Alternative synthesis of tadalafil: PDE5 inhibitor

Article abstract of DOI:10.1080/00397910802326521

Two-step alternative synthesis of tadalafil (1) is described. The synthesis features Pictet-Spengeler type reaction and DCC (N,N′- dicyclohexylcarbodiimide)/HOBt (N-hydroxybenzotriazole)-mediated double amidation employing sarcosine ethyl ester hydrochlor

Full text of DOI:10.1080/00397910802326521

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Alternative Synthesis of
Tadalafil: PDE5 Inhibitor
Raghupathi Reddy Anumula a , Lokeswara Rao
Madivada a , Goverdhan Gilla a , V. V. N. K. Prasad
Raju a , Mukkanti Kagga b , Padi Pratap Reddy a ,
Apurba Bhattacharya a & Rakeshwar Bandichhor a
a Innovation Plaza, Dr. Reddy's Laboratories Ltd.,
Bachupally, Qutubullapur, India
b Institute of Science and Technology, Center
for Environmental Science, J. N. T. University,
Kukatpally, Hyderabad, India
Version of record first published: 31 Oct 2008.
To cite this article: Raghupathi Reddy Anumula, Lokeswara Rao Madivada,
Goverdhan Gilla, V. V. N. K. Prasad Raju, Mukkanti Kagga, Padi Pratap Reddy, Apurba
Bhattacharya & Rakeshwar Bandichhor (2008): Alternative Synthesis of Tadalafil:
PDE5 Inhibitor, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 38:23, 4265-4271
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Synthetic Communications1, 38: 4265–4271, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802326521
Alternative Synthesis of Tadalafil:
PDE5 Inhibitor
Raghupathi Reddy Anumula,1 Lokeswara Rao Madivada,1
Goverdhan Gilla,1 V. V. N. K. Prasad Raju,1 Mukkanti Kagga,2
Padi Pratap Reddy,1 Apurba Bhattacharya,1 and Rakeshwar Bandichhor1
1Innovation Plaza, Dr. Reddy’s Laboratories Ltd., Bachupally,
Qutubullapur, India
2Institute of Science and Technology, Center for Environmental Science,
J. N. T. University, Kukatpally, Hyderabad, India
Abstract: Two-step alternative synthesis of tadalafil (1) is described. The synth-
esis features Pictet–Spengeler type reaction and DCC (N,N0-dicyclohexylcarbodii-
mide)=HOBt (N-hydroxybenzotriazole)–mediated double amidation employing
sarcosine ethyl ester hydrochloride.
Keywords: Double amidation, erection, phosphodiesterase, Pictet–Spengeler
reaction
INTRODUCTION
Tadalafil 1 (Fig. 1) is a phosphodiesterase type 5 (PDE5) inhibitor used in
the management of erectile dysfunction in men. Inhibition of PDE5
allows cyclic guanosine monophosphate (cGMP) to remain functional
in penile tissue, thereby relaxing the smooth muscle in the corpus
cavernosum, which leads to increase in blood flow, strengthening the
erection.[1]
Received May 3, 2008.
DRL-IPD Communication Number IPDO-IPM-00116.
Address correspondence to Rakeshwar Bandichhor, Innovation Plaza, IPD,
R & D, Dr. Reddy’s Laboratories Ltd., Survey Nos. 42, 45, 46 and 54, Bachu-
pally, Qutubullapur, R. R. District 500073, A.P., India. E-mail: rakeshwarb@
drreddys.com
4265

4266
R. R. Anumula et al.
Figure 1. Structure of tadalafil.
Precedented medicinal chemistry and large-scale synthetic routes[2]
for tadalafil 1 involve classical Pictet–Spengler-type reaction between
methyl ester of D-tryptophan 2 (racemic starting material used in medic-
inal chemistry route) or its hydrochloride salt (to avoid the use of trifluoro-
acetic acid [TFA]) and piperonal 3 to obtain cyclic intermediate 4, which
was treated with chloroacetyl chloride to afford amide 5. Intermediate 5
was further reacted with methyl amine as shown in Scheme 1a.
Another very close to formal synthesis[3] of 1 is also reported describ-
ing the acylation of hydrochloride salt of 2 with piperonyloyl chloride 6
to afford amide 7, which was treated with Lawesson’s reagent to obtain
thioamide 8. Intermediate 8 was subjected to alkylation with methyl
iodide to give thioimidate 9, which undergoes cyclization affording pen-
tacyclic structure 10. Intermediate 9 was reduced by employing sodium
borohydride to afford advanced intermediate 4 as shown in Scheme 1b.
There are a few more syntheses reported along the lines of concept
depicted in Scheme 1.[4]
RESULTS AND DISCUSSION
In our endeavor, as shown in Scheme 2, we started the synthesis with
commercially available D-tryptophan 11 analogous to the reported
synthesis, Pictet–Spengeler-type reaction between 11 and 3, in the pre-
sence of triflouroacetic acid, which allowed us to access a mixture of dia-
stereomers 12a and b [dr ¼ 7(cis):3(trans)] in 90% yield. These two
diastereomers are found to be in dynamic equilibrium; hydrochloric acid
salt of cis-isomer is less soluble in aqueous media that shifts the equili-
brium toward the conversion of trans- to cis-isomer. We were able to

Alternative Synthesis of Tadalafil
4267
Scheme 1. Precedented synthetic approach.
obtain 12a, cis-isomer, predominantaly (90% yield;>98% chiral HPLC pur-
ity) in the salt-formation event. Intermediate 12a was subjected to amida-
tion conditions (N,N0-dicyclohexylcarbodiimide=N-hydrobenzotriazole

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R. R. Anumula et al.
Scheme 2. Novel Synthesis of 1.
[DCC=HOBt]) in the presence of commercially available sarcosine ethyl
ester hydrochloride, which afforded crude tadalafil with good yield and
purity. Crystallization of crude tadalafil with a methanol and acetone
mixture afforded the optically pure API 1 in 85% yields. We have success-
fully implemented this synthesis in plants on a kilogram scale.
The Aforementioned synthesis has certain advantages over the
reported one: i) it avoids the use of toxic chloroacetyl chloride, ii) it
avoids column chromatography, which is required for separation of iso-
mers to meet the International Conference on Hormonization (ICH)
standards, and iii) this synthesis does not require relatively expensive
solvents.
CONCLUSIONS
We have developed an alternative synthesis for tadalafil 1 that appears to
be more compatible with industrial scale and has some advantages over
the existing synthesis.
EXPERIMENTAL
Solvents and reagents were obtained from commercial sources and used
without further purification. The 1H and 13C spectra were measured

Alternative Synthesis of Tadalafil
4269
in DMSO-d6 using 200 or 400 MHz on a Varian Gemini and Varian
Mercury Plus 2000 FT NMR spectrometer; the chemical shifts were
reported in d ppm. IR spectrum was recorded in the solid state as KBr
dispersion using a Perkin-Elmer 1650 FT IR spectrometer. The mass
spectrum (70 eV) was recorded on a HP 5989 A LC MS spectrometer.
The melting points were determined using the capillary method on a
Polmon (model MP-96) melting-point apparatus. The solvents and
reagents were used without further purification.
Preparation of (1R,3R)-1,2,3,4-Tetrahydro-1-(3,4-
methylene dioxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylic
Acid Hydro Chloride (12a)
Trifluoroacetic acid (808 mol; 6 L) was added to a solution of D-
tryptophan 11 (10.0 kg, 490 mol) and piperonal 3 (8.8 kg, 586 mol) in
dichloromethane (100 L), and the reaction mass was heated to 40 ꢀC.
After stirring for 10 h at 40 ꢀC, the mixture was allowed to cool down
to 35 ꢀC, and a mixture of dichloromethane=methanol (50 L each) was
added. The reaction mass was then quenched with 8% sodium bicarbo-
nate solution (50 L). The organic layer was separated, and the aqueous
layer was extracted with dichloromethane. The combined organic layers
were concentrated on a rotary evaporator to afford 12a and b. To a sus-
pension of 12a and b in water, 1 N hydrochloric acid (150 L) was added
slowly. After stirring for 15 h at 55 ꢀC, toluene (30 L) was added, and the
reaction mass was cooled to 15–20 ꢀC. After 30 min, the precipitated solid
was filtered, washed with toluene (10 L), and dried at 75 ꢀC for 6 h to
afford 12a (16.6 kg) in 90% yield and >98% HPLC purity.
1
Mp: 215–220 ꢀC; H NMR (200 MHz, DMSO-d6) 10.8 (s, 1H), 7.55
(d, 1H, J ¼ 7.0 Hz), 7.28 (d, 1H, J ¼ 7.2 Hz), 6.9–7.2 (m, 5H), 6.19 (s, 2H),
5.8 (s, 1H), 2.4–3.6 (m, 3H); 13C NMR (50 MHz (DMSO-d6) 206.6, 168.7,
148.5, 147.2, 136.8, 128.9, 127.1, 125.5, 124.9, 122.1, 119.2, 118.3, 111.7,
110.2, 108.3, 106.7, 101.6, 57.6, 55.4, 22.2; IR (KBr) 2927, 1757, 1626,
1205, 1040 cmꢁ1. MS (CI) calcd. for C19H16N2O4 (Mþ) 336.3; found
(MHþ) 337.1.
Preparation of (6R, 12aR)-2,3,6,7,12,12A-Hexahydro-2-methyl-
6-(3,4-methylene Dioxyphenyl)-pyrazino[20,10:6,1]pyrido[3,4-b]indole-
1,4-dione (1)
Triethyl amine (10 kg, 1020 mol) was added to a solution of dimethyl for-
mamide (65 L) and methylamino-acetic acid ethyl ester hydrochloride

4270
R. R. Anumula et al.
(13.2 kg, 860 mol), and then the mixture was stirred at 25–30 ꢀC for
20 min. The separated solid (triethyl amine hydrochloride) was filtered
out and washed with 15 L of dimethyl formamide. To a solution of fil-
trate 12a (10 kg, 270 mol), dicyclohexylcarbodiimide (6.6 kg, 320 mol),
1-hydroxybenzotriazole (5.4 kg, 400 mol), and triethyl amine (4.1 kg,
400 mol) were added at 25–35 ꢀC, and then reaction mass was heated to
50–55 ꢀC. After stirring for 10 h at 50–55 ꢀC, the mixture was allowed
to cool down to 10 ꢀC and unwanted dicyclohexylurea (DCU) was
filtered out. A mixture of dichloromethane=water (100 L each) was added
to the filtrate. The reaction mass was then quenched with 8% sodium
bicarbonate solution (80 L). The organic layer was separated, and aqu-
eous layer was extracted with dichloromethane. The combined organic
layers were concentrated on rotary evaporator, cooled to 0–5 ꢀC, and
recrystallized in mixture of methanol and acetone (1:1) to afford 1
(5.5 kg, 52.6%) with 99.9% purity.
1H NMR (400 MHz, DMSO-d6) 11.0 (s, 1H), 7.54 (d, 1H, J ¼
7.4 Hz), 7.29 (d, 1H, J ¼ 8.0 Hz), 7.07 (t, 1H, J ¼ 7.8 Hz), 7.03 (t, 1H,
J ¼ 7.8 Hz), 6.86 (s, 1H), 6.79 (s, 2H), 6.13 (s, 1H), 5.92 (s, 2H), 4.40
(dd, 1H, J ¼ 4.6 Hz, J ¼ 11.6 Hz), 4.17 (d, 1H, J ¼ 16.8 Hz), 3.94 (d, 1H,
J ¼ 16.8 Hz), 3.50 (dd, 1H, J ¼ 4.6 Hz, J ¼ 16.0 Hz), 2.97 (m, 1H), 2.93
(s, 3H); 13C NMR (400 MHz, DMSO-d6) 166.8, 165.5, 147.0, 146.0,
136.9, 136.2, 133.9, 125.7, 121.2, 119.3, 118.8, 118, 111.3, 107.9, 107,
104.7, 100.8, 55.5, 55.3, 51.4, 32.8, 23.1; IR (KBr) 3325, 2904, 1678,
1650, 1439, 1322, 1242, 1040 cmꢁ1. HRMS (CI) calcd. for C22H19N3O4
(Mþ) 389.4; found (MHþ) 390.5.
ACKNOWLEDGMENTS
The authors thank the management of Dr. Reddy’s Laboratories Ltd. for
supporting this work.
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