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[ CAS No. 99368-66-8 ] {[proInfo.proName]}

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Chemical Structure| 99368-66-8
Chemical Structure| 99368-66-8
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Product Details of [ 99368-66-8 ]

CAS No. :99368-66-8 MDL No. :MFCD00276983
Formula : C6H3F3N2O3 Boiling Point : -
Linear Structure Formula :- InChI Key :BHUILUYFGJBXHQ-UHFFFAOYSA-N
M.W : 208.09 Pubchem ID :2775095
Synonyms :

Calculated chemistry of [ 99368-66-8 ]

Physicochemical Properties

Num. heavy atoms : 14
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.17
Num. rotatable bonds : 2
Num. H-bond acceptors : 7.0
Num. H-bond donors : 1.0
Molar Refractivity : 40.08
TPSA : 78.94 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) : -6.48 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.95
Log Po/w (XLOGP3) : 1.54
Log Po/w (WLOGP) : 2.87
Log Po/w (MLOGP) : 0.23
Log Po/w (SILICOS-IT) : -0.15
Consensus Log Po/w : 1.09

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.29
Solubility : 1.08 mg/ml ; 0.00518 mol/l
Class : Soluble
Log S (Ali) : -2.81
Solubility : 0.325 mg/ml ; 0.00156 mol/l
Class : Soluble
Log S (SILICOS-IT) : -1.72
Solubility : 3.93 mg/ml ; 0.0189 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 2.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.06

Safety of [ 99368-66-8 ]

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

Application In Synthesis of [ 99368-66-8 ]

* 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 [ 99368-66-8 ]
  • Downstream synthetic route of [ 99368-66-8 ]

[ 99368-66-8 ] Synthesis Path-Upstream   1~6

  • 1
  • [ 99368-66-8 ]
  • [ 99368-67-9 ]
YieldReaction ConditionsOperation in experiment
86% With thionyl chloride In N,N-dimethyl-formamide at 100℃; for 10 h; SOCl2 (18.45 mL, 253 mmol) was added to a solution of 5-nitro-3-(trifluoromethyl)pyridin-2-ol (2.63 g, 12.64 mmol). DMF (1.957 mL, 25.3 mmol) was added and the mixture was at 100° C. for 10 h. Then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The resulting 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (2.46 g, 10.86 mmol, 86percent yield) was used in the next step without further purification. TLC (PE/EA=5:1, Rf=0.6): 1H NMR (400 MHz, CDCl3) δ: 9.23-9.59 (m, 1H), 8.79 (d, J=2.4 Hz, 1H).
86% at 100℃; for 10 h; SOCl2 (18.45 mL, 253 mmol) was added to a solution of 5 -nitro-3 -(trifluoromethyl)pyridin-2-ol (2.63 g, 12.64 mmol). DMF (1.957 mL, 25.3 mmol) was added and the mixture was at 100 °C for 10 h. Then the solution was concentrated and distributed between EA and saturated NaHCC>3 solution. The combined organic extract was washed with brine, dried over MgSO/i, filtered and concentrated. The resulting 2-chloro-5 -nitro-3 -(trifluoromethyl)pyridine (2.46 g, 10.86 mmol, 86percent yield) was used in the next step without further purification. TLC (PE/EA = 5: 1, Rf = 0.6): 'HNMR (400 MHz, CDCI3) δ: 9.23-9.59 (m, 1H), 8.79 (d, J = 2.4 Hz, 1H).
77% at 90℃; for 3 h; Reference Example 118 2-chloro-5-nitro-3-(trifluoromethyl)pyridine; A mixture of 5-nitro-3-(trifluoromethyl)pyridin-2-ol (2.65 g), phosphorus pentachloride (3.17 g) and phosphorus oxychloride (1.5 mL) was stirred at 90° C. for 3 hr. After cooling to room temperature, the reaction mixture was poured into ice, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1-->3:1) to give the title compound as a yellow oil (yield 2.21 g, 77percent). 1H-NMR (CDCl3) δ: 8.79-8.81 (1H, m), 9.40-9.41 (1H, m).
55.1% at 80℃; for 16 h; To a mixture of 5-nitro-3- (trifluoromethyl) pyridin-2-ol (2 g 9.61 mmol) was added SOCl2(21.04 mL 288 mmol) and DMF (0.074 mL 0.961 mmol) . Then the mixture was stirred at 80 for 16 h. The mixture was concentrated and extracted with EA (2 x 100 mL) and washed with H2O (100 mL) to give the organic layer. The combined organic extract was washed with brine dried over Na2SO4 concentrated to yield a brown solid of 2-chloro-5-nitro-3- (trifluoromethyl) pyridine (2 g 5.30 mmol 55.1yield) 1HNMR(400 MHz CD3OD) δ 8.91 (d J 2.43 Hz 1H) 9.42 (d J 2.43 Hz 1H)

