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Journal of Chemical Research (S) 1981, 192
Dibenzo-18-crown-6 as phase transfer catalyst in Bockmuhl's synthesis of methadone
http://hyperlab.bravepages.com/JChemRes1981%28S%29.djvu (http://hyperlab.bravepages.com/JChemRes1981%28S%29.djvu)
I could't get the Miniprit version of this artcle because in a library this volume is not available.
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Edit: The full Miniprint edition has been posted in
Post 481630 (missing)
(Aurelius: "PTC Synthesis of Methadone", Methods Discourse)
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Synthesis and Physico-Chemical Properties of (RS)-6-bis(Trideuteriomethyl)amino-4,4-Diphenylheptan-3-one Hydrochloride (Methadone-d6)
B.M. Gérardy, et. al.
J. Lab. Comp. Radiopharm. 22(1), 5-22 (1985) (https://www.thevespiary.org/rhodium/Rhodium/djvu/methadone-d6.djvu)
(https://www.thevespiary.org/rhodium/Rhodium/djvu/methadone-d6.djvu)
Experimental section
(R,S)-2,2-diphenyl-4-ditrideuteromethylaminopentanenitrile (1)
To a solution of 6 g (68.5 mmol) of ditrideuteromethylamine hydrochloride dissolved in 3 ml of water was added 2.8 g (70 mmol) of NaOH disolved in 5 ml H2O. Under stirring, a filtered solution of the above mixture was added over 1 h period to 4.77 g (82.2 mmol) of freshly redistilled propylene oxide. After 12 hrs at RT, 90 ml of benzene were added and the reaction mixture was fractionnally distilled. The fractions under 81 °C and above 99°C were discarded. The remaining 4.07 g consisting of a mixture of isomeric aminoalcohols (1-ditrideutromethylamino-2-propanol and 2-ditrideutromethylamino-1-propanol)were dissolved in 25 ml of dry CHCl3(ethanol free) and treated by 14.4 g (113 mmol) of freshly redistilled thionyl chloride. The reaction mixture was stirred and heated at 55°C for 2 hrs. After evaporating the solvent under reduced pressure, a residue weighing 5.42 g consisting of a mixture of isomeric beta-chloroamines was obtained. Then, to a solution of 6 g (31 mmol)of diphenylacetonitrile and 0.2 g of dibenzo-18-crown-6 in 6 ml DMSO were added under stirring 5 g (125 mmol) of NaOH in 5 ml of distilled H2O in one portion and 5.42 g of beta-chloroamines over one hour period. The reaction mixture was gradually heated up to 70 °C and this temperature was maintained for 3 h. After cooling, the basis fraction was isolated in the usual way and recrystallysed from n-hexane and then from n-heptane to yield 2.8 g (32.5%) of (1), mp=81-82°C. This material was pure in GLC.
(R,S)-4,4-diphenyl-6-ditrideuteromethylaminoheptan-3-one hydrochloride (2)
This material was synthesed according to the procedure described by Bockmuhl and Ehrhardt (J.Liebigs Ann.Chem 561(1949)52, Post 483448 (https://www.thevespiary.org/talk/index.php?topic=9346.msg48344800#msg48344800)
(Rhodium: "Bockmühl's Original Methadone Synthesis", Methods Discourse)). To a suspension of 0.24 g (10 mmol) of Mg in 5 ml of dry ether was added 2.55 g (23 mmol) of ethyl bromide. After of completition of the reaction, a solution of 2.8 g (9.86 mmol) of(1) in 3 ml of dry xylene was added to the reaction mixture under stirring. The ether was distilled off in dry conditions; the reaction mixture was heated under reflux for 1 h and then decomposed with 100 ml of 8 N HCl. After the usual work up, 2.48 g (79%) of (2) were obtained. The hydrochloride crystallized from ethanolic HCl was obtained in 72% yield. It was recrystallized from IPA to constant melting point (mp=233°C) This product was pure in GLC and HPTLC.
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Preparation of Methadone and Some Congeners Labeled with Tritium in the Aromatic Rings
J.A. Kepler, et. al.
J. Lab. Comp. Radiopharm. 19(2), 271-282 (1982) (https://www.thevespiary.org/rhodium/Rhodium/djvu/methadone-tritium.djvu)
(https://www.thevespiary.org/rhodium/Rhodium/djvu/methadone-tritium.djvu)