Synthesis of novel iodo derived bicalutamide analogs

Article abstract of DOI:10.1016/j.tetlet.2004.10.130

A series of optically active nonsteroidal selective androgen receptor modulators with structures analogous to bicalutamide was prepared by replacing the trifluoromethyl group with iodine and the sulfonyl linker by oxygen.

Full text of DOI:10.1016/j.tetlet.2004.10.130

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9475–9477
Synthesis of novel iodo derived bicalutamide analogs
Vipin A. Nair,a Suni M. Mustafa,a Michael L. Mohler,a Scott J. Fisher,b
James T. Daltonb and Duane D. Millera,*
aDepartment of Pharmaceutical Sciences, University of Tennessee, The Health Science Center,
847 Monroe Avenue, RM 227 C, Memphis, TN 38163, USA
bDivision of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University,
Columbus, OH 43210, USA
Received 24 September 2004; accepted 7 October 2004
Abstract—A series of optically active nonsteroidal selective androgen receptor modulators with structures analogous to bicalut-
amide was prepared by replacing the trifluoromethyl group with iodine and the sulfonyl linker by oxygen.
Ó 2004 Elsevier Ltd. All rights reserved.
The search for nonsteroidal antiandrogens that will
block the pharmacological effects of testosterone, led
to the development of compounds like flutamide, nilut-
amide, and (R,S)-bicalutamide, which are widely used
for the treatment of metastatic prostate cancer (Scheme
1).1–4 The commonly accepted structure–activity rela-
tionship borne out of these ligands suggest the import-
ance of an electron deficient aromatic ring, branched
alkyl group a to the amidic carbonyl, the need for a
strong hydrogen bonding and a conformational preor-
ganization, which assigns a coplanarity for the amide
linkage and hydroxyl group.5–11 It has been understood
that bicalutamide contains a stereogenic center and the
stereochemistry at this center is important in maximizing
the affinity for the androgen receptor; the (R) enantio-
mer being the active stereoisomer.12,13 The present
paper discusses the synthesis of a new class of optically
active bicalutamide analogs namely, (2S)-N-(40-cyano-
30-iodophenyl)-3-(4-substituted phenoxy)-2-hydroxy-2-
methylpropanamide derivatives 15, which are nonsteroi-
dal selective androgen receptor modulators (SARM).
A retrosynthetic strategy for the compound 15 leads to
the conclusion that it could be synthesized from the
synthons 4-amino-2-iodobenzonitrile 5, (2R)-3-bromo-
2-hydroxy-2-methylpropanoic acid 11 and 4-substituted
phenol 14. The noncommercial availability of 4-amino-
2-iodobenzonitrile prompted us to examine its synthesis.
Compound 5 was synthesized initially from 2-amino-4-
nitrobenzoic acid as shown in Scheme 2.6 A solution
of 2-amino-4-nitrobenzoic acid 1 in dilute sulfuric acid
was diazotized at 0°C by dropwise addition of an aque-
ous solution of sodium nitrite. The resulting diazonium
salt on treatment with a solution of sodium iodide
afforded 2-iodo-4-nitrobenzoic acid 2. It was converted
to the corresponding acid chloride by refluxing with
thionyl chloride in anhydrous benzene. Residual thionyl
chloride was removed from the reaction mixture by
O
F C
3
NC
F
O N
2
O
NH
O
O
S
O N
2
F C
3
N
F C
3
N
H
H
O
OH
O
(R,S)-Bicalutamide
Flutamide
Nilutamide
Scheme 1.
Keywords: Bicalutamide; Trifluoromethyl; Sulfonyl; Androgen; Receptor; Nonsteroidal; SARM.
*
Corresponding author. Tel.: +1 901 448 6026; fax: +1 901 448 3446; e-mail: dmiller@utmem.edu
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.130

9476
V. A. Nair et al. / Tetrahedron Letters 45 (2004) 9475–9477
HOOC
NC
HOOC
I
NC
I
H NOC
2
a
b
c
d
H N
2
NO
I
NO
2
NO
NH
2
I
NO
2
2
2
1
2
3
4
5
a: NaNO2, H2SO4, NaI b: SOCl2, aq. NH3 c: SOCl2 d: HCl, SnCl2.2H2O, EtOH
Scheme 2.
coevaporation with anhydrous benzene. Addition of
concentrated aqueous ammonia followed by overnight
stirring at room temperature precipitated 2-iodo-4-
nitrobenzamide 3, from which 2-iodo-4-nitrobenzonit-
rile 4 was prepared by refluxing it with thionyl chloride.
Subsequent reduction of the 2-iodo-4-nitrobenzonitrile
with tin(II) chloride dihydrate in acidic medium afforded
4-amino-2-iodobenzonitrile 5. However, due to multi-
step reactions with poor yields and drastic reaction con-
ditions, we designed a cost-effective two-step synthetic
strategy for the synthesis of 4-amino-2-iodobenzonitrile.
Compound 5 was synthesized according to Scheme 3,
wherein 2-iodo-4-nitroaniline 6 was dissolved in acetic
acid and then treated with 10% H2SO4 to obtain a
homogeneous solution. The reaction mixture was cooled
to 0°C in an ice-bath, diazotized with cold aqueous solu-
tion of NaNO2. Addition of the cold solution of diazo-
nium salt in a dropwise manner to an aqueous solution
of copper cyanide and sodium cyanide, afforded 2-iodo-
4-nitrobenzonitrile 4, which was reduced with tin(II)
chloride dihydrate in acidic medium to yield 4-amino-
2-iodobenzonitrile 5, which was identified by spectral
and elemental analyses.14
of the methacryloyl chloride. After the reaction, the
reaction mixture was acidified and extracted into ethyl
acetate to afford 1-(2-methacryloyl)pyrrolidine-2-carb-
oxylic acid 9. A solution of N-bromosuccinimide in
dimethyl formamide was added dropwise to a well
stirred solution of 1-(2-methacryloyl)pyrrolidine-2-carb-
oxylic acid in dimethyl formamide at room temperature
and the resulting mixture was stirred overnight. The
reaction mixture was poured into ice-cold distilled water
to obtain a yellow colored precipitate of the bromolac-
tone 10, which was then hydrolyzed by refluxing with
24% hydrobromic acid. Work-up of the reaction mixture
followed by recrystallization afforded colorless crystals
of optically active (2R)-3-bromo-2-hydroxy-2-methyl-
propanoic acid 11, which was identified by spectral
and elemental analyses.14
The synthetic procedure employed for the preparation
of target compound 15 is depicted in Scheme 5. A solu-
tion of (2R)-3-bromo-2-hydroxy-2-methylpropanoic
acid 11 in tetrahydrofuran was converted to the corre-
sponding acid chloride by thionyl chloride under argon
atmosphere at 0°C. Addition of a solution of 4-amino-2-
iodobenzonitrile 5 in tetrahydrofuran followed by over-
night stirring at room temperature yielded (2R)-N-(40-
cyano-30-iodophenyl)-3-bromo-2-hydroxy-2-methylpro-
panamide 12. With two electron withdrawing groups at-
tached, 4-cyano-3-iodobenzonitrile is a relatively poor
nucleophile and hence (2R)-3-bromo-2-hydroxy-2-meth-
ylpropanoic acid was used in a stochiometric excess of
1.5equiv. A solution of compound 12 in acetone when
refluxed with K2CO3 generated the epoxide, N-(40-cyano-
30-iodophenyl)-2,3-epoxy-2-methylpropanamide 13. The
epoxide was subsequently opened up by refluxing it
with 4-substituted phenol 14 and K2CO3 in 2-propanol
medium. The conversion of the intermediate 12 to
the ether linked target compound 15 through the epox-
ide formation was carried out in a two-step, one-pot
process wherein after the epoxide was formed, the sol-
vent was removed and the resulting residue was immedi-
ately carried on to the ring opening step. The (2S)-N-(40-
cyano-30-iodophenyl)-3-(4-substituted phenoxy)-2-hydr-
oxy-2-methylpropanamide derivatives obtained were
The (2R)-3-bromo-2-hydroxy-2-methylpropanoic acid
was prepared by employing (D)-proline as the starting
material as shown in Scheme 4. (D)-Proline 7 was con-
verted to 1-(2-methacryloyl)pyrrolidine-2-carboxylic
acid 9 by Schotten Baumann reaction. An acetone solu-
tion of 2-methacryloyl chloride 8 and sodium hydroxide
solution were simultaneously added to an ice-cold alka-
line solution of (D)-proline 7 in acetone. The pH of the
reaction mixture was kept alkaline during the addition
NC
I
H N
2
NC
I
e
d
NH
I
NO
2
NO
2
2
6
4
5
e: NaNO2, H2SO4, CuCN, NaCN d: HCl, SnCl2.2H2O, EtOH
Scheme 3.
H
O
Cl
H
H
g
O
h
f
N
+
O
COOH
HO
Br
COOH
N
O
N
OH
H
O
Br
O
8
10
11
7
9
f: NaOH, acetone g: NBS, DMF h: HBr
Scheme 4.

V. A. Nair et al. / Tetrahedron Letters 45 (2004) 9475–9477
9477
NC
I
O
NC
NC
I
O
O
i
j
+
HO
Br
Br
N
I
N
NH
2
O
H
OH
11
H
OH
5
13
12
R
NC
I
R
k
NC
I
O
O
+
O
N
H
HO
N
OH
O
H
14(a-d)
15(a-d)
13
i: SOCl2, THF j: K2CO3, acetone k: K2CO3, 2-propanol
R: a = F, b = Cl, c = Br, d = I
Scheme 5.
7. Tucker, H.; Chesterson, G. J. J. Med. Chem. 1988, 31, 885.
8. James, K. D.; Ekwuribe, N. N. Synthesis 2002, 7, 850.
9. Kirkovsky, L.; Mukherjee, A.; Yin, D.; Dalton, J. T.;
Miller, D. D. J. Med. Chem. 2000, 43, 581.
10. Yin, D.; Gao, W.; Kearby, J. D.; Xu, H.; Chung, K.; He,
Y.; Marhefka, C. A.; Veverka, K. A.; Miller, D. D.;
Dalton, J. T. J. Pharmacol. Exp. Ther. 2003, 304, 1334.
11. Yin, D.; Xu, H.; Kirkovsky, L. I.; Miller, D. D.; Dalton, J.
T. J. Pharmacol. Exp. Ther. 2003, 304, 1323.
12. Marhefka, C. A.; Moore, B. M., II; Bishop, T. C.;
Kirkovsky, L. I.; Mukherjee, A.; Dalton, J. T.; Miller, D.
D. J. Med. Chem. 2001, 44, 1729.
13. Marhefka, C. A.; Gao, W.; Chung, K.; Kim, J.; He, Y.;
Yin, D.; Bohl, C.; Dalton, J. T.; Miller, D. D. J. Med.
Chem. 2004, 47, 993.
