5-Thiazolemethanol

Pale-Yellow Oil

C. P. K. K. D. A mixture of 0. 54 g of g-4 and 10ml tetrahydrofurane (THF) was stirred at 0°C under a nitrogen atmosphere. The mixture of 0. 16g of lithium aluminium hydride and 5ml of ether was added drop wise. After lhour at 0°C water and 20percent sodium hydroxide were added, and stirred during 30 minutes. The mixture was filtered over decalite and the solvent was removed by azeotropique distillation with toluene yielding 0.3g (69percent) of thiazol-5-yl-methanol (g-5).C. P. K. K. D. A mixture of 0. 54 g of g-4 and 10ml tetrahydrofurane (THF) was stirred at 0°C under a nitrogen atmosphere. The mixture of 0. 16g of lithium aluminium hydride and 5ml of ether was added drop wise. After lhour at 0°C water and 20percent sodium hydroxide were added, and stirred during 30 minutes. The mixture was filtered over decalite and the solvent was removed by azeotropique distillation with toluene yielding 0.3g (69percent) of thiazol-5-yl-methanol (g-5).Thiazol-5-ylmethanol (503 mg, 4.37 mmol) and thionyl chloride (2.59 g, 21.8 mmol) were dissolved inDichloromethane (15 mL) and reacted for 3 h. The reaction mixture was poured into water (30 mL), extracted with ethyl acetate (30 mL × 3), and saturated saltWashed with water (15 mL) and dried over anhydrous sodium sulfate. The solvent was removed and the residue was subjected to column chromatography (eluent: PE / EtOAc (v / v)= 10/1) to give 512 mg of a pale yellow oil, yield: 87.73%.[000287] Synthesis of 5-(chloromethyl) thiazole (349): To a stirred solution of thiazol-5- ylmethanol 348 (1 g, 8.69 mmol) in CH2C12 (50 mL) under argon atmosphere were added mesyl chloride (1.09 g, 9.56 mmol) drop wise for 15 mi diisopropyl ethyl amine (1.23 g, 9.56 mmol) at 0-5 C; warmed to RT and stirred for 4 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was washed with saturated NaHCO3 solution (20 mL) and purified through silica gel column chromatography using 50% EtOAc/ hexanes to afford compound 349 (650 mg, 57%) as yellow liquid. TLC: 5% MeOH/ CH2C12 (R 0.7); 1H-NMR (CDC13, 500 MHz): oe 8.84 (s, 1H), 7.86 (s, 1H), 4.84 (s, 2H). (0.15mol), thionyl chloride (0.25mol) and chloroform (150 mL) under reflux conditions the reaction after 3 ~ 5hr, the solvent removed under reduced pressure and the excess of dichloro sulfoxide, to give the title was 16.6g.C. 5-(Hydroxymethyl)thiazole To a precooled (ice bath) three neck 500 mL flask containing lithium aluminum hydride (2.89 g, 76 mmol) in 250 mL of THF was added ethyl thiazole-5-carboxylate (11.82 g, 75.68 mmol) in 100 mL of THF dropwise over 1.5 hours to avoid excess foaming. The reaction was stirred for an additional hour, and treated cautiously with 2.9 mL of water, 2.9 mL of 15% NaOH, and 8.7 mL of water. The solid salts were filtered, and the filtrate set aside. The crude salts were heated at reflux in 100 mL of ethyl acetate for 30 minutes. The resulting mixture was filtered, and the two filtrates were combined, dried over Na2 SO4, and concentrated in vacuo. The product was purified by silica gel chromatography eluding sequentially with 0% -2% -4% methanol in chloroform, to provide the desired compound, Rf-0.3 (4% methanol in chloroform), which solidified upon standing in 75% yield. NMR (CDCl3) delta4.92 (s, 2H), 7.78 (s, 1H), 8.77 (s, 1H). Mass spectrum: (M+H)+ =116.P. 5-(Hydroxymethyl)thiazole To a precooled (ice bath) three neck 500 mL flask containing lithium aluminum hydride (76 mmol) in 250 mL of THF was added ethyl thiazole-5-carboxylate (11.82 g, 75.68 mmol) in 100 mL of THF dropwise over 1.5 hours to avoid excess foaming. The reaction was stirred for an additional hour, and treated cautiously with 2.9 mL of water, 2.9 mL of 15% NaOH, and 8.7 mL of water. The solid salts were filtered, and the flitrate set aside. The crude salts were heated at reflux in 100 mL of ethyl acetate for 30 min. The resulting mixture was filtered, and the two filtrates were combined, dried over Na2 SO4, and concentrated in vacuo. The product was purified by silica gel chromatography eluding sequentially with 0% -2%-4% methanol in chloroform, to provide the desired compound, Rf=0.3 (4% methanol in chloroform), which solidified upon standing in 75% yield. NMR (CDCl3)delta4.92 (s, 2H), 7.78 (s, 1H), 8.77 (s, 1H). Mass spectrum: (M+H)+ =116.K. 5-(Hydroxymethyl)thiazole To a precooled (ice bath) three neck 500 mL flask containing lithium aluminum hydride (76 mmol) in 250 mL of THF was added ethyl thiazole-5-carboxylate (11.82 g, 75.68 mmol) in 100 mL of THF dropwise over 1.5 hours to avoid excess foaming. The reaction was stirred for an additional hour, and treated cautiously with 2.9 mL of water, 2.9 mL of 15% NaOH, and 8.7 mL of water. The solid salts were filtered, and the filtrate set aside. The crude salts were heated at reflux in 100 mL of ethyl acetate for 30 min. The resulting mixture was filtered, and the two filtrates were combined, dried over Na2 SO4, and concentrated in vacuo. The product was purified by silica gel chromatography eluding sequentially with 0% - 2% - 4% methanol in chloroform, to provide the desired compound, Rf=0.3 (4% methanol in chloroform), which solidified upon standing in 75% yield. NMR (CDCl3) delta4.92 (s, 2H), 7.78 (s, 1 H), 8.77 (s, 1H). Mass spectrum: (M+H)+ =116.K. 5-(Hydroxymethyl)thiazole. To a precooled (ice bath) three neck 500 mL flask containing lithium aluminum hydride (76 mmol) in 250 mL of THF was added ethyl thiazole-5-carboxylate (11.82 g, 75.68 mmol) in 100 mL of THF dropwise over 1.5 hours to avoid excess foaming. The reaction was stirred for an additional hour, and treated cautiously with 2.9 mL of water, 2.9 mL of 15% NaOH, and 8.7 mL of water. The solid salts were filtered, and the filtrate set aside. The crude salts were heated at reflux in 100 mL of ethyl acetate for 30 min. The resulting mixture was filtered, and the two filtrates were combined, dried over Na2 SO4, and concentrated in vacuo. The product was purified by silica gel chromatography eluding sequentially with 0%-2%-4% methanol in chloroform, to provide the desired compound, Rf=0.3 (4% methanol in chloroform), which solidified upon standing in 75% yield. NMR (CDCl3) delta4.92 (s, 2H), 7.78 (s, 1H), 8.77 (s, 1H). Mass spectrum: (M+H)+ =116.D. 5-(Hydroxymethyl)thiazole To a precooled (ice bath) three neck 500 mL flask containing lithium aluminum hydride (76 mmol) in 250 mL of THF was added ethyl thiazole-5-carboxylate (11.82 g, 75.68 mmol)in 100 mL of THF dropwise over 1.5 hours to avoid excess foaming. The reaction was stirred for an additional hour, and treated cautiously with 2.9 mL of water, 2.9 mL of 15% NaOH, and 8.7 mL of water. The solid salts were filtered, and the filtrate set aside. The crude salts were heated at reflux in 100 mL of ethyl acetate for 30 min. The resulting mixture was filtered, and the two flitrates were combined, dried over Na2 SO4, and concentrated in vacuo. The product was purified by silica gel chromatography eluding sequentially with 0%-2%-4% methanol in chloroform, to provide the desired compound, Rf=0.3 (4% methanol in chloroform), which solidified upon standing in 75% yield. NMR (CDCl3) delta4.92 (s, 2 H), 7.78 (s, 1 H), 8.77 (s, 1 H). Mass spectrum: (M+H)+ =116.Example 23D 5-(Hydroxymethyl)thiazole To a slurry of lithium aluminum hydride (9.0 g) in THF (633 mL) was added a solution of crude 5-(ethoxycarbonyl)thiazole (65.6 g from Example 37C) in THF (540 mL) over 95 minutes at 0-5 C. After an additional 25 minutes, the reaction was quenched at 5 C. by sequential addition of water (8.1 mL), 15% NaOH (8.1 mL), and water (24.3 mL). After drying with Na2 SO4 (44 g) for 2 hours, the slurry was filtered, and the filter cake was washed with 100 mL THF. The combined filtrates were concentrated under vacuum at 45 C. to a brown oil (39 g). The oil was fractionally distilled through a short-path apparatus. The product fractions distilled at 97-104 C. vapor temperature at 3-5 mm, providing 20.5 g of the title compound as a turbid orange oil. 1 H NMR (CDCl3) delta8.74 (s, 1H), 7.72 (s, 1H), 4.89 (s, 2H), 3.4 (br s, 1H, OH). 13 C NMR (CDCl3) delta153.4, 140.0, 139.5, 56.6.EXAMPLE 26D 5-(Hydroxymethyl)thiazole To a slurry of lithium aluminum hydride (9.0 g) in THF (633 mL) was added a solution of crude 5-(ethoxycarbonyl)thiazole (65.6 g) in THF (540 mL) over 95 minutes at 0-5 C. After an additional 25 minutes, tile reaction was quenched at 5 C. by sequential addition of water (8.1 mL), 15% NaOH (8.1 mL), and water (24.3 mL). After drying with Na2 SO4 (44 g) for 2 hours, the slurry was filtered, and the filter cake was washed with 100 mL THF. The combined filtrates were concentrated under vacuum at 45 C. to a brown oil (39 g). The oil was fractionally distilled through a short-path apparatus. The product fractions distilled at 97-104 C. vapor temperature at 3-5 mm, providing 20.5 g of the title compound as a turbid orange oil. 1 H NMR (CDCl3) delta8.74 (s, 1H), 7.72 (s, 1H), 4.89 (s, 2H), 3.4 (br s, 1H, OH). 13 C NMR (CDCl3) delta153.4, 140.0, 139.5, 56.6.

Used as an intermediate for ritonavir

Molecular Weight:115.16
XLogP3:0.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:115.00918496
Monoisotopic Mass:115.00918496
Topological Polar Surface Area:61.4
Heavy Atom Count:7
Complexity:59.7
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes