RTI-274

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RTI-274
Identifiers
  • 2β-([3,4-Methylenedioxy)phenoxy]methyl)-3α-(4-fluorophenyl)nortropane
Chemical and physical data
JSmol)
  • c4cc1OCOc1cc4OCC2C(c3ccc(F)cc3)CC5NC2CC5
  (verify)

RTI(-4229)-274, or 2β-((3,4-Methyl​enedioxy​phenoxy)methyl)-3α-(4-fluorophenyl)​nortropane 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.

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 [3H]CFT [3H]Paroxetine [3H]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[dead link]

Notice that they are not only interested in ethers, but nitrogen containing Nu's ("TRODAT")[3]

The metal is called "

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, CH2Cl2; (e) Na, sesamol, THF; (f) 5% Na/Hg amalgam, Na2HPO4, MeOH.

MAT IC50 (Ki) N-Methyl → De-methyl
Compound [3H]CFT [3H]Nisoxetine [3H]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;

nucleophilic. In their case they used a tosyl.[3]

See also

References

  1. ^
    PMID 9457247
    .
  2. PMID 12027674
    .
  3. ^
    S2CID 36764655
    .
  4. ^
    PMID 15755646
    .
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