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[ CAS No. 436799-33-6 ] {[proInfo.proName]}

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Chemical Structure| 436799-33-6
Chemical Structure| 436799-33-6
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Product Details of [ 436799-33-6 ]

CAS No. :436799-33-6 MDL No. :MFCD04972700
Formula : C6H3BrF3N Boiling Point : -
Linear Structure Formula :- InChI Key :HEDHNDVPKRVQPN-UHFFFAOYSA-N
M.W : 225.99 Pubchem ID :11127991
Synonyms :

Calculated chemistry of [ 436799-33-6 ]

Physicochemical Properties

Num. heavy atoms : 11
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.17
Num. rotatable bonds : 1
Num. H-bond acceptors : 4.0
Num. H-bond donors : 0.0
Molar Refractivity : 36.94
TPSA : 12.89 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) : -5.95 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.85
Log Po/w (XLOGP3) : 2.43
Log Po/w (WLOGP) : 4.02
Log Po/w (MLOGP) : 2.33
Log Po/w (SILICOS-IT) : 3.05
Consensus Log Po/w : 2.73

Druglikeness

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

Water Solubility

Log S (ESOL) : -3.11
Solubility : 0.176 mg/ml ; 0.000777 mol/l
Class : Soluble
Log S (Ali) : -2.34
Solubility : 1.02 mg/ml ; 0.00453 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.77
Solubility : 0.0383 mg/ml ; 0.000169 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.66

Safety of [ 436799-33-6 ]

Signal Word:Warning Class:
Precautionary Statements:P261-P301+P312-P302+P352-P304+P340-P305+P351+P338 UN#:
Hazard Statements:H302-H315-H319-H335 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 436799-33-6 ]

* 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 [ 436799-33-6 ]
  • Downstream synthetic route of [ 436799-33-6 ]

[ 436799-33-6 ] Synthesis Path-Upstream   1~13

  • 1
  • [ 436799-33-6 ]
  • [ 112110-07-3 ]
Reference: [1] Patent: WO2014/418, 2014, A1,
[2] Patent: US2015/197511, 2015, A1,
  • 2
  • [ 124-38-9 ]
  • [ 436799-33-6 ]
  • [ 131747-40-5 ]
YieldReaction ConditionsOperation in experiment
9%
Stage #1: With n-butyllithium; butyl magnesium bromide In tetrahydrofuran; diethyl ether; hexane; toluene at -75℃;
Stage #2: at -75 - 20℃; for 3.33 h;
26a)
5-(trifluoromethyl)nicotinic acid
A solution of 1.5 g 3-bromo-5-(trifluoromethyl)pyridine in 50 ml of toluene was added dropwise at -75° C. to a mixture of 9.96 mL (15.9 mmol) 1.6 molar butyllithium solution in hexane and 3.98 mL (8 mmol) 2 molar butylmagnesium chloride solution in diethyl ether and 10 mL THF. After 20 minutes 20 g (454 mmol) dry ice were added and the mixture was again stirred for 20 minutes at -75° C. and for 3 hours at RT.
The reaction mixture was combined with 50 mL 1 molar sodium hydroxide solution and extracted twice with diethyl ether.
The aqueous phase was acidified with 4 molar hydrochloric acid and extracted three times with diethyl ether.
The combined organic phases were dried on sodium sulphate and evaporated to dryness in vacuo.
The residue was mixed with dichloromethane and the precipitate formed was suction filtered and dried in the circulating air dryer at 55° C.
Yield: 9percent of theory
C7H4F3NO2 (191.11)
Reference: [1] European Journal of Organic Chemistry, 2003, # 8, p. 1559 - 1568
[2] Patent: US2010/240669, 2010, A1, . Location in patent: Page/Page column 141
  • 3
  • [ 112110-07-3 ]
  • [ 436799-33-6 ]
Reference: [1] Patent: US2006/4018, 2006, A1, . Location in patent: Page/Page column 14; 36
  • 4
  • [ 233770-01-9 ]
  • [ 81290-20-2 ]
  • [ 436799-33-6 ]
Reference: [1] European Journal of Organic Chemistry, 2002, # 2, p. 327 - 330
  • 5
  • [ 625-92-3 ]
  • [ 436799-33-6 ]
Reference: [1] European Journal of Organic Chemistry, 2002, # 2, p. 327 - 330
  • 6
  • [ 5419-55-6 ]
  • [ 436799-33-6 ]
  • [ 947533-51-9 ]
YieldReaction ConditionsOperation in experiment
96% With n-butyllithium In tetrahydrofuran; hexane at -78 - -10℃; Inert atmosphere To a solution of 3-bromo-5-(trifluoromethyl)pyridine (2.5 g, 11.06 mmol) and triisopropylborate (3.06 mL, 13.27 mmol) in anhydrous tetrahydrofuran (20 mL) at -78° C. under nitrogen was added dropwise a solution of n-butyl lithium in hexane (2.5 M, 4.9 mL, 12.17 mmol) The reaction was stirred at -78° C. for 3 hours then allowed to warm slowly to -10° C.
The reaction mixture was then quenched by the addition of water (20 mL) and the tetrahydrofuran removed under reduced pressure.
The resulting aqueous phase was diluted with water (40 mL) and washed with ether (2*40 mL).
The aqueous phase was then acidified to pH 5 by the addition of acetic acid and the resulting suspension extracted with ethyl acetate (80 mL).
The organic phase was separated, dried (MgSO4), filtered and concentrated under reduced pressure to give 3-(trifluoromethyl)pyridine-5-boronic acid (2.022 g, 96percent yield) as a tan solid.
HPLC/MS Rt=1.47 min, m/z 192.1 (M+H+).
Reference: [1] Patent: US2014/135320, 2014, A1, . Location in patent: Paragraph 0224; 0225
  • 7
  • [ 436799-33-6 ]
  • [ 947533-51-9 ]
Reference: [1] Organic and Biomolecular Chemistry, 2009, vol. 7, # 10, p. 2155 - 2161
[2] Patent: US2009/239847, 2009, A1, . Location in patent: Page/Page column 46
[3] Journal of Medicinal Chemistry, 2013, vol. 56, # 15, p. 6022 - 6032
  • 8
  • [ 73183-34-3 ]
  • [ 436799-33-6 ]
  • [ 947533-51-9 ]
Reference: [1] Patent: WO2012/3283, 2012, A1, . Location in patent: Page/Page column 239
  • 9
  • [ 109-72-8 ]
  • [ 5419-55-6 ]
  • [ 7732-18-5 ]
  • [ 436799-33-6 ]
  • [ 947533-51-9 ]
YieldReaction ConditionsOperation in experiment
60.13%
Stage #1: at -78℃; for 1 h; Inert atmosphere
Stage #2: at -10℃;
To a solution of 3-bromo-5-(trifluoromethyl)pyridine (100 g, 442.49 mmol, 1 eq) and TRIISOPROPYL BORATE (99.86 g, 530.99 mmol, 122.08 mL, 1.2 eq) in THF (1000 mL) was added n-BuLi (2.5 M in n-hexane, 194.70 mL, 1.1 eq) dropwise at -78 °C under N2 atmosphere. The mixture was stirred at -78 °C for 1 hr under N2 atmosphere. TLC indicated reactant 1 was consumed completely. The mixture was quenched with water (100 mL) at -10 °C, and acidified by HC1 (IN) to pH = 5. The mixture was extracted with EtOAc (200 mL x 3). The organic layer was dried over Na2S04, filtered and concentrated under reduced pressure. The residue was washed with EtOAc (100 mL) and filtered. The filter cake was dried to give the product. Compound [5-(trifluoromethyl)-3-pyridyl]boronic acid (50.8 g, 266.09 mmol, 60.13percent yield) was obtained as a white solid. 1H NMR (400MHz, DMSO) 9.07 (s, 1H), 8.94 (s, 1H), 8.39 (s, 1H)
Reference: [1] Patent: WO2018/67762, 2018, A2, . Location in patent: Page/Page column 36-37
  • 10
  • [ 5419-55-6 ]
  • [ 7732-18-5 ]
  • [ 436799-33-6 ]
  • [ 947533-51-9 ]
Reference: [1] Organic and Biomolecular Chemistry, 2009, vol. 7, # 10, p. 2155 - 2161
  • 11
  • [ 73183-34-3 ]
  • [ 436799-33-6 ]
  • [ 1084953-47-8 ]
YieldReaction ConditionsOperation in experiment
82%
Stage #1: With potassium acetate In 1,4-dioxane for 0.25 h;
Stage #2: at 100℃; for 20 h;
3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-pyridine
A suspension of 3.50 g (15.50 mmol) of 3-bromo-5-trifluoromethyl-pyridine, 0.54 g (0.8 mmol) of bis(triphenylphosphine)palladium(II) chloride and 4.55 g (46.5 mmol) of potassium acetate in 75 ml of dioxane was stirred for 15 min; then, 6.42 g (24.8 mmol) of 4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl](bis-pinacolatodiboron) was added and the mixture was heated up to 100° C.
After 20 hours, it was poured into crashed ice, the pH was adjusted to 9-10 with sodium carbonate solution and the mixture then extracted three times with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated.
The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 9:1) to give 3.48 g (82percent) of the title compound as a colorless solid. MS: 273.1 (M+).
Reference: [1] Patent: US2009/48238, 2009, A1, . Location in patent: Page/Page column 20
[2] Patent: WO2013/43521, 2013, A1, . Location in patent: Page/Page column 38; 39
[3] Patent: EP2719697, 2014, A1, . Location in patent: Paragraph 0210-0212
[4] Patent: EP2891656, 2015, A1, . Location in patent: Paragraph 0266
  • 12
  • [ 123-91-1 ]
  • [ 436799-33-6 ]
  • [ 1084953-47-8 ]
Reference: [1] Patent: US2014/93505, 2014, A1, . Location in patent: Page/Page column
  • 13
  • [ 557-21-1 ]
  • [ 436799-33-6 ]
  • [ 951624-83-2 ]
YieldReaction ConditionsOperation in experiment
44%
Stage #1: at 80℃;
Stage #2: With ammonia In diethyl ether; water; N,N-dimethyl-formamide at 20℃;
Example 1.1.27: (5-(trifluoromethyl)pyridin-3-yl)methanamine; 3-bromo-5-(trifluoromethyl)pyridine (1.0 g, 4.42 mmol, 1 eq) was dissolved in 20 mL anhydrous DMF. The solution was degassed by bubbling through with Ar. Zn(CN)2 (0.312 g, 2.65 mmol, 0.6 eq) and Pd(PPh3)4 were added, and the resulting solution was heated to 80 0C with stirring overnight. The reaction was cooled to room temperature and diluted with Et2O. NH4OH (28percent) was added with stirring and the layers were separated. The organic layer was washed with water (x3), brine (xl), and dried over Na2SO4. The inorganics were filtered off, and the reaction mixture was concentrated in vacuo. Purification via flash chromatography on silica gel yielded 0.310 g (1.95 mmol, 44percent yield) of 5- (trifluoromethyl)nicotinonitrile.
Reference: [1] Patent: WO2009/42694, 2009, A1, . Location in patent: Page/Page column 84
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