An improved synthesis of enantiomerically pure RWJ 69442, a development candidate for the treatment of benign prostatic hyperplasia

Article abstract of DOI:10.1002/jhet.5570380433

This report describes an improved synthesis of enantiomerically pure (S)-2-[4-(Dimethylamino)phenyl]- 2,3-dihydro-N-[2-hydroxy-3-[4-[2-(1-methylethoxy)-phenyl]-1-piperazinyl] propyl]-1,3-dioxo-1H- isoindole-5-carboxamide (RWJ 69442), a potent and selectiv

Full text of DOI:10.1002/jhet.5570380433

Jul-Aug 2001
An Improved Synthesis of Enantiomerically
Pure RWJ 69442, A Development Candidate for
The Treatment of Benign Prostatic Hyperplasia
1003
Gee-Hong Kuo [a]*, Catherine Prouty [a],
William V. Murray [a] and Rekha D. Shah [b]
[a] Drug Discovery Division, [b] NPR/Analytical Department,The R.W. Johnson
Pharmaceutical Research Institute, 1000 Route 202, P.O. Box 300, Raritan, New Jersey 08869, USA
Received December 18, 2000
This report describes an improved synthesis of enantiomerically pure (S)-2-[4-(Dimethylamino)phenyl]-
2,3-dihydro-N-[2-hydroxy-3-[4-[2-(1-methylethoxy)-phenyl]-1-piperazinyl]propyl]-1,3-dioxo-1H-
isoindole-5-carboxamide (RWJ 69442), a potent and selective α -adrenergic receptor antagonist for the
1a
treatment of benign prostatic hyperplasia. The synthesis highlights less hazardous reagents, easier purifica-
tion and higher enantiomeric purity. The N-benzyl-N-t-butoxycarbonyl amine 6 could serve as an
enantiomerically pure chiral building block for asymmetric synthesis.
J. Heterocyclic Chem., 38, 1003 (2001).
In a program to develop a potent and selective
the chromatographic purification of azido-tosylate 2 [2]
was not trivial even on multi-gram scale. Third, in order
to obtain greater than 99% ee of RWJ 69442, column
chromatography followed by repeated recrystallizations
of the intermediates were required.
In our efforts to improve the synthesis without involving
azide functionality, we examined a variety of amine
equivalents including methoxyamine, phthalimide,
aminodiphenylmethane, benzylamine, tritylamine,
benzophenone imine, di-t-butyl iminodicarboxylate and
ammonia. We found that the use of benzylamine followed
by t-butyloxycarbonyl (Boc) protection best fulfilled our
overall requirements (Scheme II).
α -adrenergic receptor antagonist for the treatment of
1a
benign prostatic hyperplasia (BPH), (S)-2-[4-
(Dimethylamino)phenyl]-2,3-dihydro-N-[2-hydroxy-3-
[4-[2-(1-methylethoxy)-phenyl]-1-piperazinyl]propyl]-
1,3-dioxo-1H-isoindole-5-carboxamide (RWJ 69442)
was identified as a development candidate [1]. A sample
of 25 g of RWJ 69442 was prepared based upon the
approach shown in Scheme I [1]. However, there were
some drawbacks associated with this approach that were
not ideal for larger scale synthesis. First, the preparation
of azido-diol 1 [2] involved the use of the highly toxic
and potentially explosive sodium azide reagent. Second,

1004
G.-H. Kuo, C. Prouty, W. V. Murray and R. D. Shah
Vol. 38
Reaction of (S)-(+)-epichlorohydrin (97% ee) and
[2-(4-dimethylamino)phenyl]-1,3-dioxo-2,3-dihydro-
1H-isoindole-5-carboxylic acid [1] using HATU,
indeed, gave the enantiomerically pure RWJ 69442 as
determined by Chiralpak AD HPLC.
benzylamine [3] in hexane gave a white solid at 20 °C.
Simple filtration and recrystallization gave pure crystalline
product 5 in 82% yield. Protection of benzylamine 5 with
2,2-dimethylpropanoic anhydride (Boc O) gave the
It is very interesting to note that the 2-hydroxy-1,3-
diaminopropane chiral moiety present in RWJ 69442 is
also embedded in many biologically interesting molecules
such as the antibacterial drugs – Linezolid [5], Eperezolid
[5] and DUP-721 [6] and also monoamine oxidase
inactivators [7]. The synthesis of these molecules almost
all involved the usage of the sodium azide reagent. It is
conceivable that the use of compound 6 may provide a
practical and efficient alternative synthesis of these
important drugs.
2
N-benzyl-N-t-butoxycarbonyl amine 6 in 84% yield as a
white crystalline solid. Protection of 5 with t-butoxy-
carbonyl group was necessary to avoid the loss of
enantiomeric purity in the following step due to the
symmetrical attack at the azetidine intermediate [3] by
either the chloride anion or the piperazine used. In
comparison to the oily azido-tosylate 2, the N-benzyl-N-t-
butoxycarbonyl amine 6 had the advantage of easier
synthesis, higher yield, higher chemical purity and higher
enantiomeric purity that was reflected in the next step.
Attempted alkylations of 2-isopropoxyphenyl-
piperazine with 6 under a variety of reaction conditions
only resulted in poor yields. On the other hand, alkyl-
ation with the assumed epoxide intermediate generated
in situ by treatment of 6 with a base gave the desired
product 7 in 63% yield as a single enantiomer analyzed
by Chiralpak OD HPLC. Removal of the Boc-protecting
group with trifluoroacetic acid (TFA) gave the
deprotected amino alcohol 8 that was used directly
without further purification. Hydrogenolysis of 8 under
EXPERIMENTAL
1
13
H and C NMR spectra were measured on a Bruker
AC-300 spectrometer using tetramethylsilane as an internal
standard. Elemental analyses were obtained by Quantitative
Technologies Inc. (Whitehouse, New Jersey), and the results
were within 0.4% of the calculated values unless otherwise
mentioned. Melting points were determined in open capillary
tubes with a Thomas-Hoover apparatus and were uncorrected.
The optical rotations were measured at 25 °C with an Autopol
III polarimeter. Electrospray mass spectra (MS-ES) were
recorded on a Hewlett Packard 59987A spectrometer. High
resolution mass spectra (HRMS) were obtained on a
Micromass Autospec. E. spectrometer. The acronym "DMAP"
refers to dimethylaminopyridine, "TFA" refers to trifluoro-
acetic acid, "HATU" refers to O-(7-azabenzotriazol-1-yl)-
1,1,3,3-tetramethyluronium hexafluorophosphate, and "NMP"
refers to 1-methyl-2-pyrrolidinone.
standard conditions (1 atm H , 20% Pd(OH) /C) gave
2
2
only 50% conversion after seven days of reaction. We
found that de-benzylation of 8 was best achieved with
catalytic transfer hydrogenolysis [4]. Reaction of 8 with
an excess of ammonium formate in the presence of
catalytic amounts of 10% palladium on carbon gave
amino-alcohol 4 in 66% yield that was identical to the
compound prepared previously [1]. Coupling of 4 with

