3-(2-Chloro-4-pyrimidinyl)-1H-indole

3-(2-chloropyrimidin-4-yl)-1H-indole (1 g, 4.37 mmol), 2-(difluoromethoxy)-4-fluoro-5-nitroaniline (810 mg, 4.37mmol) and p-toluenesulfonic acid (750 mg, 4.37 mmol) were dissolved in 2-pentanol (40 mL), and then the reactionsolution was heated at 110 °C for 3 hours. After LCMS showed completion of the reaction, the reaction solution wascooled to room temperature naturally, and a dark solid was precipitated. The solid was filtered, and the filter cake waswashed with methanol and methyl tert-butyl ether to obtain 3-(2-chloropyrimidin-4-yl)-1H-indole (1.3 g, 79percent).Partially added to a solution of compound 1 (21 g, 0.14 mol) in dichloromethane (500 mL) under N2.AlCl3 (22.5 g, 0.17 mol) was added over 10 minutes.After the resulting suspension was stirred at room temperature for 10 minutes, the reaction system was substantially clear.Compound 2 (16.5 g, 0.14 mol) was added portionwise to the above reaction mixture at room temperature, and was added over 10 minutes.The resulting brown suspension was stirred overnight at room temperature; the reaction was monitored by TLC, and after the consumption of Compound 1 was completed, the reaction solution was poured into ice water with stirring.This system was extracted 3 times with EtOAc (300 mL).The organic phases were combined and washed with brine (200 mL) twice.After drying over sodium sulfate, it was concentrated under reduced pressure to yield 38g of brown crude.The crude product was purified by silica gel column chromatography (eluent n-hexane:EtOAc = 5:1 to 3:1).16 g of the title compound 3 were obtained as a yellow solid, yield 49percent.CHIn a period of 10 minutes at 0 in NExample 48 1. Synthesis of intermediate 048-2 The intermediate 048-1 (3.0 g, 25.6 mmol) as a raw material was dissolved in 50 mL of 1, 2-dichloroethane (DCE) in 100 mL of a three-necked flask at room temperature under a nitrogen atmosphere. The reaction mixture was cooled to 0°C. Ethylmagnesium bromide (8.5 mL, 25.6 mmol) was added dropwisely to the reaction system. After the reaction was completed, the reaction was maintained at a constant temperature for 30 min and the intermediate 001-5 (5.4 g, 36.3 mmol) was added into the reaction system at 0°C. The reaction was carried out overnight at room temperature. After the reaction was completed, the reaction mixture was quenched by adding 100 mL of ice water. The mixture was extracted with 100 mL of methylene dichloride three times. The organic phases were combined, washed with 100 mL of saturated brine three times, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (EA/PE = 1:10- 1:5) to give 2.0 g of the intermediate 048-2 (34percent) as a yellow solid. LCMS: 229.0.Under nitrogen protection, in a 100 ml (mL) three-neck flask at room temperature, Raw material 121-1 (3.0 g (g), 25.6 mmol (mmol)) was dissolved in 50 mLIn 1, 2-dichloroethane (DCE), the mixture is reduced to 0°C, Methylmagnesium bromide (8.5 mL, 25.6 mmol) was added dropwise to the reaction system at 0 °C, After the addition, the reaction was continued at a constant temperature for 30 minutes (min), and 121-2 (5.4 g, 36.3 mmol) was added at 0°C.It was added to the reaction system, and the reaction was warmed to room temperature overnight.After the reaction is complete, 100 ml of ice water is added to the reaction mixture to quench the reaction.The mixture is extracted 3 times with 100 mL of dichloromethane and the organic phase is combined with 100It was washed 3 times with saturated brine, dried over anhydrous sodium sulfate and concentrated.The crude product was purified by silica gel column chromatography (ethyl acetate (EA)/petroleum ether (PE)=1:10-1:5).2.0 g of product 121-3 (34percent) was obtained as a yellow solid.A mixture of 2, 4-dichloropyrimidine (17.9 g, 1.1 eq) was added to a round bottom flask, 100 ml of ethylene glycol dimethyl ether and anhydrous ferric chloride (21.1 g, 1.2 eq) were added, After the addition of nitrogen, the temperature was raised to 60 ° C, and 1H-indole (12.7 g, 1 eq) was added dropwise. The reaction was continued, After the TLC test reaction was complete, the system was reduced to room temperature, 150 ml of water was added, no solid precipitated, extracted with the same amount of ethyl acetate three times, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give intermediate 3- (2- Chloropyrimidin-4-yl) -1H-indole (8.8 g, yield 25percent).Under nitrogen atmosphere, compound A2 (150 g) was sequentially added to a 3 L three-necked flask.1.28 mol) and dry dichloroethane (1.5 L) were dissolved by magnetic stirring. Ice salt bath cooling to 0 °C, Methylmagnesium bromide (640 mL, 3M) was slowly added dropwise.Dropping process control temperature -5 ~ 5 °C, after the completion of dropping, to room temperature and continue the reaction 0.5h.The reaction solution was cooled to 0° C. and Compound A1 (267 g, 1.79 mol) was added dropwise.Warm to room temperature and react for 16 h. After the reaction is completed, the reaction solution is poured into ice water (2.5 L) to quench it.Dichloromethane (300mL*3) was added for extraction.The organic layers were combined, washed with saturated brine (300 mL*3), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (PE/EA=10/1 to PE/EA=4/1) to give Compound A3 (70.0 g). , 23.8percent).Methylmagnesium bromide (3 M in diethyl ether) (100 mL) was added dropwise over a period of 10 mm to a stirred solution of 1H- indole (35.2 g) in THF (500 mL) at 0 °C under nitrogen. The resulting solution was stirred for 60 mm. 2, 4-Dichloropyrimidine (44.7 g) was added in one portion. The resulting solution was heated at reflux for 5 hours and stirred at ambient temperature for 16 h. The reaction was quenched by the addition of water (400 mL) and EtOAc (500 mL). The organic layer was evaporated to dryness and purified by flash silica chromatography. Pure fractions were evaporated to dryness. 3-(2- chloropyrimidin-4-yl)-1H-indole (compound 3, 19 g) as a yellow solid.A suspension of freshly crushed NaOH (740 mg) in MeOH (20 mL) was added at 0° C. to a suspension of 1-benzenesulfonyl-3-(2-chloropyrimidin-4-yl)-1H-indole (0.91 g, 2 mmol) in MeOH/THF (1:1, 40 mL). The reaction mixture was warmed to RT and stirred for 2 h until homogeneous. The resulting mixture was neutralized with aqueous HCl (1 M), and concentrated under reduced pressure. The residue was partitioned between water and EtOAc, the organic layer separated, washed with water, dried over Na

Molecular Weight:229.66
XLogP3:3
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:229.0406750
Monoisotopic Mass:229.0406750
Topological Polar Surface Area:41.6
Heavy Atom Count:16
Complexity:248
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes