Synthesis of thiazolo[4,5-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives
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Hyuck Joo Lee
Abstract
Synthesis of a series of 8-phenylthiazolo[4,5-e][1,2,4]triazolo[1,5-c]pyrimidin-5(4H)-one and 5-piperazino-8-phenylthiazolo[4,5-e][1,2,4]triazolo[1,5-c]pyrmidine compounds with promising biological activity is described.
Much attention has been recently paid to the synthesis of thienotriazolopyrimidines and thienotriazolopyrimidinones because of their biological activities such as inhibitors of Shiga toxin trafficking and A1/A2 or A2A/A3 adenosine receptor antagonists, respectively [1–3]. We have previously designed and synthesized thienotriazolopyrimidine derivatives with promising biological activity [4–8]. By contrast, thiazolopyrimidine derivatives have been reported to possess pharmacological activities including A2A adenosine receptor antagonism, CDC25B phosphatase inhibition, and antitumor and anticancer properties [9–12]. Keeping in mind the potential biological activities of thienotriazolopyrimidine and thiazolopyrimidines, it was perceived that the synthesis of new thiazolotriazolopyrimidines might result in the formation of some valuable molecules with a synergistic biological effect. Thiazolotriazolopyrimidinethiones are known to exhibit anti-Parkinsonian and A2A adenosine receptor antagonist activities [13, 14]. Therefore, here we describe a synthesis of 8-phenylthiazolo[4,5-e][1,2,4]triazolo[1,5-c]pyrimidin-5(4H)-one and 5-piperazinyl-8-phenylthiazolo[4,5-e][1,2,4]triazolo[1,5-c]pyrmidine derivatives in the hope of obtaining compounds of diverse biological activities.
The required starting material 5-amino-2-(methylthio)thiazole-4-carboxamide (1 in Scheme 1) was prepared through a series of reactions starting with ethyl aminocyanoacetate according to a previously reported procedure [15]. Compound 1 was converted into 5-amino-2-(methylthio)thiazole-4-carbonitrile (2) using DMF/POCl3 and acidic hydrolysis [16]. The reaction of 2 with ethyl chloroformate in the presence of pyridine afforded ethyl 4-cyano-2-(methylthio)thiazol-5-ylcarbamate (3) in 76% yield. 8-Phenylthiazolo[4,5-e][1,2,4]triazolo[1,5-c]pyrimidin-5(4H)-one and its derivatives 5a–g were obtained in good yield by treatment of 3 with benzohydrazide derivatives 4 in refluxing 2-methoxyethanol for 24 h, as shown in Scheme 1. Compounds 5 were treated with excess POCl3 to form the chlorinated thiazolotriazolopyrimidines 6. Other chlorinated thiazolotriazolopyrimidines except 6a (R=H) were used in the subsequent reaction without further purification. The displacement of chlorine of 6 by piperazines 7 in the presence of triethylamine led to the final 5-piperazino-8-phenylthiazolo[4,5-e][1,2,4]triazolo[1,5-c]pyrimidines 8. The structures of all new compounds were confirmed by elemental analyses, MS and NMR spectra data. The preliminary biological test [17] of the synthesized compounds 6 and 8 for human A3 adenosine receptor showed that 5b and 8b have affinity values of 5.0 and 8.2 μM, respectively. The biological studies with compounds 5 and 8 are in progress.
Synthesis of 5a–g and 8a–k.
Experimental
Melting points were measured in capillary tubes on Büchi apparatus and are uncorrected. Each compound of the reactions was checked on thin-layer chromatography of Merck Kieselgel 60F254 and purified by column chromatography using Merck silica gel (70–230 mesh). 1H NMR spectra were recorded on a Bruker DRX-300 FT-NMR spectrometer (300 MHz) in DMSO-d6 with Me4Si as internal standard. Electron impact mass spectra were recorded on a HP 59580 B spectrometer. Elemental analyses were performed on a Carlo Erba 1106 elemental analyzer. Compounds were biologically evaluated in vitro as reported previously [17].
