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[ CAS No. 22446-38-4 ] {[proInfo.proName]}

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Chemical Structure| 22446-38-4
Chemical Structure| 22446-38-4
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Product Details of [ 22446-38-4 ]

CAS No. :22446-38-4 MDL No. :MFCD07369387
Formula : C10H12O3 Boiling Point : -
Linear Structure Formula :- InChI Key :NSQBADKMIYCCSC-UHFFFAOYSA-N
M.W : 180.20 Pubchem ID :572437
Synonyms :

Calculated chemistry of [ 22446-38-4 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 13
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.3
Num. rotatable bonds : 4
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 49.14
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) : -6.31 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.95
Log Po/w (XLOGP3) : 1.54
Log Po/w (WLOGP) : 1.5
Log Po/w (MLOGP) : 1.67
Log Po/w (SILICOS-IT) : 1.91
Consensus Log Po/w : 1.71

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.0
Solubility : 1.78 mg/ml ; 0.00989 mol/l
Class : Soluble
Log S (Ali) : -2.13
Solubility : 1.35 mg/ml ; 0.00748 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.71
Solubility : 0.354 mg/ml ; 0.00196 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.6

Safety of [ 22446-38-4 ]

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

Application In Synthesis of [ 22446-38-4 ]

* 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 [ 22446-38-4 ]
  • Downstream synthetic route of [ 22446-38-4 ]

[ 22446-38-4 ] Synthesis Path-Upstream   1~5

  • 1
  • [ 64-17-5 ]
  • [ 621-37-4 ]
  • [ 22446-38-4 ]
YieldReaction ConditionsOperation in experiment
100% at 20℃; for 6 h; Intermediate 5; (2-Cyclopropyl-5-hydroxy-phenyl)-acetic acid ethyl ester; [0089] Step A; (3-Hydroxy-phenyl)-acetic acid (10 g, 65.7 mmol) is dissolved inEtOH (50 mL). Catalytic amounts of thionyl chloride (~0.5 mL) are added and the solution is stirred for 6 h at rt. The solvent is removed in vacuo to give (3-hydroxy-phenyl)-acetic acid ethyl ester 1 (11.8 g, quant.): MS calcd. for Ci0Hi3O3 (M+H+) 181.1, found 181.0.
100% at 20℃; for 6 h; Intermediate 10; (2-Cyclopropyl-5-hydroxy-phenyl)-acetic acid ethyl ester; Step A; (3-Hydroxy-phenyl)-acetic acid (10 g, 65.7 mmol) is dissolved in EtOH (60 mL). Catalytic amounts of thionyl chloride (~0.5 mL) are added and the solution is stirred for 6 h at rt. The solvent is removed in vacuo to give (3-hydroxy-phenyl)-acetic acid ethyl ester 6 (11.8 g, quant): MS calcd. for C10Hi3O3 (M+H*) 181.1, found 181.0.
100% Reflux Ethyl 2-(3-hydroxyphenyI)acetate (S16-2).; To a solution of 2-(3-hydroxyphenyl)acetic acid (S16-1; 10 g, 65.8 mmol) in 200 mL of ethanol was added 8 mL of concentrated sulfuric acid. The resulting mixture was refluxed overnight and condensed under vacuum. The residue was dissolved in ethyl acetate and washed with water. The organic layer was combined, washed with brine, dried over MgS04, evaporated to dryness and purified by flash chromatography to give S16-2 as a colorless oil in quantitative yield. 1H NMR (500 MHz, CDC13) δ 7.35 (br, 1H), 7.12 (m, 1H), 6.69-6.78 (m, 3H), 4.12 (m, 2H), 3.53 (s, 2H), 1.21 (m, 3H).
98% for 2 h; Reflux Ethanol (616.7 mL), 12 (100.0 g, 657.9 mmol) and concentratedsulfuric acid (15.3 g, 131.6 mmol) were mixed by stirring and heatedto reflux for 2 h. The resulting mixture was cooled to ambienttemperature and evaporated under vacuum to remove the ethanol. Theresidue was then extracted with dichloromethane (50 mL × 3). Thecombined organic layer was washed with water until neutral, dried overwith anhydrous magnesium sulphate, and filtered and concentratedunder vacuum to give a pale-brown liquid (115.6 g, based on 12 yield of98percent, purity of 99percent, area normalisation method of HPLC). 1H NMR:(CDCl3, 500 MHz, δ: ppm), 7.19–7.16 (t, 1H, J = 7.5 Hz), 6.83–6.82 (d,1H, J = 8.0 Hz), 6.77 (s, 1H), 6.74–6.72 (q, 1H, J = 2.0 Hz), 5.55 (s, 1H),4.18–4.14 (q, 2H, J = 7.5 Hz), 3.56 (s, 2H), 1.27–1.24 (t, 3H, J = 7.0 Hz).1H NMR data corresponded to the literature.29
96% for 4 h; Heating / reflux Example B.5 Synthesis of 3-Hydroxyphenylacetic acid ethyl ester: Concentrated H2SO4 (2mL, 36mmol) was added to a suspension of 3- hydroxyphenylacetic acid (25.9g, 170mmol) in EtOH (34OmL). The reaction mixture was heated at reflux for 4 hours then cooled to room temperature. The volatiles were removed in vacuo and the residue was suspended in EtOAc (30OmL). The organic layer was washed with saturated aqueous NaHCOs (I x 15OmL), brine (1 x 15OmL), dried (anhydrous MgSO4), and concentrated under reduced pressure to give the ester as a colorless oil (29.3g, 96percent yield).
94.5% for 2.5 - 3 h; Heating / reflux a)
Ethyl 2-(3-hydroxyphenyl)acetate
To the flask was added EtOH (100 ml) followed by starting material (9.83 g, 64.6 mmol) and sulfuric acid (catalytic amount).
The mixture was refluxed for 3 hrs then cooled to room temperature.
The mixture was diluted with H2O (100 mL) and extracted with EtOAc (100 mL).
The organic layer was dried over MgSO4, filtered, and concentrated in vacuo.
The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (1:4) as eluant.
Pale yellow oil, yield: 94.5percent.
A solution of starting material (9.83 g, 64.6 mmol) in ethanol (100 mL) was added catalytic amounts of sulfuric acid. The mixture was refluxed for 3 hrs then cooled to room temperature. The mixture was diluted with H2O (100 μL) and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (1:4) as eluant.Pale yellow oil, yield: 94.5percent; A solution of 3-hydroxyphenylacetic acid (15.5 g) in ethanol (200 mL) was added sulfuric acid (1 mL) and refluxed for 2.5 hours. The reaction mixture was cooled to room temperature. The mixture was added water and extracted with EtOAc. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. (18.2 g, 99.0percent, pale brown oil)
91% at 0 - 20℃; for 20 h; Thionylchloride (17.5 mL, 240 mmol) was added dropwise to ethanol (200 mL) at 0C, andthe mixture was stirred for 15 min. To the solution was added 3-hydroxyphenylaceticacid (24.3 g, 160 mmol), and the mixture was stirred at room temperature for 20h. The solvent was removed under reduced pressure and the residue was dissolvedin diethyl ether (200 mL). To the solution was added calcium carbonate (16.0 g)and the mixture was stirred for 30 min. The insoluble materials were filteredoff and the filtrate was concentrated under reduced pressure. The residue wastriturated with hexane to give the title compound (26.3 g, 91percent) as a colorless solid.1H NMR(300 MHz, CDCl3) δH: 1.26 (3H, t, J = 7.1 Hz), 3.56 (2H, s), 4.16 (2H, q, J = 7.1 Hz), 6.73 (1H, dd, J= 7.8 and 1.7 Hz), 6.77 (1H, d, J =1.7 Hz), 6.82 (1H, d, J = 7.8 Hz), 7.17(1H, dd, J = 7.8 and 7.8 Hz, 1H). Thephenolic hydroxy proton was too broad to be observed. HRMS-EI (m/z):[M]+ calcd for C10H12O3, 180.0786;found 180.0779.

Reference: [1] Patent: WO2007/56366, 2007, A2, . Location in patent: Page/Page column 26
[2] Patent: WO2007/56497, 2007, A1, . Location in patent: Page/Page column 22
[3] Patent: WO2011/44394, 2011, A1, . Location in patent: Page/Page column 127-128
[4] Journal of Medicinal Chemistry, 2012, vol. 55, # 14, p. 6427 - 6437
[5] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 1, p. 299 - 302
[6] Journal of Chemical Research, 2016, vol. 40, # 8, p. 506 - 510
[7] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 22, p. 8092 - 8105
[8] Patent: WO2008/145678, 2008, A1, . Location in patent: Page/Page column 41-42
[9] Journal of Medicinal Chemistry, 1997, vol. 40, # 7, p. 1049 - 1062
[10] Tetrahedron Letters, 1993, vol. 34, # 52, p. 8549 - 8552
[11] Tetrahedron, 1994, vol. 50, # 41, p. 11945 - 11966
[12] Tetrahedron Asymmetry, 1995, vol. 6, # 6, p. 1345 - 1356
[13] Tetrahedron, 1996, vol. 52, # 42, p. 13493 - 13512
[14] Patent: US2009/156590, 2009, A1, . Location in patent: Page/Page column 40; 49; 52-53
[15] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 21, p. 5340 - 5352
[16] Journal of Medicinal Chemistry, 2007, vol. 50, # 7, p. 1495 - 1503
[17] Tetrahedron Letters, 1992, vol. 33, # 27, p. 3919 - 3922
[18] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 23, p. 5274 - 5279
[19] Journal of Medicinal Chemistry, 2005, vol. 48, # 23, p. 7153 - 7165
[20] Journal of Organic Chemistry, 2001, vol. 66, # 23, p. 7818 - 7824
[21] Patent: EP1422224, 2004, A1, . Location in patent: Page 21
[22] Patent: WO2007/56771, 2007, A2, . Location in patent: Page/Page column 37; 39
[23] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 14, p. 2539 - 2542
[24] Patent: WO2006/127133, 2006, A2, . Location in patent: Page/Page column 44
[25] Patent: WO2007/146768, 2007, A2, . Location in patent: Page/Page column 10
[26] Patent: WO2009/102893, 2009, A2, . Location in patent: Page/Page column 95
[27] Patent: WO2009/145989, 2009, A2, . Location in patent: Page/Page column 104
[28] Patent: WO2009/151695, 2009, A1, . Location in patent: Page/Page column 71-72
  • 2
  • [ 7664-93-9 ]
  • [ 621-37-4 ]
  • [ 22446-38-4 ]
Reference: [1] Patent: US6124323, 2000, A,
[2] Patent: US5656629, 1997, A,
  • 3
  • [ 621-37-4 ]
  • [ 22446-38-4 ]
Reference: [1] Patent: US5554763, 1996, A,
[2] Patent: US5679693, 1997, A,
[3] Patent: US5674881, 1997, A,
  • 4
  • [ 621-37-4 ]
  • [ 22446-38-4 ]
YieldReaction ConditionsOperation in experiment
98% With sulfuric acid In ethanol A.
2-(3,Hydroxyphenyl) propanoic acid ethyl ester
A mixture of 100 g (0.658 mol) of 3-hydroxyphenylacetic acid, 6.0 ml concentrated sulfuric acid and 800 ml of ethanol was refluxed through a soxhlet with 3A molecular sieves for 3 hours.
The reaction was cooled and concentrated to an oil on a rotovapor.
The residue was added to 500 ml ice cold saturated sodium bicarbonate and 1 liter of ether.
The ether extract was dried over magnesium sulfate and evaporated to give 116 g (98percent) of ethyl 3-hydroxyphenylacetate as an oil.
Reference: [1] Patent: US5872138, 1999, A,
[2] Patent: US5550152, 1996, A,
  • 5
  • [ 621-37-4 ]
  • [ 104-15-4 ]
  • [ 22446-38-4 ]
Reference: [1] Patent: US6110924, 2000, A,
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