3-BOC-AMINO-2,6-DIOXOPIPERIDINE

A solution OF N-(T-BUTOXYCARBONYL)-L-GLUTAMINE (4.92 g) and carbonyl diimidazole (1.70 g) in THF (100 mL) was refluxed for 9 h. The solvent was removed and the crude product was recrystallized from hot EtOAc to give compound 3 (2.04 g, 45percent) as white crystals: mp 214-215°C ; IH NMR (DMSO-d6) 5 4.22 (dd, J = 6.2 Hz, J = 11.0 Hz, 1H), 2.77-2. 65 (m, 1H), 2, 45 (m, 1 H), 1.96-1. 87 (m, 2H), 1. 40 (s, 9H) ; MS (CI/CH4) 227 [M-1] +.A mixture of 3-aminopiperidine-2, 6- dione hydrochloride (500 mg, 3.04 mmol) and triethylamine (931 µL, 6.68 mmol) in DCM (3 mL) was heated in a sealed 20 mL microwave vial at 50 °C for 30 min. The mixture was cooled to 0 °C and di-tert-butyl dicarbonate (663 mg, 3.04 mmol) in DCM (1 mL) was added via syringe, and stirring at 0 °C was continued for a further 30 min. The mixture was concentrated under vacuum and ethyl acetate (200 mL) added. The resulting mixture was washed with NaHCON-Boc--glutamine methyl ester (I) 260g (1mol) was dissolved in 3L of dry THF was added CDI (N, N- carbonyl diimidazole) 300g, DMAP (4- dimethylaminopyridine) 10g, was heated under reflux for 48 hour.Spin dry tetrahydrofuran, was added 200ml water, 300ml of methyl tert-butyl ether and extracted twice successively with dilute acid, saturated sodium bicarbonate, saturated sodium chloride, dried over anhydrous sodium sulfate.Spin dry to give a white solid 200g, ethyl acetate / petroleum ether (30/70) was recrystallized 2-3 times to give a white solid 146g, 64percent yield.To the reaction flask, 3 L of distilled water and 0.8 kg of sodium chloride were added to the solution, followed by stirring. Then, 140 g of 3-N-t-butoxycarbonylamino-2, 6-dioxopiperidine (II) obtained by the method of , And then heated under reflux to 4h. After cooling to room temperature overnight, 77 g of 3-amino-piperidine-2, 6-dione (III) was filtered and the yield of the desired product (III) was 98%reactionDissolve the 3-aminopiperidine-2, 6-dione prepared in step (4) in 200 mLMethyl tert-butyl ether, Cool and keep at 0 C, pass in hydrogen chloride gas, and react for 20min.Precipitation of a white solid, Filtration and drying gave 9.5 g of a white solid with a yield of 90%.tert-Butyl (2, 6-dioxopiperidin-3-yl)carbamate (1.8 g, 7.9 mmol) was dissolved in TFA (10 mL) and stirred at rt for 1 h. The reaction mixture was then evaporated under reduced pressure to give 3-aminopiperidine-2, 6-dione as the TFA salt as a brown solid (1.7 g, 96%). LCMS (ESI+) m/z 129 (M+H)+.Toa suspension of S3 (13.18 g, 57.76 mmol) in CH2Cl2 (30 mL) was addedtrifluoroacetic acid (30 mL) slowly at 0 C open to the air. After 10 min, theice bath was removed and within 10 min a solution had formed. After another2 h, the mixture was concentrated invacuo to give 20.786 g of 6 as alight pink solid.Assuming a quantitative yield, this corresponds to two equivalents of trifluoroaceticacid per molecule of amine.1H-NMR (DMSO-d6, 400 MHz): delta 11.27 (s, 1H), 8.53 (s, 3H), 4.21 (m, 1H), 2.76-2.67 (m, 1H), 2.62-2.56 (m, 1H), 2.19-2.12 (m, 1 H), 2.00(ddd, J = 26.1, 13.1, 5.0 Hz, 1H) ppm3-aminopiperidine-2, 6-dione trifluoroacetic acid [Show Image] 2.28 g of tert-butyl 2, 6-dioxopiperidin-3-yl carbamate was suspended in 30 mL of DCM, and 10 mL TFA was added. The reaction mixture was stirred at room temperature for 4h, and was evaporated to dryness to remove the solvent. 2.4 g of a solid were obtained.A solution OF N-(T-BUTOXYCARBONYL)-L-GLUTAMINE (4.92 g) and carbonyl diimidazole (1.70 g) in THF (100 mL) was refluxed for 9 h. The solvent was removed and the crude product was recrystallized from hot EtOAc to give compound 3 (2.04 g, 45%) as white crystals: mp 214-215C ; IH NMR (DMSO-d6) 5 4.22 (dd, J = 6.2 Hz, J = 11.0 Hz, 1H), 2.77-2. 65 (m, 1H), 2, 45 (m, 1 H), 1.96-1. 87 (m, 2H), 1. 40 (s, 9H) ; MS (CI/CH4) 227 [M-1] +.To a stirred solution of (tert-butoxycarbonyl)-L-glutamine (6.0 g, 24 mmol) in THE (60 mL) was added CDI (4.2 g, 25.9 mmol) and DMAP (0.012 g, 0.098 mmol) at rt. The resulting reaction mixture heated to 70 C. and stirred for 16 h. The reaction precipitate was filtered and washed with THF (50 mL), and dried under reduced pressure to give Theprocedure of Brown was followed for the following two steps.[1] Amixture of Boc-Gln-OH (10.00 g, 40.61 mmol), carbonyl diimidazole (7.00 g, 43.17 mmol), and DMAP (21 mg, 0.17 mmol) in anhydrous THF (100 mL) was heatedto reflux under argon for 18 h. The reaction mixture was concentrated to abouthalf the original volume in vacuo andthe resulting precipitate was filtered and washed with cold THF to give 3.872 gof S3 as a white solid. The filtratewas concentrated in vacuo until aprecipitate formed and an additional 932 mg of S3 was obtained. Repeating this procedure gave an additional 817 mgof S3 to give a total of 5.621 g(61%) of S3 as a white solid.TLC: Rf = 0.31 (5% MeOH in CH2Cl2)1H-NMR (DMSO-d6, 400 MHz): delta 10.73 (s, 1H), 7.12 (d, J =8.7 Hz, 1H), 4.22 (m, 1H), 2.71 m, 1H), 2.48 (m, 1H, partially overlapped withsolvent signal), 1.86-1.78 (m, 2H), 1.39 (s, 9H) ppm [1]Capitosti, S. M.; Hansen T. P.; Brown, M. L. Org. Lett. 2003, 5, 2865-2867.Tert-butyl 2, 6-dioxopiperidin-3-yl carbamate [Show Image] 11.4 g BOC-L-glutamine were dissolved in 120 mL of anhydrous THF. 7.776 g of CDI and a catalytic quantity of DMAP was added to the solution. The reaction mixture was refluxed and reacted for 6h. After being cooled, the reaction mixture was filtered to remove a small quantity of insoluble substances, evaporated to dryness to remove THF, and recrystallized with ethyl acetate to obtain a white solid (4.5 g). 1H NMR (DMSO-d6): delta 7.15(d, 1H, J = 3Hz), 4.26-4.19 (m, 1H), 2.76-2.67 (m, 1H), 2.49-2.47 (m, 1H), 2.01 -1.91 (m, 2H).Weigh 0.1 mol of N-Boc-glutamic acid methyl ester obtained in step (3), Dissolve in 300mL of anhydrous tetrahydrofuran, add the condensing agent N, N-diisopropylcarbodiimide, Catalyst N-hydroxysuccinimide, heated under reflux for 48h. Spin-drying tetrahydrofuran, Add 200 mL of distilled water and extract twice with 300 mL of methyl tert-butyl ether.And then washed with dilute acid, saturated sodium bicarbonate, and saturated sodium chloride, Dry over anhydrous sodium sulfate. Spin-dry to obtain 20g of white solid, Recrystallized twice in ethyl acetate / petroleum ether (30/70), 15.1 g of a white solid was obtained with a yield of 66.2%.

Pomalidomide intermediate

Molecular Weight:228.24
XLogP3:0.2
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:3
Exact Mass:228.11100700
Monoisotopic Mass:228.11100700
Topological Polar Surface Area:84.5
Heavy Atom Count:16
Complexity:319
Undefined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes