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[ CAS No. 392-04-1 ] {[proInfo.proName]}

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Chemical Structure| 392-04-1
Chemical Structure| 392-04-1
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Product Details of [ 392-04-1 ]

CAS No. :392-04-1 MDL No. :MFCD02093965
Formula : C8H7FO3 Boiling Point : -
Linear Structure Formula :- InChI Key :WPWUDDDJTIZBGL-UHFFFAOYSA-N
M.W : 170.14 Pubchem ID :2775386
Synonyms :

Calculated chemistry of [ 392-04-1 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 12
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.12
Num. rotatable bonds : 2
Num. H-bond acceptors : 4.0
Num. H-bond donors : 1.0
Molar Refractivity : 39.7
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) : -5.53 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.81
Log Po/w (XLOGP3) : 2.54
Log Po/w (WLOGP) : 1.74
Log Po/w (MLOGP) : 1.75
Log Po/w (SILICOS-IT) : 1.64
Consensus Log Po/w : 1.89

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.73
Solubility : 0.315 mg/ml ; 0.00185 mol/l
Class : Soluble
Log S (Ali) : -3.16
Solubility : 0.117 mg/ml ; 0.000685 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.17
Solubility : 1.14 mg/ml ; 0.00673 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.41

Safety of [ 392-04-1 ]

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 [ 392-04-1 ]

* 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 [ 392-04-1 ]
  • Downstream synthetic route of [ 392-04-1 ]

[ 392-04-1 ] Synthesis Path-Upstream   1~14

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Reference: [1] Organic and Biomolecular Chemistry, 2008, vol. 6, # 7, p. 1251 - 1259
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Reference: [1] Organic and Biomolecular Chemistry, 2008, vol. 6, # 7, p. 1251 - 1259
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YieldReaction ConditionsOperation in experiment
87% at 80℃; for 12 h; A solution of 4-fluoro-2-hydroxybenzoic acid (5.0 g, 32 mmol) and H2SO4 (4 mL) in MeOH (26 mL) was stirred at 80 °C for 12 h. After this time the mixture was concentrated under reduced pressure and water (10 mL) was added. The pH was adjusted to 8 by addition of an aqueous solution of NaOH (6 N) and the mixture was extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (150 mL), dried over Na2S04, filtered and concentrated under vacuum to give the title compound (4.6 g, 87percent) as a yellow oil.
87% at 0 - 70℃; for 16 h; To a solution of 100 g (0.64 mol, 1.0 eq.) of 1,4-fluoro-2-hydroxybenzoic acid (XLIa) in 1 L of MeOH at 0 °C was slowly added 100 mL of concentrated sulfuric acid at 0 °C. The mixture was allowed to warm to room temperature and then heated at 70 °C for 16 h. The mixture was then allowed to cool to room temperature and concentrated under reducedpressure. The residue was redissolved in 1 L of ethyl acetate and washed with 500 mL of sat. NaHCO3 followed by 500 mL of brine. The organic phase was dried (Na2SO4), filtered and the solvent was removed in vacuo to provide 95 g (0.56 mol, 87percent) of methyl 4-fluoro-2- hydroxybenzoate (XLIIa).
74.9% at 60℃; for 5 h; Methanol (4L) was added to a dry 10L four-necked flask,4-Fluorosalicylic acid (500 g, 3.20 mol) was added with stirring,Then SOCl2 (761 g, 6.40 mol) was added slowly,During the reaction temperature, so that it does not exceed 60 , Canada completed,Insulation reaction for about 5h, TLC test until the reaction is completed, the reaction mixture was concentrated under reduced pressure to a volume of 1.5L,Cool to -5-0 ,Stirring crystallization 2h after filtration, the filter cake with an appropriate amount of ice methanol until neutral,A white solid was obtained and dried under reduced pressure at 30 ° C for 12h,432 g of methyl 4-fluorosalicylic acid was obtained in a yield of 74.9percent.mp 39.4 ~ 40.2 ° C.
22.8 g Reflux B. Methyl-2-hydroxy-4-fluorobenzoate (3) Crude (2) was suspended in absolute methanol (500 mL), and concentrated sulfuric acid (100 mL) was added slowly. The suspension was heated at reflux overnight. To the suspension was added water (300 mL) and the methanol was mostly removed under vacuum, but without heating, to avoid sublimation of the product. The precipitate was collected, and dissolved in organic solvent (such as dichloromethane), dried with Na2SC>4, and the solvent was evaporated, again without heat, to yield (3) (22.8 g, 134 mmol).
17 g at 0 - 60℃; for 48 h; To a solution of 4-fluoro-2-hydroxybenzoic acid (20 g) in MeOH (300 mL) at 0 °C was added sulfuric acid (20.49 mL) dropwise. The reaction mixture was heated to 60 °C and was stirred for 2 days. The reaction mixture was concentrated under reduced pressure and the residue poured into water and extracted with EtOAc (2 x 200 mL). The combined EtOAc extracts were washed with saturated brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure to afford the titled compound (17 g). GSMS m/z 170.1 (M+). Alternatively, the title compound can be prepared by the following method. A mixture of 4- fluoro-2-hydroxybenzoic acid (0.800 g) in thionyl chloride (3.0 mL) was stirred at room temperature for 10 min and then heated at 70 °C for 30 min. The reaction mixture was then concentrated in vacuo to yield a light yellow semi-solid (857 mg). The solid was cooled to 0 °C and MeOH (6.0 mL) was carefully added (gas evolution observed). The reaction mixture was warmed to room temperature and then concentrated in vacuo to afford the crude title product as a white solid (754 mg). LCMS m/z 171 .1 (M+H)+.

