3-(2-chloropyrimidin-4-yl)-1-methylindole

1) 100 g of 2, 4-dichloropyrimidine, (^ The graphene-supported' Lean catalyst prepared in was placed in ethanol and methyl ethyl ketoneOf the mixed solution (500 ml, the volume ratio of ethanol to methyl ethyl ketone was 4: 1)In the 30-40 ° C stirring 20min;2) the temperature of the reaction system to 15 ° C, and then by adding 1-methyl-1H-indole, control the process of adding the reaction system temperature does not exceed 15 ° C;3) After 1-methyl-1H-indole was added dropwise, the temperature was raised to 30 ° C at a heating rate of 5 ° C / h and the incubation was carried out at 30 ° C for 3 h; then the temperature was raised to 5 ° C / h 40 ° C, 40 ° C insulation reaction 2h; the final 5 ° C / h heating rate to 50 ° C, 50 ° C insulation reaction lh;4) the end of the incubation reaction, cooling to room temperature, 0.5 micron microfiltration filter to remove the graphene-loaded FeCl3 catalyst, the filtrate at 40 ° C under reduced pressure to dry, and then add 600ml n-heptane to the system in 35- 40 ° C under the beating 6-8h, after the end of the filter, Dried to give 3- (2-chloropyrimidin-4-yl) -1-methylindole (yield 92percent, HPLC area normalized purity 99.3percent).Intermediate 7: 3-(2-chloropyrimidin-4-yl)-1-methylindole To a stirred solution 2, 4-dichloropyrimidine (70.5 g, 463.76 mmol) in dimethoxyethane (900 mL) was added FeClN-methylindole (300 mg, 2.29 mmol), 2, 4-dichloropyrimidine (340 mg, 2.30 mmol) and anhydrous aluminum trichloride (460 mg, 3.43 mmol) were dissolved in ethylene glycol dimethyl ether (12 mL). The reaction was heated to 60 °C in a nitrogen atmosphere and stirred for 3 hours. After the reaction was completed, the reaction solution was poured into an ice-water mixture (about 50 mL) and extracted with methyl tert-butyl ether (20 mL*3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography to obtain the product 3-(2-chloropyrimidin-4-yl)-1-methyl-1H-indole (400 mg, 72percent).Intermediate 2a: 3-(2-chloropyrimidin-4-yl)-l-methyl-1H-indole (0131) (0132) To a 500mL single-necked flask were added 2, 4-dichloropyrimidine (14.9 g, 100 mmol), 1-methyl-1H-indole (13 g, 100 mmol), 200 ml 1, 2-dichloroethane and aluminium chloride (13.9 g, 120 mmol). The mixture was stirred at 80°C for 1.5 hours. The reaction mixture was cooled to room temperature in an ice bath. 120 ml methanol and 400 ml water were added to quench the reaction. A solid precipitated and was filtered. The filter cake was washed with methanol, and dried in vacuum to produce 17.2 g of a product with a yield of 71percent. MS m/z: 244 [M+1], 246. (0133) This compound was prepared by the procedure of Finlay et al. 11 A suspension of 2, 4-dichloropyrimidine (5.0 g, 33.6 mmol) and aluminum chloride (1.83 mL, 33.6 mmol) in DME (1, 2-dimethoxyethane)(50 mL) was stirred at ambient temperature for 15 min. To this was added 1-methylindole (4.29 mL, 33.6 mmol), and the mixture was heated at 80 °C for 2–4 h. The cooled reaction mixture was added dropwise to vigorously stirring water (300 mL) over 20 min. Upon complete addition, the mixture was stirred for 30 min, filteredand the solid washed with water (250 mL). The crude product was purified by flash silica chromatography, eluting with DCM. Pure fractions were evaporated to dryness to afford 3-(2-chloropyrimidin-4-yl)-1-methylindole (5.08 g, 62percent) as a white solid. m.p. 201°C dec. (acetonitrile/water);1H NMR (CDCl3) δ 8.45 (m, 2H), 8.35 (m, 1H), 7.37–7.95 (m, 4H), 3.89 (s, 3H); MS calcd for C13H10ClN3 [M]+ 243.1; found: 244.1To a stirred suspension of 2, 4-dichloropyrimidine (2.637 g, 20.13 mmol) in dimethoxyethane (30 mL) was added aluminum trichloride (2.67 g, 20.134 mmol) at 10 °C. The mixture was stirred at 10 °C for 15 mins. 1 -methyl- lH-indole (3.0 g, 20.13 mmol) was added, and the mixture was heated under reflux for 2 h. The mixture was cooled to RT, poured into water (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over sodium sulphate and concentrated to afford 3-(2-chloropyrimidin-4-yl)-l-methyl-lH-indole (3.0 g, 12.34 mmol, 61percent). LC/MS (ESI) m/z 244.3 [M+H]2, 4-dichloropyrimidine (3 g, 20.1 mmol) was dissolved in DME (50 ml) and heated to 60 °C. FeClUnder nitrogen, 100mL three-mouthed flask successively add 002-2 (1.3g, 8.73mmol), 13mL DME, FeCl3 (1.414g, 8.72mmol) and 001-5 (974mg, 7.43mmol). In an oil bath at 64 deg.C react overnight. After completion of the reaction, the reaction mixture was down to room temperature, filtered, the filter cake washed 3 times with 20mL of methanol, the organic phases were combined and concentrated to dryness, and driedto give 1.0g 005-1 (47percent), as a yellow solid.Example 6 1. Synthesis of intermediate 006-2 The intermediate 001-5 (1.3 g, 8.73 mmol), 13 mL of DME, FeClIn 10 minutes at 0 ° CN2 atmosphere, CH3MgBr (3M in ether, 22.68 mL, 68.03 mmol)Was added dropwise to a solution of 1-methyl-indole (7.97 g, 68.03 mmol)In 1, 2-dichloroethane (250 mL)In the stirred solution.The resulting solution was stirred for 15 minutes, And then 2, 4-dichloropyrimidine (15.00 g, 100.69 mmol) was added in one portion.The resulting solution was allowed to warm to room temperature and stirred for an additional 16 hours.The reaction was quenched by the addition of CH3OH (25 mL)The mixture was then concentrated in vacuo to allow it to adsorb onto silica gel.Using FCC for purification, Eluting with 0-20percent CH3OH in CH2Cl2, The title compound was obtained as a yellow solid (7.17 g, 46percent).NaH (1.707 g, 42.68 mmol, 40percent dispersion in mineral oil) was added in small portions to a cooled (0°C) mixture of 3-(2-chloropyrimidin-4-yl)-1H-indole (Intermediate 131, 8.168 g, 35.57 mmol) in THF (250 mL). The resulting mixture was stirred at 0°C for 0.5h and then CHmixture of 1.5L methanol, 3-(2-chloropyrimidin-4-yl)-1H-indole (229 g), formaldehyde (90 g, 10 g of palladium on carbon (20 g) was added to the autoclave and stirred at room temperature for 3 hours in a hydrogen atmosphere (0.2 MPa). After completion of the reaction, the organic phase was evaporated to dryness and recrystallized from acetonitrile to to obtain the product 3 - (2 - chloro pyrimidine -4 - yl) -1 - methyl indole, 210g, yield: 86.4percent.

Molecular Weight:243.69
XLogP3:2.9
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:243.0563250
Monoisotopic Mass:243.0563250
Topological Polar Surface Area:30.7
Heavy Atom Count:17
Complexity:273
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes