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CAS No. : | 1121-89-7 | MDL No. : | MFCD00006670 |
Formula : | C5H7NO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | KNCYXPMJDCCGSJ-UHFFFAOYSA-N |
M.W : | 113.11 | Pubchem ID : | 70726 |
Synonyms : |
|
Num. heavy atoms : | 8 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.6 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 31.15 |
TPSA : | 46.17 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) : | -7.47 cm/s |
Log Po/w (iLOGP) : | 0.77 |
Log Po/w (XLOGP3) : | -0.68 |
Log Po/w (WLOGP) : | -0.57 |
Log Po/w (MLOGP) : | -0.08 |
Log Po/w (SILICOS-IT) : | 0.96 |
Consensus Log Po/w : | 0.08 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.11 |
Solubility : | 87.2 mg/ml ; 0.771 mol/l |
Class : | Very soluble |
Log S (Ali) : | 0.18 |
Solubility : | 173.0 mg/ml ; 1.53 mol/l |
Class : | Highly soluble |
Log S (SILICOS-IT) : | -1.04 |
Solubility : | 10.3 mg/ml ; 0.0914 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.0 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H319 | 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 phosphorus pentabromide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With urea at 140 - 175℃; for 2.66667h; | |
59.8% | With formamide In 1-methyl-pyrrolidin-2-one at 170 - 180℃; | |
58% | With urea at 140 - 175℃; for 3.16667h; | Glutarimide (2) A mixture of glutaric acid (53.15 g, 0.40 mol) and urea (36.24 g, 0.60mol) was melted for 40 min at 140 °C, and then the reaction mixture was stirred for an additional 2.5 h at 175 °C. Upon cooling, the crude product was recrystallized twice fromEtOH to produce glutarimide 2 as a white solid (26.22 g, yield 58%) [44]. 1H NMR (400MHz, CDCl3): δ 1.95-2.02 (m, 2H, CH2), 2.57 (t, 4H), 8.49 (s, 1H, NH). |
47% | With urea 145 deg C -> 210 deg C, 1 h; 210 deg C, 15 min; | |
With ammonia Man verdampft eine neutralisierte Loesung erst im Wasserbad, dann ueber Kalk und erhitzt den Rueckstand auf 170-180grad; | ||
With pyridine; SULFAMIDE | ||
With ammonia 1.) 150 deg C, 1.5 h, 2.) 200 deg C, 0.5 h; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With manganese(II) triflate; 4,4'-diamino-2,2'-bipyridyl; dihydrogen peroxide; In acetone; at 20℃; for 1h; | 5.59 mg (0.03 mmol) of 4,4'-diamino-2,2'-bipyridine (Ligand), 5.30 mg (0.015 mmol) of manganese (II) triflate (Mn(OTf) 2),1.5 mL of acetone was added to the reaction tube, and the reaction was stirred at 70 C for 10 min.Cool to room temperature and add 49.57 mg (0.5 mmol) of 2-piperidone.Then, 250 muL of 30% by mass of hydrogen peroxide was diluted with 0.5 mL of acetone and then added to the reaction tube through a flow injection pump for 60 minutes.After the addition, saturated sodium sulfite was added to the reaction solution to quench the remaining hydrogen peroxide.Extraction with ethyl acetate gave 1,2-dipiperidone in a yield of 98%. |
95% | With potassium peroxymonosulphate; water; potassium bromide; In dichloromethane; at 20℃; for 7h;Sealed tube; Irradiation; | General procedure: N-Propylbenzamide (A1) (40.8 mg, 0.25 mmol, 1.0 equiv), Oxone(307.8 mg, 0.50 mmol, 2.0 equiv), KBr (8.9 mg, 0.075 mmol, 0.3equiv), H2O (198.2 mg, 44 equiv, 0.2 mL) and CH2Cl2 (1.5 mL) wereadded to a 15 mL sealed tube containing a magnetic stir bar. The reaction mixture was stirred at room temperature for 7 hours under irradiation with an 8 W white LED. After completion of the reaction, saturated Na2SO3 (5.0 mL) was added and the mixture was extracted with CH2Cl2 (3 × 10 mL). The combined organics were washed with brine(10 mL), dried over Mg2SO4, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (EtOAc/PE,1:6) to afford N-propionylbenzamide (B1). 3b White solid; yield: 37.7 mg (85%); mp 93-94 C (Lit. 3b 93-94 C).1 H NMR (400 MHz, CDCl 3 ): delta = 8.54 (br s, 1 H), 7.84 (d, J = 7.2 Hz, 2 H),7.61 (t, J = 7.6 Hz, 1 H), 7.51 (t, J = 8.0 Hz, 2 H), 3.04 (q, J = 7.2 Hz, 2 H),1.23 (t, J = 7.6 Hz, 3 H).13 C NMR (100 MHz, CDCl 3 ): delta = 177.8, 166.0, 133.3, 133.0, 129.1,128.0, 31.5, 8.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With 18-crown-6 ether; potassium carbonate In toluene at 111℃; for 24h; Inert atmosphere; | 6.1. General procedure for the preparation of N-(4-bromobutyl)imides 25-28 General procedure: To the solution of an imide of general structure B in dry toluene anhydrous K2CO3 (2.5 equiv), 18-crown-6 (1 mol %) and 1,4-dibromobutane (4 equiv) were added. The reaction mixture was stirred under reflux for 24 h under inert gas. Then, the reaction mixture was filtered off and the filter cake washed with dichloromethane. The combined filtrates were evaporated under reduced pressure and crude product was distilled under reduced pressure. |
With tetrabutylammomium bromide; potassium carbonate In acetone for 24h; Ambient temperature; | ||
With sodium ethanolate; sodium In <i>N</i>-methyl-acetamide; ethanol | 1.A A. A. n-(4-bromobutyl)glutarimide Sodium (5g) is dissolved in 100 ml of absolute ethanol and the sodium ethoxide solution is added to a solution of 23 g of glutarimide in 160 ml of warm absolute ethanol. The mixture is allowed to cool to 25° C with stirring and the solvent is removed under vacuum. To the residue is added 70 ml of dimethylformamide and 60 ml of 1,4-dibromobutane and the mixture is refluxed for 10 minutes. The solvent is removed under vacuum and the residue is shaken with hexane to remove excess 1,4-dibromobutane. The hexane layer is decanted off, the residue is taken up in ether and the insoluble material is filtered off. The ethereal filtrate is washed with 10% sodium hydroxide, 10% hydrochloric acid, water, and dried over sodium sulfate. The solvent is removed under vacuum to yield 26 g of N-(4-bromobutyl)glutarimide. |
With tetrabutylammomium bromide; potassium carbonate In acetone Inert atmosphere; | ||
With sodium In <i>N</i>-methyl-acetamide; ethanol | 1.A A. A. N-(4-Bromobutyl)glutarimide Sodium (5g) is dissolved in 100 ml of absolute ethanol and the resulting sodium ethoxide solution is added to a solution of 23g of glutarimide in 160 ml of warm absolute ethanol. A precipitate forms almost immediately, and after allowing the mixture to cool to 25° C while stirring, the solvent is removed under vacuum. To the residue is added 70 ml of dimethylformamide and 60 ml of 1,4-dibromobutane and the mixture is refluxed for 10 minutes. The solvent is removed under vacuum and the residue is shaken with hexane to remove excess 1,4-dibromobutane. The hexane layer is decanted, the residue taken up in ether, and the insoluble material filtered off. The ethereal filtrate is washed with 10% sodium hydroxide, 10% hydrochloric acid, and water, and dried over sodium sulfate. The solvent is removed under vacuum to yield 26g of N-(4-bromobutyl)glutarimide as an oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With tetra-(n-butyl)ammonium iodide; potassium carbonate In acetone; toluene at 20℃; for 20h; Inert atmosphere; | |
76% | With tetra-(n-butyl)ammonium iodide; potassium carbonate In acetone at 40℃; for 8h; | 10.1 Example 10 Preparation of 1- {3-[ 4-(2-MethoxY-5-methyl-phenyl)-piperazin-l-yll-vropyl} -piperidine- 2,6-dione hydrochloride salt (Compound No. 48) Step 1: Preparation of 1-(3-bromopropyl)-piperidine-2,6-dione; A mixture of piperidine-2, 6-dione (2 gm, 0.017 mole), 1,3-dibromopropane (5.3 gm, 0.026 mole), potassium carbonate (4.88 gm, 0.035 mole) and tetrabutylammonium iodide 0.13 gm, 0.0035 mole) in acetone (20 mL) was stirred at 40 °C for about 8 hours. Inorganics were filtered and washed with acetone; the solvent was removed from the filtrate under pressure; and the resulting residue was suspended in water. The aqueous solution (suspension) was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated in vacuo to form the crude product. The crude product was purified on silica gel (60-120 mesh) column using dichloromethane as eluent to yield 1-(3-bromopropyl)-piperidine-2,6-dione. Yield: 3.1 gm (76%) |
With tetrabutylammomium bromide; potassium carbonate In acetone for 24h; Ambient temperature; |
With tetrabutylammomium bromide; potassium carbonate In acetone Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 25℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Into a stirred solution of glutarimide (15.00 g, 0.13 mol) in CH2Cl2 (100 mL) at -78 C under a nitrogen atmosphere, the Grignard reagent CH3MgBr was added into 2-methyltetrahydrofuran (3 M, 130 mL) dropwise. Then the reaction mixture was stirred at room temperature for 12 h. NaBH3CN (9.83 g, 0.16 mol) was added, followed by the slow addition of a 6N HCl solution to keep the pH at 3-4. The reaction was continued at 25 C for 5 h. After completion, the mixture was neutralized with 1 NNaOH and extracted with CH2Cl2 (5 × 100 mL). The combined organic extracts were driedover anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified bycolumn chromatography on silica gel using ethyl acetate:MeOH (20:1~10:1) to obtain compound 3 as a white solid (9.75 g, yield 65%) [45,46]. 1H NMR (400 MHz, CDCl3): δ 1.20(d, 3H, CH3), 1.30-1.37 (m, 1H), 1.66-1.74 (m, 1H), 1.87-1.91 (m, 2H), 2.24-2.31 (m, 1H),2.35-2.41 (m, 1H), 3.48-3.54 (m, 1H), 5.96 (s, br, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With pyridin-1-ium-1-yl[pyridin-1-ium-1-yl(sulfido)phosphinothioyl]sulfanyl-sulfido-thioxo-phosphane In acetonitrile for 0.5h; Reflux; | |
70% | With Lawessons reagent In tetrahydrofuran at 20℃; for 48h; | |
70% | With Lawessons reagent In tetrahydrofuran at 20℃; for 48h; | The mixture of glutarimide (0.45 g, 4 mmol) and LR (0.809 g, 2 mmol) in THF (30 mL) was stirred at room temperature for 2 days. The solvent was evaporated under vacuum and the residue was purified by column chromatography using petroleum ether : EtOAc (1: 1) as the eluent to give compound 218 as a yellow solid (0. 361G, 70%): mp 135°C ; 1H NMR (CDC13) 8 2.96 (t, J = 5.7 Hz, 2 H), 2. 58 (t, J = 5. 8 Hz, 2 H), 1.96 (m, 2 H); MS (CI/CH4) mlz 129 (M+) ; Anal. (C5H7NOS) C, H, N. |
With Lawessons reagent Inert atmosphere; Schlenk technique; Glovebox; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With pyridin-1-ium-1-yl[pyridin-1-ium-1-yl(sulfido)phosphinothioyl]sulfanyl-sulfido-thioxo-phosphane In dimethylsulfone at 165 - 175℃; for 0.25h; | |
66% | With Lawessons reagent In toluene for 3h; Heating; | |
66% | With Lawessons reagent In toluene for 3h; Heating / reflux; | A mixture of glutarimide (0.34 g, 3 mmol) and LR (1.22 g, 3 mmol) in toluene (30 mL) was stirred at reflux for 3 h. The solvent was evaporated under vacuum and the residue was purified by column chromatography using petroleum ether : EtOAc (20: 1) as the eluent to give compound 219 as a yellow solid (0.286 g, 66%) : mp 103°C ; IH NMR (CDC13) 8 3.02 (t, J = 6.3 Hz, 4H), 1. 98 (t, J = 6. 3 Hz, 2H) ; MS (CI/CH4) m/z 145 (M+) ; Anal. (C5H7NS2) C, H, N. |
With Lawessons reagent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With tetra-(n-butyl)ammonium iodide; potassium carbonate In acetone for 12h; | |
88% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 24h; | |
82% | With sodium hydride In dimethyl sulfoxide at 20℃; for 12h; |
8.99 g | With tetra-(n-butyl)ammonium iodide; potassium carbonate In acetone at 20℃; | 478a; 478b 1-(4-methoxybenzyl)piperidine-2,6-dione: 1-(4-methoxybenzyl)piperidine-2,6-dione: Glutarimide (5 g, 44.2 mmol) was suspended in acetone (Volume: 100 mL) and then K2CO3 (12.22 g, 88 mmol), Bu4NI (3.27 g, 8.84 mmol) and 4-methoxybenzyl chloride (6.02 mL, 44.2 mmol) were added. The mixture was agitated at room temperature overnight and filtered through celite and then concentrated in vacuo and the residue purified by flash chromatography (0-50% EtOAc/heptane) to afford 8.99 g of the desired product as a colorless solid. LCMS (m/z): (MH+), 234.2, 0.66 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With tributylphosphine; di-isopropyl azodicarboxylate In tetrahydrofuran at 0 - 20℃; for 1h; | 34.1 To a solution (5ml) of Compound 20 (140 mg, 0.394 mmol; obtained from Step1 of Ex.9) and piperidine-2,6-dione (53.5 mg, 0.473 mmol)in THF, ,tri-n-butylphosphine(0.147ml,0.590mmol) and diisopropylazodi carboxyrate (0.116 ml, 0.589 mmol) were added under ice-cooling and the mixture was stirred for 1 hour while warming to room temperature. Ethyl acetate was added and the mixture was washed with water, dried over sodiun sulfate anhydrous and concentrated in vacuo. The resulting residue was subjected to silicagel column chromatography and eluted with toluene-ethyl acetate (1:1, v/v). Fractions containing the desired compound were concentrated in vacuo to give Compound 62 (92 mg, 0.204 mmol) as colorless crystals in 52% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39.4% | With Lawessons reagent In toluene at 120℃; for 5h; Heating / reflux; | A mixture of phthalimide (436 mg, 3.40 mmol) and Lawesson's reagent (1.199 g, 3. 4Q mmol) in toluene (50 ml) was refluxed (oil bath 120°C) under nitrogen for 5 hours. The solvent was removed under vacuum and the residue was directly chromatographed (silica gel, petroleum ether: methylenedichloride/2: 3) to give dithiophthalimide as black red needle crystals (240 mg, 39.4%) : HNMR (CDCL3) 8 9.80 (br, 1H), 7.95 (d, 2H), 7.80 (d, 2H); MS (CI/CH4) M/Z 179 (MT). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With tetra-(n-butyl)ammonium iodide; potassium carbonate In acetone at 40 - 60℃; for 8 - 12h; | 2.1 Example 2: Preparation of l-{4-[4-(2-Methoxy-phenylVpiperazin-l-yll-but-2-vnyl|- piperidine-2,6-dione hydrochloride salt (Compound No. 2); Step 1: Preparation of l-(4-ChIoro-but-2-ynyl)-piperadine-2,6-dione; A mixture of glutarimide (2.0 gm, 17.7 mmole), l,4-dichloro-2-butyne (4.35 gm, 35.4 mmole), potassium carbonate (7.32 gm, 53.1 mmole) and tetrabutylammonium iodide (1.3 gm, 3 mmole) in acetone was heated at 400C to 60°C for 8 to 12 hours under stirring. Inorganic salts were filtered, washed with acetone, solvent thus obtained was removed under reduced pressure and residue suspended in water. The aqueous solution was extracted with ethyl acetate. The organic layer washed with water, dried over anhydrous sodium sulphate and evaporated in vacuo to give the crude product. The product was purified by silica gel (60-120 mesh) column chromatography using dichloromethane as eluent.Yield: 2.5 gm (71%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With bromine; In chloroform; at 110℃; for 1.5h; | 13.1 Synthesis of 3-bromopiperidine-2,6-dione a37Bromine (4.5 ml, 87.8 mmol) is added to a suspension of piperidine-2,6-dione a36 (10.2 g, 50.3 mmol) suspended in chloroform (20 ml) and the mixture is stirred in a closed vessel for 90 minutes at a bath temperature of 1 100C. After cooling, the vessel is opened and stirring is continued until no more hydrogen bromide escapes. The reaction mixture is evaporated in vacuo. The residue is dissolved in ethanol and evaporated to afford 17.1 g of 3-bromopiperidine-2,6-dione a37 as white crystals.Yield: 99 %.LC-MS (MH+): 193. |
55% | With bromine; In chloroform; at 20 - 110℃; for 1.5h;Inert atmosphere; Sealed tube; | This compound was prepared using a literature procedure1. In a sealed reaction vessel, glutarimide (2g, 17.68 mmol) was dissolved in dry chloroform under argon atmosphere and Br2 (908.54 uL, 1 equiv.) was added via a syringe at room temperature. The reaction mixture heated at 110 C (oil bath) for 1h, cap was removed and further stirred at r.t. for 30 minutes. The crude product was evaporated and brown solid was purified using SiO2 column chromatography (EtOAc-hexane, 0%-100% gradient elution). The product was obtained as a white crystalline solid (0.93 g, 55%). HPLC-MS (ESI): m/z 192.0 [100%, (M+H)+].1H NMR (400 MHz, Chloroform-d) delta 7.92 (s, 1H), 4.63 (app t, J = 3.5 Hz, 1H), 3.00-2.91 (m, 1H), 2.72-2.70 (m, 1H), 2.68- 2.66 (m, 1H), 2.36- 2.28 (m, 1H). |
54.5% | With bromine; In chloroform; at 113℃; for 1.5h;Sealed tube; | To a stirred solution of piperidine-2,6-dione (30 g, 0.266 mol) in CHCl3 (60 mL) was added Br2 (13.5 mL, 0.265 mol) in a sealed tube, then the reaction mixture was heated to 113 oC for 1.5 h. The color of the reaction mixture changed from deep yellow to pale yellow. The mixture was cooled to r.t. and transferred to a round bottom flask, concentrated to dry. To the residue was added 100 mL ice water, basified to pH = ~ 8 with saturated NaHCO3, extracted with DCM (100 mL x 5). The organic layers were dried with Na2SO4, filtered, concentrated to dry to give crude product, which was dissolved in a solution of DCM: EtOAc = 1:1 (~90 mL), then heated to 80 oC, after the solid was completely dissolved, stopped the heating treatment, cooled to r.t. for overnight. The solution was filtered; the solid was collected, dried under vacuum to give the desired product 3-bromopiperidine-2,6-dione (15.7 g) as a white solid. The filtrate was concentrated to give the crude product, and the crude product was purified by column chromatography on silica gel eluting with DCM : Petroleum ether : EtOAc = 5:5:1 to DCM : Petroleum ether : EtOAc = 5:5:2 to obtain the second batch of desired product (12 g) as a white solid (total yield: 54.5 %). 1H NMR (400 MHz, DMSO-d6) delta 11.06 (s, 1H), 5.00- 4.78 (m, 1H), 2.69- 2.54 (m, 2H), 2.45 (dd, J = 10.0, 5.1 Hz, 1H), 2.17-2.12 (m, 1H). |
54.5% | With bromine; In chloroform; at 113℃; for 1.5h;Sealed tube; | To a stirred solution of piperidine-2,6-dione (30 g, 0.266 mol) in CHCl3 (60 mL) was added Br2 (13.5 mL, 0.265 mol) in a sealed glass tube, then the reaction mixture was heated to 113 C. for 1.5 h. The mixture was cooled to r.t. and transferred to a round bottom flask and concentrated. To the residue was added 100 mL ice water, and the solution was basified to pH=8 with saturated NaHCO3 aqueous, then extracted with DCM (100 mL×5). The organic layer was dried with Na2SO4, filtered, and concentrated to give crude product, which was dissolved in a solution of DCM:EtOAc=1:1 (90 mL), then heated to 80 C. After the solid was completely dissolved, the heating was stopped and the solution was cooled to r.t. for overnight. The solution was filtered, the solid was collected, and dried under vacuum to give desired compound (15.7 g) as a white solid. The filtrate was also concentrated to dry to give crude product, which was purified by column chromatography on silica gel eluting with DCM:Petroleum ether:EtOAc=5:5:1 to DCM:Petroleum ether:EtOAc=5:5:2 to obtain desired the second batch pure product (12 g) as a white solid (total yield: 54.5%). 1H NMR (400 MHz, DMSO-d6) delta 11.06 (s, 1H), 5.00-4.78 (m, 1H), 2.69-2.54 (m, 2H), 2.45 (dd, J=10.0, 5.1 Hz, 1H), 2.17-2.12 (m, 1H). |
44% | With bromine; In 1,1,2-trichloroethane; at 20 - 110℃; for 3h; | Bromine (9.1 ml, 177 mmol, 1 eq) is added to a solution of glutarimide x54 (20 g, 177 mmol, 1 eq) in 1 ,1 ,2-trichloroethane (60 ml) at room temperature. The mixture is stirred for 2 h at 110 0C, then 1 h at room temperature. The mixture is evaporated to dryness and the residue is purified by chromatography over silicagel (dichloromethane) to afford 14.6 g of 3-bromopiperidine-2, 6-dione x55 as white crystals. Yield: 44 %. LC-MS (MH+): 193. |
44.3% | With bromine; In 1,1,2-trichloroethane; at 20 - 110℃; for 3h; | Bromine (6.4 g, 0.04 mol) was added to a solution of piperidine-2,6-dione (4.5 g,0.04 mol) in 14 mL of 1 , 1 ,2-trichloroethane at room temperature. The mixture was allowed to stir for 2 hours at 1 10 C and then for 1 hour at room temperature. The reaction mixture was concentrated in vacuo and the resulting residue was purified using flash chromatography on silica gel (eluted with PE : EtOAc = 5 : 1 ~ 2 : 1) to provide 3.4 g of 3-bromopiperidine-2,6- dione (yield: 44.3 %) as white solid. 1H-NMR (CDC13, 400 MHz) delta 8.34 (s, 1H), 4.64 (t, / = 3.6 Hz, 1H), 2.91-3.00 (m, 1H), 2.66-2.73 (m, 1H), 2.28-2.47 (m, 2H). |
44.3% | With bromine; In 1,1,2-trichloroethane; at 20 - 110℃; for 3h; | Bromine (6.4 g, 0.04 mol) was added to a solution of piperidine-2,6-dione (4.5 g,0.04 mol) in 14 mL of 1 , 1 ,2-trichloroethane at room temperature. The mixture was allowed to stir for 2 hours at 1 10 C and then for 1 hour at room temperature. The reaction mixture was concentrated in vacuo and the resulting residue was purified using flash chromatography on silica gel (eluted with PE : EtOAc = 5 : 1 ~ 2 : 1) to provide 3.4 g of 3-bromopiperidine-2,6- dione (yield: 44.3 %) as white solid. 1H-NMR (CDC13, 400 MHz) delta 8.34 (s, 1H), 4.64 (t, / = 3.6 Hz, 1H), 2.91-3.00 (m, 1H), 2.66-2.73 (m, 1H), 2.28-2.47 (m, 2H). |
44.3% | With bromine; In 1,1,2-trichloroethane; at 20 - 110℃; for 3h; | Step 1-Synthesis of 5-bromopyridine-3-carbothioamide Bromine (6.4 g, 0.04 mol) was added to a solution of piperidine-2,6-dione (4.5 g, 0.04 mol) in 14 mL of 1,1,2-trichloroethane at room temperature. The mixture was allowed to stir for 2 hours at 110 C. and then for 1 hour at room temperature. The reaction mixture was concentrated in vacuo and the resulting residue was purified using flash chromatography on silica gel (eluted with PE:EtOAc=5:1?2:1) to provide 3.4 g of 3-bromopiperidine-2,6-dione (yield: 44.3%) as white solid. 1H-NMR (CDCl3, 400 MHz) delta 8.34 (s, 1H), 4.64 (t, J=3.6 Hz, 1H), 2.91?3.00 (m, 1H), 2.66?2.73 (m, 1H), 2.28?2.47 (m, 2H). |
38% | With bromine; In chloroform; at 110℃; for 4h;Inert atmosphere; Sealed tube; | To a stirred solution of piperidine-2,6-dione (5 g, 44.20 mmol) in CHCb (10 mL) was added Br2(2.25 mL) in one portion at room temperature under nitrogen atmosphere. The reaction mixture was sealed in a tube and stirred for 4 hours at 110 C. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 50% ethyl acetate in petroleum ether to afford 3-bromopiperidine-2,6-dione as a pink solid (3.2 g, 38%): NMR (300 MHz, DMSO-i) delta 11.05 (br s, 1H), 4.89 (dd, J= 5.2, 3.9 Hz, 1H), 2.60 (dt, J= 9.8, 4.7 Hz, 2H), 2.46 (ddd, J= 9.6, 5.1, 3.9 Hz, 1H), 2.15 (dq, J= 14.9, 4.9 Hz, 1H); LC/MS (ESI, m/z): [(M + 1)]+= 192.1, 194. 1. |
38% | With bromine; In chloroform; at 110℃; for 4h;Inert atmosphere; Sealed tube; | To a stirred solution of piperidine-2,6-dione (5 g, 44.20 mmol) in CHCb (10 mL) was added Br2 (2.25 mL) in one portion at room temperature under nitrogen atmosphere. The reaction mixture was sealed in a tube and stirred for 4 hours at 110 C. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 50% ethyl acetate in petroleum ether to afford 3-bromopiperidine-2,6-dione as a pink solid (3.2 g, 38%): NMR (300 MHz, DMSO-i) delta 11.05 (br s, 1H), 4.89 (dd, J= 5.2, 3.9 Hz, 1H), 2.60 (dt, J= 9.8, 4.7 Hz, 2H), 2.46 (ddd, J= 9.6, 5.1, 3.9 Hz, 1H), 2.15 (dq, J= 14.9, 4.9 Hz, 1H); LC/MS (ESI, m/z): [(M + 1)]+ = 192.1, 194. 1. |
With bromine; In ethanol; chloroform; | Step 1 3-bromopiperidine-2,6-dione 4.5 ml bromine were added to 10.2 g glutarimide suspended in 20 ml chloroform and the mixture was stirred in a closed vessel for 90 minutes at a bath temperature of 110 C. After cooling, the vessel was opened and stirring was continued until no more hydrogen bromide escaped. The reaction mixture was evaporated in vacuo, the residue dissolved in ethanol and evaporated again. 17.1 g (99% of theoretical) of the title compound remained in the form of practically white crystals, which melted at 76 to 83 C. | |
With bromine; In chloroform; at 110℃; for 0.75h; | To a 48mL glass pressure reaction vessel fitted with a Teflon screw cap was added piperidine-2,6-dione (2.00g, 17.7mmol) and Br2 (2.82g, 0.90mL, 17.7mmol) in chloroform (15mL). The reaction mixture was then heated in a Kugelroehr oven at 110C (45min). The solvent was removed and the crude bromoglutarimide 7 was then dissolved in acetone (5mL) followed by the addition of sodium azide (3.44g, 53.1mmol) whereupon the reaction mixture turned blue-purple. The reaction mixture was stirred at room temperature (24h) and then directly applied to a silica gel column. Elution with hexane/ethyl acetate (1:1) gave a mixture of unreacted 3-bromopiperidine-2,6-dione 7 and 3-azidopiperidine-2,6-dione 8 (1:1). The mixture of azide 8 and unreacted bromide 7 was again dissolved in acetone (5mL) and sodium azide (1.15g, 17.7mmol) was added and stirring of the blue-purple reaction mixture was continued at room temperature (24h). Column chromatography (hexane/ethyl acetate, 1:1) of the reaction mixture gave pure 3-azidopiperidine-2,6-dione 9 as an off-white amorphous solid (1.44g, 53% from glutarimide): mp 144-145C; Rf 0.24 (TLC stains blue with heat); 1H NMR (400MHz, CDCl3) delta 4.21 (dd, J=9.6Hz, 8.4Hz, 1H), 2.78 (dt, J=18.4Hz, 5.6Hz, 1H) 2.63-2.54 (m, 1H), 2.23-2.16 (m, 1H), 2.04-1.95 (m, 1H). 13C NMR (400MHz, CDCl3) delta 170.7, 169.2, 58.2, 29.1, 24.0. FTIR (neat) 3090, 2112, 1710, 1676cm-1; HRMS (ESI-TOF) m/z [M+H]+ calcd for C5H6N4O2: 155.0491, Found: 155.0569. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | In water; dimethyl sulfoxide; | Example 28 This example illustrates the synthesis of 1-(8-Nonenyl)glutarimide (CT1604). Sodium hydride (1.02 g, 44 mmol) was added to a solution of glutarimide (5.00 g, 44 mmol) in dimethyl sulfoxide (150 ml). After 20 min of stirring, <strong>[89359-54-6]9-bromo-1-nonene</strong> (9.02 g, 44 mmol) was added. After 16 hr of stirring at room temperature, the reaction was poured into a separatory funnel containing 100 ml water and extracted with dichlormethane (3*70 ml). The organic portions were combined, washed with water (2*40 ml) and brine (50 ml) and dried to give the olefin CT1604 as a colorless oil (10.09 g, 97% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | Stage #1: piperidine-2,6-dione With methylmagnesium bromide In tetrahydrofuran at 0 - 20℃; for 0.5h; Inert atmosphere; Stage #2: 4-penten-1-ylmagnesium bromide In tetrahydrofuran at 0 - 20℃; for 12h; Inert atmosphere; | 1.1 1) Synthesis of the compound of formula 2 Under the protection of 0 ° C and nitrogen, To the compound of formula 1 (5.06 g, 44.76 mmol) Methylmagnesium bromide (47.4 mL) was added dropwise to a solution of tetrahydrofuran (210 mL), and the solution became white turbid. After returning to room temperature and stirring at room temperature for 30 minutes, Cool again to 0 ° C and add pent-4-en-1-ylmagnesium bromide (70.6 mL) at this temperature. Then stirring at room temperature for 12 hours; Add saturated sodium bicarbonate solution (40 mL) to the mixed system. Extracted with ethyl acetate (3 x 80 mL). Combine the obtained organic phase, Wash with saturated brine and dry over anhydrous sodium sulfate. Concentrate under reduced pressure to remove organic solvents. The obtained crude product was separated and purified by flash column chromatography (methanol: dichloromethane = 1: 60) to give a white liquid. That is, the compound of the formula 2 (5.32 g, 71%). |
71% | Stage #1: piperidine-2,6-dione With methylmagnesium bromide In tetrahydrofuran at 0 - 20℃; for 0.5h; Inert atmosphere; Stage #2: 4-penten-1-ylmagnesium bromide In tetrahydrofuran at 0 - 20℃; for 12h; Inert atmosphere; | 1.1 Synthesis of the compound of formula 2 Under the protection of 0 ° C and nitrogen,Methylmagnesium bromide (47.4 mL) was added dropwise to a solution of the compound of formula 1 (5.06 g, 44.76 mmol) in tetrahydrofuran (210 mL). The solution became white turbid, returned to room temperature and stirred at room temperature for 30 min. Cooling to 0 ° C and dropping pent-4-en-1-ylmagnesium bromide (70.6 mL) at this temperature, followed by stirring at room temperature for 12 hours;To the mixture, a saturated aqueous solution of sodium hydrogencarbonate (40 mL) was evaporated, evaporated, evaporated, evaporated The obtained crude product was separated and purified by flash column chromatography (methanol: methylene chloride = 1 : 60) to afford white crystals, Compounds of formula 2 (5.32 g, 71%). |
68% | Stage #1: piperidine-2,6-dione; 4-penten-1-ylmagnesium bromide In tetrahydrofuran Inert atmosphere; Stage #2: With sodium cyanoborohydride; acetic acid In tetrahydrofuran Inert atmosphere; Stage #3: With sodium hydroxide; water In tetrahydrofuran |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: 3-[4-(2-methoxyphenyl)piperazin-1-yl]-1-propanol With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 5℃; for 0.25h; Stage #2: piperidine-2,6-dione In tetrahydrofuran at 0 - 20℃; for 8h; | 1 DETAILED DESCRIPTION; Example 1: Preparation of l r4-(2-memoxyphenvD piperazin-l-yl]-3-(2,6-dioxopiperidin-l-yl )propane; To a crade mixture of 4-(2-methoxyphenyl-l-piperazine) propanol (0.5 g, 2 mmole; prepared äs shown in U.S. Patent No. 2,922,785, Example 5, Column 6) and triphenylphosphine (TPP) (0.524 g, 2 mmole) in dry tetrahydrofuran (20 ml) at 0 to 5°C, diisobutylazadicarboxylate (DIAD) (0.404 g, 2 mmole) was added dropwise and stirred for 15 minutes. After this 2,6-dioxopiperidine (0.113 g, l mmole) was added and the temperature of the reaction mixture was allowed to rise to room temperature and stirred for 8 hours. After completion of the reaction, tetrahydrofüran was removed at reduced pressure and the residue was taken up in water (10 ml) and extracted with dichloromethane (2xlOml). The extracts were dried over sodium sulphate and concentrated under reduced pressure to afford l-[4-(2-methoxyphenyl) piperazin-l-yl]-3-[2,6-dioxopiperidin-l-yl) propane äs an oil which was purified by column chromatography over silica gel (60-120 mesh) using dichloromethane:methanol (98:2) äs an eluent.The product was prepared in a yield of 0.27g (78%). Infrared spectroscopy of the productyielded peaks at (DCM): 1722.5,1669.8 cm"1. 1HNMR spectra of the product showedpeaks at (300 MHz, CDC13)6: 1.75-1.82 (2H, m), 1.89-2.00 (2H, m), 2.45-2.50 (2H, m),2.62-2.67 (8H, m), 3.11 (4H, m), 3.81-3.85 (5H, m), 6.83-7.01 (4H, m). The massspectrum of the product showed a peak at 346 (M++l).The hydrochloride salt was prepared in quantitative yield by the addition ofisopropanolic hydrochloride solution to an isopropanolic solution of the free base and theresultant precipitation was collected by filtration. The melting point of the salt wasmeasured äs 206-210°C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57.9% | With potassium hydroxide In acetonitrile at 20℃; for 17h; Inert atmosphere; | 4.1.7. N-(1,3-dioxopiperidin-2-yl)methyl-3-(1-oxo-1,3-dihydro-1H-isoindol-2-yl)-2,6-dioxopiperidine (11) A mixture of glutarimide (36.0 mg, 0.318 mmol) and potassium hydroxide (42 mg, 0.750 mmol) in acetonitrile (42 mL) was stirred for an hour at room temperature. Thereafter, compound 8 (93.0 mg, 0.318 mmol) was added to the reaction system and stirred for a further 17 h under an atmosphere of nitrogen at the same temperature. After removing solvent, the residues were separated with chromatography on silica gel (CH3CN/CH2Cl2 = 1/3) to afford product 11(68.0 mg, 57.9%) as a white solid: mp 216.5-217.0 °C; 1H NMR (CDCl3) δ 7.88 (d, J = 9.0 Hz, 1H, C7-H), 7.57 (d, J = 8.5 Hz, 1H, C4-H), 7.46 (t, J = 9.0 Hz, 2H, C5,6-H), 5.85 (s, 2H, CH2N2), 5.19-5.10 (m, 1H, C3'-H), 4.52 and 4.35 (AB system, J = 16.5 Hz, 2H, C3-H), 3.08-1.81 (m, 10H, C5',4'-H and glu-H) ppm; 13C NMR (CDCl3) δ 171.9, 170.3, 169.4, 169.3, 141.6, 132.0, 131.7, 128.2, 124.1, 123.0, 52.8, 47.4, 45.0, 32.9, 32.2, 22.8 and 17.0 ppm; MS (CI/CH4), m/z 300 (M-69). Anal. Calcd for C19H19N3O5H2O: C, 58.91; H, 5.46; N, 10.85. Found: C, 59.17; H, 5.38; N, 10.61. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Stage #1: piperidine-2,6-dione; ethylmagnesium bromide In diethyl ether at -78 - 20℃; Stage #2: With hydrogenchloride; sodium cyanoborohydride In diethyl ether | 35.1 (1) (±)-6-ethyl-2-piperidinone Into a reaction vessel was added a 3.0M magnesium ethyl bromide/diethyl ether solution (50 mL, 150 mmol), it was cooled down to -78°C with dry ice/acetone, and a dichloromethane solution (200 mL) of glutarimide (5.0 g, 44 mmol) was dropped. The reaction temperature was raised gradually up to room temperature, then, the mixture was stirred further overnight at room temperature. To the reaction mixture was added sodium cyanoborohydride (3.32 g, 1.2 eq), then, 6N hydrochloric acid was added slowly so as to keep pH3 to 4. After stirring for 5 hours, the mixture was neutralized with a 10% sodium hydroxide solution to cause liquid-separation, and the aqueous layer was extracted with chloroform. The organic layer was washed with water, dried over Na2SO4, then, concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (eluent: ethyl acetate/methanol = 9/1) to obtain the title compound (3.63 g, 65%) as colorless crystals. 1H-NMR (300 MHz, CDCl3): δ 0.94 (t, J = 7.5 Hz, 3H), 1.27-1.40 (m, 1H), 1.49-1.57 (m, 2H), 1.62-1.71 (m, 1H), 1.85-1.95 (m, 2H), 2.28-2.38 (m, 2H), 3.28-3.31 (m, 1H), 6.26 (brs, 1H) |
Stage #1: piperidine-2,6-dione; ethylmagnesium bromide In tetrahydrofuran; diethyl ether at 0 - 20℃; for 12h; Stage #2: With sodium cyanoborohydride; acetic acid In tetrahydrofuran; diethyl ether for 0.75h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; at 20℃; for 2h; | General procedure: Into a 100 ml three-necked flask, dichloromethane (20 ml), N-hydroxyphthalimide (5.5 g, 34 mmol) and BSTFA (13.5 ml, 51 mmol) were added. The mixture was stirred for 2 h at ambient temperature, then the solvent and the side-products were removed by evaporation in vacuo. The solid residue was dissolved in hexane and recrystallized. The alicyclic imides (TMSSI, TMSGI) were synthesized in an analogous way, however, only in quantity of milligrams. After the completion of reactions, solvent and volatiles were evaporated, then the liquid raw products were used ?as is? for the solvolysis studies. Their purity was checked by gas chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | At -40C, a solution of lithium bis(trimethylsilyl)amide 1 M in tetrahydrofuran (38.9 mmol, 38.9 mL, 2.2 eq) was added dropwise to a solution of glutarimide (2.0 g, 17.7 mmol, 1 .0 eq) in tetrahydrofuran (30 mL). The iodoalkane (53.1 mmol, 3.0 eq) was immediately added. After 15 minutes at -40C, the mixture was allowed to warm up and the mixture was stirred at room temperature for 18 hours. The reaction was quenched with a saturated solution of ammonium chloride (10 mL) and the aqueous phase was extracted with methylene chloride (3 x 20 mL). The combined organic phases were dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography using cyclohexane and ethyl acetate (1 00/0 to 0/100) to afford the expected compound. General procedure B: alkylation with LDA; 3-hex-5-ynyl-piperidine-2,6-dione was prepared according to General Procedure A using glutarimide (2.0 g, 17.7 mmol) and 6-iodo-J-hexyne (5.6 mL. 42.4 mmol). The expected compound was isolated as orange oil that solidified during storage with 17% yield (570 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82%; 80% | With aluminum (III) chloride; at 300℃; for 0.166667h;Microwave irradiation; | General procedure: Microwaves Procedure: [0077] The dinitrile (3.0 mmol, 1.0 equiv.) is added, in a glass tube designed for this purpose, to a mixture of acid (3.0 mmol) and catalyst (0.06 mmol, 0.02 equiv.). The tube is then closed using a suitable stopper and then is left under microwave activation (appliance used: Monowave 300 from Anton Paar) and magnetic stirring at 300 C. for 10 min. After reaction, the crude reaction mixture is transferred into a 50 ml round-bottomed flask with 10 ml of ethanol. If necessary, the tube is placed in an ultrasonic bath at 60 C., in order to promote the dissolution of the reaction mixture in the ethanol. 3 g of silica are subsequently added to this mixture in order to produce a solid deposit after evaporation of the ethanol. Finally, the pure nitrile is obtained after chromatography on a silica column (gradient from M1 to M9, followed by M0). For its part, the cyclic imide is obtained after elution with ethyl acetate. The conversion to the desired nitrile is determined by 1H NMR of the crude product. The yields shown are the yields of the isolated products after purification. Note: [0078] M0 is an 80:20 dichloromethane/ethyl acetate mixture. [0079] M1 is a 90:10 petroleum ether/M0 mixture. [0080] M2 is an 80:20 petroleum ether/M0 mixture, and the like. [0081] M9 is a 10:90 petroleum ether/M0 mixture |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 83% 2: 83% | With aluminum (III) chloride at 300℃; for 0.166667h; Microwave irradiation; | 7 Microwaves Procedure: [0077] The dinitrile (3.0 mmol, 1.0 equiv.) is added, in a glass tube designed for this purpose, to a mixture of acid (3.0 mmol) and catalyst (0.06 mmol, 0.02 equiv.). The tube is then closed using a suitable stopper and then is left under microwave activation (appliance used: Monowave 300 from Anton Paar) and magnetic stirring at 300° C. for 10 min. After reaction, the crude reaction mixture is transferred into a 50 ml round-bottomed flask with 10 ml of ethanol. If necessary, the tube is placed in an ultrasonic bath at 60° C., in order to promote the dissolution of the reaction mixture in the ethanol. 3 g of silica are subsequently added to this mixture in order to produce a solid deposit after evaporation of the ethanol. Finally, the pure nitrile is obtained after chromatography on a silica column (gradient from M1 to M9, followed by M0). For its part, the cyclic imide is obtained after elution with ethyl acetate. The conversion to the desired nitrile is determined by 1H NMR of the crude product. The yields shown are the yields of the isolated products after purification. Note: [0078] M0 is an 80:20 dichloromethane/ethyl acetate mixture. [0079] M1 is a 90:10 petroleum ether/M0 mixture. [0080] M2 is an 80:20 petroleum ether/M0 mixture, and the like. [0081] M9 is a 10:90 petroleum ether/M0 mixture |
52% | With aluminum (III) chloride at 300℃; for 0.166667h; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With aluminum (III) chloride at 200℃; for 5h; Sealed tube; | General procedure for 2b and 2e: General procedure: In a glass tube, the dinitrile (3.0 mmol, 1.0 equiv.) is added to a mixture of acid (3.0 mmol) and aluminum trichloride (0.06 mmol, 0.02 equiv.). The tube is then sealed (with a screw cap) and the mixture is allowed to stir at 200 °C for 5 h. After completion, the crude reaction mixture is diluted with 10 mL of ethanol, 3 g of silica are then added to this crude material to make a solid deposit after evaporation of the ethanol. A silica gel column chromatography finally afforded the pure nitrile together with the cyclic imide. 3-(3,5-dichlorophenyl)propanenitrile 2b: white solid MP = 44°C . 1H NMR (400 MHz, CDCl3) δ7.29 (s, 1H), 7.13 (s, 2H), 2.91 (t, J= 7.2 Hz, 2H), 2.63 (t, J= 7.2 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ141.0, 134.9, 127.2, 126.7, 118.3, 30.5, 18.5. IR (thin film) 2247, 2217, 1590, 1566, 1431, 1101, cm-1. HRMS (EI) m/z calcd for C9H7Cl2N: 198.9956, found 198.9958. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With aluminum (III) chloride; at 200℃; for 5h;Sealed tube; | General procedure: In a glass tube, the glutaronitrile (282 mg, 3.0 mmol, 1.0 equiv) wasadded to a mixture ofthe respective acid 1(3.0 mmol) and AlCl3(8mg, 0.06 mmol, 0.02 equiv). The tubewas then sealed (with a screwcap) and the mixture was allowed to stir at 200 C for 5 h. Aftercompletion of the reaction, the crude mixture was diluted withEtOH (10 mL), silica gel (3 g) was then added to this crude materialto make a solid deposit after evaporation of the EtOH. A silica gelcolumn chromatography (eluent: PE-EtOAc, 95:5) finally affordedthe pure nitrile together with the cyclic imide. Conversion into thedesired nitrile was determined by 1H NMR analysis of the crudemixture. Given yields were reported for isolated products (Table 2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With aluminum (III) chloride at 200℃; for 2.5h; Sealed tube; | Thermal-Catalyzed Reaction of Acids 1 with Glutaronitrile; General Procedure 1 (GP1) General procedure: In a glass tube, the glutaronitrile (282 mg, 3.0 mmol, 1.0 equiv) was added to a mixture ofthe respective acid 1(3.0 mmol) and AlCl3(8mg, 0.06 mmol, 0.02 equiv). The tubewas then sealed (with a screwcap) and the mixture was allowed to stir at 200 °C for 5 h. After completion of the reaction, the crude mixture was diluted with EtOH (10 mL), silica gel (3 g) was then added to this crude material to make a solid deposit after evaporation of the EtOH. A silica gelcolumn chromatography (eluent: PE-EtOAc, 95:5) finally afforded the pure nitrile together with the cyclic imide. Conversion into the desired nitrile was determined by 1H NMR analysis of the crude mixture. Given yields were reported for isolated products (Table 2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | General procedure for N-acyl-glutarimide synthesis (1d) An oven-dried round-bottomed flask (100 mL) equipped with a stir bar was charged with amine (8.84 mmol, 1.0 equiv.), triethylamine (typically, 2.0 equiv.), DMAP (typically, 0.25 equiv.), and dichloromethane (typically, 50 mL), placed under a positive pressure of nitrogen, and subjected to three evacuation/backfilling cycles under high vacuum.87 Acyl chloride (typically, 1.1 equiv.) was added dropwise to the reaction mixture with vigorous stirring at 0 °C, and there action mixture was stirred overnight at room temperature. After the indicated time, the reaction mixture was diluted with Et2O (20 mL) and filtered. The organic layer was washed with HCl (1.0 N, 30 mL) and brine (30 mL), dried, and concentrated. Unless stated otherwise, the crude product was purified by recrystallization (toluene) to give analytically pure product. Benzoylpiperidine-2,6-dione (1d). White solid. Yield 87%. MS = 217.1. |
84% | With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; for 15h; Schlenk technique; Inert atmosphere; | |
82% | With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; |
82% | With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; for 15h; Inert atmosphere; | |
81.4% | With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | |
80% | With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; | |
80% | With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; | |
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | ||
Stage #1: piperidin-1-yl-2,6-dione With 4-dimethylaminopyridine; triethylamine In dichloromethane Stage #2: benzoyl chloride In dichloromethane at 0℃; | ||
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 23℃; Inert atmosphere; | ||
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; Schlenk technique; | ||
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | ||
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 23℃; Inert atmosphere; Schlenk technique; | ||
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; | ||
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; | ||
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; for 15h; | ||
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; | ||
1.39 g | With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With dmap; triethylamine In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; | |
77% | With dmap; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | |
70% | With dmap; triethylamine In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; |
70% | With dmap; triethylamine In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; | |
With dmap; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | ||
Stage #1: piperidine-2,6-dione With dmap; triethylamine In dichloromethane Stage #2: 4-methyl-benzoyl chloride In dichloromethane at 0℃; | ||
With dmap; triethylamine In dichloromethane at 0 - 23℃; Inert atmosphere; | ||
With dmap; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; Schlenk technique; | ||
With dmap; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | ||
With dmap; triethylamine In dichloromethane at 0 - 20℃; | II. Synthesis of the Starting Materials General procedure: Thionyl chloride (9 mL) was added to the carboxylic acid (1.0 equiv, 10.0 mmol) and the mixture wasrefluxed for 2 h. The solution was then concentrated in vacuo. An oven-dried round-bottomed flask(100 mL) equipped with a stir bar was charged with glutarimide (909.4 mg, 0.91 equiv, 8.04 mmol), acyl chloride (1.0 equiv, 8.84 mmol), 4-dimethylaminopyridine (DMAP, 280.4 mg, 0.25 equiv, 2.5mmol) and dichloromethane (50 mL). Triethylamine (typically, 2.0 equiv) was added dropwise to the reaction mixture with vigorous stirring at 0 °C, and the reaction mixture was stirred overnight at room temperature. After the indicated time, the reaction mixture was diluted with Et2O (20 mL) and filtered.The organic layer was washed with HCl (1.0 N, 30 mL), brine (30 mL), dried, and concentrated. The residue was purified by recrystallization or chromatography on silica gel to afford the corresponding amide. | |
With dmap; triethylamine In dichloromethane at 20℃; Sealed tube; | ||
With dmap; triethylamine In dichloromethane at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; | |
92% | With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; | |
90% | With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; |
90% | With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; for 15h; Inert atmosphere; | |
89.5% | With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | |
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | ||
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 23℃; Inert atmosphere; | ||
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; Schlenk technique; | ||
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | ||
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; | II. Synthesis of the Starting Materials General procedure: Thionyl chloride (9 mL) was added to the carboxylic acid (1.0 equiv, 10.0 mmol) and the mixture wasrefluxed for 2 h. The solution was then concentrated in vacuo. An oven-dried round-bottomed flask(100 mL) equipped with a stir bar was charged with glutarimide (909.4 mg, 0.91 equiv, 8.04 mmol), acyl chloride (1.0 equiv, 8.84 mmol), 4-dimethylaminopyridine (DMAP, 280.4 mg, 0.25 equiv, 2.5mmol) and dichloromethane (50 mL). Triethylamine (typically, 2.0 equiv) was added dropwise to the reaction mixture with vigorous stirring at 0 °C, and the reaction mixture was stirred overnight at room temperature. After the indicated time, the reaction mixture was diluted with Et2O (20 mL) and filtered.The organic layer was washed with HCl (1.0 N, 30 mL), brine (30 mL), dried, and concentrated. The residue was purified by recrystallization or chromatography on silica gel to afford the corresponding amide. | |
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 23℃; Inert atmosphere; Schlenk technique; | ||
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 20℃; Sealed tube; | ||
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With dmap; triethylamine In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; | |
72% | With dmap; triethylamine In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; | |
63.1% | With dmap; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; |
63% | With dmap; triethylamine In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; | |
63% | With dmap; triethylamine In dichloromethane at 0 - 20℃; for 15h; Inert atmosphere; | |
With dmap; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | ||
Stage #1: piperidine-2,6-dione With dmap; triethylamine In dichloromethane Stage #2: 4-trifluoromethyl-phenyl acetyl chloride In dichloromethane at 0℃; | ||
With dmap; triethylamine In dichloromethane at 0 - 23℃; Inert atmosphere; | ||
With dmap; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; Schlenk technique; | ||
With dmap; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | ||
With dmap; triethylamine In dichloromethane at 0 - 23℃; Inert atmosphere; Schlenk technique; | ||
With dmap; triethylamine In dichloromethane at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.2% | With dmap; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | |
71% | With dmap; triethylamine In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; | |
71% | With dmap; triethylamine In dichloromethane at 0 - 20℃; for 15h; Inert atmosphere; |
68% | With dmap; triethylamine In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; | |
68% | With dmap; triethylamine In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; | |
With dmap; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | ||
Stage #1: piperidine-2,6-dione With dmap; triethylamine In dichloromethane Stage #2: ortho-toluoyl chloride In dichloromethane at 0℃; | ||
With dmap; triethylamine In dichloromethane at 0 - 23℃; Inert atmosphere; | ||
With dmap; triethylamine In dichloromethane at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With dmap; triethylamine In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; | |
79.1% | With dmap; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | |
79% | With dmap; triethylamine In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; |
With dmap; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | ||
Stage #1: piperidine-2,6-dione With dmap; triethylamine In dichloromethane Stage #2: 4-fluorobenzoyl chloride In dichloromethane at 0℃; | ||
With dmap; triethylamine In dichloromethane at 0 - 23℃; Inert atmosphere; | ||
With dmap; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; Schlenk technique; | ||
With dmap; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | ||
With dmap; triethylamine In dichloromethane at 0 - 20℃; | II. Synthesis of the Starting Materials General procedure: Thionyl chloride (9 mL) was added to the carboxylic acid (1.0 equiv, 10.0 mmol) and the mixture wasrefluxed for 2 h. The solution was then concentrated in vacuo. An oven-dried round-bottomed flask(100 mL) equipped with a stir bar was charged with glutarimide (909.4 mg, 0.91 equiv, 8.04 mmol), acyl chloride (1.0 equiv, 8.84 mmol), 4-dimethylaminopyridine (DMAP, 280.4 mg, 0.25 equiv, 2.5mmol) and dichloromethane (50 mL). Triethylamine (typically, 2.0 equiv) was added dropwise to the reaction mixture with vigorous stirring at 0 °C, and the reaction mixture was stirred overnight at room temperature. After the indicated time, the reaction mixture was diluted with Et2O (20 mL) and filtered.The organic layer was washed with HCl (1.0 N, 30 mL), brine (30 mL), dried, and concentrated. The residue was purified by recrystallization or chromatography on silica gel to afford the corresponding amide. | |
With dmap; triethylamine In dichloromethane at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; | |
72% | With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; | |
66% | With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; |
66% | With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; | |
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | ||
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 23℃; Inert atmosphere; | ||
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 23℃; Inert atmosphere; Schlenk technique; | ||
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 20℃; Sealed tube; | ||
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; | ||
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; | |
83% | With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; | |
74% | With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; |
74% | With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; | |
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | ||
Stage #1: piperidin-1-yl-2,6-dione With 4-dimethylaminopyridine; triethylamine In dichloromethane Stage #2: methyl 4-(chlorocarbonyl)benzoate In dichloromethane at 0℃; | ||
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | ||
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; | II. Synthesis of the Starting Materials General procedure: Thionyl chloride (9 mL) was added to the carboxylic acid (1.0 equiv, 10.0 mmol) and the mixture wasrefluxed for 2 h. The solution was then concentrated in vacuo. An oven-dried round-bottomed flask(100 mL) equipped with a stir bar was charged with glutarimide (909.4 mg, 0.91 equiv, 8.04 mmol), acyl chloride (1.0 equiv, 8.84 mmol), 4-dimethylaminopyridine (DMAP, 280.4 mg, 0.25 equiv, 2.5mmol) and dichloromethane (50 mL). Triethylamine (typically, 2.0 equiv) was added dropwise to the reaction mixture with vigorous stirring at 0 °C, and the reaction mixture was stirred overnight at room temperature. After the indicated time, the reaction mixture was diluted with Et2O (20 mL) and filtered.The organic layer was washed with HCl (1.0 N, 30 mL), brine (30 mL), dried, and concentrated. The residue was purified by recrystallization or chromatography on silica gel to afford the corresponding amide. | |
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 23℃; Inert atmosphere; Schlenk technique; | ||
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54.2% | With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | |
54% | With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; | |
53% | With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; |
53% | With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; | |
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | ||
Stage #1: piperidin-1-yl-2,6-dione With 4-dimethylaminopyridine; triethylamine In dichloromethane Stage #2: 4-acetylbenzoic acid chloride In dichloromethane at 0℃; | ||
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.2% | With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | |
85% | With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; | |
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; |
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 20℃; Sealed tube; | ||
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; | ||
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With dmap; triethylamine In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; | |
85.7% | With dmap; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | |
Stage #1: piperidine-2,6-dione With dmap; triethylamine In dichloromethane Stage #2: m-anisoyl chloride In dichloromethane at 0℃; |
With dmap; triethylamine In dichloromethane at 0 - 23℃; Inert atmosphere; | ||
With dmap; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | ||
With dmap; triethylamine In dichloromethane at 0 - 20℃; | II. Synthesis of the Starting Materials General procedure: Thionyl chloride (9 mL) was added to the carboxylic acid (1.0 equiv, 10.0 mmol) and the mixture wasrefluxed for 2 h. The solution was then concentrated in vacuo. An oven-dried round-bottomed flask(100 mL) equipped with a stir bar was charged with glutarimide (909.4 mg, 0.91 equiv, 8.04 mmol), acyl chloride (1.0 equiv, 8.84 mmol), 4-dimethylaminopyridine (DMAP, 280.4 mg, 0.25 equiv, 2.5mmol) and dichloromethane (50 mL). Triethylamine (typically, 2.0 equiv) was added dropwise to the reaction mixture with vigorous stirring at 0 °C, and the reaction mixture was stirred overnight at room temperature. After the indicated time, the reaction mixture was diluted with Et2O (20 mL) and filtered.The organic layer was washed with HCl (1.0 N, 30 mL), brine (30 mL), dried, and concentrated. The residue was purified by recrystallization or chromatography on silica gel to afford the corresponding amide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.2% | With dmap; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | |
91% | With dmap; triethylamine In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; | |
With dmap; triethylamine In dichloromethane at 0 - 23℃; Inert atmosphere; |
With dmap; triethylamine In dichloromethane at 0 - 23℃; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.2% | With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | |
71% | With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; | |
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 23℃; Inert atmosphere; |
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | ||
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; | II. Synthesis of the Starting Materials General procedure: Thionyl chloride (9 mL) was added to the carboxylic acid (1.0 equiv, 10.0 mmol) and the mixture wasrefluxed for 2 h. The solution was then concentrated in vacuo. An oven-dried round-bottomed flask(100 mL) equipped with a stir bar was charged with glutarimide (909.4 mg, 0.91 equiv, 8.04 mmol), acyl chloride (1.0 equiv, 8.84 mmol), 4-dimethylaminopyridine (DMAP, 280.4 mg, 0.25 equiv, 2.5mmol) and dichloromethane (50 mL). Triethylamine (typically, 2.0 equiv) was added dropwise to the reaction mixture with vigorous stirring at 0 °C, and the reaction mixture was stirred overnight at room temperature. After the indicated time, the reaction mixture was diluted with Et2O (20 mL) and filtered.The organic layer was washed with HCl (1.0 N, 30 mL), brine (30 mL), dried, and concentrated. The residue was purified by recrystallization or chromatography on silica gel to afford the corresponding amide. | |
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.1% | With dmap; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | |
75% | With dmap; triethylamine In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; | |
75% | With dmap; triethylamine In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; |
With dmap; triethylamine In dichloromethane at 0 - 23℃; Inert atmosphere; | ||
With dmap; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.2% | With dmap; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | |
79% | With dmap; triethylamine In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; | |
79% | With dmap; triethylamine In dichloromethane at 0 - 20℃; for 15h; Inert atmosphere; |
74% | With dmap; triethylamine In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; | |
74% | With dmap; triethylamine In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; | |
Stage #1: piperidine-2,6-dione With dmap; triethylamine In dichloromethane Stage #2: 2-Thiophenecarbonyl chloride In dichloromethane at 0℃; | ||
With dmap; triethylamine In dichloromethane at 0 - 23℃; Inert atmosphere; | ||
With dmap; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | ||
With dmap; triethylamine In dichloromethane at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With dmap; triethylamine In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; | |
83% | With dmap; triethylamine In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; | |
83% | With dmap; triethylamine In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; |
With dmap; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | ||
Stage #1: piperidine-2,6-dione With dmap; triethylamine In dichloromethane Stage #2: 2-Fluorobenzoyl chloride In dichloromethane at 0℃; | ||
With dmap; triethylamine In dichloromethane at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; | |
92% | With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; | |
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; |
Stage #1: piperidin-1-yl-2,6-dione With 4-dimethylaminopyridine; triethylamine In dichloromethane Stage #2: 2-naphthaloyl chloride In dichloromethane at 0℃; | ||
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; Schlenk technique; | ||
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | ||
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; | II. Synthesis of the Starting Materials General procedure: Thionyl chloride (9 mL) was added to the carboxylic acid (1.0 equiv, 10.0 mmol) and the mixture wasrefluxed for 2 h. The solution was then concentrated in vacuo. An oven-dried round-bottomed flask(100 mL) equipped with a stir bar was charged with glutarimide (909.4 mg, 0.91 equiv, 8.04 mmol), acyl chloride (1.0 equiv, 8.84 mmol), 4-dimethylaminopyridine (DMAP, 280.4 mg, 0.25 equiv, 2.5mmol) and dichloromethane (50 mL). Triethylamine (typically, 2.0 equiv) was added dropwise to the reaction mixture with vigorous stirring at 0 °C, and the reaction mixture was stirred overnight at room temperature. After the indicated time, the reaction mixture was diluted with Et2O (20 mL) and filtered.The organic layer was washed with HCl (1.0 N, 30 mL), brine (30 mL), dried, and concentrated. The residue was purified by recrystallization or chromatography on silica gel to afford the corresponding amide. | |
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 20℃; Sealed tube; | ||
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57.7% | Stage #1: N,N-dimethyl-formamide With oxalyl dichloride In dichloromethane at 20℃; for 2h; Inert atmosphere; Stage #2: piperidine-2,6-dione In dichloromethane for 12h; Inert atmosphere; | 1 5.1 (E)-2,6-Dichloro-5-((dimethylamino)methylene)-4,5-dihydropyridine-3-carbaldehyde (3) A dried 50 ml round-bottomed, two-necked flask under nitrogen was prepared with an addition funnel and a rubber stopper. The flask was charged with 0.4 ml (5 mmol, 1.0 equiv) of anhydrous DMF (dried over CaH2) diluted in 10 ml of dried DCM and the addition funnel with 0.9 ml of oxalyl chloride (10 mmol, 2.0 equiv) diluted in 5 ml of dried DCM. Oxalyl chloride was drop-wise added to the DMF over a period of 5 min. At the end of the addition, the mixture was stirred at room temperature for 2 h. Then, glutarimide (289 mg, 2.6 mmol, 0.5 equiv) was added in one portion to the suspension of the Vilsmeier-Haack reagent. After ca. 12 h, the orange suspension was carefully quenched with std sodium carbonate solution. The biphasic system was vigorously stirred for 30 min. The organic layer was separated and the aqueous phase extracted with DCM (3×15 ml). The combined organic layers were dried over MgSO4 and the solvent evaporated in vacuo. Flash column chromatography (1:9 hexane:AcOEt) and recrystallization from DCM-pentane yielded compound 3 as a deep red solid (366 mg, 57.7% yield.). Mp 97-100 °C (DCM-pentane); 1H NMR (CDCl3, 300 MHz) δ ppm 9.90 (s, 1 H), 7.55 (s, 1 H), 3.73 (s, 2 H), 3.31 (s, 6 H); 13C NMR (CDCl3, 75 MHz) δ ppm 189.54, 165.24, 155.22, 153.48, 113.89, 97.50, 44.21 (broad peak), 25.39. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Stage #1: piperidine-2,6-dione; 2-methoxyphenylmagnesium bromide In tetrahydrofuran; dichloromethane at -78 - 20℃; for 18h; Stage #2: With hydrogenchloride; sodium cyanoborohydride In tetrahydrofuran; dichloromethane for 4h; | 53 Preparation 53: 6-(2-Methoxyphenyl)piperidin-2-one Piperidine-2,6-dione (5.0 g, 44.2 mmol) was dissolved in dry DCM (100 mL) and cooled to -78 °C. (2- methoxyphenyl)magnesium bromide (99 mL, 1M in THF) was added and the resulting mixture was stirred for about 18 h at rt. Sodium cyanoborohydride (3.47 g, 55.3 mmol) was added followed by a slow addition of 6M HC1 solution to keep the pH between 3 and 4. After about 4 h, the reaction was neutralized with 4N NaOH and extracted into DCM. The organics were washed with excess water and then with brine. Residual water was removed by passing the organics through a Biotage phase separator and the organics evaporated to dryness followed by trituration with hexanes. The resulting solids were collected by filtration to give the title compound (7.4 g, 81%); LC/MS (Table 1, Method d) Rt = 0.67 min; MS m/z: 206 (M+ H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With 1,1'-bis-(diphenylphosphino)ferrocene; bis(η3-allyl-μ-chloropalladium(II)); caesium carbonate In toluene at 80℃; for 16h; Inert atmosphere; regioselective reaction; | 2. General Procedure for the Palladium-catalyzed Reaction of 2-Fluoroallylicacetates 1, 2 and 3. General procedure: The reaction conditions and results are shown in Tables 1-4. A typical procedure isgiven for the reaction of 2-fluorocinnamyl acetate (1a), succinimide (2a), and phenol(3a) (Table 1, Entry 7). To a solution of [Pd(π-allyl)Cl]2 (2.4 mg, 0.0065 mmol),DPPF (7.2 mg, 0.013 mmol), succinimide (2a) (58 mg, 0.59 mmol), phenol (3a) (49 mg0.52 mmol), and Cs2CO3 (169 mg, 0.52 mmol) in Toluene (0.8 mL) was added(Z)-2-fluoro-3-phenylallyl acetate (1a) (25 mg, 0.13 mmol) at room temperature, thenstirred at 80 °C for 16 h. The reaction mixture was quenched with H2O, and extractedwith diethyl ether (3 x 2 mL). The combined organic layers were dried over MgSO4and concentrated in vacuo. The residue was chromatographed on silica gel(hexane/EtOAc = 60/40) to give 34 mg (84%) of 4aa as a mixture of two stereoisomers.The pure major stereoisomer (Z-isomer) was obtained after recrystallization fromCH2Cl2/hexane (1/5) at room temperature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | |
82% | With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; | |
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; |
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; | II. Synthesis of the Starting Materials General procedure: Thionyl chloride (9 mL) was added to the carboxylic acid (1.0 equiv, 10.0 mmol) and the mixture wasrefluxed for 2 h. The solution was then concentrated in vacuo. An oven-dried round-bottomed flask(100 mL) equipped with a stir bar was charged with glutarimide (909.4 mg, 0.91 equiv, 8.04 mmol), acyl chloride (1.0 equiv, 8.84 mmol), 4-dimethylaminopyridine (DMAP, 280.4 mg, 0.25 equiv, 2.5mmol) and dichloromethane (50 mL). Triethylamine (typically, 2.0 equiv) was added dropwise to the reaction mixture with vigorous stirring at 0 °C, and the reaction mixture was stirred overnight at room temperature. After the indicated time, the reaction mixture was diluted with Et2O (20 mL) and filtered.The organic layer was washed with HCl (1.0 N, 30 mL), brine (30 mL), dried, and concentrated. The residue was purified by recrystallization or chromatography on silica gel to afford the corresponding amide. | |
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | ||
With dmap; triethylamine In dichloromethane at 0 - 20℃; | II. Synthesis of the Starting Materials General procedure: Thionyl chloride (9 mL) was added to the carboxylic acid (1.0 equiv, 10.0 mmol) and the mixture wasrefluxed for 2 h. The solution was then concentrated in vacuo. An oven-dried round-bottomed flask(100 mL) equipped with a stir bar was charged with glutarimide (909.4 mg, 0.91 equiv, 8.04 mmol), acyl chloride (1.0 equiv, 8.84 mmol), 4-dimethylaminopyridine (DMAP, 280.4 mg, 0.25 equiv, 2.5mmol) and dichloromethane (50 mL). Triethylamine (typically, 2.0 equiv) was added dropwise to the reaction mixture with vigorous stirring at 0 °C, and the reaction mixture was stirred overnight at room temperature. After the indicated time, the reaction mixture was diluted with Et2O (20 mL) and filtered.The organic layer was washed with HCl (1.0 N, 30 mL), brine (30 mL), dried, and concentrated. The residue was purified by recrystallization or chromatography on silica gel to afford the corresponding amide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | Under nitrogen, a solution of triphenylphosphine (6.73g, 25.66mmol), <strong>[58584-63-7](6-methoxypyridin-3-yl)methanol</strong> 2c (3.50g, 25.17mmol) and glutarimide (2.90g, 25.64mmol) in THF (75mL) was stirred at 0C for 5min. A solution of diisopropyl azodicarboxylate (4.99mL, 5.19g, 25.66mmol) in THF (50mL) was added dropwise over 1h at 0C and the solution was allowed to warm to room temperature and stirred for 18h. Following concentration under reduced pressure and purification by column chromatography (ethyl acetate-hexane 1:1), product 2d (3.03g, 12.94mmol, 50% yield) was obtained as a colourless oil; (found (ESI): M++H, 235.10750. C12H15N2O3 requires M, 235.10772); numax 2966, 1716, 1666, 1607, 1572, 1491, 1171cm-1; deltaH (400MHz, CDCl3) 8.22 (1H, d, J 2.5, H3), 7.63 (1H, dd, J 8.5, 2.5, H2), 6.67 (1H, d, J 8.5, H1), 4.87 (2H, s, H4), 3.90 (3H, s, CH3), 2.65 (4H, t, J 6.7, H5), 1.92 (2H, quin, J 6.7, H6); deltaC (101MHz, DMSO) 172.7, 162.7, 146.2, 139.0, 126.2, 110.0, 53.00, 52.9, 32.0, 16.4; m/z (ESI) 234.97 (M++1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With pyridine; copper(II) acetate monohydrate; In N,N-dimethyl-formamide; at 90.0℃; for 8.0h; | Step a. A Reacti-Vial was charged with tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)isoindoline-2-carboxylate (Intermediate 2, 200 mg, 0.58 mmol), glutarimide (60 mg, 0.53 mmol), copper(II) acetate monohydrate (43 mg, 0.21 mmol), DMF (0.6 ml) and pyridine (0.18 ml, 2.16 mmol), and the resulting mixture was stirred at 90C for 8 h. The mixture was cooled to rt and partitioned between EtOAc (15 ml) and water (5 ml). The aqueous phase was extracted with EtOAc (10 ml) and the combined organic extracts were washed with brine (10 ml), dried over Na2S04, filtered and evaporated under vacuum. The residue was purified by flash column chromatography (0- 5% MeOH in DCM) to give an oily solid (150 mg), which was triturated in diethyl ether to give tert- butyl 4-(2,6-dioxopiperidin-l-yl)isoindoline-2-carboxylate as a solid (120 mg, 62%). LCMS (Method I): rt 2.57 min, m/z 275 (-tBu)/231(-Boc) [M+H]+; NMR (400 MHz, CDC13) δ ppm 7.36-7.28 (m, 1H), 7.15-7.09 (m, 1H), 7.01-6.94 (m, 1H), 4.71 (s, 2H), 4.46 (d, 2H), 2.89 (m, 4H), 1.51 (d, 11H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: piperidine-2,6-dione; benzophenone With titanium tetrachloride; zinc In tetrahydrofuran at 0℃; for 12h; Stage #2: With hydrogenchloride In tetrahydrofuran; water at 0 - 25℃; for 0.25h; Stage #3: With toluene-4-sulfonic acid In toluene for 2h; Dean-Stark; Reflux; | Reductive Coupling of 1a with 2a (Workup b). General procedure: To a solution of 1a (1 mmol), 2a (2 mmol), and zinc powder (4 mmol) in THF (10 mL) was added TiCl4 (2 mmol) dropwise at 0 °C and then the dark blue suspension was stirred for 12 h at this temperature. To the mixture was added 1 M HCl (20 mL) at 0 °C and the mixture was stirred for 15 min at 25 °C. The mixture was extracted with ethyl acetate three times. The organic layer was washed with aqueous NaCl and dried over MgSO4. After the solvent was removed, the residue was purified by column chromatography on silica gel to give 3a-6a. The reductive coupling and following workup with 1 M HCl was carried out as described above. The crude product mixture and p-TsOH (10 mg) were dissolved in benzene (10 mL). The solution was refluxed using Dean-Stark apparatus for 30 min. After the solvent was removed in vacuo, the residue was purified by column chromatography on silica gel (hexanes-EtOAc) to give 5a in 80% yield. |
78% | Stage #1: piperidine-2,6-dione; benzophenone With titanium tetrachloride; zinc In tetrahydrofuran at 0℃; for 12h; Stage #2: With hydrogenchloride In tetrahydrofuran; water at 25℃; for 0.25h; Stage #3: With toluene-4-sulfonic acid In toluene for 4h; Reflux; Dean-Stark; | 4.3. Typical procedure for the reductive coupling of 1a with 2a(Table 1, run 1) General procedure: To a solution of 1a (113 mg, 1 mmol), 2a (384 mg, 2 mmol), and zinc powder (0.26 g, 4 mmol) in THF (10 mL) was added TiCl4 (0.22 mL, 2 mmol) dropwise at 0 °C and then the dark blue suspension was stirred for 12 h at this temperature. To the mixture was added 1M HCl (20 mL) and the mixture was stirred for 15 min at 25 °C. The clear solution was extracted with ethyl acetate three times. The organic layer was washed with aqueous NaCl and dried over MgSO4. After the solvent was removed in vacuo, the residuewas dissolved in benzene (10 mL). The solution was refluxed in the presence of cat. p-TsOH for 30 min using Dean-Stark apparatus.After the solvent was removed in vacuo, the residue was purified by column chromatography on silica gel to give 3a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Stage #1: piperidine-2,6-dione; benzophenone With titanium tetrachloride; zinc In tetrahydrofuran at 30℃; for 12h; Stage #2: With hydrogenchloride In tetrahydrofuran; water at 25℃; for 0.25h; Stage #3: With toluene-4-sulfonic acid In toluene for 2h; Dean-Stark; Reflux; | Reductive Coupling of 1a with 2a (Workup b). General procedure: To a solution of 1a (1 mmol), 2a (2 mmol), and zinc powder (4 mmol) in THF (10 mL) was added TiCl4 (2 mmol) dropwise at 0 °C and then the dark blue suspension was stirred for 12 h at this temperature. To the mixture was added 1 M HCl (20 mL) at 0 °C and the mixture was stirred for 15 min at 25 °C. The mixture was extracted with ethyl acetate three times. The organic layer was washed with aqueous NaCl and dried over MgSO4. After the solvent was removed, the residue was purified by column chromatography on silica gel to give 3a-6a. The reductive coupling and following workup with 1 M HCl was carried out as described above. The crude product mixture and p-TsOH (10 mg) were dissolved in benzene (10 mL). The solution was refluxed using Dean-Stark apparatus for 30 min. After the solvent was removed in vacuo, the residue was purified by column chromatography on silica gel (hexanes-EtOAc) to give 5a in 80% yield. |
72% | Stage #1: piperidine-2,6-dione; benzophenone With titanium tetrachloride; zinc In tetrahydrofuran at 30℃; Stage #2: With hydrogenchloride In tetrahydrofuran; water at 25℃; for 0.25h; Stage #3: With toluene-4-sulfonic acid In toluene for 2h; Reflux; Dean-Stark; | 4.3. Typical procedure for the reductive coupling of 1a with 2a(Table 1, run 1) General procedure: To a solution of 1a (113 mg, 1 mmol), 2a (384 mg, 2 mmol), and zinc powder (0.26 g, 4 mmol) in THF (10 mL) was added TiCl4 (0.22 mL, 2 mmol) dropwise at 0 °C and then the dark blue suspension was stirred for 12 h at this temperature. To the mixture was added 1M HCl (20 mL) and the mixture was stirred for 15 min at 25 °C. The clear solution was extracted with ethyl acetate three times. The organic layer was washed with aqueous NaCl and dried over MgSO4. After the solvent was removed in vacuo, the residuewas dissolved in benzene (10 mL). The solution was refluxed in the presence of cat. p-TsOH for 30 min using Dean-Stark apparatus.After the solvent was removed in vacuo, the residue was purified by column chromatography on silica gel to give 3a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 54% 2: 30% | Stage #1: piperidine-2,6-dione; 4,4'-Difluorobenzophenone With titanium tetrachloride; zinc In tetrahydrofuran at 0℃; for 12h; Stage #2: With hydrogenchloride In tetrahydrofuran; water at 0 - 25℃; for 0.25h; | Reductive Coupling of 1a with 2a (Workup a). General procedure: To a solution of 1a (1 mmol), 2a (2 mmol), and zinc powder (4 mmol) in THF (10 mL) was added TiCl4 (2 mmol) dropwise at 0 °C and then the dark blue suspension was stirred for 12 h at this temperature. To the mixture was added 1 M HCl (20 mL) at 0 °C and the mixture was stirred for 15 min at 25 °C. The mixture was extracted with ethyl acetate three times. The organic layer was washed with aqueous NaCl and dried over MgSO4. After the solvent was removed, the residue was purified by column chromatography on silica gel to give 3a-6a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: piperidine-2,6-dione; 4,4'-Difluorobenzophenone With titanium tetrachloride; zinc In tetrahydrofuran at 0℃; for 12h; Stage #2: With hydrogenchloride In tetrahydrofuran; water at 0 - 25℃; for 0.25h; Stage #3: With toluene-4-sulfonic acid In toluene for 2h; Dean-Stark; Reflux; | Reductive Coupling of 1a with 2a (Workup b). General procedure: To a solution of 1a (1 mmol), 2a (2 mmol), and zinc powder (4 mmol) in THF (10 mL) was added TiCl4 (2 mmol) dropwise at 0 °C and then the dark blue suspension was stirred for 12 h at this temperature. To the mixture was added 1 M HCl (20 mL) at 0 °C and the mixture was stirred for 15 min at 25 °C. The mixture was extracted with ethyl acetate three times. The organic layer was washed with aqueous NaCl and dried over MgSO4. After the solvent was removed, the residue was purified by column chromatography on silica gel to give 3a-6a. The reductive coupling and following workup with 1 M HCl was carried out as described above. The crude product mixture and p-TsOH (10 mg) were dissolved in benzene (10 mL). The solution was refluxed using Dean-Stark apparatus for 30 min. After the solvent was removed in vacuo, the residue was purified by column chromatography on silica gel (hexanes-EtOAc) to give 5a in 80% yield. |
78% | Stage #1: piperidine-2,6-dione; 4,4'-Difluorobenzophenone With titanium tetrachloride; zinc In tetrahydrofuran at 0℃; for 12h; Stage #2: With hydrogenchloride In tetrahydrofuran; water at 25℃; for 0.25h; Stage #3: With toluene-4-sulfonic acid In toluene for 2h; Reflux; Dean-Stark; | 4.3. Typical procedure for the reductive coupling of 1a with 2a(Table 1, run 1) General procedure: To a solution of 1a (113 mg, 1 mmol), 2a (384 mg, 2 mmol), and zinc powder (0.26 g, 4 mmol) in THF (10 mL) was added TiCl4 (0.22 mL, 2 mmol) dropwise at 0 °C and then the dark blue suspension was stirred for 12 h at this temperature. To the mixture was added 1M HCl (20 mL) and the mixture was stirred for 15 min at 25 °C. The clear solution was extracted with ethyl acetate three times. The organic layer was washed with aqueous NaCl and dried over MgSO4. After the solvent was removed in vacuo, the residuewas dissolved in benzene (10 mL). The solution was refluxed in the presence of cat. p-TsOH for 30 min using Dean-Stark apparatus.After the solvent was removed in vacuo, the residue was purified by column chromatography on silica gel to give 3a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | Stage #1: piperidine-2,6-dione; 4,4'-Difluorobenzophenone With titanium tetrachloride; zinc In tetrahydrofuran at 30℃; for 12h; Stage #2: With hydrogenchloride In tetrahydrofuran; water at 25℃; for 0.25h; Stage #3: With toluene-4-sulfonic acid In toluene for 2h; Dean-Stark; Reflux; | Reductive Coupling of 1a with 2a (Workup b). General procedure: To a solution of 1a (1 mmol), 2a (2 mmol), and zinc powder (4 mmol) in THF (10 mL) was added TiCl4 (2 mmol) dropwise at 0 °C and then the dark blue suspension was stirred for 12 h at this temperature. To the mixture was added 1 M HCl (20 mL) at 0 °C and the mixture was stirred for 15 min at 25 °C. The mixture was extracted with ethyl acetate three times. The organic layer was washed with aqueous NaCl and dried over MgSO4. After the solvent was removed, the residue was purified by column chromatography on silica gel to give 3a-6a. The reductive coupling and following workup with 1 M HCl was carried out as described above. The crude product mixture and p-TsOH (10 mg) were dissolved in benzene (10 mL). The solution was refluxed using Dean-Stark apparatus for 30 min. After the solvent was removed in vacuo, the residue was purified by column chromatography on silica gel (hexanes-EtOAc) to give 5a in 80% yield. |
68% | Stage #1: piperidine-2,6-dione; 4,4'-Difluorobenzophenone With titanium tetrachloride; zinc In tetrahydrofuran at 30℃; Stage #2: With hydrogenchloride In tetrahydrofuran; water at 25℃; for 0.25h; Stage #3: With toluene-4-sulfonic acid In toluene for 2h; Reflux; Dean-Stark; | 4.3. Typical procedure for the reductive coupling of 1a with 2a(Table 1, run 1) General procedure: To a solution of 1a (113 mg, 1 mmol), 2a (384 mg, 2 mmol), and zinc powder (0.26 g, 4 mmol) in THF (10 mL) was added TiCl4 (0.22 mL, 2 mmol) dropwise at 0 °C and then the dark blue suspension was stirred for 12 h at this temperature. To the mixture was added 1M HCl (20 mL) and the mixture was stirred for 15 min at 25 °C. The clear solution was extracted with ethyl acetate three times. The organic layer was washed with aqueous NaCl and dried over MgSO4. After the solvent was removed in vacuo, the residuewas dissolved in benzene (10 mL). The solution was refluxed in the presence of cat. p-TsOH for 30 min using Dean-Stark apparatus.After the solvent was removed in vacuo, the residue was purified by column chromatography on silica gel to give 3a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 77% 2: 6% | Stage #1: piperidine-2,6-dione; bis(p-methoxyphenyl)methanone With titanium tetrachloride; zinc In tetrahydrofuran at 0℃; for 12h; Stage #2: With hydrogenchloride In tetrahydrofuran; water at 0 - 25℃; for 0.25h; | Reductive Coupling of 1a with 2a (Workup a). General procedure: To a solution of 1a (1 mmol), 2a (2 mmol), and zinc powder (4 mmol) in THF (10 mL) was added TiCl4 (2 mmol) dropwise at 0 °C and then the dark blue suspension was stirred for 12 h at this temperature. To the mixture was added 1 M HCl (20 mL) at 0 °C and the mixture was stirred for 15 min at 25 °C. The mixture was extracted with ethyl acetate three times. The organic layer was washed with aqueous NaCl and dried over MgSO4. After the solvent was removed, the residue was purified by column chromatography on silica gel to give 3a-6a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: piperidine-2,6-dione; bis(p-methoxyphenyl)methanone With titanium tetrachloride; zinc In tetrahydrofuran at 30℃; for 12h; Stage #2: With hydrogenchloride In tetrahydrofuran; water at 25℃; for 0.25h; Stage #3: With toluene-4-sulfonic acid In toluene for 2h; Dean-Stark; Reflux; | Reductive Coupling of 1a with 2a (Workup b). General procedure: To a solution of 1a (1 mmol), 2a (2 mmol), and zinc powder (4 mmol) in THF (10 mL) was added TiCl4 (2 mmol) dropwise at 0 °C and then the dark blue suspension was stirred for 12 h at this temperature. To the mixture was added 1 M HCl (20 mL) at 0 °C and the mixture was stirred for 15 min at 25 °C. The mixture was extracted with ethyl acetate three times. The organic layer was washed with aqueous NaCl and dried over MgSO4. After the solvent was removed, the residue was purified by column chromatography on silica gel to give 3a-6a. The reductive coupling and following workup with 1 M HCl was carried out as described above. The crude product mixture and p-TsOH (10 mg) were dissolved in benzene (10 mL). The solution was refluxed using Dean-Stark apparatus for 30 min. After the solvent was removed in vacuo, the residue was purified by column chromatography on silica gel (hexanes-EtOAc) to give 5a in 80% yield. |
70% | Stage #1: piperidine-2,6-dione; bis(p-methoxyphenyl)methanone With titanium tetrachloride; zinc In tetrahydrofuran at 30℃; Stage #2: With hydrogenchloride In tetrahydrofuran; water at 25℃; for 0.25h; Stage #3: With toluene-4-sulfonic acid In toluene for 2h; Reflux; Dean-Stark; | 4.3. Typical procedure for the reductive coupling of 1a with 2a(Table 1, run 1) General procedure: To a solution of 1a (113 mg, 1 mmol), 2a (384 mg, 2 mmol), and zinc powder (0.26 g, 4 mmol) in THF (10 mL) was added TiCl4 (0.22 mL, 2 mmol) dropwise at 0 °C and then the dark blue suspension was stirred for 12 h at this temperature. To the mixture was added 1M HCl (20 mL) and the mixture was stirred for 15 min at 25 °C. The clear solution was extracted with ethyl acetate three times. The organic layer was washed with aqueous NaCl and dried over MgSO4. After the solvent was removed in vacuo, the residuewas dissolved in benzene (10 mL). The solution was refluxed in the presence of cat. p-TsOH for 30 min using Dean-Stark apparatus.After the solvent was removed in vacuo, the residue was purified by column chromatography on silica gel to give 3a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 70% 2: 11% | Stage #1: piperidine-2,6-dione; 10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-one With titanium tetrachloride; zinc In tetrahydrofuran at 0℃; for 12h; Stage #2: With hydrogenchloride In tetrahydrofuran; water at 0 - 25℃; for 0.25h; | Reductive Coupling of 1a with 2a (Workup a). General procedure: To a solution of 1a (1 mmol), 2a (2 mmol), and zinc powder (4 mmol) in THF (10 mL) was added TiCl4 (2 mmol) dropwise at 0 °C and then the dark blue suspension was stirred for 12 h at this temperature. To the mixture was added 1 M HCl (20 mL) at 0 °C and the mixture was stirred for 15 min at 25 °C. The mixture was extracted with ethyl acetate three times. The organic layer was washed with aqueous NaCl and dried over MgSO4. After the solvent was removed, the residue was purified by column chromatography on silica gel to give 3a-6a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | General procedure: To a solution of 1a (1 mmol), 2a (2 mmol), and zinc powder (4 mmol) in THF (10 mL) was added TiCl4 (2 mmol) dropwise at 0 C and then the dark blue suspension was stirred for 12 h at this temperature. To the mixture was added 1 M HCl (20 mL) at 0 C and the mixture was stirred for 15 min at 25 C. The mixture was extracted with ethyl acetate three times. The organic layer was washed with aqueous NaCl and dried over MgSO4. After the solvent was removed, the residue was purified by column chromatography on silica gel to give 3a-6a. The reductive coupling and following workup with 1 M HCl was carried out as described above. The crude product mixture and p-TsOH (10 mg) were dissolved in benzene (10 mL). The solution was refluxed using Dean-Stark apparatus for 30 min. After the solvent was removed in vacuo, the residue was purified by column chromatography on silica gel (hexanes-EtOAc) to give 5a in 80% yield. | |
75% | General procedure: To a solution of 1a (113 mg, 1 mmol), 2a (384 mg, 2 mmol), and zinc powder (0.26 g, 4 mmol) in THF (10 mL) was added TiCl4 (0.22 mL, 2 mmol) dropwise at 0 C and then the dark blue suspension was stirred for 12 h at this temperature. To the mixture was added 1M HCl (20 mL) and the mixture was stirred for 15 min at 25 C. The clear solution was extracted with ethyl acetate three times. The organic layer was washed with aqueous NaCl and dried over MgSO4. After the solvent was removed in vacuo, the residuewas dissolved in benzene (10 mL). The solution was refluxed in the presence of cat. p-TsOH for 30 min using Dean-Stark apparatus.After the solvent was removed in vacuo, the residue was purified by column chromatography on silica gel to give 3a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With indium(III) chloride In N,N-dimethyl-formamide at 20℃; for 24h; | 5.5. General synthesis method of compounds 6a-6g and 7a-7g General procedure: To a solution of corresponding compound 3a (for compounds6a-6g) or 3b (for compounds 7a-7g) (10 mmol) in dimethylformamidecontaining indium (III) chloride (catalytic amount) and suitable secondaryamine (morpholine, thiomorpholine, phenylpiperazine, 1-(2-pyrimidyl)piperazine, indole, piperidine-2,6-dione and piperidine(10 mmol) was added and the mixture was stirred at room temperaturein the presence of formaldehyde (37%, 50 mmol) for 24 h. The solidprecipitated was collected by filtration and recrystallized fromDMF:H2O (1:3) to give the desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With indium(III) chloride In N,N-dimethyl-formamide at 20℃; for 24h; | 5.5. General synthesis method of compounds 6a-6g and 7a-7g General procedure: To a solution of corresponding compound 3a (for compounds6a-6g) or 3b (for compounds 7a-7g) (10 mmol) in dimethylformamidecontaining indium (III) chloride (catalytic amount) and suitable secondaryamine (morpholine, thiomorpholine, phenylpiperazine, 1-(2-pyrimidyl)piperazine, indole, piperidine-2,6-dione and piperidine(10 mmol) was added and the mixture was stirred at room temperaturein the presence of formaldehyde (37%, 50 mmol) for 24 h. The solidprecipitated was collected by filtration and recrystallized fromDMF:H2O (1:3) to give the desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 63% 2: 14% | Stage #1: piperidine-2,6-dione; bis(p-methoxyphenyl)methanone With titanium tetrachloride; zinc In tetrahydrofuran at 0℃; for 12h; Stage #2: With hydrogenchloride In tetrahydrofuran; water at 25℃; for 0.25h; Stage #3: With toluene-4-sulfonic acid In toluene for 2h; Reflux; Dean-Stark; | 4.3. Typical procedure for the reductive coupling of 1a with 2a(Table 1, run 1) General procedure: To a solution of 1a (113 mg, 1 mmol), 2a (384 mg, 2 mmol), and zinc powder (0.26 g, 4 mmol) in THF (10 mL) was added TiCl4 (0.22 mL, 2 mmol) dropwise at 0 °C and then the dark blue suspension was stirred for 12 h at this temperature. To the mixture was added 1M HCl (20 mL) and the mixture was stirred for 15 min at 25 °C. The clear solution was extracted with ethyl acetate three times. The organic layer was washed with aqueous NaCl and dried over MgSO4. After the solvent was removed in vacuo, the residuewas dissolved in benzene (10 mL). The solution was refluxed in the presence of cat. p-TsOH for 30 min using Dean-Stark apparatus.After the solvent was removed in vacuo, the residue was purified by column chromatography on silica gel to give 3a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | Stage #1: piperidine-2,6-dione; xanth-9-one With titanium tetrachloride; zinc In tetrahydrofuran at 0℃; for 12h; Stage #2: With hydrogenchloride In tetrahydrofuran; water at 25℃; for 0.25h; Stage #3: With toluene-4-sulfonic acid In toluene for 2h; Reflux; Dean-Stark; | 4.3. Typical procedure for the reductive coupling of 1a with 2a(Table 1, run 1) General procedure: To a solution of 1a (113 mg, 1 mmol), 2a (384 mg, 2 mmol), and zinc powder (0.26 g, 4 mmol) in THF (10 mL) was added TiCl4 (0.22 mL, 2 mmol) dropwise at 0 °C and then the dark blue suspension was stirred for 12 h at this temperature. To the mixture was added 1M HCl (20 mL) and the mixture was stirred for 15 min at 25 °C. The clear solution was extracted with ethyl acetate three times. The organic layer was washed with aqueous NaCl and dried over MgSO4. After the solvent was removed in vacuo, the residuewas dissolved in benzene (10 mL). The solution was refluxed in the presence of cat. p-TsOH for 30 min using Dean-Stark apparatus.After the solvent was removed in vacuo, the residue was purified by column chromatography on silica gel to give 3a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | Stage #1: piperidine-2,6-dione; xanth-9-one With titanium tetrachloride; zinc In tetrahydrofuran at 30℃; Stage #2: With hydrogenchloride In tetrahydrofuran; water at 25℃; for 0.25h; Stage #3: With toluene-4-sulfonic acid In toluene for 2h; Reflux; Dean-Stark; | 4.3. Typical procedure for the reductive coupling of 1a with 2a(Table 1, run 1) General procedure: To a solution of 1a (113 mg, 1 mmol), 2a (384 mg, 2 mmol), and zinc powder (0.26 g, 4 mmol) in THF (10 mL) was added TiCl4 (0.22 mL, 2 mmol) dropwise at 0 °C and then the dark blue suspension was stirred for 12 h at this temperature. To the mixture was added 1M HCl (20 mL) and the mixture was stirred for 15 min at 25 °C. The clear solution was extracted with ethyl acetate three times. The organic layer was washed with aqueous NaCl and dried over MgSO4. After the solvent was removed in vacuo, the residuewas dissolved in benzene (10 mL). The solution was refluxed in the presence of cat. p-TsOH for 30 min using Dean-Stark apparatus.After the solvent was removed in vacuo, the residue was purified by column chromatography on silica gel to give 3a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With sodium hydroxide In acetone at 20℃; for 12h; | |
62% | With sodium hydroxide In dichloromethane at 20℃; | Preparation of general formula (I-1-I-6) General procedure: In 50ml of dimethylformamide solvent, add 0.01mol of 3,4,5-trimethoxyaniline and 0.01mol of p-methoxybenzyl chloride,0.02 mol of triethylamine was stirred and reacted at room temperature for 2 hours to prepare compound 3.Take 0.01mol compound 3 and dissolve it in 10ml acetone,Add 0.02mol potassium carbonate and 0.02mol chloroacetyl chloride, stir at room temperature for 3 hours,After extraction and concentration, 2ml of ethanol was recrystallized to obtain compound 4.Dissolve 1mmol compound 4 in 10ml dichloromethane, add 1.2mmol piperidine or its derivatives,2mmol of sodium hydroxide, stirred at room temperature, and filtered with suction to obtain compounds I-1 to I-6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With triethylamine In 1,4-dioxane at 80℃; | 3.A General Procedure A: [0620] Compound 1 (1.1 mmol) and Glutarimide (1 mmol) were dissolved in dioxane (10 mL) and NEt3 (1.3 mmol) was added. The reaction mixture was heated at 80 oC with stirring at overnight, then diluted with water (150 mL). The precipitate was filtered, washed with water (3x25ml) and recrystallization from mixture iPrOH:Water (4:1). Yield: 90%. |
Tags: 1121-89-7 synthesis path| 1121-89-7 SDS| 1121-89-7 COA| 1121-89-7 purity| 1121-89-7 application| 1121-89-7 NMR| 1121-89-7 COA| 1121-89-7 structure
[ 1123-40-6 ]
4,4-Dimethylpiperidine-2,6-dione
Similarity: 0.90
[ 1123-40-6 ]
4,4-Dimethylpiperidine-2,6-dione
Similarity: 0.90
[ 1123-40-6 ]
4,4-Dimethylpiperidine-2,6-dione
Similarity: 0.90
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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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