Reference: [1] Patent: US2014/275111, 2014, A1, . Location in patent: Paragraph 0259; 0260
[2] Patent: WO2014/141187, 2014, A1, . Location in patent: Page/Page column 49; 59; 63; 87; 88; 124
[3] Patent: US2007/60623, 2007, A1, . Location in patent: Page/Page column 39
[4] Patent: WO2016/37578, 2016, A1, . Location in patent: Page/Page column 84
[5] Patent: WO2006/42289, 2006, A2, . Location in patent: Page/Page column 52
[6] Patent: US2006/223837, 2006, A1, . Location in patent: Page/Page column 40
  • 2
  • [ 99368-66-8 ]
  • [ 99368-67-9 ]
YieldReaction ConditionsOperation in experiment
96% at 110 - 120℃; for 8 h; a mixture of 5-nitro-3- (trifluoromethyl) pyridine -2 (1H) -One, 3 (1.50g, 7.21mmol), POCl3 (2.76g, 18.02mmol) and PCl5(1.4g, 10. 09mmol) was heated 8 hours to about 110 ~ 120 and poured into ice water. Themixture was neutralized with solid NaHCO3, and extracted with ethylacetate (3 × 40ml). The organic phases were combined, dried over Na2SO4,all solvents were evaporated under reduced pressure to give 2-chloro-5-nitro-3-(trifluoromethyl) pyridine 4.
96% at 110 - 120℃; for 8 h; Synthesis of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine, 4 (0076) (0077) A mixture of 5-nitro-3-(trifluoromethyl)pyridin-2(1H)-one 3 (1.50 g, 7.21 mmol), POCl3 (2.76 g, 18.02 mmol) and PCl5 (1.4 g, 10.09 mmol) is heated to about 110-120° C. for 8 hours and then poured into ice water. The mixture is neutralized with solid NaHCO3 and extracted with ethyl acetate (3×40 ml). The combined organic phases is dried over Na2SO4 and all solvents removed under reduced pressure to obtain 2-chloro-5-nitro-3-(trifluoromethyl)pyridine 4.
Reference: [1] Patent: JP2016/11315, 2016, A, . Location in patent: Paragraph 0059-0060
[2] Patent: US9388159, 2016, B2, . Location in patent: Page/Page column 15
[3] Patent: EP1632477, 2006, A1, . Location in patent: Page/Page column 21
  • 3
  • [ 99368-66-8 ]
  • [ 99368-68-0 ]
Reference: [1] Patent: US2014/275111, 2014, A1,
[2] Patent: WO2014/141187, 2014, A1,
[3] Patent: WO2016/37578, 2016, A1,
  • 4
  • [ 99368-66-8 ]
  • [ 99368-68-0 ]
Reference: [1] Patent: JP2016/11315, 2016, A,
[2] Patent: US9388159, 2016, B2,
  • 5
  • [ 99368-66-8 ]
  • [ 573762-62-6 ]
Reference: [1] Patent: WO2016/100645, 2016, A1,
[2] Patent: US2016/152592, 2016, A1,
[3] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 12, p. 2803 - 2806
  • 6
  • [ 99368-66-8 ]
  • [ 573762-62-6 ]
Reference: [1] Patent: US9388159, 2016, B2,
[2] Patent: US9388159, 2016, B2,
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