Facile syntheses of the three major metabolites of thioridazine

Article abstract of DOI:10.1002/hlca.200590089

Efficient, mild syntheses of the three major metabolites 2-4 of the important antipsychotic drug thioridazine (1) have been developed. The cardiotoxic metabolite 2 with a ring sulfoxide moiety was prepared in 96% yield by oxidation of 1 with NaIO₄ under acidic conditions. Four different procedures were elaborated for the selective side-chain sulfide oxidation of 1 to mesoridazine (3), giving rise to yields of up to 91%. Finally, sulforidazine (4) was synthesised via oxidation of the sulfoxide 3 in the presence of either KMnO₄ or t-BuOOH under basic conditions. Except for the oxidation with t-BuOOH. all reactions took place under mild conditions within a few minutes, were nicely reproducible, and afforded medium-to-high yields of the desired products, which could be readily purified by column chromatography.

Full text of DOI:10.1002/hlca.200590089

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Facile Syntheses of the Three Major Metabolites of Thioridazine
by Ryan J. Morrow*, Jeff S. Millership, and Paul S. Collier
Queens University Belfast, School of Pharmacy, 97 Lisburn Road, Belfast BT9 7BL, UK
(phone: ‡ 44-(0)2890272338; fax: ‡ 44(0)2890247794; e-mail: r.morrow@qub.ac.uk)
Efficient, mild syntheses of the three major metabolites 2 ± 4 of the important antipsychotic drug
thioridazine (1) have been developed. The cardiotoxic metabolite 2 with a ring sulfoxide moiety was prepared in
96% yield by oxidation of 1 with NaIO4 under acidic conditions. Four different procedures were elaborated for
the selective side-chain sulfide oxidation of 1 to mesoridazine (3), giving rise to yields of upto 91%. Finally,
sulforidazine (4) was synthesised via oxidation of the sulfoxide 3 in the presence of either KMnO4 or t-BuOOH
under basic conditions. Except for the oxidation with t-BuOOH, all reactions took place under mild conditions
within a few minutes, were nicely reproducible, and afforded medium-to-high yields of the desired products,
which could be readily purified by column chromatography.
Introduction. ± Thioridazine (1)1) is a chiral, tricyclic drug used in racemic form for
the treatment of schizophrenia and other psychiatric disorders, and produces few
extrapyrimidal side effects (a regular side effect in antipsychotic therapy) [1 ± 2]. Like
all other antipsychotic agents, the ability of 1 to alleviate psychotic symptoms is
attributed to antagonistic blocking of central dopamine receptors, which compensates
for the overactivity of this neurotransmitter [3]. However, the individual enantiomers
of 1 have been shown to produce significantly different pharmacologic effects. Several
authors have reported a difference in the distribution of the enantiomers in blood
plasma and in various human tissues [4 ± 6]. Furthermore, it has been shown that (‡)-
(R)-thioridazine ((R)-1; see Scheme) has a 2.7-times higher affinity than the (À)-(S)-
isomer for the important D2 receptors, which are most strongly related to alleviation of
psychotic symptoms in rat brain [3].
It has been recognised that the pharmacologic effects of thioridazine therapy are
not only attributed to the parent drug, but also to the major metabolites: the ring
sulfoxide 2, the side-chain sulfoxide mesoridazine (3), and the side-chain sulfone
sulforidazine (4). All these compound are known to significantly contribute to the
overall pharmacological profile of thioridazine-based drug therapy [7 ± 20]. In fact,
compounds 3 and 4 have been shown to be ca. 50% more potent than the parent drug 1
[7 ± 10], and the ring sulfoxide 2, although not considered to contribute to the observed
antipsychotic activity, is reported to be the major cause of cardiotoxic side effects
associated with the administration of 1 [14 ± 20].
Despite the importance of the metabolites 2 ± 4, there is still minimal information
regarding the pharmacologic and pharmacokinetic effects of the isomers of these
compounds, and there are currently only a few useful methods for their synthesis from
1
)
Systematic name: 10-[2-(1-methylpiperidin-2-yl)ethyl]-2-(methylsulfanyl)-10H-phenothiazine.
ꢀ 2005 Verlag Helvetica Chimica Acta AG, Zürich

Helvetica Chimica Acta ± Vol. 88 (2005)
963
Scheme
a) For example: TiCl3/AlCl3, aq. 30% H2O2, MeOH, r.t., 20 min; 91%. b) For example: KMnO4, acetone, 458,
30 min; 52%. c) NaIO4, H2O/MeOH, HCl (cat.); 96%.
THD (1). The only previously documented method for the direct oxidation of the side-
chain sulfide groupof 1 to racemic mesoridazine (rac-3) is an original patented
procedure [21] based on oxidation of 1 ´ HCl by sodium metaperiodate (NaIO4), which,
reportedly, generates 3 in high yield. However, when we repeated this procedure, we
found that 3 is produced as a mixture of diastereoisomers in yields below 22%, the
other 78% of material being attributed mainly to the ring oxide 2 (69%) and some
unmodified starting material 1 (9%). Furthermore, the product detailed in the patent
[21] was reported to be a solid, with a melting point of 128 ± 1318. The free base of 3,
however, can be obtained only as an oil. It is, therefore, possible that the authors had
actually isolated the solid metabolite 2 rather than the desired 3. Indeed, the reported
melting point for 3 (128 ± 1318) lies in the upper range of the broad melting point of
diastereoisomeric 2 (113.5 ± 128.58 [21]). In addition to the lack of useful procedures for
the synthesis of 3, there are currently no procedures for the synthesis of 4 through
direct oxidation of the parent compound, and there is only one previously reported
procedure for the synthesis of 2 from 1 [22].
The present study now introduces straight-forward, reproducible procedures for the
syntheses of the three major metabolites of 1 in good yields (Scheme).
Results and Discussion. ± 1. Synthesis of Racemic Mesoridazine (3). Due to the low
yield of 3 obtained by the patent procedure [21], numerous oxidations were performed
to establish a suitable process for the specific side-chain oxidation of rac-1 to rac-3
(Scheme). A number of straight-forward, non-stereochemically controlled oxidative
procedures based on H2O2 and different metal salts were developed (in decreasing
order of efficiency): 1) TiCl3/AlCl3, H2O2 (91%); 2) V2O5, H2O2 (85%); 3)
(CF3)2CHÀOH, H2O2 (78%); and 4) SeO2, H2O2 (68%).
The high yields of 3 are most likely due to the electrophilic nature of the reagents
employed. In the case of V2O5 and TiCl3/AlCl3 oxidations, the H2O2 coordinates to the
metal ion to form a peroxo ± metal species. The metal ion activates the peroxide OÀO
bond, which leads to an increase in electrophilicity of the oxidant, promoting
nucleophilic attack by the sulfide S-atom [23 ± 27]. In the case of the reaction in the
presence of hexafluoroisopropanol, the electron-withdrawing nature of the two CF3
groups results in strong H-bonding between HFIP and H2O2, which activates the OH
leaving group, making H2O2 more reactive [28]. Finally, SeO2 reacts with H2O2 to form
perselenic acid (a peroxy acid) as the resulting oxidising agent [29]. The Se peroxy acid

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Helvetica Chimica Acta ± Vol. 88 (2005)
is a highly electrophilic oxidant that is much more reactive towards sulfides compared
to H2O2 and alkyl peroxides.
The selectivity of the above oxidants for the side-chain sulfide groupof 1 compared
to the ring sulfide centre is expected to be determined by the influence of the aromatic
rings. The ring sulfide S-atom is less nucleophilic compared to the side chain S-atom,
which, thus, is more reactive towards the electrophilic oxidants.
Upon reaction of 3 with benzenesulfonic acid, the corresponding benzenesulfonate
(ꢁbesylateꢂ) was obtained for characterisation. However, there was a discrepancy
between the melting points of the besylate isolated in this study (171 ± 1738) and that
reported (180 ± 1828) [30]. This is most probably due to the observations that the
besylate of 3 undergoes preferential crystallisation of one pair of diastereoisomers, as
shown previously by NMR [31]. The diastereoisomeric ratio of the isolated besylate is
likely to be dependent on crystallisation method and conditions. Actually, the synthesis
of 3 by any of the stereochemically nonselective oxidative procedures mentioned
above afforded a 50 :50 mixture of diastereoisomeric pairs. However, upon recrystal-
lisation of the still-racemic besylate salt, the diastereoisomeric ratio was dramatically
altered to 87:13.
2. Synthesis of Sulforidazine (4). Theoretically, the oxidation required to synthesise
the side-chain sulfone 4 could be achieved either by direct oxidation of 1 or,
alternatively, by oxidation of the SO groupof 3. The first way was expected to be more
difficult, since direct oxidation of a sulfide proceeds via the sulfoxide, followed by
further oxidation to the sulfone, two reactions based on different mechanisms. The
second approach, the conversion of an (electrophilic) SO group to an SO2 moiety
requires a nucleophilic oxidant, in contrast to the oxidation of a nucleophilic sulfide S-
atom to a sulfoxide, which proceeds best with electrophilic reagents. Nevertheless,
oxidising agents with high electrophilic O-transfer ability, such as peroxy acids, can be
strong enough to oxidise sulfides to sulfoxides, followed by further oxidation to the
sulfone [32]. This, however, would be inappropriate in the case of 1, as a highly reactive
oxidant would promote oxidation of both the ring and side-chain sulfide centres. Thus, a
more-suitable approach is to proceed through the nucleophilic oxidation of the
previously synthesised mesoridazine (3).
Selective nucleophilic oxidation of the side-chain SO group was achieved by
refluxing 3 with t-BuOOH under basic conditions [33], giving rise to nucleophilic
attack of t-BuOOÀ at the SO group. The reaction proceeded slowly and required
vigorous reflux for several hours, but did afford sulforidazine (4), however, in moderate
yield (37%) only. We, thus, developed a more-efficient method based on the use of
KMnO4. As oxidations with this reagent proceed both under milder conditions and
more rapidly with sulfoxides than with sulfides, selective oxidation of 3 was possible,
and the yield of 4 could be increased to 52% [34][35].
3. Synthesis of Metabolite 2. Oxidation of the ring sulfide S-atom of 1 could be
achieved by a previously reported oxidative method involving NaNO2 and a few drops
of concentrated HCl [22], which generated rac-2 in yields of at least 94%. Nevertheless,
upon slight modification of the reported reaction conditions, we were able to increase
the yield of 2 to > 96%. Again, all four stereoisomers were present in equal amounts.

Helvetica Chimica Acta ± Vol. 88 (2005)
965
Experimental Part
1. General. All commercial reagents were used as received. Reactions were monitored by thin-layer
chromatography (TLC; aluminium-backed plates (0.2 mm)) on silica-gel 6 0 F (Merck). Flash chromatog-
254
raphy (FC) was performed on silica gel 60 (230 ± 400 mesh; Merck). HPLC was carried out using a Milton Roy
CM4000 pump, a manual injector, and an LDC/Milton Roy Spectromonitor III detector. Melting points (m.p.)
 Â
were determined on a Griffin Gallenkamp melting-point apparatus; uncorrected. IR Spectra: Nicolet Protege-
460 spectrometer, thin film or KBr discs; in cmÀ1 1H- and 13C-NMR Spectra: General Electric QE-500
.
instrument at 500 and 125 MHz, resp.; chemical shifts d in ppm rel. to Me4Si as internal standard; coupling
constants J in Hz. EI-MS (70 eV): AEI-MS 902 instrument; accurate molecular weights were determined by the
peak-matching method using perfluorokerosene as a standard reference.
2. Special Analytical Methods. 2.1. TLC Analysis [24][28]. The TLC method used for the analysis of
thioridazine (1) and its metabolites 2 ± 4 followed that previously reported [22][35], using acetone/12n aq.
NH4OH soln. 100 :7 and Merck silica gel 6 0 F254 Al sheets (0.2 mm). For all compounds (except 4, which had not
been investigated in previous reports [22][36]), the elution order was as reported. Retention factors (Rf values;
see Table) were marginally different from those reported, which is probably due to the different silica gel plates
employed. Note that the two diastereoisomeric pairs of 2 were visually separated under these conditions,
whereas those of 3 where unresolved (single spot on TLC plate). All components were clearly visible under UV
light. Further identification could be achieved by the notable colour changes upon spraying with 10% H2SO4 in
EtOH, followed by heating at 608 in an oven (to distinguish 2 and 4) colour changes at this stage, and finally
spraying the plate with Folin ± Coiceleaus reagent (to distinguish 1 and 3).
Table. Thin-Layer Chromatographic Properties of Compounds 1 ± 4
Compound
Rf
H2SO4, 608 for 10 min
Folin ± Coiceleaus reagent
1
2
3
4
0.76
none
blue
none
bright pink
blue
none
pink/red
none
0.61/0.56a)
0.51
0.72
a) Diastereoisomeric pairs clearly separated.
2.2. HPLC Analysis [29]. The HPLC analysis of of 1 ± 4 was a modification of a previously reported method
[37]. A Hypersil (5 mm) silica-gel column (4.6 mm  250 mm) was used, and the mobile phase was 2-
chlorobutane/i-PrOH/H2O/Et3N (82 :17.9 :0.08 :0.016) at a flow rate of 1.5 ml/min, a temp. of 258, and detection
at 254 nm. These conditions resulted in different elution times for 1, 2, 3, and 4 compared to those reported [29];
however, the elution sequence was identical.
3. Mesoridazine (ˆ10-[2-(1-Methylpiperidin-2-yl)ethyl]-2-(methylsulfinyl)-10H-phenothiazine; 3). 3.1.
Method A [38]. A soln. of 30% aq. H2O2 (0.52 ml, 5.9 mmol) and TiCl3/AlCl3 (10 mg) in MeOH (20 ml) was
added dropwise over 15 min to a stirred soln. of rac-1 ´ HCl (2 g, 4.9 mmol) dissolved in MeOH (20 ml),
whereupon a colour change to blue-green was observed. The mixture was then stirred for an additional 5 min at
r.t., and quenched with H2O (50 ml). The product was extracted with CH2Cl2 (3 Â 30 ml), dried (MgSO4),
filtered, and evaporated to dryness in vacuo. The resulting yellow oily crude product consisted of 3 (91% by
HPLC) and unreacted 1 (9%), and was purified by FC (SiO2; CHCl3/MeOH 95 :5) NMR Analysis indicated a
1:1:1 :1 mixture of all four stereoisomers.
For further characterization (m.p.), the benzenesulfonate (ꢁbesylateꢂ) salt of 3 was prepared by addition of
benzene sulfonic acid (0.365 g, 2.31 mmol) to purified 3 (0.882 g, 2.28 mmol) dissolved in EtOH (10 ml). Upon
leaving this soln. in the dark, crystals of the besylate were formed in 28% yield (m.p. 171 ± 1738; lit. 180 ± 1828
[30]). The diastereoisomeric ratio of the besylate after crystallisation was 87:13, as determined by NMR.
1
Data of 3 (diastereoisomeric mixture). Yield: 91% (HPLC). IR (KBr): 1179, 1224, 1453, 3442. H-NMR
(500 MHz, CDCl3): 1.26 ± 2.16 (m, 10 H); 2.223, 2.232 (2s, MeN); 2.696, 2.699 (2s, MeSO); 2.80 (m, 1 H); 3.95
(m, 2 H); 6.9 ± 7.23 (m, 7 H). 13C-NMR (125 MHz, CDCl3): 24.03, 25.50, 29.80, 30.71 (4 CH2); 42.9 (MeSO);
44.06, 44.146 (MeN); 44.6, 57.2 (2 CH2); 62.4 (CH); 109.74, 115.93, 117.16, 123.11, 127.58, 127.60, 127.80 (7
‡
arom.CH); 124.4, 129.10, 144.37, 144.95, 146.68 (5 arom.C). EI-MS: 386 (15, M ), 126 (7), 98 (100), 70 (10), 41
‡
‡
(5). HR-EI-MS: 386.14709 (M , C21H26N2OS2 ; calc. 386.14866).

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Helvetica Chimica Acta ± Vol. 88 (2005)
3.2. Method B [39][40]. A soln. of V2O5 (20 mg) in 30% aq. H2O2 (0.52 ml, 5.9 mmol) and MeOH (20 ml)
was added to a soln. of rac-1 ´ HCl (2 g, 4.9 mmol) in MeOH (35 ml) over a period of 15 min, whereupon a
colour change to blue-green was observed. The mixture was stirred for a further 5 min, and then quenched with
H2O (50 ml). The product was extracted with CH2Cl2 (3 Â 30 ml), dried (MgSO4), filtered, and evaporated to
dryness in vacuo. The resulting yellow oil consisted of 3 (85%), and side products and starting material (15%).
3.3. Method C [41]. To a soln. of rac-1 ´ HCl (2 g, 4.9 mmol) in MeOH (15 ml) was added dropwise over
15 min a soln. of equimolar H2O2/SeO2 (0.5 ml 30% aq. H2O2 and 0.6 g of SeO2) in MeOH/H2O 50 :50 (10 ml)
with stirring. The green-blue mixture was stirred for a further 5 min, and quenched with H2O (50 ml). The
product was extracted with CH2Cl2 (3 Â 30 ml), dried (MgSO4), filtered, and evaporated to dryness in vacuo.
The resulting yellow oil consisted of 3 (68%), and side products and starting material (32%).
3.4. Method D [28]. To a soln. of rac-1 ´ HCl (0.5 g, 1.23 mmol) in hexafluoroisopropanol (6 ml), 30% aq.
H2O2 (0.15 ml, 1.48 mmol) was added dropwise over 15 min, whereupon a colour change to deep blue was
observed. Then, the soln. was stirred for another 5 min, and quenched with 1m aq. Na2SO3 soln. (10 ml). The org.
layer was separated, and the fluorinated solvent was distilled off 2). The crude product was dissolved in CH2Cl2
(20 ml), dried (MgSO4), filtered, and evaporated to dryness in vacuo. The resulting yellow oil consisted of 3
(78%), and some side products and starting material (22%).
3.5. Literature Method [21]. To a soln. of NaIO4 (0.53 g, 2.5 mmol) in H2O (25 ml) cooled to 08, a soln. of
rac-1 ´ HCl (1 g, 2.45 mmol) in H2O (25 ml) was added dropwise with stirring over 20 min. A colour change to
blue was observed. The mixture was stirred at 08 for 2 h, and then at r.t. for 24 h. After completion of the
reaction, H2O was added (50 ml), the mixture was extracted with CH2Cl2 (3 Â 30 ml), the org. layer was dried
(MgSO4), filtered, and evaporated to dryness in vacuo. The crude product contained 3 (22%) and 2 (ca. 78% by
HPLC).
3.6. Sulforidazine (ˆ10-[2-(1-Methylpiperidin-2-yl)ethyl]-2-(methylsulfonyl)-10H-phenothiazine; 4). 3.6.1.
Method A [33][34]. An aq. soln. of KMnO4 was added to a stirred soln. of rac-3 (0.81 g, 2.1 mmol) in acetone
(100 ml) at a temp. of 458. As the reaction progressed, the purple colour of KMnO4 disappeared, and a brown
precipitate occurred (MnO2). KMnO4 was continually added over a period of 30 min, until a purple tinge
remained in soln. The brown precipitate was then filtered off, and the acetone was evaporated in vacuo. The
remaining aq. soln. was extracted with CH2Cl2 (3 Â 20 ml), dried (MgSO4), and evaporated to dryness in vacuo.
