Synthesis of tadalafil analogues

Article abstract of DOI:10.1080/00397910600764626

Five novel compounds as potential phosphodiesterase type 5 (PDE-5) inhibitors were synthesized from D-tryptophan methyl ester via the Pictet-Spengler reaction and cyclization reaction. The structures of those compounds were confirmed by elemental analyses

Full text of DOI:10.1080/00397910600764626

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Synthesis of Tadalafil Analogues
Liu‐Tang Wang a , Hao Huang b , Zhong‐Lin Ye c , Yong Wu a & Xue‐Chao Wang
c
a West China School of Pharmacy, Sichuan University, Chengdu, China
b Chengdu College of Education, Chengdu, China
c Department of Research and Development Di'ao Co. Ltd, Chengdu, China
Available online: 16 Feb 2007
To cite this article: Liu‐Tang Wang, Hao Huang, Zhong‐Lin Ye, Yong Wu & Xue‐Chao Wang (2006): Synthesis
of Tadalafil Analogues, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 36:18, 2627-2632
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Synthetic Communicationsw, 36: 2627–2632, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600764626
Synthesis of Tadalafil Analogues
Liu-Tang Wang
West China School of Pharmacy, Sichuan University, Chengdu, China
Hao Huang
Chengdu College of Education, Chengdu, China
Zhong-Lin Ye
Department of Research and Development Di’ao Co. Ltd,
Chengdu, China
Yong Wu
West China School of Pharmacy, Sichuan University, Chengdu, China
Xue-Chao Wang
Department of Research and Development Di’ao Co. Ltd,
Chengdu, China
Abstract: Five novel compounds as potential phosphodiesterase type 5 (PDE-5) inhibi-
tors were synthesized from D-tryptophan methyl ester via the Pictet–Spengler reaction
and cyclization reaction. The structures of those compounds were confirmed by
1
elemental analyses, IR, H NMR, and ESI-MS spectra.
Keywords: MED, PDE-5, oxirane, synthesis
The large population of people suffering from male erectile dysfunction
(MED)[1,2] and the commercial success of sildenafil[3] have provided a
strong stimulus for the discovery and development of new generation of phos-
phodiesterase type 5 (PDE-5) inhibitors[4,5] such as launched vardenafil and
tadalafil (Fig. 1).
Received in R.O.C. February 7, 2006
Address correspondence to Liu-Tang Wang, West China School of Pharmacy,
Sichuan University, Chengdu 610041, China.
2627

2628
L.-T. Wang et al.
Figure 1. Tadalafil.
Tadalafil is one of the best PDE-5 inhibitors. The SAR studies of tadalafil
demonstrate that the cis-isomer has more potency and selectivity as PDE-5
versus other PDEs than the trans-isomer, the D-ring can be substituted with
other five-membered or six-membered rings, and that both potencies and
PDE6/5 selectivities are very sensitive to the C-6 aromatic substituents.[6,7]
According to those SAR studies, we designed five novel compounds as
tadalafil analogues. To the best of our knowledge, none of the target
compounds has been reported in the literature. They can be synthesized by the
methods described in Scheme 1. The Pictet–Spengler reaction of D-tryptophan
Scheme 1. Reagents: i, TFA, CH2Cl2, CH3OH, rt, 4 days; ii, oxirane, CH3OH, rt,
5–7 days.

Synthesis of Tadalafil Analogues
2629
methyl ester with appropriate aldehydes in dichloromethane in the presence of
trifluoroacetic acid provided cis b-carboline derivatives 2a–e.[6,7] The cycliza-
tion reaction of the appropriate b-carboline derivatives with oxirane in methanol
at room temperature provided the target compounds 3a–e with good yields
(81.9%, 76.8%, 72.9%, 77.6%, 65.4%). All the target compounds gave the
expected elemental analyses, IR, 1H NMR, and ESI-MS spectra.
In our primary view, the reaction of the b-carboline derivatives (2a–e)
with the oxirane should provide N-(2-hydroxyethyl)-b-carboline derivatives
(4a–e), which can provide the target compounds (3a–e) via transesterifi-
cation. To our surprise, it directly provides the target compounds with good
yields in mild conditions.
EXPERIMENTAL
Melting points were observed in an open capillary tube and are uncorrected.
IR spectra were recorded using KBr pellets on a Nicolet 560 FTIR spectro-
1
photometer, and H NMR and 13C NMR spectra were obtained at 600 MHz
on a Bruker Avance 600 instrument using CD3COCD3, CDCl3, or DMSO-
d6 as solvent and tetramethylsilane as internal standard. MS was measured
on an Agilent 1946B ESI-MS instrument. All commercially available
reagents were used without purification.
(1R,3R) Methyl 1-(1,3-Benzodioxol-5-yl)-2,3,4,9-tetrahydro-1H-b-
carboline-3-carboxylate (2a)
Representative example: D-Tryptophan methyl ester (13 g, 59.5 mmol) and 1,
3-benzodioxole-5-carboxaldehyde (10.7 g, 64.6 mmol) were dissolved in
CH2Cl2 (500 mL) and cooled to 08C with an ice bath. TFA (20 mL) was
added to this solution dropwise, and the mixture was stirred at room tempera-
ture for 4 days. The reaction mixture was then basified with aqueous NaHCO3,
washed with water and brine, dried over Na2SO4, filtered, and evaporated
under reduced pressure. The residue was purified by chromatography on
silica gel eluting with CH2Cl2/MeOH (99/1) to give 2a (6.2 g, 29.7%) as a
white solid. Mp 154–1558C. ESI-MS(þ): 351 (M þ H)þ.
The following compounds were prepared using a similar procedure with
appropriate aldehydes.
(1R,3R) Methyl 1-(3,4-Dimethoxylphenyl)-2,3,4,9-tetrahydro-1H-b-
carboline-3-carboxylate (2b)
The title compound was prepared from D-tryptophan methyl ester (13 g,
59.5 mmol) and 3,4-dimethoxybenzaldehyde (10.7 g, 64.6 mmol). The crude

2630
L.-T. Wang et al.
residue was purified by chromatography on silica gel eluting with CH2Cl2/
MeOH (99/1) to give 2b (9.8 g, 45%) as a white solid. Mp 174–1768C.
ESI-MS(þ): 367 (M þ H)þ.
(1R,3R) Methyl 1-(4-Methylphenyl)-2,3,4,9-tetrahydro-1H-b-
carboline-3-carboxylate (2c)
The title compound was prepared from D-tryptophan methyl ester (13 g,
59.5 mmol) and 4-methylbenzaldehyde (7.7 g, 4.6 mmol). The crude residue
was purified by chromatography on silica gel eluting with CH2Cl2/MeOH
(20/1) to give 2c (8.3 g, 43.5%) as an oil. ESI-MS(þ): 321 (M þ H)þ.
(1R,3R) Methyl 1-(4-Chlorophenyl)-2,3,4,9-tetrahydro-1H-b-
carboline-3-carboxylate (2d)
The title compound was prepared from D-tryptophan methyl ester (13 g,
59.5 mmol) and 4-chlorobenzaldehyde (9.1 g, 64.6 mmol). The crude
residue was purified by chromatography on silica gel eluting with CH2Cl2/
MeOH (19/1) to give 2d (10.0 g, 49.5%) as a white solid. Mp 208–2098C.
ESI-MS(þ): 341 (M þ H)þ.
(1R,3R) Methyl 1-(Pyrid-2-yl)-2,3,4,9-tetrahydro-1H-b-carboline-3-
carboxylate (2e)
The title compound was prepared from D-tryptophan methyl ester (13 g,
59.5 mmol) and pyridine-2-carboxaldehyde (6.9 g, 64.6 mmol). The crude
residue was purified by chromatography on silica gel eluting with CH2Cl2/
MeOH (20/1) to give 2e (4.3 g, 23.5%) as an oil. ESI-MS(þ): 308 (M þ H)þ.
(6R,12aR)-6-(1, 3-Benzodioxol-5-yl)-3,4,6,7,12,2a-
hexahydromorpholino[30,40: 1,6]pyrido[3, 4-b]indole-1-one (3a)
Representative example: (1R,3R) Methyl 1-(1,3-benzodioxol-5-yl)-2,3,4,9-
tetrahydro-1H-b-carboline-3-carboxylate (2a) (6.2 g, 17.7 mmol) was
dissolved in 200 mL of methanol and cooled to 08C with an ice bath. To
this solution was added oxirane (23 mL), which had been cooled to 08C
with an ice bath. The flask was sealed and stood without stirring at room temp-
erature for 5 days. The reaction mixture was concentrated to 50 mL and
filtered. The filter cake was recrystallized with methanol and gave 3a (5.3 g,
81.9%) as a white solid. Mp 189–1918C. 1H NMR (CDCl3) d 7.56
(d, J ¼ 7.3 Hz, 1H), 7.32–7.20 (m, 2H), 7.14 (m, 2H), 6.90 (d, J ¼ 7.7 Hz,

Synthesis of Tadalafil Analogues
2631
1H), 6.83 (m, 2H), 5.98 (d, J ¼ 12.5 Hz, 2H), 4.47 (s, 1H), 4.43 (dt, J ¼ 11.5,
2.6 Hz, 1H), 4.33 (d, J ¼ 9.0 Hz, 1H), 3.63 (dd, J ¼ 11.2, 3.8 Hz, 1H), 3.55
(m, 1H), 3.14 (t, J ¼ 13.2 Hz, 1H), 2.97 (d, J ¼ 12.1 Hz, 1H), 2.66 (dt,
J ¼ 12.3, 2.8 Hz, 1H). 13C NMR (CDCl3) d 169.9, 148.9, 148.4, 136.5,
133.3, 133.2, 127.0, 122.6, 122.3, 120.1, 118.8, 111.1, 108.8, 108.4, 108.0,
101.6, 68.6, 66.4, 62.2, 47.5, 25.7. IR (KBr): 3408, 2897, 2781, 1737, 1625,
1501, 1464, 1441, 1414, 1385, 1244, 927, 813, 790 cm21. ESI-MS(þ): 363
(M þ H)þ. Anal. calcd. for C21H18N2O4: C, 69.60; H, 5.01; N, 7.73. Found:
C, 69.68; H, 5.02; N, 7.71.
The following compounds were prepared using a similar procedure.
(6R,12aR)-6-(3, 4-Dimethoxylphenyl)-3,4,6,7,12,12a-
hexahydromorpholino[30,40: 1,6]pyrido[3,4-b]indole-1-one (3b)
The title compound was prepared from 2b (9.8 g, 6.8 mmol) and oxirane
(23 mL). The crude residue was recrystallized with methanol to give 3b
1
(7.8 g, 76.8%) as a white solid. Mp 106–1108C. H NMR (CD3COCD3) d
10.37 (s, 1H), 7.51 (d, J ¼ 6.5 Hz, 1H), 7.20 (d, J ¼ 6.8 Hz, 1H), 7.03–6.99
(m, 4H), 6.94 (d, J ¼ 8.6 Hz, 1H), 4.61 (s, 1H), 4.38–4.31 (m, 2H), 3.82
(s, 3H), 3.73 (s, 3H), 3.62 (dd, J ¼ 11.3, 4.1 Hz, 1H), 3.41 (dd, J ¼ 15.2,
2.6 Hz, 1H), 3.01 (m, 1H), 2.93 (d, J ¼ 12.1 Hz, 1H), 2.69 (m, 1H). IR
(KBr): 3331, 2993, 2957, 2933, 2833, 1717, 1594, 1515, 1463, 1381, 1296,
1266, 1229, 850, 813 cm21. ESI-MS(þ): 379 (M þ H)þ. Anal. calcd. for
C22H22N2O4: C, 69.83; H, 5.86; N, 7.40. Found: C, 69.63; H, 5.84; N, 7.42.
(6R,12aR)-6-(4-Methylphenyl)-3,4,6,7,12,12a-
hexahydromorpholino[30,40: 1,6] pyrido[3,4-b]indole-1-one (3c)
The title compound was prepared from 2c (8.3 g, 25.9 mmol) and oxirane
(23 mL). The crude residue was recrystallized with methanol to give 3c
(6.3 g, 72.9%) as a white solid. Mp 189–1918C (dec.). 1H NMR
(CD3COCD3) d 9.34 (s, 1H), 7.52 (d, J ¼ 6.7 Hz, 1H), 7.31 (d, J ¼ 7.9 Hz,
2H), 7.21–7.18 (m, 3H), 7.04–7.00 (m, 2H), 4.63 (s, 1H), 4.32–4.29
(m, 2H), 3.62 (dd, J ¼ 11.4, 3.9 Hz, 1H), 3.42 (dd, J ¼ 15.2, 3.2 Hz, 1H),
3.01 (m, 1H), 2.88 (d, J ¼ 12.6 Hz, 1H), 2.69 (m, 1H), 2.05 (s, 3H). IR
(KBr): 3369, 2957, 2901, 2851, 2780, 1737, 1625, 1512, 1464, 1382, 1290,
821 cm21. ESI-MS(þ): 333 (M þ H)þ. Anal. calcd. for C21H20N2O2:
C, 75.88; H, 6.06; N, 8.43. Found: C, 75.68; H, 6.08; N, 8.46.
(6R,12aR)-6-(4-Chlorophenyl)-3,4,6,7,12,12a-
hexahydromorpholino[30,40:1,6] pyrido[3,4-b]indole-1-one (3d)
The title compound was prepared from 2d (10.0 g, 29.4 mmol) and oxirane
(25 mL). The crude residue was recrystallized with methanol to give 3d

2632
L.-T. Wang et al.
(8.0 g, 77.6%) as a white solid. Mp 268–2708C (dec.). 1H NMR (CD3COCD3)
d 9.48 (s, 1H), 7.54 (d, J ¼ 7.0 Hz, 1H), 7.46 (d, J ¼ 8.3 Hz, 2H), 7.40
(d, J ¼ 8.3 Hz, 2H), 7.20 (d, J ¼ 7.1 Hz, 1H), 7.06–7.01 (m, 1H), 4.71
(s, 1H), 4.31 (d, J ¼ 8.3 Hz, 2H), 3.65 (dd, J ¼ 11.2, 3.9 Hz, 1H), 3.41 (dd,
J ¼ 15.4, 2.6 Hz, 1H), 3.00–2.99 (m, 1H), 2.82 (m, 1H), 2.77–2.74
(m, 1H). IR (KBr): 3347, 2903, 2784, 1722, 1489, 1465, 1412, 1319, 1216,
829 cm21. ESI-MS(þ): 353 (M þ H)þ. Anal. calcd. for C20H17ClN2O2:
C, 68.09; H, 4.86; N, 7.94. Found: C, 68.33; H, 4.84; N, 7.97.
(6R,12aR)-6-(Pyrid-2-yl)-3,4,6,7,12,12a-
hexahydromorpholino[30,40:1,6] pyrido[3, 4-b]indole-1-one (3e)
The title compound was prepared from 2e (4.3 g, 14.0 mmol) and oxirane
(20 mL). The crude residue was recrystallized with methanol to give 3e
1
(2.9 g, 65.4%) as a white solid. Mp 225–2308C. H NMR (DMSO-d6) d
10.25 (s, 1H), 8.61 (dd, J ¼ 5.6, 1.5 Hz, 1H), 7.77 (dt, J ¼ 7.6, 1.6 Hz, 1H),
7.46 (d, J ¼ 7.6 Hz, 1H), 7.38–7.35 (m, 1H), 7.20 (d, J ¼ 7.9 Hz, 1H), 6.99
(t, J ¼ 7.1 Hz, 1H), 6.96 (t, J ¼ 7.1 Hz, 1H), 4.84 (s, 1H), 4.32–4.30
(m, 2H), 3.73 (dd, J ¼ 11.3, 3.9 Hz, 1H), 3.30 (dd, J ¼ 15.2, 2.5 Hz, 1H),
2.95–2.90 (m, 1H), 2.87–2.81 (m, 1H), 2.77 (d, J ¼ 12.6 Hz, 1H). IR
(KBr): 3403, 2952, 2899, 2849, 2781, 1745, 1590, 1571, 1463, 1434, 1411,
1380, 1202, 747, 697 cm21. ESI-MS(þ): 320 (M þ H)þ. Anal. calcd. for
C19H17N3O2: C, 71.46; H, 5.37; N, 13.16. Found: C, 71.55; H, 5.36; N, 13.20.
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