14C-labeled and large-scale synthesis of the angiotensin-(1-7)-receptor agonist AVE 0991 by cross-coupling reactions.

Article abstract of DOI:10.1021/jo034372c

The synthesis of (14)C-labeled AVE 0991 ((14)()C-1a) and large-scale synthesis of AVE 0991 (1a) are described. In the key step of the synthesis, the C-C coupling reaction of the imidazole (2) and thiophene (3) building blocks was studied under Suzuki and Stille reaction conditions, respectively. Suzuki reaction gave only moderate yields, whereas the best results were obtained under Stille reaction conditions with up to 64% yield.

Full text of DOI:10.1021/jo034372c

14C-La beled a n d La r ge-Sca le Syn th esis of th e
An gioten sin -(1-7)-r ecep tor Agon ist AVE 0991 by Cr oss-Cou p lin g
Rea ction s†
Volker Derdau,* Raymond Oekonomopulos, and Gerrit Schubert
Chemical Development, Aventis Pharma Deutschland GmbH, 65926 Frankfurt am Main, Germany
volker.derdau@aventis.com
Received March 21, 2003
The synthesis of 14C-labeled AVE 0991 (14C-1a ) and large-scale synthesis of AVE 0991 (1a ) are
described. In the key step of the synthesis, the C-C coupling reaction of the imidazole (2) and
thiophene (3) building blocks was studied under Suzuki and Stille reaction conditions, respectively.
Suzuki reaction gave only moderate yields, whereas the best results were obtained under Stille
reaction conditions with up to 64% yield.
SCHEME 1
In tr od u ction
Substituted imidazole derivatives have proven to be
potent ligands for angiotensin receptors and a number
of them are used as valuable cardiovascular drugs.1
Recently, compounds of this class were found to be potent
agonists of the angiotensin-(1-7)-receptor.2 The stimula-
tion of the endothelial cell connected angiotensin-(1-7)-
receptor initiates the release of vasodilating and cardio-
protective messengers such as cyclic 3′,5′-guanosine
monophosphate (cGMP) and nitrogen monoxide (NO). As
a result, imidazole-derived angiotensin-(1-7)-agonists
may serve as valuable agents in the treatment or
prophylaxis of hypertension, heart hypertrophy, heart
failure, and coronary heart diseases such as angina
pectoris, myocardial infarct, and endothelial dysfunction,
(e.g. as a result of diabetes mellitus and arterial or venous
thrombosis). In conjunction with pharmacokinetic and
metabolism studies, the synthesis of 14C-labeled AVE
0991 (14C-1a ) became necessary. We report the elabora-
tion of suitable conditions for the radiosynthesis of 1a
with unlabeled material to gain sufficient information for
the synthesis of corresponding 14C-labeled AVE 0991.
Furthermore, we describe the synthesis of AVE 0991 in
kilogram scale. The retrosynthetic analysis (Scheme 1)
pointed to the cross-coupling of imidazole 2 and thiophene
3 as a crucial step for the synthesis of 1a . In the
consideration of possible cross-coupling conditions the
Suzuki reaction was favored initially due to the selectiv-
ity of the reaction.3
Resu lts a n d Discu ssion
Starting from 4-bromotoluene (4), a halogen-metal
exchange was performed with n-BuLi at -78 °C, followed
by quenching with isopropyl borate (Scheme 2). After
treatment with diol 5 the cyclic boronic ester 6 was
obtained in 50% yield. Without further purification,
compound 6 was brominated under radical conditions
with 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione to
yield benzylic bromide 74 in 60% yield. Alternatively, 6
could be prepared from p-tolylboroxine in one step.
Imidazole 8 was synthesized according to Matsumura et
al.5 and alkylated6 with benzyl bromide 7 in DME to give
55% of the boronic ester coupling partner 2a . Under these
† Dedicated to Dr. Gerhard Beck on the occasion of his 60th birthday.
(1) (a) Duncia, J . V.; Carini, D. J .; Chiu, A. T.; J ohnson, A. L.; Price,
W. A.; Wong, P. C.; Wexler, R. R.; Timmermans, P. B. Med. Res. Rev.
1992, 12, 149. (b) Ashton, W. T. Exp. Opin. Invest. Drugs 1994, 3, 1105.
(c) Yanagisawa, H.; Amemiya, Y.; Kanazaki, T.; Shimoji, Y.; Fujimoto,
K.; Kitahara, Y.; Sada, T.; Mizuno, M.; Ikeda, M.; Miyamoto, S.;
Furukawa, Y.; Koike, H. J . Med. Chem. 1996, 39, 323 and references
therein. (d) EP 512675A, 1992 (Merck), WO 9427597, 1994 (Smithkline
Beecham). For a review of sartans, see: (e) Birkenhager, W. H.; de
Leeuw, P. W. J . Hypertens. 1999, 17, 873. (f) Goa, K. L.; Wagstaff, A.
J . Drugs 1996, 51, 820.
(3) The Suzuki reaction has been successfully used as the key step
in the synthesis of Losartan: Smith, G. B.; Dezeny, G. C.; Hughes, D.
L.; King, A. O.; Verhoeven, T. R. J . Org. Chem. 1994, 59, 8151.
(4) Di Cesare, N.; Lakowicz, J . R. J . Photochem. Photobiol. A:
Chemistry 2001, 143, 39.
(2) (a) Heitsch, H.; Wiemer, G. Ger. Pat. Appl. DE 19920815A1 or
Eur. Pat. Appl. EP 1185527 A, 1999 (Aventis). (b) Wiemer, G.;
Dobrucki, L. W.; Louka, F. R.; Malinski, T.; Heitsch, H. Hypertension
2002, 40, 847.
