Ethyl 2-chloro-2-[2-(4-methoxyphenyl)hydrazono]acetate

100 g (0.81 mol) of the starting material (3) was added to 400 ml of water at room temperature, To the reaction solution was added dropwise 270 ml (3.24 mol) of concentrated hydrochloric acid.After the dropwise addition, 115 g (1.62O1) of a mixed solution of sodium nitrite and 460 ml of water was added dropwise to the reaction solution, and the temperature control was carried out at -5 to 10C.Drop control, control the temperature at -5 ~ -10 ° C reaction 30min.Then, 135 ml (0.97 mol 1) of the reaction solution was added dropwise to the reaction solution, A mixed solution of ethyl dichloroacetoacetate and 135 ml of methanol, The temperature during the dropwise process is controlled at -5 to 10 ° C.After completion of the reaction, a mixed solution of 207 g (2.43 mol) of anhydrous sodium acetate and 514 ml of water was added dropwise to the reaction solution, The temperature is maintained at -5 to 10 ° C during the dropwise addition. Drop finished, temperature control at _10 ° C, reaction 2h.Then transferred to room temperature, allowed to stand overnight, with a brown solid precipitated, filtered and the filter cake was washed with anhydrous methanol (2 x 300ml).To give 186.9 g of a yellow solid (theoretical yield of 208. lg) in a yield of 89percentGeneral procedure: Commercially available substituted aniline (63.4mmol) was portionwise added to a solution of concentrated HCl (13mL), ethanol (20mL) and water (7mL). To the above mixture was added dropwise a solution of NaNOIn 250 mLTo a three-necked flask was added p-methoxyaniline (13.5 g, 0.11 mol) Water (56 ml), concentrated hydrochloric acid (28 ml), Stirred and dissolved, cooled to -5°C , NaNO2 (7.9g, 0.12mol) aqueous solution was added dropwise, the temperature was controlled below 0°C , Reaction below 0 °C for 30min. A 500 mL three-necked flask was charged with ethyl 2-chloroacetoacetate (18 g, 0.11 mol) Ethanol 270mL, Water 30mL, cooled to -5°C , Sodium acetate (13.5 g, 0.16 mol) was added.Then make the above prepared diazonium salt solution into the anti-drop Should be the system, the control temperature is below 0°C . After dropping at room temperature for 4h. The reaction mixture was poured into 1 L of water and stirred until a large amount of solid was obtained After the precipitation was filtered off to give the product, a yellow solid, 20.6g, m. p. 106-109 °C, yield 73.6percent.Under room temperature, will be sequentially 4-methoxyaniline (30.0 g, 244 mmol) and water (100 ml) added to a reaction flask. Stirring of the obtained mixture, the lower the temperature to -5 to 0 °C. Then to the adding concentrated hydrochloric acid (35 ml) and sodium nitrite solution (50 ml). After the completion of the dropping, preserving heat and stirring the obtained mixture of 0.5 hours, then dropwise 2-chloro-3-oxo butyric acid ethyl ester (40.2 g, 244 mmol) of ethanol solution (200 ml), and sodium acetate (60.0 g, 732 mmol) aqueous solution (500 ml). After the completion of the dropping, at -5 to 0 °C, to the stirring mixture of 0.5 hours. Furthermore, the obtained mixture to room temperature, stirring for 6 hours. After the reaction, filtration, vacuum drying, silica gel column chromatography (PE:EA=10:1) to obtain 31.6 g product, in other words 2-chloro-2 - (2 - (4-methoxyphenyl) hydrazono) ethyl acetate (yield 50.4percent).4-methoxy-aniline (2k) (24.6 g, 0.2 mol) was dissolved in hydrochloric acid (50 mL, 0.2mol, 12N) of water (100 mL) was cooled to 0 ° C, was slowly dropwise sodium nitrite (16.6 g, 0.24 mol) in water (80 mL) solution, after the addition was complete, 0 ° C for 30 minutes, then was added sodium acetate (328 g, 0.40 mol) adjusting the reaction solution pH = 5 ~ 6, maintaining 0 ° C, was added dropwise ethyl 2-chloroacetoacetate (32.9 g, 0.2 mol) in methanol (80 mL) solution, after the addition was complete, maintaining 0. C for 1 hour. To the reaction solution was added ethyl acetate (200 mL x 2) and the combined organic phases, the organic phase was washed with saturated brine QOO mL xl), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, the residue was purified by silica gel column chromatography ( ethyl acetate / petroleum ether (v / v) = 1: 50-1: 10) to give the title compound 2-chloro-2- (2- (4-methoxyphenyl) hydrazone yl) acetate (21) , as a yellow solid (19.5 g, 19percent yield).Example 5Preparation of ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetateStep-i: Water (600 ml) was added to p-anisidine (100 g) at room temperature and the resulting mixture was cooled to 10°C, followed by the addition of concentrated hydrochloric acid (133.5 g). The resulting mixture was cooled to —5°C to 0°C, followed by portion-wise addition of 40percent aqueous sodium nitrite solution (67.2 g in 175 ml of water) over a period of 45 minutes to 1 hour. The resulting mass was stirred for 1 hour 30 minutes at —5°C to0°C, followed by slow addition of 11percent sulfamic acid solution (35 g in 325 ml of water) over a period of 1 hour to 1 hour 30 minutes to produce a reaction mass (first part).Step-2:Sodium acetate (146 g) was added to water (300 ml) at room temperature and then stirred for 10 minutes to 15 minutes, followed by the addition of ethyl 2-chloroacetoacetate (160.4g) and acetone (300 ml) at room temperature to form a reaction mixture. The resulting mixture was cooled to 0°C (second part). The resulting mixture (second part) was added to the reaction mass (first part) obtained in step-i at —5°C to 0°C and then stirred for 1 hour at the same temperature. Acetone (200 ml) was added to the resulting mass and then stirred for 30 minutes at —5°C to 0°C. The resulting mass was settled for 5 hours at —5°C to 0°Cand then filtered the solid. Methanol (150 ml) was added to the resulting solid at room temperature and then stirred for 2 hours at the same temperature. The separated solid was filtered, washed with methanol (50 ml) and then dried the material at 25°C for 24 hours to produce 105 g of ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate (Purity by HPLC: 96percent).General procedure: Method A: A mixture of thiosemicarbazone derivative 3 (0.79 g, 2.5 mmol), hydrazonoyl chlorides (4 or 8) (2.5 mmol), and catalytic amount of triethylamine(TEA) in ethanol (15 mL) was refluxed thermally for a period of time as illustratedin Table 1 or Table 4. The reaction mixture was then left to cool, and the resultingsolid was filtered, washed with methanol, and recrystallized from EtOH/dimethylformamide(DMF) to afford thiazole derivative 5a'e or 9a'g.Method B: Thiosemicarbazone derivative 3 (0.79 g, 2.5 mmol), hydrazonoylchlorides (4 or 8) (2.5 mmol), and catalytic amount of TEA in ethanol (15 mL) weremixed in a HP-500 process vial. The vial was capped properly and irradiated bymicrowave irradiation (800 W power) using pressurized condition at 110 C for aperiod of time of about 40 min (Table 1 or Table 4). The reaction mixture was thenleft to cool, and the resulting solid was filtered, washed with methanol, andrecrystallized from EtOH/dioxane to afford thiazole derivative 5a'e or 9a'g.

Apixaban intermediate