3-(Bromomethyl)-2-cyclopropyl-4-(4-fluorophenyl)quinoline

In a 100 ml three-necked flask, 29.1 g of compound I, 17.2 g of methyl dichlorosilane, 8 g of ferric chloride, 40.2 g of phosphorus tribromide, 60 ml of acetonitrile and 75 to 85 ° C under nitrogen atmosphere were stirred and refluxed to TLC The reaction was complete, the reaction was quenched by adding dilute hydrochloric acid to the reaction system, the layers were separated, the organic layer was separated, washed with sodium bicarbonate and saturated brine, and the washing liquid was separated from the organic layer. To the organic layer was added anhydrous magnesium sulfate, Dried and filtered, and the filtrate was concentrated under reduced pressure to give 30.5 g of the compound. The compound II was confirmed to be Compound II, as compared with the standard compound II melting point data. The melting point of Compound II was 138-140° C and the yield of Compound II was 86percent.Example 17: Preparation of 3-(bromomethyl)-2-cyclopropyl-4-(4-fluorophenyl)quinoline (PTVBR); PTVME PTVBR; PTVME (0.85 g, 3.06 mmol) and NBS (1.16 g, 2.1 equiv.) were dissolved in MeCN (20 mL) and CCI (5 mL). The mixture was irradiated with light of a wavelength λ = 254 nm for 4 days at ambient temperature (about 20 °C). After the reaction was complete solvent was removed under reduced pressure and residual oil was redissolved in CHAdd 200 ml of tetrahydrofuran to a 3 liter three-necked flask.Then add 23 g of active zinc powder, 0.5 g of iodine, Replace with nitrogen three times, and heat to 50 to 60 C with stirring for 30 minutes until the color of iodine disappears; 121 g of 3- (bromomethyl) -2-cyclopropyl-4- (4-fluorophenyl) -3-quin Porphyrin is dissolved in 450 ml of tetrahydrofuran and then added dropwise to the reaction flask.Control the drop acceleration to make the reaction temperature between 50 and 60 C.After the dropwise addition, the reaction was incubated for 2 hours.The temperature of the reaction system is reduced to 10 to 20 C.A solution of 88 g of tert-butyl 2-((4R, 6S) -6-formyl-2, 2-dimethyl-1, 3-dioxan-4-yl) acetate in tetrahydrofuran (250 ml) was added dropwise. The reaction flask is controlled at a temperature of 10 to 20 C. After the addition, stir for 2 hours, and then lower the temperature to 0 to 5 C.65 g of p-toluenesulfonyl chloride tetrahydrofuran (200 ml) solution was added dropwise, and the temperature was maintained at 0 to 5 C. After the addition, stirring was continued for 1 hour, and then 52 g of 1, 8-diazabicycloundec-7 was added dropwise. -Ene, hold for 3 hours after the addition is complete; add 800 grams of ice water to quench the reaction, stir for 30 minutes, concentrate the reaction mixture under reduced pressure, remove most of the tetrahydrofuran, reduce the temperature to 0 to 5 C, filter to obtain a pale yellow solid, wash with two Times, The obtained solid was put into a 1 liter reaction flask, Add 500 ml of methanol and heat to dissolve the solid.Slowly lower the temperature to 0 to 5 C and keep it for 5 hours.145 grams of white solid powder was obtained after suction filtration and drying, Yield: 82.0%, chemical purity: 99.1%, The Z configuration was 0.14%, and the chiral purity was 99.7%.Mixing a mass fraction of 10% by weight aqueous sodium hydroxide solution, 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-bromomethyl, methanol, trithiocyanuric acid, and heating to The reaction was incubated at 40 C for 15 h, and the pH was adjusted to neutral with a 5 wt% aqueous solution of hydrochloric acid. The residue was evaporated to ethyl acetate. The organic phase was extracted with ethyl acetate, dried over anhydrous sodium sulfate. Wherein, the molar ratio of 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-bromomethyl, tridecyl-triazine, sodium hydroxide is 3.05:1:3.3, 