A practical synthesis of the PPARα agonist, (R)-K-13675, starting from (S)-2-hydroxybutyrolactone

Article abstract of DOI:10.1016/j.tet.2008.06.049

A practical synthesis of optically pure PPARα agonist, (R)-K-13675, is described. This process is based on the use of (S)-2-hydroxybutyrolactone, which can be transformed into the requisite n-butyl (S)-2-hydroxybutanoate in an efficient manner. A key reaction is the etherification between the phenol and n-butyl (S)-2-trifluoromethanesulfonyloxybutanoate to give the phenyl ether in excellent yield without loss of optical purity.

Full text of DOI:10.1016/j.tet.2008.06.049

Tetrahedron 64 (2008) 8155–8158
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A practical synthesis of the PPARa agonist, (R)-K-13675, starting from
(S)-2-hydroxybutyrolactone
*
Yukiyoshi Yamazaki, Takaaki Araki, Minoru Koura, Kimiyuki Shibuya
Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd, 2-17-43, Noguchicho, Higashimurayama, Tokyo 189-0022, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 April 2008
Received in revised form 12 June 2008
Accepted 13 June 2008
Available online 19 June 2008
A practical synthesis of optically pure PPARa agonist, (R)-K-13675, is described. This process is based on
the use of (S)-2-hydroxybutyrolactone, which can be transformed into the requisite n-butyl (S)-2-
hydroxybutanoate in an efficient manner. A key reaction is the etherification between the phenol and
n-butyl (S)-2-trifluoromethanesulfonyloxybutanoate to give the phenyl ether in excellent yield without
loss of optical purity.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Practical
Coupling
Triflate
Optical purity
1. Introduction
2. Results and discussion
Peroxisome proliferator-activatedreceptor
a
(PPAR
a
)isamember
The synthesis of n-butyl (S)-2-hydroxybutanoate (4) is illus-
trated in Scheme 1. (S)-2-Hydroxybutyrolactone (6) was prepared
of one of the nuclear receptor superfamilies and its activation regu-
lates expression of key genes involved in lipid homeostasis.1 During
the course of drug discovery, we identified (R)-2-[3-[[benzoxazol-2-
yl[3-(4-methoxyphenoxy)propyl]amino]methyl]phenoxy]butanoic
using L
-malic acid according to our modified method in >99% ee.3
The lactone 6 was reacted with 1.1 equiv of iodotrimethylsilane
(TMSI) in the presence of 1.0 equiv of n-BuOH in CH2Cl2 at room
temperature to afford n-butyl (S)-2-hydroxy-4-iodobutanoate (5)
in 81% yield. When MeOH or EtOH was used, the yield of the newly
formed ester after hydrogenolysis can be decreased due to vola-
tility. Therefore, n-BuOH is used to ensure adequate chemical yield.
With n-butyl (S)-2-hydroxy-4-iodobutanoate (5) in hand, we
performed hydrogenolysis with 10% palladium carbon and tri-
ethylamine (Et3N) under a hydrogen atmosphere to afford n-butyl
(S)-2-hydroxybutanoate (4) without loss of optical purity in mod-
erate yield. In this reaction process, the palladium catalyst can be
deactivated by the generated hydrogen iodide. Therefore, we added
Et3N to avoid this deactivation.7
Next, we investigated the conditions of the etherification of the
substituted phenol 3 with n-butyl (S)-2-hydroxybutanoate (4) to
obtain the chiral ether 2 in high yield and optical purity. First, we
conducted the etherification between the phenol 3 and each sul-
fonate 7a–c of n-butyl (S)-2-hydroxybutanoate (4) under basic
conditions (Table 1). Unsatisfactory results were obtained on
treatment of 3 with the mesylate 7a or the tosylate 7b in the
presence of K2CO3 at room temperature (7a¼59%, 7b¼10%; entry 1
and 4). When the reaction was performed at 60 ꢀC, the chemical
yields of 2 were increased (7a¼59 to 93%, 7b¼10 to 69%), but this
acid ((R)-K-13675,1) as a highly potent and selective PPARa
agonist2
(Fig. 1) and reported enantioselective synthesis of (R)-K-13675
starting from (S)-2-hydroxybutyrolactone (6).3 However, the above
method involves four steps from the key intermediate 3 as a linear
synthetic route and requires the laborious purification by column
chromatography after Mitsunobu reaction.4 As our efforts were
focused on developing a practical synthetic route for multi-kg scale
preparation, we first have to establish the efficient preparation of
n-butyl (S)-2-hydroxybutanoate (4)5 as an important chiral part,
because it is too expensive for use in large-scale production. Our
synthetic plan to obtain n-butyl (S)-2-hydroxybutanoate (4) began
with the cleavage of (S)-2-hydroxybutyrolactone (6) by halogen
attack at g
-position leading to the halo ester 5,6 following hydro-
genolysis using palladium carbon under a hydrogen atmosphere
(Fig. 1).
* Corresponding author. Tel.: þ81 42 391 6211; fax: þ81 42 395 0312.
E-mail address: k-sibuya@kowa.co.jp (K. Shibuya).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.06.049

8156
Y. Yamazaki et al. / Tetrahedron 64 (2008) 8155–8158
Table 1
Etherification with phenol 3 and sulfonate (7a–c)a
N
O
O
R = Ms (7a)
= Ts (7b)
= Tf (7c)
O
RO
N
O
O
n
O Bu
N
OH
OH
O
O
O
N
O
(R)-K-13675 1
3
N
O
O
n
O Bu
O
O
N
O
N
O
2
O
n
O Bu
O
O
N
O
Entry
R
Base
Solvent
Temp
(ꢀC)
Time
(h)
Yieldb
(%)
59
93
90
10
69
77
100
99
100
100
100
100
80
Optical
purityc (% ee)
2
1
2
3
4
5
6
7
8
Ms
Ms
Ms
Ts
Ts
Ts
Tf
Tf
Tf
Tf
Tf
K2CO3
K2CO3
Cs2CO3
K2CO3
K2CO3
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Et3N
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
CHCl3
rt
60
rt
rt
60
rt
55
24
27
24
24
24
14
8
6
3
6
6
97
79
77
>99
93
93
99
99
99
99
O
O
HO
HO
n
O Bu
n
O Bu
I
4
5
rt
30
40
50
60
90
rt
N
9
OH
O
O
10
11
12
13
N
98
94
99
O
HO
O
γ
Tf
Tf
3
48
O
6
a
Conditions: phenol 3 (100 mg), sulfonate 7a–c (1.2 equiv), base (1.2 equiv), rt.
Isolated yield.
Determined by HPLC analysis.
b
c
Figure 1. Structure of (R)-K-13675 and the synthetic plan.
purity was observed (98% ee; entry 11, 94% ee; entry 12). The use of
Et3N in place of K2CO3 yielded satisfactory optical purity, but the
reaction was incomplete (80% and 99% ee; entry 13).
In this reaction system, we postulated that the racemization of
7a–c could occur before formation of the chiral ether 2. The proton
TMSI
O
H2, 10%Pd/ C
Et3N
O
n-BuOH
HO
n
O Bu
I
HO
O
CH2Cl2
-20 °C, 1 h
rt, 3 h
EtOH
rt, 16 h
6
5
at the a-position of n-butyl 2-sulfonyloxybutanoate can be easily
O
O
abstracted due to the double activation by the neighboring carbonyl
and sulfonyloxy groups. To confirm the influence of K2CO3, we
examined racemization of the triflate 7c under basic conditions.
The triflate 7c was exposed to K2CO3 in MeCN at room temperature
for various times. After treatment, the phenol 3 was added to this
mixture and stirred for 4 h. The optical purity of 2 was measured by
HPLC and the results are summarized in Table 2. In contrast to our
expectations, the optical purity of 7c was maintained even under
basic conditions. In fact, we postulated the mechanism of racemi-
zation as illustrated in Figure 2.
HO
RO
n
O Bu
n
O Bu
4
7a-c
R = Ms (7a); MsCl, 2,6-lutidine, CH2Cl2,
rt, 4 h, 100 %
= Ts (7b); TsCl, 2,6-lutidine, DMAP, CH2Cl2,
rt, 24 h, 65 %
= Tf (7c); Tf2O, 2,6-lutidine, CH2Cl2
,
-20 °C, 3 h, 98 %
In the case of the triflate 7c, the SN2 reaction (path b) occurred
much faster than racemization by phenoxide anion (path a) due to
the high leaving capability. These results can be explained in
Scheme 1. Synthesis of n-butyl (S)-2-hydroxybutanoate and the sulfonates.
was accompanied by a loss of optical purity (7a¼97 to 79% ee,
7b¼>99 to 93% ee; entry 2 and 5). Changing the base from K2CO3 to
Cs2CO3 markedly affected the chemical yield (7a¼59 to 90%, 7b¼10
to 77%) but lowered the optical purity (7a¼97 to 77% ee, 7b¼>99 to
93% ee). From these results, we should note the leaving group of 7a
and 7b to obtain the acceleration effect in this etherification. It was
reported previously that a trifluoromethanesulfonyloxy (TfO–)
group shows much higher leaving group capability than meth-
anesulfonyloxy (MsO–) and p-toluenesulfonyloxy (TsO–) groups
(TfO–/MsO–/TsO–¼56,000:1:0.7).8
Table 2
Influence of triflate 7c under basic conditionsa
Time (h)
Yieldb (%)
Optical purityb (% ee)
1
2
3
4
5
6
12
24
98
98
98
97
98
98
97
97
99
99
99
99
98
98
97
97
Therefore, we used the TfO– group instead of the MsO– or TsO–
group. Exposure of the triflate 7c with the phenol 3 at room tem-
perature in the presence of K2CO3 led to excellent results with
regard to chemical yield and optical purity (100% and 99% ee; entry
7). By raising the reaction temperature, a slight decrease in optical
a
Conditions: phenol 3 (50 mg) was added after treatment of triflate 7c (1.5 equiv)
with K2CO3 (1.5 equiv) in MeCN (2 mL) for various times at rt and the mixture was
then stirred for 4 h.
b
Determined by HPLC analysis.

Y. Yamazaki et al. / Tetrahedron 64 (2008) 8155–8158
8157
3. Conclusion
O
S
O
O
O
S
O
O-
O
S
O
O
Me
O
a
Me
b
O
Me
O
n
O Bu
n
O Bu
n
O Bu
We have established a practical method for synthesis of (R)-
K-13675 starting from (S)-2-hydroxybutyrolactone (6) via n-butyl
(S)-2-hydroxybutanoate (4). In addition, we demonstrated optimi-
zation of etherification between the phenol 3 and triflate of n-butyl
(S)-2-hydroxybutanoate (4) in excellent yield and optical purity in
large-scale production.
H
7a
path b
path a
OAr
OAr
O
S
O
O
O
O
b
F3C
O
O
O
n
O Bu
n
O Bu
n
O Bu
Ar
Ar
4. Experimental
4.1. General
H
7c
racemate
(S)
(R)
Figure 2. Plausible mechanism of racemization.
Commercially available reagents and solvents were used with-
out further purification. TLC analyses were carried out on silica gel
60 F254 plates (Merck). 1H NMR and 13C NMR spectra were recorded
on a JEOL JNM-LA 400 MHz. Tetramethylsilane was used as an in-
accordance with the reactivity (TfO–[MsO–>TsO–). We con-
cluded that rapid etherification is the key feature in this reaction
system. It is important for the synthesis of (R)-K-13675 to maintain
a high optical purity. Finally, we selected the optimized reaction
conditions shown as entry 7 in Table 1.
