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Chemical Structure| 3863-11-4 Chemical Structure| 3863-11-4
Chemical Structure| 3863-11-4

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Product Citations

Product Citations

Hwang, Dong-Jin ; Yang, Chuanhe ; Wang, Yinan ; Kelso, Hannah ; Pochampally, Satyanarayana ; Pfeffer, Lawrence M , et al.

Abstract: Background/Objectives: Human glioblastoma (GBM) is the most aggressive brain cancer in adults and a highly treatment-refractory malignancy. The overall prognosis for the GBM is extremely poor, with a median survival of 12–14 months after initial diagnosis. Many GBM patients initially respond to the DNA alkylating agent temozolomide (TMZ), but patients often become therapy-resistant, and tumors recur. We previously reported that treatment with PFI-3, which is a small molecule inhibitor of the bromodomain of the BRG1 subunit of the SW1/SNF chromatin remodeling complex, enhanced the sensitivity of GBM cells to TMZ in vitro and in vivo GBM animal models. Our general objective was to perform an SAR study of new diphenyl PFI-3 analogs. Methods: New structural analogs of PFI-3 were developed, synthesized, and tested for their ability to enhance TMZ-induced GBM cell death by ELISA. Results: Following on the enhanced activity of compounds 2a and 2b, new diphenyl PFI-3 analogs with specific structural adjustments were made to better understand the structural requirements to optimize function. Additionally, several new structurally different candidates (e.g., 4a, 4b, and 5) showed much better efficacy in sensitizing GBM cells to TMZ-induced GBM cell death. Conclusions: Four series of PFI-3 analogs (2, 3, 4, and 5) were designed, synthesized, and tested for the ability to sensitize GBM cells to TMZ-induced cell death. Series 2 optimized the A-ring and R-isomer chirality. Series 3 used a 5-membered linker with weak activity. Series 4’s di-phenyl urea compounds showed better bromodomain inhibition. Series 5’s methoxyphenyl-B-ring analogs were exceptionally strong inhibitors.

Keywords: bromodomain ; glioblastoma (GBM) ; therapeutic enhancing drug (TED) ; anti-GBM activity ; structure-activity relationship (SAR) ; PFI-3 analog ; temozolomide (TMZ)

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Product Details of 3,4-Difluoroaniline

CAS No. :3863-11-4
Formula : C6H5F2N
M.W : 129.11
SMILES Code : NC1=CC=C(F)C(F)=C1
MDL No. :MFCD00007761
InChI Key :AXNUZKSSQHTNPZ-UHFFFAOYSA-N
Pubchem ID :77469

Safety of 3,4-Difluoroaniline

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H227-H302+H332-H311-H315-H319-H335-H373
Precautionary Statements:P210-P261-P280-P305+P351+P338-P332+P313
Class:6.1
UN#:2941
Packing Group:

Application In Synthesis of 3,4-Difluoroaniline

* 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 [ 3863-11-4 ]
  • Downstream synthetic route of [ 3863-11-4 ]

[ 3863-11-4 ] Synthesis Path-Upstream   1~4

  • 1
  • [ 3863-11-4 ]
  • [ 85462-60-8 ]
References: [1] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 9, p. 2459 - 2462.
  • 2
  • [ 3863-11-4 ]
  • [ 113046-72-3 ]
References: [1] Journal of Medicinal Chemistry, 1992, vol. 35, # 25, p. 4727 - 4738.
[2] Journal of Medicinal Chemistry, 1992, vol. 35, # 25, p. 4727 - 4738.
  • 3
  • [ 3863-11-4 ]
  • [ 123447-62-1 ]
References: [1] Journal of Medicinal Chemistry, 1992, vol. 35, # 25, p. 4727 - 4738.
[2] Journal of Medicinal Chemistry, 1992, vol. 35, # 25, p. 4727 - 4738.
  • 4
  • [ 3863-11-4 ]
  • [ 847685-01-2 ]
YieldReaction ConditionsOperation in experiment
97% With iodine; sodium hydrogencarbonate In water at 20℃; for 0.5 h; 3,4-Difluoroaniline (645mg, 5mmol) was suspended in water (25 mL). Sodium bicarbonate (630 mg, 7.5 mmol) was added and then iodine (1.65 g, 6.5 mmol). The reaction mixture was stirred vigorously at ambient temperature for 30min and then poured into saturated sodium thiosulphate solution (50 mL) and extracted with ethyl acetate (2x25 mL). The combined extracts were washed with sodium thiosulphate (20 mL), water (20 mL) and brine (20 mL), dried (MgSO4) and evaporated to give the title compound as a dark oil. (1.24g, 97percent).
69% With N-iodo-succinimide In dichloromethane at 20℃; Inert atmosphere At room temperature, a solution of 3,4-difluoroaniline (100 μL, 1 mmol) and N-iodosuccinimide (225 mg, 1 mmol) in anhydrous dichloromethane (4 mL) was stirred overnight under argon atmosphere. Then an aqueous solution of sodium sulfite was added and the reaction mixture was extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography (silica gel, cyclohexane/ethyl acetate, 1/0 to 8/2) to afford 4,5-difluoro-2-iodoaniline (175 mg, 69percent) as a red oil. ESI-MS m/z 255.9 (M+H)+.
12 g With iodine; sodium hydrogencarbonate In water at 20℃; for 1 h; Reference Example 3a 2-methyl-5,6-fluoro-2,3-dihydro-1H-indole Step 1a:4,5-Difluoro-2-iodoaniline 16.5 g of iodine and 6.3 g of sodium bicarbonate are added, at ambient temperature, to a suspension of 6.45 g of 3,4-difluoroaniline in 250 ml of water. The reaction medium is stirred at ambient temperature for 1 hour.A saturated sodium thiosulfate solution is added and then the resulting mixture is extracted 3 times with ethyl acetate. The organic phases are combined, dried over magnesium sulfate, filtered, and then concentrated under reduced pressure, so as to give 12 g of 4,5-difluoro-2-iodoainiline, the characteristics of which are the following:Mass spectrometry: method ARetention time Tr (min)=0.90; [M+H]+: m/z 256; base peak: m/z 297
References: [1] Patent: WO2006/82400, 2006, A1, . Location in patent: Page/Page column 55.
[2] Tetrahedron Letters, 2005, vol. 46, # 6, p. 907 - 910.
[3] Organic Letters, 2008, vol. 10, # 13, p. 2657 - 2659.
[4] Patent: EP2141164, 2010, A1, . Location in patent: Page/Page column 44.
[5] Journal of Fluorine Chemistry, 2012, vol. 135, p. 97 - 107.
[6] Patent: US2013/274253, 2013, A1, . Location in patent: Paragraph 1281-1286.
[7] Synthesis (Germany), 2018, vol. 50, # 3, p. 555 - 564.
 

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