Short and efficient synthesis of 5-aminothiazole-4-carboxamide
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Jin Wang
Abstract
5-Aminothiazole-4-carboxamide is a precursor for the synthesis of thiazole [4,5-d] pyrimidines. In this work, a new synthesis method with a high total yield (79%) of 5-aminothiazole-4-carboxamide was reported. The starting material is aminocyanacetamide. This synthesis method is environment-friendly and is suitable for industrial production.
Introduction
Thiazole-5-carboxamide is a key intermediate in the synthesis of thiazole[5,4-d]-pyrimidine derivatives. Thiazole [5,4-d] pyrimidine compounds are the isostere of purines [1] and precursors to bioactive molecules [2] in the synthesis of antiviral, anticancer, antibacterial, anti-inflammatory, and anti-psychotic drugs [3–7]. Meanwhile, the synthesis of 5-aminothiazole-4-carboxamide (1 in Scheme 1) has rarely been reported. Tamura et al. [8] have reported the preparation of 1 by cyclization of 2-formamido-2-thiocarbamoylacetamide with acetic formic anhydride, followed by hydrolysis with 5% hydrochloric acid to give compound 1 in 28% yield. In our hands, the method has been difficult to reproduce, and therefore, it appears to be unsuitable for a large-scale preparation. Tamura et al. [8] have also reported another approach to 5-aminothiazole-4-carboxamide by heating 2-formamido-2-thiocarbamoylacetamide in polyphosphoric acid. Unfortunately, the procedure has completely failed in our hands.
Results and discussion
In this article, we report new synthesis of 5-aminothiazole-4-carboxamide as shown in Scheme 1. The reaction of aminocyanacetamide (2) with carbon disulfide furnished the substituted thiazole 3 in a 95% yield. The choice of this reaction was based on the report by Everett that sodium cyanide undergoes a reaction with carbon disulfide to produce thiazole compounds [9]. Methylation of 3 yielded a methylthio derivative 4. The desired product 1 was obtained in a total yield of 79% after reduction of 4 over a Raney nickel [10]. A direct removal of the thiol from 3 proved to be difficult; hence, the additional methylation step was introduced. It was observed that the concentration of sodium hydroxide is crucial in the methylation of 3 with dimethyl sulfate to give compound 4. The concentration of 3.5% is optimal for the highest yield of 4.
Conclusion
A simple and efficient methodology for the synthesis of 1 was developed. The approach is suitable for a large-scale industrial production.
Experimental
General
All commercial reagents were purchased from Fluka and Sinopharm Chemical Reagent Co. Ltd and used without further purification. Aminocyanoacetamide was prepared using the procedures reported previously [11–13]. Silica gel plates (F254; Sanpont, China) and silica gel (100–200 mesh; SCRC) were used for analytical and column chromatography, respectively. NMR spectra (400 MHz for 1H and 100 MHz for 13C) were recorded in DMSO-d6 on a Bruker AVANCE 400 spectrometer. Liquid chromatography-mass spectra (LC-MS) were acquired in a positive mode over 100–300 m/z range using a Waters Acquity-Quatro Premier spectrometer equipped with an electrospray ionization source. FT-IR spectra were obtained in KBr pellets on a Avatar 360 spectrometer. Elemental analyses were obtained using an Elementar Vario EL-III element analyzer.
5-Amino-2-mercaptothiazole-4-carboxamide (3)
A solution of aminocyanoacetamide (2, 6.5 g, 65.6 mmol) in 70 mL of methanol and 12 mL (199 mmol) of carbon disulfide was heated under reflux for 1 and then cooled to 5°C. The resultant yellow crystalline material was filtered and washed with ethyl acetate: yield 10.9 g (95%); mp 234.4–235.2°C; LC-MS: m/z 176.4 [M-H]+; 1H-NMR: δ 6.97 (2H, s), 7.08 (2H, s), 12.26 (1H, s); 13C-NMR: δ 176.1, 161.6, 151.6, 109.0; FT-IR (cm-1): 3388.0, 3359.4, 3319.2, 3162.0, 2923.2, 2823.8, 2758.8, 1660.8, 1594.9. Anal. Calcd for C4 H5 N3 OS2: C, 27.42; H, 2.88; N, 23.98; S, 36.60.
5-Amino-2-methylthiothiazole-4-carboxamide (4)
5-Amino-2-mercaptothiazole-4-carboxamide (3, 3.5 g, 20 mmol), water (25 mL), and NaOH (0.88 g, 22 mmol) were introduced to a 100-mL three-neck flask, and then the mixture was cooled, stirred, and treated dropwise with dimethyl sulfate (2.1 mL, 22 mmol). After 1 h, yellow solid of 4 that separated was collected, washed with water, and dried: yield 3.6 g (95%); mp 148.1–148.8°C; LC-MS: m/z 190.7 [M-H]+; 1H-NMR: δ 2.49 (3H, s), 6.98 (2H, s), 7.08 (1H, s), 7.10 (1H, s); 13C-NMR: δ 166.7, 157.7, 143.6, 123.0, 17.4; FT-IR (cm-1): 3417.0, 3304.5, 3258.8, 3184.4, 2757.0, 1734.3, 1425.9. Anal. Calcd for C5 H7 N3 OS2: C, 31.73; H, 3.73; N, 22.20; S, 33.88. Found: C, 31.75; H, 3.74; N, 22.23; S, 33.85.
5-Aminothiazole-4-carboxamide (1)
A mixture of 4 (30.0 g, 0.158 mol), Raney nickel (300 g), ammonium hydroxide (135 mL, 1.79 mol), and water (2250 mL) was heated under reflux for 3 h and then filtered while hot. The filtrate was cooled and concentrated under reduced pressure. The resultant solid of 1 was washed with ice water, dried (24.0 g), and then purified by column chromatography eluting with dichloromethane/methanol (50:1): yield 19.8 g (88%); mp 139.8–139.9°C (lit mp 140–141°C; [8]; LC-MS: m/z 144.7 [M-H]+; 1H NMR: δ 6.94 (2H, s), 7.05 (2H, s), 7.89 (1H, s); 13C-NMR: δ 167.4, 157.1, 135.4, 123.8; FT-IR (cm-1): 3417.1, 3387.6, 3276.1, 3147.6, 3072.1, 2329.7, 1659.7.
References
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Articles in the same Issue
- Frontmatter
- Review
- Synthesis and reactivity of heterocyclic hydroxylamine-O-sulfonates
- Preliminary Communication
- Synthesis of pyridine derivatives as potential antagonists of chemokine receptor type 4
- Research Articles
- Design and synthesis of novel active phosphonate esters and their application in preparation of ceftriaxone
- Synthesis of novel oxepine-containing polycyclic-fused quinoline systems
- Crystal structure of 2-aminobenzothiazolinium nitrate and theoretical study of the amino-imino tautomerism of 2-aminobenzothiazole
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- The use of diethylene glycol in the synthesis of 2,2′-bibenzimidazole from o-phenylenediamine and oxalic acid
- Facile one-pot synthesis of chromeno[4,3-b]quinoline derivatives catalyzed by Cu(II)-Schiff base/SBA-15
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