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Product Details of [ 403-43-0 ]

CAS No. :403-43-0 MDL No. :MFCD00000684
Formula : C7H4ClFO Boiling Point : -
Linear Structure Formula :- InChI Key :CZKLEJHVLCMVQR-UHFFFAOYSA-N
M.W :158.56 Pubchem ID :67879
Synonyms :

Calculated chemistry of [ 403-43-0 ]

Physicochemical Properties

Num. heavy atoms : 10
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 1
Num. H-bond acceptors : 2.0
Num. H-bond donors : 0.0
Molar Refractivity : 36.58
TPSA : 17.07 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) : -5.1 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.82
Log Po/w (XLOGP3) : 3.05
Log Po/w (WLOGP) : 2.62
Log Po/w (MLOGP) : 2.48
Log Po/w (SILICOS-IT) : 2.76
Consensus Log Po/w : 2.55

Druglikeness

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

Water Solubility

Log S (ESOL) : -3.12
Solubility : 0.12 mg/ml ; 0.000754 mol/l
Class : Soluble
Log S (Ali) : -3.07
Solubility : 0.134 mg/ml ; 0.000842 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.23
Solubility : 0.0938 mg/ml ; 0.000592 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.08

Safety of [ 403-43-0 ]

Signal Word:Danger Class:8
Precautionary Statements:P280-P305+P351+P338-P310 UN#:3265
Hazard Statements:H314 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 403-43-0 ]

* 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 [ 403-43-0 ]
  • Downstream synthetic route of [ 403-43-0 ]

[ 403-43-0 ] Synthesis Path-Upstream   1~19

  • 1
  • [ 403-43-0 ]
  • [ 147-85-3 ]
  • [ 62522-93-4 ]
YieldReaction ConditionsOperation in experiment
89%
Stage #1: With sodium hydroxide In water at 20℃; for 1 h;
Stage #2: With hydrogenchloride In waterCooling with ice
L-Prolin (2.5 g, 22 mmol) wird in NaOH (5percent, 25 mL, 31 mMol) in Loesung gebracht und nach Abkuehlen tropfenweise, unter starkem Ruehren, mit 4-Fluorhenzoesaeurechlorid (3.17 g, 20 mMol) versetzt. Die entstehende Suspension wird nochmals mit NAOH (5percent, 15 mL, 19 mmol) versetzt und 1 h bei RT geruehrt. Unter Eiskuehlung wird HCl (20 percentig, 10 mL) zugesetzt und bis zur Bildung eines absaugbaren Kristallisates geruehrt. Das anschliessend abgesaugte Kristallisat wird mit Wasser HCl-frei gewaschen und im Exsiccator ueber P2O5 getrocknet. Nach dem Trocknen verbleiben 4,21 g (88,8 percent d.Th.) Kristallisat. Y: 89 percent (4,21 g), C12H12FNO3, MW = 237.23; Mp: 174.0 °C; IR (NaCl): 1/λ (cm-1) = 1735, 1605, 1585, 1514, 1440, 1230, 1180, 1161, 856, 762, 513;1HNMR (CDCl3): δ (ppm) = 7.64-7.61 (d, 2H, J=5.4Hz), 7.59-7.57 (d, 2H, J=5.4Hz), 7.16-7.07 (t, 2H, J=8.6Hz).
79% With hydrogenchloride In sodium hydroxide; water a
N-(4-Fluorobenzoyl)proline
L-Proline (15.0 g, 130 mmol) is dissolved in NaOH (5percent, 150 ml, 190 mmol) and the solution is cooled in an ice bath (0-5° C.).
4-Fluorobenzoyl chloride (19.0 g, 120 mmol) is added dropwise with vigorous stirring, the cooling is removed and stirring is continued for 1 h.
After acidifying the reaction mixture with HCl (10percent strength, 45 ml) the amide deposits in large lumps, which are comminuted, suspended using water, filtered off with suction and washed with water (50 ml).
The substance is dried over P2O5 in vacuo: 24.41 g.
M.p.: 174.0° C., yield: 79percent; C12H12FNO3; MW=237.23.
IR (KBr): 1/λ (cm-1)=1735, 1605, 1585, 1514, 1440, 1230, 1180, 1161, 856, 762 513;
1H-NMR (CDCl3:) δ[ppm]=7.64-7.57 (m, 2H,); 7.16-7.07 (m, 2H); 4.78-4.71 (m, CH); 3.63-3.57(CH2); 2.36-1.85 (m; 2 CH2).
Reference: [1] Patent: EP1246825, 2003, B1, . Location in patent: Page 32
[2] Patent: US2003/153558, 2003, A1,
  • 2
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  • [ 25569-77-1 ]
Reference: [1] Advanced Synthesis and Catalysis, 2013, vol. 355, # 16, p. 3137 - 3140
[2] Tetrahedron Letters, 2017, vol. 58, # 26, p. 2533 - 2536
  • 3
  • [ 456-22-4 ]
  • [ 403-43-0 ]
  • [ 25569-77-1 ]
Reference: [1] New Journal of Chemistry, 2017, vol. 41, # 3, p. 931 - 939
  • 4
  • [ 403-43-0 ]
  • [ 700-85-6 ]
Reference: [1] Organic Process Research and Development, 2010, vol. 14, # 3, p. 617 - 622
  • 5
  • [ 403-43-0 ]
  • [ 456-06-4 ]
Reference: [1] European Journal of Medicinal Chemistry, 2006, vol. 41, # 11, p. 1253 - 1261
[2] Journal of Medicinal Chemistry, 2004, vol. 47, # 27, p. 6760 - 6767
[3] Farmaco, 1997, vol. 52, # 11, p. 691 - 695
[4] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 1, p. 192 - 194
[5] Journal of Chemical Research, 2014, vol. 38, # 5, p. 300 - 303
[6] Chemistry - A European Journal, 2015, vol. 21, # 26, p. 9550 - 9555
[7] RSC Advances, 2015, vol. 5, # 80, p. 65351 - 65357
[8] European Journal of Medicinal Chemistry, 2016, vol. 124, p. 270 - 283
  • 6
  • [ 403-43-0 ]
  • [ 372-09-8 ]
  • [ 4640-67-9 ]
YieldReaction ConditionsOperation in experiment
80%
Stage #1: With [2,2]bipyridinyl; n-butyllithium; magnesium sulfate In tetrahydrofuran; hexane at -78℃; for 0.5 h; Inert atmosphere
Stage #2: at -78 - 20℃; Inert atmosphere
Stage #3: With hydrogenchloride In tetrahydrofuran; methanol; hexane; water
General procedure: Cyanoacetic acid (1.7 g, 20 mmol, 2 equiv), 0.2 mg MgSO4, and ~1 mg 2,2'-bipyridyl was dissolved in tetrahydrofuran (100 mL) and placed in a 500 mL three-neck flask fitted with two dropping funnels and a mechanical stirrer. The system was flushed with nitrogen and cooled to -78 C with a dry ice/ acetone bath. An n-butyl lithium solution (25 mL, 1.6 M in hexanes; 40 mmol, 4 equiv) was added via a dropping funnel with stirring. Once the solution turned slightly purple it was stirred (30 min) after which the acid chloride (10 mmol, 1 equiv) in 5 mL of methanol was added drop-wise with stirring. During this process, the cloudy solution took on a yellow color. The solution was stirred at -78 C for one hour, then the bath was removed and the reaction was allowed to return to room temperature for one hour. An HCl solution (50 mL, 1M) was added drop-wise. At this point, the reaction became clear, while remaining yellow. Water (25 mL) and CH3Cl (50 mL) were added. The aqueous layer was extracted three times with the same volume of CH3Cl. The combined organic layers were washed with two portions (50 mL) of saturated sodium bicarbonate solution and dried over magnesium sulfate, filtered, and reduced on a rotoevaporator. Samples were purified by flash chromatography 6 Hex : 1 EtOAc resulting in percent yields from 50-80percent.
Reference: [1] Tetrahedron Letters, 2011, vol. 52, # 19, p. 2440 - 2442
  • 7
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  • [ 4640-67-9 ]
Reference: [1] Journal of Medicinal Chemistry, 1991, vol. 34, # 6, p. 1896 - 1907
  • 8
  • [ 6148-64-7 ]
  • [ 403-43-0 ]
  • [ 1999-00-4 ]
Reference: [1] Patent: WO2010/143158, 2010, A1, . Location in patent: Page/Page column 55; 88
[2] Patent: US2012/115916, 2012, A1, . Location in patent: Page/Page column 22; 35
[3] Patent: WO2012/67664, 2012, A1, . Location in patent: Page/Page column 43
  • 9
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  • [ 1999-00-4 ]
Reference: [1] Farmaco, 1992, vol. 47, # 10, p. 1323 - 1333
  • 10
  • [ 403-43-0 ]
  • [ 58656-98-7 ]
YieldReaction ConditionsOperation in experiment
69% With pyridine In dichloromethane; <i>tert</i>-butyl alcohol (a)
t-Butyl 4-fluorobenzoate
t-Butanol (6.6 ml) and pyridine (5.62 ml) were dissolved in dry dichloromethane (40 ml) and cooled in a dry ice/acetone bath to -50°C. A solution of 4-fluorobenzoic acid chloride (10.0 g) in dry dichloromethane (20 ml) was added slowly to the alcohol solution.
The solution was kept under nitrogen throughout, and allowed to warm slowly to room temperature.
It was then heated at reflux for 1d.
More t-butanol (1 ml) and pyridine (1 ml) were added and reflux continued for two days more.
After cooling the reaction mixture was washed successively with 2 M hydrochloric acid (40 ml), 10percent sodium hydrogen carbonate solution (40 ml) and saturated aqueous sodium sulphate solution.
The organic layer was dried, filtered and evaporated to leave an oil (10.62 g).
This contained the title compound and some 4-fluorobenzoic anhydride.
The two components were separated by column chromatography (100 g silica/ 30percent dichloromethane/70percent petroleum ether) to leave the title compound (8.48 g, 69percent) 1H NMR (CDCl3) δ 8.05, 7.05 (4H, m, aryl- H) and 1.60 (9H, S, C H 3).
Infra Red (Thin Film) Vmax2970, 1715, 1610, 1510, 1290, 1155, 1120, 850, and 770 cmmin1.
Reference: [1] Patent: EP284413, 1990, A3,
  • 11
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  • [ 75-65-0 ]
  • [ 58656-98-7 ]
Reference: [1] Analytical Chemistry, 1984, vol. 56, # 12, p. 2038 - 2043
  • 12
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  • [ 302-72-7 ]
  • [ 451-28-5 ]
Reference: [1] Journal of Organic Chemistry, 1952, vol. 17, p. 1661,1662
[2] Analytical Chemistry, 1985, vol. 57, # 1, p. 76 - 81
[3] Synthetic Communications, 2013, vol. 43, # 11, p. 1538 - 1542
[4] Synlett, 2013, vol. 24, # 14, p. 1801 - 1804
  • 13
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  • [ 451-28-5 ]
Reference: [1] Chemistry - A European Journal, 2012, vol. 18, # 46, p. 14792 - 14804
  • 14
  • [ 462-06-6 ]
  • [ 403-43-0 ]
  • [ 345-71-1 ]
  • [ 342-25-6 ]
  • [ 345-92-6 ]
Reference: [1] Chemical Communications, 2004, # 12, p. 1368 - 1369
  • 15
  • [ 6638-79-5 ]
  • [ 403-43-0 ]
  • [ 116332-54-8 ]
YieldReaction ConditionsOperation in experiment
97% With pyridine In dichloromethane Step 1.
N-methoxy-N-methyl-4-fluorobenzamide.
To a 0° C. solution of 4-fluorobenzoyl chloride (11.9 g, 75.0 mmol) in CH2 Cl2 (150 mL) was added N,O-dimethylhydroxylamine hydrochloride (8.00 g, 82.0 mmol) and a solution of pyridine (13.0 g, 164 mmol) in CH2 Cl2 (25 mL).
The cold bath was removed and the reaction mixture was stirred for 2 hours at ambient temperature and then was washed with 0.5N aqueous HCl (3*100 mL), saturated aqueous NaHCO3, and brine.
The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to give N-methoxy-N-methyl-4-fluorobenzamide (13.3 g, 97percent) as an oil.
96% With pyridine In chloroform at 0 - 22℃; for 1 h; 4-Fluorobenzoyl chloride (15g, 94.6 mmol) and N,O-dimethylhydroxylamine hydrochloride (10.1g, 104mmol) were dissolved in CHCl3 (200mL) and stirred at room temperature. The solution was cooled to 0°C and pyridine (17.3mL, 230mmol) was added. The mixture was warmed and stirred at room temperature for 1h and then poured into aq. sat. NaCl solution (300mL). The organic layer was separated and the aqueous layer extracted with CH2Cl2 (3×100mL). The combined organic layers were washed with water (3×50mL), dried (anhyd. Na2SO4) and then evaporated. The crude 4-fluoro-N-methoxy-N-methylbenzamide 7a was purified via distillation under vacuum to afford a colourless liquid (96percent), bp=120°C at 0.3 mmHg (lit. b.p. 70°C at 0.1mmHg [13]); νmax 583, 905, 918, 1262, 1375, 1508, 1582, 1630, 2972, 3274cm−1; δH 3.34 (3H, s, CH3), 3.52 (3H, s, OCH3), 7.08 (2H, m, Ar–H), 7.73 (2H, m, Ar–H).
88% With triethylamine In dichloromethane at 5℃; for 0.5 h; In A VOLUMETRIC flask N,O-dimethylhydroxylamine hydrochloride (25.54 g, 261.8 mmol) and CH2Cl2 (443 mL) were introduced under argon atmosphere at 0°C. 4- Fluorobenzoyl chloride (34. 59 G, 218. 2 MMOL) WAS ADDED FOLLOWED BY THE SLOW addition OF TRIETHYLAMINE (48. 13 G, 475. 6 MMOL). THE REACTION WAS STIRRED FOR 30 min at 5 C and allowed to reach room temperature. It was washed with 5percent aqueous citric acid (180 ML) and with 5percent aqueous NaHCO3 (180 ML). The aqueous phase was extracted with CH2Cl2. The organic phase was dried over NA2S04 and concentrated to dryness, to afford 20. 23 G OF THE DESIRED COMPOUND (YIELD : 88percent).
Reference: [1] Bioorganic and Medicinal Chemistry, 1997, vol. 5, # 1, p. 49 - 64
[2] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 5, p. 1352 - 1357
[3] Organic and Biomolecular Chemistry, 2013, vol. 11, # 20, p. 3337 - 3340
[4] Journal of Organic Chemistry, 2007, vol. 72, # 15, p. 5828 - 5831
[5] Patent: US5616596, 1997, A,
[6] Dyes and Pigments, 2015, vol. 113, p. 239 - 250
[7] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 3, p. 333 - 336
[8] Patent: WO2006/21449, 2006, A1, . Location in patent: Page/Page column 8; 9
[9] Patent: WO2004/76450, 2004, A1, . Location in patent: Page 37
[10] Angewandte Chemie - International Edition, 2013, vol. 52, # 33, p. 8551 - 8556[11] Angew. Chem., 2013, vol. 125, # 33, p. 8713 - 8718,6
[12] Patent: WO2004/18458, 2004, A1, . Location in patent: Page/Page column 57-58
[13] Patent: US2014/107097, 2014, A1, . Location in patent: Paragraph 0420; 0421
[14] Molecular Pharmacology, 2016, vol. 89, # 6, p. 667 - 677
[15] Journal of Organic Chemistry, 2017, vol. 82, # 2, p. 1114 - 1126
[16] Patent: US2018/237419, 2018, A1, . Location in patent: Paragraph 0314
  • 16
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YieldReaction ConditionsOperation in experiment
100% With triethylamine In dichloromethane (a)
4-Fluoro-N-methoxy-N-methylbenzamide
--To a mixture containing methoxymethylamine hydrochloride (44 g, 0.45 mol) and triethylamine (138 mL, 0.99 mol) in CH2 Cl2 (500 mL) at 0° C. was added over 30 min, 4-fluorobenzoyl chloride (50 mL, 0.41 mol).
The resulting mixture was allowed to warm to rt and stirring was continued for 30 min, at which time the mixture was poured into H2 O and extracted with Et2 O. The Organic extract was washed with saturated aqueous NaCl and dried (MgSO4).
Removal of the solvent in vacuo afforded the title compound (80 g, 100percent), which was used without further purification: 1 H NMR (CDCl3): δ7.72 (dd, 2H); 7.06 (apparent t, 2H); 3.52 (s, 3H); 3.43 (s, 3H).
Reference: [1] Patent: US5686455, 1997, A,
[2] Patent: WO2016/77724, 2016, A1, . Location in patent: Page/Page column 53
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  • [ 1117-97-1 ]
  • [ 116332-54-8 ]
Reference: [1] Organic Letters, 2005, vol. 7, # 7, p. 1427 - 1429
[2] Journal of Medicinal Chemistry, 2002, vol. 45, # 5, p. 999 - 1001
[3] Patent: US2003/96814, 2003, A1,
  • 18
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  • [ 152121-47-6 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 1997, vol. 5, # 1, p. 49 - 64
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  • [ 152121-30-7 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 1997, vol. 5, # 1, p. 49 - 64
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