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The mixture of tert-butyl 6-oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxylate (20 g, 0.11 mol) and aqueous ammonia (200 mL) was heated overnight at reflux. The reaction was concentrated in vacuo to afford the product tert-butyl 3-amino-4- hydroxypyrrolidine-1-carboxylate (21 g, 96%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3): delta 3.98-3.97 (m, IH), 3.75-3.61 (m, 2H), 3.36-3.22 (m, 2H), 3.08-3.17 (m, IH), 1.45 (s, 9H).
Reference O; Synthesis of 3-amino-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester; 6-Oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tart-butyl ester (12.1 g, 65.3 mmol) was dissolved in a 8:1 methanol/water mixture (108 mL). Ammonium chloride (15 g) andsodium azide (21.4 g, 329 mmol) was added and the reaction mixturewas heated at 60 Covernight. After dilution with ether (500 mL), the reaction mixturewas washed with saturatedaqueous NaHCOs (200 mL) and brine (200 mL), dried with MgSC>4 and evaporated undervacuum. The crude product was dissolved in methanol (200 mL). 10% Palladium on activatedcarbon (1.5 g) was added and the reaction mixturewas stirred at ambient temperature under ahydrogen atmosphere until TLC analysis showed the disappearance of the starting material. Thereaction mixture was filtered through a pad of Celite and evaporated to dryness under vacuum.The product was purified by flash chromatography on silica gel using 5% methanol in ethylacetate to 20% methanol, 3% triethylamine in ethyl acetate to give 4.3 g of 3-amino-4-hydroxy-pyrrolidine-1-carboxylic acid tert-bntyl ester as yellowish solid.
Reference M Synthesis OF 3-AMINO-4-HYDROXOPYRROLIDINE-1-CARBOXYLIC acid TERT-BUTYL ester 6-Oxa-3-aza-bicyclo [3.1. 0] hexane-3-carboxylic acid tert-butyl ester (12.1 g, 65.3 mmol) was dissolved in a 8: 1 methanol/water mixture (108 mL). Ammonium chloride (15 g) and sodium azide (21.4 g, 329 mmol) was added and the reaction mixturewas heated at 60 C overnight. After dilution with ether (500 mL), the reaction mixture was washed with saturated aqueous NAHCO3 (200 mL) and brine (200 ML), dried with MgS04 and evaporated under vacuum. The crude product was dissolved in methanol (200 mL). 10% Palladium on activated carbon (1.5 g) was added and the reaction mixturewas stirred at ambient temperature under a hydrogen atmosphere until TLC analysis showed the disappearance of the starting material. The reaction mixture was filtered through a pad OF CELITETM and evaporated to dryness under vacuum. The product was purified by flash chromatography on silica gel using 5% methanol in ethyl acetate to 20% methanol, 3% triethylamine in ethyl acetate to give 4.3 g of 3-amino-4- hydroxy-pyrrolidine-1-carboxylic acid TERT-BUTYL ester as yellowish solid.
Reference N Synthesis [OF 3-AMINO-4-HYDROXOPYRROLIDINE-1-CARBOXYLIC] acid [TERT-BUTYL] ester 6-Oxa-3-aza-bicyclo [3.1. 0] hexane-3-carboxylic acid [TERT-BUTYL] ester (12.1 g, 65.3 mmol) was dissolved in a 8: 1 methanol/water mixture (108 mL). Ammonium chloride (15 g) and sodium azide (21.4 g, 329 mmol) was added and the reaction mixturewas heated at [60 C] overnight. After dilution with ether (500 mL), the reaction mixturewas washed with saturated aqueous [NAHCO3] (200 mL) and brine (200 mL), dried with MgS04 and evaporated under vacuum. The crude product was dissolved in methanol (200 mL). 10% Palladium on activated carbon (1.5 g) was added and the reaction mixturewas stirred at ambient temperature under a hydrogen atmosphere until TLC analysis showed the disappearance of the starting material. The reaction mixture was filtered through a pad of Celite and evaporated to dryness under vacuum. The product was purified by flash chromatography on silica gel using 5% methanol in ethyl acetate to 20% methanol, 3% triethylamine in ethyl acetate to give 4.3 g [OF 3-AMINO-4-HYDROXY-PYRROLIDINE-1-CARBOXYLIC] acid [TERT-BUTYL] ester as yellowish solid.
With ammonia; In water; at 60℃; for 15.0h;
Preparation Example 1-114-23-tert-Butoxycarbonylamino-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester To 2.93 g (15.80 mmol) of the compound obtained from Preparation Example 1-114-1 was added 25 mL of ammonia water and stirred at 60 C. for 15 hours. The reaction solution was distilled in vacuo, diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous magnesium sulfate (MgSO4) and distilled in vacuo. To the residue was added 30 mL of dichloromethane and 14.21 g (65.10 mmol) of di tert-butyl dicarbonate and stirred for 4 hours. The reaction solution was distilled in vacuo and purified by column chromatography using a mixed solution of dichloromethane and methanol in the ratio of 95:5 to obtain the title compound 2.95 g (2-step 62%).1H NMR (400 MHz, CDCl3); delta 4.67 (1H, br), 4.21 (1H, br), 3.91 (1H, br), 3.76 (2H, br), 3.27 (1H, br), 3.17 (1H, br), 1.44 (18H, s)
8 g
With ammonium hydroxide; at 90℃; for 4.0h;
A solution of Example 34A (9.0 g , 48.59 mmol) in 90 ml ammonia water was heated to 90C and stirred for 4hours. The reaction solution became reddish brown. The reaction solution was rotatory evaporated until dry, into whichwere added dichloromethane 200 ml and methanol 20 ml, the mixture was dried over anhydrous sodium sulfate, andfiltered. The filtrate was concentrated to give the product Example 34B (8 g) as a reddish brown oil, which was useddirectly in the next step.
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