Novel and efficient synthesis of tert-butyl-2-(4-(2-aminoethyl)phenylthio)- 2-methylpropanoate, a key intermediate in the synthesis of ureido thioisobutyric acid

Article abstract of DOI:10.1080/00397911003644399

A convenient and cost-effective synthesis of pharmacologically important tert-butyl-2-(4-2-aminoethyl)phenylthio)-2-methylpropanoate from commercially available 2-2-phenyl-1-ethanol is described.

Full text of DOI:10.1080/00397911003644399

Synthetic Communications1, 41: 748–753, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911003644399
NOVEL AND EFFICIENT SYNTHESIS OF TERT-BUTYL-
2-(4-(2-AMINOETHYL)PHENYLTHIO)-2-
METHYLPROPANOATE, A KEY INTERMEDIATE IN THE
SYNTHESIS OF UREIDO THIOISOBUTYRIC ACID
Jigar Desai, Anil Argade, Sanjay Gite, Kiran Shah,
Laxmikant Pavase, Pravin Thombare, and Pankaj Patel
Medicinal Chemistry Division, Zydus Research Centre, Ahmedabad,
Gujarat, India
Abstract A convenient and cost-effective synthesis of pharmacologically important
tert-butyl-2-(4-2-aminoethyl)phenylthio)-2-methylpropanoate from commercially avail-
able 2-2-phenyl-1-ethanol is described.
Keywords Fibrates; hyperlipidemia; thioisobutyric acid
Hyperlipidemia is associated with an increased risk of coronary heart disease, the
leading cause of death in the western world.[1] Drug therapy with fibrate is one
way to effectively lower triglyceride and low-density lipoprotein and raise high-
density lipoprotein in human. Fibric acid analogs such as clofibrate, fenofibrate,
and bezafibrate are effective in the treatment of hyperlipidemia in humans[2] (Fig. 1).
Fibrates are relatively weak PPARa agonists and mediate their lipid-lowering
activity through PPARa activation. Ureido fibrate analogs showed moderate
PPARa selectivity on both murin and human receptors. Earlier studies showed that
ureido fibrate analogs with modified urea substituents do not increase PPARa
selectivity.[3]
However, modification of the fibrate headgroup to thioisobutyric acid (TiBA)
increased PPARa activity relative to PPARc and d. Ureido-TiBA (GW-9578) is a
Received August 5, 2009.
ZRC Communication No. 239.
Address correspondence to Jigar Desai, Medicinal Chemistry Division, Zydus Research Centre,
Ahmedabad, Gujarat, India. E-mail: jigarndesai@rediffmail.com
748

INTERMEDIATE OF UREIDO FIBRATE ANALOGS
749
Figure 1. Fibrate analogues reported in literature.
potent PPARa agonist with 300-fold selectivity on the murin receptors and 20-fold
selectivity on human receptors.
Considering the potential of GW-9578, a selective PPARa agonist, different
synthetic approaches have been published in the literature.
Brown et al.[4] reported synthesis of ureido-thio isobutyric acid (A) (GW-9578),
a subtype of selective PPARa agonist with potent lipid-lowering activity. This syn-
thetic approach suffers from various drawbacks such as the use of toxic and expens-
ive palladium acetate, transition-metal catalyst (Wilkinson’s), and the use of
malodorous thio phenols.
Boros et al.[5] reported an improved process for the synthesis of compound A.
This procedure describes reduction of the sulfonyl chloride derivative to disulfide by
using sodium bisulfide with a small amount of sodium iodide at 90 ꢀC. Iodine gener-
ated in situ was repeatedly removed by titration with aqueous NaHSO3. Solid iodine
generated during the reaction sublimates and sometimates clogs the condenser.
Methyl isothio butyrate moiety was introduced by the use of methyl trimethyl silyl
dimethyl keten acetal. The latter reaction was performed at ꢁ78 ꢀC. Chlorine dis-
placement from methyl isothio butyrate derivative with potassium phthalimide
required 0.5 eq of 18-crown-6 followed by deprotection of phthalimide with hydra-
zine hydrate to give the amine compound in 26% overall yield.
We report an easy and convenient approach for the synthesis of a key
intermediate of GW-9578 analog starting with cheap and commercially available
2-phenyl-1-ethanol (Scheme 1). 2-Phenyl-1-ethanol was converted to mesylate
derivative (B) using methane sulfonyl chloride. Mesylate derivative (B) was reacted
with potassium phthalimide to give intermediate C. Chlorosulfonation of C gave sul-
fonic acid derivative (D), which was then reduced to thiol analog (E) using triphenyl
phosphine and iodine. Thiol analog (E) was treated with tert-butyl bromoisobutyrate
followed by reaction with hydrazine hydrate to give amine compound (G) in
excellent yield.
The reported procedure represents a novel approach of using an innovative
step for the reduction of aryl sulfonic acid derivative (D) to its aryl thiol derivative

750
J. DESAI ET AL.
Scheme 1. Synthesis of key intermediate ureido fibrate analogue (G).
(E) by using triphenyl phosphine and a catalytic amount of iodine.[6] This step is a
fast and simple reduction of sulfonic acid without formation of aryl disulfide side
product.
EXPERIMENTAL
All the raw materials were obtained commercially and used without further
1
purification. H NMR spectra were recorded using CDCl3 as solvent with tetra-
methylsilane (TMS) as an internal standard on a Bruker 300-MHz instruments. J
values are expressed in hertz. Infrared (IR) spectrum was recorded on a Fourier
transform (FT)–IR-8300 Shimadzu instrument using CHCl3 as solvent. Electro-
nspray ionization–mass spectra (ESI-MS) were recorded on a Shimadzu LC-MS-
2010A instrument.
Synthesis of Methanesulfonic Acid Phenethyl Ester [B]
2-Phenyl-1-ethanol (10 g, 82 mmol) was dissolved in dichloromethane
(100 mL), and triethyl amine (16.5 g, 163 mmol) was added dropwise to the mixture
at 25 ꢀC. The reaction mixture was cooled to 10 ꢀC, and methane sulfonyl chloride
(11.26 g, 98.3 mmol) was added dropwise. The mixture was allowed to stir at 25 ꢀC
for 4 h. Completion of reaction was monitored by thin-layer chromatography
(TLC). The mixture was quenched in water (100 mL). The organic layer was sepa-
rated, washed with water (50 mL), dried over sodium sulfate, and evaporated under
1
reduced pressure to get mesilate derivative (B) as a liquid (14 g, 85.8%). H NMR
(CDCl3): d 2.82 (3H, s), 3.05 (2H, t, J¼ 6.81), 4.41 (2H, t, J¼ 6.9), 7.22–7.35 (5H, m).
ESI-MS (m=z) 218 (M þ NH4þ, 100%). IR (CHCl3) 3030, 1355, 1172 cmꢁ1
.

INTERMEDIATE OF UREIDO FIBRATE ANALOGS
751
Synthesis of 2-Phenethyl-isoindole-1,3-dione [C]
Mesilate derivative (B) (2.0 g, 10 mmol) was dissolved in dimethyl formamide
(10 mL), and potassium phthalimide (2.2 g, 12 mmol) was added to the mixture.
The reaction mixture was heated to 50 ꢀC for 4 h. Completion of reaction was mon-
itored by TLC. The mixture was quenched in water (100 mL). The solid compound
was filtered, washed with water (100 mL), and dried to afford the solid compound
(2.2 g, 88%). 1H NMR (CDCl3): 2.99 (2H, t, J ¼ 7.5), 3.92 (2H, t, J ¼ 7.5),
7.21–7.31 (5H, m), 7.70 (2H, dd, J ¼ 3.09, 5.34), 7.82 (2H, dd, J ¼ 3.09, 5.5). ESI-MS
(m=z): 252 (M þ Hþ, 100%). IR (KBr) 1708, 1396, 1101, 709 cmꢁ1
.
Synthesis of 4-[2-(1,3-Dioxo-1,3-dihydro-Isoindol-2-yl)-ethyl]-
benzenesulfonic Acid [D]
Isoindol derivative (C) (2.5 g, 10 mmol) was added in parts to a solution of
chlorosulfonic acid (2.3 g, 20 mmol) precooled at 0–5 ꢀC. The reaction mixture was
stirred for 2 h at the same temperature. Completion of the reaction was monitored
by TLC. The reaction mixture was poured in ice-cold water (150 mL). The solid
obtained was filtered, washed with water (100 mL), and dried to get the solid product
(1.2 g, 47%). 1H NMR (CDCl3): 3.14 (2H, t, J ¼ 7.2), 3.98 (2H, t, J ¼ 7.2), 7.50 (2H,
d, J ¼ 8.3), 7.72–7.76 (2H, m), 7.80–7.85 (2H, m); 7.94 (2H, d, J ¼ 8.4). ESI-MS
(m=z) 332 (M þ Hþ, 100%). IR (KBr) 1771, 1715, 1170 cmꢁ1
.
Preparation of 2-[2-(4-Mercapto-phenyl)-ethyl]-isoindole-1,3-
dione [E]
Sulfonic acid derivative (D) (2.7 g, 8.1 mmol) was dissolved in toluene (50 mL).
Triphenyl phosphine (2.35 g, 8.9 mmol) was added at 25 ꢀC followed by a catalytic
amount of iodine. The mixture was heated to 35–40 ꢀC for 4 h. The completion of
the reaction was monitored by TLC. The reaction mixture was quenched in water
(100 mL), and the organic layer was separated and distilled under reduced pressure.
The crude compound obtained was purified through column chromatography using
silica gel G, mesh size 230–400, mobile phase 30% ethyl acetate in hexane, to get a
1
white solid product (2.1 g, 91%). H NMR (CDCl3): 2.94 (2H, t, J ¼ 7.89), 3.40
(1H, s), 3.89 (2H, t, J ¼ 7.8). ESI-MS (m=z) 301.2 (M þ NHþ4 , 100%). IR (KBr)
2558, 1702, 1395, 717 cmꢁ1
.
Preparation of 2-{4-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-
phenylsulfanyl}-2-methyl-propionic Acid tert-Butyl Ester [F]
Thiol analog (E) (2.8 g, 9.8 mmol) was dissolved in acetone (20 mL). Anhy-
drous potassium carbonate (1.6 g, 12 mmol) was added to this, followed by
2-bromo-2-methyl-propionic acid tert-butyl ester (2.6 g, 12 mmol). The mixture
was allowed to reflux for 3 h. Completion of the reaction was monitored by TLC.
The mixture was cooled to 25 ꢀC and quenched in water (200 mL). The solid
obtained was filtered, washed with water (50 mL), and dried to get a solid compound
1
(4.0 g, 88%). H NMR (CDCl3): 1.40 (15H, bs), 2.96–3.01 (2H, m), 3.88–3.94 (2H,