10.1021/jo034372c CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/22/2003
5168
J . Org. Chem. 2003, 68, 5168-5173

The Angiotensin-(1-7)-receptor Agonist AVE0991
SCHEME 2
SCHEME 4
aqueous ammonia in THF to give the sulfonamide 12
(87% yield). In the last step the sulfonylurea 3a was
formed in 91% yield by refluxing with ethyl isocyanate
in acetone.10
The Suzuki coupling of 2a and 3a proved to be the
critical step in the synthesis of AVE 0991 1a (Scheme
4). As shown in Table 1, numerous optimization experi-
ments to couple imidazole boronic ester 2a and 2-bro-
mothiophene 3a under Suzuki reaction conditions11,12
were performed. Under standard conditions (entry 1-4)
with triphenylphosphine containing Pd catalysts, no or
only very small amounts of the desired coupling product
1b were found in different solvents and by using different
bases. A major improvement of the yield was observed
when the reaction was run under triphenylphosphine free
conditions by using Pd(OAc)2 as catalyst. The best results
on small scale were achieved in a mixture of DME/
ethanol (2:1) as solvent (entries 5 and 6). We identified
the deboronated imidazole 13 and the dimerization
product 14 as the main side products (Scheme 5). Under
this condition, the reaction could be successfully upscaled
to several hundred grams with acceptable yield (26%).
Variation of the organic solvent systems resulted in
neither significant improvements in yield nor avoidance
of side product formation. To suppress the formation of
the byproducts, the effect of additives was tested.
With oxidizing additives such as copper(I) chloride
(Table 1, entry 7), reducing additives such as phosphines
(entry 11), or silver oxide (entry 8), we were able to reduce
the formation of side product 13 or 14, mostly with no
effect on the isolated yield of the desired product 1b.
Finally, during the upscaling process a combination of
PdCl2(dppf) × CH2Cl2 as catalyst in 2-propanol/DME and
KOH as base gave a further improvement. This condi-
tions could be transferred to large scale successfully. By
using this method, several kilograms of 1b could be
produced in 32% isolated yield in the pilot plant (for
details see the Experimental Section). The structural
correctness of the product was confirmed by X-ray-
SCHEME 3
reaction conditions, 27% of the undesired N-substituted
regioisomer was formed but could be removed by chro-
matography. The structures of the regioisomers were
assigned on the basis of NMR measurements which
showed a NOE effect between the aldehyde proton and
the ortho protons of the phenylene ring only in the case
of 2a .
The synthesis of bromothiophene 3a started with
thiophene (9), which was acylated with isobutyryl chlo-
ride-AlCl3 (Scheme 3). Subsequent bromination was
performed without hydrolysis of the ketone-AlCl3 com-
plex to yield the bromoketone 107 in 67% yield. Wolff-
Kishner reduction8 (65% yield) followed by chlorosulfona-
tion9 produced the sulfochloride, which was treated with
(5) Matsumura, K.; Kuritani, M.; Shimadzu, H.; Hashimoto, N.
Chem. Pharm. Bull. 1976, 24, 960.
(10) Deprez, P.; Guillaume, J .; Becker, R.; Corbier, A.; Didierlaurent,
S.; Fortin, M.; Frechet, D.; Hamon, G.; Heckmann, B.; Heitsch, H.;
Kleemann, H.-W.; Vevert, J .-P.; Vincent, J .-C.; Wagner, A.; Zhang, J .
J . Med. Chem. 1995, 38, 2357.
(11) For reviews, see: (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995,
95, 2457. (b) Suzuki, A. In Metal Catalysed Cross-Coupling Reactions;
Diederich, F., Stang, O. J ., Eds.; Wiley-VCH: Weinheim, Germany,
1998; Chapter 2. (c) Stanforth, S. P. Tetrahedron 1998, 54, 263. (d)
Suzuki, A. J . Organomet. Chem. 1999, 576, 147. (e) J ack, J .; Gribble,
G. In Palladium in Heterocyclic Chemistry;, Pergamon: Oxford, UK,
2000.
(12) (a) Wolfe, J . P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J .
Am. Chem. Soc. 1999, 121, 9550. (b) Zim, D.; Monteiro, A. L.; Dupont,
J . Tetrahedron Lett. 2000, 41, 8199. (c) Kirchhoff, J . H.; Dai, C.; Fu,
G. C. Angew. Chem., Int. Ed. 2002, 41, 1945. (d) MacNeil, S.; Familoni,
O. B.; Snieckus, V. J . Org. Chem. 2001, 66, 3662.
(6) For a review on alkylation of imidazoles, see: (a) Grimmett, M.
R. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees,
C. W., Eds.; Pergamon: Oxford, UK, 1984; Vol. 5, pp 387-390. (b)
Grimmett, M. R. In Comprehensive Heterocyclic Chemistry II; Katritz-
ky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, UK,
1996; Vol. 3, pp 108-116.
(7) Wolkenschtein, Y. B.; Goldfarb, Y. L. Dokl. Akad. Nauk S.S.S.R.
1961, 138, 115.
(8) (a) Alvarez-Insua, A. S.; Conde, S.; Corral, C. J . Heterocycl. Chem.
1982, 19, 713. (b) Rao, S.; Bhalerao, U. T.; Tilak, B. D. Indian J . Chem
1985, 24B, 1275. (c) Span. Pat. Appl. ES 1980-487841, 1980 (Madaus
Cerafarm S.A).
(9) Mohamadi, F.; Spees, M. M.; Grindey, G. B. J . Med. Chem. 1992,
35, 3012.
J . Org. Chem, Vol. 68, No. 13, 2003 5169

Derdau et al.
TABLE 1. Su zu k i Rea ction s of Bor on ic Ester 2a a n d Th iop h en e 3a u n d er Differ en t Rea ction Con d ition sa
entry
catalyst
equiv of 2a
base
solvent
additive
t [h]
1b [%]b
13 [%]c
14 [%]c
d
d
d
1
2
3
4
5
6
7
8
9
10
11
12
13
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)2Br2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(dba)2
1.5
1.2
1.5
1.5
1.3
1.3
1.3
1.3
1.3
1.3
1.5
1.3
1.0
Cs2CO3
Na2CO3
K2CO3
Cs2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
K3PO4
toluene
72
44
96
72
96
96
96
96
72
72
96
96
2
-
<5
-
-
-
-
d
toluene/EtOH/H2O
DME/EtOH 2:1
toluene/EtOH/H2O
DME/EtOH 2:1
DME/EtOH 2:1
DME/EtOH 2:1
DME/EtOH 2:1
EtOH/H2O 2:1
DMF
N(n-Bu)4Br
-
22
-
42
-
d
d
9
27
26
25
22
7
5
-
11
32
15
12
46
5
38
36
17
45
50
53
NaBr
CuCl
Ag2O
9
K3PO4
N(n-Bu)4Cl
P(t-Bu)3
TSPP
22
-
-
-
d
d
d
d
Cs2CO3
Na2CO3
KOH
DME/EtOH 2:1
xylene/(CH2OH)2/H2O
DME/i-PrOH
-
d
Pd(OAc)2
PdCl2(dppf)
-
d
-
a
b
Reactions were carried out with 0.5 mmol of 3a at 80-90 °C. Isolated yield/value based on boronic ester 2a . c Determined by HPLC
d
(ν ) 290 nm) after filtration of the reaction solution. Not determined; TSPP ) tris(3-sulfonatophenyl) phosphine.
SCHEME 5
SCHEME 6
crystallography. In the last step, the coupled product 1b
was methoxylated by reaction with NaOH in methanol
to give the final product 1a in 65% yield. In the large
scale, the yield could be optimized to 96% by careful
control of the reaction time. Impurities of 1b had a
dramatic effect on the yield of the final product 1a . In
total, 1a (small scale) was prepared in five reaction steps
(Schemes 2 and 4) with only 3% overall yield based on
4-bromotoluene.
SCHEME 7
As an alternative for the synthesis of 14C-AVE 0991
(1a ) we evaluated the cross-coupling reaction under Stille
conditions.13 Imidazole derivative 2b was prepared in two
steps and 50% overall yield by bromination of 4-bromo-
toluene 4, followed by alkylation of imidazole 8. The
tributyltin compound 3b was synthesized in 62% yield
by metalation of the 3-bromo-thiophene derivative 3a
with 5 equiv of n-BuLi and quenching with tributyl-
tinchloride (Scheme 6).
The Stille reaction was performed with bromide 2b
and 2 equiv of stannane 3b in the presence of 10
mol % of Pd(PPh3)4 as catalyst in THF. The reaction
mixture turned Pd(0) black after 3 days under reflux with
90-95% consumption of bromide 2b. Incomplete con-
sumption of bromide 2b was observed in reactions with
<2 equiv of stannane 3b. After fast separation of Pd and
Sn material by fractional filtration, the coupling products
1b and the primary sulfonamide 16 were isolated as a
mixture in a ratio of 1:1.6 (Scheme 7).14,15 Compound 16
was then converted into the urea derivative 1b, in an
overall yield of 62-65%, by reaction with ethyl isocyan-
ate. The methoxylation of 1b was performed as de-
scribed above to give 1a in about 65% yield (Scheme 2).
The convergent reaction sequence yielded AVE 0991 (1a )
in six reaction steps with an overall yield of 14%
(Schemes 6 and 7).
(13) For reviews, see: (a) Mitchell, T. N. In Metal Catalysed Cross-
Coupling Reactions; Diederich, F., Stang, O. J ., Eds.; Wiley-VCH:
Weinheim, Germany, 1998; Chapter 4. (b) Farina, V. Pure Appl. Chem.
1996, 68, 73. (c) Farina, V.; Krishnamurthy, V.; Scott, W. The Stille
Reaction; Wiley-Interscience: New York, 1998.
(14) Ratios were determined by HPLC of the crude reaction mixture
(see Experimental Section for further details).
(15) The primary sulfonamide 16 was formed by basic cleavage of
1b. The ratio of the products 1b and 16 differs slightly depending on
the mol % of catalyst and the amount of solvent (solubility of the base).
5170 J . Org. Chem., Vol. 68, No. 13, 2003

The Angiotensin-(1-7)-receptor Agonist AVE0991
Finally, we carried out the 14C-labeled synthesis of
14C-1a according to the Stille variant (Schemes 6 and 7)16
in four radioactive reaction steps with 21% overall yield
starting from 4-bromo-14C-benzyl bromide (purchased
from Amersham Pharmacia Biotech). The final product
14C-1a was purified by HPLC to give >98% UV and
radiochemical purity.
were concentrated in vacuo in a separate vessel, and the
residue was transferred to a rotary evaporator and evaporated
to dryness in vacuo to yield 7 (14.7 kg, purity 79% by NMR,
76%) as a colorless powder, contaminated with 6 (14%) and
the dibromomethyl compound (7%). 1H NMR (250 MHz, CDCl3)
δ 7.75 (d, J ) 7 Hz, 2H), 7.35 (d, J ) 7 Hz, 2H), 6.5 (s,
impurity: methine proton of dibromomethyl derivative), 4.5
(s, 2H), 3.75 (s, 4H), 2.35 (s, impurity: phenyl-CH3 of 6), 1.0
(s, 6H) ppm.
5-Ch lor o-3-[4-(5,5-d im eth yl-[1,3,2]d ioxa bor in a n -2-yl)-
ben zyl]-2-p h en yl-3H-im id a zole-4-ca r ba ld eh yd e (2a ). A
suspension of 7 (10.5 g, purity 98% according to HPLC, 50
mmol) and 8 (17.7 g, purity 80% by HPLC, 50 mmol) in DME
(85 mL) was stirred at 40 °C until a clear solution resulted.
Powdered anhyd K2CO3 (6.9 g, 50 mmol) was added in one
portion and the mixture was refluxed for 6 h. After being cooled
to room temperature, the mixture was diluted with toluene
(100 mL), filtered, and evaporated to dryness. The residual
brown viscous residue (24.7 g) was purified by chromatography
on silica gel (0.06-0.2 mm, 250 g of SiO2, toluene/ethyl acetate
6:1, 2% acetic acid). The early fractions afforded, after con-
centration in vacuo, a viscous oil that was crystallized from
heptane/ethyl acetate 95:5 to give 2a (12.4 g, 55%) as a pale
yellow powder. The late fractions were also evaporated in
vacuo and the residual viscous oil was crystallized from CCl4
to give the regioisomer of 2a (5.5 g, 27%) as a pale yellow
powder. 2a : mp 130-132 °C; 1H NMR (400 MHz, CDCl3) δ
9.85 (s, 1H), 7.55 (m, 2H), 7.5 (m, 1H), 7.45 (m, 4H), 7.0 (d,
J ) 9 Hz, 2H), 5.65 (s, 2H), 3.75 (s, 4H), 1.0 (s, 6H) ppm. Anal.
Calcd for C22H22BClN2O3: C, 64.66; H, 5.43; N, 6.85. Found:
C, 64.42; H, 5.34; N, 6.84. Regioisomer of 2a : 1H NMR (250
MHz, CDCl3) δ 9.9 (s, 1H), 7.7 (d, J ) 8 Hz, 2H), 7.25-7.45
(m, 5H), 6.9 (d, J ) 8 Hz, 2H), 5.2 (s, 2H), 3.7 (s, 4H), 0.95 (s,
6H) ppm. Anal. Calcd for C22H22BClN2O3: C, 64.66; H, 5.43;
N, 6.85. Found: C, 64.68; H, 5.48; N, 6.78.
4-Br om o-2-(2-m eth ylp r op a n -1-on e)th iop h en e (10). An-
hydrous AlCl3 (25 kg, 187.5 mol) was placed in a reaction
vessel, the vessel was flushed with nitrogen, and CH2Cl2 (60
L) was added with stirring at 20-25 °C. After the solution
was cooled to 5 °C, isobutyryl chloride (16.8 kg, 157.7 mol) was
added slowly, maintaining the temperature below 23 °C. After
the reaction mixture was stirred overnight at 20-25 °C, the
temperature was reduced to 5 °C and thiophene 9 (12.6 kg,
149.8 mol) was added over 1 h at 18-23 °C. After the reaction
was stirred overnight at 20-25 °C, the temperature was
reduced to 3 °C and bromine (25.2 kg, 157.7 mol) was added
at 3-8 °C over 1 h by using a dosing pump. The temperature
was gradually raised to 20 °C within 2 h and the reaction
mixture was stirred at 20-25 °C overnight. Ice (130 kg) and
water (30 L) were placed in a second vessel and the reaction
mixture was pumped into it during 1 h during stirring. The
Con clu sion
We described a new pathway for the large-scale
synthesis of thiophene 3a . Furthermore, we discussed
different synthetic approaches for the synthesis of AVE
0991 (1a ) using several cross-coupling reaction protocols.
While Suzuki conditions proved to be the best choice in
the large-scale synthesis with respect to safety issues,
avoidance of chromatography, costs, and environmental
risks, the Stille coupling was more convenient in the
14C-labeled synthesis. This synthesis serves as a useful
example for potential total synthesis endeavors under
different perspectives and needs.
Exp er im en ta l Section
5,5-Dim et h yl-2-p -t olyl-[1,3,2]d ioxa b or in a n e
(6).17
n-BuLi (0.60 mL, 1.60 mmol, 2.7 M in heptane) was added
dropwise via syringe to a solution of 4-bromotoluene (171 mg,
1.00 mmol) in dry THF (5 mL) at -78 °C under argon. After
45 min, isopropyl borate (301 mg, 1.60 mmol) in THF (5 mL)
was added via syringe over 5 min. The reaction mixture was
allowed to warm to -10 °C (2 h) and 2,2-dimethylpropane-
1,3-diol (5, 167 mg, 1.60 mmol) was added in one portion
followed by dropwise addition of acetic acid (1.80 mmol). The
reaction mixture was allowed to warm to room temperature
and was stirred for a further 2 h. The solvent was evaporated
in vacuo and the residue was dissolved in a 1:1 water/ethyl
acetate mixture (10 mL). The aqueous phase was extracted
three times with ethyl acetate (20 mL), and the combined
organic layers were dried over Na2SO4 and concentrated in
vacuo. The crude product was purified by crystallization from
heptane/ethyl acetate 10:1 to give 102 mg (0.50 mmol, 50%)
1
of 6 as a colorless solid. H NMR (250 MHz, CDCl3) δ 7.70 (d,
J ) 7 Hz, 2H), 7.15 (d, J ) 7 Hz, 2H), 3.75 (s, 4H), 2.35 (s,
3H), 1.00 (s, 6H) ppm.
2-(4-Br om om et h yl-p h en yl)-5,5-d im et h yl-[1,3,2]d iox-
a bor in a n e (7).18 Borinane 6 (10.96 kg, 53.7 mol) and 1,3-
dibromo-5,5-dimethyl-imidazolidine-2,4-dione (3.0 kg, 10.49
mol) were added to a nitrogen-flushed vessel. A suspension of
AIBN (20 g) in cyclohexane (70 L) was added, and the mixture
was heated to gentle reflux (79 °C). After 30 min, the con-
densate turned brown, indicating the onset of the reaction.
After refluxing for another 30 min, the condensate was color-
less again, indicating the end of the reaction. Refluxing was
continued for 10 min then the reaction mixture was cooled to
60 °C and more 1,3-dibromo-5,5-dimethyl-imidazolidine-2,4-
dione (3.0 kg, 10.49 mol) was added, followed by a suspension
of AIBN (20 g) in cyclohexane. The mixture was heated as
described above. After complete reaction as indicated by color,
a third portion of 1,3-dibromo-5,5-dimethyl-imidazolidine-2,4-
dione (2.39 kg, 8.36 mol) and AIBN (20 g) was added and
reacted as above. The mixture was cooled to 20 °C and the
insoluble hydantoine was separated by pressure filtration.
After being washed with cyclohexane (3 × 10 L), the filtrates
reaction vessel was rinsed with CH
2Cl2 (20 L) and the organic
phases were separated and stirred vigorously with water (120
L) overnight to destroy the remaining Al complexes. After
phase separation and reextraction of the aqueous phase with
CH2Cl2 (10 L), the organic extract was stirred with Na2S2O3
solution (37.5%, 25 L), separated, and concentrated in vacuo.
Heptane (58 L) was added and, after being inoculated with
some crystals of the product, the mixture was cooled to 0 °C
and stirred overnight. The resulting solid was pressure filtered
to yield 10 (24.2 kg, purity 88.7% by GC, 61%) as a gray
crystalline powder: mp 48-50 °C; 1H NMR (300 MHz, CDCl3)
δ 7.6 (s, 1H), 7.55 (s, 1H), 3.35 (septet, J ) 7.5 Hz, 1H), 1.25
(d, J ) 7.5 Hz, 6H) ppm. Anal. Calcd for C8H9BrOS: C, 41.22;
H, 3.89; S, 13.75. Found: C, 41.13; H, 3.72; S, 13.60.
4-Br om o-2-isobu tyl-th iop h en e (11). In a nitrogen-flushed
glass vessel, KOH (8 kg, purity 85-100%, 140 mol) was
dissolved in triethyleneglycol (22 L) and the temperature was
allowed to rise to approximately 95 °C. A solution of 10 (8.3
kg (27.5 mol); purity 77.2% by GC) in triethyleneglycol (20 L)
was prepared and added to the KOH solution in one portion,
followed by an aqueous solution of hydrazine hydrate (80%,
(16) The yields of the 14C synthesis are listed in parentheses in
schemes 4, 6, and 7.
(17) Di Cesare, N.; Lakowicz, J . J . Photochem. Photobiol. A: Chem.
2001, 143, 39.
(18) Martin, B.; Posseme, F.; Le Barbier, C.; Carreaux, F.; Carboni,
B.; Seiler, N.; Moulinoux, J .-P.; Delcros, J .-G. J . Med Chem. 2001, 44,
3653.
J . Org. Chem, Vol. 68, No. 13, 2003 5171

Derdau et al.
3.5 L) diluted with water (5 L). The mixture was heated to
120-122 °C for 1.5 h, after which time the temperature was
raised to 160 °C and the product was co-distilled with water
for 4-5 h. The crude yellow oily product was separated,
washed subsequently with 0.2 M HCl (2.5 L) and water
(2.5 L), and filtered through Na2SO4 (1 kg) to give 11 as a clear
yellow oil (3.4 kg, purity 81.8% by GC, 46% yield). The
Na2SO4 layer was washed with CH2Cl2 and the washings were
concentrated to give another 0.38 kg (purity 83.5% by GC, 5%
ppm. Anal. Calcd for C11H17BrN2O3S2: C, 35.78; H, 4.64; N,
7.59. Found: C, 35.40; H, 4.51; N, 7.55.
Su zu k i Rea ction Con d ition s: 3-[4-(4-Ch lor o-5-for m yl-
2-p h e n y l-i m i d a z o l-1-y lm e t h y l)p h e n y l]-5-i s o b u t y l-
th iop h en e-2-(3-eth yl) Su lfon ylu r ea (1b). Large-scale con-
ditions with Pd(OAc)2 as catalyst: A nitrogen-flushed 50-L
glass vessel was filled with 3a (560 g, 1.52 mol), Pd(OAc)2
(25 g, 0.11 mol), Na2CO3 (400 g), and NaBr (200 g) and flushed
again with nitrogen. Dry dimethoxyethane (8 L) and ethanol
(3 L) were added and the mixture was stirred and heated to
slight reflux. A solution of 2a (800 g, 1.96 mol) in 4 L of dry
dimethoxyethane and 3 L of ethanol was added slowly (0.25
L/h) and the mixture was refluxed for about 4 days. The
mixture was cooled to 20 °C and 12 L of ice water was added
in one portion with stirring followed by 0.9 L of concentrated
aqueous HCl, which was added dropwise until pH 1-2. Ethyl
acetate (9 L) was added and the mixture was filtered through
a Bu¨chner funnel charged with 500 g of Celite. The residue
was washed with 2 L of ethyl acetate, the aqueous layer of
the combined filtrates containing the product was separated
and extracted with 6 L of ethyl acetate, and the combined
organic layers were concentrated in vacuo. The residue was
dried by repeated mixing with toluene and evaporation. The
crude product was purified by medium-pressure chromatog-
raphy (30 kg SiO2, 35-70 µm, toluene/ethyl acetate, 1% acetic
1
yield) of 11. H NMR (400 MHz, CDCl3) δ 7.0 (s, 1H), 6.7 (s,
1H), 2.65 (d, J ) 8 Hz, 2H), 1.85 (m, 1H), 0.95 (d, J ) 7 Hz,
6H) ppm. GC-MS (ESI): m/z 219-221 (M + H+).
