The basis of chemical reaction formula synthesis, the synthesis route is composed of some specific reactions and combined according to certain logical thinking. We look forward to the emergence of more reaction modes in the future.
Researchers who often do experiments know that organic synthesis is a process of preparing more complex target molecules from simple raw materials through one or more chemical reactions. Generally, it requires fewer steps, and cheap raw materials. 1528-41-2, name is Ethyl 2-(4-cyanophenyl)acetate, A new synthetic method of this compound is introduced below., Application In Synthesis of Ethyl 2-(4-cyanophenyl)acetate
Step 0 (Intermediate A): Chlorosulfonylisocyanate (10 g, 70.65 mmol) was added to a solution of t-butanol (6.74 mL, 70.65 mmol) in dichloromethane (50 mL) at 0 C. and stirred for 15 min. Dimethylaminopyridine (8.63 g, 70.63 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. The mixture was partitioned between water (200 mL) and dichloromethane (100 mL). The organic layer was separated and the aqueous layer extracted with dichloromethane (100 mL). Combined organic layer was washed with water (4×200 mL) and brine (500 mL), dried over sodium sulfate and concentrated. Crude compound was recrystallized with acetonitrile (130 mL) to afford N-(1-(tert-butoxycarbonyl)sulfamoyl)pyridine-4(1H)-ylidene)-N-methylmethanaminium (A) (9.5 g, 45%) as a white solid.[0567]Step 1: Ethyl 2-(4-cyanophenyl)acetate (4.0 g, 21.14 mmol) in tetrahydrofuran (20 mL) was added to a suspension of 60% sodium hydride (850 mg, 21.14 mmol) in tetrahydrofuran (20 mL) at 0 C. and stirred for 30 min. Methyl iodide (1.36 mL, 21.14 mmol) was added at 0 C.; reaction mixture was then stirred at room temperature for 4 h. Reaction mixture quenched with saturated NH4Cl solution (20 mL), diluted with water (200 mL) and extracted with ethyl acetate (2×75 mL). The combined organic layers was washed with water (50 mL) and brine (50 mL), dried over sodium sulfate, and evaporated to get crude, which was purified by column chromatography (silica gel; 60-120 mesh); the product eluted with 10% ethyl acetate in pet ether to yield ethyl 2-(4-cyanophenyl)propanoate (3.2 g, 75%) as colorless liquid.[0568]Step 2: 20% Pd/C (1.2 g) and di-tert-butyl dicarbonate (12.89 mL, 57.97 mmol) were added to a solution of ethyl 2-(4-cyanophenyl)propanoate (6.0 g, 28.98 mmol) in ethanol (60 mL) and hydrogenated at 60 psi at room temperature for 18 h. Reaction mixture was filtered through celite, washed with methanol (100 mL) and concentrated to give ethyl 2-(4-((tert-butoxycarbonylamino)methyl)phenyl)propanoate (6.0 g, 67%) as off white solid.[0569]Step 3: Trifluoroacetic acid (6 mL) was added to a solution of ethyl 2-(4-((tert-butoxycarbonylamino)methyl)phenyl)propanoate (6.0 g, 19.54 mmol) in dichloromethane (30 mL) at 0 C. and stirred for 4 h at room temperature. The volatiles were evaporated under reduced pressure, basified with saturated NaHCO3 and extracted with ethyl acetate (3×50 mL). Combined organic layers washed with water (100 mL), brine solution (50 mL), dried over sodium sulfate and concentrated to give ethyl 2-(4-(aminomethyl)phenyl)propanoate (3.5 g, 86%) as colorless liquid.[0570]Step 4: N-(1-(tert-butoxycarbonyl)sulfamoyl)pyridine-4(1H)-ylidene)-N-methylmethanaminium (A) (5.81 g, 19.32 mmol) was added to a suspension of ethyl 2-(4-(aminomethyl)phenyl)propanoate (4.0 g, 19.32 mmol) in dichloromethane (40 mL) at room temperature and stirred for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2×75 mL). Combined organic layer was washed with water (50 mL), brine (50 mL), dried over sodium sulfate and concentrated to get crude compound, which was purified by column chromatography (silica gel; 100-200 mesh). The product eluted with 20% ethyl acetate in pet ether to yielded ethyl 2-(4-((N-(tert-butoxycarbonyl)sulfamoylamino)methyl)phenyl)propanoate (3.8 g, 51%) as pale yellow solid.[0571]Step 5: Lithium hydroxide monohydrate (826 mg, 19.68 mmol) in water (10 mL) was added to a solution of ethyl 2-(4-((N-(tert-butoxycarbonyl)sulfamoylamino)methyl)phenyl)propanoate (3.8 g, 9.84 mmol) in tetrahydrofuran (30 mL) at 0 C. and stirred at room temperature for 18 h. The volatiles were evaporated; the residue diluted with water (50 mL) and extracted with diethyl ether (2×20 mL). The aqueous layer was acidified (pH ?5) with acetic acid at 0 C., precipitated solid was filtered and dried under reduced pressure to afford 2-(4-((N-(tert-butoxycarbonyl)sulfamoylamino)methyl)phenyl)propanoic acid (2.3 g, 56%) as white solid.[0572]Step 6: 2-(4-((N-(tert-butoxycarbonyl)sulfamoylamino)methyl)phenyl)propanoic acid (269 mg, 0.751 mmol) and (2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methanamine (200 mg, 0.751 mmol) were dissolved and mixed in tetrahydrofuran (5.8 mL), followed by addition of N-hydroxybenzotriazole (103 mg, 0.751 mmol) and O-(1H-benzotriazol-1-yl)-N,N,N?,N?-tetramethyluronium tetrafluorborat (238 mg, 0.751 mmol) and N-ethyldiisopropylamine (0.338 mL, 2.25 mmol). The reaction mixture was stirred for overnight at room temperature and then quenched by water and extracted with ethyl acetate. Drying over magnesium sulfate, evaporation of the ethyl acetate and purification by column chromatography gave tert-butyl N-(4-(1-oxo-1-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methylamino)propan-2-yl)benzyl)sulfamoylcarbamatein pure form (258 mg, 57%).[0573]Step 7: To a solution of tert-butyl N-(4-(1-oxo-1-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methylamino)propan-2-yl)benzyl)sulfamoylcarbamate (250 mg, 0.412…
The basis of chemical reaction formula synthesis, the synthesis route is composed of some specific reactions and combined according to certain logical thinking. We look forward to the emergence of more reaction modes in the future.
Reference:
Patent; Gruenenthal GmbH; Frank, Robert; Bahrenberg, Gregor; Christoph, Thomas; Lesch, Bernhard; Lee, Jeewoo; US2013/79377; (2013); A1;,
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