752
J. DESAI ET AL.
m), 7.22 (2H, d, J ¼ 8.19), 7.43 (2H, d, J ¼ 8.16), 7.71 (2H, dd, J ¼ 3.06, 5.46), 7.83
(2H, dd, J ¼ 2.91, 5.46). ESI-MS 443.2 (M þ NH4)þ. IR (KBr) 1770, 1712, 1398,
1361, 1143, 721 cmꢁ1
.
Preparation of 2-[4-(2-Amino-ethyl)-phenylsulfanyl]-2-methyl-
propionic Acid tert-Butyl Ester [G]
Isoindole derivative (F) (4.2 g, 9.8 mmol) was dissolved in absolute alcohol
(50 mL). To this, 99% hydrazine hydrate (0.5 g, 12 mmol) was added. The reaction
mixture was heated to 50 ꢀC for 1 h. Hydrochloric acid (5 mL, 35% commercial
grade) was added to the mixture, and the mixture was refluxed for 0.5 h. Completion
of reaction was monitored by TLC. The white solid obtained was filtered, and the
filtrate was concentrated under reduced pressure to remove excess alcohol. The
pH of the solution was adjusted to 9 by adding aqueous ammonia. The compound
was extracted by adding ethyl acetate (50 mL ꢂ 3). The combined organic layer was
washed with water (50 mL), dried over sodium sulfate, and evaporated under
1
reduced pressure to afford a solid product (3.0 g, 71%), mp 155–160 ꢀC. H NMR
(CDCl3): 1.42 (15H, s), 2.74 (2H, t, J ¼ 6.81), 2.96 (2H, t, J ¼ 6.9), 7.14 (2H, d,
J ¼ 8.01), 7.43 (2H, d, J ¼ 8.04). ESI-MS (m=z) 296.2 (M þ Hþ, 100%). IR (CHCl3)
4212, 3371, 2977, 2933, 1716, 1591, 1367, 1280, 1255, 1149, 846, 759 cmꢁ1
.
CONCLUSION
The reported synthetic methodology for the synthesis of tert-butyl 2-(4-(2-
amino ethyl)phenylthio)-2-methylpropanoate has an advantage of using cheap
and commercially available 2-phenyl-1-ethanol. All the steps involved in this meth-
odology are very facile and do not require any special conditions. It can be extended
for multikilogram synthesis. The reported procedure avoids the use of expensive and
poisonous metal catalysts such as Pt and Pd.
ACKNOWLEDGMENT
The authors are thankful to the management of Cadila Healthcare Limited for
the scientific support.
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