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Structure of 873191-23-2
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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CAS No. : | 873191-23-2 |
Formula : | C6H9BrN2 |
M.W : | 189.05 |
SMILES Code : | CC1=NN(C)C(CBr)=C1 |
MDL No. : | MFCD02681908 |
GHS Pictogram: |
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Signal Word: | Danger |
Hazard Statements: | H301-H314 |
Precautionary Statements: | P280-P301+P310-P305+P351+P338-P310 |
Class: | 8(6.1) |
UN#: | 2923 |
Packing Group: | Ⅲ |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With phosphorus tribromide; In diethyl ether; at 20℃; for 18h; | To a stirring solution of (2,5-dimethyl-2H-pyrazol-3-yl)-methanol (100 mg, 0.79 mmol) in diethyl ether (3 ml.) is added PBr3 (25 //L, 0.26 mmol). The reaction is stirred at room temperature for 18 hours, then water is added. The diethyl ether layer is separated and stored over solid NaOH and used in Step 71b without further characterization. | |
With phosphorus tribromide; In diethyl ether; at 20℃; for 18h; | 71 a) To a stirring solution of (2,5-dimethyl-2H-pyrazol-3-yl)-methanol (100 mg, 0.79 mmol) in diethyl ether (3 mL) is added PBr3 (25 muL, 0.26 mmol). The reaction is stirred at room temperature for 18 hours, then water is added. The diethyl ether layer is separated and stored over solid NaOH and used in Step 71 b without further characterization. 71b) BEMP (137 pL, 0.47 mmol) is added to a solution of (2-methyl-1H-pyrrolo[2,3- b]pyridin-3-yl)-acetic acid methyl ester (60 mg, 0.29 mmol) in DMF (0.8 mL). After 35 minutes, the diethyl ether layer from Step 71 a (1.8 mL) is added. After 3 days, the reaction is partitioned between water and 1:1 EtOAc/ether. The organic layer is washed with brine then evaporated. The residue is purified by flash column chromatography (49:1 EtOAc/MeOH elution) to furnish [1-(2,5-dimethyl-2H-pyrazol-3-ylmethyl)-2-methyl-1H- pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester; MH+ = 313. | |
Bromine (229 mg, 1.44mmol) in dichloromethane was added to a solution of triphenylphosphine (376 mg, 1.44mmol) in dichloromethane that had been cooled with an ice-water bath. The reaction stirredfor 10 rnin, then J2 (170 mg, 1.34 mmol) was added all at once, whereupon the solution wasequilibrated to room temperature over 2h. The reaction was quenched with water, then theaqueous layer was extracted with dichloromethane (2 X 25 mL). The combined organic layerwas washed with 10% aqueous sodium thiosulfate, then brine. The organic layer was driedover magnesium sulfate, filtered, and concentrated in vacua. Purified by chromatography(1:1 hexane:ethyl acetate) to yield 195 mg of a colorless solid, J3. .H NMR (400 MHz;CDC13; T=29S K): § 6.07 ppm (s, 1H), 4.44 (s, 2H), 3.83 (s, 3H), 2.23 (s, 3H) ppm. |
With bromine; triphenylphosphine; at 0 - 20℃; for 2.16667h; | Bromine (229 mg, 1.44mmol) in dichloromethane was added to a solution of triphenylphosphine (376 mg, 1.44mmol) in dichloromethane that had been cooled with an ice-water bath. The reaction stirredfor 10 min, then C2 (170 mg, 1.34 mmol) was added all at once and the mixture wasequilibrated to room temperature over 2h. The reaction was quenched with water, then theaqueous layer was extracted with dichloromethane (2 X 25 mL). The combined organic layerwas washed with 10% aqueous sodium thiosulfate, then brine. The organic layer was driedover magnesium sulfate, filtered, and concentrated in vacuo. Purified by chromatography(1:1 hexane:ethyl acetate) to yield 195 mg of a colorless solid, C3. 1H NMR (400 MHz;CDC13; T=298 K): 5 6.07 ppm (s, 1H), 4.44 (s, 2H), 3.83 (s, 3H), 2.23 (s, 3H) ppm. | |
1.31 g | With carbon tetrabromide; triphenylphosphine; In tetrahydrofuran; at 0 - 27℃; for 2h; | 5-(Bromomethyl)-1 ,3-dimethyl-1 H-pyrazole (lntE5) CBr4 (4.7 g, 14.2 mmol) was added to a solution of (1 ,3-dimethyl-1 H-pyrazol-5- yl)methanol (1.2 g, 9.5 mmol) and triphenylphosphine (3.7 g, 14.2 mmol) in THF (20 mL) at 0C and the resulting mixture was stirred for approximately 2 h at rt. After concentration in vacuo purification by column chromatography eluting with 2% EtOAc in hexane yielded the title compound (1.31 g, 6.93 mmol). TLC: Rf = 0.85 (EtOAc: hexane, 3:8) Mass spectroscopy: (ESI +ve) 189.9 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
BEMP (137 mul_, 0.47 mmol) is added to a solution of (2-methyl-1/-/-pyrrolo[2,3- 6]pyridin-3-yl)-acetic acid methyl ester (60 mg, 0.29 mmol) in DMF (0.8 ml_). After 35 minutes, the diethyl ether layer from Step 71a (1.8 mL) is added. After 3 days, the reaction is partitioned between water and 1 :1 EtOAc/ether. The organic layer is washed with brine then evaporated. The residue is purified by flash column chromatography (49:1 EtOAc/MeOH elution) to furnish [1-(2,5-dimethyl-2H-pyrazol-3-ylmethyl)-2-methyl-1/-/- pyrrolo[2,3-/)]pyridin-3-yl]-acetic acid methyl ester; MH+ = 313. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; | D4 (70 mg,0.20 mmol), C3 (37 mg, 0.20 mmol), and potassium carbonate (30 mg, 0.22 mmol) werestirred in dimethylformamide at room temperature overnight. The reaction mixture waspartitioned between 4:1 ether:dichloromethane and water. The organic layer was washedwith water and brine. It was dried over magnesium sulfate, filtered, then concentrated invacua. Purified by chromatography (2% to 5% methanol with 0.1% ammonium hydroxide indichloromethane), yielding 55 mg of D5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 44h; | Amixture of 83mg G2 (0.25 mmol, 1.00 equiv.), 48 mg S-bromomethyl-ljS-dimethyl-l//-pyrazole (C3) (0.25 mmol, 1.00 equiv.) and 38 mg potassium carbonate (0.28 mmol, 1.10equiv.) in DMF was stirred for 44 h at room temperature then partitioned between 20mL eachwater and 3:1 diethyl etherdichloromethane. The separated aqueous layer was extracted with2x20mL 3:1 diethyl ether:dichloromethane. The combined organic extracts were washedwith 3x20mL water and 20mL brine. The organic separation was dried over magnesiumsulfate, filtered and concentrated in vacuo to afford a yellow glassy solid. The product waspurified by column chromatography on silica gel, eluting with 4% methanol indichloromethane. Purified product G3 isolated as an off-white solid, 73mg. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71 a) To a stirring solution of (2,5-dimethyl-2H-pyrazol-3-yl)-methanol (100 mg, 0.79 mmol) in diethyl ether (3 mL) is added PBr3 (25 muL, 0.26 mmol). The reaction is stirred at room temperature for 18 hours, then water is added. The diethyl ether layer is separated and stored over solid NaOH and used in Step 71 b without further characterization. 71b) BEMP (137 pL, 0.47 mmol) is added to a solution of (2-methyl-1H-pyrrolo[2,3- b]pyridin-3-yl)-acetic acid methyl ester (60 mg, 0.29 mmol) in DMF (0.8 mL). After 35 minutes, the diethyl ether layer from Step 71 a (1.8 mL) is added. After 3 days, the reaction is partitioned between water and 1:1 EtOAc/ether. The organic layer is washed with brine then evaporated. The residue is purified by flash column chromatography (49:1 EtOAc/MeOH elution) to furnish [1-(2,5-dimethyl-2H-pyrazol-3-ylmethyl)-2-methyl-1H- pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester; MH+ = 313. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With sodium hydride; In tetrahydrofuran; | General procedure: The lycorine derivatives 10, 11 and 12 (0.1mmol) were dissolved in dry THF (10mL), and NaH (50mg, 2mmol) and 3-(bromomethyl)pyridine, 3-(Chloromethyl)-1,5-dimethyl-1H-pyrazole or 5-Bromomethyl-1,3-dimethyl-1H-pyrazole (1mmol) were added. The mixture was stirred at r. t. for 24h and quenched with H2O (50mL) in an ice bath. The solution was evaporated to remove the THF and extracted with CH2Cl2 (2×30mL). The organic layer was washed with saturated NaHCO3 and brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography using petroleum ether-EtOAc as the eluent to afford compounds 5, 6, 7, 8 and 9. 8-((1,3-dimethyl-1H-pyrazol-5-yl)methoxy)-5-ethyl-4-methyl-5,6-dihydro- phenanthridine (5). 78% yield. Colorless amorphous powder (from CH2Cl2); 1H NMR (500MHz, CDCl3) delta 7.59 (d, J=8.5Hz, 1H), 7.50 (d, J=7.6Hz, 1H), 7.06 (d, J=8.0Hz, 1H), 7.00 (t, J=7.5Hz, 1H), 6.86 (dd, J=8.5, 2.6Hz, 1H), 6.74 (d, J=2.5Hz, 1H), 6.04 (s, 1H), 4.94 (s, 2H), 4.01 (s, 2H), 3.79 (s, 3H), 2.62 (q, J=7.1Hz, 2H), 2.29 (s, 3H), 2.19 (s, 3H), 1.01 (t, J=7.1Hz, 3H); 13C NMR (125MHz, CDCl3) delta 157.77 (C), 147.36 (C), 146.31 (C), 137.89 (C), 135.20 (C), 133.43 (C), 129.94 (CH), 129.12 (C), 126.72 (C), 124.38 (CH), 123.89 (CH), 120.90 (CH), 113.66 (CH), 112.84 (CH), 106.77 (CH), 60.61 (CH2), 50.18 (CH2), 46.12 (CH2), 36.50 (CH3), 17.79 (CH3), 13.63 (CH3), 13.43 (CH3); HRESIMS m/z 348.2055 [M+H]+ (calcd for C22H26N3O, 348.2070). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With sodium hydride; In tetrahydrofuran; | General procedure: The lycorine derivatives 10, 11 and 12 (0.1mmol) were dissolved in dry THF (10mL), and NaH (50mg, 2mmol) and 3-(bromomethyl)pyridine, 3-(Chloromethyl)-1,5-dimethyl-1H-pyrazole or 5-Bromomethyl-1,3-dimethyl-1H-pyrazole (1mmol) were added. The mixture was stirred at r. t. for 24h and quenched with H2O (50mL) in an ice bath. The solution was evaporated to remove the THF and extracted with CH2Cl2 (2×30mL). The organic layer was washed with saturated NaHCO3 and brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography using petroleum ether-EtOAc as the eluent to afford compounds 5, 6, 7, 8 and 9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride; In tetrahydrofuran; at 20℃; for 12h; | General procedure: The phenanthridine skeletons1-8 (0.1 mmol) were dissolved in dryTHF (10 mL), and NaH (50 mg, 2 mmol), and 3-(bromomethyl)pyridine,3-(chloromethyl)-1,5-dimethyl-1H-pyrazole or <strong>[873191-23-2]5-bromomethyl-1,3-dimethyl-1H-pyrazole</strong> (1 mmol) were added. The mixture was stirred atrt. for 12 h and quenched with H2O (50 mL) in an ice bath. The solutionwas evaporated to remove the THF and extracted with CH2Cl2(2×30 mL). The organic layer was washed with saturated NaHCO3 andbrine, dried over MgSO4, filtered and concentrated. The residue waspurified by column chromatography using petroleum-EtOAc as theeluent to afford about 35 mg of each phenanthridine compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride; In tetrahydrofuran; at 20℃; for 12h; | General procedure: The phenanthridine skeletons1-8 (0.1 mmol) were dissolved in dryTHF (10 mL), and NaH (50 mg, 2 mmol), and 3-(bromomethyl)pyridine,3-(chloromethyl)-1,5-dimethyl-1H-pyrazole or <strong>[873191-23-2]5-bromomethyl-1,3-dimethyl-1H-pyrazole</strong> (1 mmol) were added. The mixture was stirred atrt. for 12 h and quenched with H2O (50 mL) in an ice bath. The solutionwas evaporated to remove the THF and extracted with CH2Cl2(2×30 mL). The organic layer was washed with saturated NaHCO3 andbrine, dried over MgSO4, filtered and concentrated. The residue waspurified by column chromatography using petroleum-EtOAc as theeluent to afford about 35 mg of each phenanthridine compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride; In tetrahydrofuran; at 20℃; for 12h; | General procedure: The phenanthridine skeletons1-8 (0.1 mmol) were dissolved in dryTHF (10 mL), and NaH (50 mg, 2 mmol), and 3-(bromomethyl)pyridine,3-(chloromethyl)-1,5-dimethyl-1H-pyrazole or <strong>[873191-23-2]5-bromomethyl-1,3-dimethyl-1H-pyrazole</strong> (1 mmol) were added. The mixture was stirred atrt. for 12 h and quenched with H2O (50 mL) in an ice bath. The solutionwas evaporated to remove the THF and extracted with CH2Cl2(2×30 mL). The organic layer was washed with saturated NaHCO3 andbrine, dried over MgSO4, filtered and concentrated. The residue waspurified by column chromatography using petroleum-EtOAc as theeluent to afford about 35 mg of each phenanthridine compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | General procedure: To a cooled solution of compound 6 (361.0 mg, 1 mmol) in DMF (10 mL) was added NaH (60% in oil, 48.0 mg, 1.2 mmol) carefully. The mixture was stirred at 0 C for 1h. A solution of R1X (X=Cl, Br; 1.2 mmol) in DMF (5 mL) was then added dropwise in the mixture. The mixture was heated to 40 C and stirred for 8-16 h. The reaction mixture was cooled and quenched at 0 C with a saturated NH4Cl aqueous solution. Then mixture was concentrated under vacuum to remove most of the DMF and re-dissolved with CH2Cl2. After filtering, the filtrate was washed with saturated NaCl aqueous solution, dried with MgSO4 and concentrated under vacuum. The crude material was purified by column chromatography (PE/EA) on silica gel to afford compound 6a-6r. |