A new approach to the synthesis of tazobactam using an organosilver compound

Article abstract of DOI:10.1055/s-2004-837299

Tazobactam (9) was synthesized in 8 steps from the readily accessible 6-APA. By the first use of silver triazole as reactant, the formation of the isomer 7 was avoided and a total yield of 50%, which was two to three times higher than that of reported procedures for 9, was obtained. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2004-837299

4
42
PAPER
A New Approach to the Synthesis of Tazobactam Using an Organosilver
Compound
S
W
ynthesis of
T
azobacta
me i Liang Xu,* Yun Zheng Li, Qing Shan Zhang, He Sun Zhu
School of Chemical Engineering and Environment, Beijing Institute of Technology, Beijing 100081, P. R. China
Fax +86(10)68913293; E-mail: xwl3831@sina.com.cn
Received 30 August 2004; revised 29 October 2004
tam antibiotic and tazobactam (9) are most effective in the
treatment of a variety of infections associated with b-lac-
tamase producing bateria.2 The industrial production of
Abstract: Tazobactam (9) was synthesized in 8 steps from the
readily accessible 6-APA. By the first use of silver triazole as reac-
tant, the formation of the isomer 7 was avoided and a total yield of
–4
5
0%, which was two to three times higher than that of reported pro- 9 has been relying on a total synthesis due to the lack of
cedures for 9, was obtained.
Key words: synthesis, 6-APA, silver triazole, b-lactamase inhibi- The most widely used procedure for the preparation of 9
tor, isomeric
an efficient fermentation method.
5–10
until today is shown in Scheme 1.
Besides drawbacks
such as need for multi-steps, use of explosive reagents and
quite low temperature, the disadvantages of the route were
Tazobactam (9), which belongs to a class of penicillanic obvious: Firstly, the isomeric products found in the reac-
acid sulfones, is novel and is the most active b-lactamase tion step e were unavoidable and the isomers could not be
1
inhibitor tested in clinic so far. Combinations of a b-lac- separated even by chromatography. Secondly, the reac-
N
O
S
S
S
H2N
O
S
Br
S
CH3
CH3
CH3
CH3
S
a
CH3
CH3
b
c
CH2
d
N
N
N
N
O
O
CH3
O
O
COOH
COOH
COOCH(Ph)2
COOCH(Ph)2
O
S
CH2N3
CH3
S
g
CH2N3
N
N
CH3
O
O
S
COOCH(Ph)2
CH2Cl
CH3
e
COOCH(Ph)2
O
f
N
+
+
O
O
COOCH(Ph)2
S
S
N3
N3
N
N
O
CH3
O
CH3
COOCH(Ph)2
COOCH(Ph)2
O
O
O
O
S
S
h
N
N
N
N
N
CH3
N
N
CH3
COOH
N
O
O
COOCH(Ph)2
9
Scheme 1
SYNTHESIS 2005, No. 3, pp 0442–0446
x
x
.
x
x
.2
0
0
5
Advanced online publication: 23.12.2004
DOI: 10.1055/s-2004-837299; Art ID: F11904SS
Georg Thieme Verlag Stuttgart · New York
©

PAPER
Synthesis of Tazobactam
443
O
O
S
S
N
KMnO4
N
N
N
CH3
N
N
O
N
CH3
N
O
CH3COOH
COOCH(Ph)2
COOCH(Ph)2
+
S
S
N
CH2Cl
CH3
N
N
N
N
+
O
O
CH3
COOCH(Ph)2
COOCH(Ph)2
S
5
N
O
CH3
COOCH(Ph)2
O
O
N
S
N
N
N
CH3
O
COOCH(Ph)2
9
Scheme 2
tion conditions were rigorous and what is most disap- up to 98%. Moreover, even when an excess amount of ox-
pointing is the low total yield, in the range of 15–20%.
idant was employed, the corresponding 4 was obtained as
the only product. Despite the fact that two reaction steps
were applied, the yield and the purity of the 4 were higher
than that of conventional processes.
Another procedure for the preparation of 9 is shown in
1
1
Scheme 2. Isomeric products were also obtained and the
total yield of the procedure was also low.
Nakai et al.12 also described a process for preparing 2-b-
Compound 4 was reduced cleanly with zinc and ammoni-
um acetate in 90% yield and then reacted with 2-mercap-
tobenzothiazole under reflux in toluene to give an
essentially quantitative yield of the unsymmetrical azetid-
inone disulfide 6 (94%).5
triazolemethylpenams which is the key intermediate of
tazobactam (9). There are also many disadvantages of this
route such as use of a large quantities of triazole and toxic
mercury compound. Herein, we report a very novel and
convenient method for the synthesis of 9. The synthetic Until recently, the most widely used procedure for the
route is shown in Scheme 3.
synthesis of compound 8 from 6 involved the formation of
benzhydryl 2b-halomethylpenicillinates, the bimolecular
nucleophilic displacement of the halide by azide ion or tri-
azole, the oxidation of azide or triazole compounds, the
separation of the isomers of azide or triazole compounds,
and finally the reaction of benzhydryl 2b-azidomethyl-
Compound 2 was prepared from 6-aminopenicillanic acid
(
6-APA) in 91% yield according to the reported proce-
5
dure. Conventionally, compound 4 is synthesized by
treatment of 2 with 40% peracetic acid and benzophenone
hydrazone in one step. Despite the careful control of the
5
6
penicillin-1,1-dioxides with acetylene to form 8. With
reaction temperature at 0 °C and paying great attention to
restrict the dosage of oxidizing reagent, the formation of
the overoxidation product was not avoided. Thus in the
modified procedure, compound 2 was first esterified with
diphenylmethanol in the presence of dicyclohexylcarbo-
diimide (DCC) using 4-dimethylaminopyridine (DMAP)
multi-steps, hazardous reagents, rigorous reaction condi-
tions and above all, the formation of isomers which were
inseparable even by chromatography, the shortcomings of
the route were obvious. The total yield of 8 from 6 was
only about 20–30%.
as catalyst in CH Cl at room temperature. Unexpectedly, Now, we wish to report here a very novel and convenient
2
2
the reaction was instantaneous and the yield of 3 was al- method for the synthesis of 8 under mild conditions. A so-
most 100%.
lution of the unsymmetrical azetidinone disulfide 6 in
dichloromethane was stirred at room temperature with sil-
ver triazole straight to obtain the benzhydryl 2b-triazolyl-
methylpenicilinate 7. Most attractively, 7 was found to be
the only product and no isomeric product was obtained.
In the oxidation reaction of 3 to 4, a novel method using
phenol as solvent and 30% aqueous H O as oxidation re-
2
2
gent at room temperature was developed in our laborato-
1
3
ry. Surprisingly, the reaction was fast and the yield was
Synthesis 2005, No. 3, 442–446 © Thieme Stuttgart · New York

4
44
W. L. Xu et al.
PAPER
Scheme 3 Reagents and Conditions: (a) NaNO , EtOH, KBr, 0–5 °C; (b) Ph CHOH, DCC, DMAP, CH Cl , 25 °C; (c) phenol, 30% H O ,
2
2
2
2
2
2
2
5 °C; (d) Zn, THF, MeCO NH , 6–8 °C; (e) 2-mercaptobenzothiazole, toluene, reflux; (f) silver triazole, I CH Cl , 25 °C; (g) KMnO , AcOH,
2
4
2
,
2
2
4
ultrasonic; (h) m-cresol, 50 °C.
Moreover, the yield of the reaction was relatively high key step of the route was the direct conversion of unsym-
78%). When triazole and silver oxide were used as reac- metrical azetidinone disulfide 6 to benzhydryl 2b-triaz-
(
tants instead of silver triazole, no reaction occurred. Other olypenicillanate 7 using silver triazole and iodine as
salts of triazole such as copper triazole and ferrous triaz- reactant without formation of isomers. The high overall
ole were also not useful. To the best of our knowledge, yield achieved is two to three times higher than that of re-
this is the first time that silver triazole is used to synthesize ported procedures. The simple operation, absence of for-
the benzhydryl 2b-triazolylmethylpenicillin-1,1-dioxides mation of isomers, and use of readily accessible regents
8
with such great efficiency. The compound 7 was then would permit not only the practical large-scale prepara-
treated by potassium permanganate to afford the benzhy- tion of tazobactam but also the synthesis of tazobactam
dryl 2b-triazolylmethylpenicillin-1,1-dioxides 8. We also derivatives having promising b-lactamase inhibit proper-
found that the oxidation reaction under ultrasonic was ties.
much more efficient. The reaction time was reduced from
3
.5 hours to less than 20 minutes and the yield of the oxi-
dation reaction was almost quantitative. The route from 6
to 8 was comprised of only 2 steps and the yield of this To a solution of H SO (1.25 mol/L, 250 mL) was added 6-APA (1;
6
a-Bromopenicillanic Acid (2)
2
4
route was up to 74%, which was much higher than that of 21.6 g, 0.1 mol) in portion, followed by KBr (60.1 g) and EtOH
(
0
95%, 200 mL) with stirring at 0–5 °C. The mixture was cooled to
the reported routes. In addition, the most significant dif-
ference from reported methods was that no isomers were
formed in the reaction, which is a relatively short proce-
dure under mild reaction conditions. The tazobactam (9)
was then obtained by treatment of 8 with m-cresol at 50 °C
–5 °C, then a solution of NaNO (10.6 g) in H O (50 mL) was add-
2
2
ed dropwise within 1 h. The temperature of the mixture was main-
tained at 0–5 °C. The reaction was followed by TLC. When the
reaction was complete, CHCl was added to the mixture and the two
phases were separated. The aqueous layer was back-extracted with
CHCl (3 ×). The combined organic layers were washed with H O,
dried (MgSO ) and the solvent was removed in vacuo to give 2 as a
3
1
4
in 90% yield according to literature.
3
2
4
In conclusion, tazobactam (9) was synthesized in 8 steps
and in 50% total yield from readily accessible 6-APA. The
sticky mass; yield: 25.48 g (91%).
–
1
IR (KBr): 1790, 1733 cm .
Synthesis 2005, No. 3, 442–446 © Thieme Stuttgart · New York

PAPER
Synthesis of Tazobactam
445
1
IR (KBr): 1780, 1747 cm–1.
H NMR (CDCl ): d = 9.87 (s, 1 H, CO H), 5.41 (d, 1 H, J = 1 Hz,
3
2
6
b-H), 4.9 (d, 1 H, J = 1 H, 5a-H), 4.65 (s, 1 H, 3-H), 1.71 (s, 3 H,
1
H NMR (CDCl ): d = 7.97–7.14 (m, 14 Harom), 7.92 [s, 1 H,
3
CH ), 1.59 (s, 3 H, CH ).
3
3
(
C H ) CH], 5.5 (dd, 1 H, J = 2, 4 Hz, 4-H), 5.1, 4.9 (s, 2 H, =CH ),
6
5
2
2
Annal. Calcd for C H BrNO S: C, 34.29; H, 3.57; N, 5.00; S,
4.98 (s, 1 H, CHCOO), 3.31 (dd, 2 H, J = 6, 16 Hz, CH CO), 1.87
8
10
3
2
1
1.43. Found: C, 34.44; H, 3.50; N, 5.21; S, 11.49.
(s, 3 H, CH3).
Anal. Calcd for C H N O S : C, 63.16; H, 4.51; N, 5.26; S, 18.05.
Found: C, 63.23; H, 4.59; N, 5.17; S, 18.16.
2
8
24
2
3 3
Benzhydryl 6a-Bromopenicillanate-1-oxide (4)
To a solution of 2 (28 g, 0.1 mol) in CH Cl (150 mL) was added
2
2
diphenylmethanol (18.4 g, 0.1 mol) and dicyclohexylcarbodiimide
DCC, 20.6 g) with stirring at r.t. Then the catalyst 4-dimethylami-
Benzhydryl 2b-Triazolylpenicillanate-1,1-dioxide (8)
(
To a stirred solution of unsymmetrical azetidinone disulfide 6 (11 g,
nopyridine (DMAP, 0.6 g) was added to the mixture. The color of
the mixture changed to black immediately. The reaction was fol-
lowed by TLC. After the reaction was over, the mixture was filtered
and the solvent was removed to give 3 (44.6 g, ca. 100%) which was
oxidized directly without further purification as follows. To a
stirred solution of 3 (44.6 g, 0.1 mol) in phenol (112.8 g, 1.2 mol) at
0
0
0
.021 mol) in CH Cl (100 mL) was added silver triazole (7.434 g,
.042 mol) and the mixture was stirred at r.t. for 20 min. I (5.33 g,
.021 mol) was added to the reaction mixture in small portions. The
2 2
2
reaction was followed by TLC. After the reaction was over, the mix-
ture was filtered and washed thoroughly with CH Cl . The filtrate
2
2
was washed successively with aq 10% Na S O solution, H O, and
2
2
3
2
2
5 °C was added 30% aq H O (22.5 mL, 0.2 mol). The progress of
2 2
brine, dried (Na SO ) and the solvent was removed in vacuo to give
2
4
the reaction was followed by TLC. After complete disappearance of
the reactant, the excess H O was quenched with sat. aq Na SO so-
the product 7 (7.1 g, 78%) as a yellow sticky liquid, which was ox-
idized directly, without further purification, as follows. To a solu-
tion of 7 (7.1 g, 0.0164 mol) in glacial AcOH (200 mL) was added
H O (20 mL) and KMnO (4.3 g, 0.027 mol) portionwise under ul-
2
2
2
3
lution and the phenol was neutralized with 10% aq NaOH solution
435 mL). The two phases were separated and the aqueous layer was
(
2
4
back-extracted with EtOAc (3 ×). The combined organic layers
trasonic conditions. After the reaction was over (usually less than 20
were washed with H O, dried (MgSO ) and the EtOAc was re-
2
4
min), the excess of KMnO was decomposed by the dropwise addi-
4
moved in vacuo to give 4 as a light yellow hard solid (45.3 g, 98%).
tion of H O and the mixture was poured into ice-cold H O (200
2
2
2
–
1
IR (KBr): 1793, 1735, 1051 cm .
mL). The precipitated solid was filtered off and dissolved in CH Cl
2 2
1
(100 mL). The aqueous layer was saturated with NaCl and back-ex-
H NMR (CDCl ): d = 7.4 (m, 10 Harom), 7.1 [s, 1 H, (C H ) CH],
3
6
5 2
tracted with additional CH Cl (3 × 50 mL). The combined organic
2
2
5
1
.1, 4.98 (AB-q, 2 H, J = 1 Hz, 5a-H and 6b-H), 4.7 (s, 1 H, 3-H),
layers were washed with NaHCO , followed by brine, and dried
3
.66 (s, 3 H, CH ), 0.9 (s, 3 H, CH ).
3
3
(
Na SO ). The solvent was removed in vacuo to give the product 8
2 4
Anal. Calcd for C H BrNO S: C, 54.51; H, 4.32; N, 3.03; S, 6.92.
Found: C, 54.33; H, 4.47; N, 3.10; S, 6.98.
21
20
4
which was recrystallized from MeOH to give a white solid; (7.24 g,
5%); mp 205–207 °C.
9
–
1
IR (KBr): 2111, 1799, 1755 cm .
Benzhydryl 6,6-Dihydropenicillanate-1-oxide (5)
To a solution of 4 (20 g, 0.0403 mol) in THF (220 mL) was added
1
H NMR (DMSO-d ): d = 7.99 (s, 1 H, 10-H), 7.69 (s, 1 H, 11-H),
6
aq 1 M NH OAc (80 mL) with stirring. The solution was maintained
7.55–7.28 (m, 10 Harom), 6.97 (s, 1 H, 12-H), 5.34–5.27 (dd, 2 H,
J = 15, 15 Hz, 9-H), 4.95 (d, 1 H, J = 15 Hz, 5-H), 3.76 (s, 1 H, 2-
H), 3.96–3.25 (dd, 2 H, J = 9 Hz, 6-H), 1.44 (s, 3 H, CH3).
4
at 0 °C and then zinc dust (14.3 g) was added in small portions with-
in 15 min. The mixture was stirred in an ice-bath and the progress
of the reaction was followed by TLC. When the reaction was com-
plete, the mixture was filtered through Celite. The layers were sep-
arated and the organic layer was concentrated. The residue was
treated with CH Cl2 (180 mL), and washed with H O, dried
Anal. Calcd for C H N O S: C, 59.23; H, 4.72; N, 12.02; S, 6.87.
2
3
22
4
5
Found: C, 59.07; H, 4.84; N, 11.87; S, 6.79.
2
2
Tazobactam (9)
A solution of 8 (8 g, 0.017 mol) in m-cresol (90 mL) was stirred at
(
MgSO ) and the CH Cl was removed in vacuo to give a light yel-
4 2 2
low oil which was crystallized from EtOAc–petroleum ether (bp
5
(
0 °C for 3 h. The mixture was cooled in an ice bath and then EtOAc
100 mL) was added. The organic layer was extracted with sat. aq
NaHCO (3 × 100 mL) and then with H O (100 mL). The combined
6
1
0–90 °C) (1:4) to give 5 as a white solid (14.94 g, 90%); mp 146–
48 °C.
3
2
–
1
IR (KBr): 1796, 1737, 1056 cm .
aqueous layers were washed with EtOAc. The aqueous solution was
then cooled to 0–5 °C and acidified to pH 1 with 10% aq HCl. Stir-
ring was continued for 30 min with ice cooling. The colorless pre-
cipitate that formed was collected by filtration. The precipitate was
1
H NMR (CDCl ): d = 7.32 (m, 10 Harom), 7.0 [s, 1 H, (C H ) CH],
3
6
5 2
4
.93 (t, 1 H, J = 3.4 Hz, 5a-H), 4.65 (s, 1 H, 3-H), 3.3 (d, 2 H,
J = 3.5 Hz, 6-H), 1.66 (s, 3 H, CH ), 0.9 (s, 3 H, CH ).
3
3
rinsed with cold H O, and dried in vacuo to give 9 as a colorless sol-
2
Anal. Calcd for C H NO S: C, 65.72; H, 5.47; N, 3.65; S, 8.34.
2
1
21
4
id (4.64 g, 90%); mp 180–182 °C.
Found: C, 65.64; H, 5.56; N, 3.71; S, 8.39.
–
1
IR (KBr): 1797, 1735 cm .
1
Unsymmetrical Azetidinone Disulfide 6
H NMR (DMSO-d ): d = 8.06 (s, 1 H, 10-H), 7.73 (s, 2 H, 11-H),
6
Benzhydryl 6,6-dihydropenicillanate-1-oxide (5; 8 g, 0.021 mol)
and 2-mercaptobenzothiazole (3.3 g, 0.020 mol) in toluene (250
mL) were stirred and heated under reflux using a Dean–Stark trap.
The reaction was followed by TLC. The toluene was removed under
reduced pressure after the reaction was complete (about 2 h). The
residue was dissolved in CH Cl (25 mL) and precipitated by the
5.21–5.13 (dd, 2 H, J = 15, 15 Hz, 9-H), 4.92 (d, 1 H, J = 15 Hz, 5-
H), 4.76 (s, 1 H, 2-H), 3.68 (dd, 1 H, J = 4, 16 Hz, 6-H), 3.31 (d, 1
H, J = 16 Hz, 6-H), 1.38 (s, 3 H, CH3).
Anal. Calcd for C H N O S: C, 40.00; H, 4.00; N, 18.67; S, 10.67.
1
0
12
4
5
Found: C, 39.89; H, 4.07; N, 18.75; S, 10.74.
2
2
slow addition of a large volume of hexane with vigorous stirring in
an ice-bath. After stirring for a while, the hexane layer was decanted
References
(
repeated 3 times). The residue was dissolved in Et O (200 mL) and
2
(
1) Iman, Z.; Nyda, K.; Avi, Y. Int. J. Pharm. 1997, 153, 115.
2) Maiti, S. N.; Spevak, P.; Wong, R.; Reddy, N. A. V.;
Micetich, R. G.; Ogawa, K. Heterocycles 1991, 32, 1505.
cooled. The precipitated solid was removed by filtration and the fil-
trate was concentrated to give the desired compound 6 as a sticky
yellow mass; yield: 10.4 g (94%).
(
Synthesis 2005, No. 3, 442–446 © Thieme Stuttgart · New York

4
46
W. L. Xu et al.
PAPER
(9) Micetich, R. G.; Maiti, S. N.; Tanaka, M.; Yamazaki, T.;
Ogawa, K. Heterocycles 1985, 23, 325.
(10) Maiti, S. N.; Spevak, P.; Ogawa, K.; Micetich, R. G. J. Org.
Chem. 1988, 53, 3803.
(11) Deng, Y.; Sheng, Y.; Zhong, Y.-G.; Tang, W.-G. Chin. J.
Med. Chem. 2001, 11, 93; Chem. Abstr. 2002, 136, 216569.
(12) Nakai, A.; Tanaka, H.; Tanaka, M.; Yamada, S.; Nakai, S.
EP 0331394, 1989; Chem. Abstr. 1990, 113, 40321.
(13) Xu, W.-L.; Li, Y.-Z.; Zhang, Q.-S.; Zhu, H.-S. Synthesis
2004, 227.
(
3) Burgess, D. S.; Hastings, R. W. Diagn. Microbiol. Infect.
Dis. 2000, 38, 37.
(
(
4) Burgess, D. S.; Waldrep, T. Clin. Ther. 2002, 7, 1090.
5) Micetich, R. G.; Maiti, S. N.; Spevak, P.; Tanaka, M.;
Yamazaki, T.; Ogawa, K. Synthesis 1986, 292.
(
(
(
6) Micetich, R. G.; Maiti, S. N.; Spevak, P.; Hall, T. W.;
Yamabe, S.; Ishida, N.; Tanaka, M.; Yamazaki, T.; Nakai,
A.; Ogawa, K. J. Med. Chem. 1987, 30, 1469.
7) Torri, S.; Tanaka, H.; Tanaka, M.; Yamada, S.; Nakai, A.;
Oohayashi, H. JP 01110689, 1987; Chem. Abstr. 1989, 111,
53523.
1
(14) Torii, S.; Tanaka, H.; Taniguchi, M.; Kameyama, Y. J. Org.
8) Taniguchi, M.; Sasaoka, M.; Matsumara, K.; Kanahara, I.;
Kaze, K.; Suzuki, D.; Shimabayashi, A. EP 0331146, 1989;
Chem. Abstr. 1990, 112, 118542.
Chem. 1991, 56, 3633.
Synthesis 2005, No. 3, 442–446 © Thieme Stuttgart · New York