It seems like the hardest part of making fentanyl is the 4-piperidone monohydrate. It can be bought, but i like to have a believable story before i order something with such a limited known use.
So what about the 2,3 secofentanyls? in the attached paper n-methylphenethylamine is the starting compound. the resulting compound is 30x LESS potent than fentanyl (5-10x stronger than morphine), but this is still considerable. especially as i dont believe this compound is controlled.
ROUTE:
1. N-methyl phenethylamine is condensed with methyl acetoacetate at 170C to yield the ketoamide (80% Yield)
2. (1) is reductively aminated with aniline in Zn dust and acetic acid to yield anilino-amide (95% Yield)
3. (2) (here is the bad part) is reductively deoxegenated with in situ formed diborane to yield diamine (80% Yield)
4. Acylation of (3) with propionyl chloride in triethylamine and precipitation of monooxalate salt (95% Yield)
A Few Questions and Ideas for the steps:
1. there are several methamphetamines that are no fun (ie PMMA), if these were usable in step 1, you would be doing the equivalent of making alpha-methylfentanyl (which is longer acting and possibly more euphoric) instead of fentanyl. Its possible the change in activity would be similar. And finding a use for PMMA to boot.
barring this, there are a few easily obtainable n-methyl-phenethylamines that could be used although there is not much point in analogs until they control the parent compound. But Synephrine (4-[1-hydroxy-2-(methylamino)ethyl]phenol), Amidephrine, Deprenyl, Dimetophrine, AND phenylephrine. Take that DEA. now the sudafed PE's arent Disney-friendly either.
2. other methods could probably be used for the reduction but this one is easy enough
3. here is the big question. Instead of using diborane, what about a huang-minlon wolf-Kichner. (i will be doing some experiments with removal of keto-functions using hydrazine sulfate in a few months.) If it was applicable here (i am not a good enough chemist to know exactly how the bonds there will react), that would make this a very facile opioid synth.
4. I had always been more interested in acetylfentanyls because the 10X decrease in potency puts some of them in the 10mg range which is safe enough for my tastes, but this compound doesnt have the high starting potency so aquisition or synthesis of propionyl chloride would be necessary.
just looking for a chemist with more knowledge than me (most) to push me toward a project that is most likely to be of benefit to the community. Thanks so much in advance.
REFERENCE:
Titre du document / Document title
The synthesis and pharmacological evaluation of (?)-2,3-seco-fentanyl analogues
Auteur(s) / Author(s)
IVANOVIC M. D. ; MICOVIC I. V. ; VUCKOVIC S. ; PROSTRAN M. ; TODOROVIC Z. ; IVANOVIC E. R. ; KIRICOJEVIC V. D. ; DJORDJEVIC J. B. ; DOSEN-MICOVIC L. J. ;
Résumé / Abstract
An efficient, five-step synthetic approach to various acyclic 1,3-diamines has been developed and applied to the preparation of a novel class of open-chained fentanyl analogues. The acyclic derivatives 5.1-5.5 (all new compounds) were synthesized with the aim of estimating the significance of the piperidine ring for the opioid analgesic activity of anilido-piperidines. The starting ?-keto-amide 1.1, prepared by the aminolysis of methyl acetoacetate with methylphenethylamine, (93 % yield), was successively reacted with NaH and BuLi, to form the highly reactive ?,?-dienolate anion 1.1a. Regio and chemoselective ?-alkylation of the dienolate with various primary and secondary alkyl halides furnished the ?-keto-amides 1.2-1.5 (76-91 %). Reductive amination of the keto-amides 1.1-1.5 with aniline and Zn powder in acetic acid, via the enamine intermediates 2.1-2.5, afforded the ?-anilino amides 3.1-3.5 (74-85 %). After reductive deoxygenation of the tertiary amide group, using in situ generated diborane, the corresponding 1,3-diamines 4.1-4.5 were obtained (87-97 %). The synthesis of (?)-2,3-seco-fentanyls 5.1-5.5 was completed by N-acylation of the diamines 4.1-4.5 with propionyl chloride, followed by precipitation of the monooxalate salts (86-95 %). The parent compound, 2,3-seco-fentanyl 5.1, was found to be a 40 times less potent narcotic analgesic than fentanyl but still 5-6 times more active than morphine in rats, while i-Pr derivative 5.3 was inactive. Apart from the pharmacological significance, the general procedure described herein may afford various functionalized, 1,3-diamines as potential complexing agents and building blocks for the synthesis of aza-crown ethers.
Revue / Journal Title
Journal of the Serbian Chemical Society ISSN 0352-5139
Source / Source
2004, vol. 69, no11, pp. 955-968 [14 page(s) (article)]
Langue / Language
Anglais
Editeur / Publisher
Serbian Chemical Society, Belgrade, SERBIE (1985) (Revue)
Localisation / Location
INIST-CNRS, Cote INIST : 5226, 35400012572294.0140
So what about the 2,3 secofentanyls? in the attached paper n-methylphenethylamine is the starting compound. the resulting compound is 30x LESS potent than fentanyl (5-10x stronger than morphine), but this is still considerable. especially as i dont believe this compound is controlled.
ROUTE:
1. N-methyl phenethylamine is condensed with methyl acetoacetate at 170C to yield the ketoamide (80% Yield)
2. (1) is reductively aminated with aniline in Zn dust and acetic acid to yield anilino-amide (95% Yield)
3. (2) (here is the bad part) is reductively deoxegenated with in situ formed diborane to yield diamine (80% Yield)
4. Acylation of (3) with propionyl chloride in triethylamine and precipitation of monooxalate salt (95% Yield)
A Few Questions and Ideas for the steps:
1. there are several methamphetamines that are no fun (ie PMMA), if these were usable in step 1, you would be doing the equivalent of making alpha-methylfentanyl (which is longer acting and possibly more euphoric) instead of fentanyl. Its possible the change in activity would be similar. And finding a use for PMMA to boot.
barring this, there are a few easily obtainable n-methyl-phenethylamines that could be used although there is not much point in analogs until they control the parent compound. But Synephrine (4-[1-hydroxy-2-(methylamino)ethyl]phenol), Amidephrine, Deprenyl, Dimetophrine, AND phenylephrine. Take that DEA. now the sudafed PE's arent Disney-friendly either.
2. other methods could probably be used for the reduction but this one is easy enough
3. here is the big question. Instead of using diborane, what about a huang-minlon wolf-Kichner. (i will be doing some experiments with removal of keto-functions using hydrazine sulfate in a few months.) If it was applicable here (i am not a good enough chemist to know exactly how the bonds there will react), that would make this a very facile opioid synth.
4. I had always been more interested in acetylfentanyls because the 10X decrease in potency puts some of them in the 10mg range which is safe enough for my tastes, but this compound doesnt have the high starting potency so aquisition or synthesis of propionyl chloride would be necessary.
just looking for a chemist with more knowledge than me (most) to push me toward a project that is most likely to be of benefit to the community. Thanks so much in advance.
REFERENCE:
Titre du document / Document title
The synthesis and pharmacological evaluation of (?)-2,3-seco-fentanyl analogues
Auteur(s) / Author(s)
IVANOVIC M. D. ; MICOVIC I. V. ; VUCKOVIC S. ; PROSTRAN M. ; TODOROVIC Z. ; IVANOVIC E. R. ; KIRICOJEVIC V. D. ; DJORDJEVIC J. B. ; DOSEN-MICOVIC L. J. ;
Résumé / Abstract
An efficient, five-step synthetic approach to various acyclic 1,3-diamines has been developed and applied to the preparation of a novel class of open-chained fentanyl analogues. The acyclic derivatives 5.1-5.5 (all new compounds) were synthesized with the aim of estimating the significance of the piperidine ring for the opioid analgesic activity of anilido-piperidines. The starting ?-keto-amide 1.1, prepared by the aminolysis of methyl acetoacetate with methylphenethylamine, (93 % yield), was successively reacted with NaH and BuLi, to form the highly reactive ?,?-dienolate anion 1.1a. Regio and chemoselective ?-alkylation of the dienolate with various primary and secondary alkyl halides furnished the ?-keto-amides 1.2-1.5 (76-91 %). Reductive amination of the keto-amides 1.1-1.5 with aniline and Zn powder in acetic acid, via the enamine intermediates 2.1-2.5, afforded the ?-anilino amides 3.1-3.5 (74-85 %). After reductive deoxygenation of the tertiary amide group, using in situ generated diborane, the corresponding 1,3-diamines 4.1-4.5 were obtained (87-97 %). The synthesis of (?)-2,3-seco-fentanyls 5.1-5.5 was completed by N-acylation of the diamines 4.1-4.5 with propionyl chloride, followed by precipitation of the monooxalate salts (86-95 %). The parent compound, 2,3-seco-fentanyl 5.1, was found to be a 40 times less potent narcotic analgesic than fentanyl but still 5-6 times more active than morphine in rats, while i-Pr derivative 5.3 was inactive. Apart from the pharmacological significance, the general procedure described herein may afford various functionalized, 1,3-diamines as potential complexing agents and building blocks for the synthesis of aza-crown ethers.
Revue / Journal Title
Journal of the Serbian Chemical Society ISSN 0352-5139
Source / Source
2004, vol. 69, no11, pp. 955-968 [14 page(s) (article)]
Langue / Language
Anglais
Editeur / Publisher
Serbian Chemical Society, Belgrade, SERBIE (1985) (Revue)
Localisation / Location
INIST-CNRS, Cote INIST : 5226, 35400012572294.0140
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