Structure of 71887-28-0
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| CAS No. : | 71887-28-0 |
| Formula : | C10H11BrO3 |
| M.W : | 259.10 |
| SMILES Code : | O=C(OC)C1=CC=CC(OC)=C1CBr |
| English Name : | Methyl 2-(bromomethyl)-3-methoxybenzoate |
| MDL No. : | MFCD04114320 |
| InChI Key : | HYLGKOGJOVGRNN-UHFFFAOYSA-N |
| Pubchem ID : | 12527050 |
| Num. heavy atoms | 14 |
| Num. arom. heavy atoms | 6 |
| Fraction Csp3 | 0.3 |
| Num. rotatable bonds | 4 |
| Num. H-bond acceptors | 3.0 |
| Num. H-bond donors | 0.0 |
| Molar Refractivity | 57.05 |
| TPSA ? Topological Polar Surface Area: Calculated from |
35.53 Ų |
| Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.51 |
| Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.3 |
| Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.22 |
| Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.37 |
| Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.75 |
| Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.43 |
| Log S (ESOL):? ESOL: Topological method implemented from |
-2.95 |
| Solubility | 0.292 mg/ml ; 0.00113 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| Log S (Ali)? Ali: Topological method implemented from |
-2.68 |
| Solubility | 0.536 mg/ml ; 0.00207 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.86 |
| Solubility | 0.0356 mg/ml ; 0.000137 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 |
-6.25 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 |
1.0 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) |
2.14 |
* 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 |
|---|---|---|
| 97% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In chloroform for 15h; Reflux; | General procedure E: Radical monobromination To a solution of methyl o-methylbenzoate (1.00 equiv) in CHCl3 (2-5 mL per mmol of methyl o-methylbenzoate) or CCl4 (5 mL per mmol of methyl o-methylbenzoate) was added NBS(1.10-2.20 equiv) and AIBN (0.02-0.04 equiv). The reaction was refluxed for 2-22 h before being cooled to rt. The solvent was then removed in vacuo (CHCl3 solvent) or via distillation (CCl4 solvent) within a fumehood to afford the desired brominated compound. CAUTION: CHCl3 and especially CCl4 are extremely toxic and carcinogenic and thus must be handled cautiously with gloves and within a fumehood appropriately ventilated. |
| 92% | With N-Bromosuccinimide In tetrachloromethane for 2h; Heating; Irradiation; | |
| 92% | Stage #1: 3-methoxy-2-methylbenzoic acid methyl ester With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane at 20℃; for 3h; Heating / reflux; Stage #2: Irradiation using a sun lamp; | 11a Example 11: (entry 103) OMe OMe OMe a Br b H tCO2Me I./COZMe/ 11a 11b 11c O ,--nN c N/1 OH I d N N O NH I NH J N / -li compound 103 Step a: A solution of 11a (2. 58 g, 14.3 [MMOL),] NBS (2. 79 g, 15. 7 mmol) and AIBN (232 mg, 1.4 [MMOL)] in CCI4 (20 mL) was refluxed for 3 h. The reaction mixture was cooled to room temperature and the resulting suspension was filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography [(HEXANE/CHZC12,] 75/25) to give [11 B] (3.4 g, 92% yield) as a white solid. |
| 92% | With N-Bromosuccinimide In tetrachloromethane for 3h; | A solution of 2a (2.58 g,14.3 mmol), NBS (2.79 g, 15.7 mmol) and AlBN (232 mg, 1.41 mmol) in CCl4 (20 mL) was refluxed for 3 h. The reaction mixture was cooled to room temperature and the resulting suspension was filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography (hexane/CH2Cl2, 75/25) to give 2b (3.4 g, 92% yield) as a white solid. |
| 85% | With N-Bromosuccinimide; 2-(4-biphenylyl)-5-phenyloxazole In tetrachloromethane at 80℃; | |
| 72% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In acetonitrile for 3h; Reflux; | |
| With N-Bromosuccinimide; Perbenzoic acid In tetrachloromethane for 1.5h; Heating; | ||
| With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 2h; Heating / reflux; | 1.7 Into a 2 L 3-neck round bottom flask was added 75 g (0.42 mol) of 2-methyl-3-methoxy methyl benzoate, 500 mL of CC4, 80.1 g (0.45 mol) of NBS, and 1 g of AIBN. The mixture was stirred and refluxed gently for 2 hours. The reaction mixture was cooled and ca. 600 mL of CH2Cl2 and 500 mL of water were added. The mixture was stirred to dissolve floating solids, transferred to a 2 L separatory funnel, and then shaken. The organic layer was separated and the water extracted with CH2Cl2. The aqueous fractions were discarded and the organic phase extracted with 400-500 mL of water to remove the NBS (note: solubility of succinimide is 1 g/3 g water, solubility of NBS is 1.47 g/100 mL water). The water extractions were repeated, the organic phase dried with MgSO4 and charcoal, and the solvent evaporated in 2 portions, to yield methyl-3-methoxy-2-bromomethylbenzoate. TLC: Rf=0.58, single spot (1:1 ethyl acetate: hexane). 1H NMR (CDCl3, 300 MHz) δ (ppm): 7.5 (d, 1H), 7.3 (t, 1H), 7.05 (d, 1H), 5.06 (s, 2H), 3.94 (s, 3H), 3.93 (s, 3H). | |
| 4.5 g | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 1h; Inert atmosphere; Reflux; | |
| With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 80℃; for 12h; | ||
| With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) | ||
| With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane at 72℃; for 3h; | ||
| With N-Bromosuccinimide; dibenzoyl peroxide In 1,2-dichloro-ethane at 80℃; for 12h; | 4.1.2 Methyl 3-(bromomethyl)-4-fluorobenzoate (11a) General procedure: A mixture of methyl 3-bromo-2-methylbenzoate (500 mg, 3.3 mmol), NBS (770.4 mg, 4.3 mmol), and di-benzoyl peroxide (BPO, 80.7 mg, 0.3 mmol) in 1,2-dichloroethane (10 mL) was heated at 80 °C for 12 h. The reaction mixture was cooled to room temperature, and the precipitated solid was removed by filtration and washed with ethers (10 mL). The filtrate was concentrated in vacuo and the residue was partitioned between 2 N NaHCO3 (15 mL) and ethers (15 mL). The organic layer was separated, dried over NaSO4, filtered and concentrated to give a crude product (683.2 mg, 89.6%), which was used in the next step reaction without further purification. | |
| With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 3h; Reflux; | 4b'.B Step B: Methyl2-(bromomethyl)-3-methoxybenzoate To a solution of the compound obtained in Step A (19.8 g; 0.11 mol) in carbon tetrachloride (100 mE) there are added N-bromosuccinimide (19.56 g; 0.18 mol) and azoisobutyronitrile (2 g; 0.012 mol). The reaction mixture is heated at reflux for 3 hours. Afier returning to ambient temperature, the reaction mixture is diluted in a mixture of dichloromethane and watet After decantation, the organic phase is washed with saturated aqueous sodium chloride solution and then dried over sodium sulphate, filtered and concentrated to dryness. The residue is taken up in dichloromethane to provide the title product in the form of a white solid, which is used in the following step without being purified.1H NMR (400 MHz, CDC13, 300 K) ö ppm: 7.51 (d, 1H), 7.31 (t, 1H), 7.08 (d, 1H), 5.05 (s, 2H), 3.91 (2s, 6H). IR: v: >C=O: 1713 cm’. | |
| With N-Bromosuccinimide; dibenzoyl peroxide In 1,2-dichloro-ethane Reflux; | 14.14-1 14-1) synthesis of methyl 2-(bromomethyl)-3-methoxybenzoate To a solution of methyl 2-methyl-3-methoxybenzoate (11.7 g, 64.9 mmol) in 1,2-dichloroethane (250 ml) wasadded 1-bromopyrrolidine-2,5-dione (11.5 g, 64.94 mmol) followed by benzoyl benzenecarboperoxoate (786 mg, 3.24mmol) at room temperature. The reaction mixture was heated to reflux for 3 hours. The reddish color disappeared uponthe reaction completion. After cooling, the reaction was washed with water and dried over MgSO4 and concentrated under reduced pressure. The crude product (16.5 g, 98.2 %) was used for the next reaction without further purification.MS (ESI, m/z): [M+l]+ = [259.4]. | |
| With N-Bromosuccinimide; dibenzoyl peroxide In 1,2-dichloro-ethane Reflux; | 14.14-1 14-1) synthesis of methyl 2-(bromomethyl)-3-methoxybenzoate To a solution of methyl 2-methyl-3-methoxybenzoate (11.7 g, 64.9 mmol) in 1,2-dichloroethane (250 ml) wasadded 1-bromopyrrolidine-2,5-dione (11.5 g, 64.94 mmol) followed by benzoyl benzenecarboperoxoate (786 mg, 3.24mmol) at room temperature. The reaction mixture was heated to reflux for 3 hours. The reddish color disappeared uponthe reaction completion. After cooling, the reaction was washed with water and dried over MgSO4 and concentrated under reduced pressure. The crude product (16.5 g, 98.2 %) was used for the next reaction without further purification.MS (ESI, m/z): [M+l]+ = [259.4]. | |
| With N-Bromosuccinimide; dibenzoyl peroxide In 1,2-dichloro-ethane Reflux; | 14.14-1 14-1) synthesis of methyl 2-(bromomethyl)-3-methoxybenzoate To a solution of methyl 2-methyl-3-methoxybenzoate (11.7 g, 64.9 mmol) in 1,2-dichloroethane (250 ml) wasadded 1-bromopyrrolidine-2,5-dione (11.5 g, 64.94 mmol) followed by benzoyl benzenecarboperoxoate (786 mg, 3.24mmol) at room temperature. The reaction mixture was heated to reflux for 3 hours. The reddish color disappeared uponthe reaction completion. After cooling, the reaction was washed with water and dried over MgSO4 and concentrated under reduced pressure. The crude product (16.5 g, 98.2 %) was used for the next reaction without further purification.MS (ESI, m/z): [M+l]+ = [259.4]. | |
| With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In dichloromethane Reflux; | ||
| 94 % | With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 77℃; | |
| With N-Bromosuccinimide; dibenzoyl peroxide In 1,2-dichloro-ethane Reflux; | A-14-1 14-1) Preparation of methyl 2-(bromomethyl)-3-methoxybenzoate 1 -Bromopyrrolidine-2,5-dione (11.5 g, 64.94 mmol) and benzoyl benzenecarboperoxoate (786 mg, 3.24 mmol) were sequentially added to a solution of methyl 2-methyl-3-methoxybenzoate (11.7 g, 64.9 mmol) in ClCH 2 CH 2 Cl (250 ml) at room temperature. The reaction mixture was heated and refluxed for 3 h. The reaction was completed when the red color disappeared. After cooling, the reaction was washed with water,driedoverMgSO4, and concentrated under reduced pressure. The crude product was used in the next reaction without further purification. (16.5 g, 98.2%) | |
| With N-Bromosuccinimide; dibenzoyl peroxide In 1,2-dichloro-ethane Reflux; | A-14-1 14-1) Preparation of methyl 2-(bromomethyl)-3-methoxybenzoate 1 -Bromopyrrolidine-2,5-dione (11.5 g, 64.94 mmol) and benzoyl benzenecarboperoxoate (786 mg, 3.24 mmol) were sequentially added to a solution of methyl 2-methyl-3-methoxybenzoate (11.7 g, 64.9 mmol) in ClCH 2 CH 2 Cl (250 ml) at room temperature. The reaction mixture was heated and refluxed for 3 h. The reaction was completed when the red color disappeared. After cooling, the reaction was washed with water,driedoverMgSO4, and concentrated under reduced pressure. The crude product was used in the next reaction without further purification. (16.5 g, 98.2%) | |
| 98.2 % | With N-Bromosuccinimide; dibenzoyl peroxide In 1,2-dichloro-ethane Reflux; | A-14.14-1 14-1) Preparation of methyl 2-(bromomethyl)-3-methoxybenzoate To a solution of methyl 2-methyl-3-methoxybenzoate (11.7 g, 64.9 mmol) in ClCH2CH2Cl (250 ml) at room temperature, 1-bromopyrrolidine-2,5-dione (11.5 g, 64.94 mmol) and benzoyl benzenecarboperoxoate (786 mg, 3.24 mmol) were sequentially added. The reaction mixture was heated and refluxed for 3 hours. The reaction was completed when the red color disappeared. After cooling, the reaction was washed with water, dried over MgSO4, and concentrated under reduced pressure. The crude product was used in the next reaction without further purification. (16.5 g, 98.2%) |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 100% | With methanol; ammonia for 2h; Reflux; | |
| 95% | With ammonium hydroxide at 20℃; for 4h; | 11b Step b: A solution of [11B] (997 mg, 3.85 [MMOL)] and ammonium hydroxide (9 mL) in THF (19 mL) was stirred at room temperature for 4 h. The reaction mixture was evaporated to dryness. The residue was purified by flash chromatography (hexane/EtOAC, 40/60, containing MeOH 1 %) to give [11C] as a white solid (595 mg, 95% yield). |
| 95% | With ammonium hydroxide In tetrahydrofuran at 20℃; for 4h; | A solution of 2b (997 mg, 3.85 mmol) in THF (19 mL) and ammonium hydroxide (9 mL) was stirred at room temperature for 4 h. The reaction mixture was evaporated to dryness. The residue was purified by flash chromatography (hexane/EtOAC, 40/60, containing MeOH 1%) to give 2c as a white solid (595 mg, 95% yield). |
| With ammonia In methanol for 2h; Reflux; |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 95 - 100% | With sodium iodide; In N,N-dimethyl-formamide; acetonitrile; for 10.0h;Heating / reflux; | Into a 500 mL 3-neck round bottom flask was added 10 g (61.75 mmol) of 2-bromomethyl, 3-methoxy methyl benzoate, 4.0 g (81.6 mmol) of NaCN, 0.30 g (2 mmol) of NaI, 100 mL of CH3CN, and 50 mL of DMF. The reaction mixture was heated and refluxed for 10 hours. The precipitate (NaBr) was filtered off, and the solution was concentrated on an evaporator. 300 mL of water and 200 mL of ether were added and then shaken in a separatory funnel. The water was extracted twice with 100 mL of ether. The ether fractions were dried over MgSO4, and concentrated to yield methyl 3-methoxy-2-cyanomethylbenzoate (95-100% yield). This ester (0.053 mmol, 10.51 g) was stirred vigorously in 100 mL of CH3OH. Ba(OH)2 H2O (0.079 mmol, 14.97 g) was added and the mixture stirred at room temperature overnight. The CH3OH was removed on a rotary evaporator. 150 mL of water, 200 mL of CH2Cl2, and 50 mL of 6N HCl were added, and then stirred in a flask to dissolve all residues. The mixture was transferred to a separatory funnel, acidified with 6N HCl to pH 1-2. The CH2Cl2 phase was separated and the aqueous phase extracted twice with 50 mL of CH2Cl2. The CH2Cl2 extracts were combined, dried over MgSO4 and charcoal, filtered, and evaporated to yield 8.8 g of a white solid, 2-cyanomethyl-3-methoxybenzoic acid, (87%). Methyl 3-methoxy-2-cyanomethylbenzoate: 1H NMR (CDCl3, 300 MHz) delta (ppm): 7.6 (d, 1H), 7.4 (t, 1H), 7.1 (d, 1H), 4.18 (s, 2H), 3.94 (s, 3H), 3.926 (s, 3H). TLC (1:1 ethyl acetate: hexane) 0.55. 2-Cyanomethyl-3-methoxybenzoic acid: 1H NMR (300 Mhz, CDCl3) delta (ppm): 7.55 (d, 1H), 7.45 (t, 1H), 7.3 (d, 1H), 4.121 (d, 2H), 3.91, (s, 3H). TLC (1:1 ethyl acetate: hexane |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 97% | With water; calcium carbonate In 1,4-dioxane at 85℃; for 4h; | Generalprocedure F: Lactone formation The methyl 2-(bromomethyl)-benzoate (1 equiv) was diluted with dioxane (2.6 mL per mmol of methyl-2-(bromomethyl)-benzoate) and H2O (2.6 mL per mmol of methyl-2-(bromomethyl)-benzoate). CaCO3 (5-10 equiv) was added and the reaction was heated to 85 °C for 4-27 h. Residual calcium carbonate was filtered off and the filter cake was washed with EtOAc and H2O. Thefiltrate was partitioned and the organics were extracted with EtOAc, combined, dried over MgSO4 and concentrated in vacuo to afford the desired lactone. |
| 95% | With calcium carbonate In 1,4-dioxane; water at 85℃; for 3.5 - 4h; | 1.8 1.8 1.8 Preparation of 4-methoxy-3H-isobenzofuran-1-one In a 500 mL round bottom flask was added 15.15 g (0.0585 mol) of 2-bromomethyl, 3-methoxy methyl benzoate, 29.3 g (0.293 mol) of CaCO3, 150 mL of dioxane and 150 mL of water. The flask was placed into an oil bath and the mixture heated with stirring at 85° C. for 3.5 to 4 hours. The CaCO3 was filtered off and washed with ethyl acetate and water. To the filtrate was added ethyl acetate (200 mL) and water (50 mL) and the mixture then shaken in separatory funnel. The water phase was extracted twice with ethyl acetate (50 mL). The ethyl acetate extracts were combined, extracted once with water, dried over MgSO4, and evaporated. This yielded 9.2 g of white crystals of 7-methoxybenzolactone (95% yield). 1H NMR (CDCl3, 300 MHz) δ (ppm): 7.5 (m, 2H), 7.1 (m, 1H), 5.26 (s, 2H), 3.93 (s, 3H). TLC: Rf=0.46 (1:1 EtOAC: hexane). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 2 steps 1: methanol; ammonia / 2 h / Reflux 2: boron tribromide / 6 h / Reflux |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 93% | Stage #1: 4-fluoro-2-methylisoindolin-1-one With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.5h; Inert atmosphere; Stage #2: methyl 2-(bromomethyl)-3-methoxybenzoate In tetrahydrofuran at -78℃; for 3h; Inert atmosphere; |

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