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CAS No. : | 62621-09-4 |
Formula : | C9H9NO4 |
M.W : | 195.17 |
SMILES Code : | COC(=O)C1=C(C)C=C(C=C1)[N+]([O-])=O |
MDL No. : | MFCD03618407 |
InChI Key : | JJHCLPDHYBSSHC-UHFFFAOYSA-N |
Pubchem ID : | 15088700 |
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 | 1.77 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by | 1.97 |
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 | 1.32 |
Log S (ESOL):? ESOL: Topological method implemented from | -2.41 |
Solubility | 0.759 mg/ml ; 0.00389 mol/l |
Class? Solubility class: Log S scale | Soluble |
Log S (Ali)? Ali: Topological method implemented from | -3.11 |
Solubility | 0.152 mg/ml ; 0.000776 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 | -6.09 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) | 1.79 |
* 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 ammonium formate;palladium 10% on activated carbon; In ethanol; at 40℃; for 2h; | Intermediate 7; Methyl 4-amino-2-methylbenzoate; To a solution of <strong>[62621-09-4]methyl 2-methyl-4-nitrobenzoate</strong> (Intermediate 5) (3.25 g, 16.6 mmol) in ethanol was added Pd/C 10% (catalytic quantity) and ammonium formate (10.5 g, 0.17 mmol). The mixture was stirred at 400C for 2 hours. The mixture was filtered on celite, washed with diethyl ether. The filtrate was evaporated and the residue was diluted with diethyl ether, washed with water. The organic phase was dried over Na2SC>4, filtered and evaporated to give the title compound as brown oil (2.8 g, quantitative yield). NMR1H NMR (300 MHz), CDCI3 delta: 7.74 (d, 1 H, J=9.20 Hz), 6.41 (m, 2H), 3.75 (s, 3H), 2.47 (s, 3H). |
With iron(III) chloride; water; hydrazine; In ethanol; for 3h;Heating / reflux; Charcoal; | Example 1: Synthesis of PDZ domain inhibitor (2-(l-HydroxypentvD-3-(2-phenvlethvl)-6-methvl)indole-5-carboxylic acid [Formula (I); Table 1A, compound 11; [0067] The general scheme for this synthesis was (Scheme D):; [0068] Methyl (4-amino-5-iodo-2-methyl)benzoate (4); A mixture of 2-iodo-5-nitrotoluene (1,10 g), triethylamine (16 mL), palladium acetate (68 mg), methanol (20 mL) and DMF (10 mL) was stirred at 90C overnight under carbon monoxide atmosphere (1 atm). The reaction mixture was diluted with ethyl acetate (200 mL), washed with water twice (100 mL each) followed by brine (100 mL), dried (Na2S04), and evaporated. The residue was filtered through a short pad of silica gel and evaporated to give 2 as a crude oil. A mixture of 2, ethanol (140 mL), water (2 mL), hydrazine monohydrate (3.8 mL), ferric trichloride (0.17 g) and charcoal (0.1 g) was stirred under reflux for 3 hours. The reaction mixture was filtrated, diluted with ethyl acetate (200 mL), washed with water twice (100 mL each) followed by brine (100 mL), dried (Na2S04), and evaporated. The residue was filtered through a short pad of silica gel and evaporated to give 3 as a crude oil. To a mixture of 3, methanol (33 mL), calcium carbonate (10 g), iodine monochloride solution (33 mL, 1M in dichloromethane) was added slowly at 4C and stirred overnight at the ambient temperature. The reaction mixture was filtrated, diluted with ethyl acetate (200 mL), washed with aqueous sodium sulfite solution (100 mL), followed by brine (100 mL), dried (Na2SC>4), and evaporated. The residue was purified by column chromatography (silica gel 0.2 L, eluent: 10% ethyl acetate in hexanes) and evaporated to give 4 (4.30 g) as pale brown crystals. *H NMR (CDC13, 400 MHz) 8 8.28 (s, 1H), 6.54 (s, 1H), 4,39 (broad s, 2H), 3.84 (s, 3H), 2.50 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With N-Bromosuccinimide; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; In tetrachloromethane; at 85℃; for 12h; | To a solution of methyl 2-methyl-4-nitro-benzoate (3.00 g, 15.4 mmol) in CCl4 (60.0 mL) was added NBS (3.28 g, 18.4 mmol) and BOP (68.0 mg, 154 umol). The reaction mixture was stirred at 85 C. for 12 hrs. On completion, the mixture was washed with saturated NaHCO3 (20.0 mL) and brine (50.0 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:AcOEt=3:1) to give the title compound (4.21 g, 100% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) delta 8.30 (d, J=2.0 Hz, 1H), 8.20 (dd, J=2.0, 6.4 Hz, 1H), 8.10 (d, J=6.4 Hz, 1H), 4.96 (s, 2H), 4.00 (s, 3H). |
96% | With N-Bromosuccinimide; In tetrachloromethane; for 2h;Reflux; | U) 2-Bromomethyl-4-nitro-benzoic acid methyl esterN-Bromosuccinimide (2.18 g, 12.30 mmol) was added to a stirred solution of 2- methyl-4-nitro-benzoic acid methyl ester (2 g, 10.25 mmol) and ABCN (626 mg, 2.56 mmol) in carbon tetra-chloride (80 ml) at room temperature. The reaction was heated at reflux for 2 hrs and then allowed to cool to room temperature and stirred for 15 hrs. The solvent was evaporated in vacuo and the resulting residue filtered through a pad of silica (eluting with dichloromethane). The solvent was evaporated in vacuo to afford the title compound as a yellow solid (2.70 g, 96%). HPLC retention time 4.49min. Mass spectrum (ES+) m/z 256 (M+H). |
88.8% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 70℃;Reflux; Irradiation; | EXAMPLE 76 2-Bromomethyl-4-nitro-benzoic acid methyl ester (2) In accordance with general method T, 4.70 g (24.00 mmol) of (1) are dissolved in 30 ml of carbon tetrachloride, with heating, and 5.00 g (28.00 mmol) of N-bromosuccinimide and 2 spatula tips of azobisisobutyronitrile are then added. The mixture is refluxed for 6 h with irradiation with a 500 W spotlight. On cooling to room temperature, succinimide separates out, and is filtered off. The filtrate is evaporated on a rotary evaporator in order to obtain the product as a yellow oil. Yield: 5.85 g (88.8%) C9H8BrNO4 (Mr=274.07); GC (method 3) 7.98 min 1H-NMR (CDCl3) in ppm: 4.96 (s, 2H, -CH2-Br), 2.71 (s, 3H, -CH3) MS m/z (%): 274 (100), 193 (38), 178 (46), 147 (12), 132 (18), 88 (9). General Method TThe substance to be halogenated is dissolved in carbon tetrachloride in a 250 ml three-necked flask with a reflux condenser and drying tube at approx. 70 C. and the stated amounts of N-bromosuccinimide and azobisisobutyronitrile are added. The mixture is refluxed for 5 h, if necessary with irradiation with a 500 W spotlight. At the end of the reaction, the N-bromosuccinimide has dissolved and has been converted into succinimide, which settles on the surface. After cooling to room temperature, the mixture is filtered with suction. The filtrate is evaporated on a rotary evaporator in order to obtain the product as a yellow - orange oil. |
78.7% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 20h;Reflux; | In a 500 mL, 3-neck round-bottomed flask, the intermediate (1) (20 g, 88.01 mmol) was charged with CC14 (100 mL). N-bromosuccinimide (39.16g, 220.03 mmol) and AIBN (2.16 g, 13.20 mmol) were added and the resulting mixture was refluxed for 20 h. The reaction mixture was quenched with water (500 mL), extracted with dichloromethane (200 mL X 3), and the combined organic layer was washed with saturated brine solution followed by drying over anhydrous sodium sulphate. The organic layer was evaporated under reduced pressure and the crude product obtained was purified by silica gel column chromatography to obtain pure methyl 2-(bromomethyl)-4-nitrobenzoate (2), 19 g; Yield: 78.7%; Eta NMR (400 MHz, OMSO-de) : delta 8.52 (s, 1H), 8.27-8.3(dd, 1H), 8.07-8. l(d, 1H), 5.1 (s, 2H), 3.94 (s, 1H). |
65% | With N-Bromosuccinimide; 1,1'-azobis(1-cyanocyclohexanenitrile); In tetrachloromethane; for 5h;Reflux; | To a solution of 2-methyl-4-nitrobenzoic acid methyl ester (2.0 g, 10.36 mmol) in carbon tetrachloride (80 mL) and l , azobis(cyclohexanecarbonitrile) (0.63 g, 2.56 mmol) was added N-bromosuccinimide (2.18 g, 12.25 mmol) and the resulting solution was heated at reflux for 5h and allowed to sit at room temperature overnight. The reaction was concentrated under reduced pressure and to the resulting residue was added DCM. The solid was filtered off and washed several times with DCM. The combined filtrate and washes were loaded onto a silica column and eluted with 10% EtOAc/hexane to provide slightly impure methyl 2-(bromomethyl)-4-nitrobenzoate (1.82 g, 65% yield) which was carried on as is to the next step. |
53% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 80℃; for 15h; | Compound methyl 2-methyl-4-nitrobenzoate 52a (5 g, 25.6 mmol) was dissolved in carbon tetrachloride (150 mL),Then N-bromosuccinimide (5.02 g, 28.2 mmol) and azobisisobutyronitrile (419 mg, 2.56 mmol) were added, heated to 80 C and stirred for 15 hours.After completion of the reaction, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100/1 to 5/1).The target product methyl 2- (bromomethyl) -4-nitrobenzoate 52b (3.7 g, white solid) was obtained, yield: 53%. |
49% | With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 85℃; for 21h; | A solution of Intermediate 58 (9.57 g, 49 mmol), NBS (9.6g, 54 mmol), benzoyl peroxide (121 mg,0.5 mmol) in carbon tetrachloride was heated at 85C for 18 h. The reaction was concentrated under vaccum, analysed by TLC and 1H NMR and found to have some remaining starting material. <n="103"/>The residues were added to CCl4 (40 ml) with NBS (4.4 g) and benzoyl peroxide (60 mg) then stirred at 85C for 3h. The reaction was concentrated, taken up in DCM then washed with aqueous NaHCO3 and brine. The organic phase was dried over Na2SO4 and concentrated under vacuum. The residues were purified by flash chromatography using a Biotage SP4. The desired product was isolated as an orange solid (6.58 g, 49%). 1H NMR (400 MHz, DMSO-^6) delta ppm 3.93 (s, 3 H), 5.10 (s, 2 H), 8.08 (d, 7=8.24 Hz, 1 H), 8.25 - 8.30 (m, 1 H), 8.51 (d, /=2.29 Hz, 1 H). |
48.2% | With N-Bromosuccinimide; dibenzoyl peroxide; In 1,2-dichloro-ethane; for 48h;Reflux; | A solution of 19 (2.57 g, 13.19 mmol) in 1,2-dichloroethane (100 mL) was treated with N-bromosuccinimide (2.3 g, 13.19 mmol) and benzoyl peroxide (0.26 g), and the mixture was kept at reflux for 2 days, then cooled, washed with water, and evaporated to a yellow oil (3.52 g). The oil was dissolved in acetone and silica gel (4.0 g) was added. A dry silica gel plug was obtained after evaporation of the solvent. The plug was loaded on to a silica gel column and eluted with 10% ethyl acetate in hexane to afford 20 (1.73 g, 48.2%) as a yellow oil; Rf 0.53 (hexane/EtOAc 3:1); 1H NMR (CDCl3) delta 3.89 (s, 3H, COOCH3), 4.86 (s, 2H, CH2Br), 7.98-8.23 (m, 3H, C6H3). |
44% | With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 7h;Inert atmosphere; Heating; | 2 - methyl-4-nitrobenzoate (. 200mg, 1 OmmoL), benzoyl peroxide (48.5mg,0.2mmoL), N_-bromosuccinimide (213mg, 1.2mmoL) was added to the CCl4 (15mL), and under protection of Ar gas, the reaction was heated at reflux for 7 hours, cooled, washed with saturated sodium bicarbonate (3 X20mL ), saturated brine (20 mL), dried and the solvent was distilled off under reduced pressure, the residue was purified by flash column chromatography, eluent PE: EpsilonAlpha = 20: 1, to give a white solid 124mg, 44% yield |
39% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 80℃; | Azobisisobutyronitrile (AIBN) (0.17 g, 1.02 mmol) was added to the solution of methyl 2-methyl-4-nitrobenzoate (61.2) (2.0 g, 10.2 mmol) and N-bromosuccinimide (NBS) (2.7 g, 15.2 mmol) in CCl4 (50 mL). The mixture was stirred at 80 C overnight. After cooling to room temperature, the reaction mixture was filtered and, the filtrate was concentrated to afford methyl 2-(bromomethyl)-4-nitrobenzoate (61.3) as a white solid (1.1 g, 39%). [00869] LCMS: 314.0 [M+CH3CN]+. |
With N-Bromosuccinimide;2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 80℃; for 22h; | 5-Nitro-2,3-dihydroisoindol-l-one02N; [695] AIBN (58.6mg, 0.357mmol), NBS (785mg, 4.46mmol), and 2-methyl-4-nitrobenzoic acid methyl ester (696mg, 3.57mmol) were suspended in CC14 (35mL) in asealed tube. The above mixture was flushed with N2 for 5min and heated at 80C for 22h.After cooling, the solid was filtered off and the filtrate was concentrated to dryness to obtain acrude light-brown solid. To above solid was added NH3 (7 N in MeOH, 5mL), and themixture was stirred at rt for 2h and concentrated in vacua to obtain a yellow solid. This crudesolid was triturated with EtOAc (15mL) and was then cooled at -20 C. The mixture wasfiltered to obtain the title compound as yellow solid. 'H NMR (DMSO-^, 400 MHz): 5 =4.51 (s, 2 H), 7.13 (bra, 2 H), 7.91 (d, 1 H, J= 8.4 Hz), 8.25 (dd, 1 H, J= 2.0 & 8.4 Hz), 8.48(d, 1 H, J= 2.0 Hz), 9.04 (brs, 1 H). MS (ES+): m/z 179.22 (100) [MH1]. HPLC: fe = 2.14min (ZQ2000, polar_5 min). | |
With N-Bromosuccinimide;dibenzoyl peroxide; In tetrachloromethane; at 85℃; for 9h;Reflux; | Step b:[00294] A mixture of 2-methyl-4-nitro-benzoic acid methyl ester (leq.), NBS (1.1 eq.), benzoyl peroxide (0.01 eq.), and 20 mL of carbon tetrachloride is heated at 85C for 8hrs. Further NBS (0.1 eq.) is added and the whole is is refluxed 1 hrs. The mixture is washed with sat. NaHCO3 and brine, dried over MgSO4, and evaporated. The residue is purified by flash chromatography to afford the compound. | |
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 85℃; | Step A: Methyl 2-(bromomethyl)-4-nitrobenzoate: Methyl 2-methyl-4-nitrobenzoate (4.2 g, 21.5 mmol) was dissolved in 100 mL CCl4 under nitrogen. N-bromosuccinimide (6.13 g, 34.4 mmol) was added, followed by benzoyl peroxide (0.104 g, 0.430 mmol). The reaction mixture was heated overnight at 85 C. Added 1 g NBS followed by 100 mg benzoyl peroxide and continued heating the reaction for 6 hours. The reaction mixture was cooled to ambient temperature, poured into 1M HCl, extracted with dichloromethane, dried over magnesium sulfate, filtered and concentrated to an oil. Purification was carried out using column chromatography (5-10% EtOAc/hexanes). | |
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 4h;Reflux; Inert atmosphere; | A degassed solution of methyl 2-methyl-4-nitrobenzoate (3.5 g, 18.19 mmol), N- bromosuccinimide (3.9 g, 21.91 mmol, 1.2 eq) and benzoyl peroxide (3.63 mmoi, 0.2eq.) in 100 ml CCWwas heated at reflux for 4 hr. it was concentrated to dryness, dissolved in ether, washed 2x with water, aq. Na2S2theta3, brine, dried over MgSO4, filtered, concentrated and purified by chromatography using 15% ethyl acetate in hexanes to provide 4.11g of methyl 2-bromomethyl-4-nitrobenzoate. | |
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 79℃;Inert atmosphere; | Preparative Example 46aPreparation of 5-amino-2-cyclopropylisoindolin-1-oneStep 1: 2-cvclopropyl-5-nitroisoindoliii-1-oneAIBN (28 mg, 0.17), NBS (0.37 gram, 2.1 mmol), and the methyl 2-methyl-4-nitrobenzoate (334 g, 1.7 mmol, as prepared in Step 1, Example 44) were suspended in CCI4 (4.2 ml), the vessel evacuated and backfilled with N2 (2x) and the mixture heated under N2 at 79 C overnight. The solution was filtered, and concentrated in vacuum. The residue was dissolved in 7 N cyclopropyl amine (2.1 g, 35.9 mmol, in methanol, 18 ml), and the solution stirred for 2 hours at RT. The volatiles were removed in vacuum and the product purified by chromatography on Sitheta2 eluting with 10% acetone : DCM to give the titled compound. | |
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 80℃; for 22h;Inert atmosphere; Sealed tube; | ^nierrrsedsaie B6 S-amsnoisoindoIin-i -one Step A: methyl 2-(bromomethyl)-4-nitrobenzoate 2-methyl-4-nitrobenzoic acid methyl ester (896 mg, 3.57 mmoi), azobisisbufyronifrile (58.6 mg, 0.357 mmol) and N-bromosuccinimide (785 mg, 4.48 mmol) were suspended in carbon tetrachloride (35 mL) in a sealed tube. The above mixture was flushed with nitrogen for 5 minutes and heated at 80 C for 22 hours. After cooling, the solid was filtered off and the filtrate was concentrated to dryness to obtain the crude product methyl 2-(bromomethyl)-4-nitrobenzoate as a light-brown solid, which was used for the next step without purification. | |
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 70℃; for 15h; | To solution of methyl 2-methyl-4-nitrobenzoate (350 mg, 1.8 mmol) in carbon tetrachloride (6 mL) was added NBS (500 mg, 2.8 mmol) and benzoyl peroxide (13 mg, 0.054 mmol). The reaction was then heated to 70 C for 15 hours and then cooled to ambient temperature. Once cooled, water (5 mL) was added and the aqueous layer was extracted with dichloromethane (3 X 10 mL). The combined organic layers were then dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified via MPLC (0- 30% EtO Ac/Hex gradient) to afford methyl 2-(bromomethyl)-4-nitrobenzoate. NMR (500 MHz, DMSO-d6): 9 (s, 1H), 8.3 (d, 1H), 8.1 (d, 1H), 7.9 (s, 1H), 4.9 (s, 2H), 4.0 (s, 3H). | |
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 60℃; for 4h; | To a solutionof compound 7B (50g, 0.26 mol) in CC14 (500 mL), N-bromosuccinimide (45.8g, 0.26 mol)and benzoyl peroxide(0.12 g, 0.5 mmol) were added. The reactionmixture wasstirred 4 hr at 60C. The mixturewas cooled to RT and was washed with IN NaOHand water and it was dried overNa2S04. The solvent was evaporated to affordcrude7C (71g) as yellow oil. | |
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 22h;Reflux; | Step 2: Synthesis of 2-bromomethyl-4-nitro-benzoic acid methyl ester To a solution of 2-Methyl-4-nitro-benzoic acid methyl ester (3.08 g, 15.79 mmole) in 125 ml carbontetrachloride was added NBS (3.1 g, 17.38 mmole) and AIBN (390 mg, 2.38 mmole). The reaction mixture was heated at reflux under light for 22 hours. The reaction mixture was cooled down, concentrated to half, filtered off, solid was washed with 25 ml carbontetrachloride. The filtrate was concentrated to give 4 g crude product, containing about 20% unreacted starting material. This was used for next step without purification. | |
1.9 g | With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 10h;Reflux; | 2-Methyl-4-nitro - benzoic acid methyl ester (3.0 g, 15 mmol) wasdissolved in carbon tetrachloride (50 mL), and then were added N- bromosuccinimide (3.0 g, 17 mmol) and benzoyl peroxide (100mg, 0.4 mmol), the addition was complete the reaction was refluxed for 10hours. Completion of the reaction, the reaction solution was cooled toroom temperature, filtered, and the filtrate was washed with saturated sodiumbicarbonate solution and water, dried over anhydrous sodium sulfate, filteredand concentrated. Was purified by silica gel column chromatography usingconcentrated to give the intermediate 2-bromomethyl-4-nitro - benzoic acidmethyl ester (pale yellow solid, 1.9 g). |
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 2h;Reflux; | Compound I (1.95 g, 10.0 mmol) was dissolved in carbon tetrachloride (20 mL), and NBS (2.14 g, 12.0 mmol, 1.2 eq) and benzoyl peroxide (0. 024 g, 0.1 mmol, 0.1 eq) was added and the mixture was heated to reflux for 2 h. At the end of the reaction, the temperature was lowered and the solid was removed by suction filtration. The mother liquor was evaporated to dryness to give Compound II in a yield of 95%. | |
With N-Bromosuccinimide; dibenzoyl peroxide; In chloroform; at 65℃; for 5h;Inert atmosphere; Schlenk technique; Reflux; | General procedure: To a solution of 6.0 g (0.04 mol) of methyl 2-methylbenzoate derivatives in 38 mL of chloroform, 7.5 g (0.042 mol) of N-bromosuccinimide and 0.078 g of benzoyl peroxide were added and carefully warmed up to 65 C until reaction started. Then the mixture was refluxed for 5 h. After cooling down to room temperature, the deposit of succinimide was filtered. The solvent was removed under reduced pressure and the crude product was used in the next step without further purification. To a solution of functionalized methyl 2-(bromomethyl)benzoate (6.55 mmol), substituted phenol (8.5 mmol), K3PO4 (16.4 mmol) and toluene 20 mL were added to Schlenk under argon. The resulting solution was stirred to 110 C for 5 h. The progress of the reaction was monitored by TLC. The mixture was extracted with EtOAc, washed with water, brine and the combined organic layers were dried over anhydrous Na2SO4and the solvent was removed under reduced pressure. The crude product was used in the next step without further purification. To the solution of the ester (0.015 mol) in MeOH (73 mL), was added 13 mL aqueous KOH (20%) and refluxed at 80C for 5 h. MeOH was removed and the aqueous phase was washed with DCM. After acidifying with HCl (10%) the deposit was collected and washed with water. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With thionyl chloride; at 70℃; for 18h; | Intermediate 5; Methyl 2-methyl-4-nitrobenzoate; SOCI2 was added to a solution of 2-methyl-4-nitrobenzoic acid (3 g, 16.5 mmol) in methanol dropwise. The reaction mixture was stirred at 70C for 18 hours. The mixture was evaporated and the residue was diluted with diethyl ether, washed with water and NaOH 1 N. The organic phase was dried over Na2SO4, filtered and evaporated to give the title compound as dark yellow solid (3.25 g, quantitative yield). NMR1H NMR (300 MHz), CDCI3 delta: 7.95 (m, 3H), 3.86 (s, 3H), 2.59 (s, 3H). |
98% | With thionyl chloride; at 70℃; for 7h; | Under ice bath was added SOCl2 dropwise anhydrous methanol (100ml) in. And then a solution of 2-methyl-4-nitrobenzoic acid (10.0 g, 55.2 mmol) in anhydrous methanol (70mL) solution, 1 hour addition was complete. This mixed system placed in an oil bath at 70 C 7 hours, TLC the reaction was complete. Cooling, the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) was added saturated sodium bicarbonate (100 mL), separated, the aqueous phase was extracted once with ethyl acetate (50mL). The combined organic phase was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure, and dried under high vacuum to give a white solid 10.5g, 98% yield |
96% | With sulfuric acid; for 15h;Reflux; | Example 1) l-MethyI-lH-imidazole-4-suIfonic acid (4-chloro-benzyI)-(2-ethyI-l- oxo-2,3-dihydro-lH-isoindol-5-yl)-amide (Method A)i) 2-Methyl-4-nitro-benzoic acid methyl ester2-Methyl-4-nitrobenzoic acid (2.00 g, 11.00 mmol) was stirred in concentrated sulfuric acid (0.6 ml) and methanol (25 ml) at reflux for 15 hrs. Reaction was cooled and the solvent evaporated. The resulting residue was partitioned between water and dichloromethane and the organic phase separated. The aqueous phase was extracted with dichloromethane (x3) and the combined organics washed with brine, then dried (MgSO4) and evaporated in vacuo to yield the title compound as a pale yellow solid (1.89 g, 96%). HPLC retention time 4.39min. |
95.3% | With sulfuric acid; at 0 - 70℃; for 24.5h; | Step 1: Synthesis of 2-Methyl-4-nitro-benzoic acid methyl ester To a solution of 2-methyl-4-nitro-benzoic acid (3 g, 16.56 mmole) in 30 ml methanol was added at 0 C. sulfuric acid (95-98%, 10 ml) slowly for ½ hr. The reaction mixture was stirred at 70 C. for 24 hrs. Mixture was cooled down, a solid precipitated out, then the mixture was concentrated, diluted with 50 ml water, stirred for 10 minutes, filtered off, the solid was washed with water, dried to afford 3.08 g of brown solid, 95.3% yield, pure by H NMR. |
94.65% | With sulfuric acid; for 15h;Reflux; | In a 250 mL, 3-neck round-bottomed flask, 2-methyl-4-nitrobenzoic acid (20 g, 93.8 mmol) was charged with methanol (100 mL) and sulfuric acid (4 mL). The reaction mixture was refluxed for 15 h. After completion, the reaction mixture was concentrated to obtain the crude product which was added water (200 mL) and basified to pH 7-8 with aqueous NaHC03 solution. Aqueous solution was extracted with dichloromethane (250 mL X 3), the organic layer was washed with saturated brine solution followed by drying over anhydrous sodium sulphate. The solvent was removed to obtain methyl 2-methyl-4- nitrobenzoate 1), 20 g; Yield: 94.65%. |
93% | With thionyl chloride; at 0 - 80℃; for 2h; | SOCl2 (2.6 g, 22.0 mmol) was slowly added to the solution of 2-methyl-4- nitrobenzoic acid (61.1) (2.0 g, 11.0 mmol) in MeOH (20 mL) at 0 C. The resulting mixture was heated at 80 C for 2 h. After cooling to room temperature, the reaction mixture was concentrated to afford methyl 2-methyl-4-nitrobenzoate (61.2) as a yellow oil (2.0 g, 93%). |
91.3% | With thionyl chloride; at 12 - 20℃; for 12h; | Thionyl chloride (4.3 g, 36.45 mmol) was added dropwise to a stirred solution of 18 (3 g, 16.57 mmol) in MeOH (25 mL) while maintaining the internal temperature below 12 C. When the addition was complete the mixture was left to stand at room temperature for 12 h to result a white precipitation. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford white solid. The solid was washed with hexane and ethyl ether to afford 19 (2.95 g, 91.3%); mp 153.7-154.4 C (lit.39 mp 153-154 C); Rf 0.43 (hexane/EtOAc 3:1); 1H NMR (CDCl3) delta 2.69 (s, 3H, CH3), 3.95 (s, 3H, COOCH3), 8.02-8.11 (m, 3H, C6H3). |
90.9% | With sulfuric acid; at 20 - 60℃; | EXAMPLE 75 2-Methyl-4-nitro-benzoic acid methyl ester (1) In accordance with general method S, 5.00 g (27.60 mmol) of 2-methyl-4-nitro-benzoic acid are dissolved in 20 ml of methanol, with heating, and 6 ml of concentrated sulfuric acid are added. The mixture is refluxed for 5 h. Yield: 4.90 g (90.9%); melting point: 73.6 C. C9H9NO3(Mr=195.18); GC (method 1) 9.55 min 1H-NMR (CDCl3) in ppm: 8.19-8.09 (m, 2H, aryl H), 7.99 (d, 1H, J=8.52 Hz, aryl H), 3.87 (s, 3H, -OCH3), 2.59 (s, 3H, -CH3) 13C-NMR (CDCl3) in ppm: 166.35 (-C=O), 159.29 (C4), 141.79 (C2), 135.14 (C1), 131.43 (C6), 126.06 (C3), 120.48 (C5), 52.37 (-OCH3), 21.50 (-CH3) IR (ATR) (cm-1): 1722, 1523, 1432, 1348, 1260, 1081, 896, 821, 786, 730 MS m/z (%): 195 (70), 164 (100), 134 (21), 118 (29), 63 (15). General Method SFor esterification of the acid group of the starting compound 2-methyl-4-nitro-benzoic acid, the stated amount is dissolved in methanol in a 100 ml one-necked flask at room temperature, concentrated H2SO4 is added and the mixture is refluxed at approx. 60 C. for 6 h. The excess alcohol is removed in vacuo, the residue is taken up in EtOAc and the mixture is deacidified repeatedly with 20% strength sodium hydroxide solution. After drying (Na2SO4), the combined organic phases are concentrated in vacuo. |
With hydrogenchloride; In 1,4-dioxane; for 48h;Heating / reflux; | Step 2:; A solution of the acid 11-2 from step 1 (3.60 g, 15.6 mmol) in MeOH (30 mL) and HCI (4N HCI in dioxane, 2.0 mL) was heated to reflux for 48 h. The solvent was evaporated to dryness under vacuum and the residue obtained was re-dissolved in EtOAc (200 mL). The solution was washed with aqueous saturated NaHC03 (100 mL) and brine (100 mL), dried over anhydrous MgS04 and evaporated to dryness to give the ester intermediate 11-3 as a yellow-colored solid (2.38 g). This material was used in step 3 without purification. | |
With sulfuric acid; at 55℃; for 50h; | 2-Methyl-4-nitrobenzoic acid methyl ester; [697] H2SO4 (98%, 0.030ml) was added dropwise into the MeOH (30mL) solutionof 2-methyl-4-nitrobenzoic acid at rt. The mixture was then heated at 55C. After 50h, thesolvent was removed in vacua and the residue was partitioned between EtOAc and H2O(25mL each). The aqueous layer was extracted with another portion of EtOAc (25mL). Thecombined extracts were washed with saturated NaHC03 (25mL), H2O (2 x 25mL), and brine(25mL), dried over MgS04, filtered and concentrated in vacua to give the title compound aslight-yellow solid. 'H NMR (CDC13,400 MHz): 5 = 2.69 (s, 3 H), 3.95 (s, 3 H), 8.03 - 8.12(m, 3 H). MS (ES+): m/z 196.25 (100) [MH4]. HPLC: /R= 3.29 min (ZQ2000, polar_5 min). | |
Preparation of 5-amino-2,3-dihydro-1H-isoindol-1-one A mixture of 2-methyl-4-nitrobenzoic acid (0.906 g, 5 mmol) in sulfurous dichloride (5.95 g, 50 mmol) was refluxed for 1 hour and concentrated. The residue was dissolved in methanol (30 mL, 741 mmol) and triethylamine (2 g, 19.76 mmol) was added. The mixture was stirred at room temperature for 1 hour, concentrated, and partitioned between ethyl acetate and water. The organic layer was separated, dried over MgSO4, and filtered through Magnesol to give 862 mg of methyl 2-methyl-4-benzoate as a tan solid. | ||
sulfuric acid; In water; at 20 - 55℃; | Example 44Preparation of 5-[(2-((lS.2SV2-?-('5-chloropyrimidin-2-yl)piperidin-4- yl] cyclopropyl ) ethvDaminolisoindolin- 1 -oneStep 1 : methyl 2-methyl-4-nitrobenzoateSulfuric acid (6 ml, 113 mmol) was added to drop wise to a solution of the 2-methyl~4- nitrobenzoic acid (5 g, 27.6 mmol) in MeOH (138 ml) at RT. After the addition was complete the mixture was heated to 55 C overnight. The volatiles were removed in vacuum and the residue partitioned between EtOAc (100 ml) and water (100 ml). The layers were separated and aqueous phase extracted with EtOAc (2x100 ml). The organic fractions were combined, washed with saturated sodium bicarbonate (aqueous, 100ml), brine, dried over Na2SO4, filtered and the volatiles removed in vacuum to give the titled compound. | |
With sulfuric acid; for 10h;Reflux; | 2-methyl-4-nitrobenzoic acid (1.81g, 10.0mmol) was dissolved in CH3OH (10mL), concentrated sulfuric acid (2.0mL, 3.7eq).The reaction system was heated to reflux, the reaction 10h.Completion of the reaction, cooled to room temperature, and thereto was added Na2CO3And sulfuric acid, and then filtered. The mother liquor after removal of methanol, to give compound I The crude yield of 89%, can be used directly in the next reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h; | Method L:Step a: [00293] A mixture of 2-methyl-4-nitrobenzoic acid (l eq.) iodomethane (1.1 eq.), K2CO3 (1.5 eq.), and 10 mL of DMF is stirred for 2hrs at room temperature, then poured into water and extracted with AcOEt. The extract is washed with water and brine, dried over anhydrous MgStheta4, and evaporated to afford the expected compound in quantative yield. |
89% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3h; | A solution of 2-methyl-4-nitro-benzoic acid (10 g, 55 mmol), MeI (3.8 ml, 61 mmol) and K2CO3 (11.4 g, 83 mmol) in DMF was stirred for 3 h at RT after which the reaction was poured onto water and extracted in EtOAc. The organic fractions were washed with water and brine, dried over Na2SO4 and concentrated to give the desired product as an orange solid (9.57g, 89%). 1H NMR (400 MHz, DMSO-^6) delta ppm 2.60 (s, 3 H), 3.88 (s, 3 H), 8.00 (d, J=8.70 Hz, 1 H), 8.10 - 8.16 (m, 1 H), 8.21 (d, J=2.29 Hz, I H). |
With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 4h; | To a solution of7A (50 g, 0.27 mol) in DMF(500 mL) was added K2C03 (65 g, 0.54 mol). The mixture was cooled to 0C, CH31 wasadded dropwise. The reaction mixturewas stirred 4 hr at room temperature. The mixture was extracted with EtOAc and washedwith water, dried over Na2S04to afford crude7B (55 g) as yellow oil. |
Tags: 62621-09-4 synthesis path| 62621-09-4 SDS| 62621-09-4 COA| 62621-09-4 purity| 62621-09-4 application| 62621-09-4 NMR| 62621-09-4 COA| 62621-09-4 structure
A152953 [482311-23-9]
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