Synthesis of (Z)-2-(2-formamido-4-thiazolyl)-2-(substituted alkoxyimino) acetic acids

Article abstract of DOI:10.1016/S0014-827X(99)00118-4

(Z)-2-(2-formamido-4-thiazolyl)-2-(substituted alkoxyimino) acetic acids were synthesized by a new method based on the following sequence of reactions: treatment of the tert-butyl acetoacetate with sodium nitrite, alkylation of the oxime formed with an appropriate alkyl halide, halogenation of methyl α-keto group and simultaneous cleavage of tert-butyl ester with sulfuryl chloride, protection of the obtained acid function with diphenyldiazomethane, formation of the 2-aminothiazole ring by the Hantzsch method with thiourea, formylation of the amino group and selective final cleavage of the diphenylmethyl ester by treatment with trifluoroacetic acid and anisol. The developed procedure allows the synthesis of (Z)-2-(2- formamido-4-thiazolyl)-2-(substituted alkoxyimino) acetic acids, with an ester function in the alkoxyimino group employing a simple method and obtaining higher yields in comparison with the habitually used classic method. (C) 2000 Elsevier Science S.A.

Full text of DOI:10.1016/S0014-827X(99)00118-4

www.elsevier.nl/locate/farmac
Il Farmaco 55 (2000) 40–46
Synthesis of (Z)-2-(2-formamido-4-thiazolyl)-2-(substituted
alkoxyimino) acetic acids
Miguel Lo´pez a, Zalua Rodr´ıguez a, Maritza Gonza´lez a, Ba´rbara Valde´s a,
Herma´n Ve´lez a, Adamo Fini b,*,1
a Department of Chemical Synthesis. Center of Pharmaceutical Chemistry, A6e 200 y 21, Atabey, Playa, Ciudad de La Habana, Cuba
b Istituto di Scienze Chimiche, 6ia San Donato 15, I-40127 Bologna, Italy
Received 20 July 1999; accepted 15 October 1999
Abstract
(Z)-2-(2-formamido-4-thiazolyl)-2-(substituted alkoxyimino) acetic acids were synthesized by a new method based on the
following sequence of reactions: treatment of the tert-butyl acetoacetate with sodium nitrite, alkylation of the oxime formed with
an appropriate alkyl halide, halogenation of methyl a-keto group and simultaneous cleavage of tert-butyl ester with sulfuryl
chloride, protection of the obtained acid function with diphenyldiazomethane, formation of the 2-aminothiazole ring by the
Hantzsch method with thiourea, formylation of the amino group and selective final cleavage of the diphenylmethyl ester by
treatment with trifluoroacetic acid and anisol. The developed procedure allows the synthesis of (Z)-2-(2-formamido-4-thiazolyl)-2-
(substituted alkoxyimino) acetic acids, with an ester function in the alkoxyimino group employing a simple method and obtaining
higher yields in comparison with the habitually used classic method. © 2000 Elsevier Science S.A. All rights reserved.
Keywords: Cephalosporins; 7-Aminocephalosporanic acid; Synthesis; Alkoxyimino group
1. Introduction
class of drugs and the syn configuration of the side
chain can be associated to a high resistance of these
drugs to hydrolytic enzymes towards the cefem ring
[1–3].
The (Z)-2-(2-formamido-4-thiazolyl)-2-(substituted
alkoxyimino) acetic acids are important synthetic inter-
mediates in the cephalosporin chemistry. These com-
pounds are used in the preparation of the third-
generation cephalosporins by acylation of various 3-
cephem nuclei [4–9] (Fig. 1).
Cephalosporins are a group of antibiotics, widely
developed for their large activity spectrum and resis-
tance to b-lactamase. They can be divided into
cephalosporins of first, second and third generation.
Moreover this last group of drugs displays an interest-
ing activity towards Gram (−) bacteria, even though
they do not operate the same towards Gram (+)
bacteria as compounds of the first generation. Among
these drugs cefixime and cefdinir are well-assessed com-
pounds. A structural characteristic of these molecules is
New compounds of this class must therefore main-
tain the above reported structural characteristics in
order to preserve activity. However the thiazolyl hete-
rocycle is rather difficult to obtain and in this
the presence in the
7
position of the 7-
aminocephalosporanic acid (7-ACA), nucleus of a 2-
aminothiazolyl moiety bounded by means of an
(alkoxyimino) acetamido grouping. The heterocyclic
ring is responsible of higher Gram (−) activity of this
* Corresponding author. Tel.: +39-051-244540; fax: +39-051-
249770.
Fig. 1. Structure of the (Z)-2-(2-formamido-4-thiazolyl)-2-(substi-
tuted alkoxyimino) acetic acids.
E-mail address: fini@biocfarm.unibo.it (A. Fini)
1 Visiting Professor in CQF.
0014-827X/00/$ - see front matter © 2000 Elsevier Science S.A. All rights reserved.
PII: S0014-827X(99)00118-4

M. Lo´pez et al. / Il Farmaco 55 (2000) 40–46
41
Scheme 1. Method A for the synthesis of I.
paper new synthetic pathways are explored both to
increase the yields and to decrease the number of the
synthetic steps.
Current synthetic methods to prepare I are outlined
in Schemes 1 (Method A) and 2 (Method B) [10–14].
In both methods the oxime 1 is the common interme-
diate, obtained from ethyl acetoacetate by treatment
with sodium nitrite in acetic acid.
higher than in Method B. Nevertheless, Method A
cannot be used when the alkoxyimino group to be
introduced contains an ester function as substituent,
because the treatment with sodium hydroxide causes
the simultaneous hydrolysis of the two ester groups of
the molecule. In this case a product with two acid
functions with similar reactivity would be obtained.
This acid function would compete during the acylation
reaction with cephalosporanic nucleus and the forma-
tion of side products would take place. This situation
causes a reduction of the yields and the degree of purity
of the resulting cephalosporins.
Method B can be used for the introduction of the
alkoxyimino group with an ester function but the yields
of reaction are much lower and it implies the execution
of many reaction steps.
The objective of this paper is to find an alternative
method for the synthesis of (Z)-2-(2-formamido-4-thia-
zolyl)-2-(substituted alkoxyimino) acetic acids, with an
ester function in the alkoxyimino group (I). We wanted
to develop a new synthetic pathway, which applies the
advantages of the method A over the method B to
prepare I.
In Method A the oxime 1 is alkylated with an alkyl
halide in the presence of potassium carbonate as a
catalyst. The methyl group of 2 is then halogenated
with sulfuryl chloride or bromine. The reaction of the
halogenated derivative 3 with thiourea afforded the
2-aminothiazole ring, according to the conditions of
Hantzsch method. In the next step the alkaline hydroly-
sis of the ester group of 4 occurs in the presence of
sodium hydroxide. Finally the amino function of (5) is
protected by formylation with a mixture of acetic anhy-
dride–formic acid to give I.
According to Method B the halogenated derivative
(6) is synthesized from the oxime 1. The formation of
the 2-aminothiazole ring is a similar reaction to that
previously described. The glyoxalate 8 is prepared by
treatment of 7 with sodium hydrogen sulfite and it is
formylated with a mixture of acetic anhydride–formic
acid. From the formylated glyoxalate (9), by means of
alkaline hydrolysis, was finally obtained the acid form
(10). Into this last compound was then introduced a
substituted alkoxyimino group, using an alkoxyamine
obtained by treatment of a substituted N-alkoxyphthal-
imide (12) with 100% hydrazine hydrate [15,16].
Method A is much less complex and the yields are
2. Chemistry
The proposed synthetic pathway is as follows
(Scheme 3):
In this method the ethyl acetoacetate used in
Methods A and B as starting material was replaced by

42
M. Lo´pez et al. / Il Farmaco 55 (2000) 40–46
Scheme 2. Method B for the synthesis of I.
tert-butyl acetoacetate. This compound reacts with
sodium nitrite in acid medium to produce the oxime,
which was alkylated with an appropriate alkyl halide.
The ester function in the alkoxyimino group was
formed and the intermediate L1 was obtained [4,5]. The
methyl group adjacent to the keto carbonyl group was
halogenated with sulfuryl chloride in acetic acid. In
these conditions the simultaneous cleavage of the tert-
butyl ester furnished the acid (L2) [4,5].
The 2-aminothiazole ring cannot be formed with the
main acid function in free form because the yield of
reaction is very low or null. For this reason the tempo-
rary protection of this acid group was carried out
through the formation of diphenylmethyl ester by treat-
ment of L2 with diphenyldiazomethane to obtain the L3
compound. Diphenyldiazomethane was obtained using
sodium hydroxide instead of sodium hydrogen carbon-
ate [17]; this change allows the preparation of a very
pure reagent, avoiding the presence of p-toluenesulfon-
amide, which is completely eliminated in these condi-
tions; this fact in turn avoids side reactions that
decrease the yield of L3.
This is the most important step of the proposed
method, because the formation of diphenylmethyl ester
facilitates the formation of 2-aminothiazole ring with
good yields, as well as allowing the introduction of a
protective group in the carboxyl group, which can be
eliminated without affecting the alkoxyimino group.
The following step was the formation of 2-aminothia-
zole ring by means of the Hantzsch method by treat-
ment of L3 with thiourea in the presence of sodium
acetate as basic catalyst. The reaction was carried in a
mixture of tetrahydrofuran–water [4,5,14], because
these conditions guarantee the almost exclusive obtain-
ment of the syn isomer, the only one that has biological
activity, and allows an easy separation of the desired
product (L4). The formylation of the amino function, in
a mixture of anhydride acetic–formic acid [18], af-
forded L5.
Finally the cleavage of the diphenylmethyl group of
L5 was obtained with an excess of trifluoroacetic acid in
the presence of anisole [18]. The stability of the alkyl
ester alkoxyimino group in acid medium in this case fa-
cilitates the selective liberation of the main acid function.

M. Lo´pez et al. / Il Farmaco 55 (2000) 40–46
43
Scheme 3. Method developed for the synthesis of (Z)-2-(2-formamido-4-thiazolyl)-2-(methoxycarbonylmethoxyimino) acetic acid.
Total yields are calculated on the basis of the ethyl and
tert-butyl acetoacetate used as initial substances.
In this chart it can be observed that in the developed
variant total yields were obtained more than 2.5 times
higher than those achieved by Method B. The yield is
only a little higher than that in the classic Method A,
but this method does not allow the use of reactants
with a function ester in the alkoxyimino group, which
undergoes unrequired hydrolysis.
The compound L6 was thus obtained with a high
degree of purity and good yields (\70–80% in the last
steps). The hydrolysis of L5 is an important step of the
overall reaction, because the free form of the acid (L6)
allows soft conditions to obtain a series of derivatives
by acylation without degrading the cephalosporanic
nucleus.
The developed technique was also used with success
for the synthesis of an analog of L6, having an ethyl
ester in the alkoxyimino group. This method could be
used in the preparation of similar alkyl esters, as well as
for other derivatives of I that contain functional groups
unstable in a basic medium.
3. Experimental
Melting points (m.p.) were determined using the Gal-
lenkamp capillary apparatus with a system of measure-
ment and temperature control. 1H NMR and 13C NMR
spectra were recorded at 250 MHz and 62.5 MHz,
respectively, on a Bruker AC 250F spectrometer, using
Me2SO-d6 as a solvent and tetramethylsilanne (TMS) as
an internal standard.
The following chart shows, in a comparative form,
the yields obtained in the synthesis of this type of
compound by Methods A and B, as well as for the
developed method.
Thin layer chromatography (TLC) was carried out in
pre-coated plates of Merck silica gel 60 F254. In the
development of chromatograms two mobile phases
were used (FM A) ethyl acetate–ethanol–water–formic
acid (60:25:15:1)) and (FM B) ethyl acetate–n-hexane
(1:1). The chromatograms were revealed in a Camag
UV–Vis lamp with a wavelength of 254 nm. Evapora-
tion of organic solvent was carried out in vacuum
(rotating evaporator). Anhydrous sodium sulfate was
always used as a drying agent.
Alkoxyimino group of I Yield (%)
(R)
Method A9 OCH2COOH
12.3
5.9
15.4
Method B9
Developed
variant
Developed
variant
OCH2COOC2H5
OCH2COOCH3
OCH2COOC2H5
14.6

44
M. Lo´pez et al. / Il Farmaco 55 (2000) 40–46
The developed procedure is exemplified with the ob-
taining of (Z)-2-(2-formamido-4-thiazolyl)-2-(methoxy-
carbonylmethoxyimino) acetic acid (L6).
1H NMR l (ppm) 1.40 (9H, s, C(CH3)3), 2.23 (3H, s,
CH3CO), 3.62 (3H, s, COOCH3), 4.86 (2H, s, OCH2R);
13C NMR l (ppm) 25.08 (CH3CO), 27.64 (R(CH3)3),
51.83 (COO*CH3), 71.93 (OCH2R), 84.18 (*C(CH3)3),
3.1. Synthesis of diphenyldiazomethane
150.65
(CꢀNꢁOR),
159.41
(COOR),
168.46
(*COOC(CH3)3), 192.70 (CH3 *COR)
Benzophenone hydrazone (10.78 g, 55 mmol) and
iodine (2.2 ml, 1% w/v) were stirred in N,N-dimethylac-
etamide (55 ml) and water (5 ml). A solution of chlor-
amine T (15.5 g, 55 mmol) in N,N-dimethylacetamide
(55 ml) and water (5 ml) was then added slowly over 30
min at 20°C. The mixture was stirred for 15 min before
partition between dichloromethane (110 ml) and 5%
3.4. 4-Chloro-2-methoxycarbonylmethoxyimino-
3-oxobutyric acid (L2)
To a solution of L1 (33.6 g, 130 mmol) in glacial
acetic acid (33 ml) was added sulfuryl chloride (77 g,
570 mmol) at 58–60°C in 3.5 h. After an additional
hour, the reaction mixture was cooled and evaporated.
The residue was dissolved in ethyl acetate (130 ml) and
the organic layer was washed with brine (3×30 ml).
After being dried, the solvent was evaporated in vac-
uum. The resulting solid was collected by filtration and
recrystallized with isopropyl ether (30 ml) and dried at
40°C in a stove to afford 10 g (32.5%) of L2. TLC (FM
sodium
hydroxide
solution
(275
ml).
The
dichloromethane layer was washed with water (1×100
ml and 3×50 ml), dried and made up to 200 ml in a
volumetric flask.
3.2. Quantitati6e determination of
diphenyldiazomethane
1
A) 0.48; m.p. 133–134°C (d); H NMR l (ppm) 3.66
Diphenyldiazomethane solution (10 ml) was exactly
measured and the solvent was evaporated until dryness
at reduced pressure. The obtained residue was dissolved
with 10 ml of 1,2-dichloroethane, cooled down to 0–
5°C and glacial acetic acid was added until the total
fading of the breakup. The content of diphenyldia-
zomethane was determined by measurement of the ni-
trogen volume that came off during the reaction to
afford 8.70 g (81.53%) of diphenyldiazomethane.
(3H, s, CH3), 4.79 (2H, s, OCH2R), 4.92 (ClCH2R); 13C
NMR l (ppm) 45.66 (ClCH2R), 51.94 (CH3), 72.13
(OCH2R), 150.00 (CꢀNꢁOR), 160.81(COOH), 168.48
(*COOCH3), 186.50 (ClCH*2 COR).
3.5. Diphenylmethyl-4-chloro-2-methoxycarbonyl-
methoxyimino-3-oxo-butirate (L3)
To a solution of diphenyldiazomethane (15 mmol) in
dichloromethane was added L2 (3.2 g, 13.5 mmol) in
small portions under ice cooling. The mixture was
stirred at r.t. for 30 min. After removal of the solvent
under reduced pressure, the residue was rinsed with
n-hexane. The resulting solid was collected by filtration,
washed with n-hexane and dried at 40°C in a stove to
give 5.1 g (93.8%) of L3. TLC (FM B) 0.82; m.p.
3.3. tert-Butyl-2-methoxycarbonylmethoxyimino-
3-oxo-butyrate (L1)
To a solution of tert-butyl-acetoacetate (25 g, 158
mmol) in glacial acetic acid (25 ml) was added a
solution of sodium nitrite (11.45 g, 166 mmol) in 20 ml
of water under ice-cooling. During the addition, the
reaction temperature was maintained below 15°C. After
addition, the mixture was stirred at 15°C for 30 min.
After removal of the acid and the water under reduced
pressure, the residue was dissolved in ethyl acetate (50
ml), and washed with 5% sodium hydrogen carbonate
solution (2×10 ml). The separated organic layer was
washed with brine, dried and evaporated.
1
92–93°C; H NMR l (ppm) 3.70 (3H, s, CH3), 4.90
(2H, s, OCH2R), 5.05 (ClCH2R), 7.03 (1H, s,
CH(C6H5)2), 7.3–7.5 (10H, m, aromatics); 13C NMR l
(ppm) 45.82 (ClCH2R), 52.00 (CH3), 72.54 (OCH2R),
78.81 (CH(C6H5)2), 148.09 (CꢀNꢁOR), 158.60
(*COOCH (C6H5)2), 168.26 (*COOCH3), 186.14
(ClCH2*COR).
The residue was dissolved in ethyl acetate (45 ml) and
dimethylformamide (45 ml) and methyl chloroacetate
(16.5 g, 152 mmol) and potassium carbonate (12 g, 152
mmol) were added at room temperature (r.t.) with
stirring. An additional amount of anhydrous potassium
carbonate (10.5 g, 76 mmol) was added 30 min later.
After stirring at r.t. for 15 h, the mixture was poured
into ice-water (100 ml) and extracted with ethyl acetate
(50 ml). The organic phase was washed with water
(3×25 ml), dried and evaporated until dryness to give
33.6 g (82%) of L1 as a reddish oil. TLC (FM A): 0.87;
3.6. Diphenylmethyl-(Z)-2-(2-amino-4-thiazolyl)-
2-(methoxycarbonylmethoxyimino) acetate (L4)
To a stirred solution of L3 (5.0 g, 12.4 mmol) in
tetrahydrofuran (25 ml) and water (25 ml) were added
thiourea (1.9 g, 25 mmol) and sodium acetate (5.1 g,
67.17 mmol). After being stirred at 40°C for 4 h, the
mixture was extracted with ethyl acetate (125 ml). The
separated organic layer was washed with brine (3×50
ml), dried and evaporated to give a 4.9 g (93%) of L4 as

M. Lo´pez et al. / Il Farmaco 55 (2000) 40–46
45
a clear yellow solid. TLC (FM B) 0.35; m.p. 143–
144°C; H NMR l (ppm) 3.70 (3H, s, CH3), 4.75 (2H,
ethyl esters, as side chain, were synthesized. Yields were
higher than those described in Method B. This proce-
dure could be useful for obtaining other similar com-
pounds in the alkoxyimino groups that contain
functional groups sensitive to the alkaline hydrolysis
and that cannot usually be prepared by traditional
Method A.
1
s, OCH2R), 6.80 (1H, s, aminothiazole), 7.03 (1H, s,
CH(C6H5)2), 7.3–7.5 (12H, m, (C6H5)2 +NH2); 13C
NMR l (ppm) 51.73 (CH3), 70.91 (OCH2R), 78.34
(CH(C6H5)2), 109.90 (C-5 aminothiazole), 140.54 (C-4
aminothiazole), 147.27 (CꢀNꢁOR), 161.28 (*COOCH-
(C6H5)2), 168.89 (C-2 aminothiazole), 169.32 (*COO-
CH3).
Acknowledgements
3.7. Diphenylmethyl-(Z)-2-(2-formamido-4-thiazolyl)-
2-(methoxycarbonylmethoxy imino) acetate (L5)
This work was partly supported by the Funds of the
University of Bologna, Italy.
A mixture of acetic anhydride (4 ml, 42.3 mmol) and
formic acid 99% (1.6 ml, 42.4 mmol) was stirred at
40°C for 1 h. To the mixture was added L4 (4.5 g; 10.59
mmol) and the reaction mixture was stirred at r.t. for 3
h. The obtained solution was stirred with n-hexane (15
ml) and ethyl acetate (15 ml). The resulting precipitate
was collected by filtration, washed with n-hexane and
dried at 40°C in a stove to afford 3.7 g (77.1%) of L5.
References
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1
TLC (FM B) 0.45; m.p. 143–144°C; H NMR l (ppm)
3.70 (3H, s, CH3), 4.80 (2H, s, OCH2R), 7.05 (1H, s,
CH(C6H5)2), 7.3–7.5 (12H, m, (C6H5)2 +NH2), 8.5
(1H, s, HCO), 12.60 (1H, s, NH); 13C NMR l (ppm)
51.77 (CH3), 71.10 (OCH2R), 78.57 (CH(C6H5)2),
115.94 (C-5 aminothiazole), 139.50 (C-4 aminothia-
zole), 146.85 (CꢀNꢁOR), 157.32 (C-2 aminothiazole),
160.14 (CHO), 160.98 (*COOCH), 169.20 (*COOCH3).
3.8. (Z)-2-(2-Formamido-4-thiazolyl)-
2-(methoxycarbonylmethoxyimino)acetic acid (L6)
To a solution of L5 (3.5 g 7.73 mmol) in 10 ml of
dichloromethane were added anisole (4.8 ml, 43.94
mmol) and trifluoroacetic acid (14 ml, 182.93 mmol)
under ice cooling. After 30 min at the same tempera-
ture, the mixture was poured into isopropyl ether. The
resulting solid was collected by filtration, washed with
isopropyl ether and dried at 40°C in stove to give 1.9 g
(85.7%) of L6. TLC (FM A) 0.58; m.p. 159–160°C (d);
1H NMR l (ppm) 3.68 (3H, s, CH3), 4.78 (2H, s,
OCH2R), 7.55 (1H, s, aminothiazole), 8.52 (1H, s,
HCO), 12.63 (1H, s, NH); 13C NMR l (ppm) 51.69
(CH3), 70.87 (OCH2R), 115.42 (C-5 aminothiazole),
140.12 (C-4 aminothiazole), 148.12 (CꢀNꢁOR), 157.08
(C-2 aminothiazole), 160.05 (CHO), 163.13 (COOH),
169.37 (*COOCH3).
4. Conclusions
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