An improved and scaleable preparation of 7-amino-3-vinylcephem-4-carboxylic acid

Article abstract of DOI:10.1021/op900053j

A practical and efficient multikilogram-scale preparation of 7-amino-3-vinylcephem-4-carboxylic acid (7-AVCA), a key intermediate used in the synthesis of cefixime and cefdinir, is described utilizing /p-methoxybenzyl 7-phenylacetamido-3-chloromethylcephe

Full text of DOI:10.1021/op900053j

Organic Process Research & Development 2009, 13, 924–927
Technical Notes
An Improved and Scaleable Preparation of 7-Amino-3-vinylcephem-4-carboxylic acid
Mingyong Chao and Aiyou Hao*
School of Chemistry and Chemical Engineering, Shandong UniVersity, Jinan 250100, P.R. China
Abstract:
and the limited availability of DCC. Although some companies
are producing 1 by the routes shown in Scheme 2, the above
shortcomings and the low overall yield make the process
uneconomical. Scheme 3 (Route B) is obviously more practical
compared with other schemes due to fewer steps, easier
availability of raw materials, and more environmental friendli-
ness. However, there are still several drawbacks regarding
Scheme 3 (Route B) in the reported methods,10,11 namely: (1)
the overall yield (41.4-58.5%) is low; (2) trifluoroacetic acid
used in the process is relatively expensive and hazardous; (3)
product purity reported by Xu, et al. is only 92.3%, which is
insufficient for cefixime or cefdinir production. Although the
purity has been improved to 98.3% by Du, et al., the improved
process requires chromatographic purification, which is ex-
tremely inconvenient for commercial production; and (4)
isolation11 or chromatographic purification12 of intermediate 3
makes the reported processes complicated.
A practical and efficient multikilogram-scale preparation of
7-amino-3-vinylcephem-4-carboxylic acid (7-AVCA), a key inter-
mediate used in the synthesis of cefixime and cefdinir, is described
utilizing p-methoxybenzyl 7-phenylacetamido-3-chloromethylceph-
em-4-carboxylate (GCLE) as a starting material. Reaction condi-
tions were optimized to simplify the process, to improve the quality
and to increase the yield. The process has been demonstrated on
a multikilogram scale in 77% overall yield with a purity of >99%.
Introduction
7-Amino-3-vinylcephem-4-carboxylic acid (7-AVCA, 1) is
a key intermediate used in the synthesis of cefixime and
cefdinir,1-4 which are orally active third-generation cepha-
losporin antibiotics with broad antibacterial spectra.5-7 Cefixime
and cefdinir can be efficiently synthesized from 1 in 80% and
70% overall yields respectively.1,3
There are several synthetic methods reported for the prepara-
tion of 7-AVCA starting from deacetyl cephalosporin C (DCC)
(Scheme 1),8 7-amino cephalosporanic acid (7-ACA) (Scheme
2),8 or GCLE, (Scheme 3)9-12 etc.
To improve the quality and the yield, as well as to reduce
the cost and simplify the process from a commercial aspect,
we developed an improved process based on Scheme 3 (Route
B). In this contribution, a simplified scaleable process with
dramatically improved yield and quality for the preparation of
1 is described that uses GCLE as a starting material.
Schemes 1 and 2 have many shortcomings such as having
a large number of steps, using expensive and hazardous raw
materials, and being not environmentally friendly. Scheme 1
is impractical on a large scale due to the above shortcomings
Results and Discussion
Starting from GCLE, one reported literature method10,11
involves introduction of C-3 vinyl group by the Wittig reaction
to give p-methoxybenzyl 7-phenylacetamido-3-chloromethyl-
cephem-4-carboxylate (2), which when deprotected with trif-
luoroacetic acid gives 7-phenylacetamido-3-chloromethylceph-
em- 4-carboxylic acid (3). 7-AVCA (1) is finally obtained by
enzymolysis in the presence of penicillin G amidase. In this
method, the overall yield and purity of 1 are only 55% and
92.3%, respectively. 3 is isolated and dried for use in the next
step. Expensive and hazardous trifluoroacetic acid is used.
Furthermore, the crude product is washed with methanol, butyl
acetate, and acetone sequentially to remove the impurities,
making solvent recovery difficult. Another improved method12
increases the yield and purity to 58.5% and 98.3% respectively,
but trifluoroacetic acid is also used in the process, and
chromatographic purification is required to improve the quality.
In the present paper, we report an improved and scaleable
process with respect to improvement of yield and product
quality, use of less expensive raw materials, and lower
consumption of solvents. In this improved process, GCLE reacts
with sodium iodide and triphenylphosphine in a mixture of
* Author for correspondence. E-mail: haoay@sdu.edu.cn. Telephone: (86-
531) 88363306.
(1) Deshpande, P. B.; Luthra, P. K. (Orchid). U.S. Patent 6,388,070 B1,
2002.
(2) Hu, A. X.; Yuan, S.; Song, Y. Q.; Tang, F.; Song, J. S. Chin. J. Pharm.
2004, 35 (1), 3–4.
(3) Rao, K. V. V. P.; Dandala, R.; Sivakumaran, M. S.; Rani, A. Synth.
Commun. 2007, 37, 2275–2283.
(4) Lee, G. S.; Chang, Y. K.; Chun, J. P.; Koh, J. H. (Hanmi). U.S. Patent
6,093,814, 2000.
(5) Brogden, R. N.; Campoli-Richards, D. M. Drugs 1989, 38, 524–550.
(6) Inamoto, Y.; Chiba, T.; Kamimura, T.; Takaya, T. J. Antibiot. 1988,
41, 828–830.
(7) Ternansky, R. J.; Christopher, L.; Jordan, F.; Bell, W.; Theresea, G.;
Kasher, S. J. Antibiot. 1993, 46, 1897–1900.
(8) Yamanaka, H.; Chiba, T.; Kawabata, K.; Takasugi, H.; Masugi, T. J.
Antibiot. 1985, 38 (12), 1738–1751.
(9) Takaya, T.; Takasugi, H.; Masugi, T.; Yamanaka, H.; Kawabata, K.
(Fujisawa) U.S. Patent 4,960,889, 1990.
(10) Hu, S. C.; Zhou, H. S.; Bi, X. L. J. Chin. Pharm. UniV 1993, 24 (4),
246–247.
(11) Xu, S. W.; Chen, S. H.; Huang, M. K. Chin. J. Pharm. 2000, 31 (8),
367–368.
(12) Du, B. S.; Sheng, C. G.; Sun, T. M. Chin. J. Med. Chem. 2006, 16
(2), 85–87.
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10.1021/op900053j CCC: $40.75  2009 American Chemical Society
Published on Web 07/02/2009

Scheme 1. Synthesis of diphenylmethyl 7-AVCA from DCC8
Scheme 2. Synthesis of diphenylmethyl 7-AVCA from 7-ACA8
water and methylene chloride to give the phosphonium salt,
which subsequently reacts with formaldehyde in the presence
of base to result in 2. The resulting 2 is then deprotected with
phenol to give 3, which when deprotected with penicillin G
amidase gives 1 in an overall yield of 77% with a purity of
>99%.
higher product purity and lower yield; conversely, one obtains
higher yield and lower purity. Further, an improved crystal-
lization method was developed, and single-stage crystallization
was optimized to multistage crystallization. Overall, this
improved crystallization method dramatically improved the yield
without compromising the quality.
During the process optimization, we paid great attention to
operation simplicity on a commercial scale. By controlling the
purity of 2 at greater than 99%, isolation or chromatographic
purification of 3 was eliminated. Two deprotection steps were
carried out sequentially without isolation of 3 by aqueous phase
extraction of the intermediate after the first deprotection.
Introducing a vinyl group by the Wittig reaction is a
traditional method, but reported methods for preparation of 2
give low yields and purity. We studied causes for the low yield
and purity during the process optimization. In the crystallization
of 2, a lower concentration of supersaturated solution gives
When deprotecting the carboxyl group, expensive, hazardous
trifluoroacetic acid is eliminated, making the process more cost-
effective and environmentally friendly. After deprotection of
the carboxyl group, 3 is extracted to water and subjected to
enzymolysis directly without isolation or chromatographic
purification, making the process simpler and giving better yield.
Upon deprotection of the phenylacetyl group with penicillin G
amidase, 1 is obtained in excellent color and purity by adjusting
the pH with sulfuric acid solution without further purification,
saving additional solvents and making recovery easier.
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Scheme 3. Synthesis of 7-AVCA from GCLE9-12
On a commercial scale, the quality and yield of 2 are also
affected by the temperature and efficiency of the distillation.
Heat input and vacuum level should be controlled such that
the internal temperature does not rise above 40 °C. The
operational time of all workup procedures should be controlled;
extended workup time compromises the quality and lowers the
yields.
The present method has the following advantages over the
reported methods. Consumption of solvents is minimized. The
yield of 2 is dramatically improved by a multistage crystalliza-
tion method without compromising the quality. The use of
expensive, hazardous trifluoroacetic acid is eliminated. Isolation
or chromatographic purification of 3 is avoided by extracting
the intermediate into the aqueous phase. The overall yield is
increased to 77% with a purity of >99%. The process has been
demonstrated in pilot scale and is amenable to large-scale
synthesis.
mL)]; flow rate: 1.5 mL/min; detection wavelength: 263 nm;
injection volume: 20 µL/mL.
Preparation of p-Methoxybenzyl-7-phenylacetamido-3-
vinylcephem-4-carboxylate (2). Sodium iodide (4.65 kg, 31
mol) was added to a mixture of water (14 L) and methylene
chloride (70 L), followed by adjusting the pH to 3.0 with
concentrated HCl. Then GCLE (15 kg, 30.8 mol) and triphenyl
phosphine (8.19 kg, 31 mol) were added. The reaction mixture
was heated to 32-36 °C with hot water and stirred at this
temperature until completion of the reaction as monitored by
HPLC (30-60 min). Upon completion of the reaction, the
mixture was cooled to 10-20 °C. Methylene chloride (28 L),
dimethylformamide (21 L) and formaldehyde solution (16.2 kg,
200 mol) were added, followed by slow addition of sodium
hydroxide solution (1.2 kg in 14 L water). The reaction mixture
was stirred at 10-20 °C until completion of the reaction
monitored by HPLC (30-60 min). After completion of the
reaction, water (112 L) and concentrated HCl (0.7 kg) were
added. The resulting mixture was again stirred for 30 min, and
then allowed to separate. The aqueous layer was extracted with
methylene chloride (14 L). The organic layers were combined
and washed with water (87 L). Then methylene chloride was
partly removed by distillation in vacuo while the internal
temperature was maintained below 40 °C to a final volume of
about 60 L. Methanol (193 L) was added, and the distillation
was continued to reach a final volume of about 170 L. Water
(45 L) was slowly added, and the resulting mixture was slowly
cooled to 18-22 °C and filtered. The cake was washed with
acetone/water (30 L/13 L) and dried in vacuo to yield 2 (12
kg, 84%). Mp 179.4-179.7 °C; HPLC purity >99%; 1H NMR
(DMSO-d6): δ 9.19 (d, 1H, NH), 7.32-6.92 (m, 9H, C6H5/4),
6.81 (dd, 1H, -CH ) CH2), 5.71 (dd, 1H, -CH-NH), 5.65 (m,
1H, -CHdCH2a), 5.34 (d, 1H, -CH)CH2b), 5.26 (d, 1H,
S-CH-N), 5.15 (m, 2H, OCH2-), 3.75 (s, 3H, -OCH3), 3.93
and 3.58 (d, 2H, OdC-CH2), 3.50 and 3.67 (d, 2H, S-CH2);
13C NMR (DMSO-d6): δ 171.4, 165.4, 162.2, 159.8, 136.3,
132.0, 130.8, 129.5, 128.7, 127.5, 127.0, 125.8, 124.5, 118.6,
114.3, 67.6, 59.7, 58.3, 55.6, 42.0, 23.6; IR (ν cm-1, KBr): 3271
(NH), 3045 (CHdCH), 2961 (CH2), 1775, 1714 (CO), 1659
(CdC), 1614, 1586, 1497, and 1456 (C6H5), 1251, 1200
(-COOCH2-), 1177, 1166 (C-O-CH3), 826 (C6H4), 697
(C6H5); MS (m/e): 465.4 [M + H]+.
In conclusion, an environmentally friendly, cost-effective and
scaleable process for the preparation of 7-amino-3-vinylcephem-
4-carboxylic acid (1) with dramatically improved yield and
quality is reported.
Experimental Section
General. Reagents were used as such without purification.
Melting points were measured using a capillary melting point
apparatus without correction. NMR spectra were recorded on
a Bruker instrument at 300 MHz for 13C and 600 MHz for 1H,
with tetramethylsilane as an internal standard. Infrared spectra
were recorded using a Thermo Scientific Nicolet iS10 instru-
ment. Mass spectra were recorded using an API 4000 (ABI)
instrument.
HPLC methods. Reaction progress was monitored by
HPLC. HPLC analysis was performed on a Waters instrument
with a UV detector using a Chemsil ODS (150 mm × 4.6 mm,
5 µm) column.
HPLC analysis for triphenylphosphine complex. Mobile
phase: pH 7.3 buffer/organic modifier ) 40:60 (v:v) [buffer
prepared as follows: dissolve ammonium dihydrogen ortho-
phosphate (0.92 g) and disodium hydrogen orthophosphate (0.17
g) in H2O (400 mL); organic modifier prepared as follows:
dissolve tetra-heptyl-ammonium bromide (2.4 g) in acetonitrile
(300 mL), add methanol (300 mL)]; flow rate: 1.0 mL/min;
detection wavelength: 263 nm; injection volume: 20 µL/mL.
