2-(5-BroMo-2-Methylbenzyl)-5-(4-fluorophenyl)thiophene

15 g (5-bromo-2-methylphenyl)[5-(p-fluorophe- nyl)thiophene-2-yl]methanone was weighed and dissolved in 150 ml tetrahydroffiran, and 30 ml of 1 M boranetetrahydroffiran complex was added. The system was reacted at —20° C. to —10° C. for 48 hours. After the complete reaction of raw materials, 30 ml water was added. The mixture was extracted with 100 ml dichloromethane, and then the extract was concentrated to give 14.25 g of 2-(2-methyl-5-bromobenzyl)-5-(4-fluorophenyl)thiophene, with a purity of 98.9percent and in a yield of 97.7percent56.5 g of (5-bromo-2-methylphenyl)[2-(4-fluorophenyl)thiophene]methanone to be prepared according to Dissolve (0.44 mol) in 600 ml of dichloromethane-acetonitrile (1:1, v/v), cool to 0°C in an ice water bath, and add dropwise triethylsilane.100 ml (0.63 mol), and then slowly added 47percent boron trifluoride ether 42 ml (0.33 mol), slowly added to the 20-The reaction was stirred at 35° C. for 4 hours. After the TLC reaction was completed, it was quenched with a saturated light carbonic acid solution and extracted with dichloromethane.The organic phase was washed with water and saturated brine, and the solvent was evaporated under reduced pressure. The residue was re-constituted with dichloromethane-methanol (1:1, v/v). Crystalline 2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl)methyl]thiophene, 13.3 g, yield 84percentSynthesis of compound 44Ci2-(5-Bromo-2-methyl-benzoyl)-5-(4-fluoro-phenyl)-phenyl)-thiophene (8, 3.75 g) was dissolved in dichloromethane (40 ml) and acetonitrile (40 ml), to which triethylsilane (4.63 ml) was added and cooled to 0 °C. Boron trifluoride etherate (3.45 ml) was added to the suspension and the reaction mixture was left to warm up to room temperature then continued to stir at that temperature for 26 h. The reaction mixture was cooled on ice and 50 ml of NaHCOTake 2-methyl-5-bromobenzyl chloride 110kg, Dissolved in 250kg of ethyl acetate, 80kg of 2-p-fluorophenylthiophene was added, Zinc chloride 70kg, Heated to reflux reaction 6h, After the reaction was completed, the mixture was cooled to room temperature, 400 kg of water was added, extracted, and 200 kg of water was washed with anhydrous sulfurSodium soda, filtration, the filtrate recovery 100kg, crystallization was light yellow crystals 141kg, a yield of 78percent.Under nitrogen protection, 2-(2-methyl-5-bromobenzyl)-5-(4-fluorophenyl)thiophene (20 g) and tetrahydrofuran (140 g) were added to the reaction flask, and the temperature was lowered to -80 to -70 °C.Slowly add n-butyllithium (2.5M, 17.1g), After stirring for 1 h, the trimethyl borate (15.1 g) was slowly added dropwise, and the mixture was stirred for 1 h.Then, the temperature was raised to room temperature, and the reaction was stirred overnight. After the reaction was completed, The aqueous phase was extracted with dichloromethane (100 mL).Compound 8 was obtained.To the compound 8, dichloromethane (100 ml) was added.Slowly add 30percent hydrogen peroxide solution to the reaction system at room temperature.The reaction was complete by TLC. After the reaction is complete, Add H2O (50ml) and stir for 30min.The liquid phase was separated and the aqueous phase was extracted with dichloromethane (50 mL).The organic phases were combined and concentrated under reduced pressure.Then, silica gel column chromatography (silica gel 100 to 20 mesh, eluent: ethyl acetate: n-hexane = 1:2) was carried out to obtain a cardinide impurity of the formula I.White solid 10.7g, The yield was 64.8percent, and the HPLC purity was 94.5percent.Take 2-chloromethyl-5-(4-fluorophenyl)thiophene 113g, 4-bromotoluene 90g, dissolve in 400g of ethyl acetate, add ice-cold aluminum chloride 70g in batches under ice bath, react at 80 °C 8h, After completion of the reaction, the mixture was cooled to room temperature, and 400 ml of ice-dilute hydrochloric acid was added to the reaction mixture.The liquid layer was separated, and the organic layer was washed with water, dried over anhydrous sodium sulfate, filtered, Recrystallization from petroleum ether: ethyl acetate = 1:1 gave 149 g of white solid, yield 87percent34.2 g of 2-(2-methyl-5-bromobenzyl)-5-(4-fluorophenyl)thiophene, anhydrous tetrahydrofuran/toluene 100 g (1:4) mixed solvent was added to 500 ml of nitrogen-dried reaction flask, liquid nitrogen was cooled to -78 ° C, and 17 ml of a 1.6 mol·L-1 n-butyllithium hexane solution was slowly added dropwise, and the mixture was stirred at this temperature for 1 h. 150 g of a toluene solution of 2, 3, 4, 6-tetra-O-trimethylsilyl-D-gluconolactone (50 g) cooled to -78 ° C was slowly added dropwise to the above reaction solutionin -78 ° C and reaction for 3h, After the basic reaction of TLC was detected, 100 g of methanesulfonic acid in methanol (methanesulfonic acid 45 g + methanol 55 g) was added at this temperature; the reaction was stirred at 0 ° C for 4 h, then the temperature was raised to 40 ° C and stirred for 6 h; 5 mol·L-1 sodium hydroxide aqueous solution was added to the reaction solution, adjusted to pH 7-8; stirred for 30 min, Extracted with ethyl acetate (200 ml × 2), The organic phase is washed with a saturated aqueous solution of sodium chloride until neutral, then dried over anhydrous sodium sulfate.Filtration, the filtrate was concentrated to dryness to give a pale yellow viscous oil 38 g, yield 83percentTo a 500 mL three-necked flask under nitrogen, 2-(2-methyl-5-bromobenzyl)-5-(4-fluorophenyl)thiophene (18.0 g, 0.05 mol) was added in sequence, 140 g of tetrahydrofuran, and stirred 10 Minutes later, Cool to -80 ° C, add n-butyl lithium (22 mL, 0.055 mol) dropwise, stir for 30 minutes.2, 3, 4, 6-tetra-O-trimethylsilyl-D-gluconolactone (28.0 g, 0.06mol), After stirring for 60 minutes, a solution of trifluoroacetic acid (17.1 g, 0.15 mol) and 200 g of water was added dropwise, and after completion of the dropwise addition, the temperature was raised to 20 to 30 ° C and stirred for 12 hours. Saturated sodium bicarbonate solution was added dropwise to neutral, extracted with ethyl acetate (200 mL) and evaporated. The obtained solid was placed in a 500 mL three-necked flask, 200 mL of acetonitrile was added, stirred for 10 minutes, sodium borohydride (2.8 g, 0.075 mol) was added, and the mixture was heated to 50-60 ° C for 2 hours, cooled to 20 ° C, and 200 mL of water was added dropwise. Evaporate acetonitrile, filter, use trueThe filter cake was dried in an empty drying oven to obtain 18.7 g of a white solid, HPLC purity: 98percent, yield 81percentS2, to a 100 ml dry three-necked flask, 30 ml of toluene was added.13g, the temperature is lowered to 010°C under the protection of nitrogen gas.30 ml of a solution of sec-butylmagnesium chloride in tetrahydrofuran was added with stirring.Incubate at -10 to 0 ° C for 1 to 2 hours.The prepared Grignard reagent was obtained.S3. In a separate 250 ml three-necked flask, 20 g of Compound 1 and 20 ml of tetrahydrofuran were added, and the temperature was lowered to -35 ° C under a nitrogen atmosphere, and the prepared Grignard reagent was added.After the incubation reaction for 1 hour, slowly add 10percent aqueous hydrochloric acid to adjust the pH to 6-7, then warm to 30-30 ° C for 30 minutes, and let stand for stratification.The organic phase is dried over anhydrous sodium sulfate and filtered.The filtrate was concentrated under reduced pressure until no liquid flowed out.The oil intermediate 2 was obtained and used directly in the next step.(1) replacing the reaction flask three times under inert gas N2, Add 300g of toluene, cool down to -70 ° C, 97 g of n-butyllithium n-hexane solution (1.6 M, 1.08 eq) was added dropwise over 1 hour;Continue to add 2-(2-methyl-5-bromobenzyl)-5-(4-fluorophenyl)thiophene (68g) in a mixture of tetrahydrofuran (137g) and toluene (137g) within 1 hour The addition is completed;After reacting for 30 minutes, a mixed solution of 2, 3, 4, 6-tetra-O-(trimethylsilyl)-D-glucono-delta-lactone (98 g) and toluene (279 g) was added dropwise.Tle addition was completed within 2 hours, and the reaction was kept for 3 hours after the completion of the dropwise addition;A mixed solution of methanesulfonic acid (48 g) and methanol (280 g) was added dropwise.After the completion of the dropwise addition, the temperature was raised to 10 ° C and the reaction was completed for 5 hours;Add saturated sodium bicarbonate solution to adjust pH 7-8, and separate the water layer.Extracting twice with ethyl acetate, washing with saturated brine and organic phase;The organic oil is removed by distillation under reduced pressure to a yellow oil, ie, an intermediate of formula I:

Molecular Weight:361.3
XLogP3:6.4
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:3
Exact Mass:359.99836
Monoisotopic Mass:359.99836
Topological Polar Surface Area:28.2
Heavy Atom Count:21
Complexity:329
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes