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CAS No. : | 454482-11-2 | MDL No. : | MFCD11506069 |
Formula : | C12H22BNO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | SQMVRFXDBRYXFQ-UHFFFAOYSA-N |
M.W : | 223.12 | Pubchem ID : | 20773371 |
Synonyms : |
|
Num. heavy atoms : | 16 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.83 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 70.96 |
TPSA : | 21.7 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.6 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 1.49 |
Log Po/w (WLOGP) : | 1.5 |
Log Po/w (MLOGP) : | 1.07 |
Log Po/w (SILICOS-IT) : | 0.91 |
Consensus Log Po/w : | 0.99 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.1 |
Solubility : | 1.79 mg/ml ; 0.00802 mol/l |
Class : | Soluble |
Log S (Ali) : | -1.55 |
Solubility : | 6.24 mg/ml ; 0.028 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.35 |
Solubility : | 0.999 mg/ml ; 0.00448 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 3.65 |
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 |
---|---|---|
63% | Stage #1: With TurboGrignard In tetrahydrofuran at -15 - -10℃; Inert atmosphere Stage #2: at 20℃; |
2nd step: under the protection of nitrogen, the 1.3M isopropyl magnesium chloride-lithium chloride (72 ml, 94mmol) into the reaction bottle, temperature control -15 ° C to -10 °C, dropwise N-methyl -1, 2, 5, 6-tetrahydro-pyridine-4-polybromide tetrahydrofuran (80 ml) solution, stirring finishing joining 1-2 hours. After the end of the exchange, then drop by adding methoxy boronic acid pinacone ester (15.8g, 0 . 1mol), subsequently maintain the reaction at room temperature overnight. Adding 10percent hydrochloric acid aqueous solution quenching reaction, adjusting PH= 4-5, by adding 150 ml ethyl acetate, saturated salt water an organic layer, the organic layer after evaporation to dryness, add ethanol/heptane 40:1 obtained after pulping 14.1g kind of white solid N-methyl -1, 2, 5, 6-tetrahydro-pyridine-4-boronic acid frequency that alcohol ester, GC: 98.3percent, yield: 63percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium acetate;1,1'-bis-(diphenylphosphino)ferrocene; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 80℃; for 15h; | A mixture of 1-methyl-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate (1.1 g, 4.47 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.24 g, 4.9 mmol), potassium acetate (1.7 mL, 17 mmol), PdCl2(dppf) (0.13 g, 0.15 mmol) and dppf (83 mg, 0.15 mmol) in 50 mL dioxane was degassed by consecutively flushing and evacuating with nitrogen 3 times. The mixture was stirred at 80° C. under nitrogen for 15 h. The reaction mixture was cooled to room temperature, diluted with 100 mL ethyl acetate and washed with H2O (2.x.25 mL) and brine (20 mL). The organic layer was dried over anhydrous Na2SO4, concentrated and purified via flash chromatography (silica gel) eluting with a gradient of 5/1 hexanes/EtOAc to 4/1 hexanes/EtOAc to give 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine as a pale yellow solid (1.1 g). Found MS (ES+): 224 (M+H)+. | |
With potassium acetate;1,1'-bis-(diphenylphosphino)ferrocene; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 80℃; for 4h; | A mixture of above triflate (5.0 g, 20 mmol), bis(pinacolato)diboron (5.6 g, 22 mmol), potassium acetate (6.5 g, 66 mmol), PdCl2dppf (0.44 g, 0.6 mmol), and (dppf)2 (0.33 g, 0.6 mmol) in 60 mL of dioxane was heated at 80° C. for 4 h. The resulting mixture was cooled to RT, diluted with Et2O (150 mL). The ethereal solution was washed with H2O followed by brine. The organic layer dried over Na2SO4, concentrated, and recrystallized in hexane-Et2O to give the title intermediate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With monopotassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In DMF (N,N-dimethyl-formamide); at 80℃; for 16h; | To a mixture of 4,4,5,5-tetramethyl-2-(1-methyl(4-1,2,5,6-tetrahydropyridyl))-1,3,2-dioxaborolane (1.0 g, 4.4 mmol), PdCl2pddf (0.16 g, 0.2 mmol) and K2CO3 (1.8 g, 13.2 mmol) and 3-amino-5-bromobenzotrifluoride (0.8 g, 3.3 mmol) in DMF (25 mL) was heated at 80° C. for 16 h. The resulting mixture was diluted with EtOAc, washed with H2O, dried over Na2SO4, and concentrated. The residue was purified by SiO2 chromatography to give the title intermediate. MS (ES+): 257 (M+H)+. Calc'd C13H15F3N2 - 256.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; ethanol; water; at 90℃; for 2h; | A mixture of 3-(1-chlorophthalazin-6-yl)-N-cyclopropyl-4-methylbenzamide (0.1 g, 0.3 mmol), <strong>[454482-11-2]1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine</strong> (70 mg, 0.3 mmol) and tetrakis(triphenylphosphine)palladium (0.03 g, 0.03 mmol) in 10 mL DME/EtOH (4:1) was treated with 2 M potassium carbonate (0.6 mL, 1.2 mmol). The mixture was stirred at 90° C. for 2 h. The mixture was cooled to room temperature, diluted with 100 mL DCM, washed with sat. NaHCO3, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified via flash chromatography (silica gel) eluting with a gradient of 2percent 2 M ammonia in MeOH/DCM to 6percent 2 M ammonia in MeOH/DCM to give N-cyclopropyl-4-methyl-3-(1-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phthalazin-6-yl)benzamide (0.10 g) as a pale yellow solid. Found MS (ES+): 399(M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 85℃; for 12h; | Add to the reaction flask5-bromo-2-nitropyridine (20.3 g, 0.1 mol)1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaboride-2-yl) -1,2,3,6-tetrahydropyridine (22.3 g , 0.1 mol), cesium carbonate (65 g, 0.2 mol), Pd (dppf) Cl2 (7.33 g,0.01 mol) and dioxane / water (250 mL / 30 mL).The mixture was heated and stirred at 85 ° C for 12 hours, cooled to room temperature, concentrated under reduced pressure,The resulting residue was purified by column chromatography (petroleum ether / ethyl acetate = 1: 1)To give the title compound (5.7 g, white solid) in 26percent yield. |
26% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 85℃; for 12h;Inert atmosphere; | Cesium carbonate ([Cs2CO3] 66.00g, 0.2mol) and Pd(dppf)Cl2 (7.33g, 0.01mol) were added to a solution of 82 5-bromo-2-nitropyridine (20.30g, 0.1mol) and 110 <strong>[454482-11-2]1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine</strong> (22.30g, 0.1mol) in 111 dioxane/112 H2O (250 mL/30mL). The mixture was allowed to stir at 85°C for 12h under nitrogen (N2). Then the solution was cooled to RT, concentrated under a vacuum, and purified by silica gel column chromatography (from 102 PE/86 EA=1:1 to 103 DCM/87 MeOH=20:1) to obtain 113 1?-methyl-6-nitro-1?,2?,3?,6?-tetrahydro-3,4?-bipyridine (5.70g; yield, 26percent) as a white solid. Next, Pd/C (0.10g) was added to the solution of 1?-methyl-6-nitro-1?,2?,3?,6?-tetrahydro-3,4?-bipyridine (657.0mg, 3.0mmol) in EA/MeOH (10 mL/10mL). The mixture was degassed by flushing with H2, stirred at RT under a H2 atmosphere for 2h, and then filtered and concentrated under a vacuum to obtain INT-4 (550.0mg; yield, 96percent) as a white solid. ESI-MS: m/z 192.2 [M+H]+. |
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 10h; | To a round-bottomed flask equipped with a stirring bar, l-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l,2,3,6-tetrahydropyridine (1.50 g, 6.72 mmol), 5- bromo-2-nitropyridine (1.64 g, 8.07 mmol), Pd(PPh3)4 (388 mg, 0.336 mmol), Na2C03 aqueous solution (1.0 N, 20.2 mL, 20.2 mmol), dioxane (60.6 mL) were added. The reaction mixture was heated at 100 °C for 10 hrs. CH2CI2 (200 mL) was added to the resulting mixture was washed with water (30 mL X 3). CH2CI2 (200 mL) was added and the resulting mixture was washed with water (30 mL X 3), brine (30 mL X 1), dried over MgS04, filtered, and removed solvent in vacuo. Silica gel column chromatography (MeOH: DCM = 5: 95) gave 5- (l-methyl-l,2,3,6-tetrahydropyridin-4-yl)-2-nitropyridine (130a) as a yellow solid. |
5.7 g | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 85℃; for 12h;Inert atmosphere; | A reaction flask was charged with 5-bromo-2-nitropyridine (20.3 g, 0.1 mol), <strong>[454482-11-2]1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine</strong> (22.3 g, 0.1 mol), dioxane/water (250 mL/30 mL), cesium carbonate (66 g, 0.2 mol) and Pd(dppf)Cl2 (7.33 g, 0.01 mol). The mixture was stirred to react at 85°C under the protection of nitrogen gas for 12 h. The reaction product was cooled to room temperature, concentrated and separated by column chromatography (PE/EA = 1:1 to DCM/MeOH = 20:1) to give the titled product (5.7 g, white solid). MS (ESI): mass calcd. for C11H13N3O2 219.1, m/z found 220.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With cesium fluoride;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; water; at 150℃; for 0.166667h;Inert atmosphere; Microwave irradiation; | Example 104: 5-(1 -methyl-1 ,2,3,6-tetrahvdropyridin-4-yl)-3-{1 -r4-(morpholin-4- ylcarbonyl)phenvn-1 H-1 ,2,3-triazol-4-yl)-1 H-indazoleA suspension of {4-[4-(5-Bromo-1 H-indazol-3-yl)-[1 ,2,3]triazol-1-yl]-phenyl}-morpholin-4- yl-methanone (150 mg; 0.33 mmol; 1.0 eq.), 1-Methyl-1 ,2,3,6-tetrahydropyridine-4-boronic acid, pinacol ester (Boron Molecular, 221 mg; 0.99 mmol; 3.0 eq.), PdCI2(PPh3)2 (23 mg; 0.03 mmol; 0.10eq.), cesium fluoride (151 mg; 0.99 mmol; 3.0 eq.) in dioxane (3 mL) and water (1.5 mL) was degassed with nitrogen flow and heat in MW at 150°C for 10 min. The reaction mixture was filtered through a celite pad, water was added to the filtrate. Aqueous phase was extracted three time with DCM using separators tubes. Combined organic phases were concentrated under reduced pressure and the crude was purified by flash chromatography on silica (DCM/MeOH , gradient from 100:0 to 90: 10) to give the title compound as a yellow powder. 1 H NMR (300 MHz, DMSO) delta 13.36 (brs, 1 H), 9.39 (s, 1 H), 8.31 (s, 1 H), 8.15 (d, J = 8.0 Hz, 2H), 7.78-7.47 (m, 4H), 6.32-6.11 (m, 1 H), 3.84-3.49 (m, 6H), 3.46-3.25 (m, 2H), 3.1 1-2.98 (m, 2H), 2.71-2.58 (m, 4H), 2.30 (s, 3H). HPLC (Condition A): Rt 2.22 min (purity 94.5percent). MS (ESI+): 470.3, MS(ESI-): 468.3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; for 2h;Inert atmosphere; Reflux; | A mixture of 4-bromo-2-methoxy-5-nitroaniline (Intermediate 4, 1.112 g, 4.5 mmol), <strong>[454482-11-2]1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine</strong> (1.004 g, 4.50 mmol) and K2CO3 (2.488 g, 18.00 mmol) was stirred in 1,4-dioxane (20 mL) and water (5 mL). The mixture was purged with N2 for 0.25h. Tetrakis(triphenylphosphine)palladium(0) (0.052 g, 0.05 mmol) was then added and the mixture was heated at reflux for 2h. The mixture was then cooled, filtered and the filtrate was concentrated in vacuo to give an aqueous mixture. This mixture was dissolved in EtOAc and water and the phases were separated. The aqueous solution was extracted with EtOAc. The combined organic solutions were then extracted twice with 2M HCl (40 mL). The aqueous solutions were basified with 2M Na2CO3 (50 mL) and extracted with EtOAc (3 x 40 mL). The combined organic solutions were dried (MgSO4) and concentrated in vacuo. The residue was dissolved in a mixture of CH2Cl2 and 2N methanolic ammonia (10:1, 10 mL) and the solution was filtered through a silica plug. The filtrate was concentrated in vacuo to give an oil which subsequently crystallised. Trituration with isohexane and diethyl ether (1:1, 5 mL) and collection of the resulting solid by filtration gave the title compound (1.093 g, 92percent) as a yellow crystalline solid; 1H NMR: 2.23 (2H, dd), 2.27 (3H, s), 2.53 (2H, t), 2.93 (2H, d), 3.87 (3H, s), 5.27 (2H, s), 5.42-5.53 (1H, m), 6.65 (1H, s), 7.23 (1H, s); m/z: ES+ MH+ 264. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 100℃; for 1h;Inert atmosphere; | 1,1?-Bis(di-tert-butylphosphino)ferrocene palladium dichloride (16.7 mg, 0.03 mmol) was added to a solution of 1-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (139 mg, 0.62 mmol), 4-bromo-6-methoxy-N-[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 137, 215 mg, 0.52 mmol), and K3PO4 (220 mg, 1.04 mmol) in 1,4-dioxane (6 mL) and water (1.5 mL, degassed for 20 minutes prior to use). The mixture was then heated at 100°C for1h and then concentrated in vacuo. The resulting residue was dissolved in EtOAc and this solution was washed three times with water, then with brine. The solution was then dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-10percent methanolic ammonia in CH2Cl2 gave the title compound (160 mg, 72percent) as a tan solid after trituration with diethyl ether; 1H NMR: 1.79-1.87 (2H, m), 1.96-2.03 (2H, m), 2.29 (3H, s), 2.34-2.40 (2H, m), 2.58 (2H, t), 2.98-3.02 (2H, m), 3.15 (2H, t), 3.75 (3H, s), 4.12 (2H, t), 4.32 (2H, br s), 5.67-5.71 (1H, m), 6.60 (1H, s), 7.01 (1H, d), 7.58 (1H, s), 7.69 (1H, s), 8.09 (1H, s), 8.32 (1H, d); m/z: ES+ MH+ 432.72. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 100℃; for 1h;Inert atmosphere; | 1,1 Bis(di-tert-butylphosphino)ferrocene palladium dichloride (16.74 mg, 0.03 mmol) was added to a solution containing 1-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (139 mg, 0.62 mmol), 4-bromo-6-methoxy-N-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 144, 220 mg, 0.52 mmol), and K3PO4 (220 mg, 1.04 mmol) in 1,4-dioxane (6 mL) and water (1.5 mL, degassed for 20 minutes prior to use). The mixture was heated at 100°C for1h and then concentrated in vacuo. The resulting residue was dissolved in EtOAc. This solution was washed with water (x3), brine, and was then dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-10percent methanolic ammonia in CH2Cl2 gave the title compound (191 mg, 84percent) as a tan solid after trituration with diethyl ether; 1H NMR: 2.31 (3H, s), 2.37-2.43 (2H, m), 2.61 (2H, t), 3.01-3.04 (2H, m), 3.76 (3H, s), 3.89 (3H, s), 4.37 (2H, br s), 5.70-5.73 (1H, m), 6.63 (1H, s), 7.18-7.22 (2H, m), 7.25-7.29 (1H, m), 7.54 (1H, d), 7.63 (1H, s), 7.81 (1H, s), 8.31 (1H, d), 8.34 (1H, s), 8.46 (1H, d); m/z: ES+ MH+ 441.57. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A microwave vial was charged with INTERMEDIATE D (0.100 g, 0.192 mmol), pyrimidin-5-ylboronic acid (Small Molecules, Inc., Hoboken, NJ, 0.036 g, 0.288 mmol), tetrakis(triphenylphosphine)palladium(0) (0.022 g, 0.019 mmol), and K2C03 (0.133 g, 0.959 mmol). The solids were diluted with dioxane (1.279 mL) and water (0.639 mL), and the reaction was heated under microwave irradiation at 100 °C for 30 minutes. The reaction mixture was diluted with water, and washed with ether (the ether layer was extracted once more with water). The combined aqueous layers were acidified with 1.0N HCl, and then washed with DCM (x2). The combined organics were dried using a phase separator and concentrated. After concentration, the material was purified by reverse-phase preparative HPLC (Column : Phenomenex 150 x 30mm, 5 micron, C18 column; 0.1percent TFA in CH3CN/H20, gradient 25percent to 90percent over 20 min ) to provide 4-(2-(pyrimidin-5-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-3,4- dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.040 g, 0.077 mmol) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 3.45 (m, J=13.00 Hz, 1 H) 3.76 (m, J=11.20 Hz, 1 H) 4.06 - 4.15 (m, 1 H) 4.31 (m, J=10.50 Hz, 1 H) 6.38 (d, J=8.22 Hz, 1 H) 6.98 - 7.00 (m, 1 H) 7.01 - 7.03 (m, 1 H) 7.73 (d, J=8.41 Hz, 1 H) 7.94 (dd, J=8.56, 2.01 Hz, 1 H) 7.99 (m, J=1.70 Hz, 1 H) 8.26 (s, 1 H) 8.90 (s, 2 H) 9.07 (s, 1 H). m/z (ESI) 520.8 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.044 g | With potassium phosphate; bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); In 1,4-dioxane; water; at 110℃; for 2h; | Step 2: N-(5-Fluorothiazol-2-yl)-5-(2-(l-methyl-l,2,3,6-tetrahydropyridin-4-yl)-4- (trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(lH)-sulfonamide A solution of Cl2Pd(AmPhos) (Sigma-Aldrich, St. Louis, MO, 0.020 g, 0.028 mmol), 1 -methyl-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)- 1 ,2,3,6-tetrahydropyridine (0.078 g, 0.350 mmol), 5-(2-bromo-4-(trifluoromethyl)phenyl)-N-(5-fluorothiazol-2-yl)-3,4- dihydroisoquinoline-2(lH)-sulfonamide (0.150 g, 0.280 mmol), and potassium phosphate (0.237 g, 1.119 mmol) in 2 mL dioxane 1 mL water, was heated to 110 °C 2 hours. After cooling to rt, the reaction mixture was diluted with EtOAc and washed with IN citric acid. The organic layer was then concentrated. Purification of the resulting residue by reverse phase column chromatography [RediSep Gold C18 50g, 10 to 100percent (0.1percent NH40H in MeOH)/(0.1percent NH40H in water)] gave N-(5-fluorothiazol-2-yl)-5-(2-(l-methyl-l,2,3,6- tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(lH)- sulfonamide (0.044 g, 0.080 mmol). [M+H]+ = 553.0 XH NMR (400 MHz, Acetone-d6) delta ppm: 7.72 (d, J = 7.8 Hz, 1H), 7.57 (s, 1H), 7.36 (d, J = 7.9 Hz, 1H), 7.03 - 7.14 (m, 2H), 6.93 (d, J = 7.5 Hz, 1H), 6.58 - 6.64 (m, 1H), 5.92 (br. s., 1H), 4.53 (d, J = 17.3 Hz, 1H), 4.19 (d, J = 17.6 Hz, 1H), 3.71 - 3.84 (m, 2H), 3.13 - 3.46 (m, 4H), 2.86 - 2.99 (m, 1H), 2.75 - 2.86 (m, 1H), 2.53 - 2.60 (s, 3H), 1.94 - 2.19 (m, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.011 g | With potassium phosphate; bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); In 1,4-dioxane; water; at 110℃; for 2h; | Step 2: N-(5-Fluorothiazol-2-yl)-5-(2-(l-methyl-l,2,3,6-tetrahydropyridin-4-yl)-5- (trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(lH)-sulfonamide A solution of Cl2Pd(AmPhos) (Sigma-Aldrich, St. Louis, MO, 0.014 g, 0.019 mmol) , 1 -methyl-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)- 1 ,2,3,6-tetrahydropyridine (0.054 g, 0.242 mmol), 5-(2-bromo-5-(trifluoromethyl)phenyl)-N-(5-fluorothiazol-2-yl)-3,4- dihydroisoquinoline-2(lH)-sulfonamide (0.104 g, 0.194 mmol), and potassium phosphate (0.165 g, 0.776 mmol) in 2 mL dioxane and 1 mL water, was heated to 1 10 °C 2 hours. The reaction mixture was allowed to cool to room temperature, was diluted with EtO Ac and washed with IN citric acid. The organic layer was then concentrated. Purification of the resulting residue by reverse phase column chromatography [RediSep Gold C18 50g, 10 to 100percent (0.1percent NH4OH in MeOH)/(0.1percent NH4OH in water)] gave N-(5-fluorothiazol-2-yl)-5- (2-(l-methyl-l,2,3,6-tetrahydropyridin-4-yl)-5-(trifluoromethyl)phenyl)-3,4- dihydroisoquinoline-2(lH)-sulfonamide (0.011 g, 0.020 mmol). [M+H]+ = 553.0 XH NMR (400mHz, Acetone-d6) delta ppm: 7.70 - 7.77 (m, 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.42 (s, 1H), 7.05 - 7.14 (m, 2H), 6.93 (d, J = 6.7 Hz, 1H), 6.62 (d, J = 0.9 Hz, 1H), 5.87 - 5.93 (m, 1H), 4.48 - 4.56 (d, J = 17.4 Hz, 1H), 4.19 (d, J = 17.4 Hz, 1H), 3.70 - 3.84 (m, 2H), 3.32 - 3.43 (m, 1H), 3.12 - 3.32 (m, 3H), 2.87 - 2.98 (m, 1H), 2.76-2.82 (m, 1H), 2.57 (s, 3H), 1.98-2.04 (m, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); In 1,4-dioxane; water; at 90℃; for 1.5h;Inert atmosphere; Sealed tube; | A pressure vial was charged with benzyl {7-bromo-2-[({4-[(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)piperidin-1-yl]pyridin-3-yl}amino)carbonyl]quinolin-3-yl}carbamate (0.032 g, 0.043 mmol), K3PO4 (0.0181 g, 0.0852 mmol), 1,4-dioxane (0.55 mL), water (0.092 mL) and <strong>[454482-11-2]1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine</strong> (0.014 g, 0.063 mmol). The mixture was purged with nitrogen for 10 min. Dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine-(2'-aminobiphenyl-2-yl)(chloro)palladium (1:1) (0.0022 g, 0.0028 mmol) was added. The mixture was sealed with screw cap, then heated at 90° C. for 1.5 h. The mixture was quenched with water, then extracted with EtOAc. The combined organic layers were dried and concentrated under reduced pressure. The residue was purified by flash chromatography on 20 g silica gel, eluting with 0-30percent MeOH in EtOAc, to yield the sub-title compound. LCMS calc. for C40H45F3N7O5 [M+H]+: m/z=760.3. found: 760.4 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With potassium phosphate; chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); In 1,4-dioxane; water; at 90℃; for 1.5h;Sealed tube; Inert atmosphere; | A pressure vial was charged with benzyl (7-bromo-2-[(4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}pyridin-3-yl)amino]carbonyl}quinolin-3-yl)carbamate (0.029 g, 0.043 mmol), K3PO4 (0.0181 g, 0.0852 mmol), 1,4-dioxane (0.55 mL), water (0.092 mL) and <strong>[454482-11-2]1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine</strong> (0.014 g, 0.063 mmol). The mixture was deoxygenated with nitrogen for 10 min. Dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine-(2'-aminobiphenyl-2-yl)(chloro)palladium (1:1) (0.0022 g, 0.0028 mmol) was added. The mixture was sealed with screw cap, then heated at 90° C. for 1.5 h. The mixture was quenched with water and extracted with EtOAc. The combined organic extracts were dried and concentrated under reduced pressure. The residue was purified by flash chromatography on 20 g silica gel, eluting with 0-30percent MeOH in EtOAc, to yield the sub-title compound (0.009 g, 30percent). LCMS calc. for C40H48N7O5 [M+H]+: m/z=706.4. found: 706.5 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With potassium phosphate; chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); In 1,4-dioxane; water; at 90℃; for 1.5h;Inert atmosphere; Sealed tube; | A pressure vial was charged with benzyl [7-bromo-2-([4-((3R,4R,5S)-3-[(tert-butoxycarbonyl)amino]-4-[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-1-yl)pyridin-3-yl]amino}carbonyl)quinolin-3-yl]carbamate (0.035 g, 0.043 mmol), K3PO4 (0.0181 g, 0.0852 mmol), 1,4-dioxane (0.55 mL), water (0.092 mL) and <strong>[454482-11-2]1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine</strong> (0.014 g, 0.063 mmol). The mixture was deoxygenated with nitrogen for 10 min. Dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine-(2'-aminobiphenyl-2-yl)(chloro)palladium (1:1) (0.0022 g, 0.0028 mmol) was added. The mixture was sealed with screw cap, then heated at 90° C. for 1.5 h. The mixture was quenched with water, extracted with EtOAc. The combined organic extracts were dried and concentrated under reduced pressure. The residue was purified by flash chromatography on 20 g silica gel, eluting with 0-100percent EtOAc in hexanes, to give the sub-title compound (0.013 g, 36percent). LCMS calc. for C46H62N7O6Si [M+H]+: m/z=836.5. found: 836.6 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With potassium phosphate; chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); In 1,4-dioxane; water; at 90℃; for 0.5h;Inert atmosphere; Sealed tube; | A pressure tube was charged with benzyl {7-bromo-2-[({4-[(3R,4S,5S)-3-[(tert-butoxycarbonyl)amino]-5-methyl-4-(1H-1,2,3-triazol-1-yl)piperidin-1-yl]pyridin-3-yl}amino)carbonyl]quinolin-3-yl}carbamate (15 mg, 0.020 mmol), K3PO4 (8.4 mg, 0.034 mmol), 1,4-dioxane (0.3 mL), water (0.04 mL) and <strong>[454482-11-2]1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine</strong> (6.6 mg, 0.03 mmol). The reaction mixture was purged with nitrogen for 5 min., then dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine-(2'-aminobiphenyl-2-yl)(chloro)palladium (1:1) (1.6 mg, 0.002 mmol) was added. The reaction mixture was sealed and heated at 90° C. for 30 min., then allowed to cool to room temperature. The crude mixture was filtered and purified by preparative LCMS (pH=10 method; XBridge? preparative C18 5 mum OBD? column, 30*10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1percent NH4OH) to give the title compound as a light yellow powder (4.7 mg, 33percent). LCMS calc. for C42H49N10O5 (M+H)+: m/z=773.4. Found: 773.4 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | With potassium phosphate; chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); In 1,4-dioxane; water; at 60℃; for 2h;Inert atmosphere; Sealed tube; | A vial was charged with <strong>[454482-11-2]1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine</strong> (107 mg, 0.477 mmol), dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine-(2'-aminobiphenyl-2-yl)(chloro)palladium (1:1) (36 mg, 0.046 mmol), and K3PO4 (175 mg, 0.824 mmol). The vial was sealed with a septum and purged with nitrogen three times. A solution of tert-butyl methyl [(3R,4S,5S)-1-(3-[(3-[(benzyloxy)carbonyl]amino}-7-bromoquinolin-2-yl)carbonyl]amino}pyridin-4-yl)-5-methylpiperidine-3,4-diyl]biscarbamate (200 mg, 0.262 mmol) in 1,4-dioxane (2.0 mL) was added, followed by deoxygenated water (0.50 mL). The reaction mixture was heated at 60° C. for 2 h. The mixture was purified by preparative LCMS (pH=10 method; XBridge? preparative C18 5 mum OBD? column, 30*10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1percent NH4OH) to give the sub-title compound as a yellow solid (40 mg, 19percent). LCMS calc. for C42H51N8O7 (M+H)+: m/z=779.4. Found: 779.4 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); XPhos; In 1,4-dioxane; water; at 110℃; for 1h;Inert atmosphere; | Preparation of 2-methoxy-4-(i -methylpiperidin-4- yl)aniline (1 9b): A 25 mE glass microwave tube was charged with potassium phosphate tribasic (3.00 g, 13.05 mmol), 2-(dicyclohexylphosphino)-2?,4?,6?,-tri-isopropyl- 1,1 ?-biphenyl (Strem Chemicals, Newburyport, Mass., 83 mg, 0.174 mmol), tris(dibenzylideneacetone) dipalladium (0) (Strem Chemicals, Newburyport, Mass., 80mg, 0.O87mmol), 1-methyl- 1 ,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (Acros Organics, New Jersey, 971 mg, 4.35 mmol) followed by 5-chloro-2-nitroanisole (Sigma Aldrich, 816 mg, 4.35 mmol). The solids were purged with argon and treated with 1 ,4-dioxane (12 mE) and water (4 mE), scaled and heated at1100 C. in a heating block for 1 h. The reaction mixture was treated with 1 N NaOH and extracted with EtOAc (3x30 mE), dried over Mg504, filtered and concentrated. The crude resi41due was purified on the ISCO Combiflash RF (80 g Thomson SingleStep column, using a gradient of 0-20percent MeOH in DCM) affording 4-(3-methoxy-4-nitrophenyl)- 1-methyl-i ,2, 3,6-tetrahydropyridine (1 9a; 970 mg, 3.91 mmol, 90percent yield) as a rust-brown solid which crystallized upon standing. mlz (ESI, +ve ion) 249.1 (M+H). ?H NMR (400 MHz, CDC13) oe ppm 7.86 (1H, d, J=8.4 Hz), 6.99-7.08 (2H, m), 6.17-6.24 (1H, m), 3.97 (3H, s), 3.15 (2H, q, J=2.8 Hz), 2.65-2.74 (2H, m), 2.53-2.62 (2H, m), 2.38-2.46 (3H, m). In a 50 mE glass reactor, 4-(3-methoxy-4-nitrophenyl)- i-methyl-i ,2,3,6-tet- rahydropyridine (940 mg, 3.79 mmol) was treated with palladium hydroxide (20 wt percent Pd, dry basis, on wet carbon, degussa type elOl ne/w, 266 mg, 0.38 mmol) and anhydrous EtOH (20 mE). The reactor was purged with hydrogen (5x) and allowed to stir under 50 psi hydrogen at RT for 4 h. The reaction mixture was filtered through a 0.45 urn acrodisc to remove the catalyst residues washing with MeOH and concentrated to dryness under high vacuum affording 2-meth- oxy-4-(i-methylpiperidin-4-yl)aniline (19b; 830 mg, 3.77 mmol, 99percent yield) as a yellow crystalline solid. mlz (ESI, +ve ion) 221.0 (M+H). ?H NMR (400 MHz, CDC13) oe ppm 6.56-6.74 (3H, m), 3.76-3.89 (3H, m), 3.54-3.76 (2H, m),2.97 (2H, d, J=ii.2 Hz), 2.34-2.47 (1H, m), 2.23-2.34 (3H,1.95-2.12 (2H, m), 1.70-1.90 (4H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
153 mg | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 1h; | Preparation Example 26 To a mixture of tert-butyl (3-[6-(4-bromophenoxy)-5-carbamoyl-3-ethylpyrazin-2-yl]oxy}phenyl)carbamate (540 mg), <strong>[454482-11-2]1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine</strong> (273 mg), and N,N-dimethylformamide (10 mL) were added a 1,1'-bis(diphenylphosphino)ferrocene palladium (II) dichloride-dichloromethane complex (83 mg) and cesium carbonate (665 mg), followed by reacting at 80° C. for 1 hour. The reaction mixture was left to be cooled, and then ethyl acetate was added thereto. The mixture was washed with water and saturated brine and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol=1:0-9:1) and silica gel column chromatography (NH2 type, eluent; chloroform:methanol=100:0-98:2) to obtain tert-butyl [3-({5-carbamoyl-3-ethyl-6-[4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenoxy]pyrazin-2-yl}oxy)phenyl]carbamate (153 mg) as a pale yellow oily substance. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72 mg | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 1h;Inert atmosphere; | Preparation Example 45 Under argon atmosphere, to a mixture of 5-bromo-3-(2,5-dimethyl-1H-pyrrol-1-yl)-1-methyl-1H-pyrazole (100 mg), <strong>[454482-11-2]1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine</strong> (105 mg), and N,N-dimethylformamide (2 mL) were added a 1,1'-bis(diphenylphosphino)ferrocene-palladium (II) dichloride-dichloromethane complex (32 mg), and cesium carbonate (256 mg), followed by reacting them at 80° C. for 1 hour. After leaving to be cooled, ethyl acetate was added thereto, and the mixture was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol=1:0-9:1) to obtain 4-[3-(2,5-dimethyl-1H-pyrrol-1-yl)-1-methyl-1H-pyrazol-5-yl]-1-methyl-1,2,3,6-tetrahydropyridine (72 mg) as a brown oily substance. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 140℃; for 0.25h;Microwave irradiation; | (Formula 2-2: methyl 4-((N-(3-(1-methyl-1,2,3,6-tetrahydropyridn-4-yl)phenyl)morpholine-4-carboxamido)methyl)benzoate)[884][885]Compound ofFormula 2-1(methyl 4-((N-(3-bromophenyl)morpholine-4-carboxamido)methyl)benzoate; 0.400 g, 0.923 mmol), <strong>[454482-11-2]1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester</strong> (0.247 g, 1.11 mmol), and Pd(dppf)Cl2(0.030 g, 0.046 mmol) were dissolved in 1,4-dioxane (4 mL), and cesium carbonate (0.897 g, 2.77 mmol) dissolved in water (1 mL) was added to the reaction solution and stirred at 140 for 15 minutes by using microwave reactor. After completion of the reaction, the organic layer was extracted with ethyl acetate and saturated sodium hydrogen carbonate aqueous solution. Then, the organic layer dehydrated with anhydrous magnesium sulfate and filtered. It was concentrated under reduced pressure, and then the residue was purified and concentrated by column chromatography (silica; methanol/dichloromethane=10percent) to give the desired compound ofFormula 2-2(0.193 g, 47percent) in the form of a brown solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 100℃;Inert atmosphere; | To a stirred mixture of 1 -allyl-2-bromo-6-(4-chlorophenyl)-5-(3, 7-dimethyl-3H-benzo[d][1 ,2,3]triazol-5-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(1 H)-one (Step 1.11) (80 mg, 0.161 mmol) in Dioxane (1.1 mL) and water (400 iL) under Ar were added K3P04 (136 mg,0.643 mmol), PdCI2(dppf).CH2CI2 adduct (20 mg, 0.0.24 mmol) and trimethylboroxine (45 iL,0.32 mmol). The resulting mixture was heated up and stirred at 100 00 overnight. PdCI2(dppf).CH2CI2 adduct (20 mg, 0.0.24 mmol) and trimethylboroxine (45 iL, 0.32 mmol) were added and the reaction was stirred 1.5 hr at 100 00 PdCI2(dppf).CH2CI2 (20 mg, 0.0.24 mmol) adduct and trimethylboroxine trimethylboroxine (45 iL, 0.32 mmol) were added and the reaction was stirred 5.5 hr at 100 00 The reaction was cooled down to RT, diluted with water and the aq. layer was extracted twice with EtOAc. Combined extracts were dried over Na2504, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (gradient 35-55 percent CH3CN in 16 mm) followed by basic workup to afford the title product (5 mg, 0.012 mmol, 7.52 percent yield). tR: 0.80 mm (LC-MS 2); ESl-MS: 393 [M+H] ESl-MS: 391 [M-H] (LC-MS 2).The title compound was prepared in analogy to the procedure described for Example 1 using1-allyl-2-bromo-6-(4-chlorophenyl)-5-(1 ,5-dimethyl-6-oxo-1 ,6-dihydropyridin-3-yl)-5,6- dihydropyrrolo[3,4-d]imidazol-4(1 H)-one (Step 4.6) and 1-methyl-i ,2,3,6-tetrahydropyridine-4- boronic acid pinacol ester as a starting materials. Purification of the crude material by preparative HPLC (column: Waters SunFire 018, 30x100x5 tim; solvent A: water/0.i percent TFA; solvent B: acetonitrile; gradient 10-30 percent B in 16 mm) afforded the title compound as a beige solid. tR: 0.57 mm (LC-MS 2); ESl-MS: 450.3 [M+H]/448.3 [M-H] (LC-MS 2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 90℃; for 14h;Inert atmosphere; | To a stirred mixture of 1 -allyl-2-bromo-6-(4-chlorophenyl)-5-(3, 7-dimethyl-3H-benzo[d][1 ,2,3]triazol-5-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(1 H)-one (Step 1.11) (80 mg, 0.161 mmol) in Dioxane (1.1 mL) and water (400 iL) under Ar were added K3P04 (136 mg,0.643 mmol), PdCI2(dppf).CH2CI2 adduct (20 mg, 0.0.24 mmol) and trimethylboroxine (45 iL,0.32 mmol). The resulting mixture was heated up and stirred at 100 00 overnight. PdCI2(dppf).CH2CI2 adduct (20 mg, 0.0.24 mmol) and trimethylboroxine (45 iL, 0.32 mmol) were added and the reaction was stirred 1.5 hr at 100 00 PdCI2(dppf).CH2CI2 (20 mg, 0.0.24 mmol) adduct and trimethylboroxine trimethylboroxine (45 iL, 0.32 mmol) were added and the reaction was stirred 5.5 hr at 100 00 The reaction was cooled down to RT, diluted with water and the aq. layer was extracted twice with EtOAc. Combined extracts were dried over Na2504, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (gradient 35-55 percent CH3CN in 16 mm) followed by basic workup to afford the title product (5 mg, 0.012 mmol, 7.52 percent yield). tR: 0.80 mm (LC-MS 2); ESl-MS: 393 [M+H] ESl-MS: 391 [M-H] (LC-MS 2).The title compound was prepared using an analogous procedure to that described in Example 1 using 2-bromo-6-(4-chlorophenyl)-5-(3,8-dimethyl-[1 ,2,4]triazolo[4,3-a]pyridin-6-yl)-1 -isopropyl5,6-dihydropyrrolo[3,4-d]imidazol-4(1 H)-one (Step 9.9) and <strong>[454482-11-2]1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine</strong> at 90 00 for 14 hr. The crude product was purified by preparative HPLC (gradient 5-100 percent CH3CN in 20 mm), followed by basic workup. tR:0.62 mm (LC-MS 2); ESl-MS: 516/518 [M+H] (LC-MS 2); 1H NMR (400 MHz, DMSO-d6) O ppm0.62 (d, J=6.8 Hz, 3 H) 1.46 (d, J=6.8 Hz, 3 H) 2.30 (5, 3 H) 2.38 (m, 1 H) 2.45 (5, 3 H) 2.6 (m, 3 H) 2.65 (5, 3 H) 3.00 (m, 1 H) 3.09 (m, 1 H) 4.60 (m, 1 H) 6.00 (m, 1 H) 6.70 (5, 1H) 7.40 (m, 1H) 7.41 (m, 4H) 8.40 (5, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 85℃; for 4h;Inert atmosphere; | To a stirred mixture of 1 -allyl-2-bromo-6-(4-chlorophenyl)-5-(3, 7-dimethyl-3H-benzo[d][1 ,2,3]triazol-5-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(1 H)-one (Step 1.11) (80 mg, 0.161 mmol) in Dioxane (1.1 mL) and water (400 iL) under Ar were added K3P04 (136 mg,0.643 mmol), PdCI2(dppf).CH2CI2 adduct (20 mg, 0.0.24 mmol) and trimethylboroxine (45 iL,0.32 mmol). The resulting mixture was heated up and stirred at 100 00 overnight. PdCI2(dppf).CH2CI2 adduct (20 mg, 0.0.24 mmol) and trimethylboroxine (45 iL, 0.32 mmol) were added and the reaction was stirred 1.5 hr at 100 00 PdCI2(dppf).CH2CI2 (20 mg, 0.0.24 mmol) adduct and trimethylboroxine trimethylboroxine (45 iL, 0.32 mmol) were added and the reaction was stirred 5.5 hr at 100 00 The reaction was cooled down to RT, diluted with water and the aq. layer was extracted twice with EtOAc. Combined extracts were dried over Na2504, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (gradient 35-55 percent CH3CN in 16 mm) followed by basic workup to afford the title product (5 mg, 0.012 mmol, 7.52 percent yield). tR: 0.80 mm (LC-MS 2); ESl-MS: 393 [M+H] ESl-MS: 391 [M-H] (LC-MS 2).The title compound was prepared in analogy to the procedure described for Example 1 using 2- bromo-6-(4-chlorophenyl)- 1 -isopropyl-5-(4-methoxy- 1-methyl-i H-benzo[d][i ,2, 3]triazol-6-yl)-5,6- dihydropyrrolo[3,4-d]imidazol-4(i H)-one (Step 60.7) and i-methyl-i ,2,3,6,-tetrahydropyridin-4- boronic acid pinacolester under heating at 85 00 for 4 hr. The reaction mixture was concentrated in vacuo and the residue diluted with CH2CI2 and aq. NaHCO3. The aq. layer was separated off and extracted with CH2CI2. Combined extracts were dried over Na2504, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography [CH2CI2/(EtOH + 5 percent NH3) 2-25 percent (EtOH + 5 percent N H3)] to afford the title compound. tR: 0.73 mm (LC-MS 2); ESl-MS: 532 [M+H] (LC-MS 2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With potassium phosphate; chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); In 1,4-dioxane; water; at 80℃; for 2h;Inert atmosphere; Sealed tube; | Step 1. Ethyl 2-[(tert-butoxycarbonyl)amino]-6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)furo[3,2-b]pyridine-3-carboxylate To a screw-cap vial equipped with a magnetic stir bar was added ethyl 6-bromo-2-[(tert-butoxycarbonyl)amino]furo[3,2-b]pyridine-3-carboxylate (1021 mg, 2.650 mmol), <strong>[454482-11-2]1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine</strong> (709.8 mg, 3.181 mmol), dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine-(2'-aminobiphenyl-2-yl)(chloro)palladium (1:1) (XPhos Pd G2, Aldrich, 314.7 mg, 0.4000 mmol), and K3PO4 (2.097 g, 9.879 mmol). The vial was sealed with a PTFE-lined septum, evacuated and backfilled with N2 (this process was repeated a total of three times). 1,4-Dioxane (9.00 mL) was added followed by deoxygenated water (3.00 mL). The reaction mixture was stirred at 80° C. for 2 h. After cooling to room temperature, the reaction mixture was filtered through a pad of diatomaceous earth (eluted with EtOAc). The filtrate was washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by chromatography on silica gel (40 g, 5percent MeOH in DCM containing 1percent Et3N) to give the product as a yellow foamy solid (875.2 mg, 82percent). LCMS calc. for C21H28N3O5 (M+H)+: m/z=402.2. found 402.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of 4-chloro-6-(hydroxy(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methyl)-2-methoxyquinolin-3-yl trifluoromethanesulfonate (40 mg, 0.067 mmol, Intermediate 39), <strong>[454482-11-2]1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine</strong> (23 mg, 0.1 mmol), PdCl2(dppf) (5 mg, 0.007 mmol) and K2CO3 (9 mg, 0.067 mmol) was sparged with nitrogen three times. To this mixture was added 1,4-dioxane (1.1 mL) and water (0.17 mL) and the suspension purged with nitrogen. The resulting solution was heated to 85° C. for 18 hours. The reaction was allowed to cool to room temperature and concentrated to dryness. The residue was dissolved in DMSO, filtered and purified by reverse-phase HPLC (acetonitrile/water+0.1percent TFA) to provide the title compound. 1H NMR (400 MHz, CD3OD) delta ppm 8.96 (s, 1H), 8.79 (d, J=2.2 Hz, 1H), 8.23 (d, J=2.4 Hz, 1H), 8.11-8.06 (m, 1H), 7.95 (d, J=8.8 Hz, 1H), 7.89 (d, J=8.3 Hz, 1H), 7.74-7.69 (m, 1H), 7.05-7.01 (m, 1H), 5.84-5.78 (m, 1H), 4.19-4.09 (m, 1H), 4.08 (s, 3H), 3.96-3.79 (m, 1H), 3.75-3.63 (m, 4H), 3.55-3.40 (m, 1H), 3.05 (s, 3H), 2.90-2.74 (m, 1H), 2.64-2.51 (m, 1H). MS (ESI): mass calcd. for C27H25ClF3N5O2, 543.2. m/z found, 544.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,2-dimethoxyethane; water; for 0.166667h;Microwave irradiation; | The compound of formula 1-2 (methyl4-((4-bromo- 1 H-pyrrolo[2,3-bJpyridin- 1 -yl)methyl)benzoate) (0.2 g, 0.523 mmol), <strong>[454482-11-2]1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester</strong> (0.140 g, 0.63 mmol), sodium carbonate (0.122 g, 1.151 mmol) and Pd(dppf)C12 (0.043 g, 0.052 mmol) were added to 1 ,2-dimethoxyethane (2 mL) / water (1 mL), and heated by microwave irradiation for 10 minutes, followed by cooling to room temperature. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, driedwith anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (Si02, 12 g cartridge; methanol / dichioromethane = from 5percent to 10percent) to afford the desired compound of formula 1-3 (0.1 g, 53percent) as a brown solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47.5% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In 1,4-dioxane; water; at 100℃; for 5h;Inert atmosphere; | Step 1. 6-Chloro-2-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-quinoline-5-carboxylic acid (4,4- difluorocyclohexylmethyl)- amide[00372] To a suspension of 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexyl methyl)-amide (150 mg, 0.37 mmol, 1.00 eq) in 1,4-Dioxane (4.00 mL, 26.67 V) and water (0.50 mL, 3.33 V) was degassed with nitrogen for 15 minutes,then to this 1-methyl-1,2,3,6- tetrahydropyridine-4-boronic acid pinacol ester (101.25mg, 0.44 mmol, 1.20 eq), cesium carbonate (362.17 mg, 1.10 mmol, 3.00 eq) and [1,1-bis(diphenyl phosphino) ferrocene] dichloropalladium(II), complexwith dichloromethane (30.15mg, 0.04 mmol, 0.10 eq) wereadded, then the reaction mixturewas heated in pressure tube at 100 oc for 5 h. After completion ofthe reaction by TLC, the reaction mixturewas cooled to room temperature, and filtered through celite, washed with ethyl acetate,and the filtrate was concentrated under reduced pressure to provide the crude compound,which was purifiedby column chromatography to afford the title compound (90 mg, 0.17 mmol, 47.5 percent) as a dark brown solid. m/z: 434.2 [M + H] + |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetone; at 20℃; for 1h; | To a solution of 1 -methyl-4-(4,4,5 ,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (0.86 g, 3.8 mmol) in acetone (20 ml) was added Mel (0.26 ml, 4.2 mmol). The resulting solution was stirred at RT for 1 hour. The mixture was concentrated to give 1,1 -dimethyl-4-(4,4,5,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1,2,3 ,6-tetrahydropyridin- 1- ium. LC-MS M: 238.15. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73.7% | A vial was charged with 1-(2-bromo-4-chlorophenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (147.5 mg, 0.233 mmol), <strong>[454482-11-2]1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine</strong> (104 mg, 0.466 mmol), PdCl2(dppf)-CH2Cl2 (19.04 mg, 0.023 mmol), and potassium carbonate (161 mg, 1.166 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (874 mul) and water (291 mul) were added in sequence. The vial was sealed and placed in an 80° C. heating bath for 30 min. The mixture was extracted with EtOAc (with a small amount of MeOH) (4*), and the combined organic extracts were concentrated. The residue was taken up in MeOH, and the resulting mixture was filtered through a 0.2 micron filter. The filtrate was purified by reverse-phase HPLC (5-50percent CH3CN/H2O with 0.1percent TFA). Fractions containing product were combined and lyophilized to give 1-(4-chloro-2-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)phenyl)-N-3-isoxazolyl-2-oxo-1,2-dihydro-6-quinolinesulfonamide 2,2,2-trifluoroacetate (105 mg, 0.172 mmol, 73.7percent yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) delta=11.83-11.21 (m, 1H), 10.04-9.51 (m, 1H), 8.67 (d, J=1.8 Hz, 1H), 8.39-8.26 (m, 1H), 8.24-8.11 (m, 1H), 7.84-7.65 (m, 1H), 7.56 (s, 2H), 7.37 (s, 1H), 6.81-6.64 (m, 2H), 6.38 (d, J=1.8 Hz, 1H), 5.45-5.30 (m, 1H), 3.71-3.49 (m, 1H), 3.41-3.13 (m, 2H), 3.00-2.72 (m, 1H), 2.64-2.46 (m, 3H), 2.35-2.08 (m, 2H). m/z (ESI) 496.9 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; at 110℃; for 2.5h;Inert atmosphere; | Under argon, 12 mg (0.015 mmol) [1,1?-bis(diphenylphosphino)ferrocene]dichloropalladium(II)was added to a mixture of 75 mg (0.15 mmol) 2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl trifluoromethanesulfonate and 65 mg (0.29 mmol) 1-5 methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )-1,2,3,6-tetrahydropyridine in 1.1 ml dioxane and 190 mg (0.58 mmol) caesium carbonate. The mixture was stirred at 110 °C for 150 minutes. After cooling, the reaction mixture was diluted with ethyl acetate and an aqueous solution of sodium chloride. The mixture was extracted with ethyl acetate (2x) and the combined organic phases were filtered using a Whatman filter. The organic phase was concentrated and the10 crude product (142 mg) was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With dichlorobis(triphenylphosphine)palladium(II); sodium carbonate; In 1,2-dimethoxyethane; at 80℃; for 16h;Sealed tube; Inert atmosphere; | 4-(1-Methyl-1,2,3,6-tetrahydropyridin-4-yl)benzaldehyde In a 30 mL sealed tube purged and maintained with an inert atmosphere of argon, 4-bromobenzaldehyde (500 mg, 2.70 mmol, 1.00 equiv), <strong>[454482-11-2]1-methyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine</strong> (723.6 mg, 3.24 mmol, 1.20 equiv), Pd(PPh3)2Cl2 (189.7 mg, 0.27 mmol, 0.10 equiv) and a solution of sodium carbonate (572.8 mg, 5.40 mmol, 2.00 equiv) were mixed in a mixture of ethylene glycol dimethyl ether/water (10:3, 13 mL) at room temperature. The resulting mixture was stirred for 16 h at 80 C. After the reaction was done, the reaction mixture was concentrated under reduced pressure. The residue was purified in a silica gel column eluting with ethyl acetate in (10% to 30% gradient) petroleum ether to afford 4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)benzaldehyde (490 mg, 86%) as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 130℃; for 1.5h;Microwave irradiation; | General procedure: Method iii: In a microwave vial, combine 2-(3-bromophenyl)acetonitrile (300 mg, 1.53 mmol), (4-chlorophenyl)boronic acid (287 mg, 1.84 mmol),tetrakis(triphenylphosphine)palladium(0) (88 mg, 0.077 mmol), 2M aqueous sodium carbonate solution (2.3 mL), and dimethoxyethane (10 mL). The reaction mixture was heated in a microwave with stirring at 140 °C for 1 h. The reaction mixture was diluted with water and DCM, extracted (2x), the organic layers were combined, dried with magesium sulfate, concentrated and purified via silica gel chromatography (0 to 25percent EtOAc/hexanes) to afford2-(4'-chloro-[l,r-biphenyl]-3-yl)acetonitrile (298 mg, 86percent); 1H NMR (400 MHz, CDC13) delta 7.62 - 7.38 (m, 7H), 7.37 - 7.28 (m, 1H), 3.82 (t, = 0.7 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | 2nd step: under the protection of nitrogen, the 1.3M isopropyl magnesium chloride-lithium chloride (72 ml, 94mmol) into the reaction bottle, temperature control -15 ° C to -10 °C, dropwise N-methyl -1, 2, 5, 6-tetrahydro-pyridine-4-polybromide tetrahydrofuran (80 ml) solution, stirring finishing joining 1-2 hours. After the end of the exchange, then drop by adding methoxy boronic acid pinacone ester (15.8g, 0 . 1mol), subsequently maintain the reaction at room temperature overnight. Adding 10percent hydrochloric acid aqueous solution quenching reaction, adjusting PH= 4-5, by adding 150 ml ethyl acetate, saturated salt water an organic layer, the organic layer after evaporation to dryness, add ethanol/heptane 40:1 obtained after pulping 14.1g kind of white solid N-methyl -1, 2, 5, 6-tetrahydro-pyridine-4-boronic acid frequency that alcohol ester, GC: 98.3percent, yield: 63percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 95℃; for 5h;Inert atmosphere; | Synthesis of 148-A. To a mixture of 147-A (600 mg, 2.36 mmol), SM-B (825 mg, 3.54 mmol) and K2CO3 (980 mg, 7.08 mmol) in dioxane/H2O (15 mL/1.5 mL) was added Pd(PPh3)4 (96 mg, 0.12 mmol) under N2 atmosphere. The mixture was stirred at 95 oC for 5 h and then concentrated in vacuo. The residue was dissolved with EtOAc (20 mL) and the solution was washed with brine (20 mL × 3). The organic layer was dried over anhydrous Na2SO4 and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE : EtOAc = 5 : 1 ~ 2 : 1) to give 148- A (285 mg, 40percent) as a yellow solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; at 95℃;Inert atmosphere; | Synthesis of AM362-A. To a degassed mixture of tert-butyl 5-bromoisoindoline-2- carboxylate (1 g, 3.3 mmol), <strong>[454482-11-2]1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester</strong> (1.12 g, 5.031 mmol ) and Cs2CO3 (3.2 g, 9.9 mmol ) in 1,4-dioxane (10 mL) was added Pd(dppf)Cl2 under N2 atmosphere and the mixture was heated at 95° C overnight. The reaction mixture was diluted with DCM (25 mL) and the catalyst was removed by filtration through the celite. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel (PE:EtOAc = 80:20~60:40) to give AM362-A (0.8 g, 76percent) as a brown gum. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 100℃; for 4h;Inert atmosphere; Sealed tube; | In a microwave pressure vessel equipped with a magnetic stirring bar was added (5 -7-chloro-3-(l,4-dimethyl-lH-l,2,3-triazol-5-yl)-5-((2-fluorophenyl)(tetrahydro-2H- pyran-4-yl)methyl)-5H-pyrrolo[2,3-b:4,5-b']dipyridine (30 mg, 0.061 mmol), l-methyl-4- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,2,3,6-tetrahydropyridine (20.45 mg, 0.092 mmol), dioxane (2 mL) and water (1 mL). Potassium carbonate (21.1 mg, 0.153 mmol) and Pd(Ph3P)4 (5.3 mg, 4.58 muetaiotaomicron) was added. Argon was bubbled into the mixture for 5 min, then the vessel was capped and placed into a preheated oil bath at 100°C. The reaction mixture was stirred for 4 h. Solids in the reaction mixture were filtered, and the filtrate was purified by preparative HPLC: Column: Waters XBridge C18, 19 x 200 mm, 5-mupiiota particles; Mobile Phase A: 5:95 methanol: water with lOmM NH40Ac; Mobile Phase B: 95:5 methanol: water with lOmM NH4OAC; Gradient: 10- 50percent B over 30 min, then a 5-min hold at 100percent B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give 27.3 mg (79percent) of the title compound with an average purity by LC/MS analysis was 97percent. Two analytical LC/MS injections were used to determine the final purity. Injection 1 conditions: Column: Waters BEH C18, 2.0 x 50 mm, 1.7mupiiota particles; Mobile Phase A: 5:95 ACN:water with 10 mM NH4OAc; Mobile Phase B: 95:5 ACN:water with 10 mM NILtOAc; Temperature: 50°C; Gradient: 0percentB, 0-100percent B over 3 min, then a 0.5-min hold at 100percent B; Flow: 1 mL/min; Detection: UV at 220 nm. Rt= 1.34 min; LC/MS (M+H) = 552.5. Injection 2 conditions: Column: Waters BEH CI 8, 2.0 x 50 mm, 1.7-mupiiota particles; Mobile Phase A: 5:95 methanol: water with 10 mM LiOAc; Mobile Phase B: 95:5 methanol: water with 10 mM NH4OAc; Temperature: 50°C; Gradient: 0percentB, 0-100percent B over 3 min, then a 0.5-min hold at 100percent B; Flow: 0.5 mL/min; Detection: UV at 220 nm. Rt= 2.77 min; LC/MS (M+H) = 552.5. NMR (500MHz, DMSO-c e) delta 8.60 (s, 1H), 8.54 (d, J=8.1 Hz, 1H), 8.47 (br. s., 1H), 8.22 (t, J=7.5 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.32 (d, J=6.6 Hz, 1H), 7.28 - 7.21 (m, 1H), 7.12 (t, J=9.4 Hz, 1H), 6.96 (br. s., 1H), 6.17 (br. s., 1H), 4.04 (s, 3H), 3.94 - 3.85 (m, 1H), 3.74 (d, J=9.9 Hz, 1H), 3.65 (br. s., 1H), 3.47 - 3.41 (m, 1H), 3.26 - 3.19 (m, 1H), 3.17 (br. s., 2H), 2.80 (d, J=18.3 Hz, 2H), 2.69 (d, J=5.5 Hz, 2H), 2.32 (s, 3H), 2.35 (s, 3H), 1.87 (s, 1H), 1.63 (d, J=1 1.7 Hz, 1H), 1.53 - 1.41 (m, 1H), 1.35 (d, J=7.7 Hz, 1H), 1.00 (d, J=13.2 Hz, 1H). LC/MS (M+H) = 552.6; HPLC conditions: Rt = 2.45 min (Phenomenex LUNA CI 8 2 x 50 mm (4 min grad) eluting with 5-95percent aq ACN containing l OmM NH4OAC, 0.8 mL/min, monitoring at 254 nm); Temperature: 40°C). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.3% | With dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); caesium carbonate; In 1,4-dioxane; water; at 100℃; for 0.333333h;Microwave irradiation; | [5514] N-(4-bromophenyl)-N-(4-(5-(difluoromethyl)-l ,3.4-oxadiazol-2-yl)-2-fluorobenzyl)t hiomorpholine-4-carboxamide 1 , 1-dioxide (0.200 g, 0.358 rrunol), l-methyl-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)- l ,2,3,6-tetrahydropyridine (0.096 g, 0.429 mmol), [ l,r-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride (Pd(dtbpf)C12, 0.012 g. 0.018 mmol) and cesium carbonate (0.349 g, 1.073 mmol) in 1 ,4-dioxane (3 mL) / water ( 1 mL) was mixed at the room temperature and then heated at 100 °C under the microwaves for 20 min and cooled down to the room temperature to terminate the reaction. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, dried with anhydrous MgS04, filtered, and concentrated in vacuo. The concentrate was purified and concentrated by column chromatography (Si02, 4 g cartridge; methanol / dichloromethane = 0 percent to 5 ) to give N- (4-(5-(difluoromethyl)- 1 ,3,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-(4-( 1 -methyl- 1 ,2,3,6-t etrahydropyridin-4-yl)phenyl)thiomo holine-4-carboxamide 1 , 1-dioxide as orange solid (0.1 9 g, 77.3 percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In 1,4-dioxane; water; at 90℃; for 1h;Inert atmosphere; | 11552] Nitrogen was bubbled for 5 minutes into a suspension of ALP19 (100 mg, 0.4 mmol), 1-methyl-1,2,3,6- tetrahydropyridine-4-boronic acid pinacol ester (CAS:454482-11-2, 109 mg, 0.5 mmol), Pd(dppf)C12.DCM (20 mg, 0.02 mmol), and cesium carbonate (240 mg, 0.7 mmol) in dioxane/water (2/1 v/v, 2 mL). The reaction mixture was heated at 90° C. for 1 hour and cooled to RT. The volatiles were removed under reduced pressure, and the crude residue was suspended in water (20 mL). The aqueous solution was acidified with a citric acid solution to pH 5. The precipitatewas filtered, washed with water and dried at 400 C. underreduced pressure to give the titled compound as the citratesalt. No further purification was performed and the compound was used as such in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65.5% | With dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); caesium carbonate; In 1,4-dioxane; at 100℃; for 0.333333h;Microwave irradiation; | In step 3 Manufactured N-(1-(4-bromophenyl)cyclobutyl)-5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyrimidin-2-amine (0.100 g, 0.237 mmol), 1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (0.063 g, 0.284 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride (Pd(dtbpf)Cl2, 0.008 g, 0.012 mmol) and cesium carbonate (0.231 g, 0.711 mmol) was dissolved in a mixture of 1,4-dioxane (3 mL)/water (1 mL) at room temperature and irradiated with microwaves at 100 °C for 20 minutes, the reaction was terminated by lowering the temperature to room temperature. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0percent to 15percent) and concentrated to give the title compound (0.068 g, 65.5percent) as a brown solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38.6% | With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 105℃; for 16h;Inert atmosphere; | Compound 3-4 (10.7 g, 39.2 mmol)Was dissolved in a mixed solvent of 300 ml of 1,4-dioxane and water (1,4-dioxane: water = 3: 1)Potassium phosphate (16.6 g, 78.2 mmol) was added at room temperature under nitrogen,<strong>[454482-11-2]1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester</strong> (8.7 g, 39.1 mmol)[1,1'-bis (diphenylphosphino) ferrocene] dichloromethane dichloromethane complex(3.2 g, 3.9 mmol),The reaction was allowed to react at 105 ° C for 16 hours,At the end of the reaction, 0.5 L of ice water was added to the system, extracted with ethyl acetate,Saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column,Compound 3-5 (5.0 g, 38.6percent) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44.2% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 82℃; for 1.5h; | To a solution of 8-bromo-9-(4-((3S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (D4) (139.3 mg, 302.58 mumol), in dioxane (2 ml) and water (1 ml), was added <strong>[454482-11-2]1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine</strong> (81.01 mg, 363.09 mumol), Cs2CO3 (197.17 mg, 605.15 mumol), and Pd(dppf)Cl2 (13.28 mg, 18.15 mumol). The reaction mixture was heated at 82° C. for 1.5 hours and partitioned between water and DCM. The aqueous phase was washed with DCM and the organic phase was concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of MeOH in DCM (0percent to 10percent) to give a solid which was further purified on strong cation exchange (SCX) column to give 63.7 mg (44.2percent) of 5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-8,9-dihydro-7H-benzo[7]annulen-2-ol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 120℃; for 1h;Microwave irradiation; Inert atmosphere; Sealed tube;Catalytic behavior; | An oven dried microwave reaction vial was charged with 86 mg (0.26 mmol) 4-iodo-6,7-dichloroindolin-2-one (52), 15 mg (13 mmol, 0.05 equiv) Pd(PPh3)4, 66 mg (0.296 mmol, 1.12 equiv) <strong>[454482-11-2]1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester</strong> and a stir bar. The microwave reaction vial was then evacuated and backfilled with nitrogen. This process was repeated for three times in total. Then 4 mL DME and 4 mL of a 2 M Na2CO3 solution were added and the microwave reaction vial sealed. The reaction mixture was stirred for 1 h at 120 °C under microwave irradiation. Upon cooling to room temperature, 10 mL water was added to the reaction mixture and extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM:methanol = 10:1, Rf = 0.1) yielding 31 mg (40percent) product as a brown solid. mp: 285 °C (decomposition). IR: nu (cm-1) = 3111, 2953, 1717, 1600, 1541, 1471, 1424, 1282, 1161, 1119, 956, 734, 636, 576. 1H NMR (500 MHz, DMSO-d6): delta = 10.98 (s, 1 H, NH), 7.11 (s, 1 H, 5-H), 6.04-5.97 (m, 1 H, 3'-H), 3.67 (s, 2 H, 3-H), 2.99 (q, J = 3.0 Hz, 2 H, 2'-H), 2.52 (t, J = 5.7 Hz, 2 H, 6'-H), 2.43-2.37 (m, 2 H, 5'-H), 2.26 (s, 3 H, CH3). 13C NMR (126 MHz, DMSO-d6): delta = 176.1 (C-2), 143.2 (C-7a), 137.4 (C-4), 132.1 (C-4'), 130.0 (C-6), 126.3 (C-3'), 122.5 (C-7), 120.4 (C-5), 110.3 (C-3a), 54.3 (C-20), 51.6 (C-6'), 45.3 (CH3), 37.2 (C-3), 28.4 (C-5'). HRMS (ESI): m/z = 297.0557 [M + H]+ calcd for C14H15Cl2N2O+ 297.0556. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 120℃; for 0.25h;Microwave irradiation; Inert atmosphere; | A mixture of intermediate 455 (500 mg; 2.07 mmol), 1-methyl-1,2,3,6- tetrahydropyridine-4-boronic acid pinacol ester (509 mg; 2.28 mmol) and potassiumphosphate (881 mg; 41.5 mmol) in 1 ,4-dioxane (7 mL) and water (4 mL) was degassed with N2. 1,1?-Bis (diphenylphosphino) ferrocene- palladium(ii) dichloride dichloromethane (17 mg; 0.0207 mmol) was added and the reaction mixture was heated at 120°C for 15 mm using one single mode microwave (Biotage Initiator EXP 60) with a power output ranging from 0 to 400 W. The mixture was poured onto water andextracted with DCM. The organic layer was washed with brine, dried over MgSO4, filtered and evaporated to dryness. The residue was purified by chromatography over silica gel (irregular SiOH, 80 g; mobile phase: DCM/MeOH: 100/0 to 95/5). The fractions containing the product were collected and evaporated to dryness to give 0.515 g (96percent) of intermediate 472. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; at 100℃;Inert atmosphere; | Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed N-benzyl-3-bromo-l-[[2-(trimethylsilyl)ethoxy]methyl]-lH-l,2,4- triazol-5-amine (1.36 g, 3.55 mmol, 1.00 equiv) in dioxane (20 mL), Pd(dppf)Ch CH2CI2 (873 mg, 1.07 mmol, 0.30 equiv), potassium carbonate (1.47 g, 10.64 mmol, 3.00 equiv), water(5 mL) and l-methyl-4-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l,2,3,6- tetrahydropyridine (1.19 g, 5.33 mmol, 1.50 equiv). The resulting solution was stirred overnight at 100 °C. The mixture was cooled to room temperature (30 °C). The resulting solution was diluted with 60 mL of H2O, extracted with 3 x 80 mL of dichloromethane, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied onto a silica gel column and eluted with dichloromethane/methanol (10/1). The collected fraction was concentrated to give 1.4 g (99percent) of N-benzyl-5-(l-methyl-l,2,3,6- tetrahydropyridin-4-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-l,2,4-triazol-3 -amine as brown oil. MS (ES, m/z) [M+H]+: 400. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With potassium phosphate; chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); In 1,4-dioxane; water; at 90℃;Inert atmosphere; | (1392) [00447] To a one dram vial was added benzyl 4-bromophenethylcarbamate (1.50 g, 4.49 mmol), l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,2,3,6-tetrahydropyridine (1.00 g, 4.49 mmol), potassium phosphate tribasic (3.8 1 g, 18.0 mmol), and XPhos 2nd generation Pd precatalyst (0.353 g, 0.449 mmol). The flask was backfilled with dry nitrogen 3 times and degassed dioxane (9.8 ml) and water (2,80 ml) were added. The reaction mixture was heated to 90 °C overnight and then cooled to RT, filtered through a bed of Celite, and concentrated m vacuo. The resulting crude product was purified by FCC eluting with 20 - 30percent EtOAc in hexanes to afford benzyl (4-(l-methyl-l,2,3,6-tetrahydropyridin-4- yl)phenethyl)carbamate as a white solid (1.2 g, 77percent). I CMS (ESI, m/z): 351 | \ H j |
Tags: 454482-11-2 synthesis path| 454482-11-2 SDS| 454482-11-2 COA| 454482-11-2 purity| 454482-11-2 application| 454482-11-2 NMR| 454482-11-2 COA| 454482-11-2 structure
[ 1462950-92-0 ]
1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride
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[ 1121057-75-7 ]
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride
Similarity: 0.97
[ 1048976-83-5 ]
1-Benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine
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[ 1227068-67-8 ]
1-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone
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[ 129636-11-9 ]
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