HPLC analysis for other reactions. Mobile phase: tetra-n-
butyl ammonium hydroxide (TBAH) solution/acetonitrile ) 50:
50 (v:v), adjusted to pH 5 with phosphoric acid. [TBAH solution
prepared as follows: dissolve TBAH (0.92 g) in water (500
Preparation of 7-Phenylacetamido-3-vinylcephem-4-car-
boxylic acid (3). Phenol (25 kg, 266 mol) was melted with hot
water and cooled to 45-50 °C followed by addition of 2 (12
kg, 25.8 mol). The reaction mixture was stirred at 45-50 °C
until completion of the reaction monitored by HPLC (12-18
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h). After completion of the reaction, the reaction mixture was
added to a mixture of butyl acetate (108 L) and water (90 L)
and cooled to 13-17 °C. Sodium bicarbonate solution (3.2 kg
of sodium bicarbonate in 48 L of water) was added. The reaction
mixture was stirred for 30 min at 13-17 °C, and then allowed
to separate. The organic layer was extracted twice with a
solution of sodium bicarbonate and sodium chloride in water
(each time with 1.4 kg of sodium chloride and 0.24 kg of
sodium bicarbonate in 24 L of water). The aqueous layers were
combined and extracted with butyl acetate (36 L) to give water
solution of 3. If the phenol content in the aqueous layer was
more than 0.5%, an additional butyl acetate (25 L) extraction
was applied. The resulting solution of 3 was held for direct use
in the next step. A small sample of the solution was removed
and adjusted to pH 2.0 with diluted HCl, filtered, and dried in
vacuo for characterization. Mp 165.4-165.6 °C; HPLC purity
>99%; 1H NMR (DMSO-d6): δ 9.17 (d, 1H, NH), 7.32-7.22
(m, 5H, C6H5), 6.91 (dd, 1H, -CHdCH2), 5.68 (dd, 1H,
-CH-NH), 5.60 (d, 1H, -CHdCH2a), 5.32 (d, 1H,
-CHdCH2b), 3.88 (d, 1H, S-CH-N), 3.58 (d, 1H,
-CH2a-CdO), 3.56 (d, 1H, -CH2b-CdO), 3.50 (d, 2H,
S-CH2); 13C NMR (DMSO-d6): δ 170.9, 164.5, 163.1, 135.7,
131.8, 128.9, 128.1, 126.4, 125.3, 124.0, 117.2, 59.0, 57.6, 41.4,
22.9; IR (ν cm-1, KBr): 3279 (NH), 3032 (CHdCH), 2956
(CH2), 1775, 1705 (CO), 1662 (CdC), 1497 and 697 (C6H5);
MS (m/e): 345.4 [M + H]+.
while maintaining at pH 8.0 with an 8-10% sodium carbonate
solution. The progress of the phenylacetyl deprotection reaction
was monitored by HPLC (1-3 h). After completion of the
reaction, the suspension was filtered, and the filtrate was cooled
to 0-5 °C. To the filtrate were added activated carbon (0.9 kg)
and chilled methanol (24 L); the resulting mixture was stirred
at 0-5 °C for 20 min and filtered. The filtrate was slowly
acidified to pH 4.0 with 16-18% sulfuric acid solution and
filtered. The cake was washed with water (18 L), slurried with
methanol (12 L), filtered, and dried under vacuum to give 1
(5.36 kg, 92% based on 2). Mp > 200 °C dec; HPLC purity
>99%; 1H NMR (DMSO-d6): δ 6.87 (dd, 1H, -CHdCH2), 5.53
(d, 1H, -CHdCH2a), 5.25 (d, 1H, -CHdCH2b), 5.00 (d, 1H,
-CH-N), 4.76 (d, 1H, -CH-NH2), 3.80 (d, 1H, S-CH2a),
3.52 (d, 1H, S-CH2b); 13C NMR (DMSO-d6): δ 169.8, 163.5,
132.2, 125.8, 122.9, 116.2, 63.6, 59.1, 22.5; IR (ν cm-1, KBr):
1801 (CO), 1613 (CdC); MS (m/e): 227.3 [M + H]+.
Acknowledgment
We are grateful to the Research and Development Center
of Heze Ruiying Pharma Group for providing raw materials
and pilot production support.
Preparation of 7-Amino-3-vinylcehpem-4-carboxylic acid
(1). Penicillin G amidase was added to a water solution of 3
from the previous step. The mixture was stirred at 29-33 °C
Received for review March 10, 2009.
OP900053J
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