* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With potassium carbonate In N,N-dimethyl-formamide at 75℃; for 3 h;
Step 1 : Preparation of intermediate 3-methyl-thiazolidine-2,4-dione (33a)A solution of thiazolidine-2,4-dione (2 g, 17.1 mmol), potassium carbonate (3.55 g, 27.7 mmol) and methyl iodide (1 .87 mL, 30 mmol) in Λ/,/V-dimethylformamide (16 mL) was stirred at 75 °C for 3 hours. The mixture was then filtered and concentrated. The residue was diluted with water (30 mL) and ethyl acetate (30 mL). The organic layer was washed with water (2x10 mL), brine (30 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to give, after purification by flash chromatography on silica gel (dichloromethane), the desired product (33a) as a white solid (1 .77 g, 13.5 mmol, 79percent).1H NMR (400 MHz, CDCI3) .pound.3.19 (s, 3H), 3.95 (s, 2H). MS m/z ([M+H]+) 132.
50%
With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃; for 12 h;
To a mixture of 233 (20 g, 171 mmol) and potassium carbonate (47.3 g, 342mmoi) in DMF (100 ml) is added Mel (32 mL, 513 mmoi) dropwise at 0 °C. After stirring at room temperature for 12 hours, the mixture is concentrated and the residue is partitioned between water (100 mL) and DCM (100 mL). The aqueous layer is extracted with DCM (60 niL, x 4). The combined organic layers are dried over anhvdrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (DCM) to give Di as an off- white solid (10 g, 50percent yield). (MS: IM-f-HL 132.2)
Reference：
[1] Journal of Chemical Research, 2005, # 8, p. 492 - 494
[2] Organic and Biomolecular Chemistry, 2011, vol. 9, # 10, p. 3801 - 3807
[3] Organic Letters, 2015, vol. 17, # 6, p. 1361 - 1364
[4] Patent: WO2012/137181, 2012, A1, . Location in patent: Page/Page column 136-137
[5] Patent: WO2017/176812, 2017, A1, . Location in patent: Paragraph 0503
[6] Justus Liebigs Annalen der Chemie, 1888, vol. 249, p. 30
[7] Gazzetta Chimica Italiana, 1966, vol. 96, p. 612 - 624
[8] Tetrahedron, 1996, vol. 52, # 9, p. 3189 - 3194
[9] European Journal of Medicinal Chemistry, 2013, vol. 59, p. 15 - 22
2
[ 186581-53-3 ]
[ 2295-31-0 ]
[ 16312-21-3 ]
Reference：
[1] Helvetica Chimica Acta, 1954, vol. 37, p. 2057,2064
[2] Yakugaku Zasshi, 1948, vol. 68, p. 245[3] Chem.Abstr., 1954, p. 3962
3
[ 2295-31-0 ]
[ 124-41-4 ]
[ 74-88-4 ]
[ 16312-21-3 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1888, vol. 249, p. 30
4
[ 2295-31-0 ]
[ 4175-76-2 ]
Yield
Reaction Conditions
Operation in experiment
76%
at 5 - 125℃; for 4.25 h;
2,4-dichlorothiazoleCool to 5 0C a mixture of thiazolidine-2,4-dione (50 g, 0.43 mol) in phosphorus oxychloride (240 mL) and add pyridine (34 mL, 0.43 mol) over 15 min. Heat the mixture to 125 0C for 4 h and then cool to 22 0C. Remove the excess phosphorus oxychloride by vacuum distillation and add the residue to water (1 L) chilled to a temperature of 5 0C. Extract the mixture with methylene chloride (3 x 400 mL). Combine the organic portions and evaporate the solvent to afford the title compound (50 g, 76percent). EI/MS m/z : (35C135C1/35C137C1/37C137C1) 153/155/157 (M+l)+.
70%
With trichlorophosphate In pyridine at 120℃; for 3 h;
A mixture of thiazole-2,4-dione (25 g), POCl3 (130 mL) and freshly distilled pyridine (17 mL) were heated at 120° C. for 3 hours. After cooling to room temperature, excess POCl3 was removed under reduced pressure. The residue was poured into ice/water, and extracted with ether. The combined ether solution was washed with aqueous 5percent NaOH, water, then dried. Removal of solvent gave the desired intermediate in 70percent yield.
26%
With pyridine; trichlorophosphate In methanol at 120℃; for 3 h;
Step 1 : 2,4-Dichloro-thiazole To a stirred solution of thiazolidine-2,4-dione (4 g, 26 mmol) in anhydrous MeOH (100 mL) was added POCl3 (130 mL) and pyridine (17 mL). The mixture was heated at 120 °C for 3 hours and then cooled to room temperature. Excess POCl3 was removed under reduced pressure. The residue was poured into ice/water, and extracted with ethyl acetate (3 x 20 mL). The combined organic layer was washed with brine (50 mL), dried over Na2S04, filtered and concentrated in vacuo to give the crude product, which was purified by column chromatography to give the pure product 2,4-dichloro-thiazole (8.4 g, 26percent yield): lH NMR (400 MHz, CDC13) δ 5.90 (s, 1H); ES-LCMS m/z 153.9 (M+H).
14%
With pyridine; trichlorophosphate In dichloromethane at 0℃; for 3 h; Reflux
To a mixture of thiazolidine-2,4-dione (5.00 g, 42.69 mmol) in phosphorous oxychloride (25 mL) at 0 °C was added pyridine (3.80 mL, 46.96 mmol) dropwise. The mixture was then stirred at reflux for 3 hours, then cooled and poured onto ice-water. The aqueous layer was then extracted by DCM, and the combined organic layers dried and evaporated. Column (0508) chromatography with 19: 1 hexanes/EtOAc afforded the product 103. Yield = 0.94 g, 14percent. 1H MR (CDC13) δ 7.02 (1H, s). Found: [M+H]=133.3
34.8 g
at 5 - 125℃; for 4.25 h;
50 g (427 mmol) thiazolidine-2,4-dione was dissolved in 240 ml POCI3 and 34 ml (422 mmol) pyridine were added at 5°C during 15 minutes. The reaction mixture was heated at 125°C for 4 hours and cooled down. Phosphoroxychloride was removed by evaporation and the residue was poured into a mixture of water and ice. 2,4-Dichlorothiazole crystallized and was filtered to give 34.8 g 2,4-dichlorothiazole in form of white crystals, Mp: 45-6°C.
Reference：
[1] Patent: WO2008/36579, 2008, A1, . Location in patent: Page/Page column 36-37
[2] Patent: US2005/234046, 2005, A1, . Location in patent: Page/Page column 60
[3] Journal of the American Chemical Society, 2013, vol. 135, # 5, p. 1986 - 1996
[4] Patent: WO2013/149362, 2013, A1, . Location in patent: Page/Page column 55
[5] Patent: WO2017/155909, 2017, A1, . Location in patent: Paragraph 0159
[6] Patent: US2007/112011, 2007, A1,
[7] Patent: WO2008/83070, 2008, A1, . Location in patent: Page/Page column 62-63
[8] Patent: WO2005/28444, 2005, A1, . Location in patent: Page/Page column 73
[9] Patent: WO2006/2981, 2006, A1, . Location in patent: Page/Page column 106
[10] Patent: EP2532661, 2012, A1, . Location in patent: Page/Page column 23
[11] Patent: WO2012/168361, 2012, A1, . Location in patent: Page/Page column 49
[12] Patent: WO2013/156433, 2013, A1, . Location in patent: Page/Page column 19; 37
5
[ 2295-31-0 ]
[ 4175-77-3 ]
Yield
Reaction Conditions
Operation in experiment
71%
Stage #1: at 130℃; for 0.5 h; Stage #2: With sodium carbonate In water at 0℃;
EXAMPLE 41; Preparation of 2-Amino-3-methyl-5-(3-pyrimidin-5-ylphenyl)-5-(1,3-thiazol-4-yl)-3,5-dihydro-4H-imidazol-4-one; Step a); Preparation of Compound 2; A mixture of 2,4-thiazolidinedione 1 (2.28 g, 19.5 mmol) and phosphorous oxybromide (25.0 g, 87.0 mmol) was heated at 130° C. for 30 min, then cooled to room temperature. The reaction was diluted with ice water (300 mL) and carefully neutralized by the addition of solid sodium carbonate in small portions. Once neutral, the mixture was extracted with dichloromethane (3.x.150 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification of the residue by flash chromatography (silica, 0:100 to 5:95 ethyl acetate/hexanes) afforded 2 (3.34 g, 71percent) as light yellow crystals: 1H NMR (500 MHz, CDCl3) δ 7.21 (s, 1H).
50%
at 80 - 125℃; for 2 h;
2-4-thiazolidinione (10 g, 0.085 mol) was added portionwise to stirred phosphorus oxybromide (160 g) at 80° C. The mixture was then warmed slowly to 125° C. with stirring (vigorous evolution of HBr occurred at approximately 118° C.) and held at 125° C. for 2 hrs. After cooling, the resultant solid was added portionwise to ice/sodium bicarbonate and the brown solid was collected by filtration. The reaction was repeated as above on 10 g and then on 20 g scale, and all three batches of the brown solids were combined. The crude combined material was purified via short path silica gel column chromatograph. The purified product was isolated as a pale yellow solid (41.23 g, 50percent).
47%
at 110℃; for 3 h;
A mixture of 21-1 (5.0 g, 38.42 mmol) and POBr3 (55.07 g, 192.09 mmol) was stirred at 110 °C for 3 h, then cooled to 55 °C and poured onto ice (300 g). Solid Na2CO3 (40g) was added portionwise and the mixture was extracted with EA (150 ml x 3). The combined organic layers were washed with brine (80 ml), dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography (pure PE to PE : EA = 50 : 1) to afford 21-2 as a white solid (4.86 g, yield 47percent).
47%
at 110℃; for 3 h;
Compound 22-2 (0434) A mixture of 22-1 (5.0 g, 38.42 mmol) and POBr3 (55.07 g, 192.09 mmol) was stirred at 110° C. for 3 h, then cooled to 55° C. and poured onto ice (300 g). Solid Na2CO3 (40 g) was added portionwise and the mixture was extracted with EA (150 mL×3). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography (pure PE to PE:EA=50:1) to afford 22-2 as a white solid (4.86 g, yield 47percent).
Reference：
[1] Journal of Organic Chemistry, 2006, vol. 71, # 10, p. 3754 - 3761
[2] Synthesis, 2012, vol. 44, # 7, p. 1026 - 1029
[3] Journal of Materials Chemistry C, 2017, vol. 5, # 45, p. 11927 - 11936
[4] Patent: US2007/4786, 2007, A1, . Location in patent: Page/Page column 21
[5] Tetrahedron, 2006, vol. 62, # 38, p. 9017 - 9037
[6] Patent: US2004/254236, 2004, A1,
[7] Patent: US2008/234267, 2008, A1, . Location in patent: Page/Page column 17
[8] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 19, p. 5849 - 5853
[9] Patent: US9138427, 2015, B2, . Location in patent: Page/Page column 298-299
[10] Journal of Chemical Crystallography, 2015, vol. 45, # 10-12, p. 461 - 465
[11] Journal of Organic Chemistry, 2017, vol. 82, # 11, p. 5947 - 5951
[12] Journal of Organic Chemistry, 2018, vol. 83, # 2, p. 664 - 671
6
[ 2295-31-0 ]
[ 21295-51-2 ]
[ 4175-77-3 ]
Reference：
[1] Patent: US4990520, 1991, A,
7
[ 2295-31-0 ]
[ 68-12-2 ]
[ 92972-48-0 ]
Yield
Reaction Conditions
Operation in experiment
52%
Stage #1: at 0 - 115℃; for 5.5 h; Stage #2: With sodium hydrogencarbonate In dichloromethane
Step 1. 2,4-dichloro-1,3-thiazole-5-carbaldehydeTo a suspension of 2,4-thiazolidinedione (10.0 g, 85.4 mmol) in phosphoryl chloride (48.0 mL, 515 mmol) at 0° C. was added DMF (7.3 mL, 94 mmol) drop-wise. The reaction mixture was allowed to warm to ambient temperature and stirred for 1 h. The mixture was then heated at 85° C. for 1 h before stirring at 115° C. for 3.5 h. After cooling to ambient temperature, the mixture was carefully poured onto ice with slow stirring. The aqueous layer was extracted with DCM three times. The combined organic extracts were washed with saturated NaHCO3, water, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel column (0percent to 20percent ethyl acetate/hexanes) to give the desired product as off white solid (8.1 g, 52percent). 1H NMR (300 MHz, DMSO-d6): δ 9.92 (s, 1H); LCMS (M+H-CO)+: 153.9
48%
Stage #1: at 20 - 115℃; for 6 h;
To a cooled solution of 2,4-thiazolidinedione (5 g, 42.7 mmol) in POCl3 (24 ml) was added DMF (3.7 mL, 26.4 mmol). The mixture was stirred at room temperature for 1 hour, and then heated at 90° C. for 1 h and 115° C. for 4 h. The mixture was poured into a large amount of cold crashed ice. The mixture was extracted with CH2Cl2, washed with water, purified by chromatography on a silica gel column using CHCl8 as an eluant to afford the title compound to afford compound II (3.6 g, 48percent) as a brown solid. 1H NMR (400 MHz, CDCl3) ppm 9.90 (s, 1H).
33%
at 0 - 120℃; for 5.25 h; Inert atmosphere
[000270] Synthesis of 2, 4-dichlorothiazole-5-carbaldehyde (330): A mixture of compound 329 (2.7 g, 23.07 mmol) in DMF (1.23 mL, 15.98 mmol) at 0 °C under argon atmosphere was added phosphorous oxychloride (8.15 mL, 87.17 mmol) dropwise for 15 mm at 0 °C; warmed to RT and stirred for 1 h; heated to 120 °C and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was poured into ice cold water slowly and extracted with CH2C12 (3 x 100 mL). The combined organic extracts were washed with saturated NaHCO3 solution (100 mL), water (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through column chromatography using 5percent EtOAc/ hexanes to afford compound 330 (1.4 g, 33percent) as brown color oil. TLC: 30percent EtOAc/ hexanes (R 0.8); 1H NMR (500 MHz, DMSO-d6): ö 9.87 (s, 1H).
30%
at 0 - 85℃; for 4 h; Reflux
DMF (68.4 g, 940.2 mmol) was added dropwise to a suspension of XLVI-1 (100 g, 854.7 mmol) in POCl3 (476 mL, 780 g, 1.71 mol) at 0° C. Then the mixture was stirred for 1 h at rt, then for 1 h at 85° C., after which the mixture was refluxed for 2 h. POCl3 was removed in vacuum and the mixture was poured onto water, then extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, concentrated in vacuum. The residue was purified by column on silica gel (PE/EA=50/1) to afford XLVI-2 (47 g, yield: 30percent).
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1992, # 8, p. 973 - 978
[2] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 1, p. 235 - 238
[3] Phosphorus, Sulfur and Silicon and the Related Elements, 2006, vol. 181, # 10, p. 2435 - 2444
[4] Patent: US2010/298334, 2010, A1, . Location in patent: Page/Page column 78
[5] Chemistry of Heterocyclic Compounds, 2010, vol. 46, # 3, p. 334 - 341
[6] Patent: US2009/270456, 2009, A1, . Location in patent: Page/Page column 8
[7] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 18, p. 6012 - 6017
[8] Patent: WO2015/138895, 2015, A1, . Location in patent: Paragraph 000270
[9] Patent: US2014/200215, 2014, A1, . Location in patent: Paragraph 1306; 1307
[10] Arzneimittel-Forschung/Drug Research, 2009, vol. 59, # 12, p. 659 - 665
[11] Journal of Enzyme Inhibition and Medicinal Chemistry, 2012, vol. 27, # 3, p. 419 - 427
[12] Patent: WO2016/132134, 2016, A1, . Location in patent: Page/Page column 92; 93
[13] Indian Journal of Heterocyclic Chemistry, 2018, vol. 28, # 3, p. 335 - 344
8
[ 2295-31-0 ]
[ 92972-48-0 ]
Reference：
[1] Patent: US5679683, 1997, A,
[2] Patent: US4555577, 1985, A,
9
[ 2295-31-0 ]
[ 10025-87-3 ]
[ 92972-48-0 ]
Reference：
[1] Patent: US2003/45546, 2003, A1,
10
[ 7647-01-0 ]
[ 39130-96-6 ]
[ 2295-31-0 ]
[ 563-41-7 ]
Reference：
[1] Journal of the Chemical Society, 1928, p. 1421
Stage #1: With phosphorus(V) oxybromide In N,N-dimethyl-formamide at 0 - 105℃; for 8 h; Stage #2: With sodium hydrogencarbonate In dichloromethane; water
Preparation of Intermediates for Example 26 and Related Analogs 2,4-Dibromo-thiazole-5-carbaldehyde To a mixture of 2,4-thiazolidinedione (technical grade, 90percent; 19.1 g, 147 mmol) and POBr3 (210 g, 734 mmol) at 0° C. was added dropwise dimethylformamide (12.5 ml, 161.5 mmol). The resulting solid was heated to 105° C. for 8 hrs. The dark oil solidified upon cooling. A large amount of ice was added to quench the excess POBr3. The precipitate was filtered and the filtrate was extracted with 3*200 ml CH2Cl2. The combined organics were washed with 50 ml saturated NaHCO3 and 100 ml brine, dried with MgSO4 and concentrated in vacuo to afford a brown solid. The crude was purified by flash chromatography with 0 to 5percent ethyl acetate/Hexanes to afford 2,4-dibromo-thiazole-5-carbaldehyde (14.8 g, 37percent) as a yellow solid. 1H NMR (300 MHz, CDCl3) 9.89 (s, 1H).
8 g
at 75 - 100℃; for 6 h;
A mixture of thiazolidine-2,4-dione (15.0 g, 128 mmol), POBr3 (183.6 g, 640 mmol) andDMF(i0.8 ml,140.9 mmol) was heated to 75 °C for 1 h and then at 100 °C for 5 h. Thereaction mixture was cooled to room temperature, diluted with CH2C12 and washed with saturated NaHCO3 solution, filtered and concentrated. Trituration of the evaporation residue with petroleum ether afforded 8.0 g of 2,4-dibromothiazole-5 -carbaldehyde 8.0 g as black solid.
Stage #1: With pyrrolidine; acetic acid In toluene at 110℃; for 2 h; Stage #2: With diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate In toluene for 13 h; Heating / reflux
A mixture of 20.0 g (78 mmol) of 4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy] benzaldehyde (IV), 9.6 g (82 mmol) of thiazolidine-2,4-dione (V), 0.3 mL (3.9 mmol) of pyrrolidine, 0.2 mL (3.9 mmol) of glacial acetic acid and 120 mL of toluene is stirred under nitrogen atmosphere at reflux temperature with azeotropic distillation of water for two hours. After cooling to room temperature, 39.5 g (156 mmol) of 3,5-dicarbethoxy-2,6-dimethyl-1,4- dihydropyridine (Hantzsch ethyl ester), 13.9 g of silica gel and 46 mL of toluene are added. The resulting suspension is heated to reflux temperature with azeotropic distillation of water for 13 hours. The reaction is cooled to room temperature, and the resulting solid is filtered. Silica gel is removed after digestion with tetrahydrofuran and filtration of the solid. The solvent is removed by distillation delivering a crude material that is purified by crystallization from n-butyl acetate, yielding 16.3 g (58percent) of Rosiglitazone (I).
With potassium carbonate; In N,N-dimethyl-formamide; at 75℃; for 3h;
Step 1 : Preparation of intermediate 3-methyl-thiazolidine-2,4-dione (33a)A solution of thiazolidine-2,4-dione (2 g, 17.1 mmol), potassium carbonate (3.55 g, 27.7 mmol) and methyl iodide (1 .87 mL, 30 mmol) in Lambda/,/V-dimethylformamide (16 mL) was stirred at 75 C for 3 hours. The mixture was then filtered and concentrated. The residue was diluted with water (30 mL) and ethyl acetate (30 mL). The organic layer was washed with water (2x10 mL), brine (30 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to give, after purification by flash chromatography on silica gel (dichloromethane), the desired product (33a) as a white solid (1 .77 g, 13.5 mmol, 79%).1H NMR (400 MHz, CDCI3) £3.19 (s, 3H), 3.95 (s, 2H). MS m/z ([M+H]+) 132.
50%
With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 12h;
To a mixture of 233 (20 g, 171 mmol) and potassium carbonate (47.3 g, 342mmoi) in DMF (100 ml) is added Mel (32 mL, 513 mmoi) dropwise at 0 C. After stirring at room temperature for 12 hours, the mixture is concentrated and the residue is partitioned between water (100 mL) and DCM (100 mL). The aqueous layer is extracted with DCM (60 niL, x 4). The combined organic layers are dried over anhvdrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (DCM) to give Di as an off- white solid (10 g, 50% yield). (MS: IM-f-HL 132.2)
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 6h;
General procedure: Thiazolidine-2,4-dione (1 mmol) and potassium carbonate (1 mmol) were dissolved in DMF (5 mL). The solution was stirred at room temperature for several minutes and then methyl or ethyl iodide (1.2 mmol) was added dropwise to the mixture. The solution was heated to 80 C for 6 h. After completion of the reaction (monitored by TLC), the mixture was cooled to room temperature and diluted with water. The precipitate was filtered and washed with water [33].
Preparation of Intermediates for Example 26 and Related Analogs 2,4-Dibromo-thiazole-5-carbaldehyde To a mixture of 2,4-thiazolidinedione (technical grade, 90%; 19.1 g, 147 mmol) and POBr3 (210 g, 734 mmol) at 0 C. was added dropwise dimethylformamide (12.5 ml, 161.5 mmol). The resulting solid was heated to 105 C. for 8 hrs. The dark oil solidified upon cooling. A large amount of ice was added to quench the excess POBr3. The precipitate was filtered and the filtrate was extracted with 3*200 ml CH2Cl2. The combined organics were washed with 50 ml saturated NaHCO3 and 100 ml brine, dried with MgSO4 and concentrated in vacuo to afford a brown solid. The crude was purified by flash chromatography with 0 to 5% ethyl acetate/Hexanes to afford 2,4-dibromo-thiazole-5-carbaldehyde (14.8 g, 37%) as a yellow solid. 1H NMR (300 MHz, CDCl3) 9.89 (s, 1H).
8 g
With phosphorus(V) oxybromide; at 75 - 100℃; for 6h;
A mixture of thiazolidine-2,4-dione (15.0 g, 128 mmol), POBr3 (183.6 g, 640 mmol) andDMF(i0.8 ml,140.9 mmol) was heated to 75 C for 1 h and then at 100 C for 5 h. Thereaction mixture was cooled to room temperature, diluted with CH2C12 and washed with saturated NaHCO3 solution, filtered and concentrated. Trituration of the evaporation residue with petroleum ether afforded 8.0 g of 2,4-dibromothiazole-5 -carbaldehyde 8.0 g as black solid.
5-[(2-benzoylbenzofuran-5-yl)methylene]-2,4-thiazolidinedione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example 8 5-[(2-Benzoylbenzofuran-5-yl)methylene]-2,4-thiazolidinedione This compound, m.p. 292-40C, was prepared from <strong>[120973-72-0]2-benzoyl-5-formylbenzofuran</strong> and 2,4-thiazolidinedione by a procedure analogous to that used in Example 3.
(Z)-5-(4-ethoxybenzylidene)thiazolidine-2,4-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With piperidine; In ethanol; at 75℃; for 24h;Inert atmosphere;
[0272] 4-Ethoxybenzaldehyde (2.78 mL, 20.0 mmol) and2,4-thiazolidinedione 1 (3.75 g, 32.0 mmol) were dissolved in80 mL of anhydrous ethanol at room temperature and pi peridine(0.60 mL, 6.0 mmol) was added to the reaction flask. Thereaction mixture was stirred at 75 C. for 1 day and thenallowed to cool down to room temperature until a yellowcrystalline precipitate formed, collected by filtration, washedwith water and dried to afford compound 3 in 77.0% (3.84 g)yield as a yellow solid.
EXAMPLE 41; Preparation of 2-Amino-3-methyl-5-(3-pyrimidin-5-ylphenyl)-5-(1,3-thiazol-4-yl)-3,5-dihydro-4H-imidazol-4-one; Step a); Preparation of Compound 2; A mixture of 2,4-thiazolidinedione 1 (2.28 g, 19.5 mmol) and phosphorous oxybromide (25.0 g, 87.0 mmol) was heated at 130 C. for 30 min, then cooled to room temperature. The reaction was diluted with ice water (300 mL) and carefully neutralized by the addition of solid sodium carbonate in small portions. Once neutral, the mixture was extracted with dichloromethane (3×150 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification of the residue by flash chromatography (silica, 0:100 to 5:95 ethyl acetate/hexanes) afforded 2 (3.34 g, 71%) as light yellow crystals: 1H NMR (500 MHz, CDCl3) delta 7.21 (s, 1H).
55%
In methanol; phosphoryl(III) bromide; dichloromethane; ethyl acetate; acetone;
A. 2,4-Dibromo-thiazole A stirred solution of 2,4-thiazolidinedione (5 g, 42.7 mmol) in phosphorus oxybromide (25 g, 87.2 mmol) was heated to 110 C. for 3 hours. After cooling to room temperature, 250 g of crushed ice was added (CAUTION). The precipitate that is formed was filtered and dissolved in a mixture of acetone/methylene chloride/MeOH. The remaining aqueous phase was extracted with ether and methylene chloride. The combined organic phases were dried over MgSO4 and the volatiles removed in vacuo. The crude product was purified by column chromatography on silica gel (EtOAc 20% to 100% in hexanes) to provide 2,4-dibromo-thiazole 26A as a yellow solid (5.36 g, 55% yield).
50%
With phosphorus(V) oxybromide; at 80 - 125℃; for 2h;
2-4-thiazolidinione (10 g, 0.085 mol) was added portionwise to stirred phosphorus oxybromide (160 g) at 80 C. The mixture was then warmed slowly to 125 C. with stirring (vigorous evolution of HBr occurred at approximately 118 C.) and held at 125 C. for 2 hrs. After cooling, the resultant solid was added portionwise to ice/sodium bicarbonate and the brown solid was collected by filtration. The reaction was repeated as above on 10 g and then on 20 g scale, and all three batches of the brown solids were combined. The crude combined material was purified via short path silica gel column chromatograph. The purified product was isolated as a pale yellow solid (41.23 g, 50%).
47%
With phosphorus(V) oxybromide; at 110℃; for 3h;
A mixture of 21-1 (5.0 g, 38.42 mmol) and POBr3 (55.07 g, 192.09 mmol) was stirred at 110 C for 3 h, then cooled to 55 C and poured onto ice (300 g). Solid Na2CO3 (40g) was added portionwise and the mixture was extracted with EA (150 ml x 3). The combined organic layers were washed with brine (80 ml), dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography (pure PE to PE : EA = 50 : 1) to afford 21-2 as a white solid (4.86 g, yield 47%).
47%
With phosphorus(V) oxybromide; at 110℃; for 3h;
Compound 22-2 (0434) A mixture of 22-1 (5.0 g, 38.42 mmol) and POBr3 (55.07 g, 192.09 mmol) was stirred at 110 C. for 3 h, then cooled to 55 C. and poured onto ice (300 g). Solid Na2CO3 (40 g) was added portionwise and the mixture was extracted with EA (150 mL×3). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography (pure PE to PE:EA=50:1) to afford 22-2 as a white solid (4.86 g, yield 47%).
With phosphorus pentoxide; tetrabutylammomium bromide; In toluene;Reflux;
This compound was prepared by reaction of commercially available thiazolidine-2,4-dione 5 with P2O5 and Bu4NBr in boiling toluene [3]. It was obtained directly as colourless crystals suitable for X-ray diffraction which gave the following data: mp 81-82 C (81.1-82.4 C [3]; 1H NMR(CDCl3) d 7.21 (1H, s); 13C NMR d 120.8 (CH), 124.3 (C-4) and 136.3 (C-2).
B) Synthesis of 2,4-thiazolidinedione (V):; 2-Imino-thiazolidin-4-one (IV) (1Og) was hydrolyzed with 2N HCl (40ml) in ethanol (40ml). The mixture was refluxed and the reaction was monitored on TLC. The reaction mixture was cooled and neutralized with, saturated solution of sodium bicarbonate (10%). Upon neutralization the crude product, 2,4-thiazolidinedione (V) separated as solid. The crude product was recrystallized from ethanol: water (40:60) mixture. The product was dried at 60C. Yield : 83% M. P. : 120-123C
77.2%
With hydrogenchloride; water; for 10h;Reflux;
2a (1 g, 8.62 mmol) was added to 15 mL of 20% dilute hydrochloric acid and refluxed for 10h. It was concentrated and cooled giving a white solid precipitate. It was filtered, washed, and recystallized with 70% ethanol. Dried to obtain 0.78 g of white needle-like crystals, yield 77.2%.
With hydrogenchloride; water;Reflux;
Equimolar amounts of chloroacetic acid (0.6 M) and thiourea (0.6 M) were dissolved each in 60 ml of water separately and mixed slowly at 0-5 C and stirred for 20 min to form a white precipitate of 2-imino-thiazolidine-4-one. Conc. HCl (60 ml) was added and refluxed for about 10-12 h. Reaction was monitored through TLC (Chloroform: Methanol, 9:1). Reaction mixture was allowed to cool to form white solid crystals, washed with water and dried. White crystals, yield 79%, m.p. 123-125 C; IR (KBr) numax in cm-1: 3132 (N-H), 1739 (CO), 1734 (CO); 1H NMR (DMSO-d6, 400 MHz) delta ppm: 4.42 (s, 2H, CH2), 12.54 (bs, 1H, NH).
With hydrogenchloride; water; for 12h;Reflux;
Thiazolidine-2,4-dione [3] was prepared according to theScheme 1. Equimolar amount of thiourea (0.3 M) and chloroacetic acid (0.3 M) was taken separately in 30 ml of water and mixedunder ice cold condition (0-5 C) with stirring for 20 min to formwhite precipitate of 2-imino-thiazolidine-4-one. ConcentratedHCl (30 ml) was added and refluxed for 12 h. Reaction was monitoredthrough TLC (ethyl acetate:pet ether, 2:3). The white crystallinesolid obtained after cooling was filtered, washed with waterand dried. The yield was found to be 80%.
(5Z)-5-(imidazo[1,2-a]pyridin-6-ylmethylidene)-1,3-thiazolidine-2,4-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With sodium acetate; acetic acid; at 170℃; for 1.0h;Biotage Initiator microwave system (0-400 W);
A suspension of imidazo[l,2-alpha]pyridine-6-carbaldehyde (Maybridge, 1.04 g, 7.1 mmol), thiazolidinedione (0.98 g, 8.3 mmol), sodium acetate ( 1.82 g, 22.2 mmol), and glacial AcOH ( 5 mL) were combined in a 20 mL Biotage microwave vial, then sealed and heated in a Biotage Initiator microwave system (0-400 W) to 170 0C for Ih. After cooling to rt, added an additional 5 mL glacial acetic acid, sonicated the mixture and filtered the resulting suspension. Washed the solid with glacial AcOH and MeOH to afford, after drying the solid in vacuo, (5Z)-5-(Imidazo[l,2-alpha]pyridin- 6-ylmethylidene)-l,3-thiazolidine-2,4-dione as a yellow solid (1.72 g, 82%). MS(ES)+ m/e 246 [M+H]+.
To a solution of 2,4-thiazolidinedione (3.50 g, 30.0 mmol) in ethanol (120 mL) was added <strong>[704-13-2]3-hydroxy-4-nitrobenzaldehyde</strong> (5.00 g, 30.0 mmol) and piperidine (0.44 mL, 4.50 mmol). The mixture was stirred at reflux for 15 hours and then cooled to 0 C. The resulting precipitate was collected and washed with cold ethanol to afford 3.53 g of the desired compound as a brown solid. Further concentration and precipitation of the mother liquor afforded an additional 3.1 g of the product. This was used without further purification in the next reaction. 1H NMR (CDCl3) 8.20 (1H, d, J = 8.8 Hz), 7.75 (1H, s), 7.26 (1H, s), 7.12 (1H, d, J=8.8 Hz).
5-(3,4-dibromobenzylidene)thiazolidine-2,4-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With piperidine; In acetic acid; at 110℃; for 16h;
A mixture of thiazolidine-2,4-dione (90%, 65 mg, 0.5 mmol), <strong>[74003-55-7]3,4-dibromobenzaldehyde</strong> (132 mg, 0.5 mmol), and piperidine (247 mul_, 2.5 mmol) was shaken in acetic acid (2 ml_) at 110 5C for 16 hours. After cooling, the mixture was concentrated to dryness in vacuo . The resulting crude product was shaken with water, centrifuged, and the supernatant was discarded. Subsequently the residue was shaken with ethanol, centrifuged, the supernatant was discarded and the residue was further evaporated to dryness to afford the title compound. EPO <DP n="155"/>1H NMR (Acetone-c(6): deltaH 7.99 (d,1 H), 7.90 (d,1 H), 7.70 (s,1 H), 7.54 (d,1 H); HPLC-MS (Method A): m/z: 364 (M+1 ); Rt = 4.31 min.
With piperidine; In acetic acid; at 110℃; for 16h;
5-(3,4-Dibromobenzylidene)thiazolidine-2,4-dione A mixture of thiazolidine-2,4-dione (90%, 65 mg, 0.5 mmol), <strong>[74003-55-7]3,4-dibromobenzaldehyde</strong> (132 mg, 0.5 mmol), and piperidine (247 muL, 2.5 mmol) was shaken in acetic acid (2 mL) at 110 C. for 16 hours. After cooling, the mixture was concentrated to dryness in vacuo. The resulting crude product was shaken with water, centrifuged, and the supernatant was discarded. Subsequently the residue was shaken with ethanol, centrifuged, the supernatant was discarded and the residue was further evaporated to dryness to afford the title compound. 1H NMR (Acetone-d6): deltaH 7.99 (d, 1H), 7.90 (d, 1H), 7.70 (s, 1H), 7.54 (d, 1H); HPLC-MS (Method A): m/z: 364 (M+1); Rt=4.31 min.
With piperidine; In acetic acid; at 110℃; for 16h;
A mixture of IODINE-2, 4-dione (90%, 65 mg, 0.5 MMOL), 3, 4-dibromobenzaldehyde (132 mg, 0.5 MMOL), and piperidine (247 AL, 2.5 MMOL) was shaken in acetic acid (2 mL) at 110 C for 16 hours. After cooling, the mixture was concentrated to dryness in vacuo. The resulting crude product was shaken with water, centrifuged, and the supernatant was discarded. Subsequently the residue was shaken with ethanol, centrifuged, the supernatant was discarded and the residue was further evaporated to dryness to afford the title com- pound. 'H NMR (Acetone-d6) : 45H 7.99 (d, 1H), 7.90 (d, 1H), 7.70 (s, 1H), 7.54 (d, 1H) ; HPLC-MS (Method A): m/z: 364 (M+1); Rt = 4.31 min.
With piperidine; acetic acid; at 110℃; for 16h;
A mixture of thiazolidine-2,4-dione (90%, 65 mg, 0.5 mmol), <strong>[74003-55-7]3,4-dibromobenzaldehyde</strong> (132 mg, 0.5 mmol), and piperidi?e (247 muL, 2.5 mmol) was shaken in acetic acid (2 ml_) at 1100C for 16 hours. After cooling, the mixture was concentrated to dryness in vacuo . The resulting crude product was shaken with water, centrifuged, and the supernatant was discarded. Subsequently the residue was shaken with ethanol, centrifuged, the supernatant was discarded and the residue was further evaporated to dryness to afford the title com¬ pound. 1H NMR (Aceto?e-dbeta): <*H 7.99 (d,1H). 7.90 (d,1H). 7.70 (s,1H), 7.54 (d,1H); HPLC-MS (Method A): m/z: 364 (M+1); Rt = 4.31 min.
With piperidine; In acetic acid; at 110℃; for 16h;
A mixture of thiazolidine-2,4-dione (90%, 65 mg, 0.5 mmol), <strong>[74003-55-7]3,4-dibromobenzaldehyde</strong> (132 mg, 0.5 mmol), and piperidine (247 muL, 2.5 mmol) was shaken in acetic acid (2 mL) at 110 C. for 16 hours. After cooling, the mixture was concentrated to dryness in vacuo. The resulting crude product was shaken with water, centrifuged, and the supernatant was discarded. Subsequently the residue was shaken with ethanol, centrifuged, the supernatant was discarded and the residue was further evaporated to dryness to afford the title compound. 1H NMR (Acetone-d6): deltaH 7.99 (d, 1H), 7.90 (d, 1H), 7.70 (s, 1H), 7.54 (d, 1H); HPLC-MS (Method A): m/z: 364 (M+1); Rt=4.31 min.
5-(3-fluoro-4-nitro-benzylidene)-thiazolidine-2,4-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With acetic acid; 3-amino propanoic acid; at 100℃;
A MIXTURE OF 3-FLUORO 4-NITRO BENZYL ALDEHYDE (280MG, 1. 65MMOL, LEQ. ), THIAZOLIDINE-DIONE (193MG, 1. 65MMOL, LEQ. ) AND (3-ALANINE (95MG, L. LMMOL, 0.65EQ.) IN ACETIC ACID (5ML) WAS] stirred over night at [100C.] The cooled reaction mixture was added to water and stirred for 1 hour. The precipitated product was filtered and washed with water and dried to yield the final product as a yellow/orange solid (77% yield). [IH] NMR : [8=] (400 MHz, (CD3) [2CO)] : 8.0 [(M,] [1H,] ArH), 7.68 [(M,] 2H, ArH), 7.53 (s, [1H,] [CH=C).]
With pyridine; trichlorophosphate; at 5 - 125℃; for 4.25h;
2,4-dichlorothiazoleCool to 5 0C a mixture of thiazolidine-2,4-dione (50 g, 0.43 mol) in phosphorus oxychloride (240 mL) and add pyridine (34 mL, 0.43 mol) over 15 min. Heat the mixture to 125 0C for 4 h and then cool to 22 0C. Remove the excess phosphorus oxychloride by vacuum distillation and add the residue to water (1 L) chilled to a temperature of 5 0C. Extract the mixture with methylene chloride (3 x 400 mL). Combine the organic portions and evaporate the solvent to afford the title compound (50 g, 76%). EI/MS m/z : (35C135C1/35C137C1/37C137C1) 153/155/157 (M+l)+.
70%
With trichlorophosphate; In pyridine; at 120℃; for 3h;
A mixture of thiazole-2,4-dione (25 g), POCl3 (130 mL) and freshly distilled pyridine (17 mL) were heated at 120 C. for 3 hours. After cooling to room temperature, excess POCl3 was removed under reduced pressure. The residue was poured into ice/water, and extracted with ether. The combined ether solution was washed with aqueous 5% NaOH, water, then dried. Removal of solvent gave the desired intermediate in 70% yield.
26%
With pyridine; trichlorophosphate; In methanol; at 120℃; for 3h;
Step 1 : 2,4-Dichloro-thiazole To a stirred solution of thiazolidine-2,4-dione (4 g, 26 mmol) in anhydrous MeOH (100 mL) was added POCl3 (130 mL) and pyridine (17 mL). The mixture was heated at 120 C for 3 hours and then cooled to room temperature. Excess POCl3 was removed under reduced pressure. The residue was poured into ice/water, and extracted with ethyl acetate (3 x 20 mL). The combined organic layer was washed with brine (50 mL), dried over Na2S04, filtered and concentrated in vacuo to give the crude product, which was purified by column chromatography to give the pure product 2,4-dichloro-thiazole (8.4 g, 26% yield): lH NMR (400 MHz, CDC13) delta 5.90 (s, 1H); ES-LCMS m/z 153.9 (M+H).
14%
With pyridine; trichlorophosphate; In dichloromethane; at 0℃; for 3h;Reflux;
To a mixture of thiazolidine-2,4-dione (5.00 g, 42.69 mmol) in phosphorous oxychloride (25 mL) at 0 C was added pyridine (3.80 mL, 46.96 mmol) dropwise. The mixture was then stirred at reflux for 3 hours, then cooled and poured onto ice-water. The aqueous layer was then extracted by DCM, and the combined organic layers dried and evaporated. Column (0508) chromatography with 19: 1 hexanes/EtOAc afforded the product 103. Yield = 0.94 g, 14%. 1H MR (CDC13) delta 7.02 (1H, s). Found: [M+H]=133.3
With pyridine; trichlorophosphate;
Synthesis of 2,4-dichlorothiazole 1.67 ml (21.0 mmol) of pyridine were added with cooling (ice bath) to 13.3 ml (145.0 mmol) of POCl3. Subsequently, 2.5 g (21.0 mmol) of thiazolidine-2,4-dione were added and the reaction solution was heated under reflux 5 h. After concentration in vacuo, the residue was taken up in DCE (20 ml) and subsequently concentrated again in vacuo. The residue was poured onto ice and extracted with ether. The organic phase was washed successively with a 5% strength aq. NaOH soln and a satd aq. NaCl soln and dried over MgSO4. After filtration and concentration in vacuo, 1.41 g of 2,4-dichlorothiazole were obtained, which was employed further reaction without further purification.
With pyridine; trichlorophosphate; for 3h;Heating / reflux;
Example 2: Preparation of:2-(4-Chloro-2-mthetaphiholinothiazol-5-yl)-3.7-dimethyl-5-fpentan-3-yl)-5H-pyrrolof3.2-blpyrazine; <n="64"/>Part A: 2,4-Dichloro-l,3-thiazole; Reflux a mixture of 2,4-thiazolidinedione (12.5 g, 107 mmol), phosphorousoxychloride (70 mL). and pyridine (8.5 mL) for 3 hrs and then cool to room temperature. Remove volatiles under vacuo, pour the residue into ice/water (30 mL) slowly, extract the resulting mixture with dichloromethane (2 x 50 mL) and dry combined organic extracts with MgSO4 Filter the mixture and concentrate in vacuo. Purify the crude product by silica gel column chromatography to afford desired product as colorless crystals. 1H NMR (400 MHz, CDCl3) 7.00 (1 H, s).
With hydrogenchloride; trichlorophosphate; In 1,4-dioxane; at 70℃;
26a) 4- (4-CHLORO-THIAZOL-2-VL)-MORPHOLINE A solution of thiazolidine-2, 4-dione (0.5 g, 4.27 MMOL) and POC13 (2 mL, 21 MMOL} in CH3CN (20 mL) and 4N HCI/DIOXANE (1 mL) was heated to 70C overnight. The mixture was poured to the ice water and neutralized with saturated NAHCO3 then extracted by EtOAc. The organic layer was dried, concentrated and treated with morpholine (1.8 g, 21 MMOL). The mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc and washed by water (3 x 50 mL) and brine (50 mL). The EtOAc phase was concentrated by reduced pressure and purified by silica gel chromatography to afford the product (126 mg, 15%). M+H+=205. 6. H NMR (300MHZ, DMSO-D6) 8 6.81 (s, 1H), 3.69 (m, 4H), 3.35 (m, 4H).
With pyridine; trichlorophosphate; at 5 - 125℃; for 4.25h;
Example P1: Preparation of 2,4-dichlorothiazole: [Show Image] 50 g (427 mmol) thiazolidine-2,4-dione was dissolved in 240 ml POCl3 and 34 ml (422 mmol) pyridine were added at 5C during 15 minutes. The reaction mixture was heated at 125C for 4 hours and cooled down. Phosphoroxychloride was removed by evaporation and the residue was poured on a mixture of water and ice. 2,4-Dichlorothiazole crystallized and was filtered to give 34.8 g white crystals, m.p.: 45-6C.
With trichlorophosphate; In pyridine; at 5 - 125℃; for 4.25h;
Example P1 : Preparation of 2,4-dichlorothiazole:50 g (427 mmol) thiazolidine-2,4-dione was dissolved in 240 ml POCI3 and 34 ml (422 mmol) pyridine were added at 5C during 15 minutes. The reaction mixture was heated at 125C for 4 hours and cooled down. Phosphoroxychloride was removed by evaporation and the residue was poured on a mixture of water and ice. 2,4-Dichlorothiazole crystallized and was filtered to give 34.8 g white crystals, m.p.: 45-6C
34.8 g
With pyridine; trichlorophosphate; at 5 - 125℃; for 4.25h;
50 g (427 mmol) thiazolidine-2,4-dione was dissolved in 240 ml POCI3 and 34 ml (422 mmol) pyridine were added at 5C during 15 minutes. The reaction mixture was heated at 125C for 4 hours and cooled down. Phosphoroxychloride was removed by evaporation and the residue was poured into a mixture of water and ice. 2,4-Dichlorothiazole crystallized and was filtered to give 34.8 g 2,4-dichlorothiazole in form of white crystals, Mp: 45-6C.
A mixture of 20.0 g (78 mmol) of 4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy] benzaldehyde (IV), 9.6 g (82 mmol) of thiazolidine-2,4-dione (V), 0.3 mL (3.9 mmol) of pyrrolidine, 0.2 mL (3.9 mmol) of glacial acetic acid and 120 mL of toluene is stirred under nitrogen atmosphere at reflux temperature with azeotropic distillation of water for two hours. After cooling to room temperature, 39.5 g (156 mmol) of 3,5-dicarbethoxy-2,6-dimethyl-1,4- dihydropyridine (Hantzsch ethyl ester), 13.9 g of silica gel and 46 mL of toluene are added. The resulting suspension is heated to reflux temperature with azeotropic distillation of water for 13 hours. The reaction is cooled to room temperature, and the resulting solid is filtered. Silica gel is removed after digestion with tetrahydrofuran and filtration of the solid. The solvent is removed by distillation delivering a crude material that is purified by crystallization from n-butyl acetate, yielding 16.3 g (58%) of Rosiglitazone (I).
4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzaldehyde sodium metabisulphite complex[ No CAS ]
[ 122320-73-4 ]
Yield
Reaction Conditions
Operation in experiment
piperidine; acetic acid; In toluene; for 5 - 6h;Heating / reflux;Product distribution / selectivity;
Example 4 Preparation of 5-(4-[2-(N-methyl-N-(2-pyridyl) aminoethoxvl benzylidene)-2,4- thiazolidinedione; 4- [2-(N-methyl-N-(2-pyridyl)amino) ethoxy] benzaldehyde sodium metabisulphite complex (lOgms, 0.027M) from Example 3 was suspended in toluene (100ml) with 2,4- thiazolidine dione (3.2gms, 0.0273M) at ambient temperature. A catalytic amount of piperidine (0.2ml) and acetic acid (O.lml) was added to the reaction mixture under stirring. The reaction mass was then refluxed using Dean stark apparatus for 5 to 6 hours. The reaction mass was then cooled to 60C and concentrated to half of its volume under vacuum. Methanol (50ml) was added drop wise to the reaction mass at 60C and cooled gradually to room temperature. The suspension was stirred at room temperature for about 2 hours and the solid filtered and washed with methanol (25ml), followed by water (200ml). The resulting solid was then dried under vacuum oven at 60C to obtain the title compound (6.5gms, 98% HPLC purity).
With sodium hydroxide; In toluene; for 18h;Heating / reflux;Product distribution / selectivity;
Example 5 Preparation of 5-(4-[2-(N-methyl-N-(2-pyridyl) aminoethoxy] benzylidene)-2,4- thiazolidinedione; 4- [2-(N-methyl-N-(2-pyridyl)amino) ethoxy] benzaldehyde sodium metabisulphite complex (lOgms, 0.027M) from Example 3 was suspended in industrial spirit (150ml) with 2,4-thiazolidine dione (6.4gms, 0.0546M) at ambient temperature. Sodiwn hydroxide pellets (6.0gms 0.15moles) were added to the reaction mixture under stirring..The reaction..mass was then refluxed for 18 hours, the reaction mass was then cooled to 0C and neutralized with (1:1) hydrochloric acid water mixture. The suspension was stirred at 10C for 1 hour. The solid was filtered and washed with demineralised water (50ml). The resulting solid was then dried under vacuum oven at 60C to obtain the title compound (9glns, 98 % HPLC purity).
With phosphorus(V) oxybromide; In N,N-dimethyl-formamide; at 20 - 108℃; for 8h;
A mixture of thiazolidine-2,4-dione (4.54 g, 34.88 mmol) and phosphorus oxybromide (50 g, 174.4 mmol) was treated with DMF (3.05 mL, 39.41 mmol), stirred at room temperature for 30 minutes, heated at 80 C. for 30 minutes, heated at 108 C. until hydrogen bromide evolution ceased (approximately 7 hours), cooled to room temperature, treated with ice/water (300 mL), and extracted with dichloromethane. The extract was washed with 5% aqueous NaHCO3 and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 98:2 hexanes/ethyl acetate to provide the desired product.
a) 2,4-Dibromo-1,3-thiazole-5-carbaldehyde. 1,3-Thiazolane-2,4-dione (3.52 g, 30 mmol) and phosphorus oxybromide (43 g, 150 mmol) were mixed with dimethyl formamide (2.56 mL, 34 mmol). The mixture was then heated at 75 C. for 1 hours and at 100 C. for 5 hours. After cooled to room temperature, the mixture was added to ice-water (500 ml) and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with saturated sodium bicarbonate, dried over MgSO4, filtered and evaporated to give a brown solid which was washed with petroleum ether. Evaporation of solvent gave 2,4-dibromo-1,3-thiazole-5-carbaldehyde (1.74 g, 6.42 mmol). 1H NMR (CDCl3-d) delta9.90 (S, 1H).
5-[2-(4-fluorophenoxy)ethyl]-2,4-thiazolidinedione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; n-butyllithium; In tetrahydrofuran; water; ethyl acetate;
EXAMPLE III 5-[2-(4-fluorophenoxy)ethyl]-2,4-thiazolidinedione (I) (according to route C) 33.4 g of 2,4-thiazolidinedione are dissolved in 1700 ml of tetrahydrofuran, under an inert atmosphere, and while the temperature of the reaction medium is maintained at -78 C, 228 ml of butyllithium (2.5 M hexane) are added dropwise. The temperature is allowed to rise to 20 C. and the mixture is stirred for 2 h at this temperature. It is cooled to -78 C. and 31.2 g of 1-(2-bromoethoxy)-4-fluorobenzene in solution in 600 ml of tetrahydrofuran are added dropwise. The temperature is then allowed to rise to room temperature and the mixture is stirred for 20 h at this temperature. The reaction medium is poured over 2300 ml of 2 N hydrochloric acid. The organic phase is decanted and concentrated. The residue is taken up in 800 ml of ethyl acetate and 1000 ml of water. The organic phase is decanted, washed 4 times with water, dried over sodium sulfate and evaporated to give an oil which is purifed on silica, eluding with a dichloromethane/acetone (97/3 by volume) mixture. The product obtained is recrystallized from diisopropyl ether. 8.5 g of 5-[2-(4-fluorophenoxy)ethyl]-2,4-thiazolidinedione are obtained in the form of a white solid whose melting point is 94-96 C.
methyl 5-(2,4-dioxothiazolidin-5-ylidene)methyl-2-methoxybenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
634 mg (86%)
With ammonium acetate; acetic acid; In acetone; benzene;
EXAMPLE 1 Methyl 5-(2,4-dioxothiazolidin-5-ylidene)methyl-2-methoxybenzoate A mixture of <strong>[78515-16-9]methyl 5-formyl-2-methoxybenzoate</strong> (490 mg), thiazolidine-2,4-dione (358 mg), ammonium acetate (401 mg), acetic acid (0.8 ml) and benzene (10 ml) was submitted to Dean-Stalk dewatering apparatus to reflux for 4 hours under heat. After cooling, the crystals deposited were collected by filtration, washed with benzene and with 20percent aqueous solution of acetone, and then dried to obtain 634 mg (86percent) of aimed compound as crystals. 1 H NMR (d6 -DMSO), delta: 3.83 (3H, s), 3.90 (3H, s), 7.34 (1H, d, J=9.3 Hz), 7.79 (1H, s), 7.76-7.83 (1H, m), 7.87-7.92 (1H, m), 12.59 (1H, s)
5-[(3,4-dihydroxy-5-nitrophenyl)methylidene]-thiazolidin-2,4-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.0 g (72%)
In acetic acid;
EXAMPLE 3 5-[(3,4-Dihydroxy-5-nitrophenyl)methylidene]-thiazolidin-2,4-dione A solution containing 0.59 g (0.005 mol) of thiazolidine-2,4-dione, 0.92 g (0.005 mol) of <strong>[116313-85-0]3,4-dihydroxy-5-nitrobenzaldehyde</strong> and 0.05 ml of piperidine in 5 ml of acetic acid was heated for 7-8 h at 80 C. The crystalls were filtered and washed with ethanol. Yield 1.0 g (72%), mp 295-298 C.
