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[ CAS No. 456-47-3 ] {[proInfo.proName]}

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Chemical Structure| 456-47-3
Chemical Structure| 456-47-3
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Product Details of [ 456-47-3 ]

CAS No. :456-47-3 MDL No. :MFCD00004631
Formula : C7H7FO Boiling Point : -
Linear Structure Formula :- InChI Key :QDHRSLFSDGCJFX-UHFFFAOYSA-N
M.W : 126.13 Pubchem ID :68008
Synonyms :

Calculated chemistry of [ 456-47-3 ]

Physicochemical Properties

Num. heavy atoms : 9
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.14
Num. rotatable bonds : 1
Num. H-bond acceptors : 2.0
Num. H-bond donors : 1.0
Molar Refractivity : 32.53
TPSA : 20.23 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) : -6.0 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.77
Log Po/w (XLOGP3) : 1.5
Log Po/w (WLOGP) : 1.59
Log Po/w (MLOGP) : 1.97
Log Po/w (SILICOS-IT) : 2.12
Consensus Log Po/w : 1.79

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.99
Solubility : 1.28 mg/ml ; 0.0101 mol/l
Class : Very soluble
Log S (Ali) : -1.53
Solubility : 3.7 mg/ml ; 0.0293 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.46
Solubility : 0.433 mg/ml ; 0.00344 mol/l
Class : Soluble

Medicinal Chemistry

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

Safety of [ 456-47-3 ]

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 [ 456-47-3 ]

* 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 [ 456-47-3 ]
  • Downstream synthetic route of [ 456-47-3 ]

[ 456-47-3 ] Synthesis Path-Upstream   1~33

  • 1
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  • [ 456-41-7 ]
Reference: [1] Nippon Kagaku Zasshi, 1958, vol. 79, p. 1428,1430[2] Chem.Abstr., 1960, p. 5518
[3] Advanced Synthesis and Catalysis, 2016, vol. 358, # 11, p. 1731 - 1735
[4] European Journal of Medicinal Chemistry, 2017, vol. 127, p. 100 - 114
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Reference: [1] Journal of the Chemical Society, 1935, p. 1815,1818
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  • [ 100-82-3 ]
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Reference: [1] Organic Letters, 2002, vol. 4, # 12, p. 2055 - 2058
  • 4
  • [ 455-68-5 ]
  • [ 391-92-4 ]
  • [ 392-04-1 ]
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Reference: [1] Organic and Biomolecular Chemistry, 2008, vol. 6, # 7, p. 1251 - 1259
  • 5
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  • [ 392-04-1 ]
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Reference: [1] Organic and Biomolecular Chemistry, 2008, vol. 6, # 7, p. 1251 - 1259
  • 6
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YieldReaction ConditionsOperation in experiment
91.2 %Chromat. With hydrogen In ethanol; water at 20℃; for 1 h; Autoclave General procedure: 0.05 g 5 wt.percent Pt catalyst was pretreated in a hydrogen flow at 673 K for 2 h before use. The catalyst was then mixed with 20 mL solvent and transferred to a 100 mL autoclave. The hydrogenation reaction began at a designated temperature after 4.0 MPa hydrogen was introduced into the autoclave. The reaction was stopped after an allotted period and the products were analyzed by GC–FID (GC-2014, Shimadzu Co.) equipped with a capillary column (DM-WAX, 30 m × 0.32 mm × 0.25 μm).
Reference: [1] Tetrahedron Letters, 1991, vol. 32, # 9, p. 1199 - 1202
[2] Organic Letters, 2007, vol. 9, # 15, p. 2791 - 2793
[3] Tetrahedron, 2008, vol. 64, # 51, p. 11783 - 11788
[4] Advanced Synthesis and Catalysis, 2014, vol. 356, # 5, p. 1093 - 1097
[5] Organic Letters, 2007, vol. 9, # 26, p. 5429 - 5432
[6] European Journal of Medicinal Chemistry, 1980, vol. 15, # 5, p. 431 - 438
[7] Bulletin of the Chemical Society of Japan, 1988, vol. 61, # 11, p. 4153 - 4154
[8] Green Chemistry, 2009, vol. 11, # 9, p. 1313 - 1316
[9] Patent: WO2010/127855, 2010, A1, . Location in patent: Page/Page column 131
[10] Chemistry - An Asian Journal, 2009, vol. 4, # 5, p. 699 - 706
[11] Journal of Catalysis, 2013, vol. 300, p. 9 - 19
[12] Catalysis Letters, 2014, vol. 144, # 2, p. 268 - 277
[13] Organic and Biomolecular Chemistry, 2014, vol. 12, # 30, p. 5781 - 5788
[14] Catalysis Communications, 2012, vol. 28, p. 147 - 151
[15] Catalysis Today, 2015, vol. 247, p. 14 - 19
[16] Journal of Medicinal Chemistry, 2014, vol. 57, # 21, p. 9042 - 9064
[17] European Journal of Organic Chemistry, 2016, vol. 2016, # 12, p. 2207 - 2211
[18] Journal of Molecular Catalysis A: Chemical, 2015, vol. 399, p. 1 - 9
[19] European Journal of Medicinal Chemistry, 2017, vol. 127, p. 100 - 114
[20] Dalton Transactions, 2018, vol. 47, # 21, p. 7272 - 7281
[21] New Journal of Chemistry, 2018, vol. 42, # 19, p. 15572 - 15577
  • 7
  • [ 455-68-5 ]
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Reference: [1] Catalysis Science and Technology, 2017, vol. 7, # 6, p. 1297 - 1304
[2] Tetrahedron Letters, 2004, vol. 45, # 31, p. 6021 - 6022
  • 8
  • [ 456-48-4 ]
  • [ 100-82-3 ]
  • [ 456-47-3 ]
Reference: [1] Organic Letters, 2002, vol. 4, # 12, p. 2055 - 2058
  • 9
  • [ 22483-09-6 ]
  • [ 456-48-4 ]
  • [ 456-47-3 ]
Reference: [1] Tetrahedron, 2008, vol. 64, # 51, p. 11783 - 11788
  • 10
  • [ 352-70-5 ]
  • [ 455-38-9 ]
  • [ 456-47-3 ]
  • [ 456-48-4 ]
Reference: [1] Patent: CN105237317, 2016, A, . Location in patent: Paragraph 0085; 0086
  • 11
  • [ 456-41-7 ]
  • [ 456-47-3 ]
Reference: [1] RSC Advances, 2014, vol. 4, # 91, p. 49974 - 49978
  • 12
  • [ 352-70-5 ]
  • [ 456-47-3 ]
  • [ 456-48-4 ]
Reference: [1] Bulletin of the Chemical Society of Japan, 2003, vol. 76, # 12, p. 2353 - 2360
  • 13
  • [ 22483-09-6 ]
  • [ 456-48-4 ]
  • [ 1099778-01-4 ]
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  • [ 56766-81-5 ]
Reference: [1] Tetrahedron, 2008, vol. 64, # 51, p. 11783 - 11788
  • 14
  • [ 1711-07-5 ]
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Reference: [1] Journal of the American Chemical Society, 1963, vol. 85, p. 709 - 724
  • 15
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Reference: [1] Journal of the American Chemical Society, 1963, vol. 85, p. 709 - 724
