The Journal of Organic Chemistry
Article
the reaction was allowed to warm to room temperature and stirred for
4 h. The reaction was cooled to 0 °C, quenched with water, and
partitioned and extracted with EtOAc. The organic layer was
concentrated and the residue filtered through a plug of silica gel
using hexanes/EtOAc as eluant to furnish methyl 2-(4-(acetylthio)-3-
oxopiperidin-1-yl)-2-(2-chlorophenyl)acetate (0.49 g, 1.4 mmol, 46%
yield). The intermediate was sufficiently pure for subsequent steps,
and no further purification was performed. To a solution of tert-butyl
2-(dimethoxyphosphoryl)acetate (0.33 mL, 1.65 mmol) in THF (6.9
mL) at −78 °C was added n-BuLi (0.66 mL, 1.7 mmol). The solution
was stirred 20 min and then treated with methyl 2-(4-(acetylthio)-3-
oxopiperidin-1-yl)-2-(2-chlorophenyl)acetate (0.49 g, 1.4 mmol) as a
solution in THF (2.3 mL). The resulting solution was allowed to warm
slowly to room temperature. The solution was then treated with 0.5
mL of Ac2O and ca. 10 mg of DMAP and stirred 10 min. The resulting
solution was partitioned between EtOAc and sat. aq bicarbonate. The
organic layer was concentrated and the residue filtered through a plug
of silica gel using hexanes/EtOAc as eluant to furnish (E)-methyl 2-(4-
(acetylthio)-3-(2-tert-butoxy-2-oxoethylidene)piperidin-1-yl)-2-(2-
chlorophenyl)acetate with (Z)-methyl 2-(4-(acetylthio)-3-(2-tert-
butoxy-2-oxoethylidene)piperidin-1-yl)-2-(2-chlorophenyl)acetate
(1:1) (0.31 g, 0.67 mmol, 49% yield). The intermediate was
sufficiently pure for subsequent steps, and no further purification
was performed. To a solution of (E)-methyl 2-(4-(acetylthio)-3-(2-
tert-butoxy-2-oxoethylidene)piperidin-1-yl)-2-(2-chlorophenyl)acetate
with (Z)-methyl 2-(4-(acetylthio)-3-(2-tert-butoxy-2-oxoethylidene)-
piperidin-1-yl)-2-(2-chlorophenyl)acetate (1:1 ratio) (0.31 g, 0.67
mmol) in CH2Cl2 (13 mL) was added TFA (1.5 mL, 20 mmol), and
the mixture was stirred for 2 h. The solution was concentrated and
purified by HPLC (Luna 5u C18 30 × 250 mm, 10−50% ACN in TFA
buffered water) to furnish four fractions.
for C18H20ClNO5S [M + H+] 398.0823, found 398.0821 (ion trap);
1H NMR (400 MHz, CDCl3) δ ppm 8.29 (br s, 3H), 7.62 (dd, J = 7.1,
2.2 Hz, 1H), 7.53 (d, J = 7.7 Hz, 1H), 7.47−7.38 (m, 2H), 5.87 (s,
1H), 5.80 (br s, 1H), 5.44 (s, 1H), 3.78 (s, 4H), 3.64 (d, J = 13.2 Hz,
1H), 3.50 (d, J = 12.1 Hz, 1H), 3.21−3.09 (m, 1H), 2.60−2.46 (m,
1H), 2.32 (s, 3H), 2.07−1.96 (m, 1H); 13C NMR (101 MHz, CDCl3)
δ ppm 192.8, 168.0, 167.5, 147.1, 135.4, 131.5, 130.9, 130.7, 128.0,
120.9, 65.9, 55.2, 53.3, 46.5, 38.3, 30.7, 28.7.
Representative Procedure for the Formation of Clopidogrel
Metabolites. (E)-2-((S)-1-((S)-1-(2-Chlorophenyl)-2-methoxy-2-ox-
oethyl)-4-mercaptopiperidin-3-ylidene)acetic Acid Trifluoroacetate
(3E,4S,7S)-3 (H1). To a solution of (E)-2-((S)-4-(acetylthio)-1-((S)-1-
(2-chlorophenyl)-2-methoxy-2-oxoethyl)piperidin-3-ylidene)acetic
acid trifluoroacetate 22 (0.050 g, 0.098 mmol) in MeOH (4.9 mL) was
added NaOH (0.293 mL, 0.29 mmol, 1 M solution in MeOH). After
60 min, the solution was treated with ca. 0.3 mL of 90/10 water/
ACN/0.1% TFA and concentrated. The residue was purified by
reverse phase HPLC (Luna 5u C18 30 × 250 mm, 10−90% ACN in
TFA buffered water) to furnish (E)-2-((S)-1-((S)-1-(2-chlorophenyl)-
2-methoxy-2-oxoethyl)-4-mercaptopiperidin-3-ylidene)acetic acid tri-
fluoroacetate (3 E,4S,7S)-3 (0.035 g, 0.074 mmol, 76%). IR (CD3CN,
cm−1) 2565, S−H; 1791, CO; 1752, CO; 1726, CO; 1198, C−
O; 1166, C−O; HRMS (ESI+) m/z Calcd for C16H19ClNO4S [M +
H+] 356.0723, found 356.0720 (ion trap); 1H NMR (500 MHz,
CD3CN) δ 7.65 (dd, J = 3.4, 1.5 Hz, 1H), 7.64 (dd, J = 3.2, 1.5 Hz,
1H), 7.59 (td, J = 7.8, 1.8 Hz, 1H), 7.55−7.50 (m, 1H), 6.28 (s, 1H),
5.56 (s, 1H), 4.75 (d, J = 13.8 Hz, 1H), 4.46 (d, J = 13.8 Hz, 1H), 4.08
(t, J = 4.8 Hz, 1H), 3.80 (s, 3H), 3.71−3.57 (m, 1H), 3.40 (d, J = 12.9
Hz, 1H), 2.49 (ddt, J = 15.4, 10.8, 4.2 Hz, 1H), 2.07−2.00 (m, 1H);
13C NMR (126 MHz, CD3CN) δ 167.4, 165.9, 147.2, 135.5, 133.4,
131.5, 129.3, 127.1, 122.8, 115.3, 66.8, 54.5, 48.9, 47.4, 39.1, 30.8.
(E)-2-((R)-1-((S)-1-(2-Chlorophenyl)-2-methoxy-2-oxoethyl)-4-
mercaptopiperidin-3-ylidene)acetic Acid Trifluoroacetate
(3E,4R,7S)-3 (H2). Prepared as for H1 (0.034 g, 72%). IR (CD3CN,
cm−1) 2565, S−H; 1790, CO; 1753, CO; 1727, CO; 1199, C−
O; 1168, C−O; HRMS (ESI+) m/z Calcd for C16H19ClNO4S [M +
H+] 356.0723, found 356.0716 (ion trap); 1H NMR (500 MHz,
CD3CN) δ 7.66−7.61 (m, 2H), 7.58 (td, J = 7.8, 1.8 Hz, 1H), 7.53
(dd, J = 7.7, 1.4 Hz, 1H), 6.34 (d, J = 1.1 Hz, 1H), 5.57 (s, 1H), 4.68
(s, 2H), 4.02 (t, J = 5.4 Hz, 1H), 3.80 (s, 3H), 3.50 (ddd, J = 12.6, 8.9,
3.3 Hz, 1H), 3.38 (ddd, J = 12.9, 7.2, 3.9 Hz, 1H), 2.49 (ddt, J = 15.2,
9.0, 4.3 Hz, 1H), 2.03−1.99 (m, 1H); 13C NMR (126 MHz, CD3CN)
δ 167.3, 166.0, 147.2, 135.5, 133.4, 131.6. 131.5, 129.3, 127.1, 122.8,
66.7, 54.5, 49.1, 48.7, 39.3, 31.3.
Peak 1: (E)-2-((S)-4-(Acetylthio)-1-((S)-1-(2-chlorophenyl)-2-
methoxy-2-oxoethyl)piperidin-3-ylidene)acetic Acid Trifluor-
oacetate 22. (0.065 g, 0.13 mmol, 19% yield), IR (neat, cm−1) 1712,
CO; 1687, CO; 1666, CO; HRMS (ESI+) m/z Calcd for
1
C18H20ClNO5S [M + H+] 398.0823, found 398.0820 (ion trap); H
NMR (400 MHz, CDCl3) δ ppm 8.77 (br s, 3H), 7.75−7.64 (m, 1H),
7.57−7.50 (m, 1H), 7.48−7.40 (m, 2H), 6.36 (s, 1H), 5.52 (s, 1H),
5.14 (d, J = 13.7 Hz, 1H), 4.47 (t, J = 4.1 Hz, 1H), 4.13 (d, J = 13.7
Hz, 1H), 3.78 (s, 3H), 3.53−3.42 (m, 1H), 3.23 (d, J = 13.2 Hz, 1H),
2.62−2.48 (m, 1H), 2.36 (s, 3H), 2.03 (dd, J = 15.4, 3.8 Hz, 1H); 13C
NMR (101 MHz, CDCl3) δ ppm 192.4, 167.4, 167.0, 144.2, 135.0,
132.1, 130.8, 128.6, 126.8, 123.5, 64.3, 53.7, 47.9, 47.5, 43.9, 30.8, 28.2.
Peak 2: (E)-2-((R)-4-(Acetylthio)-1-((S)-1-(2-chlorophenyl)-2-
methoxy-2-oxoethyl)piperidin-3-ylidene)acetic Acid Trifluor-
oacetate 23. (0.042 g, 0.081 mmol, 12% yield), IR (neat, cm−1)
1749, CO; 1697, CO; 1658, CO; HRMS (ESI+) m/z Calcd
for C18H20ClNO5S [M + H+] 398.0823, found 398.0824 (ion trap);
1H NMR (400 MHz, CDCl3) δ ppm 8.40 (br s, 3H), 7.71−7.64 (m,
(Z)-2-((S)-1-((S)-1-(2-Chlorophenyl)-2-methoxy-2-oxoethyl)-4-
mercaptopiperidin-3-ylidene)acetic acid formate (3Z,4S,7S)-3 (H3).
Prepared as for H1, except ammonium acetate was used in place of
TFA in the quench and HPLC eluent (0.026 g, 66%, contaminated
with trace H4). IR (CDCl3, cm−1) 2572, S−H; 1744, CO; 1689,
CO; 1648, CO; 1201, C−O; 1167, C−O; HRMS (ESI+) m/z
Calcd for C16H19ClNO4S [M + H+] 356.0723, found 356.0716 (ion
1H), 7.54−7.50 (m, 1H), 7.48−7.38 (m, 2H), 6.30 (s, 1H), 5.49 (s,
1H), 4.81 (d, J = 13.7 Hz, 1H), 4.41 (t, J = 5.2 Hz, 1H), 4.29 (d, J =
13.7 Hz, 1H), 3.80 (s, 3H), 3.55−3.45 (m, 1H), 3.21−3.09 (m, 1H),
2.51 (td, J = 9.9, 4.4 Hz, 1H), 2.37 (s, 3H), 2.14−2.02 (m, 1H); 13C
NMR (101 MHz, CDCl3) δ ppm 192.3, 167.0, 144.4, 135.3, 132.1,
130.9, 130.8, 128.4, 127.0, 122.6, 65.4, 53.8, 49.2, 48.3, 43.9, 30.8, 28.8.
Peak 3: (Z)-2-((S)-4-(Acetylthio)-1-((S)-1-(2-chlorophenyl)-2-
methoxy-2-oxoethyl)piperidin-3-ylidene)acetic Acid Trifluor-
oacetate 20. (0.070 g, 0.14 mmol, 20% yield), IR (neat, cm−1) 1751,
CO; 1697, CO; 1658, CO; HRMS (ESI+) m/z Calcd for
1
trap); H NMR (601 MHz, CDCl3) δ 7.58 (dd, J = 7.3, 2.0 Hz, 1H),
7.41 (dd, J = 7.3, 1.7 Hz, 1H), 7.33−7.23 (m, 2H), 5.48 (s, 1H), 5.26
(t, J = 4.9 Hz, 1H), 4.81 (s, 1H), 3.71 (s, 3H), 3.55 (d, J = 13.0 Hz,
1H), 3.01 (d, J = 13.0 Hz, 1H), 2.92−2.84 (m, 1H), 2.83−2.75 (m,
1H), 2.28−2.19 (m, 1H), 2.12 (d, J = 6.1 Hz, 1H), 1.84 (dq, J = 14.4,
1.9 Hz, 1H); 13C NMR (151 MHz, CDCl3) δ 170.9, 170.3, 159.6,
134.7, 132.9, 130.0, 129.8, 129.7, 127.2, 114.0, 67.9, 53.5, 52.3, 45.6,
32.8, 31.9.
1
C18H20ClNO5S [M + H+] 398.0823, found 398.0816 (ion trap); H
(Z)-2-((R)-1-((S)-1-(2-Chlorophenyl)-2-methoxy-2-oxoethyl)-4-
mercaptopiperidin-3-ylidene)acetic Acid Formate (3Z,4R,7S)-3 (H4).
Prepared as for H1, except ammonium acetate was used in place of
TFA in the quench and HPLC eluent (0.024 g, 62%). IR (CDCl3,
cm−1) 2567, S−H; 1740, CO; 1689, CO; 1648, CO; 1204, C−
O; 1166, C−O; HRMS (ESI+) m/z Calcd for C16H19ClNO4S [M +
H+] 356.0723, found 356.0723 (ion trap); 1H NMR (601 MHz,
CDCl3) δ 7.61−7.56 (m, 1H), 7.43−7.39 (m, 1H), 7.32−7.23 (m,
2H), 5.60 (s, 1H), 5.27 (t, J = 5.0 Hz, 1H), 4.82 (s, 1H), 3.72 (s, 3H),
3.63 (d, J = 12.7 Hz, 1H), 3.21 (d, J = 13.0 Hz, 1H), 2.73−2.64 (m,
2H), 2.24−2.15 (m, 1H), 2.13 (d, J = 6.1 Hz, 1H), 1.78 (dq, J = 14.2,
NMR (400 MHz, CDCl3) δ ppm 9.27 (br s, 3H), 7.62 (d, J = 7.1 Hz,
1H), 7.55−7.50 (m, 1H), 7.49−7.39 (m, 2H), 5.95 (s, 1H), 5.81 (br s,
1H), 5.48 (s, 1H), 3.89−3.69 (m, 5H), 3.41 (d, J = 11.5 Hz, 1H),
3.32−3.22 (m, 1H), 2.61−2.48 (m, 1H), 2.32 (s, 3H), 2.00 (d, J = 13.2
Hz, 1H); 13C NMR (101 MHz, CDCl3) δ ppm 192.8, 168.0, 167.4,
146.8, 135.2, 131.6, 131.1, 130.7, 128.1, 121.3, 65.9, 54.4, 53.4, 47.3,
38.2, 30.7, 28.7.
Peak 4: (Z)-2-((R)-4-(Acetylthio)-1-((S)-1-(2-chlorophenyl)-2-
methoxy-2-oxoethyl)piperidin-3-ylidene)acetic Acid Trifluor-
oacetate 21. (0.042 g, 0.083 mmol, 12% yield), IR (neat, cm−1)
1747, CO; 1697, CO; 1658, CO; HRMS (ESI+) m/z Calcd
J
J. Org. Chem. XXXX, XXX, XXX−XXX