RTI-274, or 2β--3α-(4-fluorophenyl)nortropane is a phenyltropane

Phenyltropane

Phenyltropanes were originally developed to reduce cocaine addiction and dependency. In general these compounds act as inhibitors of the plasmalemmal monoamine reuptake transporters. Although RTI holds a strong position in this field, they are not the only researchers that have prepared these...

 homologue of paroxetine

Paroxetine

Paroxetine is an SSRI antidepressant. Marketing of the drug began in 1992 by the pharmaceutical company SmithKline Beecham, now GlaxoSmithKline...

 developed by the group led by F Ivy Carroll in the 1990s.

Introduction

Very few ethers of phenyltropanes are actually known to have been reported. NS2330 and NS2359

NS2359

NS-2359 is a serotonin-norepinephrine-dopamine reuptake inhibitor. It was under development by GlaxoSmithKline as an antidepressant, but was discontinued in 2009 when phase II clinical trials turned up disappointing results and did not support further effort by the company...

 are exemplary, although it must be stressed that these compounds have α,β stereochemistry. Since further development of NS2214 appears to have been halted, the importance of a metabolically stable compound that is not just readily metabolized is evident.

For some reason that is not entirely clear, the authors of the present document decided that they wanted to make all 8 stereoisomers for the phenyltropane homolog of paroxetine

Paroxetine

Paroxetine is an SSRI antidepressant. Marketing of the drug began in 1992 by the pharmaceutical company SmithKline Beecham, now GlaxoSmithKline...

.

MAT Monoamine transporter Monoamine transporters are protein structures that function as integral plasma membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters. Three major classes of MATs are responsible for the reuptake of their associated amine neurotransmitters...  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
  IC50
  The half maximal inhibitory concentration is a measure of the effectiveness of a compound in inhibiting biological or biochemical function. This quantitative measure indicates how much of a particular drug or other substance is needed to inhibit a given biological process by half...
  
  .

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.

Interestingly, that is actually 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. Diagram

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

Trodat

Trodat, Inc. according to its own data, is the world’s largest manufacturer of self-inking rubber stamp . The Trodat international group of companies has its company headquarters in Wels, Austria...

") {p948, 24}.

The metal is called "Technetium

Technetium

Technetium is the chemical element with atomic number 43 and symbol Tc. It is the lowest atomic number element without any stable isotopes; every form of it is radioactive. Nearly all technetium is produced synthetically and only minute amounts are found in nature...

" and is bound by a chelating agent.

The authors state that at first the acid is halogenated, the amide is prepared, and reduced.

Erratum

MAT Monoamine transporter Monoamine transporters are protein structures that function as integral plasma membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters. Three major classes of MATs are responsible for the reuptake of their associated amine neurotransmitters...  IC50 (Ki) N-Methyl → De-methyl

Compound

[3H]CFT

[3H]Nisoxetine

[3H]paroxetine >- | R-β,β

? → 3

? → 2 (0.2)

>-

S-β,β

? → ?

? → ? (?)

>- | R-"nonane"

308 → 835

294 (27) → 480 (44)

>- | S-"nonane"

1050 → 1210

88 (8) → 424 (39)

To solve the problem of the unexpected aza-bicyclo[3.2.2]nonane rearrangement product, the original synthesis had to be modified as follows; WIN 35428 was N-demethylated and then the NH amine was reacted with a suitable protecting group

Protecting group

A protecting group or protective group is introduced into a molecule by chemical modification of a functional group in order to obtain chemoselectivity in a subsequent chemical reaction...

 so that is no longer nucleophilic. In their case they used a tosyl.
(Satendra Singh, 2000) Page 952