* 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 hydroxide In tetrahydrofuran; methanol; chloroform; water; ethyl acetate
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 15percent 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 0percent -2percent -4percent methanol in chloroform, to provide the desired compound, Rf-0.3 (4percent methanol in chloroform), which solidified upon standing in 75percent yield. NMR (CDCl3) δ4.92 (s, 2H), 7.78 (s, 1H), 8.77 (s, 1H). Mass spectrum: (M+H)+ =116.
75%
With sodium hydroxide In tetrahydrofuran; methanol; chloroform; water; ethyl acetate
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 15percent 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 0percent -2percent-4percent methanol in chloroform, to provide the desired compound, Rf=0.3 (4percent methanol in chloroform), which solidified upon standing in 75percent yield. NMR (CDCl3)δ4.92 (s, 2H), 7.78 (s, 1H), 8.77 (s, 1H). Mass spectrum: (M+H)+ =116.
75%
With sodium hydroxide In tetrahydrofuran; methanol; chloroform; water; ethyl acetate
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 15percent 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 0percent - 2percent - 4percent methanol in chloroform, to provide the desired compound, Rf=0.3 (4percent methanol in chloroform), which solidified upon standing in 75percent yield. NMR (CDCl3) δ4.92 (s, 2H), 7.78 (s, 1 H), 8.77 (s, 1H). Mass spectrum: (M+H)+ =116.
75%
With sodium hydroxide In tetrahydrofuran; methanol; chloroform; water; ethyl acetate
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 15percent 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 0percent-2percent-4percent methanol in chloroform, to provide the desired compound, Rf=0.3 (4percent methanol in chloroform), which solidified upon standing in 75percent yield. NMR (CDCl3) δ4.92 (s, 2H), 7.78 (s, 1H), 8.77 (s, 1H). Mass spectrum: (M+H)+ =116.
75%
With sodium hydroxide In tetrahydrofuran; methanol; chloroform; water; ethyl acetate
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 15percent 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 0percent-2percent-4percent methanol in chloroform, to provide the desired compound, Rf=0.3 (4percent methanol in chloroform), which solidified upon standing in 75percent yield. NMR (CDCl3) δ4.92 (s, 2 H), 7.78 (s, 1 H), 8.77 (s, 1 H). Mass spectrum: (M+H)+ =116.
Reference：
[1] Journal of Medicinal Chemistry, 2017, vol. 60, # 7, p. 3124 - 3153
[2] Journal of Medicinal Chemistry, 1998, vol. 41, # 4, p. 602 - 617
[3] Patent: US5914332, 1999, A,
[4] Patent: US5455351, 1995, A,
[5] Patent: US5559158, 1996, A,
[6] Patent: US5484801, 1996, A,
[7] Patent: US5461067, 1995, A,
[8] Patent: EP1170289, 2002, A2, . Location in patent: Page 44-45
[9] Helvetica Chimica Acta, 1952, vol. 35, p. 215
[10] Journal of Medicinal Chemistry, 1973, vol. 16, p. 978 - 984
[11] Patent: US5559158, 1996, A,
[12] Patent: US5484801, 1996, A,
2
[ 32955-22-9 ]
[ 14527-41-4 ]
Yield
Reaction Conditions
Operation in experiment
57%
With hydrogenchloride; sodium hydroxide In ethanol
The 5-[α-hydroxy-3-(naphth-2-ylmethoxy)benzyl]thiazole used as a starting material was obtained as follows: A mixture of ethyl thiazole-5-carboxylate (8.5 g), 2N sodium hydroxide solution (28 ml) and ethanol (50 ml) was stirred at ambient temperature for 2.5 hours. The mixture was concentrated and partitioned between diethyl ether and water. The aqueous layer was acidified by the addition of 2N hydrochloric acid solution and extracted with methylene chloride (6*50 ml). The combined extracts were dried (MgSO4) and evaporated to give thiazole-5-carboxylic acid (4 g, 57percent), m.p. 214°-216° C.
Reference：
[1] Patent: US5089513, 1992, A,
3
[ 32955-22-9 ]
[ 14527-41-4 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1953, vol. 72, p. 262,267
[2] Helvetica Chimica Acta, 1942, vol. 25, p. 375
[3] Journal of Physical Chemistry, 1948, vol. 52, p. 729,736, 737
[4] Journal of Chemical Research, 2011, vol. 35, # 5, p. 313 - 316
With sodium hydroxide; In tetrahydrofuran; methanol; chloroform; water; ethyl acetate;
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 <strong>[32955-22-9]ethyl thiazole-5-carboxylate</strong> (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.
75%
With sodium hydroxide; In tetrahydrofuran; methanol; chloroform; water; ethyl acetate;
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 <strong>[32955-22-9]ethyl thiazole-5-carboxylate</strong> (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.
75%
With sodium hydroxide; In tetrahydrofuran; methanol; chloroform; water; ethyl acetate;
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 <strong>[32955-22-9]ethyl thiazole-5-carboxylate</strong> (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.
75%
With sodium hydroxide; In tetrahydrofuran; methanol; chloroform; water; ethyl acetate;
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 <strong>[32955-22-9]ethyl thiazole-5-carboxylate</strong> (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.
75%
With sodium hydroxide; In tetrahydrofuran; methanol; chloroform; water; ethyl acetate;
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 <strong>[32955-22-9]ethyl thiazole-5-carboxylate</strong> (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.
With sodium hydroxide; In tetrahydrofuran; water;
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.
With sodium hydroxide; In tetrahydrofuran; water;
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.
B. Ethyl Thiazole-5-carboxylate To a round bottom flask was added 250 mL of dry acetone, 7.5 g (0.123 mol) of thioformamide, and 18.54 g (0.123 mol) of <strong>[33142-21-1]ethyl 2-chloro-2-formylacetate</strong>. The reaction was heated at reflux for 2 hours. The solvent was removed in vacuo, and the residue was purified by chromatography (SiO2, 6 cm o.d. column, 100% CHCl3, Rf =0.25) to provide 11.6 g (60%) of the desired compound as a light yellow oil. NMR (CDCl3 delta1.39 (t, J=7 Hz, 3H), 4.38 (q, J=7 Hz, 2H), 8.50 (s, 1H), 8.95 (s, 1H).
11.6 g (60%)
In chloroform; acetone;
O. Ethyl Thiazole-5-carboxylate To a round bottom flask was added 250 mL of dry acetone, 7.5 g (0.123 mol) of thioformamide, and 18.54 g (0.123 mol) of <strong>[33142-21-1]ethyl 2-chloro-2-formylacetate</strong>. The reaction was heated at reflux for 2 hours. The solvent was removed in vacuo, and the residue was purified by chromatography (SiO2, 6 cm o.d. column, 100% CHCl3, Rf =0.25) to provide 11.6 g (60%) of the desired compound as a light yellow oil. NMR (CDCl3)delta1.39 (t, J=7 Hz, 3H), 4.38 (q, J=7 Hz, 2H), 8.50 (s, 1H), 8.95 (s, 1H).
11.6 g (60%)
In chloroform; acetone;
J. Ethyl Thiazole-5-carboxylate To a round bottom flask was added 250 mL of dry acetone, 7.5 g (0.123 mol) of thioformamide, and 18.54 g (0.123 mol) of <strong>[33142-21-1]ethyl 2-chloro-2-formylacetate</strong>. The reaction was heated at reflux for 2 hours. The solvent was removed in vacuo, and the residue was purified by chromatography (SiO2, 6 cm o.d. column, 100% CHCl3, Rf =0.25) to provide 11.6 g (60%) of the desired compound as a light yellow oil. NMR (CDCl3) delta1.39 (t, J=7 Hz, 3H), 4.38 (q, J=7 Hz, 2H), 8.50 (s, 1H), 8.95 (s, 1H).
11.6 g (60%)
In chloroform; acetone;
J. Ethyl Thiazole-5-carboxylate. To a round bottom flask was added 250 mL of dry acetone, 7.5 g (0.123 mol) of thioformamide, and 18.54 g (0.123 mol) of ethyl 2-chloro-2 -formylacetate. The reaction was heated at reflux for 2 hours. The solvent was removed in vacuo, and the residue was purified by chromatography (SiO2, 6 cm o.d. column, 100% CHCl3, Rf=0.25) to provide 11.6 g (60%) of the desired compound as a light yellow oil. NMR (CDCl3) delta1.39 (t, J=7 Hz, 3H), 4.38 (q, J=7 Hz, 2H), 8.50 (s, 1H), 8.95 (s, 1H).
11.6 g (60%)
In chloroform; acetone;
C. Ethyl Thiazole-5-carboxylate To a round bottom flask was added 250 mL of dry acetone, 7.5 g (0.123 mol) of thioformamide, and 18.54 g (0.123 mol) of <strong>[33142-21-1]ethyl 2-chloro-2-formylacetate</strong>. The reaction was heated at reflux for 2 hours. The solvent was removed in vacuo, and the residue was purified by chromatography (SiO2, 6 cm o.d. column, 100% CHCl3, Rf =0.25) to provide 11.6 g (60%) of the desired compound as a light yellow oil. NMR (CDCl3) delta1.39 (t, J=7 Hz, 3 H), 4.38 (q, J=7 Hz, 2 H), 8.50 (s, 1 H), 8.95 (s, 1 H).
EXAMPLE 26C 5-(Ethoxycarbonyl)thiazole A solution of 2-amino-5-(ethoxycarbonyl)thiazole (50 g, 0.29 mmol) in a mixture of DMF (83 mL) and THF (317 mL) was added dropwise over 87 minutes to a stirred 41 C. solution of isoamyl nitrite (59 mL, 0.44 mol) in DMF (130 mL). A maximum temperature of 60 C. was observed during the exothermic addition. After another 40 minutes the THF was removed under vacuum at 45 C. The concentrated DMF solution was cooled to 25 C. and diluted with toluene (420 mL) and water (440 mL). The toluene layer was extracted with 3*120 mL water, then dried with Na2 SO4 (50 g) for 1 hour. After filtration the toluene layer was stripped on a rotary evaporate at 50 C. bath temperature, then on a vacuum pump at 21 C. The crude residue containing the title compound weighed 65.6 g. This material was used directly in the next step. A sample of similarly prepared material was purified by column chromatography to give a yellow oil. 1 H NMR (CDCl3) delta8.95 (s, 1H), 8.51 (s, 1H), 4.39 (q, 2H), 1.40 (t, 3H). 13 C NMR (CDCl3) delta161.0, 157.9, 148.6,129.8, 61.6, 14.1.
In tetrahydrofuran; N,N-dimethyl-formamide;
Example 23C 5-(Ethoxycarbonyl)thiazole A solution of 2-amino-5-(ethoxycarbonyl)thiazole (50 g, 0.29 mmol) in a mixture of DMF (83 mL) and THF (317 mL) was added dropwise over 87 minutes to a stirred 41 C. solution of isoamyl nitrite (59 mL, 0.44 mol) in DMF (130 mL). A maximum temperature of 60 C. was observed during the exothermic addition. After another 40 minutes the THF was removed under vacuum at 45 C. The concentrated DMF solution was cooled to 25 C. and diluted with toluene (420 mL) and water (440 mL). The toluene layer was extracted with 3*120 mL water, then dried with Na2 SO4 (50 g) for 1 hour. After filtration the toluene layer was stripped on a rotary evaporater at 50 C. bath temperature, then on a vacuum pump at 21 C. The crude residue containing the title compound weighed 65.6 g. This material was used directly in the next step. A sample of similarly prepared material was purified by column chromatography to give a yellow oil. 1 H NMR (CDCl3) delta8.95 (s, 1H), 8.51 (s, 1H), 4.39 (q, 2H), 1.40 (t, 3H). 13 C NMR (CDCl3) delta161.0, 157.9, 148.6,129.8, 61.6, 14.1.
5-[α-hydroxy-3-(naphth-2-ylmethoxy)benzyl]thiazole[ No CAS ]
[ 14527-41-4 ]
Yield
Reaction Conditions
Operation in experiment
57%
With hydrogenchloride; sodium hydroxide; In ethanol;
The 5-[alpha-hydroxy-3-(naphth-2-ylmethoxy)benzyl]thiazole used as a starting material was obtained as follows: A mixture of <strong>[32955-22-9]ethyl thiazole-5-carboxylate</strong> (8.5 g), 2N sodium hydroxide solution (28 ml) and ethanol (50 ml) was stirred at ambient temperature for 2.5 hours. The mixture was concentrated and partitioned between diethyl ether and water. The aqueous layer was acidified by the addition of 2N hydrochloric acid solution and extracted with methylene chloride (6*50 ml). The combined extracts were dried (MgSO4) and evaporated to give thiazole-5-carboxylic acid (4 g, 57%), m.p. 214-216 C.
In tetrahydrofuran; at 0 - 20℃; for 2h;Inert atmosphere;
Into a 250-mL 3-necked round-bottom flask purged with and maintained under nitrogen, was placed a solution of ethyl <strong>[32955-22-9]ethyl thiazole-5-carboxylate</strong> (3.75 g, 23.9 mmol) in THF (50 mL). This was followed by the addition of MeMgBr/THF (3 M, 40 mL) dropwise with stirring at 0C. The resulting solution was stirred for 2 h at RT and then was quenched by the addition of 50 mL ofNH4C1 (sat.). The resulting solution was extracted with 3x80 mL of DCM and the organic layers combined and dried over anhydrous Na2504, then concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:3 to 1:1). This resulted in 2.1 g (61%) of the title compound as yellow oil. MS-ESI: 144.0 (M+1).
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