* 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.
3-chloro-4-methoxybenzylamine (45.6 g, 0.27 mol) was dissolved in 180 mL of acetone, then triethylamine (40.4 g, 0.4 mol) was added.4-chloro-2-methylthiopyrimidine-5-carboxylic acid ethyl ester obtained in the step S2(53.3 g, 0.24 mol) dissolved in 250 mL of acetone and slowly dropped into the reaction solution.And reacted at room temperature for 3 h, and poured the reaction solution into the ice water mixture.Extracted with ethyl acetate,The combined organic phases were washed with 10percent aqueous citric acid (250 mL x 3).Dry the organic layer with anhydrous sodium sulfate.Evaporate the solvent under reduced pressure.Dry in vacuo to a white solid (86.0 g, 87.0percent).
76%
With triethylamine In dichloromethane at 20℃; for 10 h;
In DCM (100 mL) were dissolved ethyl 4-chloro-2-(methylthio) pyrimidine-5-carboxylate (5.0 g, 21.55 mmol), 3-chloro-4-methoxybenzylamine (4.0 g, 23.4 mmol) and triethylamine (4.35 g, 43.1 mmol). The reaction mixture was stirred at ambient temperature for 10 h and washed with water. The organic phase was dried over magnesium sulfate and concentrated to give ethyl 4-((3-chloro-4-methoxybenzyl)amino)-2 -(methylthio)pyrimidine-5-carboxylate as a solid (6.0 g, 76 percent yield).
145 g
With tetrabutylammomium bromide; sodium carbonate In dichloromethane; water at 25 - 30℃;
To 600ml of methylene dichloride was added lOOg of ethyl 4-chloro-2-(methylsulfanyl) pyrimidine-5-carboxylate and 91.2g of 3-chloro-4-methoxybenzylamine. The reaction mixture was stirred and 500m1 of water, 48g of sodium carbonate and Ig of tetra-butylammonium bromide were added to it. The reaction mixture was then maintained overnight at 25-30°C. After completion of reaction, methylene dichloride layer was separated, washed with water and evaporated to obtain 145g of ethyl 4-[(3-chloro-4-methoxybenzyl) amino]-2-(methyl sulfanyl) pyrimidine-5-carboxylate having 95percent of HPLC purity.
42.3 g
With triethylamine In ethyl acetate at 0 - 30℃;
After dissolving 50.0 g of 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine and 59.9 ml of triethylamine into 430 ml of ethyl acetate, respectively, the mixture was cooled to 0 ° C, 44.7g of 3-chloro-4-methoxybenzylamine was added in portions, the reaction was carried out at 0-5 ° C for 30min and the reaction was continued at 20-30 ° C for 0.5-1h. The reaction was concentrated under reduced pressure, and then added ethyl acetate and citric acid solution 400ml each wash 2 times, the organic phase was washed with water and saturated brine each time, dried, filtered and concentrated under reduced pressure to give the crude 73.0g. Finally, with anhydrous ethanol at 55 ~ 60 ° C dissolved crude, stirring crystallization 12-18h, filtered and dried to give the product 42.3g.
Stage #1: With triethylamine In tetrahydrofuran at 20℃; for 0.5 h; Stage #2: at 20℃; Cooling with ice
In a flask, tetrahydrofuran (4.5 L) was added, 3-chloro-4-methoxybenzylamine hydrochloride (500 g, 2.4 mol) was added under stirring, triethylamine (836 mL, 6.01 mol) was added dropwise, the mixture was stirred at room temperature for 30 min, cooled with ice-water, then ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate (466 g, 2.0 mol) was added, the reaction was stirred overnight at room temperature. TLC was used to monitor the reaction. After the end of reaction, solvent was removed by evaporation under reduced pressure. Ethyl acetate (2.5 L) and water (1 L) were added, the mixed liquid phases were separated, the organic phase was sequentially washed with diluted hydrochloric acid, water (1 L), saturated sodium bicarbonate (1 L) and saturated sodium chloride (1 L), dried over anhydrous sodium sulfate. After filtration, solvent was removed by evaporation under reduced pressure to obtain an oily substance, to which was added methanol (3 L), and a large white solid was precipitated. After stirring for 30 min, filtration was carried out, and the filter cake was vacuum dried to obtain the product (650 g, yield of 88.3percent).
78%
With triethylamine In N,N-dimethyl-formamide at 20℃; for 4 h; Cooling with ice
Compound 13 (5 g, 21.86 mmole) and compound 18 (5.34 g, 25.4 mmol) were added to 75 ml of dry DMF 1 and dissolved with stirring. After stirring for 10 minutes, the reaction system was placed in an ice-water mixture. Triethylamine (21.4 g, 0.217 mole) was slowly added dropwise to the reaction flask and slowly warmed to room temperature. After 4 hours, TLC showed the reaction was completed. Dichloromethane was added, washed with water five times, dried and filtered, concentrated by rotary evaporation and passed through a column (PE: EA = 25: 1). Compound 19 (7.3 g, yield 78percent) was obtained as a white powder.
74.2%
Stage #1: With triethylamine In tetrahydrofuran at 20℃; for 0.25 h; Cooling with ice Stage #2: at 20℃;
In THF (150 mL) was suspended 3-chloro-4-methoxybenzylamine hydrochloride salt (16.0 g, 76.9 mmol). The suspension was cooled in an ice bath, and triethylamine (19.4 g, 192.3 mmol) was added dropwisely. The reaction mixture was stirred at ambient temperature for 15 min, then was added ethyl 4-chloro-2-thiomethyl-5-pyrimidine carboxylate (14.9 g, 64.1 mmol). The reaction mixture was stirred at ambient temperature overnight. TLC was used to monitor the reaction. After the completion of the reaction, the solvent was removed by rotary evaporation. Acetic ether (500 mL) and water (200 mL) were added. The organic phase was separated, washed with hydrochloric acid (1N), saturated aqueous solution of sodium bicarbonate and brine, dried over sodium sulfate and filtrated. The filtrate was concentrated under reduced pressure. The solvent was removed by rotary evaporation to give oil. Methanol (100 mL) was added to precipitate a large amount of white solid. The mixture was filtrated and the solid was dried in vacuum to give ethyl 4-((3-chloro-4-methoxybenzyl)amine)-2-thiomethyl-5-pyrimidine carboxylate (21 g, 74.2 percent yield).
90 g
With sodium carbonate In water at 25 - 30℃; for 4 h;
(3-Chloro-4-methoxyphenyl) methanamine hydrochloride compound of formula-6a (76.98 g) was added to the organic layer containing ethyl 4-chloro-2-(methylthio) pyrimidine-5-carboxylate compound of formula-5, which is obtained in step-b). Water (100 ml), followed by sodium carbonate (110.3 g) were added to the reaction mixture at 25-30°C and stirred for 4 hours at the same temperature. After completion of the reaction, water was added to it. Both the organic and aqueous layers were separated; the aqueous layer was extracted with toluene. All the organic layers were combined and washed with water. Distilled off the solvent from the organic layer under reduced pressure. The reaction mixture was cooled to 30-35°C. 700 ml of cyclohexane: ethyl acetate (in 9.5:5 ratio) was added to the reaction mixture. The reaction mixture was heated to 70-75°C and stirred until complete dissolution. The reaction mixture was cooled to 10-15°C and stirred for 3 hours. Filtered the precipitated solid, washed with cyclohexane and then dried to get title compound.Yield: 90 gms; Melting range: 81 -84°C; Purity by HPLC: 95.3percent.
With tetrabutylammomium bromide; sodium carbonate In water at 25 - 30℃; for 8 h;
(3-Chloro-4-methoxyphenyl)methanamine malate compound of formula-6b (1 13.1 g) was added to the organic layer containing ethyl 4-chloro-2-(methylthio)pyrimidine-5- carboxylate compound of formula-5 obtained in step-(b). Water (200 ml), followed by sodium carbonate (147.06 g) and tetrabutyl ammonium bromide (4.47 g) were added to the reaction mixture at 25-30°C and stirred for 8 hours at the same temperature. Water was added to the reaction mixture at 25-30°C. The reaction mixture was heated to 40-45°C. Separated the both organic and aqueous layers. The organic layer was washed with water. Distilled off the solvent from the organic layer under reduced pressure and then co-distilled with cyclohexane. Cooled the obtained compound to 25-30°C and 600 ml of cyclohexane: ethyl acetate (in 9: 1 ratio) was added to it at the same temperature. The reaction mixture was heated to 65-70°C and stirred 15 minutes. The reaction mixture was cooled to 10-15°C and stirred for 3 hours. Filtered the precipitated solid and washed with cyclohexane. Water (1000 ml) was added to the wet solid. Heated the reaction mixture to 60-65°C and stirred for 30 minutes. Cooled the reaction mixture to 25-30°C and stirred for 60 minutes. Filtered the precipitated solid, washed with water and then dried to get the title compound.Yield: 102 gms; Melting range: 80-84°C; Purity by HPLC: 99.25percent
3-chloro-4-methoxybenzylamine (45.6 g, 0.27 mol) was dissolved in 180 mL of acetone, then triethylamine (40.4 g, 0.4 mol) was added.4-chloro-2-methylthiopyrimidine-5-carboxylic acid ethyl ester obtained in the step S2(53.3 g, 0.24 mol) dissolved in 250 mL of acetone and slowly dropped into the reaction solution.And reacted at room temperature for 3 h, and poured the reaction solution into the ice water mixture.Extracted with ethyl acetate,The combined organic phases were washed with 10% aqueous citric acid (250 mL x 3).Dry the organic layer with anhydrous sodium sulfate.Evaporate the solvent under reduced pressure.Dry in vacuo to a white solid (86.0 g, 87.0%).
76%
With triethylamine; In dichloromethane; at 20℃; for 10.0h;
In DCM (100 mL) were dissolved ethyl 4-chloro-2-(methylthio) pyrimidine-5-carboxylate (5.0 g, 21.55 mmol), 3-chloro-4-methoxybenzylamine (4.0 g, 23.4 mmol) and triethylamine (4.35 g, 43.1 mmol). The reaction mixture was stirred at ambient temperature for 10 h and washed with water. The organic phase was dried over magnesium sulfate and concentrated to give ethyl 4-((3-chloro-4-methoxybenzyl)amino)-2 -(methylthio)pyrimidine-5-carboxylate as a solid (6.0 g, 76 % yield).
