Multicomponent reactions as a powerful tool for generic drug synthesis

Article abstract of DOI:10.1055/s-0028-1083239

Multicomponent reactions (MCRs) are not only a powerful tool for drug discovery, they also represent an excellent methodology for synthesis rationalization. Here we wish to illustrate the potential of MCRs in the production of generic drugs by synthesizing, in racemic form, the antiplatelet agent clopidogrel and the nonsteroidal antiandrogen bicalutamide, using Ugi, Petasis and Passerini reactions. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083239

PAPER
4007
Multicomponent Reactions as a Powerful Tool for Generic Drug Synthesis
M
ulticomponent
é
Reactions
f
d
or Generic
D
r
rug Syn
i
thesis c Kalinski,* Hugues Lemoine, Jürgen Schmidt, Christoph Burdack, Jürgen Kolb, Michael Umkehrer,
Günther Ross
Priaxon AG, Gmunder Str. 37-37a, 81739 München, Germany
Fax +49(89)452130822; E-mail: kalinski@priaxon.com
Received 11 April 2008; revised 18 August 2008
MeO
N
O
Abstract: Multicomponent reactions (MCRs) are not only a power-
ful tool for drug discovery, they also represent an excellent method-
ology for synthesis rationalization. Here we wish to illustrate the
potential of MCRs in the production of generic drugs by synthesiz-
ing, in racemic form, the antiplatelet agent clopidogrel and the non-
steroidal antiandrogen bicalutamide, using Ugi, Petasis and Passe-
rini reactions.
OH
O
O
O
H
CF3
CN
S
N
S
Cl
F
1
2
Figure 1 Structures of (S)-clopidogrel (1) and bicalutamide (2)
Key words: multicomponent reactions, drugs, cleavage, clopido-
grel, bicalutamide
one-step synthetic route to the precursor 3 was carried out
using the Petasis reaction, which was discovered by
Petasis et al. in 1993.8 This reaction can be regarded as a
boronic acid version of the Mannich reaction. In a further
optimization protocol, its practical use for the synthesis of
non-natural a-amino acids from alkenyl boronic acids and
glyoxylic acid has been reported.9 Thus, we employed
compound 5, glyoxylic acid (9) and 2-chlorophenylboron-
ic acid (10) in a Petasis three-component reaction
(Petasis-3CR). Solvent optimization showed that using
DMF allowed acceptable yields for the formation of car-
boxylic acid 3. After obtaining the precursor 3 by these
two different methods, a final esterification step yielded
the desired racemic clopidogrel 4 with high conversion
and high purity (>99%). Although method B enabled a re-
duction in the number of the reaction steps, method A pre-
sented a very efficient and promising three-step synthesis
of racemic (R,S)-clopidogrel (4).
Multicomponent reactions (MCRs) are not only a power-
ful tool for the creation of chemical diversity and new
chemical entities in drug discovery,1,2 they also represent
an excellent methodology for synthesis rationalization,3
for example, in the production of generic drugs or natural
products.4 In order to demonstrate the potential of multi-
component chemistry, we herein report alternative, MCR-
based synthetic approaches to the well-known drugs, (S)-
clopidogrel (1) and bicalutamide (2) (Figure 1).
First, we report the racemic synthesis of the antiplatelet
agent (S)-methyl-a-5-(4,5,6,7-tetrahydro[3,2-c]thienopy-
ridyl)-(2-chlorophenyl)acetate (clopidogrel; 1),5 the
world’s second-highest-selling pharmaceutical in 2005
(Plavix®), via an Ugi three-component reaction. The bio-
active compound can be regarded as an ester of a non-nat-
ural a-amino acid and is therefore accessible by different
synthetic routes based on MCR chemistry. A three-com-
ponent Ugi reaction with cleavable isocyanides (methods
A/C) and a Petasis reaction (method B) with suitable start-
ing materials, were improved to synthesize the carboxylic
acid 3, a precursor of racemic (R,S)-clopidogrel (4;
Scheme 1). The Ugi reaction (U-3CR)6 involves the
4,5,6,7-tetrahydrothieno[3,2-c]pyridine (5), which is
commercially available as the corresponding hydrochloric
acid salt, 2-chlorobenzaldehyde (6) and 1-isocyanocyclo-
hexene (Armstrong isocyanide; 7) as acid-labile cleavable
isocyanide.7 The reaction was performed in methanol un-
der microwave irradiation and formic acid catalysis. The
Ugi product 8 was obtained in excellent yield after one
hour at 60 °C.
In our efforts to optimize the synthetic strategy, we inves-
tigated the use of a base-labile isocyanide – 1,1-dimethyl-
2-isocyanoethyl methyl carbonate (11) – in the U-3CR
(Scheme 2, method C). This isocyanide, reported by Lind-
horst and co-workers,10 allowed the direct formation of
racemic clopidogrel from the Ugi-product 12. The Ugi re-
action was performed at 60 °C under microwave irradia-
tion in the presence of an equimolar amount of formic
acid, followed by the cleavage of the isocyanide moiety
by treatment with potassium tert-butoxide in tetrahydro-
furan. This synthetic route allowed the formation of (R,S)-
clopidogrel (4) with moderate yields; the lower yields be-
ing due to the instability of the carbamate moiety of the
isocyanide 11, which is partially hydrolyzed during the re-
action sequence.
Subsequent cleavage of the isocyanide moiety with aque-
ous hydrochloric acid allowed fast and complete conver-
sion of 8 into the desired carboxylic acid 3. An alternative,
In conclusion, we demonstrate that three new synthetic
methods, based on MCR chemistry, give easy synthetic
access to (R,S)-clopidogrel (4). Scheme 3 summarizes
these methods and compares them with the original syn-
thesis patented by Sanofi.11 Even though method A in-
volves three synthetic steps, the route gives the best
overall yield and illustrates the efficiency of MCR chem-
SYNTHESIS 2008, No. 24, pp 4007–4011
x
x.
x
x
.
2
0
0
8
Advanced online publication: 01.12.2008
DOI: 10.1055/s-0028-1083239; Art ID: T05808SS
© Georg Thieme Verlag Stuttgart · New York

4008
C. Kalinski et al.
PAPER
O
Cl
Cl
NC
O
N
7
6
HN
O
N
OH
O
N
OMe
HCOOH, MeOH,
60 °C, MW, 83%
HCl, THF,
r.t., 98%
8
S
A
H2SO4, MeOH
90%
S
S
Cl
Cl
4 (rac-1)
NH
B
3
O
DMF, r.t., 49%
B(OH)2
S
H
5
HO
9
Cl 10
O
Scheme 1 Synthesis of (R,S)-clopidogrel (4) via U-3CR with Armstrong isocyanide (method A) or Petasis-3CR (method B) followed by
esterification
NH
OMe
Cl
Cl
O
O
S
5
HCOOH, MeOH, 60 °C, MW, 54%
KOt-Bu, THF
42%
N
N
HN
O
O
O
CN
O
Cl
S
S
O
4
11
OMe
O
12
6
Scheme 2 Two-step U-3CR synthesis of (R,S)-clopidogrel (4) using the Lindhorst isocyanide (method C)
Method A 73%
Method B 44%
NC
O
HO
NH
NH
+
B
O
HO
+
+
+
O
HO
81%
49%
S
S
Cl
Cl
O
5
7
10
6
9
5
HO
DMF, r.t.
