* 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 lithium hydroxide monohydrate In tetrahydrofuran; water at 20℃; for 16 h;
Example 18 Preparation of 2-bromo-4-methyl-thiazole-5-carboxylic acid To a solution of 2-bromo-4-methyl-thiazole-5-carboxylic acid ethyl ester (3.0 g, 12 mmol) in tetrahydrofuran (THF, 50 mL) and water (5 mL) was added lithium hydroxide hydrate (1.0 g, 24 mmol). The reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was diluted with water and ethyl acetate. The aqueous layer was made acidic to pH 1 with 2 N hydrochloric acid (HCl) and then was extracted with ethyl acetate. The organic extracts were dried over sodium sulfate (Na2SO4), filtered and concentrated to provide product as an orange solid (2.6 g, 98percent): mp 152-155 °C; 1H NMR (300 MHz, CDCl3) δ 2.74 (s, 3H); ESIMS m/z 221 (M-1).
76%
With sodium hydroxide In ethanol; water at 20℃; for 14 h;
A solution of ethanolic NaOH (5 N, 15 mL) was added to a solution of compound 4 (1 mmol) in ethanol(20 mL) and the reaction mixture was stirred at room temperature for 14 h; the reaction progress was monitored by TLC. The reaction mixture was cooled and neutralized with conc. HCl. The organic layer was extracted with EtOAc and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to obtain crude product. The crude product was purified by column chromatography using silica gel(60–120 mesh) eluting with ethyl acetate and petroleum ether to obtain 2-bromo-4-methylthiazole-5-carboxylic acid 5 as off-white solid in 76percent yield. 1HNMR spectrum (CDCl3), δ, ppm: 13.19 s (1H), 2.54 s(3H). Mass spectrum (ESI-MS): m/z 223 [M + H]+.
Reference：
[1] Patent: EP2604268, 2015, B1, . Location in patent: Paragraph 0150-0151
[2] Russian Journal of General Chemistry, 2016, vol. 86, # 7, p. 1722 - 1729[3] Zh. Obshch. Khim., 2016, vol. 86, # 7, p. 1722 - 1729,8
[4] Justus Liebigs Annalen der Chemie, 1890, vol. 259, p. 298
[5] Roczniki Chemii, 1972, vol. 46, p. 1647 - 1658
[6] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1982, p. 159 - 164
[7] Patent: WO2008/47109, 2008, A1, . Location in patent: Page/Page column 38-39
2
[ 7210-76-6 ]
[ 22900-83-0 ]
Yield
Reaction Conditions
Operation in experiment
87%
With nitrous acid isobutyl ester; trimethylsilyl bromide In ethyl acetate; acetonitrile at 0 - 20℃; for 24 h;
TO A SOLUTION OF 2-METHYL-1-NITROSOOXY-PROPANE (28.2 ML, 2.1 EQ. ) IN CH3CN (700 ML) COOLED TO 0XB0;C WAS ADDED DROPWISE BROMO-TRIMETHYL-SILANE (32 ML, 2.1 EQ. ). THE] resulting mixture was maintained at [0XB0;C.] A solution of the available 2-amino-4- methyl-thiazole-5-carboxylic acid ethyl ester (18.6 g, 0.1 mol) in CH3CN/AcOEt 75/25 was added dropwise and the reaction mixture was maintained at [0XB0;C.] The mixture was stirred for 24 hours at rt. The solvent was evaporated and water was added. The product was extracted with AcOEt, dried over [NA2SO4,] filtered and evaporated. The title compound was obtained as a yellow solid (21.74 g, 87 [MMOL)] in 87percent yield after purification by flash chromatography using DCM as eluent ; GC/MS: [M'C7H8BRNO2S] 250.
87%
Stage #1: With nitrous acid isobutyl ester; trimethylsilyl bromide In acetonitrile at 0℃; for 0.333333 h; Stage #2: at 0 - 55℃; for 0.0458333 h;
A solution of 2-methyl-1-nitrosooxy-propane (28.2 ml, 2.1 eq.) in CH3CN (700 ml) was cooled to 0C and bromo-trimethyl-silane (32 ml, 2.1 eq.) was added dropwise over 20 min. A solution of the available 2-amino-4-methyl-thiazole-5-carboxylic acid ethyl ester (18.6 g, 0.1 mot) in a mixture CH3CN/EtOAc : 75/25 heated to 55C was added dropwise over 45 min. During the addition the reaction was maintained at 0C and then allowed to warm to rt and stirred for 2 hours. After evaporation, the product was extracted with AcOEt, washed with water, dried over Na2SO4, filtered and evaporated. The title compound was obtained as a yellow solid (21.74 g, 86.96 mmol) in a 87percent yield; GC/MS : M+ C7H6BrNO2S 250.
85%
With nitrous acid isobutyl ester; trimethylsilyl bromide In ethyl acetate; acetonitrile at 0 - 20℃; for 2.75 h;
A solution of 2-methyl-1-nitrosooxypropane (20 [ML,] 2 eq) in CH3CN (700 mL) was [COOLED TO 0°C AND BROMO-TRIMETHYL-SILANE (20 ML, 2 EQ. ) WAS ADDED DROPWISE OVER 20] min. The available 2-amino-4-methyl-thiazole-5-carboxylic acid ethyl ester (14.0 g, 75.2 [MMOL)] in a mixture of CH3CN/EtOAc [(75/25)] at [55°C] was added dropwise over 45 min. During the addition the reaction was maintained at [0°C.] After return at rt, the mixture was stirred for 2 hours. After evaporation, the product was extracted with DCM, washed with water, dried over [NA2SO4,] filtered and evaporated off. The title compound was obtained as a pale orange solid (16.06 g, 75.2 [MMOL)] in a 85percent yield ; GC/MS: [M+ C7H8BRNO2S] 250
83%
Stage #1: With n-Amyl nitrite In acetonitrile at 60℃; for 4 h; Stage #2: With water; sodium hydroxide In acetonitrile at 10 - 35℃;
A solution of copper(II) bromide (3.6 g, 16.11 mmol) and n-amyl nitrite (1.07 mL, 8.06 mmol) in acetonitrile (22 mL) was heated to 60°C, and a solution of ethyl 2-amino-4-methyl-1,3-thiazole-5-carboxylate (1.0 g, 5.37 mmol) in acetonitrile (30 mL) was added dropwise thereto. The mixture was stirred for 4 hr at same temperature. The reaction mixture was allowed to cool to room temperature, and added into ice-cooled 1N aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate= 95:5→85:15) to give the title compound (1.1 g, 83percent). 1H-NMR (CDCl3) δ : 1.37 (3 H, t, J = 7.1 Hz), 2.72 (3 H, s), 4.33 (2 H, q, J = 7.1 Hz).
76%
With tert.-butylnitrite; copper(ll) bromide In acetonitrile at 0℃; for 4 h;
To a stirred solution of Intermediate 6 (0.53 g, 2.85 mmol) in MeCN (6 mL) at00C was added CuBr2 (0.70 g, 3.13 mmol) followed by dropwise addition of tert-buty\\ nitrite (0.44 mL, 3.70 mmol). After stirring at 00C for 4 h, the reaction mixture was concentrated in vacuo to give a black oil. Purification by column chromatography (SiO2, 0-50percent EtOAc/hexanes) gave the title compound (0.54 g, 76percent) as a yellow solid. 6H (CDCl3) 4.33 (2H, q, J 7.0 Hz), 2.71 (3H, s), 1.36 (3H, t, J 7.2 Hz). MS (ES+) 252.0 (M+H)+.
62%
With potassium bromide; copper(I) bromide; sodium nitrite In water at 60℃; for 1 h;
Compound 3 (1 mmol) in HBr (3 mL) was added to cold aqueous solution of CuBr (1 mmol) and KBr(0.2 mmol) followed by dropwise addition of preliminary cooled aqueous solution of NaNO2(10 mL) for 1 h. The reaction mixture was stirred at 60°C for 2 h. The reaction progress was monitored byTLC until the starting material completely disappeared.The reaction mixture was diluted with water,the obtained precipitate was filtered off to give ethyl 2-bromo-4-methylthiazole-5-carboxylate 4 as off-whitesolid in 62percent yield. 1H NMR spectrum (CDCl3), δ,ppm: 4.28 q (2H), 2.81 s (3H), 1.33 t (3H). Massspectrum (ESI-MS): m/z 251 [M + H]+.
59%
With copper(I) bromide; isopentyl nitrite In acetonitrile at 80℃; for 4 h;
To a suspension of ethyl 2-amino-4-methylthiazole-5-carboxylate (1 g, 5.36 mmol, 1 eq) and CuBr2 (1.19 g, 5.36 mol, 1 eq) in acetonitrile (25 mL) was added isoamyl nitrite (2.16 mL, 16.08 mmol, 3 eq) dropwise at 25 °C, and the reaction mixture was stirred at 80°C for 4 h. The resulting reaction mixture was gradually cooled to 25 °C and concentrated under reduced pressure to remove excess isoamyl nitrite and acetonitrile. The residue obtained was partitioned between water (250 mL) and ethyl acetate (250 mL), and the organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude compound as a brownish solid. The crude product obtained was purified by silica gel (23 0-400) column chromatography (10percent ethyl acetate in hexane) to obtain ethyl 2-bromo-4-methylthiazole- 5-carboxylate (800 mg, 59percent) as a yellow solid.
Reference：
[1] Patent: WO2004/6923, 2004, A1, . Location in patent: Page/Page column 38
[2] Patent: WO2004/6924, 2004, A1, . Location in patent: Page/Page column 31-32
[3] Patent: WO2004/7493, 2004, A1, . Location in patent: Page 24-25
[4] Patent: EP2518054, 2012, A1, . Location in patent: Page/Page column 53
[5] Patent: WO2008/47109, 2008, A1, . Location in patent: Page/Page column 38
[6] Russian Journal of General Chemistry, 2016, vol. 86, # 7, p. 1722 - 1729[7] Zh. Obshch. Khim., 2016, vol. 86, # 7, p. 1722 - 1729,8
[8] Patent: WO2017/152032, 2017, A1, . Location in patent: Paragraph 00453
[9] Journal of medicinal chemistry, 1969, vol. 12, # 3, p. 553 - 553
[10] Roczniki Chemii, 1972, vol. 46, p. 1647 - 1658
[11] Patent: WO2011/73617, 2011, A1, . Location in patent: Page/Page column 25
[12] Chinese Chemical Letters, 2016, vol. 27, # 5, p. 703 - 706
[13] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 2, p. 1625 - 1629
3
[ 7210-76-6 ]
[ 110-46-3 ]
[ 22900-83-0 ]
Yield
Reaction Conditions
Operation in experiment
70%
With trimethylsilyl bromide In ethyl acetate; acetonitrile at 0 - 20℃;
[2-BROMO-4-METHYL-THIAZOLE-5-CARBOXVLIC] acid ethyl ester To a solution of 3-methyl-1-nitrosooxy-butane (19.8 mL, 2.1 eq) in acetonitrile (700 mL) was added at [0XB0;C] trimethylsillyl bromide (19.6 mL, 2.1 eq) and the mixture was stirred at [0XB0;C] for 20 min. A solution of 2-amino-4-methyl-thiazole-5-carboxylic acid ethyl ester (14.0 g, 1.0 eq) in acetonitrile/EtOAc : 75/25 (700 mL) was added slowly at [0XB0;C.] After stirring overnight at rt, the reaction mixture was evaporated and purified by flash chromatography to give the title compound (13.2 g, 0. [051MOL)] as an orange solid in a 70percent yield ; GC/MS: [M C7H8BRNO2S] 250;'H NMR [(CDC13,] 300 MHz) 5 4.32 (q, 2H), 2.69 (s, 3H), 1.34 (t, 3H)
With water; sodium hydroxide In tetrahydrofuran; ethanol at 50℃;
98%
With lithium hydroxide monohydrate In tetrahydrofuran; water at 20℃; for 16h;
18 Example 1818 Preparation of 2-bromo-4-methyl-thiazole-5-carboxylic acid
Example 18 Preparation of 2-bromo-4-methyl-thiazole-5-carboxylic acid To a solution of 2-bromo-4-methyl-thiazole-5-carboxylic acid ethyl ester (3.0 g, 12 mmol) in tetrahydrofuran (THF, 50 mL) and water (5 mL) was added lithium hydroxide hydrate (1.0 g, 24 mmol). The reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was diluted with water and ethyl acetate. The aqueous layer was made acidic to pH 1 with 2 N hydrochloric acid (HCl) and then was extracted with ethyl acetate. The organic extracts were dried over sodium sulfate (Na2SO4), filtered and concentrated to provide product as an orange solid (2.6 g, 98%): mp 152-155 °C; 1H NMR (300 MHz, CDCl3) δ 2.74 (s, 3H); ESIMS m/z 221 (M-1).
76%
With sodium hydroxide In ethanol; water at 20℃; for 14h;
2-Bromo-4-methylthiazole-5-carboxylic acid (5).
A solution of ethanolic NaOH (5 N, 15 mL) was added to a solution of compound 4 (1 mmol) in ethanol(20 mL) and the reaction mixture was stirred at room temperature for 14 h; the reaction progress was monitored by TLC. The reaction mixture was cooled and neutralized with conc. HCl. The organic layer was extracted with EtOAc and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to obtain crude product. The crude product was purified by column chromatography using silica gel(60-120 mesh) eluting with ethyl acetate and petroleum ether to obtain 2-bromo-4-methylthiazole-5-carboxylic acid 5 as off-white solid in 76% yield. 1HNMR spectrum (CDCl3), δ, ppm: 13.19 s (1H), 2.54 s(3H). Mass spectrum (ESI-MS): m/z 223 [M + H]+.
70%
With water; sodium hydroxide at 20℃;
Synthesis of 2-bromo-4-methylthiazole-5-carboxylicacid (4)
Ethyl-2-bromo-4-methylthiazole-5-carboxylate (3) (0.05 mol) in water (50 mL) taken in a 100 mL round bottom flask was added 5 % NaOH and stirred for 10-12 h. The reaction progress was monitored by TLC until the compound 3 was completely disappeared. After completion of the reaction, the mixture was diluted with water and extracted desired compound using ethyl acetate. The organic fraction was concentrated by evaporating solvent under reduced pressure to obtain pure compound 4 with 70 % yield (Off white solid). 1H NMR(CDCl3) δ 10.63 (br, OH), 2.52 (s, 3H), 1.33 (t, 3H); ESI-MS m/z 222 (M+1)
69%
With water; lithium hydroxide In ethanol at 20℃; for 3h;
24.A Step A. Synthesis of 2-bromo-4-methylthiazole-5-carboxylic acid.
To a solution of ethyl 2-bromo-4-methylthiazole-5-carboxylate (500 mg, 2 mmol) in EtOH (10 mL) and water (1 mL) was added LiOH (479 mg, 20 mmol), The resulting mixture was stirred at room temperature for 3 hrs. The mixture was neutralized with 1 N HCl, extracted with EtOAc (60 mL). The organic phase was washed with brine (20 mL×2), dried over Na2SO4, filtered, concentrated to afford 2-bromo-4-methylthiazole-5-carboxylic acid (320 mg, 69% yield) as a white solid. LCMS (M+1): 223.
With potassium hydroxide
With sodium hydroxide In methanol
With potassium hydroxide In water Heating;
Stage #1: ethyl 2-bromo-4-methyl-1,3-thiazole-5-carboxylate With sodium hydroxide; water In tetrahydrofuran; methanol at 20℃; for 2h;
Stage #2: With hydrogenchloride In tetrahydrofuran; methanol; water
8
To a stirred solution of Intermediate 7 (0.54 g, 2.16 mmol) in MeOH (5 mL), THF (1 mL) and water (1 mL) at r.t. was added NaOH (0.095 g, 2.38 mmol). After stirring for 2 h at r.t. the reaction mixture was neutralised with IN HCl to pH 6 and the solvent removed in vacuo to give an off-white solid (0.2 g, 0.9 mmol). The solid was suspended in DCM (5 mL) and DMF (3 drops) was added, followed by oxalyl chloride (0.07 mL, 1.08 mmol). The reaction mixture was stirred at r.t. for 4 h, then cyclopropylamine (0.07 mL, 1.08 mmol) was added and stirred at r.t. for 1 h. The reaction mixture was concentrated in vacuo to give a yellow oil. Purification by column chromatography(SiO2, 0-60% EtOAc/hexanes) gave the title compound (0.096 g, 21%) as a clear oil. δH (DMSOd6) 8.39 (IH, br. s), 2.76 (IH, m), 2.48 (3H, s), 0.69 (2H, m), 0.55 (2H, m). MS (ES+) 217.0 and 219.0 (M+H)+.
