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[ CAS No. 673-22-3 ] {[proInfo.proName]}

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Chemical Structure| 673-22-3
Chemical Structure| 673-22-3
Structure of 673-22-3 * Storage: {[proInfo.prStorage]}
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Product Details of [ 673-22-3 ]

CAS No. :673-22-3 MDL No. :MFCD00003327
Formula : C8H8O3 Boiling Point : -
Linear Structure Formula :- InChI Key :WZUODJNEIXSNEU-UHFFFAOYSA-N
M.W :152.15 Pubchem ID :69600
Synonyms :
2-Hydroxy-4-methoxybenzaldehyde

Calculated chemistry of [ 673-22-3 ]

Physicochemical Properties

Num. heavy atoms : 11
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.12
Num. rotatable bonds : 2
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 40.34
TPSA : 46.53 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 : No
Log Kp (skin permeation) : -6.61 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.4
Log Po/w (XLOGP3) : 0.87
Log Po/w (WLOGP) : 1.21
Log Po/w (MLOGP) : 0.51
Log Po/w (SILICOS-IT) : 1.49
Consensus Log Po/w : 1.1

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.6
Solubility : 3.8 mg/ml ; 0.0249 mol/l
Class : Very soluble
Log S (Ali) : -1.43
Solubility : 5.64 mg/ml ; 0.0371 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.88
Solubility : 2.0 mg/ml ; 0.0132 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.14

Safety of [ 673-22-3 ]

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 [ 673-22-3 ]

* 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 [ 673-22-3 ]
  • Downstream synthetic route of [ 673-22-3 ]

[ 673-22-3 ] Synthesis Path-Upstream   1~18

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Reference: [1] Synthetic Communications, 1996, vol. 26, # 6, p. 1233 - 1245
  • 2
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  • [ 531-95-3 ]
Reference: [1] Journal of the American Chemical Society, 2012, vol. 134, # 44, p. 18245 - 18248
[2] Tetrahedron, 2018, vol. 74, # 16, p. 2020 - 2029
  • 3
  • [ 673-22-3 ]
  • [ 50551-63-8 ]
Reference: [1] Synlett, 2006, # 4, p. 567 - 570
[2] Journal of the American Chemical Society, 1951, vol. 73, p. 872
[3] Research on Chemical Intermediates, 2016, vol. 42, # 5, p. 4433 - 4442
[4] Research on Chemical Intermediates, 2016, vol. 42, # 5, p. 4433 - 4442
[5] Patent: WO2018/140513, 2018, A1,
  • 4
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  • [ 79418-41-0 ]
Reference: [1] Journal of Pharmacy and Pharmacology, 2012, vol. 64, # 5, p. 742 - 746
  • 5
  • [ 673-22-3 ]
  • [ 70-11-1 ]
  • [ 22395-22-8 ]
Reference: [1] European Journal of Organic Chemistry, 2018, vol. 2018, # 4, p. 537 - 544
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  • [ 22395-22-8 ]
Reference: [1] Tetrahedron, 1988, vol. 44, # 11, p. 3187 - 3194
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1990, # 2, p. 423 - 424
[3] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1990, # 2, p. 423 - 424
[4] Organic Letters, 2011, vol. 13, # 17, p. 4526 - 4529
[5] Tetrahedron, 2011, vol. 67, # 51, p. 9993 - 9997
[6] Advanced Synthesis and Catalysis, 2018, vol. 360, # 1, p. 153 - 160
  • 7
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  • [ 698-88-4 ]
  • [ 22395-22-8 ]
Reference: [1] Chemical Communications, 2015, vol. 51, # 99, p. 17576 - 17579
  • 8
  • [ 7647-01-0 ]
  • [ 60-29-7 ]
  • [ 74-90-8 ]
  • [ 21144-16-1 ]
  • [ 5435-44-9 ]
  • [ 673-22-3 ]
  • [ 58026-14-5 ]
  • [ 32884-23-4 ]
  • [ 18278-34-7 ]
Reference: [1] Chemische Berichte, 1925, vol. 58, p. 1702
  • 9
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  • [ 100-39-0 ]
  • [ 32884-23-4 ]
YieldReaction ConditionsOperation in experiment
95% With potassium carbonate In ethanol at 50℃; for 48 h; 2-(Benzyloxy)-4-methoxybenzaldehyde[0150] K2CO3 and benzyl bromide were added to a solution of 2-hydroxy-4- methoxy benzaldehyde (1 g, 6.57 mmol) in ethanol (100 mL), and the mixture was then heated for two days at 50 0C. The solution was concentrated and the residue was dissolved in-55-SDI-10975vl Attorney Docket No. 12560-046-228diethyl ether. The ether solution was washed with brine, 5percent aqueous NaOH, water, dried (Na2SO4) and evaporated to give the 2-benzyloxy-4-methoxybenzaldehyde (1.5 g, 95percent): LC-MS [M+H]+= 243.02.
93% With potassium carbonate In DMF (N,N-dimethyl-formamide) at 20℃; Reference Example 96 A mixture of 2-hydroxy-4-methoxybenzaldehyde (25.16 g), benzyl bromide (20 ml), potassium carbonate (25.03 g) and N, N- dimethylformamide (300 ml) was stirred overnight at room temperature. The reaction mixture was poured into dilute <Desc/Clms Page number 164>hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried(MgS04) and concentrated. The residue was subjected to silica gel column chromatography, and 2- benzyloxy-4-methoxybenzaldehyde (37.18 g, yield 93percent) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1: 4, volume ratio). 1H-NMR (CDC13) $ : 3.86 (3H, s), 5.17 (2H, s), 6.50-6. 62 (2H, m), 7.24-7. 50 (5H, m), 7.85 (1H, d, J=8.4 Hz), 10.39 (1H, s).
93% With potassium carbonate In acetonitrileReflux Step (b).
2-Benzyloxy-4-methoxybenzaldehyde
To a solution of 4-methoxy-2-hydroxybenzaldehyde (15.2 g, 100 mmol) in acetonitrile (200 ml) was added K2CO3 (16.56 g, 120 mmol) and BnBr (13.07 ml, 110 mmol), and the resultant solution was refluxed overnight.
The mixture was cooled and the solvent was then removed under vacuum.
To the residue was added H2O (100 ml), which was extracted with Et2O, brine, and dried over MgSO4. Recrystalization in MeOH gave compound 2 (22.50 g, 93percent) as a white solid.
86% With potassium carbonate In acetone for 6 h; Reflux 15.1: 2-Benzyloxy-4-methoxybenzaldehyde160 ml (1.3 mmol) of benzyl bromide and (1.3 mmol) of potassium carbonate are added to a solution of 2 g(1.3 mmol) of 2-hydroxy-4-methoxybenzaldehyde in 20 ml of acetone. The mixture is stirred at reflux for6 hours and then evaporated. 50 ml of IN aqueous solution of sodium hydroxide are added and the medium is extracted with dichloromethane . The organic phase is dried over magnesium sulphate, filtered and evaporated. The residue obtained is precipitated from 1 heptane/ethyl acetate mixture (95/5) . 2.75 g of 2- benzyloxy-4-methoxybenzaldehyde are obtained in the form of a white powder with a yield of 86percent.

Reference: [1] Patent: WO2010/111353, 2010, A1, . Location in patent: Page/Page column 55-56
[2] Patent: WO2003/99793, 2003, A1, . Location in patent: Page 163
[3] Journal of Natural Products, 2017, vol. 80, # 12, p. 3284 - 3288
[4] Patent: US2018/86772, 2018, A1, . Location in patent: Page/Page column 6
[5] Bioorganic and Medicinal Chemistry, 1998, vol. 6, # 9, p. 1429 - 1437
[6] Journal of Medicinal Chemistry, 2009, vol. 52, # 15, p. 4941 - 4945
[7] Patent: WO2010/52253, 2010, A1, . Location in patent: Page/Page column 76
[8] Tetrahedron Letters, 1991, vol. 32, # 18, p. 2035 - 2038
[9] Journal of the American Chemical Society, 1992, vol. 114, # 6, p. 2175 - 2180
[10] Chemistry - A European Journal, 2011, vol. 17, # 9, p. 2698 - 2703
[11] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 24, p. 6816 - 6821
[12] Advanced Synthesis and Catalysis, 2013, vol. 355, # 14-15, p. 2900 - 2907
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YieldReaction ConditionsOperation in experiment
69% With tetra-(n-butyl)ammonium iodide In tetrahydrofuran a
Synthesis of 2-Benzyloxy-4-methoxybenzaldehyde of Formula:
1 g of 2-hydroxy-4-methoxybenzaldehyde is dissolved in 15 ml of anhydrous tetrahydrofuran (THF) in a reactor.
The mixture is cooled to 4° C. 1.3 equivalents of sodium hydride (NaH) at 60percent in oil are added.
The mixture is left to react for 30 minutes to form the alkoxide. 1.3 equivalents of benzyl bromide and 90 mg of tetrabutylammonium iodide are then added.
The mixture is left to react for 6 hours at room temperature.
After reaction for 6 h, 50 ml of saturated sodium bicarbonate (NaHCO3) solution are added.
The mixture is washed twice with 50 ml of isopropyl ether.
The organic phases are dried over sodium sulphate and evaporated under vacuum, and the compound obtained is purified on silica gel using dichloromethane as eluent.
The mass recovered is 1.1 g, which corresponds to a yield of 69percent.
Reference: [1] Patent: US6448285, 2002, B1,
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  • [ 100-44-7 ]
  • [ 32884-23-4 ]
Reference: [1] Drug Development Research, 2016, vol. 77, # 1, p. 37 - 42
[2] Chemical and Pharmaceutical Bulletin, 2000, vol. 48, # 7, p. 964 - 973
[3] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 5, p. 1537 - 1544
[4] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1980, p. 2463 - 2469
[5] Bulletin de la Societe Chimique de France, 1960, p. 1644 - 1646
[6] Gazzetta Chimica Italiana, 1989, vol. 119, # 2, p. 87 - 94
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  • [ 74-90-8 ]
  • [ 21144-16-1 ]
  • [ 5435-44-9 ]
  • [ 673-22-3 ]
  • [ 58026-14-5 ]
  • [ 32884-23-4 ]
  • [ 18278-34-7 ]
Reference: [1] Chemische Berichte, 1925, vol. 58, p. 1702
  • 13
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  • [ 39835-11-5 ]
YieldReaction ConditionsOperation in experiment
86% With Nitroethane; sodium acetate In acetic acid for 12 h; Heating / reflux A mixture of the 2-hydroxy-4-methoxybenzaldehyde (20 g, 128.8 mmol), sodium acetate (35.05 g, 257.6 mmol) and nitroethane (19 mL, 257.6 mmol) in glacial acetic acid (100 mL) was heated at gentle reflux for 12 h.
The reaction mixture was then poured into ~1000 mL of ice water (1:1 ratio of ice and water).
The product was extracted with ethyl acetate (3*200 mL).
The organic extracts were washed with sodium bicarbonate solution until the aqueous layer had pH ~8.
The organic layers were then dried over anhydrous magnesium sulfate and concentrated in vacuo to afford 2-hydroxy-4-methoxy-benzonitrile as a yellow oil (16.5 g, 86percent).
84% With hydroxylamine hydrochloride; sodium formate In formic acid Example I
2-Hydroxy-4-methoxybenzonitrile
2-Hydroxy-4-methoxybenzaldehyde (55 g; 0.36 mol), hydroxylamine hydrochloride (30 g; 0.43 mol) and sodium formate (34 g; 0.5 mol) were refluxed in formic acid (200 ml; 98-100percent) for 1.25 h.
The solution was then rapidly chilled in an ice bath, with stirring over 30 min.
The resulting precipitate was separated by filtration and washed well with water.
Following drying, in a desicator under vacuum, the title compound was obtained (45 g; 0.3 mol; 84percent yield) as a brick-red solid, mp 169-171° C., rf (EtOAc) 0.43.
