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Product Details of [ 175596-01-7 ]

CAS No. :175596-01-7 MDL No. :MFCD04335187
Formula : C9H6FNO2 Boiling Point : -
Linear Structure Formula :- InChI Key :BTSFXVSAECXZNJ-UHFFFAOYSA-N
M.W : 179.15 Pubchem ID :15278726
Synonyms :

Calculated chemistry of [ 175596-01-7 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 13
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.11
Num. rotatable bonds : 2
Num. H-bond acceptors : 4.0
Num. H-bond donors : 0.0
Molar Refractivity : 42.39
TPSA : 50.09 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) : -6.3 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.89
Log Po/w (XLOGP3) : 1.54
Log Po/w (WLOGP) : 1.9
Log Po/w (MLOGP) : 1.71
Log Po/w (SILICOS-IT) : 2.11
Consensus Log Po/w : 1.83

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.13
Solubility : 1.33 mg/ml ; 0.00741 mol/l
Class : Soluble
Log S (Ali) : -2.2
Solubility : 1.13 mg/ml ; 0.00629 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.84
Solubility : 0.261 mg/ml ; 0.00146 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.73

Safety of [ 175596-01-7 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 175596-01-7 ]

* 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 [ 175596-01-7 ]
  • Downstream synthetic route of [ 175596-01-7 ]

[ 175596-01-7 ] Synthesis Path-Upstream   1~11

  • 1
  • [ 175596-01-7 ]
  • [ 105942-10-7 ]
Reference: [1] Patent: KR101614164, 2016, B1,
  • 2
  • [ 175596-01-7 ]
  • [ 85070-58-2 ]
YieldReaction ConditionsOperation in experiment
70% With hydrogen; acetic acid In water at 20℃; for 18 h; EXAMPLE 20B
methyl 2-fluoro-4-formylbenzoate
EXAMPLE 20A (310 mg, 1.73 mmol) was dissolved in 60percent aqueous acetic acid (10 mL) with warming.
Raney nickel (60 mg) was added and the mixture was stirred under hydrogen at ambient temperature for 18 hours.
Solid material was filtered off and the filtrate concentrated.
The residue was purified on silica gel using 1:4 ethyl acetate/hexane to give the title compound (220 mg, 70percent). MS (DCI): m/z 183 (M+H)+.
70%
Stage #1: Heating / reflux
Stage #2: With hydrogen In water at 20℃; for 18 h;
EXAMPLE 17B
methyl 2-fluoro-4-formyl-benzoate
EXAMPLE 17A (310 mg, 1.73 mmol) was dissolved in 60percent aqueous acetic acid (10 mL) with gentle heating.
Raney nickel (60 mg) was added and the mixture stirred under hydrogen at ambient temperature for 18 hours.
Solid material was filtered off and the filtrate concentrated.
The residue was purified by flash chromatography on silica gel (1:4 ethyl acetate/hexane) to give 220 mg (70percent) of the title compound. MS (DCI): m/z 183 (M+H)+.
Reference: [1] Patent: US2007/112047, 2007, A1, . Location in patent: Page/Page column 16
[2] Patent: US2007/259937, 2007, A1, . Location in patent: Page/Page column 13
[3] Patent: WO2015/25164, 2015, A1,
[4] Patent: US2015/57298, 2015, A1,
  • 3
  • [ 164149-28-4 ]
  • [ 74-88-4 ]
  • [ 175596-01-7 ]
YieldReaction ConditionsOperation in experiment
94%
Stage #1: With potassium carbonate In N,N-dimethyl-formamide at 15 - 25℃; for 0.25 h;
Stage #2: at 40℃; for 2 h;
Step (i) Potassium carbonate (3.70 g, 26.7 mmol ) was added to a solution of 4-cyano-2- fluorobenzoic acid (4 g, 24.3 mmol) in DMF (350 mL). After stirring at RT for 15 minutes, iodomethane (1.66 mL, 26.7 mmol) was added. The flask was stoppered, and the mixture stirred at 40 °C for 2 h. The mixture was concentrated under reduced pressure and the residue partitioned between DCM (50 mL) and brine (50 mL). The organic phase was passed tlirough silica and concentrated to give methyl 4-cyano-2-fluorobenzoate (4.1 g, 94percent). NMR (300 MHz, CDC13) δ ppm 3.96 (s, 311 ) 7.44-7.48 (m, 111) 7.49-7.53 (m, 111) 8.01- 8.05 (m, 1H)
94%
Stage #1: With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.25 h;
Stage #2: at 40℃; for 2 h;
Potassium carbonate (3.70 g, 26.7 mmol) was added to a solution of 4-cyano-2-fluorobenzoic acid (4 g, 24.3 mmol) in DMF (350 mL).
After stirring at RT for 15 minutes, iodomethane (1.66 mL, 26.7 mmol) was added.
The flask was stoppered, and the mixture stirred at 40° C. for 2 h.
The mixture was concentrated under reduced pressure and the residue partitioned between DCM (50 mL) and brine (50 mL).
The organic phase was passed through silica and concentrated to give methyl 4-cyano-2-fluorobenzoate (4.1 g, 94percent).
1H NMR (300 MHz, CDCl3) δ ppm 3.96 (s, 3H) 7.44-7.48 (m, 1H) 7.49-7.53 (m, 1H) 8.01-8.05 (m, 1H)
30% With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 18 h; Example 42 4-fluoromethyl-3-[4-(tetrahydropyran-4-yloxymethyl)phenoxy]benzamide (42a) methyl 4-cyano-2-fluorobenzoate 4-Cyano-2-fluorobenzoic acid (5.15 g, 31.2 mol) was dissolved in dimethylformamide (50 mL), potassium carbonate (6.47 g, 46.8 mmol) and methyl iodide (3.88 mL, 62.4 mmol) were added, and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title object compound as a white powder (1.70 g, yield 30percent). 1H-NMR (CHCl3, 400 MHz) δ: 3.97 (3H, s), 7.48 (1H, dd, J=9.8, 1.5 Hz), 7.52 (1H, dd, J=8.1, 1.5 Hz), 8.05 (1H, dd, J=8.1, 7.3 Hz).
Reference: [1] Patent: WO2015/25164, 2015, A1, . Location in patent: Page/Page column 81-82
[2] Patent: US2015/57298, 2015, A1, . Location in patent: Paragraph 0551
[3] Patent: US2016/207883, 2016, A1, . Location in patent: Paragraph 0916-0918
[4] Patent: WO2009/124962, 2009, A2, . Location in patent: Page/Page column 141
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YieldReaction ConditionsOperation in experiment
80% With dicyanozinc In N,N-dimethyl-formamide at 80℃; EXAMPLE 20A
methyl 4-cyano-2-fluorobenzoate
A solution of methyl 4-bromo-2-fluorobenzoate (10.0 g, 43 mmol), zinc cyanide (10.0 g, 86 mmol) and palladium tetrakis(triphenylphosphine) (2.5 g, 0.64 mmol) in anhydrous N,N-dimethylformamide (100 mL) was purged with nitrogen and the mixture stirred at 80° C. overnight.
After cooling, the mixture was partitioned between ethyl acetate and brine and the organic phase washed with water and concentrated.
The solid was purified on silica gel using 1:5 ethyl acetate/hexane to afford the title compound (6.1 g, 80percent). MS (DCI): m/z 180 (M+H)+.
Reference: [1] Patent: US2007/112047, 2007, A1, . Location in patent: Page/Page column 15-16
  • 5
  • [ 557-21-1 ]
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YieldReaction ConditionsOperation in experiment
84% at 100℃; for 3.5 h; STEP 2: To a solution of methyl 4-bromo-2-fluorobenzoate (9.1 mmol) in DMF (50 mL) was added zinc cyanide (641 mg, 5.5 mmol) followed by tetrakis(triphenyphosphine)palladium(0) (1.05 g, 0.91 mmol). The mixture was heated to 100 °C and stirred for 3 h. At that point, additional tetrakis(triphenyphosphine)- palladium(O) (500 mg, 0.43 mmol) was added. The mixture was stirred a further 30 min and was then cooled to room temperature. Water and ethyl acetate were added, and insoluble solids were removed by filtration through celite. The layers were then separated. The aqueous phase was extracted with ethyl acetate. The organic extracts were combined, washed with 10percent aqueous lithium chloride, dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (10percent ethyl acetate in hexanes) to provide methyl 4-cyano-2-fluorobenzoate (1.36 g, 7.6 mmol, 84percent yield). 1H NMR (400 MHz, CDCl3): 8.06 (dd, IH), 7.53 (dd, IH), 7.47 (dd, IH), 3.98 (s, 3H); MS (EI) for C9H6FNO2: 179 (M+).
