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[ CAS No. 35598-05-1 ]

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Chemical Structure| 35598-05-1
Chemical Structure| 35598-05-1
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Product Details of [ 35598-05-1 ]

CAS No. :35598-05-1MDL No. :MFCD06203918
Formula : C10H12O3 Boiling Point : 265.0±20.0°C at 760 mmHg
Linear Structure Formula :-InChI Key :-
M.W :180.20Pubchem ID :13257269
Synonyms :

Computed Properties of [ 35598-05-1 ]

TPSA : 35.5 H-Bond Acceptor Count : 3
XLogP3 : 2.1 H-Bond Donor Count : 0
SP3 : 0.30 Rotatable Bond Count : 3

Safety of [ 35598-05-1 ]

Signal Word:WarningClass:N/A
Precautionary Statements:P280-P305+P351+P338UN#:N/A
Hazard Statements:H302Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 35598-05-1 ]

  • Upstream synthesis route of [ 35598-05-1 ]
  • Downstream synthetic route of [ 35598-05-1 ]

[ 35598-05-1 ] Synthesis Path-Upstream   1~21

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Reference: [1] Helvetica Chimica Acta, 1998, vol. 81, # 2, p. 251 - 267
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YieldReaction ConditionsOperation in experiment
100% at 20℃; Reflux To a stirred mixture of 4-methoxy-2-methyl benzoic acid (1.0 g, 6 mmol) and methanol (50 mL) was added thionyl chloride (1.3 mL, 17.8 mmol), dropwise, at room temperature under a nitrogen atmosphere. The reaction mixture was heated at reflux for 3 h. The reaction mixture was allowed to cool at room temperature and concentrated to give a pale yellow liquid. The crude product was purified by flash chromatography over silica with hexanes:ethyl acetate (9:1) to give 1.11 g (100percent) of methyl 2-methyl-4-(methyloxy)benzoate as a colorless liquid. 1H NMR (400 MHz, DMSO-J6): δ 7.81 (d, J = 9 Hz, IH), 6.86 (d, J = 3 Hz, IH), 6.83 (dd, J = 9, 3 Hz, IH), 3.78 (s, 3H), 3.75 (s, 3H), 2.49 (s, 3H). ES-LCMS m/z 181(M + H)+.
98% for 48 h; Heating / reflux According to J. Org. Chem. 33: 494 (1968), a mixture of 4-methoxy-2-methylbenzoic acid (20 g, 120 mmol) and [MEOH] (97 mL) containing sulfuric acid [(CONC.,] 0.6 mL) was heated under reflux 48 h. After cooling the mixture was evaporated and the residue diluted with diethyl ether and washed with a saturated sodium hydrogen carbonate solution and brine. The organic phase was then separated and dried over sodium sulphate. After evaporation the residue was distilled through a 8 cm Vigreux column to afford the title compound (21.2 g, 98percent) as a colourless liquid. Bp 60 [C/1] mbar. MS: m/e = 180.3 (M+).
94% With sulfuric acid In water at 65℃; for 18 h; 4-Methoxy-2-methyl-benzoic acid methyl esterA solution of 4-Methoxy-2-methyl-benzoic acid (15 g, 90 mmol) in methanol {200 mL) was heated to 65 0C. Sulfuric acid (8.9 g, 90 mmol) was added and the mixture was stirred for 18 h at 65 °C. The reaction was cooled and concentrated and the residual oil was dissolved in ethyl acetate and washed with water, brine, and absorbed onto silica to perform chromatography (10 percent ethyl acetate/hexanes) to yield 4-Methoxy-2-methyl-benzoic acid methyl ester as an oil, (15.3 g, 94 percent). MS: ES M+1: 181.0 (180.1).
84% for 24 h; Reflux Benzoic acid (1 equiv) was dissolved in MeOH (1.66 mL per mmol) and H2SO4 (0.07 mL per mmol). The solution was refluxed for 7-24 h before being cooled to rt and concentrated in vacuo. The resulting mixture was dissolved in EtOAc. The organics were washed with an aqueous solution of NaOH (10 percent), combined, dried over MgSO4 and concentrated in vacuo to afford the desired ester.
81% for 3 h; Heating / reflux Preparation 67 4-Methoxy-2-methyl-benzoic acid methyl esterTo an ambient temperature suspension of 4-Methoxy-2-methyl-benzoic acid (1.0 g, 6.02 mmol) in MeOH (10 mL) is added thionyl chloride (1.10 mL, 15.04 mmol) dropwise. The reaction mixture is heated to reflux. After 3h, the reaction is concentrated and the residue is partitioned between EtOAc and NaHCO3. The aqueous layer is extracted with EtOAc and the combined organic layers are washed with brine, dried (MgSO4), filtered, and concentrated to yield the title compound (877 mg, 81percent) 1H NMR (400 MHz, CDCl3) δ 7.95-7.91 (m, IH), 6.77-6.72 (m, 2H), 3.86 (s, 3H), 3.84 (s, 3H).

Reference: [1] Patent: WO2009/5998, 2009, A1, . Location in patent: Page/Page column 214
[2] Patent: WO2004/14856, 2004, A1, . Location in patent: Page 9; 14
[3] Patent: WO2008/20306, 2008, A2, . Location in patent: Page/Page column 35
[4] Journal of Medicinal Chemistry, 2013, vol. 56, # 21, p. 8561 - 8578
[5] Tetrahedron, 2018, vol. 74, # 2, p. 224 - 239
[6] Patent: WO2007/140183, 2007, A1, . Location in patent: Page/Page column 50
[7] Journal of Medicinal Chemistry, 1987, vol. 30, # 10, p. 1798 - 1806
[8] Journal of Organic Chemistry, 1968, vol. 33, # 2, p. 494 - 503
[9] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 5, p. 1628 - 1631
[10] Inorganic Chemistry, 2014, vol. 53, # 6, p. 2932 - 2942
  • 3
  • [ 578-39-2 ]
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Reference: [1] Patent: WO2011/156518, 2011, A2, . Location in patent: Page/Page column 115
  • 4
  • [ 99548-55-7 ]
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Reference: [1] Patent: US2003/212094, 2003, A1,
  • 5
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  • [ 52289-54-0 ]
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Reference: [1] Synthesis, 1984, # 6, p. 504 - 506
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  • [ 74-88-4 ]
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Reference: [1] Tetrahedron, 1989, vol. 45, # 18, p. 5791 - 5804
[2] Tetrahedron Letters, 1989, vol. 30, # 1, p. 111 - 112
  • 7
  • [ 4685-47-6 ]
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Reference: [1] Synthesis, 1984, # 6, p. 504 - 506
[2] Inorganic Chemistry, 2014, vol. 53, # 6, p. 2932 - 2942
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Reference: [1] Synthesis, 1984, # 6, p. 504 - 506
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Reference: [1] Journal of Organic Chemistry, 1986, vol. 51, # 19, p. 3566 - 3572
  • 10
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Reference: [1] Journal of Medicinal Chemistry, 1987, vol. 30, # 10, p. 1798 - 1806
[2] Journal of Organic Chemistry, 1968, vol. 33, # 2, p. 494 - 503
  • 11
  • [ 108-31-6 ]
  • [ 91416-36-3 ]
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Reference: [1] Tetrahedron Letters, 1984, vol. 25, # 21, p. 2201 - 2204
  • 12
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Reference: [1] Tetrahedron Letters, 1984, vol. 25, # 21, p. 2201 - 2204
  • 13
  • [ 22246-27-1 ]
  • [ 124-41-4 ]
  • [ 18927-05-4 ]
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Reference: [1] Helvetica Chimica Acta, 1998, vol. 81, # 2, p. 251 - 267
  • 14
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Reference: [1] Journal of Organic Chemistry, 1986, vol. 51, # 19, p. 3566 - 3572
  • 15
  • [ 578-39-2 ]
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Reference: [1] Bulletin de la Societe Scientifique de Bretagne, 1956, vol. 31, p. Sonderheft S.9,41
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 1, p. 360 - 365
  • 17
  • [ 672-89-9 ]
  • [ 922-67-8 ]
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  • [ 108593-44-8 ]
Reference: [1] Chemische Berichte, 1987, vol. 120, p. 1339 - 1346
  • 18
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Reference: [1] Tetrahedron Letters, 1984, vol. 25, # 21, p. 2201 - 2204
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  • [ 15365-25-0 ]
YieldReaction ConditionsOperation in experiment
100% With N-Bromosuccinimide In tetrachloromethane for 2 h; Reflux To a solution of methyl 4-methoxy-2-methylbenzoate (1 g, 5.6 mmol) in CC14 (25 mL) was added dropwise N-bromosuccinimide (1.1 g, 6.2 mmol) previously dissolved in CCI4 (5 mL) and a catalytic amount of benzoylperoxide. The mixture was refluxed for 2 hours, cooled to room temperature and poured onto ice water. The aqueous mixture was extracted with DCM (3x), and the combined organics were dried over MgS04, filtered, and concentrated in vacuo to provide 2.1 g of the titled product as light yellow solid (~ 100percent yield): [M+H+] m/z 260.
100% With N-Bromosuccinimide In tetrachloromethane for 2 h; Reflux [00121] Step 1 : Methyl 2-(bromomethyl)-4-methoxybenzoate[00122] To a solution of methyl 4-methoxy-2-methylbenzoate (1 g, 5.6 mmol) inCC14 (25 mL) was added dropwise N-bromosuccinimide (1.1 g, 6.2 mmol) previously dissolved in CC14 (5 mL) and a catalytic amount of benzoyl peroxide. The mixture was refluxed for 2 hours, cooled to room temperature and poured onto iced water. The aqueous mixture was extracted with DCM (3x), and the combined organics were dried over MgS04, filtered, and concentrated in vacuo to provide 2.1 g of the titled product as light yellow solid (~ 100percent yield): [M+H+] m/z 260.
68% With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 2.5 h; Heating / reflux To a solution of 4-methoxy-2-methyl-benzoic acid methyl ester (1.47 g, 8.16 mmol, 1.0 equiv; commercially available) in CCl4 (15 mL) was added N-bromosuccinimide (1.60 g, 8.97 mmol, 1.1 equiv) and dibenzoyl peroxide (0.198 g, 0.45 mmol, 0.05 equiv). The mixture was heated to reflux for 1.5 h, when TLC indicated that still some starling material was left. Therefore, additional N-bromosuccinimide (0.16 g, 0.90 mmol, 0.11 equiv) and dibenzoyl peroxide (0.080 g, 0.41 mmol, 0.18 equiv) was added and heating continued for 1 h. The reaction mixture was cooled down, poured on crashed ice, extracted with ethyl acetate, the combined organic phases washed with a sat. solution of NaCl, dried over Na2SO4 and concentrated by evaporation under reduced pressure. The crude material was purified with silica column chromatography eluting with hexane/ethyl acetate (95:5) affording 1.43 g (68percent) of the title compound as yellow crystals. 1H NMR (300 MHz, CDCl3): δ 3.87 (s, 3H), 3.91 (s, 3H), 4.97 (s, 2H), 6.86 (dd, J=8.7 Hz, J=2.7 Hz, 1H), 6.97 (d, J=2.7 Hz, 1H), 7.99 (d, J=8.7 Hz, 1H).
62% With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 18 h; Heating / reflux 2-Bromomethyl-4-methoxy-benzoic acid methyl esterTo a solution of 4-Methoxy-2-methyl-benzoic acid methyl ester (6.92g, 38.4 mmol) in CCI4 (100 mL) was added N-bromosuccinimide (7.99 g, 1.17 mmol). Benzoyl peroxide (1.82 g, 7.54 mmol) was added to the slurry and the mixture was heated at reflux for 18 h. The reaction was cooled and the solid was filtered off. The filtrate was absorbed onto silica to perform chromatography (0-10 percent ethyl acetate/hexanes) to yield 2-Bromomethyl-4-methoxy- benzoic acid methyl ester, (6.12 g, 62 percent, CASNo. 15365-25-0). MS: ES M+1 : 258.9, M+2 260.9 (258.0, 260.0).
60% With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 24 h; Reflux Methyl 2-methyl-4-(methyloxy)benzoate (1.1 g, 6.1 mmol), N-bromosuccinimide (1.2 g, 6.74 mmol), benzoyl peroxide (0.073 g, 0.30 mmol), and carbon tetrachloride (40 mL) were combined and the stirred reaction mixture was heated at reflux for 24 h under a nitrogen atmosphere. The reaction mixture was allowed to cool at room temperature and filtered through a pad of Celite.(R).. The pad was washed with ethyl acetate. The filtrate was concentrated to give the crude product which was purified by flash chromatography over silica with a hexanes:dichloromethane gradient (100:0 to 50:50) to give 0.95 g (60percent) of methyl 2-(bromomethyl)-4-(methyloxy)benzoate as an oil which solidified to a white solid. 1U NMR (400 MHz, CDCl3): δ 7.98 (d, J = 9 Hz, IH), 6.96 (d, J = 3 Hz, IH), 6.85 (dd, J = 9, 3 Hz, IH), 4.96 (s, 2H), 3.90 (s, 3H), 3.86 (s, 3H).
58% With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 4.5 h; UV-irradiation; Heating / reflux A mixture of 4-methoxy-2-methyl-benzoic acid methyl ester (20 g, 111 mmol), N-bromo- succinimide (20.7 g, 117 mmol) and dibenzoylperoxide (0.54 g, 2 mmol) in [CC14] (150 mL) was irradiated with a 300 W lamp. The reaction maintains a steady reflux and after 4.5 h, the lamp was removed and the mixture cooled to [5 C.] The mixture was then filtered, the filtrate evaporated and the residue purified twice by chromatography [(SI02,] Heptane: Di- ethyl ether: 95: 5 to 85: 15) to afford the title product (16.6 g, 58percent) as a white solid. MS m/e = 258.1 (M-H+).

Reference: [1] Patent: WO2011/85261, 2011, A1, . Location in patent: Page/Page column 36
[2] Patent: WO2011/85128, 2011, A1, . Location in patent: Page/Page column 56
[3] Journal of Medicinal Chemistry, 1987, vol. 30, # 10, p. 1798 - 1806
[4] Patent: US2008/249101, 2008, A1, . Location in patent: Page/Page column 40
[5] Patent: WO2008/20306, 2008, A2, . Location in patent: Page/Page column 35
[6] Patent: WO2009/5998, 2009, A1, . Location in patent: Page/Page column 214
[7] Patent: WO2004/14856, 2004, A1, . Location in patent: Page 9; 14
[8] Journal of Organic Chemistry, 1988, vol. 53, # 9, p. 1912 - 1918
[9] Patent: WO2006/19768, 2006, A1, . Location in patent: Page column 90
[10] Patent: WO2006/20879, 2006, A1, . Location in patent: Page/Page column 62-63
[11] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 5, p. 1628 - 1631
[12] Journal of Medicinal Chemistry, 2012, vol. 55, # 8, p. 3975 - 3991
[13] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 1, p. 360 - 365
[14] Journal of Medicinal Chemistry, 2013, vol. 56, # 21, p. 8561 - 8578
[15] Inorganic Chemistry, 2014, vol. 53, # 6, p. 2932 - 2942
[16] Tetrahedron, 2017, vol. 73, # 20, p. 2913 - 2922
[17] Tetrahedron, 2018, vol. 74, # 2, p. 224 - 239
[18] ChemMedChem, 2018, vol. 13, # 15, p. 1530 - 1540
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Reference: [1] Chemische Berichte, 1987, vol. 120, p. 1339 - 1346
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Reference: [1] Journal of Medicinal Chemistry, 2012, vol. 55, # 8, p. 3975 - 3991
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