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[ CAS No. 22245-83-6 ] {[proInfo.proName]}

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Chemical Structure| 22245-83-6
Chemical Structure| 22245-83-6
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Product Details of [ 22245-83-6 ]

CAS No. :22245-83-6 MDL No. :MFCD00153194
Formula : C6H4F3NO Boiling Point : -
Linear Structure Formula :- InChI Key :JHDCDEHVUADNKQ-UHFFFAOYSA-N
M.W : 163.10 Pubchem ID :3678411
Synonyms :

Calculated chemistry of [ 22245-83-6 ]

Physicochemical Properties

Num. heavy atoms : 11
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.17
Num. rotatable bonds : 1
Num. H-bond acceptors : 5.0
Num. H-bond donors : 1.0
Molar Refractivity : 31.26
TPSA : 33.12 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) : -6.08 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.06
Log Po/w (XLOGP3) : 1.71
Log Po/w (WLOGP) : 2.96
Log Po/w (MLOGP) : 1.33
Log Po/w (SILICOS-IT) : 1.89
Consensus Log Po/w : 1.79

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.27
Solubility : 0.884 mg/ml ; 0.00542 mol/l
Class : Soluble
Log S (Ali) : -2.02
Solubility : 1.55 mg/ml ; 0.00952 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.33
Solubility : 0.77 mg/ml ; 0.00472 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.58

Safety of [ 22245-83-6 ]

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 [ 22245-83-6 ]

* 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 [ 22245-83-6 ]
  • Downstream synthetic route of [ 22245-83-6 ]

[ 22245-83-6 ] Synthesis Path-Upstream   1~12

  • 1
  • [ 142-08-5 ]
  • [ 2314-97-8 ]
  • [ 22245-83-6 ]
YieldReaction ConditionsOperation in experiment
50% With ferrocene; dihydrogen peroxide; dimethyl sulfoxide In water at 40 - 50℃; for 0.333333 h; 0.19 g (2.0 mmol) of 2-hydroxypyridine and 0.11 g (0.6 mmol) of ferrocene were weighed and placed in a two-neck flask and the atmosphere in the flask was replaced with argon. The following materials were added thereinto: 8.0 ml of dimethyl sulfoxide, 2.0 ml of a 3.0 mol/l dimethyl sulfoxide solution of trifluoromethyl iodide and 0.4 ml of a 30percent hydrogen peroxide aqueous solution, and the mixture was stirred for 20 minutes. During the stirring, the temperature of the reaction system rose up in the range of from 40°C to 50°C. Thereafter, the resulting solution was cooled to room temperature. Formation of 2-hydroxy-3-trifluoromethylpyridine (19F-NMR yield: 64percent) was confirmed by 19F-NMR with 2,2,2-trifluoroethanol as an internal standard. The subsequent procedure was conducted in the same manner as in Example 1 and 2-hydroxy-3-trifluoromethylpyridine was obtained as a white solid (0.081 g, yield: 50percent). 1H-NMR(deuterated chloroform):δ6. 34(dd, J=6. 9, 5. 6Hz, 1H), 7. 65 (d, J=5. 6Hz, 1H), 7. 88 (d, J=6. 9Hz, 1H), 13. 25 (brs, 1H). 13C-NMR(deuterated chloroform):δ105. 6, 120. 4(q, JCF=31. 4H z), 122. 7(q, JCF=271. 3Hz), 139. 2, 140. 7(q, JCF=4. 9Hz), 161. 4. 19F-NMR(deuterated chloroform):δ-66. 0. MS(m/z):163[M]+.
Reference: [1] Patent: EP2080744, 2009, A1, . Location in patent: Page/Page column 7-8
[2] Journal of Fluorine Chemistry, 2010, vol. 131, # 1, p. 98 - 105
  • 2
  • [ 65753-47-1 ]
  • [ 22245-83-6 ]
Reference: [1] Synthetic Communications, 2006, vol. 36, # 9, p. 1235 - 1245
[2] Patent: WO2011/113309, 2011, A1, . Location in patent: Page/Page column 27
[3] Patent: CN108003093, 2018, A,
  • 3
  • [ 183610-70-0 ]
  • [ 22245-83-6 ]
Reference: [1] Patent: CN108003093, 2018, A, . Location in patent: Paragraph 0008; 0017-0019; 0020-0022; 0023-0025
  • 4
  • [ 22245-83-6 ]
  • [ 887707-23-5 ]
YieldReaction ConditionsOperation in experiment
81% With N-iodo-succinimide In N,N-dimethyl-formamide; acetonitrile at 80℃; for 2 h; 5-iodo-3-trifluoromethyl-2-pyridinol C 800C, 2h I>80percent[0070] 3-trifluoromethyl-2-pyridinol (25 g, 153.3 mmol) is dissolved in anhydrousCH3CN (150 rnL) and DMF (150 rnL). N-iodosuccinimide (34.5 g, 153 mmol) is then added. The reaction mixture is stirred at 80 0C for 2 hours and cooled to room temperature. Aqueous 1 M NaHCO3 (150 mL) is then added to the cooled mixture. After stirring for 5 min, the solvents are evaporated to dryness. Water is added and the aqueous phase is extracted (x2) with dichloromethane. The organic phase is then evaporated and the desired product is recrystallized in water to afford 36.2 g (81 percent) of a white powder.[0071] 1H NMR (500 MHz, CDCl3) δ 7.85 (d, J= 2.3, IH); 7.98 (d, J= 2.3, IH),13.41 (br s, IH); 13C NMR (250 MHz CDCl3) δ 63.0, 121.4 (q, JC-F= 272.3 Hz), 122.2 (q, JC- F= 31.6 Hz), 144.4, 148.1 q, (JC-F= 5.0 Hz), 160.1.
80% With N-iodo-succinimide In N,N-dimethyl-formamide at 80℃; for 2 h; asolution of 2- hydroxy-3- (trifluoromethyl) pyridine C in a mixture of N-iodosuccinimide (NIS), acetonitrile and dimethyl formamide (DMF) was heated for2 hours at 80 , and 2- hydroxy-3 - trifluoromethyl-5- (iodo) pyridine I (yield of 80percentgreater) is formed.
80% With N-iodo-succinimide In N,N-dimethyl-formamide; acetonitrile at 80℃; for 2 h; A solution of 2-hydroxy-3-(trifluoromethyl)pyridine C in a mixture of N-iodosuccinimide (NIS), acetonitrile, and dimethylformamide (DMF) is heated at 80° C. for 2 hours to produce 2-hydroxy-3-trifluoromethyl-5-(iodo)pyridine I (greater than 80percent yield). The 2-hydroxy-3-trifluoromethyl-5-(iodo)pyridine I is then mixed with POCl3 in DMF and heated to 130° C. in a microwave for 20 minutes to produce 2-chloro-3-trifluoromethyl-5-(iodo)pyridine J (yield of 50 to 55percent). The 2-chloro-3-trifluoromethyl-5-(iodo)pyridine K is reacted in a solution of pMBnNH2, palladium(II) acetate, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), triethylamine, and cesium carbonate in toluene to produce 5-((4-methoxyphenyl))methylamino)-2-chloro-3-(trifluoromethyl)pyridine K (yield of 40percent). The 5-((4-methoxyphenyl))methylamino)-2-chloro-3-(trifluoromethyl)pyridine K is reacted in a solution of zinc cyanide, tris(dibenzylideneacetone)dipalladium (Pd2(dba)3), and 1,1′-bis(diphenylphosphino)ferrocene (dppf) in DMF to provide 5-(4-methoxybenzylamine)-2-cyano-3-(trifluoromethyl)pyridine K (yield of 92percent). The 5-(4-methoxybenzylamine)-2-cyano-3-(trifluoromethyl)pyridine K is reacted in a solution of dichloromethane and trifluoroacetic acid to provide 2-cyano-3-trifluoromethyl-5-(amino)pyridine H (yield greater than 95percent). The 2-cyano-3-trifluoromethyl-5-(amino)pyridine H is reacted with thiophosgene in water at 25° C. for 2 hours to provide 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile A (yield of 74percent to 95percent).
74% With N-iodo-succinimide In N,N-dimethyl-formamide; acetonitrile at 80℃; for 2 h; Step A. 5-iodo-3-(trifluoromethyl)pyridin-2-ol A mixture of 3-(trifluoromethyl)pyridin-2-ol (3.0 g, 18.5 mmol) and N-iodosuccinimide (4.2 g, 18.5 mmol) in acetonitrile (25 mL) and DMF (25 mL) was heated at 80 °C for 2 hours. After the reaction mixture was cooled to room temperature, water was added and the resulting mixture was extracted with ethyl acetate (70 mL x 2). The extracts were combined, washed with brine (120 mL x 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 5-iodo-3-(trifluoromethyl)pyridin-2-ol as a yellow solid (4.0 g, 74percent). FontWeight="Bold" FontSize="10" H NMR (500 MHz, CDC13) δ (ppm) 13.37 (bs, 1H), 7.98 (d, J = 2.0 Hz, 1H), 7.85 (d, J = 2.0 Hz, 1H); LCMS (ESI) m/z: 290 [M+H]+.
74% With N-iodo-succinimide In N,N-dimethyl-formamide; acetonitrile at 80℃; for 2 h; Step A. 5-iodo-3-(trifluoromethyl)pyridin-2-ol A mixture of 3-(trifluoromethyl)pyridin-2-ol (3.0 g, 18.5 mmol) and N-iodosuccinimide (4.2 g, 18.5 mmol) in CH3CN (25 mL) and DMF (25 mL) was heated at 80 °C for 2 hours. After the reaction mixture was cooled to room temperature, water was added and the resulting mixture was extracted with EtOAc (70 mL x 2). The extracts were combined, washed with brine (120 mL x 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 5-iodo-3-(trifluoromethyl)pyridin-2-ol as a yellow solid (4.0 g, 74percent). 1H NMR (500 MHz, CDC13) δ (ppm) 13.37 (bs, 1H), 7.98 (d, / = 2.0 Hz, 1H), 7.85 (d, / = 2.0 Hz, 1H); LCMS (ESI) m/z: 290 [M+H]+.

Reference: [1] Organic Process Research and Development, 2013, vol. 17, # 12, p. 1561 - 1567
[2] Patent: WO2008/119015, 2008, A2, . Location in patent: Page/Page column 48
[3] Patent: JP2016/11315, 2016, A, . Location in patent: Paragraph 0084
[4] Patent: US9388159, 2016, B2, . Location in patent: Page/Page column 19; 20; 21
[5] Patent: WO2015/100613, 2015, A1, . Location in patent: Page/Page column 17
[6] Patent: WO2015/100617, 2015, A1, . Location in patent: Page/Page column 36
[7] Synthetic Communications, 2006, vol. 36, # 9, p. 1235 - 1245
[8] Patent: WO2009/18656, 2009, A1, . Location in patent: Page/Page column 53
[9] Patent: WO2009/18657, 2009, A1, . Location in patent: Page/Page column 63
[10] Patent: WO2009/76747, 2009, A1, . Location in patent: Page/Page column 62
[11] Patent: WO2015/196144, , A2, . Location in patent: Paragraph 0326[11] Patent: , 2015, , . Location in patent: Paragraph 0326
[13] Patent: US2008/45516, 2008, A1, . Location in patent: Page/Page column 30
  • 5
  • [ 22245-83-6 ]
  • [ 887707-25-7 ]
Reference: [1] Synthetic Communications, 2006, vol. 36, # 9, p. 1235 - 1245
[2] Patent: WO2015/100613, 2015, A1,
[3] Patent: WO2015/100617, 2015, A1,
[4] Patent: WO2015/196144, , A2, [4] Patent: , 2015, ,
[6] Patent: JP2016/11315, 2016, A,
[7] Patent: US9388159, 2016, B2,
[8] Patent: US2008/45516, 2008, A1,
[9] Patent: WO2008/119015, 2008, A2,
  • 6
  • [ 22245-83-6 ]
  • [ 99368-67-9 ]
Reference: [1] Patent: US2014/275111, 2014, A1,
[2] Patent: WO2014/141187, 2014, A1,
[3] Patent: WO2016/37578, 2016, A1,
  • 7
  • [ 22245-83-6 ]
  • [ 99368-67-9 ]
Reference: [1] Patent: JP2016/11315, 2016, A,
[2] Patent: US9388159, 2016, B2,
  • 8
  • [ 22245-83-6 ]
  • [ 99368-68-0 ]
Reference: [1] Patent: US2014/275111, 2014, A1,
[2] Patent: WO2014/141187, 2014, A1,
[3] Patent: WO2016/37578, 2016, A1,
  • 9
  • [ 22245-83-6 ]
  • [ 99368-68-0 ]
Reference: [1] Patent: JP2016/11315, 2016, A,
[2] Patent: US9388159, 2016, B2,
  • 10
  • [ 22245-83-6 ]
  • [ 573762-62-6 ]
Reference: [1] Patent: US2016/152592, 2016, A1,
[2] Patent: US9388159, 2016, B2,
[3] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 12, p. 2803 - 2806
[4] Patent: WO2008/119015, 2008, A2,
  • 11
  • [ 22245-83-6 ]
  • [ 573762-62-6 ]
Reference: [1] Patent: US9388159, 2016, B2,
[2] Patent: US9388159, 2016, B2,
  • 12
  • [ 22245-83-6 ]
  • [ 76041-79-7 ]
YieldReaction ConditionsOperation in experiment
80% at 80℃; Step 1 : 5-Bromo-3-(trifluoromethyl)pyridin-2(1 - )-one (P45a) To a solution of 3-(trifluoromethyl)pyridin-2(1 /-/)-one (25.0 g, 0.15 mol) in AcOH (300 mL) were added NaOAc (15.1 g, 0.18 mol) and dropwise Br2 (8.6 mL, 0.17 mol). Then the mixture was stirred at 80°C overnight, concentrated, diluted with sat aq. NaHC03 and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2S04, filtered, concentrated and purified by CC (PE/EA = 7/2) to give compound P45a (29.7 g, 80percent) as a white solid.
14 g With N-Bromosuccinimide; oxygen In tetrahydrofuran at 20℃; for 4 h; To a solution of 3-(trifluoromethyl)-2(1H)-pyridinone (D15) (10 g) in tetrahydrofuran (THF) (100 mL) stirred in air at room temperature was added NBS (14.19 g) portionwise. The reaction mixture was stirred for 4 h, then diluted with water (100 mL), extracted with ethyl acetate (3*50 mL). The combined organic phases were dried over sodium sulphate and concentrated to give 5-bromo-3-(trifluoromethyl)-2(1H)-pyridinone (D16) (14 g) as yellow solid. MS (ES): C6H3BrF3NO requires 241; found 242.0 (M+H+).
Reference: [1] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 16, p. 6106 - 6122
[2] Patent: WO2012/139775, 2012, A1, . Location in patent: Page/Page column 69-70
[3] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 23, p. 6578 - 6581
[4] Patent: US2013/12491, 2013, A1, . Location in patent: Paragraph 0171; 0172
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