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Chemical Structure| 7697-23-6
Chemical Structure| 7697-23-6
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Product Details of [ 7697-23-6 ]

CAS No. :7697-23-6 MDL No. :MFCD03092906
Formula : C8H7FO2 Boiling Point : -
Linear Structure Formula :- InChI Key :ALFWHEYHCZRVLO-UHFFFAOYSA-N
M.W :154.14 Pubchem ID :2736145
Synonyms :

Calculated chemistry of [ 7697-23-6 ]

Physicochemical Properties

Num. heavy atoms : 11
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.12
Num. rotatable bonds : 1
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 38.33
TPSA : 37.3 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) : -5.19 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.43
Log Po/w (XLOGP3) : 2.89
Log Po/w (WLOGP) : 2.25
Log Po/w (MLOGP) : 2.36
Log Po/w (SILICOS-IT) : 2.09
Consensus Log Po/w : 2.2

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.56

Water Solubility

Log S (ESOL) : -2.95
Solubility : 0.171 mg/ml ; 0.00111 mol/l
Class : Soluble
Log S (Ali) : -3.33
Solubility : 0.0715 mg/ml ; 0.000464 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.42
Solubility : 0.583 mg/ml ; 0.00378 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.2

Safety of [ 7697-23-6 ]

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 [ 7697-23-6 ]

* 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 [ 7697-23-6 ]
  • Downstream synthetic route of [ 7697-23-6 ]

