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Structure of 946125-65-1
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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. : | 946125-65-1 |
Formula : | C7H5BrFNO2 |
M.W : | 234.02 |
SMILES Code : | O=[N+](C1=C(F)C(CBr)=CC=C1)[O-] |
MDL No. : | MFCD11110170 |
Boiling Point : | No data available |
InChI Key : | MIESICVJNXXYKC-UHFFFAOYSA-N |
Pubchem ID : | 59139151 |
GHS Pictogram: |
![]() |
Signal Word: | Danger |
Hazard Statements: | H314-H290 |
Precautionary Statements: | P501-P260-P234-P264-P280-P390-P303+P361+P353-P301+P330+P331-P363-P304+P340+P310-P305+P351+P338-P310-P406-P405 |
Class: | 8 |
UN#: | 3261 |
Packing Group: | Ⅱ |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.14 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 48.06 |
TPSA ? Topological Polar Surface Area: Calculated from |
45.82 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.61 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.41 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.9 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.92 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.11 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.19 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.05 |
Solubility | 0.21 mg/ml ; 0.000897 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.01 |
Solubility | 0.226 mg/ml ; 0.000968 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.32 |
Solubility | 0.112 mg/ml ; 0.000478 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) |
No |
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 |
-6.02 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<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.99 |
* 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 |
---|---|---|
100% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 24h;Reflux; | a) Preparation of Int. 14 A mixture of <strong>[437-86-5]2-fluoro-3-nitrotoluene</strong> (33 g; 213 mmol), N-bromosuccinimide (41.7 g; 234.3 mmol) and a catalytic amount of azobisisobutyronitrile in carbon tetrachloride (300 ml) was heated to reflux for 24 h. The mixture was filtered. The organic solvent was evaporated in vacuo to yield 50 g of Int. 14 (100 %). |
92% | In a 60 L reactor (containing no exposed Stainless steel, Hastelloy, or other metal parts) equipped with a reflux/return condenser and scrubber charged with a 5N NaOH solution, a mechanically stirred mixture of FN-Toluene (2.0 kg, 12.89 mol, 1.0 equiv.), N- Bromosuccinimide (3.9 kg, 21.92 mol, 1.70 equiv.), benzoyl peroxide (125.0 g, 0.03 equiv., 0.39 mol, containing 25 wt% water), and acetic acid (7.0 L, 3.5 volumes) was heated to 85 C under an atmosphere of nitrogen for 7 hours. A solution of H3PO3 (106.0 g, 1.29 mol, 0.1 equiv.) and acetic acid (200 mL, 0.1 volume), prepared in separate vessel, was added. The reaction mixture was agitated for 0.5 h and analysis of an aliquot confirmed complete decomposition of benzoyl peroxide (not detected, HPLC254 nm)- The reaction mixture was cooled to 22 C. DI Water (8.0 L, 4 volumes) and toluene (16.0 L, 8 volumes) were charged, the biphasic mixture was agitated (20 min), and the layers were separated. Aqueous 1.6N NaOH (14.0 L, 7.0 volumes) was added to the organic layer at a rate allowing the batch temperature to stay under 25 C and the pH of the resultant aqueous phase was measured (> 11). The biphasic mixture was filtered through a 5 muiotaeta Teflon cartridge line and the layers were separated. The filter line was washed with another 2L of toluene. The assay yields were 2.5 % of FN-Toluene, 62.3 % of FN-Bromide and 30.0 % of Di-Bromide. The toluene solution contained no benzoyl peroxide, succinimide, or cc- bromoacetic acid and water content by KF titration was 1030 ppm (This solution could be held under nitrogen at room temperature for > 12 h without any change in the assay yield). To this solution at room temperature was added diisopropylethylamine (880.0 g, 6.63 mol, 0.53 equiv.) followed by methanol (460 mL, 11.28 mol, 0.88 equiv.) and heated to 40 C. A solution of diethylphosphite (820.0 g, 5.63 mol, 0.46 equiv.) in methanol (460 mL, 11.28 mol, 0.88 equiv.) was prepared and added to the reaction mixture at 40 C through an addition funnel over a period of 1 hour at such a rate that the batch temperature was within 40 + 5 C. The contents were stirred for a period of 3h at 40 C from the start of addition and cooled to room temperature and held under nitrogen atmosphere for 12 hours. The assay yield of the reaction mixture was 2.5 % FN-Toluene 92.0% FN-Bromide and 0.2% Di-Bromide. This solution is used as such for the alkylation step. | |
65% | With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 5h;Heating / reflux;Product distribution / selectivity; | Compound 1a-1: 1-Bromomethyl-2-fluoro-3-nitrobenzene; [Show Image] Benzoyl peroxide (10.7 g, 44 mmol) was added under reflux under nitrogen atmosphere to a solution of <strong>[437-86-5]2-fluoro-1-methyl-3-nitrobenzene</strong> (compound 2a-1) (68.2 g, 440 mmol) and N-bromosuccinimide (95.0 g, 528 mmol) in carbon tetrachloride (1500 mL), and the mixture was stirred under reflux for 5 hours. Impurities were then removed by filtration, and a crude product was obtained by vacuum concentration. It was then purified by column chromatography (hexane), and the title compound (68.7 g, 65%) was obtained as a yellow to light brown oil. 1H NMR (DMSO-d6, 270 MHz) delta (ppm): 8.14 (dd, J = 7.0, 1.6 Hz, 1H), 7.97 (dd, J = 6.5, 1.6 Hz, 1H), 7.46 (td, J = 8.4, 1.4 Hz, 1H), 4.81 (d, J = 1.4 Hz, 2H). HPLC Rt = 2.25 min. HPLC conditions were the same as those for the manufacturing example for compound 2a-1. |
65% | With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; | 1-Bromomethyl-2-fluoro-3-nitrobenzene Benzoyl peroxide (10.7 g, 44 mmol) was added under reflux under nitrogen atmosphere to a solution of <strong>[437-86-5]2-fluoro-1-methyl-3-nitrobenzene</strong> (compound 2a-1) (68.2 g, 440 mmol) and N-bromosuccinimide (95.0 g, 528 mmol) in carbon tetrachloride (1500 mL), and the mixture was stirred under reflux for 5 hours. Impurities were then removed by filtration, and a crude product was obtained by vacuum concentration. It was then purified by column chromatography (hexane), and the title compound (68.7 g, 65%) was obtained as a yellow to light brown oil. 1H NMR (DMSO-d6, 270 MHz) delta (ppm): 8.14 (dd, J = 7.0, 1.6 Hz, 1H), 7.97 (dd, J = 6.5, 1.6 Hz, 1H), 7.46 (td, J = 8.4, 1.4 Hz, 1H), 4.81 (d, J = 1.4 Hz, 2H). |
65% | With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 5h;Reflux; Inert atmosphere; | Benzoyl peroxide (10.7 g, 44 mmol) was added under reflux under nitrogen atmosphere to a solution of <strong>[437-86-5]2-fluoro-1-methyl-3-nitrobenzene</strong> (compound 2a-1)(68.2 g, 440 mmol) and N-bromosuccinimide (95.0 g, 528 mmol) in carbontetrachloride (1500 mL), and the mixture was stirred under reflux for 5 hours.Impurities were then removed by filtration, and a crude product was obtained byvacuum concentration. It was then purified by column chromatography (hexane),and the title compound (68.7 g, 65%) was obtained as a yellow to light brownoil |
39.76% | With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 80℃; for 12h; | To a suspension of <strong>[437-86-5]2-fluoro-3-nitrotoluene</strong> (64.5 mmol, 10 g) and N-bromosuccinimide (77.4 mmol, 13.78 g) in 100 mL of CCl4 was added benzoyl peroxide (6.45 mmol, 1.56 g) and heated at 80 C for 12 h.After cooling to room temperature, insolubles were removed by filtration and concentrated under reduced pressure. Column chromatography (gradient elution: petroleum ether, petroleum ether / ethyl acetate = 30/1)(v / v), pure product was obtained to give 6 g of 2-fluoro-3-nitrobenzyl bromide as a yellow oily product in a yield of 39.76%. |
34% | With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane;Reflux; | A stirred solution of <strong>[437-86-5]2-fluoro-1-methyl-3-nitrobenzene</strong> (15.80 g, 101.94 mmol) and N-bromosuccinimide (18.14 g, 101.94 mmol) in CCl4 (400 mL) was treated with benzoyl peroxide (0.37 g, 1.52 mmol). The mixture was heated at reflux temperature overnight and then cooled to room temperature. The reaction mixture was filtered, and the filtrate was evaporated to dryness under reduced pressure. The residue was dissolved in CH2Cl2 (100 mL) and filtered again. The filtrate was evaporated to dryness under reduced pressure, and the residue was purified by MPLC on silica gel using a mixture of EtOAc and hexane as eluent to give 1-(bromomethyl)-2-fluoro-3-nitrobenzene (8.11 g, 34%) as an off-white solid. 1H NMR (400 MHz, CDCl3): delta 8.02 (m, 1H), 7.71 (m, 1H), 7.30 (td, 1H, J=8.4, 1.6 Hz), 4.55 (d, 2H, J=1.6 Hz). |
34% | With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 13h;Inert atmosphere; Reflux; | General procedure: To a stirred solution of 18(166.51 mmol), 23 (166.51 mmol) or 27 (166.51 mmol) in CCl4 (350 mL) were added NBS (199.82 mmol) and benzoyl peroxide (16.65 mmol) under nitrogen atmosphere. The mixture was heated at reflux temperature for 13 h and then cooled to room temperature. The reaction mixture was filtered and then washed with CH2Cl2 (2 × 400 mL). The combined organic layers waswashed with water (200 mL), dried over anhydrous Na2SO4, and then evaporated to dryness under reduce pressure. The residue was purified by MPLC on silica gel to afford the titled compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74%; 11% | With N-Bromosuccinimide; acetic acid; In Isopropyl acetate; water; at 10 - 80℃; for 3h; | In some specific embodiments, 2-Fluoro-3-NitroToluene (5.1 grams) is dissolved in isopropyl acetate (30 mL) and a solution of sodium bromate (14.9 grams) in water (50 mL) is added. The mixture is cooled to 10 C. A solution of sodium bisulfite (10.3 g) in water (100 mL) is added over 20 minutes. The resulting mixture is heated to 80 C for 3 h. The reaction vessel has access to visible light. The contents are cooled to 20 C and the phases separated. The organic phase is sequentially washed with 10% aqueous sodium thiosulfate and saturated aqueous sodium chloride. 1-(Bromomethyl)-2-fluoro-3-nitrobenzene (FNB) is obtained in 74% assay yield with 11 % assay yield of the dibromide product |
62.3%; 30% | With N-Bromosuccinimide; acetic acid; sodium hydroxide; dibenzoyl peroxide; In water; at 85℃; for 7h;Inert atmosphere; Large scale; | In a 60 L reactor (containing no exposed Stainless steel, Hastelloy, or other metal parts) equipped with a reflux/return condenser and scrubber charged with a 5N NaOH solution, a mechanically stirred mixture of FN-Toluene (2.0 kg, 12.89 mol, 1.0 equiv.), N- Bromosuccinimide (3.9 kg, 21.92 mol, 1.70 equiv.), benzoyl peroxide (125.0 g, 0.03 equiv., 0.39 mol, containing 25 wt% water), and acetic acid (7.0 L, 3.5 volumes) was heated to 85 C under an atmosphere of nitrogen for 7 hours. A solution of H3PO3 (106.0 g, 1.29 mol, 0.1 equiv.) and acetic acid (200 mL, 0.1 volume), prepared in separate vessel, was added. The reaction mixture was agitated for 0.5 h and analysis of an aliquot confirmed complete decomposition of benzoyl peroxide (not detected, HPLC254 nm)- The reaction mixture was cooled to 22 C. DI Water (8.0 L, 4 volumes) and toluene (16.0 L, 8 volumes) were charged, the biphasic mixture was agitated (20 min), and the layers were separated. Aqueous 1.6N NaOH (14.0 L, 7.0 volumes) was added to the organic layer at a rate allowing the batch temperature to stay under 25 C and the pH of the resultant aqueous phase was measured (> 11). The biphasic mixture was filtered through a 5 muiotaeta Teflon cartridge line and the layers were separated. The filter line was washed with another 2L of toluene. The assay yields were 2.5 % of FN-Toluene, 62.3 % of FN-Bromide and 30.0 % of Di-Bromide. The toluene solution contained no benzoyl peroxide, succinimide, or cc- bromoacetic acid and water content by KF titration was 1030 ppm (This solution could be held under nitrogen at room temperature for > 12 h without any change in the assay yield). |
62.3%; 30.0% | FN-Bromide [0084] In a 60 L reactor (containing no exposed Stainless steel, Hastelloy, or other metal parts) equipped with a reflux/return condenser and scrubber charged with a 5N NaOH solution, a mechanically stirred mixture of FN-Toluene (2.0 kg, 12.89 mol, 1.0 equiv.), N- Bromosuccinimide (3.9 kg, 21.92 mol, 1.70 equiv.), benzoyl peroxide (125.0 g, 0.03 equiv., 0.39 mol, containing 25 wt water), and acetic acid (7.0 L, 3.5 volumes) was heated to 85 C under an atmosphere of nitrogen for 7 hours. A solution of H3PO3 (106.0 g, 1.29 mol, 0.1 equiv.) and acetic acid (200 mL, 0.1 volume), prepared in separate vessel, was added. The reaction mixture was agitated for 0.5 h and analysis of an aliquot confirmed complete decomposition of benzoyl peroxide (not detected, HPLC254 nm)- The reaction mixture was cooled to 22 C. DI Water (8.0 L, 4 volumes) and toluene (16.0 L, 8 volumes) were charged, the biphasic mixture was agitated (20 min), and the layers were separated. Aqueous 1.6N NaOH (14.0 L, 7.0 volumes) was added to the organic layer at a rate allowing the batch temperature to stay under 25 C and the pH of the resultant aqueous phase was measured (> 11). The biphasic mixture was filtered through a 5 muiotaeta Teflon cartridge line and the layers were separated. The filter line was washed with another 2L of toluene. [0085] The assay yields were 2.5 % of FN-Toluene, 62.3 % of FN-Bromide and 30.0 % of Di-Bromide. The toluene solution contained no benzoyl peroxide, succinimide, or cc- bromoacetic acid and water content by KF titration was 1030 ppm (This solution could be held under nitrogen at room temperature for > 12 h without any change in the assay yield). [0086] To this solution at room temperature was added diisopropylethylamine (880.0 g, 6.63 mol, 0.53 equiv.) followed by methanol (460 mL, 11.28 mol, 0.88 equiv.) and heated to 40 C. A solution of diethylphosphite (820.0 g, 5.63 mol, 0.46 equiv.) in methanol (460 mL, 11.28 mol, 0.88 equiv.) was prepared and added to the reaction mixture at 40 C through an addition funnel over a period of 1 hour at such a rate that the batch temperature was within 40 + 5 C. The contents were stirred for a period of 3h at 40 C from the start of addition and cooled to room temperature and held under nitrogen atmosphere for 12 hours. The assay yield of the reaction mixture was 2.5 % FN-Toluene 92.0% FN-Bromide and 0.2% Di-Bromide. This solution is used as such for the alkylation step. [0087] Characterization for components of final product mixture (collected for pure compounds). [0088] 2-Fluoro-3-Nitrotoluene (FN-Toluene): 1H NMR (400 MHz, CHLOROFORM- J) delta ppm 2.37 (s, 1 H), 7.13-7.20 (m, 1 H), 7.45-7.51 (m, 1 H), 7.79-7.85 (m, 1 H). 13C NMR (100 MHz, CHLOROFORM- d) delta ppm 14.3 (d, / = 5 Hz), 123.3 (d, / = 3 Hz), 123.6 (d, / = 5 Hz), 128.2 (d, / = 16 Hz), 136.7 (d, / = 5 Hz), 137.5 (broad), 153.7 (d, / = 261 Hz); 1- (bromomethyl)-2-fluoro-3-nitrobenzene (FN-Bromide): 1H NMR (400 MHz, CHLOROFORM-J) delta ppm 4.56 (s, 1 H), 7.28-7.34 (m, 1 H), 7.69-7.76 (m, 1 H), 7.98-8.05 (m, 1 H). 13C NMR (100 MHz, CHLOROFORM- J) delta ppm 23.6 (d, / = 5 Hz), 124.5 (d, / = 5 Hz), 126.1 (d, / = 3 Hz), 128.5 (d, / = 14 Hz), 136.5 (d, / = 4 Hz), 137.7 (broad), 153.3 (d, / = 265 Hz). DSC: single melt at 53.59 C. Exact Mass [C7H5BrFN02 + H]+: calc. = 233.9566, measured = 233.9561; l-(dibromomethyl)-2-fluoro-3-nitrobenzene (Dibromide): 1H NMR (400 MHz, CHLOROFORM- d) delta ppm 6.97 (s, 1 H), 7.39-7.45 (m, 1 H), 8.03-8.10 (m, 1 H), 8.16-8.21 (m, 1 H). 13C NMR (100 MHz, CHLOROFORM-J) delta ppm 29.2 (d, / = 7 Hz), 124.9 (d, / = 5 Hz), 127.1 (d, / = 2 Hz), 132.1 (d, / = 11 Hz), 135.7 (d, / = 2 Hz), 137.2 (broad), 149.8 (d, J = 266 Hz). DSC: single melt at 49.03 C. Exact Mass [C7H4Br2FN02 + H]+: calc. = 311.8671, measured = 311.8666. |
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