Generic placeholder image

Current Organic Synthesis

Author(s): Khushbu Upadhyaya*, Shruti Shukla, Bharti Parkash Meena and Jaya Dwivedi

DOI: 10.2174/1570179420666230530095245

DownloadDownload PDF Flyer Cite As
Synthesis of Phentermine and its Derivatives

Page: [583 - 594] Pages: 12

  • * (Excluding Mailing and Handling)

Explore Articles
About Journal
For Authors
For Editors
For Reviewers

Abstract

In recent years, a growing global concern has been obesity. Patients with obesity are at major risk for developing a number of diseases. These diseases may significantly impact patient’s daily lives and increase the mortality rate. Over a year, medication for obesity has undergone substantial changes. An amphetamine-like prescription drug called Phentermine (Adipex-P, Lomaira) is used to suppress appetite. In the last few years, Phentermine and its derivatives have attracted much attention due to their use in weight reduction; by reducing appetite or prolonging the feeling of fullness, it can aid in weight reduction. So, reviewing the synthesis of Phentermine and its derivatives becomes imperative. Therefore, various synthetic routes for Phentermine (from benzaldehyde, isopropyl phenyl ketone, dimethyl benzyl carbinol) and its derivatives synthesis, involving ortho-palladation, are also reviewed here comprehensively.

Keywords: Phentermine derivatives, synthesis, palladium assisted reaction, weight loss, amphetamine, obesity.

Graphical Abstract

[1]
George, M.; Rajaram, M.; Shanmugam, E. New and emerging drug molecules against obesity. J. Cardiovasc. Pharmacol. Ther., 2014, 19(1), 65-76.
[http://dx.doi.org/10.1177/1074248413501017] [PMID: 24064009]
[2]
Ni, Y.; Zhou, Y.; Xu, M.; He, X.; Li, H.; Haseeb, S.; Chen, H.; Li, W. Simultaneous determination of phentermine and topiramate in human plasma by liquid chromatography–tandem mass spectrometry with positive/negative ion-switching electrospray ionization and its application in pharmacokinetic study. J. Pharm. Biomed. Anal., 2015, 107, 444-449.
[http://dx.doi.org/10.1016/j.jpba.2015.01.035] [PMID: 25668796]
[3]
Weintraub, M.; Hasday, J.D.; Mushlin, A.I.; Lockwood, D.H. A double-blind clinical trial in weight control. Use of fenfluramine and phentermine alone and in combination. Arch. Intern. Med., 1984, 144(6), 1143-1148.
[http://dx.doi.org/10.1001/archinte.1984.00350180055008] [PMID: 6375610]
[4]
National Center for Biotechnology Information. PubChem, 4771, Phentermine 2023. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/Phentermine
[5]
Hsu, M.C.; Lin, S.F.; Kuan, C.P.; Chu, W.L.; Chan, K.H.; Chang-Chien, G.P. Oxethazaine as the source of mephentermine and phentermine in athlete’s urine. Forensic Sci. Int., 2009, 185(1-3), e1-e5.
[http://dx.doi.org/10.1016/j.forsciint.2008.12.009] [PMID: 19157735]
[6]
Beckett, A.H.; Bélanger, P.M. The identification of three new metabolic products of phentermine after liver microsomal incubation. Xenobiotica, 1974, 4(8), 509-519.
[http://dx.doi.org/10.3109/00498257409052103] [PMID: 4421114]
[7]
Vardanyan, R.S.; Hruby, V.J. 8-Central Nervous System Stimulants. In: Synthesis of Essential Drugs; Elsevier, 2006; pp. 117-124.
[8]
Al-Khafagi, A.A.; Mashkoor, M.S.; Kahlol, M.K. Determination of Naltrexoneby using Phentermine as a New Spectrophotometric Coupling Agent. Syst. Rev. Pharm., 2020, 11(12), 1655-1660.
[9]
Elmaleh, D.R.; Kizuka, H.; Hanson, R.N.; Jones, G.S., Jr; Herman, L.W.; Strauss, H.W. Structure-localization relationships of 11C-labeled phentermine derivatives: Effect of aromatic substitution. Appl. Radiat. Isot., 1993, 44(5), 821-829.
[http://dx.doi.org/10.1016/0969-8043(93)90023-4] [PMID: 8485509]
[10]
Kizuka, H.; Elmaleh, D.R. Selective monomethylation of the primary amine function using [11C]CH3I and the N-trifluoroacetyl derivative: Preparation of N-[11C-methyl]chlorphentermine. Nucl. Med. Biol., 1993, 20(2), 239-242.
[http://dx.doi.org/10.1016/0969-8051(93)90121-A] [PMID: 8448579]
[11]
Vicente, J.; Saura-Llamas, I.; Bautista, D. Regiospecific functionalization of pharmaceuticals and other biologically active molecules through cyclopalladated compounds. 2-iodination of phentermine and L-tryptophan methyl ester. Organometallics, 2005, 24(24), 6001-6004.
[http://dx.doi.org/10.1021/om0506522]
[12]
García-López, J.A.; Frutos-Pedreño, R.; Bautista, D.; Saura-Llamas, I.; Vicente, J. Norbornadiene as a building block for the synthesis of linked benzazocinones and benzazocinium salts through tetranuclear carbopalladated intermediates. Organometallics, 2017, 36(2), 372-383.
[http://dx.doi.org/10.1021/acs.organomet.6b00795]
[13]
Vicente, J.; Saura-Llamas, I.; García-López, J.A.; Bautista, D. Eight-membered palladacycles derived from the insertion of olefins into the Pd-C bond of ortho-palladated pharmaceuticals phenethylamine and phentermine. Synthesis of stable heck-type intermediates containing accessible β-hydrogens and its use in the synthesis of 2-styrylphenethylamines, tetrahydroisoquinolines, and eight-membered cyclic amidines. Organometallics, 2010, 29(19), 4320-4338.
[http://dx.doi.org/10.1021/om100738z]
[14]
Moretti, J.L.; Poncey, M.J.; Roux, P.; Desplanches, J.; Dao, H.; Lecayon, M. Synthesis and biodistribution of labelled p-iodo phentermine (IP), N,N,-dimethyl-p-iodo phentermine (IDMP) and N-isopropyl-p-iodo phentermine (IIP) in rats. Nucl. Med. Commun., 1987, 8(6), 441-447.
[http://dx.doi.org/10.1097/00006231-198706000-00007] [PMID: 3696629]
[15]
