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[ CAS No. 3943-89-3 ] {[proInfo.proName]}

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Chemical Structure| 3943-89-3
Chemical Structure| 3943-89-3
Structure of 3943-89-3 * Storage: {[proInfo.prStorage]}
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Product Details of [ 3943-89-3 ]

CAS No. :3943-89-3 MDL No. :MFCD00002199
Formula : C9H10O4 Boiling Point : -
Linear Structure Formula :- InChI Key :KBPUBCVJHFXPOC-UHFFFAOYSA-N
M.W : 182.17 Pubchem ID :77547
Synonyms :
Ethyl protocatechuate

Calculated chemistry of [ 3943-89-3 ]

Physicochemical Properties

Num. heavy atoms : 13
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.22
Num. rotatable bonds : 3
Num. H-bond acceptors : 4.0
Num. H-bond donors : 2.0
Molar Refractivity : 46.57
TPSA : 66.76 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.1 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.74
Log Po/w (XLOGP3) : 1.84
Log Po/w (WLOGP) : 1.27
Log Po/w (MLOGP) : 1.06
Log Po/w (SILICOS-IT) : 1.08
Consensus Log Po/w : 1.4

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -2.27
Solubility : 0.973 mg/ml ; 0.00534 mol/l
Class : Soluble
Log S (Ali) : -2.86
Solubility : 0.25 mg/ml ; 0.00137 mol/l
Class : Soluble
Log S (SILICOS-IT) : -1.73
Solubility : 3.41 mg/ml ; 0.0187 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 1.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.57

Safety of [ 3943-89-3 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 3943-89-3 ]

* 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.

  • Upstream synthesis route of [ 3943-89-3 ]
  • Downstream synthetic route of [ 3943-89-3 ]

[ 3943-89-3 ] Synthesis Path-Upstream   1~30

  • 1
  • [ 3943-89-3 ]
  • [ 26309-99-9 ]
Reference: [1] Patent: US2011/98311, 2011, A1,
[2] Patent: US2015/231142, 2015, A1,
[3] Patent: WO2008/141119, 2008, A2,
  • 2
  • [ 3943-89-3 ]
  • [ 39270-39-8 ]
Reference: [1] Patent: US2011/98311, 2011, A1,
[2] Patent: US2015/231142, 2015, A1,
[3] Patent: WO2008/141119, 2008, A2,
  • 3
  • [ 99-50-3 ]
  • [ 64-17-5 ]
  • [ 3943-89-3 ]
YieldReaction ConditionsOperation in experiment
89% at 40 - 80℃; for 10 h; 3,4-dihydroxybenzoic acid (5.0 g, 32.0 mmol) was placed in a reaction flask, 40 mL of ethanol was added, and the temperature was raised to 40 ° C, and 5 mL of concentrated sulfuric acid was added dropwise. After the dropwise addition, the temperature was raised to 80 ° C and refluxed for 10 h. Cooled to room temperature, add 10M potassium hydroxide solution to adjust the pH to neutral. The solvent was evaporated under reduced pressure to precipitate a solid which was washed with a small amount of water to give ethyl 3,4-dihydroxybenzoate. Ethyl 3,4-dihydroxybenzoate: white solid; 89percent yield;
86.8% Reflux 15.4 g (0.1 mol) of 3,4-dihydroxybenzoic acid and 200 mL of absolute ethanol were added to a 500 mL flask,In the constant stirring slowly dropping 5mL 98percent concentration of concentrated sulfuric acid.The mixture was heated to reflux, the TLC was followed by the reaction, 80percent by volume of solvent was distilled off under reduced pressure,Diluted with 30 mL of ethyl acetate and 25 mL of water, and the aqueous layer was extracted with 300 mL of ethyl acetate,The organic layers were combined, washed with saturated aqueous NaHCO3, saturated brine,Anhydrous Na2SO4 dry, filtered, decompression,To obtain 15.8 g of ethyl 3,4-dihydroxybenzoate in 86.8percent yield.
70% at 0℃; Reflux; Inert atmosphere General procedure: Thionyl chloride (1.16 g, 1.5 equiv) was added drop-wise to a solution of acid (1.0 g, 1.0 equiv) in the corresponding alcohol (15 ml) at 0&d eg;C. The solution was refluxed under a nitrogen atmosphere until all starting material was consumed (TLC monitoring). Then the solvent was removed under vacuo and the residue was purified by silica gel column chromatography eluting with ethyl acetate/n-hexane to afford the corresponding carboxylic esters.#10;
15.8 g for 4 h; Reflux To a solution of 3,4-dihydroxybenzoic acid (15.4g, 0.1mol) in absolute ethanol (200mL) was added 5mL concentrated sulfuric acid. This mixture was heated at reflux for 4h. After cooling to ambient temperature, water (100mL) was slowly introduced over a period of 10min. The mixture was extracted with EtOAc, washed with diluted HCl followed by water, dried with Na2SO4. Then solvent was removed under reduced pressure, the yellow powder as ethyl 3,4-dihydroxybenzoate was used without further disposal. Yield 15.8g, 86.8percent.

Reference: [1] Inorganic Chemistry, 2015, vol. 54, # 15, p. 7571 - 7578
[2] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 6, p. 2074 - 2083
[3] Reactive and Functional Polymers, 2011, vol. 71, # 9, p. 948 - 957
[4] Chemistry Letters, 2007, vol. 36, # 10, p. 1196 - 1197
[5] Patent: CN104725327, 2017, B, . Location in patent: Paragraph 0066-0068
[6] Patent: CN106632130, 2017, A, . Location in patent: Paragraph 0020-0021
[7] Journal of Medicinal Chemistry, 2012, vol. 55, # 10, p. 4551 - 4567
[8] ChemMedChem, 2017, vol. 12, # 16, p. 1303 - 1318
[9] Journal of Agricultural and Food Chemistry, 2010, vol. 58, # 11, p. 6986 - 6993
[10] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 6, p. 1564 - 1569
[11] Justus Liebigs Annalen der Chemie, 1860, vol. 114, p. 300
[12] Current Medicinal Chemistry, 2012, vol. 19, # 26, p. 4534 - 4540,7
[13] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 12, p. 2680 - 2684
[14] European Journal of Medicinal Chemistry, 2017, vol. 136, p. 348 - 359
[15] , 2018, vol. 19, # 10,
  • 4
  • [ 617-05-0 ]
  • [ 3943-89-3 ]
YieldReaction ConditionsOperation in experiment
93% With aluminium(III) iodide; ethyl acetate; diisopropyl-carbodiimide In acetonitrile at 20℃; for 2 h; General procedure: To a suspension of AlI3 (2.75 mmol, 1.1 eq.) in CH3CN (20 mL) was added asolution of DIC (190 mg, 1.5 mmol, 0.6 eq.) and methyl vanillate (454 mg, 2.5 mmol) in EA (20 mL, desiccated by MgSO4). After stirred for 2 h at 20 °C, the mixture was was acidified with HCl (2 mol/L, 5 mL), and extracted with EA (3 × 50 mL). The organic phases were combined, washed with saturated aq Na2S2O3 (10 mL) and brine (10 mL), and was dried (MgSO4). The solvent was removed on a rotary evaporator and the residue was purified by flash column chromatography (PE/EA = 2 : 1) to afford 2 (0.349 g, 82percent) as a white solid
Reference: [1] Tetrahedron Letters, 2017, vol. 58, # 36, p. 3522 - 3524
  • 5
  • [ 64-17-5 ]
  • [ 3943-89-3 ]
  • [ 1577235-12-1 ]
YieldReaction ConditionsOperation in experiment
33% at 60℃; for 4 h; Compound 1 (50.0 mg) and AMVN (25.0 mg, 1 equiv.) were dissolved in 40 mL of EtOH, and the mixture was stirred at 60 °C for 4 h. The reaction mixture was purified by HPLC (column: NB-ODS-9) with CH3CN/H2O (20:80 v/v) containing 0.5percent trifluoroacetic acid (TFA) to obtain compound 2 (13.5 mg, 28.2percent), protocatechuic acid ethyl ester (3b; 6.2 mg, 33.0percent), and compound 2a (5.0 mg, 9.6percent). 2-(3,4-Dihydroxyphenyl)-4,6-dihydroxybenzofuran-3-carboxylic acid glucose ester 2: 1H NMR (600 MHz, CD3OD): δ 3.26 (1H, t, J = 8.9 Hz, H-2"), 3.41 (1H, t, J = 8.9 Hz, H-4"), 3.41-3.45 (1H, m, H-5"), 3.45 (1H, t, J = 8.9 Hz, H-3"), 3.75 (1H, dd, J = 4.5, 12.0 Hz, H-6"), 3.87 (1H, dd, J = 2.4, 12.0 Hz, H-6"), 5.81 (1H, d, J = 8.2 Hz, H-1"), 6.25 (1H, d, J = 2.1 Hz, H-5), 6.46 (1H, d, J = 2.1 Hz, H-7), 6.87 (1H, d, J = 8.3 Hz, H-5'), 7.27 (1H, dd, J = 2.0, 8.3 Hz, H-6'), 7.33 (1H, d, J = 2.0 Hz, H-2'); 13C NMR (150 MHz, CD3OD): δ 61.9 (C6"), 70.4 (C4"), 73.4 (C2"), 78.0 (C3"), 78.5 (C5"), 90.4 (C7), 96.5 (C1"), 100.0 (C5), 107.1 (C3), 108.1 (C9), 115.6 (C5'), 118.4 (C2'), 122.1 (C1'), 123.7 (C6'), 145.3 (C3'), 148.8 (C4'), 152.4 (C4), 157.1 (C8), 158.7 (C6), 162.4 (C2), 167.8 (C10); UV λmax (MeOH) nm (ε): 253 (15,100), 347 (9400).
Reference: [1] Food Chemistry, 2014, vol. 155, p. 221 - 226
  • 6
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Reference: [1] Patent: US4582855, 1986, A,
[2] Patent: US4402974, 1983, A,
[3] Patent: US4798892, 1989, A,
  • 7
  • [ 1344113-41-2 ]
  • [ 3943-89-3 ]
Reference: [1] Journal of the American Chemical Society, 2011, vol. 133, # 44, p. 17630 - 17633
  • 8
  • [ 20986-39-4 ]
  • [ 3943-89-3 ]
Reference: [1] Synlett, 2013, vol. 24, # 6, p. 741 - 746
  • 9
  • [ 17159-79-4 ]
  • [ 3943-89-3 ]
Reference: [1] Journal of the American Chemical Society, 2016, vol. 138, # 37, p. 12271 - 12277
  • 10
  • [ 33668-25-6 ]
  • [ 3943-89-3 ]
Reference: [1] Journal of the American Chemical Society, 2016, vol. 138, # 37, p. 12271 - 12277
  • 11
  • [ 64-17-5 ]
  • [ 3897-89-0 ]
  • [ 3943-89-3 ]
Reference: [1] Green Chemistry, 2016, vol. 18, # 1, p. 251 - 254
  • 12
  • [ 120-47-8 ]
  • [ 3943-89-3 ]
Reference: [1] Journal of the American Chemical Society, 2011, vol. 133, # 44, p. 17630 - 17633
  • 13
  • [ 120-47-8 ]
  • [ 110-44-1 ]
  • [ 64-18-6 ]
  • [ 473-81-4 ]
  • [ 3943-89-3 ]
  • [ 120-80-9 ]
  • [ 123-31-9 ]
  • [ 108-95-2 ]
  • [ 99-96-7 ]
Reference: [1] Journal of Photochemistry and Photobiology A: Chemistry, 2017, vol. 337, p. 62 - 70
  • 14
  • [ 7647-01-0 ]
  • [ 99-50-3 ]
  • [ 64-17-5 ]
  • [ 3943-89-3 ]
Reference: [1] Chemische Berichte, 1878, vol. 11, p. 133
  • 15
  • [ 3943-89-3 ]
  • [ 100-39-0 ]
  • [ 584-08-7 ]
  • [ 1570-05-4 ]
YieldReaction ConditionsOperation in experiment
92% With potassium hydroxide In methanol; water; butanone (B)
3,4-DIBENZYLOXYBENZOIC ACID
To 60 g (0.33 mole) of ethyl 3,4-dihydroxybenzoate in 50 ml of methyl ethyl ketone was added 105.5 g (0.76 mole) of K2 CO3 and 168.8 g (0.76 mole) of benzyl bromide.
The mixture was refluxed for 16 hours and filtered.
Evaporation of the filtration gave an oil.
This oil was mixed with 40 g of KOH, 350 ml of water and 350 ml of methanol and refluxed for 2.5 hours.
The methanol was evaporated and the reaction mixture was acidified with concentrated HCl.
The precipitate was filtered to give 101 g (92percent) of the desired product; m.p. 184°-185° C.
The NMR and IR spectra were consistent with the assigned structure.
92% With potassium hydroxide In methanol; water; butanone 3,4-Dibenzyloxybenzoic Acid
To 60 g (0.33 mole) of ethyl 3,4-dihydroxybenzoate in 50 ml of methyl ethyl ketone was added 105.5 g (0.76 mole) of K2 CO3 and 168.8 g (0.76 mole) of benzyl bromide.
The mixture was refluxed for 16 hours and filtered.
Evaporation of the filtration gave an oil.
This oil was mixed with 40 g of KOH, 350 ml of water and 350 ml of methanol and refluxed for 2.5 hours.
The methanol was evaporated and the reaction mixture was acidified with concentrated HCl.
The precipitate was filtered to give 101 g (92percent) of the desired product; m.p. 184°-5° C.
The NMR and IR spectra were consistent with the assigned structure.
92% With potassium hydroxide In methanol; water; butanone (b)
3,4-Dibenzyloxybenzoic Acid
To 60 g (0.33 mole) of ethyl 3,4-dihydroxybenzoate in 50 ml of methyl ethyl ketone was added 105.5 g (0.76 mole) of K2 CO3 and 168.8 g (0.76 mole) of benzyl bromide.
The mixture was refluxed for 16 hours and filtered.
Evaporation of the filtration gave an oil.
This oil was mixed with 40 g of KOH, 350 ml of water and 350 ml of methanol and refluxed for 2.5 hours.
The methanol was evaporated and the reaction mixture was acidified with concentrated HCl.
The precipitate was filtered to give 101 g (92percent) of the desired product; m.p. 184°-185° C.
The NMR and IR spectra were consistent with the assigned structure.
Reference: [1] Patent: US4582855, 1986, A,
[2] Patent: US4402974, 1983, A,
[3] Patent: US4798892, 1989, A,
  • 16
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  • [ 1570-05-4 ]
Reference: [1] Journal of Organic Chemistry, 2004, vol. 69, # 10, p. 3530 - 3537
  • 17
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  • [ 100-39-0 ]
  • [ 177429-27-5 ]
YieldReaction ConditionsOperation in experiment
25% With potassium carbonate In acetonitrile at 55℃; for 16 h; 1-(Bromomethyl)benzene (68 g, 398 mmol, 1.05 equiv) and potassium carbonate (67 g, 485 mmol, 1.50 equiv) were added to a solution of ethyl 3,4-dihydroxybenzoate (67 g, 368 mmol, 1.00 equiv) and acetonitrile (400 mL).
The resulting mixture was stirred at about 55° C. for about 16 hours.
The solids were removed by filtration and the filtrate was concentrated in vacuo.
The solids was purified by silica gel column chromotagraphy (dichloromethane/petroleum ether 1:10) to afford the title product as a white solid (25 g, yield 25percent).
Reference: [1] ChemMedChem, 2017, vol. 12, # 16, p. 1303 - 1318
[2] Patent: US2010/75916, 2010, A1, . Location in patent: Page/Page column 17
[3] Patent: WO2007/58338, 2007, A2, . Location in patent: Page/Page column 64
  • 18
  • [ 3943-89-3 ]
  • [ 100-44-7 ]
  • [ 177429-27-5 ]
YieldReaction ConditionsOperation in experiment
33% With potassium carbonate; potassium iodide In acetonitrile at 40℃; Step 9a: Ethyl 4-(benzyloxy)-3-hydroxybenzoate (Compound 502)
A mixture of ethyl 3,4-dihydroxybenzoate (9.1 g, 50 mmol), benzyl chloride (6.3 g, 50 mmol), KI (1.66 g, 10 mmol), and K2CO3 (13.8 g, 100 mmol) in acetonitrile (250 mL) was stirred at 40° C. overnight.
The mixture was then cooled to room temperature and filtered.
The filtrate was evaporated and the residue was purified by column chromatography on silica gel eluding with petroleum ether/ethyl acetate (10/1) to give the title compound 502 as a white solid (4.4 g, 33percent): LCMS: 273 [M+1]+; 1H NMR (DMSO-d6): δ 9.49 (s, 1H), 7.35 (m, 7H), 7.08 (d, J=7.8 Hz, 1H), 5.16 (s, 2H), 4.21 (m, 2H), 1.26 (t, J=7.5 Hz, 3H).
Reference: [1] Patent: US2009/76044, 2009, A1, . Location in patent: Page/Page column 30
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  • [ 100-39-0 ]
  • [ 188564-63-8 ]
  • [ 177429-27-5 ]
  • [ 174398-83-5 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 1997, vol. 5, # 2, p. 323 - 334
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  • [ 100-39-0 ]
  • [ 188564-63-8 ]
  • [ 177429-27-5 ]
Reference: [1] Journal of Medicinal Chemistry, 1994, vol. 37, # 24, p. 4076 - 4078
  • 21
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  • [ 177429-27-5 ]
Reference: [1] Patent: WO2011/53948, 2011, A1,
[2] Tetrahedron, 2012, vol. 68, # 22, p. 4194 - 4201
  • 22
  • [ 3943-89-3 ]
  • [ 6482-24-2 ]
  • [ 183322-16-9 ]
YieldReaction ConditionsOperation in experiment
100% With potassium carbonate; potassium iodide In acetone at 60℃; for 19 h; Inert atmosphere (3)
Preparation of Ethyl 3,4-dimethoxyethoxybenzoate 13
Ethyl 3,4-dihydroxy benzoate 12 (5 g, 27.45 mmol) is placed in a two-neck bottle of 250 ml, N2 is added at room temperature, and acetone (100 ml), potassium carbonate (9.48 g, 68.63 mmol), potassium iodide (0.5 g) and 2-Bromoethyl methyl ether (7.84 ml, 82.35 mmol) are added.
Then heat refluxing is carried out at 60° C. for 19 hours.
After the reaction is completed, the resultant of reaction is cooled at 5° C. and stirred for 30 minutes, then filtered and concentrated to dry.
The solid is dried by oil-less pump for 22 hours to obtain khaki compound 13 (8.19 g, 100percent).
1H-NMR (CDCl3) spectrum: 1.32 (t, 3H, J=7 Hz), 3.41 (s, 6H), 3.76 (m, 4H), 4.15 (m, 4H), 4.29 (q, 2H, J=7 Hz), 6.85 (d, 1H, J=8.4 Hz), 7.53 (dd, 1H, J=8.4 Hz, J=2.3 Hz), 7.53 (m, 1H), 7.63 (dd, 1H, J=8.4 Hz, J=2.3 Hz).
93% With potassium carbonate In acetone at 20 - 70℃; for 24 h; 3,4-Dihydroxy-benzoic acid ethyl ester (compound A') (2.0 g) was dissolved in acetone (20 ml). Potassium carbonate (4.3 g) and 1-bromo-2-methoxy-ethane (compound D) (5 ml) were added to the solution at room temperature, and the mixture was then stirred at 70°C for 24 hr. After the completion of the reaction, the reaction solution was allowed to stand for cooling at room temperature, and the reaction system was concentrated under the reduced pressure. Distilled water was added to the residue, and the mixture was then subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated under the reduced pressure. The residue was purified by column chromatography using a hexane-acetone system to give 3,4-bis-(2-methoxy-ethoxy)-benzoic acid ethyl ester (3.06 g, yield 93percent).
93% With tetra-(n-butyl)ammonium iodide; potassium carbonate In acetone for 64 h; Inert atmosphere; Reflux To ethyl 3,4-dihydroxybenzoate (36.4 g, 0.200 mol), K2CO3 (60.8 g, 0.44 mol) and tetrabutylammonium iodide(750 mg) in degassed acetone (400 mL) was added 2-bromoethyl methyl ether (69.5 g, 47 mL). The mixture was stirred under N2 at reflux for 64 hours. Ether (600 mL) was added to the mixture and after stirring 30 minutes at 20 °C theprecipitated salts were removed by filtration. The filtrate was concentrated in vacuo and the residue was triturated withhexane (500 mL) for 30 minutes and the white solid ethyl 3,4-bis(2-methoxy-ethoxy)benzoate was filtered and dried invacuo (55.5 g; 93percent; M.P. 50-51 °C). A portion of this product (45.7 g, 0.158 mol) in acetic acid (150 mL) was treateddropwise with conc. HNO3 (40 mL) at 5°C and the solution stirred 24 hours before pouring into cold H2O (1.6 L). Themixture was extracted with ethyl acetate (1.1 L), and the organic phase was washed three times with 200 mL H2O, andbrine, dried over Na2SO4, filtered and concentrated in vacuo to afford ethyl 4,5-bis-(2-methoxy-ethoxy)-2-nitro-benzoate(54.3 g) as a brown oil. This nitro product (52.0 g, 0.15 mol) was dissolved in ethanol (1000 mL) containing 1 equivalentof HCl (generated in the ethanol by prior addition of 11 mL acetyl chloride), PtO2•H2O (1.0 g) was added, and the mixturewas hydrogenated under 45 psi H2 for 6 hours. The catalyst was removed by filtration through Celite, and the filtratewas concentrated in vacuo to a thick slurry which was diluted with ether (400 mL). The solid white hydrochloride salt ofethyl 2-amino-4,5-bis-(2-methoxy-ethoxy)benzoate was filtered and dried in vacuo (44.7 g; 88percent). A portion of this material(42 g, 0.12 mol) and ammonium formate (7.6 g, 0.12 mol) were disssolved in formamide (63 mL) and the stirred mixturewas heated to 160-165 °C under an atmosphere of N2 for 3 hours. H2O (200 mL) was added and after cooling theprecipitated crude title product was recovered by filtration, washed with cold H2O, and dried in vacuo. The filtrate wasextracted five times with CHCl3, and the pooled organic extracts were washed with brine, dried over Na2SO4, andconcentrated in vacuo. The residue and crude quinazolone precipitate were combined, triturated in hot acetonitrile (250mL) for 30 minutes, cooled to 20 °C and treated with ether (250 mL). After cooling to 4 °C the white solid was filteredand dried in vacuo (30.4 g, 86percent; GC-MS m/z 294 (M+)).
Reference: [1] Patent: US2010/267949, 2010, A1, . Location in patent: Page/Page column 6
[2] Patent: EP1614676, 2006, A1, . Location in patent: Page/Page column 194
[3] Patent: EP2163546, 2016, B1, . Location in patent: Paragraph 0125
[4] European Journal of Medicinal Chemistry, 2008, vol. 43, # 7, p. 1478 - 1488
[5] Chemistry - A European Journal, 2015, vol. 21, # 41, p. 14342 - 14346
[6] Journal of Labelled Compounds and Radiopharmaceuticals, 2005, vol. 48, # 11, p. 829 - 843
[7] Molecules, 2006, vol. 11, # 4, p. 286 - 297
[8] European Journal of Medicinal Chemistry, 2013, vol. 67, p. 293 - 301
[9] Journal of Labelled Compounds and Radiopharmaceuticals, 2018, vol. 61, # 2, p. 42 - 53
  • 23
  • [ 627-42-9 ]
  • [ 3943-89-3 ]
  • [ 183322-16-9 ]
YieldReaction ConditionsOperation in experiment
95% at 90 - 95℃; In a dry, clean 500ml reaction flask, 36.4 g was added3,4-dihydroxybenzoate,82.4 g of potassium carbonate,6.0 g of 4-methylaminopyridine,145.6 g of 1-chloro-2-methoxyethane was stirred to a temperature of 90-95 ° C,Reflux insulation, the reaction is completed, cooling down to 20-30 ° C,Add water, stir, place the layer, extract the water layer, combined organic layer, distillation, steaming, cooling cooling. Add isopropyl alcohol and water, filter, filter cake with isopropyl alcohol and water leaching, drying dry product, vacuum drying to obtain 57g products, the yield of 95percent, HPLC purity of 99percent.
87% With potassium <i>tert</i>-butylate; potassium iodide In N,N-dimethyl-formamide at 100℃; for 12 h; A solution of ethyl 3,4-dihydroxybenzoate (1.7 g, 9.3 mmol) was placed in a reaction flask and 8 mL of DMF was added to dissolve it. Potassium tert-butoxide (2.0 g, 17.8 mmol) and potassium iodide (1.0 g, 6.0 mmol), and the temperature was raised to 100 ° C. 2-Chloroethyl methyl ether (3.52 g, 37.2 mmol) was added dropwise and the reaction was continued for 12 h after completion of the dropwise addition. Cooled to room temperature, ice water (200 mL) was added, and extracted three times with ethyl acetate (3 x 200 mL). The organic phase was combined, washed three times with distilled water, three times with saturated brine, dried over anhydrous sodium sulfate overnight, filtered, and the filtrate was evaporated to dryness under reduced pressure to give an oil. The elution system was petroleum ether / ethyl acetate = 1) Ethyl 3,4-bis (2-methoxyethoxy) benzoate.
95 %Chromat. With potassium carbonate In N,N-dimethyl-formamide at 90 - 100℃; for 9 h; [Synthesis Example 1]; (Synthesis of ethyl 3,4-bis(2-methoxyethoxy)benzoate); In a 20 L-volume glass reaction vessel equipped with a stirrer, a thermometer and a reflux condenser, 1,300 g (7.14 moles) of ethyl 3,4-dihydroxybenzoate, 2,324 g (21.4 moles) of 2-chloroethyl methyl ether, 2,958 g (21.4 moles) of potassium carbonate and 6,500 mL of N,N-dimethylformamide were placed. The mixture was allowed to react with each other at 90 to 100°C for 9 hours while stirring. After the reaction was complete, the reaction solution was cooled to room temperature. The reaction solution was then filtered, and washed with 6,500 mL of acetone. The filtrate was concentrated, 3,900 mL of ethyl acetate and 3,900 mL of a saturated aqueous sodium carbonate solution were added to the concentrate. The separated organic layer (ethyl acetate layer) was washed twice with 3,900 mL of a saturated aqueous sodium chloride solution to obtain a solution mixture containing ethyl 3,4-bis(2-methoxyethoxy)benzoate. The solution mixture was analyzed (according to an absolute quantitative method) by a high performance liquid chromatography. It was confirmed that 2,023 g of ethyl 3,4-bis(2-methoxyethoxy)benzoate was produced (reaction yield: 95percent). After 3,939 mL of acetic acid was added to the solution mixture, the mixture was concentrated under reduced pressure to distill ethyl acetate off. Thus, an acetic acid solution of ethyl 3,4-bis(2-methoxyethoxy)benzoate was obtained.
Reference: [1] Patent: CN106892821, 2017, A, . Location in patent: Paragraph 0029; 0030
[2] Patent: CN104725327, 2017, B, . Location in patent: Paragraph 0069-0071
[3] Molecules, 2006, vol. 11, # 4, p. 286 - 297
[4] Patent: EP1650196, 2006, A1, . Location in patent: Page/Page column 6
  • 24
  • [ 3943-89-3 ]
  • [ 17178-10-8 ]
  • [ 183322-16-9 ]
YieldReaction ConditionsOperation in experiment
89% With potassium carbonate In acetonitrile for 6 h; Reflux EXAMPLE 504-chloro-6,7-bis(2-methoxyethoxy)quinazoline (compound I-1)Ethyl 3,4-dihydroxybenzoate (36.4 g, 0.2 mol), potassium carbonate (82.8 g, 0.6 mol), and 2-methoxyethyl p-toluenesulfonate (72.0 g, 0.4 mol) were dissolved in acetonitrile (200 ml), heated and refluxed for 6 h. The solvent of the reaction mixture was evaporated under vacuum to obtain a residue. The residue was recrystallized with isopropanol, suction filtered, and dried under vacuum to obtain a white powder 3,4-bis (2-methoxyethoxy)ethyl benzoate (53.2 g, 89percent).3,4-bis(2-methoxyethoxy)benzoic acid ethyl ester (15.00 g, 0.05 mol) was added into acetic acid (50 ml) to form a mixture, and while the mixture was stirred in an ice water bath, 65-68percent nitric acid (13 ml) was added to the mixture. The mixture then was stirred for 24 h at room temperature. The reaction mixture was transferred into ice water (500 ml), and extracted with ethyl acetate. The organic phase was combined, washed with saturated sodium bicarbonate solution three times, washed with saturated sodium chloride solution, and then dried by anhydrous sodium sulfate. The organic phase was then filtered to obtain a filtrate. The filtrate was concentrated to obtain a brown oily liquid 2-nitro-4,5-bis(2-methoxyethoxy)ethyl benzoate (14.10 g, 82.22percent).2-nitro-4,5-bis(2-methoxyethoxy)benzoic acid ethyl ester (34.3 g, 0.10 mol), ammonium formate (63 g, 1.00 mol), 5percent Pd/C (5.00 g), and formamide (150 ml) were reacted for 7 h at 150° C. The reaction mixture was cooled to room temperature, and a solid precipitated. The precipitate was filtered to obtain a white powder 6,7-bis-(2-methoxyethoxy)-4(3H)quinazolinone (22.1 g, 75percent).Thionyl chloride (14.9 g) was added dropwise slowly to a solution of 6,7-bis-(2-methoxyethoxy)-4 (3H) quinazolinone (14.7 g, 0.15 mol), N,N-dimethylformamide (1 ml), and dichloromethane (150 ml). The reaction mixture was stirred at room temperature, and refluxed for 6 h. The reaction mixture was cooled to room temperature, and the pH of the reaction mixture was adjusted to 7-8 with a sodium hydroxide solution. The reaction mixture was then stirred for 30 min at room temperature, and set aside to allow the organic and aqueous layers to separate. The organic layer was collected, and concentrated under vacuum to obtain a white solid 4-chloro-6,7-bis-(2-methoxyethoxy)-quinazoline (14.1 g, 89.5percent), [M+H]+=313.
89% With potassium carbonate In acetonitrile for 6 h; Reflux Ethyl 3,4-dihydroxybenzoate (36.4 g, 0.2 mol), potassium carbonate (82.8 g, 0.6 mol), and 2-methoxyethyl p-toluenesulfonate (72.0 g, 0.4 mol) were dissolved in acetonitrile (200 ml), heated and refluxed for 6 h.
The solvent of the reaction mixture was evaporated under vacuum to obtain a residue.
The residue was recrystallized by isopropanol, suction filtered, and dried under vacuum to obtain a white powder 3,4-bis (2-methoxyethoxy)ethyl benzoate (53.2 g, 89percent).
Reference: [1] Patent: US2011/288086, 2011, A1, . Location in patent: Page/Page column 29
[2] Patent: EP2592083, 2013, A1, . Location in patent: Paragraph 0258
  • 25
  • [ 16427-44-4 ]
  • [ 3943-89-3 ]
  • [ 183322-16-9 ]
YieldReaction ConditionsOperation in experiment
95% With tetrabutylammomium bromide; potassium carbonate In toluene for 6 h; Reflux The compounds (1) (194.28), compounds (1118), potassium carbonate (252.38), toluene (222) and tetrakisbutyl ammonium bromide (5 g), heated to reflux, reacted for 6 hours, HPLC indicated that the reaction was complete, cooled to room temperature, filtered,The filtrate was washed with 1110 mL of water and the aqueous layer was extracted with toluene (555 mL X 2). The toluene layers were combined, washed with 1110 mL ofAnd brine, dried toluene to give the compound (iii) (172.6 g), 95percent yield, purity> 95percent. The NMR of the compound (iii)Identification data are as follows:
Reference: [1] Patent: CN103709110, 2016, B, . Location in patent: Paragraph 0058; 0059
[2] Research on Chemical Intermediates, 2013, vol. 39, # 6, p. 2303 - 2309
  • 26
  • [ 3943-89-3 ]
  • [ 6482-24-2 ]
  • [ 183322-16-9 ]
Reference: [1] Patent: US5821246, 1998, A,
  • 27
  • [ 3943-89-3 ]
  • [ 179688-27-8 ]
Reference: [1] Molecules, 2006, vol. 11, # 4, p. 286 - 297
[2] Molecules, 2006, vol. 11, # 4, p. 286 - 297
[3] Journal of Labelled Compounds and Radiopharmaceuticals, 2005, vol. 48, # 11, p. 829 - 843
[4] European Journal of Medicinal Chemistry, 2013, vol. 67, p. 293 - 301
[5] Journal of Labelled Compounds and Radiopharmaceuticals, 2018, vol. 61, # 2, p. 42 - 53
  • 28
  • [ 3943-89-3 ]
  • [ 179688-29-0 ]
Reference: [1] Molecules, 2006, vol. 11, # 4, p. 286 - 297
[2] Molecules, 2006, vol. 11, # 4, p. 286 - 297
[3] Journal of Labelled Compounds and Radiopharmaceuticals, 2005, vol. 48, # 11, p. 829 - 843
[4] European Journal of Medicinal Chemistry, 2013, vol. 67, p. 293 - 301
[5] Chemistry - A European Journal, 2015, vol. 21, # 41, p. 14342 - 14346
[6] Journal of Labelled Compounds and Radiopharmaceuticals, 2018, vol. 61, # 2, p. 42 - 53
  • 29
  • [ 3943-89-3 ]
  • [ 1012054-59-9 ]
Reference: [1] Patent: US2009/111772, 2009, A1,
  • 30
  • [ 3943-89-3 ]
  • [ 1384868-07-8 ]
YieldReaction ConditionsOperation in experiment
40% With isopropyl nitrate; sulfuric acid In dichloromethane at 0 - 20℃; for 0.75 h; a.
Ethyl 3,4-dihydroxy-2-nitrobenzoate
To a solution of ethyl 3,4-dihydroxybenzoate (9.5 g, 52.2 mmol), isopropyl nitrate (13.5 g, 130.5 mmol), and tetrabutylammonium hydrogensulfate (0.884 g, 2.61 mmol) in DCM (100 mL), was added sulfuric acid (14.25 g, 145.6 mmol) slowly at 0° C.
The reaction mixture was warmed to room temperature and stirred for 45 min, then quenched with ice/water (150 mL), and extracted with DCM (150 mL*2).
The extracts were combined, and the solvent removed under vacuum.
The product was purified by silica gel column (20percent v/v EtOAc in PE) to give ethyl 3,4-dihydroxy-2-nitrobenzoate (4.97 g, 40percent yield). ESI MS: m/z 228 [M+H]+.
Reference: [1] Patent: US2012/178748, 2012, A1, . Location in patent: Page/Page column 50
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