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[ CAS No. 328-74-5 ] {[proInfo.proName]}

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Chemical Structure| 328-74-5
Chemical Structure| 328-74-5
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Product Details of [ 328-74-5 ]

CAS No. :328-74-5 MDL No. :MFCD00000394
Formula : C8H5F6N Boiling Point : -
Linear Structure Formula :- InChI Key :CDIDGWDGQGVCIB-UHFFFAOYSA-N
M.W :229.12 Pubchem ID :9480
Synonyms :

Calculated chemistry of [ 328-74-5 ]

Physicochemical Properties

Num. heavy atoms : 15
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.25
Num. rotatable bonds : 2
Num. H-bond acceptors : 6.0
Num. H-bond donors : 1.0
Molar Refractivity : 40.85
TPSA : 26.02 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) : -5.16 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.69
Log Po/w (XLOGP3) : 3.57
Log Po/w (WLOGP) : 5.62
Log Po/w (MLOGP) : 3.59
Log Po/w (SILICOS-IT) : 3.2
Consensus Log Po/w : 3.53

Druglikeness

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

Water Solubility

Log S (ESOL) : -3.67
Solubility : 0.0486 mg/ml ; 0.000212 mol/l
Class : Soluble
Log S (Ali) : -3.8
Solubility : 0.0361 mg/ml ; 0.000158 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.82
Solubility : 0.0348 mg/ml ; 0.000152 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 2.0
Synthetic accessibility : 1.38

Safety of [ 328-74-5 ]

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 [ 328-74-5 ]

* 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 [ 328-74-5 ]
  • Downstream synthetic route of [ 328-74-5 ]