3-(imidazo[1,2-a]pyridin-5-yl)methylthiazolidine-2,4-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
247 mg (12.5%, light brown powder)
With thionyl chloride; In dichloromethane; water; N,N-dimethyl-formamide;
i) Synthesis of 3-(imidazo[1,2-a]pyridin-5-yl)methylthiazolidine-2,4-dione To a suspension of 1.19 g (8.0 mmol) of <strong>[167884-17-5]5-hydroxymethylimidazo[1,2-a]pyridine</strong> in 10 ml of dichloromethane, 4.05 ml (56 mmol) of thionyl chloride was added, followed by stirring at room temperature for 1 hour, after which the solvent was distilled off. To a solution of this residue and 0.94 g (8.0 mmol) of thiazolidine-2,4-dione in 15 ml of N,N-dimethylformamide, 2.40 ml (16.0 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene was added, followed by stirring at 80 C. for 16 hours. After the reaction mixture was cooled, water was added; the mixture was extracted with ethyl acetate and dried, after which the solvent was distilled off. The residue was purified by recrystallization (solvent, chloroform/ethyl acetate/diethyl ether) to yield 247 mg (12.5%, light brown powder) of the desired product. 1 H-NMR (CDCl3, 200 MHz) delta 4.02 (2H, s), 5.06 (2H, s), 6.98 (1H, d, J=6.6 Hz), 7.18 (1H, dd, J=7.0, 9.0 Hz), 7.66 (1H, d, J=9.0 Hz), 7.70 (1H, d, J=1.0 Hz), 7.89 (1H, s)
With sodium acetate; trichlorophosphate; In N-methyl-acetamide; dichloromethane; 1,2-dichloro-ethane;
REFERENCE EXAMPLE 4 Production of 2,4-dichloro-thiazol-4-yl-carboaldehyde of the formula STR22 To a solution of dimethylformamide (73.1 g) in dichloroethylene (200 ml) was added dropwise phosphorus oxychloride (122.7 g) under ice-cooling, followed by stirring for 30 minutes (for preparation of Vilsmeier reagent). The resultant solution was admixed with thiazolin-2,4-dione (23.4 g) and heated for 1 hour under refluxing. The reaction solution obtained was cooled to ambient temperature, poured onto ice (200 g), neutralized by addition of sodium acetate and then extracted 3 times with 200 ml-portions of methylene chloride. The resultant extract in methylene chloride was washed with a small volume of saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue obtained was purified chromatographically on a column of silica-gel as developed with benzene-ethyl acetate (10:1) as eluent. 4-Chloro-thiazol-5-yl-carboaldehyde (0.34 g) was afforded, and the titled compound (2.05 g) was also obtained as light yellow colored crystals. NMR, delta (CDCl3): 9.90 (1H, s) MS (m/e): 182 (M+ +1)
With sodium acetate; trichlorophosphate; In N-methyl-acetamide; dichloromethane;
REFERENCE EXAMPLE 3 Production of 4-chloro-thiazol-5-yl-carboaldehyde of the formula STR20 Phosphorus oxychloride (122.7 g) was added dropwise to dimethylformamide (73.1 g) under ice-cooling, and the mixture obtained was stirred for 30 minutes (for preparation of Vilsmeier reagent). The mixture was then admixed with thiazoline-2,4-dione STR21 (23.4 g), followed by heating at 100° C. for 3 hours. The reaction solution was cooled to ambient temperature, poured onto ice (200 g), neutralized by addition of sodium acetate and then extracted 4 times with 200 ml-portions of methylene chloride. The resultant extract in methylene chloride was washed with a small volume of saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was purified chromatographically on a column of silica gel as developed with benzene-ethyl acetate (10:1) as eluent. The titled compound (1.10 g) was obtained as light yellow colored crystals. NMR, delta (CDCl3): 8.93 (1H, d, J=1 Hz), 10.03 (1H, d, J=1 Hz). MS (m/e): 148 (M+ +1)
tert-butyl [4'-(2,4-dioxothiazolidin-5-ylidenemethyl)biphenyl-3-ylmethyl]carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
(a) tert-Butyl [4'-(2,4-dioxothiazolidin-5-ylidenemethyl)biphenyl-3-ylmethyl]carbamate In a manner similar to that of Example 1(f) by reacting 7.4 g (24 mmol) of tert-butyl (4'-formyl-biphenyl-3-ylmethyl)carbamate (prepared as in Example 1(e) from tert-butyl (3-bromo benzyl)carbamate)with 2.8 g (24 mmol) of 2,4-thiazolidine dione, 9 g (95%) of the expected product are obtained.
(E)-5-hydroxymethyl-3-(4-morpholin-4-ylmethyl-1H-pyrrol-2-ylmethylene)-1,3-dihydro-indol-2-one[ No CAS ]
[ 1265965-22-7 ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 1B3-[(3-[4-(4-Morpholinylmethyl)-1H-pyrrol-2-yl]methylene}-2-oxo-2,3-dihydro-1H-indol-5-yl)methyl]-1,3-thiazolidine-2,4-dione; 15.4 mmol of thiazolidine-2,4-dione and triphenylphosphine supported on resin (3 mmol/g, 30.8 mmol) are stirred under an inert atmosphere for 10 minutes at ambient temperature in anhydrous THF. The mixture is cooled in an ice bath, and tert-butyl azodicarboxylate(15.4 mmol) is added. After stirring for 10 minutes at 0 C., the compound obtained in Step D of Example 1 (10.2 mmol) is added. After stirring for 1 hour 30 minutes at 0 C., the mixture is filtered and the resin is washed with THF. The filtrate is evaporated to dryness and then chromatographed on silica.Mass spectrometry (ES+, m/z): 439.1435 (M+H)+
Example 5 (Z)-5-((2-(methylthio)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (5): A 40 mL round-bottomed vial was charged with <strong>[1074-68-6]2-(methylthio)pyrimidine-4-carbaldehyde</strong> (4) (771 mg, 5 mmol), thiazolidine-2,4-dione (586 mg, 5 mmol, 1.0 equiv.), and piperidine (400 muL, 4 mmol, 0.8 equiv.) in ethanol (20 mL, 0.25 M). The reaction mixture was heated to 80 C. and shaken for 20 h. The resulting yellow precipitate was isolated by filtration and washed with ethanol (1×20 mL) and dried in vacuo to afford (Z)-5-((2-(methylthio)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (5) as a yellow solid (550 mg, 898 mg theoretical, 61%). LC-MS m/z 254 (M+1).
61%
With piperidine; In ethanol; at 80℃; for 20h;
A 40 mL round-bottomed vial was charged with <strong>[1074-68-6]2-(methylthio)pyrimidine-4-carbaldehyde</strong> (4) (771 mg, 5 mmol), thiazolidine-2,4-dione (586 mg, 5 mmol, 1.0 equiv.), and piperidine (400 muL, 4 mmol, 0.8 equiv.) in ethanol (20 mL, 0.25 M). The reaction mixture was heated to 80 C. and shaken for 20 h. The resulting yellow precipitate was isolated by filtration and washed with ethanol (1×20 mL) and dried in vacuo to afford (Z)-5-((2-(methylthio)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (5) as a yellow solid (550 mg, 898 mg theoretical, 61%). LC-MS m/z 254 (M+1).
61%
With piperidine; In ethanol; at 80℃; for 20h;
(Z)-5-((2-(methylthio)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (7): A 40 mL round-bottomed vial was charged with <strong>[1074-68-6]2-(methylthio)pyrimidine-4-carbaldehyde</strong> (6) (771 mg, 5 mmol), thiazolidine-2,4-dione(586 mg, 5 mmol, 1.0 equiv.), and piperidine (400 mL, 4 mmol, 0.8equiv.) in ethanol (20 mL, 0.25 M). Thereaction mixture was heated to 80C and shaken for 20 h. The resulting yellow precipitate was isolatedby filtration and washed with ethanol (1 x 20 mL) and dried in vacuo to afford (Z)-5-((2-(methylthio)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (7)as a yellow solid (550 mg, 898 mg theoretical, 61%). LC-MS m/z 254 (M+1).
(Z)-3-((2,4-dioxothiazolidin-5-ylidene)methyl)benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67%
With piperidine; acetic acid; In ethanol; at 150℃; for 0.333333h;Microwave irradiation;
General procedure: To a suspension of thiazolidine-2,4-dione, 2-thioxothiazolidin-4-one or 2-iminothiazolidin-4-one (1.00 mmol) and benzaldehyde (1.00 mmol) in absolute ethanol (5 mL) in a 10 mL process vial, glacial acetic acid (0.10 mmol) and piperidine (0.10 mmol) were added. The vial was sealed, placed in a microwave reactor and heated at 150 °C for 20 min (max. power 30 W). The reaction mixture was cooled and the precipitate filtered off and dried.
With tetra-(n-butyl)ammonium iodide; potassium carbonate; In acetone; at 40℃; for 10h;Inert atmosphere;
General procedure: A mixture of thiazolidine-2,4-dione (68.0 mmol), various bromide compounds (80.0 mmol), K2CO3 (92.0 mmol), TBAI (6.8 mmol) in acetone (100.0 mL) was stirred at 40 C for 10 h. The reaction mixture was cooled to room temperature and filtered through a short bed of celite and the filtrate was concentrated under vacuum. The residue was purified by flash chromatography (Hexane/EtOAc = 4/1 to 2/1) to give a white solid.
With sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 20℃; for 6h;
A mixture of 1,3-thiazolidine-2,4-dione (6, 1 mmol),<strong>[204205-33-4]2-bromo-1-cyclopropyl-2-(2-fluorophenyl)ethanone</strong> (7, 1 mmol) and sodium bicarbonate (2 equiv) were dissolved in DMF and stirred atambient temperature for 6 h. After completion of the reaction as evidenced by TLC (eluent 7:3 / hexane:ethyl acetate) the reaction mixture was poured into water (25 mL), extracted with ethyl aceate and the solvent distilled under vacuum to obtain pure 8.
General procedure: A mixture of 1 (0.735 g, 5 mmol) and 2/4 (5 mmol) were added in succession insingle lots to the TBAA melt, and the reaction mixture was heated at 100 C andmaintained for 15-20 min. On completion of the reaction, as monitored by TLC,the reaction mixture was cooled to room temperature; ethanol was added to thereaction mixture and was refluxed for 5 min to extract the ionic liquid into ethanol.After cooling to room temperature, the separated product (3/5) was filtered off andwashed with ethanol (2-3 ml) to afford pure 3/5 as insoluble product. The ethanolwas evaporated to recover TBAA, which could be reused at least four times withoutloss of activity.
General procedure: A mixture of 1 (0.735 g, 5 mmol) and 2/4 (5 mmol) were added in succession insingle lots to the TBAA melt, and the reaction mixture was heated at 100 C andmaintained for 15-20 min. On completion of the reaction, as monitored by TLC,the reaction mixture was cooled to room temperature; ethanol was added to thereaction mixture and was refluxed for 5 min to extract the ionic liquid into ethanol.After cooling to room temperature, the separated product (3/5) was filtered off andwashed with ethanol (2-3 ml) to afford pure 3/5 as insoluble product. The ethanolwas evaporated to recover TBAA, which could be reused at least four times withoutloss of activity.
General procedure: A mixture of 1 (0.735 g, 5 mmol) and 2/4 (5 mmol) were added in succession insingle lots to the TBAA melt, and the reaction mixture was heated at 100 C andmaintained for 15-20 min. On completion of the reaction, as monitored by TLC,the reaction mixture was cooled to room temperature; ethanol was added to thereaction mixture and was refluxed for 5 min to extract the ionic liquid into ethanol.After cooling to room temperature, the separated product (3/5) was filtered off andwashed with ethanol (2-3 ml) to afford pure 3/5 as insoluble product. The ethanolwas evaporated to recover TBAA, which could be reused at least four times withoutloss of activity.
3-(2-hydroxyethyl)thiazolidine-2,4-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
54%
With tetra-(n-butyl)ammonium iodide; potassium carbonate; In [(2)H6]acetone; at 40℃; for 10h;
Thiazolidinedione (12.8 mmol), <strong>[624-76-0]2-iodoethanol</strong> (15.1 mmol), potassium carbonate (17.4 mmol) and tetrabutylammonium iodide (1.3 mmol) were placed in acetone (25 ml), and stirred at 40C for 10 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and concentrated under reduced pressure to yield brown oil. The residue thus obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1, v/v) to obtain the title compound as colorless oil (yield: 54%). 1H NMR (CDCl3, 400 MHz) delta 4.00(s, 2H), 3.85(brs, 4H), 1.94(brs, 1H)
54%
With tetra-(n-butyl)ammonium iodide; potassium carbonate; In acetone; at 40℃; for 10h;
Example 396 (Z)-3-(2-Hydroxyethyl)-5-[{7-(4-methoxyphenyl)furo[3,2-c]pyridin-2-yl}methylene]thiazolidine-2,4-dione Step 1: Synthesis of 3-(2-hydroxyethyl)thiazolidine-2,4-dione Thiazolidinedione (12.8 mmol), <strong>[624-76-0]2-iodoethanol</strong> (15.1 mmol), potassium carbonate (17.4 mmol) and tetrabutylammonium iodide (1.3 mmol) were placed in acetone (25 ml), and stirred at 40 C. for 10 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and concentrated under reduced pressure to yield brown oil. The residue thus obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1, v/v) to obtain the title compound as colorless oil (yield: 54%). 1H NMR (CDCl3, 400 MHz) delta 4.00 (s, 2H), 3.85 (brs, 4H), 1.94 (brs, 1H)
General procedure: The compounds were prepared according to the procedure previouslydescribed.19,30 To a refluxing solution of thiazolidine-2,4-dione (43 mmol) in ethanol (25 mL) was added a hot solutionof potassium hydroxide (45 mmol) in ethanol (25 mL). After additionalrefluxing for 30 min, the mixture was cooled to room temperatureand the precipitate was filtered and washed with coldethanol. The obtained potassium 2,4-dioxothiazolidin-3-ide (2)(5 mmol) was refluxed with alkyl halides (5.5 mmol) in DMF(15 mL) for 3-4 h. After cooling to room temperature and additionof water (50 mL), the crude product was extracted 3 times withethyl acetate, washed with brine, and purified by flash chromatography(cyclohexane/ethyl acetate).
With piperidine; benzoic acid; In toluene; for 16h;Reflux; Dean-Stark;
General procedure: To a stirred solution of the appropriate benzaldehyde derivative (1 equiv) in toluene (50 ml) were sequentially added thiazolidine-2,4-dione (3; 1 equiv), benzoic acid (0.5 equiv) and piperidine (0.5 equiv). The flask was connected to a Dean-Stark apparatus and a reflux condenser. After refluxing overnight, the reaction mixture is reduced then cooled and placed in the fridge overnight. In case of formed precipitant, the reaction suspension was filtered and the residue was washed with cold water and hexane. The washed residue was dried in oven at 45C overnight affording the desired derivatives of the 5-benzylidenethiazolidine-2,4-dione as canary yellow residues. However, in case of absence of precipitant, the reaction mixture was extracted with EtOAc (2x), washed successively with saturated aqueous NaHCO3 and brine, dried over anhydrous MgSO4, and concentrated in vacuo affording the canary yellow crude residues. In both cases, the residue was used for the next step without further purification or analysis.
With piperidine; acetic acid; In toluene; at 80.0℃;Dean-Stark;
Thiazolidine-2,4-dione 1g (0.008538 mol), 3-Ethoxy-4-hydroxy-benzaldehyde 1.419g, Piperidine 0.422ml, Acetic acid (0.182 ml) and toluene (20 ml) in a dean-stark apparatus at 80 C, After reacting for 12 hours or longer, it was recrystallized to obtain pure 5- (3-Ethoxy-4-hydroxy-benzylidene) -thiazolidine-2,4-dione. Yield: 90%.
69%
With piperidine; In ethanol;Reflux;
General procedure: Equimolar mixture of substituted benzaldehyde (20 mM)and 2,4-thiazolidinedione (20 mM) with catalytic amount ofpiperidine (1.4 g, 16 mM) and ethanol (150 mL) was refluxedcontinuously for 30-35 hours. The reaction mixturewas poured into water and filtered. On cooling, the productwas precipitated out from ethanol [36]. This step was used tosynthesize a total of ten intermediates (FP1I-FP10I).
With piperidine; acetic acid; In toluene; at 80.0℃; for 18h;Dean-Stark;
General procedure: 2,4-Thiazolidinedione 1.0 g (8.54 mmol) and 4-hydroxybenzaldehyde 1.0 g (1.0 equiv; 8.54 mmol) were dissolved in a 100-mL round flask containing 20 mL toluene. Piperidine 0.40 mL (0.5 equiv; 4.27 mmol) and 0.25 mLacetic acid (0.5 equiv; 4.27 mmol) were added slowly tothe reaction mixture and refluxed at 80 C for over 18 hwith dean-stark trap. The resulting solution was concentrated under reduced pressure to remove the solvent. The residual layer was washed with methanol and dried to afford compounds (a-e) as yellow solid. Synthesis ofcompounds a is shown in Scheme 1.
3-[2-(6-chloro-2-oxo-2,3-dihydro-1H-indol-5-yl)ethyl]-1,3-thiazolidin-2,4-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In water;Reflux;
General procedure: A mixture of <strong>[118289-55-7]6-chloro-5-(2-chloroethyl)-1,3-dihydro-2H-indol-2-one</strong> 1 (1.00mol), potassium carbonate (1.20mol), secondary amine (2a-h, 1.30mol) in water (10mL) was refluxed until completion (TLC, about 24-48h) and the reaction mass was cooled to RT and then extracted with DCM to get crude 3a-h. Recrystallized using aqueous acetone or aqueous ethanol or methanol (Yield 55-70%).
(Z)-5-(2-hydroxy-3-bromo-5-chlorobenzylidene)-1,3-thiazolidine-2,4-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
With piperidine; In ethanol; at 70℃;
General procedure: The compounds (2a-g) were synthesized according to protocoldescribed in Refs. [26,27,43]. Briefly, a solution of thiazolidine-2,4-dione (0.200 g, 1.70 103 mol) in ethanol, (7.0 mL) containingpiperidine (2 drops) and aromatic aldehyde (0.184 g,2.25 103 mol) was heated (70 C), under stirring, for 5e9 h. Thereaction progress was monitored by thin layer chromatography(TLC). After this period, the product was cooled in an ice bath,filtered and recrystallized with an appropriate solvent. The resultingprecipitate was filtered off and recrystallized from acetic acid to give the compounds (2a-g). The yields obtained were considered satisfactory.
5-(2-chloro-3-hydroxybenzylidene)thiazolidine-2,4-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
With piperidine; acetic acid; In toluene; at 80℃;Dean-Stark;
Thiazolidine-2,4-dione 1g (0.008538 mol), 2-Chloro-3-hydroxybenzaldehyde 1.337g, Piperidine 0.422ml, Acetic acid (0.182 ml) and toluene (20 ml) in a dean-stark apparatus at 80 C, After reacting for 12 hours or longer, it was recrystallized to obtain pure 5-(2-Chloro-3-hydroxybenzylidene)thiazolidine-2,4-dione. Yield: 98%.
5-(2-chloro-4-fluorobenzylidene)thiazolidine-2,4-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With piperidine; acetic acid; In toluene; at 80℃;Dean-Stark;
Thiazolidine-2,4-dione 1g (0.008538 mol), <strong>[84194-36-5]2-Chloro-4-fluoro-benzaldehyde</strong> 1.354 g, Piperidine 0.422 ml, Acetic acid (0.182 ml) and toluene (20 ml) in a dean-stark apparatus at 80 ° C, After reacting for 12 hours or longer, it was recrystallized to obtain pure 5- (2-Chloro-4-fluoro-benzylidene) -thiazolidine-2,4-dione. Yield: 81percent.
5-(4-chloro-3-fluorobenzylidene)thiazolidine-2,4-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With piperidine; acetic acid; In toluene; at 80℃;Dean-Stark;
Thiazolidine-2,4-dione 1g (0.008538 mol), <strong>[5527-95-7]4-Chloro-3-fluoro-benzaldehyde</strong> 1.354 g, Piperidine 0.422 ml, Acetic acid (0.182 ml) and toluene (20 ml) in a dean-stark apparatus at 80 C, After reacting for 12 hours or longer, it was recrystallized to obtain pure 5- (4-Chloro-3-fluoro-benzylidene) -thiazolidine-2,4-dione. Yield: 81%.
5-(4-fluoro-3-methylbenzylidene)thiazolidine-2,4-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
With piperidine; acetic acid; In toluene; at 80℃;Dean-Stark;
Thiazolidine-2,4-dione 1g (0.008538 mol), <strong>[135427-08-6]4-Fluoro-3-methyl-benzaldehyde</strong> 1.179 g, Piperidine 0.422 ml, Acetic acid (0.182 ml) and toluene (20 ml) in a dean-stark apparatus at 80 C, After reacting for 12 hours or longer, it was recrystallized to obtain pure 5- (4-Fluoro-3-methyl-benzylidene) -thiazolidine-2,4-dione. Yield: 72%.
5-(4-fluoro-2-trifluoromethylbenzylidene)thiazolidine-2,4-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
With piperidine; acetic acid; In toluene; at 80℃;Dean-Stark;
Thiazolidine-2,4-dione 1g (0.008538 mol), 4-Fluoro-2-trifluoromethyl-benzaldehyde 1.640 g, Piperidine 0.422ml, acetic acid 0.182ml and toluene 20ml were added to the dean-stark apparatus at 80 C, After reacting for 12 hours or longer, it was recrystallized to obtain pure 5- (4-Fluoro-2-trifluoromethyl-benzylidene) -thiazolidine-2,4-dione. Yield: 78%.
5-(2-methoxy-5-nitrobenzylidene)thiazolidine-2,4-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57%
Aqueous potassium carbonate (1.3 g, 0.01 mol) was added to a solution of <strong>[25016-02-8]2-methoxy-5-nitrobenzaldehyde</strong> (1.8 g, 0.01 mol) and thiazolidine-2,4-dione (1.1 g, 0.01 mol) in ethanol (20 mL). The reaction mass stir for 12 h at 20-25 C. Ethanol was completely distilled off under vacuum, acetic anhydride (10 mL) was added to the residue heated to 70-75 C for 2hr and then cooled to 20-25 C. Reaction mass was filtered to give (8). (1.75 g, 57%) as a yellow solid; mp 176-177 C (EtOH); nmax (liquid film) 3164, 2955, 1708, 1664 cm-1; dH (400 MHz, DMSO) 4.03 (3H, s, OMe), 7.34 (1ArH, d, J 9.2 Hz), 7.7 (1H, s), 8.2 (1ArH, s), 8.34 (1ArH, dd, J 9.2, 2.7 Hz), 12.72 (NH, br s); HRMS (CI, NH3): MH+ found m/z 281.0222. C11H9N2O5S requires m/z 281.0222.
(Z)-5-((quinoxalin-3-yl) methylene) thiazolidine-2,4-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With urea/choline chloride eutectic salt; In neat (no solvent); at 80℃;Green chemistry;
General procedure: A 100-mL, round-bottom flask equipped with a magnetic stirring bar was charged with TZD (1 mmole) and rhodanine(1 mmol) in ionic liquid ChCl/urea was added aldehyde (1mmol). The reaction mixture was stirred for adequate amount of time under solvent-free conditions (Table 2). The progress of the reaction was monitored by TLC(Chloroform: Methanol (4:1). After completion of the reaction, H2O (3 ml) was added and ILs separated. Then, the obtained crude compound was collected by filtration and then washed with water and methanol. Finally, products were recrystallized from ethanol to afford (1-10) a, b in the excellent yield.
95%
With Fe3O4/SiO2-NH2/Cu(II); In ethanol; for 0.5h;Reflux; Green chemistry;Catalytic behavior;
General procedure: To a mixture of thiazolidine-2,4-dione or rhodanine(0.13 g, 1 mmol), aliphatic/aromatic aldehyde (1 mmol), and ethanol (4 ml), a portion of Fe3O4/SiO2-NH2/Cu(II) (0.15 g) was added and the mixture stirred under reflux for the required time (Table 2). The progress of the reaction was monitored by TLC (n-hexane/EtOAc, 2:1). After completion of the reaction, EtOH (3 ml) was added and the nanocatalyst was separated by an external magnet. The crude product was recrystallized from EtOH.
(5-(2-chloro-3-hydroxybenzylidene)thiazolidine-2,4-dione)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71.1%
With piperidine; acetic acid; In toluene; at 80℃;Dean-Stark;
First, Compounds 76a to 90a (5-(2-chloro-3-hy- droxybenzylidene)-thiazolidine-2,4-dione), which are reactants used for synthesizing Compounds 76 to 90, were synthesized according to the following scheme.1 g (6.39 mmol) of 2-chioro-3-hydroxybenzalde-hyde and 0.748 g (6.39 mmol) of 2,4-thiazolidinedione wereplaced in a round flask equipped with a Dean-Stark trap, andthen dissolved in 20 ml of toluene, which is a reactionsolvent, and then, 0.315 ml (3.19 mmol) of piperidine and0.183 ml (3.19 mmol) of acetic acid were added thereto,followed by the reaction at a temperature of 80 C. for 18hours or more. The completion of the reaction was confirmed by TLC, and the resulting precipitate was recrystallized and then filtered under reduced pressure to obtain apure solid.Yield: 71.1%.1H NMR (300 MHz, DMSO-d6) oe 12.71 (s, 1H),oe 10.60 (s, 1H), oe 7.93 (s, 1H), oe 7.33 (t, J=8.04 Hz, 1H), oe7.09 (d, J=8.04 Hz, 1H), oe 7.02 (d, J=8.04 Hz, 1H)
(5-(2-chloro-4-hydroxybenzylidene)thiazolidine-2,4-dione)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With piperidine; acetic acid; In toluene; at 80℃;Dean-Stark;
First, Compounds 91a to 105a (5-(2-chioro-4-hy- droxybenzylidene)thiazolidine-2,4-dione), which are reactants used for synthesizing Compounds 91 to 105, were synthesized according to the following scheme.1 g (6.38 mmol) of 2-chloro-4-hydroxybenzalde- hyde and 0.748 g (6.38 mmol) of 2,4-thiazolidinedione were placed in a round flask equipped with a Dean-Stark trap, and then dissolved in 20 ml of toluene, which is a reaction solvent, and then, 0.315 ml (3.19 mmol) of piperidine and 0.183 ml (3.19 mmol) of acetic acid were added thereto, followed by the reaction at a temperature of 80° C. for 18 hours or more. The completion of the reaction was confirmed by TLC, and the resulting precipitate was recrystallized and then filtered under reduced pressure to obtain a pure solid.Yield: 95percent1H NMR (300 MHz, DMSO-d6) oe12.63 (s, 1H), oe10.76 (s, 1H), oe7.88 (s, 1H), oe7.44 (d, J=8.79 Hz, 1H), oe7.01 (d, J=2.58 Hz, 1H), oe6.95 (dd, J=8.79 and 2.58 Hz, 1 H)
To a suspension of K2CO3 (2.36 g, 17.1 mmol) in dry acetone (5 mL/1 mmol) 2,4-thiazolidinedione 3 (1 g, 8.54 mmol) was added and the mixture allowed to stir at 50-60 C for 30 min. Later, Me2SO4 (1.6 mL, 17.1 mmol) was added at the same temperature and the resulting mixture was stirred for another 12 h. After completion of the reaction (TLC), the reaction was stopped by adding water. The reaction mixture was extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was then purified by column chromatography on silica gel with EtOAc/petroleum ether 5:95 afforded N-methylthiazolidine-2,4-dione (5a, 0.95 g, 85%) as a colorless oily liquid.
(Z)-5-(benzo[b]thiophen-3-ylmethylene)thiazolidine-2,4-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With urea/choline chloride eutectic salt; In neat (no solvent); at 80℃;Green chemistry;
General procedure: A 100-mL, round-bottom flask equipped with a magnetic stirring bar was charged with TZD (1 mmole) and rhodanine(1 mmol) in ionic liquid ChCl/urea was added aldehyde (1mmol). The reaction mixture was stirred for adequate amount of time under solvent-free conditions (Table 2). The progress of the reaction was monitored by TLC(Chloroform: Methanol (4:1). After completion of the reaction, H2O (3 ml) was added and ILs separated. Then, the obtained crude compound was collected by filtration and then washed with water and methanol. Finally, products were recrystallized from ethanol to afford (1-10) a, b in the excellent yield.
(Z)-5-((5-nitrothiophen-2-yl)methylene)thiazolidine-2,4-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With copper(II)-Para-aminobenzoic acid complex supported on Fe3O4 Magnetic nanoparticle; In ethanol; for 1.56667h;Reflux; Green chemistry;
General procedure: Fe3O4PABA-Cu(II) (0.05 g) was added to a mixtureof various aldehydes (1mmol), with hydantoin or TZD(1mmol), in Ethanol (10mL), and this mixture was refluxedfor the times reported in Table2. the progress of the reactionmonitored by TLC, after completion of the reactionthe mixture was diluted with ethanol and the catalyst waseasily separated from the reaction mixture by an externalmagnet, washed with hot ethanol, dried and reused for aconsecutive run under the same reaction conditions. Afterwards,the reaction mixture was cooled to room temperatureand the crude product obtained was collected by filtrationand washed with cold ethanol to give the pure solid.
(Z)-5-((2-methylpyridin-3-yl)methylene)thiazolidine-2,4-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
With copper(II)-Para-aminobenzoic acid complex supported on Fe3O4 Magnetic nanoparticle; In ethanol; for 1.58333h;Reflux; Green chemistry;
General procedure: Fe3O4PABA-Cu(II) (0.05 g) was added to a mixtureof various aldehydes (1mmol), with hydantoin or TZD(1mmol), in Ethanol (10mL), and this mixture was refluxedfor the times reported in Table2. the progress of the reactionmonitored by TLC, after completion of the reactionthe mixture was diluted with ethanol and the catalyst waseasily separated from the reaction mixture by an externalmagnet, washed with hot ethanol, dried and reused for aconsecutive run under the same reaction conditions. Afterwards,the reaction mixture was cooled to room temperatureand the crude product obtained was collected by filtrationand washed with cold ethanol to give the pure solid.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
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