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Chemical Structure| 161957-56-8
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Product Details of [ 161957-56-8 ]

CAS No. :161957-56-8 MDL No. :MFCD00665763
Formula : C7H4BrFO2 Boiling Point : -
Linear Structure Formula :- InChI Key :UVKURTLVTLRSSM-UHFFFAOYSA-N
M.W : 219.01 Pubchem ID :2736313
Synonyms :

Calculated chemistry of [ 161957-56-8 ]

Physicochemical Properties

Num. heavy atoms : 11
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 1
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 41.06
TPSA : 37.3 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) : -6.05 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.34
Log Po/w (XLOGP3) : 2.24
Log Po/w (WLOGP) : 2.71
Log Po/w (MLOGP) : 2.79
Log Po/w (SILICOS-IT) : 2.32
Consensus Log Po/w : 2.28

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.85

Water Solubility

Log S (ESOL) : -2.95
Solubility : 0.248 mg/ml ; 0.00113 mol/l
Class : Soluble
Log S (Ali) : -2.66
Solubility : 0.48 mg/ml ; 0.00219 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.91
Solubility : 0.269 mg/ml ; 0.00123 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.42

Safety of [ 161957-56-8 ]

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 [ 161957-56-8 ]

* 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 [ 161957-56-8 ]
  • Downstream synthetic route of [ 161957-56-8 ]

[ 161957-56-8 ] Synthesis Path-Upstream   1~14

  • 1
  • [ 161957-56-8 ]
  • [ 161957-61-5 ]
Reference: [1] Patent: US2008/76771, 2008, A1,
  • 2
  • [ 1072-85-1 ]
  • [ 124-38-9 ]
  • [ 161957-56-8 ]
YieldReaction ConditionsOperation in experiment
64%
Stage #1: With n-butyllithium; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at -78℃; for 2 h;
Stage #3: With hydrogenchloride In water
INTERMEDIATE PREPARATION 76-bromo-7-fluoro-1 /-/-indole-2,3-dione3-bromo-2-fluorobenzoic acidTo a solution of diisopropylamine (84.3 mL, 600 mmol) in THF (500 mL) at -30°C was added n-BuLi (240 mL of a 2.5M solution, 600 mmol) dropwise. The resulting solution was stirred at -30°C for 30 min. This mixture was added dropwise to a solution of 1-bromo-2- fluorobenzene (100 g, 571 .43 mmol) in THF (500 mL) at -78°C. After the addition was complete, the resulting solution was stirred at -78°C for 2 h and poured over crushed solid C02. After removal of the solvent in vacuo, the resulting residue was diluted with water and washed with diethyl ether (2 x 500 mL). The aqueous phase was acidified with 1 N HCI to pH 2. The precipitate was collected by filtration and dried to afford 3-bromo-2-fluorobenzoic acid (90 g, 64percent yield) as a white solid. MS (m/z) 221.0 (M+H+).
55% With 2,2,6,6-tetramethyl-piperidine; n-butyllithium In tetrahydrofuran; hexane at -75 - -10℃; for 3.5 h; Example 16
3-Bromo-2-fluorobenzoic acid
To a stirred solution of 2,2,6,6-tetramethylpiperidine (31.1 g, 0.22 mol) in THF (200 mL) was added dropwise a solution of butyl lithium (0.22 mol) in hexane (146.7 mL) at -10° C.
The mixture was stirred for 1.5 h at -10° C. and the fluoroarene (1-bromo-2-fluorobenzene) in THF (100 mL) was consecutively added to the solution at -75° C.
The mixture was stirred for 2 h at -75° C., before being poured on excess of CO2 gas.
Then the reaction mixture was warmed to room temperature and stirred over night.
After evaporation of the solvent, the residue was dissolved in water (150 mL), washed with diethyl ether (2*50 mL), acidified (to pH 1) and the solid was filtered off and dried under vacuum to give 24.3 g of the title compound as a white solid (yield: 55percent).
55%
Stage #1: With 2,2,6,6-tetramethyl-piperidine; n-butyllithium In tetrahydrofuran; hexane; water at -75 - -10℃;
Stage #2: at -75 - 20℃;
Stage #3: With hydrogenchloride In water
Example 16
3-Bromo-2-fluorobenzoic Acid
To a stirred solution of 2,2,6,6-tetramethylpiperidine (31.1 g, 0.22 mol) in THF (200 mL) was added dropwise a solution of butyl lithium (0.22 mol) in hexane (146.7 mL) at -10° C.
The mixture was stirred for 1.5 h at -10° C. and the fluoroarene (1-bromo-2-fluorobenzene) in THF (100 mL) was consecutively added to the solution at -75° C.
The mixture was stirred for 2 h at -75° C., before being poured on excess of CO2 gas.
Then the reaction mixture was warmed to room temperature and stirred over night.
After evaporation of the solvent, the residue was dissolved in water (150 mL), washed with diethyl ether (2*50 mL), acidified (to pH 1) and the solid was filtered off and dried under vacuum to give 24.3 g of the title compound as a white solid (yield: 55percent).
55%
Stage #1: With 2,2,6,6-tetramethyl-piperidine; n-butyllithium In tetrahydrofuran; hexane at -75℃; for 2 h;
Stage #2: at -75 - 20℃;
Example 19
3-Bromo-2-fluorobenzoic Acid
To a stirred solution of 2,2,6,6-tetramethylpiperidine (31.1 g, 0.22 mol) in THF (200 mL) was added dropwise a solution of butyl lithium (0.22 mol) in hexane (146.7 mL) at -10° C.
The mixture was stirred for 1.5 h at -10° C. and the fluoroarene (1-bromo-2-fluorobenzene) in THF (100 mL) was consecutively added to the solution at -75° C.
The mixture was stirred for 2 h at -75° C. and an excess of freshly CO2 gas bubbled into the reaction mixture.
Then the reaction mixture was warmed to room temperature and stirred over night.
After evaporation of the solvent, the residue was dissolved in water (150 mL), washed with diethyl ether (2*50 mL), acidified (to pH 1) and the solid was filtered off, dried under vacuum to give 24.3 g of the title compound as a white solid (yield: 55percent).
55%
Stage #1: With 2,2,6,6-tetramethyl-piperidine; n-butyllithium In tetrahydrofuran; hexane at -75℃; for 2 h;
Stage #2: at -75 - 20℃;
Stage #3: Acidic conditions
Example 16 3-Bromo-2-fhiorobenzoic acidTo a stirred solution of 2,2,6,6-tetramethylpiperidine (31.1 g, 0.22 mol) in THF (200 mL) was added dropwise a solution of butyl lithium (0.22 mol) in hexane (146.7 mL) at -10 0C. The mixture was stirred for 1.5 h at -10 0C and the fluoroarene (l-bromo-2-fluorobenzene) in THF (100 mL) was consecutively added to the solution at -75 0C. The mixture was stirred for 2 h at -75 0C, before being poured on excess of CO2 gas. Then the reaction mixture was warmed to room temperature and stirred over night. After evaporation of the solvent, the residue was dissolved in water (150 mL), washed with diethyl ether (2 x 50 mL), acidified (to pH 1) and the solid was filtered off and dried under vacuum to give 24.3 g of the title compound as a white solid (yield: 55percent).

Reference: [1] Bulletin de la Societe Chimique de France, 1996, vol. 133, # 2, p. 133 - 141
[2] Patent: WO2011/119704, 2011, A1, . Location in patent: Page/Page column 39-40
[3] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 12, p. 4158 - 4181
[4] Patent: US2009/203657, 2009, A1, . Location in patent: Page/Page column 47
[5] Patent: US2009/203677, 2009, A1, . Location in patent: Page/Page column 50
[6] Patent: US2009/197871, 2009, A1, . Location in patent: Page/Page column 49
[7] Patent: WO2009/100169, 2009, A1, . Location in patent: Page/Page column 125
[8] Tetrahedron Letters, 1995, vol. 36, # 6, p. 881 - 884
[9] Tetrahedron Letters, 1996, vol. 37, # 36, p. 6551 - 6554
[10] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 18, p. 2115 - 2118
[11] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 23, p. 10001 - 10012
  • 3
  • [ 1072-85-1 ]
  • [ 109-72-8 ]
  • [ 161957-56-8 ]
YieldReaction ConditionsOperation in experiment
57% With lithium; diisopropylamine In tetrahydrofuran; water Intermediate 38: 3-Bromo-2-fluorobenzoic acid
Tetrahydrofuran (60 ml) was added to diisopropylamine (9.6 ml, 68 mmol) in an argon atmosphere. n-Butyllithium (hexane solution, 1.5 M, 38 ml, 57 mmol) was added dropwise thereto at -10°C, and the mixture was stirred for one hr.
Separately, 55 ml of tetrahydrofuran was added to 1-bromo-2-fluorobenzene (10 g, 57 mmol) to prepare a solution which was then added dropwise to the lithium reagent solution at -78°C.
The mixture was stirred for 2 hr and was then stirred for additional 30 min while blowing carbon dioxide thereinto.
The temperature of the reaction mixture was returned to room temperature, and the reaction mixture was concentrated under the reduced pressure.
Water (200 ml) was added to the residue to prepare a solution, and the solution was washed twice with 100 ml of diethyl ether.The aqueous layer was adjusted to pH 1 by the addition of 1.0 M hydrochloric acid, was extracted twice with 300 ml of methylene chloride, was dried over anhydrous magnesium sulfate, and was concentrated under the reduced pressure to give the title compound (7.1 g, 57percent).
Physicochemical properties of intermediate 38
Reference: [1] Patent: EP1229024, 2002, A1,
  • 4
  • [ 124-38-9 ]
  • [ 161957-56-8 ]
Reference: [1] Patent: WO2005/121087, 2005, A1, . Location in patent: Page/Page column 66
  • 5
  • [ 67-56-1 ]
  • [ 161957-56-8 ]
  • [ 206551-41-9 ]
Reference: [1] Patent: US2009/298815, 2009, A1, . Location in patent: Page/Page column 52-53
[2] Patent: WO2010/104899, 2010, A1, . Location in patent: Page/Page column 162
[3] Patent: WO2011/59610, 2011, A1, . Location in patent: Page/Page column 86
[4] ACS Medicinal Chemistry Letters, 2013, vol. 4, # 3, p. 358 - 362
[5] Patent: US9126993, 2015, B2, . Location in patent: Page/Page column 51
  • 6
  • [ 161957-56-8 ]
  • [ 149-73-5 ]
  • [ 206551-41-9 ]
Reference: [1] Patent: US2002/49204, 2002, A1,
[2] Patent: US6391907, 2002, B1,
[3] Patent: US6444668, 2002, B1,
[4] Patent: US6462032, 2002, B1,
  • 7
  • [ 161957-56-8 ]
  • [ 74-88-4 ]
  • [ 206551-41-9 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 14, p. 4502 - 4505
[2] Patent: US2012/220572, 2012, A1, . Location in patent: Page/Page column 85
[3] Organic Letters, 2017, vol. 19, # 5, p. 1112 - 1115
  • 8
  • [ 161957-56-8 ]
  • [ 840481-82-5 ]
Reference: [1] Patent: WO2016/161145, 2016, A1,
[2] Patent: WO2008/156757, 2008, A1,
  • 9
  • [ 161957-56-8 ]
  • [ 149947-15-9 ]
Reference: [1] Organic Letters, 2017, vol. 19, # 5, p. 1112 - 1115
[2] Patent: US2008/114167, 2008, A1,
  • 10
  • [ 161957-56-8 ]
  • [ 58534-95-5 ]
YieldReaction ConditionsOperation in experiment
50% With diphenyl phosphoryl azide; triethylamine In N,N-dimethyl-formamide at 0℃; for 2 h; Step 1: 3-bromo-2-fluoroaniiTo a stirred solution of 3-bromo-2-fluoro benzoic acid (10 g, 0.04566 mol) in Ν,Ν-dimethyl formamide (80 mL), were added dropwise triethylamine (19 ml_, 0.13669 mol) and diphenylphosphoryl azide (14.8 mL, 0.05378 mol) at 0°Csequentially. The reaction mixture was stirred for 2 h at 0°C. Water (27 mL) was added and the reaction mixture was heated at 80 °C for 2 h. The reaction mixture was cooled to room temperature, diluted with water (200 mL) and extracted with diethyl ether (3x150 mL). The combined organic layers were washed with cold water (2x200 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure.The residue obtained was treated with hexane (100 mL), filtered, and the filter cake was washed with hexane (2x100 mL). The filtrate was evaporated under reduced pressure to afford the title compound (4.3 g, 50percent) as a brown liquid. H NMR (400 MHz, DMSO-d6) : δ 6.82-6.70 (m, 3H), 5.43 (brs, 2H); ESI-MS: Calculated mass:188.96; Observed mass: 188.10 [M-H]\
Reference: [1] Patent: WO2014/169167, 2014, A1, . Location in patent: Page/Page column 48; 49
[2] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 24, p. 7661 - 7670
[3] Patent: EP2987787, 2016, A1,
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  • [ 161957-56-8 ]
  • [ 1195768-19-4 ]
Reference: [1] ACS Medicinal Chemistry Letters, 2013, vol. 4, # 3, p. 358 - 362
  • 12
  • [ 161957-56-8 ]
  • [ 1195768-23-0 ]
Reference: [1] ACS Medicinal Chemistry Letters, 2013, vol. 4, # 3, p. 358 - 362
  • 13
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  • [ 1188227-29-3 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 24, p. 7661 - 7670
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  • [ 1336963-95-1 ]
Reference: [1] Patent: WO2011/119704, 2011, A1,
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