Bromoacetaldehyde Dimethyl Acetal: Synthesis & Application in Erdafitinib Preparation

Bromoacetaldehyde is a lachrymatory and reactive compound, often handled in its more stable acetal form, such as bromoacetaldehyde diethyl acetal or Bromoacetaldehyde dimethyl acetal. The presence of the electron-withdrawing bromine atom significantly enhances the electrophilicity of the carbonyl carbon. Bromoacetaldehyde dimethyl acetal was first synthesized in the mid-20th century during investigations into the reactivity of brominated carbonyl compounds and their utility in organic synthesis. It is commonly prepared by the reaction of bromoacetaldehyde with methanol under acidic conditions, where the aldehyde group undergoes acetal formation with two equivalents of methanol. This transformation is typically carried out at low temperatures to control side reactions and improve yield. However, bromoacetaldehyde dimethyl acetal is considered moderately toxic based on available data from similar brominated organics. High-dose exposure may lead to systemic toxicity affecting the central nervous system and internal organs. There is currently insufficient evidence to classify the compound as a carcinogen, but caution is advised due to the presence of bromine and reactive electrophilic functionalities.

Synthesis of Bromoacetaldehyde dimethyl acetal

The synthesis of Bromoacetaldehyde dimethyl acetal involves two steps. Fristly we need to prepare the precursor of this substance: acetaldehydes (20 g, 0.45 mol) was dissolved in 40 mL of dry dichloromethane, and subsequently, dry bromine (dried with sulfuric acid) (58 g, 0.363 mol) was added dropwise at 0 °C under argon atmosphere. After stirring for 10 min, the reaction temperature was reached up to room temperature and was kept for 2 h along with vigorous stirring. During this time, the red color of the reaction mixture was converted to green. Upon completion of the reaction, the solvent was evaporated under reduced pressure to afford pure bromoacetaldehyde as yellowish oil. Secondly, In a two- necked round bottom flask equipped with Dean-stark, containing a solution of dry methanol (20 mL, 0.49 mol) and p-toluene sulfonic acid (3.78 g, 10 mol%) in toluene (100 mL), The bromoacetaldehyde (10.0 g, 0.22 mol) obtained in the previous step was slowly added, then the reaction mixture was stirred at 78 °C temperature for 24 h. After completing the reaction (almost 4 cc of water was separated in Dean-stark), a saturated aqueous solution of Na2S2O8 (100 mL) was added to the vessel. Next, the aqueous phase was extracted with DCM (100 mL × 2). The organic phases were dried over Na2SO4. Finally, the resulting organic phase was concentrated under reduced pressure to obtain bromoacetaldehyde dimethyl acetal (37.64 g, 0.22 mol, 98%) as a colorless oil[1]

Bromoacetaldehyde dimethyl acetal applied in the synthesis of erdafitinib

Erdafitinib, also named JNJ-42756493, marketed as Balversa, developed by Janssen Pharmaceutical Companies, is an oral pan-FGFR tyrosine kinase inhibitor. It has been jointly developed by the University of Newcastle, Astex medicine, and Johnson & Johnson since 2008. It is used to treat patients with metastatic urothelial carcinoma after platinum chemotherapy, which has FGFR-2 or FGFR-3 gene mutations. Bromoacetaldehyde dimethyl acetal (33.8 g, 0.2 mol) and i-propylamine (60 g, 1 mol) were put into a 250 ml high-pressure autoclave. The reaction mixture was stired and heated at 80°C for 10 h. The reaction solution was cooled to 10–15°C, the resulting solid was removed by suction filtration. The filtrate was concentrated in vacuo to give crude N-(2,2-Dimethoxyethyl)-2-propanamine (33 g), which was purified by vacuum distillation (48–53°C/ 20 mm Hg) to obtain pure N-(2,2-Dimethoxyethyl)-2-propanamine (27.0 g, 92%) as a colorless liquid. In summary, a new and convergent synthetic route of erdafitinib on a 20 g scale has been developed, from the commercially available chemicals quinoxalin-2-ol, 4-bromo-1-methyl-1H-pyrazole, and 2-bromo-1,1-dimethoxyethane. The key intermediate 3,5-dimethoxyphenyl-isopropylethane-1,2-diamine  was prepared from Bromoacetaldehyde dimethyl acetal in 89% yield over two steps and 98.8% purity. Erdafitinib was obtained from 7-bromo-2-(1-methyl-1H-pyrazol-4-yl) quinoxaline and 3,5-dimethoxyphenyl-isopropylethane-1,2-diamine in 89% yield and 99.4% purity. There are seven steps in this convergent synthesis route and the overall yield is 54%.[2]

References

[1]Salavati, R., Sarrafi, Y., & Tajbakhsh, M. (2022). A selective and “Off-On” fluorescent chemosensor based on fluorescein for Al³⁺: Synthesis, characterization, spectroscopy analyses, and DFT calculation. Journal of Fluorescence, 33, 639–651.

[2]Xu, Z., Wang, H., Jiang, S., Lu, S., & Mao, Y. (2022). New and convergent synthesis of erdafitinib. Journal of Heterocyclic Chemistry, 59(12), 2093–2097.

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