The crude product was isolated by FC (SiO2; CH3Cl/MeOH 95 :5) to afford 4 (0.439 g) in 52% yield. M.p. 118 ±
1218 ([38]: 121 ± 1238). IR (film): 1150, 1311, 1456, 3431. 1H-NMR (500 MHz, CDCl3): 1.3 ± 2.16 (m, 10 H); 2.22
(s, MeN); 2.81 (m, 1 H); 3.02 (s, MeSO); 3.9 (m, 2 H); 6.84 ± 7.37 (m, 7 H). 13C-NMR (125 MHz, CDCl3): 24.11,
25.59, 29.75, 30.78 (4 CH2); 43.04 (MeN); 44.19, 56.82 (2 CH2); 44.60 (MeSO2); 61.96 (CH); 113.41, 116.02,
121.04, 123.02, 127.63, 127.83, 127.90 (7 arom.CH); 123.64, 132.97, 139.47, 144.04, 146.10 (5 arom.C). EI-MS: 402
‡
(38, M ), 290 (12), 277 (9), 211 (12), 197 (16), 149 (13), 126 (24), 98 (100), 70 (8), 43 (13). HR-EI-MS:
‡
‡
402.14308 (M , C21H26N2O2S2 ; calc. 402.14357).
3.6.2. Method B. To a soln. of rac-3 (0.82 g, 2.1 mmol) in MeOH (30 ml) was slowly added 6m aq. NaOH
soln., until 3 began to precipitate. Then, some MeOH (ca. 5 ml) was added to redissolve the precipitate. To this
sat. soln., a 70% t-BuOOH soln (0.35 ml) was added, and the mixture was refluxed for 6 h. Then, a further
portion of t-BuOOH (0.15 ml) was added, and the mixture was heated to reflux for 16 h. After completion of the
reaction, H2O (100 ml) was added, the mixture was extracted with CH2Cl2 (3 Â 20 ml), dried (MgSO4), filtered,
and evaporated to dryness in vacuo. The crude product was purified by FC (SiO2; CHCl3/MeOH 95 :5) to afford
4 (0.31 g) in 37% yield.
10-[2-(1-Methylpiperidin-2-yl)ethyl]-2-(methylsulfanyl)-10H-phenothiazine 5-Oxide (2). A soln. of NaIO4
(0.53 g, 2.5 mmol) in 70% aq. MeOH (20 ml) containing seven drops of conc. HCl was added dropwise to a
stirred soln. of rac-1 ´ HCl (1 g, 2.46 mmol) in MeOH (30 ml), whereupon the colour changed to red. After
completion of the reaction (10 min), H2O (50 ml) was added. The mixture was extracted with CH2Cl2 (3 Â
20 ml), dried (MgSO4), and evaporated to dryness in vacuo. The product was crystallised from EtOH to afford 2
1
in 96% yield (HPLC). M.p. 114 ± 1268 ([30]: 113.5 ± 128.58). IR (KBr): 1025, 1047, 1449, 1457, 1577. H-NMR
(500 MHz CDCl3): 1.26 ± 2.16 (m, 10 H); 2.342, 2.349 (2s, MeN); 2.563, 2.570 (2s, MeSO); 2.80 (m, 1 H); 3.95
(m, 2 H); 6.9 ± 7.23 (m, 7 H). 13C-NMR (125 MHz, CDCl3): 15.83 (MeS); 24.57, 25.89, 29.66, 31.15 (4 CH2);
43.633, 43.736 (MeN); 45.63, 57.28 (2 CH2); 62.441, 62.503 (CH); 112.63, 116.16, 119.40, 122.34, 132.11, 132.45,
‡
133.25 (7 arom.CH); 121.45, 125.10, 138.52, 138.92 145.96 (5 arom. C). EI-MS: 386 (15, M ), 370 (51), 369 (29),
2
)
Hexafluoroisopropanol can be recovered and re-used.

Helvetica Chimica Acta ± Vol. 88 (2005)
967
‡
‡
258 (17), 245 (7), 185 (7), 126 (6), 98 (100), 87 (7), 69 (18), 41 (24). HR-EI-MS: 386.14813 (M , C21H26N2OS2
;
calc. 386.14866).
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Received January 10, 2005