A novel synthetic route to 7-MAC from 7-ACA

Article abstract of DOI:10.1007/s13738-016-0815-0

An efficient and practical seven-step procedure is described for the synthesis of (6R,7S)-benzhydryl-7-amino-7-methoxy-3-((1-methyl-1H-tetrazol-5-ylthio)methyl)-8-oxo-5-thia-1-aza-bicyclo [4.2.0]oct-2-ene-2-carboxylate (7-MAC, 3) with overall yield of 49?%. This synthesis features a convenient and highly selective method for the introduction of 7α-methoxy group to cephalosporin nucleus in 10 using MeOLi/t-BuOCl in THF.

Full text of DOI:10.1007/s13738-016-0815-0

J IRAN CHEM SOC
DOI 10.1007/s13738-016-0815-0
ORIGINAL PAPER
A novel synthetic route to 7‑MAC from 7‑ACA
Fei Xiong1,2,3 · Gen Li1 · Bo Song1 · Fen‑Er Chen2 · Zhao‑Sen Zeng2
Received: 8 September 2015 / Accepted: 11 January 2016
© Iranian Chemical Society 2016
Abstract An efficient and practical seven-step proce-
dure is described for the synthesis of (6R,7S)-benzhydryl-
7-amino-7-methoxy-3-((1-methyl-1H-tetrazol-5-ylthio)
methyl)-8-oxo-5-thia-1-aza-bicyclo [4.2.0]oct-2-ene-2-car-
boxylate (7-MAC, 3) with overall yield of 49 %. This syn-
thesis features a convenient and highly selective method
for the introduction of 7α-methoxy group to cephalosporin
nucleus in 10 using MeOLi/t-BuOCl in THF.
intermediate, is an attractive and reliable process in the syn-
thesis of 7α-methoxycephalosporins. A tremendous efforts
have been devoted to the search for the efficient preparation
of this chiral intermediate with possible industrial develop-
ment [10–12, 19–37]. However, their industrial application
is hampered by the lack of a convenient and highly selec-
tive installization of 7α-methoxy group to cephalosporin
nucleus. The development of practical procedure for the
synthesis of 3 from 7-aminocephalosporanic acid (7-ACA,
4) is still in high demanded.
We reported herein an efficient procedure for the synthe-
sis of 3 from 7-ACA 4 which comprises the convenient and
highly selective introduction of 7α-methoxy group in 10 in
the presence of MeOLi/MeOH and t-BuOCl in THF.
Compound 6 was prepared with 91 % yield from the
commercially available 7-aminocephalosporanic acid
(7-ACA, 4) upon treatment with 5-mercapto-1-methyl-
1H-tetrazole in anhydrous MeCN to afford 5 according to
the reported procedure [37, 38]. Regioselective acylation of
5 with phenylacetyl chloride in the presence of Na2CO3 in
acetone/H2O to afford the amide 6 in almost quantitative
yield (Scheme 1).
With compound 6 in hand, the next step is the esteri-
fication of 6 for the preparation of 9. In the synthesis of
cephalosporin antibiotics, diphenyldiazomethane was gen-
erally utilized as a masking group of the carboxylic group
in cephalosporin nucleus [33–36], the unavailability and
hazard property of this reagent make this reaction unaccep-
table on a large scale preparation of compound 9. We used
diphenylmethanol instead of diphenyldiazomethane for
this purpose. Compound 6 reacted with diphenylmethanol
in the presence of dicyclohexylcarbodiimide (DCC) and
4-dimethylaminopyridine (DMAP) in CH2Cl2 at −20 °C.
As excepted, the reaction proceeded smoothly. Surpris-
ingly, the unnatural Δ3 isomer 7 was isolated in almost
Keywords Antibiotics · Esterification · Isomerization ·
7α-Methoxycephalosporins · Stereoselectivity synthesis
Introduction
Much attention has been focused on the synthesis of
7α-methoxycephalosporin drugs such as cefbuperazone
(1) and cefmetazole (2) (Fig. 1) due to their effective activ-
ity against many pathogenic microorganisms and resistant
Gram-negative bacteria [1–3]. Although many synthetic
routes to 7α-methoxycephalosporins and their analogues
have been documented to date [4–32], the strategy, utilizing
(6R,7S)-benzhydryl-7-amino-7-methoxy-3-((1-methyl-1H-
tetrazol-5-ylthio)methyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]
oct-2-ene-2-carboxylate (7-MAC, 3) as an advanced
* Fei Xiong
feixiong09@fudan.edu.cn; fxiong@usst.edu.cn
1
Department of Chemistry, University of Shanghai for Science
and Technology, Shanghai 200093, China
2
Department of Chemistry, Fudan University,
Shanghai 200433, China
3
Hubei Key Laboratory of Drug Synthesis and Optimization,
JingChu University of Technology, Jingmen 448000, China
1 3

J IRAN CHEM SOC
Fig. 1 Sturcture of cefbuperazone and cefmetazole
Scheme 1 The approach to the
synthesis of compound 6
H H
H H
N
H2N
S
H2N
O
S
CH3
N N
N
O
O
S
N
BF3 Et2O / MeCN
50 ºC, 2.5 h, 91%
O
HS
N
+
N
N
O
N
N
OH
CH3
O
OH
4
7-ACA
5
O
H
N
H H
N
Bn
S
CH3
PhCH2COCl, NaHCO3, Aectone / H2O
0 - 20 ºC, 2 h, 97%.
S
N
O
N
N
N
O
OH
6
100 % yield, instead of the desired normal Δ2 isomer 9
(Scheme 2).
Among the various reaction conditions for conversion
of 9 to 7α-methoxy product 10, as summarized in Table 1,
the maximum yield (71 %) was obtained via using MeOLi/
MeOH and t-BuOCl in THF at −78 °C. Some other halo-
genating reagents such as NBS and NCS were also success-
fully employed as reagents for the introduce methoxy group
reaction under the similar reaction conditions in moderate
yields.
Deprotection of 10 proceeded smoothly with PCl5/
C5H5N in CH2Cl2 at 0 °C for 90 min followed by addi-
tion MeOH to afford the desired product 3 in 91 % yield
(Scheme 4). In this step, the use of a slight excess of
PCl5 and pyridine, each in equiv. molar ratio, over the
amount of ester gave optimum yields of side-chain
cleavage.
Identification of these isomers was carried out by the char-
acteristics of these isomers. (1) In the NMR spectra of prod-
uct, single peaks near 5.22 and 6.53 ppm replace the meth-
ylene protons between 3.50 and 3.60 ppm adjacent to the
sulfur in the normal Δ2-cephalosporin isomer suggested the
presence of lone protons at C-2 and C-4, respectively; (2) In
the dept 135° spectra, two negative peaks show that there are
only two methylene in the molecule 7, however, in the normal
Δ2-cephalosporin series, there should be three (Fig. 2).
Gratifyingly, the desired Δ2 isomer 9 could, in turn, eas-
ily come through a double bond shift under the chemose-
lective oxidation/reduction strategy. Strategic transforma-
tions include a chemoselective oxidation of thioether bond
of Δ3 isomer 7 to Δ2 sulfoxide isomer 8 [39] and subse-
quent reduction of 8 [40] to come back to the Δ2 sulfide
isomer 9. As expected, the reaction of m-CPBA-mediated
chemoselective oxidation and PCl3-mediated reduction pro-
ceeded smoothly to afford the normal Δ2 isomer 9, which
was outlined in Scheme 3.
In conclusion, we have successfully developed a novel
synthetic process for the synthesis of 7-MAC 3 in seven
steps and in 49.2 % total yield from readily accessible
7-ACA, which appears to be more compatible with indus-
trial scale and has some advantages over the existing
synthesis.
1 3

J IRAN CHEM SOC
Scheme 2 The esterification reaction of compound 6
Fig. 2 Dept 135° and 13C spec-
tra of compound 7
1 3

J IRAN CHEM SOC
Scheme 3 The conversion of compound 7–9
1
1084 cm−1. H NMR (400 MHz, DMSO-d6): δ = 3.56 (d,
Table 1 Effects of reaction conditions on the yield of the compound
10
2J = −18 Hz, 1H, H-4), 3.73 (d, J = −18 Hz, 1H, H-4),
2
2
3.93 (s, 3H, CH3), 4.20 (d, J = −13.6 Hz, 1H, CH2), 4.36
Entry Halogenating reagents
Reaction
Yield (%)
(d, 2J = −13.6 Hz, 1H, CH2), 4.78 (d, 3J = 5.2 Hz, 1H, H-6),
4.96 (d, 3J = 5.2 Hz, 1H, H-7).
temp. (°C)
1
2
3
4
5
t-BuOCl
t-BuOCl
−78
−40
71
48
64
38
42
(6R,7R)‑3‑((1‑methyl‑1H‑tetrazol‑5‑ylthio)methyl)‑8‑o
xo‑7‑(2‑phenylacetamido)‑5‑thia‑1‑aza‑bicyclo [4.2.0]
oct‑2‑ene‑2‑carboxylic acid (6)
N-Bromosuccimide (NBS) −78
N-Bromosuccimide (NBS) −40
N-Chlorosuccimide (NCS) −78
Compound 5 (9.84 g, 30 mmol) was transferred into a
three-necked flask, dissolved in an ice-bath solution of
sodium hydrogencarbonate (6.30 g, 75 mmol) in 180 mL
of water and of acetone. The mixture was treated drop-
wise with a solution of PhCH2COCl (5.10 g, 33 mmol)
in 20 mL of acetone at 0–5 °C during a period of 40 min.
After stirring for 3 h at 20 °C, the acetone was removed
under reduced pressure. The aqueous solution was then
poured into a separatory funnel. Ethyl acetate (180 mL)
was added to this solution and acidified to pH 2.5–3.0 with
17.5 % HCl. After shaking the aqueous layer was removed,
then extracted with ethyl acetate (3 × 20 mL). The com-
bined organic layer was washed with water, brine, dried
over anhydrous magnesium sulphate and evaporated in vac-
uum to give 6 (12.98 g, 97.1 %) as white solid. m.p.: 63.4–
65.0 °C. IR (KBr): 3292, 3029, 2951, 1778, 1718, 1664,
Experimental
Reagents and chemicals were obtained from commercial
suppliers and used without further purification. THF was
distilled from sodium benzophenone ketyl. Ethyl acetate,
acetonitrile, acetone, chloroform and methylene chloride
were all redistilled. Petroleum ether (PE) for column chro-
matography (CC) had a b.p. of 30–60 °C. Melting points
(m.p.) were determined on a WRS-1B digital metal point
apparatus. NMR spectra were measured on Bruker AV
400 in deuteriochloroform solution or DMSO-d6 solution
with tetramethylsilane as an internal standard. Mass spec-
tra were recorded on a Waters Quattro Micromass spec-
trometer. IR spectra were recorded on a Jasco FT/IR-4200
spectrometer.
1
1542, 1364, 1244, 1174, 1096, 730, 699 cm−1. H NMR
2
(400 MHz, CDCl3): δ = 3.48 (d, J = −18 Hz, 1H, H-4),
3.57 (d, 2J = −18 Hz, 1H, H-4), 3.62 (d, 2J = −18 Hz, 1H,
CH2), 3.76 (d, 2J = −18 Hz, 1H, CH2), 3.94 (s, 3H, CH3),
4.25 (d, 2J = −13.6 Hz, 1H, CH2), 4.35 (d, 2J = −13.6 Hz,
(6R,7R)‑7‑amino‑3‑((1‑methyl‑1H‑tetrazol‑5‑ylthio)
methyl)‑8‑oxo‑5‑thia‑1‑aza‑bicyclo[4.2.0]
oct‑2‑ene‑2‑carboxylic acid (5)
3
1H, CH2), 5.06 (d, J2 = 4.8 Hz, 1H, H-6), 5.67 (dd,
3
3J1 = 8.0 Hz, J2 = 4.8 Hz, 1H, H-7), 7.21–7.32 (m, 5H,
5-Mercapto-1-methyl-1H-tetrazole (6.32 g, 54.48 mmol) and
7-ACA (4, 14.8 g, 54.41 mmol) were successively added to
a stirred solution of BF3·Et2O (23.6 g) in anhydrous acetoni-
trile (75 mL). The resulting solution was allowed to react
at 50 °C for 2.5 h. After cooling in an ice-bath, the reaction
solution was diluted with H2O (75 mL) and adjusted to pH
4.0 by the addition of 28 % NH4OH. Crystals that precipi-
tated were collected by filtration, and washed with water
and then acetone, to give 5 (16.3 g, 91.3 %) as earth-yellow
solid. m.p.: 207–209 °C [lit. [37, 38]: 224–226 °C (dec.)].
IR (KBr): 3423, 3170, 1803, 1735, 1618, 1542, 1411, 1342,
3
ArH), 9.12 (d, J1 = 8.0 Hz, 1H, NH), 13.68 (s, br, 1H,
COOH). LC–MS: m/z (%) = 447 (21) [M + H]+, 469 (24)
[M + Na]+, 330.9 (100).
(6R,7R)‑benzhydryl‑3‑((1‑methyl‑1H‑tetrazol‑5‑ylthio)
methyl)‑8‑oxo‑7‑(2‑phenylacetamido)‑5‑thia‑1‑aza‑
bicyclo[4.2.0]oct‑3‑ene‑2‑carboxylic (7)
To a solution of 6 (5.58 g, 12.5 mmol) in methylene chloride
(25 mL) was added diphenylmethanol (2.3 g, 12.5 mmol)
1 3

J IRAN CHEM SOC
Scheme 4 Synthesis of target
compound 7‑MAC
O
H
N
O
H
H
H
N
O
O
S
Bn
S
CH3
CH3
Bn
N
H
O
N
S
S
N
MeOLi, t-BuOCl, THF, MeOH
N
O
N
N
N
N
N
N
O
OCHPh2
OCHPh2
10
9
H
N
O
S
H2N
O
CH3
1. PCl5, C5H5N, CH2Cl2
2. MeOH
S
N
N
N
N
O
OCHPh2
3
7-MAC
2
and dicyclohexylacrbodiimide (DCC, 2.58 g, 12.5 mmol)
while stirring at −20 °C, then the catalyst 4-dimethylami-
nopyridine (DMAP, 0.08 g) was added to the mixture. The
color of the resulting mixture changed to black immediately.
After reaction completion as monitored by TLC, the mix-
ture was filtered and the solvent was removed under reduced
pressure to give 7 (7.58 g, 99.1 %) as white solid. m.p.:
144.6–146.2 °C. IR (KBr): 3303, 3031, 2951, 1781, 1752,
1H, H-4), 4.05 (d, J = −13.6 Hz, 1H, CH2), 4.36 (d,
2J = −13.6 Hz, 1H, CH2), 4.37 (d, 3J2 = 4.8 Hz, 1H, H-6),
3
3
5.98 (dd, J1 = 10.0 Hz, J2 = 4.8 Hz, 1H, H-7), 6.71 (d,
3J1 = 10.0 Hz, 1H, NH), 6.84 (s, 1H, CH), 7.15–7.39 (m,
15H, ArH). LC–MS: m/z (%) = 629 (71) [M + H]+, 651
(100) [M + Na]+, 347 (48), 167 (79).
(6R,7R)‑benzhydryl‑3‑((1‑methyl‑1H‑tetrazol‑5‑ylthio)
methyl)‑8‑oxo‑7‑(2‑phenylacetamido)‑5‑thia‑1‑aza‑
bicyclo[4.2.0]oct‑2‑ene‑2‑carboxylate (9)
1719, 1661, 1542, 1388, 1250, 1167, 1097, 744, 700 cm−1
.
1H NMR (400 MHz, CDCl3): δ = 3.59 (d, 2J = −16 Hz, 1H,
2
CH2), 3.64 (d, J = −18 Hz, 1H, CH2), 3.84 (s, 3H, CH3),
3.89 (d, 2J = −14.4 Hz, H-4), 4.21 (d, 2J = −14.4 Hz, 1H,
Compound 8 (1.67 g, 3 mmol) was dissolved in methylene
chloride (18 mL) containing PCl3 (2.06 g, 15 mmol). The
solution was heated under reflux for 3 h. After cooling to
room temperature, the reaction was neutralized with a satu-
rated solution of aqueous NaHCO3, washed with water, and
dried over anhydrous magnesium sulphate. Removal of sol-
vent in vacuo yielded reduced material 9 (1.64 g, 89.2 %) as
yellow solid. m.p.: 101.3–103.2 °C. IR (KBr): 3423, 3170,
2938, 1803, 1735, 1719, 1654, 1637, 1617, 1543, 1524,
3
H-4), 5.17 (d, J2 = 4.0 Hz, 1H, H-6), 5.22 (s, 1H, H-2),
3
3
5.59 (dd, J1 = 8.8 Hz, J2 = 4.0 Hz, 1H, H-7), 6.10 (d,
3J1 = 8.8 Hz, 1H, NH), 6.53 (s, 1H, H-4), 6.91 (s, 1H, CH),
7.25–7.37 (m, 15H, ArH). LC–MS: m/z (%) = 613 (100)
[M + H]+, 635 (21) [M + Na]+, 331 (15), 167 (62).
(6R,7R)‑benzhydryl‑3‑((1‑methyl‑1H‑tetrazol‑5‑ylthio)
methyl)‑8‑oxo‑7‑(2‑phenylacetamido)‑5‑thia‑1‑aza‑
bicyclo[4.2.0]oct‑2‑ene‑2‑carboxylate 1‑oxide (8)
1475, 1411, 1342, 1084, 1064, 745, 699 cm−1. H NMR
1
(400 MHz, CDCl3): δ = 3.52–3.66 (m, 3H, CH2 + H-4),
Compound 7 (1.02 g, 1.67 mmol) was dissolved in chlo-
roform (10 mL), cooled in ice-bath, and stirred while
85 % m-chloroperbenzoic acid (0.38 g, 2.20 mmol) in
chloroform (2 mL) was added dropwise during a period
of 30 min. After stirring 6 h at 0 °C. The reaction mix-
ture was washed with saturated NaHCO3 and brine. The
organic solution was dried over anhydrous magnesium sul-
phate and evaporated in vacuum to give 8 (1.03 g, 98.2 %)
as yellow solid. m.p.: 124.1–126.3 °C. IR (KBr): 3367,
3031, 2929, 1793, 1751, 1719, 1685, 1676, 1627, 1542,
3.77 (s, 3H, CH3), 4.17 (d, 2J = −13.6 Hz, 1H, CH2), 4.27
2
3
(d, J = −13.6 Hz, 1H, CH2), 4.88 (d, J2 = 4.8 Hz, 1H,
H-6), 5.83 (dd, 3J1 = 9.2 Hz, 3J2 = 4.8 Hz, 1H, H-7), 6.71
(d, 3J1 = 9.2 Hz, 1H, NH), 6.84 (s, 1H, CH), 7.17–7.36 (m,
15H, ArH). LC–MS: m/z (%) = 613 (100) [M + H]+, 635
(21) [M + Na]+, 331 (15), 167 (62).
(6R,7S)‑benzhydryl‑7‑methoxy‑3‑((1‑methyl‑1H‑tetra‑
zol‑5‑ylthio)methyl)‑8‑oxo‑7‑(2‑phenylaceta‑
mid‑o)‑5‑thia‑1‑aza‑bicyclo[4.2.0]oct‑2‑ene‑2‑carboxy‑
late (10)
1
1509, 1381, 1245, 1064, 1032, 750, 699 cm−1. H NMR
(400 MHz, CDCl3): δ = 3.38 (d, 2J = −19.2 Hz, 1H, H-4),
3.51 (d, 2J = −15.2 Hz, 1H, CH2), 3.65 (d, 2J = −15.2 Hz,
A solution of 9 (0.51 g, 0.83 mmol) in THF (5 mL) was
added to a stirred mixture of LiOMe (0.11 g, 2.92 mmol),
2
1H, CH2), 3.70 (s, 3H, CH3), 3.96 (d, J = −14.4 Hz,
1 3

J IRAN CHEM SOC
THF (1.5 mL) and MeOH (4 mL) at −78 °C under dry
N2. After 2 min t-butyl hypochlorite (0.2 mL, 1.67 mmol)
was added and after a further 20 min the mixture was
poured into iced water (40 mL) containing NH4Cl and
Na2S2O5 then extracted with EtOAc (3 × 15 mL). The
combined extracts were washed with saturated NaCl,
dried and evaporated. The crude product was purified by
CC (SiO2, petroleum ether/AcOEt 7:6) to afford pure 10
(0.38 g, 71.3 %) as yellow solid. m.p.: 74–102 °C. IR
(KBr): 3289, 3030, 2936, 1776, 1720, 1701, 1686, 1543,
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1509, 1496, 1381, 1241, 1085, 1031, 750, 699 cm−1. H-
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(8 mL) at 5 °C, and the mixture was stirred at room tem-
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