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[ CAS No. 399-97-3 ] {[proInfo.proName]}

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Chemical Structure| 399-97-3
Chemical Structure| 399-97-3
Structure of 399-97-3 * Storage: {[proInfo.prStorage]}
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Product Details of [ 399-97-3 ]

CAS No. :399-97-3 MDL No. :MFCD00077451
Formula : C6H6FNO Boiling Point : -
Linear Structure Formula :- InChI Key :ULDFRPKVIZMKJG-UHFFFAOYSA-N
M.W : 127.12 Pubchem ID :2735917
Synonyms :

Calculated chemistry of [ 399-97-3 ]

Physicochemical Properties

Num. heavy atoms : 9
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 2.0
Num. H-bond donors : 2.0
Molar Refractivity : 32.83
TPSA : 46.25 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) : -6.17 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.03
Log Po/w (XLOGP3) : 1.28
Log Po/w (WLOGP) : 1.54
Log Po/w (MLOGP) : 1.24
Log Po/w (SILICOS-IT) : 1.09
Consensus Log Po/w : 1.24

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.93
Solubility : 1.5 mg/ml ; 0.0118 mol/l
Class : Very soluble
Log S (Ali) : -1.85
Solubility : 1.79 mg/ml ; 0.0141 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.7
Solubility : 2.52 mg/ml ; 0.0199 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 2.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.0

Safety of [ 399-97-3 ]

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 [ 399-97-3 ]

* 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 [ 399-97-3 ]
  • Downstream synthetic route of [ 399-97-3 ]

[ 399-97-3 ] Synthesis Path-Upstream   1~19

  • 1
  • [ 399-97-3 ]
  • [ 78-39-7 ]
  • [ 701-16-6 ]
YieldReaction ConditionsOperation in experiment
87% at 20℃; for 0.5 h; 2. 5-Fluoro-2-methylbenzoxazole; 2-Amino-4-fluorophenol (1.01g, 7.95mmol, 1.0eq), triethyl orthoacetate (1.60ml, 8.7mmol, 1.1eq) and bismuth (III) trifluoromethanesulfonate (50mg) were mixed and stirred at ambient temperature for 30mins. The resulting solution was then diluted with dichloromethane and purified by silica flash chromatography (dichloromethane) to give the title compound as a clear liquid, 1.045g (87percent). The liquid transformed to a crystalline solid at temperatures below 5°C. MS (MALDI-TOF): MH+ = 152. UV/VIS (MeOH): ABS λmax = 282, 276 230nm. δH/ppm (400MHz&1 CDCI3): 2.60 (s, 3H), 7.02 (1 H, td), 7.33 (1 H, dd) and 7.39 (1 H, dd).
1.65 g With ytterbium(III) triflate In ethanol for 2 h; Reflux (a) 5-Fluoro-2-methylbenzo[d]oxazole (2665) To a solution of 2-amino-4-fluorophenol (2.72 g) and triethyl orthoacetate (7.89 ml) in ethanol (100 ml) was added ytterbium(lll) trifluoromethanesulfonate (310 mg, 0.500 mmol). The reaction was heated at reflux for 2 hours whereupon LCMS indicated complete conversion. The resulting dark solution was cooled, concentrated to a dark residue, then purified directly on a pre-packed silica column (SF40-150g), using a gradient of 0-100percent ethyl acetate in hexanes to afford the titled compound(1 .65 g) as an orange oil, which was used without further purification. LCMS m/z 151 .9 [M+H]. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.61 (s, 3H), 7.19 (td, J=9.35, 2.53 Hz, 1 H), 7.52 (dd, J=8.84, 2.53 Hz, 1 H), 7.68 (dd, J=8.84, 4.29 Hz, 1 H).
Reference: [1] Patent: WO2008/40994, 2008, A2, . Location in patent: Page/Page column 25
[2] Patent: WO2017/98421, 2017, A1, . Location in patent: Page/Page column 223
  • 2
  • [ 399-97-3 ]
  • [ 108-24-7 ]
  • [ 701-16-6 ]
Reference: [1] International Journal of Mass Spectrometry, 2013, vol. 345-347, p. 120 - 131
  • 3
  • [ 399-97-3 ]
  • [ 530-62-1 ]
  • [ 13451-79-1 ]
YieldReaction ConditionsOperation in experiment
90% at 80℃; for 5 h; Inert atmosphere General procedure: The intermediates 4 were prepared as previously described [36] with some modification. Under the atmosphere of nitrogen, starting material aminophenol (1 equiv.) and N,N′-Carbonyldiimidazole (CDI) (1.2 equiv.) were mixed in DMF and stirred 80°C for 5h. The reaction mixture was allowed to cool to room temperature and the water was added to quench the reaction. The mixture was and extracted with ethyl acetate to afford the crude product that was purified by flash column chromatography on silica gel to yield 4a-d.
Reference: [1] European Journal of Medicinal Chemistry, 2017, vol. 138, p. 199 - 211
[2] Patent: WO2005/18529, 2005, A2, . Location in patent: Page/Page column 62
[3] Journal of Medicinal Chemistry, 2015, vol. 58, # 23, p. 9258 - 9272
[4] Organic and Biomolecular Chemistry, 2017, vol. 15, # 19, p. 4058 - 4063
[5] Patent: WO2005/18529, 2005, A2, . Location in patent: Page/Page column 62
  • 4
  • [ 399-97-3 ]
  • [ 503-38-8 ]
  • [ 13451-79-1 ]
Reference: [1] Patent: US5086062, 1992, A,
[2] Patent: US5149821, 1992, A,
  • 5
  • [ 399-97-3 ]
  • [ 7693-46-1 ]
  • [ 13451-79-1 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 19, p. 5811 - 5814
  • 6
  • [ 399-97-3 ]
  • [ 57-13-6 ]
  • [ 13451-79-1 ]
Reference: [1] Journal of Medicinal Chemistry, 1967, vol. 10, p. 408 - 410
  • 7
  • [ 394-33-2 ]
  • [ 399-97-3 ]
YieldReaction ConditionsOperation in experiment
75%
Stage #1: at 70℃; for 2 h;
Stage #2: With sodium hydroxide In water at 0 - 20℃;
Tin(II) chloride (12.1 g, 63.6 mmol) was added to a solution of 4-fluoro-2- nitrophenol (2.00 g, 12.7 mmol) in EtOH (45 mL), and the reaction mixture was heated to 70 0C. After 2 h, the reaction mixture was allowed to cool to rt and was poured onto ice (-200 mL). After warming to rt, the pH was adjusted to ~9 with 2 N aqueous NaOH, and the mixture was filtered. The filtrate was extracted with EtOAc (3 x), and the combined EtOAc extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. This gave 1.21 g (75percent) of the title compound. LC-MS: RT = 4.48 min., [M+H]+ = 128.0.
211mg With 10% palladium on activated carbon; Degussa type; hydrogen In ethanol at 1 - 40℃; for 1 h; a)
2-Amino-4-fluorophenol
300 mg of 4-fluoro-2-nitrophenol was dissolved in 3 ml of ethanol, and 120 mg of 10percent palladium/carbon was added and stirred under hydrogen atmosphere at room temperature for 1 hour.
After the insoluble matter was filtered off, the filtrate was distilled off under reduced pressure to yield 211 mg of the title compound.
1H-NMR (DMSO-d6); δ (ppm) 4.80 (2H, s), 6.09-6.14 (1H, m), 6.34-6.37 (1H, m), 6.53-6.57 (1H, m), 8.93 (1H, s).
MS (FAB); m/z 128 (M+H)+
211 mg With 10% palladium on activated charcoal; hydrogen In ethanol at 20℃; for 1 h; [0140] 300 mg of 4-fluoro-2-nitrophenol was dissolved in 3 ml of ethanol and 120 mg of 10percent palladium/carbon was added, followed by stirring under a hydrogen atmosphere at room temperature for 1 hour. The insoluble material was filtered and subsequently the filtrate was distilled off under reduced pressure to afford 211 mg of the title compound. [0141] 1H-NMR (DMSO-d6); δ (ppm) 4.80 (2H, s), 6.09-6.14 (1H, m), 6.34-6.37 (1H, m), 6.53-6.57 (1H, m), 8.93 (1H, s). [0142] MS (FAB); m/z 128 (M+H)+
211 mg With 10% palladium on activated carbon; Degussa type; hydrogen In ethanol at 1 - 40℃; for 1 h; a) 2-Amino-4-fluorophenol [0152] 300 mg of 4-fluoro-2-nitrophenol was dissolved in 3 ml of ethanol and 120 mg of 10percent palladium/ carbon was added, followed by stirring under a hydrogen atmosphere at room temperature for 1 hour. The insoluble material was filtered and subsequently the filtrate was distilled off under reduced pressure to afford 211 mg of the title compound. 1H-NMR (DMSO-d6); δ (ppm) 4.80 (2H, s), 6.09-6.14 (1H, m), 6.34-6.37 (1H, m), 6.53-6.57 (1H, m), 8.93 (1H, s). MS (FAB); m/z 128 (M+H)+
211 mg With 10% palladium on activated carbon; Degussa type; hydrogen In ethanol at 20℃; for 1 h; 300 mg of 4-fluoro-2-nitrophenol was dissolved in 3 ml of ethanol and 120 mg of 10percent palladium/carbon was added, followed by stirring under a hydrogen atmosphere at room temperature for 1 hour. The insoluble material was filtered and subsequently the filtrate was distilled off under reduced pressure to afford 211 mg of the title compound. 1H-NMR (DMSO-d6); δ (ppm) 4.80 (2H, s), 6.09-6.14 (1H, m), 6.34-6.37 (1H, m), 6.53-6.57 (1H, m), 8.93 (1H, s). MS (FAB); m/z 128 (M+H)+
211 mg With 10% palladium on activated carbon; Degussa type; hydrogen In ethanol at 20℃; for 1 h; [0170] 300 mg of 4-fluoro-2-nitrophenol was dissolved in 3 ml of ethanol and 120 mg of 10percent palladium/ carbon was added, followed by stirring under a hydrogen atmosphere at room temperature for 1 hour. The insoluble material was filtered and subsequently the filtrate was distilled off under reduced pressure to afford 211 mg of the title compound. [0171] 1H-NMR (DMSO-d6); δ (ppm) 4.80 (2H, s), 6.09-6.14 (1H, m), 6.34-6.37 (1H, m), 6.53-6.57 (1H, m), 8.93 (1H, s). [0172] MS (FAB); m/z 128 (M+H)+

Reference: [1] Patent: EP1346982, 2003, A1,
[2] Inorganic Chemistry, 2010, vol. 49, # 23, p. 11106 - 11117
[3] Patent: WO2007/146066, 2007, A2, . Location in patent: Page/Page column 80
[4] Journal of Organic Chemistry, 1951, vol. 16, p. 1345,1348
[5] J. Gen. Chem. USSR (Engl. Transl.), 1975, vol. 45, p. 2372 - 2379[6] Zhurnal Obshchei Khimii, 1975, vol. 45, # 11, p. 2414 - 2422
[7] Journal of Medicinal Chemistry, 1998, vol. 41, # 16, p. 3015 - 3021
[8] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 10, p. 3515 - 3523
[9] Patent: US5086062, 1992, A,
[10] Patent: US5149821, 1992, A,
[11] Patent: US2007/93477, 2007, A1, . Location in patent: Page/Page column 26
[12] International Journal of Mass Spectrometry, 2013, vol. 345-347, p. 120 - 131
[13] Patent: US2013/317074, 2013, A1, . Location in patent: Paragraph 0327; 0328; 0329
[14] Patent: US2014/30209, 2014, A1, . Location in patent: Paragraph 0140; 0141; 0142
[15] Patent: EP2881114, 2015, A1, . Location in patent: Paragraph 0152
[16] Patent: EP2889031, 2015, A1, . Location in patent: Paragraph 0126
[17] Patent: US2015/209301, 2015, A1, . Location in patent: Paragraph 0170-0172
[18] Archiv der Pharmazie, 2018, vol. 351, # 5,
  • 8
  • [ 394-33-2 ]
  • [ 399-97-3 ]
Reference: [1] Patent: US6262113, 2001, B1,
  • 9
  • [ 109-60-4 ]
  • [ 394-33-2 ]
  • [ 399-97-3 ]
YieldReaction ConditionsOperation in experiment
91% With sodium dithionite; potassium formate In n-heptane; water In a 500-ml flask, place 39.3 g (0.25 m) of 4-fluoro-2-nitrophenol (2a) and 120 ml of isopropyl alcohol and warm to 40° C.
Add 1.5 g of 5percent Pd/C wet with 1.5 ml of water and stir the mixture vigorously.
Add a solution of 84.1 g (1.0 m) of potassium formate in 85 ml of water in drop wise over an hour keeping the temperature at 45°-53° C.
Stir the mixture at 50° C. for 2.5 hrs.
Add 150 ml of propyl acetate and 100 ml of water and stir for a few min.
Filter off catalyst and wash with 100 ml of propyl acetate and 100 ml of water.
Separate propyl acetate solution, and wash with 150 ml water and 150 ml of brine containing 1-2 g sodium hydrosulfite.
Dry propyl acetate solution over magnesium sulfate and concentrate to approximately 75 ml.
Add 300 ml of heptane slowly with gentle stirring.
Concentrate under a reduced pressure till most of propyl acetate evaporated.
Add 150 ml of heptane to resulting mush and cool in an ice bath for about an hour.
Collect solid, wash with heptane, and dry in a vacuum oven to give 29.0 g (91percent) of 2-amino-4-fluorophenol (3a; X=F) as gray solids.
Reference: [1] Patent: US6482985, 2002, B1,
  • 10
  • [ 394-33-2 ]
  • [ 399-97-3 ]
Reference: [1] Patent: US5550125, 1996, A,
  • 11
  • [ 371-41-5 ]
  • [ 399-97-3 ]
Reference: [1] Inorganic Chemistry, 2010, vol. 49, # 23, p. 11106 - 11117
[2] International Journal of Mass Spectrometry, 2013, vol. 345-347, p. 120 - 131
  • 12
  • [ 399-97-3 ]
  • [ 135533-78-7 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 16, p. 4689 - 4693
[2] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 7, p. 1975 - 1980
[3] Journal of Medicinal Chemistry, 1994, vol. 37, # 7, p. 913 - 923
[4] Journal of Medicinal Chemistry, 1988, vol. 31, # 9, p. 1719 - 1728
[5] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 9, p. 3044 - 3049
[6] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 7, p. 798 - 803
[7] Patent: WO2016/25669, 2016, A1,
[8] Patent: WO2009/151744, 2009, A1,
  • 13
  • [ 75-15-0 ]
  • [ 399-97-3 ]
  • [ 13451-78-0 ]
YieldReaction ConditionsOperation in experiment
70% With potassium hydroxide In ethanol at 75℃; A solution of 2-amino-4-fluorophenol (10 g, 78.8 mmol), carbon disulfide (35 mL), and potassium hydroxide (5.3 g, 94.6 mmol) in ethanol (200 mL) was heated to reflux overnight. The reaction mixture was concentrated to dryness then diluted with water. This solution was neutralized with 1M HC1 then washed with ethyl acetate several times. The combined organicphases were washed with brine, dried over Na2SO4, and concentrated in vacuo giving 9.3 g (70percent yield) of the desired 5-fluorobenzo[dloxazole-2-thiol. ‘H NMR (300 MHz, DMSO-d6) ö 7.51 (ddd, J= 8.8, 4.2, 0.6 Hz, 1H), 7.15 —7.04 (m, 2H), 3.31 (brs, 1H). LC-MS (mlz): 170.2.
Reference: [1] Patent: WO2017/23941, 2017, A1, . Location in patent: Page/Page column 50; 51
[2] Journal of Medicinal Chemistry, 1994, vol. 37, # 7, p. 913 - 923
[3] Journal of Medicinal Chemistry, 1998, vol. 41, # 16, p. 3015 - 3021
[4] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 10, p. 3515 - 3523
[5] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 9, p. 3044 - 3049
  • 14
  • [ 137-26-8 ]
  • [ 399-97-3 ]
  • [ 13451-78-0 ]
YieldReaction ConditionsOperation in experiment
55%
Stage #1: With potassium carbonate In N,N-dimethyl-formamide for 0.0833333 h;
Stage #2: at 120℃; for 12 h;
General procedure: 2-Aminophenol (1.0 mmol), K2CO3 (3.0 mmol) was dissolved in DMF (3 mL) in a dried tube, equipped with a magnetic stirring bar and a septum. The mixture was stirred for 5 minutes, and then TMTD (0.6 mmol) was added. The reaction mixture was then heated at 120 °C and checked by TLC until the starting material was finished (around 12 hours). The reaction was cooled down to room temperature, and then quenched with sat. NH4Cl solution and extracted with ethyl acetate, dried over anhydrous Na2SO4 and evaporated under vacuum. The residue was purified by flash column chromatography to afford the desired product.
Reference: [1] Green Chemistry, 2017, vol. 19, # 23, p. 5591 - 5598
[2] Tetrahedron Letters, 2017, vol. 58, # 46, p. 4352 - 4356
[3] Journal of Organic Chemistry, 2018,
  • 15
  • [ 399-97-3 ]
  • [ 140-89-6 ]
  • [ 13451-78-0 ]
YieldReaction ConditionsOperation in experiment
75%
Stage #1: for 7 h; Reflux
Stage #2: With acetic acid In water
Example 32; (2S,2'S)-Dimethyl 4,4'-disulfanediyl-bis(2-(5-fluorobenzo[d]oxazol-2-ylamino) butanoate); Step 1. 5-Fluoro-2-mercaptobenzoxazole; A mixture of 2-amine-4-fluorophenol (5.0 g) and potassium ethyl xanthate (1.0 eq), dissolved in 100 mL ethanol was heated under reflux for 7 hrs. The solvent was removed in vacuum and the residue was dissolved in water. The solution was acidified to pH 5 with glacial acetic acid. The product was filtered and crystallized to obtain 5-fluoro-2-mercaptobenzoxazole (5.O g, 75percent).
Reference: [1] Patent: WO2009/151744, 2009, A1, . Location in patent: Page/Page column 118
[2] Journal of Medicinal Chemistry, 1988, vol. 31, # 9, p. 1719 - 1728
[3] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 7, p. 1975 - 1980
[4] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 16, p. 4689 - 4693
  • 16
  • [ 399-97-3 ]
  • [ 128-04-1 ]
  • [ 13451-78-0 ]
Reference: [1] European Journal of Organic Chemistry, 2018, vol. 2018, # 39, p. 5406 - 5411
  • 17
  • [ 399-97-3 ]
  • [ 35832-93-0 ]
  • [ 13451-78-0 ]
Reference: [1] Patent: WO2016/25669, 2016, A1, . Location in patent: Page/Page column 68
  • 18
  • [ 399-97-3 ]
  • [ 106-93-4 ]
  • [ 105655-00-3 ]
Reference: [1] Tetrahedron Letters, 2006, vol. 47, # 44, p. 7823 - 7826
  • 19
  • [ 399-97-3 ]
  • [ 105655-00-3 ]
Reference: [1] Archiv der Pharmazie, 2018, vol. 351, # 5,
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