Short description
RTI-274 Identifiers
2β-([3,4-Methylenedioxy)phenoxy]methyl)-3α-(4-fluorophenyl)nortropane
Chemical and physical data Formula C 21 H 22 F N O 3 Molar mass −1 3D model (JSmol )
c4cc1OCOc1cc4OCC2C(c3ccc(F)cc3)CC5NC2CC5
(verify)
RTI(-4229 )-274 , or 2β-((3,4-Methyl is a phenyltropane homologue of paroxetine developed by the group led by F Ivy Carroll in the 1990s.[ 1]
Introduction
Very few esters of phenyltropanes are actually known to have been reported.
NS2330 and NS2359 both have α,β stereochemistry.
NS2214 appears to have been abandoned now, RTI-336 was their latest compound.
RTI decided that they wanted to make all 8 stereoisomers of the phenyltropane paroxetine homolog.[ 1]
MAT IC50 (nM) Nor/tropane-Paroxetine Hybrids
Compound
[3 H]CFT
[3 H]Paroxetine
[3 H]Nisoxetine
Paroxetine
? → 623
? → 0.28
? → 535
R
"β,β"
308 → 835
294 → 480
5,300 → 37,400
α,β
172 → 142
52.9 → 90
26,600 → 2,500
β,α
3.01 → 3.86
422 → 5.62
123 → 14.4
S
"β,β"
1,050 → 1,210
88.1 → 424
27,600 → 17,300
α,β
1,500 → 27.6
447→ 55.8
2,916 → 1,690
β,α
298 → 407
178 → 19
12,400 → 1,990
N -demethylating the S -α,β (1S,2S,3R) isomer resulted in a 54-fold increase in DAT IC50 .In the case of nocaine it is understood that the SR enantiomer is the one that should be demethylated if it is wanted to improve DAT affinity.
That is the same enantiomer that is used in the production of paroxetine.
Skeletal rearrangement
Four years later some unrelated authors cited a skeletal rearrangement accounts for this.[ 2] Diagram [|permanent dead link|dead link}} ]
Notice that they are not only interested in ethers, but nitrogen containing Nu's ("TRODAT")[ 3]
The metal is called "Technetium " and is bound by a chelating agent.
The authors state that at first the acid is halogenated, the amide is prepared, and reduced.
Erratum
Taxil Synthesis[ 4] (a) (1) 1-chloroethyl chloroformate, 1,2-dichloroethane, reflux; (2) MeOH reflux; (b) p -toluenesulfonyl chloride,
triethylamine; (c) LiAlH4 , THF, rt; (d) trifluoromethanesulfonic anhydride, pyridine, CH2 Cl2 ; (e) Na, sesamol, THF; (f) 5% Na/Hg amalgam, Na2 HPO4 , MeOH.
MAT IC50 (Ki ) N -Methyl → De-methyl
Compound [3 H]CFT [3 H]Nisoxetine [3 H]paroxetine
R -β,β? → 3
? → 2 (0.2)
? → 6 (4)
S -β,β? → ?
? → ? (?)
? → ? (?)
R -"nonane"308 → 835
294 (27) → 480 (44)
5,300 (3200) → 37,400 (22,500)
S -"nonane"1050 → 1210
88 (8) → 424 (39)
27,600 (16,600) → 17,300 (10,400)
To solve the problem of the unexpected aza-bicyclo[3.2.2]nonane rearrangement product, the original synthesis had to be modified as follows;[ 4] protecting group so that N is no longer nucleophilic. In their case they used a tosyl.[ 3]
See also
References
↑ 1.0 1.1 "Synthesis and ligand binding of tropane ring analogues of paroxetine". Journal of Medicinal Chemistry 41 (2): 247–57. January 1998. doi :10.1021/jm970669p . PMID 9457247 . ↑ "Rearrangement of a mesylate tropane intermediate in nucleophilic substitution reactions. Synthesis of aza-bicyclo[3.2.1]octane and aza-bicyclo[3.2.2]nonane ethers, imides, and amines". The Journal of Organic Chemistry 67 (11): 3637–42. May 2002. doi :10.1021/jo010973x . PMID 12027674 . ↑ 3.0 3.1 "Chemistry, design, and structure-activity relationship of cocaine antagonists". Chemical Reviews 100 (3): 925–1024. March 2000. doi :10.1021/cr9700538 . PMID 11749256 . ↑ 4.0 4.1 "Synthesis, structural identification, and ligand binding of tropane ring analogs of paroxetine and an unexpected aza-bicyclo[3.2.2]nonane rearrangement product". Bioorganic & Medicinal Chemistry 13 (7): 2439–49. April 2005. doi :10.1016/j.bmc.2005.01.046 . PMID 15755646 .