1. MeOH, HCOOH, 60 °C, MW
2. THF–HClaq (9:1), r.t.
N
Petasis-3CR
Cl
3
S
MeOH, H2SO4, heat
90%
MeO
Ugi-3CR
O
N
Cl
S
4
K2CO3, DMF 90 °C, 4 h, 45%
1. MeOH, HCOOH, 60 °C, MW
2. KOt-Bu, THF
Sanofi synthesis 31%
Method C 22%
NH
O
22%
O
O
OH
O
Cl
OMe
Cl
O
S
NH
OMe
CN
Cl
+
+
OMe
O
MeOH–HCl
SOCl2, reflux
HO
HO
S
Cl
reflux, 5 h, 84%
83%
Cl
11
5
6
Scheme 3 New multicomponent syntheses of (R,S)-clopidogrel (4) with respective overall yields
Synthesis 2008, No. 24, 4007–4011 © Thieme Stuttgart · New York

PAPER
Multicomponent Reactions for Generic Drug Synthesis
4009
istry. Method B also has some advantages such as an ac- It has been shown that in the titanium tetrachloride assist-
ceptable overall yield and a two-step strategy, however, ed Passerini reaction the isocyanide forms an adduct with
the starting materials are less suitable for scale-up. Meth- the titanium tetrachloride. Depending on the structural
od C is not convenient because of its low yield and the in- properties of the isocyanide, either a 1:1 or 1:2 molar ratio
stability of the starting material. Therefore, method A is found. The adduct then reacts with the carbonyl com-
definitively represents the best synthetic route that we pound and, upon hydrolysis of the reaction mixture, an a-
have developed. The Armstrong isocyanide is easily syn- hydroxy amide 22 is formed. For the exact mechanism of
thesized in up to kilogram scales in two steps; it can be the titanium tetrachloride assisted Passerini reaction, dif-
stored at –20 °C. The only hindrance for its use arises ferent models have been discussed and investigated by X-
through is its piercing odor. Alternatively, new, cleavable ray diffraction studies.16 These studies agree on the forma-
isocyanides with promising properties could also be in- tion of a titanium-coordinated intermediate 21 with a re-
volved in the future.12 In analogy to the Sanofi synthesis, active chloroimide C–Cl bond, which is then hydrolyzed
the multicomponent reactions described here only yielded to the a-hydroxy amide 22 (Scheme 5). For our objective,
clopidogrel 4 as a racemic mixture and a further resolu- the titanium tetrachloride assisted Passerini reaction is a
tion-step will be necessary to yield the drug (S)-clopi- very attractive method since it leads directly to the a-hy-
dogrel (1). For example, a possible resolution11 consists of droxy amide moiety of bicalutamide without the need for
mixing the racemic clopidogrel with levorotatory cam- an additional ester cleavage step. A similar procedure us-
phor-10-sulfonic acid in acetone. The resulting salt can be ing trifluoroacetic acid (TFA) instead of titanium tetra-
recrystallized from acetone to generate (S)-clopidogrel chloride has been reported,17 however, this approach
(1). Further scale-up experiments and studies on the cost proved unsuccessful for the bicalutamide system in pilot
of building blocks could determine whether the reaction is experiments.
suitable for industrial application and lead to a price re-
duction of this marketed product.
Several methods for the synthesis of bicalutamide have
been reported in the patent literature and scientific publi-
As a second illustration of the potential use of MCRs in cations. Rather advanced processes include the synthesis
the field of generic drug production, we present a short, of enantiomerically pure (R)- and (S)-bicalutamide em-
efficient, two-step synthesis of the non-steroidal antian- ploying naturally occurring chiral starting materials18 and
drogen bicalutamide (16; Casodex®), which is the leading a two-step synthesis via 1,2-addition of a methyl sulfone
antiandrogen used for the treatment of prostate cancer.13 to a keto amide.19 Our MCR synthesis produces racemic
The key step is a Passerini reaction (P-3CR) assisted by ti- bicalutamide 16 from commercially available starting ma-
tanium tetrachloride (Scheme 4). The Passerini reaction is terials in a two-step process with an overall yield of 61%.
a classical MCR discovered in the 1920s.14 The reaction 1-(4-Fluorophenylsulfonyl)propan-2-one (14) was pre-
between a carbonyl compound 17, an isocyanide 18 and a pared by oxidation of 4-fluorophenylthioacetone (13)
carboxylic acid 19, leads to the formation of an a-hydroxy with 3-chloroperoxybenzoic acid (MCPBA); the reaction
amide ester 20 (Scheme 5). In a variation of the original proceeded smoothly with a yield of 92%. The 4-cyano-3-
P-3CR method, protic mineral acids and Lewis acids such (trifluoromethyl)phenylisocyanide (15) can be prepared
as titanium tetrachloride are used as promoters.15
from the corresponding aniline following known
procedures20 and is commercially available.
O
O
O
O
S
mCPBA
92%
S
OH
O
O
O
1. TiCl4
2. H2O
H
N
CF3
CN
S
14
F
13
F
66%
CF3
CN
F
16
15
CN
Scheme 4 Synthesis of (R,S)-bicalutamide (16) via a titanium tetrachloride assisted Passerini reaction
R1 OH
R2
O
O
R4
20
O
O
O
R4
NC
O
R3
+
+
R3
+
+
R1
R2
R4
OH
O
N
H
R1
R2
R3
N
17
18
19
R1
O
L
O
O
N
H2O
L
L
HO
R1
NC
R3
R2
Cl
R3
TiCl4
Ti
L
R1
R2
N
H
R2
R3
21
22
Scheme 5 Classical Passerini reaction versus titanium tetrachloride assisted Passerini reaction (L = Cl or donor group of substrate)
Synthesis 2008, No. 24, 4007–4011 © Thieme Stuttgart · New York

4010
C. Kalinski et al.
PAPER
(2-Chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-
For the titanium tetrachloride assisted Passerini reaction,
all glassware and solvents were dried carefully, as traces
of water drastically reduced the yield. The reaction had to
be performed under inert gas atmosphere. In a first step,
the isocyanide was combined with titanium tetrachloride
to form the initial adduct; the carbonyl component was
then added. Upon completion of the conversion, the reac-
tion mixture was quenched with water and an extractive
work up followed by recrystallization yielded racemic
bicalutamide with a yield of 66% and >99% purity.
yl)acetic Acid (3) from 8
Compound 8 (60 mg, 0.15 mmol) was dissolved in a mixture THF–
HClaq [9:1 (v/v), 1 mL] and the resulting solution was allowed to stir
at r.t. for 1 h. The reaction mixture was then diluted with CH2Cl2 (20
mL), washed with brine (10 mL) and the aqueous layer was extract-
ed with CH2Cl2 (2 × 10 mL). The aqueous layer was made basic
with sat. NaHCO3 (~0.5 mL) until pH 8, and extracted with CH2Cl2
(2 × 10 mL). The combined organic layer was dried over MgSO4,
evaporated to dryness, and the product was crystallized (Et2O–hex-
ane) to give 3.
Yield: 47 mg (98%); white solid.
In conclusion, we have demonstrated that multicompo-
nent reactions can be a powerful tool for the generic syn-
thesis of marketed drugs. (R,S)-Clopidogrel can be
synthesized via Ugi or Petasis reactions in two steps with
acceptable to high yields. Furthermore, a short and effi-
cient, two-step synthesis of the anticancer drug (R,S)-bi-
calutamide via a titanium tetrachloride assisted Passerini
reaction has been developed.
1H NMR (CDCl3, 250 MHz): d = 7.54 (s, 1 H), 7.45–7.41 (m, 1 H),
7.32–7.23 (m, 2 H), 7.08 (d, 3J = 5.2 Hz, 1 H), 6.66 (d, 3J = 5.0 Hz,
1 H), 4.94 (s, 1 H), 3.65 (dd, 3J = 7.9 Hz, 2J = 14.4 Hz, 2 H).
13C NMR (CDCl3, 63 MHz): d = 173.0, 135.4, 132.9, 130.4, 130.1,
129.6, 127.1, 125.2, 123.2, 69.0, 50.8, 49.1, 25.7.
MS (+ESI): m/z = 308 [M + H]+.
IR: 3468, 2923, 2358, 1655, 1578, 1418, 1255, 1090, 1034, 954,
751, 700 cm–1.
1H NMR and 13C NMR spectra were measured in CDCl3 or DMSO-
d6 with a Bruker AV 250 spectrometer. Chemical shifts are ex-
pressed in ppm (d) with respect to TMS as an internal standard.
Electrospray ionization mass spectra (ESI) were obtained using a
Varian 1200 L Quadrupole MS/MS. Purity was determined with a
Varian LC Prostar 325 system [Varian Polaris RP C18 column; 3
mm × 150 mm; 5 mm ODSA; 215 nm and 254 nm; 1 mL/min, 3 min
gradient from 90% H2O to 10% H2O (0.5% HCOOH) vs. MeCN
(0.5% HCOOH)].
(2-Chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-
yl)acetic Acid (3)
To a solution of glyoxylic acid monohydrate (9; 30 mg, 0.33 mmol)
in DMF (1 mL) was added 4,5,6,7-tetrahydrothieno[3,2-c]pyridine
(5; 46 mg, 0.33 mmol) and 2-chlorophenylboronic acid (10; 51 mg,
0.33 mmol). The reaction mixture was stirred at r.t. for one week.
After completion, the crude mixture was evaporated to dryness then
dissolved in EtOAc (20 mL) and washed with distilled H2O (10
mL). The aqueous layer was extracted with EtOAc (2 × 10 mL) and
the combined organic layer was dried over MgSO4, evaporated to
dryness and purified on a silica gel column (EtOAc–MeOH, 1:1) to
give 3 as a white solid (50 mg, 49%). Analytical data was in accor-
dance with those obtained in the synthesis from 8.
