Improved synthesis of Cefdinir and its polymorphic form, an antibacterial active pharmaceutical ingredient

Article abstract of DOI:10.1080/00397910701397284

New methods for the preparation of Cefdinir 1 and its polymorphic form Sesqui hydrate 1a are described. The synthesis of 2-mercaptobenzothiazolyl (Z)-2-(2-amino-4-thiazolyl)-2-acetoxyiminoacetate 4 was affected by using triphenylphosphine and triethylamine, and acylation of 7-amino-3-vinylcephem-4- carboxylic acid 5 followed by deprotection with K2CO3 in the presence of ammonium chloride in the same pot yielded crude Cefdinir. Purification of crude Cefdinir through resin and treatment of the resulting wet product with trifluoroacetic acid gave highly pure TFA salt of Cefdinir 6, which on neutralization afforded 1a in excellent yield. The impurity profiling of this compound has also been discussed. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701397284

Synthetic Communicationsw, 37: 2275–2283, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701397284
Improved Synthesis of Cefdinir and Its
Polymorphic Form, an Antibacterial Active
Pharmaceutical Ingredient
Korrapati V. V. Prasada Rao, Ramesh Dandala,
Meenakshisunderam S. Sivakumaran, and Ananta Rani
Research and Development Department, Aurobindo Pharma Ltd.,
Hyderabad, India
Andra Naidu
Jawaharlal Nehru Technological University, Hyderabad, India
Abstract: New methods for the preparation of Cefdinir 1 and its polymorphic form
Sesqui hydrate 1a are described. The synthesis of 2-mercaptobenzothiazolyl (Z)-2-
(2-amino-4-thiazolyl)-2-acetoxyiminoacetate 4 was affected by using triphenylpho-
sphine and triethylamine, and acylation of 7-amino-3-vinylcephem-4-carboxylic acid
5 followed by deprotection with K2CO3 in the presence of ammonium chloride in
the same pot yielded crude Cefdinir. Purification of crude Cefdinir through resin and
treatment of the resulting wet product with trifluoroacetic acid gave highly pure
TFA salt of Cefdinir 6, which on neutralization afforded 1a in excellent yield. The
impurity profiling of this compound has also been discussed.
Keywords: antibacterial drug, Cefdinir, impurities, synthesis
INTRODUCTION
Cefdinir 1, 7b-[(Z)-2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-
vinylcephem-4-carboxylic acid, is a third-generation, semisynthetic cephalos-
porin antibiotic characterized by having a broad spectrum of antibacterial
Received December 4, 2006
Address correspondence to Ramesh Dandala, Research and Development Depart-
ment, Aurobindo Pharma Ltd., 313 Bachupally, Hyderabad 500072, AP, India.
E-mail: rdandala@auribindo.com
2275

2276
K. V. V. P. Rao et al.
activity against staphylococci and streptococci. It is used for oral adminis-
tration and has a broader antibacterial spectrum over gram-positive and
gram-negative bacteria.[1,2] Our present work describes improved synthetic
methods for the preparation of Cefdinir and its polymorphic form,
sesquihydrate.
RESULTS AND DISCUSSION
Many synthetic approaches have been reported for this preparation. The key
intermediate 4 has been synthesized in literature[3] by using triethylphosphite
in the presence of tributylamine. The reported synthetic approach for the prep-
aration of 1 starts with 7-amino-3-vinylcephem-4-carboxylic acid 5, which is
then first silylated and elaborated to Cefdinir.[2,4–8] The process involves
complex reactions such as silylation with N,O-bis trimethylsilylacetamide,
no control during basic hydrolysis of protecting groups, long reaction times,
very poor yields, use of large volumes of solvents, and inferior quality of
the finished product. To circumvent difficulties, we have devised a viable
process in which the acylation of amine 5 was affected by using 2-mercapto-
benzothiazolyl (Z)-2-(2-amino-4-thiazolyl)-2-acetoxyiminoacetate 4 in the
presence of triethylamine, and the resulting acyl compound was directly
taken for hydrolysis in the presence of ammonium chloride to afford crude
Cefdinir. It was purified by passing through resin and converted to the corre-
sponding trifluoroacetic acid (TFA) salt, which on neutralization gives
Cefdinir sesquihydrate 1a in excellent purity with high yield.
In this sequence, compound 4 has been prepared from anhydrous 2-(2-
amino-4-thiazolyl)-2-syn-acetoxyiminoacetic acid 2[7] by treatment with
triphenylphosphine and triethylamine in methylene chloride (Scheme 1).
It is very important that the water content of acid 2 must be less than
0.3%. The higher amount of water causes incomplete conversions and needs
excess amounts of reagents, which leads very slow filtration of the product.
The yield was reduced by 10% when triphenylphosphine was replaced by
triethylphosphite in the presence of either tributylamine or triethylamine.
Compound 4 has been used for the acylation of compound 5 in aqueous
THF. After workup, the aqueous layer containing corresponding acyl
Scheme 1.

Synthesis of Cefdinir
2277
derivative was subjected to hydrolysis with a mixture of K2CO3 and NH4Cl in
water at ambient temperature. Several bases have been investigated for this
reaction, and K2CO3 was found to give the best results. NH4Cl is necessary
to maintain the pH between 8 and 8.2 by acting as buffer, which effectively
prevented the formation of impurities. In the absence[4,5] of NH4Cl, the
yield was very low and the purity was only 95%. This is believed to be a
result of polymerization of Cefdinir and formation of impurities. The yield
and quality of Cefdinir also depends on the addition of potassium carbonate
and reaction times during hydrolysis. Longer reaction times during hydrolysis
leads to beta lactam ring cleavage and formation of polymeric impurities,
which are not able to be removed by recrystallization methods. The product
obtained by the present method contains ꢀ1% w/w of polymeric materials,
which restricts the formation of 1a. It indicates that the formation of sesquihy-
drate depends on the quality of the product. Thus the solution of sodium salt of
crude Cefdinir has been passed through the Diaion HP 20 resin to remove the
polymeric impurities. The optimal conditions used water at the volume of 10
L/Kg of substrate for dissolution and 40 L/Kg of substrate for column elution.
This process was used just for the removal of polymers, and no improvement
was observed in chromatographic purity of the product. The wet material
obtained after resin purification was treated with TFA to yield TFA salt of
Cefdinir 6. This is a key step for getting high purity with uniform crystals
of 1a. Several acidic addition salts were investigated and converted to
Cefdinir crystal B. TFA salt was found to be the best acidic addition salt of
Cefdinir. TFA salt is not soluble in water, whereas all other acidic addition
salts are soluble in water, such as phosphate salt, sulphate salt, and methane
sulphonate salts. Finally, neutralization of TFA salt affords 1a (Scheme 2)
with 99.78% of high performance liquid chromatography (HPLC) purity.
Scheme 2.

2278
K. V. V. P. Rao et al.
Compound 1a obtained from this method contains four potential impuri-
ties in a range of 0.05% and 0.10% on a commercial scale. These are identified
as methyl Cefdinir 7, Cefdinir lactone 8, Cefdinir delactam lactone 9, and
Cefdinir anti-isomer 10. The structures of these impurities are given in
Fig. 1. Cefdinir delactam lactone and methyl Cefdinir have been synthesized
per the methods described in literature.[9,10] Cefdinir lactone and Cefdinir
anti-isomer were synthesized by new methods in the laboratory and purified
by preparative HPLC. Except for Cefdinir lactone, all other impurities are
constant in stability studies for 12 months at control room temperature,
whereas Cefdinir lactone increased to 0.2% from 0.08%.
Finally, we are able to telescope the three-step synthetic sequence into
one continuous operation in the plant to give 1a from 7-amino-3-vinylce-
phem-4-carboxylic acid 5 in 65–70% overall yield. The X-ray diffraction
pattern of compound 1a is shown in Table 1, and all the analytical data are
given in the Experimental section.
EXPERIMENTAL
The 1H NMR spectra were recorded on a Bruker 300-MHz spectrometer, and
the chemical shifts were reported on d ppm relative to TMS. The IR spectra
were recorded on a Perkin-Elmer Spectrum of Fourier transfer infrared
(FTIR) spectrometer, and mass spectra were obtained on API 2000 Perkin-
Elmer PE-SCIEX mass spectrometer. Solvents and reagents were obtained
from commercial sources and were used without purification.
Figure 1. Chemical structures of impurities present in Cefdinir.

Synthesis of Cefdinir
Table 1. X-ray diffraction data of Cefdinir sesquihydrate 1a
2279
Significant diffraction
angle (2u)
Interplanar
spacing (d)
Relative
intensity (%)
5.8
7.8
15.16
11.38
11.00
7.55
5.68
5.50
4.77
4.58
4.24
4.19
3.99
3.64
3.47
3.40
24
30
30
100
41
61
43
24
33
43
60
43
37
42
8.0
11.7
15.6
16.1
18.6
19.4
20.9
21.2
22.3
24.4
25.6
26.2
Preparation of 2-Mercaptobenzothiazolyl (Z)-2-
(2-Amino-4-thiazol)-2-acetoxyiminoacetate (4)
Triphenylphosphine (143 kg, 0.545 mol) was added in small lots to a cooled
suspension of anhydrous (Z)-2-(2-amino-4-thiazol)-2-acetoxyiminoacetic
acid (2, 100 kg, 0.436 mol), methylene chloride (1500 lit), and bis (benzothia-
zole-2-yl) disulphide (3, 173.8 kg, 0.523 mol), at 10–158C in 10 min.
Thereafter, triethylamine (52.90 kg, 0.523 mol) was added over 10 min at
the same temperature. TEA addition is exothermic, and the temperature
rises to 308C in 5–10 min. After addition is completed, stirring was
continued for another 10 min. The precipitated product was filtered and
washed with methylene chloride (100 lit) and dried at 35–408C to yield 4
as a yellow powder (132 kg, 80%).
Mp: 143–1458C; IR (KBr, cm21): 3446, 3101, 1777, 1645, 1618; 1H NMR
(DMSO, d ppm): 2.23 (s, 3H), 7.38 (s, 1H), 7.52 (br s, 2H), 7.55–7.65 (m, 2H),
8.09 (d, 1H, J ¼ 9 Hz), 8.23 (d, 1H, J ¼ 9 Hz); 13C NMR (DMSO, d ppm):
20.1, 115.0, 123.2, 124.1, 127.4, 127.9, 137.5, 139.4, 152.6, 154.3, 154.9,
167.8, 170.3, 186.2; C H N analysis: calcd. for C14H10F3N4O3S3: C, 44.43;
H, 2.66; N, 14.80. Found: C, 44.50; H, 2.66; N, 14.82.
7b-[(Z)-2-(2-Amino-4-thiazolyl)-2-hydroxyiminoacetamido]-
3-vinylcephem-4-carboxylic Acid (Cefdinir) (1)
Water (200 lit) was added to a stirred suspension of 7-amino-3-vinyl-
cephem-4-carboxylic acid (5, 40 kg, 0.177 mol), 2-mercaptobenzothiazolyl

2280
K. V. V. P. Rao et al.
(Z)-2-(2-amino-4-thiazol)-2-acetoxyiminoacetate (4, 78 kg, 0.206 mol),
and tetrahydrofuran (400 lit) at 15–208C over 15 min. Thereafter, triethyl-
amine (20 kg, 0.198 mol) was added over 60 min at 15–208C. After
complete addition, the reaction mixture was stirred for 5 h at 18–208C.
Methylene chloride (400 lit) was added, followed by DM water
(200 lit), and stirred for 10 min. The organic layer was separated and
extracted with water (200 lit). The combined aqueous layer was washed
with methylene chloride (200 lit). Thereafter, the aqueous layer was
degassed under reduced pressure at 25–308C to remove the traces of
THF and methylene chloride. Carbon (4 kg) was added and the suspen-
sion stirred for 30 min at 25–308C. Carbon was filtered and washed
with water (200 lit). Ammonium chloride (26.4 kg, 0.493 mol) was added
to the filtrate and stirred for 10 min at 18–208C. Potassium carbonate
solution (20% v/v, 128 lit) was added while maintaining the pH
between 8 and 8.2 for 30–40 min. Thereafter, the reaction mixture
was stirred for another 10 min at 20–228C, and the pH was adjusted
to 4.5–5.0 with 10% v/v aqueous sulfuric acid (ꢀ53 lit) at 20–258C.
The reaction mixture was heated to 38–408C, and the pH was brought
down to 2.5–3.0 with 10% v/v aqueous sulfuric acid (ꢀ53 lit) to pre-
cipitate the product. The suspension was stirred for 30 min at the
same temperature to complete the crystallization. The solid was filtered,
washed with water (400 lit), and dried at 45–508C to obtain the title
compound as a pale yellow crystalline powder. The wet material
(ꢀ100 kg) was suspended in water (580 lit), and pH was adjusted to
6.9–7.2 with 10% w/w aqueous ammonia (ꢀ27 lit) at 8–128C. The
mixture was stirred while maintaining the pH at 6.9–7.2 to get a clear
solution. It was passed through a column packed with Diaion HP 20 resin
(215 kg) in water (215 lit) over a period of 1 h at 8–128C. Thereafter, the
product was eluted with precooled water (1600 lit, 8–128C) in 2–3 h.
The eluate obtained was warmed to 35–408C and pH adjusted to 2.5–3.0
with 10% v/v aqueous sulfuric acid (ꢀ27 lit), and stirring continued for
30 min. The solid obtained was filtered and washed with water (300 lit)
to obtain the title compound as a pale yellow crystalline powder. This wet
material was directly taken for the formation of Cefdinir trifluoroacetic
acid salt.
Mp: 180–1908C (decompose); IR (KBr, cm21): 3302, 3176, 1784,
1668, 1611, 1429, 1545, 1350, 1334, 1050, 1017; 1H NMR (300 MHz,
DMSO, d ppm) 3.55 and 3.83 (ABq, 2H, J ¼ 17.56 Hz), 5.19 (d, 1H,
J ¼ 4.95 Hz), 5.30 (d, 1H, J ¼ 11.25 Hz), 5.60 (d, 1H, J ¼ 17.56 Hz),
5.79 (dd, 1H, J ¼ 11.25 Hz and 17.55 Hz), 6.67 (s, 1H), 6.80–6.90
(m, 1H), 7.10 (bs, 2H), 9.50 (d, 1H), 11.33 (s, 1H); 13C NMR (75 MHz,
DMSO, d ppm) 24.1, 58.6, 59.5, 108.4, 118.6, 125.7, 126.0, 132.6, 143.9,
149.0, 164.0, 164.6, 164.8, 169.2; mass: 396.2 (M)þ. Anal. calcd. for
C14H13N5O5S2: C, 42.49; H, 3.29; N, 17.70; S, 16.19. Found: C, 42.33; H,
3.28; N, 17.63; S, 16.17%.

