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[ CAS No. 57381-59-6 ] {[proInfo.proName]}

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Chemical Structure| 57381-59-6
Chemical Structure| 57381-59-6
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Product Details of [ 57381-59-6 ]

CAS No. :57381-59-6 MDL No. :MFCD06203710
Formula : C8H6BrFO2 Boiling Point : -
Linear Structure Formula :- InChI Key :DXOPSTSVRPCTOS-UHFFFAOYSA-N
M.W : 233.03 Pubchem ID :21525435
Synonyms :

Calculated chemistry of [ 57381-59-6 ]

Physicochemical Properties

Num. heavy atoms : 12
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.12
Num. rotatable bonds : 2
Num. H-bond acceptors : 3.0
Num. H-bond donors : 0.0
Molar Refractivity : 45.38
TPSA : 26.3 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) : -5.94 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.26
Log Po/w (XLOGP3) : 2.51
Log Po/w (WLOGP) : 2.8
Log Po/w (MLOGP) : 3.09
Log Po/w (SILICOS-IT) : 2.79
Consensus Log Po/w : 2.69

Druglikeness

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

Water Solubility

Log S (ESOL) : -3.1
Solubility : 0.183 mg/ml ; 0.000787 mol/l
Class : Soluble
Log S (Ali) : -2.71
Solubility : 0.456 mg/ml ; 0.00196 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.61
Solubility : 0.0569 mg/ml ; 0.000244 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.61

Safety of [ 57381-59-6 ]

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 [ 57381-59-6 ]

* 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 [ 57381-59-6 ]
  • Downstream synthetic route of [ 57381-59-6 ]

