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CAS No. : | 827026-45-9 | MDL No. : | MFCD11977267 |
Formula : | C13H11N3O5 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | JKPJLYIGKKDZDT-UHFFFAOYSA-N |
M.W : | 289.24 | Pubchem ID : | 11471781 |
Synonyms : |
|
Num. heavy atoms : | 21 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.31 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 79.35 |
TPSA : | 112.3 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -8.06 cm/s |
Log Po/w (iLOGP) : | 1.14 |
Log Po/w (XLOGP3) : | 0.01 |
Log Po/w (WLOGP) : | -0.56 |
Log Po/w (MLOGP) : | 0.97 |
Log Po/w (SILICOS-IT) : | -0.84 |
Consensus Log Po/w : | 0.14 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.72 |
Solubility : | 5.52 mg/ml ; 0.0191 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.92 |
Solubility : | 3.48 mg/ml ; 0.012 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.54 |
Solubility : | 0.844 mg/ml ; 0.00292 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 3.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 2.73 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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 |
---|---|---|
With hydrogen;palladium 10% on activated carbon; In methanol; under 4654.46 Torr; | 3-(4-nitro-1 -oxo-1 ,3-dihydroisoindol-2-yl)-pipehdine-2,6-dione (10 g), methanol (300 mL), 10% palladium on carbon (0.3 g) and methanesulfonic acid (4.5 mL; d:1 .48) are charged into a conical flask and then transferred into an autoclave. Hydrogen gas (90 psi, 6.3 Kg/cm2) is applied to the suspension at 3O0C and stirred for 3-4 hours. The reaction mixture is filtered through a celite bed and the bed is washed with methanol (20 mL). The obtained filtrate is concentrated until the reaction mass becomes about 100 mL and stirred for 20 minutes. The reaction mass is filtered and dried the solid dried for 4 hours at 500C, to give 8 g of a methanesulfonate salt of lenalidomide. Purity by HPLC 99.87%.Impurity A 0.01 %, Impurity B 0.01 %, Impurity C 0.04%, Impurity D not detected.XRD pattern substantially in accordance with Fig. 1 . DSC curve substantially in accordance with Fig. 2.TGA weight loss 0.77% w/w; curve substantially in accordance with Fig. 3. | |
With hydrogen;palladium 10% on activated carbon; In methanol; at 30℃; under 4654.46 Torr; for 3 - 4h; | Example 1Preparation of a Methanesulfonate Salt of Lenalidomide3-(4-nitro-1-oxo 1,3-dihydroisoindol-2-yl)piperidine-2,6-dione (10 g), methanol (300 mL), 10% palladium on carbon (0.3 g) and methanesulfonic acid (4.5 mL; d:1.48) are charged into a conical flask and then transferred into an autoclave. Hydrogen gas (90 psi) is applied to the suspension at 30 C. and stirred for 3-4 hours. The reaction mixture is filtered through a celite bed and the bed washed with methanol (20 mL). The obtained filtrate is concentrated to a volume of 100 mL and stirred for 20 minutes. The reaction mass is filtered and the solid dried for 4 hours at 50 C. to give 8 g of a methanesulfonate salt of lenalidomide.Purity: 99.87% by HPLC.Impurity A: 0.01%; Impurity B: 0.01%; Impurity C, 0.04%; Impurity D: not detected (ND). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.8% | With Lawessons reagent; In toluene; for 26h;Inert atmosphere; Reflux; | 3. 