Abstract
Sequential treatment of 5-bromo-2,4-dichloro-6-(chloromethyl)pyrimidine with 2-aminothiophenol and secondary amines afforded a series of 2-[(5-bromo-2-chloro-6-aminopyrimidin-4-yl)methylthio]aniline derivatives. Reaction of the latter compounds with secondary amines in ethanol gave a family of new 5,7-diamino-5,11-dihydropyrimido[5,4-e][1,4]benzothiazepines.
Introduction
1,4-Thiazepine is a privileged structure because of its presence in a number of pharmacologically important compounds [1–2]. Derivatives of 1,4-thiazepin-5-ones [3–8] and -2,4-diones [9] are drug candidates for the treatment of cancer, heart diseases, and inflammatory diseases. Synthetic approaches to these compounds are varied and involve addition, condensation, coupling, rearrangement, and thermolysis methods in multistep synthesis [10, 11]. Fused thiazepines such as dihydrodibenzothiazepines have also been in focus because of their high potential for discovery of drug candidates. Pyrimido[5,4-e][1,4]thiazepines are a new class of heterocyclic compounds that are structurally related to dibenzothiazepines. Therefore, it seems likely that these compounds might exhibit some biological activities. In line with these assumptions and owing to our interest in the synthesis of bioactive heterocycles [12–15], in the present study we wish to report on the synthesis and structural elucidation of pyrimido[5,4-e][1,4]benzothiazepines as a new class of heterocyclic compounds.
Results and discussion
Ethyl 4-chloro-3-oxobutanoate (1) was conveniently synthesized according to the literature procedure [16]. Treatment of this compound with urea in polyphosphoric acid under reflux conditions for 24 h gave 6-(chloromethyl)pyrimidine-2,4(1H,3H)-dione (2), the treatment of which with Br2 in water gave 5-bromo-6-(chloromethyl)pyrimidine-2,4(1H,3H)-dione (3). Reaction of 3 with N,N-diethylaniline and POCl3 under reflux conditions afforded 5-bromo-2,4-dichloro-6(chloromethyl)pyrimidine (4), which was subsequently transformed into 2-[(5-bromo-2,6-dichloropyrimidin-4-yl)methylthio]aniline (5) when treated with o-aminothiophenol and Et3N at -30°C. The structure of compound 5 was characterized by spectroscopic data and elemental analysis. The IR spectrum of 5 showed stretching vibration bands at 3340 and 3460 cm-1due to its NH2 group. In the 1H NMR spectrum, the CH2Cl group signal of 4 appeared at δ 4.7, while in compound 5 the same hydrogen signal was shifted to δ 4.1. The striking chemical shift difference of Δδ = 0.6 between the CH2 moieties of 4 and 5 together with the presence of an NH2 moiety in compound 5 clearly demonstrated the replacement of the chlorine atom of compound 4 by the sulfur atom of o-aminothiophenol to obtain compound 5.
2-[(5-Bromo-2-chloro-6-N,N-dialkylaminopyrimidin-4-yl)methylthio]anilines 6 and 7 were obtained by treatment of 5 in the presence of secondary amines and Et3N in chloroform at -30°C. Compounds 6 and 7 on treatment with secondary amines underwent simultaneous nucleophilic substitution and cyclization to give the desired products 8a–e and 9a–e (Scheme 1).
Synthetic pathway of the title compound.
The structural assignments of the compounds 8a–e and 9a–e were based on the spectral and microanalytical data. The IR spectra did not exhibit stretching vibration bands at 3340 and 3460 cm-1 (NH2) observed for the precursors, but showed a sharp band at 3440 cm-1for the NH vibration. Further proof came from the 1H NMR spectra, which showed a sharp NH signal. Elimination of HBr was observed in the mass spectra of compounds 8a–e and 9a–e.
Conclusion
The synthesis of a new family of tricyclic heterocycles, 5,7 diamino-5,11-dihydropyrimido[5,4-e][1,4]benzothiazepines, through simultaneous nucleophilic substitution and heterocyclization of 2-[(5-bromo-2-chloro-6-N,N-dialkylaminopyrimidin-4-yl)methylthio]anilines with secondary amines in ethanol is described.
Experimental
Melting points were recorded on an Electro thermal type 9100 melting point apparatus (UK). The IR spectra were obtained on an AVATAR 370FT-IR Thermo Nicolet spectrometer (Germany) using KBr discs. 1H NMR and 13C NMR spectra were recorded in CDCl3 on a Bruker spectrometer (Germany) at 400 MHz and 100 MHz, respectively. The mass spectra were scanned on a Varian Mat CH-7 instrument (Germany) at 70 eV. Elemental analyses were performed on a Thermo Finnigan Flash EA microanalyzer (Italy).
Synthesis of 6-(chloromethyl)pyrimidine-2,4(1H,3H)-dione (2)
A mixture of ethyl 4-chloro-3-oxobutanoate (1) (10 mmol, 1.64 g) and urea (10 mmol, 0.60 g) in polyphosphoric acid (5 mL) was heated under reflux for 24 h. After the reaction was completed, the mixture was cooled and poured into an ice-cold water bath (30 mL). The precipitate was filtered, washed well with cold water, and dried at 80°C. This compound was pure enough for the next reactions. It was obtained in 60% yield as a brown powder;mp 253–255°C (decomp.); 1H NMR: δ 4.33 (s, 2H, CH2), 5.64 (s, 1H, CH), 11.11 (brs, 2H, NH, D2O exchangeable); 13C NMR: δ 161.2, 151.5, 150.5, 101.8, 39.9; IR: ν 3150, 3041 cm-1(NH); MS: m/z 160. Anal. Calcd for C5H5ClN2O2: C, 37.40; H, 3.14; N, 17.45. Found: C, 37.38; H, 3.09; N, 17.42.
Synthesis of 5-bromo-6-(chloromethyl)pyrimidine-2,4(1H,3H)-dione (3)
To a suspension of 6-(chloromethyl)pyrimidine-2,4(1H,3H)-dione (2, 10 mmol, 1.60 g) in water (20 mL), a mixture of molecular bromine (10 mmol, 1.80 g) and water (5 mL) was added dropwise with vigorous stirring over a period of 1 min. Stirring was continued for further 30 min. The mixture was heated under reflux and then cooled to room temperature to give a solid residue, which was collected by filtration, washed with warm water (2 × 30 mL), and dried at 80°C. This compound was pure enough for the next reactions. It was obtained in 58% yield as a brown powder; mp273–275°C; 1H NMR: δ 4.75 (s, 2H, CH2), 11.21 (brs, 2H, NH, D2O exchangeable); 13C NMR: δ 158.6, 150.3, 148.7, 84.5, 31.8; IR: ν 3185, 3146 cm-1(NH); MS m/z 238. Anal. Calcd for C5H4BrClN2O2: C, 25.08; H, 1.68; N, 11.70. Found: C, 25.12; H, 1.63; N, 11.66.
Synthesis of 5-bromo-2,4-dichloro-6-(chloromethyl)pyrimidine (4)
A mixture of 5-bromo-6-(chloromethyl)pyrimidine-2,4(1H,3H)-dione (3,10 mmol, 2.39 g) and N,N-diethylaniline (3 mmol, 0.46 g) in phosphorus oxychloride (10 mL) was heated under reflux for 3 h. The solvent was removed in vacuo and the residue was treated with ice. The precipitate was collected by filtration and crystallized from n-hexane. It was obtained in 66% yield as a yellow powder;mp 32–34°C; 1H NMR: δ 4.79 (s, 2H, CH2); 13C NMR: δ 170.6, 164.7, 159.7, 115.3, 39.2; MS: m/z 274. Anal. Calcd for C5H2BrCl3N2: C, 21.73; H, 0.73; N, 10.14. Found: C, 21.90; H, 0.68; N, 10.61.
Synthesis of 2-[(5-bromo-2,6-dichloropyrimidine-4-yl)methylthio]aniline (5)
To a solution of 5-bromo-2,4-dichloro-6-(chloromethyl)pyrimidine (4, 10 mmol, 2.76 g) and triethylamine (0.11 mmol, 1.20 g) in chloroform (30 mL), 2-aminothiophenol (10 mmol, 1.25 g) was added dropwise with vigorous stirring over a minute at -30°C. After the reaction was completed, which was monitored by TLC using chloroform/methanol (20:1) as eluent, the solvent was removed under reduced pressure and the residue was washed with warm water and crystallized from ethanol. It was obtained in 63% yield as a yellow powder;mp 121–123°C; 1H NMR: δ 4.15 (bs, 2H, NH2, D2O exchangeable), 4.65 (s, 2H, CH2), 6.53–7.55 (m, 4H, Ar); 13C NMR: δ 170.9, 165.6, 158.7, 147.9, 133.5, 128.0, 119.2, 117.6, 116.4, 114.0, 34.6. IR: ν 3452, 3431 cm-1 (NH2); MS m/z 363; Anal. Calcd for C11H8BrCl2N3S: C, 36.19; H, 2.21; N, 11.51. Found: C, 36.11; H, 2.19; N, 11.49.
General procedure for the preparation of 6 and 7
A mixture of 2-[(5-bromo-2,6-dichloropyrimidine-4-yl)methylthio]benzenamine (5, 10 mmol, 3.65 g) and appropriate secondary amine (30 mmol) in ethanol (20 mL) was stirred at -30°C. After addition of water (30 mL), the precipitate was filtered off and crystallized from ethanol.
2-[(5-Bromo-2-chloro-6-N,N-diethyl amino pyrimidin-4-yl)methylthio]aniline (6)
This compound was obtained in 65% yield as a brown powder; mp 60–62°C; 1H NMR: δ 1.14 (t, 6H, CH3, J = 7 Hz), 2.81(q, 4H, CH2, J = 7 Hz), 4.15 (s, 2H, CH2), 5.12 (bs, 2H, NH2, D2O exchangeable), 6.65–6.93 (m, 1H, CHAr), 6.95–7.43 (m, 3H, Ar); 13C NMR: δ 172.4, 169.1, 157.3, 146.8, 134.0, 127.2, 118.4, 117.9, 112.9, 106.7, 44.6, 35.4, 11.9. IR: 3481, 3432 cm-1(NH2); MS m/z 400. Anal. Calcd for C15H18BrClN4S: C, 44.84; H, 4.52; N, 13.95; S, 7.98. Found: C, 44.82; H, 4.51; N, 13.92; S, 7.96.
2-[(5-Bromo-2-chloro-6-morpholinopyrimidin-4-yl)methylthio]aniline (7)
This compound was obtained in 60% yield as a brown powder;mp 108–110°C; 1H NMR: δ 3.31–3.80 (m, 8H,CH2-N, CH2-O), 4.05 (s, 2H, CH2), 5.15 (bs, 2H, NH2, D2O exchangeable), 6.45–6.85 (m, 1H, CHAr), 6.85–7.45 (m, 3H, Ar); 13C NMR: δ 173.6, 168.4, 157.3, 146.5, 133.6, 126.0, 117.9, 116.7, 112.5, 106.4, 63.9, 47.6, 34.8. IR: ν 3452, 3349 cm-1 (NH2); MS m/z 414. Anal. Calcd for C15H16BrClN4OS: C, 43.34; H, 3.88; N, 13.48; S, 7.71. Found: C, 43.32; H, 3.83; N, 13.43; S, 7.68.
General procedure for the preparation of 8a–e and 9a–e
A mixture of 2-[(5-bromo-2-chloro-6-aminopyrimidin-4-yl)methylthio]aniline (10 mmol) and secondary amine (30 mmol) in ethanol (20 mL) was heated under reflux for about 6 h. Then, the mixture was cooled and the solvent was removed under reduced pressure. The residue was washed with cooled ethanol (20 mL) and dried.
N,N-Diethyl-2-(pyrrolidino)-5,11-dihydrobenzo[b]pyrimido[5,4-e][1,4]thiazepin-4-amine (8a)
It was obtained in 58% yield as a yellow viscous liquid; 1H NMR: δ 1.28 (t, 6H, CH3, J = 7 Hz), 1.91–2.85 (m, 12H, CH2, CH2-N), 3.51 (s, 2H, CH2-S), 6.17–6.68 (m, 4H, Ar),7.13 (bs, 1H, NH, D2O exchangeable); 13C NMR: δ 154.6, 152.8, 149.7, 140.5, 133.9, 123.6, 117.9, 116.8, 115.3, 109.9, 52.6, 45.4, 31.6, 23.5, 12.0; IR: ν 3444 cm-1 (NH); MS: m/z 355. Anal. Calcd for C19H25N5S: C, 64.19; H, 7.09; N, 19.70; S, 9.02. Found: C, 64.19; H, 7.11; N, 19.65; S, 9.00.
N,N-Diethyl-2-(piperidino)-5,11-dihydrobenzo[b]pyrimido[5,4-e][1,4]thiazepin-4-amine (8b)
This compound was obtained in 62% yield as a yellow viscous liquid; 1H NMR: δ 1.31 (t, 6H, CH3, J = 7Hz), 1.88–2.92 (m, 14H, CH2, CH2-N), 3.49 (s, 2H, CH2-S), 6.21–6.74 (m, 4H, Ar), 7.20 (bs, 1H, NH, D2O exchangeable); 13C NMR: δ 154.0, 153.7, 149.6, 140.5, 133.6, 123.9, 118.9, 118.7, 118.7, 115.0, 109.3, 52.8, 46.4, 31.7, 23.6, 22.5, 12.3; IR: ν 3456 cm-1 (NH); MS: m/z 369. Anal. Calcd for C20H27N5S: C, 65.01; H, 7.36; N, 18.95; S, 8.68. Found: C, 65.11; H, 7.34; N, 18.89; S, 8.66.
N,N-Diethyl-2-(4-methylpiperazino)-5,11-dihydrobenzo[b]pyrimido[5,4-e][1,4]thiazepin-4-amine (8c)
This compound was obtained in 64% yield as a brown powder; mp 90–92°C; 1H NMR: δ 1.21–1.42 (m, 9H, CH3), 1.99–3.11 (m, 12H, CH2, CH2-N), 3.49 (s, 2H, CH2-S), 6.21–6.88 (m, 4H, Ar), 7.17 (bs, 1H, NH, D2O exchangeable); 13C NMR: δ 155.0, 152.7, 149.5, 139.6, 133.9, 123.4, 117.6, 116.7, 115.4, 110.2, 55.6, 50.3, 46.3, 45.6, 31.7, 12.3; IR: ν 3445 cm-1(NH); MS: m/z 384. Anal. Calcd for C20H28N6S: C, 62.47; H, 7.34; N, 21.85; S, 8.34. Found: C, 62.44; H, 7.31; N, 21.82; S, 8.30.
N,N-Diethyl-2-(4-ethylpiperazino)-5,11-dihydrobenzo[b]pyrimido[5,4-e][1,4]thiazepin-4-amine (8d)
This compound was obtained in 59% yield as a yellow viscous liquid; 1H NMR: δ 1.12–1.33 (m, 9H, CH3), 1.78–2.93 (m, 14H, CH2, CH2-N), 3.52 (s, 2H, CH2-S), 6.15–6.82 (m, 4H, Ar ), 7.22 (bs, 1H, NH, D2O exchangeable); 13C NMR: δ 154.3, 152.7, 148.6, 140.2, 133.3, 1234, 118.2, 116.9, 115.4, 110.6, 53.1, 50.5, 47.8, 46.4, 31.6, 11.9, 12.1. IR: ν 3440 cm-1(NH); MS: m/z 398. Anal. Calcd for C21H30N6S: C, 63.28; H, 7.59; N, 21.09; S, 8.05. Found: C, 63.30; H, 7.53; N, 21.06; S, 8.10.
N,N-Diethyl-2-(4-phenylpiperazino)-5,11-dihydrobenzo[b]pyrimido[5,4-e][1,4]thiazepin-4-amine (8e)
This compound was obtained in 55% yield as a yellow viscous liquid; 1H NMR: δ 1.35 (t, 6H, CH3, J = 7 Hz), 1.93–3.05 (m, 12H, CH2, CH2-N), 3.51 (s, 2H, CH2-S), 6.73–7.51 (m, 9H, Ar), 7.63 (bs, 1H, NH, D2O exchangeable); 13C NMR: δ 155.5, 152.5, 150.0, 148.6, 140.5, 133.6, 127.5, 123.6, 120.8, 117.9, 116.9, 115.0, 112.3, 109.3, 45.3, 47.4, 45.6, 33.0, 12.4; IR: ν 3440 cm-1(NH).MS: (m/z) 446. Anal. Calcd for C25H30N6S: C, 67.23; H, 6.77; N, 18.82; S, 7.18. Found: C, 67.23; H, 6.70; N, 18.79; S, 7.10.
4-(2-(Pyrrolidino)-5,11-dihydrobenzo[b]pyrimido[5,4-e][1,4]thiazepino)morpholine (9a)
This compound was obtained in 64% yield as a yellow powder;mp 129–131°C; 1H NMR: δ 1.44 (t, 4H, CH2, J = 7 Hz), 1.81–2.20 (m, 8H, CH2, CH2-N), 3.11–3.17 (m, 4H, CH2-O), 4.62 (s, 2H, CH2-S), 6.84–7.85 (m, 5H, NH, Ar); 13C NMR: δ 154.5, 152.4, 149.6, 128.3, 127.8, 123.3,121.2, 115.0, 64.8, 61.5, 52.7, 46.4, 45.0, 30.2, 23.5. IR: ν 3342 cm-1(NH); MS: (m/z) 369. Anal. Calcd for C19H23N5OS: C, 61.76; H, 6.27; N, 18.95; S, 8.68. Found: C, 61.765; H, 6.23; N, 18.85; S, 8.60.
4-(2-Piperidino-5,11-dihydrobenzo[b]pyrimido[5,4-e][1,4]thiazepino)morpholine (9b)
This compound was obtained in 60% yield as a yellow powder; mp 91–93°C; 1H NMR: δ 1.02–1.51 (m, 2H, CH2), 1.63–2.01 (m, 4H, CH2), 2.51–3.11 (m, 4H, CH2-N), 3.63–4.15 (m, 8H, CH2-N, CH2-O), 4.22–4.31 (m, 2H, CH2-S), 6.61–7.62 (m, 5H, NH, Ar); 13C NMR: δ 155.2, 154.5, 148.6, 129.4, 127.6, 123.2, 121.4, 116.3, 66.0, 61.7, 52.8, 46.4, 45.0, 29.8, 23.2, 22.5.IR: ν 3452 cm-1(NH); MS: m/z 383. Anal. Calcd for C20H25N5OS: C, 62.64; H, 6.57; N, 18.26; S, 8.36. Found: C, 62.59; H, 6.53; N, 18.25; S, 8.36.
4-(2-(4-Methylpiperazino)-5,11-dihydrobenzo[b]pyrimido[5,4-e][1,4]thiazepino)morpholine (9c)
This compound was obtained in 57% yield as a yellow powder;mp 187–189°C; 1H NMR: δ 1.80–2.65 (m, 11H, CH3, CH2-N), 2.95–3.42 (m, 4H, CH2-N), 3.45–3.95 (m, 6H,CH2-O, CH2-S), 6.25–6.91 (m, 5H, NH, Ar); 13C NMR: δ 155.0, 152.5, 148.7, 148.2, 139.2, 123.8, 117.9, 116.4, 115.2, 110.3, 64.9, 55.8, 50.5, 48.2, 44.3, 31.9. IR: ν 3446 cm-1(NH); MS: m/z 398. Anal. Calcd for C20H26N6OS: C, 60.28; H, 6.58; N, 21.09; S, 8.05. Found: C, 60.20; H, 6.49; N, 21.12; S, 8.00.
4-(2-(4-Ethylpiperazino)-5,11-dihydrobenzo[b]pyrimido[5,4-e][1,4]thiazepino)morpholine (9d)
This compound was obtained in 57% yield as a yellow powder;mp 149–151°C; 1H NMR: δ 1.38 (t, 3H, CH3, J = 7 Hz), 1.52–2.63 (m, 8H, CH2-N), 2.75–3.25 (m, 6H, CH2-N), 3.35–3.55 (m, 6H, CH2-O, CH2-S), 6.05–6.76 (m, 5H, NH, Ar); 13C NMR: δ 154.3, 152.3, 148.7, 140.2, 134.2, 123.6, 117.4, 116.3, 115.5, 110.2, 64.8, 53.2, 50.0, 48.2, 47.6, 33.0, 11.2.IR: ν 3341 cm-1(NH); MS: m/z 412. Anal. Calcd for C21H28N6OS: C, 61.14; H, 6.84; N, 20.37; S, 7.77. Found: C, 61.20; H, 6.84; N, 20.30; S, 7.80.
4-(2-(4-Phenylpiperazino)-5,11-dihydrobenzo[b]pyrimido[5,4-e][1,4]thiazepino)morpholine (9e)
This compound was obtained in 59% yield as a yellow powder; mp 86–88°C; 1H NMR: δ 3.00–3.41 (m, 8H, CH2-N), 3.41–3.72 (m, 4H, CH2-N), 3.72–4.12 (m, 6H, CH2-O, CH2-S), 6.64–7.45 (m, 10H, NH, Ar); 13C NMR: δ 154.7, 152.3, 148.7, 147.8, 141.0, 134.4, 128.4, 123.6, 120.4, 118.8, 117.4, 115.3, 112.8, 110.9, 65.3, 48.8, 46.3, 31.2. IR: ν 3333 cm-1(NH); MS: m/z 460. Anal. Calcd for C25H28N6OS: C, 65.19; H, 6.13; N, 18.25; S, 6.96. Found: C, 65.19; H, 6.10; N, 18.15; S, 6.95.
We are grateful to the Research Council of Ferdowsi University of Mashhad for the financial support of this project (P-383).
References
[1] Bakavoli, M.; Rahimizadeh, M.; Raissi, H.; Beyzaei, H.; Tajabadi, J. Synthesis of a functionalized tetrahydro-1,4-thiazepine in water as the solvent and theoretical investigation of its tautomeric structures. Monatsh Chem. 2008, 139, 1211–1215.Search in Google Scholar
[2] Calvo, L. A.; Gonzalez-Ortega, A.; Marcos, R.; Perez, M.; Carmen Sanudo, M. Synthesis of 2,3,4,7-tetrahydro[1,4]thiazepines from thiazolidines and b-enaminonitriles. Tetrahedron 2008, 64, 3691–3700.Search in Google Scholar
[3] Strzelczyk, M.; Matyjewska, H.; Strozynski, H. P. Some pharmacological properties of perhydro-1,4-thiazepine and perhydro-1,2,5-dithiazepine derivatives. J. Pharmacol. Pharm. 1990, 42, 377–385.Search in Google Scholar
[4] Ueyama, N.; Wakabayashi, S.; Tomiyama, T. New intracellular calcium antagonists: I. Synthesis and pharmacological evaluation of 2,3,4,5-tetrahydro-1,5-benzothiazepine analogs. J. Pharm. Soc. Jpn (Yakugaku Zasshi) 1996, 116, 106–124.Search in Google Scholar
[5] Lee, C. L.; Lam, Y.; Lee, S. Y. Solid-phase combinatorial synthesis of benzothiazole and 2,3-dihydro-[1,5]-benzothiazepine derivatives. Tetrahedron Lett. 2001, 42, 109–111.Search in Google Scholar
[6] Dandia, A.; Sehgal, V.; Upreti, M. Synthesis of dihydro-2-(2-phenyl-indole-3-yl)-4-aryl-1,5-benzothiazepines. Phosphorus Sulfur Silicon Relat. Elem. 1995, 105, 93–99.10.1080/10426509508042051Search in Google Scholar
[7] Van den Hoven, B. G.; Alper, H. Remarkable synthesis of 2-(Z)-6-(E)-4H-[1,4]-thiazepin-5-ones by zwitterionic rhodium-catalyzed chemo- and regioselective cyclohydrocarbonylative ring expansion of acetylenic thiazoles. J. Am. Chem. Soc. 2001, 123, 1017–1022.Search in Google Scholar
[8] Hankovszky, O. H.; Hideg, K.; Lloyd, D. Reaction products from 4-phenylbut-3-yn-2-one and aliphatic diamines or 2-aminoethanethiol, and from 2-aminoethanethiol and some α,β-enones. J. Chem. Soc. Perkin Trans. 1974, 1, 1614–1619.Search in Google Scholar
[9] Calvo, L.; Gonzalez-Ortega, A.; Perez, M.; Sanudo, M. C. Expansive rearrangement of N-vinylthiazolidines to 2,3,4,7-tetrahydro-1,4-thiazepines and their transformation in 3-thia-6-azabicyclo[3.2.1]oct-6-enes. Synlett 2005, 239–242.10.1055/s-2004-836069Search in Google Scholar
[10] Hackler, R. E.; Burow, K. W.; Kaster, S. V.; Wickiser, D. I. The syntheses of 5-amino-3-t-butylisothiazole and 3-amino-5-t-butylisothiazole. J. Heterocycl. Chem. 1989, 26, 1575–1578.Search in Google Scholar
[11] Ridge, D. N.; Hanifin, J. W.; Harten, L. A.; Johnson, B. D.; Menschik, J.; Nicolau, G.; Sloboda, A. E.; Watts, D. E. Potential antiarthritic agents 2-benzoylacetonitriles and β-aminocinnamonitriles. J. Med. Chem. 1979, 22, 1385–1389.Search in Google Scholar
[12] Bakavoli, M.; Seyedi, S. M.; Shiri, A.; Saberi, S.; Gholami, M.; Sadeghian, H. Synthesis of new derivatives of pyrimido[5,4-e][1,2,4]triazolo[3,4-b][1,3,4]thiadiazine and their enzyme inhibitory activity assessment on soybean 15-lipoxygenase. J. Chem. Res. 2013, 36, 48–50.Search in Google Scholar
[13] Rahimizadeh, M.; Shiri, A.; Ranaei, M.; Bakavoli, M. Synthesis and antibacterial evaluation of new heterocyclic system: [1,2,4]triazolo[3′,4′:6,1]pyridazino[4,3-e][1,3,4]thiadiazine. Heterocycl. Commun. 2012, 18, 39–42.Search in Google Scholar
[14] Bakavoli, M.; Bagherzadeh, G.; Vaseghifar, M.; Shiri, A.; Pordel, M.; Mashreghi, M. Molecular iodine promoted synthesis of new pyrazolo[3,4-d] pyrimidine derivatives as potential antibacterial agents. Eur. J. Med. Chem. 2010, 45, 647–650.Search in Google Scholar
[15] Pooryaghoobi, M.; Bakavoli, M.; Alimardani, M.; Bazzazan, T.; Sadeghian, H. New insight into the SAR of pyrimido[4,5-b][1,4]benzothiazines as 15-lipoxygenase inhibitors. Iran. J. Basic Med. Sci. 2013, 16, 784–789.Search in Google Scholar
[16] Lonza, L. Process for the production of 4-chloroacetyl chloride, 4-chloroacetic acid esters, amides and imides. E.P. Patent 2 518 043 A1, 2012.Search in Google Scholar
©2013 by Walter de Gruyter Berlin Boston
This article is distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
