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With diisopropylamine In N,N-dimethyl-formamide at 100℃; for 5 h;
The synthesis of ethyl 4-amino-2-(methylthio)thiazole-5-carboxylate Ethyl 2-mercaptoacetate (50 g, 0.416 mol) was dissolved in 500 ml of dimethylformamide and added with dimethyl N-thienodithioimino carbonate (67 g, 0.416 mol) and diisopropylamine (112 ml, 0.624 mol). After heating at 100° C. for 5 hours, the mixture was extracted with 500 ml of saturated ammonium chloride and 500 ml of ethylacetate, dried with sodium sulfate, filtered and concentrated under vacuum. After washing the solid with n-hexane, the title compound (90 g, 99percent) was obtained. 1H-NMR (400 MHz, CDCl3); δ 5.84 (brs, 2H), 4.26 (q, J=7.2 Hz, 2H), 2.63 (s, 3H), 1.32 (t, J=7.2 Hz, 3H); LC-MS 219 (MH+)
89%
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 100℃;
Ethyl 2-mercaptoacetate (5 g, 42 mmol, 1.0 eq) was dissolved in DMF (50 mL) and added with N-thienodi-thioimino carbonate (6.1 g, 42 mmol, 1.0 eq) and DIPEA (16.3 g, 126 mmol, 3.0 eq). After heating at 100 °C for 5 h, the mixture was diluted with saturated aqueous ammonium chloride (100 mL) and extracted with EtOAc (100 mLx2). The combined organic layer was washed with brine, dried, concentrated. The solid was washed with n-hexane and dried under vacuum to give the title compound (8 g, yield: 89percent) as a yellow solid. ESI-MS (M+H)+: 219.0.
Stage #1: for 1 h; Reflux Stage #2: With triethylamine In ethanol for 4 h; Reflux
The ethyl bromoacetate (1.96 g, 11.76 mmol) was added to a stirred solution of potassium methyl cyanimidodithiocarbonate 1 (2.0 g, 11.76 mmol) in EtOH (50 mL). The mixture was heated to reflux for 1 h. After cooling, Et3N (2.38 g, 23.52 mmol) was added and the mixture was heated to reflux for 4 h. The ethanol was evaporated and the residue was triturated with water (20 mL) followed by filtering. The solid was dried and then recrystallized from acetone to give compound 2 (2.4 g, 93percent). Light yellow solid; mp 101-103 °C; 1H NMR (400 MHz, CDCl3) δ (ppm): 5.80 (brs, 2H), 4.26 (q, 2H, J = 7.2 Hz), 2.63 (s, 3H), 1.32 (t, 3H, J = 7.2 Hz); HRMS (ESI) Calcd. for C7H11N2O2S2 [M+H]+: 219.0256; Found: 219.0248.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 22, p. 5911 - 5920
[2] Patent: WO2011/100838, 2011, A1, . Location in patent: Page/Page column 60; 61
3
[ 623-51-8 ]
[ 39736-29-3 ]
Reference：
[1] Patent: US5326776, 1994, A,
4
[ 84911-18-2 ]
[ 10191-61-4 ]
[ 39736-29-3 ]
Yield
Reaction Conditions
Operation in experiment
155 mg
at 20℃; for 0.333333 h; Green chemistry
General procedure: To asolution of acyclic 1,3-dicarbonyl compounds 12 (1.0 mmol) in EtOH (3.0 mL) was added NBS (178 mg, 1 mmol). Thereaction mixture was stirred for 10 min (30 min for 12b and 12e) at roomtemperature. Afterwards 7 (1 mmol)was added and the reaction mixture was stirred for another 20 min at roomtemperature. After that, the solvent was evaporated under reducedpressure, and the residue was purified viaa short silica gel column to afford the desired product 11.
General procedure: To asolution of acyclic 1,3-dicarbonyl compounds 12 (1.0 mmol) in EtOH (3.0 mL) was added NBS (178 mg, 1 mmol). Thereaction mixture was stirred for 10 min (30 min for 12b and 12e) at roomtemperature. Afterwards 7 (1 mmol)was added and the reaction mixture was stirred for another 20 min at roomtemperature. After that, the solvent was evaporated under reducedpressure, and the residue was purified viaa short silica gel column to afford the desired product 11.
32g of intermediate B was added to a 500ml three-necked bottle,Add 300ml of absolute ethanol,22g ethyl chloroacetate,Stir to warm to reflux for 15 minutes and cool to room temperature.Add 2.8g of triethylamine and reflux for 2h.TLC detection (TLC developing solvent: ethyl acetate: petroleum ether = 1: 1 volume ratio) The reaction of the raw materials was complete.The reaction solution was concentrated and added to water to precipitate a solid.Filtration, washing with petroleum ether,The filter cake was recrystallized with ethanol to obtain 36 g of 4-amino-2- (methylthio) thiazole-5-carboxylic acid ethyl ester.98.5% purity,Yield: 88%.
With diisopropylamine; In N,N-dimethyl-formamide; at 100℃; for 5h;
The synthesis of ethyl 4-amino-2-(methylthio)thiazole-5-carboxylate Ethyl 2-mercaptoacetate (50 g, 0.416 mol) was dissolved in 500 ml of dimethylformamide and added with dimethyl N-thienodithioimino carbonate (67 g, 0.416 mol) and diisopropylamine (112 ml, 0.624 mol). After heating at 100 C. for 5 hours, the mixture was extracted with 500 ml of saturated ammonium chloride and 500 ml of ethylacetate, dried with sodium sulfate, filtered and concentrated under vacuum. After washing the solid with n-hexane, the title compound (90 g, 99%) was obtained. 1H-NMR (400 MHz, CDCl3); delta 5.84 (brs, 2H), 4.26 (q, J=7.2 Hz, 2H), 2.63 (s, 3H), 1.32 (t, J=7.2 Hz, 3H); LC-MS 219 (MH+)
89%
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 100℃;
Ethyl 2-mercaptoacetate (5 g, 42 mmol, 1.0 eq) was dissolved in DMF (50 mL) and added with N-thienodi-thioimino carbonate (6.1 g, 42 mmol, 1.0 eq) and DIPEA (16.3 g, 126 mmol, 3.0 eq). After heating at 100 C for 5 h, the mixture was diluted with saturated aqueous ammonium chloride (100 mL) and extracted with EtOAc (100 mLx2). The combined organic layer was washed with brine, dried, concentrated. The solid was washed with n-hexane and dried under vacuum to give the title compound (8 g, yield: 89%) as a yellow solid. ESI-MS (M+H)+: 219.0.
With triethylamine; In N,N-dimethyl-formamide; at 100℃; for 2h;
General p Oroced "ure for the sy onthesi -s of Ul To a stirred solution of ethyl 2-mercaptoacetate (0.82 g, 6.80 mol)in N,N- dimethylformamide(8.5 mL)were added triethylamine (1.5 mL, 10.0 mmol) and dimethyl cyanocarbonimidodithioate (1.0 g, 6.80 mol)and the mixture was stirred at 100 Cfor 2 h. The reaction mixture was cooled to room temperature, diluted with EtO Ac (30 mL) and washed with water (30 mL). The organic layer was dried over MgS04 and concentrated invacuomd the resulting crude residue was purified by flash column chromatography (n- hexane:EtOAc = 20: 1) to give U1.1H NMR (400MHz, acetone-^) delta 6.56 (brs, 2H), 4.19 (q, J = 7.2 Hz, 2H), 2.67 (s, 3H), 1.27 (t, J= 7.2 Hz, 3H).
With N-ethyl-N,N-diisopropylamine; In N-methyl-acetamide;
Example 21B 4-{N-Propyl-N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}thiazole-5-carboxylic acid Ethyl 2-mercaptoacetate is reacted with dimethyl N-cyanodithioimino-carbonate under the action of N-ethyldiisopropylamine in dimethylformamide to give ethyl 4-amino-2-methylthiothiazole-5-carboxylate, according to the method of Gompper, et al., Tet. Letters, 1885 (1966).
With pyridine; In dichloromethane; at 20℃; for 1.25h;Cooling with ice; Inert atmosphere;
To an ice-cold solution of 6a3 (3.43 g, 15.7 mmol) in DCM (50 mL) under a N2 atmosphere is added pyridine (1 .91 mL, 23.6 mmol), followed by the dropwise addition of trifluoroacetic anhydride (2.66 mL, 18.8 mmol). After 15 min, the solution is warmed to RT and stirred for 1 h. The crude reaction mixture is washed with an aqueous 1 N HCI solution and then an aqueous 5% NaHC03 solution before being dried (MgS04), filtered and concentrated to give compound 6a4.
The ethyl bromoacetate (1.96 g, 11.76 mmol) was added to a stirred solution of potassium methyl cyanimidodithiocarbonate 1 (2.0 g, 11.76 mmol) in EtOH (50 mL). The mixture was heated to reflux for 1 h. After cooling, Et3N (2.38 g, 23.52 mmol) was added and the mixture was heated to reflux for 4 h. The ethanol was evaporated and the residue was triturated with water (20 mL) followed by filtering. The solid was dried and then recrystallized from acetone to give compound 2 (2.4 g, 93%). Light yellow solid; mp 101-103 C; 1H NMR (400 MHz, CDCl3) delta (ppm): 5.80 (brs, 2H), 4.26 (q, 2H, J = 7.2 Hz), 2.63 (s, 3H), 1.32 (t, 3H, J = 7.2 Hz); HRMS (ESI) Calcd. for C7H11N2O2S2 [M+H]+: 219.0256; Found: 219.0248.
To a stirred solution of 6a1 (Acros; 5.0 g, 29.4 mmol) in EtOH (50 mL) is added 6a2 (Aldrich, 3.3 mL, 29.4 mmol). The mixture is heated to reflux for 30 min. After cooling, Et3N (2.14 mL, 29.4 mmol) is added and the mixture is heated to reflux for 2 h. The ethanol is evaporated and the residue triturated with water (150 mL). before being filtered and dried. The solid recovered by filtration is dried and then recrystallized from acetone to give compound 6a3.
The synthesis of ethyl 4-formamido-2-(methylthio)thiazole-5-carboxylate The compound (30 g, 138.05 mole) synthesized in Preparation Example 31 and ammoniumacetate (13.8 g, 179.03 mol) were mixed with 200 ml of formic acid. After 46 hours of reflux, the mixture was concentrated under vacuum to remove the formic acid and extracted with ethylacetate and 300 ml of saturated sodium bicarbonate. The organic layer was dried with sodium sulfate, filtered and concentrated under vacuum. The title compound (29.5 g, 87.3%) was obtained as yellowish solid. 1H-NMR (400 MHz, CDCl3); delta 9.38 (s, 1H), 5.81 (brs, 1H), 4.32 (q, J=6.8 Hz, 2H), 2.70 (s, 3H), 1.35 (t, J=6.8 Hz, 3H); LC-MS 246 (MH+)
With tert.-butylnitrite; copper dichloride; In acetonitrile; at 20℃;
General procedure: Twelve millimoles of either anhydrous copper (II) chloride or anhydrous copper (II) bromide were added to a solution of tert-butyl nitrite (15 mmol) in acetonitrile anhydrous (40 mL). The mixture was stirred at 50 C for 1 h, and then 2,5-substituted 4-amino-1,3-thiazole was added slowly. The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched in water (100 mL). When the precipitate appeared, it was filtered, washed twice with 20 mL of water, and dried under room temperature until a constant weight was reached. The isolated solid was purified by recrystallization in isopropanol. When a viscous mixture appeared, the solution was extracted with ethyl acetate (3 x 25 mL). The organic layers were dried with MgSO4, filtered, and evaporated. The oily solid was then purified by column chromatography on silica gel.
With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 20℃;
General procedure: Twelve millimoles of either anhydrous copper (II) chloride or anhydrous copper (II) bromide were added to a solution of tert-butyl nitrite (15 mmol) in acetonitrile anhydrous (40 mL). The mixture was stirred at 50 C for 1 h, and then 2,5-substituted 4-amino-1,3-thiazole was added slowly. The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched in water (100 mL). When the precipitate appeared, it was filtered, washed twice with 20 mL of water, and dried under room temperature until a constant weight was reached. The isolated solid was purified by recrystallization in isopropanol. When a viscous mixture appeared, the solution was extracted with ethyl acetate (3 x 25 mL). The organic layers were dried with MgSO4, filtered, and evaporated. The oily solid was then purified by column chromatography on silica gel.
With copper(ll) bromide; isopentyl nitrite; In acetonitrile; at 20℃;
General procedure for the synthesis of U2 To a stirred solution of isopentyl nitrite (3.1 mL, 0.023 mmol) in acetonitrile(36.0 mL)was added CuBr2(5.1 g, 0.023 mol) at room temperature and the resulting solution was heated to 50 C . After an hour, the solution was cooled to room temperature and Ul (2.0 g, 9.0 mol) was added slowly. The reaction mixture was further stirred at room temperature for overnight. After reaction completion, the solution was diluted with water (50 mL) and extracted by EtOAc (30 mL x 2). The organic layer was dried over MgS04 and concentrated invacuo. The resulting crude residue was purified by flash column chromatography (-hexane:EtOAc = 10: 1) to give U2.
With hydrogenchloride; zinc; In ethanol; water; for 4.0h;Reflux;
1. 40 g of 4-amino-2-(methylthio)thiazole-5-carboxylic acid ethyl ester is dissolved in 500 ml of ethanol, add 50ml concentrated hydrochloric acid and add 35g zinc powder in batches while stirring. The temperature was raised to reflux for 4 hours. Use thin layer chromatography (TLC developing solvent: ethyl acetate: petroleum ether = 1: 1) to judge that the reaction of the raw materials is complete and obtain a neutralization solution;2. The neutralization solution is filtered, and the filter cake is washed 2 to 3 times with 50 ml of ethanol. The combined filtrates were concentrated under reduced pressure to obtain a concentrate;3. Add 250ml of dichloromethane and 250ml of water to the shrinkage, stir, separate, and take the organic phase;4. The organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 30 C in a water bath, and recrystallized from 120 ml of isopropanol to obtain 28 g of ethyl 4-aminothiazole-5-carboxylic acid, yield 90%.
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