  • 16
  • [ 456-42-8 ]
  • [ 456-47-3 ]
Reference: [1] Nippon Kagaku Zasshi, 1958, vol. 79, p. 1428,1430[2] Chem.Abstr., 1960, p. 5518
[3] Journal of the American Chemical Society, 1963, vol. 85, p. 709 - 724
[4] Journal of the Chemical Society, 1935, p. 1815,1818
  • 17
  • [ 456-48-4 ]
  • [ 456-47-3 ]
  • [ 24133-57-1 ]
Reference: [1] Journal of Organic Chemistry, 1999, vol. 64, # 9, p. 3230 - 3236
  • 18
  • [ 352-70-5 ]
  • [ 456-47-3 ]
Reference: [1] Journal of the American Chemical Society, 1963, vol. 85, p. 709 - 724
[2] Green Chemistry, 2013, vol. 15, # 9, p. 2408 - 2421
  • 19
  • [ 456-48-4 ]
  • [ 455-38-9 ]
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Reference: [1] European Journal of Organic Chemistry, 2016, vol. 2016, # 12, p. 2207 - 2211
  • 20
  • [ 67-56-1 ]
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  • [ 455-68-5 ]
  • [ 456-47-3 ]
Reference: [1] Organic Letters, 2007, vol. 9, # 15, p. 2791 - 2793
  • 21
  • [ 556-56-9 ]
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  • [ 24133-57-1 ]
  • [ 215320-36-8 ]
Reference: [1] Journal of Organic Chemistry, 1999, vol. 64, # 9, p. 3230 - 3236
  • 22
  • [ 455-68-5 ]
  • [ 391-92-4 ]
  • [ 392-04-1 ]
  • [ 456-47-3 ]
Reference: [1] Organic and Biomolecular Chemistry, 2008, vol. 6, # 7, p. 1251 - 1259
  • 23
  • [ 64-17-5 ]
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Reference: [1] Agricultural and Biological Chemistry, 1986, vol. 50, # 5, p. 1261 - 1266
  • 24
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Reference: [1] Journal of the Chemical Society - Perkin Transactions 1, 1998, # 19, p. 3131 - 3132
  • 25
  • [ 102606-95-1 ]
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Reference: [1] Tetrahedron Letters, 1986, vol. 27, # 26, p. 2937 - 2940
  • 26
  • [ 456-42-8 ]
  • [ 75-65-0 ]
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  • [ 351-22-4 ]
  • [ 72402-80-3 ]
Reference: [1] Journal of Organic Chemistry, 1980, vol. 45, # 6, p. 951 - 957
  • 27
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  • [ 133865-89-1 ]
Reference: [1] Synthesis (Germany), 2014, vol. 46, # 13, p. 1751 - 1756
[2] Patent: WO2014/178083, 2014, A1,
  • 28
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  • [ 211617-68-4 ]
  • [ 133865-89-1 ]
Reference: [1] Journal of Medicinal Chemistry, 2007, vol. 50, # 20, p. 4909 - 4916
  • 29
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  • [ 202197-26-0 ]
Reference: [1] Patent: WO2011/2523, 2011, A1,
[2] Journal of Medicinal Chemistry, 2010, vol. 53, # 24, p. 8546 - 8555
  • 30
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YieldReaction ConditionsOperation in experiment
92% With potassium hydroxide In acetonitrile at 35 - 40℃; for 18 h; EXAMPLE 1a
To accomplish the analogous synthesis of 3-chloro-4-(3-fluorobenzyloxy)nitrobenzene, 3-fluorobenzyl alcohol (0.30 kg, 2.39 mole, 1.05 eq) was dissolved in ACN (6.0 L) and to it was added potassium hydroxide flakes (85percent) (0.16 kg, 1.25 eq).
The resulting suspension was warmed to 35° C.
A solution of the 3-chloro-4-fluoronitrobenzene (0.40 kg, 2.28 mol) in ACN (2.0 L) was added at 35-40° C.
The mixture was held for 18 hours.
The mixture was then cooled back to 20-25° C., quenched with water (8 L) and the resulting slurry filtered and washed with water (2*0.40 L). The resulting product was dried at 45° C., under 10 mm Hg pressure, for 25 hours to give 0.59 kg (92percent yield).
92% With potassium hydroxide In acetonitrile at 35 - 40℃; for 18 h; Example 9
Preparation of N-[3-Chloro-4-(3-fluorobenzyloxy)]phenyl-2-cyanoacetamide
3-Fluorobenzyl alcohol (0.30 kg, 2.39 mole, 1.05 eq) was dissolved in acetonitrile (6.0 L) and to it was added potassium hydroxide flakes (85percent) (0.16 kg, 1.25 eq).
The resulting suspension was warmed to 35° C.
A solution of the 3-chloro-4-fluoronitrobenzene (0.40 kg, 2.28 mol) in acetonitrile (2.0 L) was added at 35-40° C.
The mixture was held for 18 h.
The mixture was then cooled to ambient temperature, quenched with water (8 L) and the resulting slurry was filtered and washed with water (2*0.40 L).
The resulting product was dried (45° C., 10 mmHg, 25 h) to give 0.59 kg (92percent yield).
A mixture of 3-chloro-4-(3-fluorobenzyloxy)nitrobenzene (20 g, 0.071 mole) and ethanol (195 ml) was added zinc (23.2 g, 5.0 eq.).
The mixture was heated to 55-60° C. A solution of ammonium chloride (7.6 g) in water (40 ml) was added over 20 min keeping the pot temperature 55-65° C. (small exotherm).
The mixture was stirred for 2 h, filtered over a celite pad and washed with ethanol (2*20 ml).
The filtrate was distilled to essentially dryness and 2-methyltetrahydrofuran (100 ml) was added to dissolve the product.
Water (40 ml) and brine (5.2 g in 15 ml water) were added, mixed and the layers were separated.
The organic layer was washed with water (30 ml) and then transferred to a 500 ml multi-necked flask.
To the 500 ml flask equipped with mechanical stirrer, temperature probe, claisen head and condenser was added ethylcyanoacetate (53.2 g, 0.47 mole, 6.6 eq.).
The reaction mixture was heated to (120-125° C.) while removing 2-methyltetrahydrofuran and residual ethanol atmospherically.
The mixture was held for a minimum of 24 h until the aniline starting material was consumed and no distillate was collected.
The mixture was cooled to ambient temperature and isopropyl acetate (75 ml) and heptane (75 ml) were added.
The mixture was mixed for 2 hr.
The mixture was filtered on a 5.5 cm diameter Buchner funnel and washed with heptane.
The product was dried at 45° C. overnight in a vacuum oven to give the titled compound (6.45 g, 29percent) as a greyish solid (WC26280-77).
1H NMR: δ (DMSO-d6) 10.31 (s, 1H, NH), 7.73 (d, 1H, Ar), 7.46-7.19 (m, 6H, Ar), 5.20 (s, 2H, OCH2Ph), 3.87 (s, 2H, NCCH2CO).
85% With sodium hydride In N,N-dimethyl-formamide at 0 - 10℃; 2-ChIoro- l-(3-fluorobenzyIoxy)-4-nitrob enzene (14) was prepared from (3-fluoro-phenyl)-methanol (13)(Aldrich) and 2-chloro-l-fluoro-4-nitro- benzene (12) (Aldrich) according to Wallace et al. (Preparation of cyanoguanidines and cyanoamidines as ErbB2 and EGFR inhibitors. 2005). Yield (20.Og; 85percent) yellow crystals. 1H- NMR (DMSO-[D6]): δ (ppm) = 5.41 (s, 2H), 7.18-7.25 (m, H), 7.31-7.35 (m, 2H), 7.43-7.50 (m, 2H), 8.26 (dd, IH, J = 9.2 Hz, 4J - 2.8 Hz), 8.35 (d, IH, 4J = 2.8 Hz).
Reference: [1] Patent: US2006/270668, 2006, A1, . Location in patent: Page/Page column 16
[2] Patent: US2006/270669, 2006, A1, . Location in patent: Page/Page column 19-20
[3] Patent: WO2009/63054, 2009, A1, . Location in patent: Page/Page column 37; 68
[4] Journal of Medicinal Chemistry, 2010, vol. 53, # 24, p. 8546 - 8555
[5] Patent: WO2011/2523, 2011, A1, . Location in patent: Page/Page column 43
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YieldReaction ConditionsOperation in experiment
93% With tributylphosphine; diamide In tetrahydrofuran at 10 - 40℃; for 1.5 h; To a 1000 ml reaction flask was added 350 ml of tetrahydrofuran, 75 g of 2-chloro-4-nitrophenol, 58.0 g 3-fluorobenzyl alcoholAnd 106gTributylphosphine,Turn agitated, cool to 10 ° C, slowly drop 90 g of tetramethylazodicarbonamide (TMAD) and 200 mlTetrahydrofuran, the solution was added dropwise and the temperature was stirred at 10 ° C for 1.5 hours. The reaction was carried out at a temperature of 40 ° CThe reaction solution was concentrated under reduced pressure to dryness, and the residue was stirred with N, N-dimethylformamide (200 ml), and the mixture was cooled to 0 ° C.The resulting solid was dried at 55-60 ° C to give 113.2 g of a pale yellow solid, 99.82percent purity and a yield of 93.0percent.
Reference: [1] Patent: CN106543007, 2017, A, . Location in patent: Paragraph 0017; 0018; 0019; 0020; 0021; 0022
  • 32
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YieldReaction ConditionsOperation in experiment
63% With potassium hydroxide; Aliquat 336 In water; toluene at 60℃; To a mixture of 3-fluorobenzyl alcohol (7.88 g, 62.5 mmol), Aliquat 336 (8.08 g, 20.0 mmol), potassium hydroxide (3.51 g, 62.5 mmol) and water (40 mL) were added toluene (80 mL) and 1,2- dichloro-4-nitrobenzene (10.0 g, 52.1 mmol). The mixture was heated to 600C overnight with vigorous stirring. The mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, and the solvent was removed in vacuo. The residue was triturated with hot petroleum ether and tert-butyl methyl ether to yield 9.20 g (63percent) of the title compound.1H-NMR (400 MHz, DMSO-d6): δ = 5.42 (s, 2H), 7.21 (dt, IH), 7.30-7.35 (m, 2H), 7.45-7.52 (m, 2H), 8.26 (dd, IH), 8.36 (d, IH).GC/MS (method 1): R, = 7.76 min; MS (DCI): m/z = 299 [M+NH^.
Reference: [1] Patent: WO2009/33581, 2009, A1, . Location in patent: Page/Page column 58-59
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  • [ 174671-46-6 ]
Reference: [1] Patent: US2007/286822, 2007, A1, . Location in patent: Page/Page column 48
[2] Patent: US2007/286822, 2007, A1, . Location in patent: Page/Page column 48
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