Pyridine, 2-chloro-4-(chloromethyl)- (9CI)

Stage b) SOCI1.00 g (6.97 mmol) of (2-chloropyridin-4-yl)methanol was dissolved in 40 ml of methylene chloride, 10 ml of thionyl chloride were slowly added at RT and the mixture was stirred at RT overnight. The mixture was then concentrated on a rotary evaporator and the residue was stirred in a mixture of methylene chloride and aqueous sodium bicarbonate solution. The phases were separated and the methylene chloride phase was dried over anhydrous magnesium sulphate, filtered and concentrated on a rotary evaporator. 1.10 g (97percent of th.) of the title compound were obtained.Example 29A; 2-Chloro-4-(chloromethyl)pyridine 1.00 g (6.97 mmol) of (2-chloropyridin-4-yl)methanol was dissolved in 40 ml of dichloromethane, 10 ml of thionyl chloride were slowly added at RT and the mixture was stirred at RT overnight. The mixture was then concentrated on a rotary evaporator and the residue was stirred in a mixture of dichloromethane and aqueous sodium bicarbonate solution. The phases were separated and the dichloromethane phase was dried over anhydrous magnesium sulphate, filtered and concentrated on a rotary evaporator. 1.10 g (97percent of theory) of the title compound were obtained.Example 43A A sample of (2-chloropyridin-4-yl)methanol (110.0 mg, 0.77 mmol) was dissolved in anhydrous THF (1.5 mL), treated with /Y, iV-diisopropylethylamine (0.29 mL, 1.69 mmol) and cooled to -78 Step 2: Preparation of 2-chloro-4-(chloromethyl)pyridine; A sample of (2-chloropyridin-4-yl)methanol (110.0 nig, 0.77 mmol) was dissolved in anhydrous THF (1.5 mL), treated with ^V.A'-diisopropylethylamine (0.29 mL, 1.69 mmol) and cooled to -78 °C. Methanesulfonyl chloride was added (0.07 mL, 0.84 mmol), and the reaction mixture was allowed to slowly warm to room temperature overnight. The reaction mixture was then diluted with dichloromethane and washed with water. The organic layerwas dried over Na2SO4 and concentrated in vacuo yielding the title compound (110.0 mg, 88.6percent).Preparation of 2-chloro-4-(chloromethyl)pyridineA sample of (2-chloropyridin-4-yl)methanol (110.0 mg, 0.77 mmol) was dissolved in anhydrous THF (1.5 mL), treated with N, iV-diisopropylethylamine (0.29 niL, 1.69 mmol) and cooled to -78 C. Methanesulfonyl chloride was added (0.07 mL, 0.84 mmol), and the reaction mixture was allowed to slowly warm to room temperature overnight. The reaction mixture was then diluted with dichloromethane and washed with water. The organic layer was dried over Na2SO4 and concentrated in vacuo yielding the title compound (110.0 mg, 88.6percent).1H NMR (300 MHz, CD3CN) ' 8.40 (d, 1 H), 7.49 (s, 1 H), 7.39 (d, 1 H) and 4.63 ppm (s, 2 H); ES-MS m/z 183.2 [M+Na]+, HPLC RT (min) 2.30.lOg of 1Og of 2-chloro-4-methylpyridine are dissolved in 50 ml of CH3CN and heated to- 85°C. Then a mixture of 32g N-Chlorosuccinimid and l, 6g AIBN is added over a period of 5 minutes. The. resulting, mixture is refluxed for two hours, then the solvent is removed in vacuo, the residue treated with 100ml of CH2Cl2 and washed with water 2 times. The organic phases are collected, dried over Na2S04 and the residue obtained after evaporation of the solvent is distilled (80°C, 100 mTorr). Yield 79percent4, 4-dimethyl-2, 2-bipyridine (921 mg, 5.00mmol) and diisopropylamine(1.48 mL, 10.5mmol) were dissolved in THF (50mL), and the solution was cooled to 78 C. A hexane solutionof n-butyllithium (1.5 M, 6.91 mL, 10.5mmol) was added tothe solution dropwise. After stirring for 2 h, 1 (1.78 g, 11.0mmol) was added. The solution was additionally stirred at78 C for 2 h, and then gradually warmed up to r.t. withcontinuous stirring overnight. H2O was added to the solutionand the product was extracted twice with ether. The combinedorganic layers were washed with brine and dried over MgSO4.The solvent was removed under reduced pressure to obtain thecrude material, which was purified by silica-gel chromatography(eluent: CH2Cl2/MeOH 95:5 v/v) to obtain a whitesolid. Yield: 1.54 g (70%). 1HNMR (400 MHz, CDCl3): /ppm, 8.58 (d, J = 5.2 Hz, 2H), 8.29 (s, 2H), 8.29 (d, J = 4.8Hz, 2H), 7.18 (s, 2H), 7.10 (dd, J = 4.8 Hz, 1.6 Hz, 2H), 7.04(dd, J = 5.2 Hz, 1.2 Hz, 2H), 3.00 (m, 8H).2-chloro-4-methylpyridine (5.51 mL, 50.0mmol) and diisopropylamine(7.40 mL, 52.5mmol) were dissolved in THF (170 mL), and thesolution was cooled to 0 C under Ar atmosphere. A 1.5Mhexane solution of n-butyl lithium (34.5 mL, 52.5mmol) wasthen added dropwise to the solution. After stirring at 0 C for30min, chlorotrimethylsilane (6.97 mL, 55.0mmol) was added, and the resulting solution was stirred for 1min. H2O (100 mL)was added to the reaction mixture, and the product was extractedtwice with hexane. The hexane solution was dried overMgSO4, and the solvent was evaporated under reduced pressureafter filtration. The obtained oil was dissolved in N, N-dimethylformamide(140 mL), followed by the addition of hexachloroethane(23.7 g, 100mmol) and CsF (15.2 g, 100mmol).After stirring at r.t. for 20 h, H2O (200 mL) was added, and theproduct was extracted three times by hexane. The combinedhexane layers were washed with brine and dried over MgSO4.The excess amount of hexachloroethane was removed by silicagelchromatography using hexane as the eluent. After theelution of hexachloroethane, CH2Cl2 was applied. The startingmaterial contained in the crude product was removed byKugelrohr (0.1 Torr, 65 C), and the target compound wasisolated as colorless oil. Yield: 5.91 g (73%). 1HNMR (400MHz, CDCl3): /ppm, 8.39 (d, J = 5.2 Hz, 1H), 7.38 (d, J =0.8 Hz, 1H), 7.25 (dd, J = 5.2 Hz, 0.8 Hz, 1H), 4.53 (s, 2H).General procedure: 4-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)phenol (Intermediate C, 80mg, 0.30mmol) was dissolved in DMF (lmL) and potassium 2-methylpropane-2-olate (1M in THF, 0.33mL, 0.33mmol) was added dropwise. The mixture was stirred for 5min and a solution of 3-(bromomethyl)-5-methylisoxazole (63.2mg, 0.36mmol) in DMF (0.5mL) was added. The resulting mixture was stirred for 30min and directly purified by column chromatography (Si02, hexane/ethyl acetate). Fraction containing the product were concentrated under reduced pressure and further purified by reversed phase flash chromatography (C18, acetonitrile/water) to yield 3-(3-(4-((lH-pyrazol-l-yl)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine (7lmg, 0.20mmol, 66%) as a white solid. 400 MHz l NMR (CDCl3) d 8.13 (s, 1H), 7.70 (dd , J= 7.7, 1.8 Hz, 1H), 7.24 - 7.16 (m, 2H), 6.98 - 6.89 (m, 2H), 6.70 (dd, J= 7.7, 4.8 Hz, 1H), 6.23 (s, 1H), 6.10 (d, J= 1.1 Hz, 1H), 5.44 (s, 2H), 5.09 (s, 2H), 3.99 (s, 2H), 2.42 (d, .7= 0.9 Hz, 3H). MS: 363.3 [M+H]+.To a stirred solution of methyl 6-bromo-5-methylquinoline-8-carboxylate (1-2), (0.25 g, 0.89 mmol) in 1, 4-dioxane (5.9 mL) cooled at RT, potassium acetate (0.27 g, 3.1 mmol) and bis(pinacolato)diboron (0.34 g, 1.33 mmol) were added. Reaction mixture was degassed with nitrogen for 15 minutes and [1 J '-bis(diphenylphosphino)ferrocene] palladium(Ii) dichloride (72.8 mg, 0.08 mmol) was added. The reaction mixture was gradually heated to 100 C and was stirred at this temperature for 10 h. After cooling it to RT, the volatiles were removed under reduced pressure. The crude product obtained was dissolved in 4: 1 mixture of 1, 4-dioxane and water (5.9 mL). Solid K2C03 (0.16 g, 1.14 mmol) and 2-chloro-4- chloromethyl-pyridine (0.19 g, 1.15 mmol) were added. The reaction mixture was degassed with nitrogen for 15 minutes and [l, r-bis(diphenylphosphino)fenOcene]palladiuxn(ll) dichloride (62.3 mg, 0.07 mmol) was added. The reaction mixture was gradually heated to 100 C and was stirred at this temperature for 8 h. After cooling it to RT, the volatiles were removed under reduced pressure and the crude boronate ester was dissolved in water and EtOAc. The reaction mass was filtered through celite bed and the two layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layer was washed once with brine solution, dried over anhydrous Na2S04 and the solvent was removed under reduced pressure to obtain a crude product which was purified by silica gel column chromatography to obtain the title compound. Yield: 111 mg (40 %); 1H-NMR (400 MHz, CDC13): delta 9..07 (d, 7=4.0 Hz, 1H), 8.44 (d, 7=8.6 Hz, 1H), 8.28 (d, 7 =5.0 Hz, 1H), 7.86 (s, 1H), 7.53 (dd, 7=4.0 , 8.6 Hz, 1H), 7.06 (s, 1H), 6.97 (d, /= .9 Hz, 1H), 4.23 (s, 2H), 4.04 (s, 3H), 2.58 (s, 3H); Mass (m z): 327.2, 328.9 (M+H)+To a solution of A 150 mL single-necked reaction flask was charged with 1.0 g (3.57 mmol) of 2-mercapto-5- (1-phenazinyl) -1, 3, 4-oxadiazole, 0.6 g (4.28 mmol) of To a solution of CIS-1-acetyl-8-(dimethylamino)-8-phenyl-1, 3-diazaspiro[4.5]decan-2-one (INT-1064) (1 g, 3.17 mmol) in DMF (37 mL) was added sodium hydride (60wt% in mineral oil, 1.25 equiv., 3.96 mmol, 159 mg) portionwise at 0C. The reaction mixture was stirred for 15 min at 0C and