A concise and efficient synthesis of [2-methyl-5-methylsulfonyl-4- (pyrrol-1-yl)benzoyl]guanidinium methanesulfonate (Eniporide)

Article abstract of DOI:10.1002/1099-0690(200006)2000:12<2253::AID-EJOC2253>3.0.CO;2-Q

A new synthesis of the benzoylguanidine-type Na⁺/H⁺ antiporter inhibitor eniporide (7) is described. Starting from 2-bromo-5-fluorotoluene (1), aromatic substituents were introduced by methanesulfonylation, Pd- catalyzed carboxylation with CO, and halogen-pyrrole exchange. Guanidine acylation was performed using Mukaiyama's procedure.

Full text of DOI:10.1002/1099-0690(200006)2000:12<2253::AID-EJOC2253>3.0.CO;2-Q

FULL PAPER
A Concise and Efficient Synthesis of [2-Methyl-5-methylsulfonyl-4-(pyrrol-
1-yl)benzoyl]guanidinium Methanesulfonate (Eniporide)
Manfred Baumgarth[a] and Rolf Gericke*[a]
Keywords: Naϩ/Hϩ Antiporter / Eniporide / Benzoylguanidine / Drug research / Synthetic methods
A new synthesis of the benzoylguanidine-type Na+/H+ anti-
porter inhibitor eniporide (7) is described. Starting from 2-
bromo-5-fluorotoluene (1), aromatic substituents were intro-
duced by methanesulfonylation, Pd-catalyzed carboxylation
with CO, and halogen−pyrrole exchange. Guanidine acyl-
ation was performed using Mukaiyama’s procedure.
Introduction
sulfone had to be simplified. M. Ono et al. have described
a one-step FriedelϪCrafts-type methanesulfonylation of de-
There is convincing evidence that the Naϩ/Hϩ antiporter activated benzenes.[4] In a favored procedure, methanesul-
plays a pivotal role in mediating tissue injury during isch- fonic acid anhydride, prepared in situ from methanesulfonic
emia and reperfusion.[1] Activation of the antiporter results acid and SOCl2, was reacted with aromatic compounds in
in a deleterious Naϩ overload and, due to coupling via the the presence of a catalytic amount of trifluoromethanesul-
Naϩ/Ca2ϩ exchanger, this causes cellular Ca2ϩ overload fonic acid. Though deactivation by halogen and nitro
and serious contractile dysfunction, arrhythmia, and cellu- groups is tolerated, we found 4-chloro-2-methylbenzoic acid
lar death. Blocking the Naϩ/Hϩ exchange is a new strategy to be totally resistant to methanesulfonylation. This led us
in cardioprotection using specific inhibitors with a benzoyl- to alter the previous strategy and to generate the meth-
guanidine structure. Two drugs of this class are under clin- anesulfonyl group before the carboxyl group. Thus, com-
ical investigation: cariporide[2] (Hoechst Marion Roussel, mercially available 2-bromo-5-fluorotoluene (1) could
GUARDIAN trial) and eniporide (7, Merck KGaA, ES- be converted into 1-bromo-4-fluoro-5-methanesulfonyl-2-
CAMI trial). A reduction of morbidity and mortality with methylbenzene (2) in reasonable yield using Ono’s method
patients undergoing coronary artery by-pass graft surgery (Scheme 1).
and myocardial infarction patients are primary objectives
of therapy.
Results and Discussion
The synthesis and structureϪactivity relationship of a
large number of benzoylguanidine-type Naϩ/Hϩ antiporter
inhibitors was described earlier.[3] Compound 7 was pre-
pared starting with 4-chlorobenzoic acid. The 2-methyl
group was introduced into the molecule using the ortho-
metalation technique followed by insertion of the 5-meth-
anesulfonyl group by a sulfochlorination, reduction, and
methylation sequence. The 4-pyrrole group was built up by
nucleophilic halogen displacement with benzylamine, cata-
lytic hydrogenation, and ring formation with 2,5-di-
methoxytetrahydrofuran. The benzoylguanidine side chain
Scheme 1. (a) MeSO3H, SOCl2, CF3SO3H, 125 °C; (b) CO, DMSO,
was prepared by treating the ester with guanidine. The free
base was finally converted into the methanesulfonate salt 7.
The overall yield of the 10-step synthesis amounts approx-
imately to 21%. Due to the high number of stages this
method is not a basis for technical synthesis.
