Structure of 72652-32-5
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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. : | 72652-32-5 |
Formula : | C6H3BrCl3NO |
M.W : | 291.36 |
SMILES Code : | ClC(Cl)(Cl)C(C1=CC(Br)=CN1)=O |
MDL No. : | MFCD00832836 |
InChI Key : | CQLTVLIUJXOOGD-UHFFFAOYSA-N |
Pubchem ID : | 2798140 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 5 |
Fraction Csp3 | 0.17 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 1.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 53.11 |
TPSA ? Topological Polar Surface Area: Calculated from |
32.86 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.92 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
3.27 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.33 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.54 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.67 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.75 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.88 |
Solubility | 0.0382 mg/ml ; 0.000131 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.63 |
Solubility | 0.0676 mg/ml ; 0.000232 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-4.3 |
Solubility | 0.0147 mg/ml ; 0.0000504 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
Yes |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
Yes |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-5.76 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
0.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<0.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.85 |
* 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 |
---|---|---|
71% | With sodium; for 0.166667h; | Step 2: Methyl 4-bromo-lH-pyrrole-2-carboxylate[00174] To a dry round bottom flask containing dry MeOH (60 mL) was added sodium (5 g, 257.7 mmol) portionwise. After all the sodium was dissolved, the solution was slowly added to a flask which contained l-(4-bromo-lH-pyrrol-2-yl)- 2,2,2-trichloroethanone (50.0 g, 171.8 mmol) in MeOH (860 mL) through a dropping funnel giving a yellow reaction mixture. After the addition was complete, the reaction was stirred for an additional 10 minutes, then concentrated and cooled in an ice bath. The resulting solid that precipitated was collected by vacuum filtration and washed with water until neutral pH. The solid was dried to yield 25 g (71%) of the title compound as a white solid. LCMS (condition A): m/z = 204.0 -ve. 1H NMR (400MHz, DMSO-i¾) δ ppm: 7.16 (1H, d, 1.2H), 6.89 (1H, d, 1.2H). |
71% | With sodium; | To a dry round bottom flask containing dry MeOH (60 mL) was added sodium (5 g, 257.7 mmol) portionwise. After all the sodium was dissolved, the solution was slowly added to a flask which contained l-(4-bromo-lH-pyrrol-2-yl)- 2,2,2-trichloroethanone (50.0 g, 171.8 mmol) in MeOH (860 mL) through a dropping funnel giving a yellow reaction mixture. After the addition was complete, the reaction was stirred for an additional 10 minutes, then concentrated and cooled in an ice bath. The resulting solid that precipitated was collected by vacuum filtration and washed with water until neutral pH. The solid was dried to yield 25 g (71%) of the title compound as a white solid. LCMS (condition A): m/z = 204.0 -ve. XH NMR (400MHz, DMSO-d6) δ ppm: 7.16 (1H, d, 1.2H), 6.89 (1H, d, 1.2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | Step 1: Synthesis of 1-(4-Bromo-1H-pyrrol-2-yl)-2,2,2-trichloro-ethanone 2,2,2-Trichloro-1-(1H-pyrrol-2-yl)-ethanone (25 g, 117.7 mmol) was dissolved in 500 mL carbon-tetrachloride. Iodine (88 mg) was added and the mixture was cooled to 0 C. A solution of 6.03 mL bromine in 50 mL carbon tetrachloride was added dropwise over a period of 30 minutes. The stirring was continued for an additional 30 minutes at the same temperature then the reaction mixture was transferred to a separatory funnel and was washed successively with 100 mL of 10% Na2S2O3, saturated NaHCO3 and brine (2*). It was then dried (sodium sulfate) and evaporated to dryness to give 33.9 g (98%) of 1-(4-bromo-1H-pyrrol-2-yl)-2,2,2-trichloro-ethanone as a white powder. H1-NMR (DMSO-d6): δ (ppm) 12.82 (s, 1H), 7.53 (m, 1H), 7.29 (m, 1H). | |
93% | 1-(4-bromo-1H-pyrrol-2-yl)-2,2,2-trichloro-ethanone (7). 2-trichloroacetyl pyrrole 6 (5.00 g, 23.3 mmol) was dissolved in anhydrous chloroform (20 mL). The solution was cooled to -10 C. before the drop-wise addition of bromine (1.20 mL, 23.3 mmol) to the flask. Once addition was complete the reaction was allowed to warm to room temperature on its own accord while stirring for an additional 30 minutes. The reaction was poured into water (40 mL) and extracted with chloroform (3*20 mL). The combined organic layers were washed with sat. NaHCO3 (2*30 mL), brine (1*20 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Purification of the residue by column chromatography (Hexanes/Diethyl Ether 95:5) yielded the title compound 7 (6.37 g, 93%) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 12.86 (s, 1H), 7.54 (s, 1H), 7.32 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 171,67, 129.06, 122.01, 121.54, 97.60, 94.56; HRMS (FAB) calcd for C6H3BrCl3NO (M+) 288.8464, found 288.8479. | |
93% | With bromine; In chloroform; at -10 - 20℃; for 0.5h; | 1-(4-bromo-1H-pyrrol-2-yl)-2,2,2-trichloro-ethanone (7). 2-Trichloroacetyl pyrrole 6 (5.00 g, 23.3 mmol) was dissolved in anhydrous chloroform (20 mL). The solution was cooled to -10 C. before the drop-wise addition of bromine (1.20 mL, 23.3 mmol) to the flask. Once addition was complete the reaction was allowed to warm to room temperature on its own accord while stirring for an additional 30 minutes. The reaction was poured into water (40 mL) and extracted with chloroform (3×20 mL). The combined organic layers were washed with sat. NaHCO3 (2×30 mL), brine (1×20 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Purification of the residue by column chromatography (Hexanes/Diethyl Ether 95:5) yielded the title compound 7 (6.37 g, 93%) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 12.86 (s, 1H), 7.54 (s, 1H), 7.32 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 171.67, 129.06, 122.01, 121.54, 97.60, 94.56; HRMS (FAB) calcd for C6H3BrCl3NO (M+) 288.8464, found 288.8479. |
73% | With bromine; In chloroform; at 20℃;Cooling; | Example IB. 4-Bromo-2-trichloroacetylpyrrole[00119] To a solution of Example IA (21.2 g, 99 mmol) in CHCl3 (100 mL), cooled in an ice-bath, bromine (17 g, 106 mmol) was added dropwise. The resulting solution was stirred at ambient temperature for 10 min and then poured into water. The organic phase was separated, washed with saturated aq. NaHCO3 (50 mL) and water (50 mL), dried (MgSO4) and evaporated under reduced pressure. Recrystallization of the residue from hexane gave the product 4-bromo-2- trichloroacetylpyrrole (Example IB, 21 g, 73%) as an off-white solid. LC-MS, [M- H]+ = 289. 1H NMR (DMSO-d6, 300MHz): δ 12.9 (brs, IH), 7.55 (s, IH), 7.31 (s, IH). |
60% | With bromine; iodine; In Carbon tetrachloride; at 0℃; for 0.666667h; | Preparation 5; 6-bromo-4-chloropyrrolo[l,2-b]pyridazine-3-carboxamideStep 1 : l-(4-Brom -lH-pyrrol-2-yl)-2,2,2-trichloroethanone[00173] To a 100 mL 3-neck round bottom equipped with a dropping funnel was added trichloroacetyl pyrrole (50 g, 236.4 mmol) and CC14 (1.0 L). After trichloroacetyl pyrrole was dissolved, the reaction was cooled to 0 C and iodine (0.176 g) was added to the reaction. At this time, a solution of bromine (12 mL) in CC14 (100 mL) was added dropwise very slowly to the reaction through a dropping funnel over 20 minutes and the resulting mixture was stirred at 0 C for additional 20 minutes. The resulting mixture was transferred into a separatory funnel and washed with 10% a2S203 solution, saturated aHC03 solution and brine (2x). The organic layer was dried and concentrated to give 50 g (60%) of the title compound as a white solid. LCMS (condition A): m/z = 287.8, 289.8, 290.8 -ve. XH NMR (400MHz, CDC13) δ ppm: 12.8 (1H, br.s), 7.56 (1H, m), 7.33 (1H, m). |
60% | With bromine;iodine; In Carbon tetrachloride; at 0℃; for 0.666667h; | To a 100 niL 3-neck round bottom equipped with a dropping funnel was added trichloroacetyl pyrrole (50 g, 236.4 mmol) and CC14 (1.0 L). After trichloroacetyl pyrrole was dissolved, the reaction was cooled to 0 C and iodine (0.176 g) was added to the reaction. At this time, a solution of bromine (12 mL) in CC14 (100 mL) was added dropwise very slowly to the reaction through a dropping funnel over 20 minutes and the resulting mixture was stirred at 0 C for additional 20 minutes. The resulting mixture was transferred into a separatory funnel and washed with 10% a2S203 solution, saturated NaHCC solution and brine (2x). The organic layer was dried and concentrated to give 50 g (60%) of the title compound as a white solid. LCMS (condition A): m/z = 287.8, 289.8, 290.8 -ve. XH NMR (400MHz, CDC13) δ ppm: 12.8 (1H, br.s), 7.56 (1H, m), 7.33 (1H, m). |
57% | With bromine; In chloroform; at 0 - 20℃; | Synthesis of 4-Bromo-2-trichloroacetylpyrrole (20) via Scheme 4; Bromine (2.12 g, 10 mmol) was added dropwise to a stirred solution of 2- trichloroacetylpyrrole (19, 1.71 g, 10.7 mmol) in CHCl3 (15 mL) at 0 C. The mixture was then stirred at 0 C for 20 min and at rt for 5 min before quenched with water. The organic layer was washed with sat. NaHCO3 and water, dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel using hexane/ethyl acetate (90: 10 to 75:25) to give 20 as a white solid (1.65 g, 57%). 1H NMR (CDCl3, 500 MHz) δ 9.21 (br. s, IH), 7.35 (dd, J = 1 .5, 2.5 Hz, I H), 7.15 (dd, J = I .5, 2.5 Hz, I H); mp 135-137 C (lit.,16 136-138 0C ). |
45% | With bromine; In dichloromethane; at 0 - 20℃; for 0.166667h;Inert atmosphere; | To a stirring solution of pyrrole 2a (9.6 g, 0.045 mol) in CH2Cl2 (100 mL) at 0 C, was addeddropwise a solution of bromine (2.55 mL, 0.05 mol) in CH2Cl2 (20 mL). The mixture wasallowed to warm to r.t. and stirred for 10 min before being poured onto water and the organiclayer extracted from CH2Cl2 (3 x 40 mL). The combined organic extracts were washed withsat. aq. sodium bicarbonate (50 mL), water (50 mL), and dried (MgSO4). The solvent wasremoved in vacuo to give the crude product which was purified by flash chromatography (1:19EtOAc:petroleum ether) to afford the title compound 2d (6 g, 45%) as a silvery, metallic solid.Rf = 0.17 (1:19 EtOAc:petroleum ether). m.p. 134-136 C. (lit. m.p. 140-143 C). |
With bromine; In chloroform; at 0 - 20℃; for 0.666667h; | SYNTHETIC EXAMPLES Example 1 4-Bromo 2-trichloracetyl pyrrole: A solution of 2-trichloracetyl pyrrole (10.6 g, 50 MMOL) in CHC13 (10 mL) was cooled to 0 C and to this solution bromine (8.53 g, 53.5 MMOL) was added in a dropwise fashion. The reaction mixture was stirred for 10 minutes at 0 C then 30 minutes at room temperature. The solution was diluted with H20 and extracted with CHC13, washed with saturated NAHCO3 solution, dried over anhydrous NA2SO4 then concentrated in vacuo. The crude product was recrystallized from hexane and the product was obtained as white crystalline solid (8.0 g). HPLC Rt 5.66 min and MS 287.9 as M-1 peak. | |
With N-Bromosuccinimide; In acetonitrile; at 0 - 20℃;Large scale; | Example 1 A solution of Compound 1 in acetonitrile (1238.0 kg, 264.9 kg after correction) was charged into a 5000 L glass-lined reactor at a temperature of 20-30 C. The mixture was added with stirring over about 2 h and then cooled to 0 C. NBS (221.8 kg) was charged into the mixture at intervals of 20-30 min at 0-20 C. The mixture was cooled to 0-5 C and reacted until the content of Compound 8 was < 1.0%. Purified water (2650.0 kg) was added over about 1.5 - 2.5 h at 0-20 C. The mixture was cooled to 0-5 C and then stirred for about 1 h for crystallization. The mixture was filtered and the filter cake was rinsed with water. | |
With bromine; at 0℃; | 4-Bromopyrrole-2-carboxylic acid (3) is prepared by bromination of the commercially available 2-trichloroacetylpyrrole (6), which selectively gives the 4- bromo-2-trichloroacerylpyrroIe (7); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With triethylamine; In tetrahydrofuran; at 20℃; for 72h;Inert atmosphere; | General procedure: the coupling of substituted pyrroles with amine for synthesis of di-pyrroleanalogues 12-19.To a solution of pyrrole 2 (2 equiv.) in dry THF at r.t., under an atmosphere of nitrogen, amine(1 equiv.) and triethylamine (4 equiv.) were added dropwise. The mixture was stirred for 18-72 h and the solvent was removed in vacuo to give the crude product, which was purified as stated. |
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