Structure of 61940-22-5
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CAS No. : | 61940-22-5 |
Formula : | C9H9NO4 |
M.W : | 195.17 |
SMILES Code : | COC(=O)C1=C(C)C=CC=C1[N+]([O-])=O |
MDL No. : | MFCD11042453 |
InChI Key : | XPVBLOOMFDNJTH-UHFFFAOYSA-N |
Pubchem ID : | 596057 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 14 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.22 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 51.51 |
TPSA ? Topological Polar Surface Area: Calculated from |
72.12 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.74 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.08 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.69 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.16 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.03 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.14 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.85 |
Solubility | 2.76 mg/ml ; 0.0141 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.19 |
Solubility | 1.27 mg/ml ; 0.00651 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.25 |
Solubility | 1.11 mg/ml ; 0.00568 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 |
-6.72 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) |
2.11 |
* 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 |
---|---|---|
98% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 5h; | Step 1: Methyl-(2-methyl-6-nitro)benzoate Into a suspension of 100 g (552 mmol) of <strong>[13506-76-8]2-methyl-6-nitrobenzoic acid</strong>, 114.4 g (828 mmol) of potassium carbonate in 500 mL of dimethylforamide was added dropwise 86 g (606 mmol) of iodomethane with stirring at ambient temperature. After addition, the suspension was stirred for additional 5 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. Any solid was removed by filtration and the filtrate was concentrated to a 105.6 g of colorless oil as product in 98% yield. 1H NMR (CDCl3) (300 MHz) δ 2.7 (s, 3H), 3.95 (s, 3H), 8.01 (d, 3JHCCH=8.6 Hz, 1H), 7.62 (dd, 3JHCCH=8.6 Hz, 3JHCCH=7.6 Hz, 1H), 7.8 (d, 3JHCCH=7.6 Hz, 1H) |
98% | With potassium carbonate; In acetone; for 15h;Reflux; | To the solution of <strong>[13506-76-8]2-methyl-6-nitrobenzoic acid</strong> (15 g, 82.8 mmol) dissolved in acetone (350 ml), iodomethane (25.8 ml, 414.0 mmol) and potassium carbonate (57.2 g, 414.0 mmol) were added, and the reaction mixture was refluxed for 15 hours and was stirred. The reaction mixture was cooled to a room temperature and was filtered. The filtrates were concentrated, and the residues were diluted, and then were extracted with EtOAc (250 ml*2times). The combined organic layer was dried on MgSO4, and the solvent was removed under vacuum to obtain yellow oil. The combined organic layer was concentrated under reduced pressure to obtain methyl 2-methyl-6-nitro benzoate (compound <16-1>) (15.9 g, 81.5 mmol, 98%) as a white solid. |
94% | With potassium carbonate;Reflux; | To a solution of <strong>[13506-76-8]2-methyl-6-nitrobenzoic acid</strong> (5.0 g, 27.6 mmol) in acetone (60 mL) was added K2CO3 (5.7 g, 41.4 mmol) and MeI (4.3 g, 30.4 mmol), the resulting reaction mixture was heated to reflux overnight. Then it was quenched with water, extracted with EtOAc, and the combined organic phase was concentrated in vacuo to give a residue, which was purified by column chromatography (PE/EtOAc = 50/1 to 10/1) to give methyl 2-methyl-6-nitrobenzoate (5.1 g, yield 94%) as a light oil.1H NMR (300 MHz, DMSO-d6): d 8.03 (d, J = 8.1 Hz, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.65 (dd, J = 8.1, 7.6 Hz, 1H), 3.87 (s, 3H) ppm. |
With potassium carbonate; In acetone; for 15h;Heating / reflux; | To a solution of the 2-methyl-6-nitro-benzoic acid (5.6 g, 30.9 mmol, 1.0 eq, Aldrich) and acetone (100 mL) was added crushed K2CO3 (21.4 g, 154.6 mmol, 5 eq) and MeI (9.6 mL, 154.6 mmol, 5.0 eq.). The reaction was heated to reflux for 15 h then cooled to RT, filtered and concentrated in vacuo. The filtrate was dissolved in EtOAc, washed with H2O and brine, dried (MgSO4) and concentrated in vacuo to give the desired compound as a reddish-brown oil which upon standing at RT crystallized as tan needles. | |
With potassium carbonate; In acetone; for 15h;Heating / reflux; | To a solution of 2-methyl-6-nitro-benzoic acid (5.6 g, 30.9 mmol, 1.0 eq, Aldrich) and acetone (100 mL) was added crushed K2CO3 (21.4 g, 154.6 mmol, 5 eq) and MeI (9.6 mL, 154.6 mmol, 5.0 eq). The reaction was heated to reflux for 15 h then cooled to RT, filtered and concentrated in vacuo. The filtrate was dissolved in EtOAc, washed with H2O and brine, dried (MgSO4) and concentrated in vacuo to give the desired compound as a reddish-brown oil which upon standing at RT crystallized to tan needles | |
With potassium carbonate; In butanone; for 18h;Reflux; | Example 1. Preparation of N-(3-oxo-2-(3-(trifluoromethyl)phenyl)isoindolin-4- yl)pyrazine-2-carboxamide (Compound 100):Step 1) Synthesis of methyl 2-methyl-6-nitrobenzoate (2):2-Methyl-6-nitrobenzoic acid (1; 10 g, 0.0552 mol) was taken up in 200 mL of methyl ethyl ketone along with methyl iodide (17.2 mL, 0.276 mol) and anhydrous potassium carbonate (38.1 g, 0.276 mol). The reaction mixture was stirred under reflux for 18 h. It was then cooled to room temperature and filtered. The filtrate was diluted with EtOAc (300 mL), washed with water (2 x 50 mL), brine, dried (Na2SO4) and concentrated under reduced pressure to afford methyl 2- methyl-6-nitrobenzoate 2 (10.80 g). | |
With potassium carbonate; In butanone; for 18h;Reflux; | Example 1. Preparation of N-(l-oxo-2-(3-(trifluoromethyl)phenyl)-l,2,3,4- tetrahydroisoquinolin-8-yl)pyrazine-2-carboxamide (Compound 101): Step 1) Synthesis of methyl 2-methyl-6-nitrobenzoate (2): 2-Methyl-6-nitrobenzoic acid (1; 10 g, 55.2 mol) was taken up in 200 mL of methyl ethyl ketone along with methyl iodide (17.2 mL, 276.0 mmol) and anhydrous potassium carbonate (38.1 g, 276.0 mmol). The reaction mixture was stirred under reflux for 18 h. It was then cooled to room temperature and filtered. The filtrate was diluted with EtOAc (300 mL), washed with water (2 x 50 mL), brine, dried (Na2SO4) and concentrated under reduced pressure to afford 10.80 g of methyl 2- methyl-6-nitrobenzoate 2. MS (ESI) calcd for C9H9NO4: 195.05; found: 196 [M + H]. | |
10.80 g | With potassium carbonate; In butanone; for 18h;Reflux; | Step 1) Synthesis of methyl 2-methyl-6-nitrobenzoate (2) 2-Methyl-6-nitrobenzoic acid (1; 10 g, 55.2 mol) was taken up in 200 mL of methyl ethyl ketone along with methyl iodide (17.2 mL, 276.0 mmol) and anhydrous potassium carbonate (38.1 g, 276.0 mmol). The reaction mixture was stirred under reflux for 18 h. It was then cooled to room temperature and filtered. The filtrate was diluted with EtOAc (300 mL), washed with water (2*50 mL), brine, dried (Na2SO4) and concentrated under reduced pressure to afford 10.80 g of methyl 2-methyl-6-nitrobenzoate 2. MS (ESI) calcd for C9H9NO4: 195.05. found: 196 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | A mixture of commercial <strong>[13506-76-8]2-methyl-6-nitrobenzoic acid</strong> (2.00 g, 11.0 mmol, 1 eq.) and thionyl chloride(9 mL) was stirred at 80 C for 3.5 h. An excess of the thionyl chloride was distilled off under reducedpressure and the obtained residue was dissolved with CH2Cl2 (3 mL). The solution was addeddropwise to a methanol (6 mL) solution of triethylamine (2 mL) at 0 C and stirred at roomtemperature for 3 h. Then, the solvent was distilled off under reduced pressure. Water was added to theobtained residue and the mixture was extracted three times with ethyl acetate. The organic layer wasdried with magnesium sulfate, filtrated and evaporated under reduced pressure. The crude productwas purified by silica column chromatography employing a mixture of n-hexane : ethylacetate (9 : 1) as eluent to obtain the desired product 13c. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8.1 g viscous product which solidified on standing (90%) | In methanol; chloroform-d1; water; | Example 19 Synthesis of methyl-2-methyl-6-nitrobenzoate: A portion of <strong>[13506-76-8]2-methyl-6-nitrobenzoic acid</strong> (9.05 g, 50 mmols) and phosphorous pentachloride (10.4 g, 50 mmols) were mixed together. Soon, HCl gas started coming out and the solids changed into a transparent liquid. The evolution of HCl gas was trapped in a water container, and when no more gas evolved (about 20 min.), the reaction was stopped. Phosphorus oxychloride by-product was distilled under vacuum. On adding 20 mL MeOH, an exothermic reaction occurred and then solvents were evaporated under reduced pressure. The product was purified by flash silica gel column eluted with Hex/CHCl3. 1:1 mixture to give 8.1 g viscous product which solidified on standing (90%). 1H NMR in CDCl3 confirmed the product as methyl-2-methyl-6-nitrobenzoate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | at 20 - 100℃; for 2h;Inert atmosphere; | Example 1Preparation of Methyl 2-Methyl-6-nitrobenzoateA mixture of <strong>[13506-76-8]2-methyl-6-nitrobenzoic acid</strong> (300.0 g, 1.66 moles, from Acros Organics, Morris Plains, N.J.) and trimethyl orthoacetate (298.3 g, 2.48 moles, from Aldrich Chemicals, Milwauke, Wis.) was charged into a 3-L 3-necked flask at about 20-25 C. under nitrogen. The reaction mixture was gradually heated and the low-boiling point components generated during the reaction were distilled off to an internal temperature of 95-100 C. After 2 hours, the reaction mixture was cooled to 20-25 C. over 1-2 hours. After heptane (1.50 L, from Aldrich Chemicals) was charged into the reaction mixture over 1.0-1.5 hours, the reaction mixture was seeded with methyl 2-methyl-6-nitrobenzoate (0.5 g) when it became turbid. The suspension was cooled to 0-5 C. over 0.5-1 hour and kept at 0-5 C. for another 1.5-2 hours. The solid was collected by filtration under vacuum, washed with heptane (3x300 mL), and dried to a constant weight in a tray at 30-35 C. under a vacuum at 100-120 torr. The yield of methyl 2-methyl-6-nitrobenzoate was 292.0 g (91%), based on 300.0 g of <strong>[13506-76-8]2-methyl-6-nitrobenzoic acid</strong>. 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. |
91% | at 20 - 100℃; for 2h;Inert atmosphere; | [0116j A mixture of <strong>[13506-76-8]2-methyl-6-nitrobenzoic acid</strong> (300.0 g, 1.66 moles, from Acros Organics, Morris Plains, NJ) and trimethyl orthoacetate (298.3 g, 2.48 moles, from Aldrich Chemicals, Milwaukee, WI) was charged into a 3-L 3-necked flask at about 20-25C under nitrogen. The reaction mixture was gradually heated and the low-boiling point components generated during the reaction were distilled off to an internal temperature of 95-100C. After 2 hours, the reaction mixture was cooled to 20-25C over 1-2 hours. After heptane (1.50 L, from Aldrich Chemicals) was charged into the reaction mixture over 1.0-1.5 hours, the reaction mixture was seeded with methyl 2-methyl-6-nitrobenzoate (0.5 g) when it became turbid. The suspension was cooled to 0-5C over 0.5-1 hour and kept at 0-5C for another 1.5-2 hours. The solid was collected by filtration under vacuum, washed with heptane (3x300 mL), and dried to a constant weight in a tray at 30-35C under a vacuum at 100-120 torr. The yield of methyl 2- methyl-6-nitrobenzoate was 292.0 g (9 1%), based on 300.0 g of <strong>[13506-76-8]2-methyl-6-nitrobenzoic acid</strong>. 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. |
91% | at 95 - 100℃; for 2h;Inert atmosphere; | [0191] A mixture of <strong>[13506-76-8]2-methyl-6-nitrobenzoic acid</strong> (300.0 g, 1.66 moles, from Acros (0628) Organics, Morris Plains, NJ) and trimethyl orthoacetate (298.3 g, 2.48 moles, from Aldrich Chemicals, Milwaukee, WI) was charged into a 3-L 3-necked flask at about 20-25C under nitrogen. The reaction mixture was gradually heated and the low-boiling point components generated during the reaction were distilled off to an internal temperature of 95-100C. After 2 hours, the reaction mixture was cooled to 20-25C over 1-2 hours. After heptane (1.50 L, from Aldrich Chemicals) was charged into the reaction mixture over 1.0-1.5 hours, the reaction mixture was seeded with methyl 2-methyl-6-nitrobenzoate (0.5 g) when it became turbid. The suspension was cooled to 0-5C over 0.5-1 hour and kept at 0-5C for another 1.5-2 hours. The solid was collected by filtration under vacuum, washed with heptane (3x300 mL), and dried to a constant weight in a tray at 30-35C under a vacuum at 100-120 torr. The yield of methyl 2- methyl-6-nitrobenzoate was 292.0 g (91%), based on 300.0 g of <strong>[13506-76-8]2-methyl-6-nitrobenzoic acid</strong>. The product was found to have a purity of >99% measured by HPLC based on area percentage, and a water content of |
91% | at 20 - 100℃; for 2h;Inert atmosphere; | 10219] A mixture of<strong>[13506-76-8]2-methyl-6-nitrobenzoic acid</strong> (300.0 g,1.66 moles, from Acros Organics, Morris Plains, N.J.) and trimethyl orthoacetate (298.3 g, 2.48 moles, from Aldrich Chemicals, Milwaukee, Wis.) was charged into a 3-L 3-necked flask at about 20-25 C. under nitrogen. The reaction mixture was gradually heated and the low-boiling point components generated during the reaction were distilled off to an internal temperature of 95-100 C. After 2 hours, the reaction mixture was cooled to 20-25 C. over 1-2 hours. After heptane (1.50 L, from Aldrich Chemicals) was charged into the reaction mixture over 1.0-1.5 hours, the reaction mixture was seeded with methyl 2-methyl-6-nitrobenzoate (0.5 g) when it became turbid. The suspension was cooled to 0-5 C. over 0.5-1 hour and kept at 0-5 C. for another 1.5-2 hours. The solid was collected by filtration under vacuum, washed with heptane (3x300 mL), and dried to a constant weight in a tray at 30-35 C. under a vacuum at 100-120 ton. The yield of methyl 2-methyl-6-nitrobenzoate was 292.0 g (91%), based on 300.0 g of <strong>[13506-76-8]2-methyl-6-nitrobenzoic acid</strong>. 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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | at 95 - 100℃; for 2h; | 6.5.1. Preparation of Methyl 2-methyl-6-nitrobenzoate (0174) A mixture of <strong>[13506-76-8]2-methyl-6-nitrobenzoic acid</strong> (300.0 g, 1.66 moles, from Acros Organics, Morris Plains, N.J.) and trimethyl orthoacetate (298.3 g, 2.48 moles, from Aldrich Chemicals, Milwaukee, Wis.) was charged into a 3-L 3-necked flask at about 20-25 C. under nitrogen. The reaction mixture was gradually heated and the low-boiling point components generated during the reaction were distilled off to an internal temperature of 95-100 C. After 2 hours, the reaction mixture was cooled to 20-25 C. over 1-2 hours. After heptane (1.50 L, from Aldrich Chemicals) was charged into the reaction mixture over 1.0-1.5 hours, the reaction mixture was seeded with methyl 2-methyl-6-nitrobenzoate (0.5 g) when it became turbid. The suspension was cooled to 0-5 C. over 0.5-1 hour and kept at 0-5 C. for another 1.5-2 hours. The solid was collected by filtration under vacuum, washed with heptane (3×300 mL), and dried to a constant weight in a tray at 30-35 C. under a vacuum at 100-120 ton. The yield of methyl 2-methyl-6-nitrobenzoate was 292.0 g (91%), based on 300.0 g of <strong>[13506-76-8]2-methyl-6-nitrobenzoic acid</strong>. 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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With potassium carbonate; In acetonitrile; at 81 - 83℃; for 2h; | [0195] (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.), (lS)-l-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonyl-ethylamine (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 refiuxed at 81-83C for about two hours until there was less than 2% of unreacted methyl 2-bromomethyl-6-nitrobenzoate. After the reaction mixture was cooled to 45-50C, methanol (200 mL) was charged over 5-10 minutes. After the mixture was allowed to cool to 20-25C and stirred for 2 hours, deionized water (1.40 L) was charged over 0.5-1 hour and stirred at 20-25C for 30 minutes and at 0-5C for 1-2 hours. The solid was filtered, washed with deionized water (3x300 mL), and dried to 99% measured by HPLC based on area percentage, and a water content of <1.0% measured by Karl Fisher titration. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With oxalyl dichloride; In dichloromethane; for 2h;Reflux; | In a 1L eggplant-shaped flask, 54.3g of compound 2-1 was dissolved in 600mL CH2Cl2,Add 38 g of oxalyl chloride at low temperature, then slowly add 5 mL of DMF dropwise, and heat to reflux after the system is stable.After 2h, the system was drained, Add 9.6 g of methanol to the reaction flask containing the residue at low temperature, and react for about 30 minutes. TLC monitors until the reaction of the raw materials is complete, and the system is dried to obtain Intermediate 2-2 with a yield of 100%. |
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