All starting materials used are commercially available. Isocyanides
7 and 15 are available from Priaxon AG. Compound 14 is now com-
mercially available from Otava.
2-(2-Chlorophenyl)-N-cyclohex-2-enyl-2-(6,7-dihydro-4H-
thieno[3,2-c]pyridin-5-yl)acetamide (8)
(R,S)-Clopidogrel (4) from 3
To a solution of 3 (20.0 mg, 0.065 mmol) in MeOH (2 mL) was add-
ed concd H2SO4 (0.065 mmol). The mixture was refluxed for 3 d
(HPLC analysis showed complete conversion into the correspond-
ing methyl ester). The crude product was evaporated to dryness and
dissolved in CH2Cl2 (10 mL). The organic layer was washed with
sat. NaHCO3 (5 mL), dried over MgSO4 and evaporated to yield 4.
To a solution of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochlo-
ride (5; 100 mg, 0.57 mmol) in MeOH (0.5 mL) was added Et3N (58
mg, 0.57 mmol). The mixture was stirred at r.t. for 5 min, then 2-
chlorobenzaldehyde (6; 80 mg, 0.57 mmol) was added and the so-
lution was again stirred at r.t. for 1 h. Formic acid (26 mg, 0.57
mmol) in MeOH (1 mL) was added dropwise, followed by addition
of 1-isocyanocyclohexene (7; 61 mg, 0.57 mmol). The mixture was
stirred at 60 °C under microwave irradiation for 1 h. Subsequently,
the crude reaction mixture was diluted with CH2Cl2 (20 mL),
washed with brine (10 mL) and the aqueous layer was extracted
with CH2Cl2 (2 × 10 mL). The combined organic layer was dried
over MgSO4, evaporated to dryness and purified on a silica gel col-
umn (EtOAc–hexane, 1:3) to give 8.
Yield: 18.8 mg (90%); colorless oil.
1H NMR (CDCl3, 250 MHz): d = 7.72–7.68 (m, 1 H), 7.42–7.30 (m,
1 H), 7.29–7.25 (m, 2 H), 7.05 (d, 3J = 5.0 Hz, 1 H), 6.66 (d,
3J = 5.2 Hz, 1 H), 4.92 (s, 1 H), 3.72 (s, 3 H), 3.79–3.59 (m, 2 H),
2.88 (s, 4 H). Data are in accordance with those previously pub-
lished.11
Yield: 92 mg (83%); white solid.
2-{2-(2-Chlorophenyl)-2-(6,7-dihydro-4H-thieno[3,2-c]pyridin-
5-yl)acetylamino}-1,1-dimethylethyl Methyl Carbonate (12)
To a solution of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochlo-
ride (5; 100 mg, 0.57 mmol) in MeOH (0.5 mL) was added Et3N (58
mg, 0.57 mmol), and the mixture was stirred at r.t. for 5 min. 2-
Chlorobenzaldehyde (6; 80 mg, 0.57 mmol) was added and the so-
lution was again stirred at r.t. for 1 h. Formic acid (26 mg, 0.57
mmol) in MeOH (1 mL) was added dropwise followed by addition
of 1,1-dimethyl-2-isocyanoethyl methyl carbonate (11; 90 mg, 0.57
mmol). The mixture was stirred at 60 °C under microwave irradia-
tion for 1 h. Subsequently, the crude reaction mixture was diluted
with CH2Cl2 (20 mL) and washed with brine (10 mL). The obtained
aqueous layer was extracted with CH2Cl2 (2 × 10 mL) and the com-
bined organic layers were dried over MgSO4, evaporated to dryness
and purified on a silica gel column (EtOAc–hexane, 1:4→1:1) to
give 12.
1H NMR (CDCl3, 250 MHz): d = 8.36 (s, 1 H), 7.44–7.40 (m, 2 H),
7.28–7.24 (m, 2 H), 7.08 (d, 3J = 5.2 Hz, 1 H), 6.66 (d, 3J = 5.0 Hz,
1 H), 6.16 (t, 3J = 11.4 Hz, 1 H), 4.89 (s, 1 H), 3.62 (dd, 3J = 7.4 Hz,
2J = 14.4 Hz, 2 H), 2.9 (s, 4 H), 2.16–2.10 (m, 4 H), 1.74–1.55 (m,
4 H).
13C NMR (CDCl3, 63 MHz): d = 168.6, 135.6, 133.6, 133.2, 139.9,
130.4, 130.1, 129.4, 127.0, 125.3, 123.1, 113.0, 69.7, 50.7, 49.2,
28.0, 26.0, 23.9, 22.5, 21.9.
