* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With sodium tetrahydroborate; water; lithium chloride In tetrahydrofuran for 2 h;
Preparation of (2-bromothiazol-4-yl)methanol (5) To a solution of ester 4 (10.0 g, 42.4 mmol, 1 equiv) in THF (200 mL) was added NaBH4 (4.81 g, 127 mmol, 3 equiv), LiCl (5.4 g, 130 mmol, 3 equiv) and H2O (40 mL). The resulting biphasic mixture was vigorously stirred for 2 h, after which TLC (20percent EtOAc:hexanes) showed complete consumption of starting material. The reaction was quenched with saturated aqueous NH4Cl (200 mL), diluted with EtOAc (200 mL), and the layers were separated. The aqueous layer was extracted with EtOAc (100 mL), and the organic layers were combined, dried (Na2SO4), filtered, and concentrated under reduced pressure to give the title compound as a yellow semi-solid (7.82 g, 95percent). Rf= 0.2 (SiO2, 20percent EtOAcrhexanes); 1H and 13C NMR of the product matched those previously reported (Wipf and Wang 2007).
91%
at 20 - 70℃; for 8 h;
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).
87%
With sodium tetrahydroborate In ethanol at 0 - 70℃; for 7.5 h;
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).
87%
With sodium tetrahydroborate In ethanol at 0 - 20℃; for 3 h;
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 NaBH4 (2.3 g, 60.53 mmol) in portions at 0oC. The resulting solution was stirred for 3 h at RT and then was quenched by the addition of 100 mL of water. The resulting solution was extracted with 2x200 mL of DCM and the organic layers combined and dried over anhydrous Na2SO4, then concentrated under vacuum. This resulted in 10 g (87percent) of the title compound as colorless oil. MS-ESI: 195.9, 193.9 (M+1).
68%
With sodium tetrahydroborate; lithium chloride In tetrahydrofuran; water at 0 - 20℃; for 16 h;
NaBH4 (2.49 g, 0.066 mol, 3 equiv), LiCl (2.79 g, 0.066 mol, 3 equiv) and H20 (30 mL) were added to a stirred solution ethyl 2-bromothiazole-4-carboxylate (1) (5.0 g, 0.022 mol, 1 equiv) in THF (50 mL) at 0 °C. The reaction mixture was allowed to warm to ambient temperature and stirred for 16 h. The reaction mixture was quenched with 1.5 M hydrochloric acid and the resulting mixture was extracted with ethyl acetate (2X150 mL). The combined organic layers were washed with water (150 mL), brine (150 mL), dried over Na2S04, filtered through celite bed and concentrated to provide compound 2 as a pale brown liquid (3.0 g, 68percent). LC-MS (ESI+): m/z 195.9 (M+H)+ 1H-NMR (300 MHz, DMSO-d6): δ 7.48 (s, 1H), 5.43 (t, J = 5.7 Hz, 1H), 4.52 (d, J = 5.7 Hz, 2H).
67%
Stage #1: With lithium borohydride In tetrahydrofuran for 1 h; Cooling with an ice bath Stage #2: With methanol In tetrahydrofuran for 3.5 h;
Step 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 (Na2SO4), concentrated and purified by column chromatography (EtOAc/Petroleum ether 1: 1) to give the required product as a colorless oil (4.3Og, 67percent Yield). 1H NMR (CDCl3, 400 MHz) δ 2.51 (IH, m), 4.75 (2H, m), 7.19 (IH, s); MS (ES+) 195.96
Reference：
[1] Patent: WO2015/57585, 2015, A1, . Location in patent: Page/Page column 27; 28
[2] Patent: CN104478866, 2017, B, . Location in patent: Paragraph 0281; 0283; 0284
[3] Patent: CN104478869, 2017, B, . Location in patent: Paragraph 0142; 0143; 0144; 0145
[4] Patent: WO2017/184624, 2017, A1, . Location in patent: Page/Page column 185; 186
[5] Journal of Organic Chemistry, 2016, vol. 81, # 21, p. 10302 - 10320
[6] Russian Journal of General Chemistry, 2017, vol. 87, # 12, p. 2766 - 2775[7] Zh. Obshch. Khim., 2017, vol. 87, # 12, p. 1947 - 1956,10
[8] Organic Letters, 2007, vol. 9, # 8, p. 1605 - 1607
[9] Patent: WO2018/200674, 2018, A1, . Location in patent: Page/Page column 72
[10] Patent: WO2010/129668, 2010, A1, . Location in patent: Page/Page column 48
[11] Journal of Medicinal Chemistry, 2008, vol. 51, # 6, p. 1530 - 1533
[12] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 22, p. 5172 - 5177
[13] Organic Process Research and Development, 2017, vol. 21, # 10, p. 1602 - 1609
2
[ 170235-26-4 ]
[ 5198-86-7 ]
Yield
Reaction Conditions
Operation in experiment
49%
at 0 - 90℃; for 1.33 h; Inert atmosphere
A 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 NaBH4 (170 mg, 4.50 mmol) portion- wise over 5 min. After stirring for 15 min at 0 °C, the reaction mixture was heated at 90 °C for 1 h. The cooled mixture was then quenched with saturated aqueous NH4C1 (15 mL) and stirring was continued for 20 min. Ethyl acetate (50 mL) was then added and the organic phase was separated, washed with brine, dried over MgS04 and concentrated to give the title compound (0.212 g, 49percent) which was used as such in the next step. 1H NMR (CDCl3, 400 MHz) δ ppm: 7.18 (s, 1H), 4.76 (s, 2H), 2.21 (br s, 1H).
With oxalyl dichloride; dimethyl sulfoxide; triethylamine In dichloromethane at -75 - 10℃; for 3 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.
81%
With Dess-Martin periodane In dichloromethane at 20℃; for 2 h;
Into a 250-mL round-bottom flask, was placed (2-bromothiazol-4-yl)methanol (10 g, 51.53 mmol), DCM (100 mL) and Dess-Martin reagent (24 g, 56.60 mmol). The resulting solution was stirred for 2 h at RT and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:50 to 1:20). This resulted in 8 g (81percent) of the title compound as yellow oil. MS-ESI: 193.9, 191.9 (M+1).
Reference：
[1] Russian Journal of General Chemistry, 2017, vol. 87, # 12, p. 2766 - 2775[2] Zh. Obshch. Khim., 2017, vol. 87, # 12, p. 1947 - 1956,10
[3] Patent: WO2017/184624, 2017, A1, . Location in patent: Page/Page column 185; 186
With sodium tetrahydroborate; water; lithium chloride; In tetrahydrofuran; for 2h;
Preparation of (2-bromothiazol-4-yl)methanol (5)To a solution of ester 4 (10.0 g, 42.4 mmol, 1 equiv) in THF (200 mL) was added NaBH4 (4.81 g, 127 mmol, 3 equiv), LiCl (5.4 g, 130 mmol, 3 equiv) and H2O (40 mL). The resulting biphasic mixture was vigorously stirred for 2 h, after which TLC (20percent EtOAc:hexanes) showed complete consumption of starting material. The reaction was quenched with saturated aqueous NH4Cl (200 mL), diluted with EtOAc (200 mL), and the layers were separated. The aqueous layer was extracted with EtOAc (100 mL), and the organic layers were combined, dried (Na2SO4), filtered, and concentrated under reduced pressure to give the title compound as a yellow semi-solid (7.82 g, 95percent). Rf= 0.2 (SiO2, 20percent EtOAcrhexanes); 1H and 13C NMR of the product matched those previously reported (Wipf and Wang 2007).
91%
With sodium tetrahydroborate; ethanol; at 20 - 70℃; for 8h;
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).
87%
With sodium tetrahydroborate; In ethanol; at 0 - 70℃; for 7.5h;
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).