With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 0.833333h;
(1) To a solution of 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine (25.33 g) in N,N-dimethylformamide (85 ml) are added a solution of 3-chloro-4-methoxybenzylamine (19.62 g) in N,N-dimethylformamide (15 ml) and triethylamine (16.7 ml) under ice-cooling. The mixture is stirred at room temperature for 20 minutes, and thereto is added 3-chloro-4-methoxybenzylamine (940 mg), and the mixture is further stirred for 15 minutes. To the mixture is further added said amine (940 mg), and the mixture is stirred for 15 minutes. The reaction mixture is poured into a mixture of ice water and citric acid, and extracted with ethyl acetate. The extract is washed successively with a 10 % aqueous citric acid solution, water and brine, and dried over anhydrous sodium sulfate. The solvent is evaporated in vacuo, and the residue is washed with n-hexane to give 4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonyl-2-methylthiopyrimidine (38.34 g).
With triethylamine; citric acid; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; N,N-dimethyl-formamide;
(1) To a solution of 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine (25.33 g) in N,N-dimethylformamide (85 ml) are added a solution of 3-chloro-4-methoxybenzylamine (19.62 g) in N,N-dimethylformamide (15 ml) and triethylamine (16.7 ml) under ice-cooling. The mixture is stirred at room temperature for 20 minutes, and thereto is added 3-chloro-4-methoxybenzylamine (940 mg), and the mixture is further stirred for 15 minutes. To the mixture is further added said amine (940 mg), and the mixture is stirred for 15 minutes. The reaction mixture is poured into a mixture of ice water and citric acid, and extracted with ethyl acetate. The extract is washed successively with a 10% aqueous citric acid solution, water and brine, and dried over anhydrous sodium sulfate. The solvent is evaporated in vacuo, and the residue is washed with n-hexane to give 4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonyl-2-methylthiopyrimidine (38.34 g).
With triethylamine; citric acid; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; N,N-dimethyl-formamide;
(1) To a solution of 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine (25.33 g) in N,N-dimethylformamide (85 ml) are added a solution of 3-chloro-4-methoxybenzylamine (19.62 g) in N,N-dimethylformamide (15 ml) and triethylamine (16.7 ml) under ice-cooling. The mixture is stirred at room temperature for 20 minutes, and thereto is added 3-chloro-4-methoxybenzylamine (940 mg), and the mixture is further stirred for 15 minutes. To the mixture is further added said amine (940 mg), and the mixture is stirred for 15 minutes. The reaction mixture is poured into a mixture of ice water and citric acid, and the mixture is extracted with ethyl acetate. The extract is washed successively with a 10% aqueous citric acid solution, water and brine, and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, and the residue is washed with n-hexane to give 4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonyl-2-methylthiopyrimidine (38.34 g), m.p. 86 C.
With triethylamine; In tetrahydrofuran;
(1)-a) A mixture of 2-methylthio-4-chloro-5-ethoxycarbonylpyrimidine 1.0 g, (3-chloro-4-methoxyphenyl)methylamine 0.81 g, triethylamine 0.66 ml and tetrahydrofuran 12 ml is stirred for 4 hours at room temperature. The reaction mixture is diluted with an aqueous 10% citric acid solution and the mixture is extracted twice with ethyl acetate. The combined organic layer is washed with water and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is purified by silica gel chromatography (solvent; hexane:ethyl acetate=5:1) and concentrated in vacuo to give a colorless oil. The oil is left overnight at room temperature to give 2-methylthio-5-ethoxycarbonyl-4-(3-chloro-4-methoxybenzylamino)pyrimidine as crystals, 1.58 g. mp 82-83 C.
With triethylamine; In N,N-dimethyl-formamide;
(1) To a solution of 2-methylthio-4-chloro-5-ethoxy-carbonylpyrimidine (25.33 g) in N,N-dimethylformamide (85 ml) are added a solution of 3-chloro-4-methoxybenzylamine (19.62 g) in N,N-dimethylformamide (15 ml) and triethylamine (16.7 ml) under ice-cooling. The mixture is stirred at room temperature for 20 minutes, and thereto is added 3-chloro-4-methoxybenzylamine (940 mg), and the mixture is further stirred for 15 minutes. To the mixture is further added said amine (940 mg), and the mixture is stirred for another 15 minutes. The reaction mixture is poured into a mixture of ice water and citric acid, and extracted with ethyl acetate. The extract is washed successively with a 10 % aqueous citric acid solution, water and brine, and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure, and the residue is washed with n-hexane to give 2-methylthio-4-(3-chloro-5-methoxybenzylamino)-5-ehoxy-carbonylpyrimidine (38.34 g). M.p. 86 C.
145 g
With tetrabutylammomium bromide; sodium carbonate; In dichloromethane; water; at 25 - 30℃;
To 600ml of methylene dichloride was added lOOg of ethyl 4-chloro-2-(methylsulfanyl) pyrimidine-5-carboxylate and 91.2g of 3-chloro-4-methoxybenzylamine. The reaction mixture was stirred and 500m1 of water, 48g of sodium carbonate and Ig of tetra-butylammonium bromide were added to it. The reaction mixture was then maintained overnight at 25-30C. After completion of reaction, methylene dichloride layer was separated, washed with water and evaporated to obtain 145g of ethyl 4-[(3-chloro-4-methoxybenzyl) amino]-2-(methyl sulfanyl) pyrimidine-5-carboxylate having 95% of HPLC purity.
42.3 g
With triethylamine; In ethyl acetate; at 0 - 30℃;
After dissolving 50.0 g of 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine and 59.9 ml of triethylamine into 430 ml of ethyl acetate, respectively, the mixture was cooled to 0 C, 44.7g of 3-chloro-4-methoxybenzylamine was added in portions, the reaction was carried out at 0-5 C for 30min and the reaction was continued at 20-30 C for 0.5-1h. The reaction was concentrated under reduced pressure, and then added ethyl acetate and citric acid solution 400ml each wash 2 times, the organic phase was washed with water and saturated brine each time, dried, filtered and concentrated under reduced pressure to give the crude 73.0g. Finally, with anhydrous ethanol at 55 ~ 60 C dissolved crude, stirring crystallization 12-18h, filtered and dried to give the product 42.3g.
With ascorbic acid; In toluene; at 25℃; under 760.051 Torr; for 8.0h;
4-(3-chloro-4-methoxybenzylamino) 5-ethoxycarbonyl-2-methylthiopyrimidine (36.8 g, 100 mmol), ascorbic acid (52.8 g, 300 mmol) was dissolved in 500 mL of toluene, and tetraphenylporphyrin iron (0.67 g, 1 mmol) was added thereto, and the mixture was thoroughly stirred to be uniformly dispersed, and transferred to a pressurized reaction vessel. Air was introduced at 25 C, the reaction pressure was adjusted to 1.0 atm, and the reaction was stirred for 8 h. After the completion of the reaction, the metal porphyrin catalyst in the reaction liquid is removed by filtration, and the organic phase is washed once with purified water, saturated NaCl, and concentrated under reduced pressure to give a white thick liquid to obtain an intermediate of 4-(3-chloro-4-methoxybenzylamino) 5-ethoxycarbonyl-2-methylsulfinylpyrimidine 36.47g (yield 95.0%, purity 99.3%), directly used in the next step .
With 3-chloro-benzenecarboperoxoic acid; In chloroform; for 2.0h;
(2) To a solution of the compound (5.00 g) obtained in the above (1) in chloroform (50 ml) is added a solution of m-chloroperbenzoic acid (4.00 g) in chloroform (50 ml) under ice-cooling, and the mixture is stirred for 2 hours. The reaction mixture is washed with a saturated aqueous sodium hydrogen carbonate solution and brine, and the organic layer is dried over anhydrous sodium sulfate, and the solvent is evaporated in vacuo to give crude 4-(3-chloro-4-methoxybenzylamino) -5-ethoxycarbonyl-2-methylsulfinylpyrimidine.
With 3-chloro-benzenecarboperoxoic acid; In chloroform;
(1) To a solution of 4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonyl-2-methylthiopyrimidine (972 mg) obtained in the above Example 1-(1) in chloroform (8 ml) is added a solution of m-chloroperbenzoic acid (80%, 598 mg) in chloroform (10 ml) under ice-cooling over a period of 30 minutes. The reaction mixture is stirred under ice-cooling for one hour. The reaction mixture is diluted with a saturated aqueous sodium hydrogen carbonate solution, and the chloroform layer is collected, washed successively with a saturated aqueous sodium hydrogen carbonate solution, water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to quantitatively give 2-methylsulfinyl-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine as colorless caramels, MS (m/z): 384 (MH+).
With 3-chloro-benzenecarboperoxoic acid; In chloroform;
(1) To a solution of 2-methylthio-5-ethoxycarbonyl-4-(3-chloro-4-methoxybenzylamino)pyrimidine (prepared in Example 67-(1)) 500 mg in chloroform 5 ml is dropped a solution of m-chloroperbenzoic acid (80%) 323 mg in chloroform 4 ml over a period of 30 minutes under ice cooling. The mixture is stirred at the same temperature for 1 hour. The reaction mixture is diluted with an aqueous saturated sodium hydrogen carbonate solution. The chloroform layer is separated, washed with water and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated in vacuo to give 2-methylsulfinyl-5-ethoxycarbonyl-4-(3-chloro-4-methoxybenzylamino)pyrimidine as a colorless caramel, 545 mg. IR(neat)cm-1: 3333, 1694, 1588, 1574, 1503, 1463, 1440 MS(m/z): 384(M+H)+
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 0 - 5℃; for 1.0h;
A mixture of Ethyl 4-(3-chloro-4-methoxybenzylamino)-2-(methylthio)pyrimidine-5- carboxylate compound of formula-7 (65 g) and dichloromethane (325 ml) was cooled to 0 to 5C. 70% meta-chloroperbenzoic acid (43.5 g) was added slowly to the reaction mixture in a lot wise at 0-5C and stirred for 1 hour at the same temperature. Quenched the reaction mixture with 10% aqueous sodium bicarbonate solution and separated the organic and aqueous layers. The organic layer containing title compound was washed with 10% aqueous sodium sulphite solution at a temperature below 10C.
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 20℃; for 2.0h;Cooling with ice;
In DCM (80 mL) was dissolved ethyl 4-((3-chloro-4-methoxybenzyl)amine) -2-thiomethyl-5-pyrimidine carboxylate (8.0 g, 21.75 mmol). The solution was cooled in an ice bath, and 3-chloroperbenzoic acid (4.88 g, 28.27 mmol) was added. The reaction mixture was stirred at ambient temperature for 2 h. The reaction was monitored by TLC. After the completion of the reaction, the reaction mixture was washed with saturated aqueous solution of sodium bicarbonate (800 mL). The organic phase was separated. The aqueous phase was extracted with EA twice.
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 20℃; for 4.0h;Cooling with ice;
To a reaction flask, dichloromethane (3 L) was added, <strong>[330785-81-4]ethyl 4-(3-chloro-4-methoxy-benzylamino)-2-methylthiopyrimidine-5-carboxylate</strong> (500 g, 1.359 mol) was added under stirring, then m-chloroperoxybenzoic acid (235 g, 1.359 mol) in dichloromethane (1 L) solution was added dropwise under ice-water bath. After the end of dropwise addition, the temperature of the reaction was naturally elevated to room temperature. TLC was used to monitor the reaction. After stirring for 2 h, raw materials did not react completely, m-chloroperoxybenzoic acid (70 g, 0.4 mol) was added, and the reaction was continuously stirred for 2 h. After the end of reaction, saturated sodium bicarbonate solution (1 L) was used to quench the reaction. The organic phase was separated, and the water phase was extracted with dichloromethane. The organic phases were combined, washed sequentially with saturated sodium bicarbonate, saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, filtrated, and directly used in next reaction without further purification.
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; water; at 20℃; for 5.0h;Cooling with ice;
Ethyl 4-(3-chloro-4-methoxybenzylamino)-2-(methylthio)pyrimidine-5-carboxylate (200 mg, 0.59 mmol) was dissolved in dichloromethane (20 mL), m-CPBA (101 mg, 0.59 mmol) was added under ice-water bath, the reaction was heated to room temperature and conducted for 5 h. Water was added to the reaction and extracted with dichloromethane. The organic layer was dried, concentrated to obtain solid. The product was used in next reaction without any purification.
13.1 kg
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at -10 - 0℃;Large scale;
Ethyl 2-methylthio-4- (3-chloro-4-methoxybenzylamino)pyrimidine-5-carboxylate (Intermediate -MI, Figure 1, retention time 16.671) 12.0Kg and dichloromethane 134.0Kg added to the reactor, stirring, dissolved; The reaction temperature was controlled at -5 ± 5 C and a solution of m-CPBA 6.9 Kg and 178.0 Kg in dichloromethane was added slowly. After the addition, with 0.3% ammonium acetate solution - methanol (20:80) as the mobile phase, the detection wavelength of 265nm; Column temperature: 30 C, flow rate: 1.0 ml / min, HPLC endpoint of the reaction. (No intermediate -MI peak, as the reaction was complete; if the reaction is not complete, then extend the reaction time.) The reaction was completed (Figure 2), the reaction solution was washed with sodium bicarbonate solution 132.0kg twice, standing stratification, the organic phase separation; Adding sodium chloride solution 168.0kg washing, standing stratification, separating the organic phase; adding 120.0kg purified water was washed, standing stratification, the organic phase was collected; Dried over anhydrous sodium sulfate, filtered and the filter cake washed with a small amount of methylene chloride; The filtrate was concentrated under reduced pressure to give an ethyl 2-methanesulfinyl-4-(3-chloro-4-methoxybenzylamino)pyrimidine-5-carboxylate (Intermediate-MII), 13.1 Kg, yield 109%, purity> 98%.
With lithium aluminium tetrahydride; In tetrahydrofuran;
(2) To a suspension of lithium aluminum hydride (4.15 g) in tetrahydrofuran (150 ml) is added a solution of 2-methylthio-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine (38.32 g) in tetrahydrofuran (100 ml) under ice-cooling at temperature ranging from 5 C to 10 C over a period of 1 hour. After the addition is completed, the ice bath is removed, and the reaction mixture is stirred at room temperature for 1 hour. To the reaction mixture is added water (4.15 ml) under ice-cooling, and thereto is further added 3N aqueous sodium hydroxide solution (4.15 ml). To the mixture is added water (4.15 ml) three times, and the mixture is stirred at room temperature for 1 hour. The reaction mixture is treated with magnesium sulfate, and the solid precipitates are collected by filtration and washed with tetrahydrofuran. The filtrate and the washings are combined, concentrated under reduced pressure, and triturated with a mixture of ethyl acetate and isopropyl ether. The resulting crystals are collected by filtration, and washed thoroughly with isopropyl ether to give 2-methylthio-4-(3-chloro-4-methoxybenzylamino)-5-hydroxymethylpyrimidine as pale yellow crystalline powder.First crop yield, 25.10 g; m. p. 162-163 CSecond crop yield, 2.32 g; m. p. 159-160 C The above solid precipitates are washed again with isopropyl ether, and the filtrate is concentrated under reduced pressure to give colorless crystals. The resulting solids are suspended in isopropyl ether, filtered, and the precipitates are washed thoroughly with isopropyl ether and hexane to give 2-methylthio-4-(3-chloro-4-methoxybenzylamino)-5-hydroxymethylpyrimidine (4.26 g) as colorless crystals, m.p. 161-162 C.
