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With thionyl chloride; |
SYNTHESIS EXAMPLE 2 Process (a): After thionyl chloride (10 ml) had been added to <strong>[18480-53-0]3,4-dichloro-5-isothiazole-carboxylic acid</strong> (1.28 g), the mixture was refluxed by heating for 2 hours. The excess of thionylchloride was then distilled off under reduced pressure, and <strong>[18480-53-0]3,4-dichloro-5-isothiazolecarboxylic acid</strong> chloride was obtained. |
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With thionyl chloride; In N-methyl-acetamide; |
Preparation of the starting material: At room temperature, 146 g (1.23 mol) of thionyl chloride are added dropwise with stirring over a period of 5 minutes to 8.92 g (0.045 mol) of <strong>[18480-53-0]3,4-dichloro-isothiazole-5-carboxylic acid</strong>. 4 drops of dimethylformamide are then added, and the reaction mixture is heated at reflux for one hour. The reaction mixture is subsequently cooled to room temperature and concentrated under reduced pressure. This gives 12.19 g of 3,4-dichloro-isothiazole-5-carbonyl chloride in the form of an orange oil. The compounds of the formula (I) listed in the table below are also prepared by the method given above. |
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With thionyl chloride; In N-methyl-acetamide; |
Preparation of the Starting Material At room temperature, 146 g (1.23 mol) of thionyl chloride are added dropwise with stirring over a period of 5 minutes to 8.92 g (0.045 mol) of <strong>[18480-53-0]3,4-dichloro-isothiazole-5-carboxylic acid</strong>. Four drops of dimethylformamide are then added and the reaction mixture is heated under reflux for one hour. The reaction mixture is subsequently cooled to room temperature and concentrated under reduced pressure. In this manner, 12.19 g of 3,4-dichloro-isothiazole-5-carbonyl chloride are obtained in the form of an orange oil. |
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With thionyl chloride;N,N-dimethyl-formamide; In toluene; at 100℃; for 16h; |
A mixture of <strong>[18480-53-0]3,4-dichloroisothiazole-5-carboxylic acid</strong> (2.0 g) and toluene (20 mL) was treated with thionyl chloride (5.0 ml_) and lambda/,lambda/-dimethylformamide (0.5 mL), and the resulting mixture was heated at 1000C for 16 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in tetrahydrofuran (5.0 mL). The mixture was cooled to -780C and treated dropwise over a period of 1 hour with a 2.0 M solution of sodium borohydride in lambda/,lambda/-dimethylformamide (8.5 mL). The mixture was stirred at - 780C for 5 minutes, diluted with 1.0 M aqueous hydrochloric acid solution and extracted with ethyl acetate. The combined organic extract was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and <n="80"/>concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and dichloromethane (1:0 to 0:1 by volume) to afford the title compound as a pale yellow solid (1.1 g).1H NMR (CDCI3): delta 4.96 (s, 2H). |
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With oxalyl dichloride;N,N-dimethyl-formamide; at 50℃; for 0.5h; |
(To 4.0 g (20.3 mmol) of <strong>[18480-53-0]3,4-dichloroisothiazole-5-carboxylic acid</strong> were added 8 ml of oxalyl chloride and a catalytic amount of N,N-dimethylformamide (DMF). The mixture was stirred at 50°C for 30 minutes. The reaction mixture was concentrated under vacuum to obtain 3,4-dichloroisothiazole-5-carbonyl chloride. |
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With thionyl chloride;N,N-dimethyl-formamide; In toluene; at 100℃; for 16h; |
(3,4-dichloroisothiazol-5-yl)methanolA solution of <strong>[18480-53-0]3,4-dichloroisothiazole-5-carboxylic acid</strong> (2.0 g), N1N- dimethylformamide (few drops) and thionyl chloride (20 mL) in toluene (60 mL) was heated at 1000C for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), cooled to -200C under a nitrogen atmosphere and treated dropwise with a 1.0 M sodium borohydride solution in N, N- dimethylformamide (8.5 ml.) over 1 hour. The mixture was stirred for 5 minutes after the end of addition and quenched with 1.0 M aqueous hydrochloric acid solution. The mixture was concentrated to low bulk under reduced pressure and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and dichloromethane (1 :0 to 0:1 by volume), to afford the title compound as a pale yellow solid (1.1 g).1H NMR (300 MHz, CDCI3): delta 2.60 (s, 1H); 4.96 (s, 2H). |
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With oxalyl dichloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 4h; |
3,4-Dichloroisothiazol-5-carboxylic acid (0.235 g, 1.2 mmol), dichloromethane (6 ml), N,N-dimethylformamide (2 drops) were added dropwise to the reaction flask. Add oxalyl chloride (1 g, 8 mmol),The reaction solution was stirred at room temperature for 4 hours.The solvent was then evaporated to give 3,4-dichloroisothiazol-5-carbonyl chloride, which was dissolved in dichloromethane (2 mL).Then 4-fluoro-2-(2-pentyloxy)aniline (0.197 g, 1 mmol) was added to the reaction flask and triethylamine (0.13 mL) was added.Further, a 3,4-dichloroisothiazol-5-formyl chloride solution was added dropwise to the reaction flask, and the mixture was stirred at room temperature for 16 hours.Then after monitoring the reaction by thin layer chromatography,Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine.After drying over anhydrous sodium sulfate, it was concentrated under reduced pressure.The residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 20:1).Obtained a fresh yellow solid of 0.236 g.The yield was 62.76percent. |
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With oxalyl dichloride;N,N-dimethyl-formamide; at 80℃; for 2h; |
To a suspension of <strong>[18480-53-0]3,4-dichloroisothiazole-5-carboxylic acid</strong> (0.15 g, 0.76 mmol) in oxalyl chloride (2 mL) was added a catalytic amount of dimethylformamide (2 drops) and the mixture was heated to 80° C. and stirred for 2 h. The excess oxalyl chloride was removed on the rotary evaporator. Meanwhile, 5-fluoro-2-(4-fluorobenzyloxy)-pyrimidin-4-ylamine (0.17 g, 0.68 mmol) was dissolved in THF (1 mL), treated with LiHMDS (1M in THF, 0.76 mL, 0.76 mmol) and stirred for 10 min. The freshly prepared 3,4-dichlorothiazole-5-carbonyl chloride*, dissolved in THF (1 mL), was added and the reaction was capped and stirred for 12 h. The reaction was diluted with water and the target compound was extracted with CH2Cl2 (3.x.5 mL). The combined extracts were dried over MgSO4 and then evaporated under reduced pressure. The mixture was eluted with CH2Cl2 through an anionic-exchange solid phase extraction column and then further purified by reverse-phase chromatography to give <strong>[18480-53-0]3,4-dichloroisothiazole-5-carboxylic acid</strong> [5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl]amide (0.035 g, 12percent) as a tan solid: mp 87-90° C.; 1H NMR (400 MHz, DMSO-d6) delta 11.78 (s, 1H), 8.67 (s, 1H), 7.51-7.48 (m, 2H), 7.24-7.19 (m, 2H), 5.25 (s, 2H); MS (ESI) m/z 417 (M+H)+, 415 (M-H)-. *Nagata, T.; Kogure, A.; Yonekura, N.; Hanai, R.; Kaneko, I.; Nakano, Y. JP 2007211002 A |
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With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃;Cooling with ice-brine; |
To a solution of S^-dichloroisothiazole-delta-carboxylic acid (4.0Og, 20.1 mmol) in dichloromethane (75 ml_), cooled with an ice-brine bath, was added N,N-dimethylformamide (78 mul_, 1 mmol) followed dropwise by oxalyl chloride (1.94 ml_, 22.2 mmol). After stirring at room temperature for 2h, meanwhile gas evolution had completely stopped, all volatiles were removed in vacuo to affor the crude acid chloride (4.30 g). |
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