Purity | Size | Price | VIP Price | USA Stock *0-1 Day | Global Stock *5-7 Days | Quantity | |||||
{[ item.p_purity ]} | {[ item.pr_size ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} | Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]} | {[ item.pr_usastock ]} | Inquiry - | {[ item.pr_chinastock ]} | Inquiry - |
* Storage: {[proInfo.prStorage]}
CAS No. : | 120-43-4 | MDL No. : | MFCD00005964 |
Formula : | C7H14N2O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | LNOQURRKNJKKBU-UHFFFAOYSA-N |
M.W : | 158.20 | Pubchem ID : | 8431 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.86 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 48.85 |
TPSA : | 41.57 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) : | -7.38 cm/s |
Log Po/w (iLOGP) : | 2.1 |
Log Po/w (XLOGP3) : | -0.16 |
Log Po/w (WLOGP) : | -0.71 |
Log Po/w (MLOGP) : | -0.09 |
Log Po/w (SILICOS-IT) : | 0.17 |
Consensus Log Po/w : | 0.26 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.52 |
Solubility : | 47.6 mg/ml ; 0.301 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.26 |
Solubility : | 87.3 mg/ml ; 0.552 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.85 |
Solubility : | 22.6 mg/ml ; 0.143 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.0 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33.7% | at 0 - 25℃; for 4 h; | The reaction flask was charged with piperazine (2 g, 23.2 mmol)And water (10 mL),25 ° C Stir and dissolve completely,Cooled to 0 ° C,A solution of ethyl chloroformate (1.26 g, 11.6 mmol) in methanol (20 mL) was slowly added dropwise.Drop finished,Stirring at 25 ° C for 4 h,Stop stirring.A saturated aqueous sodium chloride solution (30 mL) was added to the reaction solution,Dichloromethane (200 mL),Extraction stratification,The organic layer was dried over anhydrous sodium sulfate.The solvent was distilled off under reduced pressure,Purification by crude column chromatography (dichloromethane / methanol (V / V) = 40/1)A white solid (0.62 g, 33.7percent) |
33.7% | at 0 - 25℃; for 4 h; | piperazine (2g, 23.2 mmol) was added to the dry reaction flask in this order,Water (10mL), stirred at 25 °C to dissolve completely,After cooling to 0 °C, a solution of ethyl chloroformate (1.26 g, 11.6 mmol) in methanol (20 mL) was slowly added dropwise.Bi completed, stirring at 25°C 4h, stop stirring.To the reaction mixture, saturated aqueous sodium chloride solution (30 mL) and methylene chloride (200 mL) were sequentially added, and the layers were separated and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the crude product was purified by column chromatography (methylene chloride / methanol (V / V) = 40/1) to give a white solid (0.62 g, 33.7percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.5% | at 80℃; for 3 h; | In the case of a rectification unit, A thermometer and a stirrer were charged 177.2 g of diethyl carbonate and 129.2 g of anhydrous piperazine;Stirring evenly, gradually warming to 80°C , constant temperature reaction 3h,The temperature of the distillate is controlled at about 60~70°C ,After the basic non-distillate is separated,Heating to 90°C ~ 100°C vacuum distillation to remove low boiling point by-products and impurities,A clear colorless product was obtained 233.8 g (actual yield 98.5percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With triethylamine In diethyl ether | Example 6a 1-Ethoxycarbonyl 4-(3-nitrobenzyl)-piperazine (6a). To a solution of 3-nitrobenzylbromide (2.2 g; 10.0 mmol) in NMP (5 ml) was added ethyl piperazine-1-carboxylate dropwise with stirring. At the end of the addition the temperature had reached 35° C. Triethylamine (1.39 ml) was added causing the temperature to rise to 40° C. The mixture was stirred for additionally 30 min. prior to dilution with diethyl ether (25 ml). The mixture was filtered and the filtrate was washed with water, dried over magnesium sulphate and concentrated under reduced pressure. The concentrate was suspended in diethyl ether and filtered. The filtrate was diluted with ethyl acetate and extracted with diluted hydrochloric acid. The aqueous phase was rendered alkaline by addition of saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phase was dried over magnesium sulphate and evaporated to dryness to leave 6a (1.72 g; 59percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33.7% | In methanol; water; at 0 - 25℃; for 4h; | The reaction flask was charged with piperazine (2 g, 23.2 mmol)And water (10 mL),25 C Stir and dissolve completely,Cooled to 0 C,A solution of ethyl chloroformate (1.26 g, 11.6 mmol) in methanol (20 mL) was slowly added dropwise.Drop finished,Stirring at 25 C for 4 h,Stop stirring.A saturated aqueous sodium chloride solution (30 mL) was added to the reaction solution,Dichloromethane (200 mL),Extraction stratification,The organic layer was dried over anhydrous sodium sulfate.The solvent was distilled off under reduced pressure,Purification by crude column chromatography (dichloromethane / methanol (V / V) = 40/1)A white solid (0.62 g, 33.7%) |
33.7% | In methanol; water; at 0 - 25℃; for 4h; | piperazine (2g, 23.2 mmol) was added to the dry reaction flask in this order,Water (10mL), stirred at 25 C to dissolve completely,After cooling to 0 C, a solution of ethyl chloroformate (1.26 g, 11.6 mmol) in methanol (20 mL) was slowly added dropwise.Bi completed, stirring at 25C 4h, stop stirring.To the reaction mixture, saturated aqueous sodium chloride solution (30 mL) and methylene chloride (200 mL) were sequentially added, and the layers were separated and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the crude product was purified by column chromatography (methylene chloride / methanol (V / V) = 40/1) to give a white solid (0.62 g, 33.7%). |
In chloroform; at 1 - 20℃; for 3h; | According to scheme 1, step 1: Commercially available anhydrous piperazine (13.4 mmol) was dissolved in chloroform. To this solution, triethylamine (13.4 mmol) was added keeping the temperature 1 C and then ethyl chloromethanoate (6.7 mmol) dissolved inchloroform (10 mL) was added slowly within two hours with stirring at I C keeping the reaction condition dry. The reaction mixture was further stirred for one hour at room temperature. The reaction was over and solvent was evaporated under reduced pressure to get crude. The desired product 1-acetylpiperazine was obtained by column chromatography using chloroform-methanol as eluent. The compound 1-(ethoxycarbonyl)piperazine was obtained as colourless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With triethylamine; at 20℃; for 3h; | Compound VIII (160 g, 1.013 mol) was added to a three-necked flask, and then triethylamine (2.5 L) was added thereto, stirring was started, and ethylsulfonyl chloride (141.9, 1.1 mol) was added dropwise at room temperature, and the addition was continued, and stirring was continued at room temperature. After 3 hours, TLC dot plate (iodine color development) was used to monitor the disappearance of the spot of the raw material, and the mixture was diluted with hydrochloric acid and ethyl acetate, and the mixture was separated, and the organic layer was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.The white solid compound VII 227.85 g was obtained in a yield of 90% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With sodium carbonate; In water; acetonitrile; at 70℃; for 15h; | 1-(2-Chloroethyl)-4-methoxybenzene (14) (1.13mL, 7.5mmol) and ethyl piperazine-1-carboxylate (0.36mL, 2.5mmol) were added to a mixture of CH3CN-H2O (25mL:15mL). Then Na2CO3 (1.33g, 12.5mmol) was added and the resulting reaction mixture was refluxed at 70C for 15h. The solvents were removed under reduced pressure. An aqueous NaOH solution was added to adjust the pH to 14. The aqueous phase was extracted with CH2Cl2, and the combined organic phase was dried over Na2SO4, concentrated, and subjected for flash column chromatography to afford the product (15) (0.38g, 52%) as colorless oil. 1H NMR (300MHz, CDCl3) delta=7.16-7.06 (m, 2H), 6.90-6.77 (m, 2H), 4.14 (q, J=7.1Hz, 2H), 3.77 (s, 3H), 3.57-3.43 (m, 4H), 2.78-2.68 (m, 2H), 2.64-2.53 (m, 2H), 2.53-2.42 (m, 4H), 1.26 (t, J=7.1Hz, 3H)ppm. 13C NMR (75MHz, CDCl3) delta=158.05, 155.54, 132.14, 129.61, 113.90, 61.35, 60.72, 55.27, 52.95, 43.70, 32.62, 14.72ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium iodide; sodium carbonate; In ethyl acetate; isopropyl alcohol; toluene; | I.5.1.1. 164 g (1.04 mol) of ethyl piperazinecarboxylate, 156.9 g (1.14 mol) of (2-chloroethoxy)acetamide, 241.7 g (2.28 mol) of sodium carbonate, 1 g of potassium iodide and 200 ml of toluene are introduced into a 2 1 three-necked round-bottomed flask fitted with a water-cooled condenser and a mechanical stirrer. The mixture is brought at the reflux temperature for 3 hours 30. The mixture is allowed to cool to 50 C., and 200 ml of isopropanol are added. The reaction mixture is filtered and the filtration residue is washed with 150 ml of isopropanol. The filtrate is concentrated on a rotary evaporator under reduced pressure. 272.2 g of crude product are obtained, which product is recrystallized from 500 ml of ethyl acetate. 219.2 g (81.6%) of ethyl (2-carbamoylmethoxyethyl)piperazine-1-carboxylate are obtained in the form of a white solid. NMR: delta: 1.24 (3H, t, 7.05 Hz); 2.46 (4H, m); 2.57 (2H, t, 5.2 Hz); 3.44 (4H, m); 3.62 (2H, t, 5.2 Hz); 3.95 (2H, s); 4.1 (2H, 9, 7.1 Hz); 5.72 (1H, bs); 7.34 (1H, bs). Mass spectrum: 260 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃; for 24h;Nitrogen atmosphere; | 2,5-Dichlorobenzyl chloride (2.01 g) was added to a mixture of 1.94 g of 1-ethoxycarbonyl-piperazine and 3.45 g of anhydrous potassium carbonate in 20 ml of dimethylformamide stirred at room temperature under a nitrogen atmosphere. After 24 h of stirring at the same temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The organic phase, which was dried on anhydrous sodium sulphate, was evaporated to dryness under vacuum. The oily residue was purified via flash chromatography (petroleum ether : ethyl acetate 85:15) giving 2 g (63%) of 1-(2,5-dichlorobenzyl)-4-ethoxycarbonyl-piperazine.1H-NMR (CDCl3, delta): 7.50 (d, 1H, aromatic H6), 7.27 (d, 1H, aromatic H3), 7.15 (dd, 1H, aromatic H4), 4.13 (q, 2H, CH3CH2O), 3.58 (s, 2H, benzyl CH2), 3.55-3.45 (m, 4H, piperazine protons), 2.50-2.42 (m, 4H, piperazine protons), 1.26 (t, 3H, CH3CH2O). A solution containing 13 g of 1-(2,5-dichlorobenzyl)-4-ethoxycarbonyl-piperazine, prepared as above described, in 35 ml of 37% hydrochloric acid was stirred for 40 h at reflux. Subsequently, 30 ml of water and 30 ml of ethyl acetate were added at room temperature, adjusting the pH to 11 via addition of 35% sodium hydroxide. The organic phase was dried on anhydrous sodium sulphate and evaporated to dryness under vacuum. The crude was purified via flash chromatography (chloroform : methanol 7:3) giving 4.46 g (50%) of 1-(2,5-dichlorobenzyl)-piperazine.1H-NMR (CDCl3, delta): 7.50 (d, 1H, aromatic H6), 7.26 (d, 1H, aromatic H3), 7.14 (dd, 1H, aromatic H4), 3.55 (s, 2H, benzyl CH2), 3.00-2.85 (m, 4H, piperazine protons), 2.55-2.48 (m, 4H, piperazine protons), 1.76 (s, 1H, NH). 1-[N-(2-nitrophenyl)-2-aminoethyl)-4-(2,5-dichlorobenzyl)-piperazine was prepared and purified following the method described in Example 5, first step, but using 1-(2,5-dichlorobenzyl)-piperazine, prepared as above described, in place of 1-(4-indolyl)-piperazine and using 4-dimethylaminopyridine in place of triethylamine and carrying out the reaction at 120C for 8 h. Yield: 35%.1H-NMR (CDCl3, delta): 8.45 (bs, 1H, NH), 8.10 (d, 1H, aniline H3), 7.45 (d, 1H, dichlorophenyl ring H6), 7.38 (dd, 1H, aniline H5), 7.25 (d, 1H, dichlorophenyl ring H3), 7.10 (dd, 1H, dichlorophenyl ring H4), 6.77 (d, 1H, aniline H6), 6.55 (dd, 1H, aniline H4), 3.59 (s, 2H, benzyl CH2), 3.35 (dt, 2H, NHCH2CH2), 2.73 (t, 2H, NHCH2CH2), 2.70-2.38 (m, 8H, piperazine protons). The title compound was prepared following the procedure described in Example 1, second step, except that 1-[N-(2-nitrophenyl)-2-aminoethyl)-4-(2,5-dichlorobenzyl)-piperazine, prepared as described above, was used in place of 1-[N-(2-nitrophenyl)-2-aminoethyl]-4-(2-methoxyphenyl)-piperazine, and heating was 12 h at reflux. The crude was purified via flash chromatography (ethyl acetate : petroleum ether 4:6). Yield: 22%.1H-NMR (CDCl3, delta): 8.03 (dd, 1H, nitrophenyl ring H3), 7.75-7.40 (m, 4H, dichlorophenyl ring H6 and nitrophenyl ring H4,5,6), 7.25 (d, 1H, dichlorophenyl ring H3), 7.10 (dd, 1H, dichlorophenyl ring H4), 4.05-3.90 (m, 1H, C(O)NC(H)HCH2), 3.65-3.50 (m, 1H, C(O)NC(H)HCH2, 3.52 (s, 2H, benzyl CH2), 2.70-2.20 (m, 10H, C(O)NCH2CH2, piperazine protons), 2.00-0.70 (m, 11H, cyclohexyl protons). |
63% | With potassium carbonate; In water; N,N-dimethyl-formamide; | a) 1-(2,5-dichlorobenzyl)-<strong>[120-43-4]4-ethoxycarbonylpiperazine</strong> (Compound 14A) To a mixture comprising 1.94 g 1-ethoxycarbonylpiperazine and 3.45 g anhydrous potassium carbonate, in 20 mL of N,N-dimethylformamide, stirred at room temperature, under a nitrogen atmosphere, there was added 2.01 g of 2,5-dichlorobenzyl chloride. Then after 24 hr stirring at room temperature, this reaction mixture was poured into 200 mL of water, followed by extraction with ethyl acetate (3*100 mL). The obtained organic phase was dried over anhydrous sodium sulphate, followed by evaporation under vacuum. The obtained residue was then purified by flash chromatography (petroleum ether-ethyl acetate 85:15). The solvents were then evaporated off completely to give 2 g of Compound 14A (yield 63%). 1H-NMR 200 MHz (CDCl3, delta): 7.50 (d, 1H, H6); 7.27 (d, 1H, H3); 7.15 (dd, 1H, H4); 4.13 (q, 2H, CH3CH2O); 3.58 (s, 2H, benzyl CH2); 3.50 (m, 4H, piperazine protons 2.47 (m, 4H, piperazine protons); 1.26 (t, 3H, CH3CH2O). |
With potassium carbonate; In N,N-dimethyl-formamide; | Preparation of 1-(2,5-dichlorobenzyl)-<strong>[120-43-4]4-ethoxycarbonylpiperazine</strong> (Compound 14A) 2,5-Dichlorobenzyl chloride (2.01 g) was added to a mixture of 1.94 g of 1-ethoxycarbonylpiperazine and 3.45 g of anhydrous potassium carbonate in 20 ml of N,N-dimethylformamide stirred at room temperature in nitrogen atmosphere. After 24 h of stirring at the same temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The organic phase, which was dried on anhydrous Na2SO4, was evaporated to dryness under vacuum. The oily residue was purified via flash chromatography (petrolium ether-ethyl acetate 85:15) giving 2 g (63%) of the title compound. 1H-NMR(CDCl3, delta): 7.50 (d, 1H, aromatic H6), 7.27 (d, 1H, aromatic H3), 7.15 (dd, 1H, aromatic H4), 4.13 (q, 2H, CH3CH2O), 3.58 (s, 2H, benzyl CH2), 3.55-3.45 (m, 4H, piperazine protons), 2.50-2.42 (m, 4H, piperazine protons), 1.26 (t, 3H, CH3CH2O). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With triethylamine; In dichloromethane; at 20℃; | To a mixture of ethyl 1-piperazinecarboxylate (4.64 ML, 31.6 mmol) and triethylamine (3.8 ML, 27.2 mmol) in dichloromethane (80 ML) was added dropwise the title compound of Preparation 12 (6.26 g, 22.6 mmol) in dichloromethane (20 ML) and the resulting mixture was stirred at room temperature overnight.The reaction mixture was diluted with dichloromethane, washed with water, aqueous solution of sodium bicarbonate brine, dried (MgSO4) and evaporated under reduced pressure.The resulting crude residue was purified by flash column chromatography on silica-gel (hexane-ethyl acetate 1:1) to yield the title compound (7.60 g, 84%) as a white solid. delta(CDCl3): 1.12 (t, 3H), 1.20 (t, 3H), 1.92 (m, 2H), 2.63 (s, 3H), 2.95 (m, 4H), 3.56 (m, 4H), 4.12 (m, 4H), 7.08 (d, 1H), 7.82 (d, 1H), 8.10 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | titanium tetrachloride; In dichloromethane; at -10℃; for 24h;Heating / reflux; | To a stirred solution of TiCl4 (1 M solution in [CH2CI2,] 32 ml) and [7-METHOXY-BENZOFURAN-3-ONE] (5.0 g, 30.5 [MMOL)] in methylene chloride (200 ml) at - 10C, ethyl-1-piperazine carboxylate (18.96 g, 120 [MMOL)] was slowly added. After the addition, the reaction mixture was warmed to room temperature and slowly refluxed for 24 hrs. After cooling to room temperature, the reaction was quenched with 2 N aqueous HCI. The organic layer was separated and the aqueous layer was extracted with chloroform. The combined organic layers were washed well with water and dried over anhydrous [MGS04,] then filtered and concentrated. The brown residue was triturated with diethyl ether and the separated brown solid was filtered and air-dried. The product was pure enough and taken to next step without further purification. Yield : 8.3 g, (90%); Mp [121C] ; MS (ESI) [M/Z305 [M+H] + |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.1% | With potassium carbonate; In acetonitrile; at 20℃; | The title compound (45.6 mg, 99. [1%)] was obtained from [PIPERAZINE-1-CARBOXYLIC] acid ethyl ester (23.2 [PL,] 0.158 mmol), 3-chloromethyl-5- (2-fluoro-5-methyl-phenyl)- [1, 2,4] oxadiazole (30 mg, 0.132 mmol), and K2C03 (45.3 mg, 0.328 mmol) in acetonitrile (0.5 [ML)] at room temperature overnight. Purification was performed by SPE chromatography on silica gel with 20-40% ethyl acetate in [HEXANES. 1H-NMR (CDC13),] 8 (ppm): 7.95 (dd, 1H), 7.37 (m, 1H), 7.15 (t, 1H), 4.13 (q, 2H), 3.82 (s, 2H), 3.54 (t, 4H), 2.60 (t, 4H), 2.41 (s, 3H), 1.26 (t, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78.1% | With potassium carbonate; In acetonitrile; at 20℃; | The title compound (57.2 mg, 78.1%) was obtained from [PIPERAZINE-1-CARBOXYLIC] acid ethyl ester (33. 1 [L,] 0.226 [MMOL),] 3-chloromethyl-5- (2, 5-dichloro-phenyl) - [1, 2,4] oxadiazole (50 mg, 0.189 mmol), [AND K2C03] (65 mg, 0.47 mmol) in acetonitrile (0.75 mL) at room temperature overnight. Purification was performed by SPE chromatography on silica gel with 50% ethyl acetate in [HEXANES. LH-NMR (CDC13), 6] (ppm): 8.13 (m, 1H), 7.50 (m, 2H), 4.14 (m, 2H), 3.84 (s, 2H), 3.56 (t, 4H), 2.62 (t, 4H), 1.28 (q, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.1% | With potassium carbonate; In acetonitrile; at 20℃; | The title compound (61.2 mg, 86.1%) was obtained from [PIPERAZINE-1-CARBOXYLIC] acid ethyl ester (29.6 muL, 0.202 mmol), 5- (5-Bromo-2-fluoro-phenyl)-3-chloromethyl- [[1,] 2,4] oxadiazole (50 mg, 0.172 [MMOL),] and [K2CO3] (72.9 mg, 0.528 mmol) in acetonitrile (0.5 mL) at room temperature overnight. Purification was performed by SPE chromatography on silica gel with 20-30% ethyl acetate in [HEXANES. LH-NMR (CDC13), 6] (ppm): 8.32 (dd, 1H), 7.70 (m, 1H), 7.18 (q, 1H), 4.13 (m, [2H),] 3.82 (s, 2H), 3.54 (t, 4H), 2.60 (t, 4H), 1.26 (q, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.5% | With potassium carbonate; In acetonitrile; at 20℃; | [4- [5- (3-CHLORO-PHENYL)-OXAZOL-2-YLMETHYL]-PIPERAZINE-L-CARBOXYLIC] acid ethyl ester (24 mg, 68.5 %) as clear oil was obtained from [2-BROMOMETHYL-5- (3-CHLORO-PHENYL)-OXAZOLE] (27.3 mg, O. [1 M] mol) reacted with [PIPERAZINE-1-CARBOXYLIC] acid ethyl ester (47.4 mg, 0.3 mmol) and K2C03 (41.4 mg, 0.3 mmol) in acetonitrile (lmL) at room temperature [OVERNIGHT. 1H-NMR (CDC13) B] (ppm): 7.64 (s, [1H),] 7.51 (dd, [1H),] 7.29 (m, 3H), 4.13 (q, 2H), 3.79 (s, 2H), 3.54 (m, 4H), 2.58 (m, 4H) and 1.26 (t, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With potassium carbonate; In acetonitrile; at 50℃; | 4- {1-[5-(3-Chloro-phenyl)-[1, 2,4] [OXADIAZOL-3-YL]-ETHYL}-PIPERAZINE-L-CARBOXYLIC] acid ethyl ester (113.9 mg, 60%, colorless oil) was obtained from methanesulfonic acid 1- [5- (3- [CHLORO-PHENYL)- [1,] 2,4] oxadiazol-3-yl] -ethyl ester (158 mg, 0.52 mmol), potassium carbonate (289 mg, 2. 1 mmol), and [PIPERAZINE-1-CARBOXYLIC] acid ethyl ester (0. 229 mL, [1.] 6 mmol) in acetonitrile (4 mL) at [50C.] Purification was performed by SPE (flash) chromatography first using 10 % ethyl acetate in hexanes and the [RE-PURIFIED] using 5-30% ethyl acetate in [DICHLOROMETHANE. 1H NMR (CDC13) 8] (ppm): 8.17 (s, [1H),] 8.05 (d, [1H),] 7.59 (m, [1H),] 7.50 (m, [1H),] 4.08 (m, 3H), 3.52 (t, 4H), 2.60 (t, 4H), 1.57 (d, 3H), 1.26 (t, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | gold(III) bromide; In water; at 100℃; | Example 37: 4- [3- (3-Chloro-phenyl)-1- (2-methoxy-phenyl)-prop-2-ynyl]- piperazine-l-carboxylic acid ethyl ester; 3-chloro-1-ethynyl-benzene (0.136 mL, 1.10 mmol), ethyl-1-piperizinecarboxylate (0.119 mL, 0.81 mmol), gold (III) bromide (3.2 mg, 0.0074 mmol), 2-methoxy- benzaldehyde (0.090 mL, 0.74 mmol) and deoxygenated water (0. 8 mL) were added to a vial, sealed, and stirred at 100 C overnight. The reaction mixture was cooled and then extracted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated onto silica gel. Purification chromatography (SPE) using 4-10% ethyl acetate in hexanes afforded the titled compound (232.2 mg, 76%, yellow oil). 1H NMR (CDC13) 8 (ppm): 7.60 (m, 1H), 7.46 (m, 1H), 7.31 (m, 4H), 6.98 (m, 2H), 5.26 (s, 1H), 4.14 (q, 2H), 3. 89 (s, 3H), 3.51 (m, 4H), 2.63 (m, 4H), 1.26 (t, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | gold(III) bromide; In water; at 100℃; for 16h; | Example 18: 4- [3- (3-Chloro-phenyl)-l-cyclopropyl-prop-2-ynyl]-piperazine-1- carboxylic acid ethyl ester; Water (1 mL) was deoxygenated with argon for 1 minute in a vial. 3-chloro-1- ethynyl-benzene (0.166g, 1.2 mmol), Ethyl-1-piperizinecarboxylate (0.226 g, 1.4 mmol), gold (III) bromide (30 mg, 0.17 mmol) and cyclpropanecarboxaldehyde (0.100 mL, 1.4 mmol) were added, and the reaction heated to 100 C, sealed and stirred for 16 h. Reaction mixture was extracted with EtOAc (40 mL) and washed with brine (10 mL), then dried (Na2S04), filtered and concentrated onto silica gel. Chromatography (SPE) eluting with 10 % EtOAc/hexanes afforded 0.344 g (83 %) of the title compound as a brown oil. 1H-NMR (CDC13), 5 (ppm): 7.40 (dd, 1 H), 7.27 (m, 3 H), 4.15 (q, 2H), 3.62 (d, 1H), 3.54 (m, 4H), 3.99 (m, 2H), 2.80 (m, 2H), 2.56 (m, 2H), 1.28 (d, 3H), 1.11 (m, 1H), 0.57 (m, 3H), 0.42 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate; In acetonitrile; at 0℃; for 1.5h; | Example 1: 4-Prop-2-ynyl-piperazine-1-carboxylic acid ethyl ester; To a stirred suspension of K2CO3 (11.6 g, 84.0 mmol) in acetonitrile cooled to 0C was added piperazine-1-carboxylic acid ethyl ester (31. 0 ml, 210 mmol), followed by propargyl bromide (3.75 mL, 34 mmol). The reaction was allowed to stir for 1.5 hours. Reaction mixture was diluted with CH2C12, washed with water, then brine followed by drying over sodium sulphate (anhydrous). The crude organic product was concentrated in vacuo and purified by flash chromatography afforded quantitative yield of the product as a yellow oil. 1H NMR (CDC13) 8 (ppm): 4.14 (q, 2H), 3. 51 (t, 4H), 3.33 (d, 2H), 2.53 (t, 4H), 2.28 (t, 1H) 1.27 (t, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); at 20℃; | Example 55; 4- (3-Phenyl-propynoyl)-piperazine-l-carboxylic acid ethyl ester; Phenyl-propynoic acid (50 mg, 0.342 mmol), EDCI (65.58 mg, 0.342 mmol), dimethylaminopyridine (2.78 mg, 0.023 mmol) and piperazine-1-carboxylic acid ethyl ester (36.73 pL, 0.251 mmol) were combined in a screw cap vial and dissolved in dimethylformamide (2 mL). The reaction was stirred overnight at room temperature. The solution was then diluted with dichloromethane and washed with water. The organic phase was dried (Na2S04), filtered and concentrated in vacuo. Chromatography in 0-50% ethyl acetate in hexanes yielded the product (67.6 mg, 94%). lH NMR (300 MHz, CDC13) 8 =1.29 (t, J = 7.1 Hz, 3H); 3.51 (m, 2H); 3.58 (m, 2H); 3.69 (m, 2H); 3.83 (m, 2H); 4.17 (q, J = 7.1 Hz, 2H) ; 7.41 (m, 3H); 7.55 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With potassium carbonate; In acetone; at 0 - 20℃; for 0.48h; | General procedure: To a stirred solution of piperazine (10 mmol) in acetone (20 ml) and 20 mmol K2CO3, 1-bromo-3-chloropropane (20 mmol) was added slowly at 0C. After the addition was completed the reaction mixture was stirred at room temperature for about 48 h.The solvent was removed under reduced pressure and water was added to the residue. The resulting mixture was then extracted with CH2Cl2(3*10 ml), dried by magnesium sulfate and evaporated to yield the desired product, which was used without further purification. |
70% | With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃; | Intermediate 15: 4-(3-Chloro-propyl)-piperazine-1-carboxylic acid ethyl ester; [] Piperazine-1-carboxylic acid ethyl ester (3.0g, 18.9mmol), K2CO3 (2.8g, 1.1eq.), DMF (30ml, 10vol) and 1-bromo-3-chloropropane (1.8ml, 18.9mmol, 1eq.) were reacted together at room temperature overnight. The reaction was quenched with water (100ml) and extracted with DCM (3 x 50ml). The combined DCM extracts were dried over MgSO4, filtered washed with DCM and concentrated in vacuo to give the title compound (3.1 g, 70%th) as a pale yellow oil.1H NMR (400MHz, CDCl3) delta4.06 (q, 2H), 3.53 (t, 2H), 3.40 (t, 4H), 2.42 (t, 2H), 2.32 (t, 4H), 1.87 (p, 2H), 1.18 (t, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tris(acetoxy)borohydride; sodium carbonate; In tetrahydrofuran; methanol; acetic acid; | a N-(1-Benzyl-3-pyrrolidinyl)-N-ethoxycarbonyl-piperazine hydrochloride 14.5 g of sodium triacetoxyborohydride are added in portions to a solution of 9.4 g of 1-benzyl-3-pyrrolidinone, 8.8 g of ethyl piperazine-N-carboxylate and 3.0 ml of glacial acetic acid in 100 ml of tetrahydrofuran. The suspension is stirred at room temperature for 16 hours. Sodium carbonate solution is added and the aqueous phase is extracted with ethyl acetate. The organic phase is dried over sodium sulphate. After addition of a little methanol, a pH of 3 is established with ethereal hydrochloric acid and the solvent is evaporated off under reduced pressure. The residue is triturated with acetone and filtered off with suction. Yield: 15.4 g (87% of theory), Rf value: 0.56 (silica gel; methylene chloride/methanol/concentrated ammonia=9:1:0.1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With potassium iodide; sodium carbonate; In isopropyl alcohol; toluene; | I.5.1.2. 15.13 g of (2-chloroethoxy)acetamide (0.11 mol), 14.6 ml of ethyl piperazine carboxylate (0.1 mol), 23.3 g of sodium carbonate (0.22 mol) and 1.0 g of potassium iodide in 25 ml of toluene are introduced into a round-bottomed flask fitted with a water-cooled condenser and a mechanical stirrer. The mixture is heated at the reflux temperature for 4 hours and is allowed to cool to room temperature. The reaction is continued, still with stirring, for a further 16 hours. 100 ml of isopropanol are added and the solid materials formed are filtered off. The solvent is evaporated from the filtrate under reduced pressure to dryness. The product obtained after evaporation of the solvents is recrystallized from toluene. 21.35 g of ethyl 4-(2-carbamoylmethoxyethyl)piperazine-1-carboxylate are obtained. Yield: 82%. Mass spectrum: 260 (MH+), 214 (M+ -OEt). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | In neat (no solvent); at 125℃; for 1h; | General procedure: A mixture of 2-chlorobenzazoles 4a-c (1 equivalent) and ethoxycarbonylpiperazine 5 (3 equivalents) was heated at 120C under stirring and the reaction followed by TLC (CH2Cl2/EA 7:3). After completion the reaction mixture was allowed to cool to room temperature and the mixture dissolved in 200 ml CH2Cl2. The organic phase was extracted with saturated NaHCO3 solution (3 x 100 ml), then with dist. H2O (2 x 50 ml), sat. NaCl solution (100 ml) and dried over anhy. Na2SO4. After filtration, the organic phase was evaporated to dryness. The precipitate formed after treatment of the residue with DIPE and stirring in the cold (ice/water mixture) was filtered and dried. |
81% | at 120℃; for 3h; | General procedure: A mixture of 2-chlorobenzazoles 1a, 1b,or 1d (1 equivalent) and ethoxycarbonylpiperazine 2 (3 equivalents) was heated at 120Cunder stirring and the reaction followed by TLC (CH2Cl2/EA 7:3). After completion the reactionmixture was allowed to cool to room temperature and the mixture dissolved in 200 mLCH2Cl2. The organic phase was extracted with saturated NaHCO3 solution (3 x 100 mL), thenwith dist. H2O (2 x 50 mL), sat. NaCl solution (100 mL) and dried over anhy. Na2SO4. After filtration,the organic phase was evaporated to dryness. The precipitate formed after treatment ofthe residue with DIPE and stirring in the cold (ice/water mixture) was filtered and dried. |
With sodium hydroxide; | EXAMPLE 2 Preparation of 1-methyl-2-[(4-ethoxycarbonyl)-1-piperazinyl]-1H-benzimidazole A mixture of 3.3 g (20 mmol) of <strong>[1849-02-1]2-chloro-1-methyl-1H-benzimidazole</strong> and 3.2 g (20 mmol) of 1-ethoxycarbonylpiperazine was heated for 25 minutes at 120 C. The reagent mixture was provided with a 10% NaOH aqueous solution and extracted with dichloromethane (3*20 ml). The organic extracts were gathered, dried with anhydrous sodium sulphate and the solvent was eliminated at diminished pressure. 4.8 g (84% yield) of the product was obtained as a white solid that was purified by column chromatography, using dichloromethane/methanol (95/5) as eluent. MP: 122-4 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 16 8-chloro-10,11-dihydro-10-[(4-propyl-1-piperazinyl)carbonyl]dibenz[b,f][1,4]oxazepine STR23 By the methods of Example 14, ethyl 1-piperazinecarboxylate was reacted with the methanesulfonate of n-propanol and the product, ethyl 4-propyl-1-piperazinecarboxylate, was converted to 1-propylpiperazine. | ||
Example 16 8-chloro-10,11-dihydro-10-[(4-propyl-1-piperazinyl)carbonyl]dibenz[b,f][1,4]oxazepine STR23 By the methods of Example 14, ethyl 1-piperazinecarboxylate was reacted with the methanesulfonate of n-propanol and the product, ethyl 4-propyl-1-piperazinecarboxylate, was converted to 1-propylpiperazine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13 parts (44%) | In methanol; N,N-dimethyl acetamide; water; | (a) A mixture of 32 parts of ethyl 1-piperazinecarboxylate, 17 parts of <strong>[7716-66-7]3-chloro-1,2-benzisothiazole</strong> and 45 parts of N,N-dimethylacetamide was stirred for 0.5 hours at 150° C. After cooling to 50° C., the reaction mixture was poured into ice water. The aqueous layer was decanted and the oily layer was stirred in water. The product from the oil layer was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 13 parts (44percent) of ethyl 4-(1,2-benzisothiazol-3-yl)-1-piperazinecarboxylate as a residue (int. 3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | (a) By the reaction of 1-ethoxycarbonylpiperazine with 4-(2-bromoethyl)-acetophenone analogously to Example 22, there is obtained a yield of 69% of theory of 4-[2-(1-ethoxycarbonylpiperazin-4-yl)-ethyl]-acetophenone hydrochloride; m.p. 182-185 C. (recrystallized from ethanol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium iodide; sodium hydrogencarbonate; In hydrogenchloride; ethanol; water; acetone; | EXAMPLE 3 2-(1-Piperazinylmethyl)quinoline, trihydrochloride A mixture of 21.4 g. of quinolylmethyl chloride hydrochloride, 18 g. of ethyl 1-piperazinecarboxylate, 20 g. of sodium bicarbonate and one gram of potassium iodide in 500 ml. of ethanol was stirred at reflux for 18 hours, cooled and then filtered. The filtrate was evaporated in vacuo to an oil. The oil was dissolved in 250 ml. of acetone, treated with charcoal, filtered and 55 ml. of 3.85 N hydrochloric acid in ethanol were added. A 250 ml. of portion of acetone was added, the solid was collected, washed with 100 ml. of acetone and 200 ml. of ether and dried giving 32 g. of 4-(2-quinolylmethyl)-1-piperazinecarboxylic acid, ethyl ester, hydrochloride. A 27 g. portion of this ester was dissolved in 250 ml. of concentrated hydrochloric acid and refluxed overnight. A 200 ml. portion of methyl cellosolve was added and the solution was evaporated to turbidity, then filtered. The filtrate was evaporated to dryness in vacuo and the residue was taken up in 300 ml. of boiling ethanol and 35 ml. of water. This solution was filtered while hot, cooled to -10 C. and 200 ml. of acetone were added. The solid was collected, washed with 200 ml. of acetone and dried, giving 18 g. of 2-(1-piperazinylmethyl)quinoline, trihydrochloride. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide; In ethanol; water; toluene; | The starting material can be manufactured, for example, as follows: 50 ml of ethanol, 50 g of potassium hydroxide and 8.8 ml of water are added to 39.8 g of 1-ethoxycarbonyl-4-[2-(3-chlorophenyl)-ethyl]-piperazine, obtainable by reacting 17.7 g of 1-ethoxycarbonylpiperazine and 24.6 g of 2-(3-chlorophenyl)-ethyl bromide while heating at 120-125 under nitrogen, and the whole is heated under reflux for 3 hours. The whole is then allowed to cool, is diluted with 300 ml of water and 300 ml of toluene and shaken thoroughly, and then the organic phase is separated off, washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated to dryness by evaporation under reduced pressure. 1-[2-(3-chlorophenyl)-ethyl]piperazine is obtained and can be purified via the hydrochloride (m.p. 260) from which it can then be freed again by treatment with sodium hydroxide solution, separation with diethyl ether and evaporation of the latter. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1,4-dioxane; water; | EXAMPLE A 2-(N'-carbethoxy-piperazino)-4-chloro-6-amino-pyrimidine 29.0 gm of 2,4 -dichloro-6-aminopyrimidine [H. Bretschneider et al, Monatsh. f. Chemie 92, 132 (1961)]were suspended in 150 ml of dioxane, the suspension was heated to 80C, and 60.2 gm of N-carbethoxy-piperazine were added. After standing for 40 minutes at this temperature, the mixture was poured into 500 ml of water, and the aqueous solution was on an ice bath while stirring. The initially oily precipitating product crystallized after about 15 minutes. The crystals were suction-filtered off and recrystallized from 300 ml of methanol. Yield: 28.8 gm (57.3% of theory); m.p. 163-166C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; mercury; In hydrogen bromide; | EXAMPLE 1 1-(5-Amino-4H-1,2,4-triazol-3-yl)-4-(4-pyridylmethyl)-piperazine A mixture of 37.2 g of 4-picolyl chloride hydrochloride, 39.6 g of ethyl-1-piperazine carboxylate, 400 ml of 2-propanol and 55.0 ml of 10N sodium hydroxide was refluxed for 18 hours. The reaction mixture was evaporated in vacuo to give a dark red syrup. The syrup was distilled collecting 26.0 g of 4-(4-pyridylmethyl)-1-piperazinecarboxylic acid, ethyl ester as a colorless syrup, bp 157-160 C./0.02 mm of mercury. A 25.0 g portion of the preceding product was refluxed for 16 hours in 100 ml of 47-49% hydrobromic acid. The solution was evaporated near dryness with crystal formation. The mixture was cooled and filtered and the collected solid was washed with ethanol and gave 27.0 g of 1-(4-pyridylmethyl)piperazine trihydrobromide, mp 268-269 C. (dec.). A 26.0 g portion of the preceding material in water was adjusted to pH 7.0 with 10N sodium hydroxide, and extracted with two 50 ml portions of chloroform. The combined chloroform extract was dried over magnesium sulfate, evaporated in vacuo and gave 11.3 g of a colorless syrup. The syrup was distilled, and the fraction, bp 166-168 C./15 mm, was collected and gave 9.4 g of 1-(4-pyridylmethyl)piperazine as a colorless liquid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13 parts (44%) | In methanol; water; | a) A mixture of 32 parts of ethyl 1-piperazinecarboxylate, 17 parts of <strong>[7716-66-7]3-chloro-1,2-benzisothiazole</strong> and 45 parts of N , N -dimethylacetamide was stirred for 0.5 hour at 150°C. After cooling to 50°C, the reaction mixture was poured into ice water. The aqueous layer was decanted and the oily layer was stirred again in water. The product from the oily layer was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 13 parts (44percent) of ethyl 4-(1,2-benzisothiazol-3-yl)-1-piperazinecarboxylate as a residue (interm. 12). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With 1-ethyl-3-(3-aminopropyl)carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; | General Procedure: Ethyl-3-aminopropyl carbodiimide hydrochloride (EDCI) Couplings of piperazines with cinnamic acids Cinnamic acid (1.3 mmol), EDCI (1.3 mmol), dimethylaminopyridine (0.1 mmol) and substituted piperazine (1 mmol) were combined in a screw cap vial and dissolved in dimethylformamide (6 mL). The reaction was stirred overnight at room temperature. The solution was then diluted with dichloromethane and washed with water. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo, then chromatographed in 0?50% ethyl acetate in hexanes to yield the desired product.; The following compounds were made in this manner: Example Structure Name Yield 11.1 ethyl 4-[(2E)-3-(4-chloro- phenyl prop-2-enoyl]piperazine-1-carboxylate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With lithium perchlorate; In acetonitrile; for 4h; | From <strong>[75390-09-9]1-benzyl-3,4-epoxypyrroline</strong> (122 mg, 0.69 mmol), ethyl-1-piperazinecarboxilate (133 mg, 0.83 mmol), LiClO4 (151 mg, 1.39 mmol) and acetonitrile (5 ml). Reaction time: 4 hours. Purification: silica gel, gradient dichloromethane to dichlorometane:methanol 8%, afforded the product (90 mg, 39%) as brown oil. 1H NMR (400 MHz, CDCl3): delta (ppm) 7.30 (m, 5H), 4.14 (m, 1 H), 4.12 (q, J=7Hz, 2H), 3.56 (AB system, 2H), 3.46 (m, 4H), 3.00 (t, J=8Hz, 1H), 2.75 (m, 1H), 2.67 (td, J1=3Hz, J2=8Hz, 1H), 2.62 (m, 1H), 2.52 (m, 2H), 2.36 (m, 2H), 2.18 (t, J=8Hz, 1H), 1.24 (t, J=7Hz, 3H). 13C NMR (75 MHz, CDCl3):delta (ppm) 137.99, 128.90, 128.41, 127.28, 74.59, 74.55, 62.35, 61.42, 60.20, 57.35, 51.41, 43.45, 14.65. MS (EI+) m/z: 334.2 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In acetonitrile; at 20℃; for 48h; | Intermediates; a) 4-[2-(4-Ethoxycarbonyl-piperazine-1-carbonyl)-1-isopropyl-1H-indole-5-carbonyl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester To a mixture of 5-(4-tert-butoxycarbonyl-[1,4]diazepane-1-carbonyl)-1-isopropyl-1H-indole-2-carboxylic acid (144 mg) and 4-ethoxy carbonyl piperazine (1 eq., 53 mg) in acetonitrile (5 ml) was added N-hydroxybenzotriazole (0.2 eq., 9 mg). The mixture was stirred 5 min before the addition of N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride (1.1 eq., 77 mg). The mixture was stirred two days at room temperature. The mixture was evaporated under reduced pressure and the residue purified by column chromatography on silica gel (19:1 EtOAc/MeOH) to afford the product as an off-white powder (195 mg, 89%). MS (m/z): 570.3 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.1. 4-((S)-2-benzyloxycarbonylamino-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid ethyl ester; Z-(L)Glu(OtBu)-OH (5 g), HOBT hydrate (2.5 g) and EDCI hydrochloride (3.1 g) were dissolved in DCM/THF (1/1, 42 ml). After 15 min stirring, 1-ethoxycarbonylpiperazine (2.6 g) was added and the stirring was continued overnight at RT. 150 ml of EA and 60 ml of a NaHCO3 solution were added to the mixture and the phases were separated. The org. phase was washed with 60 ml of a 1M NaHSO4 solution and 60 ml of a NaCl solution, was dried (Na2SO4) and evaporated off. After HV drying, 7 g of the desired compound were obtained.LC-MS (A): tR=1.12 min; [M+H]+: 478.12. | ||
To a solution of Z-(L)GIu(OtBu)-OH (5 g) in DCM/THF (1 :1, 42 ml) were added at RT HOBT (2.5 g) and EDCI (3.1 g). After 15 min stirring at RT, 1-ethoxycarbonylpiperazine (2.6 g) was added and the stirring was continued at RT overnight. 150 ml of EA and 60 ml of a NaHCO3 solution were added to the reaction mixture and the phases were separated. The org. <n="80"/>phase was washed with an aq. NaHSO4 (IM) solution and with brine, dried over Na2SO4 and evaporated off. After HV drying, 7 g of the desired compound were obtained. LC-MS (A): tR = 1.12 min; [M+H]+: 478.12. | ||
With N-ethylmorpholine;; O-((cyano(etoxycarbonyl)methylene)amino)-1,1,3,3-tetramethyluronium tetrafluoroborate; In N,N-dimethyl-formamide; at 20℃; for 16h; | Example 1 : 4-((S)-4-Carboxy-2-[5-(1-ethoxycarbonyl-cyclobutoxy)-1-phenyl-1 H-pyrazole- 3-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester; (i) 4-((S)-2-Benzyloxycarbonylamino-4-tert-butoxycarbonyl-butyryl)-piperazine-1- carboxylic acid ethyl ester; To a solution of 15 g of (S)-2-Benzyloxycarbonylamino-pentanedioic acid 5-tert-butyl ester, 20.4 g of NEM and 14.5 g of TOTU in 75 ml of DMF, 7.4 g of Piperazine-1-carboxylic acid ethyl ester was added at RT and stirred for 16 h. The reaction mixture was then diluted with saturated aqueous sodium hydrogen carbonate solution and then extracted with 300 ml of ethyl acetate. The organic phase was washed with diluted saturated aqueous sodium hydrogen carbonate solution and dried over MgSO4. The solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with n-heptane/ethyl acetate (1/1). The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 20.6 g. |
With N-ethylmorpholine;; O-<[cyano(ethoxycarbonyl)methylene]amino>-1,1,3,3-tetramethyluronium tetrafluoroborate; In N,N-dimethyl-formamide; for 12h; | Example 1 : 4-[(S)-4-Carboxy-2-({5-[2-((S)-2-cyclopropylcarbamoyl-pyrrolidin-1-yl)-2-oxo- ethoxy]-1 -phenyl-1 H-pyrazole-3-carbonyl}-amino)-butyryl]-piperazine-1 -carboxylic acid ethyl ester; (i) 4-((S)-2-Benzyloxycaronylamino-4-tert-butoxycarbonyl-butyryl)-piperazine-1- carboxylic acid ethyl ester; To a solution of 15.0 g (S)-2-Benzyloxycarbonylamino-pentanedioic acid 5-tert-butyl ester in 75 ml DMF were added 6.9 ml 1-ethoxycarbonylpiperazine, 22.6 ml N-ethylmorpholine and 14.6 g TOTU. After stirring for 12 h the solution was diluted with ethyl acetate and subsequently washed with aqueous LiCI (4 %) and saturated aqueous NaHCO3. The crude product obtained after evaporation of the solvent was used without further purification. Yield: 20.9 g. | |
1.1. 4-((S)-2-benzyloxycarbonylamino-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid ethyl ester Z-(L)Glu(OtBu)-OH (5 g), HOBT hydrate (2.5 g) and EDCI hydrochloride (3.1 g) were dissolved in DCM/THF (1/1, 42 ml). After 15 min stirring, 1-ethoxycarbonylpiperazine (2.6 g) was added and the stirring continued overnight at RT. 150 ml of EA and 60 ml of a NaHCO3 solution were added to the mixture and the phases were separated. The org. phase was washed with 60 ml of a 1M NaHSO4 solution and 60 ml of a NaCl solution, dried (Na2SO4) and evaporated off. After HV drying, 7 g of the desired compound were obtained. LC-MS: tR=0.97 min; [M+H]+: 478.28. | ||
Example 1: 4-[(S)-4-carboxy-2-({6-[2-(2-methox-ethoxy)-ethoxy]-2-phenyl-pyrimidine-4-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid ethyl ester; 1.1. 4-((S)-2-benzyloxycarbonylamino-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboaylic acid ethyl ester; Z-(L)Glu(OtBu)-OH (5 g), HOBT hydrate (2.5 g) and EDCI hydrochloride (3.1 g) were dissolved in DCM/THF (1/1, 42 ml). After 15 min stirring, 1-ethoxycarbonylpiperazine (2.6 g) was added and the stirring continued overnight at RT. 150 ml of EA and 60 ml of a NaHCO3 solution were added to the mixture and the phases were separated. The org. phase was washed with 60 ml of a 1M NaHSO4 solution and 60 ml of a NaCl solution, dried (Na2SO4) and evaporated off. After HV drying, 7 g of the desired compound were obtained. LC-MS: tR = 0.97 min; [M+H]+: 478.28. | ||
With N-ethylmorpholine;; O-<[cyano(ethoxycarbonyl)methylene]amino>-1,1,3,3-tetramethyluronium tetrafluoroborate; In N,N-dimethyl-formamide; at 20℃; for 16h; | (in) 4-((S)-2-Benzyloxycarbonylamiotano-4-tert-butoxycarbonyl-butyryl)-piotaperaziotane-1- carboxyhc acid ethyl ester; To a solution of 15 g of (S)-2-Benzyloxycarbonylamiotano-pentanediotaoiotac acid 5-tert-butyl ester, 20 4 g of NEM and 14 5 g of TOTU in 75 ml of DMF, 7 4 g of Piotaperaziotane-1-carboxyliotac acid ethyl ester was added at RT and stirred for 16 h The reaction mixture was then diluted with saturated aqueous sodium hydrogen carbonate solution and then extracted with 300 ml of ethyl acetate The organic phase was washed with diluted saturated aqueous sodium hydrogen carbonate solution and dried over MgSO4 The solvents were removed under reduced pressure The crude product was purified by chromatography on silica gel eluting with n-heptane/ethyl acetate (1/1) The fractions containing the product were combined and the solvent evaporated under reduced pressure Yield 20 6 g |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With polymer-bound trimethyl ammonium cyanoborohydride; acetic acid; In 1,2-dichloro-ethane; at 20℃; for 24 - 36h;Combinatorial reaction / High throughput screening (HTS); | All sixty diamines were separated in four groups based on their steric and electronic characteristics, Figures 1-4. Each diamine was measured in the amount of 0.05 g (approximately 0.3 mmol) and pooled together with the others in the group. Obtained diamine mixtures were dissolved in 5 ml of 1,2-dichloroethane and used for the syntheses. Each well of the 96-well filterplates was loaded with 0.2 ml of 1: 10 mixture of acetic acid: DCE, 0.03 ml of the diamine mixture in DCE (group 1, group 2, group 3, or group 4) to assure 0.04 mmol of the diamines per well, and shaken for 5 min at room temperature. Appropriate carbonyl compounds from the master plate (0.1 ml of 1.2 M solution) were added into corresponding wells of the reaction plates followed by the addition of (polystyrylmethyl) trimethylammonium cyanoborohydride, (0.020 g, 0.08 mmol per well). The reaction plates were sealed and placed on a shaker. The reaction was allowed to proceed 24-36 hours at room temperature. At the end, the reaction mixtures were filtered using a filtration manifold, and products were collected into four (one per group) collection plates. Solvents were evaporated in SpeedVac and formed residues were analyzed by mass spectrometry prior to biological screening. Mono and double alkylated products were observed in 1: 0.5 to 1: 2 ratios by mass spectral analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.1% | 1, 1, 1-trifluoro-3-nitro-propan-2-ol (2.46 g, 15.5 mmol) was mixed with acetyl chloride (1. [36] g, 17.3 mmol) at [30-35 C] for 3 days. The reaction mixture was quenched with ethanol (20 mL), followed by the addition [OF PIPERAZINE-1-CARBOXYLIC] acid ethyl ester (2.45 g, 15.5 mmol) and stirred at room temperature for an hour. Dichlormethane was added to the reaction mixture and washed with water and brine. The organic layer was dried with [MGS04] and concentrated. The residue was triturated with hexanes to give 3.3 g [(71. 