[ 7697-23-6 ] Synthesis Path-Upstream   1~12

  • 1
  • [ 352-70-5 ]
  • [ 865-47-4 ]
  • [ 7697-23-6 ]
YieldReaction ConditionsOperation in experiment
45% With tert.-butyl lithium In tetrahydrofuran; pentane at -78℃; for 2.5 h; Step A: 1-Fluoro-3-methyl-benzene (compound 1g; 18.7 g, 170 mmol) was added to a three neck 500 mL flask and cooled to -78 C. Next, solution of potassium t-butoxide (11.0 g, 170 mmol) in THF was added slowly by syringe. After 10 minutes, t-BuLi (19.0 g, 170 mmol) in pentane was added slowly by cannula under nitrogen to the reaction. After 2.5 hours of stirring, the reaction was quenched with large amount of crushed fresh dry ice, taken off the -78 C. bath and manually stirred with a metal spatula to turn the dark brown material into a much lighter yellow slurry. After 20 minutes of mixing by hand, about 500 mL of water were added and reaction mixture was stirred. The reaction mixture was then washed With Et2O and then acidified with 6 N HCl to pH less than 3 and extracted with Et2O. The organic was washed with brine, dried over MgSO4 filtered and concentrated to yield 10 gm (45percent yield) of compound 2g. 1H NMR (400 MHz, CDCl3) d 7.90 (t, 1H), 7.04 (d, 1H), 6.97 (d, 1H), 2.39 (s, 3H).
Reference: [1] Patent: US2004/176325, 2004, A1, . Location in patent: Page/Page column 31; sheet 33
  • 2
  • [ 124-38-9 ]
  • [ 452-74-4 ]
  • [ 7697-23-6 ]
Reference: [1] Journal of Fluorine Chemistry, 2002, vol. 116, # 2, p. 173 - 179
[2] Journal of Medicinal Chemistry, 2008, vol. 51, # 24, p. 8124 - 8134
[3] Patent: WO2014/144380, 2014, A1, . Location in patent: Paragraph 0541
  • 3
  • [ 5326-34-1 ]
  • [ 7697-23-6 ]
Reference: [1] Journal of Fluorine Chemistry, 2002, vol. 116, # 2, p. 173 - 179
  • 4
  • [ 53078-85-6 ]
  • [ 7697-23-6 ]
Reference: [1] Journal of Fluorine Chemistry, 2002, vol. 116, # 2, p. 173 - 179
  • 5
  • [ 612-45-3 ]
  • [ 7697-23-6 ]
Reference: [1] Journal of Fluorine Chemistry, 2002, vol. 116, # 2, p. 173 - 179
  • 6
  • [ 696-01-5 ]
  • [ 7697-23-6 ]
Reference: [1] Journal of Organic Chemistry, 1967, vol. 32, p. 134 - 136
  • 7
  • [ 124-38-9 ]
  • [ 352-70-5 ]
  • [ 7697-23-6 ]
Reference: [1] Chemistry - A European Journal, 1998, vol. 4, # 10, p. 1969 - 1973
  • 8
  • [ 95-78-3 ]
  • [ 7697-23-6 ]
Reference: [1] Journal of Organic Chemistry, 1967, vol. 32, p. 134 - 136
  • 9
  • [ 67-56-1 ]
  • [ 7697-23-6 ]
  • [ 74733-29-2 ]
YieldReaction ConditionsOperation in experiment
98% at 20℃; for 18 h; Method G; Example G-1; 2-Fluoro-4-r3-oxo-4-(2-tπfluoroιinethyl-benzyl)-3,4-clihvdro-2H-benzori ,41thiazin-2- ylmethyli-benzoic acid; Preparation of G-1 -a; 2-Fluoro-4-methyl-benzoic acid methyl ester; To a mixture of 2-fluoro-4-methylbenzoic acid (2.5g, 16mmol) in methyl alcohol (30ml_),thionyl chloride (1.36ml_, 18.9mmol) was added and the mixture was stirred at room temperature for 18h. The solvent was evaporated to provide the title compound (2.6g, 98percent yield). 1H NMR (400 MHz, METHANOL-^) δ ppm 7.79 (t, J=7.83 Hz, 1 H), 7.07 (d, J=8.08 Hz, 1 H), 7.02 (d, J=12.38 Hz, 1 H), 3.88 (s, 3 H), 2.39 (s, 3 H)
90% Reflux Method A: To a stirred mixture of 2-fluoro-4-methylbenzoic acid (2.0 g, 13.0 mmol), K2CO3 (3.6 g, 26.0 mmol) in acetonitrile (15 mL) was added CH3I (1.6 mL, 25.6 mmol) dropwise. After the reaction mixture was heated to reflux overnight, the solvent was removed in vacuo. The residual was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography with hexanes/EtOAc (6:1) to afford 5 as a white solid (1.73 g, 79percent), mp 51–53°C. 1H NMR (CDCl3): δ 7.83 (t, J=8.0Hz, 1H), 7.00 (dd, J=8.0, 1.0Hz, 1H), 6.95 (d, J=12.0Hz, 1H), 3.91 (s, 3H), 2.39 (s, 3H). Method B: To a stirred solution of 2-fluoro-4-methylbenzoic acid (7.0 g, 45.4 mmol) in MeOH (100 mL) was added concentrated sulfuric acid (5 mL) dropwise. The reaction mixture was heated to reflux overnight; the solvent was removed in vacuo. The residual was diluted with EtOAc, washed with saturated NaHCO3 aqueous solution and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography with hexanes/EtOAc (6:1) to afford 5 as a white solid (6.88 g, 90percent). Analytical data were same as above.
90% Reflux (f) Methyl 2-fluoro-4-methylbenzoate (5): Method A: To a stirred mixture of 2-fluoro-4-methylbenzoic acid (2.0 g, 13.0 mmol), K2CO3 (3.6 g, 26.0 mmol) inacetonitrile (15 mL) was added CH3I (1.6 mL, 25.6 mmol) dropwise. After thereaction mixture was heated to reflux overnight, the solvent was removed invacuo. The residual was diluted with EtOAc, washed with water and brine,dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crudeproduct was purified by column chromatography with hexanes/EtOAc (6:1) toafford 5 as a white solid (1.73 g, 79percent), mp 51–53 C. 1H NMR (CDCl3): d 7.83 (t,J = 8.0 Hz, 1H), 7.00 (dd, J = 8.0, 1.0 Hz, 1H), 6.95 (d, J = 12.0 Hz, 1H), 3.91 (s,3H), 2.39 (s, 3H). Method B: To a stirred solution of 2-fluoro-4-methylbenzoicacid (7.0 g, 45.4 mmol) in MeOH (100 mL) was added concentrated sulfuricacid (5 mL) dropwise. The reaction mixture was heated to reflux overnight; thesolvent was removed in vacuo. The residual was diluted with EtOAc, washedwith saturated NaHCO3 aqueous solution and brine, dried over anhydrousNa2SO4, filtered and concentrated in vacuo. The crude product was purified bycolumn chromatography with hexanes/EtOAc (6:1) to afford 5 as a white solid(6.88 g, 90percent). Analytical data were same as above.
77%
Stage #1: With thionyl chloride In toluene for 2.5 h; Heating / reflux
Stage #2: at 20℃; for 2.5 h;
To a solution of 2-fluoro-4-methylbenzoic acid (6.04 g, 39.18 mmol) in toluene (80 ml) was added thionyl chloride (65 ml, 89.11 mmol). The mixture was heated at reflux for 2.5 h, cooled and concentrated in vacuo. The residue was dissolved in dichloromethane (50ml) and methanol (50 ml) was added. The mixture was stirred at room temperature for 2.5 h and then concentrated in vacuo. The residue was dissolved in dichloromethane (100 ml), washed with saturated sodium bicarbonate solution and brine, dried over MgSO4, and concentratedin vacuo to give a tan solid identified as methyl 2-fluoro-4-methylbenzoate (5.07 g, 77percent).
77%
Stage #1: With thionyl chloride In toluene for 2.5 h; Heating / reflux
Stage #2: at 20℃; for 2.5 h;
To a solution of 2-fluoro-4-methylbenzoic acid from Example D1 (6.04 g, 39.18 mmol) in toluene (80 ml) was added thionyl chloride (6.5 ml, 89.11 mmol). The mixture was heated at reflux for 2.5 h, cooled and concentrated in vacuo. The residue was dissolved in dichloromethane (50 ml) and methanol (50 ml) was added. The mixture was stirred at room temperature for 2.5 h and then concentrated in vacuo. The residue was dissolved in dichloromethane (100 ml), washed with saturated sodium bicarbonate solution and brine, dried over MgSO4, and concentrated in vacuo to give a tan solid; yield 5.07 g (77percent).
75% for 24 h; Reflux INTERMEDIATE 28 - PREPARATION OF Methyl 2-fluoro-4-methylbenzoate. Sulfuric acid (2 ml_) was added to the solution of 2-fluoro-4-methylbenzoic acid (0.848 g; 5.34 mmol) in methanol (30 ml_). The mixture was refluxed for 24 hours. After cooling, the solution was made alkaline by addition of an aqueous solution of sodium carbonate, concentrated under reduced pressure in order to remove methanol, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and was concentrated under reduced pressure to give 0.672 g (75percent) of methyl 2-fluoro-4-methylbenzoate as a solid.ESI/APCI(+) : 169 (M+H).
75% for 24 h; Reflux Sulfuric acid (2 mL) was added to the solution of 2-fluoro-4-methylbenzoic acid (0.848 g; 5.34 mmol) in methanol (30 mL). The mixture was refluxed for 24 hours. After cooling, the solution was made alkaline by addition of an aqueous solution of sodium carbonate, concentrated under reduced pressure in order to remove methanol, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and was concentrated under reduced pressure to give 0.672 g (75percent) of methyl 2-fluoro-4-methylbenzoate as a solid. [0609] ESI/APCI(+): 169 (M+H).
10.01 g at 90℃; In a 500 ml one-neck round bottom flask, equipped with a magnetic stir-bar and condenser was added 2-fluoro-4-methyl-benzoic acid (10.0 g, 64.88 mn1ol), 250 ml of methanol and 5 ml of sulfuric acid. The reaction was heated at 90°C overnight. The methanol was evaporated and residue was purified on 125g Filter Silica ISCO column using a hexane/ethyl acetate gradient to give 10.Olg of IXS-4-52-1. Overall yield is 91.75percent. ‘H NMR (CDcI3, 400 MHz) ö 7.80 (t, 1H), 6.95 (2d, 2K), 3.89 (s, 3H), 2.37 (s, 3H).

Reference: [1] Patent: WO2010/116270, 2010, A1, . Location in patent: Page/Page column 55
[2] Organic Process Research and Development, 2011, vol. 15, # 3, p. 565 - 569
[3] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 7, p. 1742 - 1747
[4] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 24, # 7, p. 1742 - 1747
[5] Patent: EP1449844, 2004, A1, . Location in patent: Page 22
[6] Patent: US6664249, 2003, B1, . Location in patent: Page column 12
[7] Patent: WO2012/80221, 2012, A1, . Location in patent: Page/Page column 81
[8] Patent: US2013/274260, 2013, A1, . Location in patent: Paragraph 0608-0609
[9] Patent: WO2005/97762, 2005, A2, . Location in patent: Page/Page column 55
[10] Patent: US2008/318951, 2008, A1, . Location in patent: Page/Page column 47
[11] Patent: EP2305641, 2011, A1, . Location in patent: Page/Page column 16
[12] Patent: WO2014/144380, 2014, A1, . Location in patent: Paragraph 0542
[13] Journal of Medicinal Chemistry, 2017, vol. 60, # 18, p. 7703 - 7724
  • 10
  • [ 74-88-4 ]
  • [ 7697-23-6 ]
  • [ 74733-29-2 ]
YieldReaction ConditionsOperation in experiment
79% Reflux Method A: To a stirred mixture of 2-fluoro-4-methylbenzoic acid (2.0 g, 13.0 mmol), K2CO3 (3.6 g, 26.0 mmol) in acetonitrile (15 mL) was added CH3I (1.6 mL, 25.6 mmol) dropwise. After the reaction mixture was heated to reflux overnight, the solvent was removed in vacuo. The residual was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography with hexanes/EtOAc (6:1) to afford 5 as a white solid (1.73 g, 79percent), mp 51–53°C. 1H NMR (CDCl3): δ 7.83 (t, J=8.0Hz, 1H), 7.00 (dd, J=8.0, 1.0Hz, 1H), 6.95 (d, J=12.0Hz, 1H), 3.91 (s, 3H), 2.39 (s, 3H). Method B: To a stirred solution of 2-fluoro-4-methylbenzoic acid (7.0 g, 45.4 mmol) in MeOH (100 mL) was added concentrated sulfuric acid (5 mL) dropwise. The reaction mixture was heated to reflux overnight; the solvent was removed in vacuo. The residual was diluted with EtOAc, washed with saturated NaHCO3 aqueous solution and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography with hexanes/EtOAc (6:1) to afford 5 as a white solid (6.88 g, 90percent). Analytical data were same as above.
79% With potassium carbonate In acetonitrileReflux (f) Methyl 2-fluoro-4-methylbenzoate (5): Method A: To a stirred mixture of 2-fluoro-4-methylbenzoic acid (2.0 g, 13.0 mmol), K2CO3 (3.6 g, 26.0 mmol) inacetonitrile (15 mL) was added CH3I (1.6 mL, 25.6 mmol) dropwise. After thereaction mixture was heated to reflux overnight, the solvent was removed invacuo. The residual was diluted with EtOAc, washed with water and brine,dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crudeproduct was purified by column chromatography with hexanes/EtOAc (6:1) toafford 5 as a white solid (1.73 g, 79percent), mp 51–53 C. 1H NMR (CDCl3): d 7.83 (t,J = 8.0 Hz, 1H), 7.00 (dd, J = 8.0, 1.0 Hz, 1H), 6.95 (d, J = 12.0 Hz, 1H), 3.91 (s,3H), 2.39 (s, 3H). Method B: To a stirred solution of 2-fluoro-4-methylbenzoicacid (7.0 g, 45.4 mmol) in MeOH (100 mL) was added concentrated sulfuricacid (5 mL) dropwise. The reaction mixture was heated to reflux overnight; thesolvent was removed in vacuo. The residual was diluted with EtOAc, washedwith saturated NaHCO3 aqueous solution and brine, dried over anhydrousNa2SO4, filtered and concentrated in vacuo. The crude product was purified bycolumn chromatography with hexanes/EtOAc (6:1) to afford 5 as a white solid(6.88 g, 90percent). Analytical data were same as above.
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 7, p. 1742 - 1747
[2] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 24, # 7, p. 1742 - 1747
[3] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 17, p. 4804 - 4807
  • 11
  • [ 7697-23-6 ]
  • [ 74733-29-2 ]
YieldReaction ConditionsOperation in experiment
77% With thionyl chloride In methanol; dichloromethane; toluene E2.
Methyl 2-fluoro-4-methylbenzoate
To a solution of 2-fluoro-4-methylbenzoic acid from Example E1 (6.04 g, 39.18 mmol) in toluene (80 ml) was added thionyl chloride (65 ml, 89.11 mmol).
The mixture was heated at reflux for 2.5 h, cooled and concentrated in vacuo.
The residue was dissolved in dichloromethane (50 ml) and methanol (50 ml) was added.
The mbture was stirred at room temperature for 2.5 h and then concentrated in vacuo.
The residue was dissolved in dichloromethane (100 ml), washed with saturated sodium bicarbonate solution and brine, dried over MgSO4, and concentrated in vacuo to give a tan solid; yield 5.07 g (77percent).
Reference: [1] Patent: US2004/38962, 2004, A1,
  • 12
  • [ 7697-23-6 ]
  • [ 85070-58-2 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 7, p. 1742 - 1747
[2] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 7, p. 1742 - 1747
[3] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 24, # 7, p. 1742 - 1747
[4] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 24, # 7, p. 1742 - 1747
[5] Patent: WO2011/28685, 2011, A1,
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