characterized by spectral and elemental analyses (data
shown for 15a).14
In general, this work provides a facile route to the syn-
thesis of a new class of optically active bicalutamide
analogs with trifluoromethyl and sulfonyl groups being
replaced by iodine and oxygen, respectively. Preliminary
biological results have shown that these compounds
exhibited good activity and binding affinity to the
androgen receptor.15 However studies are ongoing for
the development of these target compounds as drug candi-
dates for therapeutic and diagnostic uses in prostate
cancer. Investigations are also carried out to replace
the iodine with a radioactive isotope (I125), through a tri-
methyltin intermediate, for imaging studies so as to con-
vincingly establish the mechanism of action of the tissue
selective androgen receptor modulator, which we dis-
covered in 1998.16
14. Spectral data 5: white solid (yield: 40%), mp 137°C; NMR
(1H, 300MHz, CDCl3): 6.62 (m, 1H, ArH, J = 1.9Hz,
8.3Hz), 7.15 (m, 1H, ArH, J = 0.5Hz, 8.3Hz) 7.35 (m, 1H,
ArH, J = 0.5Hz, 1.9Hz); MS: 245 CHN: C7H5IN2 calcd:
C, 34.45; H, 2.07; N, 11.48; found: C, 34.39; H, 1.96;
N, 11.41. Compound 11: White solid (yield: 85%), mp
25
108°C; ½aꢀD +10.5 (c 2.6, MeOH); NMR (1H, 300MHz,
DMSO): 1.35 (s, 3H, CH3), 3.5 (s, 1H, CH), 3.6 (s, 1H,
CH), 4.0 (br, 1H, OH); MS: 205 (M+Na+) CHN:
C4H7BrO3C, 26.25; H, 3.86; found: C, 26.28; H, 3.75.
Acknowledgements
25
We would like to thank the Department of Defense
(DOD) for the grant ÔNovel Strategy for Prostate Can-
cer Imaging: Synthesis and Pharmacology of Nonsteroi-
dal LigandsÕ DAMD17-01-1-0103. The American
Chemical Society, Division of Medicinal Chemistry is
gratefully acknowledged for support via a pre-doctoral
fellowship for Michael L. Mohler.
Compound 12: white solid (yield: 35%), mp 152°C; ½aꢀD
+47.3 (c 1.0, MeOH); NMR (1H, 300MHz, CDCl3): 1.7 (s,
3H, CH3), 3.1 (br, 1H, OH), 3.6 (s, 1H, CH), 4.1 (s, 1H,
CH), 7.6 (m, 1H, ArH, J = 1.8Hz, 7.2Hz), 7.7 (m, 1H,
ArH, J = 0.5Hz, 7.2Hz), 8.3 (m, 1H, ArH, J = 0.5Hz,
1.8Hz), 8.9 (br, 1H, NH); MS: 407.8 C11H10BrIN2O2
calcd: C, 32.30; H, 2.46; N, 6.85; found: C, 32.28; H, 2.35;
N, 6.82. Compound 15a: (R = F) white solid (yield: 65%),
25
mp 101°C; ½aꢀD ꢁ72.1 (c 1.0, MeOH); NMR (1H,
300MHz, CDCl3): 1.5 (s, 3H, CH3), 3.3 (br, 1H, OH),
3.9 (s, 1H, CH), 4.4 (s, 1H, CH), 6.9 (m, 2H, ArH,
J = 3.0Hz, 9.2Hz,), 7.0 (m, 2H, ArH, J = 3.0Hz, 9.2Hz),
7.6 (m, 1H, ArH, J = 1.8Hz, 7.2Hz), 7.7 (m, 1H, ArH,
J = 0.4Hz, 7.2Hz), 8.3 (m, 1H, ArH, J = 0.4Hz, 1.8Hz),
8.9 (br, 1H, NH); MS: 438.9 (MꢁH) C17H14FIN2O3 calcd:
C, 46.38; H, 3.21; N, 6.36; found: C, 46.27; H, 3.15; N, 6.24.
15. Nair, V. A.; Mustafa, S. M.; Mohler, M. L.; Fisher, S. J.;
Dalton, J. T.; Miller, D. D. Unpublished results—
Presented at the 228th American Chemical Society Meet-
ing; Division of Medicinal Chemistry: Philadelphia, 2004.
16. Dalton, J. T.; Mukherjee, A.; Zhu, Z.; Kirkovsky, L.;
Miller, D. D. Biochem. Biophys. Res. Commun. 1998,
244(1), 1.
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