Reference: [1] Synthetic Communications, 2004, vol. 34, # 11, p. 2025 - 2029
[2] Patent: US2004/259867, 2004, A1, . Location in patent: Page/Page column 7
[3] Patent: US6399657, 2002, B1,
[4] Journal of Medicinal Chemistry, 2003, vol. 46, # 8, p. 1470 - 1477
[5] Synlett, 2000, # 8, p. 1169 - 1171
[6] Chemische Berichte, 1934, vol. 67, p. 859,864
[7] Biochemical Journal, 1936, vol. 30, p. 1303,1313
[8] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 18, p. 8419 - 8426
[9] Organic Letters, 2011, vol. 13, # 6, p. 1426 - 1428
[10] Journal of Organic Chemistry, 2015, vol. 80, # 2, p. 1229 - 1234
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  • [ 79-24-3 ]
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YieldReaction ConditionsOperation in experiment
86% With sodium acetate In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; acetic acid EXAMPLE 18
4,5-bis-(4-Chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole
A mixture of the 2-hydroxy-4-methoxybenzaldehyde (20 g, 128.8 mmol), sodium acetate (35.05 g, 257.6 mmol) and nitroethane (19 mL, 257.6 mmol) in glacial acetic acid (100 mL) was heated at gentle reflux for 12 h.
The reaction mixture was then poured into ~1000 mL of ice water (1:1 ratio of ice and water).
The product was extracted with ethyl acetate (3*200 mL).
The organic extracts were washed with sodium bicarbonate solution until the aqueous layer had pH ~8.
The organic layers were then dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford 2-hydroxy-4-methoxy-benzonitrile as a yellow oil (16.5 g, 86percent).
65% With sodium acetate In acetic acid; ethyl acetate EXAMPLE 9
[4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone hydrochloride
A mixture of 2-hydroxy-4-methoxybenzaldehyde (25.0 g, 164 mmol), sodium acetate (26.4 g, 322 mmol), nitroethane (23 g, 307 mmol) in acetic acid (45 mL) was heated at reflux for 6 h.
The mixture was then cooled to room temperature and poured onto ice water.
The solids were filtered off, washed with water and dried.
Recrystallization of the crude solid in ethyl acetate gave 2-hydroxy-4-methoxy-benzonitrile as a brown solid (15.9 g, 65percent).
Reference: [1] Patent: US6617346, 2003, B1,
[2] Patent: US2003/153580, 2003, A1,
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Reference: [1] Journal of Organic Chemistry, 2015, vol. 80, # 17, p. 8657 - 8667
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YieldReaction ConditionsOperation in experiment
87% With hydrogen In ethanol; acetic acid Example 84 3- [4- (5-Hydroxy-2-methyl-phenoxy)-2-methyl-phenyl]-propionic acid ethyl ester Step A 5-Methoxy-2-methyl-phenol A solution of 2-hydroxy-4-methoxy-benzaldehyde (5.00 g, 32.86 mmol) and palladium under carbon (10 percent) (3.50 g, 3.28 mmol) in ethanol (32 mL) and acetic acid (3 mL) is stirred under 60 psi of hydrogen. After stirring overnight, the mixture is filtered off through Celite and washed with methanol. The mixture is concentrated under reduced pressure, and purified by flash chromatography by eluting with hexane: ethyl acetate 2: 1 to afford the title compound (3.96 g, 87 percent). Rf= 0.58 (hexane: ethyl acetate 2: 1). 8'H NMR (300 MHz, CDC13) : 2.18 (s, 3 H), 3.75 (s, 3 H), 6.42 (m, 2 H), 7.00 (d, 1 H, J= 8. 9 Hz).
Reference: [1] Patent: WO2005/37763, 2005, A1, . Location in patent: Page/Page column 130-131
[2] Tetrahedron Letters, 1988, vol. 29, # 31, p. 3741 - 3744
[3] Monatshefte fuer Chemie, 1964, vol. 95, p. 649 - 670
[4] Journal of Organic Chemistry, 1980, vol. 45, # 2, p. 208 - 212
[5] Patent: US2003/207916, 2003, A1,
[6] Patent: US2003/207924, 2003, A1,
[7] Patent: US5916922, 1999, A,
[8] Patent: EP944636, 2003, B1,
[9] Patent: US2004/209936, 2004, A1,
[10] Patent: US2003/225158, 2003, A1, . Location in patent: Page 22
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Reference: [1] Patent: WO2018/140513, 2018, A1,
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  • [ 1196473-37-6 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 8, p. 2533 - 2536
[2] Patent: US2010/256092, 2010, A1,
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