Synthesis of Cefdinir
2281
7b-[(Z)-2-(2-Amino-4-thiazolyl)-2-hydroxyiminoacetamido]-
3-vinylcephem-4-carboxylic Acid, Trifluoroacetic Acid Salt
(Cefdinir TFA Salt) (6)
Trifluoroacetic acid (67 lit) was added to a stirred suspension of wet Cefdinir
(1, ꢀ80 kg, obtained as described previously) and water (1600 lit) at 35–408C
in 30 min. The addition to the suspension turned white, was stirred for 30 min
at the same temperature, and was cooled to 10–158C. The solid was filtered
and washed with cold water (40 lit, 2–58C) to yield the title compound as
an off-white powder with 99.7% chromatographic purity.
Mp: 155–1568C; IR (KBr, cm21): 3297, 3242 (NH), 1769 (b-lactam
CO), 1673 (amide CO) 1592 and 1429 (acid CO), 1352 and 1319 (NH2),
1015 (NO); 1H NMR (DMSO, d ppm): 3.58 and 3.83 (ABq, 2H,
J ¼ 17.84 Hz), 5.20 (d, 1H, J ¼ 4.94 Hz), 5.32 (d, 1H, J ¼ 11.25 Hz), 5.60
(d, 1H, J ¼ 17.56 Hz), 5.79 (dd, 1H, J ¼ 4.94 Hz and 8.23 Hz), 6.76
(s, 1H), 6.92 (dd, 1H, J ¼ 11.25 Hz and 17.56 Hz), 9.60 (d, 1H,
J ¼ 7.96 Hz); 13C NMR (DMSO, d ppm): 24.1, 58.6, 59.7, 108.5, 118.2,
125.4, 126.3, 132.8, 139.6, 147.3, 159.7, 160.2, 163.7, 164.1, 164.5, 170.1;
mass: 396 (Mþ). C H N analysis: calcd. for C16H14F3N5O7S2: C, 37.72; H,
2.77; F, 11.19; N, 13.75. Found: C, 37.90; H, 2.77; F, 11.20; N, 13.80.
7b-[(Z)-2-(2-Amino-4-thiazolyl)-2-hydroxyiminoacetamido]-
3-vinylcephem-4-carboxylic Acid, Sesquihydrate (Cefdinir
Sesquihydrate) (1a)
Aqueous ammonia solution (1:1 v/v, ꢀ21 lit) was added to a stirred suspen-
sion of wet TFA salt of Cefdinir (6, ꢀ70 kg, obtained as described previously)
and water (1400 lit) at 16–208C to adjust the pH to 3–3.2 in 30 min. The pre-
cipitated product was stirred for 30 min at the same temperature to complete
the precipitation. The solid was filtered and washed with cold water (185 lit,
5–108C). The wet material was dried at 45–508C to yield compound 1a
(48.5 kg, 65%).
Mp: 1908C (decomp). Water (% W/W, by KF): 6.1; IR (Nujol, cm21):
3302, 3176 (NH), 1784 (b-lactam CO), 1668 (amide CO) 1611 and 1429
1
(acid CO), 1350 and 1334 (NH2), 1017 (NO) cm21; H NMR (DMSO, d
ppm): 3.53 and 3.83 (ABq, 2H, J ¼ 17.56 Hz), 5.19 (d, 1H, J ¼ 4.94 Hz),
5.31 (d, 1H, J ¼ 11.25 Hz), 5.59 (d, 1H, J ¼ 17.56 Hz), 5.79 (m, 1H), 6.67
(s, 1H), 6.90 (dd, 1H, J ¼ 11.25 Hz and 17.56 Hz), 7.15 (bs, 2H), 9.50
(d, 1H, J ¼ 8.23 Hz), 11.32 (s, 1H), 13.62 (brs, 1H); 13C NMR (DMSO, d
ppm): 24.1, 58.6, 59.5, 108.4, 118.6, 125.7, 126.0, 132.6, 143.9, 149.0,
164.0, 164.6, 164.8, 169.2; mass: 396 (Mþ). C H N analysis: calcd. for
C14H13N5O5S2 (395.42): C, 42.49; H, 3.29; N, 17.70; S, 16.19. Found: C,
42.33; H, 3.28; N, 17.63; S, 16.17.

