2-BROMO-4-HYDROXYMETHYLTHIAZOLE

Preparation of (2-bromothiazol-4-yl)methanol (5)2-Bromothiazol-4-Carboxylic acid ethyl ester (11.8g, 50.0mmol)Was dissolved in absolute ethanol (100 mL)Sodium borohydride (3.8 g, 100 mmol) was added, stirred at room temperature for 4 hours, and then heated to 70 ° C for 4 hours.The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography (ethyl acetate / petroleum ether (v / v) = 1/5) to give a pale yellow oil (8.85 g, 91percent).At 0 , 2-bromo-thiazole-4-carboxylate (13.30g, 56.33mmol)In ethanol (150 mL) was added portionwiseSodium borohydride (4.263 g, 112.7 mmol), Stirring was continued at 0 0.5 hours.The mixture was stirred at room temperature for 3 hours, And heated to 70 ° C for 4 hours.The solvent was distilled off under reduced pressure, Slowly add water (100 mL)Extracted with ethyl acetate (100 mL x 3).Combine organic phase, Washed with saturated brine (50 mL)Dried over anhydrous sodium sulfate.Filtration, evaporation of the solvent under reduced pressure, The crude product was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 5/1)To give a colorless oil (9.5 g, 87percent).Into a 500-mL round-bottom flask, was placed ethyl 2-bromothiazole-4-carboxylate (14 g, 59.30 mmol) and EtOH (200 mL). This was followed by the addition of NaBHNaBHStep 3 : (2-bromothiazol-4-yl)methanolA solution of ethyl 2-bromothiazole-4-carboxylate (7.821 g, 33.13 mmol) in THF (100 mL) was cooled in an ice-bath and treated portionwise with lithium borohydride (1.083 g, 49.70 mmol). After 1 hour MeOH (1.614 g, 2.040 mL, 50.36 mmol) was added over a period of half an hour. The reaction was allowed to stir for 3 hours and then the solvent was concentrated in vacuo and the resultant residue was dissolved in EtOAc, washed with HCl (2x), saturated sodium bicarbonate, followed by brine, dried (NaA solution of methyl 2-bromothiazole-4-carboxylate (0.500 g, 2.25 mmol) in EtOH (10 mL) in a 50 mL flask under a nitrogen atmosphere was cooled to 0 °C and treated with NaBHPreparation of (2-bromothiazol-4-yl)methanol (5)2-Bromothiazol-4-Carboxylic acid ethyl ester (11.8g, 50.0mmol)Was dissolved in absolute ethanol (100 mL)Sodium borohydride (3.8 g, 100 mmol) was added, stirred at room temperature for 4 hours, and then heated to 70 ° C for 4 hours.The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography (ethyl acetate / petroleum ether (v / v) = 1/5) to give a pale yellow oil (8.85 g, 91percent).At 0 , 2-bromo-thiazole-4-carboxylate (13.30g, 56.33mmol)In ethanol (150 mL) was added portionwiseSodium borohydride (4.263 g, 112.7 mmol), Stirring was continued at 0 0.5 hours.The mixture was stirred at room temperature for 3 hours, And heated to 70 ° C for 4 hours.The solvent was distilled off under reduced pressure, Slowly add water (100 mL)Extracted with ethyl acetate (100 mL x 3).Combine organic phase, Washed with saturated brine (50 mL)Dried over anhydrous sodium sulfate.Filtration, evaporation of the solvent under reduced pressure, The crude product was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 5/1)To give a colorless oil (9.5 g, 87percent).Into a 500-mL round-bottom flask, was placed ethyl 2-bromothiazole-4-carboxylate (14 g, 59.30 mmol) and EtOH (200 mL). This was followed by the addition of NaBHInto a 500-mL round-bottom flask was placed a solution of ethyl 2-bromothiazole-4-carboxylate(14 g, 59.3 mmol), EtOH (200 mL). This was followed by the addition of NaBHInto a 100-mL round-bottom flask was placed a solution of ethyl 2-bromo-1, 3-thiazole-4- carboxylate (3 g, 12.71 mmol) in EtOH (30 mL). NaBH4 (1.0 g, 25.41 mmol) was added in portions with an ice/water bath. The resulting solution was stirred for 3 hr at room temperature. The reaction was then quenched by the addition of 100 mL of water in an ice/water bath. The resulting solution was extracted with 3x100 ml of ethyl acetate, and the combined organic layers were concentrated. This resulted in 2 g (81percent) of the title compound as yellow oil. MS-ESI: 196.2, 194.2 (M+1).NaBHStep 3 : (2-bromothiazol-4-yl)methanolA solution of ethyl 2-bromothiazole-4-carboxylate (7.821 g, 33.13 mmol) in THF (100 mL) was cooled in an ice-bath and treated portionwise with lithium borohydride (1.083 g, 49.70 mmol). After 1 hour MeOH (1.614 g, 2.040 mL, 50.36 mmol) was added over a period of half an hour. The reaction was allowed to stir for 3 hours and then the solvent was concentrated in vacuo and the resultant residue was dissolved in EtOAc, washed with HCl (2x), saturated sodium bicarbonate, followed by brine, dried (NaA solution of methyl 2-bromothiazole-4-carboxylate (0.500 g, 2.25 mmol) in EtOH (10 mL) in a 50 mL flask under a nitrogen atmosphere was cooled to 0 °C and treated with NaBHCompound 46 & (30011^, 1.511111101, as described in the patent application '102015057585' under argon atmosphereThe method disclosed in of the book on page 27 is prepared by dissolving in 5 mL of 1, 4-dioxane and 1 mL of water.(4-(pyrrolidinyl-1-carbonyl)phenyl)boronic acid 46b (406 mg, 1.9 mmol, Prepared by the method disclosed in the patent application 'Example 252 of page 199 of the specification in WO2008021926, [1, 1'-bis(diphenylphosphino)ferrocene]palladium dichloride (113 mg, 0.1 mmol) and potassium carbonate (426 mg, 3. lmmol), The reaction was stirred for 12 hours while heating to 80 C.The reaction solution was concentrated under reduced pressure.The obtained residue was purified by silica gel column chromatography using eluent system C.The title compound 46c was obtained (400 mg, yield: 90%)Into a 500-mL round-bottom flask was placed 4-fluoro-2, 6-bis(prop-1-en-2-yl)aniline (9.2 g, 48.1mmol) in MeOH (200 mL). Then Pd/C (10percent wt, 900 mg) was added. The flask was evacuated andflushed three times with hydrogen. The resulting solution was stirred for 12 h at RT under an atmosphere of hydrogen. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:10 to 1:8). This resulted in 7.2 g (77percent) of the title compound as brownoil. MS-ESI: 196.1 (M+1).(2-Bromothiazol-4-yl)methanol (2) (3.1 g, 16.18 mmol, 1.5 equiv) and CMTP (5.56 g, 21.58 mmol, 2 equiv) were added to a stirred solution of methyl 4-(4-chloro- lH-pyrrole-2- carboxamido)benzoate (4) (3.0 g, 10.79 mmol, 1 equiv) in toluene (50 mL) at ambient temperature. The reaction mixture was warmed to 120 °C and stirred for 16 h, and then reaction mixture was cooled to ambient temperature, concentrated under vacuum. The crude product was purified by silica gel column chromatography (20percent ethyl acetate-hexanes) to provide compound 5 as a pale brown solid (1 g, 20percent). LC-MS (ESI+): m/z 456.0 (M+2H)+(2-Bromothiazol-4-yl)methanol (1.25 g, 6.44 mmol, 1.5 equiv) and CMTP (3.14 g, 0.013 mol, 2 equiv) were added to a stirred solution of N-(2-fluoro-4-iodophenyl)-4-methyl- lH-pyrrole-2-carboxamide (17) (1.50 g, 4.35 mmol, 1 equiv) in Toluene (50 mL) at ambient temperature. The reaction mixture was warmed to 120 °C and stirred for 16 h, and then reaction mixture was cooled to ambient temperature, concentrated under vacuum. The crude product was purified by silica gel column chromatography (20percent ethyl acetate-hexanes) to provide compound 18 as a pale brown solid (300 mg, 13percent). LC-MS (ESI+): m/z 521.5 (M+H)+A solution of 0.22 mol of dimethyl sulfoxide in 50 mL of dichloromethane was added dropwise to a solution of 0.11 mol of oxalyl chloride in 200 mL of dichloromethane in a temperature range of '75 to '65°C. The mixture was stirred for 0.5 h, and then a solution of 0.1 mol of 11 in 100 mL of dichloromethane was added dropwise at '75 to '65°C. The mixture was stirred for an additional 2 h, and then 0.5 mol of triethylamine was added dropwise at '75 to '65°C. After the temperature of the reaction mixture was raised to '10°C for 1 h, the mixture was poured into a solution of 0.4 mol of sodium bicarbonate in 400 mL of water, stirred for 0.5 h and extracted with dichloromethane. The organic layer was dried with sodium sulfate, the solvent was removed at a reduced pressure, and the residue was chromatographed.Into a 250-mL round-bottom flask, was placed Into a 250-mL round-bottom flask was placed a solution of At 0 , To a solution of (2-bromothiazol-4-yl) methanol (3.88 g, 20.0 mmol) in dichloromethane (40 mL)Was added phosphorus tribromide (3.8mL, 40.0mmol), Rise up to room temperature overnight.Water (40 mL) was added, Extracted with dichloromethane (60 mL x 3)Combine organic phase, Washed with saturated brine (50 mL)Dried over anhydrous sodium sulfate.Filtration, evaporation of the solvent under reduced pressure, The crude product was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 20/1)A white solid (3.1 g, 60%) was obtained.To a solution of To a mixture of (2-bromo-l, 3-thiazol-4-yl) methanol (5.0 g) and THF (50 ml) was added phosphorous tribromide (6.97 g) at 0°C. The mixture was stirred overnight under nitrogen atmosphere at room temperature. The mixture was poured into ice water at room temperature, and extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium hydrogencarbonate solution and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (3.90 g) . MS: [M+H]+ 255.7.

Molecular Weight:194.05
XLogP3:1.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:192.91970
Monoisotopic Mass:192.91970
Topological Polar Surface Area:61.4
Heavy Atom Count:8
Complexity:82.4
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes