A novel and efficient synthesis of (6R,7R)-7-amino-3-hydroxymethyl cephalosporanic acid: A versatile precursor of cefuroxime acid

Article abstract of DOI:10.1081/SCC-120021837

A novel process has been developed for the synthesis of (6R,7R)-7-amino-3-hydroxymethyl cephalosporanic acid (7-AHCA) using a combination of reagents [triethyl amine/tetrabutyl ammonium hydroxide (TBAH)] at ambient temperature, with improved yield. This intermediate was exploited for the synthesis of cefuroxime acid and its sodium salt.

Full text of DOI:10.1081/SCC-120021837

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A Novel and Efficient Synthesis of (6R,7R)-7-Amino-3-
hydroxymethyl Cephalosporanic Acid: A Versatile
Precursor of Cefuroxime Acid
a
b
Santosh Kumar Singh , R. P. Tiwari & Praveen Jain
a
Verdayani Society , Pashan , Pune, India
b
Government M. L. B. Girls P. G. College , Bhopal, India
Published online: 20 Aug 2006.
To cite this article: Santosh Kumar Singh , R. P. Tiwari & Praveen Jain (2003) A Novel and Efficient Synthesis of (6R,7R)-7-
Amino-3-hydroxymethyl Cephalosporanic Acid: A Versatile Precursor of Cefuroxime Acid, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 33:14, 2475-2482, DOI: 10.1081/
SCC-120021837
To link to this article: http://dx.doi.org/10.1081/SCC-120021837
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Õ
SYNTHETIC COMMUNICATIONS
Vol. 33, No. 14, pp. 2475–2482, 2003
A Novel and Efficient Synthesis of
(6R,7R)-7-Amino-3-hydroxymethyl
Cephalosporanic Acid: A Versatile
Precursor of Cefuroxime Acid
1
2,
Santosh Kumar Singh, R. P. Tiwari, and Praveen Jain *
1
Verdayani Society, Pashan, Pune, India
Government M. L. B. Girls P. G. College,
Bhopal, India
2
ABSTRACT
A novel process has been developed for the synthesis of (6R,7R)-
7
-amino-3-hydroxymethyl cephalosporanic acid (7-AHCA) using a
combination of reagents [triethyl amine/tetrabutyl ammonium
hydroxide (TBAH)] at ambient temperature, with improved yield.
This intermediate was exploited for the synthesis of cefuroxime
acid and its sodium salt.
*Correspondence: Praveen Jain, Government M. L. B. Girls P. G. College,
Bhopal 462 003, MP, India; E-mail: pjainmlb@hotmail.com.
2
475
DOI: 10.1081/SCC-120021837
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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2
476
Singh, Tiwari, and Jain
INTRODUCTION
Cefuroxime i.e., (6R,7R)-7-[2-furanyl-(Z)-2-methoxyimino]aceta-
mido-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (1) is av la u-
able semi-synthetic second generation broad-spectrum cephalosporin
antibiotic characterized by its high activity against a wide range of
[
1a]
gram-positive and gram-negative microorganisms.
Cefuroxime and its salts are principally of value as injectable anti-
biotics as they are poorly absorbed from the gastro-intestinal tract. The
absorption is increased by converting the free 4-carboxylic acid group to
its corresponding esters. The ester gets hydrolyzed in-vivo and thus the
[
1b–e]
absorption of cefuroxime in the gastro-intestinal is increased.
[2]
Cefuroxime acid, a precursor of an oral prodrug cefuroxime
i.e., (1R,S)-[1-acetyloxy]ethyl-7-[2-furanyl-(Z)-2-methoxyimino]
[1h]
axetil
acetamido-3-carbamoyloxymethyl-3-cephem-4-carboxylate 2 (Sch. 1)
involves synthesis by various routes. The preferred commercial route
has a key step of the hydrolysis of (6R,7R)-7-amino-3-acetoxymethyl-3-
cephem-4-carboxylic acid 3 (7-ACA) to (6R,7R)-7-amino-3-hydroxy-
methyl-3-cephem-4-carboxylic acid 4 (7-AHCA, Sch. 2). 7-AHCA has
been synthesized from 7-ACA by reagents like red yeast (Rhodotorula
[
2a]
rubra), yellow yeast (Rhodosporidium toruloides),
hydroxide,
aqueous sodium
potassium hydroxide, lithium hydroxide, and sodium
[3]
carbonate. Organic transformation of 7-ACA to 7-AHCA is quite
sensitive with these reagents due to the following three reasons:
(
i) Susceptibility of 7-ACA to alkaline pH resulting in cleavage of
the b-lactam ring;
ꢁ
(
ii) Requires alow temper at ure below ꢀ40 C during hydrolysis;
and
iii) Formation of other impurities resulting poor yield.
(
In addition, to the above disadvantages, utilization of an enzyme is
very costly and takes a longer reaction time.
H
N
H
N
O
H
H
O
O
H
H
O
S
S
O
O
O
O
O
O
NH2
O
NH2
N
N
O
OCH3
O
OCH3
O
CH3
OH
2
CH3
1
O
Scheme 1.

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(
6R,7R)-7-Amino-3-hydroxymethyl Acid
2477
H H
S
H H
O
S
H2N
O
H2N
O
CH3
OH
i
O
O
O
OH
OH
3
4
O
O
-
+
ONH4
Cl
O
ii
O
N
N
OCH3
OCH3
5
O H H H
N
O H H H
N
S
O
S
O
O
NH2
O
OH
N
O
iii
N
O
OCH3
O
OH
OCH3
O
OH
1
6
iv
Reagents & Conditions:
i) (a) Et3N, CH3OH-H2O, 0 - 5° C. (b) TBAH, -10° C.
(ii) (a) PCl5 / DMAC, 5 - 10° C. (b) Cmpound 5, -15 to -10° C
(
O H H H
N
S
O
O
(iii) CSI, CH CN, 0 - 5° C.
3
O
NH2
N
(iv) Sodium-2-ethyl hexanoate, THF-EtOH, 25° C.
O
OCH3
O
ONa
7
Scheme 2.
Herein, we report anew hydrolysis re ac tion condition of 7-ACA to
-AHCA where the transformation takes place without the above draw-
7
backs. Triethyl amine/tetrabutyl ammonium hydroxide (TBAH) were
found to be reagents effective at ambient temperature, which obviate
formation of impurities and as a result gives an improved yield.
CHEMISTRY
The new condition discovered involves hydrolysis of (6R,7R)-
-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid (3) in aqueous
7
ꢁ
methanol at ꢀ10 C using triethyl amine for dissolution of 7-ACA and
tetrabutylammonium hydroxide for hydrolysis. Acidification with formic
acid to pH 4.5 at ꢀ10 to þ5 C afforded 7-AHCA (4) in 88% isolated
ꢁ
yield. The highlights of this reaction are
ꢁ
(
i) Reaction is carried out at higher temperature (ꢀ10 C) as
compared to other reagents like NaOH, KOH and LiOH

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478
Singh, Tiwari, and Jain
ꢁ
where very low temperature below ꢀ40 C are required. In case
of Na CO , reaction was performed at ambient temperature,
2
3
but the quality and yield of 7-AHCA was inferior due to
cleavage of the b -lactam ring;
(
ii) Formation of impurities, particularly b-lactam ring opening is
minimized even at higher temperature and
(
iii) Yield as well as purity is higher as a result of low impurity
formation.
7-AHCA is then condensed with 2-furanyl-(Z)-2-methoxyiminoacetic
acid ammonium salt 5 (SMIA) followed by reaction with chlorosulfonyl
isocyanate (CSI) to give cefuroxime (1).
EXPERIMENTAL PART
Melting points were determined on using an electro thermal 2000
apparatus and are not corrected. The NMR spectra were run on a
Brucker DRX 2000 instrument using TMS as an internal standard.
Infrared spectra were recorded on a FTIR Shimadzu 8201 spectropho-
tometer. Mass spectra were run on a Perkin Elmer-PE Sciex API 3000
mass spectrometer using API mode. Raw materials used were commer-
cially available.
(6R,7R)-7-Amino-3-hydroxymethyl-3-cephem-4-carboxylic acid (4).
To a suspension of (6R,7R)-7-amino-3-acetoxymethyl-3-cephem-4-car-
boxylic acid 3 (5.0 g, 0.0183 mol) in amixture of meth an ol (40 mL) an d
water (25 mL), triethyl amine (2.2 g, 0.022 mol) was added in 10 min at
ꢁ
5
nium hydroxide (40% solution in water, 16.7 g, 0.0257 mol) was added at
C which resulted in a clear solution. To this solution tetrabutylammo-
ꢁ
ꢁ
ꢀ
10 C in 30 min. The temperature was maintained at ꢀ10 C for an
additional 4.0 h. The mixture was acidified to pH 4.5 with formic acid
ꢁ
(98%) at ꢀ10 to þ10 C. The crystalline precipitate was collected by
filtration and washed with a mixture of MeOH-H O (1:1, 20 mL) fol-
2
[
4]
lowed by acetone to give 7-AHCA (3.7 g) in 88% yield, with HPLC
purity ꢂ98%. IR (KBr): 3369.4 (OH), 3166.9, 2925.8, 1797.5 (b-lactam
ꢀ1
C¼O), 1618.2, 1541.0 cm . Anal. calcd. for C H N O S: C, 41.73; H,
8
10
2
4
4
.38; N, 12.17. Found: C, 41.88; H, 4.07; N, 12.02.
6R,7R)-7-[2-Furanyl-(Z)-2-methoxyimino]acetamido-3-hydroxymethyl-
-cephem-4-carboxylic acid (6). Compound 4 (3.5g, 0.0152mol) was
(
3
dissolved with a10% aq ueous N aO H solution in amixture of ac etone
ꢁ
(7.0 mL) and water (42 mL) between pH 7.0 to 7.5 at 3 to 6 C while
stirring.

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(
6R,7R)-7-Amino-3-hydroxymethyl Acid
2479
To asuspension of phosphorus pent ac hloride (4.5 g, 0.0216 mol) in
dichloromethane (50 mL), N,N-dimethyl acetamide (DMAC, 7.5 mL)
ꢁ
was added in 10 min at 0 to 5 C followed by 2-furanyl-(Z)-2-methoxy-
ꢁ
iminoacetic acid ammonium salt 5 (3.9 g, 0.0211 mol) at ꢀ15 to ꢀ10 C.
ꢁ
The mixture was stirred for 120 min atꢀ10 C. Cold water (15 mL) was
ꢁ
added at ꢀ15 to 0 C in 10 min and the organic layer was washed with
cold water (2 ꢃ 15 mL) after separating the phases.
To the above solution of compound (4), the organic phase of the
above extraction was added between pH 7.0 to 7.5, adjusted with 10%
ꢁ
NaOH, at 0 to 5 C in 30 min and maintained at the same conditions for
additional 120 min. After separating layers, the aqueous layer was acid-
ified to pH 2.0 with 10% hydrochloric acid at 0 to 5 C. The precipitate
was filtered and washed with water followed by dichloromethane to give
ꢁ
[
4]
compound 6 (5.4 g, 77.1%) of HPLC purity ꢂ97%. IR (KBr): 3571.9
(
1
OH), 3392.6, 3234.4, 1764.7 (b-lactam C¼O), 1728.1, 1681.8, 1643.2,
ꢀ
569.9 cm . H NMR (DMSO-d , 200 MHz, ꢀ in ppm) ꢀ 3.4, 3.5 (2H,
6
1 1
ABq, JAB ¼ 18.2 Hz, SCH ), 3.77 (1H, s, OH), 3.77 (3H, s, OCH ), 4.13
2
3
(
2H, ABq, J ¼ 13.5 Hz, CH ), 5.02 (1H, d, J ¼ 4.7 Hz, 6-H), 5.63 (1H,
I 2
AB
2
dd, J ¼ 4.68 Hz, J ¼ 4.72 Hz, 7-H), 6.51 (1H, m, furyl-H), 6.6 (1H, m,
1
3
furyl-H), 7.7 (1H, m, furyl-H), 9.66 (1H, d, J ¼ 7.95 Hz, NH). C NMR
(
DMSO-d , 200 MHz, ꢀ in ppm) ꢀ 27.5, 59.2, 60.4, 61.7, 64.1, 113.8,
6
1
14.7, 125.3, 135.1, 146.7, 147.2, 147.3, 163.4, 165.0, 165.3. MS (ESI)
þ
þ
m/z [M þ N H ] : 399.3. Anal. calcd. for C H N O S: C, 47.24; H,
4
15 15
3
7
3
.96; N, 11.O2. Found: C, 47.38; H, 3.68; N, 10.88.
(6R,7R)-7-[2-Furanyl-(Z)-2-methoxyimino]acetamido-3-carbamoyloxy-
methyl-3-cephem-4-carboxylic acid (1) and its sodium salt (7). To astirred
suspension of compound 6 (5.0 g, 0.0131 mol) in dry acetonitrile (25 mL)
ꢁ
chlorosulfonyl isocyanate (CSI, 2.0 mL, 0.0229 mol) was added at 0–5 C
in 15 min and stirring was continued for an additional 45 min at the same
temperature. The clear solution of the reaction mass was poured into cold
ꢁ
water (25 mL) and stirred at 25 C for 60 min. The reaction mixture was
extracted with ethyl acetate (50 mL) after basifying to pH 7.5 with an
ꢁ
ammonia solution (25%) at 5 C. The aqueous phase was stirred with
ꢁ
activated carbon (1.0 g) between pH 5.0–5.5 at 5 C and the carbon
was filtered through a celite bed. The filtrate was acidified to pH 2.0
ꢁ
with 10% HCl at 0–5 C. The precipitated product was collected through
filtration, washed with a mixture of acetonitrile–water (1:4, 3 ꢃ 10 mL)
ꢁ
and dried under vacuum at 40 C to give compound 1 (4.6 g, 82.7%) with
ꢁ
[5]
HPLC purity ꢂ98.0%. IR (KBr): m.p. 171.5–173 C (decomposition).
IR (KBr): 3489.0, 3373.3, 3261.4, 2937.4, 1764.7 (b-lactam C¼O), 1732.0,
ꢀ
1 1
660.6, 1593.1, 1537 cm . H NMR (DMSO-d , 200 MHz, ꢀ in ppm) ꢀ
1
3
6
.3, 3.5 (2H ABq, JAB ¼ 18.16 Hz, SCH ), 3.77 (3H, s, OCH ), 4.49, 4.77
2
3

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480
Singh, Tiwari, and Jain
(
2H, ABq, JAB ¼ 12.8 Hz, CH ), 5.07 (H, d, J ¼ 4.8 Hz, 6-H), 5.68 (1H,
2
dd, J ¼ 4.79 Hz, J ¼ 4.78 Hz, 7-H), 6.5 (1H, m, furyl-H), 6.58 (1H, m,
1
2
furyl-H), 7.7 (1H, d, J ¼ 1.1 Hz, furyl-H), 9.67 (1H d, J ¼ 7.95 Hz, NH).
þ
þ
MS (ESI) m/z [M þ N H ] : 442.4. Anal. calcd. for C H N O S: C,
4
16 16
4
8
4
5.28; H, 3.79; N, 13.2. Found: C, 45.44; H, 3.57; N, 13.11.
Compound 1 (4.0 g, 0.0094 mol) was dissolved in a mixture of THF–
EtOH (1:1, 40 mL). To this mixture an ethanolic solution (20 mL) of
ꢁ
sodium-2-ethyl hexanoate (1.9 g, 0.0113 mol) was added slowly at 25 C.
The crystalline precipitate was recovered after filtration and washed with
[
5]
acetone to give sodium salt 7 (4.0 g, 95.2% with HPLC purity ꢂ98.5%.
ꢁ
M.p.: 184–186 C (decomposition). IR (KBr): 3527.6, 3494.8, 3365.6,
3
1
058.9, 2937.4, 1757.0 (b-lactam C¼O), 1699.2, 1666.4, 1625.9,
ꢀ
2
1
1
541.0 cm . H NMR (D O, 200 MHz, ꢀ in ppm) ꢀ 3.22, 3.49 (2H,
ABq, JAB ¼ 17.87 Hz, SCH ), 3.81 (3H, s, N-OCH ), 4.46, 4.49 (2H,
2
3
ABq, JAB ¼ 12.6 Hz, CH ), 5.0 (1H, d, J ¼ 4.66 Hz, 6-H), 5.6 (1H, d,
2
J ¼ 4.5 Hz, 7-H), 6.4 (1H, s, furyl-H), 6.7 (1H, d, J ¼ 3.3 Hz, furyl-H),
1
.5 (1H, s, furyl-H). C NMR (D O, 200 MHz, ꢀ in ppm) ꢀ 25.1, 56.7,
3
7
5
1
3
2
8.4, 62.3, 63.8, 111.9, 114.8, 116.8, 130.6, 143.6, 144.2, 145.8, 158.6,
63.1, 163.3, 167.9. Anal. calcd. for C H N O SNa: C, 43.05; H,
.39; N, 12.55. Found: C, 43.18; H, 3.19; N, 12.38.
1
6
15
4
8
CONCLUSION
The work described in this communication has demonstrated the
potential of the novel reagent in the synthesis of a well known clinically
effective broad-spectrum cephalosporins such as cefuroxime.
ACKNOWLEDGMENT
Author is thankful to the HOD, Chemistry Department, Govt.
M. L. B. Girls P. G. College, Barkatullaha University, Bhopal, India,
for his support.
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(
6R,7R)-7-Amino-3-hydroxymethyl Acid
2481
Cefuroxime Axetil Having a Low Melting Point. PCT Int. WO
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R.; Khanna, J.M. A Process for the Preparation of the Cefuroxime
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i) Cabri, W.; Siviero, E.; Daverio, P.L. A Process for the Synthesis of
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34, 17346a; (k) Honda, V.K.; Dandala, R.; Khanna, J.M. Process
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Cephaloxime. Jpn. Kokai Tokkyo Koho JP 58167593, Oct 03, 1983.
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. (a) Nomura, H.; Fugono, T.; Hitaka, T.; Minami, I.; Azuma, T.;
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2
482
Singh, Tiwari, and Jain
4
. HPLC Conditions ¼ Column: Inertsil ODS 3V 15 cm; Mobile phase:
.008 M Na HPO þ 0.05% tetraheptyl ammonium bromide, H O:
0
CH CN (65:35), pH 5.0 adjusted by H PO ; Flow rate: 1.5 mL/min;
2
4
2
3
3
4
Dector: UV ꢁ 235 nm (Shimadzu SPD-10A).
5
. HPLC Conditions ¼ Column: Zorbax Cyano 25 cm; Mobile phase:
0.01 M Na HPO H O: CH CN (86:14), pH 2.8 adjusted by H PO ;
Flow rate: 1.5 mL/min; Dector: UV ꢁ 235 nm (Shimadzu SPD-10A).
2 4 2 3 3 4
Received in the Netherlands August 23, 2002