3
28
Helvetica Chimica Acta – Vol. 96 (2013)
standard procedures. A chiral HPLC method was used for determination of the enantiomeric purity. As a
stationary phase, an Ultron ES-OVM column (5 mm; 4.6 mm ꢁ 150 mm i.d.) was used. The mobile phase
consisted of a mixture of MeCN and 0.01m KH PO soln. (25 :75 (v/v)); further conditions: flow rate,
2
4
1
1
.0 ml/min; column temp., 178; injection volume, 10 ml; detection wavelength, 220 nm. H-NMR Spectra:
Varian Unity 300 NMR spectrometer at 300 MHz; d in ppm rel. to Me Si as internal standard, J in Hz.
4
[
4-(Bromomethyl)phenoxy]methyl Resin (3). Wang resin (2; 0.87 mmol/g, 1 g, 0.87 mmol) and Ph P
3
(
0.684 g, 2.7 mmol) in CH Cl (20 ml) was stirred for 10 min, and Br (0.134 ml, 2.61 mmol) was added
2 2 2
slowly to this suspension. After 5 min at r.t., the resin was washed consecutively with H O, H O/DMF
2
2
1
:1, DMF, MeOH, MeOH/CH Cl 1:1, and CH Cl (50 ml each), and dried under vaccum.
2
2
2
2
[
4-({[(2R)-2-(2-Chlorophenyl)-2-hydroxyacetyl]oxy}methyl)phenoxy]methyl Resin (5). A mixture
of 3, (R)-2-chloromandelic acid (4; 647.3 mg, 3.48 mmol), and CsCO (5.1 g, 15.7 mmol) was dissolved in
3
DMF (50 ml) and stirred for 4 h at r.t. The resulting resin was then washed with H O, H O/DMF 1:1,
2
2
DMF, MeOH, MeOH/CH Cl 1:1, and CH Cl (50 ml each), and dried under vacuum.
2
2
2
2
{
4-[({(2R)-2-(2-Chlorophenyl)-2-[(phenylsulfonyl)oxy]acetyl}oxy)methyl]phenoxy}methyl Resin
(
6). A stirred suspension of resin 5 in CH Cl (30 ml) was dissolved in PhSO Cl (0.23 ml, 1.74 mmol),
2
2
2
Et N (0.36 ml, 2.61 mmol) and a cat. amount of DMAP were added, and the mixture was stirred for 12 h
3
at r.t. The resin was washed with H O, H O/DMF 1:1, DMF, MeOH, MeOH/CH Cl 1:1, and CH Cl
2
2
2
2
2
2
(
50 ml each), and dried under vacuum.
[
4-({[(2S)-2-(2-Chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetyl]oxy}methyl)phen-
oxy]methyl Resin (8). A stirred soln. of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride (7; 454 mg,
.61 mmol) in CH Cl (30 ml) was dissolved in Et N (0.73 ml, 5.22 mmol) and stirred for 30 min at r.t.,
2
2
2
3
resin 6 was added, and the mixture was stirred for 12 h at r.t. The resin was washed with H O, H O/DMF
2
2
1
:1, DMF, MeOH, MeOH/CH Cl 1:1, and CH Cl (50 ml each), and dried under vacuum.
2
2
2
2
(
2S)-2-(2-Chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetic Acid (9). A mixture of
the resin 8 in TFA/CH Cl 1:4 (20 ml) was stirred for 6 h at r.t. The mixture was then filtered and washed
2
2
with MeOH (2 ꢁ 10 ml). The resulting soln. was evaporated in vacuo to reduce the volume (1/3), the
soln. was carefully filtered through a SiO pad and washed with 5% MeOH in CH Cl (30 ml). The
2
2
2
filtrate was evaporated and solidified by the addition of Et O and hexane. The vacuum drying gave 9 [10];
2
1
1
65 mg, overall yield 62% over 5 steps). Solid. [a]
D
¼ þ7.4 (c ¼ 1, CH
2
Cl
2
). H-NMR (CDCl
3
): 10.61 (br.
s, 1 H); 7.81 – 7.84 (m, 1 H); 7.37 – 7.40 (m, 1 H); 7.20 – 7.31 (m, 2 H); 7.16 (d, J ¼ 5.1, 1 H); 6.66 (d, J ¼ 5.1,
1
H); 5.29 (s, 1 H); 4.17 – 4.30 (m, 2 H); 3.44 – 3.64 (m, 2 H); 3.06 (br. s, 2 H). ESI-MS: 308 (100, [M þ
þ
H] ).
(
þ)-(S)-Clopidogrel (¼ Methyl (2S)-2-(2-Chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-
yl)acetate; 1). To a stirred soln. of 9 (40 mg, 0.13 mmol) in MeOH (2 ml) was added SOCl (0.013 ml,
2
0
.16 mmol), and the mixture was stirred at 708 for 6 h. After cooling to r.t., the solvent was evaporated in
vacuo. Sat. NaHCO (aq.) was then added, and the mixture was extracted with CH Cl . The org. layers
3
2
2
were collected, evaporated, filtered through a SiO pad, and washed with AcOEt/hexane 1:6 to give 1
2
1
(
7
3
84%). Pale yellow oil. [11]: [a] ¼ þ44.8 (c ¼ 1, MeOH). H-NMR (CDCl ): 7.66 – 7.70 (m, 1 H); 7.37 –
D
3
.44 (m, 1 H); 7.27 – 7.31 (m, 2 H); 7.07 (d, J ¼ 5.1, 1 H); 6.66 (d, J ¼ 5.1, 1 H); 4.92 (s, 1 H); 3.73 (s, 3 H);
þ
.60 – 3.80 (m, 2 H); 2.89 (br. s, 4 H). ESI-MS: 322 (100, [M þ H] ).
REFERENCES
[
1] M. Botta, F. Corelli, G. Maga, F. Manetti, M. Renzulli, S. Spadari, Tetrahedron 2001, 57, 8357.
[
2] C. W e´ ber, A. Bielik, A. Demeter, I. Borza, G. I. Szendrei, G. M. Keseru, I. Greiner, Tetrahedron
2005, 61, 9375.
[3] Y. Yu, H. M. El Abdellaoui, J. M. Ostresh, R. A. Houghten, Tetrahedron Lett. 2001, 42, 623.
[4] M. Postuła, S. Akram, F. Akram, Recent Pat. Cardiovasc. Drug Discovery 2009, 4, 55.
[5] R. Zambahari, O.-H. Kwok, S. Javier, K. H. Mak, S. Piyamitr, H. Q. T. Ho, J. J. Hwang, R. Suryawan,
W. H. Chow, Int. J. Clin. Pract. 2007, 61, 473.
[
6] W. Weintraub, B. Jçnsson, M. Bertrand, Pharmacoeconomics 2004, 22, 29.