An improved synthesis of (4-{4-hydroxy-3-isopropyl-5-[(4-nitrophenyl) ethynyl] benzyl}-3,5-dimethylphenoxy)acetic acid (NH-3)

Article abstract of DOI:10.1055/s-0028-1088041

Sonogashira coupling of methyl {4-[3-iodo-5-isopropyl-4-(methoxymethoxy) benzyl]-3,5-dimethylphenoxy}acetate with (trimethylsilyl)acetylene afforded the corresponding (trimethylsilyl) ethynyl derivative in quantitative yield. Copper-free palladium-catalyz

Full text of DOI:10.1055/s-0028-1088041

1428
SHORT PAPER
An Improved Synthesis of (4-{4-Hydroxy-3-isopropyl-5-[(4-nitrophenyl)ethy-
nyl]benzyl}-3,5-dimethylphenoxy)acetic Acid (NH-3)
An
Improved
S
ynthesi
aof NH-3 dathil B. Gopinathan, Kenneth S. Rehder*
RTI International, Center for Organic and Medicinal Chemistry, Research Triangle Park, NC 27709-2194, USA
Fax +1(919)5418868; E-mail: krehder@rti.org
Received 4 November 2008
Thyroid receptors (TRs) exert profound effects on devel-
Abstract: Sonogashira coupling of methyl {4-[3-iodo-5-isopropyl-
4-(methoxymethoxy)benzyl]-3,5-dimethylphenoxy}acetate with
(trimethylsilyl)acetylene afforded the corresponding (trimethylsi-
lyl)ethynyl derivative in quantitative yield. Copper-free palladium-
opment and homeostasis in mammals.1 Development of
TR antagonists is of current interest because of their po-
tential clinical use in treatment of thyrotoxicosis and hy-
catalyzed coupling of this intermediate with 1-iodo-4-nitrobenzene perthyroidism.2 The compound known as NH-3 (5,
afforded methyl (4-{3-isopropyl-4-(methoxymethoxy)-5-[(4-nitro-
Scheme 1) selectively and completely blocks TR and
shows in vivo activity in a tadpole tail resorption assay.3
phenyl)ethynyl]benzyl}-3,5-dimethylphenoxy)acetate in high
yield. Saponification of the ester group, followed by the removal of
A recent study4 describes the pharmacological profile of 5
the methoxymethyl group afforded (4-{4-hydroxy-3-isopropyl-5-
in rats.
[(4-nitrophenyl)ethynyl]benzyl}-3,5-dimethylphenoxy)acetic acid
(NH-3).
Compound 5 was previously synthesized as shown in
Scheme 1.5 The key step was the Suzuki–Miyaura cou-
Key words: coupling, Sonogashira coupling, palladium catalysis,
1-iodo-4-nitrobenzene, hydrolysis
pling of 5¢-iodinated intermediate 1 with the boronate de-
rivative of 4-ethynylaniline to afford 5¢-(phenylethynyl)
intermediate 2 in 58% yield on a 2.3 mmol scale.6 This re-
action required cannula transfer of the boronate deriva-
H
NH2
KHMDS, 9-BBN–OMe
MOMO
MOMO
O
O
CO2Me
[PdCl2(PPh3)2]
I
1
MOMO
O
CO2Me
CO2Me
MCPBA
NO2
NH2
2
3
HO
O
CO2H
HO
O
CO2Me
LiOH⋅H2O
HCl
NO2
NO2
5
4
Scheme 1
SYNTHESIS 2009, No. 9, pp 1428–1430
x
x
.
x
x
.2
0
0
9
Advanced online publication: 25.03.2009
DOI: 10.1055/s-0028-1088041; Art ID: M06808SS
© Georg Thieme Verlag Stuttgart · New York

SHORT PAPER
An Improved Synthesis of NH-3
1429
H
TMS
[PdCl2(PPh3)2]
CuI, Et3N
MOMO
MOMO
O
O
CO2Me
CO2Me
I
1
6
TMS
I
NO2
LiOH⋅H2O
MOMO
O
CO2Me
Pd(OAc)2
TBAF
3
NO2
HO
O
CO2H
MOMO
O
CO2H
HCl
7
5
NO2
NO2
Scheme 2
tive, generated in situ under basic conditions with 9- yield. The overall yield of 5 from 1 was 55% (4 steps),
methoxy-9-borabicyclo[3.3.1]nonane in anhydrous tet- compared to the literature yield of 17% (4 steps).
rahydrofuran at –78 °C, to a mixture containing 1 and
In summary, an efficient and scalable synthesis of NH-3
dichlorobis(triphenylphosphine)palladium(II) and further
has been developed. This general method can be used to
refluxing of the mixture for 15 hours. Subsequent m-chlo-
synthesize other NH-3 analogues and would provide
roperoxybenzoic acid oxidation of 2 gave nitro compound
35 in 61% yield, and in an overall yield of 35% from 1 to
3. Compound 3 was then converted into target compound
5 via a standard deprotection and hydrolysis sequence.
products without benzofuran impurities.6
Reagents were obtained from Aldrich Chemical Company and were
used as received unless mentioned otherwise. Melting points were
determined on a Fisher–John’s apparatus and are uncorrected.
HRMS was performed at the University of Michigan, Ann Arbor,
MI. The 1H and 13C NMR spectra of samples in CDCl3, with TMS
as internal standard, were recorded on a Bruker Avance spectrome-
ter (300 MHz). Mass spectra were run on a Perkin-Elmer Sciex
APR150 EX mass spectrometer outfitted with APCI (atmospheric
pressure chemical ionization) or ESI (turbospray) sources. Flash
column chromatography was carried out on a CombiFlash Compan-
ion system using Isco prepacked silica gel columns or by using E.
Merck silica gel 60 (230–400 mesh). Analytical TLC was carried
out on EMD silica gel 60 F254 TLC plates. Elemental analyses were
done by Atlantic Microlab Inc., Norcross, GA.
As part of an ongoing research program, gram-scale quan-
tities of 5 were required. Unfortunately, attempts to repli-
cate the synthetic sequence of 1 to 3 were not successful,
possibly due to the stringent experimental conditions.
Therefore, a more efficient, scalable, and potentially more
versatile synthesis of 5 was developed (Scheme 2).
Sonogashira7 coupling of 5¢-iodinated intermediate 1, ob-
tained according to the literature procedure,6 with (tri-
methylsilyl)acetylene afforded (trimethylsilyl)ethynyl
intermediate 6 in quantitative yield under mild conditions
(Scheme 2). This reaction was performed on a 10 mmol
scale and could be scaled up readily. Subsequent reaction
of 6 with 1-iodo-4-nitrobenzene, tetrabutylammonium
fluoride, and palladium(II) acetate afforded intermediate
3 in 76% yield. Conversion of 3 into target compound 5
according to the literature procedure (Scheme 1) pro-
duced a product mixture, which, in addition to 5, con-
tained traces of impurities8 that could not be removed.
Reversing the final sequence, 3 was first hydrolyzed with
lithium hydroxide to give acid 7 in quantitative yield
(Scheme 2). Subsequent hydrogen chloride deprotection
of the methoxymethyl group from 4 afforded 5 in 73%
Methyl (4-{3-Isopropyl-4-(methoxymethoxy)-5-[(trimethylsi-
lyl)ethynyl]benzyl}-3,5-dimethylphenoxy)acetate (6)
A soln of 1 (5.12 g, 10 mmol) in Et3N (120 mL) was degassed by
having argon bubbled through it for 10 min. [PdCl2(PPh3)2] (350
mg, 0.5 mmol) and CuI (95 mg, 0.5 mmol) were added to the solu-
tion. (Trimethylsilyl)acetylene (1.57 g, 16 mmol) was added, and
the mixture was stirred at r.t. under argon for 3 h. Then the mixture
was filtered through a pad of Celite, which was subsequently
washed with Et3N (100 mL). The filtrate and the washings were
combined and evaporated under vacuum. Purification of the residue
by column chromatography (silica gel, EtOAc–hexane, 1:9) afford-
ed 6.
Synthesis 2009, No. 9, 1428–1430 © Thieme Stuttgart · New York

1430
M. B. Gopinathan, K. S. Rehder
SHORT PAPER
Pale brown oil; yield: 4.82 g (100%).
(4-{4-Hydroxy-3-isopropyl-5-[(4-nitrophenyl)ethynyl]benzyl}-
3,5-dimethylphenoxy)acetic Acid (5, NH-3)
1H NMR (300 MHz, CDCl3): d = 0.22 (s, 9 H), 1.14 (d, J = 6.9 Hz,
6 H), 2.19 (s, 6 H), 3.38 (hept, J = 6.9 Hz, 1 H), 3.59 (s, 3 H), 3.81
(s, 3 H), 3.88 (s, 2 H), 4.6 (s, 2 H), 5.18 (s, 2 H), 6.63 (s, 2 H), 6.80
(s, 1 H), 6.91 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = –0.2, 20.5, 23.3, 26.3, 33.8, 52.1,
57.4, 65.3, 97.9, 99.6, 102.5, 114.1, 116.3, 126.8, 129.9, 135.5,
138.6, 141.8, 154.6, 155.9, 169.6.
Concd aq HCl (3.6 mL) was added to a stirred solution of 7 (1.00 g,
1.93 mmol) in THF (44 mL), and the mixture was stirred at r.t. for
18 h. It was then filtered and the filtrate was evaporated under vac-
uum. The residue was partitioned between CH2Cl2 (40 mL) and
H2O (20 mL). The organic layer was washed with brine (30 mL),
dried (Na2SO4), and evaporated under vacuum. Purification of the
residue on an ISCO prepacked silica column (MeOH–CH2Cl2, 2:98
to 15:85) afforded a yellow solid (753 mg). This material was dis-
solved in CH2Cl2 (10 mL) and treated with hexane (60 mL). The
precipitated solid was collected and dissolved again in warm
CH2Cl2 (25 mL). The CH2Cl2 solution was treated with hexane
(160 mL). The precipitate was collected, washed with hexane, and
dried under vacuum; this afforded 5.
ESI-HRMS: m/z [M + Na]+ calcd for C28H38NaO5Si: 505.2386;
found: 505.2378.
Methyl (4-{3-Isopropyl-4-(methoxymethoxy)-5-[(4-nitrophe-
nyl)ethynyl]benzyl}-3,5-dimethylphenoxy)acetate (3)
Pd(OAc)2 (110 mg, 0.49 mmol) was added to a stirred soln of 6
(4.67 g, 9.67 mmol) and 1-iodo-4-nitrobenzene (2.4 g, 9.67 mmol)
in anhyd THF (55 mL) under argon. A 1.0 M solution of TBAF in
THF (9.6 mL) was then added. The dark-colored mixture was
stirred at r.t. for 70 min and then at 65 °C for 10 min. The mixture
was cooled to r.t., poured into sat. aq NaHCO3 (220 mL) and ex-
tracted with EtOAc (3 × 200 mL). The combined extracts were
washed with brine (250 mL), dried (Na2SO4), and evaporated under
vacuum. Flash column purification of the residue (silica gel,
EtOAc–hexane, 10:90 to 20:80) afforded 3.
Yellow solid; yield: 669 mg (73%); mp 173–174 °C.
1H NMR (300 MHz, CDCl3): d = 1.23 (d, J = 6.9 Hz, 6 H), 2.23 (s,
6 H), 3.26 (hept, J = 6.9 Hz, 1 H), 3.90 (s, 3 H), 4.69 (s, 2 H), 5.69
(br, 1 H), 6.67 (s, 2 H), 6.71 (s, 1 H), 7.02 (s, 1 H), 7.64 (d, J = 8.8
Hz, 2 H), 8.22 (d, J = 8.8 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 20.5, 22.3, 27.6, 33.6, 64.9, 89.4,
93.9, 107.9, 114.2, 123.7, 127.3, 128.7, 129.4, 130.6, 131.8, 132.1,
134.7, 138.8, 147.2, 152.5, 155.4, 172.5.
