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[ CAS No. 53312-80-4 ]

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Chemical Structure| 53312-80-4
Chemical Structure| 53312-80-4
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CAS No. :53312-80-4 MDL No. :MFCD07368709
Formula : C7H5FN2 Boiling Point : 288.2°C at 760 mmHg
Linear Structure Formula :- InChI Key :N/A
M.W :136.13 g/mol Pubchem ID :2783413
Synonyms :

Safety of [ 53312-80-4 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 53312-80-4 ]

  • Upstream synthesis route of [ 53312-80-4 ]
  • Downstream synthetic route of [ 53312-80-4 ]

[ 53312-80-4 ] Synthesis Path-Upstream   1~13

  • 1
  • [ 53312-80-4 ]
  • [ 446-31-1 ]
Reference: [1] Patent: WO2010/35166, 2010, A1, . Location in patent: Page/Page column 68
  • 2
  • [ 53312-80-4 ]
  • [ 86776-51-4 ]
Reference: [1] Molecular crystals and liquid crystals, 1984, vol. 109, # 2-4, p. 169 - 178
  • 3
  • [ 53312-80-4 ]
  • [ 82380-18-5 ]
Reference: [1] Molecular crystals and liquid crystals, 1984, vol. 109, # 2-4, p. 169 - 178
  • 4
  • [ 3939-09-1 ]
  • [ 80517-22-2 ]
  • [ 53312-80-4 ]
YieldReaction ConditionsOperation in experiment
39%
Stage #1: at 140℃; for 0.666667 h;
Stage #2: at 20℃;
2,4-Difluorobenzonitrile (2.78 g, 20 mmol) and 3,4,5-trimethoxybenzylamine (3.94 g, 20 mmol) are combined and heated at 140 C for 40 m.
The mixture is allowed to cool to RT and is then dissolved in TFA (20 mL) and stirred at RT overnight.
The mixture is then concentrated on the rotavap and partitioned between 1N NaOH (enough till basic, ~100 mL) and ethyl acetate (100 mL).
The organic layer is removed and the aqueous layer is extracted with more ethyl acetate (100 mL).
The combined layers are washed with brine (50 mL), dried (MgSO4) and concentrated to an oil.
The mixture is chromatographed (10 to 40percent, EtOAc in hexanes) giving the isomers as two well separated products.
The later eluding product is concentrated to give 4-Amino-2-fluoro-benzonitrile (1.07 g, 39percent) as a white solid. (LC/MS m/z=177.8 for M+H+acetonitrile)
Reference: [1] Patent: US2008/76813, 2008, A1, . Location in patent: Page/Page column 28
  • 5
  • [ 34667-88-4 ]
  • [ 53312-80-4 ]
YieldReaction ConditionsOperation in experiment
100%
Stage #1: With tin(II) chloride dihdyrate In ethyl acetate at 25℃;
Stage #2: With potassium carbonate In ethyl acetate at 20℃; for 4 h;
Step A. Preparation of 4-amino-2-fluorobenzonitrile [00175] The mixture of 2-fluoro-4-nitrobenzonitrile (8.31 g, 50 mmol) and tin (II) chloride dihydrate (56.4 g, 250 mmol) in 250 mL of EtOAc was stirred at 25 °C overnight. LCMS (78109-084) indicated the reaction was completed. 25 mL of sat. K2CO3 was added to the reaction. The resulting mixture was stirred at room temperature for 2h and was followed by addition of lOOg of solid K2CO3. The mixture was stirred at room temperature for 2 hours. Solid was removed by filtration and further washed with EtOAc (50 mLx2). The filtrate was concentrated to yield 6.81 g (100percent) of 4-amino-2-fluorobenzonitrile as an off white solid. 1H NMR (400 MHz, CDCl3) δ ppm 4.30 (s, 2 H) 6.29 - 6.51 (m, 2 H) 7.27 - 7.40 (m, 1 H). MS (ESI) 137 (M+H).
96% With iron; acetic acid In ethyl acetate for 2 h; Heating / reflux A mixture of 4-nitro-2-fluorobenzonitrile (1.83 g, 5 mmol) and iron (1.68 g, 6 mmol) in a mixture of acetic acid (40 ml) and ethyl acetate (40 ml) was refluxed for 2 hours. The solid was filtered off and the filtrate was washed with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, concentrated and chromatographed (dichloromethane:acetone, 95:5) to yield 4- amino-2-fluorobenzonitrile (54a) (0.653 g, 4.8 mmol, 96percent).
96% With hydrogen In ethanol; ethyl acetate for 1 h; To 2-fluoro-4-nitrobenzonitrile (8.5 g, 51.2 mmol) was added 10percent palladium on carbon (0.5 g) and EtOAc (42.5 mL) and EtOH (170 mL) and the reaction was hydrogenated at 50 psi for 1 h. The reaction was filtered through Celite and the reaction mixture was concentrated to afford 6.7 g (96percent yield) as a light brown solid. LCMS m/z 135.1[M + H]+.
70% With palladium 10% on activated carbon; hydrogen In methanol for 3 h; Reference Example 114
4-Amino-2-fluorobenzonitrile
To a solution of 2-fluoro-4-nitrobenzonitrile (2.51 g) in methanol (125 mL) was added 10percent palladium carbon (50percent containing water, 237 mg), and the mixture was stirred under a hydrogen atmosphere for 3 hr.
The reaction mixture was filtrated, and the filtrate was concentrated under reduced pressure.
The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) to give the title compound as a pale-yellow solid (yield 1.43 g, 70percent).
1H-NMR (CDCl3)δ: 4.31 (2H, brs), 6.37-6.45 (2H, m), 7.31-7.36 (1H, m).

Reference: [1] Journal of Medicinal Chemistry, 2001, vol. 44, # 23, p. 3856 - 3871
[2] Patent: WO2010/9183, 2010, A1, . Location in patent: Page/Page column 84
[3] Patent: WO2006/124118, 2006, A1, . Location in patent: Page/Page column 75
[4] Patent: WO2008/157162, 2008, A1, . Location in patent: Page/Page column 145
[5] Patent: WO2006/36024, 2006, A1, . Location in patent: Page/Page column 153
[6] Patent: EP2336107, 2015, B1, . Location in patent: Paragraph 0288
[7] Molecular crystals and liquid crystals, 1984, vol. 109, # 2-4, p. 169 - 178
[8] Patent: EP1803709, 2007, A1,
[9] Patent: US2008/81802, 2008, A1, . Location in patent: Page/Page column 11
[10] Patent: WO2007/3960, 2007, A1, . Location in patent: Page/Page column 26-27
[11] Patent: WO2013/55984, 2013, A1, . Location in patent: Paragraph 00324
[12] European Journal of Medicinal Chemistry, 2018, vol. 143, p. 1325 - 1344
  • 6
  • [ 1338209-74-7 ]
  • [ 53312-80-4 ]
YieldReaction ConditionsOperation in experiment
92%
Stage #1: With hydrogenchloride In 1,4-dioxane at 20℃; for 0.25 h; Inert atmosphere
Stage #2: With sodium hydrogencarbonate In 1,4-dioxane; waterInert atmosphere
General procedure for deprotection of tert-butylsulfinyl group: N-(4-cyano-3-fluorophenyl)-2-methylpropane-2-sulfinamide (240 mg, 1.0 mmol) in 1,4-dioxane (4 ml) was added 4.0M HCl in dioxane (4ml) and stirred at room temperature for 15 min. Reaction mixture was diluted with water, basified with saturated NaHCO3 solution and extracted with ethyl acetate (3 x 25 ml). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to give 4-amino-2-fluorobenzonitrile 125 mg, 92 percent [table-1, entry-9].
Reference: [1] Tetrahedron Letters, 2011, vol. 52, # 43, p. 5625 - 5628
  • 7
  • [ 3939-09-1 ]
  • [ 80517-22-2 ]
  • [ 53312-80-4 ]
YieldReaction ConditionsOperation in experiment
39%
Stage #1: at 140℃; for 0.666667 h;
Stage #2: at 20℃;
2,4-Difluorobenzonitrile (2.78 g, 20 mmol) and 3,4,5-trimethoxybenzylamine (3.94 g, 20 mmol) are combined and heated at 140 C for 40 m.
The mixture is allowed to cool to RT and is then dissolved in TFA (20 mL) and stirred at RT overnight.
The mixture is then concentrated on the rotavap and partitioned between 1N NaOH (enough till basic, ~100 mL) and ethyl acetate (100 mL).
The organic layer is removed and the aqueous layer is extracted with more ethyl acetate (100 mL).
The combined layers are washed with brine (50 mL), dried (MgSO4) and concentrated to an oil.
The mixture is chromatographed (10 to 40percent, EtOAc in hexanes) giving the isomers as two well separated products.
The later eluding product is concentrated to give 4-Amino-2-fluoro-benzonitrile (1.07 g, 39percent) as a white solid. (LC/MS m/z=177.8 for M+H+acetonitrile)
Reference: [1] Patent: US2008/76813, 2008, A1, . Location in patent: Page/Page column 28
  • 8
  • [ 1427-07-2 ]
  • [ 53312-80-4 ]
Reference: [1] Journal of Medicinal Chemistry, 2001, vol. 44, # 23, p. 3856 - 3871
[2] European Journal of Medicinal Chemistry, 2018, vol. 143, p. 1325 - 1344
  • 9
  • [ 403-24-7 ]
  • [ 53312-80-4 ]
Reference: [1] Journal of Medicinal Chemistry, 2001, vol. 44, # 23, p. 3856 - 3871
[2] European Journal of Medicinal Chemistry, 2018, vol. 143, p. 1325 - 1344
  • 10
  • [ 350-32-3 ]
  • [ 53312-80-4 ]
Reference: [1] Journal of Medicinal Chemistry, 2001, vol. 44, # 23, p. 3856 - 3871
[2] European Journal of Medicinal Chemistry, 2018, vol. 143, p. 1325 - 1344
  • 11
  • [ 403-23-6 ]
  • [ 53312-80-4 ]
Reference: [1] Journal of Medicinal Chemistry, 2001, vol. 44, # 23, p. 3856 - 3871
[2] European Journal of Medicinal Chemistry, 2018, vol. 143, p. 1325 - 1344
  • 12
  • [ 4110-33-2 ]
  • [ 53312-80-4 ]
Reference: [1] Molecular crystals and liquid crystals, 1984, vol. 109, # 2-4, p. 169 - 178
  • 13
  • [ 105942-08-3 ]
  • [ 53312-80-4 ]
Reference: [1] Tetrahedron Letters, 2011, vol. 52, # 43, p. 5625 - 5628
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