An improved synthetic route for preparative process of vardenafil

Article abstract of DOI:10.1021/op900235p

A new, convergent synthetic route for the process optimization of vardenafil (Levitra), a potent and effective PDE5 inhibitor, is described. Key improved steps in the preparative process are that the chlorosulfonation reaction is at the beginning and the dehydration-cyclisation reaction is at a later stage so that the synthetic route has a better overall yield and simpler workup operations. The yield of vardenafil produced from this synthetic route is around 45% over seven steps with purity at 99.2% (HPLC).

Full text of DOI:10.1021/op900235p

Organic Process Research & Development 2009, 13, 1206–1208
Technical Notes
An Improved Synthetic Route for Preparative Process of Vardenafil
Yongjun Mao,† Guanghui Tian,† Zheng Liu,‡ Jingkang Shen,† and Jingshan Shen*,†,‡
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Pudong,
Shanghai 201203, China, and Topharman Shanghai Co., Ltd., 1088 Chuansha Road, Pudong, Shanghai 201209, China
Abstract:
A new, convergent synthetic route for the process optimization of
vardenafil (Levitra), a potent and effective PDE5 inhibitor, is
described. Key improved steps in the preparative process are that
the chlorosulfonation reaction is at the beginning and the dehydra-
tion-cyclisation reaction is at a later stage so that the synthetic
route has a better overall yield and simpler workup operations.
The yield of vardenafil produced from this synthetic route is
around 45% over seven steps with purity at 99.2% (HPLC).
Figure 1. Chemical structure of vardenafil.
This synthetic route had been used for preparing vardenafil
on multikilogram scale, whereas the synthesis of imidazolo-
triazinone 11 gave a yield of around 50% over four steps.4
Further, the sulfonation reaction of 11 was carried out with
concentrated sulfuric acid (8-9 equiv), which afforded the
sulfonic acid 12 in 80% yield. Then, 12 was converted to the
sulfonyl chloride with thionyl chloride (10-11 equiv) while
the intermediate was liable to hydrolysis whereby it was directly
reacted with 1-ethylpiperazine to provide the title com-
pound 1.
Hence, we reviewed the earlier synthesis, modified the
reaction conditions, and developed a new process for producing
vardenafil.5 This improved method, whose details are presented
in this paper, is a potential process for scale-up preparation of
vardenafil.
Introduction
Vardenafil (1, Figure 1) is a selective inhibitor of phophodi-
esterase 5 (PDE5) for the treatment of male erectile dysfunction
(MED).1 Vardenafil (Levitra) has been approved as a new drug
by the FDA and launched in late 2003. Further uses are being
proposed and investigated, such as therapy for pulmonary
hypertension.2
Several synthetic methods were reported for the preparation
of vardenafil and related intermediates.3 The commonly em-
ployed larger-scale synthetic route of 1 is shown in Scheme
1.4 Commercially available 2-ethoxybenzamide (5) was used
as the starting material and converted to the benzonitrile 6 at
first. The benzamidine 8, obtained from the benzamidoxime 7,
was converted to the benzamidrazone, 9. The intermediate 9
was then condensed with 4, afforded by Dakin-West reaction
of the acylated alanine 3, to give the cyclisation product 10,
which was transformed to the imidazolotriazinone 11 by
dehydration-cyclisation reaction with acetyl chloride or POCl3.
The title compound 1 was produced from the intermediate 11
by sulfonation, chlorination, and sulfonamide formation with
1-ethylpiperazine in sequence.
Results and Discussion
In the present synthetic route (Scheme 2), 5 is first converted
to the sulfonyl chloride 13 by treating with chlorosulfonic acid
(∼1.2 equiv) in dichloromethane at room temperature. The
product 13 is relatively stable to ice-water and results in
convenient operations with good yield. Then, 13 is treated with
1-ethylpiperazine at room temperature to provide 14, which is
dehydrated with POCl3 at 80-90 °C to give the benzonitrile
15 in 70-75% yield (three steps). As reported by Dunn,6 15
could be also prepared from 2-ethoxybenzonitrile (6) only in
17.8% yield via column chromatography.
* Author for correspondence. Telephone: +86 21 50805891. Fax: +86 21
64319573. E-mail: jsshen@mail.shcnc.ac.cn; jingshan.shen@topharman.com.
† Shanghai Institute of Materia Medica, Chinese Academy of Sciences.
‡ Topharman Shanghai Co., Ltd.
(1) (a) Haning, H.; Niewohner, U.; Schenke, T.; Es-Sayed, M.; Schmidt,
G.; Lampe, T.; Bischoff, E. Bioorg. Med. Chem. Lett. 2002, 12, 865.
(b) Dunn, P. J. Org. Process Res. DeV. 2005, 9, 88.
(2) Wilkens, H.; Guth, A.; Konig, J.; Forestier, N.; Cremers, B.; Hennen,
B.; Bohm, M.; Sybrecht, G. W. Circulation. 2001, 104, 1218.
(3) (a) Niewohner, U.; Es-Sayed, M.; Haning, H.; Schenke, T.; Schlemmer,
K. H.; Keldenich, J.; Bischoff, E.; Perzborn, E.; Dembowsky, K.; Serno,
P.; Nowakowski, M.; Vetter, A. Chem. Abstr. 1999, 130, 352283. PCT
Int. Appl. WO 199924433, 1999. (b) Nowakowski, M.; Vetter, A. Chem.
Abstr. 2002, 137, 47232. PCT Int. Appl. WO 200250075, 2002. (c)
Heim-Riether, A.; Healy, J. J. Org. Chem. 2005, 70, 7331.
The benzamidine 16 is afforded by the reaction of 15 with
lithium hexamethyldisilazane (∼1.2 equiv) in THF at room
temperature in 80-85% yield. Then 16 is converted to the
(5) Tian, G. H.; Liu, Z.; Zheng, J.; Shen, J. S. Chem. Abstr. 2009, 151,
124043. PCT Int. Appl. WO 20090828456, 2009.
(6) Dunn, P. J.; Dunne, C. Chem. Abstr. 2001, 136, 69817. PCT Int. Appl.
WO 200198284, 2001.
(4) Nowakowski, M.; Gehring, R.; Heilman, W.; Wahl, K. H. Chem. Abstr.
2002, 137, 47233. PCT Int. Appl. WO 200250076, 2002.
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10.1021/op900235p CCC: $40.75  2009 American Chemical Society
Published on Web 11/02/2009

Scheme 1. Reported large-scale synthesis of vardenafila
a Reagents and conditions: (a) n-PrCOCl, NaOH, 68%; (b) ClCOCO2Et, DMAP, THF; (c) SOCl2, toluene; (d) NH2OH· HCl, i-PrOH, 68.2%; (e) H2, Pd-C, AcOH,
90.7%; (f) N2H4 · H2O, MeOH; (g) MeOH; (h) AcCl, HOAc, 54%; (i) H2SO4, 80.1%; (j) SOCl2; 1-ethylpiperazine, 93.2%. (yield 24.8% from 5 to 1).
Scheme 2. Improved synthetic route of vardenafila
a Reagents and conditions: (a) ClSO3H, CH2Cl2, < 20 °C; (b) 1-ethylpiperazine, rt, 86%; (c) POCl3, 80-90 °C, 85%; (d) LHMDS, THF, rt, 83%; (e) N2H4 · H2O,
EtOH, rt, 88%; (f) EtOH, reflux; (g) POCl3, 70 °C, 84%. (yield 45% from 5 to 1).
benzamidrazone 17 by treating with hydrazine hydrate in
ethanol. The intermediate 17 can be isolated as a crystalline
compound which is probably purer than the benzamidrazone 9
(which does not crystallize and therefore has to be used in
solution) of the original synthesis, which gives a better yielding
coupling reaction with 4. Compound 4 is prepared from (R,S)-
alanine according to the method reported by Nowakowski.4
Without isolation, 4 is reacted with 17 to afford the intermediate
18, which is directly transformed into the title compound 1 by
dehydration-cyclisation reaction (around 90% yield) with
POCl3 at 70-80 °C. The pure product 1 is produced by
recrystallization from ethyl acetate-petroleum ether, resulting
in 84% yield (over two steps).
and simpler workup operations. Second, the key dehydration-
cyclisation reaction to form the imidazo-triazinone ring of 1
is at a later stage of the route, which has a better yield (over
80%). Third, this new route is more convergent than the original
synthesis, which leads to a higher yield. The overall yield of 1
obtained from this route is around 45% (from 5, seven steps)
with purity at 99.2% (HPLC).
Conclusions
In conclusion, we have developed a new, convergent
synthetic route for preparative process of vardenafil. Key
improved steps in the process are that the chlorosulfonation of
5 is introduced with chlorosulfonic acid at an early stage and
the dehydration-cyclisation of 18 is carried out at a later stage
of the route so that this synthetic route has a better overall yield
and simpler workup operations, which makes it a potential
preparative process of vardenafil.
This new synthetic route has several advantages. First, the
chlorosulfonation reaction is now carried out, as a single step,
at the beginning of the route, instead of two steps involving
sulfonation and chlorination reactions, which gives purer product
Vol. 13, No. 6, 2009 / Organic Process Research & Development
•
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Experimental Section
All commercially available materials and solvents were used
as received products without further purification. H NMR
ethanol (200 mL). The mixture was stirred at rt for 1 h then
concentrated to around 60 mL. The resulting solid was collected
via suction filtration, washed with ethyl acetate and dried to
1
1
spectra were recorded with a Gemini-300 spectrometer using
TMS as an internal standard. The mass spectra were obtained
from a Finnigan MAT-95/711 spectrometer. Melting points
were measured on a Bu¨chi-510 melting point apparatus.
2-Ethoxy-5-[(4-ethyl-1-piperazinyl)sulfonyl]-benzamide
(14). Chlorosulfonic acid (24 mL, 0.36 mol) was added
dropwise to an ice-cooled solution of 2-ethoxybenzamide (50
g, 0.3 mol) in dichloromethane (400 mL), keeping the reaction
temperature below 20 °C. The resulting mixture was stirred for
4-6 h at rt and then quenched with ice-water. The organic
solution was washed with water and then cooled in an ice bath.
1-Ethylpiperazine (46 mL, 0.36 mol) was added to the mixture,
which was further stirred at rt for 30 min. The organic layer
was washed with water, dried, and concentrated to about 100
mL. Petroleum ether (200 mL) was added, and the resulting
white solid was collected via suction filtration and dried to
provide 14 (88.0 g, 86%). 1H NMR (CDCl3, 300 MHz): δ 1.01
(t, 3H, J ) 6.9 Hz), 1.56 (t, 3H, J ) 6.9 Hz), 2.38 (q, 2H, J )
6.9 Hz), 2.50 (t, 4H, J ) 4.5 Hz), 3.03 (t, 4H, J ) 4.5 Hz),
4.28 (q, 2H, J ) 6.9 Hz), 6.14 (s, 1H), 7.06 (d, 1H, J ) 8.9
Hz), 7.67 (s, 1H), 7.82 (dd, 1H, J ) 8.9 Hz, 2.7 Hz), 8.58 (d,
1H, J ) 2.7 Hz). EI-MS m/z 341 (M+). Anal. Calcd for
C15H23N3O4S: C, 52.77; H, 6.79; N, 12.31. Found: C, 52.61;
H, 6.77; N, 12.02.
yield a white solid 17 (31.2 g, 88%). H NMR (CDCl3, 300
MHz): δ 1.02 (t, 3H, J ) 6.9 Hz), 1.49 (t, 3H, J ) 6.9 Hz),
2.39 (q, 2H, J ) 6.9 Hz), 2.51 (br, 4H), 3.05 (br, 4H), 4.18 (q,
2H, J ) 6.9 Hz), 7.00 (d, 1H, J ) 8.7 Hz), 7.69 (dd, 1H, J )
8.7 Hz, 2.1 Hz), 8.13 (d, 1H, J ) 2.1 Hz). ESI-MS m/z 356.3
(M + 1). Anal. Calcd for C15H25N5O3S: C, 50.68; H, 7.09; N,
19.70. Found: C, 50.51; H, 7.17; N, 19.85.
N-[1-[3-[2-Ethoxy-5-[(4-ethyl-1-piperazinyl)sulfonyl]-phe-
nyl]-2,5-dihydro-5-oxo-1,2,4-triazin-6-yl]ethyl]-butanamide
(18). As reported by Nowakowski,4 compound 4 was prepared
from (R,S)-alanine in 70-80% yield which was used in this
step without isolation. A mixture of 4 (22.0 g, 0.1 mol) and the
benzamidrazone 17 (14.5 g, 0.04 mol) in ethanol (100 mL) was
heated to reflux for 2 h. The resulting solution was filtered,
and the filtrate was concentrated to provide crude 18 (21.0 g)
which was used directly in the next step. A small reference
sample was obtained by chromatography on silica gel, 1H NMR
(CDCl3, 300 MHz): δ 0.93 (t, 3H, J ) 7.2 Hz), 1.02 (t, 3H, J
) 7.2 Hz), 1.53 (d, 3H, J ) 7.2 Hz), 1.63 (t, 3H, J ) 7.2 Hz),
1.66 (m, 2H), 2.19 (t, 2H, J ) 7.2 Hz), 2.44 (q, 2H, J ) 7.2
Hz), 2.54 (br, 4H), 3.06 (br, 4H), 3.10 (m, 1H), 4.42 (q, 2H, J
) 7.2 Hz), 6.85 (d, 1H, J ) 9.0 Hz), 7.18 (d, 1H, J ) 8.7 Hz),
7.90 (dd, 1H, J ) 8.7 Hz, 2.4 Hz), 8.84 (d, 1H, J ) 2.4 Hz),
12.32 (s, 1H). EI-MS m/z 506 (M+). Anal. Calcd for
C23H34N6O5S: C, 54.53; H, 6.76; N, 16.59. Found: C, 54.34;
H, 6.90; N, 16.39.
2-[2-Ethoxy-5-[(4-ethyl-1-piperazinyl)sulfonyl]phenyl]-5-
methyl-7-propyl- imidazo[5,1-f][1,2,4]triazin-4(1H)-one (1).
A mixture of the amide 18 (21 g, 0.04 mol) and POCl3 (60
mL) was stirred at 70-80 °C for 2 h. The POCl3 was recovered,
and the residue was added to ice slowly. The mixture was
basified to pH ≈ 9 with 2 M NaOH. The resulting pale solid
was then collected via suction filtration and dried. The target
compound 1 was produced as a white solid (16.1 g, 84%) via
recrystallization from ethyl acetate-petroleum ether, purity at
99.2% (HPLC). 1H NMR (CDCl3, 300 MHz): δ 1.00 (t, 3H, J
) 7.2 Hz), 1.08 (t, 3H, J ) 7.2 Hz), 1.58 (t, 3H, J ) 6.9 Hz),
1.86 (m, 2H), 2.49 (q, 2H, J ) 7.2 Hz), 2.54 (br, 4H), 2.64 (s,
3H), 2.99 (t, 2H, J ) 7.2 Hz), 3.15 (br, 4H), 4.32 (q, 2H, J )
6.9 Hz), 7.15 (d, 1H, J ) 9.0 Hz), 7.88 (dd, 1H, J ) 9.0 Hz,
2.1 Hz), 8.48 (d, 1H, J ) 2.1 Hz), 9.52 (s, 1H). ESI-MS m/z
488.8 (M + 1), 511.4 (M + 23). HPLC Conditions: ZORBAX
SB-C 18 4.6 mm × 150 mm × 5 µm; Detection: UV operated
at 226 nm; Flow rate: 1.0 mL/min; Temperature: 25 °C;
Injection load: 10 µL; Concentration: 0.5 mg/mL; Run time:
30 min; Mobile phase A: buffer (0.02 M KH2PO4 + 0.5% TEA,
pH adjusted to 6.0 with dilute H3PO4); Mobile phase B:
acetonitrile; Gradient program: time (min): 0 10 20 30; % of
mobile phase A: 65, 65, 30, 30; % of mobile phase B: 35, 35,
70, 70; Retention time of 1: 9.438 min.
2-Ethoxy-5-[(4-ethyl-1-piperazinyl)sulfonyl]-benzoni-
trile (15). A mixture of the benzamide 14 (68.2 g, 0.2 mol)
and POCl3 (150 mL) was stirred at 80-90 °C for 1 h. The
POCl3 was then recovered, and the residue was added to ice
slowly. The mixture was basified to pH ≈ 6 with 2 M NaOH,
and the resulting solid was collected via suction filtration and
dried. 15 was yielded as a white solid (55.0 g, 85%) via
recrystallization from ethyl acetate-petroleum ether. Mp 84-87
1
°C (lit.6 86-88 °C). H NMR (CDCl3, 300 MHz): δ 1.47 (t,
3H, J ) 7.2 Hz), 1.54 (t, 3H, J ) 7.2 Hz), 2.97 (q, 2H, J ) 7.2
Hz), 3.10 (br, 4H), 3.55 (br, 4H), 4.26 (q, 2H, J ) 7.2 Hz),
7.10 (d, 1H, J ) 8.7 Hz), 7.85 (dd, 1H, J ) 8.7 Hz, 2.4 Hz),
7.96 (d, 1H, J ) 2.4 Hz). ESI-MS m/z 324.1 (M + 1).
2-Ethoxy-5-[(4-ethyl-1-piperazinyl)sulfonyl]-benzami-
dine (16). Lithium hexamethyldisilazane (180 mL of 1 M
solution in THF, 0.18 mol) was slowly added to a solution of
the benzonitrile 15 (48.5 g, 0.15 mol) in anhydrous THF (100
mL) at rt. The reaction mixture was stirred for 10 h and then
acidified to pH∼3 with 1 M HCl. The solvent was removed
and the solution was basified to pH∼12 with 2 M NaOH. The
resulting solid was collected via suction filtration, dried to
provide 16 (42.0 g, 83%). 1H NMR (CDCl3, 300 MHz): δ 1.02
(t, 3H, J ) 6.9 Hz), 1.49 (t, 3H, J ) 6.9 Hz), 2.40 (q, 2H, J )
6.9 Hz), 2.52 (t, 4H, J ) 4.8 Hz), 3.03 (t, 4H, J ) 4.8 Hz),
4.18 (q, 2H, J ) 6.9 Hz), 7.02 (d, 1H, J ) 8.7 Hz), 7.74 (dd,
1H, J ) 8.7 Hz, 2.1 Hz), 7.94 (d, 1H, J ) 2.1 Hz). ESI-MS
m/z 341.2 (M + 1).
2-Ethoxy-5-[(4-ethyl-1-piperazinyl)sulfonyl]-benzamidra-
zone (17). Hydrazine hydrate (6.5 mL, 0.11 mol) was added
slowly to a solution of the benzamidine 16 (34.0 g, 0.1 mol) in
Received for review September 3, 2009.
OP900235P
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