With sodium hydroxide; magnesium sulfate; In tetrahydrofuran; water; ethyl acetate;
(1) To a suspension of lithium aluminum hydride (4.15 g) in tetrahydrofuran (150 ml) is added a solution of 2-methylthio-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine (38.32 g) in tetrahydrofuran (100 ml) under ice-cooling at 5 C. to 10 C. over a period of one hour. After the addition, the ice bath is removed, and the reaction mixture is stirred at room temperature for one hour. To the reaction mixture is added water (4.15 ml) under ice-cooling, and thereto is further added 3N aqueous sodium hydroxide solution (4.15 ml). To the mixture is added water (4.15 ml) three times, and the mixture is stirred at room temperature for one hour. The reaction mixture is treated with magnesium sulfate, and the solid precipitates obtained are filtered. The precipitates are washed with tetrahydrofuran. The filtrate and the washings are combined, and concentrated under reduced pressure, and triturated with a mixture of ethyl acetate and isopropyl ether. The resulting crystals are collected by filtration, and washed well with isopropyl ether to give 2-methylthio-4-(3-chloro-4-methoxybenzylamino)-5-hydroxymethylpyrimidine as pale yellow crystalline powder. First production: yield; 25.10 g, m.p. 162-163 C. Second production: yield; 2.32 g, m.p. 159-160 C. In addition, the above solid precipitates are washed again with isopropyl ether, and the filtrate is concentrated under reduced pressure to give colorless crystals. The resulting solid is suspended in isopropyl ether, filtered, and the precipitates are washed well with isopropyl ether and hexane to give 2-methylthio-4-(3-chloro-4-methoxybenzylamino)-5-hydroxymethylpyrimidine (4.26 g) as colorless crystals, m.p. 161-162 C.
With methanol; sodium hydroxide; at 20 - 30℃; for 4.5h;
ethyl 4-[(3-chloro-4-methoxybenzyl)amino]-2-methylthiopyrimidine-5carboxylate obtained in the step S3 (98.0 g, 0.27 mol) was dissolved in 300 mL of methanol.Temperature control below 30 C,After dropping a 16% aqueous solution of NaOH (150 mL, 0.71 mol),After reacting at room temperature for 4.5 h, methanol was distilled off under reduced pressure.Adjust the pH to 6 with concentrated hydrochloric acid,A large amount of gray solid was precipitated, and after stirring for 1 hour, it was suction filtered and washed with water.Vacuum drying gave a gray powder (97.7 g, 94%).
93.3%
With sodium hydroxide; In ethanol; at 20 - 55℃;
The product VI obtained in the step (1) is added to 450 ml of ethanol, heated and stirred at 50-55 C until the temperature of the material is cooled to 20-30 C, 105 ml of 10% sodium hydroxide solution is added and stirred at 20-30 C for 1.5-2 hours. The mixture was added dropwise with 10% citric acid solution to adjust the pH of the solution to about 4 ~ 5. A large amount of solid was precipitated and the mixture was stirred at 20-30 C for 1-1.5h. The solid was washed with water and dried under vacuum at 50 C for 3h to obtain 14.0g of white solid. Yield 93.3%.
87.6%
50ml three reaction flask was added 19 (1.30g, 3.53mmol) was added at room temperature a mixed solution of tetrahydrofuran and methanol (v / v = 1: 1, 10 ml). After stirring for 15 minutes, an aqueous solution of potassium hydroxide (346 mg, 6.18 mmol, dissolved in 1.7 ml of water) was added and the mixture was stirred at room temperature overnight. TLC showed the reaction was completed. The reaction mixture was concentrated by heating and the organic phase was evaporated. The aqueous phase was washed twice with methylene chloride. The aqueous phase was slowly added dropwise with 1 M dilute hydrochloric acid. The pH of the solution was adjusted to 2-3 and extracted three times with ethyl acetate. The organic phases were combined, dried and filtered, and concentrated by rotary evaporation to give Compound 21 (1.05 g, 87.6%) as a white powder.
76%
With water; sodium hydroxide; In tetrahydrofuran; methanol; at 60℃; for 10.0h;
In a mixture of water (10 mL), methanol (30 mL) and THF (30 mL) were dissolved ethyl 4-((3-chloro-4-methoxybenzyl)amino)-2-(methylthio) pyrimidine-5-carboxylate (6.0 g, 16.3 mmol) and sodium hydroxide (1.14 g, 28.57 mmol). The reaction was conducted for 10 h at 60 C. The reaction mixture was cooled to ambient temperature and adjusted to a pH of 4 by addition of dilute hydrochloric acid dropwise. A solid was precipitated, filtrated, washed with methanol and dried to give 4-((3-chloro-4-methoxybenzyl)amino)-2 -(methylthio)pyrimidine-5-carboxylic acid (4.2 g, 76 % yield).
With sodium hydroxide; citric acid; In water; dimethyl sulfoxide;
(1) A suspension of 2-methylthio-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine (2.00 g) obtained in Example 1 (1) in dimethylsulfoxide (10 ml) is treated with 10% aqueous sodium hydroxide solution (10 ml) at room temperature. To the reaction mixture is added dimethylsulfoxide (5 ml), and the mixture is stirred at room temperature overnight. To the resulting colorless solution is added citric acid until the solution becomes acidic. To the solution is added an excess amount of water (about 50 ml), and the resulting precipitates are collected by filtration. The precipitates are washed with isopropyl alcohol and isopropyl ether successively, and dried under reduced pressure to give 2-methylthio-4-(3-chloro-4-methoxybenzylamino)-5-carboxypyrimidine (1.864 g) as pale yellow impalpable powder, m.p. 238-240 C. (dec.).
With sodium hydroxide; In dimethyl sulfoxide;
Example 79 2-Methylthio-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine (prepared in Example 67-(1)) 2.00 g is suspended in dimethyl sulfoxide 10 ml, and the suspension is treated with a 10% aqueous sodium hydroxide solution 10 ml. The reaction mixture is still in suspension even 6 hours later. After addition of dimethyl sulfoxide 5 ml the mixture is stirred at room temperature over night. The resulting clear reaction solution is acidified with citric acid. The excess water (about 50 ml) is added thereto and resulting precipitate is filtered, washed with isopropylalcohol and then isopropyl ether, and concentrated in vacuo to give 2-methylthio-4-(3-chloro-4-methoxybenzylamino)-5-carboxypyrimidine as a pale yellow impalpable powder, 1.864 g. mp 238-240 C. (decomposition)
87 g
With water; sodium hydroxide; In methanol;Reflux;
To 600ml of methanol was added bOg of ethyl 4-[(3-chloro-4-methoxybenzyl) amino] -2-(methyl sulfanyl) pyrimidine-5 -carboxylate (Referential Example 1) and an aqueous solution of sodium hydroxide (15g of NaOH in 140rn1 of water). The reaction mixture was heated to reflux temperature. After completion of reaction, the pH of mixture was adjusted to 1-2 using concentrated hydrochloric acid followed by stirring the mixture for 1 hour at 10-15C. The solid product obtained was filtered, washed sequentially with water and methanol, and dried overnight at 70-75C to get 87g of 4-[(3-chloro-4-methoxybenzyl) aminoj-2-(methyl sulfanyl) pyrimidine-5- carboxylic acid.
With 3-chloro-benzenecarboperoxoic acid; In chloroform;
(2) To a solution of 2-methylthio-5-ethoxycarbonyl-4-(3-chloro-4-methoxybenzylamino)pyrimidine (prepared in above (1)-a) 300 mg in chloroform 5 ml is added under ice cooling m-chloroperbenzoic acid (80%) 369 mg. The mixture is stirred at room temperature for 5 hours. Further m-chloroperbenzoic acid (80%) 106 mg and chloroform 6 ml are added thereto and the mixture is stirred at room temperature for 2 hours. The reaction mixture is diluted with an aqueous saturated sodium hydrogen carbonate solution and the water layer is extracted with chloroform. The combined organic layer is washed with water and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is separated with silica gel chromatography (solvent; hexane:ethyl acetate=3:1?3:2) to give 2-methylsulfonyl-5-ethoxycarbonyl-4-(3-chloro-4-methoxybenzylamino)pyrimidine as a colorless caramel, 133 mg. IR(CHCl3)cm-1: 3333, 1695, 1593, 1572, 1503 MS(m/z): 400(M+H)+
Example 93 To a solution of 2-methylsulfinyl-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine (prepared in Example 68-(1)) 200 mg in tetrahydrofuran 4 ml is added under ice cooling potassium tert-butoxide 58 mg, and the reaction mixture is stirred at the same temperature for 1 hour. The reaction mixture is diluted with an aqueous citric acid solution, extracted twice with ethyl acetate. The combined organic layer is washed with water and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is purified by silica gel chromatography (silica gel 10 g, solvent; chloroform sole?chloroform:methanol=20:1) to give the following two fractions. The first fraction is concentrated in vacuo to give 2-methylthio-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine as a slightly brawn oil, 33 mg. The second fraction is concentrated in vacuo to give 2-hydroxy-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine as a slightly brawn crystalline powder, 132 mg. mp 195-197 C.
N-((trans)-4-hydroxylcyclohexan-1-yl)-4-((3-chloro-4-methoxybenzyl)amino)-2-((S)-2-(hydroxymethyl)tetrahydropyrrole-1-yl)-5-pyrimidine formamide[ No CAS ]
In a flask, tetrahydrofuran (4.5 L) was added, <strong>[41965-95-1]3-chloro-4-methoxybenzylamine hydrochloride</strong> (500 g, 2.4 mol) was added under stirring, triethylamine (836 mL, 6.01 mol) was added dropwise, the mixture was stirred at room temperature for 30 min, cooled with ice-water, then ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate (466 g, 2.0 mol) was added, the reaction was stirred overnight at room temperature. TLC was used to monitor the reaction. After the end of reaction, solvent was removed by evaporation under reduced pressure. Ethyl acetate (2.5 L) and water (1 L) were added, the mixed liquid phases were separated, the organic phase was sequentially washed with diluted hydrochloric acid, water (1 L), saturated sodium bicarbonate (1 L) and saturated sodium chloride (1 L), dried over anhydrous sodium sulfate. After filtration, solvent was removed by evaporation under reduced pressure to obtain an oily substance, to which was added methanol (3 L), and a large white solid was precipitated. After stirring for 30 min, filtration was carried out, and the filter cake was vacuum dried to obtain the product (650 g, yield of 88.3%).
78%
With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 4h;Cooling with ice;
Compound 13 (5 g, 21.86 mmole) and compound 18 (5.34 g, 25.4 mmol) were added to 75 ml of dry DMF 1 and dissolved with stirring. After stirring for 10 minutes, the reaction system was placed in an ice-water mixture. Triethylamine (21.4 g, 0.217 mole) was slowly added dropwise to the reaction flask and slowly warmed to room temperature. After 4 hours, TLC showed the reaction was completed. Dichloromethane was added, washed with water five times, dried and filtered, concentrated by rotary evaporation and passed through a column (PE: EA = 25: 1). Compound 19 (7.3 g, yield 78%) was obtained as a white powder.
74.2%
In THF (150 mL) was suspended <strong>[41965-95-1]<strong>[41965-95-1]3-chloro-4-methoxybenzylamine hydrochloride</strong> salt</strong> (16.0 g, 76.9 mmol). The suspension was cooled in an ice bath, and triethylamine (19.4 g, 192.3 mmol) was added dropwisely. The reaction mixture was stirred at ambient temperature for 15 min, then was added ethyl 4-chloro-2-thiomethyl-5-pyrimidine carboxylate (14.9 g, 64.1 mmol). The reaction mixture was stirred at ambient temperature overnight. TLC was used to monitor the reaction. After the completion of the reaction, the solvent was removed by rotary evaporation. Acetic ether (500 mL) and water (200 mL) were added. The organic phase was separated, washed with hydrochloric acid (1N), saturated aqueous solution of sodium bicarbonate and brine, dried over sodium sulfate and filtrated. The filtrate was concentrated under reduced pressure. The solvent was removed by rotary evaporation to give oil. Methanol (100 mL) was added to precipitate a large amount of white solid. The mixture was filtrated and the solid was dried in vacuum to give ethyl 4-((3-chloro-4-methoxybenzyl)amine)-2-thiomethyl-5-pyrimidine carboxylate (21 g, 74.2 % yield).
90 g
With sodium carbonate; In water; at 25 - 30℃; for 4h;
(3-Chloro-4-methoxyphenyl) methanamine hydrochloride compound of formula-6a (76.98 g) was added to the organic layer containing ethyl 4-chloro-2-(methylthio) pyrimidine-5-carboxylate compound of formula-5, which is obtained in step-b). Water (100 ml), followed by sodium carbonate (110.3 g) were added to the reaction mixture at 25-30C and stirred for 4 hours at the same temperature. After completion of the reaction, water was added to it. Both the organic and aqueous layers were separated; the aqueous layer was extracted with toluene. All the organic layers were combined and washed with water. Distilled off the solvent from the organic layer under reduced pressure. The reaction mixture was cooled to 30-35C. 700 ml of cyclohexane: ethyl acetate (in 9.5:5 ratio) was added to the reaction mixture. The reaction mixture was heated to 70-75C and stirred until complete dissolution. The reaction mixture was cooled to 10-15C and stirred for 3 hours. Filtered the precipitated solid, washed with cyclohexane and then dried to get title compound.Yield: 90 gms; Melting range: 81 -84C; Purity by HPLC: 95.3%.
(3-chloro-4-methoxyphenyl)methanamine malate[ No CAS ]
[ 330785-81-4 ]
Yield
Reaction Conditions
Operation in experiment
102 g
With tetrabutylammomium bromide; sodium carbonate; In water; at 25 - 30℃; for 8.0h;
(3-Chloro-4-methoxyphenyl)methanamine malate compound of formula-6b (1 13.1 g) was added to the organic layer containing ethyl 4-chloro-2-(methylthio)pyrimidine-5- carboxylate compound of formula-5 obtained in step-(b). Water (200 ml), followed by sodium carbonate (147.06 g) and tetrabutyl ammonium bromide (4.47 g) were added to the reaction mixture at 25-30C and stirred for 8 hours at the same temperature. Water was added to the reaction mixture at 25-30C. The reaction mixture was heated to 40-45C. Separated the both organic and aqueous layers. The organic layer was washed with water. Distilled off the solvent from the organic layer under reduced pressure and then co-distilled with cyclohexane. Cooled the obtained compound to 25-30C and 600 ml of cyclohexane: ethyl acetate (in 9: 1 ratio) was added to it at the same temperature. The reaction mixture was heated to 65-70C and stirred 15 minutes. The reaction mixture was cooled to 10-15C and stirred for 3 hours. Filtered the precipitated solid and washed with cyclohexane. Water (1000 ml) was added to the wet solid. Heated the reaction mixture to 60-65C and stirred for 30 minutes. Cooled the reaction mixture to 25-30C and stirred for 60 minutes. Filtered the precipitated solid, washed with water and then dried to get the title compound.Yield: 102 gms; Melting range: 80-84C; Purity by HPLC: 99.25%
tert-butyl 2-((2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)pyrimidine-5-formamido)methyl)-7-azaspiro[3.5]nonane-7-carboxylate[ No CAS ]
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