Structure of 3-Chloro-4-fluoronitrobenzene
CAS No.: 350-30-1
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| CAS No. : | 350-30-1 |
| Formula : | C6H3ClFNO2 |
| M.W : | 175.54 |
| SMILES Code : | FC1=CC=C([N+]([O-])=O)C=C1Cl |
| MDL No. : | MFCD00007206 |
| InChI Key : | DPHCXXYPSYMICK-UHFFFAOYSA-N |
| Pubchem ID : | 67688 |
| GHS Pictogram: |
|
| Signal Word: | Warning |
| Hazard Statements: | H302-H312-H332 |
| Precautionary Statements: | P280 |
| Num. heavy atoms | 11 |
| Num. arom. heavy atoms | 6 |
| Fraction Csp3 | 0.0 |
| Num. rotatable bonds | 1 |
| Num. H-bond acceptors | 3.0 |
| Num. H-bond donors | 0.0 |
| Molar Refractivity | 40.23 |
| TPSA ? Topological Polar Surface Area: Calculated from |
45.82 Ų |
| Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.51 |
| Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.57 |
| Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.81 |
| Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.9 |
| Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.77 |
| Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.91 |
| Log S (ESOL):? ESOL: Topological method implemented from |
-2.89 |
| Solubility | 0.229 mg/ml ; 0.0013 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| Log S (Ali)? Ali: Topological method implemented from |
-3.18 |
| Solubility | 0.116 mg/ml ; 0.00066 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.67 |
| Solubility | 0.375 mg/ml ; 0.00214 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) |
No |
| 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 |
-5.55 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 |
1.0 |
| 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 |
2.0 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) |
1.87 |
* 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% | Stage #1: With sodium hydride In DMF (N,N-dimethyl-formamide) at 0℃; for 0.25 h; Stage #2: for 36 h; |
Sodium hydride (95percent, 0.935 g, 37 mmol) is suspended in dry DMF (20 ml) under a nitrogen atmosphere and the resulting mixture is cooled in ice water. To above suspension is added dropwise over 15 minutes pyridin-2-yl-methanol (3.42 g, 31. 3 mmol) in dry DMF (20 mL). Next, to the cold reaction mixture is added dropwise over 20 minutes a solution of 2- CHLORO-L-FLUORO-4-NITRO-BENZENE (5 g, 28.5 mmol) in dry DMF (20 ml). Upon the end of addition the cold bath is removed and the reaction mixture is stirred for another 36 HOURS. Water (80 mL) was added slowly to the reaction mixture, and a yellow precipitate resulted. The resultant solid is isolated by suction filtration, washed with water (80 ml), and air dried to yield 7. 52 g (28.5 mmol, 100percent) of the clean desired material as a yellow powder. |
| 100% | Stage #1: With sodium hydride In DMF (N,N-dimethyl-formamide) at 0℃; for 0.583333 h; Stage #2: at 0℃; for 36 h; |
Sodium hydride (95percent, 0.935 g, 37 mmol) is suspended in dry DMF (20 ml) under a nitrogen atmosphere and the resulting mixture is cooled in ice water. To above suspension is added dropwise over 15 minutes pyridin-2-yl-methanol (3.42 g, 31.3 mmol) in dry DMF (20 mL). Next, to the cold reaction mixture is added dropwise over 20 minutes a solution of 2-Chloro-1-fluoro-4-nitro-benzene (5 g, 28.5 mmol) in dry DMF (20 ml). Upon the end of addition the cold bath is removed and the reaction mixture is stirred for another 36 hours. Water (80 mL) was added slowly to the reaction mixture, and a yellow precipitate resulted. The resultant solid is isolated by suction filtration, washed with water (80 ml), and air dried to yield 7.52 g (28.5 mmol, 100percent) of the clean desired material as a yellow powder. |
| 85% | Stage #1: With potassium hydroxide In acetonitrile for 0.333333 - 0.5 h; Stage #2: at 40℃; for 18 h; |
A mixture of 160 g of potassium hydroxide and 2-pyridylcarbinol in 8 L acetonitrile was stirred for 20-30 minutes. To this was added 400 g of 3-chloro-4-fluoronitrobenzene and the mixture was stirred at 40° C. for a minimum of 18 hours until the reaction was complete. Water was added and the precipitated yellow solids were filtered and washed with water. The product was dried (40-50° C., 10 mm Hg, 24 h) to the product in 85-95percent yield. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 87.5% | With potassium hydroxide In tetrahydrofuran at 20 - 25℃; for 20 h; | Synthesis of 3-chloro-4-(2-pyridylmethoxy)nitrobenzene 2-pyridinyl carbinol (31.08 g, 1.05 eq) was dissolved in ACN (750 mL) and KOH flakes (85percent) were added (20.6 g, 1.25 eq.). The resulting suspension was warmed to 35° C. A solution of the 3-chloro-4-fluoronitrobenzene (50.0 g, 0.285 mol) in ACN (250 mL) was added at 35-40° C. The mixture was held for 14 hours. The mixture was then cooled back to 20-25° C., quenched with H2O (1 L) and the resulting slurry filtered and washed with H2O (3.x.100 mL). The resulting product was isolated as a tan solid in 93percent yield with a greater than 99.5percent purity as determined by HPLC area.; Experimental results for the reaction of Example 1 with different bases and solvents are shown in Table 1. The last three entries on Table 1 are large scale runs in which a 5percent excess of pyridyl carbinol was used. TABLE 1 Preparation of Nitroaryl Intermediate Scale Vol- Base Time Temp Yield Purity (g) Solvent umes Base Eq. (h) (° C.) (percent) (percent) 2.0 DMF 20 KOH 1.1 20 RT 90.5 94.7 2.0 NMP 10 NaH 1.2 20 RT 48.7 78.4 2.0 ACN 20 KOH 1.1 4 RT 93.2 98.4 2.0 EtOAc 10 KOH 1.1 72 RT NA NA 10.0 DMF 15 KOH 1.1 23 RT 76.5 96.7 4 35 10.0 ACN 15 KOH 1.1 23 RT 91.8 99.4 2.0 THF 20 KOH 1.1 20 RT 87.5 99.2 2.0 DMF 20K2CO3 1.0 26 RT 81.9 98.5 extra 3 40 2.0eqK2CO3 3 40 2.0 ACN 20K2CO3 1.0 18 RT NA NA 3 40 2.0 THF 20K2CO3 1.0 18 RT NA NA 50.0 ACN 20 KOH 1.1 20 40 93.5 99.8 200 ACN 20 KOH 1.1 16 40 86.0 97.6 200 ACN 20 KOH 1.25 16 40 93.5 96.9 400 ACN 20 KOH 1.25 16 40 91.5 98.4 400 ACN 20 KOH 1.25 16 40 93.8 98.1 NA = not applicable RT = room temperature (20-25° C.) |
| 86% | With potassium hydroxide In acetonitrile at 20 - 40℃; for 4 - 23 h; | EXAMPLE 1 Synthesis of 3-chloro-4-(2-pyridylmethoxy)nitrobenzene 2-pyridinyl carbinol (31.08 g, 1.05 eq) was dissolved in ACN (750 mL) and KOH flakes (85percent) were added (20.6 g, 1.25 eq.). The resulting suspension was warmed to 35° C. A solution of the 3-chloro-4-fluoronitrobenzene (50.0 g, 0.285 mol) in ACN (250 mL) was added at 35-40° C. The mixture was held for 14 hours. The mixture was then cooled back to 20-25° C., quenched with H2O (1 L) and the resulting slurry filtered and washed with H2O (3*100 mL). The resulting product was isolated as a tan solid in 93percent yield with a greater than 99.5percent purity as determined by HPLC area. Experimental results for the reaction of Example 1 with different bases and solvents are shown in Table 1. The last three entries on Table 1 are large scale runs in which a 5percent excess of pyridyl carbinol was used. TABLE 1 Preparation of Nitroaryl Intermediate Scale Vol- Base Time Temp Yield Purity (g) Solvent umes Base Eq. (h) (° C.) (percent) (percent) 2.0 DMF 20 KOH 1.1 20 RT 90.5 94.7 2.0 NMP 10 NaH 1.2 20 RT 48.7 78.4 2.0 ACN 20 KOH 1.1 4 RT 93.2 98.4 2.0 EtOAc 10 KOH 1.1 72 RT NA NA 10.0 DMF 15 KOH 1.1 23 RT 76.5 96.7 4 35 10.0 ACN 15 KOH 1.1 23 RT 91.8 99.4 2.0 THF 20 KOH 1.1 20 RT 87.5 99.2 2.0 DMF 20K2CO3 1.0 26 RT 81.9 98.5 extra 3 40 2.0eqK2CO3 3 40 2.0 ACN 20K2CO3 1.0 18 RT NA NA 3 40 2.0 THF 20K2CO3 1.0 18 RT NA NA 50.0 ACN 20 KOH 1.1 20 40 93.5 99.8 200 ACN 20 KOH 1.1 16 40 86.0 97.6 200 ACN 20 KOH 1.25 16 40 93.5 96.9 400 ACN 20 KOH 1.25 16 40 91.5 98.4 400 ACN 20 KOH 1.25 16 40 93.8 98.1 NA = not applicable RT = room temperature (20-25° C.) |
| 85% | Stage #1: With potassium hydroxide In acetonitrile for 0.333333 - 0.5 h; Stage #2: at 40℃; for 18 h; |
A mixture of 160 g of potassium hydroxide and 2-pyridylcarbinol in 8 L acetonitrile was stirred for 20-30 minutes. To this was added 400 g of 3-chloro-4- fluoronitrobenzene and the mixture was stirred at 40 °C for a minimum of 18 hours until the reaction was complete. Water was added and the precipitated yellow solids were filtered and washed with water. The product was dried (40-50 °C, 10 mm Hg, 24 h) to the product in 85-95percent yield. |
| 84% | With potassium hydroxide In acetonitrile at 35 - 40℃; for 18 h; | Example 3 Preparation of N-[3-Chloro-4-(2-pyridinylmethoxy)]phenyl-2-cyanoacetamide In a 12-L multi-necked flask, 2-pyridyl carbinol (0.13 kg, 1.19 mole, 1.05 eq) was dissolved in acetonitrile (0.88 L) and to it was added potassium hydroxide flakes (85percent) (80 g, 1.25 eq). The resulting suspension was warmed to 35° C. A solution of 3-chloro-4-fluoronitrobenzene (0.20 kg, 1.14 mol) in acetonitrile (1.0 L) was added at 35-40° C. The mixture was held for 18 h until reaction completion. The mixture was then cooled back to 20-25° C., quenched with water (4 L) and the resulting slurry was filtered and washed with water (3.x.200 mL). The resulting product was isolated as a tan solid (251 g, 84percent yield). A mixture of 3-chloro-4-(2-pyridylmethoxy)nitrobenzene (0.149 kg, 0.56 mole) and 2percent (w/w) of 5percent Pt/C (6.0 g, 50percent water wet) in tetrahydrofuran (0.895 L) was hydrogenated in a 2-L stainless steel Parr reactor at 25 psi, 25° C. for a minimum of 8 h. The mixture was filtered through a celite pad (50 g, 15 cm diameter) and washed with tetrahydrofuran (0.45 L). The filtrate was distilled to a volume of 0.30 L and the concentrate was transferred to a 2-L multi-neck flask and used as is in the next step. To the 2-L flask equipped with mechanical stirrer, temperature probe, claisen head and condenser was added ethylcyanoacetate (0.421 kg, 3.72 mole, 6.6 eq.). The reaction mixture was heated to (100-115° C.) while removing tetrahydrofuran and ethanol. The temperature was raised to 125° C. and the mixture was held for a minimum of 24 h until the aniline starting material was consumed and no distillate was collected. The mixture was cooled to room temperature over 1 h. At 50-60° C., solids crystallized out and ethyl acetate (0.15 L) was added. The mixture was further cooled to 0-10° C. and held for 1 h. The mixture was filtered on a 15 cm diameter Buchner funnel and washed with 50 mL of the filtrate followed by pre-cooled (0-10° C.) ethyl acetate (0.15 L). The product was dried at 60° C. for a minimum of 16 h in a vacuum oven to give the titled compound (0.12 kg, 71percent) as a brown solid. The product was purified by slurrying in cold ethyl acetate (1-1.3 volumes) for 1 hr. 1H NMR: δ (DMSO-d6) 10.31 (s, 1H, NH), 8.58 (dd, 1H, Ar), 7.86 (dt, 1H, Ar), 7.75 (d, 1H, Ar), 7.55 (d, 1H, Ar), 7.39-7.32 (m, 2H, Ar), 7.21 (d, 1H, Ar), 5.25 (s, 2H, OCH2Pyr), 3.88 (s, 2H, NCCH2CO). |
| 81.9% | With potassium carbonate In N,N-dimethyl-formamide at 20 - 40℃; for 32 h; | Synthesis of 3-chloro-4-(2-pyridylmethoxy)nitrobenzene 2-pyridinyl carbinol (31.08 g, 1.05 eq) was dissolved in ACN (750 mL) and KOH flakes (85percent) were added (20.6 g, 1.25 eq.). The resulting suspension was warmed to 35° C. A solution of the 3-chloro-4-fluoronitrobenzene (50.0 g, 0.285 mol) in ACN (250 mL) was added at 35-40° C. The mixture was held for 14 hours. The mixture was then cooled back to 20-25° C., quenched with H2O (1 L) and the resulting slurry filtered and washed with H2O (3.x.100 mL). The resulting product was isolated as a tan solid in 93percent yield with a greater than 99.5percent purity as determined by HPLC area.; Experimental results for the reaction of Example 1 with different bases and solvents are shown in Table 1. The last three entries on Table 1 are large scale runs in which a 5percent excess of pyridyl carbinol was used. TABLE 1 Preparation of Nitroaryl Intermediate Scale Vol- Base Time Temp Yield Purity (g) Solvent umes Base Eq. (h) (° C.) (percent) (percent) 2.0 DMF 20 KOH 1.1 20 RT 90.5 94.7 2.0 NMP 10 NaH 1.2 20 RT 48.7 78.4 2.0 ACN 20 KOH 1.1 4 RT 93.2 98.4 2.0 EtOAc 10 KOH 1.1 72 RT NA NA 10.0 DMF 15 KOH 1.1 23 RT 76.5 96.7 4 35 10.0 ACN 15 KOH 1.1 23 RT 91.8 99.4 2.0 THF 20 KOH 1.1 20 RT 87.5 99.2 2.0 DMF 20K2CO3 1.0 26 RT 81.9 98.5 extra 3 40 2.0eqK2CO3 3 40 2.0 ACN 20K2CO3 1.0 18 RT NA NA 3 40 2.0 THF 20K2CO3 1.0 18 RT NA NA 50.0 ACN 20 KOH 1.1 20 40 93.5 99.8 200 ACN 20 KOH 1.1 16 40 86.0 97.6 200 ACN 20 KOH 1.25 16 40 93.5 96.9 400 ACN 20 KOH 1.25 16 40 91.5 98.4 400 ACN 20 KOH 1.25 16 40 93.8 98.1 NA = not applicable RT = room temperature (20-25° C.) |
| 76.5% | With potassium hydroxide In N,N-dimethyl-formamide at 20 - 35℃; for 20 - 27 h; | Synthesis of 3-chloro-4-(2-pyridylmethoxy)nitrobenzene 2-pyridinyl carbinol (31.08 g, 1.05 eq) was dissolved in ACN (750 mL) and KOH flakes (85percent) were added (20.6 g, 1.25 eq.). The resulting suspension was warmed to 35° C. A solution of the 3-chloro-4-fluoronitrobenzene (50.0 g, 0.285 mol) in ACN (250 mL) was added at 35-40° C. The mixture was held for 14 hours. The mixture was then cooled back to 20-25° C., quenched with H2O (1 L) and the resulting slurry filtered and washed with H2O (3.x.100 mL). The resulting product was isolated as a tan solid in 93percent yield with a greater than 99.5percent purity as determined by HPLC area.; Experimental results for the reaction of Example 1 with different bases and solvents are shown in Table 1. The last three entries on Table 1 are large scale runs in which a 5percent excess of pyridyl carbinol was used. TABLE 1 Preparation of Nitroaryl Intermediate Scale Vol- Base Time Temp Yield Purity (g) Solvent umes Base Eq. (h) (° C.) (percent) (percent) 2.0 DMF 20 KOH 1.1 20 RT 90.5 94.7 2.0 NMP 10 NaH 1.2 20 RT 48.7 78.4 2.0 ACN 20 KOH 1.1 4 RT 93.2 98.4 2.0 EtOAc 10 KOH 1.1 72 RT NA NA 10.0 DMF 15 KOH 1.1 23 RT 76.5 96.7 4 35 10.0 ACN 15 KOH 1.1 23 RT 91.8 99.4 2.0 THF 20 KOH 1.1 20 RT 87.5 99.2 2.0 DMF 20K2CO3 1.0 26 RT 81.9 98.5 extra 3 40 2.0eqK2CO3 3 40 2.0 ACN 20K2CO3 1.0 18 RT NA NA 3 40 2.0 THF 20K2CO3 1.0 18 RT NA NA 50.0 ACN 20 KOH 1.1 20 40 93.5 99.8 200 ACN 20 KOH 1.1 16 40 86.0 97.6 200 ACN 20 KOH 1.25 16 40 93.5 96.9 400 ACN 20 KOH 1.25 16 40 91.5 98.4 400 ACN 20 KOH 1.25 16 40 93.8 98.1 NA = not applicable RT = room temperature (20-25° C.) |
| 48.7% | With sodium hydride In 1-methyl-pyrrolidin-2-one at 20 - 25℃; for 20 h; | Synthesis of 3-chloro-4-(2-pyridylmethoxy)nitrobenzene 2-pyridinyl carbinol (31.08 g, 1.05 eq) was dissolved in ACN (750 mL) and KOH flakes (85percent) were added (20.6 g, 1.25 eq.). The resulting suspension was warmed to 35° C. A solution of the 3-chloro-4-fluoronitrobenzene (50.0 g, 0.285 mol) in ACN (250 mL) was added at 35-40° C. The mixture was held for 14 hours. The mixture was then cooled back to 20-25° C., quenched with H2O (1 L) and the resulting slurry filtered and washed with H2O (3.x.100 mL). The resulting product was isolated as a tan solid in 93percent yield with a greater than 99.5percent purity as determined by HPLC area.; Experimental results for the reaction of Example 1 with different bases and solvents are shown in Table 1. The last three entries on Table 1 are large scale runs in which a 5percent excess of pyridyl carbinol was used. TABLE 1 Preparation of Nitroaryl Intermediate Scale Vol- Base Time Temp Yield Purity (g) Solvent umes Base Eq. (h) (° C.) (percent) (percent) 2.0 DMF 20 KOH 1.1 20 RT 90.5 94.7 2.0 NMP 10 NaH 1.2 20 RT 48.7 78.4 2.0 ACN 20 KOH 1.1 4 RT 93.2 98.4 2.0 EtOAc 10 KOH 1.1 72 RT NA NA 10.0 DMF 15 KOH 1.1 23 RT 76.5 96.7 4 35 10.0 ACN 15 KOH 1.1 23 RT 91.8 99.4 2.0 THF 20 KOH 1.1 20 RT 87.5 99.2 2.0 DMF 20K2CO3 1.0 26 RT 81.9 98.5 extra 3 40 2.0eqK2CO3 3 40 2.0 ACN 20K2CO3 1.0 18 RT NA NA 3 40 2.0 THF 20K2CO3 1.0 18 RT NA NA 50.0 ACN 20 KOH 1.1 20 40 93.5 99.8 200 ACN 20 KOH 1.1 16 40 86.0 97.6 200 ACN 20 KOH 1.25 16 40 93.5 96.9 400 ACN 20 KOH 1.25 16 40 91.5 98.4 400 ACN 20 KOH 1.25 16 40 93.8 98.1 NA = not applicable RT = room temperature (20-25° C.) |


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