[ 57381-59-6 ] Synthesis Path-Upstream   1~7

  • 1
  • [ 57381-59-6 ]
  • [ 7364-27-4 ]
YieldReaction ConditionsOperation in experiment
89% With hydrazine hydrate In ethanol at 100℃; for 1 h; Microwave irradiation Part B: A solution of compound 301 B (1.02 g, 4.2 mmol) in 8 ml_ EtOH was treated with hydrazine monohydrate (4.0 mL, 80 mmol) and the reaction mixture stirred at 100 °C for 30 minutes in a Biotage microwave. Conversion was incomplete as determined by LCMS; therefore, the mixture was concentrated, and fresh EtOH (6 mL) and hydrazine monohydrate (6 mL) were added. The reaction mixture was again stirred at 100 0C for 30 minutes in a microwave apparatus, then concentrated to dryness to provide desired product 301 C (801 mg, 89percent). HPLC-MS tR = 1.21 min (UV 254 nm); mass calculated for formula C7H5BrN2O 212.0/214.0, observed LCMS m/z 213.1/215.1 (M+H).
43% With hydrazine hydrate In ethanol at 100℃; for 2 h; Microwave irradiation CAP-004-20-1 (500 mg, 2.15 mmol) and hydrazine hydrate (2 ml) were added to ethanol (3ml). This reaction mixture was stirred for 2 h at 100 oc under microwave. The mixture was purified by preparative TLC (petroleum ether/ethyl acetate = 1 /2) to afford CAP-004-20-2(200 mg, 43 percent) as a white solid.
Reference: [1] Patent: WO2010/54279, 2010, A1, . Location in patent: Page/Page column 109-110
[2] Patent: WO2017/46318, 2017, A1, . Location in patent: Page/Page column 54; 55
[3] Patent: WO2015/150565, 2015, A1, . Location in patent: Page/Page column 75; 76
  • 2
  • [ 67-56-1 ]
  • [ 146328-85-0 ]
  • [ 57381-59-6 ]
YieldReaction ConditionsOperation in experiment
99% for 2 h; Reflux 5-Bromo-2-fluorobenzoic acid (1.2 g, 5.48 mmol), and H2S04 (2 ml) were added tomethanol (20 ml). This reaction mixture was stirred for 2 h at reflux. The mixture wasconcentrated in vacuo. The residue was diluted with saturated aqueous NaHC03 solutionand then extracted with ethyl acetate. The organic layer was dried over Na2S04, filtered and concentrated in vacuo to afford the crude product (1.3 g, 99 percent) as a yellow oil.
92% Heating / reflux Heat a solution of 5-bromo-2-fluorobenzoic acid (20 g, 92 mmol) and p- toluenesulfonic acid monohydrate (52 g, 275 mmol) in methanol (200 mL) at reflux overnight. Concentrate and dissolve the residue in ethyl acetate, wash twice with an aqueous saturated solution of sodium bicarbonate, once with an aqueous saturated solution of sodium chloride, dry (sodium sulfate), filter and concentrate to give the title compound as a clear liquid (19. 7 g, 92percent). 1H NMR (400 MHz, CDCl3) 6 3. 92 (s, 3H), 7. 00-7. 05 (m, 1H), 7. 58-7. 62 (m, 1H), 8. 04 (dd, J=2. 6Hz, J=6. 2Hz, 1H).
91% at 20℃; for 18 h; To a solution of 5-bromo-2-fluorobenzoic acid (4.85 g, 22.8 mmol) in methanol (45 mL) was added H2SO4 (4.5 mL). The reaction mixture was stirred at room temperature for 18 h and the solution was concentrated. The residue was treated with an aqueous NaOH [10percent w/v] solution and the organic material was extracted with CHCI3. The organic layer was dried over Na2S04, filtered and concentrated to afford the corresponding ester (4.69 g, 91percent) which was used without further purification.
88% for 8 h; Heating / reflux 5-Bromo-2-fluorobenzoic acid (100 g, 0.457 mol) was added to a solution of HCI in methanol (400 mL; about 11 percent). The suspension was refluxed for 8 hours, and then evaporated in vacuo. The residue was dissolved in benzene (500 mL), and the solution was washed with aqueous K2CO3 solution (2 x 50 mL) and water (3 x 100 mL), dried over Na2SO4 and evaporated in vacuo to give methyl 5-bromo-2- fluorobenzoate as a yellow oil in 88percent (93.7 g) yield.Methyl 5-bromo-2-fluorobenzoate (154.2 g, 0.66 mol), dry benzene (450 mL), ethynyl(trimethyl)silane (78.0 g, 0.79 mol), diisopropylamine (100 g, 0.99 mol) and tetra(triphenylphosphine)palladium (20.0 g, 0.017 mol) were placed under an atmosphere of argon in a three-necked round-bottomed 1 liter flask, equipped with a magnetic stirrer and a thermometer. The mixture was stirred for 30 minutes and then cooled to 10 0C. Copper iodide (12.5 g, 0.066 mol) was added, and the obtained suspension was stirred <n="36"/>for 2.5 hours at 20 °C and then at 60 0C for 3 hours and finally left to stand at room temperature overnight. After this, the mixture was diluted with ether (200 mL), and the precipitate was separated by filtration and washed with ether (2 x 100 mL). The obtained organic solution (800 mL) was washed with saturated aqueous solutions of NH4CI and NaCI, dried over Na2SO4 and evaporated. The crude product was purified by chromatography (hexane/ethylacetate 10:1) on a silica gel column to give methyl 2-fluoro- 5-(2-trimethylsilyl)ethynyl)benzoate containing about 13percent of methyl 5-bromo-2-fluorobenzQate, in about 80percent (148.1 g) yield.A suspension of 2-fluoro-5-(2-trimethylsilyl)ethynyl)benzoate (171.1 g, 0.684 mol), mercury(2+) diacetate (12.0 g, 0.051 mol) in THF (400 mL) and concentrated H2SO4 (74 mL, 1.37 mol) was stirred at 50-60 0C for 2 h. Then the mixture was cooled, and THF (350 mL) was evaporated in vacuo. The residue was diluted with ether (700 mL) and filtered to remove mercury salts, which were washed from acid. The ether solution was then dried OVeP-Na2SO4 and concentrated. The crude product (125 g) was purified by chromatography on a silica gel column, eluting at first with hexane/ethyl acetate (10:1) mixture to remove admixture of methyl 5-bromo-2-fluorobenzoate, and then with hexane/ethyl acetate (1:1) to give methyl 5- acetyl-2-fluorobenzoate in 75percent (90.0 g) yield.(Dimethoxymethyl)dimethylamine (92 mL, 0.69 mol) was added to a suspension of methyl 5-acetyl-2- . fluorobenzoate (90.0 g, 0.46 mol) in toluene (90 mL). The mixture was refluxed for 7 hours,. during which time forming methanol was distilled off. The solution was then concentrated in vacuo, and the residue (115.2 g) was purified by crystallization to give methyl 5-(3-(dimethylamino)acryloyl)-2-fluorobenzoate as yellow prisms in 80percent (93.9 g) yield.A mixture of methyl 5-(3-(dimethylamino)acryloyl)-2-fluorobenzoate (50 g, 0.2 mol), hydrazine hydrate (11.0 g, 0.22 mol) in methanol (500 mL) was allowed to stand at 20 0C for 48 hours. Then solvent was evaporated, and the residue was purified by chromatography (ethylacetate/hexane 1:2) on a silica gel column to afford 22.0 g of methyl 2-fluoro-5-(1 H-pyrazol-3-yl)benzoate, containing an impurity. The _pχoduct was. purified by crystallization from ethano.Lto.give methyl.2-fluoro-5-(1 H-pyrazol-3-yl)benzoate as yellow prisms in 45percent (19.9 g) yield.A solution of methyl 2-fluoro-5-(-1 H-pyrazol-3-yl)benzoate (25.2 g, 0.115 mol) was refluxed for 2 hours in concentrated HCI (150 ml). Then the reaction mixture was cooled and filtered. The separated precipitate was washed with ethanol, dried and then refluxed in water (200 mL) for 30 minutes to remove traces of methyl ester and HCIf cooled and filtered. The separated precipitate was washed with water and dried to give the title compound in 90.7percent (21.4 g) yield.
49%
Stage #1: at 80℃;
Stage #2: at 20℃;
To 5-bromo-2-fluoro-benzoic acid (6.38 g, 29.1 mmol, 1 equiv) was added thionyl chloride (10 mL, 290 mmol, 10 equiv). The mixture was stirred at 80 °C until complete, then concentrated. K2CO3 (10.87 g, 78.6 mmol, 2.7 equiv) was added, followed by MeOH (30 mL). This solution was stirred at room temperature. The reaction was filtered and the solid was rinsed with CH2Cl2. The organic was then washed with H2O, dried over MgSO4, filtered and concentrated to give the product (3.29 g, 14.1 mmol, 49percent).

Reference: [1] Patent: WO2017/46318, 2017, A1, . Location in patent: Page/Page column 54
[2] Journal of Agricultural and Food Chemistry, 2016, vol. 64, # 18, p. 3533 - 3537
[3] Patent: WO2005/94822, 2005, A1, . Location in patent: Page/Page column 44-45
[4] Patent: WO2015/89067, 2015, A1, . Location in patent: Page/Page column 123
[5] Patent: WO2008/65508, 2008, A1, . Location in patent: Page/Page column 34-35
[6] Patent: WO2016/187393, 2016, A1, . Location in patent: Paragraph 0253
[7] Patent: CN107954995, 2018, A, . Location in patent: Paragraph 0107; 0108; 0109
  • 3
  • [ 146328-85-0 ]
  • [ 57381-59-6 ]
YieldReaction ConditionsOperation in experiment
81% With sulfuric acid In methanol Intermediate 33: Methyl 3-bromo-6-fluorobenzoate
Methanol (30 ml) was added to 3-bromo-6-fluorobenzoic acid (3.0 g, 14 mmol) to prepare a solution, 3.0 ml of concentrated sulfuric acid was added to the solution, and the mixture was heated under reflux for 1.5 hr.
The temperature of the reaction mixture was returned to room temperature, the reaction mixture was then slowly poured into 500 ml of a saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted twice with 500 ml of diethyl ether.
The combined organic layers were washed with 300 ml of saturated brine, were dried over anhydrous magnesium sulfate, and were concentrated under the reduced pressure to give the title compound (2.6 g, 81percent).
Physicochemical properties of intermediate 33
Reference: [1] Patent: EP1229024, 2002, A1,
  • 4
  • [ 146328-85-0 ]
  • [ 18107-18-1 ]
  • [ 57381-59-6 ]
YieldReaction ConditionsOperation in experiment
83% With ethanol In acetonitrile Example 7; Part A; Compound 301 A (1.15g, 5.00 mmol) was dissolved in 10 mL of a 1:1 mixture ofEtOH:MeCN followed by the dropwise addition of (trimethylsilyl)diazomethane (2.0M solution in THF, 3.30 ml_, 6.50 mmol) The reaction was stirred for 15 minutes, then treated with 0.5 ml_ trifluoroacetic acid to quench any remaining diazomethane reagent. 50 ml_ EtOAc was added, and the mixture poured into a separating funnel containing 20 ml_ saturated sodium bicarbonate. The EtOAc layer was further washed with brine, dried over magnesium sulfate, then concentrated to provide desired product 301 B (1.02 g, 83percent).
Reference: [1] Patent: WO2010/54279, 2010, A1, . Location in patent: Page/Page column 109
  • 5
  • [ 146328-85-0 ]
  • [ 74-88-4 ]
  • [ 57381-59-6 ]
Reference: [1] Patent: US2008/81803, 2008, A1, . Location in patent: Page/Page column 47
  • 6
  • [ 773140-42-4 ]
  • [ 67-56-1 ]
  • [ 57381-59-6 ]
Reference: [1] Patent: WO2005/123680, 2005, A1, . Location in patent: Page/Page column 92
  • 7
  • [ 445-29-4 ]
  • [ 57381-59-6 ]
Reference: [1] Patent: WO2017/46318, 2017, A1,
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