[ 328-74-5 ] Synthesis Path-Upstream   1~22

  • 1
  • [ 328-70-1 ]
  • [ 328-74-5 ]
Reference: [1] Organic Letters, 2005, vol. 7, # 6, p. 1169 - 1172
[2] Organic Letters, 2013, vol. 15, # 14, p. 3734 - 3737
  • 2
  • [ 328-70-1 ]
  • [ 32707-86-1 ]
  • [ 328-74-5 ]
Reference: [1] Journal of the American Chemical Society, 2009, vol. 131, # 31, p. 11049 - 11061
  • 3
  • [ 328-75-6 ]
  • [ 105653-15-4 ]
  • [ 328-74-5 ]
Reference: [1] Synthesis, 2006, # 19, p. 3316 - 3340
  • 4
  • [ 328-75-6 ]
  • [ 75092-04-5 ]
  • [ 328-74-5 ]
Reference: [1] Journal of Organic Chemistry USSR (English Translation), 1980, vol. 16, p. 1031 - 1038[2] Zhurnal Organicheskoi Khimii, 1980, vol. 16, # 6, p. 1194 - 1202
  • 5
  • [ 328-73-4 ]
  • [ 328-74-5 ]
Reference: [1] Tetrahedron, 2010, vol. 66, # 38, p. 7642 - 7650
[2] Journal of Organic Chemistry, 2016, vol. 81, # 1, p. 330 - 335
  • 6
  • [ 328-75-6 ]
  • [ 75092-05-6 ]
  • [ 328-74-5 ]
Reference: [1] Journal of Organic Chemistry USSR (English Translation), 1980, vol. 16, p. 1031 - 1038[2] Zhurnal Organicheskoi Khimii, 1980, vol. 16, # 6, p. 1194 - 1202
  • 7
  • [ 23165-29-9 ]
  • [ 328-74-5 ]
YieldReaction ConditionsOperation in experiment
187 mg With triethylamine In dichloromethane; chloroform General procedure: To a ice cooled solution of N-Boc-aminoacid (L-tertleucine, L-Leu, L-Val, L-Phe, L-Ala) 1mmol in DCM 10 ml, HOBt hydrate (0.153 g, 1 mmol) and DCC (0.205 g, 1 mmol) was added. Reaction mixture was stirred at 0°C through 30 minutes, and amine 7 a-g (2 mmol) was added. Resulting reaction mixture was stirred for 12 h and allowed to warm to room temperature. Then a few drops of acetic acid was added, solvents was removed under reduced pressure. Residue was dissolved in AcOEt and cooled to 4°C, precipitate of urea was removed by filtration. Organic phase was washed with aqueous solution of KHSO4 (10percent, 20ml) followed by aqueous solution of NaHCO3 (5percent, 20ml) and dried with MgSO4. Solvents were removed under reduced pressure and residue was dissolved in 10ml mixture of TFA:DCM (1:1). Progress of N-deprotection was monitored with TLC. Then mixture of TFA:DCM was evaporated and trifluoroacetate salt was dissolved in DCM 10 ml. To a resulted mixture NEt3 (0.303 g, 3 mmol) and chloroform solution of isothiocyanate 9a,b[2] was added dropwise. After completion of the reaction, the solvent was removed under vacuum, and the residue was purified with flash column chromatography. (S)-N-benzyl-2-(3-(3,5-bis(trifluoromethyl)phenyl)thioureido)-3,3-dimethylbutanamide (10a)Purification by flash column chromatography, (EtOAc/Hex, gradient elution 1:5 to 1:3),(187 mg, 38percent over two steps). white solid; mp 149–151 °C; [α]D26 −12.5° (c 0.4,CHCl3); 1H NMR (500 MHz, C6D6) δ 8.60 (s, 1H), 8.06 (d, J 9.2 Hz, 1H), 7.99 (s, 2H),7.42 (s, 1H), 6.96–6.90 (m, 4H), 6.89–6.84 (m, 1H), 5.51 (s, 1H), 5.02 (d, J 9.2 Hz,1H), 4.08 (dd, J2 14.7 Hz, J3 6.4 Hz, 1H), 3.88 (dd, J2 14.7 Hz, J3 5.3 Hz, 1H),0.97 (s, 9H); 13C NMR (CDCl3, 100 MHz): δ 181.9, 172.1, 139.9, 136.2, 131.7 (q, JC–F 33.3 Hz), 128.8, 127.9, 127.6, 124.2 (m), 123.0 (q, JC–F 271.1 Hz), 118.5 (m), 66.4, 44.2,35.1, 27.2; HRMS (ESI): m/z [MNa] calcd for C22H23F6N3OSNa: 514.1364; found:514.1368.
Reference: [1] Synthetic Communications, 2018, vol. 48, # 1, p. 14 - 25
  • 8
  • [ 1246566-49-3 ]
  • [ 328-74-5 ]
Reference: [1] Tetrahedron, 2010, vol. 66, # 38, p. 7642 - 7650
  • 9
  • [ 328-75-6 ]
  • [ 328-74-5 ]
Reference: [1] Journal of the American Chemical Society, 1946, vol. 68, p. 1602,1603
[2] Journal of the American Chemical Society, 1951, vol. 73, p. 3579
[3] Journal of the American Chemical Society, 1953, vol. 75, p. 4967
  • 10
  • [ 402-31-3 ]
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Reference: [1] Journal of the American Chemical Society, 1953, vol. 75, p. 4967
  • 11
  • [ 201230-82-2 ]
  • [ 328-75-6 ]
  • [ 110-83-8 ]
  • [ 328-74-5 ]
  • [ 727741-42-6 ]
Reference: [1] Tetrahedron, 2004, vol. 60, # 23, p. 4989 - 4994
  • 12
  • [ 328-74-5 ]
  • [ 328-70-1 ]
Reference: [1] Patent: US2547679, 1950, ,
[2] Collection of Czechoslovak Chemical Communications, 1987, vol. 52, # 5, p. 1340 - 1351
  • 13
  • [ 328-74-5 ]
  • [ 349-58-6 ]
Reference: [1] Patent: US2547679, 1950, ,
  • 14
  • [ 328-74-5 ]
  • [ 328-73-4 ]
Reference: [1] Organic Letters, 2017, vol. 19, # 10, p. 2518 - 2521
[2] Journal of the American Chemical Society, 1953, vol. 75, p. 4967
[3] Australian Journal of Chemistry, 1979, vol. 32, p. 1521 - 1530
[4] Organic Letters, 2018, vol. 20, # 17, p. 5167 - 5171
  • 15
  • [ 328-74-5 ]
  • [ 367-65-7 ]
Reference: [1] Tetrahedron, 2012, vol. 68, # 5, p. 1452 - 1459
  • 16
  • [ 328-74-5 ]
  • [ 367-65-7 ]
Reference: [1] Patent: US5514680, 1996, A,
  • 17
  • [ 328-74-5 ]
  • [ 39234-86-1 ]
Reference: [1] Journal of the American Chemical Society, 1990, vol. 112, # 12, p. 4976 - 4977
[2] Tetrahedron Letters, 1990, vol. 31, # 26, p. 3715 - 3718
[3] Journal of the American Chemical Society, 1982, vol. 104, # 8, p. 2183 - 2189
[4] Organic and Biomolecular Chemistry, 2010, vol. 8, # 23, p. 5324 - 5332
  • 18
  • [ 13675-18-8 ]
  • [ 328-74-5 ]
  • [ 73852-19-4 ]
Reference: [1] Chemistry - A European Journal, 2014, vol. 20, # 22, p. 6608 - 6612
  • 19
  • [ 328-74-5 ]
  • [ 73852-19-4 ]
Reference: [1] Chemistry - A European Journal, 2014, vol. 20, # 22, p. 6608 - 6612
  • 20
  • [ 328-74-5 ]
  • [ 69807-91-6 ]
Reference: [1] Advanced Synthesis and Catalysis, 2013, vol. 355, # 6, p. 1083 - 1088
[2] Tetrahedron Letters, 2014, vol. 55, # 10, p. 1702 - 1705
  • 21
  • [ 321-14-2 ]
  • [ 328-74-5 ]
  • [ 978-62-1 ]
YieldReaction ConditionsOperation in experiment
85.5% With phosphorus trichloride In toluene for 3 h; Heating / reflux A mixture of 5-chlorosalicylic acid(6.90g, 40mmol), 3,5-bis(trifluoromethyl)aniline(9.16g, 40mmol), phosphorus trichloride(1.74mL, 20mmol) and toluene(80mL) was refluxed for 3 hours under argon atmosphere. After the reaction mixture was cooled to room temperature, it was diluted with ethyl acetate(240mL). After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=4:1) to give the title compound(13.12g, 85.5percent) as a light yellow solid.1H-NMR(DMSO-d6): δ 7.05(1H, d, J=8.7Hz), 7.49(1H, dd, J=8.7, 2.7Hz), 7.85(1H, s), 7.87(1H, d, J=2.7Hz), 8.45(2H, s), 10.85(1H, s), 11.39(1H, s).
62% With phosphorus trichloride In chlorobenzeneMicrowave irradiation General procedure: All salicylanilides(1a-8d) were synthesized via a previously described microwave assisted (MicroSYNTH Milestone) method.25 Briefly,the appropriately substituted salicylic acid (1 eq) and the substituted aniline (1 eq) were suspended or dissolved in chlorobenzene(1 mL/0.15 mmol of acid). Phosphorus trichloride (PCl3) was added(0.5 eq) and the mixture was stirred (600 rpm) and radiated(530 W) for 30–60 min. The mixture was filtrated while hot and was let cool, initially at r.t. and overnight at 4 °C. The formed pre-cipitate was filtered and recrystallized with ethanol or mixture of hexane/AcOEt in order to afford the final compounds with yields of 41–83percent.
57% With trichlorophosphate In toluene for 6 h; Inert atmosphere; Reflux To 30 ml and of toluene were added 5-chlorosalicylic acid (862 mg, 5 mmol), 3,5-bis(trifluoromethyl)aniline (1.37 g, 6 mmol), and phosphoroustrichloride (755 mg, 5.5 mmol) in the presence of argon gas, followed by stirring for 6 hours through heat-reflux.
Sodium hydrogen carbonate was added to the mixture to adjust pH to 7, followed by concentration under reduced pressure.
The mixture was dissolved in 60 ml and of ethylacetate, which was washed with water (40 ml*2).
The organic layer was concentrated under reduced pressure, followed by column chromatography to give 1.09 g of the target compound (yield: 57percent).
m.p: 172-173° C.;
1H-NMR (300 MHz, DMSO-d6): δ 7.05 (1H, d, J=8.7 Hz), 7.49 (1H, dd, J=8.7, 2.7 Hz), 7.85 (1H, s), 7.87 (1H, d, J=2.7 Hz), 8.45 (2H, s), 10.85 (1H, s), 11.39 (1H, s).
28% With pyridine; phosphorus trichloride In toluene for 12 h; Inert atmosphere; Reflux General procedure: The salicylic acid (1.2 equiv) was added to a mixture of toluene (0.3 M), aniline (1.0 equiv), phosphorus trichloride (1.1 equiv), and pyridine (0.05 equiv) in a Radley’s Carousel reaction tube (modified from Itai et al.20). The mixture was refluxed under nitrogen for 12 h then cooled to room temperature. Aqueous sodium bicarbonate was added dropwise to attain pH 6–7. The resultant mixture was extracted with EtOAc. The organic extracts were combined, dried (MgSO4), and concentrated under vacuum. After chromatography (1:10 EtOAc:Hex) compounds were recrystallized (EtOAc/Hex).
28% With pyridine; phosphorus trichloride In tolueneInert atmosphere; Reflux Phosphorus trichloride (0.13ml, 1.5mmol) was added to a stirred solution of 3,5-bis(trifluoromethyl)aniline (0.47ml, 3mmol), a catalytic amount of pyridine and 5-chloro salicylic acid (621.3mg, 3.6mmol) in anhydrous toluene (10ml) in in a Radley’s Carousel reaction tube under an argon atmosphere. After the reaction mixture was refluxed for overnight, it was cooled to room temperature and aq. sodium bicarbonate was added dropwise until PH=6 - 7. After extracting with ethyl acetate, the organic layers was dried, dried (MgSO4) and concentrated in vacuo. After chromatography (EA-Hex, 1:10) of the crude product, and followed by recrystalization from EtOAc/hexane provided 2a as a white solid (320mg, 28percent). mp 172 - 173 oC. 1H NMR (DMSO-d6) δ 11.37(brs, 1H), 10.91(s, 1H), 8.43(s, 2H), 7.85-7.88(m, 2H), 7.49(dd, J1=8.7Hz, J2=2.9Hz, 1H), 7.05(d, J=8.7Hz, 1H).

Reference: [1] Patent: EP1352650, 2003, A1,
[2] Patent: EP1512397, 2005, A1, . Location in patent: Page/Page column 77
[3] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 4, p. 1524 - 1532
[4] Patent: US2014/221411, 2014, A1, . Location in patent: Paragraph 0192; 0193
[5] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 1, p. 114 - 126
[6] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 6, p. 1748 - 1751
[7] Journal of Medicinal Chemistry, 2012, vol. 55, # 19, p. 8375 - 8391,17
[8] Journal of Medicinal Chemistry, 2012, vol. 55, # 19, p. 8375 - 8391
  • 22
  • [ 328-74-5 ]
  • [ 268733-18-2 ]
YieldReaction ConditionsOperation in experiment
340 mg With N-Bromosuccinimide In N,N-dimethyl-formamide at 50℃; for 1 h; 3,5-Bis(trifluoromethyl)aniline (2 g, 8.7 mmol, 1 equiv) was dissolved in DMF (6 mL, 1.5 M). N-bromosuccinimide (1.7 g, 9.6 mmol, 1.1 equiv) was added, and this mixture was stirred at 50 °C for one hour.
After cooling to room temperature, water was added (100 mL) followed by extraction with EtOAc.
The crude product was purified by column chromatography (1:10 → 1:5 EtOAc:Hex) to give 4-bromo-3,5-bis-(trifluoromethyl)-aniline (340 mg) & 2-bromo-3,5-bis-(trifluoromethyl)aniline (680 mg).
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 6, p. 1748 - 1751
[2] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 1, p. 114 - 126
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