Synthesis of the major metabolites of Tolvaptan

Article abstract of DOI:10.1016/j.cclet.2012.11.001

Tolvaptan is a nonpeptide arginine vasopressin (AVP) V₂-receptor antagonist and used in the treatment of heart failure, cirrhosis, syndrome of inappropriate antidiuretic hormone secretion or other high-volume capacity of hyponatremia. The metab

Full text of DOI:10.1016/j.cclet.2012.11.001

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 1343–1346
www.elsevier.com/locate/cclet
Synthesis of the major metabolites of Tolvaptan
*
Wei Li Wan, Jian Bo Wu, Fan Lei, Xiao Long Li, Li Hai, Yong Wu
Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, Department of Medicinal Chemistry,
West China School of Pharmacy, Sichuan University, Chengdu 610041, China
Received 29 July 2012
Available online 16 November 2012
Abstract
Tolvaptan is a nonpeptide arginine vasopressin (AVP) V2-receptor antagonist and used in the treatment of heart failure, cirrhosis,
syndrome of inappropriate antidiuretic hormone secretion or other high-volume capacity of hyponatremia. The metabolites of
tolvaptan are mainly produced by CYP3A4, including two major compounds named DM-4103 and DM-4107. Herein, the chemical
synthesis of those two metabolites is described in this article for further study.
# 2012 Yong Wu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Tolvaptan; Metabolites; Synthesis
Tolvaptan (N-[Æ-4-[(7-chloro-2,3,4,5-tetrahydro-5-hydroxy-1H-1-benzazepin-1-yl) carbonyl]-3-methylphenyl]-2-
methyl-benzamide) was researched and developed by Otsuka Pharmaceutical Company of Japan (Otsuka Pharm) [1]. As
the only oral selective V2 receptor antagonist, Tolvaptan made great progress in the treatment of heart failure, cirrhosis,
syndrome of inappropriate antidiuretic hormone secretion and other high-volume capacity of hyponatremia [2–4].
Tolvaptan is metabolized by the CYP3A4 in the liver. However, till date the pharmacokinetic data for its metabolites
in human is still limited. Meanwhile, many side effects such as polyuria and pollakiuria were reported [5,6]. Therefore,
it is essential to investigate the pathway and the metabolites of tolvaptan in human. We are particularly interested in
two main metabolites of tolvaptan in vivo named DM-4103 and DM-4107 (Fig. 1) [7]. To the best of our knowledge,
there is no report on the synthesis of those two important compounds yet.
Retrosynthetic analysis (Fig. 2) led us to compound i as the key intermediate. It has been reported that N-acetyl-p-
toluidine cannot be acetylated [8]. Here, we found that N-(4-chlorophenyl)acetamide still cannot be acetylated under
any F–C conditions. Thus, we tried another way to synthesis i involved using 4-chloroaniline as the starting material,
which was coupled with succinic anhydride to form amide 2 as shown in Scheme 1. Jarikote et al. have reported that
compound 2 can be cycled to get 3 by heating in PPA/AcOH [9]. However, the 1H NMR spectra indicated a product
with a highly symmetrical structure. Combined with the MS, the final product proved to be 4 actually.
As shown in Scheme 2, after aldol condensation and nitration reaction, we successfully synthesized compound 3a
in 57.6% yield, the next step requires reducing 3a to get i. A number of reducing conditions were investigated,
including reduction catalyzed by PtO2, Pt, and Raney Ni/N2H4ÁH2O. However, all attempts leaded to complicate
* Corresponding author.
E-mail address: wyong@scu.edu.cn (Y. Wu).
1001-8417/$ – see front matter # 2012 Yong Wu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2012.11.001

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W.L. Wan et al. / Chinese Chemical Letters 23 (2012) 1343–1346
Fig. 1. Proposed metabolic pathway of tolvaptan in humans.
OH
O
Cl
COOH
Cl
COOH
NH
NH
NH
NH
O
O
O
O
DM-4107
DM-4103
NH
O
2
COOH
Cl
i
H N
O
2
+
COOH
or
N
COOH
COOH
H
ii
iii
iv
Fig. 2. Retrosynthetic analysis of the metabolites.
results. When using Pd/C as the catalyst, the main product is compound 5a. In this case it is necessary to separate the
reduction into two single steps.
Then we went though a lot of effort to find a convenient and efficient route to synthesis DM-4103 and DM-4107
(Scheme3). First, condensationof1-(3-chlorophenyl)ethanonewiththe2-oxoaceticacidgavecompound2. Compound2
NH
O
O
H
N
2
c
COOH
Cl
NH
Cl
2
H
N
O
Cl
COOH
b
a
3
i
O
Cl
O
2
1
N
O
Cl
4
Scheme 1. Reagents and conditions: (a) succinic anhydride, acetone, rt, 95%; (b) PPA, AcOH, reflux, 2 h; (c) aqueous HCl.

W.L. Wan et al. / Chinese Chemical Letters 23 (2012) 1343–1346
1345
NH
O
O
2
COOH
COOH
O
O
NO
O
2
a
b
c
COOH
COOH
Cl
i
Cl
1a
NH
Cl
Cl
2
2a
3a
5a
Scheme 2. Reagents and conditions: (a) glyoxylic acid monohydrate, concd. H2SO4, 1,4-dioxane, reflux, 80%; (b) HNO3, concd H2SO4, À20 8C,
72%; (c) H2, 5% Pd/C, EtOH, rt, 62%.
O
O
O
NO
O
2
a
b
c,d
COOH
COOH
COOMe
Cl
Cl
Cl
Cl
4b
2b
3b
1b
O
O
Cl
Cl
COOMe
NO
NH
O
COOMe
NH
2
e
f
g
NH
COOMe
NH
2
2
O
O
Cl
6b
7b
5b
O
O
OH
NH
Cl
Cl
Cl
COOH
COOMe
COOH
j
h
i
NH
NH
NH
NH
O
NH
O
O
O
O
O
DM-4107
8b
DM-4103
Scheme 3. Reagents and conditions: (a) glyoxylic acid monohydrate, concd. H2SO4, 1,4-dioxane, reflux, 80%; (b) Zn, CH3COOH/H2O = 27:1, rt,
91%; (c) HNO3, concd. H2SO4, À20 8C, 72%; (d) MeOH, H2SO4, reflux, 95%; (e) H2, 1% Pt/C, EtOH, 85%; (f) 2-methyl-4-nitrobenzoyl chloride,
pyridine, DCM, 87%; (g) H2, 1% Pt/C, EtOH, rt, 88%; (h) 2-methylbenzoyl chloride, Et3N, DCM, rt, 89%; (i) 10% NaOH, MeOH, rt, 95%; (j)
NaBH4, MeOH, rt, 96%.
was then reduced to give 3, which was converted to compound 4 via nitration reaction in concentrated sulfuric acid and
nitric acid. Finally, we obtained the key intermediate 5 from 4 through hydrogenation catalyzed by 1% Pt.
The condensation of intermediate 5 with 2-methyl-4-nitrobenzoic acid was catalyzed by pyridine to afford 6. After
reducing the nitro into the free amino 7, the intermediate was then condensated with 2-methylbenzoic acid to give 8.
The following hydrolysis of 8 in methanol solution of sodium hydroxide got the target compound DM-4103, which can
easily be reduced into DM-4107 by sodium borohydride in excellent yield. Both of those two target compounds were
confirmed by elemental analyses, IR, NMR and MS data analysis [10].
In summary, we herein reported the synthesis of tolvaptan main metabolites, 4-(5-chloro-2-(2-methyl-4-(2-
methylbenzamido)benzamido)phenyl)-4-oxobutanoic acid DM-4103 and 4-(5-chloro-2-(2-methyl-4-(2-methyl-
benzamido)benzamido)phenyl)-4-hydroxybutanoic acid DM-4107, which are crucial for our future in vivo studies
on the metabolism of tolvaptan.
Acknowledgment
We are grateful for financial support from the Sichuan Baili Pharmaceutical Co., Ltd.

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[9] D.V. Jarikote, V.G. Pawar, S.R. Bhusare, et al. Russ. J. Org. Chem. 40 (4) (2004).
[10] Physical and spectral data of the target compounds. DM-4103: Mp: 230–232 8C; 1H NMR (400 MHz, DMSO-d6): d 12.24 (br, 1H), 11.41 (s,
1H), 10.50 (s, 1H), 8.41 (d, 1H, J = 8.8 Hz), 8.09 (d, 1H, J = 2.4 Hz), 7.70–7.72 (m, 3H), 7.56 (d, 1H, J = 7.6 Hz), 7.48 (d, 1H, J = 7.6 Hz), 7.41
(t, 1H, J = 7.2), 7.31 (t, 2H, J = 7.6), 3.31–3.35 (m, 4H), 2.57 (t, 2 H, J = 6.4 Hz), 2.43 (s, 3 H), 2.40 (s, 3 H); 13C NMR (200 MHz, CDCl3): d
19.557, 20.393, 28.345, 35.152, 39.073, 117.097, 121.969, 123.037, 125.925, 126.824, 127.213, 127.423, 127.518, 128.236, 130.066, 130.741,
130.827, 133.734, 135.556, 137.162, 137.655, 137.872, 141.500, 167.410, 168.404, 174.009; HRMS calcd. for C26H23ClN2O5 m/z: 478.1295.
Found: 501.1120 [M+Na]+. Anal. Calcd. for C26H23ClN2O5: C, 65.20; H, 4.84; Cl, 7.40; N, 5.85. Found: C, 65.14; H, 4.58; Cl, 7.45; N, 5.90.
DM-4107: Mp: 144–146 8C; 1H NMR (400 MHz, DMSO-d6): d 10.44 (s, 1H), 9.99 (s, 1H), 7.77 (d, 1H, J = 8.4 Hz), 7.67–7.69 (m, 2H), 7.53 (d,
1H, J = 7.6 Hz), 7.46 (d, 1H, J = 7.6 Hz), 7.30–7.43 (m, 5H), 4.84 (d, 1H, J = 4.4 Hz), 2.43 (s, 3H), 2.39 (s, 3H), 2.24-2.31 (m, 2H), 1.89 (m,
1H), 1.79 (m, 1H); 13C NMR (200 MHz, CDCl3): d 19.651, 20.362, 30.908, 33.010, 69.408, 116.971, 121.795, 126.015, 126.837, 127.133,
127.277, 127.559, 128.255, 129.448, 130.113, 130.908, 131.623, 134.574, 135.583, 137.265, 137.341, 140.445, 140.976, 167.760, 168.433,
174.851; HRMS calcd. for C26H23ClN2O5 m/z: 480.1452. Found: 503.1355 [M+Na]+; Anal. Calcd. for C26H25ClN2O5: C, 64.93; H, 5.24; Cl,
7.37; N, 5.82. Found: C, 64.66; H, 5.35; Cl, 7.54; N, 5.62.