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Structure of 61940-21-4
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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. : | 61940-21-4 |
Formula : | C9H8BrNO4 |
M.W : | 274.07 |
SMILES Code : | O=C(OC)C1=C([N+]([O-])=O)C=CC=C1CBr |
MDL No. : | MFCD04114314 |
Boiling Point : | No data available |
InChI Key : | SJJJFLXTGHEZJB-UHFFFAOYSA-N |
Pubchem ID : | 21708527 |
GHS Pictogram: |
![]() ![]() |
Signal Word: | Danger |
Hazard Statements: | H302-H314 |
Precautionary Statements: | P260-P264-P270-P280-P301+P330+P331-P303+P361+P353-P304+P340-P305+P351+P338-P310-P363-P405-P501 |
Class: | 8 |
UN#: | 3261 |
Packing Group: | Ⅱ |
Num. heavy atoms | 15 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.22 |
Num. rotatable bonds | 4 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 59.38 |
TPSA ? Topological Polar Surface Area: Calculated from |
72.12 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.79 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.27 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.12 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.61 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.6 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.48 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.37 |
Solubility | 1.17 mg/ml ; 0.00425 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.38 |
Solubility | 1.13 mg/ml ; 0.00413 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.11 |
Solubility | 0.213 mg/ml ; 0.000776 mol/l |
Class? Solubility class: Log S scale |
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 |
-7.07 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 |
3.0 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) |
2.43 |
* 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 |
---|---|---|
93% | With potassium carbonate; In acetonitrile; at 81 - 83℃; for 2h;Product distribution / selectivity; | Example 4B Alternative Preparation of Compound (1)Compound (1) was also prepared by the following procedure. A mixture of methyl 2-bromomethyl-6-nitrobenzoate (100.0 g, 365 mmol, prepared previously in Example 2), <strong>[608141-42-0](1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethylamine</strong> (104.7 g, 383 mmol, prepared previously in Example 3), and potassium carbonate powder (100.8 g, 730 mmol, from Aldrich Chemicals) was suspended in acetonitrile (500 mL) at room temperature. The reaction mixture was refluxed at 81-83 C. for about two hours until there was less than 2% of unreacted methyl 2-bromomethyl-6-nitrobenzoate. After the reaction mixture was cooled to 45-50 C., methanol (200 mL) was charged over 5-10 minutes. After the mixture was allowed to cool to 20-25 C. and stirred for 2 hours, deionized water (1.40 L) was charged over 0.5-1 hour and stirred at 20-25 C. for 30 minutes and at 0-5 C. for 1-2 hours. The solid was filtered, washed with deionized water (3×300 mL), and dried to <10% of water content as measured by Karl Fisher titration. The solid was suspended in methanol (750 mL) and refluxed for 1-1.5 hours. The suspension was cooled to 0-5 C. over 1.5-2 hours and kept at 0-5 C. for 1-1.5 hours. The solid was filtered, washed with 0-5 C. methanol (2×200 mL) and heptane (200 mL), and then dried at 40-45 C. under vacuum to a constant weight. The yield of Compound (1) was 148.0 g (93%), based on 100.0 g input of methyl 2-bromomethyl-6-nitrobenzoate. The product was found to have a purity of >99% measured by HPLC based on area percentage, and a water content of <1.0% measured by Karl Fisher titration. |
93% | With potassium carbonate; In acetonitrile; at 81 - 83℃; for 0.2h; | (1 S)-7-nitro-2-[ 1 -(3 -ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-ethyl]isoindolin-1-one was prepared by the following procedure. A mixture of methyl 2-bromomethyl-6-nitrobenzoate (100.0 g, 365 mmol, prepared previously in Example 6.5.2.), (iS)1 -(3 -ethoxy-4-methoxyphenyl)-2-methanesulfonylethylamine (104.7 g, 383 mmol, preparedpreviously in Example 6.5.3.), sodium hydrogen carbonate (67.5 g, 8.03 moles, from Aldrich Chemicals) and dimethyl formamide (500 mL) was charged into a 1-L 3-necked flask at room temperature under nitrogen. The reaction mixture was gradually heated to an internal temperature of 70-75C for two hours until there was less than 99% measured by HPLC based on area percentage, and a water content of <0.1% measured by Karl Fisher titration. |
93% | With potassium carbonate; In acetonitrile; at 81 - 83℃; for 2h;Inert atmosphere; | 6.5.5. Alternative Preparation of (1S)-7-nitro-2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]isoindolin-1-one (0178) (1S)-7-nitro-2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl] isoindolin-1-one was also prepared by the following procedure. A mixture of methyl 2-bromomethyl-6-nitrobenzoate (100.0 g, 365 mmol, prepared previously in Example 6.5.2.), <strong>[608141-42-0](1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethylamine</strong> (104.7 g, 383 mmol, prepared previously in Example 6.5.3.), and potassium carbonate powder (100.8 g, 730 mmol, from Aldrich Chemicals) was suspended in acetonitrile (500 mL) at room temperature. The reaction mixture was refluxed at 81-83 C. for about two hours until there was less than 2% of unreacted methyl 2-bromomethyl-6-nitrobenzoate. After the reaction mixture was cooled to 45-50 C., methanol (200 mL) was charged over 5-10 minutes. After the mixture was allowed to cool to 20-25 C. and stirred for 2 hours, deionizer water (1.40 L) was charged over 0.5-1 hour and stirred at 20-25 C. for 30 minutes and at 0-5 C. for 1-2 hours. The solid was filtered, washed with deionizer water (3×300 mL), and dried to <10% of water content as measured by Karl Fisher titration. The solid was suspended in methanol (750 mL) and refluxed for 1-1.5 hours. The suspension was cooled to 0-5 C. over 1.5-2 hours and kept at 0-5 C. for 1-1.5 hours. The solid was filtered, washed with 0-5 C. methanol (2×200 mL) and heptane (200 mL), and then dried at 40-45 C. under vacuum to a constant weight. The yield of (1S)-7-nitro-2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]isoindolin-1-one was 148.0 g (93%), based on 100.0 g input of methyl 2-bromomethyl-6-nitrobenzoate. The product was found to have a purity of >99% measured by HPLC based on area percentage, and a water content of <1.0% measured by Karl Fisher titration. |
93% | With potassium carbonate; In acetonitrile; at 81 - 83℃; for 20h;Reflux; | 10223] (1 S)-7-nitro-2-[1 -(3-ethoxy-4-methoxyphenyl)-2- (methylsulfonyl)ethyl]isoindolin-1 -one was also prepared by the following procedure. A mixture of methyl 2-bromom- ethyl-6-nitrobenzoate (100.0 g, 365 mmol, prepared previously in Example 5.7.2), (1S)-1-(3-ethoxy-4-methoxyphe- nyl)-2-methanesulfonyl-ethylamine (104.7 g, 383 mmol, prepared previously in Example 5.7.3), and potassium carbonate powder (100.8 g, 730 mmol, fromAldrich Chemicals) was suspended in acetonitrile (500 mE) at room temperature. The reaction mixture was refluxed at 81-83 C. for about two hours until there was less than 2% of unreacted methyl 2-bro- momethyl-6-nitrobenzoate. Afier the reaction mixture was cooled to 45-50 C., methanol (200 mE) was charged over 5-10 minutes. Afier the mixture was allowed to cool to 20-25 C. and stirred for 2 hours, deionized water (1.40 L) was charged over 0.5-1 hour and stirred at 20-25 C. for 30 minutes and at 0-5 C. for 1-2 hours. The solid was filtered, washed with deionized water (3 x3 00 mE), and dried to 99% measured by HPLC based on area percentage, and a water content of <1.0% measured by Karl Fisher titration |
54% | With triethylamine; In N,N-dimethyl-formamide; at 80 - 90℃; for 24h; | Step 1 :; A solution of 2-bromomethyl-6-nitro-benzoic acid methyl ester (4.0g, 14.6 mmol), (l S)- l-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine (4.0g, 14.6 mmol) and triethylamine (4.4 mL, 31.6 mmol) in DMF (40 mL) was heated at 80C-90C for 1 day. The solvent was removed in vacuo to give an oil. The oil was extracted with ethyl acetate (150 mL) and HC1 (2N, 50 mL). The organic layer was washed with HC1 (2N, 2X50 mL), water (2X50 mL), brine (2X50 mL) and dried over MgS04. The solvent was removed in vacuo to give a yellow oil. The oil was slurried in ether (50 mL) to give a suspension. The suspension was filtered and washed with ether to give 2-[(l S)- 1 -(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-7-nitro-2,3-dihydro- isoindol- l -one as a yellow solid (3.43 g, 54% yield): lH NMR (CDC13) delta 1.5 (t, J= 7 Hz, 3H, CH3), 2.99 (s, 3Eta, CH3), 3.69 (dd, J= 5, 15 Hz, 1H, CHH), 3.86 (s, 3H, CH3), 4.07 (q, J = 7 Hz, 2H, G¾), 4.27 (dd, J = 1 1 , 15 Hz, 1H, CHH), 4.30 (d, J = 17 Hz, 1H, NCHH), 4.54 (d, J = 17 Hz, 1H, NCHH), 5.70 (dd, J = 5, 10 Hz, 1H, NCH), 6.85 (d, J= 8 Hz, 1H, Ar), 6.94-7.00 (m, 2H, Ar), 7.58- 7.76 (m, 3H, Ar). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium bicarbonate; In methanol; water; | A mixture of methyl 2-bromomethyl-6-nitrobenzoate (100.0 g, 365 mmol, prepared previously in Example 6.5.2.), (1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethylamine (104.7 g, 383 mmol, prepared previously in Example 6.5.3.), sodium hydrogen carbonate (67.5 g, 8.03 moles, from Aldrich Chemicals) and dimethyl formamide (500 mL) was charged into a 1-L 3-necked flask at room temperature under nitrogen. The reaction mixture was gradually heated to an internal temperature of 70-75 C. for two hours until there was less than <2% of unreacted methyl 2-bromomethyl-6-nitrobenzoate. The reaction mixture was gradually heated to an internal temperature of 95-100 C. for 18 hours. The reaction mixture was cooled to 20-25 C. and transferred to an 1-L addition funnel. After purified water (1500 mL) was charged into a 5-L 3-necked flask, the reaction mixture in the addition funnel was added into water in the 5-L 3-necked flask at room temperature over 1-2 hours maintaining an internal temperature below 30 C. The reaction mixture was stirred for 2 hours at room temperature. The solid was filtered out under vacuum, washed with water (3*300 mL) and methanol (2*400 mL), and then charged into a 2-L 3-necked flask followed by methanol (1000 mL). The mixture was refluxed for 1 hour. The mixture was cooled to room temperature. The solid was collected by filtration under vacuum, washed with 200 mL methanol (2 vol), and dried to a constant weight at 40-45 C. under a vacuum at 100-120 torr. The yield of (1S)-7-nitro-2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]isoindolin-1-one was 123.0 g (78%), based on 100.0 g input of methyl 2-bromomethyl-6-nitrobenzoate. The product was found to have a purity of >99% measured by HPLC based on area percentage, and a water content of <0.1% measured by Karl Fisher titration. |
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