Short and efficient synthesis of 5-aminothiazole-4-carboxamide

Article abstract of DOI:10.1515/hc-2014-0054

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.

Full text of DOI:10.1515/hc-2014-0054

Heterocycl. Commun. 2014; 20(3): 175–176
JSinhWaonrg,tJiaannyudGueo,fYfihiocnigeTanngt, SsuyxianZthhaneg,sJiainsweoi Tfao5a-nadmYaniLnu*othiazole-
4-carboxamide
Abstract: 5-Aminothiazole-4-carboxamide is a precur- by heating 2-formamido-2-thiocarbamoylacetamide in
sor for the synthesis of thiazole [4,5-d] pyrimidines. In polyphosphoric acid. Unfortunately, the procedure has
this work, a new synthesis method with a high total yield completely failed in our hands.
(79%) of 5-aminothiazole-4-carboxamide was reported.
The starting material is aminocyanacetamide. This syn-
thesis method is environment-friendly and is suitable for
industrial production.
Results and discussion
Keywords: aminocyanacetamide; 5-aminothiazole-4-car- In this article, we report new synthesis of 5-aminothi-
boxamide; synthesis.
azole-4-carboxamide as shown in Scheme 1. The reac-
tion 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]. Methyla-
tion of 3 yielded a methylthio derivative 4. The desired
product 1 was obtained in a total yield of 79% after reduc-
tion of 4 over a Raney nickel [10]. A direct removal of the
thiol from 3 proved to be difficult; hence, the additional
DOI 10.1515/hc-2014-0054
Received April 8, 2014; accepted April 14, 2014; previously published
online May 7, 2014
Introduction
Thiazole-5-carboxamide is a key intermediate in the methylation step was introduced. It was observed that
synthesis of thiazole[5,4-d]-pyrimidine derivatives. the concentration of sodium hydroxide is crucial in the
Thiazole [5,4-d] pyrimidine compounds are the isostere methylation of 3 with dimethyl sulfate to give compound
of purines [1] and precursors to bioactive molecules 4. The concentration of 3.5% is optimal for the highest
[2] in the synthesis of antiviral, anticancer, antibacte- yield of 4.
rial, anti-inflammatory, and anti-psychotic drugs [3–7].
Meanwhile, the synthesis of 5-aminothiazole-4-carboxa-
mide (1 in Scheme 1) has rarely been reported. Tamura
Conclusion
et al. [8] have reported the preparation of 1 by cycliza-
tion of 2-formamido-2-thiocarbamoylacetamide with
A simple and efficient methodology for the synthesis of 1
acetic formic anhydride, followed by hydrolysis with 5%
was developed. The approach is suitable for a large-scale
hydrochloric acid to give compound 1 in 28% yield. In
industrial production.
our hands, the method has been difficult to reproduce,
and therefore, it appears to be unsuitable for a large-
H2N
scale preparation. Tamura et al. [8] have also reported
CN
NH2
S
CS2
(Me)2SO4
H2N
SH
another approach to 5-aminothiazole-4-carboxamide
H2N
N
NaOH, H2O
O
O
2
3
*Corresponding author: Yan Lu, School of Engineering and
Innovation, Shanghai Institute of Technology, Shanghai 201418,
China, e-mail: luuyann@sit.edu.cn
Jin Wang, Yihong Tang, Suxia Zhang and Jianwei Tao: School of
Chemical and Environmental, Shanghai Institute of Technology,
Shanghai 201418, China
H2N
H2N
H2N
S
S
N
Raney Ni
NH3, H2O
SMe
H2N
N
O
O
4
1
Jianyu Guo: Department of Chemistry, Shanghai Normal University,
Shanghai 200234, China
Scheme 1
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176ꢀ ꢀJ. Wang et al.: 5-Aminothiazole-4-carboxamide
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:
Experimental
General
1
m/z 144.7 [M-H]+; H NMR: δ 6.94 (2H, s), 7.05 (2H, s), 7.89 (1H, s);
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 chro-
matography, respectively. NMR spectra (400 MHz for 1H and 100 MHz
for 13C) were recorded in DMSO-d6 on a Bruker AVANCE 400 spectrom-
eter. Liquid chromatography-mass spectra (LC-MS) were acquired in
a positive mode over 100–300 m/z range using a Waters Acquity-Qua-
tro 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.
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
[1] Chattopadhyay, G.; Saha, D.; Ray, P. S.; Naskar, S.; Sarkar, S.
Synthesis of novel thiazolo[5,4-d]pyrimidines. Indian J.Chem.
2010, 41, 1229–1234.
[2] Schmidt, C. L.; Townsend, L. B. Synthesis of 4-and
6-Ribofuranosyl- thiazolo[5,4-d]pyrimidines and
4-Arabinofuranosylthiazolo[5,4-d]pyrimidines. J. Org. Chem.
1975, 40, 2476–2481.
[3] Habib, N. S.; Soliman, R.; EI-Tombaray, A. A.; EI-Hawash, S. A.;
Shaaban, O. G. Synthesis of thiazolo[4,5-d]pyrimidine deriva-
tives as potential antimicrobial agents. Arch. Pharm. Res.
2007, 30, 1511–1520.
[4] Rahmizadeh, M.; Bakavoli, M.; Shiri, A.; Faridnia, R. Pordeli, P.
Thiazolo[4,5-d] pyrimidines: synthesis and antibacterial evalu-
ation. Heterocycl. Commun, 2011, 17, 43–47.
[5] Liang, Y.; He, H. Chin. Recent progress in the synthesis of
thiazolopyrimidine analogues. Chinese J. Org. Chem. 2007, 27,
166–174.
[6] Bekhit, A. A.; Fahmy, H. T. Y.; Rostom, S. A. F. Design and
synthesis of some substituted 1H-pyrazolyithiazolo[4,5-d]-
pyrimidines as anti-inflammatory-antimicro- bial agent. Eur. J.
Med. Chem. 2003, 38, 27–36.
[7] Vicini, P.; Geronikaki, A.; Incerti, M. Synthesis and biological
evaluation of benzo[d]isothiazole, benzothiazole and thiazole
Schiff bases. Bioorg. Med. Chem. 2003, 11, 4785–4789.
[8] Tamura, Y.; Miyamoto, T.; Shimooka, K. Preparation of
5-aminothiazole-4-carboxylic acid derivatives. Chem. Pharm.
Bull. 1971, 19, 119–123.
[9] Everett, A. M. 3,4-Dichloroisothiazoles and process for making
them. US patent 3341547; 1967.
[10] Chen, A. Synthesis of 3-methylthio-2,5-diarylfuran. Master’s
Thesis. Central China Normal University: Wuhan, 2007.
[11] Mettler, H. P.; Previdoli, F. Method for the production of amino-
cyanoacetamide. US patent 5003099A; 1991.
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 crystal-
line 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 C4H5N3OS2: C, 27.42; H, 2.88; N, 23.98; S, 36.60.
5-Amino-2-methylthiothiazole-4-carboxam-
ide (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). Afer 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 C5H7N3OS2: 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.
[12] Müller, H. R.; Bollinger, H.; Schwaninger, P; Kurz, M. Method
of producing aminocyanoacetamide. US patent 6194600B1;
2001.
[13] Terrett, N. K. Purinone antianginal agents. US patent 5734053;
1998.
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
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