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[ CAS No. 446-36-6 ] {[proInfo.proName]}

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Product Details of [ 446-36-6 ]

CAS No. :446-36-6 MDL No. :MFCD00007107
Formula : C6H4FNO3 Boiling Point : -
Linear Structure Formula :- InChI Key :QQURWFRNETXFTN-UHFFFAOYSA-N
M.W : 157.10 Pubchem ID :9937
Synonyms :

Calculated chemistry of [ 446-36-6 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 11
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 1
Num. H-bond acceptors : 4.0
Num. H-bond donors : 1.0
Molar Refractivity : 37.24
TPSA : 66.05 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) : -5.9 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.86
Log Po/w (XLOGP3) : 1.91
Log Po/w (WLOGP) : 1.86
Log Po/w (MLOGP) : 0.7
Log Po/w (SILICOS-IT) : -0.35
Consensus Log Po/w : 1.0

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.35
Solubility : 0.694 mg/ml ; 0.00442 mol/l
Class : Soluble
Log S (Ali) : -2.92
Solubility : 0.189 mg/ml ; 0.0012 mol/l
Class : Soluble
Log S (SILICOS-IT) : -1.47
Solubility : 5.34 mg/ml ; 0.034 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 2.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.65

Safety of [ 446-36-6 ]

Signal Word:Danger Class:9
Precautionary Statements:P261-P264-P270-P272-P273-P280-P301+P312+P330-P302+P352-P305+P351+P338+P310-P333+P313-P391-P501 UN#:3077
Hazard Statements:H302-H315-H317-H318-H410 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 446-36-6 ]

* 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 [ 446-36-6 ]
  • Downstream synthetic route of [ 446-36-6 ]

[ 446-36-6 ] Synthesis Path-Upstream   1~19

  • 1
  • [ 372-20-3 ]
  • [ 446-36-6 ]
  • [ 385-01-3 ]
  • [ 394-41-2 ]
YieldReaction ConditionsOperation in experiment
27% at 15 - 26℃; for 1.5 - 2 h; 3-Fluorophenol (5Og, 446mmol, lequiv) is dissolved glacial acetic acid (250 mL) and nitric acid 99percent (29.8g, 468mmol, 1.05equiv) is added slowly over approximately 1 h, maintaining the temperature at 20-250C. After complete addition, the reaction mixture is stirred for 30-60 min at ambient temperature and disappearance of 3-fluorophenol is confirmed by HPLC. The mixture is quenched by addition of water (500 mL). The resulting mixture is extracted with cyclohexane (4*67mL) to remove most of the regioisomers. The combined organic phases are extracted with water (167mL) to recover any desired regioisomer. The combined aqueous phases are extracted with TBME (3*167 mL) TBME to recover the desired product. The TBME phase, containing the desired regioisomer, is washed with a 10percent solution of sodium carbonate (4* 10OmL) to remove any acetic acid.TBME is replaced by toluene by distillation at atmospheric pressure, resulting in a solution of the product in approximately 100 mL of toluene. The solution is slowly cooled down to ambient temperature, which led to the precipitation of the desired product. The product was collected by filtration. The solid was dried in an oven overnight to give the title compound in 29percent yield and 97.9percent purity by HPLC. 1H-NMR (399.822 MHz, DMSO) δ 11.49 (s, IH), 8.07 (m, IH), 6.84-6.76 (m, 2H). 19F-NMR (376.209MHz, DMSO) δ - 114.28. m/z LCMS (ESI -ve) 156.00 (M-H); Method B: 3-Fluorophenol (1 mol equiv) is dissolved glacial acetic acid (2.5 rel vol) and nitric acid99percent (1.16 mol equiv) is added slowly over approximately 1 h, maintaining the temperature at 20-250C. After complete addition, the reaction mixture is stirred for Ih at ambient temperature and disappearance of 3-fluorophenol is confirmed by HPLC. The mixture is quenched by addition of water (2.5 rel vol). The resulting mixture is extracted 7 times with cyclohexane (1.675 rel vol) to remove most of the regioisomers. The combined organic phases are extracted with water (1 rel vol) to recover any desired regioisomer. The <n="21"/>combined aqueous phases are extracted twice with TBME (2.5 rel vol) to recover the desired product. The combined TBME phases, containing the desired regioisomer, are washed three times with a solution of 3percent aqueous potassium carbonate (1.25 rel vol) to remove any acetic acid. The TBME solution is concentrated at atmospheric pressure, then activated charcoal (0.017 rel weight) is added along with toluene (4.0 rel vol). The TBME is totally removed by atmospheric distillation. The warm solution at 50-800C is filtered over a filteraid to remove any insoluble particles. The toluene solution is then cooled to 0-50C which led to the precipitation of the desired product which was collected by filtration. The crude product was washed with toluene (0.17 rel vol) and petroleum ether (0.25 rel vol). The solid was dried in an oven overnight to give the title compound in 27percent yield and 97.4percent purity by HPLC.Crude 3-fluoro-4-nitrophenol (1 mol eq) is heated up to 110-115°C in toluene (3.24 rel vol) for 30 minutes. The mixture is cooled to 80-1000C and filtered over filteraid to remove any insoluble particles. The solution is further cooled to 0-50C which led to the precipitation of the desired product which was collected by filtration. The crude product was washed with toluene (0.17 rel vol). The solid was dried in an oven overnight to give the title compound in 77percent yield (recrystallisation only) and 99.2percent purity by HPLC. 1H-NMR (399.822 MHz, DMSO) δ 11.49 (s, IH), 8.07 (m, IH), 6.84-6.76 (m, 2H). 19F-NMR (376.209MHz, DMSO) δ -114.28. m/z LCMS (ESI -ve) 156.00 (M-H)
Reference: [1] Patent: WO2009/35407, 2009, A1, . Location in patent: Page/Page column 8; 19-20
  • 2
  • [ 446-36-6 ]
  • [ 77-78-1 ]
  • [ 448-19-1 ]
YieldReaction ConditionsOperation in experiment
94.1% With potassium carbonate In N,N-dimethyl-formamide at 60 - 100℃; In a 5L four-necked flask, DMF 2500 g, 4-fluoro-2-hydroxy nitrobenzene (500 g, 3.20 mol) and potassium carbonate (483 g, 3.50 mol) were added and heated to 60°C. 424 g (3.36 mol) of dimethyl sulfate was added dropwise for about 2-3 hours. After completion of dripping, heated to 90-100°C for 5-6 hours. Sampling GC analysis of 4-fluoro-2-hydroxy nitrobenzene was found to<0.5percent. The mixture was cooled to 50°C, generating monomethyl sulfate potassium salt. The filtrate was distilled under reduced pressure to recover DMF to give 515 g of 4-fluoro-2-methoxynitrobenzene as a yellow oily liquid. GC content of 99.5percent, yield 94.1percent.
Reference: [1] Chemical and Pharmaceutical Bulletin, 1991, vol. 39, # 9, p. 2323 - 2332
[2] Patent: CN106083536, 2016, A, . Location in patent: Paragraph 0035; 0036
[3] Heterocycles, 1992, vol. 34, # 12, p. 2301 - 2311
[4] Patent: WO2010/71885, 2010, A1, . Location in patent: Page/Page column 443
[5] Patent: WO2010/115688, 2010, A1, . Location in patent: Page/Page column 146
  • 3
  • [ 446-36-6 ]
  • [ 74-88-4 ]
  • [ 448-19-1 ]
YieldReaction ConditionsOperation in experiment
100% With potassium carbonate In N,N-dimethyl-formamide at 60℃; Cooling with ice Example 127; Preparation of 3-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-propylphenoxy)-2-methoxyphenethyl)-5-(1-(1-methylethoxy)phenyl-4-yl)-5-methylimidazolidine-2,4-dione; 127-a-1) Preparation of 4-fluoro-2-methoxy-1-nitro-benzene; A solution of 4-fluoro-2-hydroxy-1-nitrobenzene (100 mg, 0.637 mmol) in N,N-dimethylformamide (3.2 mL) was added with potassium carbonate (132 mg, 0.955 mmol), then added with methyl iodide (48 μL, 0.764 mmol) under ice-cold conditions, and stirred at room temperature for 1 hour. The reaction solution was further added with potassium carbonate (132 mg, 0.955 mmol), then with methyl iodide (48 μL, 0.764 mmol) under ice-cold conditions, and stirred at 60° C. for 1 hour. The reaction solution was added with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. 4-fluoro-2-methoxy-1-nitro-benzene (118 mg, yield >100percent) was obtained as a yellow oil.1H-NMR (CDCl3) δ: 3.97 (3H, s), 6.74 (1H, ddd, J=2.4, 7.8, 9.0 Hz), 6.80 (1H, dd, J=2.4, 10.2 Hz), 7.97 (1H, dd, J=6.1, 9.0 Hz).
99% With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 1 h; To a stirred suspension of 4-fluoro-2-hydroxy- 1-nitrobenzene(35) (100 mg, 0.64 mmol) and K2CO3(132 mg, 0.96 mmol) in DMF (3.2 mL) was added methyl iodide (108 mg, 0.76 mmol)at 0 °C. The reaction mixture was stirred at 60 °C for 1 h. The reaction mixture was diluted with waterand extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4and concentrated in vacuo to give thetitle compound (118 mg, 99percent) as a yellow oil;
99.1%
Stage #1: With potassium carbonate In acetone at 20℃; for 0.5 h; Inert atmosphere
Stage #2: at 60℃;
5-fluoro-2-nitrophenol (10 g, 63.65 mmol), potassium carbonate (8.8 g, 63.65 mmol) and acetone (100mL) wereadded in a 250 mL three-necked flask and stirred at room temperature for 30 minutes under the protection of nitrogengas. Iodomethane (9.03 g, 63.65 mmol) was then slowly added dropwise thereto, and the mixture was warmed up to60°C and reacted overnight. After the reaction was completed, the reaction solution was added with water (200 mL),extracted with ethyl acetate (100 mL 3 4), washed with 1M sodium hydroxide (100mL 3 3) and saturated brine (100mL 3 2) successively, dried over anhydrous sodium sulfate, filtered by suction and evaporated under reduced pressureto remove the solvent, to give 4-fluoro-2-methoxynitrobenzene (10.8 g, 99.1percent yield).
98%
Stage #1: With potassium carbonate In acetone at 20℃; for 0.5 h;
Stage #2: at 20 - 60℃; for 30 h;
4-fluoro-2-methoxy-1-nitro-benzene 20 g (126 mmol) 5-fluoro-2-nitro-phenol are dissolved in 300 ml acetone. 22.6 g (163 mmol) potassium carbonate are added and the mixture is stirred for 30 min at 20° C. Over a period of 10 min, 9.4 ml (150 mmol) methyl iodide, diluted in 50 ml acetone, is added and the mixture is stirred for a further 18 h at 20° C. Then it is left for another 12 h at 65° C. with stirring. The solvent is eliminated in vacuo, the residue is taken up in water and extracted three times with ethyl acetate. Then the combined organic phases are extracted three times with 10percent aqueous sodium carbonate solution. The organic phase is dried over magnesium sulphate. The solvent is eliminated in vacuo. Yield: 21.1 g (123 mmol; 98percent) UV max: 230/266/322 nm.
98% With potassium carbonate In acetonitrile at 50℃; for 3 h; (0540) 5-Fluoro-2-nitrophenol (7.85 g, 0.05 mol), iodomethane (8.52 g, 0.06 mol) and potassium carbonate (10.35 g, 0.075 mol) were added to acetonitrile (150 mL). The mixture was heated at 50° C. for 3 h, and the solvent was removed under reduced pressure. Water (200 mL) was added, and the mixture was extracted with ethyl acetate (200 mL). The organic phase was dried and concentrated to get the product (8.4 g, yield: 98percent).
97% With potassium carbonate In acetone for 4 h; Heating / reflux 5.60.1 4-Fluoro-2-methoxy-1-nitrobenzene A mixture of 5-fluoro-2-nitrophenol (5.0 g, 31.8 mmol), iodomethane (13.5 g, 95.4 mmol), and potassium carbonate (16.7 g, 159 mmol) in acetone (80 mL) was heated to reflux for 4 hours. The mixture was cooled and evaporated under vacuum, and the residue was dissolved in ethyl acetate (200 mL) and washed with water (3.x.250 mL), dried (MgSO4), and evaporated, providing 5.25 g, in 97percent yield: 1H NMR (CDCl3) δ 3.97 (s, 3H), 6.69-6.82 (m, 2H), 7.97 (dd, J=8.9 Hz, J=6.0 Hz, 1H).
96% With potassium carbonate In acetone for 3 h; Reflux To a stirred solution of   23 (0.60 g, 3.82 mmol) in   acetone (20 mL) was added   K2CO3 (1.1 g, 7.6 mmol) and   iodomethane (0.5 mL, 7.6 mmol). The reaction mixture was refluxed for 3 h and concentrated in vacuo. The residue was diluted with EtOAc, washed with water and brine and dried over Na2SO4. The suspension was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography to afford   24 as a white solid (0.63 g, 96percent).
94% With potassium carbonate In acetonitrile at 16 - 85℃; for 5 h; Step 1 : K2C03 (131 g, 955 mmol) and CH3I (66.7 mL) were added to a solution of 5-fluoro-2-nitrophenol (75.0 g, 478 mmol) in MeCN (750 mL) at rt and the resulting mixture was heated to 85°C for 5 h. The RM was chilled, filtered and washed with MeCN. The volatiles were removed under reduced pressure and the residue was diluted with water and was extracted with EtOAc. The combined organic layers were washed with water, brine, were dried and the volatiles were removed under reduced pressure to give the desired compound (75 g, 94percent).
94% With potassium carbonate In acetonitrile at 85℃; for 5 h; Step 1: K2C03 (131 g, 955 mmol) and Mel (66.7 mL) were added to a solution of 5-fluoro-2-nitrophenol (75.0 g, 478 mmol) in acetonitrile (750 mL) at rt and the resulting mixture was heated to 85 C for 5 h. The reaction mixture was chilled, filtered and washed with acetonitrile. The volatiles were removed under reduced pressure and the residue was diluted with water and was extracted with EtOAc. The combined organic layers were washed with water, brine, were dried and the volatiles were removed under reducedpressure to give the desired compound (75 g, 94percent).
92% With potassium carbonate In N,N-dimethyl-formamide at 20℃; To 2-nitro-5-fluoro-phenol (56.0 g, 357 mmol) and iodomethane (24.5 mL, 393 mmol) in DMF (200 mL) was added K2CO3 (54.2 g, 393 mmol). Significant bubbling occurred. The mixture was stirred at rt overnight. The mixture was poured into H2O (800 mL) and the H2O washed with diethyl ether (3.x.200 mL). The ether washes were combined and washed with H2O (2.x.400 mL). The ether layer was dried (MgSO4), filtered, and rotovaped down to give the title compound (56.0 g, 327 mmol, 92percent) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 7.96-7.90 (m, 1H), 6.79-6.67 (m, 2H), 3.93 (s, 3H).
92% With potassium carbonate In N,N-dimethyl-formamide at 20℃; Inert atmosphere To 2-nιtro-5-fluoro-phenol (56 0 g, 357 mmol) and iodomethane (24 5 mL, 393 mmol) in DMF (200 mL) was added K2CO3 (54 2 g, 393 mmol) Significant bubbling occurred The mixture was stirred at rt overnight The mixture was poured into H2O (800 mL) and the H2O washed with ether (3 x 200 mL) The ether washes were combined and washed with H2O (2 x 400 mL) The ether layer was dried (MgSO4), filtered, and rotovaped down to give the title compound of step A (56 0 g, 327 mmol, 92 percent) as a yellow solid 1H-NMR (400 MHz, CDCI3) δ 7 96 - 7 90 (m, 1 H), 6 79 - 6 67 (m, 2 H) and, 3 93 (s, 3 H)
88% With potassium carbonate In acetone at 20℃; for 96 h; Methyl iodide (11.94 mL, 191 mmol) was added dropwise to a stirred suspension of 5-fluoro-2-nitrophenol (10 g, 63.7 mmol) and potassium carbonate (17.59 g, 127 mmol) in acetone (318 mL) at room temperature. The reaction mixture was allowed to stir at room temperature for 4 days, whereupon the acetone was evaporated under reduced pressure and the residue was partitioned between water and ethyl acetate. The aqueous layer was neutralised with concentrated hydrochloric acid. The organic layer was separated, washed with water and brine, dried (MgSO.)), filtered and evaporated to give an off-white solid that was recrystallised from isopropanol/dichloromethane to give 4-fiuoro-2-methoxy-l- nitrobenzene as an off-white solid (9.6 g, 88percent).
38% With potassium carbonate In N,N-dimethyl-formamide at 140℃; for 23 h; A mixture of commercially available 5-fluoro-2-nitrophenol (1.00 g, 6.37 mmol), MeI (1.36 g, 9.58 mmol), and potassium carbonate (1.32 g, 9.55 mmol) in DMF (10 mL) was heated at 140° C. for 23 hours. The reaction was diluted with aq. 0.5 N NaOH (50 mL) and extracted with EtOAc (2.x.50 mL). The EtOAc-extracts were washed once more with aq. 0.5 N NaOH (50 mL). The combined organic layers were dried (Na2SO4), filtered, and evaporated to dryness in vacuo. The crude product was purified by flash column chromatography (EtOAc/heptane: 1/1) to obtain 4-fluoro-2-methoxy-nitrobenzene (416 mg, 38percent, purity (GC)>95percent).MS: [M]+=171.
26% With potassium carbonate In N,N-dimethyl-formamide at 140℃; Sealed pressure flask 4-Fluoro-2-methoxy-l-nitro-benzene was synthesized by suspending 5-fluoro-2-nitrophenol (5.0 g, 31.8 mmol, 1.0 equiv.), potassium carbonate (6.59 g, 47.7 mmol, 1.5 equiv.), and Iodomethane (2.98 mL, 47.7 mmol, 1.5 equiv.) in DMF (50 mL) and allowing the resulting reaction mixture to stir overnight at 14O0C inside a sealed pressure flask. The reaction mixture was partitioned between ethyl acetate and distilled water three times. The organic layer was washed once with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo. The product was isolated by column chromatography in 30percent ethyl acetate and hexanes as a yellow solid (1.44 g, 26percent). 1H NMR (300 MHz, CDCl3): δ(pρm) 7.98(dd, IH), 6.77(m, 2H), 3.99(s, 3H).
9.7% With potassium carbonate In ethanol for 12 h; Heating / reflux Potassium carbonate(14.5 g, 105.1 mol) and iodomethane(7.1 ml, 114.6 mmol) were added to a solution of 2-nitro-5-fluorophenol(15 g, 95.5 mmol) in ethanol (100 ml), which was then refluxed for 12 hours. The resulting solid was filtered, washed with ethanol, and concentrated. The resulting oily residue was diluted with ethyl acetate and washed with water. The separated organic layer was concentrated and the residual oil was purified by column chromatography(ethylacetate/hexane=1/3) to give 1.65 g of the titled compound. (Yield 9.7percent).
NMR (CDCl3): 4.0 (s, 3H), 6.8 (m, 2H), 8.0 (m, 1H).
4.5 g
Stage #1: With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 1 h;
Stage #2: at 60℃; for 2 h;
To a solution of 4-fluoro-2-hydroxy-l -nitrobenzene (5.0 g, 31.8 mmol) in DMF (10 mL) was added K2CO3 (13.1 g, 95.4 mmol). The reaction mixture was stirred at RT for 1 h followed by addition of methyl iodide (9.93 g, 69.9 mmol) and the reaction mixture was stirred at 60 C for 2 h. The reaction mass was concentrated and quenched in water. The reaction mass was basified with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 4.5 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.93 (s, 3H), 6.97 (t, J= 7.8 Hz, 1H), 7.31 (d, J = 8.7 Hz, 1H), 8.02 (s, 1H).

Reference: [1] Patent: US2010/48610, 2010, A1, . Location in patent: Page/Page column 73
[2] Journal of the American Chemical Society, 2009, vol. 131, # 38, p. 13860 - 13869
[3] Journal of Medicinal Chemistry, 2013, vol. 56, # 17, p. 7025 - 7048
[4] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 16, p. 3436 - 3446
[5] Patent: EP3381925, 2018, A1, . Location in patent: Paragraph 0159;
[6] Patent: US2006/46990, 2006, A1, . Location in patent: Page/Page column 6
[7] Patent: US2017/112833, 2017, A1, . Location in patent: Paragraph 0539-0540
[8] Journal of Molecular Structure, 2017, vol. 1147, p. 266 - 280
[9] Patent: US2007/49618, 2007, A1, . Location in patent: Page/Page column 82
[10] European Journal of Medicinal Chemistry, 2013, vol. 68, p. 233 - 243
[11] Patent: WO2015/22073, 2015, A1, . Location in patent: Page/Page column 52
[12] Patent: WO2015/90580, 2015, A1, . Location in patent: Page/Page column 32
[13] Patent: US2008/300242, 2008, A1, . Location in patent: Page/Page column 51
[14] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 3, p. 1004 - 1008
[15] Patent: WO2010/104899, 2010, A1, . Location in patent: Page/Page column 143
[16] Patent: WO2009/84970, 2009, A1, . Location in patent: Page/Page column 73
[17] Patent: US2010/280268, 2010, A1, . Location in patent: Page/Page column 48
[18] Patent: WO2006/71730, 2006, A1, . Location in patent: Page/Page column 78
[19] Patent: US6352993, 2002, B1, . Location in patent: Page column 29-30
[20] Journal of Medicinal Chemistry, 1997, vol. 40, # 17, p. 2674 - 2687
[21] Patent: US2003/93866, 2003, A1,
[22] Patent: US6455528, 2002, B1,
[23] Patent: US2004/97589, 2004, A1,
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[32] Patent: WO2018/45104, 2018, A1, . Location in patent: Paragraph 00125
  • 4
  • [ 446-36-6 ]
  • [ 448-19-1 ]
YieldReaction ConditionsOperation in experiment
100% With potassium carbonate; dimethyl sulfate In acetone at 20℃; for 24 h; A mixture of 5-fluoro-2-nitrophenol (3.0 g, 19.1 mmol), potassium carbonate (2.50 g, 21.0 mmol) and dimethyl sulfate (2.65 g, 21.0 mmol) in acetone was stirred at ambient temperature for 24 hours. The solvents were removed under reduced pressure and then water (30 mL) and dichloromethane (30 mL) was added to the residue. The combined organics solutions were dried over magnesium sulfate then filtered and the filtrate concentrated under reduced pressure to provide an oil. This was purified by flash chromatography on silica gel using dichloromethane/heptane (7:3) as an eluent to provide the title compound as a crystalline solid (3.24 g, 100percent): 1H NMR (CDCl3, 400 MHz) δ7.96 (M, 1H), 6.80 (m, 1H), 6.73 (m, 1H), 3.96 (s, 3H); RP-HPLC (Hypersil HS C18, 5 μm, 100A, 250.x.4.6 mm; 5percent-100percent acetonitrile-0.05 M ammonium acetate over 25 min, 1 mL/min) tr 17.82 min; MS:MH+ 172.2
Reference: [1] Patent: US2003/225098, 2003, A1, . Location in patent: Page 28 - 29
  • 5
  • [ 372-20-3 ]
  • [ 446-36-6 ]
  • [ 385-01-3 ]
  • [ 394-41-2 ]
YieldReaction ConditionsOperation in experiment
27% at 15 - 26℃; for 1.5 - 2 h; 3-Fluorophenol (5Og, 446mmol, lequiv) is dissolved glacial acetic acid (250 mL) and nitric acid 99percent (29.8g, 468mmol, 1.05equiv) is added slowly over approximately 1 h, maintaining the temperature at 20-250C. After complete addition, the reaction mixture is stirred for 30-60 min at ambient temperature and disappearance of 3-fluorophenol is confirmed by HPLC. The mixture is quenched by addition of water (500 mL). The resulting mixture is extracted with cyclohexane (4*67mL) to remove most of the regioisomers. The combined organic phases are extracted with water (167mL) to recover any desired regioisomer. The combined aqueous phases are extracted with TBME (3*167 mL) TBME to recover the desired product. The TBME phase, containing the desired regioisomer, is washed with a 10percent solution of sodium carbonate (4* 10OmL) to remove any acetic acid.TBME is replaced by toluene by distillation at atmospheric pressure, resulting in a solution of the product in approximately 100 mL of toluene. The solution is slowly cooled down to ambient temperature, which led to the precipitation of the desired product. The product was collected by filtration. The solid was dried in an oven overnight to give the title compound in 29percent yield and 97.9percent purity by HPLC. 1H-NMR (399.822 MHz, DMSO) δ 11.49 (s, IH), 8.07 (m, IH), 6.84-6.76 (m, 2H). 19F-NMR (376.209MHz, DMSO) δ - 114.28. m/z LCMS (ESI -ve) 156.00 (M-H); Method B: 3-Fluorophenol (1 mol equiv) is dissolved glacial acetic acid (2.5 rel vol) and nitric acid99percent (1.16 mol equiv) is added slowly over approximately 1 h, maintaining the temperature at 20-250C. After complete addition, the reaction mixture is stirred for Ih at ambient temperature and disappearance of 3-fluorophenol is confirmed by HPLC. The mixture is quenched by addition of water (2.5 rel vol). The resulting mixture is extracted 7 times with cyclohexane (1.675 rel vol) to remove most of the regioisomers. The combined organic phases are extracted with water (1 rel vol) to recover any desired regioisomer. The <n="21"/>combined aqueous phases are extracted twice with TBME (2.5 rel vol) to recover the desired product. The combined TBME phases, containing the desired regioisomer, are washed three times with a solution of 3percent aqueous potassium carbonate (1.25 rel vol) to remove any acetic acid. The TBME solution is concentrated at atmospheric pressure, then activated charcoal (0.017 rel weight) is added along with toluene (4.0 rel vol). The TBME is totally removed by atmospheric distillation. The warm solution at 50-800C is filtered over a filteraid to remove any insoluble particles. The toluene solution is then cooled to 0-50C which led to the precipitation of the desired product which was collected by filtration. The crude product was washed with toluene (0.17 rel vol) and petroleum ether (0.25 rel vol). The solid was dried in an oven overnight to give the title compound in 27percent yield and 97.4percent purity by HPLC.Crude 3-fluoro-4-nitrophenol (1 mol eq) is heated up to 110-115°C in toluene (3.24 rel vol) for 30 minutes. The mixture is cooled to 80-1000C and filtered over filteraid to remove any insoluble particles. The solution is further cooled to 0-50C which led to the precipitation of the desired product which was collected by filtration. The crude product was washed with toluene (0.17 rel vol). The solid was dried in an oven overnight to give the title compound in 77percent yield (recrystallisation only) and 99.2percent purity by HPLC. 1H-NMR (399.822 MHz, DMSO) δ 11.49 (s, IH), 8.07 (m, IH), 6.84-6.76 (m, 2H). 19F-NMR (376.209MHz, DMSO) δ -114.28. m/z LCMS (ESI -ve) 156.00 (M-H)
Reference: [1] Patent: WO2009/35407, 2009, A1, . Location in patent: Page/Page column 8; 19-20
  • 6
  • [ 372-20-3 ]
  • [ 446-36-6 ]
  • [ 394-41-2 ]
Reference: [1] Journal of the Chemical Society, 1928, p. 1881
[2] Journal of the Chemical Society, 1925, vol. 127, p. 1602[3] Journal of the Chemical Society, 1926, p. 159
  • 7
  • [ 446-36-6 ]
  • [ 74-88-4 ]
  • [ 16292-95-8 ]
Reference: [1] Patent: WO2018/45106, 2018, A1, . Location in patent: Paragraph 00100
  • 8
  • [ 446-36-6 ]
  • [ 16292-95-8 ]
Reference: [1] European Journal of Medicinal Chemistry, 2013, vol. 68, p. 233 - 243
[2] Patent: US2017/112833, 2017, A1,
[3] Patent: WO2018/45104, 2018, A1,
  • 9
  • [ 446-36-6 ]
  • [ 704-14-3 ]
YieldReaction ConditionsOperation in experiment
93% With hydrogenchloride; sodium methylate In methanol Part A
5-Fluoro-2-nitrophenol (5.00 g, 31.8 mmol) and methanol (120 mL) were combined and the mixture was treated with sodium methoxide (4.6 mL, 190.8 mmol, 25percent w/w solution in MeOH).
The reaction mixture was heated at 60° C. for 40 h.
The mixture was transferred to a separatory funnel containing cold 1 N HCl and the aqueous layer was extracted with EtOAc (3*).
The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to afford 5-methoxy-2-nitrophenol (5.0 g, 93percent yield) as a yellow solid: mp 93.0-94.0° C., 1H NMR (300 MHz, CDCl3): δ 11.05 (s, 1H), 8.03 (d, J=10.3 Hz, 1H), 6.55-6.51 (m, 2H), 3.89 (s, 3H).
Reference: [1] Patent: US2003/171380, 2003, A1,
  • 10
  • [ 446-36-6 ]
  • [ 450-91-9 ]
Reference: [1] Journal of Medicinal Chemistry, 1997, vol. 40, # 17, p. 2674 - 2687
[2] Heterocycles, 1992, vol. 34, # 12, p. 2301 - 2311
[3] Patent: CN106083536, 2016, A,
  • 11
  • [ 446-36-6 ]
  • [ 450-88-4 ]
Reference: [1] Patent: CN106083536, 2016, A,
  • 12
  • [ 446-36-6 ]
  • [ 345-25-5 ]
Reference: [1] Journal of the Chemical Society, 1949, p. 3437
  • 13
  • [ 446-36-6 ]
  • [ 53981-24-1 ]
YieldReaction ConditionsOperation in experiment
94% With hydrogen In ethanol for 1.5 h; Intermediate 13
2-Amino-5-fluorophenol
A solution of 5-fluoro-2-nitrophenol (commercially available, for example, from Aldrich) (2.50 g, 15.9 mmol) in ethanol (50 ml) was hydrogenated over 10percent palladium on carbon (980 mg) for 1.5 h. The catalyst was removed by filtration and the filtrate was concentrated. The solid residue was taken up in ether and an equal volume of cyclohexane was added. Removal of ether in vac at room temperature afforded a pale grey solid which was filtered and washed with cyclohexane (1.90 g, 94percent). Found: C, 56.4; H, 4.8; N, 10.9. C6H6FNO requires C, 56.7; H, 4.8; N, 1 1.0percent.
93% With hydrogen In ethanol a.
2-amino-5-fluorophenol
To 500 mg of 10percent palladium on carbon in a Parr bottle with 50 ml of anhydrous ethanol was added a solution of 10 g (64 mmol) 5-fluoro-2-nitrophenol in 150 ml ethanol.
The flask was evacuated, charged with hydrogen and shaken on a Parr apparatus for 1 hour.
The catalyst was removed by filtration through Celite.(R). and the filtrate was evaporated to dryness in vacuo to give 7.54 g (93percent yield) of a dark solid shown to be the desired product by 1 H NMR.
93% With hydrogen In ethanol a.
2-amino-5-fluorophenol
To 500 mg of 10percent palladium on carbon in a Parr bottle containing 50 ml of anhydrous ethanol was added a solution of 10 g (64 mmol) 5-fluoro-2-nitrophenol in 150 ml ethanol.
The flask was evacuated, charged with hydrogen and shaken on a Parr apparatus for 1 hour.
The catalyst was removed by filtration through.
Celite.(R). and the filtrate was evaporated to dryness in vacuo to give 7.54 g (93percent yield) of a dark solid.
82% With 10% palladium on activated carbon; Degussa type; hydrogen In methanol for 3 h; To a of solution of 5-fluoro-2-nitrophenol (6.37 mmol, 1.00 g) in methanol (100 mL), 10percent palladium on activated carbon (10 wtpercent of 5-fluoro-2-nitrophenol, 0.10 g) was added. The reaction was flushed with argon followed by hydrogen for fifteen minutes each with constant magnetic stirring. The reaction was then maintained under hydrogen atmosphere at ordinary pressure (15 psi) for three hours. Argon was again flushed through the reaction vessel for 15 minutes. Then the reaction contents were filtered over a thin pad of celite which was then washed with methanol (70 mL). The filtrate was concentrated in vacuo yielding a brown solid. Silica gel column chromatography (10:1 hexanes/chlorofrom) provided a crystalline orange solid in an 82percent yield.
