Method for preparing cyclopropyl boronic acid

Abstract

The invention discloses a method for preparing cyclopropyl boronic acid. Cyclopropyl methanoic acid is adopted as a raw material and added into a solution obtained after n-butyllithium reacts with organic alkali at the low temperature, and then a boronizing reagent is added into the mixture; after boronation is finished, acid is added for quenching to obtain 1-carboxyl cyclopropyl boronic acid; the intermediate is added into high-boiling-point solvent and heated until the temperature is 80 DEG C-150 DEG C, after reaction deacidification, methylbenzene is added into the mixed solution for dehydration to form cyclopropyl boronic acid trimer, and the cyclopropyl boronic acid trimer is hydrolyzed to obtain the cyclopropyl boronic acid; the melting point of the obtained cyclopropyl boronic acid is 90 DEG C-95 DEG C, and the HNMR purity of the obtained cyclopropyl boronic acid is over 98%. The method is easy to operate and suitable for industrial scale-up production, and no highly toxic chemical is used in the whole process.

Description

technical field

[0001] The invention relates to a method for preparing cyclopropylboronic acid, which belongs to the field of synthesis of fine chemical intermediates. Background technique

[0002] Cyclopropyl structural units are widely found in drugs under research and new drugs already on the market, such as the blood lipid-lowering drug pitavastatin calcium and antibacterial drugs: ciprofloxacin, moxifloxacin hydrochloride, etc. Due to the particularity of the structure of the cyclopropyl group, the simplest and most effective way to connect this group in the molecule is to use cyclopropylboronic acid for Suzuki coupling.

[0003]

[0004] Pitavastatin Calcium Ciprofloxacin

[0005] The current synthetic method of cyclopropyl boronic acid has fewer open reports. In the existing data, it is all about reacting cyclopropyl bromide with metal magnesium or metal lithium / butyllithium to obtain cyclopropyl Grignard or lithium reagent, and then Reaction with boron reagent...

Examples

Embodiment 1

[0022] Synthesis of 1-carboxycyclopropylboronic acid:

[0023] Under the protection of nitrogen, add 120 ml of anhydrous 2-methyltetrahydrofuran and diisopropylamine (0.24 mol) into the reaction flask equipped with a dropping device, cool to -70°C, and start adding 2.5M n-butyllithium solution dropwise 88 ml. After completion of the dropwise addition, keep stirring for 1 hour. Dissolve cyclopropyl formic acid (0.1 mol) in 50 ml of anhydrous tetrahydrofuran, mix well, transfer to the above-mentioned dropping funnel, start adding the mixed solution dropwise, and keep the reaction temperature at -70°C to - 60°C. After the dropwise addition, continue to stir and react for 1-2 hours, and add deuterated water to confirm that the conversion rate is greater than 95%. Then, a mixed solution of trimethyl borate (0.20 mol) dissolved in 40 ml of anhydrous 2-methyltetrahydrofuran was added into the dropping funnel, and the reaction temperature was kept at -70°C to -60°C during the dr...

Embodiment 2

[0029] Synthesis of 1-carboxycyclopropylboronic acid:

[0030] Under the protection of nitrogen, add 120 ml of anhydrous tetrahydrofuran and 2,2,6,6-tetramethylpiperidine (0.26 mol) into the reaction flask equipped with a dropping device, cool to -50 °C, and start dropping 2.5 M n-BuLi solution 90 ml. After completion of the dropwise addition, keep stirring for 1 hour. Dissolve cyclopropyl formic acid (0.1 mol) in 50 ml of anhydrous tetrahydrofuran, mix well, transfer to the above-mentioned dropping funnel, start adding the mixed solution dropwise, and keep the reaction temperature at -70°C to - 60°C. After the dropwise addition, continue to stir and react for 1-2 hours, and add deuterated water to confirm that the conversion rate is greater than 95%. Then, a mixed solution of triisopropyl borate (0.30 mol) dissolved in 40 ml of anhydrous tetrahydrofuran was added into the dropping funnel, and the reaction temperature was kept at -70°C to -60°C during the dropwise additi...

Embodiment 3

[0036] Synthesis of 1-carboxycyclopropylboronic acid:

[0037] Under the protection of nitrogen, add 120 ml of anhydrous tetrahydrofuran and hexamethyldisilazane (0.26 mol) into the reaction flask equipped with a dropping device, cool to -40°C, and start to add 2.5M n-butyllithium solution dropwise 96 ml. After completion of the dropwise addition, keep stirring for 1 hour. Dissolve cyclopropyl formic acid (0.11 mol) in 55 ml of anhydrous tetrahydrofuran, mix well and transfer it into the above-mentioned dropping funnel, start adding the mixed solution dropwise, during the dropping process, keep the reaction temperature at -70°C to - 60°C. After the dropwise addition, continue to stir and react for 1-2 hours, and add deuterated water to confirm that the conversion rate is greater than 95%. Then, a mixed solution of tris(trimethylsilyl)boron (0.20 mol) dissolved in 40 ml of anhydrous 2-methyltetrahydrofuran was added to the dropping funnel, and the reaction temperature was...

technical field

[0001] The invention relates to a method for preparing cyclopropylboronic acid, which belongs to the field of synthesis of fine chemical intermediates. Background technique

[0002] Cyclopropyl structural units are widely found in drugs under research and new drugs already on the market, such as the blood lipid-lowering drug pitavastatin calcium and antibacterial drugs: ciprofloxacin, moxifloxacin hydrochloride, etc. Due to the particularity of the structure of the cyclopropyl group, the simplest and most effective way to connect this group in the molecule is to use cyclopropylboronic acid for Suzuki coupling.

[0003]

[0004] Pitavastatin Calcium Ciprofloxacin

[0005] The current synthetic method of cyclopropyl boronic acid has fewer open reports. In the existing data, it is all about reacting cyclopropyl bromide with metal magnesium or metal lithium / butyllithium to obtain cyclopropyl Grignard or lithium reagent, and then Reaction with boron reagent...

Examples

Embodiment 1

[0022] Synthesis of 1-carboxycyclopropylboronic acid:

[0023] Under the protection of nitrogen, add 120 ml of anhydrous 2-methyltetrahydrofuran and diisopropylamine (0.24 mol) into the reaction flask equipped with a dropping device, cool to -70°C, and start adding 2.5M n-butyllithium solution dropwise 88 ml. After completion of the dropwise addition, keep stirring for 1 hour. Dissolve cyclopropyl formic acid (0.1 mol) in 50 ml of anhydrous tetrahydrofuran, mix well, transfer to the above-mentioned dropping funnel, start adding the mixed solution dropwise, and keep the reaction temperature at -70°C to - 60°C. After the dropwise addition, continue to stir and react for 1-2 hours, and add deuterated water to confirm that the conversion rate is greater than 95%. Then, a mixed solution of trimethyl borate (0.20 mol) dissolved in 40 ml of anhydrous 2-methyltetrahydrofuran was added into the dropping funnel, and the reaction temperature was kept at -70°C to -60°C during the dr...

Embodiment 2

[0029] Synthesis of 1-carboxycyclopropylboronic acid:

[0030] Under the protection of nitrogen, add 120 ml of anhydrous tetrahydrofuran and 2,2,6,6-tetramethylpiperidine (0.26 mol) into the reaction flask equipped with a dropping device, cool to -50 °C, and start dropping 2.5 M n-BuLi solution 90 ml. After completion of the dropwise addition, keep stirring for 1 hour. Dissolve cyclopropyl formic acid (0.1 mol) in 50 ml of anhydrous tetrahydrofuran, mix well, transfer to the above-mentioned dropping funnel, start adding the mixed solution dropwise, and keep the reaction temperature at -70°C to - 60°C. After the dropwise addition, continue to stir and react for 1-2 hours, and add deuterated water to confirm that the conversion rate is greater than 95%. Then, a mixed solution of triisopropyl borate (0.30 mol) dissolved in 40 ml of anhydrous tetrahydrofuran was added into the dropping funnel, and the reaction temperature was kept at -70°C to -60°C during the dropwise additi...

Embodiment 3

[0036] Synthesis of 1-carboxycyclopropylboronic acid:

[0037] Under the protection of nitrogen, add 120 ml of anhydrous tetrahydrofuran and hexamethyldisilazane (0.26 mol) into the reaction flask equipped with a dropping device, cool to -40°C, and start to add 2.5M n-butyllithium solution dropwise 96 ml. After completion of the dropwise addition, keep stirring for 1 hour. Dissolve cyclopropyl formic acid (0.11 mol) in 55 ml of anhydrous tetrahydrofuran, mix well and transfer it into the above-mentioned dropping funnel, start adding the mixed solution dropwise, during the dropping process, keep the reaction temperature at -70°C to - 60°C. After the dropwise addition, continue to stir and react for 1-2 hours, and add deuterated water to confirm that the conversion rate is greater than 95%. Then, a mixed solution of tris(trimethylsilyl)boron (0.20 mol) dissolved in 40 ml of anhydrous 2-methyltetrahydrofuran was added to the dropping funnel, and the reaction temperature was...

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