Preparation method of 3-fluoro-2-isobutylpyridine

Abstract

The invention provides a preparation method of 3-fluoro-2-isobutylpyridine, relates to the technical field of synthesis of chemical intermediates, and provides a new synthesis route of 3-fluoro-2-isobutylpyridine. The route comprises the following steps of by using 2-bromo-3-fluoropyridine as a raw material, preparing (3-fluoropyridin-2-yl) magnesium chloride by a Grignard reagent exchange method;performing addition on the (3-fluoropyridin-2-yl) magnesium chloride and isobutyraldehyde to obtain 1-(3-fluoropyridin-2-yl)-2-methylpropane-1-ol; and reacting the 1-(3-fluoropyridin-2-yl)-2-methylpropane-1-ol and triethylsilane for dehydroxylation to obtain the final product 3-fluoro-2-isobutylpyridine. The 3-fluoro-2-isobutylpyridine is synthesized by using a commercially available reagent through a simple process, the post-treatment is simple, the product yield is high, and the cost is low.

Description

technical field [0001] The invention relates to the technical field of chemical intermediate synthesis, in particular to a preparation method of 3-fluoro-2-isobutylpyridine. Background technique [0002] Pyridine compounds are important pharmacophores in therapeutic drugs, but their exact function is the combined effect of nitrogen-containing fused heterocycles and their modified substituents. Alkylated pyridines are particularly common pyridine compounds, such as: esomeprazole as a proton pump inhibitor, an alternative therapy for gastroesophageal reflux disease; nevirapine is a non-nucleoside reverse transcriptase inhibitor of HIV-1, and Other antiretroviral drugs are used in combination to treat HIV-1 infection; pioglitazone is an insulin sensitizer and an antidiabetic drug. Alkyl groups play a variety of roles in drug development, such as acting as hydrophobic chains, altering the binding properties of the Lewis basic nitrogen atom, preventing oxidative metabolism, and ...

AI Technical Summary

Problems solved by technology

[0007] Route (1) uses 2-bromo-3-fluoropyridine as a raw material, under palladium catalyst conditions, reacts with vinyl fluoroborate or alkenyl boronic acid to generate 2-(2-alkyl) vinyl 3-fluoropyridine, and then passes through Ammonium formate methanol solution is heated to reflux, or iron powder ammonium chloride alcohol solution, or palladium carbon, etc. are reduced to generate 2-(2-alkyl)vinyl 3-fluoropyridine; this method needs to use expensive palladium catalyst, and the actual operation There is also the problem of incomplete reaction in the process. Raw materials, products, by-products and palladium catalysts are difficult to separate during post-treatment, which affects purification. For cost considerations, this route is suitable for mass production of technology; the method of route (2) and route (3) Similarly, the aldehyde is prepared first, and then the aldehyde is reacted with the ylide reagent to form an alkene, and the alkene is then reduced to obtain the product; these two routes have many steps, which are tedious and time-consuming

[0008] For route (2), the starting raw material cost that it adopts is more expensive, and the cost price of the reduction reagent lithium aluminum hydride, borane that process selects is also higher, and the reaction condition of reaction process is also higher

For route (3), it and route (1) all need to use expensive palladium catalyst, meanwhile, ozone is a kind of unstable, easy to decompose strong oxidant, generally make on-site with ozone generator, the operation and maintenance of ozone generator , requires a special person to be responsible, further increasing the cost

In addition, the use of borane as a reducing agent is highly toxic, and it will form an explosive mixture when mixed with air, which has potential safety hazards

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