* 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.
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1, 2000, # 10, p. 1601 - 1608
[2] Patent: WO2018/138354, 2018, A1,
[3] Patent: WO2018/138359, 2018, A1,
[4] Patent: WO2009/105712, 2009, A1,
[5] Patent: WO2005/34869, 2005, A2,
2
[ 644-36-0 ]
[ 287119-83-9 ]
Yield
Reaction Conditions
Operation in experiment
42%
With sulfuric acid; nitric acid In dichloromethane at -20 - 20℃;
Intermediate 80A: Preparation of 2-(2-methyl-5-nitrophenyl)acetic acid [00224] A solution of 2-o-tolylacetic acid (3.54 g, 23.6 mmol) in DCM (12 mL) was added to a pre-cooled mixture of concentrated sulfuric acid (10 mL, 188 mmol) and 90percent nitric acid (1 mL, 22.4 mmol) at - 20 0C. The reaction mixture was stirred at - 20 0C for 30 minutes, then slowly warmed to room temperature and stirred overnight. The reaction mixture was poured into ice-water. The white solid was collected by filtration, rinsed with water, and concentrated. The solid was triturated with ether and filtered to obtain Intermediate 8OA (2.4 g, 42percent) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.62 (1 H, br. s.), 8.13 (1 H, d, J = 2.51 Hz), 8.04 (1 H, dd, J = 8.28, 2.51 Hz), 7.47 (1 H, d, J = 8.53 Hz), 3.80 (2 H, s), 2.34 (3 H, s).
34.6%
Stage #1: With sulfuric acid In dichloromethane at 0℃; for 0.5 h; Stage #2: With nitric acid In dichloromethane at -2 - 3℃; for 16 h;
The starting material 2-methyl-phenylacetic acid (200.0 g, 1.33 mol)Was dissolved in dichloromethane (700 mL)0 ° C below slowly addedConcentrated sulfuric acid (584 mL),After the addition reaction was continued for 0.5 hours,Then concentrated nitric acid (30 mL)Maintain the temperature at -2 ~ 3 reaction 16 hours;After the reaction,Poured into 500 mL of water,Extracted with dichloromethane, dried,Concentrated to give Compound 1-2 (90.0 g) in a yield of 34.6percent.
32%
With sulfuric acid; nitric acid In dichloromethane at -10℃; for 1 h;
Step 1: a 500 mL round bottom flask was charged with conc. sulfuric acid (130 mL) and cooled to -10°C. A solution of o-tolyacetic acid (10 g, 66.58 mmol) in CH2CI2 (35 mL) was added dropwise. After that, a solution of conc. sulfuric acid(27 mL) and nitric acid (2.7 mL) was slowly added dropwise. The reaction mixture was stirred at -10°C for 1 h and then poured onto ice. The aqueous phase was extracted with EtOAc. The organic layer was washed with water and brine, dried, filtered and the solution was concentrated under reduced pressure. The resulting solid was triturated in Et20 and filtered off to afford 2-(2-methyl-5-nitrophenyl)acetic acid as white solid (4.21 g, 32percent).
With triethylamine; In tetrahydrofuran; dichloromethane;
B. Alkylating Reagents 2-(2-Methanesulfonyloxyethyl)-1-methyl-4-nitrobenzene A 500 mL round bottom flask was charged with <strong>[287119-83-9](2-methyl-5-nitrophenyl)acetic acid</strong> (15 g, 77 mmol) and dry THF (300 mL). The mixture was cooled on ice-water and treated dropwise with borane-tetrahydrofurane complex (90 mL, 1M in THF, 90 mmol) during one hour. The reaction mixture was stirred for two hours at room temperature and then poured on ice. The aqueous phase was extracted with ethyl acetate (3*600 mL). The combined organic phases were washed with brine (2*1L) and water (2*1L), dried (Na2SO4) and concentrated in vacuo. The residue was redissolved in dichloromethane (200 mL) and triethylamine (10.8 mL, 78 mmol). The mixture was cooled on ice-water and a mixture of methanesulfonyl chloride (6.05 mL, 78 mmol) dissolved in dichloromethane (100 mL) was added dropwise during 20 minutes. The reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography on silicagel (eluent:ethyl acetate/heptane 2:3) to give the title compound (7.8 g). 1H NMR (CDCl3): 2.45 (s, 3H); 2.96 (s, 3H); 3.15 (t, 2H); 4.45 (t, 2H); 7.33 (d, 1H); 7.98-8.11 (m, 2H).
Example 4 4a, 3-[1-(2-{5-[2-(4-Fluorophenyl)ethanoylamino]-2-methylphenyl}ethyl)piperidin-4-yl]-7-chloro-1H-indole A mixture of <strong>[287119-83-9](2-methyl-5-nitrophenyl)acetic acid</strong> (2.5 g) and 1,1'-carbonyldiimidazole (2.1 g) in dimethyl formamide (50 mL) was stirred at room temperature for 15 min and subsequently added a solution of 7-chloro-3-(piperidin-4-yl)-1H-indole (3.0 g) in dimethyl formamide (50 mL). The resulting mixture was stirred at room temperature for 1 h and poured onto an ice/water mixture. The compound was isolated by filtration and dissolved in tetrahydrofuran. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give 7-chloro-3-{1-[2-(2-methyl-5-nitrophenyl)-1-oxoethyl]-piperidin-4-yl}-1H-indole (4.7 g).
4. 2-(2-Methyl-5-nitrophenyl)acetic acid To a solution of the product of the preceding step (1.27 g, 7.21 mmol) in methanol (30 mL) was added a solution of potassium hydroxide (4.06 g, 72.4 mmol) in water (30 mL). The reaction was heated at reflux overnight and the methanol removed in vacuo. The remaining aqueous layer was acidified with 3N HCl and filtered, the solid washed with diethyl ether, and the filtrate separated. The aqueous layer was washed with DCM and diethyl ether, and the combined organic layers washed with brine, dried over sodium sulfate, and filtered. The evaporated filtrate gave the title compound (0.84 g, 60%) as an orange solid. 1H NMR (300 MHz, acetone-d6) delta 8.17 (d, 1H, J=2.3 Hz), 8.06 (dd, 1H, J=8.4 Hz, 2.5 Hz), 7.29 (d, 1H, J=8.4 Hz), 3.88 (s, 2H), 2.45 (s, 3H).
16
[ 409082-11-7 ]
[ 287119-83-9 ]
Yield
Reaction Conditions
Operation in experiment
With methanol; potassium hydroxide; water; for 14h;Heating / reflux;
2-(2-Methyl-5-nitrophenyl)ethanenitrile 12 (87 g, 494 mmol) is dissolved in methanol : water = 1 : 1 (1.2 L). Potassium hydroxide (277 g, 4.94 mol) in water (1 L) is added and the reaction is heated at reflux for 14 h. After cooling to rt and removing the methanol in vacuo, the aqueous layer is washed with DCM and ether. The combined organic layer is washed with brine, dried over sodium sulfate, and filtered. After removing the solvent in vacuo, the product 13 is obtained as an orange solid. 1H NMR (300MHz, CDCl3) delta 8.07 (m, 2H), 7.35 (d, J= 8.1 Hz, IH), 3.78 (s, 2H), 2.43 (s, 3H).
With water; potassium hydroxide; In methanol; for 14h;Reflux;
[00124] 2-(2-Methyl-5-nitrophenyl)ethanenitrile 12 (87 g, 494 mmol) was dissolved in methanol : water = 1 : 1 (1.2 L). Potassium hydroxide (277 g, 4.94 mol) in water (1 L) was added and the reaction was heated at reflux for 14 h. After cooling to rt and removing the methanol in vacuo, the aqueous layer was washed with DCM and ether. The combined organic layer was washed with brine, dried over sodium sulfate, and filtered. After removing the solvent in vacuo, the product 13 was obtained as an orange solid. 1H NMR (300MHz, CDCI3) delta 8.07 (m, 2H), 7.35 (d, J= 8.1 Hz, IH), 3.78 (s, 2H), 2.43 (s, 3H).
With potassium hydroxide; water; In methanol; for 14h;Heating / reflux;
2- (2-methyl-5-nitrophenyl)-ethanenitrile (2. 5g, 14. 2mmol) is dissolved in 50mL methanol. Potassium hydroxide (8. 0g, 142mmol) in 50mL water is added and the reaction is heated to reflux for 14 hours. After cooling down and removing the methanol, the aqueous layer is washed with DCM and ether. The combined organic layer is washed with brine and dried over sodium sulfate and filtered. After removing the solvent under the vacuum, the final product compound (15) 2- (2-methyl-5-nitrophenyl)-acetic acid is the orange solid, 1. 9g.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 6h;
Compound [SI-119] (195 mg, 1.00 mmol) stirred in DMF (5.0 mL), compound [SI-120] (414 mg, 1.00 mmol) and 1-hydroxybenzotriazole monohydrate and EDC hydrochloride (211 mg, 1.10 mmol) was added to a solution containing the compound (149 mg, 1.10 mmol), the resulting mixture was stirred at room temperature for 6 hours. The reaction was quenched with water, the mixture was extracted with AcOEt. After washing the combined organic layer with brine, And dried over Na 2 SO 4. After concentration under vacuum, The obtained residue was dissolved in water Purification by flash column chromatography (SiO 2, hexane / AcOEt = 7/1) Amino compound was obtained.
N-[(2-{3-azabicyclo[3.1.0]hexan-3-yl}-4-methylphenyl)(5-methylfuran-2-yl)methyl]-2-[5-(1,1-dioxo-1-thiomorpholin-4-yl)-2-methylphenyl]acetamide[ No CAS ]
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