One-pot pictet-spengler reaction and esterification for the preparation of a key tadalafil synthetic intermediate

Article abstract of DOI:10.2174/157017810791130667

A new method is reported for the preparation of 2,3,4,9-tetrahydro-1H- β-carboline-3-carboxylic acid methyl ester, a key intermediate in the synthesis of Tadalafil which is used for the treatment of male erectile dysfunction, via one-pot esterification and Pictet-Spengler reaction.

Full text of DOI:10.2174/157017810791130667

Letters in Organic Chemistry, 2010, 7, 311-313
311
One-Pot Pictet-Spengler Reaction and Esterification for the Preparation of
a Key Tadalafil Synthetic Intermediateꢀ
Dina Scarpi*,a, Ernesto G. Occhiatoa, Antonio Guarnaa and Valerio Borzattab
aDipartimento di Chimica "U. Schiff", Università degli Studi di Firenze, Via della Lastruccia 13, I-50019 Sesto
Fiorentino, Italy
bENDURA S.p.A., Viale Pietramellara 5, 40121 Bologna, Italy
Received October 22, 2009: Revised March 10, 2010: Accepted March 15, 2010
Abstract: A new method is reported for the preparation of 2,3,4,9-tetrahydro-1H-ꢀ-carboline-3-carboxylic acid methyl
ester, a key intermediate in the synthesis of Tadalafil which is used for the treatment of male erectile dysfunction, via
one-pot esterification and Pictet-Spengler reaction. ꢀ
Keywords: Pictet-Spengler, esterification, isomerization, Tadalafil.
The synthesis of compound 1 (Scheme 1) and its analogs
have been recently studied extensively because of their
importance as precursors to obtain pharmaceutical
compounds such as alkaloids and drugs, the best and well-
known being the Tadalafil (Scheme 1) [1]. This compound,
commercialized as CialisTM (Icos/Lilly), was approved in
2003 by the FDA for the treatment of male erectile
dysfunction (MED) and received much attention because of
its decreased side effects and increased and effective
duration when compared to Sildenafil (ViagraTM, Pfizer).
Only 1a, i.e. the (1R,3R)- or cis-diastereoisomer, can be used
in the synthesis of Tadalafil and in the literature, countless
methods have been reported to obtain cis-1a, many of them
are patented. Despite the fact that numerous methods have
been published or patented, the interest in 1a and Tadalafil is
still high as observed by the continuous emergence
appearance of new procedures for its preparation [2]. The
reaction of 1a with chloroacetyl chloride, followed by
treatment with methylamine of the so formed N-
chloroacetylcarboline, afforded the target compound
Tadalafil [2, 3].
being usually obtained as a 1:1 mixture of diastereoisomers
by means of an acid-catalyzed Pictet-Spengler reaction [4].
The reaction conditions varied for solvent (chlorinated
solvents [3], isopropyl alcohol [5], methanol [6], ethyl
acetate [7], and N,N-dimethyl acetamide [8]), temperature
(from 25 [3] to 80 °C [5]), reaction time (from 16 h [5] to 7
days [7]) and isolation of the desired cis-1a (preparative
chromatography [3], fractioned crystallization [6]). The 1:1
diastereomeric mixture could be isomerized in good yield to
cis-1a by heating in aqueous HCl for 2-3 days [3].
The method that we report here allows to obtain
compound 1 starting from the amino acid D-tryptophan 2
(and aldehyde 3) in methanol so that Pictet-Spengler reaction
occurs concomitantly with the esterification of the
carboxylic moiety, with further advantage in using the less
expensive D-Trp-OH instead of its methyl ester.
We studied two different strategies. The first one
employed SOCl2 for the esterification, with the HCl that
developed during the reaction acting as acid catalyst for the
Pictet-Spengler reaction [9]. Although the yield was very
good (92% in the final product as hydrochloride) with this
procedure, the use of SOCl2 as a reagent is not appealing for
possible industrial purposes, and therefore, we decided to
test some protic acids that could act as catalysts for both
reactions.
O
CO2Me
H
N
3
NH
N
1
N
H
N
H
Whereas H2SO4 proved to be efficient but afforded the
final product with low purity grade, HCl gave the best
results, both for yield (89%) and purity of the final product
[10].
O
Tadalafil
1a: (1R,3R)
O
O
O
O
To drive the esterification to completion, the water
formed had to be removed. The use of dehydrating agents,
such as trimethyl orthoformate failed, mainly because the
Pictet-Spengler reaction did not occur; moreover, both
molecular sieves [6] and anhydrous sodium sulfate [8] were
used in recent patented procedures and their use was not
interesting for industrial scale-up. We therefore removed the
water by a continuous stripping with methanol (i.e. removal
of the solvent and its continuous replacement with fresh
Scheme 1.
All of the methods published so far always employed D-
tryptophan methyl ester as a precursor together with 3,4-
(methylenedioxy)benzaldehyde (3, Scheme 2), compound 1
*Address correspondence to this author at the Dipartimento di Chimica "U.
Schiff", Università degli Studi di Firenze, Via della Lastruccia 13, I-50019
Sesto Fiorentino, Italy; Fax: +39-055-4573531; E-mail: dina.scarpi@unifi.it
1570-1786/10 $55.00+.00
© 2010 Bentham Science Publishers Ltd.

312 Letters in Organic Chemistry, 2010, Vol. 7, No. 4
Scarpi et al.
CO2H
CO2Me
NH
O
O
SOCl2, CH3OH,
70°C, 24 h; or
HCl 1.2 N, CH3OH
reflux, 25 h; then
distillation
NH2
Ar =
+
Ar CHO
N
Ar
1a: 1R,3R
1b: 1S,3R
N
H
2
3
H
Scheme 2.
[3]
(a) Daugan, A. C. M. Tetracyclic derivatives, process of
preparation and use. U.S. Patent 5,859,006, January 12, 1999; (b)
Daugan, A. C. M.; Gellibert, F. Tetracyclic cyclic GMP-specific
phosphodiesterase inhibitors, process of preparation and use. U.S.
Patent 6,143,746, November 7, 2000; (c) Daugan, A. C. M.;
Labaudinière, R. F. Chemical compounds. U.S. Patent 6,143,757,
November 7, 2000; (d) Daugan, A.; Grondin, P.; Rualt, C.; Le
Monnier de Gouville, A.-C.; Coste, H.; Linget, J. M.; Kirilovsky,
J.; Hyafil, F.; Labaudinière, R. The discovery of Tadalafil: A Novel
and Highly Selective PDE5 Inhibitor. 2: 2,3,6,7,12,12a-
hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione Analog-
ues. J. Med. Chem. 2003, 46, 4533.
For a review on the Pictet-Spengler reaction see: Coz, E. D.; Cook,
J. M. The Pictet-Spengler condensation: a new direction for an old
reaction. Chem. Rev. 1995, 95, 1797. For recent examples of P.S.
reactions in aqueous medium see: (a) López-Rodríguez, M. L.;
Morcillo, M. J.; Garrido, M.; Benhamú, B.; Pérez, V.; de la Campa,
J. G. Stereospecificity in the reaction of tetrahydro-ꢀ-carboline-3-
carboxylic acids with isocyanates and isothiocyanates: kinetic vs
thermodynamic control. J. Org. Chem. 1994, 59, 1583; (b) Herraiz,
T.; Galisteo, J.; Chamorro, C. L-tryptophan reacts with naturally
occurring and food-occurring phenolic aldehydes to give phenolic
tetrahydro-ꢀ-carboline alkaloids: activity as antioxidants and free
radical scavengers. J. Agric. Food Chem. 2003, 51, 2168; (c) Saha,
B.; Sharma, S.; Sawant, D.; Kundu, B. Water as an efficient
methanol, see ref. [10]; water is driven off under non-
equilibrium conditions) until the final ester percentage
reached the desired value (usually 90-95%). The residual
carboxylic acid could be isolated and separated from the
corresponding ester by treatment with aqueous NaHCO3. As
for the diastereomeric ratio, we always obtained an
approximately 1:1 mixture of 1a and 1b, which completely
isomerized to 1a under the patented conditions [3]. It should
be highlighted that no hydrolysis occurred during the
isomerization.
[4]
The method was studied and fine-tuned for possible
industrial applications too, aiming at obtaining
a
reproducible synthetic protocol that was tested up to 100 g of
reagents.
With the method reported herein, scaled up to 50 g of
starting D-Trp-OH, compound 1a was obtained in 67% yield
(I cycle, after isomerization), that increased in the
subsequent recycling steps from 84% (II cycle) onwards
[11].
In the process herein described two reactions occurred in
the same reactor without any separation of the intermediates,
i.e. the Pictet-Spengler reaction and the esterification of the
carboxylic group. The process uses an inorganic acid such as
hydrochloric acid which is easily available, low cost,
industrially applicable and easily handling. Furthermore, D-
Trp-OH is less expensive than its methyl ester so that the
entire process results as economically interesting and
promising for possible industrial applications.
medium for the synthesis of tetrahydro-ꢀ-carbolines via Pictet-
Spengler reactions. Tetrahedron Lett. 2007, 48, 1379.
Orme, M. W.; Martinelli, M. J.; Doecke, C. W.; Pawlak, J. M.;
Chelius, E. C. Modified Pictet-Spengler reaction and products
prepared therefrom. PCT WO2004/011463 A1, February 5, 2004.
Lohray, B. B.; Lohray, V. B.; Patel, S. I. Process for preparing
Tadalafil and its intermediates. PCT WO2005/068464 A2, July 28,
2005.
Dolitzky, B. Z.; Diller, D. Preparation of Tadalafil intermediates.
PCT WO2006/110893 A2, October 19, 2006.
Deshpande, P. B.; Boda, B. B.; Surti, S. S.; Shah, P. P. Process for
preparing Tadalafil and its intermediates. U.S. Patent
2006/0258865 A1, November 16, 2006.
[5]
[6]
[7]
[8]
[9]
D-Trp-OH (511 mg, 2.5 mmol) was added to a solution of SOCl2
ACKNOWLEDGEMENT
(274 μL, 3.75 mmol) in methanol (15 mL) cooled at 0°C. Piperonal
(375 mg, 2.5 mmol) was added after 10 min and the ice bath
removed. The resulting solution was then heated at 70 °C for 24 h.
After cooling at r.t., the solvent was evaporated to dryness and the
residue washed with Et2O (2 x 10 mL) and suspended into aqueous
satd NaHCO3 (40 mL). The product was extracted with CHCl3 (3 x
25 mL) and the combined organic phases were dried over Na2SO4.
After filtration and evaporation of the solvent, compound 1 - a pale
yellow solid - was obtained (806 mg, 92%) as a 1:1 diastereomeric
mixture.
To a suspension of D-tryptophan (5.10 g, 25.0 mmol) in methanol
(22.5 mL), an aqueous solution of HCl 37% (2.5 mL) was added.
Piperonal (3.75 g, 25.0 mmol) was then added to the resulting
solution, which was allowed to react at reflux temperature for 25 h.
The solvent was removed by distillation and continuously replaced
with fresh methanol up to a total volume of 400 mL of the distilled.
The methanol was evaporated to dryness and the residue washed
with Et2O (10 mL) and suspended into aqueous satd NaHCO3 (20
mL). The product was extracted with EtOAc (3 x 20 mL) and the
combined organic phases were dried over Na2SO4. After filtration
and evaporation of the solvent, compound 1 - a pale yellow foam -
was obtained (7.80 g, 89%) as a 1:1 diastereomeric mixture. 1a: 1H
Ministero dello Sviluppo Economico is acknowledged
for financial support.
REFERENCES
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[10]
[2]
(a) Xiao, S.; Lu, X.; Shi, X. X.; Sun, Y.; Liang, L. L.; Yu, X. H.;
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5.87 (s br, 1 H), 4.73 (s br, 1 H), 3.84 (s, 3 H), 3.38-3.26 (m, 2 H).

One-Pot Pictet-Spengler Reaction
13C NMR (50.33 MHz, DMSO-d6) ꢀ (ppm): 168.5 (s), 148.5 (s),
Letters in Organic Chemistry, 2010, Vol. 7, No. 4
313
aqueous 1.0 N HCl (see Ref. 3 for experimental conditions of the
isomerization). The product was recovered by filtration (I cycle
yield: 67% in 1a). The residue, resulting from the mother liquor
and containing a mixture of 1a, 1b and their corresponding
carboxylic acids, was added to fresh reagents (i.e. D-Trp-OH and
piperonal) in the next process, allowing the recovery of 1a in 84%
yield (II cycle only). The experiments stopped with the second
cycle, but we believe that following cycles could further improve
the overall yield.
147.1 (s), 136.7 (s), 128.9 (s), 127.0 (s), 125.4 (s), 125.0 (d), 122.0
(d), 119.2 (d), 118.2 (d), 111.6 (d), 110.4 (d), 108.3 (d), 106.3 (s),
101.5 (t), 57.6 (d), 55.2 (d), 53.0 (q), 22.2 (t).ꢀ
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preparation of 2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylic
esters. PCT WO2009/103787 A1, August 27, 2009. The procedure
differs from the one reported in ref. 10, because compound 1 was
not isolated but directly isomerized to 1a by treatment with
[11]