80% at 80℃; EXAMPLE 17A
methyl 4-cyano-2-fluoro-benzoate
A solution of methyl 4-bromo-2-fluorobenzoate (10.0 g, 43 mmol), zinc cyanide (10.0 g, 86 mmol) and palladium tetrakis(triphenylphosphine) (2.5 g, 0.64 mmol) in N,N-dimethylformamide (100 mL) was stirred at 80° C. overnight.
After cooling, the mixture was partitioned between ethyl acetate and brine and the organic phase washed with water and concentrated.
The residue was purified by flash chromatography on silica gel (1:5 ethyl acetate/hexane) to afford 6.1 g (80percent) of the title compound. MS (DCI): m/z 180 (M+H)+.
Reference: [1] Patent: WO2009/55077, 2009, A1, . Location in patent: Page/Page column 447
[2] Patent: US2007/259937, 2007, A1, . Location in patent: Page/Page column 13
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YieldReaction ConditionsOperation in experiment
95% Reflux Preparation of methyl 4-(aminomethyl)-2-fluorobenzoate: A solution of 4-cyano-2-fluorobenzoic acid (4.02 g, 24.36 mmol, Aldrich) in methanol (50 mL) was treated with p-toluenesulfonic acid monohydrate (0.46 g, 2.43 mmol) and heated to reflux overnight. The solvent was removed and the reaction residue was extracted with EtOAc, washed with saturated Na2CO3, brine and dried over Na2SO4 to give Methyl 4-cyano-2-fluorobenzoate (4.46 g, 95percent).
Reference: [1] Patent: US2011/86854, 2011, A1, . Location in patent: Page/Page column 44
[2] Patent: WO2009/80663, 2009, A1, . Location in patent: Page/Page column 96
[3] Patent: US2010/16373, 2010, A1, . Location in patent: Page/Page column 14
[4] Patent: WO2009/43889, 2009, A2, . Location in patent: Page/Page column 111
[5] Patent: WO2010/112461, 2010, A1, . Location in patent: Page/Page column 75
[6] Patent: WO2007/3960, 2007, A1, . Location in patent: Page/Page column 28
[7] Patent: US2012/129832, 2012, A1, . Location in patent: Page/Page column 9
[8] Patent: WO2016/97004, 2016, A1, . Location in patent: Page/Page column 71; 72
  • 7
  • [ 77-78-1 ]
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YieldReaction ConditionsOperation in experiment
84% With potassium carbonate In acetone for 20 h; Reflux Example 33A
Methyl 4-cyano-2-fluorobenzoate
13.20 g (79.9 mmol) of 4-cyano-2-fluorobenzoic acid are dissolved in 300 ml of acetone.
Then 22.10 g (159.9 mmol) of potassium carbonate and 9.08 ml (95.9 mmol) of dimethyl sulfate are successively added.
The mixture is stirred at reflux temperature for 20 h.
The reaction mixture is then mixed with 300 ml of water and the acetone is removed in a rotary evaporator.
Several extractions with dichloromethane are carried out.
The combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulfate.
The solvent is then removed in vacuo.
The remaining solid is used further without further purification. 16.1 g (84percent of theory) of the title compound are obtained as a colorless solid.
GC-MS (method 7): Rt=6.23 min; [M]+ (EIpos): m/z=179
1H-NMR (300 MHz, DMSO-d6): δ=3.90 (s, 3H), 7.83 (dd, 1H), 8.01-8.08 (m, 2H).
84% With potassium carbonate In acetone for 20 h; Reflux 4-cyano-2-fluoro-benzoic acid 13.20 g (79.9 mmol) was dissolved in acetone 300 mL. Then, 22.10 g of potassium carbonate A (159.9 mmol) and dimethyl sulfate 9.08 ml (95.9 mmol) were added consecutively. The mixture was refluxed at a temperature of 20 hour Stirred . Then, the reaction mixture was mixed with 300 mL of water, and the acetone on a rotary evaporator It was removed. It can in turn was extracted with dichloromethane. The combined organic phases are washed with a saturated aqueous sodium chloride solution, and sulfuric acid Dried over sodium. Then, the solvent was removed in vacuo. The remaining solid was used without further purification. The title compound was 16.1 g (84percent of theory) as a colorless solid
Reference: [1] Patent: US2010/305052, 2010, A1, . Location in patent: Page/Page column 23
[2] Patent: KR101614164, 2016, B1, . Location in patent: Paragraph 0349-0351
  • 8
  • [ 164149-28-4 ]
  • [ 18107-18-1 ]
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Reference: [1] Patent: US2016/207883, 2016, A1, . Location in patent: Paragraph 0692-0694
[2] Patent: WO2007/116229, 2007, A1, . Location in patent: Page/Page column 23
  • 9
  • [ 1149388-52-2 ]
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Reference: [1] Patent: WO2009/55077, 2009, A1, . Location in patent: Page/Page column 448
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  • [ 164149-28-4 ]
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Reference: [1] Patent: US2010/136142, 2010, A1,
  • 11
  • [ 175596-01-7 ]
  • [ 1149388-51-1 ]
YieldReaction ConditionsOperation in experiment
43% at 45℃; for 15 h; STEP 3: To a flask containing methyl 4-cyano-2-fluorobenzoate (1.61 g, 9.0 mmol) was added fuming nitric acid (15 mL) followed by concentrated sulfuric acid (4 mL). The mixture was heated to 45 °C for 15 h before cooling to room temperature. The solution was then poured into ice water and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, filtered, and concentrated to provide methyl 4-cyano-2-fluoro-5-nitrobenzoate (859 mg, 3.83 mmol, 43percent yield). <n="450"/>1H NMR (400 MHz, CDCl3): 8.95 (d, IH), 7.72 (d, IH), 4.04 (s, 3H); MS (EI) for C9H5FN2O4: 224 (M+).
Reference: [1] Patent: WO2009/55077, 2009, A1, . Location in patent: Page/Page column 447-448
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