2-Carboxymethyl Esters (3,4-Disubstituted Phenyl)-tropanes Arylcarboxy Carboxyalkyl Acyl β,α Stereochemistry α,β Stereochemistry Heterocycles: 3-Substituted-isoxazol-5-yl Heterocycles: 3-Substituted-1,2,4-oxadiazole N-alkyl N-replaced (S,O,C) Irreversible Nortropanes (N-demethylated)
Adamantanes Adenosine antagonists Alkylamines Ampakines Arylcyclohexylamines Benzazepines Cholinergics Convulsants Eugeroics Oxazolines Phenethylamines
1-(4-Methylphenyl)-2-aminobutane 1-Methylamino-1-(3,4-methylenedioxyphenyl)propane 2-Fuoroamphetamine 2-Fuoromethamphetamine 2-OH-PEA 2-Phenyl-3-aminobutane 2,3-MDA 3-Fuoroamphetamine 3-Fluoroethamphetamine 3-Fluoromethcathinone 3-Methoxyamphetamine 3-Methylamphetamine 3,4-DMMC 4-BMC 4-CMC 4-Fluoroamphetamine 4-Fluoromethamphetamine 4-MA 4-Methylbuphedrone 4-Methylcathinone 4-MEAP 4-MMA 4-Methylpentedrone 4-MTA 6-FNE AL-1095 Alfetamine a-Ethylphenethylamine Amfecloral Amfepentorex Amfepramone Amidephrine 2-Amino-1,2-dihydronaphthalene 2-Aminoindane 5-(2-Aminopropyl)indole 2-Aminotetralin Acridorex Amphetamine (Dextroamphetamine , Levoamphetamine )Amphetaminil Arbutamine β-Methylphenethylamine β-Phenylmethamphetamine Benfluorex Benzedrone Benzphetamine BDB BOH 3-Benzhydrylmorpholine BPAP Buphedrone Bupropion Butylone Camfetamine Cathine Cathinone Chlorphentermine Cilobamine Cinnamedrine Clenbuterol Clobenzorex Cloforex Clortermine Cypenamine D -DeprenylDenopamine Dimethoxyamphetamine Dimethylamphetamine Dimethylcathinone Dobutamine DOPA (Dextrodopa , Levodopa )Dopamine Dopexamine Droxidopa EBDB Ephedrine Epinephrine Epinine Etafedrine Ethcathinone Ethylnorepinephrine Ethylone Etilamfetamine Etilefrine Famprofazone Fencamfamin Fencamine Fenethylline Fenfluramine (Dexfenfluramine , Levofenfluramine )Fenproporex Feprosidnine Flephedrone Fludorex Formetorex Furfenorex Gepefrine Hexapradol Hexedrone HMMA Hordenine 4-Hydroxyamphetamine 5-Iodo-2-aminoindane Ibopamine Indanylamphetamine Iofetamine Isoetarine Isoethcathinone Isoprenaline L -DeprenylLefetamine Lisdexamfetamine Lophophine MBDB MDA (tenamfetamine) MDBU MDEA MDMA (midomafetamine) MDMPEA MDOH MDPR MDPEA Mefenorex Mephedrone Mephentermine Metanephrine Metaraminol Mesocarb Methamphetamine (Dextromethamphetamine , Levomethamphetamine )Methoxamine Methoxyphenamine MMA Methcathinone Methedrone Methoxyphenamine Methylenedioxycathinone Methylone Mexedrone MMDA MMDMA MMMA Morforex N,alpha-Diethylphenylethylamine N-Ethylbuphedrone N-Ethylhexedrone N,N-Dimethylphenethylamine Naphthylamphetamine Nisoxetine Norepinephrine Norfenefrine Norfenfluramine Normetanephrine L -NorpseudoephedrineOctopamine (drug) Orciprenaline Ortetamine Oxifentorex Oxilofrine PBA PCA PCMA PHA Pentorex Pentedrone Pentylone Phenatine Phenpromethamine Phentermine Phenylalanine Phenylephrine Phenylpropanolamine Pholedrine PIA PMA PMEA PMMA PPAP Phthalimidopropiophenone Prenylamine Propylamphetamine Pseudoephedrine Ropinirole Salbutamol (Levosalbutamol )Sibutramine Solriamfetol Synephrine Theodrenaline Tiflorex Tranylcypromine Tyramine Tyrosine Xylopropamine Zylofuramine Phenylmorpholines Piperazines Piperidines Pyrrolidines Racetams Tropanes Tryptamines Others
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