Ethyl 4-cyano-2-(methylthio)thiazol-5-ylcarbamate (3)
To ethyl chloroformate (30 mL) was added pyridine (1 mL) and 2 (1.71 g, 10 mmol), and the resultant mixture was heated under reflux for 4 h. The resultant solid product 3 was filtered off, washed with cold water, and crystallized from ethanol; yield 76%; mp 137–139°C; 1H NMR: δ 4.18 (q, 2H, J = 7 Hz, O–CH2), 2.62 (s, 3H, S–Me), 1.22 (t, 3H, J = 7 Hz, –CH3); MS: m/z 243 (M+). Anal. Calcd for C9H11N3OS2: C, 44.79; H, 4.59; N, 17.41. Found: C, 44.60; H, 4.66; N, 17.60.
General procedure for the preparation of thiazolotriazolopyrimidinones 5a–g
To a solution of 3 (1.2 mmol) in 2-methoxyethanol (20 mL), the appropriate benzohydrazide derivative 4 (1.2 mmol) was added with stirring and the resulting solution was heated at reflux for 24 h. After cooling, the resultant solid product 5 was filtered, washed with water, and crystallized from ethanol.
2-(Methylthio)-8-phenylthiazolo[4,5-e][1,2,4]triazolo[1,5-c]pyrimidin-5(4H)-one (5a)
This compound was obtained in 68% yield; mp 258–260°C; 1H NMR: δ 7.97 (d, 2H, J = 8.4 Hz), 7.61 (t, 1H, J = 8.4 Hz), 7.51 (t, 2H, J = 8.4 Hz), 2.74 (s, 3H, -SMe), MS: m/z 315 (M+). Anal. Calcd for C13H9N5OS2: C, 49.51; H, 2.88; N, 22.21. Found: C, 49.79; H, 2.73; N, 22.10.
8-(4-tert-Butylphenyl)-2-(methylthio)thiazolo[4,5-e][1,2,4]triazolo[1,5-c]pyrimidin-5(4H)-one (5b)
This compound was obtained in 72% yield; mp 269–270°C; 1H NMR: δ 7.90 (d, 2H, J = 8.4 Hz), 7.52 (d, 2H, J = 8.4 Hz), 2.68 (s, 3H), 1.28 (s, 9H, tert-Bu), MS: m/z 372 (M+). Anal. Calcd for C17H17N5OS2: C, 54.96; H, 4.61; N, 18.85. Found: C, 54.82.79; H, 4.72; N, 18.77.
8-(4-Chlorophenyl)-2-(methylthio)thiazolo[4,5-e][1,2,4]triazolo[1,5-c]pyrimidin-5(4H)-one (5c)
This compound was obtained in 75% yield; mp 270–272°C; 1H NMR: δ 7.96 (d, 2H, J = 8.4 Hz), 7.64 (d, 2H, J = 8.4 Hz), 2.68 (s, 3H), MS: m/z 349 (M+). Anal. Calcd for C13H8ClN5OS2: C, 44.63; H, 2.31; N, 20.02. Found: C, 44.65; H, 2.38; N, 19.91.
8-(4-Methoxyphenyl)-2-(methylthio)thiazolo[4,5-e][1,2,4]triazolo[1,5-c]pyrimidin-5(4H)-one (5d)
This compound was obtained in 68% yield; mp 255–257°C; 1H NMR: δ 7.93 (d, 2H, J = 8.4 Hz), 7.03 (d, 2H, J = 8.4 Hz), 3.80 (s, 3H, -OMe), 2.70 (s, 3H), MS: m/z 345 (M+). Anal. Calcd for C14H11N5O2S2: C, 48.68; H, 3.21; N, 20.28. Found: C, 48.77; H, 3.36; N, 20.11.
8-(3-Methoxyphenyl)-2-(methylthio)thiazolo[4,5-e][1,2,4]triazolo[1,5-c]pyrimidin-5(4H)-one (5e)
This compound was obtained in 59% yield; mp 217–219°C; 1H NMR: δ 7.88 (m, 1H), 7.46 (m, 2H), 7.00 (m, 1H), 3.78 (s, 3H), 2.68 (s, 3H), MS: m/z 345 (M+). Anal. Calcd for C14H11N5O2S2: C, 48.68; H, 3.21; N, 20.28. Found: C, 48.59; H, 3.29; N, 20.15.
