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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
5-Amino-Thalidomide is a derivative of Thalidomide, functionalized with an amino group, and used in the synthesis of PROTAC molecules to recruit CRBN for targeted protein degradation.
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CAS No. : | 191732-76-0 |
Formula : | C13H11N3O4 |
M.W : | 273.24 |
SMILES Code : | O=C1N(C(CC2)C(NC2=O)=O)C(C3=C1C=CC(N)=C3)=O |
MDL No. : | MFCD30188077 |
InChI Key : | IICWMVJMJVXCLY-UHFFFAOYSA-N |
Pubchem ID : | 9816958 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302 |
Precautionary Statements: | P280-P305+P351+P338 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With palladium 10% on activated carbon; hydrogen; In acetone; at 20℃; for 20h; | Following a literature procedure, a catalytic amount of Pd/C (50 mg, 10%) was assed to a solution of 16 (500 mg/1.65 mmol) in 30 mL of acetone. The mixture was stirred at ambient temperature for 20 hours under an atmosphere of H2 (g). The mixture was then filtered through a pad of celite and the celite was washed with copious amounts of acetone. The solvent was evaporated in vacuo to yield 451 mg (66%) of 5-amino-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione. |
0.62 g (69%) | palladium-carbon; In 1,4-dioxane; | EXAMPLE 1 A mixture of 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-5-nitroisoindoline {alternatively named as N-(2,6-dioxopiperidin-3-yl)-4-nitrophthalimide} (1 g, 3.3 mmol) and 10% Pd/C (0.13 g) in 1,4-dioxane (200 mL) was hydrogenated at 50 psi for 6.5 hours. The catalyst was filtered through Celite and the filtrate concentrated in vacuo. The residue was crystallized from ethyl acetate (20 mL) to give 0.62 g (69%) of 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline {alternatively named as N-(2,6-dioxopiperidin-3-yl)-4-aminophthalimide} as an orange solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With triethylsilane; potassium fluoride; palladium diacetate; In tetrahydrofuran; water; at 20℃; for 1h; | General procedure: A solution of 2-(2,6-dioxopiperidin-3 -yl)-4-nitroisoindoline- 1,3 -dione (173 mg, 0.854 mmol), Pd(OAc)2 (12.8 mg, 0.0854 mmol, 10 mol%) and potassium fluoride (66 mg, 1.71 mmol, 2 equiv) in THF:water (8:1) (5.7 mL, 0.1 M) was stirred at room temperature. Triethylsilane (3651iL, 3.41 mmol, 4 equiv) was added slowly, and the resulting black solution was stirred at room temperature for 1 hour. The reaction mixture was filtered through a pad of celite, which was washed excessively with ethyl acetate. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (CH2C12:MeOH (7:1)) to afford the titlecompound as a yellow powder (72 mg, 46%). 1H NMR (500 IVIHz, DMSO-d6) 11.08 (s, 1H),7.47 (dd, J 8.5, 7.0 Hz, 1H), 7.06 - 6.95 (m, 1H), 6.59 -6.44 (m, 1H), 5.04 (dd, J= 12.7, 5.4Hz, 1H), 2.93 - 2.82 (m, 1H), 2.64 - 2.45 (m, 2H), 2.05 - 1.98 (m, 1H); MS (ESI) calcd forC13H11N304 [M+H] 274.08, found 274.23. |
37% | With triethylsilane; potassium fluoride; palladium diacetate; In tetrahydrofuran; water; at 20℃; for 1h; | General procedure: A solution of 2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindoline-1,3-dione (173 mg, 0.854 mmol), Pd(OAc)2 (12.8 mg, 0.0854 mmol, 10 mol%) and potassium fluoride (66 mg, 1.71 mmol, 2 equiv) in THF:water (8:1) (5.7 mL, 0.1 M) was stirred at room temperature. Triethylsilane (365 muL, 3.41 mmol, 4 equiv) was added slowly, and the resulting black solution was stirred at room temperature for 1 hour. The reaction mixture was filtered through a pad of celite, which was washed excessively with ethyl acetate. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (CH2Cl2:MeOH (7:1)) to afford the title compound as a yellow powder (72 mg, 46%). 1H NMR (500 MHz, DMSO-d6) delta 11.08 (s, 1H), 7.47 (dd, J = 8.5, 7.0 Hz, 1H), 7.06- 6.95 (m, 1H), 6.59- 6.44 (m, 1H), 5.04 (dd, J = 12.7, 5.4 Hz, 1H), 2.93- 2.82 (m, 1H), 2.64- 2.45 (m, 2H), 2.05- 1.98 (m, 1H); MS (ESI) calcd for C13H11N3O4 [M+H]+ 274.08, found 274.23. |
Specific immunomodulatory compounds include, but are not limited to: ... 1-oxo-2-(2,6-dioxopiperidin-3-yl)-7-aminoisoindoline; 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline; and 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline. |
Specific immunomodulatory compounds include, but are not limited to: ... 1-oxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline; 1-oxo-2-(2,6-dioxopiperidin-3-yl)-6-aminoisoindoline; 1-oxo-2-(2,6-dioxopiperidin-3-yl)-7-aminoisoindoline; 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline; and 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline. | ||
Particularly preferred compounds include: ... 1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline 1-oxo-2-(2,6-dioxopiperidin-3-yl)-6-aminoisoindoline 1-oxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline 1,3dioxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline 1,3dioxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline | ||
Specific immunomodulatory compounds include, but are not limited to: ... 1-oxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline; 1-oxo-2-(2,6-dioxopiperidin-3-yl)-6-aminoisoindoline; 1-oxo-2-(2,6-dioxopiperidin-3-yl)-7-aminoisoindoline; 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline; and 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline. | ||
Specific immunomodulatory compounds include, but are not limited to: ... 1-oxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline; 1-oxo-2-(2,6-dioxopiperidin-3-yl)-6-aminoisoindoline; oxo-2-(2,6-dioxopiperidin-3-yl)-7-aminoisoindoline; 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline; and 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | In tetrahydrofuran;Reflux; | In a 4 mL glass vial, a mixture of 5-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- dione(30 mg, 0.110 mmol, 1 equiv) and acetyl chloride (26 pL, 0.220 mmol, 2 equiv) in THF (1.8mL, 0.1 M) was heated to reflux overnight. The reaction mixture was filtered, and the filter cake was washed with Et20 to give the title compound as a white solid (27 mg, 47%), that was used without further purification. ?HNMR(500 MHz, DMSO-d6) 11.11 (s, 1H), 10.63 (s, 1H), 8.24 (d, J 1.5 Hz, 1H), 7.91 -7.83 (m, 2H), 5.11 (dd, J 12.8, 5.4 Hz, 1H), 2.88 (ddd, J= 17.0, 13.8, 5.4 Hz, 1H), 2.63 -2.46 (m, 2H), 2.13 (s, 3H), 2.09-2.00 (m, 1H); MS (ESI) calcd for C15H14N305[M+H] 316.09, found 316.23. |
47% | In tetrahydrofuran;Reflux; | In a 4 mL glass vial, a mixture of 5-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- dione (30 mg, 0.110 mmol, 1 equiv) and acetyl chloride (26 muL, 0.220 mmol, 2 equiv) in THF (1.8 mL, 0.1 M) was heated to reflux overnight. The reaction mixture was filtered, and the filter cake was washed with Et2O to give the title compound as a white solid (27 mg, 47%), that was used without further purification.1H NMR (500 MHz, DMSO-d6) delta 11.11 (s, 1H), 10.63 (s, 1H), 8.24 (d, J = 1.5 Hz, 1H), 7.91- 7.83 (m, 2H), 5.11 (dd, J = 12.8, 5.4 Hz, 1H), 2.88 (ddd, J = 17.0, 13.8, 5.4 Hz, 1H), 2.63- 2.46 (m, 2H), 2.13 (s, 3H), 2.09- 2.00 (m, 1H); MS (ESI) calcd for C15H14N3O5 [M+H]+ 316.09, found 316.23. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 4h; | To a solution of <strong>[191732-76-0]5-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione</strong> (2) (30 mg, 0.11 mmol) in DMF (1 mL) was added Cs2CO3 (35.77 mg, 0.11 mmol) and CH3I (0.01 ml, 0.11 mmol) at room temperature. The reaction mixture was stirred for 2 h at the same temperature, and additional 1 eq of CH3I (0.01 ml, 0.11 mmol) was added. Reaction mixture stirred for an additional 2 h at room temperature. The reaction was diluted with AcOEt (10 mL) and then quenched with aqueous HCl (1 N, 1 mL), the pH was adjusted to 7-8 using an aqueous solution of NaHCO3. Organic phase was separated, washed with brine (5 mL, 5*), dried (Na2SO4), and evaporated under vacuum. Crude product was purified by PTLC (DCM:MeOH:NH4OH, 90:9:1) to give 28 mg of pure product (3) as a yellow solid (88% yield). 1H NMR (500 MHz, DMSO-d6) delta 7.52 (d, J=8.2 Hz, 1H), 6.94 (d, J=2.0 Hz, 1H), 6.83 (dd, J=8.2, 1.5 Hz, 2H), 6.57 (s, 2H), 5.09 (dd, J=13.0, 5.3 Hz, 1H), 3.00 (s, 3H), 2.96-2.85 (m, 1H), 2.78-2.68 (m, 1H), 2.61-2.43 (m, 1H), 2.01 (ddd, J=9.9, 5.5, 2.7 Hz, 1H). 13C NMR (151 MHz, DMSO-d6) delta 172.24, 170.35, 168.08, 167.56, 155.70, 134.63, 125.69, 117.38, 116.56, 107.49, 49.59, 31.57, 27.02, 21.85 LC/MS (ESI); m/z [M+H]+ Calcd. for C14H14N3O4, 288.0984. Found 288.0987. |