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[ CAS No. 288385-88-6 ] {[proInfo.proName]}

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Chemical Structure| 288385-88-6
Chemical Structure| 288385-88-6
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Product Details of [ 288385-88-6 ]

CAS No. :288385-88-6 MDL No. :MFCD07368140
Formula : C9H8FNO Boiling Point : -
Linear Structure Formula :- InChI Key :UMWRMOYYUHIPDT-UHFFFAOYSA-N
M.W : 165.16 Pubchem ID :10352036
Synonyms :

Calculated chemistry of [ 288385-88-6 ]

Physicochemical Properties

Num. heavy atoms : 12
Num. arom. heavy atoms : 9
Fraction Csp3 : 0.11
Num. rotatable bonds : 0
Num. H-bond acceptors : 2.0
Num. H-bond donors : 2.0
Molar Refractivity : 45.25
TPSA : 36.02 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.75 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.72
Log Po/w (XLOGP3) : 2.19
Log Po/w (WLOGP) : 2.74
Log Po/w (MLOGP) : 1.65
Log Po/w (SILICOS-IT) : 2.9
Consensus Log Po/w : 2.24

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.8
Solubility : 0.263 mg/ml ; 0.00159 mol/l
Class : Soluble
Log S (Ali) : -2.58
Solubility : 0.434 mg/ml ; 0.00263 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.37
Solubility : 0.0711 mg/ml ; 0.000431 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.67

Safety of [ 288385-88-6 ]

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 [ 288385-88-6 ]

* 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 [ 288385-88-6 ]
  • Downstream synthetic route of [ 288385-88-6 ]

[ 288385-88-6 ] Synthesis Path-Upstream   1~7

  • 1
  • [ 288385-98-8 ]
  • [ 288385-88-6 ]
YieldReaction ConditionsOperation in experiment
61% With ammonium formate In methanol at 20℃; To a solution of compound E from previous step (20.00 g, 66.03. 30 mmol) in methanol under a nitrogen atmosphere (300 ml) at room temperature in the absence of light were added 10 percent Pd/C (2.0 g) and ammonium formate (60.0 g, 0.95 mol). The reaction mixture was stirred for 3.5 h and then diluted with ethyl acetate (200 ml) and filtered through a Celite/silica gel pad. The residue can then be purified by either of the following methods: After concentration in vacuo, the resulting residue was purified by chromatography eluting with 30 percent ethyl acetate/hexanes to afford (7.32 g, 67 percent) of the desired compound as a white solid after trituration with dichloromethane/hexanes. After concentration in vacuo, the residue was dissolved in dichloromethane and passed through a silica gel pad washing with dichloromethane. The filtrate was concentrated in vacuo to afford (6.66 g, 61 percent) of the title compound as a white solid
30% With acetic acid In ethanol; ethyl acetate A solution of 3-acetylmethyl-1-benzyloxy-2-fluoro-4-nitrobenzene (300 mg, 0.99 mmol) in ethanol (10 ml) and acetic acid (1 ml) containing 10percent palladium on charcoal (30 mg) was hydrogenated at 2 atmospheres pressure for 2 hours.
The mixture was filtered and the filtrate was evaporated.
The residue was dissolved in ethyl acetate and the organic layer was washed with aqueous sodium hydrogen carbonate, brine and evaporated to give 4-fluoro-5-hydroxy-2-methylindole.
The residue was purified by column chromatography eluding with ethyl acetate/petroleum ether (3/7) to give 4-fluoro-5-hydroxy-2-methylindole (63 mg, 30percent).
MS-ESI: 166 [MH]+
1H NMR Spectrum: (DMSOd6) 2.35 (s, 3H); 6.05 (s, 1H); 6.65 (dd, 1H); 6.9 (d, 1H); 8.75 (s, 1*); 10.9 (s, 1H)
13C NMR Spectrum: (DMSOd6) 13.5; 94,0; 106,0; 112; 118.5 (d); 132 (d); 136 (d), 136.5; 142.5 (d)
30% With acetic acid In ethanol; ethyl acetate A solution of 3-acetylmethyl-1-benzyloxy-2-fluoro-4-nitrobenzene (300 mg, 0.99 mmol) in ethanol (10 ml) and acetic acid (1 ml) containing 10percent palladium on charcoal (30 mg) was hydrogenated at 2 atmospheres pressure for 2 hours.
The mixture was filtered and the filtrate was evaporated.
The residue was dissolved in ethyl acetate and the organic layer was washed with aqueous sodium hydrogen carbonate, brine and evaporated to give 4-fluoro-5-hydroxy-2-methylindole.
The residue was purified by column chromatography eluding with ethyl acetate/petroleum ether (317) to give 4-fluoro-5-hydroxy-2-methylindole (63 mg, 30percent).
MS-ESI: 166 [MH]+
1H NMR Spectrum: (DMSOd6) 2.35 (s, 3H); 6.05 (s, 1H); 6.65 (dd, 1H); 6.9 (d, 1H); 8.75 (s, 1H); 10.9 (s, 1H)
13C NMR Spectrum: (DMSOd6) 13.5; 94,0; 106,0; 112; 118.5 (d); 132 (d); 136 (d); 136.5; 142.5 (d)
Reference: [1] Patent: WO2004/9542, 2004, A2, . Location in patent: Page 36
[2] Patent: US2003/207878, 2003, A1,
[3] Patent: US2003/212055, 2003, A1,
  • 2
  • [ 288385-93-3 ]
  • [ 288385-88-6 ]
YieldReaction ConditionsOperation in experiment
70% With boron tribromide In dichloromethane To a solution of 4-fluoro-5-methoxy-2-methylindole (709 mg, 3.95 mmol) in methylene chloride (9 ml) cooled at -30° C. was added a solution of boron tribromide (2.18 g, 8.7 mmol) in methylene chloride (1 ml).
After stirring for 1 hour at ambient temperature, the mixture was poured onto water and was diluted with methylene chloride.
The pH of the aqueous layer was adjusted to 6.
The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated.
The residue was purified by column chromatography, eluding with ethyl acetate/petroleum ether (3/) to give 4-fluoro-5-hydroxy-2-methylindole (461 mg, 70percent).
MS-ESI: 166 [MH]+
1H NMR Spectrum: (DMSOd6) 2.35 (s, 3H); 6.05 (s, 1H); 6.65 (dd, 1H); 6.9 (d, 1H); 8.75 (s,1); 10.9 (s, 1H)
13C NMR Spectrum: (DMSOd6) 13.5; 94,0; 106,0; 112; 118.5 (d); 132 (d); 136 (d); 136.5; 142.5 (d)
70% With boron tribromide In dichloromethane To a solution of 4-fluoro-5-methoxy-2-methylindole (709 mg, 3.95 mmol) in methylene chloride (9 ml) cooled at -30° C. was added a solution of boron tribromide (2.18 g, 8.7 mmol) in methylene chloride (1 ml).
After stirring for 1 hour at ambient temperature, the mixture was poured onto water and was diluted with methylene chloride.
The pH of the aqueous layer was adjusted to 6.
The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated.
The residue was purified by column chromatography, eluding with ethyl acetate/petroleum ether (3/7) to give 4-fluoro-5-hydroxy-2-methylindole (461 mg, 70percent).
MS-ESI: 166 [MH]+
1H NMR Spectrum: (DMSOd6) 2.35 (s, 3H); 6.05 (s, 1H); 6.65 (dd, 1H); 6.9 (d, 1H); 8.75 (s, 1H); 10.9 (s, 1H)
13C NMR Spectrum: (DMSOd6) 13.5; 94,0; 106,0; 112; 118.5 (d); 132 (d); 136 (d); 136.5; 142.5 (d)
70% With boron tribromide In dichloromethane To a solution of 4-fluoro-5-methoxy-2-methylindole (709 mg, 3.95 mmol) in methylene chloride (9 ml) cooled at -30° C. was added a solution of boron tribromide (2.18 g, 8.7 mmol) in methylene chloride (1 ml).
After stirring for 1 hour at ambient temperature, the mixture was poured onto water and was diluted with methylene chloride.
The pH of the aqueous layer was adjusted to 6.
The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated.
The residue was purified by column chromatography, eluding with ethyl acetate/petroleum ether (3/7) to give 4-fluoro-5-hydroxy-2-methylindole (461 mg, 70percent).
MS-ESI: 166 [MH]+
1H NMR Spectrum: (DMSOd6) 2.35 (s, 3H); 6.05 (s, 1H); 6.65 (dd, 1H); 6.9 (d, 1H); 8.75 (s, 1H); 10.9 (s, 1H)
13C NMR Spectrum: (DMSOd6) 13.5; 94,0; 106,0; 112; 118.5 (d); 132 (d); 136 (d); 136.5; 142.5 (d)
Reference: [1] Patent: US2003/199491, 2003, A1,
[2] Patent: US2003/212055, 2003, A1,
[3] Patent: US2003/207878, 2003, A1,
[4] Patent: US2003/199491, 2003, A1,
[5] Patent: US2003/212055, 2003, A1,
[6] Patent: US2003/207878, 2003, A1,
  • 3
  • [ 649736-31-2 ]
  • [ 288385-88-6 ]
YieldReaction ConditionsOperation in experiment
81% With sodium dithionite In water at 0 - 30℃; for 1 h; 1-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one from previous step (50 g, 0.234 mol) was added to 2 liter round bottom flask. Water (1L) was added, and the yellow suspension was stirred at Rt. Sodium dithionite (225 g, 5.5 eq) was added in one portion and the reaction mixture was stirred and kept < 30 C until HPLC analysis indicated no starting material remained (typically less than 1 hour). Upon completion, the reaction mixture was cooled to 0 C and the tan solid product was collected by vacuum filtration. The wet product was dried at <50 C under house vacuum to afford 4-fluoro-2-methyl-1H-indol-5-ol (31.4 g, 81 percent yield) which was isolated as a tan crystalline powder. The material had an HPLC purity of >99.8. 1H NMR (CDC3, 400 MHz) δ 7.8 (s, 1H), 6.9-6.7 (m, 2H), 6.2 (s, 1H), 4.7 (s, 1H), 2.4 (s, 3H). 13 C NMR (CDCl3, 100 MHz) δ 145.7, 143.4, 137.5, 136.7, 134.4, 120.1, 112.7, 106.8, 95.4, 13.3
68% With sodium dithionite; potassium carbonate In water at 25℃; for 2 h; Industry scale Preparation of 4-fluoro-2 -methyl- lH-indol-5-ol (large scale)To a solution of potassium carbonate (79 kg) in water (800 kg) was added l-(2-fluoro-3- hydroxy-6-nitrophenyl)-propan-2-one (61 kg) and the mixture stirred to give a solution. To this solution at 250C was added a solution of sodium dithionite (298 kg) in water (750 kg).The mixture was held at 250C for 2 hours. The product was isolated by filtration, washing the filter cake with water (366 kg). The product was dried under reduced pressure (50 mbar) at350C. Yield: 34 kg, 72percent. The crude 4-fluoro-2-methyl-lH-indol-5-ol (33 kg) was dissolved in dichloromethane(880 1) and filtered through silica (33 kg). The filter was washed with dichloromethane (4401). The combined filtrates were distilled, removing 835 1 of distillate. This concentrate was EPO <DP n="43"/>added rapidly to σhexane (360 kg), resulting in a suspension. The batch was distilled, removing 436 1 of distillate. The batch was cooled to 00C, aged for 1 hour and then filtered. The filter cake was washed with /soehexane (73 kg). The product was dried under reduced pressure (50 mbar) at 35°C. Yield: 31 kg, 68percent based on l-(2-fluoro-3-hydroxy-6- s nitrophenyl)-propan-2-one.
17% With hydrogen In ethanol at 20℃; for 8 h; Step 3c:
4-Fluoro-2-methyl-1H-indol-5-ol (Compound 304)
A mixture of 303 (900 mg, 4.2 mmol), Pd/C (90 mg) and ethanol (20 mL) was stirred under H2 at ambient temperature for 8 h.
The solvent was removed and the residue was purified by column chromatography on silica gel (EtOAc/petroleum ether=1/15) to give the title compound 304 as a brown solid (120 mg, 17percent): LCMS: 166 [M+1]+; 1H NMR (DMSO-d6): δ 2.34 (s, 3H), 6.05 (s, 1H), 6.64 (t, J=8.4 Hz, 1H), 6.86 (d, J=8.4 Hz, 1H), 8.70 (s, 1H), 10.84 (s, 1H).
Reference: [1] Patent: WO2004/9542, 2004, A2, . Location in patent: Page 35
[2] Organic Process Research and Development, 2014, vol. 18, # 1, p. 89 - 102
[3] Patent: WO2008/53221, 2008, A2, . Location in patent: Page/Page column 41-42
[4] Patent: US2009/76044, 2009, A1, . Location in patent: Page/Page column 28
[5] Patent: WO2008/53221, 2008, A2, . Location in patent: Page/Page column 39-40
[6] Patent: WO2004/9542, 2004, A2, . Location in patent: Page 26
  • 4
  • [ 771-69-7 ]
  • [ 288385-88-6 ]
Reference: [1] Organic Process Research and Development, 2014, vol. 18, # 1, p. 89 - 102
[2] Chinese Chemical Letters, 2015, vol. 26, # 9, p. 1165 - 1168
  • 5
  • [ 1022112-32-8 ]
  • [ 288385-88-6 ]
Reference: [1] Organic Process Research and Development, 2014, vol. 18, # 1, p. 89 - 102
[2] Chinese Chemical Letters, 2015, vol. 26, # 9, p. 1165 - 1168
  • 6
  • [ 121247-16-3 ]
  • [ 288385-88-6 ]
Reference: [1] Organic Process Research and Development, 2014, vol. 18, # 1, p. 89 - 102
[2] Chinese Chemical Letters, 2015, vol. 26, # 9, p. 1165 - 1168
  • 7
  • [ 288385-99-9 ]
  • [ 288385-88-6 ]
Reference: [1] Organic Process Research and Development, 2014, vol. 18, # 1, p. 89 - 102
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