I have read with much intrigue the "OTC piperidone --> fentanyl" thread, and feel that is an interesting avenue of opioid research. Highly overlooked has been modifications to the oxymorphone molecule. When the 14-HO of oxymorphone is replaced with an alkyl group, this class of drugs is called the 14-alkoxymorphinans. The 14-alkoxymorphinans include some of the strongest opiates known to man
Pharmacological Data:14-Methoxymetopon, A Potent Opioid, Induces No Respiratory Depression, Less Sedation, and Less Bradycardia than Sufentanil in the Dog
Anesth. Analg. 1999, 88, 332.
http://www.anesthesia-analgesia.org/cgi/content/abstract/90/6/1359 14-methoxymetopon (HS-198), which is 20,000 times more potent than morphine in the acethylcholine-writhing test, was given in graded IV doses (3, 6, and 12 µg/kg) to awake, trained canines (n = 7).
14-Methoxymetopon, a very potent mu-opioid receptor-selective analgesic with an unusual pharmacological profile
Eur J Pharmacol. 2003 Jan 17;459(2-3):203-9
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12524147&dopt=Abstract 14-Methoxymetopon is a potent opioid analgesic. When given systemically, it is approximately 500-fold more active than morphine. However, this enhanced potency is markedly increased with either spinal or supraspinal administration, where its analgesic activity is more than a million-fold greater than morphine.
https://www.hindawi.com/journals/ijmc/2012/208039/
2. Synthesis of 5-Substituted N-Methylmorphinan-6-ones
The starting point of extensive research in the area of N-methylmorphinan-6-ones with new substitution patterns was represented by the synthesis of 14-O-methyloxymorphone. While 14-O-methyloxymorphone can be prepared starting from oxymorphone in four synthetic steps, 14-alkoxy-N-methylmorphinan-6-ones substituted in position 5 have to be prepared from thebaine as starting material. Introduction of an alkyl substituent in position 5 of thebaine can be accomplished by formation of the thebaine anion using n-butyllithium in THF at low temperature, followed by alkylation with the respective alkylating agent (methyl fluorosulfonate, dimethyl sulfate, or benzyl chloride), yielding 5-methylthebaine and 5-benzylthebaine, respectively. Treatment with performic acid afforded 14-hydroxy-5-methylcodeinone and its 5-benzyl analogue. The β-orientation of the 14-hydoxy group was proved by X-ray analysis. 14-O-Alkylation of 5 with dimethyl or diethyl sulfate in DMF in the presence of NaH gave the respective 14-alkoxycodeinones 7 and 8 which were catalytically hydrogenated to afford 10 and 11. Ether cleavage of both compounds with 48% HBr solution yielded 77% of 14-methoxymetopon and 75% of 14-ethoxymetopon. Analogously, 5-benzyl-14-O-methyloxymorphone (75% from 12) was obtained from 14-hydroxy-5-benzylcodeinone via intermediates 9 and 12.
14-Benzyloxymetopon was prepared from 14-hydroxy-5-methylcodeinone. Compound 5 was first 3-O-demethylated using 48% HBr solution to give phenol 16 which was 3,14-bis-O-benzylated to afford compound 17. Concomitant hydrogenation of the 7,8 double bond and hydrogenolysis of the 3-O-benzyl ether over Pd/C yielded 73% of 18 (Scheme 2). 14-Hydoxy-5-methylcodeinone was also used for the synthesis of 14-phenylpropoxymetopon (PPOM; 21) and its 3-O-methyl ether 20. 14-O-Alkylation with cinnamyl bromide in DMF in the presence of NaH gave compound 19 which was catalytically hydrogenated to afford 73% of 3-O-methylated PPOM (20). Ether cleavage using 48% HBr solution yielded 88% of PPOM (21) (Scheme 3).
