| 98% |
With methanesulfonyl chloride; triethylamine; In dichloromethane; at 0 - 20℃; for 24h; |
Dissolve 22.38g (62mmol, 1.0eq.) of the amino-protected product (Compound A) in dichloromethane, cool the system to 0C, and slowly add triethylamine (2.5eq., 11.0mL) and MsCl (1.5 equiv., 3.7mL). After the addition is complete, the ice-salt bath is removed, and the system is naturally restored to room temperature and stirred for 24 hours. TLC detects that the reactants have completely disappeared. The reaction is quenched by adding deionized water, and the dichloromethane layer is obtained by liquid separation. It was washed with saturated brine, dried with anhydrous sodium sulfate, evaporated to remove the solvent, and recrystallized in a mixed solvent of n-hexane/methyl tert-butyl ether to obtain 20.9 g of white solid (compound B) with a yield of 98%. |
| 76% |
|
Methyl (2R)-3-hydroxy-2-(tritylamino)propanoate (93 g, 0.26 mol) soluble in chloroform (500mL), add triethylamine (95 mL, 0.68 mol) at 0 C And 4-dimethylaminopyridine (2.8 g, 26 mmol), after stirring for 5 minutes, methanesulfonyl chloride (28 mL, 0.36 mol) was added slowly. After reacting for 4 hours at room temperature, The mixture was heated to 62 C for 12 hours. The reaction solution was cooled to room temperature. Wash with water (800 mL) and saturated sodium chloride solution (600 mL), respectively. Dry over anhydrous sodium sulfate and concentrate by suction filtration. Ethanol (600 mL) was added to the residual solid.Stir for 10 minutes, filter, collect the filter cake, The title compound was obtained (67 g, yield 76%). It is a white solid. |
|
With dmap; methanesulfonyl chloride; triethylamine; In chloroform; at 0 - 20℃; for 16h;Heating / reflux; |
Example 1: Preparation of (R)-4-[(R)-3-amino-4-(2,4,5-trifluorophenvDbutanoyll- 3-(t-butoxymethyl)piperazin-2-one hydrochloride; Step 1: Preparation of (R)-methyl l-tritylaziridine-2-carboxylate; 200 g of D-serine methyl ester hydrochloride was added to 1.8 L of chloroform, and the reaction solution was cooled to 0C, to which 448 mL of triethylamine was then slowly added. 358.4 g of trityl chloride was slowly added to the reaction mixture which was then stirred for 1 hour. The reaction mixture was warmed to room temperature, and 1 L of chloroform was added thereto, followed by washing with 2.5 L of water. The organic layer was dried over magnesium sulfate and cooled to 0C, to which 484 mL of triethylamine and 15.7 g of 4- methylaminopyridine were then sequentially and slowly added. The reaction mixture was stirred for 5 min and 139 mL of methane sulfonyl chloride was slowly added thereto. The reaction mixture was warmed to room temperature, stirred for another 4 hours and then refluxed for 12 hours. The reaction mixture was cooled to room temperature, and washed with 4 L of water and then 3 L of brine. The organic layer was dried over magnesium sulfate and <n="17"/>concentrated to dryness under reduced pressure. 3 L of ethanol was added to the resulting residue which was then stirred. The resulting solids were filtered to afford 329 g of the title compound.IH NMR (400 MHz, CDC13): 7.42 to 7.49(m, 6H), 7.18 to 7.32(m, 9H), 7.68(s, IH),3.74(s, 3H), 2.24(m, IH), 1.87(m, IH), and 1.40(m, IH) |
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