PAPER
A Practical Synthesis of Cefcapene Pivoxil
213
13C NMR (100 MHz, DMSO-d6): d = 168.5, 165.0, 163.0, 159.9,
157.4, 153.3, 147.1, 134.2, 133.1, 132.4, 113.9, 108.4, 81.6, 64.1,
59.2, 60.0, 46.2 (2 C), 28.3 (4 C), 25.8, 23.0, 19.1 (3 C), 14.3.
MS (ESI): m/z = 655.2 [M + H+].
HRMS (ESI): m/z [M + H+] calcd for C28H43N6O8S2: 655.2584;
(7.8 mL, 9.3 g, ca. 0.09 mol) was slowly added over 30 min at this
temperature and the mixture was stirred for a further 3 h to allow
crystallization. The crystallized precipitate was collected by suction
filtration, washed with the precooled MIBK (100 mL, 0 °C) and
CH2Cl2 (100 mL, 0 °C), and dried in a vacuum oven at 30 °C for 5
h to give 3 (29.3 g, 78%) as a white powder; mp >140 °C (dec);
[a]D22 +51.2 (c 1.048, MeOH).
found: 655.2585.
Boc-cefcapene Pivoxil (8)1a
Cefcapene Pivoxil (2)
Mp >150 °C dec; [a]D22 +72.2 (c 1.102, MeOH).
Compound 13 (65.5 g, 0.10 mol) was added to a mixture of H2O (80
mL) and MIBK (300 mL) and the mixture was stirred for 30 min at
r.t. 10% H2SO4 (ca. 56.4 mL, 0.062 mol) was added to adjust to
pH 2.0–3.0 and the mixture was stirred for 30 min to give 2 clear
layers in the solution; the aqueous layer was discarded. To the or-
ganic layer was added sequentially 6% aq NaHCO3 (ca. 160 mL)
and acetone (75 mL) with stirring; the mixture again separated into
two layers and the organic layer was discarded. To the aqueous lay-
er was added a soln of POMI (31.5 g, 0.13 mol) and TBAB (3.0 g)
in MIBK (35 mL) over 10 min, and the mixture was stirred for a fur-
ther 5 h at r.t. Thiourea (2.3 g, 0.03 mol) and MeOH (200 mL) were
added to the reaction, and the mixture was stirred for 2 h and then
cooled to 0 °C to aid crystallization. The crystallized precipitate was
collected by suction filtration, washed with the precooled MIBK
(150 mL, 0 °C), and dried in a vacuum oven at 40 °C for 10 h to give
8 (47.7 g, 71%) as a pale-white solid; mp >150 °C dec; [a]D22 +51.0
(c 1.162, MeOH).
1H NMR (400 MHz, CDCl3): d = 7.89 (d, J = 8.8 Hz, 1 H, NH), 6.43
(t, J = 7.6 Hz, 1 H, =CH), 6.39 (s, 1 H, Hthiazole), 5.99–5.93 (m, 1 H,
H7), 5.94, 5.87 (ABq, J = 5.6 Hz, 2 H, OCH2O), 5.10 (br s, 2 H,
NH2), 5.06, 4.82 (ABq, J = 13.6 Hz, 2 H, CH2O), 5.05 (d, J = 4.8
Hz, 1 H, H6), 4.84 (br s, 2 H, CONH2, overlapping), 3.59, 3.44
(ABq, J = 18.8 Hz, 2 H, H2), 2.44 (quint, J = 7.6 Hz, 2 H,
=CHCH2), 1.23 (s, 9 H, CH3), 1.08 (t, J = 7.6 Hz, 3 H, CH3).
13C NMR (100 MHz, CDCl3): d = 171.1, 167.9, 167.7, 165.1, 160.2,
156.4, 147.8, 139.8, 129.9, 128.8, 124.5, 104.6, 80.2, 63.3, 59.6,
57.7, 38.8, 26.8 (3 C), 26.5, 23.2, 13.9.
MS (ESI): m/z = 568.1 [M + H+], 590.1 [M + Na+].
HRMS (ESI): m/z [M + H+] calcd for C23H30N5O8S2: 568.1536;
found: 568.1531; m/z [M + Na+] calcd for C23H29N5NaO8S2:
590.1355; found: 590.1362.
1H NMR (400 MHz, CDCl3): d = 8.31 (br s, 1 H, NH), 7.66 (d,
J = 8.4 Hz, 1 H, NH), 6.79 (s, 1 H, Hthiazole), 6.45 (t, J = 7.6 Hz, 1 H,
=CH), 5.97–5.93 (m, 1 H, H7, overlapping), 5.94, 5.87 (ABq,
J = 5.2 Hz, 2 H, OCH2O), 5.10, 4.82 (ABq, J = 13.6 Hz, 2 H,
CH2O), 5.05 (d, J = 4.8 Hz, 1 H, H6), 4.74 (br s, 2 H, CONH2), 3.60,
3.44 (ABq, J = 18.8 Hz, 2 H, H2), 2.51 (quint, J = 7.6 Hz, 2 H,
=CHCH2), 1.55 (s, 9 H, CH3), 1.24 (s, 9 H, CH3), 1.11 (t, J = 7.6 Hz,
3 H, CH3).
The sample of 2 was deliberately allowed to stand until the follow-
ing day and then the 1H and 13C NMR spectra were re-recorded. The
NMR spectra had become obviously intricate and appeared that
isomerization of 2 was occurring. Related to the behavior, we found
that the cleavage of Boc group in 7 resulted in isomerization. This
will be investigated further.
Cefcapene Pivoxil Monohydrochloride Monohydrate (3)
1H NMR (400 MHz, DMSO-d6): d = 9.42 (d, J = 8.0 Hz, 0.8 H,
NH), 9.06 (d, J = 8.0 Hz, 0.2 H, NH), 8.50 (br s, 2 H, NH2), 6.90–
6.76 (t and s, irregular, 1 H, HCl), 6.60 (br s, 2 H, NH2), 6.45 (s, 1
H, Hthiazole), 6.32 (t, J = 7.6 Hz, 1 H, =CH), 5.90, 5.81 (ABq, J = 6.0
Hz, 2 H, OCH2O), 5.84–5.77 (m, 1 H, H7, overlapping), 5.24 (d,
J = 4.8 Hz, 0.8 H, H6), 5.19 (d, J = 4.8 Hz, 0.2 H, H6), 4.83, 4.60
(ABq, J = 13.2 Hz, 2 H, CH2O), 3.65, 3.54 (ABq, J = 18.0 Hz, 2 H,
H2), 2.23 (quint, J = 7.6 Hz, 2 H, =CHCH2), 1.17 (s, 9 H, CH3), 1.03
(t, J = 7.6 Hz, 3 H, CH3).
13C NMR (100 MHz, CDCl3): d = 177.0, 167.3, 164.7, 160.2, 160.1,
156.5, 152.3, 147.1, 141.6, 129.5, 128.5, 124.5, 109.1, 82.8, 80.3,
63.2, 59.6, 57.7, 38.8, 28.1 (3 C), 26.8 (3 C), 26.4, 23.2, 13.9.
MS (ESI): m/z = 668.2 [M + H+], 690.2 [M + Na+], 706.1 [M + K+].
HRMS (ESI): m/z [M + H+] calcd for C28H38N5O10S2: 668.2060;
found: 668.2060; m/z [M + Na+] calcd for C28H37N5NaO10S2:
690.1880; found: 690.1895; m/z [M
+
K+] calcd for
C28H37KN5O10S2: 706.1619; found: 706.1639.
13C NMR (100 MHz, DMSO-d6): d = 176.5, 170.5, 166.7, 164.5,
160.7, 156.7, 135.8, 128.6, 124.4, 104.1, 80.2, 62.4, 59.9, 58.1,
38.7, 26.9 (3 C), 26.4, 23.3, 13.9.
Cefcapene Pivoxil (2) and Cefcapene Pivoxil Monohydrochlo-
ride Monohydrate (3)1a,7
Compound 8 (40.1 g, 0.06 mol) was added to a mixture of CH2Cl2
(300 mL) and 98% HCO2H (1.5 mL), and the mixture was stirred at
r.t. to give a clear soln. The resulting soln was cooled to 0 °C, TiCl4
(14.8 mL, 25.1 g, 0.132 mol) was added dropwise over 15 min, and
the mixture was stirred for a further 15 min at this temperature.
TiCl4 (14.8 mL, 25.1 g, 0.132 mol) was again added to the reaction
soln over 15 min and the mixture was stirred for a further 30 min at
0 °C. The resulting mixture was cooled to –15 to –5 °C, and 4% aq
NaOH (480 mL, 0.48 mol) was added slowly over 30 min. The
aqueous layer was discarded, 6% aq NaHCO3 (ca. 120 mL) was
added to the remaining organic layer carefully to adjust to pH 7.0,
and the mixture was stirred for 30 min. The aqueous layer was again
discarded and the organic phase was washed with H2O (200 mL)
and concentrated in vacuo at 18 °C to a final volume of ca. 100 mL.
At this point chromatography of a small portion of the crude product
gave sufficient 2 to confirm its structure (EtOAc–petroleum ether,
1:1).
MS (ESI): m/z = 568.1 [(M – HCl – H2O) + H+], 590.1 [(M – HCl –
H2O) + Na+].
Anal. Calcd for C23H29N5O8S2·HCl·H2O: C, 44.40; H, 5.18; N,
11.26. Found: C, 44.25; H, 5.14; N, 11.07.
TGA test: calcd for C23H29N5O8S2·HCl·H2O: H2O, 2.90%. Found:
H2O, 2.91% (60–120 °C).
Supporting Information for this article is available online at
Acknowledgment
We thank the National Natural Science Foundation of China (Pro-
ject No. 21176074) and Shandong Haoyuan Co. Ltd. for financial
support.
A mixture of MIBK (200 mL) and 95% EtOH (50 mL) was added
to the remaining soln and this was cooled to 0 °C. 35% Concd HCl
© Thieme Stuttgart · New York
Synthesis 2012, 44, 207–214