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
CDCl3)
d
0.93 (t, J¼7.3 Hz, 3H), 1.05 (t, J¼7.3 Hz, 3H), 1.34–1.43 (m,
1. (a) Staels, B.; Auwerx, J. Curr. Pharm. Des. 1997, 3, 1–14; (b) Staels, B.; Dallonge-
ville, J.; Auwerx, J.; Schoonjans, K.; Leitersdorf, E.; Fruchart, J. C. Circulation 1998,
89, 2088–2093; (c) Fruchart, J. C.; Duriez, P.; Staels, B. Curr. Opin. Lipidol. 1999, 10,
245–258.
2. Yamazaki, Y.; Abe, K.; Toma, T.; Nishikawa, M.; Ozawa, H.; Okuda, A.; Araki, T.;
Oda, S.; Inoue, K.; Shibuya, K.; Staels, B.; Fruchart, J. C. Bioorg. Med. Chem. Lett.
2007, 17, 4689–4693.
3. Yamazaki, Y.; Araki, T.; Koura, M.; Shibuya, K. Synthesis 2008, 1017–1022.
4. (a) Wada, M.; Mitsunobu, O. Tetrahedron Lett. 1972, 13, 1279–1282; (b)
Mitsunobu, O. Synthesis 1981, 1–28; (c) Tsunoda, T.; Yamamiya, Y.; Ito, S.
Tetrahedron Lett. 1993, 34, 1639–1642; (d) Tsunoda, T.; Otsuka, J.; Yamamiya, Y.;
Ito, S. Chem. Lett. 1994, 539–542; (e) Tsunoda, T.; Nagaku, M.; Nagino, C.;
Kawamura, Y.; Ozaki, F.; Hioki, H.; Ito, S. Tetrahedron Lett. 1995, 36, 2531–2534;
(f) Tsunoda, T.; Ozaki, F.; Ito, S. Tetrahedron Lett. 1994, 35, 5081–5082; (g)
Tsunoda, T.; Nagino, C.; Oguri, M.; Ito, S. Tetrahedron Lett. 1996, 37, 2459–2462;
(h) Sakamoto, I.; Kaku, H.; Tsunoda, T. Chem. Pharm. Bull. 2003, 51, 474–476; (i)
Hughes, D. L. Org. React. 1992, 42, 335–656.
5. (a) Burk, M. J.; Kalberg, C. S.; Pizzano, A. J. Am. Chem. Soc. 1998, 120, 4345–4353;
(b) Nakamura, K.; Inoue, K.; Ushio, K.; Oka, S.; Ohno, A. J. Org. Chem. 1988, 53,
2589–2593; (c) Hale, K. J.; Cai, J.; Manaviazar, S.; Peak, S. A. Tetrahedron Lett.
1995, 36, 6965–6968; (d) Otsubo, K.; Inanaga, J.; Yamaguchi, M. Tetrahedron
Lett. 1987, 28, 4435–4436; (e) Otsubo, K.; Inanaga, J.; Yamaguchi, M. Tetrahedron
Lett. 1987, 28, 4437–4440.
6. (a) Olah, G. A.; Narang, S. C. Tetrahedron 1982, 38, 2225–2277; (b) Trybulski, E. J.;
Kramss, R. H.; Mangano, R. M.; Brabander, H. J. Bioorg. Med. Chem. Lett. 1992, 2,
827–832; (c) Durand, J. O.; Larcheveque, M.; Petit, Y. Tetrahedron Lett. 1998, 39,
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,