44%
Stage #1: at 20℃;
Stage #2: With sodium hydrogencarbonate In dichloromethane; water
Example 62; 6-Fluoro-2-(4-(pyddin-2-yl)but-3-3Dyl)benzordloxazole ;62 (A) ;2-Amino-5-fluorophenol; A suspension of 3-fluoro-6-nitrophenol (500 mg, 3.18 mmol) and zinc (2.10 g, 31.8 mmol) in acetic acid (7.3 mL) was stirred overnight at room temperature. The reaction mixture was filtered through celite and washed with DCM. After evaporation and distillation under vacuum (2.10-2 mbar) of the solvents, the residue was dissolved in DCM. The organic phase was washed with a saturated solution of NaHC03 and brine, dried over MgS04, filtered and evaporated. The crude residue was purified by flash chromatography (DCM/MeOH 99.5: 0.5) to yield 177 mg (1.39 mmol, 44percent) of 2- amino-5-fluorophenol as an orange solid.
21.6 g With 10% palladium on activated carbon; Degussa type; hydrogen In ethanol at 20℃; Inert atmosphere To 5-fluoro-2-nitrophenol (26.63 g, 170 mmol) in Ethanol (250 ml) under N2 atmosphere was added palladium on carbon (10 wt percent, 250 mg, 0.235 mmol). The mixture was flushed with H2 and stirred at RT under H2 (balloon) until complete conversion according to thin layer chromatography (TLC) analysis. Pd/C was removed by filtration and the filtrate was concentrated to yield 21.6 g of the title compound. [0535] 1H NMR (DMSO): 4.5 (br, 2H); 6.35 (dd, 1H); 6.45 (dd, 1H); 6.50 (dd, 1H); 9.5 (br, 1H).

Reference: [1] Journal of Medicinal Chemistry, 2015, vol. 58, # 24, p. 9742 - 9753
[2] Patent: WO2010/94643, 2010, A1, . Location in patent: Page/Page column 46
[3] Patent: US5238908, 1993, A,
[4] Patent: US5393735, 1995, A,
[5] Chemistry - A European Journal, 2011, vol. 17, # 33, p. 9076 - 9082
[6] Patent: WO2005/85202, 2005, A1, . Location in patent: Page/Page column 53
[7] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 15, p. 3521 - 3525
[8] Advanced Synthesis and Catalysis, 2010, vol. 352, # 11-12, p. 1834 - 1840
[9] Patent: US5886044, 1999, A,
[10] Patent: US5780483, 1998, A,
[11] Patent: US6262113, 2001, B1,
[12] Patent: WO2005/123703, 2005, A2, . Location in patent: Page/Page column 121-122
[13] Collection of Czechoslovak Chemical Communications, 1994, vol. 59, # 9, p. 2119 - 2122
[14] Patent: US6136831, 2000, A,
[15] Patent: EP2172453, 2010, A1, . Location in patent: Page/Page column 14-15
[16] Patent: WO2010/145992, 2010, A1, . Location in patent: Page/Page column 87; 88
[17] Patent: WO2011/57935, 2011, A1, . Location in patent: Page/Page column 67
[18] Patent: WO2012/41789, 2012, A1, . Location in patent: Page/Page column 77
[19] Patent: WO2012/80239, 2012, A1, . Location in patent: Page/Page column 69
[20] Patent: US2013/267417, 2013, A1, . Location in patent: Paragraph 0533-0535
[21] Journal of Materials Chemistry A, 2017, vol. 5, # 22, p. 10986 - 10997
[22] Archiv der Pharmazie, 2018, vol. 351, # 5,
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  • [ 148583-65-7 ]
Reference: [1] Journal of Medicinal Chemistry, 1998, vol. 41, # 12, p. 1997 - 2009
[2] Patent: WO2013/152198, 2013, A1,
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  • [ 135838-04-9 ]
Reference: [1] Chemical Communications, 2006, # 18, p. 1941 - 1943
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  • [ 446-36-6 ]
  • [ 122833-04-9 ]
Reference: [1] European Journal of Medicinal Chemistry, 2014, vol. 77, p. 75 - 83
  • 17
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  • [ 103361-99-5 ]
Reference: [1] Tetrahedron, 2011, vol. 67, # 6, p. 1187 - 1192
[2] Patent: WO2011/151361, 2011, A1,
[3] Patent: WO2013/153539, 2013, A1,
[4] Patent: WO2014/122674, 2014, A1,
[5] European Journal of Medicinal Chemistry, 2017, vol. 132, p. 90 - 107
[6] Journal of Agricultural and Food Chemistry, 2017, vol. 65, # 26, p. 5278 - 5286
[7] Archiv der Pharmazie, 2018, vol. 351, # 5,
[8] Patent: CN108727367, 2018, A,
  • 18
  • [ 446-36-6 ]
  • [ 944317-92-4 ]
Reference: [1] Patent: CN106083536, 2016, A,
  • 19
  • [ 446-36-6 ]
  • [ 1213269-23-8 ]
Reference: [1] European Journal of Medicinal Chemistry, 2014, vol. 77, p. 75 - 83
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