2,5-Dichloro-N-[2-[(1-methylethyl)sulfonyl]phenyl]

To a solution of 2-(isopropylsulfonyl)aniline (3.0 g, 15.1 mmol) in DMF (80 mL) was added sodium hydride (1.2 g, 30.1 mmol, 60percent in mineral oil) at 0 °C. After stirring for 30 min, 2, 4, 5-trichloropyrimidine was added to the reaction mixture followedby warming the mixture to room temperature. After stirringfor 2 h, the reaction mixture was quenched with ice and dilutedwith excess water. The precipitate was filtered and the solid wasdried by blowing nitrogen gas to obtain 3c as an off-white solid(3.75 g, 72percent). 1H NMR (500 MHz, DMSO-d6) δ 9.81 (s, 1H), 8.56 (s, 1H), 8.33-8.31 (m, 1H), 7.89 (dd, J = 7.9, 1.5 Hz, 1H), 7.88-7.84 (m, 1H), 7.48 (td, J = 7.6, 1.2 Hz, 1H), 3.58-3.48 (m, 1H), 1.16 (d, J = 6.7, 6H); LC/MS (ESI) m/z 346.18 [M+H]+.To a stirred solution of 40 g (0.200mole) of 2-isopropylsulfonyl aniline [formula- XI] in 400 ml of toluene into a flask under nitrogen atmosphere. 49.7 g (0.27 mole) of 2, 4, 5-trichlropyrimidine (formula-XII), 81.7g (0.25 mole) of caesium carbonate, 4.5 g (0.02 mole) of palladium(II)acetate, 13.1 g (0.05 mole) of triphenylphosphine were added. Raised the reaction mass temperature to reflux under nitrogen and maintained for 4 hours. Checked the TLC for 2-isopropylsulfonyl aniline content by TLC. 2-isopropylsulfonyl aniline content is absent. Reaction mass was cooled to 25-30°C and filtered the mass. Washed the solid with 400 ml of ethyl acetate. Toluene and ethyl acetate were removed by distillation under vacuum at a temperature 60°C to give crude compound. Crude compound was further purified by column chromotography to 45.6 g of 2, 5-dichloro-N-(2-(isopropyl sulfonyl) phenyl) pyrimidin-4-amine [formula-XIII] as a light yellow solid product with 65.6 percent yield by theory.11. To the suspension of NaH (4.5 g, 0.12 mol) in DMF (160 mL), 2-(isopropylsulfonyl)aniline (16.0 g, 0.08 mol) was added at 0 °C. 2-(Isopropylsulfonyl)aniline (2 g, 10 mmol) was dissolved ina mixed solvent of DMF (10 mL) and DMSO(1 mL). 2-(isopropylsulfonyl)aniline (1g, 5.02mmol) and 2, 4, 5-trichloropyrimidine (1.1g, 6mmol) was dissolved in N, N-dimethylformamide (30 mL) and added sodium hydride (content 60percent, 0.4g, 10mmol) then reacted at 25°C for 12 hours. Water (20mL) was added then extracted with ethyl acetate (30mL × 3). The organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 25: 1) gave the product (0.8g, 46percent yield).A mixture of 2- (isopropylsulfonyl) aniline (1 g, 5 mmol)And 2, 4, 5-trichloropyrimidine (1.1 g, 6 mmol)Was dissolved in N, N-dimethylformamide (30 mL)Sodium hydride (60percent, 0.4 g, 10 mmol) was added, 25 ° C for 12 hours.(30 mL x 3), the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated in vacuo, The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 25: 1)The product (0.8 g, yield 46percent) was obtained.Sodium hydride (60.00percent, 1.219 g, 30.471 mmol) was added to a solution ofTo a solution of N, N-dimethylformamide (25 mL) / dimethylsulfoxide (2.5 mL) at 0 & lt;To the solution was added 2- (isopropylsulfonyl) aniline (2.530 g, 12.696 mmol)DMF / DMSO (10 ml, 9: 1 ratio)The dissolved solution was added dropwise at 0 ° C, and the mixture was stirred at the same temperature for 0.5 hour.To the reaction mixture was added 2, 4, 5-trichloropyrimidine (4.658 g, 25.393 mmol) in DMF / DMSO (10 ml, 9: 1 ratio)The solution prepared by dissolving was added dropwise at 0 deg. C, the temperature was gradually raised to room temperature, and further stirred for 15 hours.The reaction mixture was cooled in an ice bath and treated with AcOH (2 ml, ca. 33 mmol)Water (1.8 ml, 100 mmol) was slowly added to terminate the reaction. The filtrate was filtered through celite and the filtrate was poured into 50 ml of water and extracted with ethyl acetate (50 ml × 3).The combined organic layers were washed with a half-brine (100 ml) saturated sodium chloride and water mixture, and dried over anhydrous magnesium sulfateAfter filtration, the filtrate was concentrated under reduced pressure. The concentrate was purified and purified by column chromatography (SiO2, 80 g cartridge; ethyl acetate / hexane = 10percent to 20percent) to give 2, 5-dichloro-N- (2- (isopropylsulfonyl) phenyl) Amin-4-amine (1.783 g, 40.6percent) as a white solid.To a suspension of NaH (1.0 g, 25 mmol) in a mixtureof DMF (30 mL) was added dropwise 2-(isopropylsulfonyl)benzenamine (1.99 g, 10 mmol) in DMF (10 mL) at 0 °C. The solutionwas stirred for 30 min, and then 2, 4, 5-trichloropyrimidine (1.82 g, 10 mmol) in DMF (10 mL) was added slowly. The solution was warmed to room temperature and stirred for 12 h. Water was added and the mixture was extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purifiedby column chromatography (20percent EtOAc in petroleum ether) to afford compound 51a (1.38 g, 40percent) as a white solid. 1H NMR(400 MHz, DMSO-d6) δ 9.82 (s, 1H), 8.55 (s, 1H), 8.32 (d, J 7.2 Hz, 1H), 7.90e7.85 (m, 2H), 7.47 (d, J 6.4 Hz, 1H), 3.50e3.30 (m, 1H), 1.16 (d, J 6.4 Hz, 6H); 13C NMR (100 MHz, DMSO-d6) δ 157.15, 157.09, 156.34, 156.34, 137.14, 135.66, 131.62, 126.63, 125.60, 124.75, 115.29, 55.11, 15.27; HRMS (ESI, m/z) [M+H]+ calcd forC13H14Cl2N3O2S: 346.0184, found: 346.0186.39.8 g (0.20 mol) of intermediate IV was added to 400 mLDried N, N-dimethylformamide (DMF)Under ice bath, 32.0 g (0.80 mol)60percent sodium hydride, ice bath for 30min, A solution of 73.4 g (0.40 mol)2, 4, 5-trichloropyrimidine, ice bath for 10 h. The reaction solution was poured into a large amount of ammonium chloride saturated solution, Stir for 30 min at room temperature, suction filter, brown red solid.The acetonitrile was recrystallized to give a pale yellow solid27.6 g, Yield 40.0percent.39.8 g (0.20 mol) of intermediate IV was added to 400 mL of dry N, N-dimethylformamide (DMF).Under ice-cooling, 32, 0 g (0.80 mol) of 60percent sodium hydride was added portionwise, and the mixture was stirred for 30 min under ice-cooling, and 73, 4 g (0.40 mol) of 2, 4, 5-trichloropyrimidine was slowly added thereto, and the mixture was reacted for 10 hours under ice bath. The reaction solution was poured into a large amount of a saturated solution of ammonium chloride, stirred at room temperature for 30 min, and suction filtered to give a brown solid. The acetonitrile was recrystallized to give a pale yellow solid (27.6 g).2-(isopropylsulfonyl)phenylamine (9.96 g, 50 mmol) was weighed and dissolved in N, N-dimethylformamide(DMF, 100 mL), to which sodium hydride (NaH, 2.4 g, 100 mmol) was slowly added on an ice bath and stirred for 0.5 h.A solution of 2, 4, 5-trichloropyrimidine (11.0 g, 60 mmol) dissolved in 20 mL of DMF was slowly added dropwise on anice bath. After the addition, the mixture was reacted overnight at room temperature, washed with water, and extractedwith ethyl acetate. After drying and concentration, the crude material was purified by column chromatography to give awhite solid 1-1 (6.9 g, 40percent). MS(ESI): m/z 346.0 (M + H)+. 1H NMR (400 MHz, CDCl3) δ 10.07(s, 1 H), 8.63 (d, J = 8.0Hz, 1 H), 8.30 (s, 1 H), 7.92 (d, J = 7.4 Hz, 1 H), 7.73 (t, J = 7.4 Hz, 1 H), 7.33 (t, J = 7.0 Hz, 1 H), 3.22 (heptet, J = 6.0Hz, 1 H), 1.32 (d, J = 6.0 Hz, 6 H). 13C NMR (100 MHz, CDCl3) δ 157.8, 156.3, 155.6, 137.3, 135.2, 131.4, 124.5, 124.2, 122.7, 115.2, 56.1, 15.3.In Scheme 2In the synthesis of Compound 2-5, The starting material 2-fluoronitrobenzene (i.e., compound 2-1)The remaining synthetic methods were the same as those of Scheme 1 of Scheme 1, To give compound 2-5, yield: 33percent.Step 4: Preparation of 2, 5-dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine (5); 2-(isopropylsulfonyl)aniIine (4, 3 g, 15 mmol) was taken up in DMF (30 mL) to form a mixture, and the mixture was cooled in a water bath. NaH (0.723 g, 30 mmol) was then added to the mixture in portions and the mixture was stirred for 15 min. 2, 4, 5-trichloropyrimidine (3.31 g, 18 mmol) was then added dropwise to the mixture and the mixture was stirred at room temperature overnight (16 h).Compound 5 was detected in the reaction mixture by LC-MS. The reaction mixture was then quenched with ice and water, and the product was extracted with ethyl acetate. The organic extract was dried over sodium sulfate and concentrated to obtain a crude product. The crude product was purified by column chromatography (silica gel 20percent ethyl acetate (EA) in Hexane) to afford 2, 5-dichloro-N-(2- (isopropylsulfonyl)phenyl)pyrimidin-4-amine (5, 1 .7 g, 32.69percent). 'HNMR (CDC1Compound 24 (30 g, 150 mmol) was dissolved in DMF (300 mL) under ice-cooling, and sodium hydride (7. 23 g, 300 mmol) was slowly added to the reaction system at 0 ° C for 15 minutes.2, 4, 5-trichloropyrimidine(33. lg, 180 mmol) was added dropwise to the reaction system and the reaction was stirred at room temperature overnight. After cooling, pour 500mL of water, ethyl acetateThe ester was extracted and dried and concentrated by silica gel column chromatography to give compound 2-5 (17.33, yield: 32percent).The reaction flask was charged with 9 g of 2- (isopropylsulfonyl) aniline and 90 mL of N, N-dimethylformamide. The reaction liquid is coldBut to 0 ~ 5 , 2.2g sodium hydrogen was added to the reaction solution in batches, plus the end of stirring for 15 minutes. The temperature was controlled at 0-5 , 9.9g 2, 4, 5-trichloropyrimidine was added dropwise to the reaction solution, and the mixture was stirred for 16-20 hours while dropping to room temperature. The reaction was quenched with ice water and extracted with ethyl acetateTake, the organic phase was concentrated to give the crude product. The crude product was isolated by column chromatography to give compound 3. (5.1 g, molar yield 32.7percent).2, 5-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (0440) To a solution of 1-Amino-2-(isopropylsulphonyl)benzene (0.955 g, 4.80 mmol) in 2 mL of DMF at 0° C. was added NaH (60percent in oil, 0.349 g, 8.72 mmol) in one portion. After stirring fro 20 min, 2, 4, 5-trichloropyrimidine was added. The mixture was stirred at 0° C. for 30 minutes, and then at room temperature for 2 h. After quenching with saturated ammonium chloride solution, the mixture was poured in water and ethyl acetate mixture. Yellow suspension was filtered as final product (0.3 g, 20percent yield). MS/ES+: m/z=346.A solution of 2-(isopropylsulfonyl)benzenamine (10 g) in dimethylacetamide (30 mL) was added slowly to a mixture of sodium hydride (7.43 g) in dimethyl acetamide (40 mL) at 0°C and stirred for 1 hour. A solution of 2, 4, 5-trichloropyrimidine (17.26 mL) in dimethylacetamide (30 mL) was added to the above reaction mixture and warmed to 20-25°C. The reaction mass was stirred for 2 hours and quenched by a saturated solution of ammonium chloride (300 mL). The reaction mass was extracted with ethyl acetate (3 x 200 mL). The combined organic layer was washed with water (3 x 150 mL) and dried over sodium sulfate. The organic layer was distilled under reduced pressure to afford the crude compound, which was purified by silica gel column chromatography using 5percent ethyl acetate in hexane to obtain the desired product. Yield: 9.1 g, Purity (by HPLC): 99.2percent2-(isopropylsulfonyl)aniline (3g, 14mmol), add DMF 30ml. Under ice-water bath add batchwise sodium hydride (0.73g, 30mmol), Addition is completed. Room temperature stirring 30min. Add 2, 4, 5-trichloropyrimidine (3.31g, 18mmol). Stirring at the room temperature 16h. ice water quenching of the reaction, ethyl acetate (30 ml * 3), the combined organic layer, water washing, salt is washed with water, concentrated to dryness to obtain white solid 1.7g, yield 37percent, in order to 2 - (isopropyl sulfonyl) aniline calculation.Compound b1-4 (1 g, 5 mmol) was placed in a 100 mL three-necked flask and added to DMF (70 mL).Then NaH (0.4 g, 10.1 mmol) was added and stirred for 15 minutes, then a solution of compound b2 (1.83 g, 10.1 mmol) in DMF was added.Stir at room temperature overnight, After adding 100 mL of water, ethyl acetate was extracted, and the organic phase was washed with brine, dried over anhydrous magnesium sulfateYield 0.5 g of a white solid,

Molecular Weight:346.2
XLogP3:4.3
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:4
Exact Mass:345.0105532
Monoisotopic Mass:345.0105532
Topological Polar Surface Area:80.3
Heavy Atom Count:21
Complexity:441
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes