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Chemical Structure| 71887-28-0 Chemical Structure| 71887-28-0

Structure of 71887-28-0

Chemical Structure| 71887-28-0

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Product Details of [ 71887-28-0 ]

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

Safety of [ 71887-28-0 ]

Computational Chemistry of [ 71887-28-0 ] Show Less

Physicochemical Properties

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
Ertl P. et al. 2000 J. Med. Chem.

35.53 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

2.51
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

2.3
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

2.22
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

2.37
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

2.75
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.43

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-2.95
Solubility 0.292 mg/ml ; 0.00113 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-2.68
Solubility 0.536 mg/ml ; 0.00207 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-3.86
Solubility 0.0356 mg/ml ; 0.000137 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble

Pharmacokinetics

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)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

No
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

Yes
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

No
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

No
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

No
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

No
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-6.25 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

0.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.55

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

1.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<0.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

2.14

Application In Synthesis of [ 71887-28-0 ]

* 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.

  • Downstream synthetic route of [ 71887-28-0 ]

[ 71887-28-0 ] Synthesis Path-Downstream   1~7

  • 1
  • [ 13321-74-9 ]
  • [ 71887-28-0 ]
  • [ 71887-29-1 ]
  • 2
  • [ 42981-93-1 ]
  • [ 71887-28-0 ]
YieldReaction ConditionsOperation 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%)

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[2]Whitlock; Whitlock [Journal of Organic Chemistry, 1980, vol. 45, # 1, p. 12 - 15].
[3]Current Patent Assignee: BOEHRINGER INGELHEIM (CANADA) LTD - WO2004/26875, 2004, A1 Location in patent: Page 38.
[4]Current Patent Assignee: BOEHRINGER INGELHEIM (CANADA) LTD - US2004/106791, 2004, A1 Location in patent: Page 9.
[5]Location in patent: scheme or table Fu, Li Qiang; Ling, Chen Yu; Guo, Xing Sheng; He, Hui Li; Yang, Yu She [Chinese Chemical Letters, 2012, vol. 23, # 1, p. 9 - 12].
[6]Park, Sun-Gil; Heo, Jung-Nyoung [Journal of Organic Chemistry, 2025, vol. 90, # 45, p. 16218 - 16230].
[7]Schultz, Arthur G.; Taylor, Richard E. [Journal of the American Chemical Society, 1992, vol. 114, # 10, p. 3937 - 3943].
[8]Current Patent Assignee: INTREXON - US2006/20146, 2006, A1 Location in patent: Page/Page column 31-32.
[9]Location in patent: experimental part Tang, Ying; Wei, Zhenhong; Zhong, Wei; Liu, Xiaoming [European Journal of Inorganic Chemistry, 2011, vol. 7, p. 1112 - 1120].
[10]Location in patent: scheme or table Fu, Liqiang; Liu, Xin; Ling, Chenyu; Cheng, Jianjun; Guo, Xingsheng; He, Huili; Ding, Shi; Yang, Yushe [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 2, p. 814 - 819].
[11]Ruchelman, Alexander L.; Man, Hon-Wah; Zhang, Weihong; Chen, Roger; Capone, Lori; Kang, Jian; Parton, Anastasia; Corral, Laura; Schafer, Peter H.; Babusis, Darius; Moghaddam, Mehran F.; Tang, Yang; Shirley, Michael A.; Muller, George W. [Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 1, p. 360 - 365].
[12]Baur, Benjamin; Storch, Kirsten; Martz, Kathrin E.; Goettert, Marcia I.; Richters, André; Rauh, Daniel; Laufer, Stefan A. [Journal of Medicinal Chemistry, 2013, vol. 56, # 21, p. 8561 - 8578].
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[14]Current Patent Assignee: VERNALIS R D - US2020/253993, 2020, A1 Location in patent: Paragraph 0243-0245.
[15]Current Patent Assignee: INNOCURE THERAPEUTICS - EP4116298, 2023, A1 Location in patent: Paragraph 0170-0172.
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  • 3
  • [ 71887-28-0 ]
  • [ 366453-22-7 ]
YieldReaction ConditionsOperation 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;

  • 4
  • [ 143-33-9 ]
  • [ 71887-28-0 ]
  • [ 145498-86-8 ]
YieldReaction ConditionsOperation 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
  • 5
  • [ 71887-28-0 ]
  • [ 4792-33-0 ]
YieldReaction ConditionsOperation 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).
  • 6
  • [ 71887-28-0 ]
  • [ 366453-21-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: methanol; ammonia / 2 h / Reflux 2: boron tribromide / 6 h / Reflux
  • 7
  • [ 1378819-13-6 ]
  • [ 71887-28-0 ]
  • [ 3108103-67-6 ]
YieldReaction ConditionsOperation 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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