MS (+ESI): m/z = 387 [M + H]+.
IR: 3303, 2925, 2835, 1686, 1509, 1472, 1437, 1219, 1038, 1017,
753, 702 cm–1.
Synthesis 2008, No. 24, 4007–4011 © Thieme Stuttgart · New York

PAPER
Multicomponent Reactions for Generic Drug Synthesis
4011
Yield: 134 mg (54%); colorless oil.
2J = 14.5 Hz, 1 H, CH2), 1.67 (s, 3 H, CH3). Data are in accordance
with those previously published.18
1H NMR (CDCl3, 250 MHz): d = 7.68 (t, 3J = 6.0 Hz, 1 H), 7.45–
7.39 (m, 2 H), 7.29–7.21 (m, 2 H), 7.06 (d, 3J = 5.2 Hz, 1 H), 6.65
(d, 3J = 5.1 Hz, 1 H), 4.9 (s, 1 H), 3.74 (s, 3 H), 3.66–3.46 (m, 4 H),
2.89 (s, 3 H), 1.45 (s, 6 H).
References
(1) (a) Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39,
3168. (b) Dömling, A. Chem. Rev. 2006, 106, 17.
(2) Hulme, C. In Multicomponent Reactions; Zhu, J.; Bienayme,
H., Eds.; Wiley-VCH: Weinheim, 2005.
13C NMR (CDCl3, 63 MHz): d = 170.9, 154.0, 135.3, 133.5, 133.4,
133.1, 130.3, 130.0, 129.3, 126.9, 125.2, 122.9, 83.35, 69.4, 54.2,
50.8, 49.3, 47.5, 25.7, 23.6.
MS (+ESI): m/z = 437 [M + H]+.
(3) (a) Rossen, K.; Pye, P. J.; DiMichele, L. M.; Volante, R. P.;
Reider, P. J. Tetrahedron Lett. 1998, 39, 6823. (b) Askin,
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Chem. 1959, 71, 386. (b) Ugi, I. Angew. Chem., Int. Ed.
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2000, 112, 3300.
IR: 3350, 2952, 2844, 1743, 1680, 1514, 1471, 1439, 1278, 1148
cm–1.
(R,S)-Clopidogrel (4) from 12
To a solution of 12 (134 mg, 0.3 mmol) in anhydrous THF (2 mL),
was added t-BuOK (44 mg, 0.39 mmol). The resulting suspension
was stirred at r.t. for 1 h. The crude reaction mixture was diluted
with CH2Cl2 (20 mL) and washed with H2O (10 mL). The aqueous
layer was extracted with CH2Cl2 (2 × 10 mL) and the combined or-
ganic layer was dried over MgSO4, evaporated to dryness and puri-
fied on a silica gel column (EtOAc–hexane, 1:1.5) to give 4 as a
colorless oil (41 mg, 42%). Analytical data were in accordance with
those observed for the same product synthesized from 3.
(7) Keating, T. A.; Armstromg, W. J. Am. Chem. Soc. 1996,
118, 2574.
(8) Petasis, N. A.; Akritopoulou, I. Tetrahedron Lett. 1993, 34,
583.
(9) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119,
445.
1-(4-Fluorophenylsulfonyl)propan-2-one (14)
MCPBA (8.96 g, 52 mmol) was added to a solution of (4-fluorophe-
nylthio)acetone (13; 3.18 g, 17.3 mmol) in CH2Cl2 (75 mL). The so-
lution was stirred at r.t., during which time a white precipitate
formed. After 2 h, TLC (silica gel, EtOAc–CHCl3, 1:1) indicated
complete conversion of the starting materials. The precipitate was
removed by filtration and washed with CH2Cl2 (10 mL). The clear
solution was evaporated to dryness and the residue was purified by
recrystallization (EtOAc–hexane) to give 14.
(10) Lindhorst, T.; Bock, H.; Ugi, I. Tetrahedron 1999, 55, 7411.
(11) (a) Eliel, E. L.; Fisk, M. T.; Prosser, T. Org. Synth. Coll. Vol.