2282
K. V. V. P. Rao et al.
(Z)-2-(2-Amino-4-thiazolyl)-2-(hydroxyimino)-N-[(2RS, 5RS)-
1,2,5,7-tetrahydro-5-methyl-7-oxo-4H-furo[3,4-d][1,3]thiazin-2-yl]
methyl] Acetamide (8)
Trifluoroacetic acid (200 g, 1.75 mol) was added to a stirred suspension of
compound 1a (100 g, 0.236 mol) and DM water (1000 ml) at 25–308C over
30 min. Thereafter, the contents were stirred at 35–408C for 1 h, cooled to
10–158C, and stirred for 15 h. The remaining solid was filtered and washed
with water (200 ml). The filtrate, containing 12% of title compound, was
subjected to preparative HPLC to isolate the title compound as an off-white
amorphous material (1 g, 1%).
IR (KBr, cm21): 3200 (OH), 1785 (b-lactam CO), 1749 (g-lactone CO),
1
1666 (CONH), 1533 (NH), 1039 (NO); H NMR (DMSO, d ppm): 1.39 (2d,
3H, J ¼ 6.8 Hz), 3.81 (s, 2H), 5.18 (2d, 1H, 5.1 Hz), 5.31 (q, 1H,
J ¼ 6.8 Hz), 5.95 (d, 1H, J ¼ 5.1 and 8.1 Hz), 6.81 (s, 1H), 9.75 (2d, 1H,
J ¼ 8.1 Hz); mass: 396.2 (Mþ). C H N analysis: calcd. for C14H13N5O5S2
(395.42): C, 42.53; H, 3.31; N, 17.71; S, 16.19. Found: C, 42.43; H, 3.30;
N, 17.70; S, 16.20.
7b-[(E)-2-(2-Amino-4-thiazolyl)-2-hydroxyiminoacetamido]-
3-vinylcephem-4-carboxylic Acid (Cefdinir Anti-isomer) (10)
2-(2-Tritylamino-4-thiazolyl)-2-trityloxyimino acetic acid[11] anti-isomer
(32.5 g, 0.048 mol) was suspended in methylene chloride (1000 ml), and the
methylene chloride (600 ml) was distilled to remove the water. The reaction
mixture was cooled to 215 to 2108C under a nitrogen atmosphere. PCl5
(11 g, 0.052 mol) was added in small lots over 30 min at the same tempera-
ture. Water (60 ml) was added and separated the layers. The organic layer
was washed with water (50 ml) and dried over sodium sulphate. It was
added to a suspension of 7-amino-3-vinylcephem-4-carboxylic acid (10 g,
0.044 mol) and N-trimethylsilylacetamide (30 g, 0.22 mol) at 215 to
2108C over 15 min. Thereafter, the temperature was raised to 25–278C
and stirred for 10 h. DM water (100 ml) was added and the layers
separated. The organic layer was dried over sodium sulphate and concentrated
to get a foamy solid. Aqueous trifluoroacetic acid (1:1 v/v, 150 ml) was added
to the resulting solid and stirred for 4 h at 12–158C. The by-product tritanol
was filtered off, and the filtrate was cooled to 08C. pH was adjusted to
2.5–2.6 with 1:1 v/v aqueous ammonia solution, and the mixture was
stirred for 2 h. The resulting solid was filtered and washed with precooled
water (25 ml) to yield the title compound as a pale brown amorphous
powder (2 g, 11.5%). It was suspended in water (10 ml), and pH was
adjusted to 6.5–7.0 with sodium bicarbonate (1.4 g, 0.0076 mol). It was
stirred for 30 min to get a clear solution. The resulting solution was filtered,
and the pH of the filtrate was adjusted to 2.5–2.6 with 1:1 v/v HCl to

Synthesis of Cefdinir
2283
precipitate the product. The solid was filtered, washed with water (10 ml), and
dried to obtain the title compound as a pale brown powder (1.5 g, 8.6%).
IR (KBr, cm21): 3188 (OH, NH), 1759 (b-lactam CO), 1671 (CONH),
1
1525 (NH), 1029 (NO); H NMR (DMSO, d ppm): 3.50 and 3.64 (ABq,
2H, J ¼ 17.8 Hz), 5.01 and 5.23 (ABq, 2H, J ¼ 5.0 Hz), 5.06 (d, 1H,
J ¼ 11.3 Hz), 5.68 (dd, 1H, J ¼ 4.9 Hz and 8.2 Hz), 7.0 (dd, 1H, J ¼ 11.3 Hz
and 17.4 Hz), 7.21 (s, 1H), 7.58 (s, 1H), 9.30 (d, 1H, J ¼ 8.2 Hz), 12.61 (brs,
1H); mass: 396.1 (Mþ). C H N analysis: calcd. for C14H13N5O5S2 (395.42):
C, 42.53; H, 3.31; N, 17.71; S, 16.19. Found: C, 42.33; H, 3.31; N, 17.73;
S, 16.18.
ACKNOWLEDGMENT
The authors thank the management of Aurobindo Pharma Ltd., Research and
Development Department, for supporting this work. The authors also thank
the Analytical Research Department for their valuable contribution to
this work.
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