4-Nitro-1-thioxo-2-(2-oxo-6-thioxopiperidine-3-yl)phthalimidine (4) A mixture of 2-(2,6-dioxopiperidine-3-yl)-4-nitrophthalimidine (3) (1.3 g, 4.6 mmol) and Lawesson's reagent (3.0, 7.4 mmol) in toluene (900 mL) was refluxed under an atmosphere of nitrogen for 26.0 h. The crude product was purified by column chromatography using EtOAc:petroleum ether (1:2) as the eluent to afford compound (4) (1.3 g, 85.8%) as yellow needle crystals: mp 250.0-251.0 C.; 1H NMR (DMSO-d6) delta 12.40 (s, 1H, NH), 8.47 (d, J=6.3 Hz, 1H, C5-H), 8.28 (d, J=6.3 Hz, 1H, C7-H), 7.81 (t, J=6.3 Hz, 1H, C6-H), 5.96 (d, J=12.5 Hz, 1H, C3'-H), 5.25 and 5.15 (AB system, J=21.6 Hz, 2H, C3-H), 3.31-3.13 (m, 2H), 2.81-2.61 (m, 1H) and 2.11-1.99 (m, 1H) ppm; 13C NMR (DMSO-d6) delta 210.5, 191.2, 166.9, 143.5, 141.5, 136.6, 131.6, 130.7, 127.3, 56.8, 56.4, 41.2 and 23.5 ppm; MS (CI/CH4), m/z 322 (MH+); Anal. Calcd for C13th1N3O3S2: C, 48.58; H, 3.45; N, 13.08. Found: C, 48.89; H, 3.60; N, 12.67. |
64% | With Lawessons reagent; In 1,4-dioxane; for 5h;Reflux; | A stirred suspension of 3-(4-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-,6-dione (1.5 g, 5.2 mmol) and Lawesson's reagent (2.1 g, 5.2 mmol) in 1,4-dioxane (110 mL) was refluxed for 5 hours. Reaction mixture was concentrated and residue was purified by chromatography (SiO2, CH2Cl2:EtOAc 9:1) to give 3-(4-nitro-1-thioxo-1,3-dihydro-isoindol-2-yl)-6-thioxo-piperidin-2-one (1.1 g, 64%): mp 248-250 C.; 1H NMR (DMSO-d6) delta 2.07-2.15 (m, 1H), 2.72-2.79 (m, 1H), 3.24-3.32 (m, 2H), 5.23 (d, J=21.8 Hz, 1H), 5.27 (d, J=21.8 Hz, 1H), 5.98-6.04 (dd, J=3.8 and 12.1 Hz, 1H), 7.86 (t, J=8.0 Hz, 1H), 8.30-8.33 (dd, J=0.8 and 7.7 Hz, 1H), 8.49-8.52 (dd, J=0.9 and 8.2 Hz, 1H), 12.67 (s, 1H); 13C NMR (DMSO-d6) delta 23.15, 40.78, 55.97, 56.42; 126.93, 130.27, 131.26, 136.17, 141.08, 143.12, 166.57, 190.81, 210.09; Anal. Calcd. For C13H11N3O3S2:C, 48.59; H, 3.45; N, 13.07; S, 19.95. Found: C, 48.37; H, 3.34; N, 12.80; S, 19.73. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen;palladium 10% on activated carbon; In methanol; at 30℃; under 4654.46 Torr; | 3-(4-nitro-1 -oxo 1 ,3-dihydroisoindol-2-yl) piperidine-2,6-dione (10 g), methanol (300 ml_), 10% palladium on carbon (0.3 g) and methanesulfonic acid (4.5 ml d:1.48) are charged into a conical flask and then transferred into an autoclave. Hydrogen gas (90 psi) is applied to the suspension at 3O0C and stirred for 3-4 hours. The reaction mixture is filtered through a celite bed and the bed washed with methanol (20 ml_). The obtained filtrate is concentrated to a volume of 100 ml_ and stirred for 20 minutes. The reaction mass is filtered and the solid dried for 4 hours at 500C to give 8 g of a methanesulfonate salt of lenalidomide.Purity: 99.87% by HPLC.Impurity A: 0.01 %; Impurity B: 0.01 %; Impurity C: 0.04%; Impurity D: not detected (ND). | |
With palladium 10% on activated carbon; hydrogen; In water; at 25 - 30℃; under 4654.46 Torr; | To a suspension of compound of Formula 11(7.00 g), Water (105 mL, lSvol), Methane sulfonic acid (3.92 mL) and Pd/C (10% loading, 50% wet, 0.70 g), hydrogen gas (90 psi) was purged at 25-30 C. The progress of the reaction was monitored by HPLC. After the completion of the reaction, the mass was filtered, washed with water (20 mL). pH of the filtrate was adjusted to by adding triethylamine (9.0 mL). The slurryobtained was washed with water (2 x 35 mL) followed by the addition of compound of Formula lIla (4.58 g). The mass was heated between 65 and 70 C for 5-6 h. It was cooled between 60 and 70 C, filtered and dried at 45-50 C under reduced pressure to obtain Lenalidomide-Resorcinol co-crystal of Formula Va as a crystalline solid. It was characterized by 1H NMR, DSC, FT-IR, PXRD and TGA. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With thionyl chloride; In N,N-dimethyl-formamide; at 0℃; | To a mixture of 3-(4-nitro-l,3-dihydro-l-oxo-2H-isoindol-2-yl)- isoglutamine (9g) in N5N- dimethylformamide (80ml), was added thionyl chloride (6.6g) by droplet below 0C for stirred reaction in heat preservation for 2 ~ 3 hours. The resulting solution was added by droplet into mixture of ice and water and pH value was adjusted to 7 ~ 8 with sodium carbonate. The mixture was stirred for 30 minutes and filtered to get light yellow crude. Refining with methanol gave 6.6g of target yield as a light yellow solid, yield: 78%.FAB(M+1): 290Element analysis: theoretical data: C 53.98%, H 3.83%, N 14.53% measured data: C 54.06%, H 3.95%, N 14.61% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.5% | Preparation of Lenalidomide HClA suspension of 253. 1 g rac-3-( 1 -oxo-4-nitroisoindoline-2-yl)piperidine-2 ,6- dione (0.875 mol) in 6.2 1 (4.75 kg) MeOH was charged into the hydrogenation reactor (Kiloclave Buchi 10 1). Thereafter, 10. 15 g 10% Pd (0.01 eq. Pd) on charcoal, suspended in 500 ml MeOH was added, the stirrer was set to 400 rpm, and hydrogen gas supply (bpc Biichi-Glas Uster) was regulated to keep a constant pressure of 50 psi (3.2 bar). After an induction period of 5 min. the inner temperature raised within the first 5 hours continuously from 2 1 C to 35 C , while hydrogen was continuously charged to maintain the preset pressure. After 2 h the speed of the stirrer was set to 600 rpm and the reaction was terminated after 18 h.The reaction mixture was released from the reactor and equipment rinsed with additional MeOH (793.9 g/ 1 1). The combined suspension was filtered under vacuum on a pre-weighed Buchner Funnel equipped with a filter paper. 245.6 g wet solid was collected on the filter paper and after air drying for 16 h at RT, 214g were obtained. This mass was transferred into hot aqueous hydrochloric acid (prepared from 600 g water and 86 ml 32% HCl), immediately transferred onto a pre-weighed Buchner funnel, equipped with filter paper and filtered under vacuum. A light yellow colored filtrate was obtained, from which a light solid started to crystallize immediately. The crystal suspension was chilled in an ice bath for 60 min, the obtained crystals were collected by vacuum filtration through a Buchner funnel on filter paper. The cake of crystals was rinsed with 100 ml of cold MeOH sucked to dryness on the filter, and dried on air overnight. 216.5 g dry lenalidomide hydrochloride was collected (83.5% from theory 258.8g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | In N,N-dimethyl-formamide; for 3h;Reflux; | 2-Chloromethyl-3-nitrobenzoate (IV) 230g (1mol) and the compound (III) 173g (1.35mol) was dissolved in DMF2L.It was heated with stirring under reflux for 3h.Cooled to room temperature, poured slowly into ice-water and 50L, stirring was continued for 2h, filtered, washed with water and dried, to give the product compound (V) 277.6g, a yield of 96% (in terms of Compound IV). |
79.5% | [00123] A nitrogen-purged 1600 L Hastelloy reaction vessel was charged with methyl-2- bromomethyl-3-nitrobenzoate (61 kg, 1.0 mole eq.), racemic a-aminoglutarimide (36.6 kg, 1.0 mole eq.), and acetonitrile (478 kg). The mixture was stirred at ambient temperature and then cooled to 5-8 C. Sodium bicarbonate (46.7 kg, 2.5 mole eq.) was charged to the reaction vessel and the mixture was heated to reflux. The reaction vessel contents were vigorously stirred at reflux until the remaining brominated nitrobenzoate level is <3.0 mol% as determined by 1H- NMR. The reaction mixture was then cooled to 58-62 C. [00124] A hydrochloric acid solution was prepared from concentrated hydrochloric acid (12.9 kg) and purified water (355 L) in a nitrogen-purged, stirred 1000 L Hastelloy vessel and heated to 58-62 C. A portion of this hydrochloric acid solution (329 L) was added to the reaction mixture in the 1600 L vessel over at least 10 minutes while maintaining the temperature at 58-62 C. The mixture was stirred for approximately 30 minutes, then pH of the reaction mixture was checked. If the pH was >6, 6.1 L aliquots of hydrochloric acid were added, while maintaining the temperature at approximately 58-62 C, until the pH of the reaction mixture was <6. The mixture was then cooled to ambient temperature over approximately 2.5 hours and stirred for an additional hour. [00125] The solid was collected by vacuum/pressure filtration on an Oyster filter. The collected solid was washed on the Oyster filter with a mixture of acetone (76 kg) and purified water (90 kg), and de-liquored using vacuum pressure. The collected solid was washed with 147 kg of acetone and de-liquored using vacuum pressure. The solid was dried under vacuum in a VPD at <45 C until loss on drying is <0.5% to provide 3-(4-nitro-l-oxoisoindolin-2- yl)piperidine-2,6-dione. The yield of a recent lot was 79.5%. | |
With triethylamine; In N,N-dimethyl-formamide; at 25 - 100℃; for 7h;Inert atmosphere; | Preparation of 3-(4-nitro-l-oxo-l , 3 dihydro-isoindol-2-yl)-piperidine-2, 6-dione: Into a 2.0 L dried 4 necked round bottom flask equipped with a condenser, an addition funnel and nitrogen gas bubbler under stirring, charged 50.0 g of methyl 2- bromomethyl-3-nitro-benzoate, 29.2g of racemic 3-amino-piperidine-2,6-dione and 835.0 ml of DMF. Charged triethyl amine to the reaction mass at 25-35C in about 30-45 min. Raise the mass temperature to 95-100C. Maintained the reaction mass at 95-100C for 6-6 ½ hrs under nitrogen atmosphere. The progress of the reaction is monitored by TLC. Poured the reaction mass slowly into 2.6 L of DM water at 25-35C under stirring, in about 30-45 min. Maintained the reaction mass at 25-35C for 60-90 min under stirring. Filtered the material under vacuum, wash the wet cake with 215.0 ml of DM water, suck died the material. Dried the wet material in a oven at 60-65C for 4-5 hours. Weight of the dry material is- 30. Og. |
With triethylamine; In N,N-dimethyl-formamide; at 75℃; for 20h; | To a solution of alpha-aminoglutarimide (1.0 equiv.) and methyl 2-(bromomethyl)-3- nitrobenzoate (1.3 equiv) in DMF is added triethylamine (3.0 equiv), and the mixture is heated to 75 C and stirred for 20 h. Then it is cooled to RT and poured into LiCl (5% in H2O). It is extracted with EtOAc, and the combined organic phases are washed with LiCl (5% in H2O) and saturated aqueous NaCl, dried (Na2SO4), filtered, and concentrated in vacuo. The crude is purified by column chromatography on silica gel to give 3-(7-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione. (Org. Lett., 2013, 15 (17), pp 4312-4315) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77 g | 3-(Benzyloxycarbonylamino)piperidine-2,6-dione (100 gm), methanol (1000 ml) and 10% palladium carbon (15 gm) were added and then applied hydrogen pressure at room temperature. The reaction mass was maintained for 2 hours and filtered over on celyte bed. The solvent was distilled off under vacuum from the filtrate thus obtained to obtain a crystalline solid. To the crystalline solid was added a mixture of dimethylformamide (400 ml), triethylamine (100 ml) and 2-(bromomethyl)-3-nirobenzoic acid methyl ester (100 gm) as obtained in example 1. The reaction mass was stirred for 6 hours at room temperature, filtered and then dried to obtain a solid. The solid obtained was dissolved in methanol (250 ml) and stirred for 1 hour at room temperature. The solid obtained was collected by filtration and dried to obtain 77 gm of 3-(4-nitro-l-oxo-l,3- dihydro-2H-isoindol-2-yl)piperidine-2,6-dione |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73.0% | With potassium carbonate; In N,N-dimethyl acetamide; at 20 - 50℃; for 40.5h;Inert atmosphere; | 2. 2-(2,6-Dioxopiperidine-3-yl)-4-nitrophthalimidine (3) A mixture of methyl 2-bromomethyl-3-nitrobenzoate (2) (3.5 g, 12.8 mmol), (2,6-dioxopiperidine-3-yl)amine trifluoroacetate (3.1 g, 12.8 mmol) and potassium carbonate (3.6 g, 26.0 mmol) in N,N-dimethylacetamide (DMA) (12.5 mL) was stirred for 24.0 h under a nitrogen atmosphere at room temperature, and then continuously reacted for 16.5 h at 50 C. After removing solvent, the residues were washed with water and methanol to afford product (3) (2.7 g, 73.0%) as yellowish crystals: mp 274.0-276.0 C.; 1H NMR (DMSO-d6) delta 11.09 (s, 1H, NH), 8.48 (d, J=7.2 Hz, 1H, C7-H), 8.19 (d, J=7.2 Hz, 1H, C5-H), 7.83 (t, J=7.2 Hz, 1H, C6-H), 5.27-5.14 (m, 1H, C3'-H), 4.91 and 4.78 (AB system, J=8.0 Hz, 2H, C3-H), 3.00-2.82 (m, 1H, C5'-H), 2.63-2.44 (m, 2H, C5'-H, C4'-H) and 2.09-1.98 (m, 1H, C4'-H) ppm; 13C NMR (DMSO-d6) delta 174.7, 172.6, 167.8, 145.3, 139.3, 136.6, 132.1, 131.5, 128.9, 53.7, 50.3, 33.1 and 24.1 ppm; MS (CI/CH4), m/z 290 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.5% | A nitrogen-purged 1600 L Hastelloy reaction vessel was charged with methyl-2-bromomethyl-3-nitrobenzoate (61 kg, 1.0 mole eq.), racemic a-aminoglutarimide (36.6 kg, 1.0 mole eq.), and acetonitrile (478 kg). The mixture was stirred at ambient temperature and then cooled to 5-8C. Sodium bicarbonate (46.7 kg, 2.5 mole eq.) was charged to the reaction vessel and the mixture was heated to reflux. The reaction vessel contents were vigorously stirred at reflux until the remaining brominated nitrobenzoate level is 6, 6.1 L aliquots of hydrochloric acid were added, while maintaining the temperature at approximately 58-62C, until the pH of the reaction mixture was |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.7% | With N,N,N,N,-tetramethylethylenediamine; zinc dibromide; In 1,4-dioxane; at 95℃; | 1) 19.5 g (100 mmol) of <strong>[59382-59-1]methyl 2-methyl-3-nitrobenzoate</strong>,3-Amino-2,6-piperidinedione 15.4 g(120 mmol), 58.1 g (500 mmol) of tetramethylethylenediamine,45.8 g (150 mmol) of zinc bromide was added to the reaction vessel,250 ml of 1,4-dioxane was added and the mixture was heated to 95 C for 10 to 16 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure.Water washing and recrystallization (petroleum ether: dichloromethane = 10: 1) afforded 3-(4-nitro-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione 26.2 g,The yield was 90.7%, HPLC purity 99.51%; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium permanganate; In water; at 50 - 70℃; | 3-(4-Nitro-1,3-dihydroisoindol-2-yl)piperidine-2,6-dione 13.8 g (50 mmol), AIBX 33.7 g(100 mmol) was added to the reaction flask. and added to 120ml mixed solution (volume ratio of PEG600 and water is 1: 6) as a reactionshould be a solvent, warmed to 50 ~ 70 C(55 ~ 65 C),the reaction was stirred for 6 to 8 hours, cooled to room temperature, the reaction solution was poured into In water,extracted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give lenalidomide intermediate 3-(4-nitro-1-oxo-1,3-dihydroisoindole-2-yl) piperidine-2,6-dione 27 g, yield 93.5%, HPLC purity 99.23%; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.1% | With 5-trimethylammonio-1,3-dioxo-1,3-dihydro-1lambda5-benzo[d][1,2]-iodoxol-1-ol anion; In water; at 50 - 70℃; | 2) 3-(4-Nitro-1,3-dihydroisoindol-2-yl)piperidine-2,6-dione 27.5 g (100 mmol), AIBX50.6 g (150 mmol) was added to the reaction flask and added 160ml mixed solution (volume ratio of PEG600 and water was 1: 5) as thetemperature was raised to 50 ~ 70 C(55 ~ 65 C),for 6 to 8 hours to the reaction solvent with stirring, cooled to room temperature, the reaction solution poured into waterand extracted with CH2C12, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, column chromatography give intermediate lenalidomide 3- (4-nitro-1-oxo-1,3-dihydro Isoindolin-2-yl)piperidine-2,6-dione 27.2 g, yield 94.1%, HPLC purity99.06%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39.6 g | With sodium dichromate; sulfuric acid; In 1-methyl-pyrrolidin-2-one; ethyl acetate; at 58℃; | Generated by step (1) 3-(4-nitro-1-hydroxy-1,3-dihydro-2H-isoindol-2-yl)-2,6-dihydroxypiperidine (III) (47.1 g, 12.8 mol)In a mixed solvent N-methylpyrrolidone (50ml) and ethyl acetate (40ml) mixture, Oxidizer sodium dichromate (4.0g) Heating to 58 C in the presence of a mineral acid sulfuric acid solution (80 ml), An oxidation reaction occurs, Generation of 3-(4-nitro-1-oxo-1,3-dihydroisoindol-2-yl)piperidine-2,6-dione (IV) (39.6 g, 9.5 mol); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27.1 g | at 40 - 45℃; for 5h; | Under nitrogen protection,Stirring,Thermometer and air condenser tube in a 500 ml four-necked flask,Add 120 grams of N,N-dimethylformamide,12.8 g (0.1 mol) of 3-aminopiperidine-2,6-dione,16.5 g (0.11 mol) of methyl 1-chloroacetoacetate,40 g of potassium carbonate, stirred at 40 to 45 C for 4 hours,The reaction was stirred at 90 to 95 C for 3 hours.Distilling methanol formed by the amidation reaction; cooling to 40 C, adding 16.5 (0.11 mole)2-Chloro-4-nitro-n-butyraldehyde, stirred at 40-45 C for 5 hours, filtered, the filter cake was washed with 40 g of N,N-dimethylformamide, the filtrate was combined, and N,N-dimethyl was recovered by distillation. Carboxamide, adding 90 grams of isopropanol, recrystallizing,Obtained 27.1 g of 3-(7-nitro-3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione,The yield is 93.7%.The liquid phase purity was 99.7%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26.9 g | at 40 - 45℃; for 5h; | Under the protection of nitrogen, it is stirred,Thermometer and air condenser tube in a 500 ml four-necked flask,Add 140 g of N,N-dimethylformamide, 12.8 g (0.1 mol)3-aminopiperidine-2,6-dione,21.5 g (0.11 mol)Tert-butyl 1-chloroacetoacetate,40 g of potassium carbonate, stirred at 35 to 40 C for 4 hours,The reaction was stirred at 120 to 125 C for 3 hours.Distilling off the tert-butanol formed by the amidation reaction; cooling to 40 C,21.5 (0.11 mol) of 2-bromo-4-nitro-n-butyraldehyde was added, and the reaction was stirred at 40 to 45 C for 5 hours.Filtered, the filter cake was washed with 40 g of N,N-dimethylformamide.Combine the filtrate,Distillation of N,N-dimethylformamide, addition of 90 g of isopropanol, recrystallization,Got 26.9 grams3-(7-nitro-3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione,The yield was 93.0%, and the liquid phase purity was 99.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65.2% | With triethylamine; In acetonitrile; at 20 - 80℃; for 10h; | Add 55.0 g (0.263 mol) of 3-amino-2,6-piperidinone hydrobromide to a 1000 ml reaction flask.Triethylamine 75ml, 200ml acetonitrile, stirred and mixed at room temperature, heated to 80 C, adding a mixture of 72.1g (0.263mol) of methyl 2-bromomethyl-3-nitrobenzoate and 150ml of acetonitrile, heat preservation reaction for 10h, Cold to room temperature,Slowly add 200ml of water and stir for 0.5h.The product was obtained as an off-white solid, 49.6 g, yield 65.2%. |
Tags: 827026-45-9 synthesis path| 827026-45-9 SDS| 827026-45-9 COA| 827026-45-9 purity| 827026-45-9 application| 827026-45-9 NMR| 827026-45-9 COA| 827026-45-9 structure
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Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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