Improved synthesis of tadalafil using dimethyl carbonate and ionic liquids

Article abstract of DOI:10.1039/c3ra45982a

An improved synthesis of tadalafil, a drug for the treatment of male erectile dysfunction, involves the use of safer solvents and reagents as well as a reduced number of steps.

Full text of DOI:10.1039/c3ra45982a

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Improved synthesis of tadalafil using dimethyl
carbonate and ionic liquids†
Cite this: RSC Adv., 2014, 4, 1204
a
b
Martyn J. Earle, Marco Noe, Alvise Perosab and Kenneth R. Seddona
*
*
`
Received 21st October 2013
An improved synthesis of tadalafil, a drug for the treatment of male erectile dysfunction, involves the use of
Accepted 14th November 2013
safer solvents and reagents as well as a reduced number of steps.
DOI: 10.1039/c3ra45982a
www.rsc.org/advances
compounds have gathered much interest from synthetic and
medicinal chemists,1–3 because it is a specic PDE-5 inhibitor
Introduction
with an improved PDE5/PDE6 selectivity compared with silde-
nal (Viagra™, Pzer) and vardenal (Levitra™, Bayer/Glax-
oSmithKline). The improved selectivity for the PDE-5 enzyme
can prevent a series of side effects related to inhibition of other
PDE enzymes. Furthermore, tadalal has a longer half-life (17 h)
than sildenal and vardenal (5 h and 4 h, respectively).3
PDE-5 (phosphodiesterase type 5) inhibitors (Fig. 1) such as
Viagra™ (sildenal citrate), Levitra™ (vardenal) and Cialis™
(tadalal) are successful in the treatment of male erectile
dysfunction (MED),1 and are highly protable.
These compounds operate by increasing the level of the
cyclic guanosine-3,5-monophosphate (cGMP), which is an
important secondary messenger that controls many physiolog-
ical processes. The level of intracellular cGMP is determined by
the activities of the cyclase enzyme which produces it, and the
type-V phosphodiesterase (PDE-5) that degrades it. The inhibi-
tion of PDE-5 increases the level of cGMP, and therefore can be
used in a therapeutic strategy for male erectile dysfunction, and
also for the treatment of cardiovascular diseases.2
State of the art: process details
The reported synthesis of tadalal4 requires four steps and a
number of different reagents and solvents (Scheme 1).
It starts with the esterication of D-tryptophan (the unnatural
enantiomer) with thionyl chloride (sulfurous chloride; SOCl2) in
Recently the synthesis of tadalal (Cialis™, Icos/Lilly; (6R-
trans)-6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-
pyrazino[10,20:1,6]pyrido[3,4-b]indole-1,4-dione) and related
Fig. 1 Structures of three PDE-5 inhibitors in their non-protonated
form.
aThe QUILL Research Centre, School of Chemistry and Chemical Engineering, The
Queen's University of Belfast, Belfast, UK, BT9 5AG. E-mail: quill@qub.ac.uk
bDipartimento di Scienze Molecolari e Nanosistemi dell'Universita Ca' Foscari Venezia,
Centre for Sustainable Technologies, Calle Larga S. Marta, 2137-30123 Venezia, Italy.
E-mail: marco.noe@unive.it
† Electronic supplementary information (ESI) available: Experimental details, and
results of the Pictet–Spengler reaction in ionic liquids, selected NMR spectra and
calculation of mass indices. See DOI: 10.1039/c3ra45982a
Scheme 1 Literature synthesis of tadalafil.4
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methanol to obtain the methyl ester hydrochloride salt, 1$HCl,
followed by reaction with piperonal (benzo[d][1,3]dioxole-5-
carbaldehyde) in a Pictet–Spengler reaction5 to give 2$HCl.
Intermediate 3 is obtained by the reaction of 2 with 2-chlor-
oethanoyl chloride under basic conditions in an aprotic solvent.
Finally reaction of 3 with methylamine (in a polar solvent)
proceeds by a nucleophilic displacement followed by cyclisa-
tion, to afford tadalal, 4.
This synthetic route presents a number of drawbacks.
Thionyl chloride, for example, is hazardous and produces two
major pollutants (SO2 and HCl): in addition, it is also poorly
atom economic,6 since none of its atoms end up in the nal
product. Solvents are also an issue in the synthesis, since up to
six different organic solvents are needed (methanol, ethaneni-
trile, toluene, dichloromethane, N,N-dimethylformamide and
dimethyl sulfoxide), most of which are undesirable. Efforts to
avoid the use of these solvents were reported. In fact, the large
scale process, patented by Lilly4d makes use of 2-propanol for
the Pictet–Spengler reaction, while the replacement of
dichloromethane in the third step with ethyl ethanoate is also
described.7
However the procedure reported by Shi et al.8 in 2008 was
selected as benchmark in the present case since it was the most
recent and efficient procedure for a lab scale preparation of
tadalal available in the open literature.
A comparison with the commercial process developed by
Orme et al.4d that operates on multi-kilogram scale is inappro-
priate in this context as it would imply comparing laboratory
scale with industrial scale, where efficiency is intrinsically much
higher due to the mass involved.
Scheme 2 Compound 2 epimerisation under acidic conditions.8,10
Aim of this work
The goals of the present work were the reduction of the number
of steps, and the use of more acceptable solvents as reaction
media in as many of the steps as possible. The following is a
breakdown of the improvements proposed for each step. In the
rst step, a thionyl chloride free procedure for the esterication
of D-tryptophan is described. In the highly atom economic (AE ¼
100%) second step, the use of ethanenitrile or nitromethane
represents a serious drawback, and both these solvents can be
replaced. In the last step, dimethyl sulfoxide and N,N-dime-
thylformamide can be avoided, e.g. by using an ionic liquid,
where amine alkylation has been reported to be accelerated.11
The initial approach focussed on nding a solvent where two or
more reaction steps could be conducted without the need of
intermediate isolation and purication. Subsequently, we tried
to revise every single step of this drug synthesis, to develop an
improved overall process.
Diastereoselectivity: the CIAT process
Product stereochemistry is of vital importance, since only the
enantiomerically pure (R,R)-stereoisomer of tadalal is thera-
peutically active,3 and so a highly diastereoselective synthesis is
needed in the formation of the second stereocentre during the
Pictet–Spengler reaction of 1.9 The diastereoselectivity of this
reaction depends dramatically on the solvent.8
By using ethanenitrile or nitromethane as the solvent, in
which both the product and the reagent are insoluble, excel-
lent yields and very high diastereoselectivity towards the
desired cis-compound can be attained. In contrast, by using
more polar solvents like methanol or dimethyl sulfoxide,
where reagent and product are both solubilised, little or no
diastereoselectivity was observed. Better diastereoselectivity
was observed in solvents where the product is insoluble, since
the cis-diastereoisomer is less soluble than the trans-form. In
solution, the diastereoisomers can interconvert via an acid-
catalysed mechanism (Scheme 2), and, since the cis-
compound is less soluble, the equilibrium is driven towards
this particular diastereoisomer.
Results and discussion
Synthesis of tadalal
1. Esterication of tryptophan with dimethyl carbonate
(step 1). Both the rst and the second steps require acid catal-
ysis, thus acidic ionic liquids [C4mim][HSO4], [C4mim][H2PO4]
and [P6 6 6 14][HSO4] ([C4mim]+ ¼ 1-butyl-3-methylimidazolium;
[P6 6 6 14]+ ¼ trihexyl(tetradecyl)phosphonium) were tested as
solvents/catalysts. No reaction was observed, so this approach
was abandoned. A literature review revealed that is possible to
obtain methyl esters of amino acids using dimethyl carbonate
(DMC) and an equimolar amount of sulfuric acid. A recent
It is therefore possible to enrich the mixture in the cis-isomer
simply by heating (80–100 ꢀC) in an appropriate solvent for the
optimal time (4–10 h). This process is named Crystallisation
Induced Asymmetric Transformation (CIAT).10
Scheme 3 The dehydration reaction of dimethyl carbonate.12
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patent12 claims that DMC can act as a dehydrating agent (see decompose at high temperature releasing HF,14 which explains
Scheme 3), driving the esterication reaction to completion. why under those conditions no added acid catalyst was needed.
In our case, the reaction proceeded smoothly, yielding O-Me- This was substantiated by our tests that indicated that the
tryptophan hydrogensulfate almost quantitatively (Scheme 4). analogous ionic liquid, [C4dmim][NTf2] ([NTf2]ꢁ ¼ bis{(tri-
Screening of the experimental conditions was carried out with uoromethyl)sulfonyl}amide), is not by itself able to promote
L-tryptophan (the natural enantiomer) and then applied to the reaction at 100 ꢀC aer 18 h: under such conditions, the
D-tryptophan.
Schiff base (Fig. 2) was the sole product, as usually observed in
The nal reaction mixture consisted of two separate phases: an aprotic medium and in the presence of a dehydrating
the upper was dimethyl carbonate, and the lower was mainly the agent.15 As anticipated previously, the second step in the
product in which some dimethyl carbonate was dissolved. The synthesis of tadalal is stereoselective through a crystallisation
product was an ionic liquid at the reaction temperature.
induced asymmetric transformation that causes precipitation
Evaporation of DMC yielded the crude methyl ester hydro- of the desired diastereoisomer.
gensulfate salt 1$H2SO4 as an amorphous, amber-coloured
The caveat in applying this strategy to ionic liquids is that it
solid, which was impossible to use in the second step. To is difficult to nd an ionic liquid in which the Pictet–Spengler
overcome this drawback, different procedures were studied in adduct is insoluble, since this is obtained as a salt. Therefore,
order to obtain a crystalline product. In particular, by using an ionic liquid with a strong interaction with the cis-adduct
phosphoric instead of sulfuric acid, it was possible to obtain O- would be needed in order to disfavour the trans-adduct. To this
Me-tryptophan dihydrogenphosphate as depicted in Scheme 5. end, three ionic liquids were investigated: 1-butyl-2,3-dimethy-
A 4 : 1 mixture of dimethyl carbonate and methanol led to limidazolium bis{(triuoromethyl)sulfonyl}amide ([C4dmim]-
complete conversion aer 48 h at the reux temperature (ca. [NTf2]),
1-ethyl-3-methylimidazolium
triuoroethanoate
80 ꢀC). Isolation of the O-Me-tryptophan dihydrogenphosphate ([C2mim][CF3CO2]), and 1-ethyl-3-methylimidazolium hydro-
salt by ltration afforded a white, microcrystalline solid. The gensulfate ([C2mim][HSO4]). A series of reactions were carried
use of methanol was unavoidable, as in its absence the dihy- out varying tryptophan salt, anion, HX, acid catalyst, and reac-
drogenphosphate salt was insoluble to the point of inhibiting tion temperature and times. The mixtures were analysed by
the reaction.
1H-NMR spectroscopy for conversion, selectivity towards the
Treatment of the D-tryptophan methyl ester phosphate salt Pictet–Spengler adduct, and the diastereoselectivity as the cis- to
with aqueous sodium hydrogencarbonate yielded the free base trans-ratio. Selected results are summarised in Table 1,
D-tryptophan 1, which could be isolated by extraction with the complete data are presented in the SI section. At 80 ꢀC, the
same dimethyl carbonate used as reaction medium. The solvent product formed in moderate to good yields aer 24 h; however,
was removed under reduced pressure, and the product isolated at this temperature, no diastereoselectivity was observed (Table
as a pale yellow solid. Different salts of the D-tryptophan methyl 1, entries 1 and 2). At 20 ꢀC, albeit with low conversion, a
ester with various anions (Clꢁ, [HSO4]ꢁ, or [CH3COO]ꢁ) were cis : trans ratio of 80 : 20 could be reached (Table 1, entry 3).
prepared simply by adding the appropriate amount of acid to Triuoroethanoic acid, commonly used as a catalyst in this kind
the free D-tryptophan methyl ester, 1, and then used as starting of reaction,16 was then tested; unfortunately mainly mixtures of
materials in the second step.
diastereoisomers were obtained. The best selectivity toward the
2. Pictet–Spengler reaction in ionic liquids (step 2). The desired cis-product was only 80% for prolonged reaction times
Pictet–Spengler reaction is hardly ever reported in ionic liquids. (Table 1, entry 4), so no competition with the established
Only one paper13 describes this reaction, using [C2mim][BF4] as procedure was possible.
a solvent in the absence of an added acid catalyst, operating at a
3. Pictet–Spengler reaction in dimethyl carbonate (step 2).
relatively high temperature (100 ꢀC). However, the authors A CIAT approach to the Pictet–Spengler adduct was then
failed to recognise that tetrauoroborate ionic liquids investigated by using dimethyl carbonate as solvent, in order to
use the same solvent in more than one step. The properties of
dimethyl carbonate seemed promising, since hydrochloride
salts are largely insoluble in this solvent, and its boiling point
(90 ꢀC) is just 10 ꢀC lower than that of nitromethane, which was
used in the reported procedure.4 Dimethyl carbonate is water
immiscible, as opposed to nitromethane and ethanenitrile,
Scheme 4 The methylation of tryptophan with dimethyl carbonate.
Fig. 2 The Schiff base product from the reaction of R-(O-methyl)
tryptophan and piperonal in ionic liquids.
Scheme 5 The methylation of tryptophan with dimethyl carbonate.
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Table 1 The reaction of tryptophan methyl ester with piperonal in different ionic liquidsa
T
(ꢀC)
Time
(h)
Conv.
(%NMR)
Schiff base
(%NMR)
cis + trans
(%NMR)
cis/trans
(NMR)
Entry
HX
Ionic liquid
Catalyst
1
2
3
4
HCl
HCl
CF3CO2H
None
[C2mim][HSO4]
[C4dmim][NTf2]
[C2mim][CF3CO2]
[C4dmim][NTf2]
None
None
80
80
20
20
6
24
23
70
>80
21
—
—
13
—
70
>80
5
60/40
50/50
80/20
80/20
None
CF3CO2Hb
288
>80
>80
a
All reactions were carried out using 1.25 g of ionic liquid as the solvent. The molar ratio tryptophan methyl ester : piperonal was 1.1.
CF3CO2H : tryptophan methyl ester molar ratio was 2.0.
b
allowing it to be used as the solvent without having to dry it. of our experience in multiphase reactions, we carried out the
This reaction was rst conducted directly on the crude mixture amination/cyclisation step in the biphasic system obtained by
of 1$HCl obtained in step 1 by addition of piperonal (benzo[d]- adding aqueous methylamine. This allowed us to combine the
[1,3]dioxole-5-carbaldehyde) directly in to the reaction ask at advantage of using cheap and easy to handle aqueous methyl-
the end of the esterication with H2SO4 or H3PO4 in dimethyl amine, with the easy removal of the water soluble methyl-
carbonate: both attempts resulted in the formation of a dark oil ammonium chloride by-product. The reaction proceeds with
composed by unreacted O-Me-tryptophan, and the Pictet– very high yield towards tadalal (91%, Scheme 8).
Spengler adduct (approximately 30% by 1H NMR spectroscopy).
Tadalal was obtained as a white solid, which could be
In an improved procedure, treating crystalline O-methyl-tryp- simply ltered from the biphasic suspension at the end of the
tophan hydrochloride in dimethyl carbonate with piperonal reaction and washed.
(Scheme 6) gave the desired Pictet–Spengler adduct in very good
6. Integrated procedure (steps 3 + 4). As shown above, a
yield (95%) and with excellent diastereoselectivity (98%). biphasic system can be used to remove salt by-products from
Moreover, dimethyl carbonate is known as a “green” alternative the organic phase. For each mole of reagent, step 3 produces
to common solvents,17 such as nitromethane and ethanenitrile. two moles of salt, that can be therefore removed by integrating
4. Ethanoylation in ionic liquids (step 3). The third step is a steps 3 and 4 in a single procedure in which two reactions are
simple ethanoylation of the amine functionality with 2-chlor- performed in the same ask using [C4mim][NTf2] as the solvent.
oethanoyl chloride, aer neutralisation of the 2$HCl. This In the rst stage hydrochloride 2 was reacted with 2-chlor-
reaction was performed in [C4dmim][NTf2] as the solvent by oethanoyl chloride in the presence of triethylamine, as
using 2 equivalents of triethylamine, necessary to free the described earlier. At the end of the ethanoylation step aqueous
starting amine function, and to later neutralise the HCl methylamine was simply added to the reaction mixture to form
(Scheme 7).
the biphasic system. At this stage product 3 is dissolved in the
5. Amination and cyclisation (step 4). In order to test its ionic liquid, tadalal precipitates out of solution as a white
reactivity, pure 3 was synthesised using a reported procedure.8 It solid, and the salt by-products remain in the aqueous phase.
was then suspended in [C4dmim][NTf2] and, taking advantage Remarkably reaction times during the last step are signicantly
lower using this procedure (5 h) than in N,N-dimethylforma-
mide (16–18 h).10 Tadalal was obtained in very good yield (88%
considering both steps) and with good optical purity (96%).
1H-NMR and 13C-NMR spectra conrmed the product identity,
and revealed no traces of ionic liquid in the nal product.
7. Ionic liquid recycling. In order to verify the recyclability
of the ionic liquid, the mother liquor (comprised of water,
methanol, ionic liquid and salt by-product) was concentrated at
reduced pressure. Once volatile materials (methanol and water)
were removed, ethyl ethanoate was added to the mixture. The
Scheme
6 The Pictet–Spengler reaction of 1 with piperonal in
organic phase was collected and washed with 5% hydrochloric
dimethyl carbonate.
Scheme 7 2-Chloroethanoylation of 2 in an ionic liquid.
Scheme 8 The amination and cyclisation of 3 in [C4dmim][NTf2].
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acid, then with water. The ionic liquid containing organic phase
A simple calculation of the mass indices18 allows comparison
was separated and dried by heating at 70 ꢀC in vacuum. The of the reported literature process with our two processes (A and
ionic liquid recovery was around 90%.
B). As is clear in Fig. 3, both our processes are characterised by
Recovered [C4mim][NTf2] was then used to carry out the better performance in terms of raw material usage with respect
integrated procedure. By using the recycled ionic liquid tadalal to the previously reported procedure. This is thanks to the
was obtained in 85% yield, conrming that the ionic liquid can integrated procedure replacing steps 3 and 4: by avoiding
be recycled using a simple purication procedure, employing isolation of the intermediate 3 (Scheme 1) and by using the
only dilute hydrochloric acid, water and ethyl ethanoate.
same solvent ([C4dmim][NTf2]) for both the last two steps, it is
However it must be underlined that the removal of water possible to cut the mass index by over 50%, from 66.3 to 30.3
from the recycled ionic liquid (see Experimental section) is (Fig. 3).
somewhat energy intensive. This aspect could represent a
serious drawback at industrial scale.
Comparison of processes A and B highlights what we already
stated: purely from a mass index point of view, the thionyl
chloride route (B) seems globally more acceptable than the
DMC process involving hydrogensulfate or phosphate followed
by anion exchange (A).
Processes comparison
All the experiments here described can be summarised by two
different processes (A and B in Scheme 9). Both procedures
represent improvements in terms of raw material reduction and
process simplication with respect to those reported in the
literature.
In Process A, tryptophan esterication is achieved by using
dimethyl carbonate with phosphoric acid. In this case the
advantage of avoiding SOCl2 is balanced by the added steps and
reagents: aqueous Na2CO3, HCl and solvent for extraction are
needed for the unavoidable anion exchange, causing an incre-
ment in wastes.
In Process B, O-Me-tryptophan hydrochloride is obtained
using SOCl2 and methanol, without added anion exchange
steps, simply by removal of solvent and excess reactant under
vacuum.
Fig. 3 Mass indices of the three different processes for tadalafil
preparation.
Table 2 Process comparison using green chemistry metrics
Parametera
Literature21
Process A
Process B
AE
Yield
ME
0.542
0.818
0.015
0.058
0.531
0.769
0.027
0.084
0.542
0.811
0.033
0.196
ME (with solvent reclamation)
a
Calculated following the work of Andraos.22
Scheme 9 Reagent and conditions; Process A: (a1) DMC, reflux, 24 h;
(a2) Na2CO3(aq); (a3) HCl in DMC, RT; Process B: (b) SOCl2/CH3OH, 40
ꢀC, 4 h. (c) DMC, reflux, 10 h; (d) 2-chloroethanoyl chloride, NEt3, Fig.
4
Processes comparison using common green chemistry
[C4dmim][NTf2], 5 ꢀC, 2 h; (e) CH3NH2(aq), [C4dmim][NTf2], RT, 6 h.
metrics.
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However, if material toxicity is instead considered, the DMC integrated procedure, and the reaction with methylamine
route avoids the use of corrosive and toxic materials, and might proved much faster than in the traditional solvent systems.
be considered more environmental compatible.19 Atom
In summary, process A and B are high-yielding methods for
economy6 (AE), and mass efficiency20 (ME) are summarised in the preparation of tadalal using only [C4mim][NTf2] (an ionic
Table 2 and in Fig. 4. For all three processes the reaction mass liquid) and dimethyl carbonate as reaction media. Both have
efficiency (ME) is low (<0.033), as expected based of the high better mass indices, MRP and RME than the published process,
mass indices (30.3–66.3). However, if the solvents were to be and the ionic liquid can be recycled.
recovered and recycled, the ME value of Process B would raise to
a theoretical 0.196 (more than three times greater than the
literature reported process). The generally low values of ME
Experimental
General
should not be a surprise, since these processes involve at least
three synthetic steps. Remarkably, the two nal steps can be Reagents were ACS grade and used as received. 1H and 13C{1H}
integrated and carried out in a single ask.
NMR spectra were recorded on a Bruker Avance spectrometer
Other metrics, such as atom economy (AE) and reaction yield DPX 300; chemical shis were reported in d values downeld
indicate that the three processes perform similarly. Atom from TMS. Optical rotation measurements were performed on a
economy is identical for the published method and Process B Perkin Elmer 241 polarimeter.
(0.542), and only slightly lower for Process A (0.531) due to the
The tryptophan methyl esters salts were characterised aer
anion exchange steps. This small 2% decrease indicates that the basic treatment to obtain the neutral methyl ester. Properties
DMC route to obtain tryptophan methyl ester, does not affect AE and NMR data were in agreement with those reported in the
signicantly. In terms of reaction yield, the literature process literature.23
remains the best (81.8%), followed by Process B (81.1%), while
for Process A this value is 6% lower (76.9%).
All the ionic liquids used in this work ([C4dmim][NTf2],
[C4mim][HSO4], and [C2mim][CF3CO2]) were prepared following
reported procedures.24
1$H2SO4 by esterication of tryptophan using dimethyl
carbonate and H2SO4. In a round-bottomed ask, D-tryptophan
Conclusions
Each step of the published synthesis of tadalal was investi- (2.00 g, 9.79 mmol) was suspended in dimethyl carbonate
gated in view of the design of an improved process. Two alter- (7 cm3). To the stirred suspension, concentrated sulfuric acid
native processes A and B were developed (Scheme 9). The (0.53 cm3, 10.6 mmol) was slowly added and the resulting
principal improvements of processes A and B compared to the mixture was heated to reux temperature (92 ꢀC) for 18 h. At the
published synthesis is that they both do without solvents such end of that time, two liquid phases were observed. Both phases
as CH3CN, toluene, CH2Cl2, N,N-dimethylformamide and were slowly added to a solution of aqueous Na2CO3 {10% (w/w);
dimethyl sulfoxide, and both combine the nal two steps of 20 cm3}, with vigorous stirring. The organic phase was then
Scheme 1 by using an ionic liquid as solvent.
separated and the aqueous phase extracted with dimethyl
Processes A and B are identical in the last two steps, but carbonate (2 ꢂ 5 cm3). Extracts were collected and dried over
differ in the rst step, i.e. the esterication of tryptophan to anhydrous Na2SO4: the solvent was then removed at reduced
yield its methyl ester hydrochloride salt 1$HCl. Process A pressure, yielding compound 1 (2.00 g, 9.16 mmol, 94%) as an
requires 5 steps, one more than the 4 of the published oil that slowly crystallised into an off-white solid.
synthesis, and it uses dimethyl carbonate as reagent and
1$H3PO4 by esterication of tryptophan using dimethyl
solvent, thus avoiding thionyl chloride. The dimethyl carbonate carbonate and H3PO4. In a round-bottomed ask, L-tryptophan
Process A, produces the hydrogensulfate or hydrogenphosphate (2.00 g, 9.79 mmol) was suspended in a mixture of dimethyl
methyl ester salt, which must be then ion-exchanged with carbonate (7 cm3) and methanol (2 cm3). To the stirred suspen-
chloride in order for the second step in the preparation of sion, phosphoric acid (1.04 g, 10.6 mmol) was added and the
tadalal to be stereoselective. Process B requires 3 steps, and is resulting mixture was heated to reux temperature (ca. 85 ꢀC) for
the most efficient with respect to mass. However, as in the 24 h. The resulting suspension was then ltered yielding
published method, it still uses noxious thionyl chloride for compound 1$H3PO4 (2.88 g, 9.10 mmol, 93%) as a white solid.
esterication, and since mass ow should not be the only aspect
1$HCl by esterication of tryptophan using MeOH and thi-
considered, the use of a safer reagent in Process A should also onyl chloride. Method A: The title compound, 1$HCl, was prepared
be considered as an improvement to the chemistry of the according to a reported procedure,23 which was slightly modied.
process, even if the overall mass ow is higher.
To a cooled (ice bath), stirred suspension of D-tryptophan (2.00 g,
Dimethyl carbonate proved to be a good alternative to 9.79 mmol) in methanol (30 cm3), thionyl chloride (1.0 cm3,
traditional solvents (i.e. nitromethane or ethanenitrile) for the 13.7 mmol) was slowly added. The resulting clear solution was
diastereoselective Pictet–Spengler reaction. Both its lower then heated to 40 ꢀC and kept at that temperature for 4 h. Excess of
toxicity and the water immiscibility contribute to process' effi- thionyl chloride, HCl and SO2, and the solvent were removed at
ciency. The acetylation of 2 to 3, as well as the last step with reduced pressure. The resulting white solid 1$HCl (2.41 g, 9.46
methylamine, could be carried out stepwise in the same reactor mmol, 97%) was pure enough to use without further purication.
by using [C4dmim][NTf2] (an ionic liquid) as the solvent.
Method B: To the mixture at the end of the reaction of trypto-
Intermediate 3 dissolves better in the ionic liquid using the phan with dimethyl carbonate in presence of phosphoric acid (see
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previous paragraph), an aqueous solution of Na2CO3 {10% (w/w); ¼ 7.7 Hz, 1H), 3.71 (s, 3H), 3.29 (dd, J ¼ 4.8 Hz, J ¼ 14.4 Hz, 1H),
20 cm3} was slowly added. The organic phase was then separated 3.06 (dd, J ¼ 7.7 Hz, J ¼ 14.4 Hz, 1H). 13C NMR (75 MHz, CDCl3)
and the aqueous phase extracted with dimethyl carbonate (2 ꢂ d/ppm. 176.2, 136.7, 127.8, 123.4, 122.5, 119.9, 119.1, 111.6,
5 cm3). Extracts were collected, then a solution prepared by 111.5, 55.4, 52.4, 31.2.
bubbling gaseous HCl (365 mg, 10 mmol) into dimethyl carbonate
(1R,3R)-1-(3,4-Methylenedioxyphenyl)-2,3,4,9-tetrahidro-9H-
(5 cm3) was slowly added to the stirred solution. The resulting pyrido[3,4-b]indole-3-carboxylic methyl ester hydrochloride,
suspension was then ltered and the solid washed with dimethyl 2-cis $HCl. [a]2D0 ¼ ꢁ81.1 (c 1.0, MeOH). 1H NMR (300 MHz,
ꢀ
carbonate. The white solid was dried at 70 C for 10 h, yielding dmso-d6) d/ppm. 10.83 (s, 1H), 10.59 (s, 1H), 10.13 (s, 1H), 7.54
compound 1$HCl (2.29 g, 8.99 mmol, 92%).
(d, J ¼ 7.6 Hz, 1H), 7.29 (d, J ¼ 7.9 Hz, 1H), 7.15–6.95 (m, 4H),
2$HCl by Pictet–Spengler reaction in dimethyl carbonate. 6.10 (s, 2H), 5.86 (brs, 1H), 4.70–4.80 (m, 1H), 3.85 (s, 3H), 3.36–
Solid 1$HCl (2.00 g 9.16 mmol) was added into a solution of 3.19 (m, 2H). 13C NMR (75 MHz, dmso-d6) d/ppm. 168.5, 148.4,
benzo[d][1,3]dioxole-5-carbaldehyde (1.650 g, 10.99 mmol) in 147.1, 136.7, 128.8, 125.4, 124.8, 122.0, 119.1, 118.1, 111.5,
dimethyl carbonate (20 cm3). The suspension was heated to 110.2, 108.2, 106.2, 101.5, 57.5, 55.1, 53.0, 22.1.
reux and kept at that temperature with stirring for 18 h. Aer
(1R,3R)-1-(3,4-Methylenedioxyphenyl)-2,3,4,9-tetrahidro-9H-
the reaction was complete (monitored by TLC), the mixture was pyrido[3,4-b]indole-3-carboxylic methyl ester, 2-cis. 1H NMR
gradually cooled to room temperature. The pale yellow solid was (300 MHz, CDCl3), 7.52 (dd, J ¼ 7.7 Hz, J ¼ 9.6 Hz, 2H), 7.09–7.29
collected by ltration (Buchner funnel), washeꢀd with small (m, 3H), 6.78–6.90 (m, 3H), 5.95 (s, 2H), 5.17 (s, 1H), 3.95 (dd, J ¼
amounts of dimethyl carbonate, and dried at 70 C for 10 h to 4.2 Hz, J ¼ 11.1 Hz, 1H), 3.82 (s, 3H), 3.21 (ddd, J ¼ 1.7 Hz, J ¼
yield 2$HCl as a pale yellow solid (3.658 g, 10.44 mmol, 95%).
4.1 Hz, J ¼ 14.9 Hz, 1H), 2.94–3.04 (m, 1H). 13C NMR (75 MHz,
Tadalal, 4. Method A: To a suspension of 3 (ref. 25) (427 mg, CDCl3) d/ppm. 173.0, 148.1, 147.7, 136.0, 134.6, 127.0, 121.9,
1.00 mmol) in [C4dmim][NTf2] (2.00 g), aqueous methylamine 119.5, 118.1, 110.8, 108.7, 108.2, 101.1, 58.3, 56.8, 52.2, 25.6.
(40%; 0.8 cm3, 9.2 mmol) was added. The resulting mixture was
(1R,3R)-1-(3,4-Methylenedioxyphenyl)-2-chloroacetyl-2,3,4,9-
stirred for 20 h and then ltered and washed with methaꢀnol to tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylic methyl ester, 3.
remove the ionic liquid. The white solid was dried at 70 C for [a]2D0 ¼ 109.9 (c 1.0, CHCl3). 1H NMR (300 MHz, dmso-d6) d/ppm.
6 h, yielding pure tadalal, 4 (355 mg, 0.912 mmol, 91%).
10.88 (s, 1H), 7.55 (d, J ¼ 7.6 Hz, 1H), 7.28 (d, J ¼ 7.9 Hz, 1H),
Method B: In a round-bottomed ask sealed with a septum, 7.0–7.14 (m, 2H), 6.81 (d, J ¼ 8.1 Hz, 1H), 6.76 (s, 1H), 6.64 (s,
compound 2$HCl (194 mg, 0.500 mmol) was suspended in 1H), 6.46 (d, J ¼ 7.7 Hz, 1H), 5.98 (d, J ¼ 5.9 Hz, 2H), 5.20 (d, J ¼
[C4dmim][NTf2] (1.5 g), triethylamine (109 mg, 1.08 mmol) was 6.5 Hz, 1H), 4.84 (d, J ¼ 13.9 Hz, 1H), 4.45 (d, J ¼ 13.8 Hz, 1H),
added, and the resulting mixture was stirred for 1 h until a clear 3.47 (d, J ¼ 16.0 Hz, 1H), 3.08 (dd, J ¼ 16.0 Hz, 6.9 Hz, 1H), 3.04
solution was obtained. Then the mixture was cooled to 0 ꢀC by (s, 3H). 13C NMR (75 MHz, dmso-d6) d/ppm. 170.3, 166.7, 146.8,
means of an ice bath, and 2-chloroethanoyl chloride (113 mg, 146.5, 136.3, 133.4, 129.8, 125.72, 122.3, 121.5, 118.6, 118.0,
1.00 mmol) was slowly added through the septum with a 111.1, 109.0, 107.5, 106.1, 100.9, 52.2, 51.7, 51.2, 43.1, 20.9.
syringe. The mixture was kept at 0 ꢀC for 1 h, and then allowed
(6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-methyl-6-(3,4-methyl-
to warm to room temperature. Aer an additional hour, enedioxyphenyl)-pyrazino-[20,10:6,1]pyrido[3,4-b]indole-1,4-
aqueous methylamine (40%; 0.4 cm3, 4.6 mmol) was added. dione, 4. [a]D20 ¼ 68.2 (c 1.0, CHCl3). 1H NMR (300 MHz, dmso-
Aer 6 h, using the procedure described in method A, tadalal, d6) d/ppm. 11.03 (s, 1H), 7.54 (d, 1H, J ¼ 7.6 Hz), 7.30 (d, 1H, J ¼
4, was isolated as a white solid (171 mg, 0.439 mmol, 88%).
7.7 Hz), 7.02 (td, J ¼ 6.9 Hz, J ¼ 18.3 Hz, 2H), 6.87 (s, 1H), 6.78 (s,
Ionic liquid recycling. The mother liquor from the prepara- 2H), 6.13 (s, 1H), 5.92 (s, 2H), 4.40 (dd, J ¼ 3.7 Hz, J ¼ 11.1 Hz,
tion of tadalal, 4, using method B and methanol used for 1H), 4.18 (d, J ¼ 17.2 Hz, 1H), 3.95 (d, J ¼ 17.2 Hz, 1H), 3.52 (dd,
washing, were collected in a ask. Methanol was removed under J ¼ 4.3 Hz, J ¼ 15.7 Hz, 1H), 2.97 (m, dd, J ¼ 11.3 Hz, J ¼ 15.5 Hz,
reduced pressure (rotary evaporation). The resulting mixture 1H), 2.93 (s, 1H). 13C NMR (75 MHz, dmso-d6) d/ppm. 166.7,
was constituted by two phases: the upper was [C4dmim][NTf2], 166.4, 146.9, 145.9, 136.8, 136.0, 133.8, 125.6, 121.1, 119.1,
the lower an aqueous solution of by-product salts formed 118.7, 117.9, 111.1, 107.8, 106.8, 104.6, 100.7, 55.4, 55.1, 51.3,
during the integrated procedure. Ethyl ethanoate (5 cm3) was 32.7, 23.0.
added to the mixture, and the resulting biphasic system was
stirred for ten minutes; the organic phase was separated and the
aqueous phase was washed with additional ethyl ethanoate (2 ꢂ
Notes and references
3 cm3). Extracts were collected, dried over anhydrous sodium
sulfate, and the solvent removed under reduced pressure
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Determination in Ionic Liquids, in Ionic Liquids IIIB: 25 Compound 3 was prepared from compound 2$HCl and
Fundamentals, Progress, Challenges, and Opportunities –
chloroethanoyl chloride using the method reported in ref. 8.
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