IV; John Wiley & Sons: London, 1963, 169. (b) Aubert, D.;
Ferrand, C.; Maffrand, J.-P. French Patent FR2530247,
1984. (c) Badorc, A.; Frehel, D. US Patent 4847265, 1989.
(d) Tucker, H. US Patent 4636505, 1987. (e) Soeroes, B.;
Tuba, Z.; Galik, G.; Bor, A.; Demeter, A.; Trischler, F.;
Horvath, J.; Brlik, J. US Patent 7199257, 2007.
(12) (a) Pirrung, M. C.; Ghorai, S. J. Am. Chem. Soc. 2006, 128,
11772. (b) Kreye, O.; Westermann, B.; Wessjohann, L. A.
Synlett 2007, 3188. (c) Gilley, C. B.; Buller, M. J.;
Kobayashi, Y. Org. Lett. 2007, 9, 3631.
Yield: 3.43 g (92%); white solid.
1H NMR (CDCl3, 200 MHz): d = 7.92 (dd, 3JH–H = 8.5 Hz, 4JH–F
=
5.0 Hz, 2 H), 7.26 (app t, 3JH–H = 3JH–F = 8.5 Hz, 2 H), 4.16 (s, 2 H,
CH2), 2.42 (s, 3 H, CH3).
(R,S)-Bicalutamide (16)
4-Cyano-3-(trifluoromethyl)phenylisocyanide (15; 0.67 g, 3.5
mmol) was dissolved in anhydrous CH2Cl2 (20 mL) and cooled in
an ice–water bath. TiCl4 (1 M in CH2Cl2, 3.9 mL, 1.2 equiv) was
added, (a precipitate was formed) and the resulting suspension was
stirred for 1 h. 1-(4-Fluorophenylsulfonyl)propan-2-one (14; 0.76 g,
3.5 mmol) was added and the mixture was stirred until TLC (silica
gel, EtOAc–hexane, 1:1) indicated complete consumption of the
starting materials (~3 h). H2O (20 mL) was added and the mixture
was stirred for another 20 min. The phases were separated and the
aqueous phase was extracted with CH2Cl2 (2 × 10 mL). The pooled
organic phases were washed with sat. NaHCO3 (15 mL), H2O (15
mL) and brine (15 mL). After drying over MgSO4, the solvent was
removed in vacuo and the residue was crystallized (EtOAc–hexane)
to afford 16 with >99% purity.
(13) (a) Masiello, D.; Cheng, S.; Bubley, G. J.; Lu, M. L.; Balk,
S. P. J. Biol. Chem. 2002, 29, 26321. (b) Hodgson, M. C.;
Astapova, I.; Hollenberg, A. N.; Balk, S. P. Cancer Res.
2007, 67, 8388.
(14) (a) Passerini, M. Gazz. Chim. Ital. 1921, 51, 126.
(b) Passerini, M. Gazz. Chim. Ital. 1921, 51, 181.
(15) (a) Schiess, M.; Seebach, D. Helv. Chim. Acta 1983, 66,
1618. (b) Seebach, D.; Adam, G.; Gees, T.; Schiess, M.;
Weigand, W. Chem. Ber. 1988, 121, 507. (c) Seebach, D.;
Beck, A. K.; Schiess, M.; Widler, L.; Wonnacott, A. Pure
Appl. Chem. 1983, 55, 1807.
(16) Carofiglio, T.; Cozzi, P. G.; Floriani, C. Organometallics
1993, 12, 2726.
(17) Semple, J. E.; Owens, T. D.; Nguyen, K.; Levy, O. E. Org.
Lett. 2000, 2, 2769.
(18) James, K. D.; Ekwuribe, N. N. Tetrahedron 2002, 58, 5905.
(19) James, K. D.; Ekwuribe, N. N. Synthesis 2002, 850.
(20) Obrecht, R.; Herrmann, R.; Ugi, I. Synthesis 1985, 400.
Yield: 0.99 g (66%).
1H NMR (CDCl3, 200 MHz): d = 7.99–7.87 (m, 3 H), 7.41–7.22 (m,
4 H), 4.3 (br s, 1 H, OH), 3.93 (d, 2J = 14.5 Hz, 1 H, CH2), 3.62 (d,
Synthesis 2008, No. 24, 4007–4011 © Thieme Stuttgart · New York