1-Bromo-4-cyclopropylbenzene

(Reference example 9) 4-(4-Cyclopropylphenyl)butyric acid Bromine (12.5 mL, 244 mmol) was dropwise added to a solution of cyclopropylbenzene (25.0 g, 212 mmol) in chloroform (430 mL) with stirring at -78°C and the mixture was stirred for 45 minutes. A 10percent aqueous sodium sulfite solution and water were added to the reaction mixture at -78°C and chloroform was added thereto to separate it. The thus obtained organic phase was separated, washed with a saturated aqueous NaCl solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (hexane) to obtain 1-bromo-4-cyclopropylbenzene (35.5 g, yield: 85percent). Tetrakis-(triphenylphosphine)palladium (5.33 g, 4.61 mmol) and 3-butyn-1-ol (31.5 g, 450 mmol) were added to a solution of the obtained 1-bromo-4-cyclopropylbenzene (35.5 g, 180 mol) in piperidine (345 mL) and the mixture was stirred at 80°C under nitrogen atmosphere for 3 hours. The reaction mixture was evaporated under reduced pressure and ethyl acetate and a 1N aqueous hydrochloric acid solution were added to the residue to separate it. The thus obtained organic phase was separated, washed with a 1N aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous NaCl solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (hexane:ethyl acetate, 4:1-3:1) to obtain 4-(4-cyclopropylphenyl)but-3-yn-1-ol (30.2 g, yield: 90percent). A 6N aqueous sulfuric acid solution (250 mL) was added to a solution of the obtained 4-(4-cyclopropylphenyl)but-3-yn-1-ol (27.8 g, 149 mmol) in methanol (300 mL) and the mixture was heated under reflux for 6 hours. After it was left to stand, methanol of the reaction mixture was evaporated under reduced pressure and ethyl acetate was added thereto to separate it. The thus obtained organic phase was separated, washed with a saturated aqueous NaCl solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The thus obtained residue was purified by silica gel chromatography (hexane:ethyl acetate, 4:1-2:1) to obtain 1-(4-cyclopropylphenyl)-4-hydroxybutan-1-one (18.7 g, yield: 61percent). Hydrazine monohydrate (10.4 mL) and potassium hydroxide (14.4 g) were added to a solution of the obtained 1-(4-cyclopropylphenyl)-4-hydroxybutan-1-one (17.5 g, 85.8 mmol) in ethylene glycol (90 mL) and the mixture was heated under reflux at 180°C for 6 hours. Water was added to the reaction mixture to dilute it and ethyl acetate was added thereto to separate it. The thus obtained organic phase was separated, washed with a saturated aqueous NaCl solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel chromatography (hexane:ethyl acetate, 5:1-3:1) to obtain 4-(4-cyclopropylphenyl)butan-1-ol (15.8 g, yield: 97percent). TEMPO (2, 2, 6, 6-tetramethylpiperidine 1-oxyl free radical) (905 mg, 5.79 mmol) and a sodium hydrogenphosphate buffer solution (300 mL, 0.67M, pH 6.7) were added to a solution of the obtained 4-(4-cyclopropylphenyl)butan-1-ol (15.7 g, 83.0 mmol) in acetonitrile (300 mL) and the mixture was stirred at 35°C for 10 minutes. After an aqueous sodium chlorite solution (16.4 g, water 80 mL) was added to the reaction mixture, a 2percent aqueous hypochlorous acid solution (42.3 mL) was further added dropwise thereto and the mixture was stirred at 35°C for 2 hours. A 1N aqueous sodium hydroxide solution (250 mL) was added to the reaction mixture and the mixture was poured into ice-water (300 mL) added with sodium sulfite (30 g), followed by stirring of the mixture for 5 minutes. Ether was added thereto to separate it. An aqueous phase was taken, concentrated hydrochloric acid was added thereto to acidify it and ether was added thereto to separate it. The thus obtained organic phase was separated and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain 4-(4-cyclopropylphenyl)butyric acid (15.8 g, yield: 88percent) as a white solid.;In a flame dried flask under N2 blanket, compound D (1.5 g, 4.9 MMOL) was dissolved in dry THF (30 mL) and COOLED TO-78°C. N-BUTYL lithium (1.9 M in hexanes, 5.4 mL, 9.7 MMOL) was added followed after 45 min by compound E (1.27 g, 6.3 MMOL). The cold bath was removed after 2 h and the reaction mixture was allowed to warm to rt over 45 minutes then quenched with aq NH4CI. EtOAc (30 mL) was added to dilute the reaction mixture. The reaction mixture was washed with brine (100 mL x 2). The organic layer was dried over NA2SO4 and then concentrated to dryness. The crude material was purified via sgc (25percent EtOAc/Hexanes) to give 545 mg (27percent) of compound F. Compound i (120 g, 1.0 mml) was dissolved in CH2CI2 (1.2 L) with HG20 (6.0 g, 14.4 MMOL) and K2CO3 (24.0 g, 0.17 mol) and cooled to-30 °C. Br2 (85.2 g, 1.1 mol) was added over 10 min period of time. The reaction mixture was stirred at-30 °C for 4.5 h. The reaction mixture was washed with H20 (1 L) and brine (1 L). The organic layer was dried over NA2SO4 and concentrated to dryness. The crude material was distilled under reduced pressure to give 103.8 g (52percent) of compound ii. In a flame dried flask under N2 blanket, compound ii (6.0 g, 30.5 MMOL) was dissolved in dry THF (30 mL) and cooled TO-78 °C. A solution of n-butyl lithium (1.75 M in hexanes, 17.4 mL, 30.5 MMOL) was added and the reaction mixture was stirred for 20 min. S02 was bubbled in the reaction for 20 min. It was slowly warmed up to rt. CH2CI2 (50 mL) was added and the mixture was reacted with NCS (5.0 g, 37.4 MMOL) at rt overnight. The reaction mixture was washed with brine (100 mL x 2). The organic layer was dried over NA2SO4 and then concentrated to dryness. The crude material was purified via sgc (5percent EtOAC/Hexanes) to give 3.65 g (55percent) of compound II. To a round-bottom flask was added compound iii (3.0 g, 13.8 MMOL) and KF (2.4 g, 41.4 MMOL) followed by addition of acetone (50 mL) and water (30 mL). The reaction mixture was stirred at room temperature overnight. The solvent was then removed. Methylene chloride (40 mL) was added and it was washed with brine (40 mL). The organic layer was dried over NA2SO4 and then concentrated to dryness to give 2.77 g (100percent) of compound E.EXAMPLE XIX Compound 44. Cyclopropyl benzene (48.5 g, 410 mmol), glacial acetic acid (510 mL), and sodium acetate (38.9 g, 474 mmol) were added to a roundbottomed flask. The flask was cooled in an ice-water bath. A solution of bromine (66.3 g, 414 mmol) dissolved in 105 mL of acetic acid was added dropwise over 90 min. The reaction mixture was stirred at temperatures between 0 C. and 10 C. for 5 h. The reaction was then allowed to warm to rt overnight. Hexanes (1300 mL) and water (250 mL) were added. Aqueous NaHSO3 (1M) was added until the reaction mixture changed from yellow to clear. The layers were separated. The organic layer was washed with water, 1M aq Na2CO3, and brine, then dried with Na2SO4. The solvent was evaporated and the crude product was purified to give 17 g of p-cyclopropylbromobenzene (21percent) (Compound 44).EXAMPLE XIX General procedure: A total of 1.0 g of 1-octanol (7.69 mmol) was taken in a 50-mL round-bottomed flask, to it NaBr 0.523 g (0.66 eq.), NaBrO 3 0.383 g (0.33 eq.), and 10 mL of H 2 O [comprises the bromide and bromate in 2:1 molar ratio] were added[6f]. The reaction mixture was stirred vigorously to dissolve the contents completely. To the above reaction mixture, the aqueous H 2 SO 4 solution (0.5 eq.) was added slowly under stirring over a period of 2.5 h at room temperature (prepared by adding 0.21 mL of 98percent H 2 SO 4 to 1 mL of water). The reaction mixture was allowed to stir for up to 24 h. After the completion of reaction, the product was extracted with CH 2 Cl 2 (3 15 mL), the organic layer was dried with Na 2 SO 4 and removal of the solvent obtained octyloctanoate in 98percent yield (0.953 g) as colorless liquid. The product was confirmed by GC–MS as well as by NMR.A stirred mixture of [5-(3-chloro-6-fluoro-2-vinyl-phenyl)-1 , 3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate (300 mg, 1.0 eq), chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)] palladium(ll) (21 mg, 0.05 eq), Pd2(DBA)3 (1.1g) was added to the dried flask, Sodium tert-butoxide (7.3 g) and t-BuXPhos (2.7 g), Then replace the air with nitrogen, Toluene (75 mL) was then added to the reaction flask.P-cyclopropyl bromide 60170 (5.0 g) and60114 (6.1g), After the reaction at 80 C is complete, The reaction solution is filtered, The filtrate was concentrated and purified by column chromatography to obtain 8.8 g of product.Yield: 97%, Purity: 98%, Ee: 98%.