Jul-Aug 2001
An Improved Synthesis of Enantiomerically Pure RWJ 69442
1005
(2S)-1-Chloro-3-[(phenylmethyl)amino]-2-propanol (5).
Chiralpak OD 4.6 x 250 mm. 1 mL/minute, 254 nm, mobile
phase: 90/10/0.1 of hexane/IPA/diethylamine) as a yellowish
A mixture of (S)-(+)-epichlorohydrin (10 g, 108.1 mmol,
Aldrich, 97% ee) and benzylamine (11.57 g, 108.1 mmol) in
hexane (40 mL) were stirred at 20 °C for 62 hours. A white solid
precipitated. More hexane (~ 350 mL) was added, the mixture
was stirred for 20 minutes, and then sonicated to break up the big
chunks of the white solid. The white solid was collected by
filtration, washed with hexane, and dried under vacuum to give
19.8 g (92%) white solid. The white solid was recrystallized from
EtOAc/hexane to give 17.76 g (82%) of 5 as a white crystalline
25
1
oil; [α]
= +8.2° (c = 1, CHCl ); H NMR (300 MHz,
CDCl ): δ 7.26-7.35 (m, 5 H), 6.91 (m, 4 H), 4.68 (d, J = 15.6
D
3
3
Hz, 1 H), 4.59 (m, 3 H), 3.95 (m, 1 H), 3.35 (m, 2 H), 3.11 (m,
4 H), 2.75 (m, 2 H), 2.54 (m, 2 H), 2.38 (m, 2 H), 1.45 (m, 9
13
H), 1.34 (d, J = 6.1 Hz, 6 H); C NMR (75 MHz, CDCl ): δ
3
156.9, 150.7, 143.2, 139.1, 128.9, 127.7, 127.5, 122.9, 122.0,
118.8, 116.8, 80.3, 70.6, 67.4, 62.2, 54.1, 52.7., 51.5, 50.9,
+
28.8, 22.8; MS (ES) m/z: 484 (M+H ).
Anal. Calcd. for C
H N O : C, 69.54; H, 8.54; N, 8.69.
28 41 3 4
25
1
solid; mp 88.5-90.5 °C; [α]
= -14.5° (c = 1, CHCl ); H NMR
D
3
Found: C, 69.27; H, 8.60; N, 8.45.
(300 MHz, CDCl ): δ 7.31 (m, 5 H), 3.88 (m, 1 H), 3.79 (m, 2 H),
3.53 (d, J = 5.3 Hz, 2 H), 2.89 (m, 2 H), 2.81 (dd, J = 12.4, 4.1 Hz,
1 H), 2.69 (dd, J = 12.2, 7.9 Hz, 1 H); C NMR (75 MHz,
3
(αS)-α-(Aminomethyl)-4-[2-(1-methylethoxy)phenyl]-1-piper-
azineethanol (4).
13
DMSO-d ): δ 141.1, 128.5, 128.2, 126.9, 70.0, 53.3, 52.2, 48.5;
6
A mixture of compound 7 (10.1 g, 21.91 mmol) and 25%
TFA/methylene chloride (100 mL) was stirred at 20 °C for
22 hours. The solvent was removed under reduced pressure,
+
MS (ES) m/z: 200 (M+H ).
Anal. Calcd. for C
H NOCl: C, 60.15; H, 7.07; N, 7.01.
10 14
Found: C, 60.10; H, 7.02; N, 6.92.
the residue was basified with 20% NaOH
and extracted
(aq)
((2S)-3-Chloro-2-hydroxypropyl)(phenylmethyl)carbamic Acid,
1,1-Dimethylethyl ester (6).
with methylene chloride (3x). The combined extracts were
dried (Na SO ) and concentrated to give 7.61 g of de-Boc
2
4
product 8 as an oil which was used directly without further
2,2-Dimethylpropanoic anhydride (Boc O) (11 g,
2
1
purification; H NMR (300 MHz, CDCl ): δ 7.30 (m, 5 H),
3
50.1 mmol) and triethylamine (10.12 g, 100 mmol) were
dissolved in THF (25 mL) and cooled to 0 °C. The amine 5
(10 g, 50.1 mmol) was added in portions and the reaction
mixture was stirred for 20 hours while allowing to warm to
20 °C overnight. The solvent was removed under reduced
pressure and water was added to the residue. The mixture was
6.91 (m, 4 H), 4.59 (m, 1 H), 3.90 (m, 3 H), 3.10 (m 7 H), 2.80
(m, 2 H), 2.70-2.38 (m, 5 H), 1.34 (d, J = 6.2 Hz, 6 H); MS
+
(ES) m/z: 384 (M+H ).
A mixture of 8 (7.3 g, 19.06 mmol) in CH OH (100 mL) under
3
nitrogen was stirred and treated with 10% Pd/C (1.46 g, 20% by
wt.) followed by a solution of ammonium formate (6 g, 95.3
mmol) in water (20 mL). The resulting mixture was stirred at
55-60 °C for 23 hours. The cooled reaction mixture was filtered
through celite and the celite was further washed with methanol.
extracted with ether (3x), dried (Na SO ) and concentrated.
2
4
The crude residue was recrystallized from EtOAc/hexane to
give 9.9 g (66%) of 6 as a white crystalline solid. The filtrate
was concentrated (3.1 g of oil) and more product was obtained
by column chromatography (short column, 8 cm height of
The filtrate was concentrated to remove CH OH. The residue
3
was diluted with water, extracted with CH Cl (3x), dried
SiO , EtOAc/hexane as eluent). The oil was recrystallized
2
2
2
(Na SO ) and concentrated. The product was purified by a short
from EtOAc/hexane to give another 2.78 g (18%) of 6 as a
2
4
25
column (5 cm height of SiO ) to give 3.85 g (66%) of 4 as an oil
white crystalline solid; mp 64.5-65.5 °C; [α]
= -10.2° (c =
2
D
1
that was identical to an authentic sample [1] in all respects.
1, CHCl ); H NMR (300 MHz, CDCl ): δ 7.22-7.36 (m, 5 H),
4.52 (m, 2 H), 4.30 (brs, 0.5 H), 3.96 (m, 1 H), 3.36-3.97 (m,
4 H), 1.47 (s, 9 H); C NMR (75 MHz, CDCl ): δ 158.2,
3
3
(S)-2-[4-(Dimethylamino)phenyl]-2,3-dihydro-N-[2-hydroxy-3-
[4-[2-(1-methylethoxy)-phenyl]-1-piperazinyl]propyl]-1,3-
dioxo-1H-isoindole-5-carboxamide (RWJ 69442).
13
3
138.2, 129.0, 127.8, 127.7, 81.5, 71.9, 53.0, 51.1, 46.8, 28.7;
MS (ES) m/z: 322 (M+Na).
The amine 4 (176 mg, 0.6 mmol) was dissolved in a mixture of
N,N-diisopropylethylamine (310 mg, 2.4 mmol) and methylene
chloride (5 mL). To this solution was added [2-(4-dimethyl-
amino)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-
carboxylic acid [1] (205 mg, 0.66 mmol) and HATU (251 mg,
0.66 mmol) and the mixture was stirred at 20 °C for 22 hours
Anal. Calcd. for C
Found: C, 60.26; H, 7.42; N, 4.63.
H NO Cl: C, 60.10; H, 7.40; N, 4.67.
15 22 3
[(2R)-2-Hydroxy-3-[4-[2-(1-methylethoxy)phenyl]-1-piper-
azinyl]propyl]-(phenylmethyl)-carbamic acid, 1,1-dimethylethyl
Ester (7).
under N . The reaction mixture was diluted with more methylene
KOH (11.23 g, 200.5 mmol) was dissolved in methanol
(280 mL), and the fumarate salt of 1-(2-isopropoxyphenyl)-
piperazine (10.9 g, 33.4 mmol) was added. The reaction
mixture was stirred at 20 °C for 20 minutes and then cooled to
0 °C. The Boc-protected amine 6 (10 g, 33.4 mmol) was added
to the methanol solution at 0 °C and stirred for another
20 hours while allowing the temperature to warmed to 20 °C.
The solvent was removed under reduced pressure, and water
was added. The product was extracted with ether (3x), dried
2
chloride, washed with 3% K CO
, dried (Na SO ) and
2
3(aq)
2 4
concentrated. The product was purified by column chromato-
graphy (SiO ) to give 193 mg (55%) of RWJ 69442 as a yellow
2
solid (100% ee, Chiralpak AD 4.6 x 250 mm. 0.75 mL/min,
220 nm, mobile phase: 100% ethanol, retention time 43.9 min);
25
[α]
= +10.5° (c = 0.2 , CHCl ). All other spectra data were
D
3
identical to that of the compound prepared previously [1].
Acknowledgements.
(Na SO ) and concentrated. The product was purified by
2
4
column chromatography (short column, 8 cm height SiO ,
EtOAc/hexane as eluent) to give 10.22 g (63%) of 7 (100% ee,
We thank Dr. David Palmer and Dr. Ahmed F. Abdel-Magid
for helpful discussions.
2

1006
G.-H. Kuo, C. Prouty, W. V. Murray and R. D. Shah
Vol. 38
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