The triflate 7c was prepared on the kg scale from n-butyl (S)-2-
hydroxybutanoate (4) on treatment with Tf2O and pyridine or 2,6-
lutidine in CH2Cl2 (Fig. 3). In the case of pyridine, 2-pyridinium
ternal standard. Chemical shifts (d) are given in parts per million
(ppm), coupling constants J values are given in hertz (Hz) and are
reported to the nearest 0.1 Hz. Infrared (IR) spectra were recorded
on a Thermo Nicolet 370 FT-IR (ATR) spectrometer. Mass spectra
were obtained on a JEOL MS-BU20 mass spectrometer. Elemental
analyses (C, H, N) were performed by Yanaco MT-5. Melting points
were determined in open glass capillaries on a Buchi B-545 melting
point apparatus. The chiral HPLC analyses were performed on
a SHIMADZU LC-2010A HT liquid chromatograph using CHIRALPAK
AS and AD columns (manufactured by Daicel), 5.0 cmꢁ0.46 cm.
O
O
O
N
N
+
TfO-
TfO
+
N
N
n
O Bu
n
O Bu
n
O Bu
TfO-
4.2. Synthesis of n-butyl (S)-2-hydroxy-4-iodobutanoate (5)
8
9
7c
Toasolutionof(S)-2-hydroxybutyrolactone(6)(1.60 kg,15.7 mol)
and n-BuOH (1.16 kg, 15.7 mol) in CH2Cl2 (7.0 L) was added TMSI
(3.31 kg,16.7 mol) at ꢂ10 ꢀC over 0.5 h under a nitrogen atmosphere
and stirred for 1 h. The reaction mixture was allowed to warm to
room temperature and stirred for 3 h. The mixture was diluted with
water (7.0 L) and extracted with CH2Cl2 (5.5 L). The organic layer was
washed with saturated aq NaHCO3 (3.0 L),1% aq NaHSO3 (4.0 L), and
brine (3.0 L), dried over Na2SO4, and concentrated in vacuo to give 5
as a yellowish oil (3.67 kg, 81%). An analytically pure sample was
obtained via silica gel column chromatography: 1H NMR (400 MHz,
Figure 3.
butanoate 8 could be generated as a major product when the
reaction temperature was allowed to warm over 0 ꢀC. Pyridine
worked as a nucleophile, not as a base, toward the highly reactive
triflate 7c. To avoid the formation of 8, we attempted to use 2,6-
lutidine. As expected, the reproducible preparation of triflate 7c
was established without regard to the reaction temperature.
The phenyl ether 2 was hydrolyzed with aq NaOH to afford (R)-K-
13675 in satisfactory yield with excellent optical purity (Scheme 2).
CDCl3)
d
0.89(t, J¼7.4 Hz,3H),1.33(qt, J¼7.5, 7.4 Hz,2H),1.60 (tt, J¼7.1,
7.1 Hz, 2H), 1.98–2.07 (m, 1H), 2.22–2.29 (m, 1H), 2.75 (d, J¼4.6 Hz,
1H), 3.23–3.29 (m, 2H), 4.12–4.18 (m, 3H); 13C NMR (100 MHz, CDCl3)
d
0.71, 13.56, 18.99, 30.41, 37.95, 65.81, 70.23, 174.27; IR (neat) 3448,
O
2960, 1732, 1464, 1212, 1148, 1086 cmꢂ1; MS (EI) m/z 286 [Mþ]. Anal.
TfO
20
n
O Bu
Calcd for C8H15IO3: C, 33.58; H, 5.28. Found: C, 33.53; H, 5.23; [a]
D
ꢂ6.14 (c 1.08, CHCl3).
N
7c
K2CO3
OH
O
O
N
4.3. Synthesis of n-butyl (S)-2-hydroxybutanoate (4)
MeCN
rt, 22 h
O
To a solution of 5 (3.61 kg, 12.6 mol) and Et3N (3.83 kg, 37.8 mol)
in EtOAc (5.5 L) was added 10% Pd/C (365 g) at room temperature
under a nitrogen atmosphere. The reaction mixture was stirred at
room temperature for 16 h under a hydrogen atmosphere and then
was diluted with water (2.0 L). The catalyst was removed by fil-
tration through a pad of Celite and washed with EtOAc (2.5 L) and
water (1.0 L). The organic layer was partitioned and washed with
1 M HCl (4.0 Lꢁ5), water (4.0 L), saturated aq NaHCO3 (4.0 L), and
brine (2.0 L), dried over Na2SO4, and concentrated in vacuo to give
a yellowish oil. The oil was distilled under reduced pressure (0.8–
1.6 kPa, 55–72 ꢀC) to give 4 as a colorless oil (1.18 kg, 59%):9 1H NMR
3
N
O
4M aq. NaOH
O
n
O Bu
O
O
N
EtOH
rt, 1.5 h
75 % (2 steps)
O
2
N
O
O
O
O
N
OH
(400 MHz, CDCl3)
d
0.93 (t, J¼7.8 Hz, 3H), 0.94 (t, J¼7.8 Hz, 3H), 1.37
O
(qt, J¼7.5, 7.4 Hz, 2H), 1.59–1.72 (m, 3H), 1.77–1.85 (m, 1H), 2.71 (d,
J¼5.6 Hz, 1H), 4.11–4.23 (m, 3H); 13C NMR (100 MHz, CDCl3)
d 8.72,
(R)-K-13675
13.40, 18.85, 27.31, 30.41, 65.14, 71.25, 175.13; IR (neat) 3468, 2962,
1731, 1463, 1244, 1206, 1132 cmꢂ1; MS (EI) m/z 161 [Mþþ1]. Anal.
Scheme 2. Synthesis of (R)-K-13675 from the phenol 3.

8158
Y. Yamazaki et al. / Tetrahedron 64 (2008) 8155–8158
20
Calcd for C8H16O3: C, 59.97; H, 10.07. Found: C, 59.71; H, 9.88; [
ꢂ3.53 (c 1.01, CHCl3).
a
]
18.92, 26.16, 27.54, 30.49, 45.12, 52.08, 55.71, 64.95, 65.55, 77.63,
108.75, 113.77, 114.65, 114.68, 115.42, 116.16, 120.37, 120.69, 123.94,
129.82, 138.67, 143.50, 148.92,152.83,153.89,158.33, 162.65, 171.65;
IR (neat) 1751, 1637, 1578, 1508, 1459, 1230, 1058 cmꢂ1; MS (EI) m/z
D
4.4. Determination of optical purity of 4
546 [Mþ]. Anal. Calcd for C32H38N2O6: C, 70.31; H, 7.01; N, 5.12.
20
To a solution of 4 (30.0 mg, 0.19 mmol) and pyridine (0.02 mL)
in CH2Cl2 (1.0 mL) was added 4-nitrobenzoyl chloride (35.0 mg,
0.19 mmol) at 0 ꢀC and stirred at room temperature for 5 h. The re-
action mixture was diluted with EtOAc and the organic layer was
washed with 4 M HCl, water, and brine, dried over Na2SO4, and con-
centrated in vacuo. The residue was purified by preparative TLC (silica
gel, n-hexane/CHCl3¼1:1) to give a colorless oil (31.0 mg, 54%): 1H
Found: C, 70.40; H, 7.09; N, 5.10; [
a
]
þ22.4 (c 0.51, CHCl3).
