tert-Butyl (trans-3-hydroxy-2,2,4,4-tetramethylcyclobutyl)carbamate
trans-tert-Butyl 3-hydroxy-2,2,4,4-(tetraMethyl)cyclobutylcarbaMate
CAS: 1338812-41-1
Molecular Formula: C13H25NO3
tert-Butyl (trans-3-hydroxy-2,2,4,4-tetramethylcyclobutyl)carbamate - Names and Identifiers
tert-Butyl (trans-3-hydroxy-2,2,4,4-tetramethylcyclobutyl)carbamate - Physico-chemical Properties
| Molecular Formula | C13H25NO3 |
| Molar Mass | 243.34 |
| Density | 1.03±0.1 g/cm3(Predicted) |
| Boling Point | 326.7±31.0 °C(Predicted) |
| pKa | 12.28±0.70(Predicted) |
| Storage Condition | Room Temprature |
tert-Butyl (trans-3-hydroxy-2,2,4,4-tetramethylcyclobutyl)carbamate - Reference Information
| application | 3-hydroxy-2, 2,4,4-(tetramethoxy) cyclobutyl carbamate tert-butyl ester is a pharmaceutical intermediate, and it has been reported in the literature that it can be used to prepare a new type of androgen receptor antagonist. |
| preparation | step 1:3-(hydroxyimino)-2,2,4,4-tetramethylcyclobutanone (32): add tetramethylcyclobutane -1 to NH2OH.HCl(124g,1.78 mol) in water (200 mL) and ethanol (1000 mL) solution, 3-dione (Alfa Aesar,A16297)250g,1.78 mol) and NaOAc(146g,1.78 mol). The resulting mixture was stirred under reflux for 2 hours. TLC(4:1 PE:EtOAc,KMnO4 staining) indicated that the reaction was complete. The ethanol was removed under reduced pressure and the residue was azeotropic to dryness with toluene (1000mL). The resulting residue was suspended in toluene (1500mL) and heated to reflux. The suspension was filtered hot and the filter cake was washed with toluene (500mL). The filtrate is then vacuum concentrated. Compound 32(186.5g,67.4%) is a white solid. Step 2: 3-hydroxy-2, 2,4, 4-tetramethylcyclobutanone oxime (33): NaBH4(32.0g,0.84 mol,0.7 eq) was added in batches to a solution of compound 32(186.5g,1.20 mol) in isopropanol (IPA)(1200 mL) at 25°C. The resulting mixture was stirred at room temperature for 16 hours. TLC(1:1 EtOAc/heptane, KMnO4 staining: ketone Rf = 0.6 alcohol Rf = 0.47) indicated that the reaction was complete. NaOH aqueous solution (298g,7.45mol) was added dropwise at 5 ℃ to water (2000mL) to quench excess NaBH4. The mixture was extracted with EtOAc(1000mL × 3). The combined organic phase was dried by Na2SO4 and concentrated to obtain compound 33(175.9g,93%) as a white solid. Step 3:3-amino -2,2,4, 4-tetramethylcyclobutanol (34): Add Ni/Al alloy (383.3g,4.47 mol) to a solution of compound 33(175.8g,1.12 mol) in THF(1500 mL). The suspension was stirred at 60°C for 30 minutes. Drop NaOH(208g,5.20mol) of water (1500mL) solution to keep the mixture refluxed. After addition, the mixture is refluxed for another 2 hours. TLC(1:1 EtOAc/heptane, KMnO4 staining: oxime Rf = 0.47 amine Rf = 0) showed that the reaction was complete. The mixture was filtered and the filter cake was washed with THF(500mL × 3). The filtrate was concentrated and extracted with EtOAc(1000mL × 3). The combined organic phase was dried by Na2SO4 and concentrated to dry compound 34(147.9g,92%) in a light yellow slurry and cured by standing (1H NMR showed a trans: cis ratio of 5:3). Step 4:(1r,3r)-3-amino -2,2,4, 4-tetramethylcyclobutanol (35): A solution of H3PO4(70mL,1.03 mol) of ethanol (140mL) was added dropwise to a solution of compound 34(147.9g,1.03 mol) in ethanol (4400 mL,30 mL/g) at 60°C. The resulting suspension was refluxed and stirred for 2 hours, and then cooled to room temperature. The suspension was filtered and the filter cake was washed with ethanol (500mL) and dried in vacuum to obtain crude 35(152g). The crude product was suspended in ethanol (760mL,5mL/g) and stirred at room temperature for 16 hours. The suspension was filtered and the filter cake was washed with additional ethanol (200mL) and dried in vacuum. 35 is phosphate and white solid (147.2g,59%). Step 5:3-hydroxy -2,2,4,4-(tetramethoxy) cyclobutylcarbamate tert-butyl ester (7): suspend (1r,3r)-3-amino -2,2,4, 4-tetramethylcyclobutanol (19.2g,79.6 mmol) in dioxane (240 mL), and then add K2CO3(22.6g) dropwise at 0°C, 164 mmol) in H2O(80 mL). After addition, BOC2O(VWR,EM8.18282.0025)(18.9g,86.7mmol) was added. The resulting mixture was stirred overnight at room temperature. TLC(2 ∶ 1 petroleum ether/EtOAc) indicated that the reaction was complete. The reaction mixture was evaporated and the residue was diluted with water (200mL) and CH2Cl2(400mL). The organic layer was separated and the water layer was extracted with CH2Cl2(100mL × 3). The combined organic layer was washed with salt water (100mL), dried by Na2SO4, filtered and evaporated. The crude product was purified by column chromatography (10 ∶ 1 petroleum ether/EtOAc) to obtain compound 7(17g,88%), which is a white solid. |
Last Update：2024-04-09 20:45:29
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