8-(2-Chlorophenyl)-2-(methylthio)thiazolo[4,5-e][1,2,4]triazolo[1,5-c]pyrimidin-5(4H)-one (5f)
This compound was obtained in 71% yield; mp 247–248°C; 1H NMR: δ 8.31 (d, 1H, J = 8.4 Hz), 7.55 (d, 1H, J = 8.4 Hz), 7.43–7.40 (m, 2H), 2.65 (s, 3H), MS: m/z 349 (M+). Anal. Calcd for C13H8ClN5OS2: C, 44.63; H, 2.31; N, 20.02. Found: C, 44.78; H, 2.40; N, 20.15.
8-(4-Bromophenyl)-2-(methylthio)thiazolo[4,5-e][1,2,4]triazolo[1,5-c]pyrimidin-5(4H)-one (5g)
The compound was obtained in 66% yield, mp 253–255°C; 1H NMR: 7.87 (d, 2H, J = 8.4 Hz), 7.73 (d, 2H, J = 8.4 Hz), 2.67 (s, 3H), MS: m/z 393 (M+). Anal. Calcd for C13H8BrN5OS2: C, 39.60; H, 2.05; N, 17.76. Found: C, 39.48; H, 2.11; N, 17.88.
5-Chloro-2-(methylthio)-8-phenylthiazolo[4,5-e][1,2,4]triazolo[1,5-c]pyrimidine (6a)
A solution of 5a (3.15 g, 10 mmol) in phosphorus oxychloride (20 mL) was heated at reflux for 10 h. The excess phosphorus oxychloride was removed under reduced pressure, and the residue was diluted with chloroform and concentrated. The crude product was purified with column chromatography (ethyl acetate:hexane, 1:2) to give 6a (2.60 g, 78%); mp 218–220°C; 1H NMR: 7.97 (d, 2H, J = 8.4 Hz), 7.60 (d, 1H, J = 8.4 Hz), 7.52 (t, 2H, J = 8.4 Hz), 2.83 (s, 3H), MS: m/z 333 (M+). Anal. Calcd for C13H8ClN5S2: C, 46.77; H, 2.42; N, 20.98. Found: C, 46.60; H, 2.49; N, 20.83.
General procedure for the preparation of 5-piperazino-8-phenylthiazolo[4,5-e][1,2,4]triazolo[1,5-c]pyrimidines 8a–k
To a solution of the appropriate 6 (2.0 mmol) in dichloromethane (15 mL), piperazine derivatives 7 (2.2 mmol) and triethylamine (0.5 mL) were added. The mixture was stirred at room temperature for 5 h and then concentrated. The residue was washed with water and recrystallized from ethanol to afford the product.
5-(4-Ethylpiperazino)-2-(methylthio)-8-phenylthiazolo[4,5-e][1,2,4]triazolo[1,5-c]pyrimidine (8a)
This compound was obtained in 76% yield; mp 233–235°C; 1H NMR: δ 7.97 (d, 2H, J = 8.4 Hz), 7.60 (d, 1H, J = 8.4 Hz), 7.51 (t, 2H, J = 8.4 Hz), 4.17 (bs, 4H, N–CH2–), 2.86 (s, 3H, S–Me), 2.74 (bs, 4H, –CH2–N), 2.55 (q, 2H, J = 6.8 Hz, –CH2–), 1.17 (t, 3H, J = 6.8 Hz, –CH3), MS: m/z 412 (M+). Anal. Calcd for C19H21N7S2: C, 55.45; H, 5.14; N, 23.82. Found: C, 55.59; H, 5.25; N, 23.70.
5-(4-Methylpiperazino)-2-(methylthio)-8-phenylthiazolo[4,5-e][1,2,4]triazolo[1,5-c]pyrimidine (8b)
This compound was obtained in 70% yield, mp 242–243°C; 1H NMR: δ 7.97 (d, 2H, J = 8.4 Hz), 7.61 (d, 1H, J = 8.4 Hz), 7.52 (t, 2H, J = 8.4 Hz), 4.15 (bs, 4H, N–CH2–), 2.86 (s, 3H, S-Me), 2.69 (bs, 4H, –CH2–N), 2.41 (s, 3H, N-Me), MS: m/z 397 (M+). Anal. Calcd for C18H19N7S2: C, 54.39; H, 4.82; N, 24.66. Found: C, 54.22; H, 4.88; N, 24.50.
8-(4-Chlorophenyl)-5-(4-ethylpiperazin-1-yl)-2-(methylthio)thiazolo[4,5-e][1,2,4] triazolo[1,5-c]pyrimidine (8c)
The compound was obtained in 77% yield, mp 192–193°C; 1H NMR: δ 8.31 (d, 2H, J = 8.4 Hz), 7.47 (d, 2H, J = 8.4 Hz), 4.14 (bs, 4H, N–CH2–), 2.85 (s, 3H, S–Me), 2.72 (bs, 4H, –CH2–N), 2.54 (q, 2H, J = 6.8 Hz, –CH2–), 1.17 (t, 3H, J = 6.8 Hz, –CH3), MS: m/z 446 (M+). Anal. Calcd for C19H20ClN7S2: C, 51.17; H, 4.52; N, 21.98. Found: C, 51.29; H, 4.46; N, 21.85.
8-(4-Chlorophenyl)-5-(4-isopropylpiperazino)-2-(methylthio)thiazolo[4,5-e][1,2,4] triazolo[1,5-c]pyrimidine (8d)
This compound was obtained in 62% yield; mp 176–178°C; 1H NMR: δ 8.32 (d, 2H, J = 8.4 Hz), 7.47 (d, 2H, J = 8.4 Hz), 4.14 (bs, 4H, N–CH2–), 2.86 (s, 3H, S-Me), 2.80 (bs, 4H, –CH2–N), 2.50 (m, 1H, –CH–), 1.13 (d, 6H, J = 6.8 Hz, –Me2), MS: m/z 460 (M+). Anal. Calcd for C20H22ClN7S2: C, 52.22; H, 4.82; N, 21.31. Found: C, 52.10; H, 4.90; N, 21.44.
8-(4-Chlorophenyl)-5-(4-methylpiperazino)-2-(methylthio)thiazolo[4,5-e][1,2,4] triazolo[1,5-c]pyrimidine (8e)
This compound was obtained in 66% yield; mp 201–203°C; 1H NMR: δ 8.33 (d, 2H, J = 8.4 Hz), 7.48 (d, 2H, J = 8.4 Hz), 4.13 (bs, 4H, N–CH2–), 2.86 (s, 3H, S-Me), 2.67 (bs, 4H, –CH2–N), 2.40 (s, 3H, -N-Me), MS: m/z 432 (M+). Anal. Calcd for C18H18ClN7S2: C, 50.05; H, 4.20; N, 22.70. Found: C, 50.18; H, 4.11; N, 22.59.
5-(4-Ethylpiperazino)-8-(4-methoxyphenyl)-2-(methylthio)thiazolo[4,5-e][1,2,4] triazolo[1,5-c]pyrimidine (8f)
This compound was obtained in 56% yield; mp 195–197°C; 1H NMR: δ 8.08 (d, 2H, J = 8.4 Hz), 7.06 (d, 2H, J = 8.4 Hz), 4.15 (bs, 4H, N–CH2–), 3.89 (s, 3H, O-Me), 2.86 (s, 3H, S-Me), 2.71 (bs, 4H, –CH2–N), 2.54 (q, 2H, J = 6.8 Hz, –CH2–), 1.17 (t, 3H, J = 6.8 Hz, –CH3), MS: m/z 442 (M+). Anal. Calcd for C20H23N7OS2: C, 54.40; H, 5.25; N, 22.20. Found: C, 54.28; H, 5.20; N, 22.10.
5-(4-Isopropylpiperazino)-8-(4-methoxyphenyl)-2-(methylthio)thiazolo[4,5-e][1,2,4] triazolo[1,5-c]pyrimidine (8g)
The compound was obtained in 60% yield; mp 198–199°C; 1H NMR: δ 8.08 (d, 2H, J = 8.4 Hz), 7.06 (d, 2H, J = 8.4 Hz), 4.13 (bs, 4H, N–CH2–), 3.89 (s, 3H, O–Me), 2.85 (s, 3H, S–Me), 2.72 (bs, 4H, –CH2–N), 2.52 (m, 1H, –CH–), 1.13 (d, 6H, J = 6.8 Hz, –Me2), MS: m/z 456 (M+). Anal. Calcd for C21H25N7OS2: C, 55.36; H, 5.53; N, 21.52. Found: C, 55.49; H, 5.44; N, 21.66.
8-(4-Methoxyphenyl)-5-(4-methylpiperazino)-2-(methylthio)thiazolo[4,5-e][1,2,4] triazolo[1,5-c]pyrimidine (8h)
The compound was obtained in 60% yield; mp 175–177°C; 1H NMR: δ 8.33 (d, 2H, J = 8.4 Hz), 7.07 (d, 2H, J = 8.4 Hz), 4.15 (bs, 4H, N–CH2–), 3.90 (s, 3H, O–Me), 2.86 (s, 3H, S–Me), 2.70 (bs, 4H, –CH2–N), 2.42 (s, 3H, N–Me), MS: m/z 428 (M+). Anal. Calcd for C19H21N7OS2: C, 53.38; H, 4.95; N, 22.93. Found: C, 53.20; H, 5.01; N, 22.79.
8-(2-Chlorophenyl)-5-(4-ethylpiperazino)-2-(methylthio)thiazolo[4,5-e][1,2,4] triazolo[1,5-c]pyrimidine (8i)
This compound was obtained in 79% yield; mp 187–189°C; 1H NMR: δ 8.31 (d, 1H, J = 8.4 Hz), 7.55 (d, 1H, J = 8.4 Hz), 7.42–7.40 (m, 2H), 4.20 (bs, 4H, –N–CH2–), 2.84 (s, 3H, S-Me), 2.70 (bs, 4H, –CH2–N), 2.52 (q, 2H, J = 6.8 Hz, –CH2–), 1.15 (t, 3H, J = 6.8 Hz, –CH3), MS: m/z 446 (M+). Anal. Calcd for C19H20ClN7S2: C, 51.17; H, 4.52; N, 21.98. Found: C, 50.07; H, 4.60; N, 21.90.
8-(4-Bromophenyl)-5-(4-ethylpiperazino)-2-(methylthio)thiazolo[4,5-e][1,2,4] triazolo[1,5-c]pyrimidine (8j)
The compound was obtained in 66% yield; mp 189–190°C; 1H NMR: δ 8.25 (d, 2H, J = 8.4 Hz), 7.64 (d, 2H, J = 8.4 Hz), 4.15 (bs, 4H, N–CH2–), 2.86 (s, 3H, S–Me), 2.73 (bs, 4H, –CH2–N), 2.54 (q, 2H, J = 6.8 Hz, –CH2–), 1.17 (t, 3H, J = 6.8 Hz, –CH3), MS: m/z 490 (M+). Anal. Calcd for C19H20BrN7S2: C, 46.53; H, 4.11; N, 19.99. Found: C, 46.71; H, 4.05; N, 20.11.
8-(4-Bromophenyl)-5-(4-isopropylpiperazino)-2-(methylthio)thiazolo[4,5-e][1,2,4] triazolo[1,5-c]pyrimidine (8k)
The compound was obtained in 72% yield; mp 191–193°C; 1H NMR: δ 8.25 (d, 2H, J = 8.4 Hz), 7.62 (d, 2H, J = 8.4 Hz), 4.16 (bs, 4H, N–CH2–), 2.86 (s, 3H, S–Me), 2.82 (bs, 4H, –CH2–N), 2.50 (m, 1H, –CH–), 1.15 (d, 6H, J = 6.8 Hz, –Me2), MS: m/z 504 (M+). Anal. Calcd for C20H22BrN7S2: C, 47.62; H, 4.40; N, 19.44. Found: C, 47.59; H, 4.26; N, 19.29.
This work was supported by the Korea Research Foundation (project number 2010-0021038).
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- Efficient oxidative cyclization of N-acylhydrazones for the synthesis of 2,5-disubstituted 1,3,4-oxadiazoles using t-BuOI under neutral conditions
- Synthesis and transformations of 1-[2-(toluene-4-sulfonamido)ethyl]thiourea
- Synthesis of new heterocyclic compounds containing benzimidazole moiety as inhibitors of breast cancer cell growth
- An approach to C-glycosidic conjugates of isoflavones
- Ionic liquid catalyzed one-pot synthesis of spiropyran derivatives via three-component reaction in water
