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EXAMPLE 1 To a solution of 76.5 g of sodium hydroxide in 470 ml of water are added, in a nitrogen atmosphere, 30.5 g of thioglycolic acid and then 64 g of 3-chloroacetamido-2-oxo-tetrahydrothiophene. The mixture is heated to reflux for 5 mins. then cooled, acidified with hydrochloric acid concentrated up to pH 1 to 2 and filtered. By crystallization with 500 ml of ethanol, 40 g of [(2-oxo-3-tetrahydrothienylcarbamoyl)-methylthio]acetic acid are obtained (PV 144), m.p. 156 to 158 C.
[00102] 4-neck round bottom flask was equipped with a magnetic stirrer, temperature read out/controller, and an addition funnel with a nitrogen inlet. The exhaust gas was vented to a caustic scrubber. Compound 3, <strong>[84611-23-4]erdosteine</strong> (1.0 eq), dichloromethane (DCM) (10 vols), and triethylamine (2.0 eq) were charged to the flask. An exothermic reaction was observed during the TEA addition. The clear reaction mixture was cooled to -25 C in dry ice/acetone bath. A solution of compound 2 acid chloride (1.2 eq) in 5 vols of DCM was added over 15- 20 minutes. The reaction temperature was maintained below -10 C. during addition. After the addition was completed, the reaction mixture was slowly brought to room temperature and was stirred for two hours. The resulting solids were removed by filtration though celite. The filter cake was washed with DCM and acetone. The filtrate was concentrated in vacuo to obtain compound 4 with 90% yield. Mol. Formula: C13H1806N2S3 ; Mol. Wt.: 394.49.
With sodium hydrogencarbonate In water at 10℃; for 0.5h;
5; 1
Dissolve 20 g of homocysteine thiolactone hydrochloride in water, add sodium bicarbonate to adjust the pH to 7-9, the temperature of the reaction solution is lower than 10°C, and then add the thioglycolic anhydride prepared in Example 1 (1.2 equivalents), keep the pH of the reaction solution at 6-7, react for half an hour, add hydrochloric acid to adjust the pH to 2-3, precipitate and filter to obtain crude erdosteine,According to the conventional purification method, 26.6 g of erdosteine was obtained (yield 82%)
With 2,4,6-trimethyl-pyridine; 2,4,6-Triisopropylthiophenol; water-d2; 9-(2-mesityl)-10-methylacridinium perchlorate In dichloromethane at 20℃; Irradiation;
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane
1 Example 1: Preparation method of compound of formula 2
1.0 g of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide was added to a suspension of 1.0 g of erdosteine, 226 mg of 4-hydroxybenzyl alcohol, and 89 mg of dimethylaminopyridine in 23 ml of dichloromethane, followed by stirring overnight. It was extracted by dilution with dichloromethane and water. The separated organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The concentrated residue was purified by eluting with a column packed with silica gel (methanol : dichloromethane = 1 : 20). The fractions were concentrated under reduced pressure to obtain 0.46 g of the title compound.
With triethylamine In tetrahydrofuran; water monomer; acetone
1 Preparation of erdosteine using l,4-oxathiane-2,6-dione
A solution of l,4-oxathiane-2,6-dione (47.2 g) in THF (421 mL), and a second solution of homocysteine thiolactone hydrochloride (50 g) in a mixture of THF (166 mL), water (166 mL), acetone (166 mL) and triethylamine (32.9 g), are prepared. The two solutions are pumped into a microreactor with an internal volume of 5.4 mL at flow rates of 1 mL/min for both (corresponding to a residence time of 2.7 minutes) at 60°C. 640 mL of solution is collected, evaporated until the residue only contains water, and diluted with isopropanol (160 mL). After cooling, filtration and drying, 16.7 g of pure erdosteine is obtained.
With acetic anhydride; triethylamine In water monomer; acetone at 175℃; for 0.0416667h; Flow reactor;
4 Preparation of erdosteine with formation in situ of internal anhydride
A solution of thiodi glycolic acid (100 g) in acetone (400 mL), a solution of acetic anhydride (68.3 g) in acetone (370 mL), and a solution of homocysteine thiolactone hydrochloride (96 g) in water (160 mL), acetone (540 mL) and triethylamine (63.2 g), are prepared. The first two solutions are pumped into the first module of a microreactor with an internal volume of 2.7 mL at flow rates of 0.65 mL/min at 175°C. The output of the first module is pumped simultaneously with the third solution into the second module of the microreactor with an internal volume of 2.7 mL at flow rates of 1.2 mL/min (total residence time 2.5 minutes) at 175°C. 450 mL is collected, the acetone is evaporated, and the residue is diluted with isopropanol. After filtration and drying, 24.4 g of pure erdosteine is obtained.