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Fentanyl Synthetic Methodology: A Comparative Study - Fu-Lian Hsu, Harold D. Banks - CRDEC-TR-334 (March 1992) ADA250611

Fentanyl Synthetic Methodology: A Comparative Study - Fu-Lian Hsu, Harold D. Banks - CRDEC-TR-334 (March 1992) ADA250611

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Fentanyl Synthetic Methodology: A Comparative Study

Report Number: CRDEC-TR-334
Accession Number: ADA250611
Report Date: March 1992
Authors: Fu-Lian Hsu and Harold D. Banks
Research Directorate
Chemical Research, Development & Engineering Center
U.S. Army Armament Munitions Chemical Command
Aberdeen Proving Ground, MD 21010-5423
Final Report, Sept 1988 - Dec 1991
Funding Numbers: PR-1C161102A71A
18 pages

ABSTRACT:
A literature review has identified six promising methods for the synthesis of fentanyl. Those methods have been compared for overall efficiency. The best method to date is identified.

Meperidine, 4-phenyl-4-ethoxycarbonyl-1-methylpiperidine is much simpler structurally than morphine. Prepared in reasonably good yield starting from nitrogen mustard, it has about 60% of morphine's analgesic potency in studies. The reversed ester of meperidine, i.e., the propionate ester of 4-phenyl-4-hydroxyl-1-methylpiperidine, was found to have about twice the potency of morphine in pharmacological tests with animals. This discovery spurred further modification of the 4-phenylpiperidine structure, culminating in the 1960's with the discovery of fentanyl, described as a "chemical congener" of the reversed ester. This appears to be a rather broad use of the term congener: Conversion of the 4-position of the reversed ester into that of fentanyl requires replacement of oxygen by nitrogen, followed by transposition of the phenyl group from C4 to nitrogen. In any event, fentanyl, 4-[1-(2-phenylethyl)piperidinyl]-propanamide, is an extremely potent analgesic, having a potency of about 300 times that of morphine in animal tests. Although it is not the "ideal analgesic," retaining many of the side effects that compromise the use of morphine, it does have significantly lower cardiac depressive effects, and has found extensive use in cardiac surgical procedures.

With the recent expiration of the patent on fentanyl, the following timely report schematically presents six useful routes for the synthesis of fentanyl. Where appropriate, starting material costs, reaction yields and comments concerning advantages and disadvantages of particular approaches are offered to guide the reader in his selection of the appropriate synthesis or to catalyze new syntheses.

Fentanyl synthesis chemistry, C22H28N2O, N-(1-PHENETHYL-4-PIPERIDYL)PROPIONANILIDE, opiates opioid analgesics, phenylpiperidines, carfentanil, Anilidopiperidine, Anilinopiperidine, Sigfried, sufentanil, alfentanil, lofentanil, AMF, alphamethylfentanyl, Ohmefentanil, NPP, ANPP, piperidone, piperidine, Strecker addition, Mefentanyl, super FIT, 1-phenethyl, N-phenethyl-4-piperidone, phenylethyl, 3-methyl-4-piperidone, aniline, 2-fluoroaniline, reductive alkylation, N-methylation, O-methylation, HCN, KCN, TMSCN, trimethylsilyl cyanide, hydantoin, p-TSA, p-toulenesulfonic acid, N-esterification, N-acylation, propionic anhydride, propionyl chloride, Aminomethano Desilyation Cyclization, opioid, brifentanil, acetylfentanyl, 3-methylfentanyl, 3MF, TMF, beta-hydroxy, alpha-methyl, 4-methoxymethylcarbonyl, 4-methoxycarbonyl, 4-substituted, 4,4-disubstituted, 4-piperidines, fentanil, phentanyl, phentanil, N-phenylethyl-4-piperidone, piperid-4-one, piperidinone, super FIT, isothiocyanate, Wildnil, N-phenylethyl-4-piperidinone, piperidin-4-one, NPP, ANPP, opioid synthesis, opiate, mu opioid receptor, MOR, u opioid receptor, u receptor, mu receptor, mu, Sigfreid, Sigfried fentanyl synthesis, anesthesia, analgesia, alkaloid, poppy, heroin, methadone, buprenorphine, subutex, suboxone, drug synthesis, controlled substance, NaBH4 reduction, sodium borohydride, reducing agents, LiAlH4, lithium aluminum hydride, adam's catalyst, PtO, platinum oxide, catalytic hydrogenation, N-debenzylation, Pd/C, palladium over carbon, platinum on carbon, oxirane, 4-propionanilidopiperidine, morphine, morphine-like analgesics, PAJ, P., P.A.J., Paul AJ Janssen, Janssen Pharmaceutica, Pharmaceuticals
Fentanyl Synthetic Methodology: A Comparative Study

Report Number: CRDEC-TR-334
Accession Number: ADA250611
Report Date: March 1992
Authors: Fu-Lian Hsu and Harold D. Banks
Research Directorate
Chemical Research, Development & Engineering Center
U.S. Army Armament Munitions Chemical Command
Aberdeen Proving Ground, MD 21010-5423
Final Report, Sept 1988 - Dec 1991
Funding Numbers: PR-1C161102A71A
18 pages

ABSTRACT:
A literature review has identified six promising methods for the synthesis of fentanyl. Those methods have been compared for overall efficiency. The best method to date is identified.

Meperidine, 4-phenyl-4-ethoxycarbonyl-1-methylpiperidine is much simpler structurally than morphine. Prepared in reasonably good yield starting from nitrogen mustard, it has about 60% of morphine's analgesic potency in studies. The reversed ester of meperidine, i.e., the propionate ester of 4-phenyl-4-hydroxyl-1-methylpiperidine, was found to have about twice the potency of morphine in pharmacological tests with animals. This discovery spurred further modification of the 4-phenylpiperidine structure, culminating in the 1960's with the discovery of fentanyl, described as a "chemical congener" of the reversed ester. This appears to be a rather broad use of the term congener: Conversion of the 4-position of the reversed ester into that of fentanyl requires replacement of oxygen by nitrogen, followed by transposition of the phenyl group from C4 to nitrogen. In any event, fentanyl, 4-[1-(2-phenylethyl)piperidinyl]-propanamide, is an extremely potent analgesic, having a potency of about 300 times that of morphine in animal tests. Although it is not the "ideal analgesic," retaining many of the side effects that compromise the use of morphine, it does have significantly lower cardiac depressive effects, and has found extensive use in cardiac surgical procedures.

With the recent expiration of the patent on fentanyl, the following timely report schematically presents six useful routes for the synthesis of fentanyl. Where appropriate, starting material costs, reaction yields and comments concerning advantages and disadvantages of particular approaches are offered to guide the reader in his selection of the appropriate synthesis or to catalyze new syntheses.

Fentanyl synthesis chemistry, C22H28N2O, N-(1-PHENETHYL-4-PIPERIDYL)PROPIONANILIDE, opiates opioid analgesics, phenylpiperidines, carfentanil, Anilidopiperidine, Anilinopiperidine, Sigfried, sufentanil, alfentanil, lofentanil, AMF, alphamethylfentanyl, Ohmefentanil, NPP, ANPP, piperidone, piperidine, Strecker addition, Mefentanyl, super FIT, 1-phenethyl, N-phenethyl-4-piperidone, phenylethyl, 3-methyl-4-piperidone, aniline, 2-fluoroaniline, reductive alkylation, N-methylation, O-methylation, HCN, KCN, TMSCN, trimethylsilyl cyanide, hydantoin, p-TSA, p-toulenesulfonic acid, N-esterification, N-acylation, propionic anhydride, propionyl chloride, Aminomethano Desilyation Cyclization, opioid, brifentanil, acetylfentanyl, 3-methylfentanyl, 3MF, TMF, beta-hydroxy, alpha-methyl, 4-methoxymethylcarbonyl, 4-methoxycarbonyl, 4-substituted, 4,4-disubstituted, 4-piperidines, fentanil, phentanyl, phentanil, N-phenylethyl-4-piperidone, piperid-4-one, piperidinone, super FIT, isothiocyanate, Wildnil, N-phenylethyl-4-piperidinone, piperidin-4-one, NPP, ANPP, opioid synthesis, opiate, mu opioid receptor, MOR, u opioid receptor, u receptor, mu receptor, mu, Sigfreid, Sigfried fentanyl synthesis, anesthesia, analgesia, alkaloid, poppy, heroin, methadone, buprenorphine, subutex, suboxone, drug synthesis, controlled substance, NaBH4 reduction, sodium borohydride, reducing agents, LiAlH4, lithium aluminum hydride, adam's catalyst, PtO, platinum oxide, catalytic hydrogenation, N-debenzylation, Pd/C, palladium over carbon, platinum on carbon, oxirane, 4-propionanilidopiperidine, morphine, morphine-like analgesics, PAJ, P., P.A.J., Paul AJ Janssen, Janssen Pharmaceutica, Pharmaceuticals

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Categories:Types, Research, Science
Published by: jtjdp4 on May 12, 2010
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Disclaimer
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findings
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report
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