3-Br om o-5-isobu tyl-th iop h en e-2-su lfon yl Ch lor id e. To
a solution of 11 (7.58 kg, purity 81% by GC, 28.0 mol) in
CH2Cl2 (50 L) in
a nitrogen-flushed vessel was pumped
chlorosulfonic acid (16.2 kg, 139 mol) at -5 °C over 1.5 h with
use of a dosing pump, and the resulting mixture was stirred
at 2-4 °C for 4 h. A second vessel was charged with NaCl
(5 kg), ice (115 kg), and heptane (110 L) under nitrogen and
the reaction mixture was quickly pumped into it (5 min) under
vigorous stirring. The reaction vessel was rinsed with CH2Cl2
(5 L) and the washing was transferred to the second vessel.
After being stirred for another 10 min at room temperature,
the mixture was transferred to a separatory funnel and the
vessel was rinsed with heptane (30 L). The turbid organic
1
phase was separated and dried by filtration through
a
acid) to yield 1b (231 g, 26%): mp 190 °C dec; H NMR (500
Na2SO4 layer (15 kg). Reextraction of the aqueous phase with
heptane (30 L), phase separation, and filtration through the
used Na2SO4 layer was followed by evaporation of the organic
solution in vacuo, using a thin layer evaporator at 45 °C.
Traces of residual solvent were removed with use of a rotary
evaporator to yield the sulfonyl chloride (8.3 kg, 84% yield;
purity 90.2% by GC) as a colorless oil. 1H NMR (250 MHz,
CDCl3) δ 6.9 (s, 1H), 2.7 (d, J ) 7 Hz, 2H), 1.95 (m, 1H), 1.0
(d, J ) 7 Hz, 6H) ppm. Anal. Calcd for C8H10BrClO2S2: C,
30.25; H, 3.17; S, 20.19. Found: C, 30.44; H, 2.98; S, 20.20.
MHz, CDCl3) δ 9.79 (s, 1H), 7.53 (d, J ) 7.2 Hz, 2H), 7.50-
7.42 (m, 5H), 7.03 (d, J ) 7.6 Hz, 2H), 6.74 (s, 1H), 6.09 (br s),
5.64 (s, 2H), 3.09-3.02 (m, 2H), 2.68 (d, J ) 6.9 Hz, 2H,), 1.94-
1.87 (m, 1H), 0.99-0.96 (m, 9H). 13C NMR (125 MHz, CDCl3)
δ 178.2, 152.7, 150.7, 150.7, 145.5, 144.0, 136.8, 133.6, 131.8,
130.9, 129.9, 129.8, 129.3, 129.1, 127.7, 126.1, 125.2, 49.6, 39.3,
35.2, 30.6, 22.2, 14.8 ppm. X-ray analysis: crystal size 0.52 ×
0.3 × 0.15 mm3, monoclinic, space group P21/c, a ) 16.180(1)
Å, b ) 9.701(1) Å, c ) 20.007(1) Å, â ) 108.45(1)°, V ) 2785.25
Å3, Fcalcd ) 1.395 Mg/m3, T ) 293 K, Z ) 4, 7113 independent
reflexes, 4830 refined parameters, R1 ) 0.0357, wR2 ) 0.0838.
Anal. Calcd for C28H29ClN4O4S2: C, 57.47; H, 5.00; N, 9.57; S,
10.96. Found: C, 56,95; H, 4.99; N, 9.46; S, 10.91. Byproducts
13: 1H NMR (250 MHz, CDCl3) δ 9.85 (s, 1H), 7.4-7.65
(m, 5H), 7.3 (m, 3H), 7.0 (m, 2H), 5.65 (s, 2H) ppm. Anal.
Calcd for C17H13ClN2O: C, 68.81; H, 4.42; N, 9.44. Found: C,
68.53; H, 4.34; N, 9.26. 14: mp 239-240 °C; 1H NMR (300
MHz, CDCl3) δ 9.85 (s, 2H), 7.55 (d, J ) 7 Hz, 4H), 7.5 (m,
10H), 7.05 (d, J ) 7 Hz, 4H), 5.65 (s, 4H) ppm. Calcd for
3-Br om o-5-isobu tyl-th iop h en e-2-su lfon ic Acid Am id e
(12). Aqueous ammonia (22.4%, 8.6 L) and THF (16.0 L) were
placed in a nitrogen-flushed vessel at 10 °C. A solution of
3-bromo-5-isobutyl-thiophene-2-sulfonyl chloride (8.3 kg, 23.6
mol, purity 90.2% according to GC) in THF (24 L) was added
with stirring and cooling in such a way that the temperature
was maintained between 10 and 15 °C (about 1 h) and the
resulting solution was stirred at this temperature for an
additional hour. The solvent was evaporated to dryness in
vacuo at 20 °C, heptane (24 L) and water (20 L) were added,
and the mixture was stirred for 15 min. The mixture was
cooled and stirred at 0-1 °C to initiate crystallization. The
product was pressure filtered, washed with water, and dried
at 35 °C in vacuo to afford 12 (6.88 kg, 98%) as pale yellow
C
34H25Cl2N4O4 (M
+
H+) 591.13565, found 591.13546
(HRMS).
3-[4-(5-F or m yl-4-m eth oxy-2-p h en yl-im id a zol-1-ylm eth -
yl)p h en yl]-5-isobu tyl-th iop h en e-2-(3-eth yl) Su lfon ylu r ea
(1a ). Compound 1b (280 mg, 0.48 mmol) was suspended in
methanol and a freshly prepared methanolic NaOH solution
(48 mg in 5 mL of methanol) was added dropwise over 5 min.