With nitrous acid isobutyl ester; trimethylsilyl bromide; In ethyl acetate; acetonitrile; at 0 - 20℃; for 24h;
TO A SOLUTION OF 2-METHYL-1-NITROSOOXY-PROPANE (28.2 ML, 2.1 EQ. ) IN CH3CN (700 ML) COOLED TO 0XB0;C WAS ADDED DROPWISE BROMO-TRIMETHYL-SILANE (32 ML, 2.1 EQ. ). THE] resulting mixture was maintained at [0XB0;C.] A solution of the available 2-amino-4- methyl-thiazole-5-carboxylic acid ethyl ester (18.6 g, 0.1 mol) in CH3CN/AcOEt 75/25 was added dropwise and the reaction mixture was maintained at [0XB0;C.] The mixture was stirred for 24 hours at rt. The solvent was evaporated and water was added. The product was extracted with AcOEt, dried over [NA2SO4,] filtered and evaporated. The title compound was obtained as a yellow solid (21.74 g, 87 [MMOL)] in 87% yield after purification by flash chromatography using DCM as eluent ; GC/MS: [M'C7H8BRNO2S] 250.
87%
A solution of 2-methyl-1-nitrosooxy-propane (28.2 ml, 2.1 eq.) in CH3CN (700 ml) was cooled to 0C and bromo-trimethyl-silane (32 ml, 2.1 eq.) was added dropwise over 20 min. A solution of the available 2-amino-4-methyl-thiazole-5-carboxylic acid ethyl ester (18.6 g, 0.1 mot) in a mixture CH3CN/EtOAc : 75/25 heated to 55C was added dropwise over 45 min. During the addition the reaction was maintained at 0C and then allowed to warm to rt and stirred for 2 hours. After evaporation, the product was extracted with AcOEt, washed with water, dried over Na2SO4, filtered and evaporated. The title compound was obtained as a yellow solid (21.74 g, 86.96 mmol) in a 87% yield; GC/MS : M+ C7H6BrNO2S 250.
85%
With nitrous acid isobutyl ester; trimethylsilyl bromide; In ethyl acetate; acetonitrile; at 0 - 20℃; for 2.75h;
A solution of 2-methyl-1-nitrosooxypropane (20 [ML,] 2 eq) in CH3CN (700 mL) was [COOLED TO 0C AND BROMO-TRIMETHYL-SILANE (20 ML, 2 EQ. ) WAS ADDED DROPWISE OVER 20] min. The available 2-amino-4-methyl-thiazole-5-carboxylic acid ethyl ester (14.0 g, 75.2 [MMOL)] in a mixture of CH3CN/EtOAc [(75/25)] at [55C] was added dropwise over 45 min. During the addition the reaction was maintained at [0C.] After return at rt, the mixture was stirred for 2 hours. After evaporation, the product was extracted with DCM, washed with water, dried over [NA2SO4,] filtered and evaporated off. The title compound was obtained as a pale orange solid (16.06 g, 75.2 [MMOL)] in a 85% yield ; GC/MS: [M+ C7H8BRNO2S] 250
83%
A solution of copper(II) bromide (3.6 g, 16.11 mmol) and n-amyl nitrite (1.07 mL, 8.06 mmol) in acetonitrile (22 mL) was heated to 60C, and a solution of ethyl 2-amino-4-methyl-1,3-thiazole-5-carboxylate (1.0 g, 5.37 mmol) in acetonitrile (30 mL) was added dropwise thereto. The mixture was stirred for 4 hr at same temperature. The reaction mixture was allowed to cool to room temperature, and added into ice-cooled 1N aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate= 95:5→85:15) to give the title compound (1.1 g, 83%). 1H-NMR (CDCl3) δ : 1.37 (3 H, t, J = 7.1 Hz), 2.72 (3 H, s), 4.33 (2 H, q, J = 7.1 Hz).
76%
With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 0℃; for 4h;
To a stirred solution of Intermediate 6 (0.53 g, 2.85 mmol) in MeCN (6 mL) at00C was added CuBr2 (0.70 g, 3.13 mmol) followed by dropwise addition of tert-buty nitrite (0.44 mL, 3.70 mmol). After stirring at 00C for 4 h, the reaction mixture was concentrated in vacuo to give a black oil. Purification by column chromatography (SiO2, 0-50% EtOAc/hexanes) gave the title compound (0.54 g, 76%) as a yellow solid. 6H (CDCl3) 4.33 (2H, q, J 7.0 Hz), 2.71 (3H, s), 1.36 (3H, t, J 7.2 Hz). MS (ES+) 252.0 (M+H)+.
62%
With potassium bromide; copper(I) bromide; sodium nitrite; In water; at 60℃; for 1h;
Compound 3 (1 mmol) in HBr (3 mL) was added to cold aqueous solution of CuBr (1 mmol) and KBr(0.2 mmol) followed by dropwise addition of preliminary cooled aqueous solution of NaNO2(10 mL) for 1 h. The reaction mixture was stirred at 60C for 2 h. The reaction progress was monitored byTLC until the starting material completely disappeared.The reaction mixture was diluted with water,the obtained precipitate was filtered off to give ethyl 2-bromo-4-methylthiazole-5-carboxylate 4 as off-whitesolid in 62% yield. 1H NMR spectrum (CDCl3), δ,ppm: 4.28 q (2H), 2.81 s (3H), 1.33 t (3H). Massspectrum (ESI-MS): m/z 251 [M + H]+.
59%
With copper(I) bromide; isopentyl nitrite; In acetonitrile; at 80℃; for 4h;
To a suspension of ethyl 2-amino-4-methylthiazole-5-carboxylate (1 g, 5.36 mmol, 1 eq) and CuBr2 (1.19 g, 5.36 mol, 1 eq) in acetonitrile (25 mL) was added isoamyl nitrite (2.16 mL, 16.08 mmol, 3 eq) dropwise at 25 C, and the reaction mixture was stirred at 80C for 4 h. The resulting reaction mixture was gradually cooled to 25 C and concentrated under reduced pressure to remove excess isoamyl nitrite and acetonitrile. The residue obtained was partitioned between water (250 mL) and ethyl acetate (250 mL), and the organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude compound as a brownish solid. The crude product obtained was purified by silica gel (23 0-400) column chromatography (10% ethyl acetate in hexane) to obtain ethyl 2-bromo-4-methylthiazole- 5-carboxylate (800 mg, 59%) as a yellow solid.
With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 60℃; for 1h;
Preparation of ethyl 2-bromo-4-methyithiazole-5-carboxylate (compound B: L=bromo: R=ethyl) To a solution of CuBr2 (75 gms/0.335 moles) in 750 ml acetonitrile was added t-butyl nitrite (28.6 gms/0.277 moles). The resultant mixture was heated to 60C and ethyl 2- amino-4-methylthiazole-5-carboxylate (35.0 gms/0.188moles) was further added in lots. The reaction mass was stirred for 1 hour at 60C. After completion of reaction, the reaction mass was cooled to 25C and about 150 ml water was added. The reaction mass was neutralized using 2N NaOH and extracted in ethyl acetate (300 ml). The organic layer was washed with water until a neutral pH. The separated organic layer was treated with charcoal. After drying the organic layer over anhydrous sodium sulphate, a clear filtrate was distilled off and 17.1 gms of the titled compound was obtained after drying at 40-45C as an off-white colored solid. Efficiency: 36%
4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 100℃; for 16h;
To a solution of 2-bromo-4-methyl-thiazole-5-carboxylic acid ethyl ester (2.0 g, 7.99 mmol) in toluene (60 mL), water (20 mL) and ethanol (20 mL) was added IH- pyrazole-5-boronic acid (1.79 g, 15.99 mmol), Pd(PPh3^ (0.92 g, 0.80 mmol), and <n="82"/>50352potassium carbonate (3.30 g, 23.98 mmol). The resulting mixture was degassed three times and heated to 100 0C for 16 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (200 mL) and washed with brine (2 x 100 mL). The organic phase was dried (Na2SO4) and evaporated. The residue was purified by flash column chromatography (hexanes:ethyl acetate, 1 : 1) to provide 4-methyl-2-(2H-pyrazol- 3-yl)-thiazole-5-carboxylic acid ethyl ester (1.5 g, 83percent yield) as a yellow solid. MS (M+eta)+ = 238; R, = 1.2 min.
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In DMF (N,N-dimethyl-formamide); water; at 100℃; for 48h;
To a solution of intermediate 29 (10.0 g, 40 mmol) in DMF (200 ml) was added Pd(PPh3)4 (2.76 g, 0.06 eq.), A 2M Na2CO3 solution (50 ml, 2.5 eq.) and 4-cyanophenyboronic acid (11.68 g, 2.0 eq. ) and the mixture was stirred at 100C for 2 days. After evaporation of DMF, water was added and the product was extracted with DCM and the organic layer was filtered through a bed of celite. The filtrate was dried over Na2SO4 and evaporated. The title compound was obtained as a white solid (10.1 g, 37 mmol) in a 92. 8% yield after purification by flash chromatography using DCM/cyclohexane 80/20 and 90/10 as eluent; GC/MS: M+ C14H12N202S 272.
60%
A solution of intermediate 8 (16.06g, 64.2 [MMOL),] 4-cyanophenyboronic acid (14.15 [G, 1.5 EQ. ) AND PD (PPH3) 4 (3. 71G, 0.05 EQ. ) IN DME (200 ML) WAS STIRRED AT RT FOR 30 MIN. 2M NA2CO3 SOLUTION (80 ML, 2.5 EQ. ) WAS ADDED AND THE REACTION MIXTURE WAS] heated at [80C] overnight. The resulting solution was filtered and the filtrate was evaporated. The product was extracted with DCM, washed with a NaHCO3 saturated solution, dried over [NA2S04,] filtered and evaporated. Purification by flash chromatography using [DCM/CYCLOHEXANE] 80/20 and 90/10 as eluents gave the title compound as a yellow solid (10.4 g, 38.23 [MMOL)] in 60% yield; m. p. [144C.]
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In DMF (N,N-dimethyl-formamide); at 100℃; for 24h;Heating / reflux;
To a solution of intermediate 42 (10. 0g, 40 [MMOL)] in DMF (200 mL) was added [PD (PPH3) 4 (2.76 G, 0.06 EQ. ), A 2M NA2CO3 SOLUTION (50 ML, 2.5 EQ. ) AND 4-] cyanophenyboronic acid (11.68 g, 2.0 eq) and the mixture was heated at [100XB0;C] for 24 hours. After evaporation of the solvent, water and DCM were added and the resulting solution was filtered through a bed of celite. Evaporation of the filtrate gave a residue which was purified by flash chromatography using DCM/cyclohexane 80/20 and [DCM/CYCLOHEXANE] 90/10 as eluents to give the title compound; GC/MS: M+ [C, 4H, 2N202S] 272.
With trimethylsilyl bromide; In ethyl acetate; acetonitrile; at 0 - 20℃;
[2-BROMO-4-METHYL-THIAZOLE-5-CARBOXVLIC] acid ethyl ester To a solution of 3-methyl-1-nitrosooxy-butane (19.8 mL, 2.1 eq) in acetonitrile (700 mL) was added at [0XB0;C] trimethylsillyl bromide (19.6 mL, 2.1 eq) and the mixture was stirred at [0XB0;C] for 20 min. A solution of 2-amino-4-methyl-thiazole-5-carboxylic acid ethyl ester (14.0 g, 1.0 eq) in acetonitrile/EtOAc : 75/25 (700 mL) was added slowly at [0XB0;C.] After stirring overnight at rt, the reaction mixture was evaporated and purified by flash chromatography to give the title compound (13.2 g, 0. [051MOL)] as an orange solid in a 70% yield ; GC/MS: [M C7H8BRNO2S] 250;'H NMR [(CDC13,] 300 MHz) 5 4.32 (q, 2H), 2.69 (s, 3H), 1.34 (t, 3H)
With potassium carbonate; In ethanol; water; toluene;Heating / reflux;
Ethyl 2-bromo-4-methyl-l,3-thiazole-5-carboxylate (1 g, 1.3 eq, 4 mmol) is added to a mixture of 2-chloro-5 -pyridine boronic acid (0.48 g, 1 eq, 3.07 mmol), tetrakis(triphenylphosphine)palladium (0.18 g, 0.05 eq, 0.15 mmol) and an aqueous solution of 2 Mpotassium carbonate (3 ml, 2 eq, 6.14 mmol) in toluene/ethanol (18 ml, 2:1 v/v). The mixture is refluxed overnight and the solvent is evaporated, then taken up in ethyl acetate, and washed two times with an aqueous solution of sodium hydrogenocarbonate. EPO <DP n="121"/>The organic layer is dried over magnesium sulfate, filtered and concentrated under vacuum. Purification by chromatography over silicagel (eluent: dichloromethane 100 %) affords 0.6 g of ethyl 2-(6-chloropyridin-3-yl)-4-methyl-l,3-thiazole-5-carboxylate i97.Yield: 69 %. LC-MS (MH+): 283/285.
With sodium tetrahydroborate In ethanol; water at 20℃; for 12h;
65%
With sodium tetrahydroborate In ethanol; water at 20℃;
97
PREPARATION 97(2-Bromo-4-methylthiazol-5-yl)methanol To a solution of ethyl 2-bromo-4-methylthiazole-5-carboxylate (7 g, 28 mmol) in EtOH (120 mL) and H20 (20 mL) was added portion-wise NaBH4 (3.2 g, 84 mmol). After the addition, the mixture was stirred at room temperature overnight. TLC (petroleum ether/EtOAc = 5:1 ) showed the reaction was complete. The reaction mixture was carefully concentrated in vacuum. The residue was separated between EtOAc (50 mL) and H2O (50 mL). The inorganic layer was extracted with EtOAc (50 mLx2). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuum to give the title compound as a colorless oil (3.8 g, 65%).
58%
With sodium tetrahydroborate In ethanol; water at 0 - 20℃; for 16h;
34 Preparation of (2-bromo-4-methylthiazol-5-yl)methanol:
To a solution of ethyl 2-bromo-4-methylthiazole-5-carboxylate prepared in Example 1 Step 2 (8.0 g, 32 mmol) in ethanol (60 mL) and water (10 mL) was added NaBH4 (3.0 g, 80 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were concentrated and purified by silica gel column chromatography with petroleum ether/ethyl acetate (2: 1) to provide (2-bromo-4-methylthiazol-5- yl)methanol (3.8 g, 58%) as a yellow oil. MS (ESI) m/z: 208.1, 210.1 (M + H)+
With sodium tetrahydroborate In ethanol; water; ethyl acetate at 20℃; for 12h;
44
sodium borohydride (1.2 g, 31.2 mmol) is carefully added to a solution of 2-Bromo-4-methyl-thiazole-5-carboxylic acid ethyl ester (3.6 g, 15.6 mmol) in ethanol (100 mL) and water (1 mL) and stirred at room temperature for twelve hours. The solvent is carefully removed under reduced pressure, the residue is taken up in ethylacetate and washed with water. The organic phase is separated and dried over MgSO4. The organic solvent is removed under reduced pressure to give 3.2 g of (2-Bromo-4-methyl-thiazol-5-yl)-methanol, which was used without further purification.C5H6BrNOS (208.08), MS (ESI): 208.0 (M+H+).
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; toluene; at 70 - 75℃; for 1h;
Preparation of ethyl-2-(3-cvano-4-isobutoxyphenyl)-4-methyl thiazole-5 carboxylate (ethyl ester of febuxostat) 3-cyano-4-isobutoxyphenyl boronic acid (2.0 gms/0.009132 moles), ethyl-2-bromo-4-methylthiazole-5-carboxylate (2.28 gms/0.009132 moles) and 20 ml of 2M aqueous sodium carbonate solution were charged in 30 ml toluene, followed by tetrakis (triphenyl phosphine) palladium (0.6 gms/5 molepercent). The resultant mixture was stirred at 70- 75°C for 1 hour. After completion of reaction, the reaction mass was cooled to 25°C and extracted in ethyl acetate (30ml). The organic layer was washed with brine. After drying the organic layer over anhydrous sodium sulphate, clear filtrate was distilled off and the residue was stirred in diisopropyl ether (30 ml). The resulting solid was isolated by filtration to yield 2.0 gms of the titled compound. Efficiency: 63percent
With sodium carbonate In 1,2-dimethoxyethane; water at 120℃; for 0.5h;
32
Thiazole 32-112 (250 mg, 1 mmol), boronic ester 16-61 (360 mg, 1.5 mmol), and Pd(PPh3)4 (60 mg, 0.05 mmol) are combined with 2 N aqueous Na2C03 solution (1.5 mL, 3 mmol) in 1,2-DME (9 mL), and then irradiated at 120 °C for 30 min. The solvent is evaporated under N2, and the crude residue purified by column chromatography on silica gel (using a gradient of 5-100% EtO Ac/heptane) to afford intermediate 32-113 (77 mg).
ethyl 2-(4-fluorophenoxy)-4-methyl-1,3-thiazole-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With caesium carbonate In dimethyl sulfoxide at 45℃; for 16h;
1.1 Example 1.1 : ethyl 2-(4-fluorophenoxy)-4-methylthiazole-5-carboxylate
4-Fluorophenol (Sigma-Aldrich; 2 g; 17.84 mmol), ethyl 2-bromo-4-methylthiazole-5- carboxylate (Ark Pharm; 4 g; 16 mmol), and cesium carbonate (Sigma-Aldrich; 6.24 g; 19.15 mmol) were thoroughly mixed in 32 ml anhydrous dimethylsulfoxide, and the resulting slurry stirred vigorously 16 h at 45°C. After cooling to 25°C, the reaction mixture was poured into 200 ml water. Organics were extracted with 4x100 ml ether, and the pooled extracts were washed with 50 ml water, washed with 50 ml brine, dried over anhydrous sodium sulfate, filtered, and concentrated to 4.51 g brown solid. NMR showed the desired product, ethyl 2- (4-fluorophenoxy)-4-methylthiazole-5-carboxylate, which was used in the next step without further purification. Yield: 4.51 g (100%).1H NMR (400 MHz, CDCb): d 7.21 (m, 2H), 7.05 (m, 2H), 4.28 (q, 2H),) 2.48 (s, 3H), 1.32 (t, 3H
92%
With potassium carbonate In N,N-dimethyl-formamide at 95℃; for 15h;
1 Step 1: ethyl 2-(4-fluorophenoxy)-4-methyl-1 ,3-thiazole-5-carboxylate
A mixture of 1.0 g (4.0 mmol) ethyl 2-bromo-4-methyl-1,3-thiazole-5-carboxylate,0.54 g (4.8 mmol) 4-fluorophenol and 0.72 g (5.2 mmol) potassium carbonate in 10 mL DMF was heated for 15 hours at 95°C. After cooling to room temperature the mixture was diluted with 50 mL ethylacetate and 50 mL water. After separation of the phases the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with 30 mL each of water, 2M NaOH and brine, thendried over sodium sulfate and after filtration concentrated under reduced pressure. The residue was purified via a Biotage chromatography system (25g snap KP-Sil column, hexane I 0 - 100% ethyl acetate, then ethyl acetate I 0 - 100% methanol) to give 1.15 g (92% yield) of the desired title compound.
With tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 20℃; for 36h;
The above prepared mixture was added to ethyl 2-bromo-4-methylthiazole-5-carboxylate (249 mg, 1 mmol) under anhydrous anaerobic conditions,And Pd (PPh3) 4 (116 mg, 0.1 mmol).Stirring at room temperature, TLC monitoring reaction.After completion of the reaction, brine (20 mL) was added and extracted with ethyl acetate (100 mL x3).The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated and chromatographed (petroleum ether: ethyl acetate (v / v) = 10: 1) to give the title compound as a white solid (0.21 g, 61percent)
ethyl 2-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)-4-methylthiazole-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In water; N,N-dimethyl-formamide; at 90℃; for 24h;Inert atmosphere;
General procedure: Under nitrogen protection,tert-Butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate ( 0.50 g, 1.3 mmol), 2-chloro-4,6-dimethoxypyrimidine (0.23 g, 1.3 mmol), sodium carbonate(0.41 g, 3.9 mmol) and Pd(dppf)Cl2 (0.51 g, 0.07 mmol) were added to DMF (10 mL) and water (5 mL).After three times of gas, the temperature was raised to 90 C for 24 h, the reaction was completed, cooled to room temperature, and the mixture was washed with water (30 mL), dichloromethane(20 mL × 3), the combined organic phases were dried over anhydrous sodium sulfate and filtered.The filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column ( petroleum ether / ethyl acetate (v/v) = 8/1).concentrate,Dry to give the title compound as a white solid(0.32g, 62.1%).
2-(2-(4-(Boc)piperazin-1-yl)pyrimidin-5-yl)-4-methylthiazole-5-carboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72.6%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 2-methyltetrahydrofuran; water; at 100℃;Inert atmosphere;
The title compound of this step was prepared by the method described in Example 7, Step 1, namely, 2-(4-Boc-piperazin-1-yl)pyrimidine-5-boronic acid pinacol ester (1.50 g, 3.84 mmol), ethyl 2-bromo-4-methylthiazole-5-formate (1.15 g, 4.61 mmol), cesium carbonate (3.13 g, 9.60 mmol) and [1,1?-bis(diphenylphosphino)ferrocene]palladium dichloride (II) (141 mg, 0.19 mmol) were added to a mixed solvent of 2-methyltetrahydrofuran (15 mL) and water (3 mL), the mixture was heated to 100 C and reacted overnight under N2. The residue was further purified by a silica gel column chromatography (dichloromethane/methanol (v/v) = 60/1) to give the title compound as a faint yellow solid (1.21 g, 72.6%).MS (ESI, pos. ion) m/z: 434.25 [M+Hfb;?HNMR (600 MHz, DMSO-d6) (ppm): 8.84 (s, 2H), 4.27 (q, J= 7.1 Hz, 2H), 3.913.79 (m, 4H), 3.43 (dd, J= 14.7, 10.3 Hz, 4H), 2.59 (s, 3H), 1.45 (s, 9H), 1.30 (t, J= 7.1 Hz, 3H).
72.6%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 2-methyltetrahydrofuran; water; at 100℃;Inert atmosphere;
The title compound of this step is prepared by the method described in the first step of Example 7,2-(4-Boc-piperazin-1-yl)pyrimidine-5-boronic acid pinacol ester (1.50 g, 3.84 mmol),Ethyl 2-bromo-4-methylthiazole-5-carboxylate (1.15 g, 4.61 mmol) and cesium carbonate (3.13 g, 9.60 mmol) and[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (141 mg, 0.19 mmol) in 2-methyltetrahydrofuran (15 mL)A mixed solvent of water (3 mL) was prepared by reacting at 100 C overnight under a nitrogen atmosphere.The obtained crude product was further purified by silica gel chromatography (dichloromethane:methanol (V:V)=60:1) to give the title compound(light yellow solid, 1.21 g, 72.6%).
ethyl 2-{5-[(tert-butoxy)carbonyl]-octahydropyrrolo[3,4-c]pyrrol-2-yl}-4-methyl-1,3-thiazole-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75.1%
With sodium carbonate In acetonitrile at 80℃; for 4h;
9.1 Step 1) Synthesis of 2-(5-(tert-Butoxycarbonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)-4-methylthiazole-5-carboxylate
According to Synthetic Method 2: 2-bromo-4-methylthiazole-5-carboxylic acid ethyl ester (2.592 g, 10.36 mmol),Hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (2.000 g, 9.42 mmol), sodium carbonate (2.51 g, 23.6 mmol) and acetonitrile (40 mL) were added to a 100 mL reaction flask The reaction was carried out under reflux at 80 ° C for 4 hours.The reaction was completed by TLC and the reaction was stopped. Cool to room temperature, spin dry, purified by silica gel column ( petroleum ether / ethyl acetate (v / v) = 3 / 1), concentrated and dried to give the title compoundThe material was a pale yellow solid (2.70 g, yield: 75.1%).
2-(5-(tert-butoxycarbonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)-4-methylthiazole-5-carboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With sodium carbonate; In acetonitrile; for 15h;Reflux;
The title compound of this step is prepared by the method described in the second step of Example 1,That is, cis-2-Boc-hexahydropyrrolo[3,4-c]pyrrole (0.53 g, 2.50 mmol) was sequentially added to a 100 mL eggplant-shaped flask.Sodium carbonate (1.06 g, 10.00 mmol), ethyl 2-bromo-4-methylthiazole-5-carboxylate (0.66 g, 2.64 mmol) and acetonitrile (15 mL).Then, the temperature was raised to reflux and the reaction was carried out for 15 hours.After the reaction is completed, the solvent is dried, and then dichloromethane and water are added, and the layers are separated.The aqueous phase was extracted with dichloromethane (3×50 mL).It was washed with saturated brine (50 mL) to give a pale yellow liquid.(= 2/1 petroleum ether / ethyl acetate (v / v)) to give the title compound by silica gel column chromatography as a pale yellow viscous liquid (0.77g, 81%).
With tetrakis(triphenylphosphine) palladium(0) In tetrahydrofuran at 70℃; for 2h;
Tetrakis(triphenylphosphine)palladium(0) (0.235 g, 0.204 mmol) was added to ethyl 2-bromo-4-methylthiazole-5-carboxylate (1 .018 g, 4.07 mmol) in tetrahydrofuran (3 ml_). Then a solution of (3-chlorophenyl)zinc(l l) iodide (12.21 ml_, 6.1 1 mmol) was added via syringe (exothermic). The reaction mixture was stirred in a heating block at 70 °C. An additional portion of (3-chlorophenyl)zinc(ll) iodide (1 .2 ml_) was added after 75 minutes and heating resumed for 45 minutes. After cooling, the reaction mixture was poured into saturated ammonium chloride and extracted with ethyl acetate (3X). The combined organics were washed with water and saturated sodium chloride, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with ethyl acetate:hexanes (0: 1 to 1 :0) to afford ethyl 2-(3-chlorophenyl)-4-methylthiazole- 5-carboxylate (1 .019 g, 3.62 mmol, 89 % yield) as a colorless solid . 1 H NMR (400 MHz, CD3SOCD3) d 1 .31 (t, J = 7 Hz, 3 H), 2.69 (s, 3 H), 4.30 (q, J = 7 Hz, 2 H), 7.55 (t, J = 8 Hz, 1 H), 7.62 (ddd , J = 8, 2, 1 Hz, 1 H), 7.94 (ddd , J = 8, 2, 1 Hz, 1 H), 8.00 (t, J = 2 Hz, 1 H); LC-MS (LC-ES) M+H = 282.
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