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CAS No. : | 13754-38-6 | MDL No. : | MFCD00810192 |
Formula : | C11H14N2O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | VUNXBQRNMNVUMV-UHFFFAOYSA-N |
M.W : | 190.24 | Pubchem ID : | 762654 |
Synonyms : |
Benzoylpiperazine
|
Num. heavy atoms : | 14 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.36 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 62.47 |
TPSA : | 32.34 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) : | -7.55 cm/s |
Log Po/w (iLOGP) : | 1.98 |
Log Po/w (XLOGP3) : | -0.12 |
Log Po/w (WLOGP) : | -0.03 |
Log Po/w (MLOGP) : | 1.17 |
Log Po/w (SILICOS-IT) : | 1.5 |
Consensus Log Po/w : | 0.9 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.13 |
Solubility : | 14.1 mg/ml ; 0.0743 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.11 |
Solubility : | 149.0 mg/ml ; 0.784 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.85 |
Solubility : | 0.272 mg/ml ; 0.00143 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.15 |
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 |
---|---|---|
92% | With acetic acid at 60℃; for 0.0666667h; Sonication; Irradiation; | |
75% | In ethanol at 20℃; for 5h; Inert atmosphere; | Preparation of phenyl(piperazin-1-yl)methanone (36) To a solution of piperazine (1 mmol) in ethanol (10 mL), benzoyl chloride (1 mmol) was added drop-wise and the reaction was allowed to proceed for 5 h at room temperature. To the contents of the reaction mixture, distilled water was then added and the precipitate was filtered out. The water was brought at pH>12 with NaOH 1 M, extrated with dichloromethane (25 mL), dried with MgSO4 and concentrated in vacuo to afforded the crude product, which was then purified by flash column chromatography on silica gel (DCM: MeOH 100:0 v/v, increasing to 90:10 v/v then DCM: MeOH: Et3N 90:9:1 v/v) to give the pure product. Obtained in 75% yield as a white solid. 1H-NMR (CDCl3) δ: 1.65 (bs, 1H, NH), 2.81-2.92 (m, 4H, CH2-piperazine), 3.39 (bs, 2H, CH2-piperazine), 3.73 (bs, 2H, CH2-piperazine), 7.38-7.41 (m, 5H, H-aromatic). |
56% | With acetic acid |
55% | With pyridine; aluminum oxide at 94 - 96℃; for 0.0166667h; microwave irradiation; | |
With water bei pH 2.7; | ||
With acetone bei pH 4.5; | ||
With acetic acid In tetrahydrofuran at 20℃; for 1h; | ||
With acetic acid | ||
With sodium acetate; acetic acid | ||
With triethylamine In chloroform at 1 - 20℃; for 1h; | 17 I -Benzoylpiperazine: 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. benzoyl chloride (6.7 mmol) dissolved in chloroform (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-benzoylpiperazine was obtained by column chromatography usingchloroform-methanol as eluent. The compound 1-benzoylpiperazine was obtained as colourless oil. | |
With potassium carbonate In N,N-dimethyl-formamide at 80℃; | Synthesis of phenyl(piperazine-1-yl)methanone fromanhydrous Piperazine and Benzoyl chloride 10 A solution of Benzoyl chloride 9(8.26 g,0.058mol) and Piperazine 8(10.12 g, 0.117mol) inN, N dimethylformamide was taken in a RBF K2CO3(3gm) was added to the reaction mixture. The reactionmixture was stirred for 8 hr at 80°C on a magneticstirrer (heat + stirring). The progress of the reactionwas monitored by thin layer chromatography (TLC).Upon completion of the reaction, water was added tothe reaction mixture and the product extracted by shaking the reaction mixture with dichloromethane in a separating funnel.The dichloromethane layer was washed successively with water and brine, driedover anhydrous sodium sulfate. Evaporation of the solvent gave the product 10. Recrystallized with chloroform. | |
Stage #1: piperazine With acetic acid In water; acetone for 0.333333h; Cooling; Stage #2: benzoyl chloride In water; acetone for 3h; Stage #3: With sodium hydroxide In water; acetone | Preparation of N-benzoylpiperazine hydrochloride Acetic acid (45 mL) is added to 10 g (0.116 mol) of anhydrous piperazine under cooling and vigorous stirring. Then, acetone (20 mL) and water (20 mL) are added. After 20 minutes of stirring, 6.7 mL (0.058 mol) of benzoyl chloride are added. The solution is stirred for additional 3 hours. Then the reaction mixture is concentrated by half. 40% NaOH is added in an amount of 450 mL. The precipitated residue is filtered off, and the aqueous stock solution is extracted with 100 mL of chloroform three times, dried, and stripped off to dryness. The obtained yellow oil in an amount of 13.4 g comprises about 60% of the main substance. | |
With acetic acid In chloroform at 20℃; for 3h; | General procedure: For intermediate g, 0.02 mol aryl carboxylic acid was dissolved in 20 mL thionyl chloride, and the solution was stirred at reflux for 4 h. Then, 20 mL anhydrous chloroform was added into the solution, and thionyl chloride was removed in vacuo under reduced pressure to give intermediate e. Subsequently, intermediate e was dissolved in 10 mL chloroform and added dropwise into anthalazine dissolved in acetic acid. The solution was kept stirring at room temperature for 3 h, and then was alkalized in an ice bath with 20% sodium hydroxide till the pH value reached 9~10. Finally, the organic phase was extracted with chloroform (50 mL x 5), dried over anhydrous sodium sulfate overnight, and then evaporated under vacuum. | |
Stage #1: piperazine With n-butyllithium In tetrahydrofuran; hexane at 20℃; for 1h; Inert atmosphere; Stage #2: benzoyl chloride In tetrahydrofuran; hexane for 0.166667h; Inert atmosphere; | ||
With pyridine In dichloromethane at 20℃; for 0.5h; | Synthesis of compounds 9a-9f General procedure: A mixture of commercial carboxylic acid 7a-7f (1 mmol) infreshly distilled thionyl chloride was heated to reflux for2 h, then cooled to room temperature and evaporated undervacuum to dryness to afford quantitatively correspondingacid chlorides. The acid chlorides were dissolved indichloromethane, followed by the slow addition of a mixtureof piperazine (86 mg, 1 mmol) and pyridine (197 mg,2.5 mmol) at room temperature and stirring was continuedfor 30 min. After completion of reaction, the solvent waswashed with aq. sodium bicarbonate. The organic layer wascollected, dried with sodium sulfate, filtered and removedunder vacuum to obtain products 9a-9f without purificationin the yields of above 90%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: piperazine With n-butyllithium In tetrahydrofuran at 20℃; for 1h; Stage #2: benzoyl chloride In tetrahydrofuran for 0.166667h; | |
Stage #1: piperazine With n-butyllithium In tetrahydrofuran at -78℃; Stage #2: benzoyl chloride In tetrahydrofuran at -78℃; | ||
Stage #1: piperazine With 9-borabicyclo[3.3.1]nonane dimer In tetrahydrofuran; hexane at 20℃; for 1h; Stage #2: benzoyl chloride In tetrahydrofuran; hexane at 20℃; for 2h; |
In tetrahydrofuran | ||
In ethanol at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With trifluoroacetic acid In dichloromethane for 6h; | |
53% | Stage #1: 4-benzoylpiperazine-1-carboxylic acid tert-butyl ester With trifluoroacetic acid In dichloromethane at 20℃; for 18h; Stage #2: With hydrogenchloride In dichloromethane; water Stage #3: With sodium hydroxide In water | 1.2; 1.B General procedure B. Phenyl-piperazin-1-yl-methanoneTo a solution of (1.0 g, 3.44 mmol) 4-benzoyl-piperazine-l-carboxylic acid tert-butyl ester in dichloromethane (9 ml) was added TFA (1 ml) and the resulting mixture shaken at room temperature for 18 hours. The reaction mixture was concentrated at reduced pressure then partitioned between 1:1 DCM / IM HCl aq (50 ml). The aqueous phase was basified with NaOH solid (until pH 10), extracted with DCM (2 x 25 ml), dried (Na2SO4), filtered and evaporated at reduced pressure. The resulting semi-transparent oil was azeotroped with MeOH (2 x 10 ml) to give product (348 mg, 53 %, 1.83 mmol) as viscous colourless oil. LC/MS: 91% MH+, m/z 192, Rt = 0.63 mins. |
With trifluoroacetic acid In dichloromethane |
With trifluoroacetic acid In dichloromethane | 118.B STEP B The product from Step A above, was dissolved in a 50% trifluoroacetic ACID/DICHLOROMETHANE solution and stirred overnight. After this time the reaction was diluted with 1 N potassium hydroxide (200mL) and the organic layer was separated. The aqueous phase was then extracted six times with dichloromethane. The organic fractions were combined and dried over magnesium sulfate. Filtration and concentration provided product (2.93g). 1H NMR (CDC13, 300 MHz) 1.92 (s, 1H), 2.87 (m, 4H), 3.52 (m, 4H), 7.39 (s, 5H). MS: calculated : 190.11, found: 191.1. | |
Stage #1: 4-benzoylpiperazine-1-carboxylic acid tert-butyl ester With trifluoroacetic acid In dichloromethane Stage #2: With potassium hydroxide In dichloromethane; water | 118.B Step B The product from Step A above, was dissolved in a 50% trifluoroacetic acid/dichloromethane solution and stirred overnight. After this time the reaction was diluted with IN potassium hydroxide (200 mL) and the organic layer was separated. The aqueous phase was then extracted six times with dichloromethane. The organic fractions were combined and dried over magnesium sulfate. Filtration and concentration provided product (2.93 g).[1302] ^ NMR (CDC13, 300 MHz) 1.92 (s, 1H), 2.87 (m, 4H), 3.52 (m, 4H), 7.39 (s, 5H).[1303] MS: calculated: 190.11, found: 191.1. | |
Stage #1: 4-benzoylpiperazine-1-carboxylic acid tert-butyl ester In dichloromethane; trifluoroacetic acid Stage #2: With potassium hydroxide In H20 | 118 Preparative example 118 The product from Step A above, was dissolved in a 50% trifluoroacetic acid/dichloromethane solution and stirred overnight. After this time the reaction was diluted with 1 N potassium hydroxide (200 mL) and the organic layer was separated. The aqueous phase was then extracted six times with dichloromethane. The organic fractions were combined and dried over magnesium sulfate. Filtration and concentration provided product (2.93 g). | |
With trifluoroacetic acid In dichloromethane | 118.B The product from Step A above, was dissolved in a 50% trifluoroacetic acid/dichloromethane solution and stirred overnight. After this time the reaction was diluted with 1 N potassium hydroxide (200mL) and the organic layer was separated. The aqueous phase was then extracted six times with dichloromethane. The organic fractions were combined and dried over magnesium sulfate. Filtration and concentration provided product (2.93g). 1H NMR (CDCI3, 300 MHz) 1.92 (s, 1 H), 2.87 (m, 4H), 3.52 (m, 4H), 7.39 (s, 5H). MS: calculated : 190. 11, found: 191.1. | |
With hydrogenchloride; water In dichloromethane at 20℃; | ||
With trifluoroacetic acid In dichloromethane | ||
With hydrogenchloride In methanol; diethyl ether | ||
With trifluoroacetic acid In dichloromethane | ||
With trifluoroacetic acid In dichloromethane at 25℃; | ||
0.83 g | With trifluoroacetic acid In dichloromethane at 25℃; for 2.5h; Cooling with ice; | 41.2 Step 2: Step 2: Tert-butyl 4-benzoylpiperazine-1-carboxylate (1 g; 3.44 mmol) was dissolvedDCM (8 ml) and cooled in an ice bath. Trifluoroacetic acid (5.3 ml, 69 mmol) was addedslowly. The reaction was stirred at 25 °C for 2.5 h and then evaporated. The residue was taken up in ethyl acetate and saturated sodium bicarbonate solution, the phases were separated and the aqueous phase was extracted five times with ethyl acetate. The combined organics were dried over sodium sulfate, filtered and evaporated to a glassy residue of 1- benzoylpiperazine (0.83 g). |
With trifluoroacetic acid In chloroform at 20℃; for 8h; | ||
With trifluoroacetic acid In chloroform; water at 20℃; for 2h; | ||
0.583 g | With trifluoroacetic acid In dichloromethane at 20℃; | 8 Example 8 phenylpiperazin-1-yl-methanone (3-1) 1.487 g (5.13 mmol) of compound 2-1 was dissolved in 15 ml of dichloromethane, then 1.5 ml (20 mmol) of TFA was added. room temperature reaction, After completion of the TLC monitoring reaction, the product was concentrated, dissolved in 40 ml of 1 M HCl solution, stirred for half an hour, and then washed with 40 ml of dichloromethane. Then add 1M sodium hydroxide solution to the aqueous layer to adjust the pH to about 10, It was extracted with 2×40 ml of dichloromethane, dried over anhydrous sodium sulfate and evaporated to obtained colorless oil 0.583g |
With trifluoroacetic acid In dichloromethane at 0 - 25℃; | ||
With trifluoroacetic acid In dichloromethane | ||
With trifluoroacetic acid In dichloromethane at 20℃; | ||
With hydrogenchloride; sodium hydroxide In dichloromethane | ||
With trifluoroacetic acid In dichloromethane at 0 - 20℃; for 3h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium; sodium chloride In tetrahydrofuran | Preparation of Benzoylpiperazines XXVIII and XXIX Preparation of Benzoylpiperazines XXVIII and XXIX To a stirred solution of substituted piperazine (1.0 g, 11.6 mmol) in dry THF (50 ml) under argon was added 2.5M n-BuLi in THF (10.23 ml, 25.5 mmol) at room temperature. After stirring for 1 hour at room temperature, benzoyl chloride (1.27 ml, 11.0 mmol) was added to the solution of dianion and the reaction mixture was stirred for an additional 10 minutes. The reaction mixture was quenched with MEOH, and the solvents evaporated. The residue was partitioned between EtOAc (50 ml) and sat. NaHCO3. The aqueous layer was saturated with NaCl and extracted with EtOAc (2*30 ml). The organic layer was dried over MgSO4 and concentrated to afford the crude product benzoylpiperazine, which was generally of sufficient purity to be used directly without further purification. Chromatography on a silica gel column (EtOAc/MeOH/Et3N, 7:3:1) gave the purified product. | |
Multi-step reaction with 2 steps 1: triethylamine / diethyl ether 2: water; acetonitrile / 25 °C | ||
Multi-step reaction with 2 steps 1: diethyl ether 2: water / 25 °C |
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 20 °C 2: hydrogenchloride; water / dichloromethane / 20 °C | ||
Multi-step reaction with 2 steps 1: triethylamine / tetrahydrofuran 2: trifluoroacetic acid / dichloromethane | ||
Multi-step reaction with 2 steps 1: dichloromethane 2: acetonitrile / 25 °C | ||
Multi-step reaction with 2 steps 1: triethylamine / diethyl ether 2: acetonitrile / 25 °C | ||
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 3 h / 25 °C / Cooling with ice 2: trifluoroacetic acid / dichloromethane / 2.5 h / 25 °C / Cooling with ice | ||
Multi-step reaction with 2 steps 1: triethylamine / acetonitrile / 20 °C 2: trifluoroacetic acid / water; chloroform / 2 h / 20 °C | ||
Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h / 25 °C 2.1: trifluoroacetic acid / dichloromethane / 20 °C 2.2: 0.5 h | ||
Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h / 0 - 20 °C 2.1: trifluoroacetic acid / dichloromethane / 18 h / 20 °C 2.3: pH 10 | ||
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h / 0 - 25 °C 2: trifluoroacetic acid / dichloromethane / 20 °C | ||
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / dichloromethane / 3 h / 20 °C 2: trifluoroacetic acid / dichloromethane / 0 - 25 °C | ||
Multi-step reaction with 2 steps 1: 20 °C 2: trifluoroacetic acid / dichloromethane / 20 °C | ||
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h / 0 - 20 °C / Inert atmosphere 2: trifluoroacetic acid / dichloromethane / 3 h / 0 - 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With sodium hydroxide;Et2AlCl; Me2AlCl; In dichloromethane; | Preparation of Benzoylpiperazine XXX To a stirred solution of 2-methylpiperazine (10.0 g, 0.1 mol) in dry CH2Cl2 (500 ml) under argon was added a solution of 1.0 M Me2AlCl or Et2AlCl in hexanes (100 ml, 0.1 mmol) and methyl benzoate (12.4 ml, 0.1 mmol) at room temperature. The reaction mixture was then stirred for 2 days before 2N NaOH (200 ml) was added. Aqueous layer was extracted with EtOAc (3*100 ml). The combined organic layer was dried over MgSO4 and concentration of solution provided 20.0 g of crude product (98%), with was pure enough for the further reactions. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With lithium perchlorate; In acetonitrile; for 5h; | From <strong>[75390-09-9]1-benzyl-3,4-epoxypyrroline</strong> (253 mg, 1.44 mmol), 1-benzoylpiperazine (330 mg, 1.73 mmol), LiClO4 (308 mg, 2.89 mmol) and acetonitrile (10 ml). Reaction time: 5 hours. Purification: silica gel, gradient dichloromethane to dichlorometane:methanol 8%, afforded the product (317 mg, 60%) as brown solid. M.p. 130-134C. 1H NMR (400 MHz, CDCl3): delta (ppm) 7.38 (m, 5H), 7.30 (m, 5H), 4.14 (m, 1H), 3.84 (bs, 1H), 3.71 (bs, 1H), 3.56 (AB system, 2H), 3.42 (bs, 2H), 3.00 (t, J=8Hz, 1H), 2.71 (bs, 1H), 2.66-2.54 (m, 4H), 2.33 (m, 1H), 2.19 (t, J=8Hz, 1H). 13C NMR (75 MHz, CDCl3): delta (ppm) 170.29, 138.00, 135.60, 129.72, 128.82, 128.47, 128.35, 127.24, 127.06, 74.47, 74.45, 62.27, 60.12, 57.16, 47.50, 42.00. MS (El+) m/z: 366.2 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Stage #1: di-<i>tert</i>-butyl dicarbonate; 1-aminocyclohexanecarboxylic acid benzyl ester With dmap In dichloromethane at 20℃; for 0.5h; Stage #2: N-Benzoylpiperazine With triethylamine In dichloromethane at 20℃; | 87 A solution of 114 mg (0.9 mmol) of N,N-dimethylaminopyridine and 2.17 g (9.3 mmol) of 1-aminocyclohexanecarboxylic acid phenylmethyl ester in methylene chloride was added to a solution of 2.03 g (9.3 mmol) of di-t-butyl dicarbonate in 60 ml of methylene chloride, and the mixture was stirred at room temperature for 30 minutes. Thereafter, a solution of 1.88 g (18.6 mmol) of triethylamine and 1.86 g (9.8 mmol) of 1-(benzoyl)piperazine in methylene chloride was added, and the mixture was stirred at room temperature overnight. After the reaction solution was concentrated, the residue was dissolved in ethyl acetate, and the mixture was successively washed with water, a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, followed by drying with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the obtained crystal was washed with diethyl ether to obtain 3.60 g (86%) of the title compound.1H-NMR (CDCl3, δ): 1.26-1.38 (1H, m), 1.39-1.50 (2H, m), 1.53-1.68 (3H, m), 1.85-1.93 (2H, m), 2.02-2.08 (2H, m), 3.28-3.57 (6H, m), 3.66-3.85 (2H, m), 4.57 (1H, br-s), 5.15 (2H, s), 7.31-7.39 (4H, m), 7.40-7.48 (6H, m) |
86% | Stage #1: di-<i>tert</i>-butyl dicarbonate; 1-aminocyclohexanecarboxylic acid benzyl ester With dmap In dichloromethane at 20℃; for 0.5h; Stage #2: N-Benzoylpiperazine With triethylamine In dichloromethane at 20℃; | 87 REFERENCE EXAMPLE 871-[[(4-Benzoyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acid phenylmethyl ester A solution of 114 mg (0.9 mmol) of N,N-dimethylaminopyridine and 2.17 g (9.3 mmol) of 1-aminocyclohexanecarboxylic acid phenylmethyl ester in methylene chloride was added to a solution of 2.03 g (9.3 mmol) of di-t-butyl dicarbonate in 60 ml of methylene chloride, and the mixture was stirred at room temperature for 30 minutes. Thereafter, a solution of 1.88 g (18.6 mmol) of triethylamine and 1.86 g (9.8 mmol) of 1-(benzoyl)piperazine in methylene chloride was added thereto, and the mixture was stirred at room temperature overnight. After the reaction solution was concentrated, the residue was dissolved in ethyl acetate, and the mixture was successively washed with water, a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, followed by drying with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the obtained crystal was washed with diethyl ether to obtain 3.60 g (86%) of the title compound.1H-NMR (CDCl3, δ): 1.26-1.38 (1H, m), 1.39-1.50 (2H, m), 1.53-1.68 (3H; m), 1.85-1.93 (2H, m), 2.02-2.08 (2H, m) 3.28-3.57 (6H, m), 3.66-3.85 (2H, m), 4.57 (1H, br-s), 5.15 (2H, s), 7.31-7.39 (4H, m), 7.40-7.48 (6H, m) |
86% | Stage #1: di-<i>tert</i>-butyl dicarbonate; 1-aminocyclohexanecarboxylic acid benzyl ester With dmap In dichloromethane at 20℃; for 0.5h; Stage #2: N-Benzoylpiperazine In dichloromethane at 20℃; | 87 1-[[(4-Benzoyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acid phenylmethyl ester Reference Example 87 1-[[(4-Benzoyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acid phenylmethyl ester A solution of 114 mg (0.9 mmol) of N,N-dimethylaminopyridine and 2.17 g (9.3 mmol) of 1-aminocyclohexanecarboxylic acid phenylmethyl ester in methylene chloride was added to a solution of 2.03 g (9.3 mmol) of di-t-butyl dicarbonate in 60 ml of methylene chloride, and the mixture was stirred at room temperature for 30 minutes. Thereafter, a solution of 1.88 g (18.6 mmol) of triethylamine and 1.86 g (9.8 mmol) of 1-(benzoyl)piperazine in methylene chloride were added thereto, and the mixture was stirred at room temperature overnight. After the reaction solution was concentrated, the residue was dissolved in ethyl acetate, and the mixture was successively washed with water, a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, followed by drying with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the obtained crystal was washed with diethyl ether to obtain 3.60 g (86%) of the title compound. 1H-NMR (CDCl3, δ): 1.26-1.38 (1H, m), 1.39-1.50 (2H, m), 1.53-1.68 (3H, m), 1.85-1.93 (2H, m), 2.02-2.08 (2H, m), 3.28-3.57 (6H, m), 3.66-3.85 (2H, m), 4.57 (1H, br-s), 5.15 (2H, s), 7.31-7.39 (4H, m), 7.40-7.48 (6H, m) |
86% | Stage #1: di-<i>tert</i>-butyl dicarbonate; 1-aminocyclohexanecarboxylic acid benzyl ester With dmap In dichloromethane at 20℃; for 0.5h; Stage #2: N-Benzoylpiperazine With triethylamine In dichloromethane at 20℃; | 87 Reference example 87 ; 1-[[(4-Benzoyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acid phenylmethyl ester [Show Image] A solution of 114 mg (0.9 mmol) of N,N-dimethylaminopyridine and 2.17g (9.3 mmol) of 1-aminocyclohexanecarboxylic acid phenylmethyl ester in methylene chloride was added to a solution of 2.03 g (9.3 mmol) of di-t-butyl dicarbonate in 60 ml of methylene chloride, and the mixture was stirred at room temperature for 30 minutes. Thereafter, a solution of 1.88 g (18.6 mmol) of triethylamine and 1.86 g (9.8 mmol) of 1-(benzoyl)piperazine in methylene chloride was added thereto, and the mixture was stirred at room temperature overnight. After the reaction solution was concentrated, the residue was dissolved in ethyl acetate and successively washed with water, a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, followed by drying with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the obtained crystal was washed with diethyl ether to give 3.60 g (86%) of the title compound. 1H-NMR (CDCl3, δ): 1.26-1.38 (1H, m), 1.39-1.50 (2H, m), 1.53-1.68 (3H, m), 1.85-1.93 (2H, m), 2.02-2.08 (2H, m), 3.28-3.57 (6H, m), 3.66-3.85 (2H, m), 4.57 (1H, br-s), 5.15 (2H, s), 7.31-7.39 (4H, m), 7.40-7.48 (6H, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | In dichloromethane at 20℃; for 24h; | 1; 1.C General procedure C. 4-Benzoyl-piperazine-l-carbothioic acid (4-tert- butyl-phenyl)-amideTo a solution of (leqv, 67 mg, 0.35 mmol) phenyl-piperazin-1-yl-methanone in DCM (1 ml) was added dropwise a solution of (1.0 eqv, 67 mg, 0.35 mmol) 4-tert- butylphenyl isothiocyanate in DCM (1 ml). The resulting mixture was stirred at room temperature for 1 day then concentrated at reduced pressure. The crude material was purified by chromatography [SiO2, EtOAc / cyclohexane, 1 :1] to give pure product (110 mg, 82 %, 0.288 mmol) as an off-white solid. LC/MS: 93% MH+, m/z 382, Rt = 1.50 mins. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | Stage #1: tert-butyl (2S)-2-[((2S)-2-[(benzyloxy)carbonyl]amino}-4-methylpentanoyl)amino]-3-(4-hydroxyphenyl)propanoate; bis(trichloromethyl) carbonate With N-ethyl-N,N-diisopropylamine In tetrahydrofuran; dichloromethane at 20℃; for 4h; Stage #2: N-Benzoylpiperazine With N-ethyl-N,N-diisopropylamine In tetrahydrofuran; dichloromethane for 18h; | 18 Intermediate 18: 4-[(2S)-2-[((2S)-2-[(Benzyloxy)carbonyl]amino}-4-methyl pentanoyl)amino]-3-(tert-butoxy)-3-oxopropyl]phenyl 4-benzoyl-1-piperazine carboxylate To a solution of triphosgene (0.24g) in anhydrous dichloromethane (5ml), under a nitrogen atmosphere, was added a solution of Intermediate 11 (1g) in anhydrous THF (10ml) followed by diisopropylethylamine (0.43ml).. After stirring for 4h at 20°C Intermediate 56 (0.78g) was added followed by diisopropylethylamine (1.15ml).. Stirring was continued for 18h then the mixture was partitioned between 1M hydrochloric acid (100ml) and ethyl acetate (75ml).. The layers were separated and the aqueous phase was further extracted with ethyl acetate (75ml).. The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate (50ml), water (50ml) and brine (30ml), dried over sodium sulphate and evaporated in vacuo.. The crude product was purified by flash column chromatography on silica gel eluding with ethyl acetate/petroleum ether (1:1 switching to 2:1) to give the title compound as a white foam (1.02g, 71%). LCMS: Rt 3.71 min; m/z 701 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With potassium carbonate In acetonitrile at 20℃; for 1h; | 10 Manufacturing example 10: 1-(4-benzoylpiperazine-1-yl)propan-2-one [Show Image] 0.10 g (0.53 mmol) 1-benzoylpiperazine and potassium carbonate 0.22 g (1.58 mmol, 3.0 eq.) were added to 5 ml acetonitrile and 0.05 g (0. 53 mmol, 1.0 eq.) chloroacetone were added dropwise slowly at room temperature. After mixing for one hour, 5 ml purified water were added, and the reaction mixture was extracted with 10 ml ethylacetate three times. After collecting organic layer, drying with anhydrous magnesium sulfate, and concentrating with decompression, residues obtained were purified with silicagel chromatography (mobile phase: dichloromethane/methnol=10:1) and 0.11 g (83%) target compound as yellow syrup were yielded. 1H NMR(400MHz,CDCl3) 2.18(3H,s), 2.41-2.69(4H,m), 3.27(2H,s), 3.42-3.54(2H,m), 3.81-3.93(2H,m), 7.40-7.46(5H,m) |
83% | With potassium carbonate In acetonitrile at 20℃; for 1h; | 10 Manufacturing Example 10 1-(4-benzoylpiperazine-1-yl)propan-2-one 0.10 g (0.53 mmol) 1-benzoylpiperazine and potassium carbonate 0.22 g (1.58 mmol, 3.0 eq.) were added to 5 ml acetonitrile and 0.05 g (0.53 mmol, 1.0 eq.) chloroacetone was added dropwise slowly at room temperature. After mixing for one hour, 5 ml purified water was added, and the reaction mixture was extracted with 10 ml ethylacetate three times. After collecting organic layer, drying with anhydrous magnesium sulfate, and concentrating with decompression, residues obtained were purified with silicagel chromatography (mobile phase: dichloromethane/methnol=10:1) and 0.11 g (83%) target compound as yellow serup were yielded. 1H NMR (400 MHz, CDCl3) 2.18 (3H, s), 2.41-2.69 (4H, m), 3.27 (2H, s), 3.42-3.54 (2H, m), 3.81-3.93 (2H, m), 7.40-7.46 (5H, m) |
With potassium carbonate In acetonitrile |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With sodium hydrogencarbonate In ethanol for 10h; Reflux; | General procedure for the synthesis of piperazinium salts 14 General Procedure: N-Aryl-N,N-bis(2-chloroethyl)amine or N-aryl-N,N-bis(2-(methylsulfonyloxy)ethyl)amine (5 mmol), HNR2R3 (5 mmol) and NaHCO3 (20 mmol) were added to ethanol (20 mL) and the mixture was refluxed for 10 h. After filtration, the filtrate was concentrated, and crystallized to afford the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With potassium carbonate In acetonitrile at 20℃; Reflux; | 9 Manufacturing example 9: (4-(2-hydroxy-2-methylpropyl)piperazine-1-yl)phenylmethanon e [Show Image] 500 mg (2.63 mmol) 1-benzoylpiperazine and 1.10 g (7.96 mmol, 3.0 eq.) potassium carbonate were suspended to 20 ml acetonitrile at room temperature. After adding 570 mg (7.90 mmol, 3.0 eq.) isobutylene oxide, it was heated at reflux and stirred overnight. After cooling to room temperature and adding 30 ml purified water, it was extracted twice with 30 ml ethylacetate. After collecting the organic layer and drying with anhydrous magnesium sulfate, it was concentrated with decompression. The obtained residue was purified by chromatography using silicagel (mobile phase: dichloromethane/methanol= 20:1) and 276 mg (40%) target compound as light-yellow solid were yielded. 1HNMR(400MHz,DMSO-d6) 1.10(6H,s), 2.23(2H,s), 2.43-2.52(2H,m), 2.53-2.62(2H,m), 3.35-3.45(2H,m), 3.55-3.65(2H,m), 4.13(1H,s), 7.35-7.38(2H,m), 7.43-7.46(3H,m) |
40% | With potassium carbonate In acetonitrile Reflux; | 9 Manufacturing Example 9 (4-(2-hydroxy-2-methylpropyl)piperazine-1-yl)phenylmethanone 500 mg (2.63 mmol) 1-benzoylpiperazine and 1.10 g (7.96 mmol, 3.0 eq.) potassium carbonate were suspended to 20 ml acetonitrile at room temperature. After adding 570 mg (7.90 mmol, 3.0 eq.) isobutylene oxide, it was heated at reflux and stirred overnight. After cooling to room temperature and adding 30 ml purified water, it was extracted twice with 30 ml ethylacetate. After collecting organic layer and drying with anhydrous magnesium sulfate, it was concentrated with decompression. The obtained residue was purified by chromatography using silicagel (mobile phase: dichloromethane/methanol=20:1) and 276 mg (40%) target compound as light-yellow solid was yielded. 1H NMR (400 MHz, DMSO-d6) 1.10 (6H, s), 2:23 (2H, s), 2.43-2.52 (2H, m), 2.53-2.62 (2H, m), 3.35-3.45 (2H, m), 3.55-3.65 (2H, m), 4.13 (1H, s), 7.35-7.38 (2H, m), 7.43-7.46 (3H, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | Stage #1: N-[1-(2-hydroxypropyl)-pyrrolidine-(3R)-yl-carbamoyl]-methyl}-3-trifluoromethylbenzamide With methanesulfonyl chloride; triethylamine In dichloromethane at 3℃; for 0.5h; Inert atmosphere; Stage #2: N-Benzoylpiperazine With potassium carbonate In acetonitrile at 20℃; for 2h; | 18 Example 18: N-[1-(2-(4-benzoylpiperazine-1-yl)propane-1-yl)-pyrrolidin e-(3R)-yl-carbamoyl]-methyl}-3-trifluoromethylbenzamide [Show Image] 400 mg (1.07 mmol) N-[1-(2-hydroxypropyl)-pyrrolidin e-(3R)-yl-carbamoyl]-methyl}-3-trifluoromethylbenzamide and 0.18 ml(1.29 mmol, 1.2 eq.)triethylamine described in manufacturing example 6 were dissolved to 20 ml dichloromethane and cooled to 3°C under argon gas. 135 mg (1.18 mmol, 1.1 eq.) methansulfonyl chloride were slowly added to reaction solution and stirred at same temperature for 30 min. 20 ml purified water were added and then the organic layer was separated and concentrated with decompression. After 10 ml acetonitrile were added to obtained residues and dissolved them, 444 mg (3.21 mmol) potassium carbonate and 202 mg (1.06 mmol) 1-benzoylpiperazine were added. After stirring for 2 hours at room temperature, 15 ml saturated sodium chloride aqueous solution were added to the reaction solution and was extracted twice with 15 ml ethylacetate. After the organic layer was collected and dried with anhydrous magnesium sulfate, it was concentrated with decompression. 30 mg (51%) target compound as light-yellow solid were yielded by purifying obtained residues with chromatography using silicagel (mobile phase: dichloromethane/methanol=5:1 and 1:1). 1H NMR(400MHz,DMSO-d6) 1.05(3H,s), 1.55-1.65(1H,m), 2.00-2.10(1H,m), 2.15-2.25(1H,m), 2.28-2.55(9H,m), 2.70-2.85(2H,m), 3.17(1H,d) 3.54-3.65(2H,m), 3.87(2H,d), 4.10-4.20(1H,m) 7.35-7.40(2H,m), 7.40-7.47(3H,m), 7.74(1H,t), 7.92(1H,d), 8.14(1H,s) 8.18(1H,d) 8.23(1H,s), 9.01(1H,t) MS (M)+ 545.6 |
51% | Stage #1: N-[1-(2-hydroxypropyl)-pyrrolidine-(3R)-yl-carbamoyl]-methyl}-3-trifluoromethylbenzamide With methanesulfonyl chloride; triethylamine In dichloromethane at 3℃; for 0.5h; Inert atmosphere; Stage #2: N-Benzoylpiperazine With potassium carbonate In acetonitrile at 20℃; for 2h; | 18 Example 18 N-[1-(2-(4-benzoylpiperazine-1-yl)propane-1-yl)-pyrrolidine-(3R)-yl-carbamoyl]-methyl}-3-trifluoromethylbenzamide 400 mg (1 . 07 mmol) N-[1-(2-hydroxypropyl)-pyrrolidine-(3R)-yl-carbamoyl]-methyl}-3-trifluoromethylbenzamide and 0.18 ml (1.29=01, 1.2 eq.) triethylamine described at manufacturing example 6 were dissolved to 20 ml dichloromethane and cooled to 3° C. under argon gas. 135 mg (1.18 mmol, 1.1 eq.) methansulfonyl chloride was slowly added to reaction solution and was stirred at same temperature for 30 min. 20 ml purified water was added and then organic layer was separated and concentrated with decompression. After 10 ml acetonitrile were added to obtained residues and dissolved them, 444 mg (3.21 mmol) potassium carbonate and 202 mg (1.06 mmol) 1-benzoylpiperazine were added. After stirring for 2 hours at room temperature, 15 ml saturated sodium chloride aqueous solution was added to reaction solution and was extracted twice with 15 ml ethylacetate. After organic layer was collected and dried with anhydrous magnesium sulfate, it was concentrated with decompression. 30 mg (51%) target compound as light-yellow solid was yielded by purifying obtained residues with chromatography using silicagel (mobile phase:dichloromethane/methanol=5:1 and 1:1). 1H NMR (400 MHz, DMSO-d6) 1.05 (3H, s), 1.55-1.65 (1H, m), 2.00-2.10 (1H, m), 2.15-2.25 (1H, m), 2.28-2.55 (9H, m), 2.70-2.85 (2H, m), 3.17 (1H, d), 3.54-3.65 (2H, m), 3.87 (2H, d), 4.10-4.20 (1H, m), 7.35-7.40 (2H, m), 7.40-7.47 (3H, m), 7.74 (1H, t), 7.92 (1H, d), 8.14 (1H, s), 8.18 (1H, d), 8.23 (1H, s), 9.01 (1H, t) MS (M)+ 545.6 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.4% | With tetrabutoxytitanium In 2-methyltetrahydrofuran for 3h; Inert atmosphere; Reflux; | A separate vessel was purged with inert gas.• To the vessel was charged 5.2 L of the above solution of the compound(1.3 eq.). This was followed by the addition of 1 kg of compound 11 was charged resulting in a white slurry. Finally, 260 ml of Ti(0"Bu)4 and 800 ml ofMeTHF were charged.• The mixture was heated to reflux. After 3 hours the mixture was seeded with 2 g of the compound of formula 11. The reaction was allowed to continue to reflux.• Upon completion, the slurry was cooled to 10 °C and allowed to agitate for 2 hours.The product was filtered, washed with 2 L of MeTHF then 3.15 L of EtOH. The product was dried at 50 °C in a vacuum oven until reaching a constant weight. The yield was 1.07 kg (80.4%) of off white crystals of compound of formula 12.• Analytical Data: m.p. 162 °C. 1H-NMR (CDC13) (δ, ppm): 2.54 (s, 3H), 3.52 (bs, 4H), 3.74 (bs, 4H), 4.08 (s, 3H), 5.52 (s, 2H), 6.96 (d, J = 8.2 Hz, 2H), 7.2 (d, J = 8.8 Hz, 2H), 7.44 (bs, 5H), 7.62 (s, 1H), 7.91 (s, 1H), 8.62 (s, 1H): 13C-NMR (CDC13) (δ, ppm): 13.91, 41.6, 45.9, 56.5, 56.8, 1 14.3, 122.3, 125.1, 126.7, 127.0, 128.64, 129.5, 129.6, 129.8, 130.2, 134.9, 135.2, 135.7, 140.8, 145.5, 150.6, 161.9, 165.9, 170.6,184.4; HRMS; cacld for C3iH29ClN704S [M+l]+: 630.1685; found: 630.1688. Elemental Analysis: C: 59.09, H: 4.47, N: 15.56, S: 5.08, CI: 5.62; found: C: 59.05, H: 4.28, N: 15.57, S: 5.07, CI: 5.66. |
With tetrabutoxytitanium In 2-methyltetrahydrofuran Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sodium hydroxide In ethanol for 1h; | |
With sodium hydroxide In 2-methyltetrahydrofuran; water at 20 - 25℃; for 1h; Inert atmosphere; | A reaction vessel was purged with inert gas. All steps were performed under inert gas protection.• 20-25 °C. Next, charged 800 g. To the slurry was charged 488 ml of water and 388 ml of 1 N NaOH. No exotherm was observed.• Agitation was removed after 1 hour and the layers were allowed to settle. The bottom aqueous layer was removed. The remaining organic layer was heated to reflux and approximately 3 L of MeTHF was distilled. At this point the distillation was performed under constant volume conditions• When a KF of < 500 ppm was obtained the mixture was allowed to cool to room temperature. The organic layer was filtered and the concentration of benzoyl piperazine was measured |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With caesium carbonate In toluene at 100℃; for 7h; Inert atmosphere; Sealed vessel; | 55 TRV 1094[00289] To a degassed solution of 5-bromo-2-chloro-N-phenylaniline (172 mg, 0.61 mmol), phenyl(piperazin- l -yl)methanonein, ( 139mg, 0.73 mmol), Cs2C03 ( 396mg, 1.22 mmol), BINAP ( 18.9 mg, 0.03 mmol) in toluene was charged Pd2(dba)3 ( 27.9 mg, 0.03 mmol). The reaction was sealed under an atmosphere of argon and heated to 100 °C for 7h. The mixture was cooled, filtered through celite, washed with ethyl acetate and then concentrated in vacuum. The residue was subjected to silica gel column chromatography (60 % hexane/ ethyl acetate) to furnish the title compound (4-(4-chloro-3-(phenylamino)phenyl)piperazin- l -yl)(phenyl)methanone, TRV 1094 as a colorless solid ( 168mg, 0.43 mmol) 70%. NMR (500 MHz, CDC13) δ (ppm) 3.02-3.95 (m, 8H), 6.09 (bs, 1H), 6.45 (m, 1 H), 6.86 (d, J = 2 Hz, 1 H), 7.08 (t, J = 7.5Hz, 1 H), 7.19 (m, 2H), 7.24 (d, J = 8.5 Hz, 1 H), 7.36 (m, 2H), 7.40-7.50 (m, 5H |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With caesium carbonate In toluene at 100℃; for 7h; Inert atmosphere; | 55 Example 55Synthesis of TRV 1094 and TRV 1095toluene / 100°C X = CI, BCW 109416h X = F, BCW 1095 TRV 1095[00288] To a degassed solution of 5-bromo-2-fluoro-N-phenylaniline (500 mg, 1.89 mmol), phenyl(piperazin-l -yl)methanonein, (538mg, 2,83 mmol) Cs2C03 ( 1.22g, 3.78 mmol), BINAP ( 55.9 mg, 0.09 mmol) in toluene was charged Pd2(dba)3 ( 86.4 mg, 0.09 mmol). The reaction was sealed under an atmosphere of argon and heated to 100 °C for 7h. The mixture was cooled, filtered through celite, washed with ethyl acetate and then concentrated in vacuum. The residue was subjected to silica gel column chromatography (60 % hexane/ ethyl acetate) to furnish the title compound (4-(4- fluoro-3-(phenylamino)phenyl)piperazin-l -yl)(phenyl)methanone, TRV 1095 as an off white solid (387mg, 1.03 mmol) 55%. NMR (500 MHz, CDC13) δ (ppm) 2.90-4.00 (m, 8H), 5.77 (bs, 1H), 6.39 (m, 1H), 6.88 (m, 1 H), 6.97-7.01 (m, 2H), 7.12 (m, 2H), 7.30 (m, 2H), 7.40-7.50 (m, 5H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide | ||
With sodium hydroxide In water; ethyl acetate at 2 - 20℃; for 1h; | 17 Sodium 4-benzoylpiperazine-1 -carbodithioate: According to scheme 1, step 2: 1 -benzoylpiperazine (5.0 mmol) was taken in ethyl acetate(20 mL), to this, aqueous sodium hydroxide (6.2 mmol, 30%) was added keeping thetemperature 2 °C, carbon disulfide (6.2 mmol) dissolved in ethyl acetate (5 mL) wasadded drop-wise with stirring at 2 °C. The reaction mixture was further stirred at room temperature for one hour to furnish a white solid. Solvent was distilled off and the crude was recrystallised by methanolic ether to get sodium 4-benzoylpiperazine-1-carbodithioate as a white powder. | |
With sodium hydroxide In ethyl acetate at 0 - 5℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With 4-methyl-morpholine; HATU In N,N-dimethyl-formamide at 20℃; for 18h; Inert atmosphere; | 126 Example 126: 4-(6-(4-(4-b.enzoylpiperazine-l -carbonyl)phenyl)imidazo[ 1 ,2-a]pyridin-3- yPbenzonitrile To a solution of 4-(3-(4-cyanophenyl)imidazo[l,2-a]pyridin-6-yl)benzoic acid (100 mg, 0.294 mmol) in DMF (1.5 mL) were added HATU (168 mg, 0.441 mmol), N-methyl morpholine (129 iL, 1.18 mmol) and 1-benzoylpiperazine (67 mg, 0.441 mmol). The reaction mixture was stirred at room temperature under inert atmosphere for 18 h then, was diluted with water (15 mL) and extracted with EtOAc (3x30 mL). The combined organic layer was dried over Na2S04 and was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent CHCl3/MeOH 92:8) to afford 4-(6-(4- (4-benzoylpiperazine- 1 -carbonyl)phenyl)imidazo[ 1 ,2-a]pyridin-3 -yl)benzonitrile (75 mg, 50%, AUC HPLC 99%) as a white solid. NMR (400 MHz, DMSO- 6) δ 8.75 (s, 1H), 7.95-7.89 (m, 4H), 7.88 (s, 1H), 7.82-7.55 (m, 4H), 7.59 (d, J= 8.0 Hz, 2H), 7.63-7.43 (m, 5H), 4.00-3.40 (m, 8H); 13C NMR (100 MHz, CD3OD): δ 172.90, 172.34, 147.49, 140.29, 136.50, 136.11, 134.87, 134.76, 134.43, 131.43, 129.87, 129.48, 129.22, 128.63, 128.59, 128.21, 127.85, 126.61, 122.92, 119.55, 118.51, 112.76; MS (ESI) m/z 512 [C32H25N50 + H]+.. |
50% | With 4-methyl-morpholine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 18h; Inert atmosphere; | 126 Example 126 To a solution of 4-(3-(4-cyanophenyl)imidazo[1,2-a]pyridin-6-yl)benzoic acid (100 mg, 0.294 mmol) in DMF (1.5 mL) were added HATU (168 mg, 0.441 mmol), N-methyl morpholine (129 μL, 1.18 mmol) and 1-benzoylpiperazine (67 mg, 0.441 mmol). The reaction mixture was stirred at room temperature under inert atmosphere for 18 h then, was diluted with water (15 mL) and extracted with EtOAc (3*30 mL). The combined organic layer was dried over Na2SO4 and was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent CHCl3/MeOH 92:8) to afford 4-(6-(4-(4-benzoylpiperazine-1-carbonyl)phenyl)imidazo[1,2-a]pyridin-3-yl)benzonitrile (75 mg, 50%, AUC HPLC 99%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 7.95-7.89 (m, 4H), 7.88 (s, 1H), 7.82-7.55 (m, 4H), 7.59 (d, J=8.0 Hz, 2H), 7.63-7.43 (m, 5H), 4.00-3.40 (m, 8H); 13C NMR (100 MHz, CD3OD): δ 172.90, 172.34, 147.49, 140.29, 136.50, 136.11, 134.87, 134.76, 134.43, 131.43, 129.87, 129.48, 129.22, 128.63, 128.59, 128.21, 127.85, 126.61, 122.92, 119.55, 118.51, 112.76; MS (ESI) m/z 512 [C32H25N5O+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.35% | With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 8h; | General procedure: A solution of 2-chloroalkyl/aryl substitutedwith or without N-substitution as well as with or without 5 and/or 6-substituted benzimidazole derivative (1.75g,0.01051mol) and 1-[(4-phenyl)carbonyl]piperazine (3g,0.0105mol) in N, N dimethylformamide was taken in a RBF.K2CO3(2gm,) was added to the reaction mixture. The reaction mixture was stirred for 8h at 80C on a magnetic stirrer (heat + stirring). The progress of the reaction was monitored by thin layer chromatography (TLC).Upon completion of the reaction, water was added to the reaction mixture and the product extracted by shaking the reaction mixture with dichloromethane in a separating funnel.The dichloromethane layer was washed successively with water and brine, dried over anhydrous sodium sulfate. Evaporation of the solvent gave theproduct. 11a-l Recrystallized with various solvent like chloroform, ethanol, methanol.(4-((1H-benzo[d]imidazol-2-yl) methyl) piperazin-1-yl)(Phenyl) methanone (11a) Compound 11a was obtained as a white solid (yield: 74.35%; MP:224-226; IR (KBr): 3220(N-H), 2365 (C-H), 1670(C=O),1604(C=N),1556(C=C), 1232 (C-N) cm-1; 1H NMR (300 MHz,CDCl3)ppm: 3.45-3.51(m, 4H,PIP-H), 4.34(s, 2H,-CH2-), 4.79(s, 1H, N-H), 7.30-7.45 (m, 4H, Ar -H of Benzim) 7.89-8.07 (4H, Ar -H of benzoyl) ; 13C-NMR(400 MHz, CDCl3, TMS): 52.14 (CH2), 55.4(CH2),61.7 (CH2), 117(arom. CH), 124 (arom. CH),129(arom. CH), 133.5 (quat. C), 139.8 (quat. C), 145.6(quat. C),171.6 (carbonyl C).ESI-MS m/z:320,243,189,131.Anal. Calcd. for C19H20N4O(320): C, 71.23; H, 6.29; N, 17.49; O, 4.99. Found: C,71.10; H, 6.23; N, 17.43; O, 4.91 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.25% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 8h; | Synthesis of Substituted Benzimidazole Derivatives Bearing 1-[(4-phenyl)carbonyl]piperazinyl alkyl benzo(d) imidazole derivatives11a-l General procedure: A solution of 2-chloroalkyl/aryl substitutedwith or without N-substitution as well as with or without 5 and/or 6-substituted benzimidazole derivative (1.75g,0.01051mol) and 1-[(4-phenyl)carbonyl]piperazine (3g,0.0105mol) in N, N dimethylformamide was taken in a RBF.K2CO3(2gm,) was added to the reaction mixture. The reaction mixture was stirred for 8h at 80°C on a magnetic stirrer (heat + stirring). The progress of the reaction was monitored by thin layer chromatography (TLC).Upon completion of the reaction, water was added to the reaction mixture and the product extracted by shaking the reaction mixture with dichloromethane in a separating funnel.The dichloromethane layer was washed successively with water and brine, dried over anhydrous sodium sulfate. Evaporation of the solvent gave theproduct. 11a-l Recrystallized with various solvent like chloroform, ethanol, methanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65.45% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 8h; | Synthesis of Substituted Benzimidazole Derivatives Bearing 1-[(4-phenyl)carbonyl]piperazinyl alkyl benzo(d) imidazole derivatives11a-l General procedure: A solution of 2-chloroalkyl/aryl substitutedwith or without N-substitution as well as with or without 5 and/or 6-substituted benzimidazole derivative (1.75g,0.01051mol) and 1-[(4-phenyl)carbonyl]piperazine (3g,0.0105mol) in N, N dimethylformamide was taken in a RBF.K2CO3(2gm,) was added to the reaction mixture. The reaction mixture was stirred for 8h at 80°C on a magnetic stirrer (heat + stirring). The progress of the reaction was monitored by thin layer chromatography (TLC).Upon completion of the reaction, water was added to the reaction mixture and the product extracted by shaking the reaction mixture with dichloromethane in a separating funnel.The dichloromethane layer was washed successively with water and brine, dried over anhydrous sodium sulfate. Evaporation of the solvent gave theproduct. 11a-l Recrystallized with various solvent like chloroform, ethanol, methanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 8h; | Synthesis of Substituted Benzimidazole Derivatives Bearing 1-[(4-phenyl)carbonyl]piperazinyl alkyl benzo(d) imidazole derivatives11a-l General procedure: A solution of 2-chloroalkyl/aryl substitutedwith or without N-substitution as well as with or without 5 and/or 6-substituted benzimidazole derivative (1.75g,0.01051mol) and 1-[(4-phenyl)carbonyl]piperazine (3g,0.0105mol) in N, N dimethylformamide was taken in a RBF.K2CO3(2gm,) was added to the reaction mixture. The reaction mixture was stirred for 8h at 80°C on a magnetic stirrer (heat + stirring). The progress of the reaction was monitored by thin layer chromatography (TLC).Upon completion of the reaction, water was added to the reaction mixture and the product extracted by shaking the reaction mixture with dichloromethane in a separating funnel.The dichloromethane layer was washed successively with water and brine, dried over anhydrous sodium sulfate. Evaporation of the solvent gave theproduct. 11a-l Recrystallized with various solvent like chloroform, ethanol, methanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.15% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 8h; | Synthesis of Substituted Benzimidazole Derivatives Bearing 1-[(4-phenyl)carbonyl]piperazinyl alkyl benzo(d) imidazole derivatives11a-l General procedure: A solution of 2-chloroalkyl/aryl substitutedwith or without N-substitution as well as with or without 5 and/or 6-substituted benzimidazole derivative (1.75g,0.01051mol) and 1-[(4-phenyl)carbonyl]piperazine (3g,0.0105mol) in N, N dimethylformamide was taken in a RBF.K2CO3(2gm,) was added to the reaction mixture. The reaction mixture was stirred for 8h at 80°C on a magnetic stirrer (heat + stirring). The progress of the reaction was monitored by thin layer chromatography (TLC).Upon completion of the reaction, water was added to the reaction mixture and the product extracted by shaking the reaction mixture with dichloromethane in a separating funnel.The dichloromethane layer was washed successively with water and brine, dried over anhydrous sodium sulfate. Evaporation of the solvent gave theproduct. 11a-l Recrystallized with various solvent like chloroform, ethanol, methanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.55% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 8h; | Synthesis of Substituted Benzimidazole Derivatives Bearing 1-[(4-phenyl)carbonyl]piperazinyl alkyl benzo(d) imidazole derivatives11a-l General procedure: A solution of 2-chloroalkyl/aryl substitutedwith or without N-substitution as well as with or without 5 and/or 6-substituted benzimidazole derivative (1.75g,0.01051mol) and 1-[(4-phenyl)carbonyl]piperazine (3g,0.0105mol) in N, N dimethylformamide was taken in a RBF.K2CO3(2gm,) was added to the reaction mixture. The reaction mixture was stirred for 8h at 80°C on a magnetic stirrer (heat + stirring). The progress of the reaction was monitored by thin layer chromatography (TLC).Upon completion of the reaction, water was added to the reaction mixture and the product extracted by shaking the reaction mixture with dichloromethane in a separating funnel.The dichloromethane layer was washed successively with water and brine, dried over anhydrous sodium sulfate. Evaporation of the solvent gave theproduct. 11a-l Recrystallized with various solvent like chloroform, ethanol, methanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.35% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 8h; | Synthesis of Substituted Benzimidazole Derivatives Bearing 1-[(4-phenyl)carbonyl]piperazinyl alkyl benzo(d) imidazole derivatives11a-l General procedure: A solution of 2-chloroalkyl/aryl substitutedwith or without N-substitution as well as with or without 5 and/or 6-substituted benzimidazole derivative (1.75g,0.01051mol) and 1-[(4-phenyl)carbonyl]piperazine (3g,0.0105mol) in N, N dimethylformamide was taken in a RBF.K2CO3(2gm,) was added to the reaction mixture. The reaction mixture was stirred for 8h at 80°C on a magnetic stirrer (heat + stirring). The progress of the reaction was monitored by thin layer chromatography (TLC).Upon completion of the reaction, water was added to the reaction mixture and the product extracted by shaking the reaction mixture with dichloromethane in a separating funnel.The dichloromethane layer was washed successively with water and brine, dried over anhydrous sodium sulfate. Evaporation of the solvent gave theproduct. 11a-l Recrystallized with various solvent like chloroform, ethanol, methanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 8h; | Synthesis of Substituted Benzimidazole Derivatives Bearing 1-[(4-phenyl)carbonyl]piperazinyl alkyl benzo(d) imidazole derivatives11a-l General procedure: A solution of 2-chloroalkyl/aryl substitutedwith or without N-substitution as well as with or without 5 and/or 6-substituted benzimidazole derivative (1.75g,0.01051mol) and 1-[(4-phenyl)carbonyl]piperazine (3g,0.0105mol) in N, N dimethylformamide was taken in a RBF.K2CO3(2gm,) was added to the reaction mixture. The reaction mixture was stirred for 8h at 80°C on a magnetic stirrer (heat + stirring). The progress of the reaction was monitored by thin layer chromatography (TLC).Upon completion of the reaction, water was added to the reaction mixture and the product extracted by shaking the reaction mixture with dichloromethane in a separating funnel.The dichloromethane layer was washed successively with water and brine, dried over anhydrous sodium sulfate. Evaporation of the solvent gave theproduct. 11a-l Recrystallized with various solvent like chloroform, ethanol, methanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 8h; | Synthesis of Substituted Benzimidazole Derivatives Bearing 1-[(4-phenyl)carbonyl]piperazinyl alkyl benzo(d) imidazole derivatives11a-l General procedure: A solution of 2-chloroalkyl/aryl substitutedwith or without N-substitution as well as with or without 5 and/or 6-substituted benzimidazole derivative (1.75g,0.01051mol) and 1-[(4-phenyl)carbonyl]piperazine (3g,0.0105mol) in N, N dimethylformamide was taken in a RBF.K2CO3(2gm,) was added to the reaction mixture. The reaction mixture was stirred for 8h at 80°C on a magnetic stirrer (heat + stirring). The progress of the reaction was monitored by thin layer chromatography (TLC).Upon completion of the reaction, water was added to the reaction mixture and the product extracted by shaking the reaction mixture with dichloromethane in a separating funnel.The dichloromethane layer was washed successively with water and brine, dried over anhydrous sodium sulfate. Evaporation of the solvent gave theproduct. 11a-l Recrystallized with various solvent like chloroform, ethanol, methanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 8h; | Synthesis of Substituted Benzimidazole Derivatives Bearing 1-[(4-phenyl)carbonyl]piperazinyl alkyl benzo(d) imidazole derivatives11a-l General procedure: A solution of 2-chloroalkyl/aryl substitutedwith or without N-substitution as well as with or without 5 and/or 6-substituted benzimidazole derivative (1.75g,0.01051mol) and 1-[(4-phenyl)carbonyl]piperazine (3g,0.0105mol) in N, N dimethylformamide was taken in a RBF.K2CO3(2gm,) was added to the reaction mixture. The reaction mixture was stirred for 8h at 80°C on a magnetic stirrer (heat + stirring). The progress of the reaction was monitored by thin layer chromatography (TLC).Upon completion of the reaction, water was added to the reaction mixture and the product extracted by shaking the reaction mixture with dichloromethane in a separating funnel.The dichloromethane layer was washed successively with water and brine, dried over anhydrous sodium sulfate. Evaporation of the solvent gave theproduct. 11a-l Recrystallized with various solvent like chloroform, ethanol, methanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 8h; | Synthesis of Substituted Benzimidazole Derivatives Bearing 1-[(4-phenyl)carbonyl]piperazinyl alkyl benzo(d) imidazole derivatives11a-l General procedure: A solution of 2-chloroalkyl/aryl substitutedwith or without N-substitution as well as with or without 5 and/or 6-substituted benzimidazole derivative (1.75g,0.01051mol) and 1-[(4-phenyl)carbonyl]piperazine (3g,0.0105mol) in N, N dimethylformamide was taken in a RBF.K2CO3(2gm,) was added to the reaction mixture. The reaction mixture was stirred for 8h at 80°C on a magnetic stirrer (heat + stirring). The progress of the reaction was monitored by thin layer chromatography (TLC).Upon completion of the reaction, water was added to the reaction mixture and the product extracted by shaking the reaction mixture with dichloromethane in a separating funnel.The dichloromethane layer was washed successively with water and brine, dried over anhydrous sodium sulfate. Evaporation of the solvent gave theproduct. 11a-l Recrystallized with various solvent like chloroform, ethanol, methanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 8h; | Synthesis of Substituted Benzimidazole Derivatives Bearing 1-[(4-phenyl)carbonyl]piperazinyl alkyl benzo(d) imidazole derivatives11a-l General procedure: A solution of 2-chloroalkyl/aryl substitutedwith or without N-substitution as well as with or without 5 and/or 6-substituted benzimidazole derivative (1.75g,0.01051mol) and 1-[(4-phenyl)carbonyl]piperazine (3g,0.0105mol) in N, N dimethylformamide was taken in a RBF.K2CO3(2gm,) was added to the reaction mixture. The reaction mixture was stirred for 8h at 80°C on a magnetic stirrer (heat + stirring). The progress of the reaction was monitored by thin layer chromatography (TLC).Upon completion of the reaction, water was added to the reaction mixture and the product extracted by shaking the reaction mixture with dichloromethane in a separating funnel.The dichloromethane layer was washed successively with water and brine, dried over anhydrous sodium sulfate. Evaporation of the solvent gave theproduct. 11a-l Recrystallized with various solvent like chloroform, ethanol, methanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 25℃; for 24h; | 6 4.1.4. General procedure for the synthesis of 9a-j General procedure: The solution of 8 (1 equiv) and substituted phenyl piperazine (1 equiv) in dry DMF (5 ml) was cooled to 0 °C. The N-ethyl-N′-(dimethyaminopropyl)carbodimide hydrochloride (EDC·HCl) (1 equiv), 1-hyroxybenzotriazole hydrate (HOBt·H2O) (1 equiv) and DIPEA (2 equiv) were added and the resulting mixture stirred for 24 h at room temperature. H2O (40 ml) was added to reaction mass and extracted with ethylacetate (40 ml × 3). The combined organic layer was washed with saturated aqueous NaHCO3 solution (30 ml), brine (30 ml), dried over MgSO4 and concentrated to give crude mass which were purified on silica gel CC to afforded desired products 9a-j. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 0 - 20℃; | Preparation of Compound 2004., 4E-1-(4-benzoylpiperazin-1 -yl)-3-(1-3- (dimethylamino)propyl)-2-methyl-1 H-indol-3-yI)prop-2-en-1 -one To a stirred suspension of (E)3-(1-(3-(dimethylamino)propyl)-2-methyl-1H-’ndol-3-yl)acrylic acid (86 mg, 0 3 mmol) in DCM was added phenyl (piperazin-1-yl) methanone(86 mg, 0 45 mmol) Et3N (60 mg, 06 mmol), EDC (115 mg, 06 mmol) and HOBt(81 mg, 0.6 mmcl) were then added one by one at 0 C. The mixture was then allowedto warm to room temperature and stirred overnight. The resultant was quenched withwater, extracted with ethyl acetate, washed with solutions of NH4CI and brine,concentrated and purified by prep-HPLC to give a colorless oil (29 mg, 20%).1H NMR (400 MHz, CDCI3): 68.07 (d, J= 15.6 Hz, IH), 7.83 (s, IH), 7.46-7.39 (im, 6H),7.29-7.24 (m, 2H), 6.85 (d, J = 16.4 Hz, 1H), 4.21 (t, J = 7.2 Hz, 2H), 3.86-3.74 (m,6H), 3.56-3.52 (m, 2H), 2.59 (s, 3H), 2.31 (it, J = 6.4 Hz, 2H), 2.26 (is, 6H), 1.97-1.91(m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: N-Benzoylpiperazine; tert-butyl methyl(3-oxopropyl)carbamate In methanol for 1h; Stage #2: With sodium tetrahydroborate In methanol for 4h; | 9 Synthesis of tert-butyl (3-(4-benzoylpiperazin-l-yl)propyl)(methyl)carbamate To a solution tert-butyl methyl(3-oxopropyl)carbamate (0.57g, 3.29mmol) in methanol (20ml), 1- Benzoylpiperazine (0.63g, 3.29mmol) was added. The reaction mixture was stirred for an hour, and sodium borohydride (0.25g, 6.58mmol) was added. The mixture was then stirred for another 4h and extracted with ethyl acetate/water. The organic layer was collected and dried over sodium sulfate. The solvent was evaporated, and the residue was purified by flash chromatography to give the product as a white solid (0.84g, 70%). 1HNMR (300 MHz, CD2C12, δ): 7.41 (m, 5H), 3.50 (m, 4H), 3.24 (t, J = 6.0Hz, 2H), 2.83 (s, 3H), 2.36 (m, 6H), 1.69 (m, 2H), 1.43 (s, 9H). |
With sodium borohydrid In methanol | 9 Synthesis of tert-butyl (3-(4-benzoylpiperazin-1-yl)propyl)(methyl)carbamate Synthesis of tert-butyl (3-(4-benzoylpiperazin-1-yl)propyl)(methyl)carbamate To a solution tert-butyl methyl(3-oxopropyl)carbamate (0.57 g, 3.29 mmol) in methanol (20 ml), 1-Benzoylpiperazine (0.63 g, 3.29 mmol) was added. The reaction mixture was stirred for an hour, and sodium borohydride (0.25 g, 6.58 mmol) was added. The mixture was then stirred for another 4 h and extracted with ethyl acetate/water. The organic layer was collected and dried over sodium sulfate. The solvent was evaporated, and the residue was purified by flash chromatography to give the product as a white solid (0.84 g, 70%). 1HNMR (300 MHz, CD2Cl2, δ): 7.41 (m, 5H), 3.50 (m, 4H), 3.24 (t, J=6.0 Hz, 2H), 2.83 (s, 3H), 2.36 (m, 6H), 1.69 (m, 2H), 1.43 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With potassium carbonate In N,N-dimethyl-formamide at 60℃; | |
98% | With potassium carbonate In N,N-dimethyl-formamide at 0 - 60℃; | (4-(3-Methoxy-4-nitrophenyl)piperazin-1-yl)(phenyl)methanone (12) Following the same procedureadopted for the synthesis of 5, the reaction of amine 4 with compound 10 (1.49 g, 8.71 mmol) affordedthe title compound 12 as as bright yellow amorphous solid (2.91 g, 98%), m.p. 185-187 °C. IR (KBr):3021, 1627, 1575, 1488, 1461, 1436, 1383, 1336, 1314, 1245, 1156, 1102, 1080 cm-1. 1H-NMR (DCl3):δ 3.40-3.50 (br. s, 4H, -CH2NCH2-), 3.94 (s, 3H, -OCH3), 4.64 (br. s, 4H, -CH2NCH2-), 6.33 (d, 1H,J = 2.4 Hz, Ar-H), 6.43 (dd, 1H, J = 2.4, 9.1 Hz, Ar-H), 7.45 (m, 5H, Ar-H), 8.00 (d, 1H, J = 9.1 Hz,Ar-H). 13C-NMR (CDCl3): δ 47.01, 56.23, 97.62, 105.75, 127.08, 128.61, 128.74, 130.16, 134.97,155.23, 156.07, 170.55. Anal. Calcd for C18H19N3O4: C, 63.33; H, 5.61; and N, 12.31. Found: C,63.26; H, 5.66; and N, 12.26. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With potassium carbonate In N,N-dimethyl-formamide at 60℃; | |
97% | With potassium carbonate In N,N-dimethyl-formamide at 0 - 60℃; | (4-(3-(Methoxymethoxy)-4-nitrophenyl)piperazin-1-yl)(phenyl)methanone (13) Following the sameprocedure adopted for the synthesis of 5, the reaction of amine 4 with compound 11 (4.10 g, 21.39 mmol)afforded the title compound 13 as light yellow solid (7.34 g, 97%), m.p. 189-190 °C. IR (KBr): 3032,1675, 1620, 1575, 1490, 1461, 1436, 1383, 1336, 1314, 1249, 1150, 1102, 1078, 1035 cm-1. 1H-NMR(CDCl3): δ 3.31-3.33 (br. s, 4H, -CH2NCH2-), 3.45 (s, 3H, -OCH3), 3.85 (br. s, 4H, -CH2NCH2-), 5.21(s, 2H, -OCH2O-), 6.42 (dd, 1H, J = 2.4, 9.4 Hz, Ar-H), 6.56 (d, 1H, J = 2.4 Hz, Ar-H), 7.36 (m, 5H,Ar-H), 7.85 (d, 1H, J = 9.3 Hz, Ar-H). 13C-NMR (CDCl3): δ 46.99, 56.53, 67.02, 95.38, 101.37,106.83, 126.91, 128.24, 128.42, 129.92, 134.87, 153.48, 154.77, 162.33, 170.28. Anal. Calcd forC19H21N3O5: C, 61.45; H, 5.70; and N, 11.31. Found: C, 61.41; H, 5.75; and N, 11.25. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With dipotassium hydrogenphosphate In N,N-dimethyl-formamide at 0 - 20℃; for 3h; Inert atmosphere; | |
With potassium carbonate In dichloromethane at 0 - 25℃; Inert atmosphere; | ||
With potassium carbonate In dichloromethane at 20℃; Inert atmosphere; |
With potassium carbonate In dichloromethane at 0 - 20℃; Inert atmosphere; | ||
With dipotassium hydrogenphosphate In N,N-dimethyl-formamide at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With palladium diacetate; sodium carbonate at 50℃; for 9h; chemoselective reaction; | |
65% | With palladium diacetate; sodium carbonate at 50℃; for 9h; | 26 Palladium acetate (0.01 mmol) was added to the 25 mL reaction flask in turn.Iodo indole (0.5mmol),Amine (0.5 mmol),Sodium carbonate (1.0 mmol) and polyethylene glycol-400 (2.0 g),And introduce an atmospheric pressure of carbon monoxide.The mixture was stirred at 50 ° C for 9 hours.Cool to room temperature,Then add 15 mL of saturated brine.It was extracted three times with ethyl acetate.Finally, the organic solvent is distilled off under reduced pressure, and then subjected to column chromatography to obtain a white solid product.The yield was 65%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 24h; | 1 4.2.14. General procedure for 28-35 General procedure: To a mixture of 1-benzoylpiperazine (1.0 eq) and potassium carbonate (2.0 eq) in dimethylformamide was added dropwise a solution of the corresponding substituted 9-bromo-9H-fluorene (1.0 eq) in dimethylformamide (The synthesis of 9-bromo-9H-fluorene derivatives is reported in supporting information). After stirring for 24 h at room temperature, solvent was removed and the crude residue was dissolved in diethyl ether, washed with brine, dried over magnesium sulfate,filtered and concentrated under vacuum. The residue was purified by flash chromatography as indicated in each case to afford the title compound. Reagents: 1-Benzoylpiperazine (0.15 mmol, 29 mg), potassium carbonate (0.30 mmol, 42 mg) and 9-bromo-2-hexyl-9H-fluorene (0.15 mmol, 50 mg). The crude product was purified by flash chromatography (isocratic, petroleum ether/ethyl acetate 80/20) to afford a yellow oil (66 mg, 99%). TLC Rf: 0.34 (petroleum ether/ethyl acetate 80/20). IR (cm-1): 697, 708, 739, 766, 1001, 1137, 1256, 1277, 1426, 1455, 1632, 1674, 1715, 2854, 2925. HPLC: method 2, rt = 2.67 min purity 98%. 1H NMR (300 MHz, CDCl3) δ (ppm): 0.93 (t, J = 7.2 Hz, 3H); 1.24-1.48 (m, 6H); 1.63-1.76 (m, 2H); 2.44 (s, 2H); 2.72 (t, J = 7.8 Hz, 2H); 2.91 (s, 2H); 3.38 (s, 2H); 3.84 (s, 2H); 4.88 (s, 1H); 7.23 (dd, J = 1.5 Hz, 7.5 Hz, 1H); 7.29 (td, J = 1.2 Hz, 7.5 Hz, 1H); 7.34-7.42 (m, 6H); 7.46 (s, 1H); 7.61 (d, J = 7.5 Hz, 1H); 7.63 (d, J = 7.5 Hz, 1H); 7.67 (d, J = 7.5 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ (ppm): 14.1 (CH3); 22.7 (CH2); 29.0 (CH2); 31.8 (2 * CH2); 36.2 (CH2); 43.0 (CH2); 48.5 (CH2); 48.8 (CH2); 49.7 (CH2); 69.9 (CH); 119.5 (CH); 119.6 (CH); 125.9 (CH); 126.0 (CH); 126.7 (CH); 127.1 (2 * CH); 128.3 (CH); 128.4 (2 * CH); 128.5 (CH); 129.6 (CH); 135.9 (C); 138.7 (C); 141.2 (C); 142.4 (C); 143.3 (C); 143.6 (C); 170.3 (C). MS (DCI/CH4) m/z: 438.27 [M]. HRMS (DCI/CH4): for C30H34N2O [M]: calcd: 438.2671; found: 438.2660. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 24h; | 2 4.2.14. General procedure for 28-35 General procedure: To a mixture of 1-benzoylpiperazine (1.0 eq) and potassium carbonate (2.0 eq) in dimethylformamide was added dropwise a solution of the corresponding substituted 9-bromo-9H-fluorene (1.0 eq) in dimethylformamide (The synthesis of 9-bromo-9H-fluorene derivatives is reported in supporting information). After stirring for 24 h at room temperature, solvent was removed and the crude residue was dissolved in diethyl ether, washed with brine, dried over magnesium sulfate,filtered and concentrated under vacuum. The residue was purified by flash chromatography as indicated in each case to afford the title compound. Reagents: 1-Benzoylpiperazine (0.16 mmol, 30 mg), potassium carbonate (0.31 mmol, 43 mg) and 9-bromo-2-octyl-9H-fluorene (0.16 mmol, 55 mg). The crude product was purified by flash chromatography (gradient, 100% petroleum ether to 100% ethyl acetate in 15 min) to afford a yellow oil (38 mg, 53%). TLC Rf: 0.10 (petroleum ether/ethyl acetate 90/10). IR (cm-1): 697, 708, 740, 765, 828, 1001, 1015, 1141, 1154, 1255, 1277, 1302, 1425, 1455, 1634, 1715, 2853, 2923. HPLC: method 2, rt = 7.63 min, purity 97%. 1H NMR (300 MHz, CDCl3) δ (ppm): 0.82-1.01 (m, 3H); 1.23-1.47 (m, 10H); 1.59-1.78 (m, 2H); 2.43 (s, 2H); 2.72 (t, J = 7.8 Hz, 2H); 2.92 (s, 2H); 3.38 (s, 2H); 3.85 (s, 2H); 4.88 (s, 1H); 7.23 (d, J = 7.8 Hz, 1H); 7.30 (td, J = 1.5 Hz, 7.5 Hz, 1H); 7.34-7.43 (m, 6H); 7.47 (s, 1H); 7.61 (d, J = 7.5 Hz, 1H); 7.63 (d, J = 7.5 Hz, 1H); 7.67 (d, J = 7.1 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ (ppm): 14.2 (CH3); 22.7 (CH2); 29.3 (CH2); 29.4 (CH2); 29.5 (CH2); 31.8 (CH2); 31.9 (CH2); 36.2 (CH2); 43.0 (CH2); 48.4 (CH2); 48.5 (CH2); 49.7 (CH2); 69.9 (CH); 119.5 (CH); 119.6 (CH); 125.8 (CH); 125.9 (CH); 126.7 (CH); 127.1 (2 * CH); 128.3 (CH); 128.4 (2 * CH); 128.5 (CH); 129.6 (CH); 135.9 (C); 138.7 (C); 141.2 (C); 142.4 (C); 143.3 (C); 143.6 (C); 170.3 (C). MS (DCI/CH4) m/z: 467.31 [M+H+], 277.20 [M-189]. HRMS (DCI/CH4): for C32H39N2O [M+H+]: calcd: 467.3062; found: 467.3063. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 24h; | 3 4.2.14. General procedure for 28-35 General procedure: To a mixture of 1-benzoylpiperazine (1.0 eq) and potassium carbonate (2.0 eq) in dimethylformamide was added dropwise a solution of the corresponding substituted 9-bromo-9H-fluorene (1.0 eq) in dimethylformamide (The synthesis of 9-bromo-9H-fluorene derivatives is reported in supporting information). After stirring for 24 h at room temperature, solvent was removed and the crude residue was dissolved in diethyl ether, washed with brine, dried over magnesium sulfate,filtered and concentrated under vacuum. The residue was purified by flash chromatography as indicated in each case to afford the title compound. Reagents: 1-Benzoylpiperazine (0.08 mmol, 15 mg), potassium carbonate (0.15 mmol, 20 mg) and 9-bromo-3-hexyl-9H-fluorene (0.08 mmol, 25 mg). The crude product was purified by flash chromatography (isocratic, petroleum ether/ethyl acetate 70/30 in 15 min) to afford a yellow oil (18 mg, 56%). TLC Rf: 0.11 (petroleum ether/ethyl acetate 80/20). IR (cm-1): 630, 674, 697, 708, 739, 768, 787, 1001, 1015, 1142, 1155, 1255, 1277, 1301, 1424, 1447, 1633, 2854, 2925. HPLC: method 2, rt = 2.56 min, purity 97%. 1H NMR (300 MHz, CDCl3) δ (ppm): 0.85-1.00 (m, 3H); 1.29-1.48 (m, 6H); 1.62-1.77 (m, 2H); 2.46 (s, 2H); 2.72 (t, J = 7.5 Hz, 2H); 2.86 (s, 2H); 3.38 (s, 2H); 3.82 (s, 2H); 4.87 (s, 1H); 7.15 (dd, J = 1.5 Hz, 7.5 Hz, 1H); 7.32 (td, J = 1.5 Hz, 7.5 Hz, 1H); 7.35-7.48 (m, 6H); 7.53 (s, 1H); 7.55 (d, J = 5.4 Hz, 1H), 7.64 (d, J = 7.5 Hz, 1H); 7.70 (d, J = 7.5 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ (ppm): 14.1 (CH3); 22.6 (CH2); 29.1 (CH2); 31.7 (CH2); 31.8 (CH2); 36.1 (CH2); 43.0 (CH2); 48.4 (CH2); 48.8 (CH2); 49.5 (CH2); 69.7 (CH); 119.7 (CH); 119.8 (CH); 125.6 (CH); 125.9 (CH); 127.0 (CH); 127.1 (2 * CH); 127.5 (CH); 128.2 (CH); 128.4 (2 * CH); 129.6 (CH); 135.9 (C); 140.7 (C); 141.1 (C); 141.2 (C); 143.3 (C); 143.8 (C); 170.3 (C). MS (DCI/CH4) m/z: 438.26 [M+H+], 249.16 [M-188]. HRMS (DCI/CH4): for C30H34N2O [M+H+]: calcd: 438.2671; found: 438.2674. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 24h; | 4 4.2.14. General procedure for 28-35 General procedure: To a mixture of 1-benzoylpiperazine (1.0 eq) and potassium carbonate (2.0 eq) in dimethylformamide was added dropwise a solution of the corresponding substituted 9-bromo-9H-fluorene (1.0 eq) in dimethylformamide (The synthesis of 9-bromo-9H-fluorene derivatives is reported in supporting information). After stirring for 24 h at room temperature, solvent was removed and the crude residue was dissolved in diethyl ether, washed with brine, dried over magnesium sulfate,filtered and concentrated under vacuum. The residue was purified by flash chromatography as indicated in each case to afford the title compound. Reagents: 1-Benzoylpiperazine (0.20 mmol, 38 mg), potassium carbonate (0.40 mmol, 55 mg) and 9-bromo-3-methoxy-9H-fluorene (0.20 mmol, 55 mg). The crude product was purified by flash chromatography (isocratic, petroleum ether/ethyl acetate 80/20 in 15 min) to afford a brown solid (64 mg, 83%). TLC Rf: 0.17 (petroleum ether/ethyl acetate 80/20); mp: 90 °C; IR (cm-1): 615, 632, 669, 709, 739, 769, 846, 1000, 1016, 1031, 1169, 1212, 1277, 1427, 1453, 1489, 1577, 1628, 2830, 2934. HPLC: method 2, rt = 1.94 min, purity 97%. 1H NMR (300 MHz, CDCl3) δ (ppm): 2.44 (s, 2H); 2.85 (s, 2H); 3.37 (s, 2H); 3.82 (s, 2H); 3.91 (s, 3H); 4.85 (s, 1H); 6.88 (dd, J = 2.4 Hz, 8.4 Hz, 1H); 7.33 (td, J = 1.2 Hz, 7.2 Hz, 1H); 7.36-7.45 (m, 7H); 7.54 (d, J = 8.4 Hz, 1H); 7.64 (d, J = 6.6 Hz, 1H); 7.68 (d, J = 6.9 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ (ppm): 42.9 (CH2); 48.5 (CH2); 48.7 (CH2); 49.5 (CH2); 69.4 (CH); 105.2 (CH); 113.1 (CH); 119.8 (CH); 125.8 (CH); 126.6 (CH); 127.1 (2 * CH); 127.3 (CH); 128.3 (CH); 128.4 (2 * CH); 129.6 (CH); 135.4 (C); 135.9 (C); 140.9 (C); 142.6 (C); 144.4 (C); 160.3 (C); 170.3 (C). MS (DCI/CH4) m/z: 384.18 [M]. HRMS (DCI/CH4): for C25H24N2O2 [M]: calcd: 384.1838; found: 384.1835. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 24h; | 5 4.2.14. General procedure for 28-35 General procedure: To a mixture of 1-benzoylpiperazine (1.0 eq) and potassium carbonate (2.0 eq) in dimethylformamide was added dropwise a solution of the corresponding substituted 9-bromo-9H-fluorene (1.0 eq) in dimethylformamide (The synthesis of 9-bromo-9H-fluorene derivatives is reported in supporting information). After stirring for 24 h at room temperature, solvent was removed and the crude residue was dissolved in diethyl ether, washed with brine, dried over magnesium sulfate,filtered and concentrated under vacuum. The residue was purified by flash chromatography as indicated in each case to afford the title compound. Reagents: 1-Benzoylpiperazine (0.23 mmol, 43 mg), potassium carbonate (0.45 mmol, 62 mg) and 9-bromo-3-propoxy-9H-fluorene (0.23 mmol, 68 mg). The crude product was purified by flash chromatography (gradient, 100% petroleum ether to 100% ethyl acetate in 15 min) to afford a brown oil (20 mg, 22%). TLC Rf: 0.20 (petroleum ether/ethyl acetate 70/30). IR (cm-1): 670, 709, 727, 768, 907, 980, 1001, 1016, 1142, 1192, 1256, 1277, 1427, 1448, 1490, 1577, 1628, 2855, 2928. HPLC: method 2, rt = 3.40 min, purity 95%. 1H NMR (300 MHz, CDCl3) δ (ppm): 1.11 (t, J = 7.5 Hz, 3H); 1.89 (quint, J = 7.5 Hz, 2H); 2.44 (s, 2H); 2.86 (s, 2H); 3.37 (s, 2H); 3.80 (s, 2H); 4.04 (t, J = 6.6 Hz, 1H); 4.86 (s, 1H); 6.87 (dd, J = 2.4 Hz, 8.4 Hz, 1H); 7.24 (d, J = 2.4 Hz, 1H); 7.32 (td, J = 1.2 Hz, 7.2 Hz, 1H); 7.36-7.45 (m, 6H); 7.53 (d, J = 8.4 Hz, 1H); 7.63 (d, J = 7.2 Hz, 1H); 7.67 (d, J = 7.2 Hz, 1H). C NMR (75 MHz, CDCl3) δ (ppm): 10.6 (CH3); 22.7 (CH2); 48.6 (2 * CH2); 49.5 (2 * CH2); 69.4 (CH); 69.8 (CH2); 105.8 (CH); 113.6 (CH); 119.7 (CH); 125.8 (CH); 126.6 (CH); 127.1 (2 * CH); 127.2 (CH); 128.3 (CH); 128.4 (2 * CH); 129.6 (CH); 135.2 (C); 135.9 (C); 141.0 (C); 142.5 (C); 144.4 (C); 159.9 (C); 170.3 (C). MS (DCI/CH4) m/z: 441.25 [M+C2H5+], 412.22 [M], 223.11 [M-189]. HRMS (DCI/CH4): for C27H28N2O2 [M]: calcd: 412.2151; found: 412.2158. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 24h; | 6 4.2.14. General procedure for 28-35 General procedure: To a mixture of 1-benzoylpiperazine (1.0 eq) and potassium carbonate (2.0 eq) in dimethylformamide was added dropwise a solution of the corresponding substituted 9-bromo-9H-fluorene (1.0 eq) in dimethylformamide (The synthesis of 9-bromo-9H-fluorene derivatives is reported in supporting information). After stirring for 24 h at room temperature, solvent was removed and the crude residue was dissolved in diethyl ether, washed with brine, dried over magnesium sulfate,filtered and concentrated under vacuum. The residue was purified by flash chromatography as indicated in each case to afford the title compound. Reagents: 1-Benzoylpiperazine (0.21 mmol, 40 mg), potassium carbonate (0.42 mmol, 58 mg) and 9-bromo-3-hexyloxy-9H-fluorene (0.21 mmol, 63 mg). The crude product was purified by flash chromatography (gradient, 100% petroleum ether to 100% ethyl acetate in 15 min) to afford a brown oil (54 mg, 57%). TLC Rf: 0.20 (petroleum ether/ethyl acetate 70/30). IR (cm-1): 615, 633, 670, 708, 734, 768, 788, 847, 1000, 1016, 1142, 1190, 1256, 1277, 1301, 1426, 1449, 1490, 1578, 1630, 2857, 2929. HPLC: method 2, rt = 5.36 min, purity 98%. 1H NMR (300 MHz, CDCl3) δ (ppm): 0.91-1.02 (m, 3H); 1.33-1.47 (m, 4H); 1.47-1.61 (m, 2H); 1.87 (quin, J = 6.9 Hz, 2H); 2.44 (s, 2H); 2.86 (s, 2H); 3.37 (s, 2H); 3.82 (s, 2H); 4.07 (t, J = 6.6 Hz, 2H); 4.85 (s, 1H); 6.87 (dd, J = 2.4 Hz, 8.4 Hz, 1H); 7.24 (d, J = 2.4 Hz, 1H); 7.32 (td, J = 1.5 Hz, 7.5 Hz, 1H); 7.36-7.45 (m, 6H); 7.52 (d, J = 8.4 Hz, 1H); 7.63 (d, J = 5.2 Hz, 1H); 7.67 (d, J = 6.9 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ (ppm): 14.1 (CH3); 22.7 (CH2); 25.8 (CH2); 29.4 (CH2); 31.7 (CH2); 42.9 (CH2); 48.5 (CH2); 48.6 (CH2); 49.5 (CH2); 68.3 (CH2); 69.4 (CH); 105.8 (CH); 113.6 (CH); 119.7 (CH); 125.8 (CH); 126.6 (CH); 127.1 (2 * CH); 127.2 (CH); 128.2 (CH); 128.4 (2 * CH); 129.6 (CH); 135.2 (C); 135.9 (C); 141.0 (C); 142.5 (C); 144.4 (C); 159.9 (C); 170.3 (C). MS (DCI/CH4) m/z: 454.26 [M], 265.16 [M-189]. HRMS (DCI/CH4): for C30H34N2O2 [M]: calcd: 454.2620; found: 454.2607. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 24h; | 7 4.2.14. General procedure for 28-35 General procedure: To a mixture of 1-benzoylpiperazine (1.0 eq) and potassium carbonate (2.0 eq) in dimethylformamide was added dropwise a solution of the corresponding substituted 9-bromo-9H-fluorene (1.0 eq) in dimethylformamide (The synthesis of 9-bromo-9H-fluorene derivatives is reported in supporting information). After stirring for 24 h at room temperature, solvent was removed and the crude residue was dissolved in diethyl ether, washed with brine, dried over magnesium sulfate,filtered and concentrated under vacuum. The residue was purified by flash chromatography as indicated in each case to afford the title compound. Reagents: 1-Benzoylpiperazine (0.06 mmol, 11 mg), potassium carbonate (0.12 mmol, 16 mg) and 9-bromo-2-propoxy-9H-fluorene (0.06 mmol, 18 mg). The crude product was purified by flash chromatography (gradient, 100% petroleum ether to 100% ethyl acetate in 15 min) to afford a yellow oil (10 mg, 42%). TLC Rf: 0.34 (petroleum ether/ethyl acetate 70/30). IR (cm-1): 708, 738, 766, 824, 1002, 1141, 1277, 1454, 1632, 1716, 2868, 2927, 3047, 3449. HPLC: method 2, rt = 4.12 min, purity 95%. 1H NMR (300 MHz, CDCl3) δ (ppm): 1.12 (t, J = 7.5 Hz, 3H); 1.89 (sex, J = 6.6 Hz, 2H); 2.47 (s, 2H); 2.89 (s, 2H); 3.38 (s, 2H); 3.83 (s, 2H); 4.03 (t, J = 6.6 Hz, 2H); 4.85 (s, 1H); 6.95 (dd, J = 2.4 Hz, 8.4 Hz, 1H); 7.20 (s, 1H); 7.25 (t, J = 6.9 Hz, 1H); 7.33-7.44 (m, 6H); 7.56-7.64 (m, 3H). 13C NMR (75 MHz, CDCl3) δ (ppm): 10.3 (CH3); 22.7 (CH2); 29.7 (CH2); 42.8 (CH2); 48.6 (CH2); 49.6 (CH2); 69.9 (CH); 77.2 (CH2); 112.4 (CH); 114.5 (CH); 119.0 (CH); 120.5 (CH); 125.8 (CH); 125.9 (CH); 127.1 (2 * CH); 128.3 (CH); 128.4 (2 * CH); 129.6 (CH); 133.8 (C); 135.9 (C); 141.2 (C); 142.9 (C); 145.3 (C); 159.1 (C); 170.3 (C). MS (DCI/CH4) m/z: 413.22. HRMS (DCI/CH4): C27H29N2O2 [M+H+]: calcd: 413.2229; found: 413.2235. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 24h; | 8 4.2.14. General procedure for 28-35 General procedure: To a mixture of 1-benzoylpiperazine (1.0 eq) and potassium carbonate (2.0 eq) in dimethylformamide was added dropwise a solution of the corresponding substituted 9-bromo-9H-fluorene (1.0 eq) in dimethylformamide (The synthesis of 9-bromo-9H-fluorene derivatives is reported in supporting information). After stirring for 24 h at room temperature, solvent was removed and the crude residue was dissolved in diethyl ether, washed with brine, dried over magnesium sulfate,filtered and concentrated under vacuum. The residue was purified by flash chromatography as indicated in each case to afford the title compound. Reagents: 1-Benzoylpiperazine (0.23 mmol, 44 mg), potassium carbonate (0.46 mmol, 64 mg) and 3-(benzyloxy)-9-bromo-9H-fluorene (0.23 mmol, 81 mg). The crude product was purified by flash chromatography (gradient, 100% petroleum ether to 100% ethyl acetate in 15 min) to afford a yellow oil (54.3 mg, 50%). TLC Rf: 0.40 (petroleum ether/ethyl acetate 80/20). IR (cm-1): 697, 710, 770, 1001, 1017, 1186, 1257, 1278, 1427, 1448, 1488, 1578, 1628, 2851, 2920. HPLC: method 2, rt = 3.65 min, purity 98%. 1H NMR (300 MHz, CDCl3) δ (ppm): 2.45 (bs, 2H); 2.86 (bs, 2H); 3.38 (bs, 2H); 3.83 (bs, 2H); 4.86 (s, 1H); 5.18 (s, 2H); 6.97 (dd, J = 2.4 Hz, 8.1 Hz, 1H); 7.34 (td, J = 2.1 Hz, 7.8 Hz, 2H); 7.37-7.48 (m, 9H); 7.51 (s, 1H); 7.53 (t, J = 8.4 Hz, 2H); 7.65 (t, J = 8.1 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ (ppm): 42.9 (CH2); 48.6 (2 * CH2); 49.5 (CH2); 69.4 (CH2); 70.4 (CH2); 106.3 (CH); 113.8 (CH); 119.8 (CH); 125.9 (CH); 126.6 (CH); 127.1 (2 * CH); 127.4 (CH); 127.6 (2 * CH); 128.1 (CH); 128.3 (CH); 128.4 (2 * CH); 128.7 (2 * CH); 129.6 (CH); 135.7 (C); 135.9 (C); 137.0 (C); 140.9 (C); 142.6 (C); 144.4 (C); 159.5 (C); 170.3 (C). MS (DCI/CH4) m/z: 461.22 [M+H+]. HRMS (DCI/CH4): for C31H29N2O2 [M+H+]: calcd: 461.2229; found: 461.2235. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With C32H36ClNO2P2Ru; hydrogen In tetrahydrofuran at 120℃; for 20h; Autoclave; Green chemistry; | 36 Example 14: Morpholine formylation catalyzed by a one millionth molar amount of ruthenium complex 1c General procedure: In the nitrogen atmosphere of the glove box, 3.33 mg of ruthenium complex 1c was dissolved in 50 mL of tetrahydrofuran. After stirring, a catalyst 1c stock solution was formed. 1 ml of the above solution was added to a 125-mL Parr autoclave (0.067 mg, 0.0001 mmol). 1c), And added 9mL of tetrahydrofuran, Morpholine (8.712 g, 100 mmol). After the autoclave is sealed, it is taken out of the glove box. The carbon dioxide gas and hydrogen gas were each charged at 40 atm. The reaction system is heated to 120 ° C in an oil bath. The pressure rises to about 120 atm, After stirring for 181 hours, The reactor was then cooled to room temperature in a water bath. Slowly release the remaining gas in the fume hood, A pale yellow liquid was obtained. P-xylene (200 μL) was added to the mixture as an internal standard. The yield of N-formylmorpholine was determined by gas chromatography to be 94%. |
85% | With CF3O3S(1-)*C25H42N6Rh(1+); diphenylsilane In dichloromethane at 25℃; for 24h; High pressure; Autoclave; | |
78% | With diphenylsilane; C21H41N3NiP2 In acetonitrile at 20℃; for 24h; Autoclave; chemoselective reaction; |
With C25H42N6Rh(1+)*CF3O3S(1-); diphenylsilane In dichloromethane at 25℃; for 4h; | ||
86 %Chromat. | With dmap; hydrogen; copper diacetate In tetrahydrofuran at 90℃; for 20h; Sealed tube; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; Inert atmosphere; | General procedure for compounds 7-34. General procedure: A mixture of compound 4-6 (1 mmol) in 5 ml of dry DCM and piperazine derivative (1 mmol) was cooled in an ice bath. Then, 1.1 mmol of DCC in 5 ml of dry dichloromethane was added tothe mixture under nitrogen (N2) atmosphere. Reaction mixture was stirred for 0.5 hour in an ice bath, then 10-16 hours at room temperature. Reaction solvent was evaporated to the dryness. Residue was dissolved in hot acetonitrile then cooled in refrigerator to get the DCU precipitated. White crystalline DCU was removed by filtration. Liquid part was evaporated and crystallized from appropriate solvents to give compound 7-34 |
28% | With dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; Inert atmosphere; | General procedure for compounds 7-34. General procedure: A mixture of compound 4-6 (1 mmol) in 5 ml of dry DCM and piperazine derivative (1 mmol) was cooled in an ice bath. Then, 1.1 mmol of DCC in 5 ml of dry dichloromethane was added to the mixture under nitrogen (N2) atmosphere. Reaction mixture was stirred for 0.5 hour in an ice bath, then 10-16 hours at room temperature. Reaction solvent was evaporated to the dryness. Residue was dissolved in hot acetonitrile then cooled in refrigerator to get the DCU precipitated. White crystalline DCU was removed by filtration. Liquid part was evaporated and crystallized from appropriate solvents to give compound 7-34 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | In ethanol for 1h; Reflux; | 8 3-(1-naphthyloxy)-1-(4-(phenylcarbonyl)piperazinyl)propan-2-ol (HUHS1012) Example 8 3-(1-naphthyloxy)-1-(4-(phenylcarbonyl)piperazinyl)propan-2-ol (HUHS1012) To a solution of 2-((1-naphthyloxy)methyl)oxirane (50 mg, 0.25 mmol) in ethanol (0.50 mL) was added 4-(phenylcarbonyl)piperazine (57 mg, 0.30 mmol) at room temperature. The mixture was stirred under reflux for 1 hr. The reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give HUHS1012 (58 mg, 59%). 1H-NMR (400 MHz, CDCl3) δ 2.48-2.81 (m, 6H), 3.49 (br s, 2H), 3.86 (br s, 2H), 4.14-4.18 (dd, J=10.5 and 5.0 Hz, 1H), 4.22 (dd, J=10.5 and 5.0 Hz 1H), 4.27-4.32 (m, 1H), 6.83 (d, J=7.3 Hz, 1H), 7.37 (t, J=7.8 Hz, 1H), 7.40-7.52 (m, 8H), 7.80-7.82 (m, 1H), 8.22-8.25 (m, 1H); ESI-HRMS (positive ion, sodium formate) calcd. for C24H27N2O3 ([M+H+]): 391.2016. Found 391.2022. |
59% | In ethanol at 20℃; for 1h; | 8 Example 8: 3-(1-naphthyloxy)-1-(4-(phenylcarbonyl)piperazinyl)propan-2-ol (HUHS 1012) 2-((1-naphthyloxy)methyl) (50 mg, 0.25 mmol) 4 - (phenylcarbonyl) piperazine (0.50 ml) of the ethanol solution of oxirane (57 mg, 0.30 mmol) was added at room temperature. The mixture was stirred refluxing 1. The reaction mixture was concentrated under reduced pressure. (58 mg, 59%) was obtained by silica gel column chromatography of the crude product was purified HUHS1012 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With potassium carbonate In N,N-dimethyl-formamide at 0 - 60℃; | 4-(4-Benzoylpiperazin-1-yl)-2-nitrobenzonitrile (5) To a solution of amine 4 (1.82 g, 9.56 mmol) inDMF (20 mL) at 0 °C was added K2CO3 (3.61 g, 26.13 mmol) followed by the addition of compound 3(1.96 g, 8.67 mmol) and the reaction mixture was stirred overnight at 60 °C. After completion of thereaction (TLC analysis), the mixture was cooled to room temperature and diluted with ethyl acetate(75 mL). The solution was washed with H2O (30 mL × 3), brine (20 mL × 2) and the organic layer wasseparated, dried over Na2SO4 and evaporated under vacuum to afford the title compound 5 as as lightyellow amorphous solid (2.16 g, 74%), m.p. 196-197 °C. IR (KBr): 3063, 2999, 2929, 2233, 1670,1622, 1596, 1578, 1457, 1430, 1389, 1341, 1294, 1249, 1155, 1094, 1072 cm-1. 1H-NMR (CDCl3): δ3.47 (br. s, 4H, -CH2NCH2-), 3.79 (br. s, 4H, -CH2NCH2-), 6.99 (dd, 1H, J = 2.6, 9.4 Hz, Ar-H), 7.14(d, 1H, J = 2.7 Hz, Ar-H), 7.40-7.48 (m, 5H, Ar-H), 8.19 (d, 1H, J = 9.5 Hz, Ar-H). 13C-NMR(CDCl3): δ 46.44, 46.84, 110.05, 115.66, 118.89, 126.93, 127.10, 127.79, 128.67, 130.33, 134.69,137.79, 153.10, 170.61. Anal. Calcd for C18H16N4O3: C, 64.28; H, 4.79; and N, 16.66. Found: C,64.22; H, 4.84; and N, 16.60. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | In ethyl acetate at 20 - 60℃; | General procedure: The mixture of compound 3 (1g, 4.6mmol) and 95% ethanol (30ml) was added to morpholine (0.4g, 4.6mmol).The mixture was stirred at room temperature for 30min, then warmed up to 60°C. After the starting 3 was completely consumed (the reaction courses was monitored by TLC), evaporation of the ethanol, the crude yellow compound 4j was obtained and purified by preparative thin-layer chromatography over silica gel PF 254 (2mm, ethyl acetate: petroleum ether=1:1). Yield: 78%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With potassium carbonate In N,N-dimethyl-formamide at 130℃; | 7 4.2. General procedure for synthesis of 4-(4-substitutedpiperazin-1-yl)benzaldehyde (14-25) General procedure: A mixture of substituted piperazine (10 mmol), 4-uoroben-zaldehyde (10 mmol) and K2CO3 (2 mmol) were reuxed at130 C in DMF for 15-24 h. Thereafter, the reaction mixture waspoured into ice cold water and the precipitate that appeared wasltered and dried to accomplish formyl derivatives (14-25) in ayield of 80-90% |
78% | With potassium carbonate In N,N-dimethyl-formamide at 80 - 100℃; | |
With sodium carbonate; potassium carbonate In N,N-dimethyl-formamide at 100 - 130℃; |
With sodium carbonate; potassium carbonate In N,N-dimethyl-formamide at 90 - 100℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In tetrahydrofuran; N,N-dimethyl-formamide at 25℃; for 18h; | 5-1 Intermediate 5-1 tert-Butyl {2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-6-methyl-2H-indazol-5-yl}carbamate Intermediate 5-1 tert-Butyl {2-[2-(4-benzoylpiperazin-1-yl)-2-oxoethyl]-6-methyl-2H-indazol-5-yl}carbamate (0828) (0829) 181 mg (0.59 mmol) of {5-[(tert-butoxycarbonyl)amino]-6-methyl-2H-indazol-2-yl}acetic acid (Intermediate 4-1) and 169 mg (0.89 mmol) of phenyl(piperazin-1-yl)methanone were initially charged in 5 ml of tetrahydrofuran and 0.5 ml of N,N-dimethylformamide 91 mg (0.59 mmol) of 1-hydroxy-1H-benzotriazole hydrate, 227 mg (1.19 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.25 ml (1.79 mmol) of triethylamine were added and the mixture was stirred at 25° C. for 18 h. The mixture was diluted with water and ethyl acetate and the precipitated solid was filtered off, washed with water and diethyl ether and dried under reduced pressure. This gave 248 mg (85% of theory) of the title compound. (0830) UPLC-MS (Method A1): Rt=1.07 min (0831) MS (ESIpos): m/z=478 (M+H)+ (0832) 1H NMR (400 MHz, DMSO-d6): δ=1.42 (s, 9H), 2.24 (s, 3H), 3.32-3.82 (m, 8H), 5.41 (br. s., 2H), 7.33 (s, 1H), 7.38-7.48 (m, 5H), 7.52 (s, 1H), 8.12-8.16 (m, 1H), 8.35 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Stage #1: [6-fluoro-5-([6-(trifluoromethyl)pyridin-2-yl]carbonyl}amino)-2H-indazol-2-yl]acetic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran; N,N-dimethyl-formamide at 25℃; for 0.5h; Stage #2: N-Benzoylpiperazine In tetrahydrofuran; N,N-dimethyl-formamide at 25℃; for 0.5h; | 28 General Procedure 2a General procedure: General Procedure 2a (1470) 1.0 equivalent of the respective intermediate, 1.0 equivalent of 1-hydroxy-1H-benzotriazole hydrate and 2.0 equivalents of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were stirred in 3 ml of tetrahydrofuran and 0.33 ml of dimethylformamide at 25° C. for 30 min. 1.5 equivalents of the amine were then added and the mixture was stirred at 25° C. for 30 min. The mixture was poured into 50 ml of water, filtered off with suction, washed with water and dried. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In tetrahydrofuran at 25℃; for 18h; | 54 General Procedure 2c General procedure: General Procedure 2c (1472) 1.0 equivalent of the respective intermediate, 1.0 equivalent of 1-hydroxy-1H-benzotriazole hydrate, 2.0 equivalents of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 3.0 equivalents of triethylamine and 1.2 equivalents of the amine were stirred in tetrahydrofuran at 25° C. for 18 h. Water was added to the reaction mixture. The solid was filtered off with suction, washed with water and diethyl ether and dried. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium carbonate In dichloromethane at 40℃; for 0.5h; Green chemistry; | General procedure for the synthesis of compound I and 13. General procedure: A mixture of compounds 11 (2.74 g, 10 mmol), amine 12(11 mmol), and K2CO3 (1.66 g, 12 mmol) in CH2Cl2 (10 ml) wereheated at 40 C for 0.5 h. The progress of the reaction was monitoredby TLC, after completion of the reaction, the reaction mixturewas extracted with three portions of CH2Cl2. The orange extractswere washed with brine until neutrality, then dried over anhydrousNa2SO4 and concentrated in vacuo. Then the residue waspurified by a silica-gel column chromatography (PE/EtOAc 3:1) togive the desired compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | General procedure: General procedure for the synthesis of compounds (8a, 8b).A solution of anhydrous piperazine (5, 8.6 g, 0.1 mol) and <strong>[142-64-3]piperazine dihydrochloride</strong> (6, 31.8 g 0.2 mol) in ethanol (80 mL) were heated with vigorous stirring at 75 C for 2 h. Then a solution benzylchloride (13.9 g, 0.11 mol) or benzoyl chloride (15.4 g,0.11 mol) was added dropwise over a period of 40 min to the hotsolution. The reaction mixture was refluxed for another 2 h, the progress of the reaction was monitored by TLC. The mixture wascooled and the precipitated <strong>[142-64-3]piperazine dihydrochloride</strong> 6 was collected and washed three times with ethanol. The filtrate combined with the washes was concentrated in vacuo to give the N-benzylpiperazineor N-benzoylpiperazine hydrochloride which was then treated with 6 M NaOH to pH > 12. The aqueous layerof crude N-benzylpiperazine or N-benzoylpiperazine was extractedinto CH2Cl2 (3 50 mL). The combined organic extracts were driedover Na2SO4 and concentrated in vacuo. The crude oily product was purified by flash column chromatography on silica gel (MeOHCH2Cl21:3) to give 8a (18.4 g, 95%) or 8b (17.8 g, 94%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | Stage #1: 2-[2,5-bis(4-cyanophenyl)furan-3-yl]acetic acid With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate In tetrahydrofuran for 0.166667h; Stage #2: N-Benzoylpiperazine With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; | 5.1.14. General method for the synthesis of amides 13a-y General procedure: A mixture of 12 (0.3 mmol) and PyBOP (0.45 mmol) in THF (20 mL) was stirred for 10 min. Afterwards, the corresponding amine (0.34 mmol) and DIPEA (0.76 mmol) were given to the mixture and stirred overnight at RT. The crude mixture was evaporated, the product was dissolved in EtOAc, washed with Na2CO3 solution, and dried over Na2SO4. After evaporation, the product was purified by column chromatography (eluent: CHCl3/MeOH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With potassium carbonate In acetone for 8h; Reflux; | 3.2.2. [1,2,4]triazolo[4,3-a] quinoxaline Derivatives Bearing Substituted BenzoylpiperazineMoieties (7a-e) General procedure: A mixture of 5 (0.20 g, 1.0 mmol), monosubstituted piperazine (2.0 mmol) and anhydrouspotassium carbonate in acetone was heated at reflux with stirring for 8 h. The solvent was evaporatedunder reduced pressure, and the resulting residue dissolved in DCM. The DCM solution was washedsequentially with water and brine, dried over MgSO4, and distilled to dryness under reduced pressure.The resulting residue was purified by silica gel column chromatography with DCM and methanol(20:1). The yield, melting point, and spectral data of each compound were recorded. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With triethylamine In acetonitrile at 20℃; for 3h; | General Procedure A. Coupling using EDC/NHS to afford irreversibleinhibitors 149-154: General procedure: Compound 101 (1 equiv) (Marrano, C. et al., Bioorg. Med. Chem. (2001), 9 (7): 1923-1928) was dissolved in ACN and EDC•HC1 (1 equiv) and NHS (1 equiv) were added. The solution was stirred at room temperature for 16 h. The solution was diluted with ethyl acetate and washed with water, saturated NaHCO3solution and brine. The ethyl acetate solution was dried with MgSO4, filtered and concentrated to afford the crude NHS ester typically as a white solid. The NHS ester was carried forward without further purification. Cmde NHS ester (1.05 equiv) was dissolved in 10 mL ACN. Triethylamine (1 equiv) and the desired amine intermediate (1 equiv) were added and the reaction was left to stir at room temperature for 3 h or kept overnight. The solution was diluted with ethyl acetate, washed with saturated NaHCO3 solution and brine, dried with MgSO4, filtered and concentrated to afford typically white sticky foams.; yl)carbamate (149): Compound 149 was prepared from Boc-deprotected 140 and compound 101 using General Procedure A to collect 151 mg (31 %) of the desired product as a white, sticky foam. ‘H NMR (300 MI-Tz, (CD3)250 at 80 C) 7.73-7.65 (br s, 1H), 7.44-7.22 (m, 10 H), 7.05-6.98 (br s, 1H), 6. 17-6.09 (dd, J= 17.1, 10.0 Hz, 1H), 6.01-5.95 (dd, J= 17.1, 2.3 Hz, 1H), 5.47-5.44 (dd, J 10.0, 2.3 Hz, 1H), 4.97 (s, 2H), 4.41-4.36 (m, 1H), 3.55-3.36 (m, 8H), 3.09-3.02 (m, 2H), 1.61-1.49 (m, 2H), 1.44-1.33 (m, 2H), 1.32-1.20 (m, 2H), ‘3C NMR (75 MHz, (CD3)250 at 80 C)170.1, 168.9, 164.2, 136.7, 135.4, 131.7, 129.1, 127.9, 127.8, 127.2, 127.1, 126.4,123.7, 65.1, 50.3, 37.9, 30.8, 28.3, 22.2; HRMS (ESI-QTOF) m/z [M + Naib calcd for C28H34N4O5Na 529.2427; found 529.2433. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | In tetrahydrofuran at 20℃; for 18h; | 131 Example 131 2-((6-(4-Benzoylpiperazin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2- phenylacetamide A solution of 2-[(6-bromo-3,5-dicyano- -e y- -pyr y su any -2-phenyl-acetamide, (synthesis described in example 6, step 1, 15 mg, 0.04 mmol) in tetrahydrofuran (1 mL) was treated with N-benzoylpiperazine (17.78 mg, 0.09 mmol) and stirred at ambient temperature for 18 hours. The product mixture was dry loaded onto SiO2 (0.9 g) and purified by silica gel chromatography (4 g RediSep cartridge eluting with 0-10% MeOH, 0-1% NH3/CH2Cl2) followed by trituration with diethyl ether to furnish 2-[[6-(4-benzoylpiperazin-1- yl)-3,5-dicyano-4-ethylpyrindin-2-yl)thio)-2-phenylacetamide (13 mg, 0.0255 mmol, 68% yield) as an off-white solid.. LCMS m/z = 509.1 [M-H]-. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.87 (br s, 1H), 7.56 - 7.43 (m, 7H), 7.43 - 7.30 (m, 4H), 5.52 (s, 1H), 3.98 (br s, 4H), 3.77 (br s, 2H), 3.52 (br s, 2H), 2.78 (q, J=7.3 Hz, 2H), 1.22 (t, J=7.3 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With potassium carbonate In tetrahydrofuran at 20℃; for 2h; Reflux; | 34.2 34.2 Preparation of N-(2-(4-benzoylpiperazin-1-yl)ethyl)-2-nitrosulfonamide 3.09 (10.0 mmol) of N-(2-bromoethyl)-2-nitrobenzenesulfonamide,1.90 g (10.0 mmol) of benzoylpiperazine and 2.76 g (20.0 mmol) of potassium carbonate were added toThe reaction was carried out in 150 ml of tetrahydrofuran at room temperature for 2 h, warmed to reflux, and the reaction was followed by TLC.After the completion of the reaction, the solvent was evaporated, evaporated, evaporated, evaporated.Column chromatography, 2.59 g of white solid, yield 62% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With N-ethyl-N,N-diisopropylamine In tetrahydrofuran Reflux; | 36.2 36.2 Preparation of 2-(2-(4-benzoylpiperazin-1-yl)ethyl)naphthyridine-1(2H)-one 2-(2-Bromoethyl)naphthyridin-1(2H)-one 0.89 g (3.5 mmol),0.67 g (3.5 mmol) of benzoylpiperazine and 0.68 g (5.25 mmol) of N,N-diisopropylethylamine were added to 25 ml of tetrahydrofuran, and the mixture was heated to reflux. The reaction was followed by TLC. In addition to the solvent, a saturated sodium chloride solution (100 mL) was added to the residue.A white solid product of 0.85 g was obtained in a yield of 67%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With potassium carbonate In acetonitrile Reflux; | 40.3 40.3 Preparation of 3-(2-(4-benzoylpiperazin-1-yl)ethyl)quinazolin-4(3H)-one 3-(2-chloroethyl)quinazolin-4(3H)-one 0.42 g (2 mmol),0.38 g (2 mmol) of benzoylpiperazine and 0.276 g (2 mmol) of potassium carbonate were added to 15 ml of acetonitrile, and the mixture was heated to reflux. The reaction was followed by TLC.Extracted with dichloromethane (50 mL×2), EtOAcq.The column was separated to give a white solid product 0.55 g, yield 76% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | Stage #1: N-(2-chloroacetyl)-N'-[bis(4-fluorophenyl)methyl]piperazine With potassium carbonate In acetone for 0.166667h; Stage #2: N-Benzoylpiperazine In acetone at 20℃; for 48h; | 2.2.2. Synthesis of Target Compounds N-[2-(4-substitutedpiperazine-1-yl)acetyl)-N’-[bis(4-fluorophenyl)methyl]piperazine (2a-i) General procedure: 0.0017 Moles (0.6484 g) of N-(2-chloroacetyl)-N’-[bis(4-fluorophenyl)methyl]-piperazine was dissolved in dry acetone (20 ml) and 0.0017 moles (0.4167 g) of potassium carbonate was added to the solution. After ten minutes of mixing, piperazine derivative (0.0017 moles) in 10 ml of acetone was added drop by drop into the mixture. Ther eaction continued mixing for two days at room temperature.The reaction was followed by thin layer chromatography inn-hexane: ethyl acetate (10:90) mobile phase and silica gel stationary phase. After the reaction was over, potassium carbonate was removed by filtration. Acetone was evaporated under vacuum. Solid crude products were crystallized by absolute ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40.36% | With benzotriazol-1-ol; diisopropyl-carbodiimide In dichloromethane at 20℃; for 2h; | 4.1.2. Preparation of derivatives 11-23 General procedure: Compound 10 (0.8 mmol, 1 eq) was dissolved into dichloromethane(5 mL) , then HOBt (1.20 mmol, 1.5 eq) , DIC (1.20 mmol, 1.5 eq) and nitrogen substituent (0.8 mmol, 1 eq) were added into the solution inturn, the mixture was stirred at room temperature for 2 h and monitoredby TLC. The reaction mixture was washed with saturated brine(15 mL) and extracted with ethyl acetate (15 mL×2). The organic layers were combined and dried by anhydrous sodium sulfate. The organiclayer was concentrated in vacuo. The residue was purified byflash column-chromatography on silica gel using ethyl petroleum/ethyl(2:1) as eluent to obtain 11-23. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: piperazine With C58H92La2N6O4Si4 In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere; Stage #2: benzaldehyde In tetrahydrofuran for 3h; Inert atmosphere; | 28 Under the protection of anhydrous oxygen-free and inert gas, 0.0153 g (1.08×10-5 mol) {L1La[N(SiMe3) was added to the reaction flask, and then 0.0931 g (1.08×10-3 mol) of piperazine was added. The azine was added to 1.35 mL of tetrahydrofuran and stirred at room temperature for 0.5 hour. Further, 0.65 mL (6.48×10-3 mol) of benzaldehyde was added, and after stirring for 3 hours, the reaction was completed, and the reaction liquid was poured into an eggplant-shaped bottle.Add a small amount of ethyl acetate to the reaction flask and wash it three times, still pour into the eggplant-shaped bottle.Add appropriate amount of silica gel, spin dry, and then load on the packed column of silica gel.The appropriate eluent (ethyl acetate: petroleum ether = 1:1) was passed through the column.Get the product,Yield 92% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With potassium carbonate In acetonitrile for 4h; Reflux; | |
70% | With potassium carbonate In acetonitrile at 100℃; for 2h; Inert atmosphere; | 8 Synthesis of (4-(2-amino-9-(3-(4-ethylpiperazin-l-yl)propyl)-9H-purin-6-yl)piperazin-l- yl)(phenyl)methanone (18): Compound 17 was dissolved in acetonitrile (5 mL), potassium carbonate (1.2 g, 0.03 mmol) and phenyl(piperazine-l -yl) methanone (0.84 g, 0.03 mmol) were added. The reaction was stirred for 2 hours under N2 atmosphere condition at 100 °C. Acetonitrile was evaporated under the vacuum, then water was added to the reaction mixture to get precipitate which was filter off to get precipitate (0.8 g, yield 70%) of product 18. 1H NMR (300 MHz, CDCI3) δ ppm 7.49 (s, 1H), 7.42 (d, J = 9 Hz, 4H), 4.63 (s, 2H), 4.26 (s, 3H), 4.09 (t, J = 6 Hz, 2H), 3.89 (s, 2H), 3.54 (s, 2H), 2.42 (d, J = 6 Hz, 8H), 2.28-2.40 (m, 3H), 1.85-2.03 (m, 3H), 1.08 (t, J = 6 Hz, 3H). ESI-MS m/z 478.34 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With nickel dichloride; 1,3-bis[2,6-diisopropylphenyl]imidazolium chloride In tetrahydrofuran at 100℃; for 15h; Inert atmosphere; | General Procedure for the synthesis of sulfinamides General procedure: An oven-dried pressure tube (15 mL) was charged with a magnetic stir bar, catalyst (5 mmol%), ligand (20 mmol%). The solvent (1.2 mL) was then added. Afterwards methyl sulfinates (0.30 mmol, 1 equiv) and amine (0.6 mmol, 2 equiv) were subsequently added into the reaction mixture. The reaction was stirred under an argon atmosphere at 100 for 15 h. After cooling to room temperature, the reaction mixture was directly removed under reduced pressure and subjected to flash column chromatography in petroleum ether/ethyl acetate to obtain the desired products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; XPhos In 2-methyltetrahydrofuran at 20℃; for 4h; | 2.2. Synthesis of triazolo-pyridazine-6-yl-substituted piperazines(5a-l) General procedure: A two-step synthesis was executed in order to obtain the target compounds’ triazolo-pyridazine-6-yl-substituted piperazines (5a-l). The first step was synthesizing the intermediate 6-chloro-3-(m-tolyl)-[1,2,4]triazolo[4,3-b]pyridazine (4) according to Jasmin et al.,2011 [23]. Compound 4 prepared by adding 10 mmol (0.89 g) pyridine (1) to a 3 mmol (0.45 g) solution of 3,6-dichloropyridazine (2) and 9 mmol (0.96 g) 5-(3-methyl- phenyl)tetrazole (3) in toluene (15 ml). The above mixture was heated to reflux for 4-5h, filtered followed by cooled and concentrated. The obtained crude residue was purified by chromatography. In the second step, compound 4 was undergone Buchwald-Hartwig reaction with corresponding 2° amines in presence of 10 mol % of Pd2(dba)3, 10 mol % of X-Phos, Sodium t-butoxide (t-BuONa) in 2-Methyltetrahydrofuran (2-Me-THF) at room temperature for 4h to obtain triazolo-pyridazine-6-yl-substituted piperazines (5a-l) in excellent yield (92-98%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | In butan-1-ol at 25℃; for 3h; | |
69% | In butan-1-ol at 25℃; for 3h; | General procedure for monoacylation of aliphaticdiamines in n-butanol General procedure: In a round bottom flask, piperazine (2c) or ethylenediamine(2d) (15 mmol) were dissolved in 10 cm3 n-butanol. To thedissolved solution the corresponding N-acylbenzotriazoles1a-1g (10 mmol) were added. The mixture was stirred at25 °C for 3 h. The reaction mixture was filtered and then-butanol was removed under reduced pressure. The residuewas dissolved in 2 cm3 methanol and loaded on a silicagel column. A mixture of hexane-ethylacetate-methanol(2:3:5) was used for elution of the pure monoacylated productswhich were dried under reduced pressure (Table 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With potassium carbonate In acetonitrile at 80℃; for 16h; Inert atmosphere; | 4.1.1 General procedures for synthesis of derivatives 2a-k General procedure: To a solution of the corresponding N-piperazinyl benzamide 1a-k in dry CH3CN (10mL/mmol of 1a-k) was added 4-chloroacetyl-piperazine-1-carboxylic acid tert-butyl ester (1 eq) and K2CO3 (3 eq) and the resulting suspension was stirred at reflux temperature (80°C) under N2 for 16h. Solvent was evaporated under reduced pressure and AcOEt (20mL) and water (20mL) were added. The organic layer was collected, dried (MgSO4) and concentrated. The residue was purified by column chromatography CH2Cl2:MeOH 30:1→9:1 yielding the pure product with good to excellent yields (69-91%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 20℃; | 4.1.8. General procedure for the synthesis of the emisuccinamides23-25 General procedure: 41 (1 equiv.) was solubilized in DMF and subsequentially EDC HCl (1equiv.), HOBt (1 equiv.), and 1-benzylpiperazine (1 equiv.), 4-benzylpiperidine (1 equiv.) or 1-benzoylpiperazine (1 equiv.) were added at 0°C. The temperature rose spontaneously at room temperature and the mixture stirred in this condition for 4-18h. The reaction was diluted with AcOEt, and the organic phase was washed with a saturated solution of NaHCO3, 1N aqueous HCl, or a saturated solution of NH4Cl and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 2h; | 4.1.3 General procedure for the preparation of final compounds 21-34 General procedure: The appropriate analogue 19a-d or 20a-b (0.3mmol) was dissolved in DMF (4mL). The appropriate product 8 or 13-15 as obtained above (0.3mmol) and K2CO3 (0.9mmol) were added and the resulting mixture was stirred at 90°C for 2h [70]. After the completion of the reaction (monitored by TLC), the mixture was diluted with DCM (200mL) and redistilled water (50mL). The resulting solution was vigorously stirred at r.t. for 1h. The organic phase was then separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (DCM:MeOH or CHCl3:MeOH=100:0→98:2→90:10 v/v). The final compounds 21-34 were converted to their respective hydrochloride salts by mixing with a few drops of hydrochloric acid (37% aq.) in MeOH at r.t. while stirring for 1h. |
36% | With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 2h; | 4.1.3 General procedure for the preparation of final compounds 21-34 General procedure: The appropriate analogue 19a-d or 20a-b (0.3mmol) was dissolved in DMF (4mL). The appropriate product 8 or 13-15 as obtained above (0.3mmol) and K2CO3 (0.9mmol) were added and the resulting mixture was stirred at 90°C for 2h [70]. After the completion of the reaction (monitored by TLC), the mixture was diluted with DCM (200mL) and redistilled water (50mL). The resulting solution was vigorously stirred at r.t. for 1h. The organic phase was then separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (DCM:MeOH or CHCl3:MeOH=100:0→98:2→90:10 v/v). The final compounds 21-34 were converted to their respective hydrochloride salts by mixing with a few drops of hydrochloric acid (37% aq.) in MeOH at r.t. while stirring for 1h. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 2h; | 4.1.3 General procedure for the preparation of final compounds 21-34 General procedure: The appropriate analogue 19a-d or 20a-b (0.3mmol) was dissolved in DMF (4mL). The appropriate product 8 or 13-15 as obtained above (0.3mmol) and K2CO3 (0.9mmol) were added and the resulting mixture was stirred at 90°C for 2h [70]. After the completion of the reaction (monitored by TLC), the mixture was diluted with DCM (200mL) and redistilled water (50mL). The resulting solution was vigorously stirred at r.t. for 1h. The organic phase was then separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (DCM:MeOH or CHCl3:MeOH=100:0→98:2→90:10 v/v). The final compounds 21-34 were converted to their respective hydrochloride salts by mixing with a few drops of hydrochloric acid (37% aq.) in MeOH at r.t. while stirring for 1h. |
33% | With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 2h; | 4.1.3 General procedure for the preparation of final compounds 21-34 General procedure: The appropriate analogue 19a-d or 20a-b (0.3mmol) was dissolved in DMF (4mL). The appropriate product 8 or 13-15 as obtained above (0.3mmol) and K2CO3 (0.9mmol) were added and the resulting mixture was stirred at 90°C for 2h [70]. After the completion of the reaction (monitored by TLC), the mixture was diluted with DCM (200mL) and redistilled water (50mL). The resulting solution was vigorously stirred at r.t. for 1h. The organic phase was then separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (DCM:MeOH or CHCl3:MeOH=100:0→98:2→90:10 v/v). The final compounds 21-34 were converted to their respective hydrochloride salts by mixing with a few drops of hydrochloric acid (37% aq.) in MeOH at r.t. while stirring for 1h. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 2h; | 4.1.3 General procedure for the preparation of final compounds 21-34 General procedure: The appropriate analogue 19a-d or 20a-b (0.3mmol) was dissolved in DMF (4mL). The appropriate product 8 or 13-15 as obtained above (0.3mmol) and K2CO3 (0.9mmol) were added and the resulting mixture was stirred at 90°C for 2h [70]. After the completion of the reaction (monitored by TLC), the mixture was diluted with DCM (200mL) and redistilled water (50mL). The resulting solution was vigorously stirred at r.t. for 1h. The organic phase was then separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (DCM:MeOH or CHCl3:MeOH=100:0→98:2→90:10 v/v). The final compounds 21-34 were converted to their respective hydrochloride salts by mixing with a few drops of hydrochloric acid (37% aq.) in MeOH at r.t. while stirring for 1h. |
27% | With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 2h; | 4.1.3 General procedure for the preparation of final compounds 21-34 General procedure: The appropriate analogue 19a-d or 20a-b (0.3mmol) was dissolved in DMF (4mL). The appropriate product 8 or 13-15 as obtained above (0.3mmol) and K2CO3 (0.9mmol) were added and the resulting mixture was stirred at 90°C for 2h [70]. After the completion of the reaction (monitored by TLC), the mixture was diluted with DCM (200mL) and redistilled water (50mL). The resulting solution was vigorously stirred at r.t. for 1h. The organic phase was then separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (DCM:MeOH or CHCl3:MeOH=100:0→98:2→90:10 v/v). The final compounds 21-34 were converted to their respective hydrochloride salts by mixing with a few drops of hydrochloric acid (37% aq.) in MeOH at r.t. while stirring for 1h. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 2h; | 4.1.3 General procedure for the preparation of final compounds 21-34 General procedure: The appropriate analogue 19a-d or 20a-b (0.3mmol) was dissolved in DMF (4mL). The appropriate product 8 or 13-15 as obtained above (0.3mmol) and K2CO3 (0.9mmol) were added and the resulting mixture was stirred at 90°C for 2h [70]. After the completion of the reaction (monitored by TLC), the mixture was diluted with DCM (200mL) and redistilled water (50mL). The resulting solution was vigorously stirred at r.t. for 1h. The organic phase was then separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (DCM:MeOH or CHCl3:MeOH=100:0→98:2→90:10 v/v). The final compounds 21-34 were converted to their respective hydrochloride salts by mixing with a few drops of hydrochloric acid (37% aq.) in MeOH at r.t. while stirring for 1h. |
37% | With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 2h; | 4.1.3 General procedure for the preparation of final compounds 21-34 General procedure: The appropriate analogue 19a-d or 20a-b (0.3mmol) was dissolved in DMF (4mL). The appropriate product 8 or 13-15 as obtained above (0.3mmol) and K2CO3 (0.9mmol) were added and the resulting mixture was stirred at 90°C for 2h [70]. After the completion of the reaction (monitored by TLC), the mixture was diluted with DCM (200mL) and redistilled water (50mL). The resulting solution was vigorously stirred at r.t. for 1h. The organic phase was then separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (DCM:MeOH or CHCl3:MeOH=100:0→98:2→90:10 v/v). The final compounds 21-34 were converted to their respective hydrochloride salts by mixing with a few drops of hydrochloric acid (37% aq.) in MeOH at r.t. while stirring for 1h. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | Stage #1: benzoic acid With N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: 1-t-Butoxycarbonylpiperazine With triethylamine In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 18h; Stage #3: With trifluoroacetic acid In dichloromethane at 0 - 20℃; for 18h; | 4.1.2 General procedure for the preparation of intermediates 13-15 General procedure: To a stirred solution of the appropriate carboxylic acid (10-12) (8.0mmol) and HOBt (8.4mmol) in dichloromethane (DCM) (48mL) and DMF (8mL) was added EDC (8.4mmol) at room temperature. The reaction mixture was stirred for another 30min at room temperature (r.t.) and then triethylamine (TEA) (8mmol) and 9 (8mmol) were added. The reaction mixture was then stirred for 18h. After completion of the reaction (monitored by TLC), the mixture was concentrated under reduced pressure, and DCM (300mL) and redistilled water (100mL) were added. The water phase was washed with DCM (2×300mL), and the combined organic phases were washed successively with saturated solutions of NaHCO3 and NaCl. The organic layer was dried over Na2SO4, filtered and concentrated [65]. The crude residue was filtered through a short column of silica gel using DCM/MeOH (50:1 v/v) as eluentTo a solution of the resulting acyl derivative in DCM (20mL) was slowly added TFA (64mmol) at 0°C. The reaction mixture was stirred for an additional 15min at 0°C and then for 18h at r.t. The mixture was diluted with DCM (300mL) and quenched with an ice-cold saturated aqueous solution of Na2CO3 (75mL). The organic layer was then extracted with DCM (3×200mL). The combined organic layers were then dried over Na2SO4, filtered and concentrated under reduced pressure [66]. The crude residue was purified by silica gel chromatography (DCM:MeOH=100:0→90:10 v/v). The 1H NMR spectrum and reaction yield for compound 13 can be found at Supplementary Information |
51% | Stage #1: benzoic acid With N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: 1-t-Butoxycarbonylpiperazine With triethylamine In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 18h; Stage #3: With trifluoroacetic acid In dichloromethane at 0 - 20℃; for 18h; | 4.1.2 General procedure for the preparation of intermediates 13-15 General procedure: To a stirred solution of the appropriate carboxylic acid (10-12) (8.0mmol) and HOBt (8.4mmol) in dichloromethane (DCM) (48mL) and DMF (8mL) was added EDC (8.4mmol) at room temperature. The reaction mixture was stirred for another 30min at room temperature (r.t.) and then triethylamine (TEA) (8mmol) and 9 (8mmol) were added. The reaction mixture was then stirred for 18h. After completion of the reaction (monitored by TLC), the mixture was concentrated under reduced pressure, and DCM (300mL) and redistilled water (100mL) were added. The water phase was washed with DCM (2×300mL), and the combined organic phases were washed successively with saturated solutions of NaHCO3 and NaCl. The organic layer was dried over Na2SO4, filtered and concentrated [65]. The crude residue was filtered through a short column of silica gel using DCM/MeOH (50:1 v/v) as eluentTo a solution of the resulting acyl derivative in DCM (20mL) was slowly added TFA (64mmol) at 0°C. The reaction mixture was stirred for an additional 15min at 0°C and then for 18h at r.t. The mixture was diluted with DCM (300mL) and quenched with an ice-cold saturated aqueous solution of Na2CO3 (75mL). The organic layer was then extracted with DCM (3×200mL). The combined organic layers were then dried over Na2SO4, filtered and concentrated under reduced pressure [66]. The crude residue was purified by silica gel chromatography (DCM:MeOH=100:0→90:10 v/v). The 1H NMR spectrum and reaction yield for compound 13 can be found at Supplementary Information |
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Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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