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CAS No. : | 5271-27-2 | MDL No. : | MFCD03411603 |
Formula : | C11H16N2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | IRMBVBDXXYXPEW-UHFFFAOYSA-N |
M.W : | 176.26 | Pubchem ID : | 2760009 |
Synonyms : |
|
Num. heavy atoms : | 13 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.45 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 62.05 |
TPSA : | 15.27 Ų |
GI absorption : | Low |
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) : | -6.57 cm/s |
Log Po/w (iLOGP) : | 2.34 |
Log Po/w (XLOGP3) : | 1.14 |
Log Po/w (WLOGP) : | 0.18 |
Log Po/w (MLOGP) : | 1.46 |
Log Po/w (SILICOS-IT) : | 1.72 |
Consensus Log Po/w : | 1.37 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.93 |
Solubility : | 2.09 mg/ml ; 0.0118 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.05 |
Solubility : | 15.5 mg/ml ; 0.0881 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -3.05 |
Solubility : | 0.158 mg/ml ; 0.000895 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.72 |
Signal Word: | Danger | Class: | 8,6.1 |
Precautionary Statements: | P260-P264-P270-P280-P301+P310+P330-P301+P330+P331-P303+P361+P353-P304+P340+P310-P305+P351+P338+P310-P363-P405-P501 | UN#: | 2923 |
Hazard Statements: | H301-H314 | Packing Group: | Ⅲ |
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 |
---|---|---|
76% | With triethylamine; In dichloromethane;Cooling; | -Methyl-3-phenylpiperazine (17.6 g; 0.1 mol) was dissolved in 100 dichloromethane.Triethylamine (5 ml; ca 0.03 mol) was added. A solution of methyl chlorooxalate (10 ml; 0.10 mol) in dichloromethane was slowly added under cooling. After the total addition a white suspension was formed. TLC showed complete conversion. The mixture was quenched with 10percent sodium carbonate. The organic layer was washed again with carbonate, dried and evaporated to an oil (25.5 g; 97 percent).TLC: quite pure, some minor polar impurities. GC: chiral separation possible15.7/16.0 min (contains ca. 0.4percent of 3.8 min impurity (present in starting piperazine) that can be used as internal standard).The material solidifies on standing. Attempt to recrystallise from CH2CI2/hexane. This gives 20 g of light-brown solid (76 percent). mp 103-5°C.GC: 3.8 min impurity is removed. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With triethylamine; In dichloromethane;Cooling; | 1 -Methyl-3-phenylpiperazine (123.2 g; 0.70 mol) was dissolved in 500 dichloromethane. Triethylamine (30 ml; ca 0.2 mol) was added. A solution of ethyl chlorooxalate (107 g; 0.78 mol) in dichloromethane was slowly added under cooling. At 2/3 of the total addition a thick suspension was formed. Even after addition of more solvent, stirring remained difficult. The mixture was quenched with 10percent sodium carbonate. The organic layer is washed again with carbonate, dried and evaporated to an orange oil (191.2 g; 0.69 mol; 99 percent). Crystallisation with seeding proved difficult. Deep evaporation and storage as oil.TLC: very pure, a small amount of coloured polar material on baseline. No trace of the dioxamide (prepared from oxalylchloride and piperazine). GC: 18.0/18.2 min, 0.36 areapercent of 3.8 min impurity. A small sample (20 g) was stirred with water to induce crystallisation. <n="15"/>mp ca 45 °C. The main bulk of the oil solidified after a few days of standing. Melting was needed before use. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With triethylamine; In dichloromethane; water; | 1 -Methyl-3-phenylpiperazine (17.6 g; 0.1 mol) was dissolved in 100 dichloromethane. Acetic anhydride and triethylamine were added. Aqueous work-up yielded >100 percent of smelly oil (excess Ac2O). Kugelrohr distillation at 160 "C/0.05 mbar yielded 20.6 g oil (94 percent). Chiral GC: 10.3/10.6 min |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With triethylamine; In dichloromethane;Cooling; | -Methyl-3-phenylpiperazine (17.6 g; 0.1 mol) was dissolved in 100 dichloromethane. Triethylamine (15 ml; 0.1 mol) was added. A solution of propionyl chloride (10 g; 0.11 mol) in dichloromethane was slowly added under cooling. After the total addition a white suspension was formed. The mixture was quenched with 10percent sodium carbonate. The organic layer was washed again with carbonate, dried and evaporated to an oil (23.34g; 100 percent). Kugelrohr distillation at 187 "C/0.05 mbar yielded 21.6 g oil (93 percent). Chiral GC: 10.25/10.39 min |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With triethylamine; In dichloromethane;Cooling; | 1 -Methyl-3-phenylpiperazine (17.6 g; 0.1 mol) was dissolved in 100 dichloromethane. Triethylamine (5 ml; 0.05 mol) was added. A solution of butyroyl chloride (11.6 g; 0.1 1 mol) in dichloromethane was slowly added under cooling. After the total addition a white suspension was formed. The mixture was quenched with 10percent sodium carbonate. The organic layer was washed again with carbonate, dried and evaporated to an oil (24g). Kugelrohr distillation of 22.5 g at >200 °C/0.05 mbar yielded 22.0 g oil (95 percent). Chiral GC: 12.87/12.98 min, severe overlap. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With triethylamine; In dichloromethane;Cooling; | 1 -Methyl-3-phenylpiperazine (17.6 g; 0.1 mol) was dissolved in 100 dichloromethane. Triethylamine (15 ml; 0.1 mol) was added. A solution of benzoyl chloride (16 g; 0.1 14 mol) in dichloromethane was slowly added under cooling. After the total addition a white suspension was formed. The mixture was quenched with 10percent sodium carbonate. The organic layer was washed again with carbonate, dried and evaporated to an oil (ca 30 g). Purification by silica filtration using CH2CI2/Me0H (95:5). Evaporation of the appropriate fractions yielded 26.2 g oil (94 percent) Chiral GC: no separation using various methods. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With triethylamine; In dichloromethane; | 1-Methyl-3-phenylpiperazine (1.8 g; 0.01 mol) was dissolved in 50 dichloromethane. Triethylamine (1 ml; 0.07 mol) was added. Trifluoroacetic anhydride (2 ml) was added neat. The mixture was quenched with 10percent sodium carbonate. The organic layer was washed again with carbonate, dried and evaporated to an oil (2.5 g; 92 percent). TLC very pure. Chiral GC: 5.9/6.2 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40.9% | In N,N-dimethyl-formamide; at 120 - 125℃; for 18h;Product distribution / selectivity; | Comparative Example 2 In 86.2 g of dimethylformamide solution containing 32.1 g of <strong>[5271-27-2]1-methyl-3-phenylpiperazine</strong>, 36.3 g of 2-chloro-3-cyanopyridine was added, the mixture was reacted at 120 to 125 C for 18 hours under a nitrogen atmosphere. The reaction solution was concentrated under a reduced pressure. The solution was subjected to after-treatments in the same manner as in Example 3, and then measured with the HPLC. 2-(4-Methyl-2-phenylpiperazin-1-yl)-3-cyanopyridine was generated in 40.9 % yield based on <strong>[5271-27-2]1-methyl-3-phenylpiperazine</strong>. |
With sodium hydroxide; potassium iodide; triethylamine; In N-methyl-acetamide; nitrogen; water; ethyl acetate; | Example 7 Preparation of Piperazine Derivative To 11 ml of dimethylformamide were added 5.51 g (31.3 mmol) of <strong>[5271-27-2]1-methyl-3-phenylpiperazine</strong> obtained in Example 6, 4.47 g (31.3 mmol) of 2-chloro-3-cyanopyridine, 4.1 g (31.3 mmol) of triethylamine and 5.20 g (31.3 mmol) of potassium iodide, and the resulting mixture was reacted at 125 to 130 C. for 24 hours in nitrogen gas atmosphere. Next, triethylamine and dimethylformamide were distilled off from the reaction mixture under reduced pressure, and thereafter 20 ml of water and 25 ml of ethyl acetate were added to the resulting mixture. The pH of the reaction mixture was adjusted to 8 to 9 with a 10% aqueous sodium hydroxide. The mixture was allowed to separate into two layers. Thereafter, the aqueous layer was extracted twice with 30 ml of ethyl acetate, and the organic layers were combined together. The combined organic layer was washed with 5% aqueous sodium hydrogencarbonate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was crystallized from petroleum ether, to give 3.14 g of pale yellow 2-(4-methyl-2-phenylpiperazin-1-yl)-3-cyanopyridine (yield based on <strong>[5271-27-2]1-methyl-3-phenylpiperazine</strong>: 36%, melting point: 65.7 to 66.8 C.). Its HPLC purity was 97.1%. | |
With potassium fluoride; In dimethyl sulfoxide; at 150℃; for 2h;Inert atmosphere; Large scale; | To a 300 L reactor was added 2-chloronicotinonitrile (13.86 kg, 100 mol), <strong>[5271-27-2]1-methyl-3-phenylpiperazine</strong> (18.51 kg, 105 mol), potassium fluoride (17.42 kg, 300mol), dimethyl sulfoxide (DMSO) (100L), replaced with nitrogen three times, heated to 150 C, stirred for 2 hours. The reaction was completed by TLC, and direct distillation was carried out, and ethyl acetate 60 L was added to the residue. After centrifugation, 20 L of methanol, oxalic acid (12.6 kg, 100 mol) was added to the filtrate, and the mixture was stirred at 15-25 C for 6 hours, and filtered to give a pale yellow solid, 36.5 kg, yield 99%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.15% | NaBH4 (75.4 g, 1.99 mol) and compound (I) obtained in example 3 (80 g, 0.332 mol) were placed in a 2 L cylindrical reactor. The mixture was cooled to 0° - 5° C with an ice water bath and 1,2-dimethoxyethane (640 mL) was loaded, with an exothermic reaction of approximately 8° C being observed and hardly any gas release. The suspension was cooled to 0° - 5° C and a solution of 1,2-dimethoxyethane/HCl 6.5 N (297 mL, 1.93 mol) was slowly added without exceeding 20° C, with an exothermic reaction being observed and an intense gas release. The mixture was heated to 42° +/- 3° C for 6 hours, it was cooled to 10° - 15° C and an aqueous solution of HCl 6 N was added to pH 1 (305 mL), with an exothermic reaction being observed and an intense gas release. The resulting whitish suspension was stirred at 20° +/- 2° C for at least 1 hour, it was cooled to 10° - 15° C, alkalinised with an aqueous solution of NaOH 50percent (p/p) to pH 12-14 (170 mL) and extracted with dichloromethane (3 x 250 mL). The accumulated organic phases were evaporated at reduced pressure, giving a yellowish liquid residue corresponding to the title product (56.33 g, 96.15percent). | |
81.97% | With borane-THF; In tetrahydrofuran; for 6.66667h;Heating / reflux; | Compound (I) of the previous example (0.5 g, 2.077 mmol) and tetrahydrofurane (5 mL) were placed in a 25 mL flask, and for approximately 10 minutes the BH3.THF complex 1 M (10.4 mL, 10.386 mmol) was added to the white suspension. The resulting colourless solution was heated to reflux temperature for 6.5 hours, it was cooled to 19° +/- 1 ° C and an aqueous solution of HCl 6 N (1.82 mL) was added slowly. The mixture was distilled at reduced pressure to remove the tetrahydrofurane. Ethyl acetate (5 mL) was added and was extracted with an aqueous solution of HCl 2 N (3 x 5 mL). The accumulated acidic phases were alkalinised with an aqueous solution of NaOH 50percent (p/p) to pH 12-13 (1.1 mL), saturated with NaCl (6.25 g) and were extracted with ethyl acetate (3 x 5 mL). The accumulated organic phases were dried with anhydrous Na2SO4, they were filtered and evaporated at reduced pressure, giving a yellowish liquid residue which corresponded to the title product (0.3 g, 81.97percent).1H-NMR (300 MHz, CDCl3)delta:2.05 (pseudo t, J=10.7 Hz) and 2.20 (pseudo dt, J=11.0 Hz, J'=4.4 Hz) (2H, piperazine-2H), 2.34 (s, 3 H, CH3), 2.7-3.0 (abs. compl., 3 H, NH and piperazine-2H), 3.04-3.16 (abs. compl., 2 H, piperazine-2H), 3.91 (dd, J=10.2 Hz, J'=2.7 Hz, 1 H, piperazine-CH), 7.26-7.42 (abs. compl., 5 H, Ar-H).13C NMR (75.4 MHz, CDCl3)delta:46.0 (CH2, C5), 46.1 (CH3, N-CH3), 55.0 (CH2, C6), 60.1 (CH, C3), 62.9 (CH2, C2), 126.9 and 128.4 (CH, Ar-Cortho and Ar-Cmeta), 127.5 (CH, Ar-Cpara, 142.0 (C, Ar-Cipso). ME (IE, direct introduction, 70 eV), m/z (percent): 176 (M+, 1), 118 (3), 104 (C8H8+, 12), 58 (C3H8N+, 100). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60 g of 4-benzyl-1-methyl-3-phenylpiperazine (0.226 moles) obtained above was dissolved in acetic acid (300 ml) and 3 g of 5percent palladium on charcoal (50percent wet) was added and the reaction mass was subjected to hydrogenation at 80-100 psi for 4 hours at 25-30° C. After completion of the reaction by HPLC, the reaction mixture was filtered and acetic acid was concentrated under reduced pressure. 150 ml of water was added to dissolve the residue and washed with 60 ml of toluene. pH was adjusted to 11.0-12.0 with 50percent sodium hydroxide solution and the product was extracted with toluene (1.x.300 ml, 1.x.180 ml). Toluene was concentrated under reduced pressure and highly pure title compound was isolated in cyclohexane (80 ml, 10° C.) having HPLC purity 100percent. [0028] m.p.: 58-60° C. [0029] MASS: m/z; 177.0 [(MH)+][0030] 1H NMR (300 MHz) in CDCl3: delta(ppm); 1.76 (bs, 1H), 1.93-2.16 (m, 2H), 2.29 (s, 3H), 2.76-3.07 (m, 4H), 3.85-3.86 (m, 1H), 7.21-7.39 (m, 5H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Lithium aluminium hydride (3.04 g, 0.8 moles) was suspended in tetrahydrofuran (60 ml) under nitrogen atmosphere. A solution of 1-methyl-2-oxo-3-phenylpiperazine (10 g in 10 ml of tetrahydrofuran) was added at 10-15° C. Slowly, raised the temperature of reaction mass and refluxed for 2 hours. Cooled the reaction mass to 5° C. and quenched successively with 3 ml of water, 3 ml of 15percent aqueous sodium hydroxide solution and 9 ml of water. Reaction mass was stirred for 1 hour at 25-30° C. Filtered the reaction mass and the filtrate was concentrated under reduced pressure. Dissolved the residue in DM water (25 ml) and concentrated hydrochloric acid (8 ml) and the solution was washed with cyclohexane (20 ml). pH was adjusted to 11.0-12.0 with 50percent w/w aqueous sodium hydroxide solution and extracted the product with methylene chloride (2.x.50 ml). Methylene chloride layer was concentrated under reduced pressure and 7.54 g of pure 1-Methyl-3-phenylpiperazine was isolated in cyclohexane having HPLC purity 99.7percent. [0034] 1H NMR (300 MHz) in CDCl3: delta(ppm); 1.80 (bs, 1H), 1.95-2.18 (m, 2H), 2.31 (s, 3H), 2.79-3.12 (m, 4H), 3.85-3.89 (m, 1H), 7.23-7.40 (m, 5H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60.5% | EXAMPLE-4 Preparation of 1-Methyl-3-phenylpiperazine of Formula 1 (R=CH3): Lithium aluminum hydride (LiAlH4) solid (193.8 g, 5.1 mol) was added in portions to a solution of THF (2.88 L) under nitrogen atmosphere. To the LiAlH4 suspension was added 1-methyl-3-phenyl-3,4-dehydropiperazine-2-one 12 (480.0 g, 2.55 mol) in THF (0.96 L) at 10-15° C. The reaction mixture was heated to 50-55° C. for 3-4 hrs. After completion of the reaction, the reaction mixture was cooled to 15-20° C. and ethyl acetate (200 ml) was added and stirred for 30 mins followed by water (194 ml). To the resultant thick slurry was added ethyl acetate (300 ml) and sodium hydroxide solution (15.0percent,194 ml) and stirred for 30 min. To the stirred solution at 15-20° C. was added water (582 ml) and stirred for 1.5 hrs. The inorganic solids were filtered, the solid bed was washed with ethyl acetate, and the combined organic layer was concentrated under vacuum to furnish oily product. To the oil was added hexane (2.4 L) refluxed for 1.0 hr, and treated with charcoal and filtered. The filtrate was concentrated under vacuum to obtain 1-methyl-3-phenylpiperazine 1 (272 g, yield 60.5percent) | |
Example 6 Preparation of 1-Methyl-3-Phenylpiperazine To 132 g (2.175 moles) of a 28percent aqueous ammonia were added 100 ml of ethyl acetate, 460 mg of tetrabutylammonium bromide and 20.1 g (0.075 moles) of hydrochloride of the dichloro-compound obtained in Example 3 at room temperature. The resulting mixture was stirred at 40° to 45° C. for 3 hours. The resulting reaction mixture was allowed to separate into two layers, and the aqueous layer was extracted twice with 30 ml of ethyl acetate at 400 to 45° C., and the collected organic layers were combined together. Thereafter, the combined organic layer was distilled under reduced pressure, to give 7.1 g of a product (yield based on hydrochloride of the dichloro-compound: 53.8percent). It was confirmed that the resulting compound was 1-methyl-3-phenylpiperazine from the finding that the resulting product had the following physical properties. 1H-NMR (400 MHz, CDCl3) delta ppm: 1.8-1.9 (br, 1H), 1.95-2.19 (m, 2H), 2.31 (s, 3H), 2.78-3.15 (m, 4H), 3.84-3.89 (m, 1H), 7.22-7.41 (m, 5H) Boiling point (400 Pa): 107° to 112° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
potassium fluoride; N,N-dimethyl-formamide; | EXAMPLE-5 Preparation of 1,2,3,4,10,14b-hexahydro-2-methyl-pyrazino[2,1-a] pyrido{2,3-c} [2]Benzazepine of Formula 17: 1-Methyl-3-phenylpiperazine (50.0 g, 0.284 mol) was heated with 2-chloro-3-cyanopyridine (39.35 g, 0.284 mol) in the presence of potassium fluoride (49.51 g, 0.852 mol) and N,N-dimethylformamide (750.0 ml) as a solvent for 30.0 hrs at 148-154° C., followed by quenching with water and extraction with ethyl acetate gave 1-(3-cyanopyridyl-2-)-<strong>[5271-27-2]4-methyl-2-phenylpiperazine</strong> (70.0 g). 1-(3-Cyanopyridyl-2)-<strong>[5271-27-2]4-methyl-2-phenylpiperazine</strong> on hydrolysis with saturated alcoholic potassium hydroxide solution (850.0 ml) at 80-85° C. followed by extraction with chloroform gave 1-(3-carboxypyridyl-2)-<strong>[5271-27-2]4-methyl-2-phenylpiperazine</strong> (20.0 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium fluoride; In water; N,N-dimethyl-formamide; | 1. 1-(3-cyanopyridyl-2)-<strong>[5271-27-2]2-phenyl-4-methylpiperazine</strong>. 17.43 g (0.3 mol) dry potassium fluoride is added to a solution of 13.85 g (0.1 mol) 2-chloro-nicotinonitrile and 17.62 g (0.1 mol) <strong>[5271-27-2]1-methyl-3-phenylpiperazine</strong> in 250 ml dry DMF and the suspension is heated at 140° C under a nitrogen atmosphere for 20 hours. After cooling, the reaction mixture is poured out into 1,250 ml water. The aqueous phase is extracted four times with 300 ml ethyl acetate, after which the combined organic extracts are washed with 100 ml water. After drying, the ethyl acetate extracts are evaporated. The crude oil may be used as such for the following step. The nitrile obtained may however also be purified by column chromatography on SiO2, with hexane-acetone (95:5). In this way, 21.9 g (79percent) pure 1-(3-cyanopyridyl-2)-<strong>[5271-27-2]4-methyl-2-phenylpiperazine</strong> is obtained; the substance crystallizes from petroleum ether 40/60; melting point 66.5°-67.5° C. Rf in toluene: ethanol (6:4) = 0.74 (SiO2) Rf in toluene: acetone (6:4) = 0.27 (SiO2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | In water; at 20℃; for 2h;Heating / reflux; Resolution of racemate;Purification / work up; | (S)-<strong>[5271-27-2]1-methyl-3-phenylpiperazine</strong>.(+)Anicyphos salt; 100 g of (R,S)-<strong>[5271-27-2]1-methyl-3-phenylpiperazine</strong> (1) (567 mmole) and 154.5 g of (+)-Anicyphos (571 mmole) were dissolved in 250 ml of water by heating the mixture to reflux. After cooling down to room temperature a seed crystal was added. After two hours, the white crystals formed were collected by filtration and dried in a vacuum oven at 40° C. for 21 hours. This provided 121 g (48percent) with an ee of 85.5percent. The crystals were dissolved in water (119 ml) at reflux temperature. After cooling down the crystallization started. After one hour the crystals were collected by filtration and dried in a vacuum oven at 40° C. The yield of the crystals of (S)-<strong>[5271-27-2]1-methyl-3-phenylpiperazine</strong>. Anicyphos salt was 105.8 g (42percent, ee 99.0percent).The ee was determined by HPLC analysis: Chiralcel OD 250*4.6 mmID (Daicel), 5percent iso-propylalcohol in hexane, flow rate 1.0 ml*min -, UV-detector, column temperature 40° C., retention times 5.6 min, 6.3 min. |
42% | In water; at 20℃; for 2h;Heating / reflux; | (S)-1 -methyl-3-phenylpiperazine.(+)Anicyphos salt 100 g of (R,S)-<strong>[5271-27-2]1-methyl-3-phenylpiperazine</strong> (1 ) (567 mmole) and 154.5 g of (+)- Anicyphos (571 mmole) were dissolved in 250 ml of water by heating the mixture to reflux. After cooling down to room temperature a seed crystal was added. After two hours, the white crystals formed were collected by filtration and dried in a vacuum oven at 40 0C for 21 hours. This provided 121 g (48 percent) with an ee of 85.5percent. The crystals were dissolved in water (119 ml) at reflux temperature. After cooling down the crystallization started. After one hour the crystals were collected by filtration and dried <n="12"/>in a vacuum oven at 40 0C. The yield of the crystals of (S)-1-methyl-3- phenylpiperazine.Anicyphos salt was 105.8 g (42 percent, ee 99.0percent). The ee was determined by HPLC analysis: Chiralcel OD 250*4.6mmlD (Daicel), 5 percent iso-propylalcohol in hexane, flow rate 1.0 ml.min"1, UV-detector, column temperature 40 0C, retention times 5.6 min, 6.3 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 100℃; for 0.5h;Microwave irradiation; | Example 119 and 120lambda/-Cyclopropyl-4-methyl-3-[3-(4-methyl-2-phenyl-1-piperazinyl)-2-oxo-1(2H)- pyrazinylj-benzamide (Example 119) and 3-[5-bromo-3-(4-methyl-2-phenyl-1 - piperazinyl)-2-oxo-1(2H)-pyrazinyl]-lambda/-cyclopropyl-4-methyl-benzamide (Example 120).A mixture of 3-(3,5-dibromo-2-oxo-2/-/-pyrazin-1-yl)-4-methyl-benzoic acid, methyl ester (Example 1 b, 1 15 mg), <strong>[5271-27-2]1-methyl-3-phenyl-piperazine</strong> (77 mg), lambda/,lambda/-diisopropylethylamine (0.1 mL) and tetrahydrofuran (1 mL) was heated within a microwave for 30 minutes at 100°C before being cooled to room temperature. The mixture was transferred to a mixture <n="136"/>of palladium on carbon (10percent, 50 mg) and tetrahydrofuran (1 mL) and 1 ,4-cyclohexadiene (1 mL) was added. The mixture was heated under atmosphere of nitrogen within a microwave for 2.5 h at 120°C. An additional portion of palladium on carbon (50 mg) in tetrahydrofuran (1 mL) was added and the mixture was heated for 1 h at 120°C. After cooling, cyclopropylamine (0.3 mL) was added followed by dropwise addition of a solution of /so-propylmagnesium chloride (2M in tetrahydrofuran, 2.5 mL). The mixture was stirred for 10 min. and quenched with sat. aqueous NH4CI and extracted into ethyl acetate. The organic phase was dried (Na2SO4), filtered and concentrated. Purification by preparative HPLC (Gemini column, 0.1 percent ammonia: acetonitrile eluent) afforded lambda/-cyclopropyl-4- methyl-3-(4-methyl-3'-oxo-2-phenyl-3,4,5,6-tetrahydro-2/-/,3'/-/-[1 ,2']bipyrazinyl-4'-yl)- benzamide (49 mg) and 3-(6'-Bromo-4-methyl-3'-oxo-2-phenyl-3,4,5,6-tetrahydro-2/-/,3'/-/- [1 ,2']bipyrazinyl-4'-yl)-lambda/-cyclopropyl-4-methyl-benzamide (8 mg).lambda/-Cyclopropyl-4-methyl-3-[3-(4-methyl-2-phenyl-1-piperazinyl)-2-oxo-1(2H)- pyrazinylj-benzamideMS: APCI(+ve) 444 (M+H+).1H NMR .5(DMSO-Cl6, 400MHz) 8.45 (1 H, m), 7.88-7.83 (1 H, m), 7.75 and 7.71 (1 H, 2 x d), 7.52 - 7.42 (3H, m), 7.37 - 7.28 (2H, m), 7.25 - 7.16 (1 H, m), 6.98 (2H, s), 6.17 and 6.07 (1 H, 2 x br s), 3.27 - 3.10 (1 H, m), 2.90 - 2.70 (2H, m), 2.48 - 2.37 (2H, m), 2.20 (3H, m), 2.15 (2H, m), 2.1 1 and 2.04 (3H, 2 x s), 0.69 (2H, m), 0.55 (2H, m).3-[5-Bromo-3-(4-methyl-2-phenyl-1-piperazinyl)-2-oxo-1(2H)-pyrazinyl]-lambda/- cyclopropyl-4-methyl-benzamideMS: APCI(+ve) 522 (M+H+). 1H NMR 5(DMSO-Cl6, 400MHz) 8.42 (1 H, m), 7.85 (1 H, m), 7.77 and 7.74 (1 H, 2 x d), 7.52 - 7.41 (3H, m), 7.37 - 7.28 (2H, m), 7.27 - 7.19 (2H, m), 6.28 and 6.16 (1 H, 2 x br s), 3.29 (3H, s), 3.18 - 3.03 (1 H, m), 2.89 - 2.72 (2H, m), 2.48 - 2.36 (1 H, m), 2.20 (3H, m), 2.15 and 2.07 (3H, 2 x s), 0.69 (2H, m), 0.55 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 180℃; for 0.5h;microwave irradiation; | A mixture of 3,6-dichloropyridazine (845mg) and <strong>[5271-27-2]1-methyl-3-phenylpiperazine</strong> (1g) in N- methyl-2-pyrrolidone (5ml) and Hunig's base (2.5ml) was heated in the microwave at18O0C for thirty minutes.The reaction mixture was diluted with ethyl acetate (60ml) and washed with water (3 x30ml) then evaporated.The reaction mixture was loaded onto a Biotage Si 40+M column and purified using the Biotage SP4 eluting with 0 to 5percent methanol/dichloromethane over 10CV to afford the title compound (204mg) as a brown solidWeight of brown solid = 204mgMS (ES) Ci5H1735CIN4 requires 288; found 289 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Example 17; A. 4-Methyl-2-phenyl-piperazin-1-ylamine. To a solution of <strong>[5271-27-2]1-methyl-3-phenyl-piperazine</strong> (2.50 g, 14.18 mmol) in 1N HCl (18 mL) was added dropwise 1N KOH until the solution reached pH 3. Potassium cyanate (1.38 g, 17.02 mmol) was added and the reaction mixture was stirred overnight. EtOH was added to the reaction mixture, the resulting precipitate was removed by filtration, and the supernatant was concentrated in vacuo to give a white powder. To this white powder in EtOH (15 mL) cooled to 0° C. was added dropwise a premixed solution of NaOCl (13-15percent active chlorine, 11.43 mL) and 15percent aqueous NaOH (20.58 mL), and the reaction mixture was allowed to warm to rt and stirred at rt for 1 h. 1N HCl was added dropwise until the reaction mixture reached pH 1, and stirring was continued for 15 min. The reaction mixture was made basic by the addition of solid K2CO3, extracted with CH2Cl2, dried over Na2SO4, filtered, and concentrated in vacuo to give Compound 17a (2.21 g, 81percent). MS 192.2 (M+1)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61.7 - 66.8% | Example 1 2-(4-methyl-2-phenylpiperazin-1-yl)-3-cyanopyridine oxalate After adding 21.1 g (119.7 mmol) of <strong>[5271-27-2]1-methyl-3-phenylpiperazine</strong>, 20.0 g (144.4 mmol) of 2-chloro-3-cyanopyridine, and 16.6 g (164.1 mmol) of triethylamine to 42 g of dimethylformamide, the mixture was reacted at 125 to 130 °C for 24 hours under a nitrogen atmosphere. After distilling out triethylamine and dimethylformamide from the reactant solution under a reduced pressure, the residue was added with 32 ml of water and 87 g of ethyl acetate, and then a pH value thereof was adjusted to 8 to 9 with 10 percent aqueous sodium hydroxide solution. After phase-separating the solution, an organic layer was added with 24 g of methanol, and then 15.2 g of oxalic acid. This solution was filtrated to collect crystals, and then the crystals collected were dried to obtain 31.6 g of an objective compound (HPLC content: 86.1 percent, the yield from <strong>[5271-27-2]1-methyl-3-phenylpiperazine</strong> was 61.7 percent). IR (KBr) gamma=3039, 2223, 1733, 1636, 1578, 1567, 1436, 758, 701 cm-11H-NMR (CDC13, 400 MHz) delta ppm: 8.29, 7.77, 6.76 (dd, each 1H); 7.1-7.44 (m, 5H); 5.46 (t, 1H, CHPh); 3.83, 3.59 (m, each H); 2.95 (dd, 1H); 2.65-2.80 (m, 4H); 2.25 (m, 1H); 2.33 (s, 3H, NCH3). Example 2 2-(4-methyl-2-phenylpiperazin-1-yl)-3-cyanopyridine oxalate After adding 21.1 g (119.7 mmol) of <strong>[5271-27-2]1-methyl-3-phenylpiperazine</strong>, 24.0 g (173.2 mmol) of 2-chloro-3-cyanopyridine, and 16.6 g (164.1 mmol) of triethylamine to 42 g of dimethylformamide, the mixture was reacted at 125 to 130 °C for 24 hours under a nitrogen atmosphere. After distilling out triethylamine and dimethylformamide from the reactant solution under a reduced pressure, the solution was added with 32 ml of water and 87 g of ethyl acetate, and then a pH value thereof was adjusted to 8 to 9 with 10 percent aqueous sodium hydroxide solution. After phase-separating the solution, an organic layer was added with 24 g of methanol, and then 15.2 g of oxalic acid. This solution was filtrated to collect crystals, and then the crystals collected were dried to obtain 31.9 g of an objective compound (HPLC content: 92.4 percent, the yield from <strong>[5271-27-2]1-methyl-3-phenylpiperazine</strong> was 66.8 percent). Example 3 2-(4-methyl-2-phenylpiperazin-1-yl)-3-cyanopyridine oxalate In 57.3 kg of dimethylformamide solution containing 21.3 kg of <strong>[5271-27-2]1-methyl-3-phenylpiperazine</strong>, 22.2 kg of 2-chloro-3-cyanopyridine and 15.3 kg of triethylamine were added, the mixture was reacted at 114 to 125 °C for 17 hours under a nitrogen atmosphere. The reaction solution was concentrated under a reduced pressure. The distillated amount was 36 kg. The residue was added with 29.3 kg of water and then a pH value thereof was adjusted to 8.45 with 25 percent aqueous sodium hydroxide solution. This solution was added with 79.2 kg of ethyl acetate, washed with 20 kg of 5 percent sodium chloride solution, and then subjected to a phase separation. An organic layer was added with 23.1 kg of methanol, and then added with 13.9 kg of oxalic acid dihydrate at a temperature of 45 to 48 °C for about 1 hour. The solution was stirred at the temperature for 1 hour, filtrated at around 35 °C to collect crystals, and then the crystals collected were washed with a mixture of 42.2 kg of ethyl acetate and 12.4 kg of methanol. The crystals were dried at around 50 °C under a reduced pressure to obtain 32.65 kg of an objective compound (HPLC content: 90.2 percent, the yield from <strong>[5271-27-2]1-methyl-3-phenylpiperazine</strong> was 66.2 percent). | |
56.6% | Comparative Example 1 After adding 21.1 g (119.7 mmol) of <strong>[5271-27-2]1-methyl-3-phenylpiperazine</strong>, 20.0 g (144.4 mmol) of 2-chloro-3-cyanopyridine, 12.8 g (126.3 mmol) of triethylamine, and 2.0 g (12.0 mmol) of potassium iodide to 42 g of dimethylformamide, the mixture was reacted at 125 to 130 °C for 24 hours under a nitrogen atmosphere. After distilling out triethylamine and dimethylformamide from the reactant solution under a reduced pressure, the residue was added with 32 ml of water and 87 g of ethyl acetate, and then a pH value thereof was adjusted to 8 to 9 with 10 percent aqueous sodium hydroxide solution. After phase-separating the solution, an organic layer was added with 24 g of methanol, and then 15.2 g of oxalic acid. This solution was filtrated to collect crystals, and then the crystals collected were dried to obtain 26.6 g of 2-(4-methyl-2-phenylpiperazin-1-yl)-3-cyanopyridine oxalate (HPLC content: 93.8 percent, the yield from <strong>[5271-27-2]1-methyl-3-phenylpiperazine</strong> was 56.6 percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | 1-Methyl-3-phenyl-piperazine (31.7 mg, 0.18 mmol) were weighted into a reaction vial and dissolved in 1 ml THF. 1 ml of a DMF stock solution containing N-methylmorpholine (51 mg, 0.5 mmol), 6-(4-Hydroxy-phenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (48 mg, 0.18 mmol), and HOBt (28 mg, 0.21 mmol) was added, followed by EDC (32 mg, 0.21 mmol). The vial was closed with a screw cap and shaken at r.t. over night. The mixture was treated with 0.1 ml TFA, filtered and purified by preparative HPLC to give the TFA salt. Conversion of the TFA salt into the HCl salt (and deprotection of amines containing a BOC-protection group) was achieved by shaking the compound with 2 ml 4M HCl in dioxane at r.t. overnight. Then 5 ml water were added and the mixture was freeze-dried to obtain the final product as the hydrochloride salt (17 mg, 19percent). LC/MS (Method LC10): Rt=2.23 min; m/z=428.22 [M+H]+. 1H-NMR (500 MHz, d6-DMSO): 2.30 (s, 1H), 2.63 (s, 3H), 2.85-2.95 (m, 2H), 3.62-3.68 (m, 4H), 4.31-4.43 (m, 1H), 6.22 (m, 1H), 6.90 (d, 2H), 7.2-7.6 (m, 4H), 7.70 (s, 1H), 8.07 (d, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 372: [6-(4-Hydroxy-phenyl)-3-methyl-1 H-pyrazolo[3,4-b]pyridin-4-yl]-(4- methyl-2-phenyl-piperazin-1 -yl)-methanoneH1 -Methyl-3-phenyl-piperazine (31 .7 mg, 0.18 mmol) were weighted into a reaction vial and dissolved in 1 ml THF. 1 ml of a DMF stock solution containing N-methyl-morpho- line (51 mg, 0.5 mmol), 6-(4-Hydroxy-phenyl)-3-methyl-1 H-pyrazolo[3,4-b]pyridine-4- carboxylic acid (48 mg, 0.18 mmol), and HOBt (28 mg, 0.21 mmol) was added, followed by EDC (32 mg, 0.21 mmol). The vial was closed with a screw cap and shaken at r.t. over night. The mixture was treated with 0.1 ml TFA, filtered and purified by preparative HPLC to give the TFA salt. Conversion of the TFA salt into the HCI salt (and deprotection of amines containing a BOC-protection group) was achieved by shaking the compound with 2 ml 4M HCI in dioxane at r.t. overnight. Then 5 ml water were added and the mixture was freeze-dried to obtain the final product as the hydro- chloride salt (17 mg, 19percent).LC/MS (Method LC10): Rt = 2.23 min; m/z = 428.22 [M+H]+.1H-NMR (500MHz, d6-DMSO): 2,30 (s, 1 H), 2,63 (s, 3H), 2,85-2.95 (m, 2H), 3,62-3.68 (m, 4H), 4.31 -4.43 (m, 1 H), 6.22 (m, 1 H), 6,90 (d, 2H), 7,2-7.6 (m, 4H), 7.70 (s, 1 H), 8,07 (d, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With [m-(1,4-diazabicyclo[2.2.2]octanekN1:kN4)]hexamethyldialuminum; In toluene; for 3h;Inert atmosphere; Reflux; | General procedure: 4.2 General procedures: C. Reflux. Carried out under an inert atmosphere in the normal way. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium fluoride; In N,N-dimethyl-formamide; at 120 - 130℃; | General procedure: A mixture of 3 (2.91 g, 10 mmol), 4 (1.76 g, 10 mmol)and KF (18 mmol) were heated at 120-130 °C in DMF (30mL) for 16 - 18 h. At the end of this period, the reactionmixture was cooled to room temperature and diluted withwater (30 mL). The separated solid was filtered, washed anddried to obtain crude 6a-i. The obtained crude product wasthen purified by recrystallization using ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium fluoride; In N,N-dimethyl-formamide; at 120 - 130℃; | General procedure: A mixture of 3 (2.91 g, 10 mmol), 4 (1.76 g, 10 mmol)and KF (18 mmol) were heated at 120-130 °C in DMF (30mL) for 16 - 18 h. At the end of this period, the reactionmixture was cooled to room temperature and diluted withwater (30 mL). The separated solid was filtered, washed anddried to obtain crude 6a-i. The obtained crude product wasthen purified by recrystallization using ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium fluoride; In N,N-dimethyl-formamide; at 120 - 130℃; | General procedure: A mixture of 3 (2.91 g, 10 mmol), 4 (1.76 g, 10 mmol)and KF (18 mmol) were heated at 120-130 °C in DMF (30mL) for 16 - 18 h. At the end of this period, the reactionmixture was cooled to room temperature and diluted withwater (30 mL). The separated solid was filtered, washed anddried to obtain crude 6a-i. The obtained crude product wasthen purified by recrystallization using ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With potassium fluoride; In N,N-dimethyl-formamide; at 120 - 130℃; | General procedure: A mixture of 1a-c (1.93 g, 10 mmol), 4 (1.76 g, 10mmol) and KF (18 mmol) were heated at 120-130 °C inDMF (30 mL) for 16 - 18 h. At the end of this period, thereaction mixture was cooled to room temperature and dilutedwith water (30 mL). The separated solid was filtered, washedand dried to obtain crude 5a-i. The obtained crude productwas then purified by recrystallization using ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With potassium fluoride; In N,N-dimethyl-formamide; at 120 - 130℃; | General procedure: A mixture of 1a-c (1.93 g, 10 mmol), 4 (1.76 g, 10mmol) and KF (18 mmol) were heated at 120-130 °C inDMF (30 mL) for 16 - 18 h. At the end of this period, thereaction mixture was cooled to room temperature and dilutedwith water (30 mL). The separated solid was filtered, washedand dried to obtain crude 5a-i. The obtained crude productwas then purified by recrystallization using ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With potassium fluoride; In N,N-dimethyl-formamide; at 120 - 130℃; | General procedure: A mixture of 1a-c (1.93 g, 10 mmol), 4 (1.76 g, 10mmol) and KF (18 mmol) were heated at 120-130 °C inDMF (30 mL) for 16 - 18 h. At the end of this period, thereaction mixture was cooled to room temperature and dilutedwith water (30 mL). The separated solid was filtered, washedand dried to obtain crude 5a-i. The obtained crude productwas then purified by recrystallization using ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 120℃; for 3h;Microwave irradiation; | Compound 6 (0.20 g, 1.02 mmol), 1-methyl-3-phenylpiperazine (0.22 g, 1.22 mmol) obtained in the above,Ethyl-3- (3-dimethylaminopropyl) carbodiimide (0.39 g, 2.04 mmol),1-hydroxybenzotriazole (0.13 g, 1.02 mmol), 1-hydroxybenzotriazoleN, N-diisopropylethylamine (0.18 mL, 1.02 mmol) and N, N-diisopropylethylamineThe mixture of 4 mL of solvent DMF was mixed well at the same time while performing a microwave irradiation (Biotage Initiator) at 120 ° C for 3 hours. The mixture was concentrated under reduced pressure, And purified by MPLC (Biotage SNAP Cartridge KP-C18-HS column) to obtain Compound 1 at a yield of 27percent. Rf = 0.32 (8: 2 ethyl acetate: hexane). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium fluoride; In N,N-dimethyl-formamide; at 140℃; for 16h; | To a 1000 ml three-necked flask, 600 ml of N, N-dimethylformamide and 2-chloronicotinamide (153 g, 0.98 mol) were added.<strong>[5271-27-2]1-methyl-3-phenylpiperazine</strong> (172 g, 0.98 mol) and potassium fluoride (114 g, 1.96 mol) were added and the mixture was heated to 140 ° C and stirred for 16 hours. The crude product was added to 1000 ml of ice water, stirred for 1 hour, Isolated by filtration to give a white solid. The white solid was further dried by blowing with air at 50 ° C to give 261 g of 2-(4-methyl-2-phenyl-1-piperazinyl)nicotinamide as a white solid in a yield of 90percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) dichloromethane; caesium carbonate; at 100℃; for 16h;Inert atmosphere; | (0667) A mixture of 4-iodobenzonitrile (300 mg, 1.31 mmol), <strong>[5271-27-2]1-methyl-3-phenylpiperazine</strong> (346 mg, 1.96 mmol), cesium carbonate (1.28 g, 3.93 mmol) and chloro(2-dicyclohexylphosphino- 2',6'-dimethoxy-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) dichloromethane adduct (176 mg, 0.262 mmol) in tert-amyl alcohol (5 mL) was stirred at 100 °C for 16 h under N2. After cooling to ambient temperature, the mixture was concentrated under reduced pressure to give a residue, which was diluted with H2O (10 mL). The water layer was extracted with EtOAc (20 mL x 2). The collected organic layers were washed with brine (10 mL) and dried over anhydrous Na2SO4. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 065percent EA/PE gradient (at) 40 mL/min) to give 4-(4-methyl-2- phenylpiperazin-1-yl)benzonitrile as an oil. ESI-MS m/z [M+H]+: 277.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With N-ethyl-N,N-diisopropylamine; sodium iodide; In dimethyl sulfoxide; at 135℃; for 48h; | The solution of compound 1 (150 mg, 0.64 mmol), 1-Methyl-3-phenylpiperazine (112 mg, 0.64 mmol), NaI (190 mg, 1.27 mmol) and DIPEA (0.22 ml, 1.27 mmol) DMSO (3.5 mL) was stirred at 135° C. for 48 h with oil bath. TLC was used to monitor the reaction. After cooled to room temperature, the reaction mixture was added to half-saturated ammonium chloride in water (80 mL) and stirred for 30 min. The solids were collected by filtration, washed by water. The crude product was purified by column chromatography (0-10percent MeOH in DCM) to give compound 65 as yellow solids. (51 mg, 21percent yield). 1H NMR (400 MHz, DMSO-d6) delta 11.91 (s, 1H), 9.12 (s, 1H), 8.08 (s, 1H), 7.30-7.00 (m, 5H), 6.70 (b, 1H), 5.75 (b, 1H), 5.54 (br, 1H), 4.02 (br, 1H), 3.32 (m, 1H), 3.12 (m, 1H), 2.80 (m, 1H), 2.32 (m, 1H), 2.16 (s, 3H), 1.98 (m, 1H), 1.82 (m, 1H), 0.88 (m, 2H), 0.62 (m, 2H); ESI-MS: calcd for (C21H25N7) 375, found 376 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 120℃; for 3h;Microwave irradiation; | 24. (2,4-bis(allyloxy)-5-isopropylphenyl)(4-methyl-2-phenylpiperazin-1-yl)methanone (16) Compound 14 (0.18 g, 0.66 mmol), <strong>[5271-27-2]1-methyl-3-phenylpiperazine</strong> (0.18 g, 0.99 mmol), 1-ethyl-3-(3-dimethylaminopropyl) (0.25 g, 1.33 mmol), 1-hydroxybenzotriazole (0.09 g, 0.66 mmol) and N,N-diisopropylethylamine (0.09 mL, 0.66 mmol) were dissolved in 4 ml of DMF and stirred at 120° C. for 3 hours under a microwave irradiation (Biotage Initiator). The reaction mixture was diluted with ethyl acetate and the organic layer was washed with 1 N HCl solution. It was dried over Na2SO4, concentrated under pressure and purified by MPLC to obtain Compound 16 in a yield of 92percent. Rf=0.24 (3:7 ethyl acetate:hexane). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 120℃; for 3h;Microwave irradiation; | 20. (5-chloro-2,4-dihydroxyphenyl)(4-methyl-2-phenylpiperazin-1-yl)methanone (11j) Compound 18 (0.20 g, 1.05 mmol), <strong>[5271-27-2]1-methyl-3-phenylpiperazine</strong> (0.28 g, 1.58 mmol), 1-ethyl-3-(3-dimethylaminopropyl) (0.40 g, 2.10 mmol), 1-hydroxybenzotriazole (0.14 g, 1.05 mmol) and N,N-diisopropylethylamine (0.19 mL, 1.05 mmol) were dissolved in 4 ml of DMF and stirred at 120° C. for 3 hours under a microwave irradiation (Biotage Initiator). The reaction mixture was diluted with ethyl acetate and the organic layer was washed with 1 N HCl solution. It was dried over Na2SO4, concentrated under pressure and purified by MPLC to obtain Compound 11j in a yield of 23percent. Rf=0.21 (8:2 ethyl acetate:hexane). 1H NMR (400 MHz, CDCl3) delta 7.46 (d, J=4.4 Hz, 2H), 7.37 (t, J=7.2 Hz, 7.2 Hz, 2H), 7.27 (t, J=7.2 Hz, 6.8 Hz, 1H), 7.17 (s, 1H), 6.61 (s, 1H), 5.58 (s, 1H), 4.24 (s, 1H), 3.24 (d, J=12.0 Hz, 1H), 3.22 (t, J=12.4 Hz, 10.4 Hz, 1H), 2.81 (d, J=10.8 Hz, 1H), 2.50 (dd, J=12.0 Hz, 4.0 Hz, 1H), 2.32 (s, 3H), 2.21-2.14 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With potassium fluoride; In dimethyl sulfoxide; at 140℃; for 12h;Inert atmosphere; | The steps are: 1.72g of 2-chloro-3methyl-5-nitropyridine is added to a 100mL single-necked bottle,1.76g of 1-methyl-3-phenylpiperazine and 1.74g of potassium fluoride (which can be replaced with sodium fluoride, etc.),Using argon protection, add 20ml of dimethyl sulfoxide (the solvent can be replaced by ethylene glycol, N, N-dimethylformamide or N-methylpyrrolidone, etc.)The temperature was raised to 140 C for 12h.After the reaction, the pH was adjusted to basic, extracted with ethyl acetate, and passed through the column to obtain 2.9 g of dark black crystal compound 1, with a yield of 93%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With potassium phosphate; copper(l) iodide; diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate; C13H12F3NO In dimethyl sulfoxide at 90℃; for 24h; Inert atmosphere; Molecular sieve; |
Tags: 5271-27-2 synthesis path| 5271-27-2 SDS| 5271-27-2 COA| 5271-27-2 purity| 5271-27-2 application| 5271-27-2 NMR| 5271-27-2 COA| 5271-27-2 structure
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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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