A method for synthesizing 2-fluoro-3-formyl-pyridine-4-boric acid pinacol ester
Through a two-step reaction method, the reaction was carried out in tetrahydrofuran and dioxane, and the 2-fluoro-3-formyl-pyridin-4-boronic acid pinna alcohol ester was successfully synthesized, which solved the difficulty of synthesis of this compound and the low yield. Problem, high yield synthesis method is achieved.
Patent Information
- Application Number
- CN202310154437.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2023-02-23
- Publication Date
- 2025-02-18
- Estimated Expiration
- 2043-02-23
AI Technical Summary
The prior art has failed to effectively synthesize 2-fluoro-3-formyl-pyridin-4-boronic acid pinenol ester, and the synthesis of this compound is difficult and has low yields.
The compound was synthesized by a two-step reaction method: the first step was to react with organic base and acylation reagent in tetrahydrofuran to obtain compound 1; the second step was to react with bisected boron-pinol ester in dioxane under a palladium catalyst in dioxane. The target compound was obtained.
The efficient synthesis of this compound was achieved, with a yield of up to 85%, filling the gap in the synthesis method, and easy to obtain raw materials, short synthesis route, and simple product purification method.
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Abstract
Description
Technical Field
[0001] The invention relates to a method for synthesizing boric acid ester compounds, in particular to a method for synthesizing 2-fluoro-3-formyl-pyridine-4-boric acid pinacol ester. Background Art
[0002] Reactions involving borate compounds have the advantages of mild reaction conditions, no strong acids or bases involved, a wide range of applications, and can react with halogenated hydrocarbons and sulfonate compounds, few reaction by-products, high yields, and simple post-processing.
[0003] The aldehyde group in 2-fluoro-3-formyl-pyridine-4-boronic acid pinacol ester (cas: 1310384-06-5) is chemically active and difficult to synthesize. So far, no synthesis method for this compound has been reported. Similar borate compounds are generally synthesized under palladium catalysis, acetate as a base, and dioxane as a solvent. The yield of this compound is low (0-5%) under such conventional conditions, and even no target product is generated. This is mainly because the fluorine at the 2-position of the compound is easily hydrolyzed or substituted, and the aldehyde group at the 3-position is easily oxidized or disproportionated. Summary of the invention
[0004] The invention aims to provide a method for synthesizing 2-fluoro-3-formyl-pyridine-4-boric acid pinacol ester, mainly to solve the technical problem of lack of a method for synthesizing the compound.
[0005] The technical scheme of the present invention is: a method for synthesizing 2-fluoro-3-formyl-pyridine-4-boronic acid pinacol ester, which is characterized by comprising the following steps: a first step, adding a reaction auxiliary agent to 2-fluoro-4-bromopyridine in tetrahydrofuran, and reacting with an organic base and an acylating agent in sequence at low temperature to obtain compound 1; a second step, adding an alkaline substance to compound 1 in dioxane and an auxiliary solvent, reacting with bisboronic acid pinacol ester under a palladium catalyst, and obtaining compound 2 after treatment.
[0006] The synthetic route is as follows:
[0007]
[0008] In the first step, 2-fluoro-4-bromopyridine is added to tetrahydrofuran, HMPA (hexamethylphosphoramide), and reacted with LDA (lithium diisopropylamide) and ethyl formate at low temperature to obtain compound 1; in the second step, compound 1 is added to dioxane and DMSO (dimethyl sulfoxide), potassium 2-isooctanoate, and reacted with bis(boron pinacol) ester in the presence of PdCl2(dppf)2 catalyst to obtain compound 2 after treatment.
[0009] Beneficial effects of the invention: The invention discloses the synthesis method of the compound for the first time, solving the problem of the synthesis method of the compound. It has the advantages of easy availability of raw materials, short synthesis route, simple product purification method, etc. The yield can be as high as 85%, filling the gap in the synthesis method.
[0010] Specific implementation method
[0011] Step 1
[0012] Dissolve 2-fluoro-4-bromopyridine (17.5 g, 0.1 mol) in 170 ml of anhydrous tetrahydrofuran, add HMPA (0.11 mol) and cool to -60℃--70℃. Slowly add LDA (0.11 mol) dropwise under nitrogen protection. After stirring for 0.5 hour, add ethyl formate (0.22 mol) dropwise. Continue to react at this temperature for 0.5 hour. TLC detection shows that the reaction is complete. Remove the dry ice acetone bath, pour the reaction solution into saturated aqueous ammonium chloride solution, add dichloromethane and extract twice. Combine the organic phases, wash the organic phases once with water and once with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a yellow oil solid. After column chromatography, 18.5 g of 2-fluoro-3-formyl-4-bromopyridine was obtained with a yield of 91%.
[0013] Step 2
[0014] Dissolve 2-fluoro-3-formyl-4-bromopyridine (20.3 g, 0.1 mol) in 200 ml of dioxane and 10 mL of dimethyl sulfoxide, add bis(boron pinacol) ester (25.4 g, 0.1 mol) and potassium 2-isooctanoate (45.5 g, 0.25 mol), then add PdCl2(dppf)2 (2.0 g) under nitrogen protection, replace the reaction system with nitrogen twice, heat to 95-100 ° C and stir for 3 hours. After TLC detection, cool down, add diatomaceous earth and filter with Buchner funnel, rinse with dichloromethane, concentrate the filtrate, dissolve in ethyl acetate, decolorize with activated carbon for half an hour, filter, concentrate, and recrystallize from petroleum ether to obtain 21.3 g of 2-fluoro-3-formyl-pyridine-4-boronic acid pinacol ester, with a yield of 85%.
[0015] HNMR (400 M, CDCl3): 10.33 (s, 1H), 8.41 (d, J = 4.8 Hz, 1H), 7.37 (dd, J = 4.8 Hz, 1.2 Hz, 1H), 1.44 (s, 12H).
Claims
1. A method for synthesizing 2-fluoro-3-formyl-pyridine-4-boric acid pinacol ester, characterized in that: The following steps are involved: In the first step, 2-fluoro-4-bromopyridine is added to tetrahydrofuran, and a reaction aid is added, and the reaction is carried out in sequence with an organic base and an acylating agent at -60°C to -70°C to obtain compound 1; in the second step, compound 1 is added to dioxane and an auxiliary solvent dimethyl sulfoxide, and an alkaline substance potassium 2-isooctanoate is reacted with bis(boron)pinacol ester in the presence of a palladium catalyst PdCl2(dppf)2, and the compound 2 is obtained by post-treatment. The reaction formula is as follows: 。 2. A method for synthesizing 2-fluoro-3-formyl-pyridine-4-boric acid pinacol ester according to claim 1, characterized in that: The reaction aid in the first step reaction is hexamethylphosphoramide.
3. A method for synthesizing 2-fluoro-3-formyl-pyridine-4-boric acid pinacol ester according to claim 1, characterized in that: The organic base in the first step of the reaction is lithium diisopropylamide.
4. A method for synthesizing 2-fluoro-3-formyl-pyridine-4-boric acid pinacol ester according to claim 1, characterized in that: The acylating agent in the first step of the reaction is ethyl formate.
Citation Information
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