New practical synthesis of the key intermediate of candesartan

Article abstract of DOI:10.1021/op700041z

The development of a new, practical synthesis of methyl 3-amino-N-(2′-cyanobiphenyl-4-yl)methyl]anthranilate, key intermediate of candesartan, is described, starting from methyl anthranilate. The features of our approach are as follows: (i) introduction of the 3-nitro group by acid catalysed rearrangement of the corresponding methyl N-nitroanthranilate; (ii) introduction of a (2′-cyanobiphenyl-4-yl)methyl side chain by N-alkylation of the appropriate N-nitroanthranilic acid derivative. In the most efficient procedure methyl N,3-dinitroanthranilate was N-alkylated with 4′-bromomethyl-biphenyl-2-nitrile. Catalytic reduction of the aromatic nitro group was accompanied with the removal of the N-nitro function to afford the required key intermediate in good yield.

Full text of DOI:10.1021/op700041z

Organic Process Research & Development 2007, 11, 490−493
New Practical Synthesis of the Key Intermediate of Candesartan
M a´ rta Porcs-Makkay,* Tibor Mezei, and Gyula Simig
EGIS Pharmaceuticals PLC., Chemical Research DiVision P.O. Box 100, H-1475 Budapest, Hungary
Abstract:
The development of a new, practical synthesis of methyl
3-amino-N-[(2′-cyanobiphenyl-4-yl)methyl]anthranilate, key in-
termediate of candesartan, is described, starting from methyl
anthranilate. The features of our approach are as follows: (i)
introduction of the 3-nitro group by acid catalysed rearrange-
ment of the corresponding methyl N-nitroanthranilate; (ii)
introduction of a (2′-cyanobiphenyl-4-yl)methyl side chain by
N-alkylation of the appropriate N-nitroanthranilic acid deriva-
tive. In the most efficient procedure methyl N,3-dinitroanthra-
nilate was N-alkylated with 4′-bromomethyl-biphenyl-2-nitrile.
Catalytic reduction of the aromatic nitro group was ac-
companied with the removal of the N-nitro function to afford
the required key intermediate in good yield.
Figure 1. Candesartan cilexetil and its key intermediate.
Scheme 1
Introduction
Candesartan cilexetil (1), an angiotensin II receptor
blocker, has been available for several years for the treatment
1
of hypertension and for use in heart failure. Several methods
have been described for the synthesis of compound 1
involving key intermediate 22 (Figure 1).
-4
The synthesis of 1,2,3-trisubstituted aromatic compounds
is generally cumbersome by conventional methods. The
4
presumable manufacturing synthesis of Takeda started with
nitro derivative 3 (available as the minor product by nitration
of phthalic anhydride followed by hydrolysis). After selective
esterification (4) the required amino function was introduced
by Curtius reaction resulting carbamate 5, which is an
inconvenient method for scaling-up (Scheme 1). N-Alkylation
with compound 6 followed by removal of the tert-butoxy-
carbonyl group and subsequent reduction of nitro derivative
7
afforded key intermediate 2.
The most powerful method for the synthesis of 1,2,3-
trisubstituted benzenes is lithiation of benzene derivatives
substituted with 1,3-interrelated directing metalation groups
+
lowed by reaction with a N synthon (electrophilic amina-
6
tion) does not promise a more efficient industrial scale
synthesis of the required compound.
(
DMGs) at their common site followed by introduction of
5
the new substituent with an appropriate nucleophile. How-
ever, lithiation of benzene derivatives substituted with 1,3-
Results and Discussions
related carbon and nitrogen based DMGs (e.g., -CONR
2
,
Here we report a convenient synthesis of key intermediate
starting from methyl anthranilate 8 (Scheme 2). Our
oxazolino and -NHCOR, -NHCOOR, respectively) fol-
2
strategy for the introduction of the second amino substituent
was to use the rearrangement of N-nitroamine 9, which is
expected to give the 1,2,3-trisubstituted nitro derivative 10
as the major product.
N-Nitration of anilines and their rearrangement on treat-
ment with acids to afford ortho- and para-nitroanilines, with
*
To whom correspondence should be addressed. E-mail: pmmarta@
freemail.hu.
1) Drugs of the Future 1993, 18 (7), 609.