D
4.7. Synthesis of (R)-2-[3-[[benzoxazol-2-yl[3-(4-meth-
oxyphenoxy)propyl]amino]methyl]phenoxy]butanoic acid;
(R)-K-13675 (1)
To a solution of 2 (5.28 kg, 9.67 mol) in EtOH (23 L) was added
4 M aq NaOH (3.9 L) at 0 ꢀC. The reaction mixture was stirred at
room temperature for 1.5 h and then concentrated in vacuo. The
residue was dissolved in water (30 L) and washed with tert-butyl
methyl ether (16 Lꢁ2). The aqueous layer was acidified with concd
HCl (1.7 L) at 0 ꢀC and extracted with EtOAc (30 L). The organic layer
was washed with brine (20 L), dried over Na2SO4 (1.0 kg), and
concentrated in vacuo. The residue was recrystallized from EtOAc
(54 L)/n-heptane (94 L) to give (R)-K-13675 as pale yellow needles
NMR (400 MHz, CDCl3)
d
0.83 (t, J¼7.3 Hz, 3H), 1.03 (t, J¼7.6 Hz, 3H),
1.25–1.34 (m, 2H), 1.53–1.60 (m, 2H), 1.95–2.02 (m, 2H), 4.10–4.14 (m,
2H), 5.16 (dd, J¼6.8, 5.4 Hz,1H), 8.18(d, J¼8.9 Hz, 2H), 8.23(d,J¼8.9 Hz,
2H); optical purity: >99%ee. HPLCcondition:column;CHIRALPAKAD,
column temperature; 35 ꢀC, eluent; n-hexane/EtOH¼60:40, flow rate;
1 mL/min, retention time; 6.55 min (R-form; 4.85 min).
4.5. Synthesis of n-butyl (S)-2-trifluoromethanesulfonyl-
oxybutanoate (7c)
(3.24 kg, 75%). All spectroscopic data were identical with those
25
already reported (see Ref. 3): mp 98–99 ꢀC; [
a
]
þ17.0 (c 1.00,
D
To a stirred solution of 4 (1.55 kg, 9.67 mol) and 2,6-lutidine
(1.14 kg, 10.6 mol) in CH2Cl2 (15 L) was added dropwise Tf2O
(3.00 kg, 10.6 mol) at ꢂ20 ꢀC during 2 h under a nitrogen atmo-
sphere. After stirring for 2 h, further 2,6-lutidine (104 g, 0.97 mol)
and Tf2O (273 g, 0.97 mol) were added additionally to this mixture
at same temperature and stirred for 1 h. The reaction mixture was
quenched with 0.1 M aq KHSO4 (8.0 L) at 0 ꢀC and the organic layer
was partitioned, washed with 0.1 M aq KHSO4 (8.0 Lꢁ2), water
(8.0 L), and brine (6.0 L), dried over Na2SO4, and concentrated in
vacuo to give a reddish oil. The oil was dissolved in CHCl3 (5.0 L) and
silica gel (1.3 kg) was added to the solution at room temperature.
The mixture was stirred at room temperature for 10 min, filtered off
the silica gel. The filtrate was concentrated in vacuo to give 7c as
a reddish oil (2.76 kg, 98%). An analytically pure sample was
obtained via silica gel column chromatography: 1H NMR (400 MHz,
CHCl3); optical purity: 99% ee. HPLC condition: column; CHIRALPAK
AD, column temperature; 35 ꢀC, eluent; n-hexane/2-propanol/tri-
fluoroacetic acid¼100:30:0.1, flow rate; 2 mL/min, retention time;
4.19 min (S-form; 3.68 min). An analytically pure sample for ele-
mental analysis was obtained via recrystallization from EtOAc/n-
heptane. Anal. Calcd for C28H30N2O6: C, 68.56; H, 6.16; N, 5.71.
Found: C, 68.63; H, 6.23; N, 5.69.
Acknowledgements
We are grateful to Dr. K. Sawanobori, Director of Tokyo Research
Laboratories, Kowa Co., Ltd., for his encouragement and support.
References and notes
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d
0.93 (t, J¼7.3 Hz, 3H), 1.05 (t, J¼7.3 Hz, 3H), 1.34–1.43 (m,
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Lett. 1987, 28, 4435–4436; (e) Otsubo, K.; Inanaga, J.; Yamaguchi, M. Tetrahedron
Lett. 1987, 28, 4437–4440.
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5743–5746; (d) White, J. D.; Hrnciar, C. J. Org. Chem. 2000, 65, 9129–9142.
7. When the hydrogenolysis was conducted in the absence of Et3N, the reaction
was hampered due to the deactivation of catalyst. (a) Trost, B. M.; Fleming, I. In
Comprehensive Organic Synthesis: Selectivity, Strategy and Efficiency in Modern
Organic Chemistry, 1st ed.; Pregamon: Oxford, 1991; Vol. 8, p 794; (b) Pinder,
A. R. Synthesis 1980, 425–452.
8. Stang, P. J.; Hanack, M.; Subramanian, L. R. Synthesis 1982, 85–126.
9. In order to ensure the production of the triflate 7c from n-butyl (S)-2-hydroxy-
butanoate (4), we decided to conduct the purification of 4 by distillation. As
a result, the yield was significantly decreased in a kg scale operation. On the
contrary, this reaction process showed 76% of yield in a 50 g scale operation.
2H), 1.65 (quintet, J¼7.1 Hz, 2H), 1.97–2.08 (m, 2H), 4.23 (td, J¼6.7,
2.9 Hz, 2H), 5.06 (dd, J¼7.1, 4.6 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
8.80, 13.44, 18.84, 25.48, 30.32, 66.36, 84.78, 118.45 (q,
J¼317.8 Hz), 167.05; IR (neat): 2966, 1763, 1418, 1245, 1203, 1146,
947 cmꢂ1; MS (EI) m/z 293 [Mþþ1]. Anal. Calcd for C9H15F3O5S: C,
20
36.98; H, 5.17. Found: C, 36.82; H, 5.11; [
a
]
ꢂ39.7 (c 1.01, CHCl3).
D
4.6. Synthesis of n-butyl (R)-2-[3-[[benzoxazol-2-yl-
[3-(4-methoxyphenoxy)propyl]amino]methyl]-
phenoxy]butanoate (2)
To a solution of 3 (3.03 kg, 7.49 mol) and K2CO3 (1.55 kg,
11.2 mol) in MeCN (58 L) was added a solution of 7c (2.63 kg,
8.99 mol) in MeCN (6.0 L) for 5 min under a nitrogen atmosphere
and stirred at room temperature for 22 h. The reaction mixture was
filtered off and the filtrate was concentrated in vacuo. The residue
was dissolved in EtOAc (27 L) and washed with water (19 L), brine
(12 L). The organic layer was dried over Na2SO4, concentrated in
vacuo to give crude product 2 as a brown oil (4.52 kg). An analyt-
ically pure sample was obtained via silica gel column chromatog-
raphy: 1H NMR (400 MHz, CDCl3)
d
0.83 (t, J¼7.3 Hz, 3H), 1.03 (t,
J¼7.3 Hz, 3H), 1.18–1.29 (m, 2H), 1.44–1.55 (m, 2H), 1.93 (quintet,
J¼7.3 Hz, 2H), 2.12 (quintet, J¼6.5 Hz, 2H), 3.67 (t, J¼7.1 Hz, 2H),
3.74 (s, 3H), 3.94 (t, J¼6.0 Hz, 2H), 3.98–4.13 (m, 2H), 4.51 (t,
J¼6.2 Hz, 1H), 4.72 (d, J¼3.2 Hz, 2H), 6.74 (dd, J¼8.3, 2.0 Hz, 1H),
6.78 (s, 4H), 6.84 (t, J¼2.0 Hz, 1H), 6.88 (d, J¼7.6 Hz, 1H), 6.99 (td,
J¼7.8, 1.2 Hz, 1H), 7.14 (td, J¼7.8, 1.2 Hz, 1H), 7.19–7.24 (m, 2H), 7.34
(dd, J¼7.8, 0.6 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 9.65, 13.58,