 ml), dried (MgSO4), and evaporated down to a yellow oil. This was chilled and triturated with cold hexane (50 ml) to give a white solid which was collected by filtration and washed thoroughly with a further portion of cold hexane (100 ml). 14.65 g (33%) of S-(+)-2,2- diphenyl-4-dimethylaminopentanenitrile were obtained, melting point 100°- 101°C (recrystallised from hexane).
All apparatus was dried and the reaction was carried out under an inert atmosphere of argon. A solution of S-(+)-2,2-diphenyl-4- dimethylaminopentanenitrile (10.0 g, 0.018 mol) in toluene (15 ml) was added to a stirred solution of 3 M ethyl magnesium bromide in ether (10.7 ml, 0.03 mol). The ether was removed under reduced pressure and the remaining solution heated at reflux (135°-140°C) for 3 h. The solution went slightly cloudy but there was no significant precipitation. After cooling to room temperature 2 N HCl (30 ml) was added with care and then stirring was continued at 135°-140°C for a further 30 min. The two phases were allowed to separate and cool to room temperature. After scratching the sides of the flask a solid started to crystallise from the aqueous phase. The flask was cooled to complete crystallisation and the white solid was collected by filtration. This solid was recrystallised from water to yield 6.6 g (53%) of S- (+)-methadone hydrochloride (6-dimethylamino-4,4-diphenyl-3-heptanone hydrochloride) were obtained, melting point 240°-241°C.
S-(+)-Methadone hydrochloride (600.0 mg,1.74 mmol) was dissolved in ethanol (10 ml) and the solution was stirred whilst sodium borohydride (3.47 mmol) was added portion-wise over a period of 5 min. When the addition was complete a spatula end of cerium (III) chloride heptahydrate was added. The resultant solution was allowed to stir at room temperature for 30 min then the ethanol was removed under reduced pressure. The residue was portioned between diethyl ether (40 ml) and water (40 ml). The aqueous layer was extracted with more diethyl ether (2 times 20 ml) and then the combined organics were washed with brine (40 ml) and dried (MgSO4). The ether was removed under reduced pressure to leave 435.0 mg, (80%) of 6- dimethylamino-4,4-diphenyl-3-heptanol.
6-Dimethylamino-4,4-diphenyl-3-heptanol (435.0 mg, 1.40 mmol) dissolved in ethyl acetate (10 ml) was treated with acetyl chloride (183.0 mg, 2.33 mmol). The mixture was refluxed for 2 h. After allowing the solution to cool to room temperature the solvent was removed under reduced pressure to leave a white foam, this crystallised from ethyl acetate to give 6-dimethylamino-4,4- diphenyl-3-acetoxyheptane hydrochloride (levo-α-acetyl methadol hydrochloride) (420.0 mg, 79%).
The 6-dimethylamino-4,4-diphenyl-3-acetoxyheptane may be produced by treatment of the 6-dimethylamino-4,4-diphenyl-3-acetoxyheptane hydrochloride with sodium hydroxide.

Therapeutic Function

Narcotic analgesic