Reference: [1] Chemical and Pharmaceutical Bulletin, 2012, vol. 60, # 2, p. 223 - 234
[2] Patent: WO2018/148204, 2018, A1, . Location in patent: Page/Page column 176
[3] Patent: WO2018/172852, 2018, A1, . Location in patent: Page/Page column 214; 222-223
[4] Patent: CN107501260, 2017, A, . Location in patent: Paragraph 0030; 0031; 0032; 0035; 0036
[5] Acta Chemica Scandinavica, 1997, vol. 51, # 8, p. 881 - 888
[6] Patent: US2004/176325, 2004, A1, . Location in patent: Page/Page column 25; sheet 26
[7] Patent: WO2013/148857, 2013, A1, . Location in patent: Paragraph 00394; 00408; 00418
[8] Tetrahedron Letters, 2016, vol. 57, # 48, p. 5301 - 5303
[9] Patent: WO2017/153952, 2017, A1, . Location in patent: Page/Page column 91
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YieldReaction ConditionsOperation in experiment
78% With oxone; Ru(MesCO2)(4,4'-dibromobipyridine)(p-cymene); trifluoroacetic acid; trifluoroacetic anhydride In 1,2-dichloro-ethane at 110℃; for 8 h; Sealed tube; Green chemistry General procedure: The Ru(MesCO2)(L) (p-cymene) [L- 2,2’-bypyridine or 4,4’-dibromobipyridine] (2.5 molpercent), oxidant (2.0 eq) and ester (1.0 eq) were added to a sealed tube. Following that, trifluoroacetic acid (TFA) and trifluoroacetic anhydride (TFAA) in the ratio of 0.6 ml: 0.4 were added. The reaction mixture was kept on a pre-heated bath at 110°C and stirred until its completion. It was continuously monitored by TLC. Ice water was added to quench the reaction mixture and it was extracted with dichloromethane. The organic layer was dried over Na2SO4 and rota-evaporated. Finally the residue was purified by silica gel column chromatography to give corresponding products.
Reference: [1] Tetrahedron Letters, 2017, vol. 58, # 38, p. 3743 - 3746
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YieldReaction ConditionsOperation in experiment
95% With sulfuric acid In methanolHeating / reflux Example 33: Intermediate 87--Methyl 4-fluoro-2-hydroxybenzoate [0418] To 4-fluoro-2-hydroxybenzoic acid (5.33g, 0. 034MOL) in anhydrous methanol (26mL), under nitrogen at room temperature, was added sulfuric acid (1. 5ML). The reaction mixture was brought to reflux and kept under reflux overnight. More sulfuric acid (2. 5mL) was added and the reaction mixture kept under reflux overnight. Half the solvent was removed in vacuo and the remaining solution poured over ice-H2O. The product was then extracted with ET20 (2X). The combined ether extracts were washed with a cold solution of saturated sodium bicarbonate, treated with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. 5.49g (95percent) of methyl 4-fluoro-2-hydroxybenzoate were isolated as a white solid. Its identity was confirmed BY#x0;HNMR.
92%
Stage #1: With sulfuric acid In methanol for 48 h; Heating / reflux
Reference Example 48
methyl 2-[[(dimethylamino)carbothioyl]oxy]-4-fluorobenzoate
4-Fluorosalicylic acid (10.0 g, 64 mmol) was dissolved in methanol (300 ml), and concentrated sulfuric acid (6.3 g, 64 mmol) was added thereto..
The reaction mixture was refluxed for 48 hrs..
The solvent was evaporated, and the residue was neutralized with 2 N aqueous sodium hydroxide solution..
ethyl acetate was added to the mixture..
The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate..
The solvent was evaporated to give methyl 4-fluorosalicylate (10.0 g, 92 percent) as white crystals..
Reference: [1] Patent: WO2005/12291, 2005, A1, . Location in patent: Page/Page column 72
[2] Patent: EP1424336, 2004, A1, . Location in patent: Page 132
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YieldReaction ConditionsOperation in experiment
98% at 0 - 20℃; A solution of 4-fluoro-2-hydroxybenzoic acid (9.8 g, 62.3 mmol) in benzene (100mL) and MeOH (20 mL) was cooled in an ice bath and a 2 M hexane solution of (trimethylsilyl) diazomethane (50 mL) was added dropwise. The reaction was stirred overnight at ambient temperature, diluted with benzene (348 mL) and MeOH (39 mL), and treated with more of the (trimethylsilyl) diazomethane solution (15 mL). The mixture was concentrated in vacuo to dryness to give the title compound (10.4 g, 98percent) as a solid. 1NMR FD-MS, m/e 170 (m+) Analysis forCgH7FO3 :Calcd: C, 56.48 ; H, 4.15 ;Found: C, 56.17 ; H, 4.28.
Reference: [1] Patent: WO2005/49604, 2005, A2, . Location in patent: Page/Page column 40
[2] Patent: WO2006/57845, 2006, A1, . Location in patent: Page/Page column 45
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Reference: [1] Patent: US2009/197882, 2009, A1, . Location in patent: Page/Page column 14
[2] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 13, p. 4396 - 4403
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Reference: [1] Patent: WO2013/148857, 2013, A1,
[2] Patent: CN107501260, 2017, A,
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Reference: [1] Organic and Biomolecular Chemistry, 2008, vol. 6, # 7, p. 1251 - 1259
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Reference: [1] Organic and Biomolecular Chemistry, 2008, vol. 6, # 7, p. 1251 - 1259
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Reference: [1] Synlett, 2004, # 13, p. 2391 - 2393
[2] Helvetica Chimica Acta, 1950, vol. 33, p. 1269
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Reference: [1] Organic and Biomolecular Chemistry, 2008, vol. 6, # 7, p. 1251 - 1259
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Reference: [1] Patent: US2004/220194, 2004, A1, . Location in patent: Page 35
[2] Patent: US2005/239795, 2005, A1, . Location in patent: Page/Page column 30
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Reference: [1] Patent: CN107235978, 2017, A,
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