The reaction mixture was heated at 70 °C for 9 h and the
conversion was followed by TLC. The reaction was cooled to
room temperature and acidified with 2 N HCl to pH 2. The
solvent was nearly evaporated in vacuo, then ethyl acetate
(20 mL) was added and the organic and aqueous phases were
separated. The aqueous phase was extracted twice with ethyl
acetate (20 mL), the combined organic phases were washed
with brine (20 mL) and dried over MgSO4, and the solvent was
evaporated in vacuo to give the crude product as a yellow oil.
Purification by HPLC [Zorbax Sil, 250 × 9.4 mm; 5 µm, Fa.
Bischoff with toluene/(ethyl acetate/2% acetic acid) 2:1, flow 5
mL/min] yielded 1a (181 mg, 0.31 mmol, 65%) as a colorless
solid; purity 99.6% (HPLC); Rf (heptane/ethyl acetate/acetic
acid 100:50:1) 0.40, mp 191-192 °C; 1H NMR (500 MHz,
CDCl3) δ 9.69 (s, 1H), 7.61-7.45 (m, 7H), 7.12 (d, J ) 7.9 Hz,
2H), 6.78 (s, 1H, th), 6.13 (br s, 1H), 5.61 (s, 2H), 4.19 (s, 3H),
3.12-3.08 (m, 2H), 2.72 (d, J ) 7.0 Hz, 2H), 1.99-1.92 (m,
1H), 1.03-1.00 (m, 9H); 13C NMR (125 MHz, CDCl3) δ 175.7,
150.7, 150.5, 145.6, 137.5, 133.3, 131.9, 130.6, 129.7, 129.6,
129.2, 129.0, 128.4, 126.0, 113.0, 56.3, 49.6, 39.3, 35.0, 30.5,
1
crystals: mp 87-88 °C; H NMR (400 MHz, DMSO-d6) δ 7.8
(s, 2H), 7.0 (s, 1H), 2.7 (d, J ) 7 Hz, 2H), 1.85 (m, 1H), 0.9 (d,
J ) 7 Hz, 6H) ppm. Anal. Calcd for C8H12BrNO2S2: C, 32.22;
H, 4.06; N, 4.70; S, 21.50. Found: C, 32.28; H, 4.01; N, 4.77;
S, 21.39.
3-Br om o-5-isobu tyl-th iop h en e-2-(3-eth yl) Su lfon ylu r ea
(3a ). A nitrogen-flushed vessel was charged with 12 (8.0 kg,
26.8 mol), anhyd K2CO3 (8.6 kg, 62.2 mol), and acetone
(60 L). The vessel was set under slight vacuum and ethyliso-
cyanate (3.2 kg, 45 mol) was siphoned in through a PTFE tube.
The tube was rinsed with acetone (2 L) and the mixture was
heated to 54 °C (0.5 h) with stirring. After being refluxed for
2 h, the mixture was pressure filtered and the K-salts were
washed with acetone (2 × 10 L). Water (58 L) and HCl (37%,
12 L) were placed in a separate vessel at 10 °C and the K-salts
were added in several portions to prevent foaming. The product
was allowed to crystallize overnight at room temperature,
pressure filtered, washed with a little water, and dried in
vacuo at 60 °C to furnish 3a (10.2 kg, 91%) as a colorless
crystalline powder: mp 191-191.5 °C; 1H NMR (300 MHz,
CDCl3) δ 11.0 (br s, 1H), 7.05 (s, 1H), 6.35 (br t), 3.0 (pentet,
J ) 7 Hz, 2H), 2.7 (d, J ) 7 Hz, 2H), 1.9 (m, 1H), 0.9 (m, 9H)
5172 J . Org. Chem., Vol. 68, No. 13, 2003

The Angiotensin-(1-7)-receptor Agonist AVE0991
22.2, 14.7 ppm. MS (ESI) m/z 581 (100) [M+ + H]. Anal. Calcd
for C29H32N4O5S2: C, 59.88; H, 5.72; N, 9.63; S, 11.02. Found:
C, 59.82; H, 5.44; N, 9.77; S, 11.02.
Stille Rea ction Con d ition s: 3-[4-(4-Ch lor o-5-for m yl-2-
ph en yl-im idazol-1-ylm eth yl)ph en yl]-5-isobu tyl-th ioph en e-
2-(3-eth yl) Su lfon ylu r ea (1b). Into a oven or flame-dried and
argon-filled 50-mL two-necked flask with reflux condenser
were added imidazole 2b (375 mg, 1.00 mmol), stannane 3b
(1.16 g, 2.00 mmol), Pd(PPh3)4 (100 mg), and dry THF (20 mL).
The reaction mixture was refluxed for 72 h, the solvent was
removed under vacuum, and the crude material was purified
by a fast chromatography-filtration process (SiO2): 300 mL of
heptane eluted the excess and degration products of tin
derivatives, and coupling products were obtained by elution
with heptane/ethyl acetate/acetic acid (100:50:1) to give a
mixture of 1b and 16 (413 mg, ratio 1.6:1 determined by
HPLC). This mixture was added to a 100-mL two-necked flask
with condenser, which was filled with argon over 20 min. After
addition of potassium carbonate (295 mg, 2.10 mmol), DME
(25 mL), and ethyl isocyanate (178 mg, 2.50 mmol) the reaction
mixture was refluxed for 2 h (TLC monitoring). After the
solution was cooled to room temperature, the pH was adjusted
to 5.2 by addition of a 5% aqueous citric acid solution.
Dichloromethane was added until a clear solution with two
phases was obtained. The phases were separated, the aqueous
phase was extracted with dichloromethane (3 × 20 mL), the
combined organic layers were dried over Na2SO4, and the
solvent was evaporated in vacuo. Flash chromatography with
heptane/ethyl acetate/acetic acid (100:50:1) as eluent gave 1b
as a colorless solid (360 mg, 0.62 mmol, 62%). 16: Rf (heptane/
ethyl acetate/acetic acid 100:50:1) 0.53; 1H NMR (500 MHz,
CDCl3) δ 9.86 (s, 1H), 7.60-7.48 (m, 7H), 7.09 (d, J ) 6.8 Hz,
2H), 6.78 (s, 1H), 5.70 (s, 2H), 4.60 (s, 2H), 2.72 (d, J ) 5.7
Hz, 2H), 1.97-1.92 (m, 1H), 1.01-0.99 (m, 6H) ppm.
4-Br om oben zyl Br om id e (15). 4-Bromotoluene (4, 1.00 g,
5.80 mmol) was dissolved in cyclohexane (10 mL) and
N-bromosuccinimide (1.04 g, 5.80 mmol) and AIBN (10 mg,
0.8 mmol) were added in one portion. The reaction mixture
was refluxed (100 °C) for 4 h, cooled to room temperature, and
filtered and the solid was washed twice with cyclohexane
(5 mL). The filtrate was evaporated to dryness and the residue
was purified by chromatography (heptane/ethyl acetate 3:1)
to give 15 (1.10 g, 4.40 mmol, 75%).
3-(4-Br om oben zyl)-5-ch lor o-2-p h en yl-3H-im id a zole-4-
ca r ba ld eh yd e (2b ). Imidazole 8 (207 mg, 1.00 mmol) and
4-bromobenzyl bromide (15, 250 mg, 1.00 mmol) were added
to a 50-mL round-bottom flask and dissolved in dry DMF (5
mL). Then K2CO3 (97 mg, 0.70 mmol) was added and the
reaction mixture was stirred for 48 h at room temperature.
The solvent was completely evaporated in vacuo and the
residue was suspended in ethyl acetate and purified by
chromatography (heptane/ethyl acetate 2:1) to give 2b (281
1
mg, 0.75 mmol, 75%) as a colorless solid. H NMR (500 MHz,
CDCl3) δ 9.76 (s, 1H), 7.52 (d, J ) 7.1 Hz, 2H), 7.48 (t, J ) 7.3
Hz, 1H), 7.42 (dd, J ) 7.1/7.3 Hz, 2H), 7.39 (d, J ) 8.5 Hz,
2H), 6.85 (d, J ) 8.5 Hz, 2H), 5.51 (s, 2H). 13C NMR (125 MHz,
CDCl3) δ 178.3, 152.8, 144.0, 135.7, 132.4, 131.3, 129.6, 129.4,
128.3, 128.0, 125.5, 122.3, 49.7 ppm. No regioisomer of 2b was
detected.
5-Isobu tyl-3-tr ibu tylstan n an e-th ioph en e-2-(3-eth yl) Su l-
fon ylu r ea (3b). Into a 250-mL flask was added 3a (1.85 g,
5.00 mmol) and the flask was filled with argon over 15 min.
The solid was dissolved in dry THF (45 mL) and the solution
was cooled to -78 °C and treated with n-BuLi (10 mL, 25
mmol, 2.5 M in toluene), added dropwise via syringe. The
solution was stirred for 45 min at -78 °C and tributyltinchlo-
ride (6 mL, 25 mmol) was added dropwise. The solution was
allowed to warm to room temperature (2 h) and stirred for
another hour at room temperature. After addition of water
(10 mL) the THF was removed in vacuo. The aqueous phase
was extracted with ethyl acetate (3 × 50 mL), the combined
organic fractions were dried over Na2SO4, and the solvent was
evaporated in vacuo. The crude product was purified by
chromatography with 500 mL of heptane to remove the excess
tributyltinchloride and heptane/ethyl acetate 2:1 to elute 3b
(1.80 g, 3.10 mmol, 62%) as a colorless oil. 1H NMR (500 MHz,
CDCl3) δ 6.76 (s, 1H), 6.59 (br s, 1H), 3.34-3.30 (m, 2H), 2.74
(d, J ) 7.0 Hz, 2H), 1.95-1.87 (m, 1H), 1.70-1.52 (m, 7H),
Ack n ow led gm en t. We want to thank Bernd Becker,
Rudi Eisenacht, Antje Fo¨rst, Bernd Kulitzscher, J u¨rgen
Michalowsky, Dirk Schanz, Gerald Scholz, and Klaus
Weihl for experimental support and Dr. Gerhard Beck,
Dr. Gu¨nter Billen, and Dr. Bernhard Seuring for helpful
discussions. Thanks to Dr. H. Berchtold, W. Heyse, Dr.
N. Nagel, and H. Schweitzer for X-ray diffraction
experiments. Special thanks go to Dr. Steve MacNeil
for his corrections.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal details and procedures which were optimized for the large-
scale process (large-scale synthesis of compounds 6, 2a , 1b,
1
and 1a ; H NMR spectra for 1a , 1b, 2b, 3b, and 16 and 13C
NMR spectra for 1a and 1b; X-ray data for 1b. This material
is available free of charge via the Internet at http://pubs.acs.org.
1.39-1.29 (m, 8H), 1.21-1.16 (m, 8H), 0.98-089 (m, 14H). 13
C
NMR (125 MHz, CDCl3) δ 150.7, 133.2, 130.6, 129.2, 113.0,
39.5, 31.1, 29.4, 27.7, 22.6, 15.3, 14.1, 11.9 ppm.
J O034372C
J . Org. Chem, Vol. 68, No. 13, 2003 5173