Hanson, R.N.; Jones, G.S., Jr; Franke, L.; Kizuka, H.; Elmaleh, D.R. Preparation and evaluation of 3-[125I]iodo-4-aminophentermine as a brain perfusion imaging agent. Comparison with labeled phentermine derivatives. Int. J. Nucl. Med. Biol., 1985, 12(4), 321-325.
[http://dx.doi.org/10.1016/0047-0740(85)90187-1] [PMID: 4086198]
[16]
Choi, Y.J.; Sim, A.; Kim, M.K.; Suh, S.; In, M.K.; Kim, J.Y. Determination of phentermine, N -hydroxyphentermine and mephentermine in urine using dilute and shoot liquid chromatography–tandem mass spectrometry. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2016, 1029-1030, 22-27.
[http://dx.doi.org/10.1016/j.jchromb.2016.06.045] [PMID: 27398632]
[17]
United Nations Office on Drugs and Crime..Recommended methods for the identification and analysis of amphetamine methamphetamine and their ring-substituted analogues in seized materials: manual for use by national drug testing laboratories (Rev. and updated); United Nations, United Nations Office on Drugs and Crime, 2006.
[18]
Tolmie, M.B. Clandestine manufacture of amphetamine from benzaldehyde: an investigative analysis of its synthesis., PhD diss.,; University of Western Australia, 2001.
[19]
Coutts, R.T.; Benderly, A.; Mak, A.L.C.; Taylor, W.G. Synthesis of two in vivo metabolites of N -(n -propyl)phentermine. Can. J. Chem., 1978, 56(24), 3054-3058.
[http://dx.doi.org/10.1139/v78-499]
[20]
Beckett, A.H.; Bélanger, P.M. The metabolism, distribution and elimination of chlorphentermine in man. Br. J. Clin. Pharmacol., 1977, 4(2), 193-200.
[http://dx.doi.org/10.1111/j.1365-2125.1977.tb00693.x] [PMID: 16634]
[21]
Mori, M.A.; Kobayashi, M.; Uemura, H.; Miyahara, T.; Kozuka, H. Intestinal metabolism of mephentermine and its biliary metabolites in male Wistar rats. Xenobiotica, 1992, 22(6), 701-708.
[http://dx.doi.org/10.3109/00498259209053132] [PMID: 1441593]
[22]
Mori, M.A.; Uemura, H.; Kobayashi, M.; Miyahara, T.; Kozuka, H. Metabolism of phentermine and its derivatives in the male Wistar rat. Xenobiotica, 1993, 23(6), 709-716.
[http://dx.doi.org/10.3109/00498259309059408] [PMID: 8212744]
[23]
Beckett, A.H.; Belanger, P.M. The disposition of phentermine and its N-oxidized metabolic products in the rabbit. Xenobiotica, 1978, 8(1), 55-60.
[http://dx.doi.org/10.3109/00498257809060383] [PMID: 24306]
[24]
Caldwell, J.; Köster, U.; Smith, R.L.; Williams, R.T. Species variations in the N-oxidation of chlorphentermine. Biochem. Pharmacol., 1975, 24(24), 2225-2232.
[http://dx.doi.org/10.1016/0006-2952(75)90259-2] [PMID: 814901]
[25]
García-López, J.A.; Oliva-Madrid, M.J.; Saura-Llamas, I.; Bautista, D.; Vicente, J. Insertion of benzyne into the Pd–C bond. Synthesis of unnatural amino acid derivatives by sequential insertion of benzyne and CO: 2,2′-functionalized biaryls containing alkylamino and carboxymethyl substituents. Isolation of stable carbopalladated-benzyne intermediates. Chem. Commun., 2012, 48(53), 6744-6746.
[http://dx.doi.org/10.1039/c2cc32975a] [PMID: 22644258]
[26]
Woźniak, M.K.; Wiergowski, M.; Aszyk, J.; Kubica, P.; Namieśnik, J.; Biziuk, M. Application of gas chromatography–tandem mass spectrometry for the determination of amphetamine-type stimulants in blood and urine. J. Pharm. Biomed. Anal., 2018, 148, 58-64.
[http://dx.doi.org/10.1016/j.jpba.2017.09.020] [PMID: 28957720]
[27]
Oliva-Madrid, M.J.; García-López, J.A.; Saura-Llamas, I.; Bautista, D.; Vicente, J. Reactivity toward neutral N- and P-donor ligands of eight-membered palladacycles arising from mono insertion of alkynes into the Pd-C bond of ortho palladated homoveratryl amine and phentermine. A new example of the transphobia effect. Organometallics, 2014, 33(1), 33-39.
[http://dx.doi.org/10.1021/om401090b]
[28]
Shin, Y.; Kim, J.Y.; Cheong, J.C.; Kim, J.H.; Kim, J.H.; Lee, H.S. Liquid chromatography-high resolution mass spectrometry for the determination of three cannabinoids, two (−)-trans-Δ9-tetrahydrocannabinol metabolites, and six amphetamine-type stimulants in human hair. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2020, 1149, 122157.
[http://dx.doi.org/10.1016/j.jchromb.2020.122157] [PMID: 32447253]