Product manager: Emma Song Email: emma@coreychem.com
Background and overview:
Tert-butyl sulfonamide, as an effective synthetic method for chiral amines, has been widely used in drug synthesis. Over 75% of drugs and candidate drugs contain amine functional groups. Although this is the case, the development of asymmetric amines, compared to other common functional group asymmetry synthesis, is much later. In recent years, tert-butyl sulfonamide has received increasing attention and application in asymmetric synthesis.
Preparation
Report 1:
a) Synthesis of N-methyltriphenylamine: In the presence of argon protection, in a 1-liter reaction flask equipped with mechanical stirring and a cold bath, add triphenylchloromethane (0.1076 moles), maintain the temperature between -50 and 60 degrees Celsius, slowly introduce 600 mL of liquid ammonia, add 1% of triphenylchloromethane by weight of toluene as an internal standard for analysis, the internal standard analysis of triphenylchloromethane is less than 1%, the reaction stops after 4-6 hours. The reaction solution is raised to room temperature, the ammonia gas is completely evaporated, add 500 mL of methyl tert-butyl ether (MTBE), wash the organic layer with 70 g of 10% sodium carbonate by mass, wash the organic layer twice with 75 g of water, dry, concentrate, obtain the crude N-methyltriphenylamine 24 g. 1.5 * 24 g of ether slurry, after 1.5 hours of filtration, the dried product is 0.0860 moles.
b) Synthesis of N-methyl(triphenyl)amino lithium: In an 1-liter reaction flask protected by argon gas, equipped with a constant-pressure feeding funnel and a cold bath, add the N-methyl triphenylamine obtained in step a), along with 400 mL of tetrahydrofuran. At -60 to -70℃, slowly add the n-BuLi (0.0716 mol) solution dropwise. After the dropwise addition is completed, continue stirring for 1 hour to obtain the N-methyl(triphenyl)amino lithium reaction solution. This solution is directly used in the next synthesis step under argon protection.
c) Synthesis of (S)-N-methyl-(triphenyl) tert-butyl sulfonylamide: Under argon protection, a solution of (S)-tert-butyl sulfonyl tert-butyl ester (0.0143 mol) of equal mass in THF was dropped into the reaction bottle in a temperature range of -60 to -70℃. After the dropwise addition, the mixture was stirred for 1 hour, and then 11 alkanes were added as an internal standard. The internal standard recovery rate was 95.8%. At a temperature range of -5 to -15℃, 8 g of water was used for extraction, 12 g of dimethyl sulfate for deodorization, 17.2 g of ammonia water for destroying the excess dimethyl sulfate and stirring at 15℃ for 1 hour. 120 mL * 2 ethyl acetate was used for extraction, drying, and obtaining the crude product of (S)-N-methyl-(triphenyl) tert-butyl sulfonylamide. The product was pulped with a mixture of ethyl acetate and n-hexane in a volume ratio of 1:5, and filtered to obtain the pure product (S)-N-methyl-(triphenyl) tert-butyl sulfonylamide.
(d) Synthesis of (S)-tert-butyl sulfonylimide: Take the product obtained in step c), add 2N dilute hydrochloric acid, adjust the pH to 3, stir for 30 minutes, neutralize with 40% sodium hydroxide to pH 13-14, extract with 100 mL * 3 ethyl acetate, dry, concentrate, pulp with 50 mL n-hexane, and then process to obtain (S)-tert-butyl sulfonylimide 4.0g, with a yield of 91.3%. GC > 97%, EE > 99%, melting point is 90-107 degrees, determination of the structure of the organic compound: 1H NMR, 13C NMR and IR are consistent with the standard spectra.
Report 2:
200g of tert-butyl disulfide, 400g of tert-butanol and 1.5g of VO(acac)2 were added to the reaction flask. Starting from 20 to 25℃, 1.10 to 1.15 equivalents of 25-30% hydrogen peroxide were gradually added. The reaction was carried out for 5 hours, with the temperature of the material in the reactor controlled at 20 to 25℃. After the addition was completed, the reaction was maintained at 25 to 30℃ for 5 to 8 hours, and samples were taken for HPLC analysis. After the reaction was completed, the system was depressurized for concentration, and tert-butanol was evaporated. A salt water solution was added for washing, and the system was depressurized for further concentration until it became a non-flowing liquid. The resulting tert-butyl sulfoximine tert-butyl ester had a HPLC purity of 89%. The yield was 82%.
Add 198 grams of tert-butyl isothiocyanate and 562 grams of dichloromethane to the reaction flask. Dropwise add the 1.01 Eq bromine solution diluted with dichloromethane. Control the temperature inside the flask at -5 to 0 degrees. Slowly dropwise add, and after the addition is completed, keep the reaction warm for 2 hours. Take samples and perform HPLC detection after methanol derivatization (impurities are tert-butyl bromide and tert-butyl thio). After the reaction is completed, add it to 10 Eq concentrated ammonia water solution, control the temperature at 0 to 5 degrees. After the addition is completed, reduce the pressure for concentration, add dichloromethane/normal heptane = 1:10) for extraction, then extract with normal heptane. TLC detection removes small polar impurities. Add ethyl acetate for extraction, dry, filter, concentrate to twice the weight of the product, filter out trace insoluble substances, and continue to concentrate the filtrate to dryness. Add normal heptane to replace twice, then add a small amount of normal heptane for grinding, obtaining a white product, with a yield of 77%.
