The Vespiary

Great Aurelius! As a cross-reference, I'd like to add that other PTC preparations of Methadone Nitrile can be found here:

Post 432796 (https://www.thevespiary.org/talk/index.php?topic=9391.msg43279600#msg43279600)

(murmur: "PTC alkylation of diphenylacetonitrile", Methods Discourse)

Post 437755 (https://www.thevespiary.org/talk/index.php?topic=12029.msg43775500#msg43775500)

(murmur: "Deuterated Methadone", Novel Discourse)

Ueber eine neue Klasse von spasmolytisch und analgetisch wirkenden Verbindungen
Max Bockmühl & Gustav Ehrhart

Ann. Chem. 561, 52-85 (1949) (https://www.thevespiary.org/rhodium/Rhodium/pdf/bockmuhl-erhardt.pdf)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/bockmuhl-erhardt.pdf)

[About a novel class of compounds having spasmolytic and analgetic effects]

The original german article describing the invention of Methadone and a huge number of analogs, all with preparative, analytical and pharmacological details given in the experimental section. A truly classic article in the field of opioid chemistry.

_{Analgesics. Part I.}
Esters and Ketones derived from (https://www.thevespiary.org/rhodium/Rhodium/hive/hiveboard/picproxie_docs/000481630-file_lwwo.gif)-Amino-(https://www.thevespiary.org/rhodium/Rhodium/hive/hiveboard/picproxie_docs/000481630-file_qbk6.gif)-cyano-(https://www.thevespiary.org/rhodium/Rhodium/hive/hiveboard/picproxie_docs/000481630-file_qbk6.gif),(https://www.thevespiary.org/rhodium/Rhodium/hive/hiveboard/picproxie_docs/000481630-file_qbk6.gif)-diarylalkanes
By D. J. Dupré. J. Elks. B. A. Hems. (Miss) K. N. Speyer and (in part) R. M. Evans

J. Chem. Soc. 500-510 (1949) (https://www.thevespiary.org/rhodium/Rhodium/pdf/amidone.analgesics-1.pdf)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/amidone.analgesics-1.pdf)

Abstract
A number of basic cyanides (V) have been prepared either (a) by reaction of a diarylmethyl cyanide with a chloro-amine R₂N[CH₂]_nCl, or (b) by treatment of a diarylmethyl cyanide with an (https://www.thevespiary.org/rhodium/Rhodium/hive/hiveboard/picproxie_docs/000481630-file_lwwo.gif),(https://www.thevespiary.org/rhodium/Rhodium/hive/hiveboard/picproxie_docs/000481630-file_qbk6.gif)-dihalogeno-paraffin, and reaction of the resulting halogeno-cyanide with a secondary amine. The amino-cyanides were converted into amino-ketones by treatment with Grignard reagents. and into amino-esters by direct esterification with alcoholic sulphuric acid.
The acids R₂NCH₂CH₂CPh₂CO₂H (R = Me or Et) on treatment with thionyl chloride gave the 3,3-diphenyl-1-alkylpyrrolid-2-one; the homologous acid.  Et₂NCH₂CH₂CH₂CPh₂CO₂H, on similar treatment, gave an acid chloride which showed no tendency to cyclise.
The analgesic activities of the amino-esters and amino-ketones are given.
____ ___ __ _

_{Analgesics. Part II.}
The Synthesis of Amidone and Some of its Analogues
By J. Attenburrow. J. Elks. B. A. Hems. and (Miss) K. N. Speyer

J. Chem. Soc. 510-518 (1949) (https://www.thevespiary.org/rhodium/Rhodium/pdf/amidone.analgesics-2.pdf)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/amidone.analgesics-2.pdf)

Abstract
Treatment of 1-chloro-2-dimethylaminopropane with diphenylmethyl cyanide in the presence of sodamide gave a mixture of compounds. from which 3-dimethylamino-1,1-diphenylbutyl cyanide (II) was isolated in 36% overall yield. Amidone (III) was obtained from (II) by treatment with ethylmagnesium iodide. Both 1-chloro-2-morpholinopropane and 2-chloro-1-morpholinopropane, on reaction with diphenylmethyl cyanide. gave a mixture of 1,1-diphenyl-3-morpholinobutyl cyanide (VIII) and 1,1-diphenyl-3-morpholinoisobutyl cyanide (XI), both of which have been converted into the corresponding ethyl ketones.
Treatment of diphenylmethyl cyanide with ethylene oxide or propylene oxide gave lactones instead of the hydroxy-cyanides required. Attempts to prepare the cyanide (VIII) by addition of hydrogen bromide or hydrogen iodide to 1,1-diphenylbut-3-enyl cyanide (XII) and reaction of the product with morpholine gave the required compound. but only in poor yield. Attempts to reduce selectively the double bond of 3-bromo-1,1-diphenylbut-3-enyl cyanide (XXI) were unsuccessful.