Yellow solid; yield: 3.91 g (76%).
ESI-HRMS: m/z [M + Na]+ calcd for C28H27NNaO6: 496.1736;
found: 496.1741.
1H NMR (300 MHz, CDCl3): d = 1.20 (d, J = 6.9 Hz, 6 H), 2.22 (s,
6 H), 3.40 (hept, J = 6.9 Hz, 1 H), 3.62 (s, 3 H), 3.82 (s, 3 H), 3.93
(s, 2 H), 4.64 (s, 2 H), 5.22 (s, 2 H), 6.65 (s, 2 H), 6.84 (s, 1 H), 7.05
(s, 1 H) 7.63 (d, J = 8.9 Hz, 2 H), 8.20 (d, J = 8.9 Hz, 2 H).
Anal. Calcd for C28H27NO6: C, 71.02; H, 5.75; N, 2.96. Found: C,
70.80; H, 5.91; N, 3.07.
13C NMR (75 MHz, CDCl3): d = 20.4, 23.2, 26.4, 33.7, 52.1, 57.5,
65.2, 90.9, 92.4, 99.9, 114.2, 115.5, 123.5, 127.9, 129.6, 129.7,
130.2, 132.0, 136.0, 138.5, 142.2, 146.8, 154.2, 156.0, 169.5.
Acknowledgment
This work was supported by the National Institute of Mental Health
under contract N01-MH-32005.
ESI-MS: m/z = 532.6 [M + H]+.
(4-{3-Isopropyl-4-(methoxymethoxy)-5-[(4-nitrophenyl)ethy-
nyl]benzyl}-3,5-dimethylphenoxy)acetic Acid (7)
References
A soln of LiOH·H2O (312 mg, 7.44 mmol) in H2O (16 mL) was
added to a stirred suspension of 3 (1.59 g, 3 mmol) in MeOH
(120 mL). After stirring at r.t. for 50 min, the mixture was heated to
reflux, to give a clear solution. After the mixture had stirred for an-
other 20 min at r.t., the solvent was removed under vacuum. The
residue was treated with H2O (80 mL), acidified to pH 1 with 1 N
aq HCl, and extracted with CH2Cl2 (1 × 100 mL, 2 × 50 mL). The
combined extracts were washed with brine (100 mL) and dried
(Na2SO4). Evaporation of the solvent under vacuum afforded 7.
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Yellow foamy solid; yield: 1.55 g (100%); mp 90–95 °C.
1H NMR (300 MHz, CDCl3): d = 1.16 (d, J = 6.9 Hz, 6 H), 2.07 (s,
6 H), 3.37 (hept, J = 6.9 Hz, 1 H), 3.59 (s, 3 H), 3.82 (s, 2 H), 4.47
(s, 2 H), 5.19 (s, 2 H), 6.60 (s, 2 H), 6.78 (s, 1 H), 6.99 (s, 1 H) 7.54
(d, J = 8.8 Hz, 2 H), 8.13 (d, J = 8.8 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 20.3, 23.3, 26.4, 33.7, 57.5, 66.1,
91.0, 92.3, 99.9, 114.5, 115.5, 123.7, 127.9, 129.5, 129.9, 130.1,
131.9, 135.9, 138.5, 142.3, 146.9, 154.3, 155.6, 174.8.
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(8) The spectral properties of the impurity were suggestive of a
substituted benzofuran, but this was not verified.
ESI-HRMS: m/z [M + Na]+ calcd for C30H31NNaO7: 540.1998;
found: 540.2000.
Anal. Calcd for C30H31NO7·0.5H2O: C, 68.43; H, 6.13; N, 2.66.
Found: C, 68.53; H, 5.98; N, 2.75.
Synthesis 2009, No. 9, 1428–1430 © Thieme Stuttgart · New York