2-cyclopropyl The weight-volume (g/ml) ratio of -4-(4-fluorophenyl)quinoline-3-bromomethyl and methanol is 356:3000;Mixing a mass fraction of 10% by weight aqueous sodium hydroxide solution, 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-bromomethyl, methanol, trithiocyanuric acid, and heating to The reaction was incubated at 40 C for 15 h, and the pH was adjusted to neutral with a 5 wt% aqueous solution of hydrochloric acid. The residue was evaporated to ethyl acetate. The organic phase was extracted with ethyl acetate, dried over anhydrous sodium sulfate. Wherein, the molar ratio of 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-bromomethyl, tridecyl-triazine, sodium hydroxide is 3.05:1:3.3, 2-cyclopropyl The weight-volume (g/ml) ratio of -4-(4-fluorophenyl)quinoline-3-bromomethyl and methanol is 356:3000;Operation steps: under the protection of nitrogen, Compound (II) (10.7 g, 30 mmol) was added to a 250 ml reaction flask.50 ml of anhydrous tetrahydrofuran, stirred and cooled to 10-20 C, Zinc bromide (13.5 g, 60 mmol) was added in portions and stirred for 10 minutes.Drip the above lithium naphthalene reagent, After the reaction temperature is stable, Heat to reflux (65-75 C) and stir the reaction for 5-6 h.The resulting reaction solution is an organozinc reagent (III).Anhydrous potassium carbonate (7.76 g, 0.056 mol, 2 eq.) was added to a solution of 1 Kg of alcohol compound of formula (VI) and 8 L of methylene dichloride were taken in reactor at 0C. 0.462 Kg of freshly prepared phosphonium bromide solution in 2 L methylene dichloride was added slowly and stirred at 25C for 2 hours. After the completion of the reaction as monitored by TLC, the reaction mixture was quenched with 5% sodium bicarbonate solution to adjust the pH from 7-8. The organic layer was separated and washed with 5 L water followed by removal of solvent under vacuum at 45C. The residue was treated with 2.5 L heptane at 60C and cooled to 15C. The product was filtered at 15C and dried under vacuum at 55C for 8 hours to , obtain Preparation-1 Preparation of Prepa ration- 1:Preparation of 3-rbromomethvn-2-cvclopropyl-4-(4, -flourophenvnquinoline (V):1 Kg of alcohol compound of Formula (VI) and 8 L of methylene dichloride were taken in reactor at 0C. 0.462 Kg of freshly prepared phosphonium bromide solution in 2 L methylene dichloride was added slowly and stirred at 25C for 2 hours. After the completion of the reaction as monitored by TLC, the reaction mixture was quenched with 5% sodium bicarbonate solution to adjust the pH from 7-8. The organic layer was separated and washed with 5 L water followed by removal of solvent under vacuum at 45C. The residue was treated with 2.5 L heptane at 60C and cooled to 15C. The product was filtered at 15C and dried under vacuum at 55C for 8 hours to obtain (2-Cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)methanol (42 gm) as obtained in step-I was dissolved in methylene dichloride (630 ml) and stirred for 10 minutes. The solution was then cooled to 0 to 5C and then added phosphorus tribromide (11.4 ml) and stirred for 10 minutes at 0 to 5C. The temperature of the reaction mass was raised to room temperature and stirred for 3 hours at room temperature. The reaction mass was quenched with saturated aqueous potassium bromide solution (700 ml) and then the layers were separated. The aqueous layer was extracted with methylene chloride and the combined organic layers were dried with sodium sulfate and then concentrated to obtain 40 gm of 3 -(bromomethyl)-2-cyclopropyl-4-(4-fluorophenyl)quinoline.

Molecular Weight:356.2
XLogP3:5.1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:3
Exact Mass:355.03719
Monoisotopic Mass:355.03719
Topological Polar Surface Area:12.9
Heavy Atom Count:22
Complexity:378
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes