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Product Details of [ 490-78-8 ]

CAS No. :490-78-8 MDL No. :MFCD00002343
Formula : C8H8O3 Boiling Point : -
Linear Structure Formula :- InChI Key :WLDWSGZHNBANIO-UHFFFAOYSA-N
M.W : 152.15 Pubchem ID :10279
Synonyms :
DHAP;2-Acetylhydroquinone;Quinacetophenone;2',5'-Dihydroxyacetophenone
Chemical Name :1-(2,5-Dihydroxyphenyl)ethanone

Calculated chemistry of [ 490-78-8 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 11
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.12
Num. rotatable bonds : 1
Num. H-bond acceptors : 3.0
Num. H-bond donors : 2.0
Molar Refractivity : 40.68
TPSA : 57.53 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 : Yes
Log Kp (skin permeation) : -6.06 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.39
Log Po/w (XLOGP3) : 1.65
Log Po/w (WLOGP) : 1.3
Log Po/w (MLOGP) : 0.51
Log Po/w (SILICOS-IT) : 1.19
Consensus Log Po/w : 1.21

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.16
Solubility : 1.05 mg/ml ; 0.00691 mol/l
Class : Soluble
Log S (Ali) : -2.47
Solubility : 0.514 mg/ml ; 0.00338 mol/l
Class : Soluble
Log S (SILICOS-IT) : -1.57
Solubility : 4.13 mg/ml ; 0.0272 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.04

Safety of [ 490-78-8 ]

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

Application In Synthesis of [ 490-78-8 ]

* 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 [ 490-78-8 ]
  • Downstream synthetic route of [ 490-78-8 ]

[ 490-78-8 ] Synthesis Path-Upstream   1~14

  • 1
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  • [ 26964-24-9 ]
Reference: [1] Journal of the Chinese Chemical Society, 2004, vol. 51, # 6, p. 1389 - 1394
  • 2
  • [ 490-78-8 ]
  • [ 23997-94-6 ]
Reference: [1] Journal of Organic Chemistry, 2015, vol. 80, # 17, p. 8657 - 8667
  • 3
  • [ 77-78-1 ]
  • [ 490-78-8 ]
  • [ 705-15-7 ]
YieldReaction ConditionsOperation in experiment
40% at 20℃; To a suspension of 2’,5’-dihydroxyacetophenone (100 mg, 0.66 mmol) and potassium carbonate (95 mg, 0.69 mmol) was added dimethyl sulfate (87 mg, 0.69 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was filtered and concentrated under reduced pressure. The resultant residue was treated with 2N NaOH and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane-EtOAc (10:1) to give 2’-hydroxy-5’-methoxyacetophenone in 40percent yield as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 11.9 (s, 1H), 7.18 (d, J = 2.8 Hz, 1H), 7.12 (dd, J = 8.8, 2.8 Hz, 1H), 6.93 (d, J = 8.8 Hz, 1H), 3.81 (s, 3H), 2.63 (s, 3H).
Reference: [1] Journal of the Chinese Chemical Society, 2004, vol. 51, # 6, p. 1389 - 1394
[2] European Journal of Medicinal Chemistry, 2018, vol. 157, p. 1143 - 1152
[3] Journal fuer Praktische Chemie (Leipzig), 1937, vol. <2> 149, p. 324,325
[4] Journal of the Indian Chemical Society, 1990, vol. 67, # 6, p. 478 - 481
[5] European Journal of Medicinal Chemistry, 2009, vol. 44, # 6, p. 2552 - 2562
  • 4
  • [ 490-78-8 ]
  • [ 74-88-4 ]
  • [ 705-15-7 ]
Reference: [1] Chemische Berichte, 1987, vol. 120, p. 1151 - 1174
[2] Pharmacy and Pharmacology Communications, 1999, vol. 5, # 5, p. 323 - 329
[3] Org.Synth.Coll.Vol. IV <1963>836,
[4] Phytochemistry (Elsevier), 1982, vol. 21, # 3, p. 517 - 524
[5] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 21, p. 5996 - 6001
[6] Bioorganic Chemistry, 2018, vol. 80, p. 674 - 692
  • 5
  • [ 1201-38-3 ]
  • [ 705-15-7 ]
  • [ 490-78-8 ]
Reference: [1] Synthesis, 2005, # 10, p. 1575 - 1577
  • 6
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  • [ 705-15-7 ]
Reference: [1] Chemical Biology and Drug Design, 2015, vol. 85, # 6, p. 685 - 695
  • 7
  • [ 7446-70-0 ]
  • [ 1200-06-2 ]
  • [ 705-15-7 ]
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Reference: [1] Journal of the Indian Chemical Society, 1950, vol. 27, p. 531,532
  • 8
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  • [ 30992-63-3 ]
YieldReaction ConditionsOperation in experiment
95% With 18-crown-6 ether; potassium carbonate; potassium iodide In toluene at 115℃; for 14 h; The second alternate way consists in making at first the protection of the OH function with a benzylic group by involving the same conditions as for the previous O-alkylation reaction to furnish the acetophenone derivative (1-6) in a very good yield (95percent). To form the product (1- 7), beforehand synthesized by the other methodology, acetophenone derivative (1-6) was submitted to VilsmeierHaack reaction using standard conditions (70percent). Knoevenagel condensation of the resulting product (1-7) with diethyl malonate provided in an ultimate stage the expected diester (1-8) in high yield (94percent). In view of these results (Scheme 2), we can notice that in priori both ways can be used to synthesize the intermediate (1-7) in an overall yield of 42percent and 66percent, respectively, from the dihydroxy-acetophenone (1-4) as the raw material; with however the second way more effective in term of yield.
75.6% With potassium carbonate In 4-methyl-2-pentanone at 60℃; for 20 h; 1-[2-hydroxy-5-(phenylmethoxy)-phenyl]-ethanone: 20 kg (131.4 mol) 2-acetyl-hydroquinone 6a are dissolved in 150 l methylisobutylketone and combined with 19.98 kg (144.6 mol) potassium carbonate. At 60° C., 22.48 kg (131.5 mol) benzyl bromide are added. The reaction mixture is stirred for 20 hours at 60° C. The reaction mixture is cooled to 25° C. and the solid is filtered off. The filtrate is washed twice with a solution of 0.96 kg (11.8 mol) sodium hydroxide solution (50percent) and 60 l water at 25° C. The methylisobutylketone is largely distilled off in vacuo, and the residue is dissolved in 80 l methanol at 60° C. The solution is cooled to 0° C. and stirred for 1 hour at this temperature to complete the crystallisation. Yield (5a): 24.07 kg (75.6percent), chemical purity according to HPLC: 99.2percent.
75.6% With potassium carbonate In 4-methyl-2-pentanone at 60℃; for 20 h; Industry scale 1-[2-hydroxy-5-(phenylmethoxy)-phenyl]-ethanone: 20 kg (131.4 mol) 2-acetyl-hydroquinone 6a are dissolved in 150 L methylisobutylketone and combined with 19.98 kg (144.6 mol) potassium carbonate. At 60° C., 22.48 kg (131.5 mol) benzyl bromide are added. The reaction mixture is stirred for 20 hours at 60° C. The reaction mixture is cooled to 25° C. and the solid is filtered off. The filtrate is washed twice with a solution of 0.96 kg (11.8 mol) sodium hydroxide solution (50percent) and 60 L water at 25° C. The methylisobutylketone is substantially distilled off in vacuo, and the residue is dissolved in 80 L methanol at 60° C. The solution is cooled to 0° C. and stirred for 1 hour at this temperature to complete the crystallisation.Yield (5a): 24.07 kg (75.6percent), chemical purity according to HPLC: 99.2percent.
82% With potassium carbonate In acetone EXAMPLE 9
Stage A: 5-Benzyloxy-2-hydroxyacetophenone
A mixture of 2,5-dihydroxyacetophenone (6.10 g = 40 mM), benzyl bromide (5 ml = 42 mM) and anhydrous potassium carbonate (5,6 g = 40 mM in anhydrous acetone (120 ml)) is heated under reflux for 5 hours.
Then, the mixture is concentrated under reduced pressure, the residue is taken up with 1N HCl (120 ml) and extracted with ethyl ether.
The combined extracts are washed with water and with a saturated ammonium sulfate solution, anhydrated (Na2SO4) and concentrated to give a crude solid compound that is then purified by flash-chromatography (4:1, n-hexane: ethyl acetate as the eluent) to give 8 g (82percent) of a yellow solid, m.p. 63-65°C.
49 g With potassium carbonate In acetone for 16 h; Reflux 1000 ml three-neck bottle , the compound 1 - 4 (44 g, 290 mmol), potassium carbonate (44 g, 319 mmol) dissolved in acetone (750 ml), heated to 60 °C, continue adding benzyl bromide (57.7 g, 304.5 mmol), reflux reaction 16 h. Cooling the reaction liquid to room temperature, the solid in filtering system, concentrated, continue adding ethyl acetate (400 ml), sequentially for cold aqueous solution of sodium hydroxide (1 M, 50 ml), water (200 ml) and saturated salt water (200 ml).The organic phase drying, filtering, concentrated and methanol recrystallization to obtain a yellow solid product 49 g.

Reference: [1] Patent: WO2018/156459, 2018, A1, . Location in patent: Page/Page column 22; 23
[2] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 1, p. 249 - 266
[3] Patent: US2007/88160, 2007, A1, . Location in patent: Page/Page column 10-11
[4] Patent: US2010/22770, 2010, A1, . Location in patent: Page/Page column 5-6
[5] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 4, p. 1410 - 1414
[6] Journal of Medicinal Chemistry, 2008, vol. 51, # 11, p. 3326 - 3329
[7] Arzneimittel-Forschung/Drug Research, 1984, vol. 34, # 8, p. 843 - 849
[8] Bioorganic and Medicinal Chemistry Letters, 1996, vol. 6, # 2, p. 115 - 120
[9] Patent: EP401517, 1990, A1,
[10] Patent: CN107188865, 2017, A, . Location in patent: Paragraph 0051; 0056; 0057
  • 9
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  • [ 30992-63-3 ]
YieldReaction ConditionsOperation in experiment
81.3% With potassium iodide In acetone for 6 h; Reflux 2 ', 5'-hydroxyacetophenone (7.60g, 0.05mol),Anhydrous potassium carbonate (8.00g, 0.06 mol),Potassium iodide (1.00g, 0.006mol),100mL of acetone is placed in a 250mL eggplant-shaped bottle.Stir at room temperature.Benzyl chloride (7.87 g, 0.06 mol) was diluted with 10 mL of acetone and dropped into the reaction solution at a constant rate. The addition was completed in about 10 minutes. The reaction was heated at reflux for 6 h and the reaction was monitored by TLC. After the reaction was completed, it was cooled to room temperature and the organic solvent was distilled off under reduced pressure to give yellow crystals.Recrystallization from 50 mL of ethanol gave 9.84 g of yellow crystals with a yield of 81.3percent.
81.3% With potassium carbonate; potassium iodide In acetone for 6 h; Reflux The 2',5'-dihydroxyacetophenone(7.60g, 0.05mol),Anhydrous potassium carbonate (8.00g, 0.06mol), potassium iodide (1.00g, 0.006mol),100 mL of acetone was placed in a 250 mL eggplant-shaped flask and stirred at room temperature.Benzyl chloride (7.87g, 0.06mol) was diluted with 10mL of acetone and dropped into the reaction solution at a constant rate.About 10 minutes after the completion of the drop. The reaction was heated at reflux for 6 h and the reaction was monitored by TLC.After the reaction was completed, it was cooled to room temperature and the organic solvent was distilled off under reduced pressure to give yellow crystals.Recrystallization from 50 mL of ethanol gave 9.84 g of yellow crystals with a yield of 81.3percent
Reference: [1] Journal of Chemical Research, Miniprint, 1981, # 7, p. 2564 - 2572
[2] Patent: CN107857748, 2018, A, . Location in patent: Paragraph 0036; 0044; 0045
[3] Patent: CN107935972, 2018, A, . Location in patent: Paragraph 0036; 0037; 0038
[4] Journal of the Chemical Society, 1935, p. 868
[5] Journal of the Chemical Society, 1948, p. 2138,2141
  • 10
  • [ 100-39-0 ]
  • [ 584-08-7 ]
  • [ 490-78-8 ]
  • [ 30992-63-3 ]
Reference: [1] Patent: US5248685, 1993, A,
  • 11
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  • [ 30992-63-3 ]
Reference: [1] Journal of the Chemical Society - Perkin Transactions 1, 1999, # 20, p. 3039 - 3048
  • 12
  • [ 98-86-2 ]
  • [ 121-71-1 ]
  • [ 85918-30-5 ]
  • [ 490-78-8 ]
Reference: [1] Tetrahedron Letters, 1983, vol. 24, # 30, p. 3095 - 3098
[2] Tetrahedron Letters, 1983, vol. 24, # 30, p. 3095 - 3098
  • 13
  • [ 77-78-1 ]
  • [ 490-78-8 ]
  • [ 1201-38-3 ]
Reference: [1] Org.Synth.Coll.Vol.IV <1963>836,
[2] Journal of the Indian Chemical Society, 1983, vol. 60, # 10, p. 1002 - 1004
[3] Bioorganic Chemistry, 2018, vol. 80, p. 674 - 692
  • 14
  • [ 490-78-8 ]
  • [ 869478-09-1 ]
Reference: [1] Patent: CN107188865, 2017, A,
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