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With sodium chlorite; aminosulfonic acid; water In tetrahydrofuran at 20℃; for 2 h;
To a solution of compound II (500 mg, 2.74 mmol) in THF (18 ml) and water (12 ml) was added a mixture of sulfanylamide (346 mg, 3.56 mmol) and NaClO2 (323 mg, 3.56 mmol) in water (2 ml). The mixture was stirred at room temperature for 2 hours, diluted with AcOEt, and washed with water. The organic phase was separated, concentrated in vacuo to afford the title compound of formula III (440 mg, 88percent) as a yellow solid.
With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78 - 20℃; for 18 h; Cooling
Diisopropylamine (42 ml, 297 mmol) was dissolved in 1000 ml THF and cooled to -70°C. 181 .2 ml nBuLi (1.6M in hexane, 290 mmol) was added. The temperature was briefly raised to 0°C and the reaction mixture was again cooled down to -70°C. 2,4-Dichlorothiazole (40.8 g, 265 mmol) in 200 ml THF was slowly added at -70°C. Dry ice was put in a separate vessel connected to the reaction mixture with a teflon tube and the C02 formed bubbled in the reaction mixture at -78°C. The mixture was stirred for 18 hours in the cooling bath and the temperature reached 20°C. The mixture was quenched with 2N HCI. After saturating the water phase with NaCI, the mixture was extracted with ethyl acetate, dried with MgS04 and evaporated to give 48.0 g 2,4-dichloro-thiazole-5-carboxylic acid, Mp: 165 - 166°C.
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1992, # 2, p. 215 - 219
[2] Patent: EP2532661, 2012, A1, . Location in patent: Page/Page column 23-24
[3] Patent: WO2012/168361, 2012, A1, . Location in patent: Page/Page column 49-50
[4] Patent: WO2013/156433, 2013, A1, . Location in patent: Page/Page column 19; 37-38
[5] Patent: WO2017/156493, 2017, A1, . Location in patent: Paragraph 0182; 0214
Example P2: Preparation of 2,4-dichloro-thiazole-5-carboxylic acid: [Show Image] Diisopropylamine (42 ml, 297 mmol) was dissolved in 1000 ml THF and cooled to -70C. 181.2 ml nBuLi (1.6M in hexane, 290 mmol) was added. The temperature was briefly raised to 0C and the reaction mixture was again cooled down to -70C. 2,4-Dichlorothiazole (40.8 g, 265 mmol) in 200 ml THF was slowly added at -70C. Dry ice was put in a separate vessel connected to the reaction mixture with a Teflon tube and the CO2 formed bubbled in the reaction mixture at -78C. The mixture was stirred for 18 hours in the cooling bath and the temperature reached 20C. The mixture was quenched with 2N HCl. After saturating the water phase with NaCl, the mixture was extracted with ethyl acetate, dried with MgSO4 and evaporated to give 48.0 g 2,4-dichloro-thiazole-5-carboxylic acid, mp: 165 - 166C.
With n-butyllithium; diisopropylamine; In tetrahydrofuran; hexane; at -78 - 0℃; for 18h;
Example P2: Preparation of 2,4-dichloro-thiazole-5-carboxylic acid: Case 73264FFTDiisopropylamine (42 ml, 297 mmol) was dissolved in 1000 ml THF and cooled to -70C. 181 .2 ml nBuLi (1 .6M in hexane, 290 mmol) was added. The temperature was briefly raised to 0C and the reaction mixture was again cooled down to -70C. 2,4-Dichlorothiazole (40.8 g, 265 mmol) in 200 ml THF was slowly added at -70C. Dry ice was put in a separate vessel connected to the reaction mixture with a Teflon tube and the C02 formed bubbled in the reaction mixture at -78C. The mixture was stirred for 18 hours in the cooling bath and the temperature reached 20C. The mixture was quenched with 2N HCI. After saturating the water phase with NaCI, the mixture was extracted with ethyl acetate, dried with MgS04 and evaporated to give 48.0 g 2,4-dichloro-thiazole-5-carboxylic acid, mp: 165 - 166C.
48 g
With n-butyllithium; diisopropylamine; In tetrahydrofuran; hexane; at -78 - 20℃; for 18h;Cooling;
Diisopropylamine (42 ml, 297 mmol) was dissolved in 1000 ml THF and cooled to -70C. 181 .2 ml nBuLi (1.6M in hexane, 290 mmol) was added. The temperature was briefly raised to 0C and the reaction mixture was again cooled down to -70C. 2,4-Dichlorothiazole (40.8 g, 265 mmol) in 200 ml THF was slowly added at -70C. Dry ice was put in a separate vessel connected to the reaction mixture with a teflon tube and the C02 formed bubbled in the reaction mixture at -78C. The mixture was stirred for 18 hours in the cooling bath and the temperature reached 20C. The mixture was quenched with 2N HCI. After saturating the water phase with NaCI, the mixture was extracted with ethyl acetate, dried with MgS04 and evaporated to give 48.0 g 2,4-dichloro-thiazole-5-carboxylic acid, Mp: 165 - 166C.
To a solution of LDA (2 M, 178.55 mL) in THF (50mL) was added a solution of 2,4-dichlorothiazole (50 g, 324.63 mmol) dropwise in THF (200 mL) at-78C over 30 mm. After addition, the mixture was stirred at this temperature for 30 mi andthen carbon dioxide (14.29 g, 324.63 mmol) was added at -78C. The resulting mixture was warmed to 25 C and stirred for lh. The cmde mixture cmde poured into iN HCl (1 L) and extracted with EtOAc (3 x 500 mL). The combined organic phase was washed with brine (500 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was washed with PE (300 mL), filtered and the filtrate was concentrated under reduced pressure to afford 2, 4-dichlorothiazole-5-carboxylic acid as a yellow solid. 1H NMR (400 MHz, CDCl3): 9.69 (s, 1H).
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 5h;
To a solution of compound III (1.04 g, 5.2 mmol), K2CO3 (1.078 g, 7.8 mmol) in DMF (20 ml) was added MeI (0.36 ml, 6.24 mmol). After stirring at room temperature for 5 hours, the mixture was diluted with AcOEt, and washed with water. The organic phase was separated, concentrated in vacuo, and then purified by chromatography on a silica gel column using CHCl3 as an eluant to afford the title compound of formula IV (832 mg, 79%) as a pale yellow solid 1H NMR (400 MHz, CDCl3) ppm 3.91 (s, 3H)
With sodium chlorite; aminosulfonic acid; water; In tetrahydrofuran; at 20℃; for 2h;
To a solution of compound II (500 mg, 2.74 mmol) in THF (18 ml) and water (12 ml) was added a mixture of sulfanylamide (346 mg, 3.56 mmol) and NaClO2 (323 mg, 3.56 mmol) in water (2 ml). The mixture was stirred at room temperature for 2 hours, diluted with AcOEt, and washed with water. The organic phase was separated, concentrated in vacuo to afford the title compound of formula III (440 mg, 88%) as a yellow solid.
Example P3: Preparation of 4-chloro-2-pyridin-3-yl-thiazole-5-carboxylic acid: [Show Image] 9.0 g (45 mmol) <strong>[62019-56-1]2,4-dichloro-thiazole-5-carboxylic acid</strong> and 7.5 g (60 mmol) 3-pyridine boronic acid were dissolved in 180 ml dimethoxyethane. 12.0 g Na2CO3 in 60 ml water was added and the mixture was purged with argon for 5 min. Pd(PPh3)4 (1.5 g, 1.3 mmol) was added and the reaction was heated at 85C for 18 hours. After cooling, 100 ml NaOH 1 N and 150 ml ethyl acetate were added and the mixture was stirred 15 min. The water phase was separated and acidified with HCl 1N to pH 2-3. Crystals separated which were filtered and digested with diethyl ether/acetonitrile to give 9.4 g brown crystals of 4-chloro-2-pyridin-3-yl-thiazole-5-carboxylic acid. M.p.: 238-251C.
Example P3: Preparation of 4-chloro-2-pyridin-3-yl-thiazole-5-carboxylic acid:9.0 g (45 mmol) <strong>[62019-56-1]2,4-dichloro-thiazole-5-carboxylic acid</strong> and 7.5 g (60 mmol) 3-pyridine boronic acid were dissolved in 180 ml dimethoxyethane. 12.0 g Na2C03 in 60 ml water was added and the mixture was purged with argon for 5 min. Pd(PPh3)4 (1 .5 g, 1.3 mmol) was added and the reaction was heated at 85C for 18 hours. After cooling, 100 ml NaOH 1 N and 150 ml ethyl acetate were added and the mixture was stirred 15 min. The water phase was separated and acidified with HC1 1 N to pH 2-3. Crystals separated which were filtered and digested with diethyl ether/acetonitrile to give 9.4 g brown crystals of 4-chloro-2-pyridin-3-yl- thiazole-5-carboxylic acid. M.p.: 238-251 C.
9.4 g
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 85℃; for 18h;Inert atmosphere;
9.0 g (45 mmol) <strong>[62019-56-1]2,4-dichloro-thiazole-5-carboxylic acid</strong> and 7.5 g (60 mmol) 3-pyridine boronic acid were dissolved in 180 ml dimethoxyethane. 12.0 g Na2C03 in 60 ml water was added and the mixture was purged with argon for 5 min. Pd(PPh3)4 (1 .5 g, 1.3 mmol) was added and the reaction was heated at 85C for 18 hours. After cooling, 100 ml NaOH 1 N and 150 ml ethyl acetate were added and the mixture was stirred 15 min. The water phase was separated and acidified with HC1 1 N to pH 2-3. Crystals separated which were filtered and digested with diethyl ether/acetonitrile to give 9.4 g brown crystals of 4-chloro-2-pyridin-3-yl- thiazole-5-carboxylic acid. Mp.: 238-251 C.
Example 60 Preparation of 2,4-dichloro-thiazole-5-carbonyl-azide To a solution of <strong>[62019-56-1]2,4-dichloro-thiazole-5-carboxylic acid</strong> (1.98 g, 10 mmol) in toluene (50 mL) was added Et3N (1.01 g, 10 mmol) followed by diphenyl phosphoryl azide (2.75 g, 10 mmol). The reaction mixture was stirred at room temperature for 20 h. The reaction mixture was concentrated in vacuo and purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes) to afford product as a brown solid (1.82 g, 82%): 13C NMR (75 MHz, CDCl3) delta 163.33, 156.83, 143.94, 124.02.
tert-butyl 2,4-dichlorothiazole-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
A suspension of <strong>[62019-56-1]2,4-dichlorothiazole-5-carboxylic acid</strong> (112 g, 565.57 mmol) in SOC12 (656 g, 5.51 mol, 400 mL) under N2 was stirred at 85 C for 2 h. The mixture was concentrated under reduced pressure. The residue in THF (500 mL) and DCM (500 mL) was added with t-BuOK (76.16 g, 678.68 mmol) slowly at 0 C under N2. The mixture was stirred at 0 C for 3 h. The mixture was poured into ice-water (1000 mL) and extracted with EtOAc (3 x 600 mL). The combined organic phase was washed with brine (600 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was adjusted pH=7 by 6 N NaOH, extracted with EtOAc (3 x 600 mL), washed with brine (600 mL), dried with anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (PE:EtOAc = 1:0 to 10:1) to give tert-butyl 2,4- dichlorothiazole-5-carboxylate as a yellow oil. 1H NMR (400 MHz, CDCl3): 1.56 (s, 9H).
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