2) Naka, T.; Nishikawa, K.; Kato, T. (Takeda Chem. Ind.) EP 459136 (filed
4.12.1991); U.S. Patent 5196444 (filed 23.03.1993).
3) Naka, T.; Kato, T.; Nishikawa, K. (Takeda Chem. Ind.) EP 720982 (filed
9.04.1991).
4) Hashimoto, H.; Hanaoka, T.; Kato, M. (Takeda Chem. Ind.) EP 881212
filed 20.05.1998).
5) Snieckus, V. Chem. ReV. 1990, 90, 879.
(
(
0
(
(
(
1
(
(6) Greck, Ch.; Gen eˆ t, J.-P. Synlett 1997, 741.
4
90
•
Vol. 11, No. 3, 2007 / Organic Process Research & Development
10.1021/op700041z CCC: $37.00 © 2007 American Chemical Society
Published on Web 04/25/2007

Scheme 2
Scheme 3
the ortho compounds predominating, is well documented in
7
the literature. The method has also been described starting
8
from anthranilic acid. However, it was not reproducible in
our hands. We performed N-nitration of methyl anthranilate
8
with a mixture of fuming nitric acid, acetic acid, and acetic
anhydride at 18-20 °C generating compound 9 in 60% yield.
The reaction was reproducible and appropriate for scaleup.
Treatment of N-nitro derivative 9 with sulfuric acid resulted
in a mixture of 3- and 5-nitro derivatives (10 and 11) in a
1
ratio of 6:1 (as determined by H NMR). After recrystalli-
zation of the crude mixture from methanol, pure isomer 10
was obtained in 55% yield based on N-nitro derivative 9.
8
As indicated in the literature, 80% aqueous sulfuric acid
was used in the rearrangement reaction. The formation of
Scheme 4
3
,5-dinitro derivative was observed in more concentrated
(85-90%) sulfuric acid, presumably as the result of inter-
molecular processes. When using more diluted sulfuric acid,
lower yields were obtained.
As it was to be expected, the amino group of compound
1
6
0 could not be alkylated with biphenylylmethyl bromide
. However, N-alkylation of the conjugate base of N-nitro
derivative 9 and subsequent rearrangement might also offer
a reasonable route to the required intermediate 7 (Scheme
3). N-Alkylation of compound 9 afforded derivative 12
(Scheme 3). Migration of the nitro group induced by acidic
treatment of 12 produced a mixture of 3- and 5-nitro
derivatives (7 and 13) in a ratio of 3:1, a mixture inseparable
by crystallization. The primary product obtained after
catalytic reduction of the nitro compound mixture was a 5:1
mixture of the hydrochlorides of phenylenediamines 2 and
both dinitro derivatives 15 and 16 do not indicate any
decomposition of the compounds which could give rise to
safety problems.
In the next step reduction of the aromatic nitro function
by catalytic hydrogenation was accompanied with the
removal of the N-nitro group providing intermediate 2 in
14. After tedious conventional separation procedures the
desired product 2 was isolated in low (26%) yield.
Nevertheless, the conception to use N-nitro compounds
for the introduction of the biphenyl side chain could be
successfully applied starting from ortho-nitroaniline 10
8
1% yield, isolated as its hydrochloride.
The studies described above allowed the development
of a new manufacturing procedure for the preparation of
key intermediate 2 of active pharmaceutical ingredient
candesartan cilexetil (1).
(Scheme 4). It is worth mentioning that attempts to activation
of the aniline nitrogen of compound 10 by acylation with
ethyl chloroformate, acetic anhydride, and acetyl chloride
under conventional conditions resulted in the recovery of
the starting compound. N-Nitration of 10 afforded N,3-dinitro
derivative 15, which was N-alkylated with biphenylylmethyl
bromide (6) to compound 16 in good yield. DSC studies of
Experimental Section
Melting points are uncorrected. Infrared spectra were
1
recorded as KBr pellets. H NMR spectra were recorded at
2
00 or 500 MHz. All unspecified reagents were from
commercial resources. Methyl anthranilate was acquired from
a Fluka catalogue, and 4′-bromomethyl-biphenyl-2-nitrile was
synthetized according to the procedure described.3
(
7) Williams, D. L. H. In The Chemistry of Functional Groups, Supplement
F; Patai, S., Ed.; Wiley: New York, 1982; Part 1, pp 127-153.
8) Macciotta, E. Gazz. Chim. Ital. 1939, 69, 330.
,4
(
Vol. 11, No. 3, 2007 / Organic Process Research & Development
•
491

Methyl N-Nitroanthranilate (9). Methyl anthranilate
177.4 g; 152.0 mL; 1.17 mol) was dissolved in a mixture
133.8, 133.7, 132.9, 132.3, 130.0, 129.9, 129.9, 129.1, 129.0,
127.7, 126.8, 118.5, 111.2, 57.5, 52.1.
(
of acetic acid (1000 mL) and fuming nitric acid (304.0 g,
00 mL; 4.83 mol) at 20 °C. To the solution acetic anhydride
216.0 g; 200 mL; 2.12 mol) was added at 18-20 °C, and
the mixture was stirred at room temperature for 20 min. It
was poured into ice-water (2000 g). The crystalline product
was filtered and washed with water to give 9 (138.0 g; 60%)
as light gray crystals, mp 65-67 °C.
Mixture of Methyl 3- and 5-Nitro-N-[(2′-cyanobi-
phenyl-4-yl)methyl]anthranilate (7 and 13). Methyl N-[(2′-
cyanobiphenyl-4-yl)methyl]- N-nitroanthranilate (12, 22.6 g;
58 mmol) was added to a solution of 80% sulfuric acid (95
mL) at 0 °C, and the mixture was stirred at this temperature
for 30 min. It was poured into crushed ice (200 g), and the
reddish solid product was filtered, washed with water and
refluxed in methanol (220 mL) for 1 h. After cooling the
mixture was stirred at 0-5 °C for 1 h. The crystalline product
was filtered to give a mixture of 7 and 13 (18.2 g; 80%) in
a ratio of 3:1 as yellow crystals. The ratio of compounds 7
2
(
Anal. Calcd for C
8 8 2 4
H N O (196.16): C, 48.98; H, 4.11;
N, 14.28%. Found: C, 48.86; H, 4.28; N, 14.30%. IR (KBr,
-1
1
cm ) 3133 (NH), 1692 (CdO), 1568, 1257 (NO
CDCl ) δ 13,29 (1H, s); 8.19 (1H, dd, J ) 8.4 Hz, J ) 1.1
Hz); 8.09 (1H, dd, J ) 8.0 Hz, J ) 1.9 Hz); 7.67 (1H, dt, J
8.4 Hz, J ) 1.9 Hz); 7.28 (1H, dt, J ) 8.0 Hz, J ) 1.1
2
); H NMR
(
3
1
and 13 was determined by H NMR measurements on the
basis of the intensity ratio of signals corresponding to the
)
Hz); 3.97 (3H, s).
aromatic protons of the isomers.
1
Methyl 3-Nitroanthranilate (10). Methyl N-nitroanthra-
nilate (9, 138.0 g; 0.7 mol) was added to a solution of sulfuric
acid (80%, 690 mL) at 0 °C, and the mixture was stirred for
Signals assigned to compound 7: H NMR (DMSO-d
6
)
δ 8.65 (1H, t, J ) 5.5 Hz), 8.10 (1H, dd, J ) 8.1, J ) 1.8
Hz), 7.95 (1H, d, J ) 7.7 Hz), 7.78 (1H, dt, J ) 7.7, J )
1.4 Hz), 7.68-7.50 (5H, m), 7.46 (2H, d, J ) 8.1, Hz), 6.87
30 min at this temperature. It was poured into crushed ice
(
690 g), and the crystalline product was filtered and washed
(1H, t, J ) 8.0 Hz), 4.26 (2H, d, J ) 5.1 Hz), 3.84 (3H, s).
1
with water to give a mixture of 10 and 11 (121.0 g; 87.5%)
in a ratio of 6:1, as determined by H NMR measurements
on the basis of the intensity ratio of signals corresponding
to the aromatic protons of the isomers.
Signals assigned to 13: NMR (DMSO-d
6
) δ 9.09 (1H,
1
t, J ) 5.5 Hz), 8.68 (1H, d, J ) 2.5 Hz), 8.20 (1H, dd, J )
9.5 Hz, J ) 2.5 Hz), 8.10 (1H, m), 7.68-7.50 (5H, m), 7.46
(2H, d, J ) 8.1, Hz), 6.94 (1H, d, J ) 9.5 Hz), 4.76 (2H, d,
J ) 5.8 Hz), 3.91 (3H, s).
1
H NMR (DMSO-d ) for the 3-nitro derivative: δ 8.35
6
(
1H, dd, J ) 8.4 Hz, J ) 1.1 Hz); 8.23 (1H, dd, J ) 8.0 Hz,
Methyl 3-Amino-N-[(2′-cyanobiphenyl-4-yl)methyl]an-
thranilate (2) and Methyl 5-Amino-N-[(2′-cyanobiphenyl-
4-yl)methyl]anthranilate (14) by the Reduction of a
Mixture of Methyl 3- and 5-Nitro-N-[(2′-cyanobiphenyl-
4-yl)methyl]anthranilate (7 and 13). The 3:1 mixture of
methyl 3- and 5-nitro-N-[(2′-cyanobiphenyl-4-yl)methyl]-
anthranilate (7 and 13; 34.9 g, 0.09 mol) in THF (177 mL)
was hydrogenated in the presence of Raney nickel (∼10 g)
at room temperature, under 10 bar. The reaction mixture was
filtered and concentrated. The oily residue was dissolved in
ethyl acetate (150 mL), and concd aqueous hydrochloric acid
(7.6 mL; 0.09 mol) was added to the stirred solution at 0
°C. It was stirred for an additional 3 h at this temperature,
and the crystalline product was filtered to give a 5:1 mixture
of the hydrochlorides of 2 and 14 (32.0 g, 90%), as
J ) 1.4 Hz); 6.75 (1H, t, J ) 8.4 Hz); 3.86 (3H, s) and for
the 5-nitro derivative: δ 8.60 (1H, d, J ) 2.6 Hz); 8.10 (1H,
dd, J ) 9.2 Hz, J ) 1.4 Hz); 6.90 (1H, d, J ) 9.5 Hz); 3.86
(
3H, s).
The crude product was recrystallized from methanol
resulting in 10 (76.0 g; 55%, based on 9) as yellow crystals,
mp 94-95 °C. Anal. Calcd for C (196.16): C,
8.98; H, 4.11; N, 14.28%. Found: C, 49.10; H, 4.12; N,
8 8 2 4
H N O
4
1
1
-
1
4.09%. IR (KBr, cm ) 3455, 3320 (NH
2
), 1703 (CdO),
1
620, 1353 (NO ); H NMR (CDCl ) δ 8.47 (2H, bs); 8.37
2 3
(1H, dd, J ) 8.4 Hz, J ) 1.4 Hz); 8.23 (1H, dd, J ) 8.4 Hz,
J ) 1.4 Hz); 6.65 (1H, t, J ) 8.4 Hz); 3.92 (3H, s).
Methyl N-[(2′-Cyanobiphenyl-4-yl)methyl]-N-nitro-
anthranilate (12). To a solution of methyl N-nitroanthra-
nilate (9, 19.6 g; 0.10 mol) and triethylamine (11.1 g; 15.3
mL; 0.11 mol) in DMF (80 mL) was added a solution of
1
determined by H NMR measurements on the basis of the
intensity ratio of signals corresponding to the aromatic
protons of the isomers. The mixture of the hydrochlorides
was suspended in a mixture of ethyl acetate (250 mL) and
water (250 mL) and stirred at room temperature for 3 h. The
crystalline product was filtered to give the hydrochloride of
14 (3.60 g; 10%), mp 220-223 °C (50% aqueous ethanol).
4
2
′-bromomethyl-biphenyl-2-nitrile (27.2 g; 0.10 mol) at 20-
5 °C, and the reaction mixture was stirred at room
temperature for 6 h. After cooling to 0-5 °C it was diluted
with water (200 mL), the solvents were decanted, and the
thick oily residue was triturated with methanol (60 mL) to
give a crystalline product. It was filtered and recrystallized
from ethanol to give 12 (18.7 g; 48.3%) as colorless crystals,
Anal. Calcd for hydrochloride-monohydrate C22
3 3
H22ClN O
(411.89): C, 64.15; H, 5.38; Cl, 8.61; N, 10.20%. Found:
-1
mp 96-97 °C. Anal. Calcd for C22
H
17
N
3
O
4
(387.40): C,
C, 63.89; H, 5.48; Cl, 8.69; N, 10.23%. IR (KBr, cm ) 3565,
3346, 2857, 2622 (NH ), 2221 (CN), 1685 (CdO), 1520,
1442, 1239, 1210 (NO
6
1
1
1
8.21; H, 4.41; N, 10.85%. Found: C, 67.93; H, 4.42; N,
2
-
1
1
0.59%. IR (KBr, cm ) 2228 (CN), 1724 (CdO), 1533,
2 6
); H NMR (DMSO-d ) δ 9.98 (2H,
1
289 (NO
2
); H NMR (CDCl
3
) δ 8.17 (1H, dd, J ) 7.3, J )
bs), 8.29 (1H, bs); 7.94 (1H, d, J ) 7.7 Hz); 7.86 (1H, d, J
) 2.5 Hz); 7.79 (1H, t, J ) 7.7 Hz); 7.62 (2H, t, J ) 7.7
Hz); 7.58 (2H, d, J ) 7.7 Hz); 7.49 (2H, d, J ) 8.0 Hz);
7.37 (1H, dd, J ) 9.1 Hz, J ) 2.5 Hz); 6.85 (1H, d, J ) 9.1
Hz); 4.62 (2H, d, J ) 3.3 Hz); 3.87 (3H, s).
.8 Hz), 7.77 (1H, dt, J ) 7.7 Hz, J ) 1.4 Hz), 7.70-7.41
(9H, m), 7.19 (1H, dd, J ) 7.1 Hz, J ) 2.1 Hz), 5.84 (1H,
d, J ) 15.6 Hz), 4.71 (1H, d, J ) 15.6 Hz), 3.90 (3H, s).
1
3
C NMR (CDCl ): δ 164.9, 144.7, 139.2, 138.1, 135.3,
3
492
•
Vol. 11, No. 3, 2007 / Organic Process Research & Development

1
The filtrate was evaporated to dryness. The solid residue
was dissolved in a mixture of water (250 mL), ethyl acetate
2 3
(NO ); H NMR (CDCl ) δ 8.28 (1H, dd, J ) 8.0 Hz, J )
1.8 Hz); 8.14 (1H, dd, J ) 8.0 Hz, J ) 1.8 Hz); 7.78-7.59
(3H, m); 7.50-7.39 (4H, m); 7.29-7.22 (2H, m); 5.34 (1H,
d, J ) 13.9 Hz); 5.21 (1H, d, J ) 13.9 Hz); 3.84 (3H, s).
Methyl 3-Amino-N-[(2′-cyanobiphenyl-4-yl)methyl]an-
thranilate Hydrochloride (2‚HCl). A solution of methyl
N-[(2′-cyanobiphenyl-4-yl)methyl]-N,3-dinitroanthranilate (16,
4.3 g; 10 mmol) in THF (60 mL) was hydrogenated at 50
°C, under 10 bar of hydrogen in the presence of Raney nickel
(∼4.5 g). The reaction mixture was filtered and evaporated.
The red oily residue was dissolved in ethyl acetate (5 mL),
and concd aqueous hydrochloric acid solution (0.8 mL; 10
mmol) was added at 0 °C under vigorous stirring. It was
stirred for an additional 3 h at this temperature and filtered
to give the hydrochloric salt of 2 (3.2 g, 81%) as colorless
crystals, mp 172-173 °C (acetonitrile). Anal. Calcd for
(
2
(
250 mL), and aqueous ammonium hydroxide solution (25%,
5 mL). The organic layer was separated, washed with water
50 mL), dried, and evaporated. The dark solid residue was
recrystallized from isopropyl ether (800 mL) to give 2 (8.4
3
g, 26.1%) as yellow crystals, mp 106-110 °C [lit 110-
19 3 2
111 °C]. Anal. Calcd for C22H N O (357.42): C, 73.93;
H, 5.36; N, 11.76%. Found: C, 73.77; H, 5.40; N, 11.83%.
-
1
IR (KBr, cm ) 3396, 3331 (NH
2
), 2221 (CN), 1692 (CdO);
1
NMR (DMSO-d
6
) δ 7.76 (1H, dd, J ) 7.7 Hz, J ) 1.4
Hz); 7.64 (1H, td, J ) 7.7 Hz, J ) 1.4 Hz); 7.56-7.42 (6H,
m); 7.40-7.33 (1H, m), 6.94-6.87 (2H, m); 6.40 (1H, bs);
4.23 (2H, s); 3.97 (2H, bs); 3.81 (3H, s).
Methyl N,3-Dinitroanthranilate (15). This compound
was prepared analogously to 9, starting from 10 (11.8 g; 0.06
mol). The resulting light gray crystalline product (15, 9.3 g;
C
22
H
20ClN
O
3 2
(393.88): C, 67.09; H, 5.12; Cl, 9.00; N,
6
4.5%), can be used in the next reaction step without further
10.67%. Found: C, 66.81; H, 5.20; Cl, 9.10; N, 10.67%. IR
-
1
purification. A small sample was recrystallized from a
mixture of ethyl acetate/methanol to give yellow crystals,
(KBr, cm ) 3292, 3181 (NH
2
), 2218 (CN), 1682 (CdO);
1
H NMR (DMSO-d
6
) δ 7.96 (1H, d, J ) 7.7 Hz); 7.81 (1H,
mp 64-66 °C. Anal. Calcd for C
8
H
7
N
3
O
6
(241.16): C,
9.84; H, 2.93; N, 17.42%. Found: C, 39.60; H, 2.95; N,
7.19%. IR (KBr): 3200 (NH), 1699 (CdO), 1602, 1538,
td, J ) 7.7 Hz; J ) 1.4 Hz); 7.62 (2H, d, J ) 7.7 Hz), 7.57
(4H, d, J ) 1.8 Hz); 7.48 (2H, t, J ) 8.2 Hz); 7.15 (1H, t,
J ) 7.7 Hz); 4.46 (2H, s); 3.77 (3H, s).
3
1
1
-
1
1
2 3
359, 1318 (NO ) cm ; H NMR (CDCl ) δ 12.60 (1H,
Note Added after ASAP Publication: In the version
published on the Internet April 25, 2007, the file for the
Supporting Information was missing from the Internet. The
file is present for the version published April 27, 2007.
bs); 8.36 (1H, dd, J ) 7.9 Hz, J ) 1.5 Hz); 8.26 (1H, dd, J
)
8.2 Hz, J ) 1.5 Hz); 7.61 (1H, t, J ) 8.2 Hz; J ) 7.9
Hz); 4.03 (3H, s).
Methyl N-[(2′-Cyanobiphenyl-4-yl)methyl]-N,3-dinitro-
anthranilate (16). To a suspension of methyl N,3-dinitro-
anthranilate (15, 20.3 g; 84 mmol) and 4′-bromomethyl-
biphenyl-2-nitrile (22.9 g; 84 mmol) in THF (60 mL) was
added triethylamine (9.4 g; 12.8 mL; 92.4 mmol). The
reaction mixture was refluxed for 6 h, diluted with water
Supporting Information Available
1
DSC results for compounds 15 and 16; H NMR and IR
spectra for compounds 9, 10, 12, 14‚HCl, 2, 15, 16, and 2‚
1
HCl; and H NMR spectra for the mixtures 10/11, 7:13, and
(
120 mL), and stirred at 0-5 °C for 1 h. The crystalline
2‚HCl/14‚HCl, respectively. This information is available
free of charge via the Internet at http://pubs.acs.org.
product was filtered and recrystallized from ethanol (95%)
to give 16 (23.0 g; 63.5%) as yellow crystals, mp 150-151
°
C. Anal. Calcd for C22
16 4 6
H N O (432.40): C, 61.11; H, 3.73;
Received for review February 16, 2007.
OP700041Z
N, 12.96%. Found: C, 60.92; H, 3.75; N, 12.84%. IR (KBr,
cm ) 2220 (CN), 1731 (CdO), 1600, 1531, 1358, 1293
-
1
Vol. 11, No. 3, 2007 / Organic Process Research & Development
•
493