87%
With sodium tetrahydroborate; In ethanol; at 0 - 20℃; for 3h;
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 NaBH4 (2.3 g, 60.53 mmol) in portions at 0oC. The resulting solution was stirred for 3 h at RT and then was quenched by the addition of 100 mL of water. The resulting solution was extracted with 2x200 mL of DCM and the organic layers combined and dried over anhydrous Na2SO4, then concentrated under vacuum. This resulted in 10 g (87percent) of the title compound as colorless oil. MS-ESI: 195.9, 193.9 (M+1).
87%
With sodium tetrahydroborate; ethanol; at 0 - 20℃; for 3h;
Into 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 NaBH4(2.3 g, 60.5 mmol) in portions at 0°C. The resulting solution was stirred for 3 h at RT and then was quenched by the addition of 100 mL of water. The resulting solution was extracted with 2x200 mL of DCM.The organic layers were combined, dried over anhydrous Na2S04 and then concentrated under vacuum. This resulted in 10.0 g (87percent) of the title compound as colorless oil. MS-ESI: 195.9, 193.9(M+l).
81%
With sodium tetrahydroborate; ethanol; at 20℃; for 3h;Cooling;
Into 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).
68%
With sodium tetrahydroborate; lithium chloride; In tetrahydrofuran; water; at 0 - 20℃; for 16h;
NaBH4 (2.49 g, 0.066 mol, 3 equiv), LiCl (2.79 g, 0.066 mol, 3 equiv) and H20 (30 mL) were added to a stirred solution ethyl 2-bromothiazole-4-carboxylate (1) (5.0 g, 0.022 mol, 1 equiv) in THF (50 mL) at 0 °C. The reaction mixture was allowed to warm to ambient temperature and stirred for 16 h. The reaction mixture was quenched with 1.5 M hydrochloric acid and the resulting mixture was extracted with ethyl acetate (2X150 mL). The combined organic layers were washed with water (150 mL), brine (150 mL), dried over Na2S04, filtered through celite bed and concentrated to provide compound 2 as a pale brown liquid (3.0 g, 68percent). LC-MS (ESI+): m/z 195.9 (M+H)+ 1H-NMR (300 MHz, DMSO-d6): delta 7.48 (s, 1H), 5.43 (t, J = 5.7 Hz, 1H), 4.52 (d, J = 5.7 Hz, 2H).
67%
Step 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 (Na2SO4), concentrated and purified by column chromatography (EtOAc/Petroleum ether 1: 1) to give the required product as a colorless oil (4.3Og, 67percent Yield). 1H NMR (CDCl3, 400 MHz) delta 2.51 (IH, m), 4.75 (2H, m), 7.19 (IH, s); MS (ES+) 195.96
With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 18.16h;Cooling with ice; Inert atmosphere;
To an ice-cold solution of <strong>[5198-86-7](2-bromothiazol-4-yl)methanol</strong> (0.212 g, 1.09 mmol) in DMF (10 mL) was added TBDMSCl (0.329 g, 2.19 mmol), followed by imidazole (0.171 g, 2.51 mmol). The reaction mixture was then allowed to warm to room temperature over 10 min and stirred for 18 h under N2. The reaction was quenched by the addition of EtOH at 0 °C and the mixture was stirred at 20 °C for 10 min before being partitioned with EtOAc and saturated aqueous NaHC03. The organic layer was separated, washed with brine, dried over MgS04 and filtered. The residue was purified on the ISCO using a REDISEP® 12 g column (0 to 5percent EtOAc-DCM) to afford the desired product as yellow oil (0.333 g, 99percent). LCMS (APCI): calcd for Ci0Hi9BrNOSSi [M+H] m/z 308.01 , found 308.0. 1H NMR (CDCl3, 400 MHz) delta ppm: 7.14 (t, J = 1.5 Hz, 1H), 4.83 (d, J= 1.6 Hz, 2H), 0.95 (s, 9H), 0.12 (s, 6H).
95%
With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 2h;
A mixture of 2-bromothiazol-4-yl) methanol (leq), imidazole (4eq) and tert-butyl- dimethylsilylchloride (2eq) in DMF(I OmI) was stirred 2h at room temperature. The reaction mixture was partitioned between ethylacetate and water. Ethylacetate layer was separated and washed with water, brine and dried over sodium sulfate. Filtered, evaporated and purified by flash chromatography (10percentEtOAc / Hexane) to provide pure product as a colorless liquid in 95percentyield ES/MS m/z 307.9 / 309.9 (MH+).
79%
Into a 100-mL round-bottom flask was placed a solution of <strong>[5198-86-7](2-bromo-1,3-thiazol-4-yl)methanol</strong> (2.0 g, 10.31 mmol) in THF (20 mL). To the solution was added NaH (60percent wt., 1.2 g, 30.92 mmol) in portions with an ice/water bath. After stirring for 15 minutes at RT, a solution of TBSC1 (4.7 g, 30.92 mmol) in THF (5 mL) was added dropwise in an ice/water bath. The resulting solution was stirred for 2 hr at RT. The reaction was then quenched by the addition of 50 mL of water. Theresulting solution was extracted with 3x100 ml of ethyl acetate, the organic layers were combined, dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:30). This resulted in 2.5 g (79percent) of the title compound as yellow oil. MS-ESI: 310.2, 308.2 (M+1).
333 mg
With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 18.2h;Cooling with ice;
To an ice-cold solution of <strong>[5198-86-7](2-bromothiazol-4-yl)methanol</strong> (212 mg, 1.09 mmol) in DMF (10 mL) was added TBS-Cl (329 mg, 2.19 mmol), followed by imidazole (171 mg, 2.51 mmol). The mixture was allowed to warm to room temperature over 10 min and stirring was continued for 18 h. The reaction was quenched by the addition of EtOH at 0°C and then the mixture was stirred at room temperature for 10 min before being partitioned with EtOAc-saturated aqueous NaHC03. The organic layer was separated, washed with brine, dried over MgS04 and concentrated to dryness. The residue was purified on the ISCO using a REDISEP® 12 g column (0-5percent EtOAc-DCM) to give the title compound (333 mg, 99percent) as a yellow oil. MS (APCI): calcd for Ci0Hi9BrNOSSi [M+H]+ m/z, 308.0, found 308.0. *HNMR (400 MHz, CDC13) delta ppm 7.14 (t, J= 1.5 Hz, 1H), 4.83 (d, J= 1.6 Hz, 2H), 0.92 (s, 9H), 0.12 (s, 6H).
3 g
With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 5h;
To a solution of 2-Bromo-4-Hydroxymethylthiazole [0210j (2 g, 10.30 mmol) in N,N-dimethylformamide (20 mL) was added tert-butyl dimethylsilyl chloride (3.2 g, 20.6 mmol) and imidazole (2.80 g, 41.2 mmol), then the reaction mixture was stirred at ft for 5h. After the completion of the reaction, to the reaction mixture was added ice cold water and extracted with ethyl acetate (2x75 mL), the combined organic layer was dried over anhydrous sodium sulfate and concentrated to afford as an colorless liquid and which was purified by column of silica gel (60-120 mesh) using 15percent ethyl acetate in hexane as eluent to afford 3 g of 2-bromo-4-(((tert-butyl dimethylsilyl)oxy)methyl)thiazole [021 ij as an colorless liquid.
STAGE B 2-bromo 4-thiazolemethanol and 2-bromo 4-thiazolecarboxaldehyde 141 ml of 1.2 molar DIBAL in hexane were added at -60° C. to a solution of 20 g of the product of Stage A and 200 ml of tetrahydrofuran and the reaction mixture was stirred for one hour. The temperature was allowed to rise to -20° C. and the reaction mixture was poured into a molar solution of sodium and potassium double tartrate. Extraction was carried out with ethyl acetate and the extracts were dried, filtered and evaporated to dryness. The residue was chromatographed on silica, eluding with a hexane-ethyl acetate mixture (7-3) to obtain 14.9 g of 2-bromo 4-thiazole methanol (Rf=0.06) and 1 g of 2-bromo 4-thiazole-carboxaldehyde (RF=0.29) melting at 124° C.
6
[ 5198-86-7 ]
[ 58479-61-1 ]
[ 263169-23-9 ]
Yield
Reaction Conditions
Operation in experiment
85%
With 1H-imidazole; dmap; In N,N-dimethyl-formamide; for 48h;
Preparation of 2-bromo-4-((tert-butyldiphenylsilyloxy)methyl)thiazole (6)To a solution of alcohol 5 (22.55 g, 0.116 mol, 1 equiv) in DMF (50 mL) was added imidazole (7.923 g, 0.116 mol, 1 equiv), DMAP (1.421 g, 0.0116 mol, 0.1 equiv), and TBDPSCl (30.5 mL, 0.116 mol, 1 equiv). After 48 h, TLC (20percent EtOAc:hexanes) showed complete consumption of starting material. The reaction was quenched with H2O (330 mL), diluted with EtOAc (300 mL), and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 200 mL), and the combined organic layers were washed with H2O (330 mL), 1 M aqueous HCl (330 mL), and saturated aqueous NaCl (330 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by flash chromatography (0-10percent EtOAc:hexanes) afforded the title compound as a white solid (42.45 g, 85percent). Rf= 0.8 (SiO2, 20percent EtOAc:hexanes); 1H and 13C NMR of the product matched those previously reported (Raghavan et al. 2008).
With triethylamine; In dichloromethane; at -5 - 20℃; for 2h;
(2-bromothiazol-4-yl) methanol (8.85 g, 45.6 mmol) and triethylamine (14 mL, 100 mmol)Was dissolved in dichloromethane (120 mL), and methylsulfonyl chloride (10.45 g, 91.21 mmol) was added at -5 ° C,The mixture was stirred at room temperature for 2 hours and extracted with dichloromethane (30 mL x 3).The organic phases were combined, washed successively with water (20 mL x 2), saturated brine (30 mL), and dried over anhydrous sodium sulfate.The solvent was evaporated under reduced pressure to give a colorless oil (11.2 g, 91percent).Directly take the next step.
With triethylamine; In dichloromethane; at 20℃;
To a solution of intermediate 24 (200mg, lmmol) in anhydrous CH2Cl2 (5 ml) cooled at O0C was added triethylamine (172mul, 1.2mmol) followed by methanesulfonyl chloride 20 (88mul, 1. lmmol), and the mixture allowed to warm to room temperature overnight. Diluted with more CH2Cl2 (15 ml), washed with water, sat. NaCl, dried over Na2SO4, filtered and evaporated.The residue was purified by MPLC on silica gel eluting with a gradient rising from 100percent hexanes to 25percent EtOAc in hexanes to give the title compound. 1HNMR (500 MHz, CDCl3) delta:7.42 (s, IH), 5.29 (s, 2H), 3.08 (s, 3H). 25
With sodium tetrahydroborate; In methanol; at 0℃; for 2.5h;
Sodium borohydride (99mg, 26mmol) was added portionwise to a solution of 2- bromothiazole-4-carbaldehyde (Ig, 5.2mmol) in anhydrous methanol (20ml) cooled in an ice10 bath. After the addition was complete the cooling was removed and the mixture stirred for 150 mins. The mixture was evaporated and the residue partitioned between IN HCl (50ml) and EtOAc (50ml). the organic layer was washed with sat. NaCl (20ml), dried over Na2SO4, filtered and evaporated to give the title compound. 1HNMR (500 MHz, CDCl3) delta: 7.19 (s, IH), 4.77 (s, 2H), 2.76 (br s, IH).
With triethylamine;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; at 110℃; for 0.5h;Microwave irradiation;
(+/-)-tert-Butyl 4-(4-(hydroxymethyl)thiazol-2-yl)- 1 -(4-(trifluoromethyl)phenyl)but-3-yn-2-ylcarbamate. In a 20 mL microwave tube, tert-butyl l-(4-(trifluoromethyl)phenyl)but-3-yn-2-ylcarbamate (0.70 g, 2.23 mmol) was dissolved in TEA (10 mL), and bis(triphenylphosphine)palladium(II) chloride (78.1 mg, 111 mumol, Aldrich) and copper(I) iodide (63.6 mg, 0.33 mmol, Aldrich) were added in one portion. The reaction mixture was heated to 110 0C for 30 minutes in the microwave. The reaction mixture was concentrated. The residue was purified by silica gel chromatography, eluting with 0 - 50 percent EtOAc/hexane to give the title compound (0.60 g, 63 percent). MS m/z: All (M+ 1).
