β-Benzoylacrylic acids, maleamic acids, maleanilic acids, and maleic acid monophenylhydrazides condense with p-H₂NC₆H₄SH (I) to form 6-membered heterocyclic rings in a manner analogous to maleic acid.The appropriate β-benzoylacrylic acid derivative in boiling PhMe treated with an equivalent amount I, the mixture heated 1 h. with the azeotropic removal of H₂O, cooled, filtered, and the crystalline deposit recrystallized gave the corresponding 3,4-dihydro-3-oxo-2-aracyl-2H-1,4-benzothiazine derivative (Ar of the 2-ArCOCH₂ group, % yield, and corrected m.p. given): Ph (II), 80, 173-5° (PhMe); p-MeC₆H₄, 78, 205-6° (aqueous AcOH); p-iso-PrC₆H₄, 39, 157-60° (aqueous MeOH); p-BuC₆H₄, 60, 131-2° (absolute EtOH); p-C₈H₁₇C₆H₄, 83, 117-19° (absolute EtOH); p-C₁₂H₂₅C₆H₄, 85, 118-20° (absolute EtOH); p-AcNHC₆H₄ (III), 64, 236-8° (Me₂CO); p-FC₆H₄ (IV), 62, 171-3° (PhMe) [from p-FC₆H₄COCH:CHCO₂H, m. 132-8° (uncorrected) (C₆H₆)]; p-Cl, 77, 193-5° (aqueous dioxane); 3,4-Cl₂C₆H₃, 56, 192-4° (aqueous dioxane); 2,4-Cl₂C₆H₃, 70, 186-90° (PhMe); 2,4-(HO)₂C₆H₃, 39, 253° (decomposition) (aqueous Me₂CO); p-MeOC₆H₄, 71, 194-6° (dioxane); p-MeSC₆H₄, 73, 191-5° (xylene).II was also prepared from I and BzCH:CHCO₂H (V) in Et₂O containing 1 drop piperidine at room temperature, and also by allowing a mixture of BzCH₂CHClCO₂H and I in absolute EtOH to stand 1 wk under N.II refluxed 0.5 h. with Ac₂O was recovered unchanged.II (14 g.), 5.0 g. NH₂OH.HCl, and 11.0 g. NaOAc.3H₂O in 400 cc. absolute EtOH heated 1 h. on the steam bath, filtered hot, diluted with 100 cc. H₂O, and cooled gave 11 g. oxime of II, m. 196-201°.The oxime treated with PhSO₂Cl by the method of Roberts and Chambers (C.A. 46, 3506b) gave a poor yield of 3,4-dihydro-3-oxo-2H-1,4-benzothiazine-2-acetanilide, m. 267-9° (uncorrected).III (16.5 g.) in 500 cc. absolute EtOH and 100 cc. concentrated HCl refluxed 2 h., kept overnight, and filtered yielded 6.7 g. 2-(p-aminophenacyl)-3,4-dihydro-3-oxo-2H-1,4-benzothiazine (VII), m. 194-6°.VII with (PrCO)₂O gave 83% p-PrCONH analog of VII, m. 218-20° (aqueous Me₂CO).VII with (AmCO)₂CO gave 82% p-AmCONH analog of VII, m. 175-85° (Me₂CO-95% EtOH-Skellysolve C).Crude 4,2-Cl(O₂N)C₆H₃NHNH₂ (13 g.) and 12 g. BzCH:CHCO₂H in 100 cc. glacial AcOH containing 1 cc. piperidine heated about 15 min. on the steam bath, treated with 30 g. Zn dust, heated until the mixture turned pale green, diluted with 200 cc. glacial AcOH, filtered hot, cooled, and refiltered yielded 6 g. 6-chloro-3,4-dihydro-3-oxo-2-phenacyl-2H-1,4-benzothiazine (VIII), m. 215-19° (PhMe).Similarly was prepared the p-FC₆H₄CH₂CO analog of VIII, m. 243-5°, 54%.By standard methods were prepared the following cis-HO₂CCH:CHCONHR (R, % yield, and corrected m.p. given): C₈H₁₇, 96, 80-2° (C₆H₆-Skellysolve C); C₆H₁₁, 60, 150-3° (CHCl₃-Et₂O); p-FC₆H₄, 95, 204-6° (absolute EtOH); 2,3-Cl₂C₆H₃, 54, 138-9° (MeOH-C₆H₆); 3,4-Cl₂C₆H₃, 81, 211-12° (MeOH-absolute EtOH); 2,4-Cl₂C₆H₃, 95, 175-7° (CHCl₃-MeOH); 2,5-Cl₂C₆H₃, 92, 144-6° (CHCl₃); 3,4-ClMeC₆H₃, 100, 196-7° (decomposition) (Et₂O); p-BrC₆H₄, 75, 197-9° (Et₂O); p-MeSC₆H₄, 98, 175-8° (Et₂O); p-EtOCOC₆H₄, 50, 191-2° (decomposition).Also prepared was cis-HO₂CCH:CHCONMePh, 78, 88-92° (Et₂O).By standard methods were prepared the following cis-HO₂CCH:CHCONHNHAr (Ar, % yield, and corrected m.p. given): p-FC₆H₄, 42, 155-6° (absoluteEtOH-C₆H₆); p-ClC₆H₄, 55, 162-5° (MeOH-C₆H₆); 2,3-Cl₂C₆H₃, 79, 189-90° (MeOH-C₆H₆); 3,4-Cl₂C₆H₃ (IX), 75, 175-7° (MeOH-C₆H₆); 2,4-Cl₂C₆H₃, 54, 166-7° (decomposition) (MeOH-C₆H₆); 2,5-Cl₂C₆H₃, 80, 153-6° (decomposition) (absolute EtOH-C₆H₆); 2,4,6-Cl₃C₆H₂, 65, 159-61° (MeOH); p-BrC₆H₄, 65, 165° (decomposition) (MeOH); 2,4,6-Br₃C₆H₂, 82, 169-71° (MeOH). m-ClC₆H₄NH₂ (13 g.) in 50 cc. C₅H₅N treated with 10 g. powd. maleic anhydride with cooling, warmed to room temperature, treated after 5 min. with 12.5 g. I, heated 1 h. on the steam bath, diluted with 150 cc. C₆H₆, boiled to remove H₂O, diluted further with C₆H₆, and filtered yielded 8 g. 3,4-dihydro-3-oxo-2H-1,4-benzothiazine-2-(m-chloroacetanilide), m. 229-30° (absolute EtOH) (method A).IX (18.5 g.) in 15 cc. C₅H₅N treated with 8.4 g. I, warmed shortly on the steam bath, refluxed azeotropically with 200 cc. C₆H₆ to remove the H₂O, cooled, and filtered yielded 12 g. 3,4-dihydro-3-oxo-2H-1,4-benzothiazine-2-aceto-(3,4-dichlorophenyl)hydrazide, m. 260-2° (aqueous C₅H₅N) (method B).3,4-Dihydro-3-oxo-2H-1,4-benzothiazine-2-acetic acid (X) (22.3 g.) and 10 g. Et₃N in 800 cc. dry Me₂CO treated with 13.6 g. iso-BuOCOCl in Me₂CO and then with 12.7 g. p-ClC₆H₄NH₂ in Me₂CO, and the mixture worked up in the usual manner yielded 4 g. 3,4-dihydro-3-oxo-2H-1,4-benzothiazine-2-(p-chloroacetanilide), m. 275-8° (uncorrected) (method C), also obtained in 36% yield from p-chloromaleanilic acid by method B.X (4.4 g.) in 15 cc. C₅H₅N treated with 1.7 g. PhSO₂Cl, kept several min. at room temperature, treated with 1 g. PhNHNH₂, warmed briefly on a steam bath, cooled, diluted with 50 cc. 5% aqueous NaOH containing a small amount of NaHSO₃, diluted further with H₂O, and filtered yielded 1.3 g. 3,4-dihydro-3-oxo-2H-1,4-benzothiazine-2-acetophenylhydrazide, m. 224-5° (uncorrected) (aqueous C₅H₅N) (method D), also obtained in 24% yield by method B.By these methods were prepared the following 3,4-dihydro-3-oxo-2H-1,4-benzothiazine-2-acetic acid monosubstituted amides (substituent, method, % yield, and corrected m.p. given): H, B, 30, 223-5° (absoluteEtOH); Ph, B, 37 (D, 62), 265-70° (aqueous C₅H₅N); C₈H₁₇, B, 26, 188-91° (MeOH); C₆H₁₁, A, 8, 250-2° (MeOH-dioxane); p-FC₆H₄, B, 25, 267-70° (C₅H₅N-C₆H₆-Skellysolve C); ο-ClC₆H₄, A, 13.5, 232-7° (C₅H₅N-EtOH-H₂O); 2,3-Cl₂C₆H₃, B, 45, 270-2° (aqueous C₅H₅N); 3,4-Cl₂C₆H₃, B, 34, 242-4° (aqueous C₅H₅N); 2,4-Cl₂C₆H₃, A, 23, 241-2° (C₅H₅N-C₆H₆-Skellysolve C); 2,5-Cl₂C₆H₃, B, 41.5, 261-5° (C₅H₅N-C₆H₆-Skellysolve C); 3,4-ClMeC₆H₃, B, 40, 240-2° (aqueous C₅H₅N); p-BrC₆H₄, B, 42, 284° (decomposition) (aqueous C₅H₅N); p-EtOC₆H₄, A, 23 (D, 29), 267-9° (C₅H₅N-C₆H₆); p-MeSC₆H₄, B, 42, 263-5° (MeOH); p-EtOCOC₆H₄ (XI), A, 22, 205-6° (MeOH); p-EtSC₆H₄, D, 58, 235-7° (aqueous C₅H₅N);p-MeSO₂C₆H₄, D, 52, 234-6° (aqueous C₅H₅N); p-H₂NSO₂C₆H₄, D, 69, 280-3° (aqueous C₅H₅N).Also prepared were the di-Et amide of X, B, 35, 156-8° (MeOH); the methylphenylamide of X, B, 40, 172-3° (absolute EtOH-C₆H₆-Skellysolve C).By the same methods were prepared the following 3,4-dihydro-3-oxo-2H-1,4-benzothiazine-2-acetoarylhydrazines (aryl group, method, % yield, and corrected m.p. given): p-FC₆H₄, B, 39, 225-7° (aqueous C₅H₅N); p-ClC₆H₄, B, 43, 235-7° (aqueous C₅H₅N); 2,3-Cl₂C₆H₃, B, 58, 264-6° (aqueous C₅H₅N); 2,4-Cl₂C₆H₃, B, 27, 262-3° (C₅H₅N-C₆H₆); 2,5-Cl₂C₆H₃, A, 28, 266-7° (aqueous dioxane); 2,4,6-Cl₃C₆H₂, A, 24, 248-51° (C₅H₅N-EtOH-H₂O); p-BrC₆H₄, B, 42, 230.2° (aqueous C₅H₅N); 2,4,6-Br₃C₆H₂, B, 38, 253-5° (aqueous C₅H₅N).XI (15 g.) in 350 cc. hot absolute EtOH treated with 30 cc. 85% N₂H₄.H₂O in 20 cc. absolute EtOH, refluxed gently 5 h., evaporated slowly during 1 mo at room temperature, the residual pasty mass suspended in 300 cc. hot absolute EtOH, filtered, and the filter cake suspended in hot C₅H₅N, filtered, and washed with H₂O, EtOH, and dry Et₂O yielded 7.5 g. 3,4-dihydro-3-oxo-2H-1,4-benzothiazine-2-(p-carbohydrazido)acetanilide, m. 261-3°.I and maleic acid (equivalent amounts) mixed gave X, m. 196-9° (aqueous EtOH).Di-Et maleate (51 g.) at 190° treated dropwise with 37.5 g. I under N, the mixture heated slowly to 215° with the removal of EtOH, cooled, dissolved in the min. volume of hot absolute EtOH, diluted with 2 volumes Skellysolve C, and cooled gave 64 g. Et ester (XII) of X, m. 127-8°.X (4.5 g.) in 50 cc. absolute EtOH (saturated with dry HCl at 0°) warmed on the steam bath to solution, cooled after 1 h., and filtered yielded 5.0 g. XII. α-Bromo-γ-butyrolactone (16.5 g.) in 25 cc. absolute EtOH treated with 12.5 g. I, heated 15 min. on the steam bath, neutralized with NaHCO₃, diluted with H₂O, the precipitated oil kept several days at room temperature, and the solid recrystallized from absolute EtOH-Skellysolve C gave 9.0 g. 2-(2-hydroxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzothiazine (XIII), m. 105-7° (absolute EtOH-Skellysolve C).XII (25 g.) added in portions to 6.5 g. LiAlH₄ in 600 cc. dry Et₂O, refluxed 3 h., and worked up in the usual manner, and the solution of the product in Et₂O treated with HCl in Et₂O gave 12 g. 2-(2-hydroxyethyl)-3,4-dihydro-2H-1,4-benzothiazine-HCl (XIV), m. 145-8° (absolute EtOH-Et₂O).XIII (4 g.) in 200 cc. dry Et₂O added to 1 g. LiAlH₄ in Et₂O and the mixture worked up in the usual manner gave 1.25 g. XIV.3,4-Dihydro-3-oxo-2H-1,4-benzothiazine reduced in the usual manner with LiAlH₄ gave nearly 100% 3,4-dihydro-2H-1,4-benzothiazine, m. 36-7°; 4-phenylthiocarbamyl derivative, m. 128-9°.

Journal of Pharmaceutical Research (Bangalore, India)

Microwave-assisted efficient synthesis and antimicrobial evaluation of some N-aryl-2-(3'-oxo-1,4-benzothiazin-2'-yl)acetamide derivatives

作者: Devender, Pathak ; Sameer, Rastogi

Microwave assisted organic reaction enhancement has emerged as a new lead in organic synthesis.The technique offers simple, clean, fast, efficient, and economic and environment friendly method for the synthesis of a large number of organic mols.During these studies, the conventional synthesis of N-aryl-2-(3'-oxo-1,4-benzothiazin-2'-yl)acetamides required time (12-16 h) and the yield were often poor (36.9-48.6%).Hence application of microwave technique for synthesis of the title compounds with an objective to reduce reaction time and increase yield was explored.Using microwave irradiation, all the reactions could be completed in very short duration (4-7 min) with considerable increase in the yields (53.2-80.8%).All the synthesized compounds were evaluated for their antifungal activity against Tricophyton rubrum, Epidermophyton floccosum and Malassazia furfur and for antibacterial activity against Bacillus subtilis, Streptococcus Venezuela, S.gresious and Escherichia coli.The min. inhibitory concentration was found to be ranging between 13-19 μg/mL.

American Journal of PharmTech Research

2D and 3D quantity structure activity relationship studies on 1,4-Benzothiazine derivatives for designing potent antifungal

作者: Jain, Usha N. ; Jain, Nitin P. ; Kashid, Girish A. ; Upasani, Chandrashekhar D.

1,4-Benzothiazine derivatives having variable antifungal activity against four species of fungus such as Candida albicans, Trichophyton rubrum, Epidermophyton floccosum and Malassazia furfur were selected to develop 2D and 3DQSAR models.The best 2DQSAR model was selected, having correlation coefficient r² (0.8747) and cross validated squared correlation coefficient q2 (0.7145) with external predictive ability of pred_r² (0.9658).2DQSAR parameters are Quadrople1, SssCH2count, XA Average hydrophobicity, X AMOST hydrophilic area and Polar surface area excluding P and S contributed in the model.The best 3DQSAR model having the correlation coefficient r²= 0.8635 was selected for further study.The model was further validated by means of crossed squared correlation coefficient q² =0.7614 and pred_r² =0.6654, which show that the model has good predictive ability and was developed by Forward SW-MLR.From QSAR model it concluded that the bulky substitution is require at para and meta position of Ph ring and less bulky substitution at ortho position of Ph ring for antifungal activity.

100 项与 YHV98-4 相关的药物交易

登录后查看更多信息