1%)] of 4- (2, 2, [2-TRIFLUORO-1-NITROMETHYL-ETHYL)-PIPERAZINE-1-CARBOXYLIC] acid ethyl [ESTER. LH-] NMR [(CDC13)] [S] (ppm): 4.67 (dd, 1H), 4.57 (dd, 1H), 4.13 (m, 3H), 3.43 (m, 4H), 2.95 (m, 2H), 2.68 (m, 2H) and 1.27 (t, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With triethylamine; In tert-butyl methyl ether; at 0 - 20℃; for 2h; | Piperazine-1-carboxylic acid ethyl ester (18 g) was dissolved in TBME (50 ml) and triethylamine (15.9 ml) added. The stirred TBME solution was cooled to 0 0C prior to dropwise addition of n-propylsulfonyl chloride (12.8 ml). The stirred reaction mixture was allowed to warm to RT over 2h before being partitioned between IM HCl and DCM. The DCM was dried and the solvent was removed under vacuum to give the expected product as a solid (22.73 g, 76%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 16h; | Example 133: 4-((S)-2-[5-(3,3-Dimethyl-2-oxo-butoxy)-1 -phenyl-1 H-pyrazole-3-carbonyl]- aminoJ-S-methoxycarbonylamino-propionyO-piperazine-i-carboxylic acid ethyl ester; (i) 4-((S)-2-Benzyloxycarbonylamino-3-tert-butoxycarbonylamino-propionyl)- piperazine-1-carboxylic acid ethyl ester; To a solution of 5 g of (S)-2-Benzyloxycarbonylamino-3-tert-butoxycarbonylamino- propionic acid, 3 g of triethylamine, 2.2 g of HOBT and 2.8 g of EDC in 50 ml of DCM, 2.3 g of Piperazine-1-carboxylic acid ethyl ester was added at RT and stirred for 16 h. The reaction mixture was then diluted with water and then extracted with 300 ml of DCM. The organic phase was washed with diluted saturated aqueous sodium hydrogen carbonate solution and dried over MgSO4. The solvents were removed under reduced pressure. The crude product was subjected to the next reaction step without further purification. Yield: 10.7 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethylmorpholine;; O-((cyano(etoxycarbonyl)methylene)amino)-1,1,3,3-tetramethyluronium tetrafluoroborate; In N,N-dimethyl-formamide; at 20℃; for 16h; | Example 163: 4-((S)-3-Carboxy-2-[5-(3,3-dimethyl-2-oxo-butoxy)-1-phenyl-1 H-pyrazole-3- carbonyl]-amino}-propionyl)-piperazine-1 -carboxylic acid ethyl ester; (i) 4-((S)-2-Benzyloxycarbonylamino-3-tert-butoxycarbonyl-propionyl)-piperazine-1- carboxylic acid ethyl ester; To a solution of 15.4 g (S)-2-Benzyloxycarbonylamino-succinic acid 4-tert-butyl ester, 24.4 ml NEM and 15.6 g TOTU in 80 ml DMF 7.5 g Piperazine-1 -carboxylic acid ethyl ester were added at RT and stirred for 16 h. The reaction mixture was then diluted with ethyl acetate and washed with aqueous LiCI (4 % w/w) and saturated aqueous sodium hydrogen carbonate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was used in the subsequent reaction. Yield: 23.0 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethylmorpholine;; O-<[cyano(ethoxycarbonyl)methylene]amino>-1,1,3,3-tetramethyluronium tetrafluoroborate; In N,N-dimethyl-formamide; for 12h; | Example 115: 4-[(S)-2-({5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1- phenyl-1 H-pyrazole-3-carbonyl}-amino)-4-hydroxy-butyryl]-piperazine-1 -carboxylic acid ethyl ester; i) 4-((S)-4-Benzyloxy-2-tert-butoxycarbonylamino-butyryl)-piperazine-1 -carboxylic acid ethyl ester; To a solution of 900 mg (S)-4-benzyloxy-2-tert-butoxycarbonylamino-butyric acid in 10 ml DMF were added 1.5 ml N-ethylmorpholine, 0.43 ml 1-ethoxycarbonylpiperazine and 955 mg TOTU. The solution was stirred for 12 h before being diluted with ethyl acetate and extracted subsequently with aqueous LiCI (4 %), 0.1 M HCI and saturated NaHCO3. The crude product obtained after evaporation of the solvent was used without further purification. Yield: 1.23 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethylmorpholine;; O-<[cyano(ethoxycarbonyl)methylene]amino>-1,1,3,3-tetramethyluronium tetrafluoroborate; In N,N-dimethyl-formamide; at 0℃; for 1h; | Example 92: 4-[(S)-4-Acetylamino-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1- yl)-2-oxo-ethoxy]-1 -phenyl-1 H-pyrazole-3-carbonyl}-amino)-butyryl]-piperazine-1 - carboxylic acid ethyl ester; i) 4-[(S)-4-tert-Butoxycarbonylamino-2-(9H-fluoren-9-ylmethoxycarbonylamino)- butyryl]-piperazine-1 -carboxylic acid ethyl ester; To a solution of 1.33 ml 1-ethoxycarbonylpiperazine, 1.27 ml N-ethylmorpholine and 4.0 g N-alpha-Fmoc-N-beta-Boc-L-diaminobutyric acid in 40 ml DMF were added 2.98 g TOTU at 0 0C. After 1 h the reaction mixture was diluted with 100 ml ethyl acetate and subsequently extracted with aqueous LiCI (4 percent), half-saturated aqueous NaHCO3 and water. The crude <n="118"/>product obtained after evaporation of the solvent was used in the subsequent reaction. Yield: 4.96 g colorless foam. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethylmorpholine;; O-<[cyano(ethoxycarbonyl)methylene]amino>-1,1,3,3-tetramethyluronium tetrafluoroborate; In N,N-dimethyl-formamide; at 0℃; for 1h; | Example 87: 4-[(S)-3-Acetylamino-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1 - yl)-2-oxo-ethoxy]-1 -phenyl-1 H-pyrazole-3-carbonyl}-amino)-propionyl]-piperazine-1 - carboxylic acid ethyl ester; i) 4-[(S)-3-tert-Butoxycarbonylamino-2-(9H-fluoren-9-ylmethoxycarbonylamino)- propionyl]-piperazine-1 -carboxylic acid ethyl ester; To a solution of 0.86 ml 1-ethoxycarbonylpiperazine, 0.83 ml N-ethylmorpholine and 2.50 g N-alpha-Fmoc-N-beta-Boc-L-diaminopropionic acid in 50 ml DMF were added 1.92 g TOTU at 0 °C. After 1 h the reaction mixture was diluted with 100 ml ethyl acetate and subsequently extracted with aqueous LiCI (4 percent), half-saturated aqueous NaHCO3 and water. The crude product obtained after evaporation of the solvent was used in the subsequent reaction. Yield: 3.3 g colorless foam. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In benzene; at 45℃; for 6h;Reflux; | A mixture of ethylpiperazine-1-carboxylate (3 mL, 20 mmol) and phenylisothiocyanate (2.4 mL, 20 mmol) was refluxed in benzene (20 mL) at 45 C for 6 h. A white precipitate was obtained upon cooling the reaction mixture in ice, which was filtered off, washed with methanol and ether and recrystallized from MeOH:CHCl3 mixture (50:50 v/v). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With potassium carbonate; In acetone; at 20℃; for 20h; | General procedure: Anhydrous K2CO3 (1 equiv.) was added to the solution of relevant amine (1 equiv.) in 20 mL of solvent (acetonitrile, DCM or Me2CO) and the mixture was stirred at room temperature for 0.5 h. Then a solution of 3-bromodihydrofuran-2(3H)-one (1 equiv.) in 5 mL of appropriate solvent was added dropwise and stirring was continued for 3-20 h. In the synthesis of compounds 11 and 12 tetrabutylammonium bromide (TBAB) (0.1 equiv.) was added. After the reaction was completed, the precipitate was filtered off and the filtrate was concentrated under vacuum. Obtained crude products were recrystallized from suitable solvent (solid) or purified by column chromatography (oil). Lactone 11 was isolated as a hydrochloride salt and recrystallized from DCM. Synthesis of compound 13 was described elsewhere [24] B. Malawska and S. Gobaille, Pharmazie 50 (1995), pp. 390-393. View Record in Scopus | Cited By in Scopus (10)[24]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 18h; | General procedure: To a solution of compound 7 (0.16 g, 0.37 mmol) and isonipecotic acid ethyl ester (0.086 ml, 0.56 mmol) in CH2Cl2 was added WSCI·HCl (0.11 g) and HOBt (0.085 g), and then the mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with water and the organics were extracted with CH2Cl2. The extract was washed with brine, dried over Na2SO4, then concentrated in vacuo, and then the residue was purified with silica gel column chromatography (0-5% MeOH-CH2Cl2 as eluent) to give compound 8 (0.16 g, 0.28 mmol, 76%) as a colorless powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 140℃; | EXAMPLE 64-(l - {2-Methoxy-6-[2-(4-trifluoromethoxy-phenyl)-ethylamino]-pyrimidin-4-yl} - piperazine- 1-carboxylic acid ethyl esterA mixture of ethyl piperazine carboxylate (1.06 g, 6.51 mmol), (6-chloro-2-methoxy- pyrimidin-4-yl)-[2-(4-trifluoromethoxy-phenyl)-ethyl] -amine (1.01 g, 2.91 mmol) and potassium carbonate (1.26 g, 9.09 mmol) in l-methyl-2-pyrrolidone (70 mL) was heated at 140C overnight. The mixture was cooled to rt, partitioned between H20 and EtOAc. The two layers were separated and the organic layer was washed with brine, dried over MgS04, filtered, and concentrated in vacuo. The crude material was purified on silica gel with heptane/EtOAc (40/60) as eluent to yield a light orange solid (1.30 g, 95%). 1H NMR (300 MHz, CDCls) delta 7.25-7.22 (m, 2H), 7.16-7.14 (m, 2H), 5.11 (s, 1H), 4.75 (br s, 2H), 4.17 (q, 2H), 3.86 (s, 3H), 3.54 (br s, 6H), 2.91 (t, 2H), 2.07-2.04 (m, 3H), 1.28 (t, 3H). 19F NMR (282 MHz, CDCI3) delta -58.4 (s, 3F). MS m/z: [M+H]+= 470hPRP IC50 = 609 nM |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Preparation 6: Synthesis of 4-[(S)-5-({Amino-[(E)-2,2,4,6,7-pentamethyl-2,3-dihydro-benzofuran-5-sulfonylimino]-methyl}-amino)-2-tert-butoxycarbonylamino-pentanoyl]-piperazine-1-carboxylic acid ethyl ester (F); To a solution of <strong>[200124-22-7]Boc-Arg(Pbf)-OH</strong> (13.3 g, 25.3 mmol) in DMF (10 mL) was added DIEA (22.0 mL, 126.5 mmol) at room temperature and stirred for 15 min. The reaction mixture was then cooled to 5 C. and HATU (11.5 g, 30.3 mmol) was added in portions and stirred for 30 min, followed by the dropwise addition of ethyl-1-piperazine carboxylate (4.0 g, 25.3 mmol) in DMF (30 mL). After 40 min, the reaction mixture was diluted with EtOAc (400 mL) and poured in to H2O (1 L). Extracted with EtOAc (2×400 mL) and washed with H2O (800 mL), 2% H2SO4 (500 mL), H2O (2×800 mL) and brine (800 mL). Organic layer was separated, dried over MgSO4 and solvent removed in vacuo. The resultant oily residue was dried in vacuo to afford compound F (16.4 g, 24.5 mmol) as foamy solid. LC-MS [M+H] 667.2 (C31H50N6O8S+H, calc: 667.8). Compound F was used without further purification. | ||
16.4 g | To a solution of <strong>[200124-22-7]Boc-Arg(Pbf)-OH</strong> (13.3 g, 25.3 mmol) in DMF (10 mL) was added DIEA (22.0 mL, 126.5 mmol) at room temperature and stirred for 15 min. The reaction mixture was then cooled to ~5 C and HATU (11.5 g, 30.3 mmol) was added in portions and stirred for 30 min, followed by the dropwise addition of ethyl-1-piperazine carboxylate (4.0 g, 25.3 mmol) in DMF (30 mL). After 40 min, the reaction mixture was diluted with EtOAc (400 mL) and poured into H2O (1 L). Extracted with EtOAc (2 x 400 mL) and washed with H2O (800 mL), 2% H2SO4 (500 mL), H2O (2 x 800 mL) and brine (800 mL). Organic layer was separated, dried over MgSO4 and solvent was removed in vacuo. The resultant oily residue was dried in vacuo to afford compound F (16.4 g, 24.5 mmol) as foamy solid. LC-MS [M+H] 667.2 (C31H50N6O8S+H, calc: 667.8). Compound F was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | General procedure: An appropriate N1-substituted piperazine (7.5 mmol), K2CO3 (3 g), TEBA (0.2 g) were suspended in acetone (15-20 ml) and stirred under reflux for 30 min. N-1-bromoalkyl- 5,5-diphenylhydantoin derivatives 36-40 (7.5-8.5 mmol) dissolved in acetone (20-23 ml) were added. The mixture was stirred under reflux for 3.5-8.5 h and stirring was continued at room temperature overnight. The inorganic precipitate was separated by filtration and washed with acetone (3 × 10 ml). Combined filtrates were evaporated. Pure compounds (16, 18-20, 41) in basic form were obtained from the residue using one of the following methods: (A)- crystallization with methanol; (B)- the residue was dissolved in methylene chloride (10-15 ml), washed with 1% solution of HCl (2 × 10-15 ml) and water (2 × 10 ml), dried with Na2SO4 anhydrous, evaporated to give a new residue that was crystallized with methanol; (C)- purification using chromatography column with solvent system (IV). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | General procedure: An appropriate N1-substituted piperazine (7.5 mmol), K2CO3 (3 g), TEBA (0.2 g) were suspended in acetone (15-20 ml) and stirred under reflux for 30 min. N-1-bromoalkyl- 5,5-diphenylhydantoin derivatives 36-40 (7.5-8.5 mmol) dissolved in acetone (20-23 ml) were added. The mixture was stirred under reflux for 3.5-8.5 h and stirring was continued at room temperature overnight. The inorganic precipitate was separated by filtration and washed with acetone (3 × 10 ml). Combined filtrates were evaporated. Pure compounds (16, 18-20, 41) in basic form were obtained from the residue using one of the following methods: (A)- crystallization with methanol; (B)- the residue was dissolved in methylene chloride (10-15 ml), washed with 1% solution of HCl (2 × 10-15 ml) and water (2 × 10 ml), dried with Na2SO4 anhydrous, evaporated to give a new residue that was crystallized with methanol; (C)- purification using chromatography column with solvent system (IV). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | In dichloromethane; at 20℃; for 2h; | To a solution of ethyl piperazine-1-carboxylate (1.0 g, 6.32 mmol) in dichloromethane (30 ml) was added m-tolylisocyanate (0.90 mg, 6.95 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with dichloromethane and washed with water, brine and dried over Na2SO4. After removing the solvents, the residue was purified by chromatography on silica gel (CH2Cl2/MeOH 50:1) to yield the title compound as a white solid (1.6 g, 87%).1H NMR (300 MHz, CDCl3, 25 C.): delta=7.18 (s, 1H, PhH), 7.10-7.15 (m, 2H, PhH), 6.83 (d, J=6.4 Hz, 1H, PhH), 4.14 (q, J=7.1 Hz, 2H, OCH2CH3), 3.42 (br s, 8H, N(CH2)2), 2.27 (s, 3H, CH3), 1.26 (t, J=7.1 Hz, 3H, OCH2CH3) ppm.MS 289.7 [M-H] |
87% | In dichloromethane; at 20℃; for 2h; | Example 59 Synthesis of ethyl 4-(m-tolylcarbamoyl)piperazine-1-carboxylate To a solution of ethyl piperazine-1-carboxylate (1.0 g, 6.32 mmol) in dichloromethane (30 ml) was added m-tolylisocyanate (0.90 mg, 6.95 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with dichloromethane and washed with water, brine and dried over Na2SO4. After removing the solvents, the residue was purified by chromatography on silica gel (CH2Cl2/MeOH 50:1) to yield the title compound as a white solid (1.6 g, 87%). 1H NMR (300 MHz, CDCl3, 25 C.): delta=7.18 (s, 1H, PhH), 7.10-7.15 (m, 2H, PhH), 6.83 (d, J=6.4 Hz, 1H, PhH), 4.14 (q, J=7.1 Hz, 2H, OCH2CH3), 3.42 (br s, 8H, N(CH2)2), 2.27 (s, 3H, CH3), 1.26 (t, J=7.1 Hz, 3H, OCH2CH3) ppm. MS 289.7 [M-H] |
87% | In dichloromethane; at 20℃; for 2h; | Example 59 Synthesis of ethyl 4-(m-tolylcarbamoyl)piperazine-1-carboxylate To a solution of ethyl piperazine-1-carboxylate (1.0 g, 6.32 mmol) in dichloromethane (30 ml) was added m-tolylisocyanate (0.90 mg, 6.95 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with dichloromethane and washed with water, brine and dried over Na2SO4. After removing the solvents, the residue was purified by chromatography on silica gel (CH2Cl2/MeOH 50:1) to yield the title compound as a white solid (1.6 g, 87%). 1H NMR (300 MHz, CDCl3, 25 C.): delta=7.18 (s, 1H, PhH), 7.10-7.15 (m, 2H, PhH), 6.83 (d, J=6.4 Hz, 1H, PhH), 4.14 (q, J=7.1 Hz, 2H, OCH2CH3), 3.42 (br s, 8H, N(CH2)2), 2.27 (s, 3H, CH3), 1.26 (t, J=7.1 Hz, 3H, OCH2CH3) ppm. MS 289.7 [M-H] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With triethylamine; In dichloromethane; at 20℃; for 2h; | Ethyl piperazine-1 -carboxylate (800 mg, 5.06 mmol) was treated with 4-chlorobutanoyl chloride (856 mg, 6.07 mmol) in anhydrous CH2CI2 (25 mL) containing Et3N (1 .54 kg, 15.17 mmol) at 20 C for 2 h, and then washed with 1 M HCI(aq). The organic phase was dried over MgS04, and concentrated under reduced pressure to give ethyl 4-(4-chlorobutanoyl)piperazine-1 -carboxylate (1 .315 kg, 99% yield). C11 H19CIN2O3; pale yellow oil; 1 H NMR (400 MHz, CDCI3) delta 4.13 (2 H, q, J = 7.2 Hz), 3.62 (2 H, t, J = 5.6 Hz), 3.58 (2 H, m), 3.46 (6 H, m) 2.49 (2 H, t, J = 6.8 Hz), 2.1 1 (2 H, m), 1 .25 (3 H, t, J = 7.2 Hz); 13C NMR (100 MHz, CDCI3) delta 170.1 , 155.1 , 61 .7, 45.2, 44.8, 43.7 (2 x), 41 .4, 29.8, 27.8, 14.7; ESI-HRMS calcd for C11 H20CIN2O3: 263.1 162, found: m/z 263.1 175 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 27℃; for 4h; | Piperazine-1 -carboxylic acid ethyl ester (200 mg, 1 .26 mmol) was treated with chloroacetyl chloride (186 mg, 1 .65 mmol) in anhydrous CH2CI2 (10 ml_) containing DIEA (490 mg, 3.80 mmol) at 0 C. The mixture was stirred and warmed to 27 C for 4 h. The mixture was washed with 1 M HCI(aq). The organic phase was dried over MgS04, and concentrated under reduced pressure to give ethyl 4-(2-chloroacetyl)piperazine-1 -carboxylate (275 mg, 93% yield). C9Hi5CIN203; transparent oil; 1 H NMR (400 MHz, CDCI3) delta 4.15 (2 H, q, J = 7.2 Hz) 4.06 (2 H, s), 3.60 (2 H, m), 3.54 (2 H, m), 3.49 (4 H, m), 1 .27 (3 H, t, J = 7.2 Hz); 13C NMR (100 MHz, CDCI3) delta 164.3, 154.3, 61 .4, 45.8, 43.5, 43.1 , 41 .8, 40.8, 14.7; ESI-HRMS calcd for C9Hi6CIN203: 235.0849, found: m/z 235.0852 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.1% | With triethylamine; In ethanol; at 0 - 20℃; | General procedure: To a cold suspension (-10-0 C) of 1.80 mmol of 4 in 20.0 mL of ethanol was added, with stirring, a solution of appropriate secondary amine (2.0 mmol) and triethylamine (3 mL) in 5 mL of ethanol. Stirring was continued at 0-5 C for 2-4 h, and then at ambient temperature for additional 2 h then the solution poured onto water (100 mL), the resulting crude solid product was collected by suction filtration, washed with water, dried and purified on preparative silica gel TLC plates. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With trichlorophosphate; In acetonitrile; at 0℃; for 48h; | To a solution of phosphoryl chloride (10 mmol, 1.54 g) in dry acetonitrile, N-4-ethoxy carbonylpiperazine (60 mmol, 3.11 g) was added dropwise at 0 C and the mixture stirred for 48 h. Then the precipitate (by-product) was filtered and the solution was evaporated. The resulting yellow solid was washed with CCl4 and diethyl ether. Yield: 62%; Anal. Calc. For C21H39N6O7P: C, 48.64; H, 7.58; N, 16.21%. Found: C, 48.62; H, 7.57; N, 16.20%. 31P{1H} NMR (CDCl3): delta = 18.27 (s). 1H NMR (CDCl3): delta = 1.18 (t, 3J(H,H)= 7.0 Hz, CH3), 3.00 (m, 4H, CH2-ring), 3.36 (m, 4H, CH2-ring), 4.06 (q, 3J(H,H)= 7.0 Hz, OCH2). 13C NMR (CDCl3): delta = 14.49 (s, CH3), 44.28 (s, CH2-ring), 48.26 (s, CH2-ring), 61.48 (s, OCH2), 150.15 (s, CO). IR (KBr, cm-1): 2982 (nuCH), 2906 (nuCH), 2849 (nuCH), 1687 (nuCO), 1426, 1241 (nuPO), 1130, 986 (nuPN), 961, 766, 724. MS (70 eV, EI): m/z (%): 518 [M]+ (2), 344 [P(O)(N(CH2)2N(CH2)2C(O)(OC2H5))(N(CH2)2N(CH2)2C(O)(OCH2))]+ (9), 287 [P(O)(N(CH2)2N(CH2)2C(O)(OC2H5))(N(CH2)2N(CH2)2)]+ (8), 274 [P(O)(N(CH2)2N(CH2)2C(O)(OC2H5)) (N(CH2)2NCH2)]+ (55), 246 [P(O)(N(CH2)2N(CH2)2C(O)(OC2H5))(N(CH2)2)]+ (71), 174 [P(N(CH2)2N(CH2)2C(O)(OCH3))]+ (22), 158 [N(CH2)2N(CH2)2C(O)(OC2H5)]+ (30), 101 [NCH2C(O)(OC2H5)]+ (24), 85 [N(CH2)2N(CH2)2]+ (16), 72 [OC(O)NCH2]+ (17), 56 [CH3CH2C]+ (88), 44 [OC(O)]+ (100). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | A solution of l-ethoxycarbonylpiperazine (5.42 g, 34.0 mmol) in 60 mL of anhydrous ether and methanol (1:1) was placed in a Parr bottle. The solution was treated with sodium methoxide (NaOMe) (2.03 g, 37.0 mmol) and the Parr apparatus was clamped. The apparatus was purged and evacuated with nitrogen (3x) followed by charging with 5 atm. nitric oxide (NO) at 25 C for 48 h. The excess NO was then vented by purging with nitrogen followed by addition of anhydrous ether. The white precipitate was collected by filtration and washed with cold methanol as well as with copious amounts of anhydrous ether. The product was dried under vacuum to afford the title compound as a white solid (3.90 g, 47%). M.p. 184 C (dec), lit. m.p. 184-185 C; 1H NMR (300 MHz, 0.1 M NaOD in D2O) delta 1.69 (t, J = 7.1 Hz, 3H, CHs), 3.02 (m, 4H, 2 CH2), 3.59 (m, 4H, 2 CH2), 4.05 (q, J= 7.1 Hz, 2H, OCH2); 13C NMR (75.6 MHz, 0.1M NaOD in D2O) delta 13.7 (CHs), 42.5 (CH2), 44.1 (CH2), 51.2 (CH2), 62.7 (CH2), 156.8 (C=0). | |
With nitrogen(II) oxide; sodium methylate; In methanol; under 4137.29 Torr; for 24h;Inert atmosphere; Autoclave; | General procedure: Diazeniumdiolates were synthesized according to previously reportedprocedures [34]. In brief, the piperazine starting material (1a-c,1 equiv.) was stirred to dissolve in anhydrous methanol (2.1 M) in ahigh pressure reaction vessel. Sodium methoxide (30% in methanol, 1equiv.) was added. The reaction vessel was attached to a high-pressurestainless-steel nitric oxide reactor system, purged with high purityargon, then charged with nitric oxide gas (80 psi, 99%). After stirringunder pressure for 24 h, the white precipitate that formed was washedwith methanol, then diethyl ether and dried under vacuum for 1 h. Theproducts 2a-c were stored at -20 C until further use. Spectra matchedthe previously reported values. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | In tetrahydrofuran; methanol; for 4.0h;Reflux; | General procedure: Compound 1 was dissolved in MeOH/THF (5/30 mL), and the required amine base (2-3.6 equiv) was added. The mixture was heated under reflux for 4h prior to the solvent being removed, 5% NH3 (aq) (50 mL) was added and the mixture was extracted with CH2Cl2 (50×3 mL). The organic layers were collected, washed with brine and dried over anhydrous sodium sulfate. After removal all solvent, the residue was purified using flash chromatography with dichloromethane- methanol- triethylamine to obtain the target compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | In methanol; at 65℃; | General procedure: The flavonoid compound (1.0mmol, 1.0eq) was dissolved in methanol followed by the addition of 37% formaldehyde solution (97mul, 1.2mmol, 1.2eq) and the corresponding amine (1.2mmol, 1.2eq). The mixture was then stirred at 65C for various hours. After the reaction, the solvent was removed under reduced pressure and the residue was purified on silica gel column using dichloromethane/methanol in gradient to obtain the desired compound |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69.1% | N-ethoxycarbonylpiperazine (4.24 g, 0.025 mol), 1,4-dibromobutane (5.3 g, 0.025 mol), potassium carbonate (6.2 g, 0.05 mol), acetone ) In turn into 1L three-necked flask, warmed to reflux.The progress of the reaction was monitored by gas chromatography. If the gas phase detection of N-ethoxycarbonylpiperazine content is low and no longer changes (about 22h) to stop the reaction, the reaction was stopped hot filtered and concentrated to dryness, adding 7-hydroxyquinolinone (4.0 g, 0.025 mol), potassium carbonate (8.5 g, 0.04 mol) MIBK (75.7 g) and DMAc (11.4 g) were added and warmed to a gentle reflux with an internal temperature of about 116-118 C. After reaction for about 20h, TLC analysis showed that when the content of 7-hydroxyquinolinol remained low and the content remained unchanged, the reaction was stopped, the solvent was distilled off first, then the mixture was stirred with water, extracted with dichloromethane, washed with 5% sodium hydroxide solution, Washed with water and stripped of solvent to give 5.1 g of pale yellow solid (III, R = -COOCH2CH3) in a yield of 69.1%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | In methanol; at 20℃; for 12h; | General procedure: Lactone (1 mmol) in MeOH (5 mL) wasstirred, treated with a solution of piperazine (1 mmol) in MeOH (2 mL), and left at room temperature. The course of thereaction was monitored by TLC. If the product did not precipitate, the solvent was evaporated in vacuo after the reaction wascomplete. The residue was recrystallized from a suitable solvent (usually C6H6-hexane mixtures). Compounds 5a-e, 6a-d,and 7a,d,e were prepared by this method. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In methanol; at 20℃; for 12h; | General procedure: Lactone (1 mmol) in MeOH (5 mL) wasstirred, treated with a solution of piperazine (1 mmol) in MeOH (2 mL), and left at room temperature. The course of thereaction was monitored by TLC. If the product did not precipitate, the solvent was evaporated in vacuo after the reaction wascomplete. The residue was recrystallized from a suitable solvent (usually C6H6-hexane mixtures). Compounds 5a-e, 6a-d,and 7a,d,e were prepared by this method. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.7% | With triethylamine; In acetonitrile; for 4.5h;Reflux; | 2-Chloro-5-nitrobenzonitrile (0.91 g, 5.0 mmol) was added to the reaction flask.Ethyl piperazine-1-carboxylate (0.84 g, 5.3 mmol),Triethylamine (1.1 g, 10.9 mmol) and acetonitrile 20 mL were refluxed for 4.5 h.After the reaction, the reaction solution was cooled to room temperature, diluted with water and extracted with ethyl acetate.The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated.The residue was recrystallized from ethyl acetate to give 1a, yield 71.7% |
Tags: 120-43-4 synthesis path| 120-43-4 SDS| 120-43-4 COA| 120-43-4 purity| 120-43-4 application| 120-43-4 NMR| 120-43-4 COA| 120-43-4 structure
[ 50606-32-1 ]
Butyl piperazine-1-carboxylate
Similarity: 0.90
[ 219509-79-2 ]
1-tert-Butyl 4-methyl piperazine-1,4-dicarboxylate
Similarity: 0.88
[ 76535-75-6 ]
Di-tert-butyl piperazine-1,4-dicarboxylate
Similarity: 0.88
[ 53788-49-1 ]
tert-Butyl 4-methylpiperazine-1-carboxylate
Similarity: 0.88
[ 57260-71-6 ]
tert-Butyl piperazine-1-carboxylate
Similarity: 0.88
[ 50606-32-1 ]
Butyl piperazine-1-carboxylate
Similarity: 0.90
[ 219509-79-2 ]
1-tert-Butyl 4-methyl piperazine-1,4-dicarboxylate
Similarity: 0.88
[ 76535-75-6 ]
Di-tert-butyl piperazine-1,4-dicarboxylate
Similarity: 0.88
[ 53788-49-1 ]
tert-Butyl 4-methylpiperazine-1-carboxylate
Similarity: 0.88
[ 57260-71-6 ]
tert-Butyl piperazine-1-carboxylate
Similarity: 0.88
[ 50606-32-1 ]
Butyl piperazine-1-carboxylate
Similarity: 0.90
[ 219509-79-2 ]
1-tert-Butyl 4-methyl piperazine-1,4-dicarboxylate
Similarity: 0.88
[ 76535-75-6 ]
Di-tert-butyl piperazine-1,4-dicarboxylate
Similarity: 0.88
[ 53788-49-1 ]
tert-Butyl 4-methylpiperazine-1-carboxylate
Similarity: 0.88
[ 57260-71-6 ]
tert-Butyl piperazine-1-carboxylate
Similarity: 0.88
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
Home
* Country/Region
* Quantity Required :
* Cat. No.:
* CAS No :
* Product Name :
* Additional Information :