With iodine; 1H-2,2,4-triazole; triphenylphosphine; In tetrahydrofuran; for 1h;Inert atmosphere;
Step 4 : 2-bromo-4-(iodomethyl)thiazoleA cooled solution of 2-bromothiazol-4-yl)methanol (1.488 g, 7.668 mmol) , triphenylphosphine(3.016 g, 2.664 mL, 11.50 mmol) and 4H-imidazole (1.044 g, 15.34 mmol) in THF (20 mL) under nitrogen was treated with molecular iodine (2.919 g, 592.1 muL, 11.50 mmol) in one portion and the reaction maintained at this temperature. After 1 hour the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with 1percent sodium metabisulfite solution followed by brine and dried over MgSO4 The mixture was concentrated in vacuo and purified using column chromatography (3: 1 Petroleum ether/EtOAc) to give the pure product as a white solid (2.12g, 91percent Yield). 1H NMR (CDCl3, 400 MHz) delta 4.49 (2H, s), 7.22 (IH, s); MS (ES+)
With sodium tetrahydroborate; ethanol; at 0 - 90℃; for 1.33h;Inert atmosphere;
A solution of <strong>[170235-26-4]methyl 2-bromothiazole-4-carboxylate</strong> (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 NaBH4 (170 mg, 4.50 mmol) portion- wise over 5 min. After stirring for 15 min at 0 °C, the reaction mixture was heated at 90 °C for 1 h. The cooled mixture was then quenched with saturated aqueous NH4C1 (15 mL) and stirring was continued for 20 min. Ethyl acetate (50 mL) was then added and the organic phase was separated, washed with brine, dried over MgS04 and concentrated to give the title compound (0.212 g, 49percent) which was used as such in the next step. 1H NMR (CDCl3, 400 MHz) delta ppm: 7.18 (s, 1H), 4.76 (s, 2H), 2.21 (br s, 1H).
With sodium tetrahydroborate; ethanol; at 0 - 90℃; for 1.3h;Inert atmosphere;
A solution of <strong>[170235-26-4]methyl 2-bromothiazole-4-carboxylate</strong> (500 mg, 2.25 mmol) in EtOH (10 mL) was cooled at 0°C under nitrogen and NaB (170 mg, 4.50 mmol) was added portion- wise over 5 min. The mixture was stirred at the same temperature for 15 min and then it was heated at 90°C for 1 h. The cooled mixture was quenched with saturated aqueous NtLtCl (15 mL) and stirring was continued for 20 min. Ethyl acetate (50 mL) was then added and the organic phase was separated, washed with brine, dried over MgS04 and concentrated to dryness to give the title compound (0.212 g, 49percent) which was used as such in the next step. *HNMR (400 MHz, CDC13) delta ppm 7.18 (s, 1H), 4.76 (s, 2H), 2.21 (br s, 1H).
ethyl 2-((3-(4-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)phenyl)oxetan-3-yl)oxy)acetate[ No CAS ]
ethyl 2-((3-(4-((3-(4-(hydroxymethyl)thiazol-2-yl)benzyl)oxy)phenyl)oxetan-3-yl)oxy)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
22.62%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 80℃; for 5h;Inert atmosphere;
A solution of ethyl 2-((3-(4-((3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzyl)oxy)phenyl)oxetan-3-yl)oxy)acetate (compound of step 1 , 10.25 g, 0.534 mmol), <strong>[5198-86-7](2-bromothiazol-4-yl)methanol</strong> (commercial source, 0.104 g, 0.534 mmol) and K2C03 (0.148 g, 1 .068 mmol) in a solvent mixture of dioxane (20 ml) and water (5 ml) was sonicated for 30 minutes and degassed under argon for 20 minutes. Tetrakis(triphenylphosphine)palladium(0) (10.79 mg, 0.037 mmol) was added and the reaction mixture was again degassed for 20 minutes. The reaction mixture was heated to 80 °C for 5 h. After completion of reaction, the reaction mixture was diluted with ethyl acetate and water. The organic layer was washed with brine (30 ml), dried over sodium sulfate and concentrated to obtain the title compound (0.055 g, 0.121 mmol). Yield: 22.62 percent.
With phosphorus(V) oxybromide; In dichloromethane; at 0 - 20℃;
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.
With carbon tetrabromide; triphenylphosphine; In dichloromethane; at 0 - 20℃; for 0.5h;
To a solution of <strong>[5198-86-7](2-bromothiazol-4-yl)methanol</strong> (1.9 g, 9.8 mmol) and triphenylphosphine (2.6 g, 9.8 mmol) in DCM (20 ml) was added a DCM solution of CBr4 (3.2 g, 9.8 mmol) at 0C. The reaction was allowed to warm to RT after 30 minutes. LC showedgood reaction after 1 hour. About 20 mL of hexanes was added to the reaction, and the white precipitate was filtered off. The filtration was adsorbed onto silica gel, and purified by MPLC with a 40G ISCO column, eluting with hexanes and EtOAc. LC-MS [M+H]: 258.2
3.9 g
With phosphorus tribromide; In tetrahydrofuran; at 0 - 35℃;Inert atmosphere;
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.
With oxalyl dichloride; dimethyl sulfoxide; triethylamine; In dichloromethane; at -75 - 10℃; for 3h;
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.
81%
With Dess-Martin periodane; In dichloromethane; at 20℃; for 2h;
Into a 250-mL round-bottom flask, was placed <strong>[5198-86-7](2-bromothiazol-4-yl)methanol</strong> (10 g, 51.53 mmol), DCM (100 mL) and Dess-Martin reagent (24 g, 56.60 mmol). The resulting solution was stirred for 2 h at RT and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:50 to 1:20). This resulted in 8 g (81percent) of the title compound as yellow oil. MS-ESI: 193.9, 191.9 (M+1).
81%
With Dess-Martin periodane; In dichloromethane; at 20℃; for 2h;
Into a 250-mL round-bottom flask was placed a solution of <strong>[5198-86-7](2-bromothiazol-4-yl)methanol</strong> (10.0 g, 51.5 mmol) in DCM (100 mL). To the solution was added Dess-Martin reagent (24.0 g, 56.6 mmol). The resulting solution was stirred for 2 h at RT and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with a gradient of ethyl acetate/petroleum ether (1 :50 to 1 0). This resulted in 8.0 g (81percent) of the title compound as yellow oil. MS-ESI: 193.9, 191.9 (M+l).
N-(2-fluoro-4-iodophenyl)-4-methyl-1H-pyrrole-2-carboxamide[ No CAS ]
1-((2-bromothiazol-4-yl)methyl)-N-(2-fluoro-4-iodophenyl)-4-methyl-1H-pyrrole-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
13%
With cyanomethylenetributyl-phosphorane; In toluene; at 120℃; for 16h;
(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)+
methyl 4-(4-chloro-1H-pyrrole-2-carboxamido)benzoate[ No CAS ]
methyl 4-(1-((2-bromothiazol-4-yl)methyl)-4-chloro-1H-pyrrole-2-carboxamido)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
20%
With cyanomethylenetributyl-phosphorane; In toluene; at 120℃; for 16h;
(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)+
With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 12h;
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).
(4-(4-(hydroxymethyl)thiazol-2-yl)phenyl)(pyrrolidin-1-yl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 80℃; for 12h;Inert atmosphere;
Compound 46 & (30011^, 1.511111101, as described in the patent application "102015057585" under argon atmosphereThe method disclosed in Example 1 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%)
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