* 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.
Compound 6 (500.0 g, 1.1 mol) and 10percent palladium on charcoal (25.0 g) was dissolved in acetic acid (5.0 liters, 5percent by weight) under the conditions of hydrogen pressure 1.50MPa and stirred at 60 ° C for 6 h. The catalyst was removed by filtration. The filtrate was concentrated to dryness, to the residue was added acetic acid (500 ml) and water (500 ml), stirred for 1 hour ,filtered, a white solid (475.0 g) was obtained. Melting point: 220.0~221.5. The above solid was dissolved in ethyl formate (5.0 liters), a solution of concentrated hydrochloric acid (150 ml) was added dropwise with stirring. After stirring, the mixture was stirred at room temperature for 6 hours.filtered,the filter cake was washed with ethyl acetate and dried under vacuum at 45 ° C for 10 hours to obtain white solid 1 (516.2 g, 95.7percent).
With palladium 10% on activated carbon; hydrogen; acetic acid; at 60℃; under 11251.1 Torr; for 6h;
Compound 6 (500.0 g, 1.1 mol) and 10% palladium on charcoal (25.0 g) was dissolved in acetic acid (5.0 liters, 5% by weight) under the conditions of hydrogen pressure 1.50MPa and stirred at 60 C for 6 h. The catalyst was removed by filtration. The filtrate was concentrated to dryness, to the residue was added acetic acid (500 ml) and water (500 ml), stirred for 1 hour ,filtered, a white solid (475.0 g) was obtained. Melting point: 220.0~221.5. The above solid was dissolved in ethyl formate (5.0 liters), a solution of concentrated hydrochloric acid (150 ml) was added dropwise with stirring. After stirring, the mixture was stirred at room temperature for 6 hours.filtered,the filter cake was washed with ethyl acetate and dried under vacuum at 45 C for 10 hours to obtain white solid 1 (516.2 g, 95.7%).
In step A, TF(4 mmol) is reacted with trityl chloride (8.8 mmol) and TEA (8 mmol) (Aldrich, 99%) in 40 ml of CHCl3 for four hours at room temperature. A clear solution is obtained. In step B, 40 ml of methanol is added into the above clear solution. The mixture is heated to 50 C. and stirred for one hour, a lot of precipitates appeared in the solution. After the reaction mixture is cooled down to room temperature, precipitates were collected by filtration. They were further purified from CHCl3/methanol. 3.4 mmol of Product B were obtained.
Multi-step reaction with 4 steps
1: sodium iodide / N,N-dimethyl-formamide / 4 h / 20 °C
2: potassium hydroxide / water / 15 h / 65 - 70 °C / Large scale
3: palladium 10% on activated carbon; acetic acid; hydrogen / 6 h / 60 °C / 11251.1 Torr
4: hydrogenchloride / 6 h / 20 °C
Compound 6 (500.0 g, 1.1 mol) and 10% palladium on charcoal (25.0 g) was dissolved in acetic acid (5.0 liters, 5% by weight) under the conditions of hydrogen pressure 1.50MPa and stirred at 60 C for 6 h. The catalyst was removed by filtration. The filtrate was concentrated to dryness, to the residue was added acetic acid (500 ml) and water (500 ml), stirred for 1 hour ,filtered, a white solid (475.0 g) was obtained. Melting point: 220.0~221.5. The above solid was dissolved in ethyl formate (5.0 liters), a solution of concentrated hydrochloric acid (150 ml) was added dropwise with stirring. After stirring, the mixture was stirred at room temperature for 6 hours.filtered,the filter cake was washed with ethyl acetate and dried under vacuum at 45 C for 10 hours to obtain white solid 1 (516.2 g, 95.7%).
N-(butylsulfonyl)-O-[4-(4-piperidinyl)butyl]-L-tyrosine methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.13 g
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetone; at 30 - 50℃; for 5h;
Weigh 2 · 2 g (5 mmol) of <strong>[144494-65-5]tirofiban</strong>, 1.99 g (12.5 mmol) of 1,8-dicarbonheterocyclo [5.44] undec-(DBU) was added to a 50 ml three-necked flask in turn,And then take 11ml of acetone to join them,Stirring dissolved,1.78 g was added dropwise at room temperature(12.5 mmol) of methyl iodide,After completion of the reaction, heating to 30-50 C reaction, stirring reaction 5 hours. TLC to monitor the end of the reactionAfter completion of the addition of 22ml of purified water, and then were extracted with ethyl acetate 22ml 2 times, combined with ethyl acetate layer, ethyl acetate layer with pureThe organic layer was separated and the organic layer was separated and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2.13 g of a product as a pale yellow oil
With 5%-palladium/activated carbon; hydrogen; acetic acid at 60℃; for 2.5h; Autoclave;
4 Preparation of N-n-butylsulfonyl-O-(4-(piperidin-4-yl)but-1-yl)-L-tyrosine (Formula V).
Add N-n-butylsulfonyl-O-(4-(pyridin-4-yl)but-3-yn-1-yl)-L-tyrosine (Formula IV, R2=( 33.0g, 76.7mmol) and acetic acid (400mL).Subsequently, under the protection of nitrogen, a thin slurry of acetic acid (25 mL) containing Pd/C (containing Pd 5%) (2.0 g) was added to the autoclave. After closing the autoclave and replacing with nitrogen three times, the reaction system was hydrogenated under hydrogen pressure (10atm) and 60°C for 2.5 hours. The temperature was lowered to room temperature, the system was filtered, and the solvent was removed from the residue under high vacuum (a small amount of acetic acid was left in the system at the end, and it does not need to be completely dried), and then H2O (400 mL) was added to the residue, and stirred at room temperature overnight. Filter, wash the solid with H2O (200mL), and dry the obtained wet product to obtain N-n-butylsulfonyl-O-(4-(piperidin-4-yl)but-1-yl)-L-tyrosine (formula V) (28.8g, 85.1%).
Stage #1: 4-(4-pyridyl)butyl chloride hydrochloride; N-(butanesulfonyl)-L-tyrosine With potassium <i>tert</i>-butylate; potassium iodide In dimethyl sulfoxide at 60℃;
Stage #2: With acetic acid at 130℃;
1-3 Example 1
Dissolve 1 mol of 4-(4-pyridyl) butyl chloride hydrochloride, 1 mol of N-(butylsulfonyl)-L-tyrosine, 1.8 mol of potassium tert-butoxide, and 0.65 mol of potassium iodide in 3.5 In dimethyl sulfoxide in L, the temperature was controlled at 60°C for 9 hours. After the reaction, the solvent was evaporated under reduced pressure, and the pH was adjusted to 3 with hydrochloric acid. The combined organic phase was extracted with ethyl acetate, dried with anhydrous sodium sulfate, and reduced again. The solvent was removed by autoclaving to give the intermediate (308.8 g, 78.6%).Take 100g of the prepared intermediate, place 10g of Raney nickel in 540g of glacial acetic acid, and react at 130°C for 7h,After the reaction was completed, impurities were removed by filtration, and the filtrate was evaporated to remove the solvent under reduced pressure. After adding 100 mL of acetic acid and 1000 mL of water, stirred at 150 rpm for 3 h, and filtered to obtain a white solid (96.1 g, 96.1%), which was tirofiban.