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Communication

Efficient and Eco-Friendly Preparation of 4-Methyl-5-formyl-thiazole

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.
Molecules 2008, 13(4), 943-947; https://doi.org/10.3390/molecules13040943
Submission received: 6 April 2008 / Revised: 17 April 2008 / Accepted: 17 April 2008 / Published: 21 April 2008

Abstract

:
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.

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].
4-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 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 MnO2, CrO3, or NaOCl [4,5,6,7] and the reduction of carboxylic ester with LiAlH4, NaBH4, or Red-Al [4,8,9,10]. However, these methods are eco-unfriendly and too expensive for industrial production. One reported better method is Cr-ZrO2 catalyzed the gas phase hydrogenation of the corresponding carboxylic ester [11]. However, the 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.
Figure 1. Structure of cefditoren pivoxil and 4-methyl-5-formylthiazole.
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Scheme 1. Synthesis of 4-methyl-5-formylthiazole.
Scheme 1. Synthesis of 4-methyl-5-formylthiazole.
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Results and Discussion

Effects of BaSO4 particle size

We have found that nano-scale carbon can reduce the palladium content greatly while keeping good catalytic activity [12]. However, smaller nano-scale Pd/BaSO4 may change its catalytic property due to nano-effects or congregation. Various BaSO4 particles were tested while the Pd/BaSO4 ratio (25% to acid) and palladium content (2.5%) were kept unchanged, as shown in Figure 2. The yield increased markedly along with the decrease of BaSO4 size until the size of the BaSO4 reached 5 μm. Subsequently, the yield decreased slowly.
Figure 2. Effect of Pd/BaSO4 size on product yield.
Figure 2. Effect of Pd/BaSO4 size on product yield.
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Effects of palladium content

Higher Pd content should have higher activity and make the reaction time shorter until the surface of the BaSO4 is fully occupied. Based on above results, therefore, 5 μm-size BaSO4 was used for 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.
Figure 3. Effect of Pd content on reaction time.
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Activation of the acyl chloride bond

The optimal temperature was 140°C. When TsOH, AlCl3, BF3, and FeCl3 were added to activate the acyl chloride bond, adverse effects on the yield were found.

Conclusions

4-Methyl-5-formylthiazole can be efficiently prepared by Pd/BaSO4 (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

1H-NMR and 13C-NMR spectra were recorded in CDCl3 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.

Catalyst Preparation

The Pd/BaSO4 was prepared according to a literature method [13]. Various types of commercial BaSO4 were used directly instead of this reagent being prepared in situ.

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/BaSO4 the mixture was heated to 140°C while hydrogen was passed into it. The reaction was 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, pure product was obtained. 1H-NMR (CDCl3) δ: 10.1064 (s, 1H, -CHO), 8.9481 (s, 1H, 2-CH), 2.7571 (s, 3H, -CH3); 13C-NMR (CDCl3) δ: 182.4214 (1C, -CHO), 161.8374 (1C, 5-C), 158.8544 (1C, 2-CH), 132.8399 (1C, 4-C), 16.2193 (1C, -CH3); IR (cm-1, KBr): 3447 (m, w), 3091 (s), 2869 (s), 1660 (s), 1522 (s), 1409 (s), 1319 (s).

References

  1. Wellington, K.; Curran, M.P. Cefditoren Pivoxil: A Review of its Use in the Treatment of Bacterial Infections. Drugs 2004, 64, 2597–2618. [Google Scholar] [CrossRef]
  2. 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. [Google Scholar]
  3. Buchman, E.R.; Richardson, E.M. Thiamin Analogs. I. β-(4-Methylthiazolyl-5)-alanine. J. Am. Chem. Soc. 1939, 61, 891–893. [Google Scholar] [CrossRef]
  4. 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. [Google Scholar]
  5. 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. [Google Scholar] [CrossRef]
  6. 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. [Google Scholar]
  7. Hideo, A.; Manabu, K.; Yutaka, K. Manufacturing method of 4-alkyl-5-formylthiazole derivatives having high yields. JP Pat. Appl. 2003261547, 2003. [Google Scholar]
  8. 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. [Google Scholar]
  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. [Google Scholar]
  10. Kazutake, H.; Hideki, T.; Osamu, M. Preparation of aromatic aldehydes. JP Pat. Appl. 2003155259, 2003. [Google Scholar]
  11. 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. [Google Scholar] [CrossRef]
  12. 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. [Google Scholar] [CrossRef]
  13. Nishimura, S. Handbook of Heterogeneous Catalytic Hydrogenation for Organic Synthesis; John Wiley & Sons,Inc.: New York, 2001; pp. 35–36. [Google Scholar]
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MDPI and ACS Style

Bai, N.; Sha, Y.; Meng, G. Efficient and Eco-Friendly Preparation of 4-Methyl-5-formyl-thiazole. Molecules 2008, 13, 943-947. https://doi.org/10.3390/molecules13040943

AMA Style

Bai N, Sha Y, Meng G. Efficient and Eco-Friendly Preparation of 4-Methyl-5-formyl-thiazole. Molecules. 2008; 13(4):943-947. https://doi.org/10.3390/molecules13040943

Chicago/Turabian Style

Bai, Nan, Yaowu Sha, and Ge Meng. 2008. "Efficient and Eco-Friendly Preparation of 4-Methyl-5-formyl-thiazole" Molecules 13, no. 4: 943-947. https://doi.org/10.3390/molecules13040943

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