Efficient and eco-friendly preparation of 4-methyl-5-formyl-thiazole

Article abstract of DOI:10.3390/molecules13040943

4-Methyl-5-formylthiazole, an intermediate for synthesizing cefditoren pivoxil, was prepared in good yield by Pd/BaSO₄ catalyzed hydrogenation of 4-methylthiazole-5-carboxylic acid chloride. Detailed reaction conditions have been studied.

Full text of DOI:10.3390/molecules13040943

Molecules 2008, 13, 943-947
molecules
ISSN 1420-3049
2008 by MDPI
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Communication
Efficient and Eco-Friendly Preparation of
4-Methyl-5-formyl-thiazole
Nan Bai, Yaowu Sha* and Ge Meng
The Key Laboratory of Bioorganic Phosphorous Chemistry and Chemical Biology, Department of
Chemistry, Tsinghua University, Beijing 100084, P.R. China
*
Author to whom correspondence should be addressed; E-mail: shayw@tsinghua.edu.cn
Received: 6 April 2008; in revised form: 17 April 2008 / Accepted: 17 April 2008 / Published: 21 April
008
2
Abstract: 4-Methyl-5-formylthiazole, an intermediate for synthesizing cefditoren pivoxil,
was prepared in good yield by Pd/BaSO catalyzed hydrogenation of 4-methylthiazole-5-
carboxylic acid chloride. Detailed reaction conditions have been studied.
4
4
Keywords: 4-Methyl-5-formylthiazole, Pd/BaSO catalyzed hydrogenation.
Introduction
Cefditoren pivoxil (a, Figure 1) is a third-generation cephalosporin antibacterial with broad-
spectrum and enhanced stability against many common β-lactamases. It has been approved in many
countries for the treatment of adults and adolescents with acute exacerbations of chronic bronchitis
(
AECB), community-acquired pneumonia (CAP), streptococcal pharyngitis/tonsillitis, and
uncomplicated skin and skin structure infections [1].
-Methyl-5-formylthiazole (b, Figure 1) is a key intermediate for the synthesis of cefditoren pivoxil
2], which was first synthesized in 1939 [3]. The formation of the aldehyde group in this substance has
4
[
been the focus of much research. Recently developed methods include the oxidation of 4-methyl-5-(2-
hydroxyethyl)thiazole or 4-methyl-5-(hydroxymethyl)thiazole with MnO , CrO , or NaOCl [4-7] and
2
3
the reduction of carboxylic ester with LiAlH , NaBH , or Red-Al [4,8-10]. However, these methods
4
4
are eco-unfriendly and too expensive for industrial production. One reported better method is Cr-ZrO
2
catalyzed the gas phase hydrogenation of the corresponding carboxylic ester [11]. However, the

Molecules 2008, 13
944
stability of product also causes difficulty in large scale production. We have found that Pd/BaSO4
catalyzed hydrogenation of carboxylic chloride could give high yield and, moreover, be more eco-
friendly and suitable for industrial production (Scheme 1).
Figure 1. Structure of cefditoren pivoxil and 4-methyl-5-formylthiazole.
O
O
O
N
O
(
H C) C
3 3
O
N
S
N
S
H
O
NH2
H C
3
S
S
CH3
H H H
N
N
MeO
a
b
Scheme 1. Synthesis of 4-methyl-5-formylthiazole.
O
O
O
S
SOCl
2
S
N
H2
S
N
OH
CH3
Cl
H
N
Pd/BaSO4
CH3
CH3
Results and Discussion
Effects of BaSO particle size
4
We have found that nano-scale carbon can reduce the palladium content greatly while keeping
good catalytic activity [12]. However, smaller nano-scale Pd/BaSO may change its catalytic property
due to nano-effects or congregation. Various BaSO particles were tested while the Pd/BaSO ratio
25% to acid) and palladium content (2.5%) were kept unchanged, as shown in Figure 2. The yield
4
4
4
(
4 4
increased markedly along with the decrease of BaSO size until the size of the BaSO reached 5 μm.
Subsequently, the yield decreased slowly.
4
Figure 2 Effect of Pd/BaSO size on product yield.
60
50
40
30
20
0
5
10
15
20
25
Size of BaSO (um)
4

Molecules 2008, 13
945
Effects of palladium content
Higher Pd content should have higher activity and make the reaction time shorter until the surface
of the BaSO is fully occupied. Based on above results, therefore, 5 μm-size BaSO was used for
4
4
checking the effects of palladium content. As the palladium content increased from 2.5%, the reaction
time shortened linearly (Figure 3). An inflexion point was noted at 7.5% palladium content. Beyond
that, additional palladium had little effect.
Figure 3. Effect of Pd content on reaction time.
1
0
8
6
4
2
2
4
6
8
10
12
14
Pd content of Pd/BaSO (%)
4
Activation of the acyl chloride bond
The optimal temperature was 140°C. When TsOH, AlCl , BF , and FeCl were added to activate
3
3
3
the acyl chloride bond, adverse effects on the yield were found.
Conclusions
4
-Methyl-5-formylthiazole can be efficiently prepared by Pd/BaSO
4
(5 μm, Pd: 7.5%) catalyzed
hydrogenation of 4-methylthiazole-5-carboxylic chloride in xylene at refluxing temperature. This
method is more eco-friendly and better suited for industrial production than previous methods.
Experimental
General
1
13
3
H-NMR and C-NMR spectra were recorded in CDCl on a JEOL JNM-ECA300 spectrometer
operating at 300 and 75 MHz, respectively. Chemical shifts (δ) are reported in parts per million (ppm)
relative to tetramethylsilane (TMS) as an internal standard, and coupling constants (J) are given in
hertz (Hz). IR spectra were recorded on Nicolet AVATAR 360 FT-IR E.S.P. All reagents were
purchased and used without further purification.

Molecules 2008, 13
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Catalyst Preparation
The Pd/BaSO was prepared according to a literature method [13]. Various types of commercial
4
BaSO were used directly instead of this reagent being prepared in situ.
4
Synthesis of 4-methylthiazole-5-carboxylic acid chloride
4
-Methylthiazole-5-carboxylic acid (1.5 g) was added to thionyl chloride (10 mL). After refluxing
for 2 hours, the excess thionyl chloride was distilled off under reduced pressure. The remaining
product was used directly for the next step without further purification.
General procedure for the synthesis of 4-methyl-5-formylthiazole
Xylene (30 mL) was added to the newly prepared carboxylic acid chloride. After the addition of
Pd/BaSO the mixture was heated to 140°C while hydrogen was passed into it. The reaction was
4
monitored by TLC (petroleum ether-acetone = 3:1). When the reaction was finished, the mixture was
filtered and extracted with 10% HCl (3×30 mL). The water solution was neutralized to pH = 8 with
sodium carbonate and further extracted with chloroform (3×30 mL). After distillation of chloroform,
1
pure product was obtained. H-NMR (CDCl
3
) δ: 10.1064 (s, 1H, -CHO), 8.9481 (s, 1H, 2-CH), 2.7571
1
3
(
s, 3H, -CH
3
); C-NMR (CDCl
32.8399 (1C, 4-C), 16.2193 (1C, -CH
522 (s), 1409 (s), 1319 (s).
3
) δ: 182.4214 (1C, -CHO), 161.8374 (1C, 5-C), 158.8544 (1C, 2-CH),
-1
1
1
3
); IR (cm , KBr): 3447 (m, w), 3091 (s), 2869 (s), 1660 (s),
References
1
2
3
4
5
.
.
.
.
.
Wellington, K.; Curran, M.P. Cefditoren Pivoxil: A Review of its Use in the Treatment of
Bacterial Infections. Drugs 2004, 64, 2597-2618.
Mohan, P.; Yatendra, K.; Kaptan, S. Process for selective preparation of Z-isomer of cefditoren
and pharmaceutically acceptable salts and esters thereof. WO Pat. Appl. 2005016936, 2005.
Buchman, E.R.; Richardson, E.M. Thiamin Analogs. I. β-(4-Methylthiazolyl-5)-alanine. J. Am.
Chem. Soc. 1939, 61, 891-893.
Yatendra, K.; Mohan, P.; Kaptan, S.; Ashok, P.; Santosh, R. Preparation of intermediates for the
synthesis of 3-[2-(4-methylthiazole-5-yl)vinyl]cephalosporins. WO Pat. Appl. 2005100330, 2005.
Hideo, T.; Chou, J.Y.; Machiko, M.; Manabu, K. The oxidation of alcohols in N-Oxyl-
immobilized silica gel/aqueous NaOCl disperse systems. A prominent access to a column-flow
system. Bull. Chem. Soc. Jpn. 2004, 77, 1745-1755.
6
7
8
.
.
.
Nikolaevna, Y.A.; Victrovana, S.Z.; Nikolaevich, P.A.; Vladimirovich, R.V.; Serafimovich, Z.N.
Preparation of 4-methyl-5-formylthiazole. JP Pat. Appl. 2004107346, 2004.
Hideo, A.; Manabu, K.; Yutaka, K. Manufacturing method of 4-alkyl-5-formylthiazole derivatives
having high yields. JP Pat. Appl. 2003261547, 2003.
Balwant, D.P.; Kumar, L.P.; Rajesh, V.; Ramakrishna, K. Oxidation and reduction process for the
preparation of 5-formyl-4-methylthiazole. US Pat. Appl. 2003204095, 2003.

Molecules 2008, 13
947
9
.
Kazutake, H.; Sunao, M.; Hiroaki, T. A facile and selective synthetic method for the preparation
of aromatic dialdehydes from diesters via the amine-modified SMEAH reduction system.
Synthesis 2003, 6, 823-828.
1
1
0. Kazutake, H.; Hideki, T.; Osamu, M. Preparation of aromatic aldehydes. JP Pat. Appl.
003155259, 2003.
2
1. Yokoyama, T.; Setoyama, T.; Fujita, N.; Maki, T. Novel direct hydrogenation process of aromatic
carboxylic acids to the corresponding aldehydes with zirconia catalyst. Stud. Surf. Sci. Catal.
(
Acid-Base Catal. II) 1994, 90, 47-58.
1
1
2. Pan, Z.Z.; Sha, Y.W. Effect and regeneration of heterogeneous palladium/charcoal catalysts
poisoned by tetramethylthiourea-quinoline in the stereoselective hydrogenation of methacycline to
α-doxycycline., Appl. Catal. A-Gen. 2003, 252, 347-352.
3. Nishimura, S. Handbook of Heterogeneous Catalytic Hydrogenation for Organic Synthesis; John
Wiley & Sons, Inc.: New York, 2001; pp. 35-36.
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