H2O, KOAc, Pd(OAc)2, dppf, 25 atm., 82 °C; (c) pyrrole, NaH,
DMSO; (d) 2-chloro-1-methylpyridinium iodide, NMP, N-Cbz-gu-
anidine, (iPr)2NEt; (e) H2, Pd/C, Me2CO
The conversion of the bromide into a carboxylic acid was
the next step. The plan to do this by halogenϪmetal ex-
change and carbon dioxide trapping of the lithium salt
failed because the primary attack occurred at the meth-
anesulfonyl group. Palladium-catalyzed carboxylation with
carbon monoxide,[5] however, gave 4-fluoro-2-methyl-5-
methanesulfonylbenzoic acid (3)[3] in high yield. The pre-
In a more straightforward conception of the synthesis,
inefficient procedures such as the multistage insertion of the
[a]
Merck KGaA,
64271 Darmstadt, Germany
E-mail: gericke@merck.de
Eur. J. Org. Chem. 2000, 2253Ϫ2255
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1434Ϫ193X/00/0612Ϫ2253 $ 17.50ϩ.50/0
2253

M. Baumgarth, R. Gericke
FULL PAPER
(1; 100 g, 529 mmol) and trifluoromethanesulfonic acid (8.80 mL,
100 mmol). The mixture was heated at 125 °C for 3 h, cooled,
poured into ice water (600 mL), and extracted with EtOAc (2 ϫ
400 mL). The organic phase was washed with 1  NaOH (3 ϫ
300 mL), dried, and evaporated. Recrystallization of the residue
from Et2O gave pure 2 (92.2 g, 65%) as white crystals, m.p.
catalyst chosen was the 1,1Ј-bis(diphenylphosphanyl)-ferro-
cene complex with palladium(II) acetate. The reaction was
performed in a steel vessel and addition of water was neces-
sary to release the acid from the putative intermediate acyl
bromide.
Aromatic halides can be displaced with an alkali metal
salt of pyrrole.[6] With compound 3 the nucleophilic reac-
tion is favored by the two electron-withdrawing groups in
the ortho and para positions, as well as by the choice of the
113Ϫ114 °C. Ϫ IR (KBr): ν˜ ϭ 1313, 1145, 1085, 517, 508 cmϪ1
.
1
Ϫ H NMR: δ ϭ 2.45 (s, 3 H, Me), 3.33 (s, 3 H, SO2Me), 7.62 (d,
J ϭ 10.2 Hz, 1 H, Ar 3-H), 7.92 (d, J ϭ 6.7 Hz, 1 H, Ar 6-H). Ϫ
EI-MS (70 eV): m/z (%) ϭ 266/268 (96/95) [Mϩ], 251/253 (43/45)
leaving group. Actually the FϪpyrrole exchange 3 Ǟ 4 in [Mϩ Ϫ CH3], 203/205 (54/52) [Mϩ Ϫ SOCH3], 187/189 (50/48) [Mϩ
Ϫ SO2CH3], 108 (100) [Mϩ Ϫ SO2CH3 Ϫ Br], 107 (78) [Mϩ
Ϫ
DMSO took place in high yield at room temperature while
the corresponding 4-chloro-2-methyl-5-methanesulfonyl-
benzoic acid required prolonged heating at 65 °C.
SO2CH3 Ϫ HBr]. Ϫ C8H8BrFO2S (267.1): calcd. C 35.97, H 3.02,
Br 29.91, S 12.00; found C 36.00, H 2.90, Br 29.80, S 12.00.
Esters, acid chlorides, and imidazolides were the activ-
ated acid derivatives of choice in the preparation of
4-Fluoro-2-methyl-5-(methylsulfonyl)benzoic Acid (3): A 750-mL
steel autoclave equipped with a magnetic stirrer, Teflon insert, tem-
benzoylguanidines.[3] The yield of the reaction 4 Ǟ 6 was perature sensor, CO inlet, and a manometer was charged with
DMSO (200 mL), H2O (40 mL), KOAc (34.0 g, 346 mmol), 1-
bromo-4-fluoro-5-methanesulfonyl-2-methylbenzene (2, 44.8 g,
168 mmol), Pd(OAc)2 (1.20 g, 5.35 mmol), and dppf (5.60 g,
10.1 mmol). The vessel was closed and CO (25 atm.) was intro-
duced. The stirred mixture was autoclaved at 82 °C for 89 h, while
the pressure rose to 30 atm. during the reaction. With occasional
ice cooling the solution was then mixed with EtOAc (1 L), ex-
tracted with 2  NaOH (2 ϫ 320 mL), and the combined aqueous
phases were acidified with concentrated HCl. The white crystals
separated on cooling were collected, washed with water (200 mL),
not fully satisfactory and was obviously diminished by oxid-
ative and hydrolytic secondary processes. When Mukai-
yama’s procedure[7] with its outstanding mild conditions
was used a partial double acylation of guanidine could not
be prevented. Cbz-protected guanidine,[8] however, gave
pure and stable 5 in high yield. Simple process handling
as well as the development of a continuous flow technique
enabled scale-up.
The Cbz group was split off by catalytic hydrogenation
in acetone. The reaction conditions used prevented any ox- and air-dried to give the title compound 3 (36.0 g, 92%), m.p.
212Ϫ214 °C. The m.p. given in ref.[3] is incorrect.
idative and hydrolytic attacks on the sensitive base 6. After
removal of the catalyst, the methanesulfonate 7 was precip-
itated from the hydrogenation solution without isolating the
Na was prepared by adding NaH (60% in mineral oil, 808 mg,
base. The purity of the material thus produced was Ͼ99.5%.
2-Methyl-5-methylsulfonyl-4-(pyrrol-1-yl)benzoic Acid (4): PyrroleϪ
20.2 mmol) to a solution of pyrrole (1.40 mL, 20.2 mmol) in
The use of protected guanidine increased the number of
DMSO (20 mL). In parallel, the acid 3 (3.60 g, 15.5 mmol) was also
stages by one, but this disadvantage was made up for by a treated with NaH (620 mg, 15.5 mmol) in DMSO (20 mL). After
stirring for 1 h at room temperature, the second mixture was added
dropwise to the first one, and stirring was continued for an addi-
tional 3 h under N2 protection. The solution was poured into ice-
cold diluted HCl (150 mL H2O ϩ 150 mL 1  HCl) and the white
crystals of the title compound which separated were collected and
dried at 50 °C (3.34 g, 77%). An analytical sample was prepared
by recrystallization from PhMe, m.p. 192 °C. Ϫ IR (KBr): ν˜ ϭ
simpler and safer procedure, protection of the base 6, and
last but not least by a higher overall yield for the conversion
of the acid 4 into the benzoylguanidine salt 7.
In summary, this new concise synthesis is feasible for
large-scale preparation of eniporide (7). The number of
stages was reduced from ten to five, while the overall yield
could roughly be doubled. The early methanesulfonylation
in one step as well as the direct halogenϪpyrrole exchange
are of particular importance. In contrast to the old process,
no low-temperature technique was required here.
1
1697 (CO2H), 1304, 1263, 1153, 737 cmϪ1. Ϫ H NMR: δ ϭ 2.65
(s, 3 H), 2.67 (s, 3 H), 6.33 (t, J ϭ 2 Hz, 2 H, pyrrole 3-H), 7.08 (t,
J ϭ 2 Hz, 2 H, pyrrole 2-H), 7.52 (s, 1 H, Ar 3-H), 8.50 (s, 1 H,
Ar 6-H), 13.45 (s br, 1 H, H/D exchangeable). Ϫ EI-MS (70 eV):
m/z (%) ϭ 279 (100) [Mϩ], 262 (7) [Mϩ Ϫ OH], 214 (33) [Mϩ
Ϫ
C4H3N], 154 (14) [Mϩ Ϫ SO2CH3 Ϫ HCO2H]. Ϫ C13H13NO4S
(279.3): calcd. C 55.89, H 4.70, N 5.02, S 11.48; found C 56.01, H
4.84, N 5.00, S 11.51.
Experimental Section
Melting points were determined with a Büchi 535 melting point
apparatus and are uncorrected. Ϫ IR, NMR, and MS spectra are
consistent with the structures cited and were recorded on a Bruker
IFS 48 IR spectrophotometer, a Bruker AM 250 NMR spectro-
meter, and a Vacuum Generators VG 70 E or 70Ϫ250 SE mass
spectrometer, respectively. All NMR spectra were recorded in
[D6]DMSO, and chemical shifts given in parts per million (δ)
downfield from tetramethylsilane. Ϫ Microanalyses were obtained
with an elementar vario EL analyzer.
1-(Benzyloxycarbonyl)-3-[2-methyl-5-methylsulfonyl-4-(pyrrol-1-yl)-
benzoyl]guanidine (5): Compound 4 (2.75 g, 9.85 mmol) was treated
with 2-chloro-1-methylpyridinium iodide (2.81 g, 11.0 mmol) in N-
methyl-2-pyrrolidone (28 mL) for 90 min at room temperature. The
reddish-brown solution was cooled, N-Cbz-guanidine[8] (2.31 g,
12.0 mmol) and (iPr)2NEt (5.00 mL, 29.4 mmol) were consecutively
added, and stirring continued for an additional 2 h at room temp.
The mixture was poured into ice/water (100 mL) and the solid
which separated was recrystallized from iPrOH (75 mL) to give 5
(3.9 g, 87%) as a light beige powder, m.p. 163 °C. Ϫ IR (KBr): ν˜ ϭ
1694 (CϭO), 1268, 1116 cmϪ1. Ϫ 1H NMR: δ ϭ 2.60 (s, 3 H), 2.66
(s, 3 H), 5.22 (s, 2 H, OCH2), 6.30 (t, J ϭ 2 Hz, 2 H, pyrrole 3-H),
7.07 (t, J ϭ 2 Hz, 2 H, pyrrole 2-H), 7.33Ϫ7.45 (m, 5 H, Ar-H),
1-Bromo-4-fluoro-2-methyl-5-(methylsulfonyl)benzene (2): A mix-
ture of methanesulfonic acid (162 mL, 2.50 mol) and SOCl2
(72.6 mL, 1.00 mol) was heated under reflux for 1 h. To the reac-
tion mixture, cooled to 25 °C, were added 2-bromo-5-fluorotoluene
2254
Eur. J. Org. Chem. 2000, 2253Ϫ2255

[2-Methyl-5-methylsulfonyl-4-(pyrrol-1-yl)benzoyl]guanidinium Methanesulfonate (Eniporide)
FULL PAPER
7.43 (s, 1 H, Ar 3-H), 8.47 (s, 1 H, Ar 6-H), 8.81 (s br, 1 H, NH,
[1] [1a]
[1b]
H/D exchangeable), 9.67 (s br, 1 H, NH, H/D exchangeable), 11.33
(s br, 1 H, NH, H/D exchangeable). Ϫ FAB-MS: m/z (%) ϭ 455
(100) [M ϩ H]ϩ, 411 (40) [(M ϩ H)ϩ Ϫ CO2], 262 (36) [(M ϩ H)ϩ
Ϫ CbzϪCH4N3]. Ϫ C22H22N4O5S (454.5): calcd. C 58.14, H 4.88,
N 12.33, S 7.05; found C 58.11, H 4.99, N 12.33, S 7.10.
´
P. Theroux, Am. J. Cardiol. 1999, 83, 1GϪ9G. Ϫ
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[1d]
1999, 83, 19GϪ22G. Ϫ
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Sci. 1999, 874, 326Ϫ334. Ϫ [1e] M. Avkiran, Eur. Heart J. 1999,
[1f]
20, 995Ϫ996. Ϫ
H. W. Kleemann, A. G. Weichert,
[2-Methyl-5-methylsulfonyl-4-(pyrrol-1-yl)benzoyl]guanidinium
Methanesulfonate (7, Eniporide): The foregoing Cbz-protected com-
pound 5 (16.5 g, 36.3 mmol) was hydrogenated with a Pd/C catalyst
(5%, 4 g) in Me2CO (400 mL) at atmospheric pressure for 9.5 h at
room temperature. The catalyst was removed over a suitable fine
filter. MeSO3H (4.00 mL, 61.6 mmol) was added to the resulting
clear solution of the base 6 and white crystals of the methanesul-
fonate 7 (14.8 g, 95%) were allowed to separate with stirring in an
ice bath for 1 h. They were then vacuum-dried at room temper-
ature, m.p. 273 °C. Ϫ IR (KBr): ν˜ ϭ 3399 (NH), 1719 (CϭO), 1695
IDrugs 1999, 2, 1009Ϫ1025.
[2] [2a]
L. R. W. Erhardt, Am. J. Cardiol. 1999, 83, 23GϪ25G. Ϫ
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1
(CϭO), 1293, 1182 cmϪ1. Ϫ H NMR: δ ϭ 2.09 (s, Me2CO), 2.39
Bondinell, K. F. Erhard, W. F. Huffman, J. W. Venlavsky, C.
[5c]
(s, 3 H, MeSO3H), 2.55 (s, 3 H, Me), 2.71 (s, 3 H, SO2Me), 6.34
(t, J ϭ 2 Hz, 2 H, pyrrole 3-H), 7.11 (t, J ϭ 2 Hz, 2 H, pyrrole 2-
H), 7.60 (s, 1 H, Ar 3-H), 8.30 (s, 1 H, Ar 6-H), 8.43 (s br, 4 H,
NH2, H/D exchangeable), 11.73 (s, 1 H, MeSO3H, H/D exchange-
able). Ϫ EI-MS (70 eV): m/z (%) ϭ 320 (100) [Mϩ], 303 (26) [Mϩ
Ϫ NH3], 278 (30) [Mϩ Ϫ NH2CN], 262 (40) [Mϩ Ϫ NϭC(NH2)2],
261 (60) [Mϩ Ϫ HNϭC(NH2)2], 154 (37) [Mϩ Ϫ MeSO2 Ϫ HNϭ
C(NH2)2 Ϫ CO], 96 (11) [MeSO3Hϩ], 86 (40) [(NH2)2CϭNCOϩ].
Ϫ C14H16N4O3S CH4O3S 0.25C3H6O (431.00): calcd. C 43.89, H
5.03, N 13.00, S 14.88; found C 43.98, H 4.99, N 12.78, S 15.16.
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Received January 7, 2000
[O00006]
Acknowledgments
We wish to thank Sylvia Heiß, Günther Kritzinger, and Horst
Schiefer for their skillful experimental work.
Eur. J. Org. Chem. 2000, 2253Ϫ2255
2255