Benzoic acid, 2-ethoxy-4-methyl-, ethyl ester

Potassium carbonate (68.0 g, 0.492 mole) was added to a well-stirred solution of 4-methylsalicylic acid (25 g, 0.164 mole) in dimethylsulfoxide (75 ml ). The mixture was stirred at 35-40° C. and 1st lot of ethyl bromide (27.0 g, 0.247 mole) was added slowly over a period of 30 minutes then stirred for two hours and a second lot of ethyl bromide (27.0 g, 0.247 mole) was added over a period of 30 minutes at 35-40° C. The reaction mixture was further stirred at 35-40° C. for eight hours, cooled to 20-25° C., and diluted with dichloromethane (50 ml). The inorganics were removed by filtration and washed with dichloromethane. The combined filtrate and washings were diluted with water (50 ml), stirred for 30 minutes, and the organic layer was separated. The aqueous layer was further extracted with dichloromethane and the combined dichloromethane layer was washed with water (2.x.50 ml). The solvent was removed under vacuum to afford ethyl 2-ethoxy-4-methylbenzoate 34.2 g (quantitative yield).To a mixture of 2-hydroxy-4-methylbenzoic acid (20.0 g, 131.5 mmol) and K2CO3 (54.5 g, 394.5 mmol) in DMSO (50 mL) at 40 °C was added bromoethane (21 .5 g, 197.2 mmol) over 30 minutes. The reaction was then stirred at 40 C for 2 hours. Further bromoethane (21.5 g, 197.2 mmol) was then added dropwise and the reaction stirred at 40 °C for 8 hours. DCM (200 mL) was added and the mixture was filtered. The organic layer was washed with water (4 x 150 mL), dried (Na2SO.i) and concentrated to give the title compound (24.1 g, 88percent) as a clear oil. LCMS-C: RT 2.77 min; m/z 209.1 [M+H] To a mixture of 2-hydroxy-4-methylbenzoic acid (8.2 g, 54 mmol) and K2CO3 (22.4 g, 162 mmol) in DMSO (70 mL) at 40 C was added ethyl iodide (12.6 g, 80.8 mmol) drop-wise over a period of 30 minutes. The reaction was stirred for 2 hours then further ethyl iodide (12.6 g, 80.8 mmol) was added over 30 minutes. The resulting mixture was stirred for another 8 hours at 40 C, then diluted with DCM (150 mL) and filtered. The filtrate was washed with water (200 mL To a mixture of 2-hydroxy-4-methylbenzoic acid (8.2 g, 53.9 mmol) and K2CO3 (22.4 g, 161.7 mmol) in dimethylsulfoxide (70 mL) at 40 ^C was added and ethyl iodide (12.6 g, 80.8 mmol) dropwise over a period of 30 min. The reaction was stirred for 2 h then further ethyl iodide (12.6 g, 80.8 mmol) was added over 30 min. The resulting mixture was stirred a further 8 h at 40 ^C, then diluted with CH2Cl2 (150 mL) and filtered. The filtrate was washed with water (200 mL x 10) and brine (200 mL x 2), dried (NaTo a mixture of 2-hydroxy-4-methylbenzoic acid (8.2 g, 53.9 mmol) and K2CO3 (22.4 g, 161 .7 mmol) in dimethylsulfoxide (70 mL) at 40 °C was added ethyl iodide (12.6 g, 80.8 mmol) dropwise over a period of 30 min. The reaction was stirred for 2 hours then further ethyl iodide (12.6 g, 80.8 mmol) was added over 30 min. The resulting mixture was stirred a further 8 hours at 40 °C, diluted with CH2CI2 CI 5O mL) and filtered. The filtrate was washed with water (200 mL x 10) and brine (200 mL x 2), dried (Na2SC>4), filtered and concentrated to give the desired compound as a yellow liquid (10.1 g, 90percent): LCMS: RT 2.70min; m/z 209.1 [M+H][00463] Intermediate 48: Synthesis of ethyl 2-ethoxy-4-formylbenzoate[00464] Step 1: Synthesis of ethyl 2-ethoxy-4-methylbenzoate: To a mixture of 2- hydroxy-4-methylbenzoic acid (5.0 g, 32.9 mmol), KAdded 260 ml (3.0 mol) of diethyl sulfate to the mixture of 1000 ml of toluene, 272.5 g (3.0 mol) of potassium carbonate and 100 g (1.0 mol) of 2-Hydroxy-4-methyl-benzoic acid at 25-45° C. for 1 hr to 1 hr 30 min. Heated the reaction mass to azeotropic reflux for 20-30 hr. Cooled the reaction mixture to 25-35° C. and collected the unwanted material by filtration, washed the unwanted material with 500 ml of toluene. Combined filtrate was washed with water (1.x.1000 ml and 1.x.500 ml) at 80-85° C. Total organic layer was concentrated to residue under vacuum at below 70° C. The yield of the title compound is 128 g (94.11percent). [0036] The obtained product was characterised by analytical techniques like IR, Mass and 1H-NMR4-Methyl salicylic acid (5 g, 32.89 mmol), diethyl sulfate (20.26 g, 0.131 mole) and anhydrous potassium carbonate (18.15 g, 0.132 mole) were mixed thoroughly in dry acetonitrile and mixture was refluxed for 12 hr. Reaction mixture was cooled and filtered through Celite bed. Filtrate was concentrated under vacuum. Residue was purified by fractional distillation at 0.5 mm vacuum. 1st fraction dis tilled at 48-51 C. (oil bath temperature 80 C.). Product (ethyl-2-ethoxy-4-methylbenzoate) 3 distilled at 90-93 C. (oil bath temperature 120 C.) Yield=6 g (87percent).4-Methyl salicylic acid (5 g, 32.89 mmol), diethyl sulfate (20.26 g, 0.131 mole) and anhydrous potassium carbonate (18.15 g, 0.132 mole) were mixed thoroughly in dry dioxane and mixture was refluxed for 16 hr. Reaction mixture was cooled and filtered through Celite bed. Filtrate was concentrated under vacuum. Residue was purified by fractional distillation at 0.5 mm vacuum. 1st fraction dis tilled at 48-51 C. (oil bath temperature 80 C.). Product (ethyl-2-ethoxy-4-methylbenzoate) 3 distilled at 90-93 C. (oil bath temperature 120 C.) Yield=5.8 g (84percent).4-Methyl salicylic acid (5 g, 32.89 mmol), diethyl sulfate (20.26 g, 0.131 mole) and anhydrous potassium carbonate (18.15 g, 0.132 mole) were mixed thoroughly in dry acetone and mixture was refluxed for 16 hr. Reaction mixture was cooled and filtered through Celite bed. Filtrate was concentrated under vacuum. Residue was purified by fractional distillation at 0.5 mm vacuum. 1st fraction dis tilled at 48-51 C. (oil bath temperature 80 C.). Product (ethyl-2-ethoxy-4-methylbenzoate) 3 distilled at 90-93 C. (oil bath temperature 120 C.) Yield=5.2 g (75percent)

Molecular Weight:208.25
XLogP3:2.8
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:5
Exact Mass:208.109944368
Monoisotopic Mass:208.109944368
Topological Polar Surface Area:35.5
Heavy Atom Count:15
Complexity:203
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes