A method for preparing methyl-substituted organic compounds by one-step reduction of carboxylic acids, aldehyde groups and benzyl alcohols using borane complexes

Abstract

The present application relates to the technical field of organic synthesis, and particularly relates to a method for preparing methyl-substituted organic compounds by one-step reduction of carboxylic acid, aldehyde group and benzyl alcohol using borane complex. The method comprises the following steps: under anhydrous and anaerobic conditions, dissolving a reaction substrate in a solvent, adding borane complex for reaction, and obtaining the methyl-substituted organic compounds through post-treatment after the reaction is completed; the reaction substrate contains at least one functional group selected from carboxyl, aldehyde group and benzyl alcohol; and the borane complex includes at least one of borane-tetrahydrofuran complex or borane-dimethyl sulfide complex. Through the specific preparation method, the present application realizes one-step deep deoxygenation methylation of three different active functional groups of carboxyl, aldehyde group and benzyl alcohol, and compresses the traditional 4-5-step indirect synthesis process to one step, thereby greatly shortening the reaction route.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and more specifically, to a method for preparing methyl-substituted organic compounds by one-step reduction of carboxylic acids, aldehydes, and benzyl alcohols using borane complexes. Background Technology

[0002] The conversion of carboxyl groups (-COOH), aldehyde groups (-CHO), and benzyl alcohols (-CH2OH) to methyl groups (-CH3) is one of the three core deoxygenation reduction reactions in organic synthesis, widely used in the molecular construction of pharmaceutical intermediates, natural products, and functional materials. Due to the significant differences in reactivity among these three functional groups, completely different reduction systems are typically required, often resulting in harsh reaction conditions, lengthy steps, and poor functional group compatibility. For the methylation of carboxylic acids, the mainstream process is a 4-5 step indirect synthesis or an extreme strong reduction system such as lithium aluminum hydride or high-temperature, high-pressure hydrogenation, resulting in low overall yield and large amounts of waste. For the methylation of aldehyde groups, the traditional Clemmensen reduction requires strong acid reflux, and the Wolff-Kishner reduction requires strong base and high temperature, neither of which is compatible with acid-sensitive or base-sensitive groups. For the methylation of benzyl alcohols, catalytic hydrogenation is commonly used to easily reduce intramolecular double bonds, nitro groups, and other unsaturated functional groups; silane reduction requires expensive metal catalysts, leading to high costs.

[0003] Chinese invention patent CN17138839B discloses a flow chemistry method for reducing carboxylic acids to alcohols using diisobutylaluminum hydride. While this method achieves the conversion of carboxylic acids to primary alcohols under mild conditions, the reduction depth is limited, and it cannot yield methyl products in one step. Furthermore, it can only process single functional groups of carboxylic acids and has no reducing activity for aldehydes and benzyl alcohols, failing to meet the need for simultaneous methylation of multiple functional groups in complex molecules. Therefore, developing a universal, mild, and efficient method that can simultaneously achieve one-step reductive methylation of carboxylic acids, aldehydes, and benzyl alcohols has significant industrial application value. Summary of the Invention

[0004] The first aspect of this invention provides a method for preparing methyl-substituted organic compounds by one-step reduction of carboxylic acid, aldehyde, and benzyl alcohol using a borane complex, comprising the following steps: dissolving the reaction substrate in a solvent under anhydrous and oxygen-free conditions, adding a borane complex to carry out the reaction, and obtaining the methyl-substituted organic compound after post-treatment after the reaction is completed; wherein the reaction substrate contains at least one functional group selected from carboxyl (-COOH), aldehyde (-CHO), and benzyl alcohol (-CH2OH).

[0005] In existing technologies, the methylation of carboxylic acids, aldehydes, and benzyl alcohols requires completely different reduction systems and is processed stepwise. Furthermore, most reducing agents can only achieve partial reduction and cannot complete deep deoxygenation to methylation in one step. In this invention, the borane complex releases an active three-coordinate borane under anhydrous and oxygen-free conditions. As a strong Lewis acid, it first coordinates with the lone pair electrons of the oxygen-containing functional groups in the substrate molecule, activating the carbon-oxygen bond. For carboxylic acid substrates, the borane first coordinates with the two oxygen atoms of the carboxyl group, and is subsequently reduced to an aldehyde intermediate and a benzyl alcohol borane adduct via two hydride transfers. The adduct then undergoes intramolecular dehydration to generate a benzyl carbocation, which is then captured by hydride ions provided by excess borane in the system to generate a methyl group. For aldehyde substrates, the reaction skips the reduction of carboxylic acid to aldehyde, directly generating the benzyl alcohol borane adduct via coordination and hydride transfer, followed by subsequent deoxygenation reduction. For benzyl alcohol substrates, the hydroxyl group directly coordinates with borane, undergoes dehydration to generate a carbocation, and is then reduced to a methyl group. Since the reduction pathways of the three types of functional groups are continuous, and borane can stably complete all three-step reduction processes under conditions of 0-25℃, universal one-step deep deoxymethylation of three different active functional groups can be achieved without adding reagents stepwise or changing reaction conditions.

[0006] The borane complex includes at least one of borane tetrahydrofuran complex or borane dimethyl sulfide complex.

[0007] The general structural formula of the reaction substrate includes at least one of Formulas 1-4: R1 is selected from -COOH, -CHO, and -CH2OH; R2 is selected from -Boc (tert-butyloxycarbonyl) or -Fmoc (fluorenemethyloxycarbonyl); R3 is selected from -CH3 or -CH2CH3.

[0008] The general structural formula of the reaction substrate is shown in Formula 5: .

[0009] The compound of Formula 5 is 4-(4-carboxyphenyl)piperazine-1-carboxylic acid tert-butyl ester (CAS No.: 162046-66-4).

[0010] The solvent is selected from at least one of tetrahydrofuran, diethyl ether, and methyl tert-butyl ether.

[0011] The mass-to-volume ratio of the reaction substrate to the solvent is 1 g: (5-15) mL.

[0012] Optionally, the mass-to-volume ratio of the reaction substrate to the solvent is 1 g: (8-12) mL.

[0013] The molar ratio of the reaction substrate to the borane complex is 1:(3-6).

[0014] Optionally, the molar ratio of the reaction substrate to the borane complex is 1:(3-5).

[0015] The reaction conditions include: first, adding a borane complex dropwise at 0-10℃; after the addition is complete, raising the temperature to 20-25℃ and stirring the reaction for 8-16 hours to obtain a reaction solution.

[0016] The post-processing includes quenching and separation / purification.

[0017] The quenching process includes the following steps: cooling the reaction solution to 0-10℃, adding the quenching agent dropwise, and continuing to stir for 0.5-1.5h after the addition is complete.

[0018] The quenching agent includes at least one of methanol, ethanol, isopropanol, n-butanol, deionized water, dilute hydrochloric acid, dilute sulfuric acid, and saturated ammonium chloride aqueous solution.

[0019] The separation and purification process includes the following steps: the quenched reaction solution is concentrated under reduced pressure and then extracted, the organic phases are combined, dried and concentrated under reduced pressure, and then purified by column chromatography to obtain methyl-substituted organic compounds.

[0020] Optionally, the separation and purification includes the following steps: concentrating the quenched reaction solution under reduced pressure to remove the solvent, extracting with ethyl acetate and saturated brine, combining the organic phases, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and then purifying by column chromatography to obtain the methyl-substituted organic compound.

[0021] Beneficial effects 1. This invention achieves universal one-step deep deoxymethylation of three different active functional groups—carboxyl, aldehyde, and benzyl alcohol—through a specific preparation method, compressing the traditional 4-5 step indirect synthesis process into 1 step and significantly shortening the reaction route.

[0022] 2. The reaction of this invention is carried out under normal pressure at 0-25℃, without the need for high temperature and high pressure, strong acid and strong alkali or precious metal catalysts, which reduces production safety risks and equipment investment costs.

[0023] 3. This invention has excellent functional group compatibility. While reducing the target functional group, it has no effect on the Boc and Fmoc amino protecting groups and inert substituents such as methyl and ethyl groups on the benzene ring, and can be directly used for the synthesis of complex drug intermediates.

[0024] 4. This invention supports the simultaneous one-step reductive methylation of carboxyl, aldehyde, and benzyl alcohol groups in the same substrate molecule, eliminating the need for stepwise reactions and intermediate separation, thus avoiding yield losses caused by stepwise operations.

[0025] 5. The yield of the target product of this invention can reach over 90%, and the purity is ≥95%, which reduces raw material waste and subsequent purification steps, and significantly improves production efficiency.

[0026] 6. The one-step reaction process of this invention significantly reduces the discharge of high COD and high-salt wastewater generated by multi-step synthesis. The post-treatment steps are simple, and the organic solvents can be recycled and reused, which meets the requirements of green chemical production. Attached Figure Description

[0027] Figure 1 The NMR spectrum of the methyl-substituted organic compound prepared in Example 1 is shown.

[0028] Figure 2 The image shows the LCMS (liquid chromatography-mass spectrometry) spectrum of the methyl-substituted organic compound prepared in Example 1. Detailed Implementation

[0029] Example 1 A method for preparing methyl-substituted organic compounds by one-step reduction of carboxylic acids using a borane complex comprises the following steps: 200 g of the reaction substrate 4-(4-carboxyphenyl)piperazine-1-carboxylic acid tert-butyl ester and 2000 mL of THF are added sequentially to a 5000 mL flask. Nitrogen gas is introduced, and 270 mL of a borane dimethyl sulfide complex (10.0 M, DMS solvent) is added to the reaction solution at 0 °C. The mixture is then stirred at 25 °C for 12 h. The reaction progress is monitored by TLC (thin-layer chromatography). The reaction mixture should be completely cooled to 0℃ and quenched with 150 mL of methanol. After quenching, stir for about 1 hour. After quenching, stir for about 1 hour, evaporate to dryness, add 200 mL of saturated brine, and extract three times with 200 mL of ethyl acetate. Combine the organic phases, dry to anhydrous sodium sulfate, and concentrate. Purify by column chromatography, eluting the product with PE / EA (petroleum ether / ethyl acetate) at a volume ratio of 10 / 1. Combine and concentrate to obtain 166 g of white solid, which is a methyl-substituted organic compound. The calculated yield (based on the reaction substrate) is 92%.

[0030] Performance testing methods and data The methyl-substituted organic compounds prepared in Example 1 were subjected to purity testing (LCMS, area normalization method) and structural characterization using nuclear magnetic resonance (HNMR, DMSO solvent).

[0031] MRI results as follows Figure 1 As shown, 1 The HNMR results are as follows: 1 HNMR (400MHz, DMSO) δ7.03(d,J=8.3Hz,2H),6.85(d,J=8.6Hz,2H),3.53-3.36(m,4H),3.05-2.95(m,4H),2.20(s,3H),1.41(s,9H).

[0032] like Figure 2 As shown, the purity of the prepared compound is 98.65%.

Claims

1. A method for preparing methyl-substituted organic compounds by one-step reduction of carboxylic acids, aldehydes, and benzyl alcohols using borane complexes, characterized in that, The reaction includes the following steps: under anhydrous and oxygen-free conditions, the reaction substrate is dissolved in a solvent, a borane complex is added to carry out the reaction, and after the reaction is completed, a methyl-substituted organic compound is obtained through post-treatment; the reaction substrate contains at least one functional group selected from carboxyl, aldehyde, and benzyl alcohol; the borane complex includes at least one selected from borane tetrahydrofuran complex or borane dimethyl sulfide complex.

2. The method according to claim 1, characterized in that, The general structural formula of the reaction substrate includes at least one of Formulas 1 to 4: R1 is selected from -COOH, -CHO, and -CH2OH; R2 is selected from -Boc or -Fmoc; and R3 is selected from -CH3 or -CH2CH3.

3. The method according to claim 2, characterized in that, The general structural formula of the reaction substrate is shown in Formula 5: .

4. The method according to claim 1, characterized in that, The solvent is selected from at least one of tetrahydrofuran, diethyl ether, and methyl tert-butyl ether.

5. The method according to claim 1, characterized in that, The mass-to-volume ratio of the reaction substrate to the solvent is 1 g: (5-15) mL.

6. The method according to claim 5, characterized in that, The molar ratio of the reaction substrate to the borane complex is 1:(3-6).

7. The method according to claim 1, characterized in that, The reaction conditions include: first, adding a borane complex dropwise at 0-10℃; after the addition is complete, raising the temperature to 20-25℃ and reacting for 8-16 hours to obtain a reaction solution.

8. The method according to claim 1, characterized in that, The post-processing includes quenching and separation / purification.

9. The method according to claim 8, characterized in that, The quenching process includes the following steps: cooling the reaction solution to 0-10℃, adding the quenching agent dropwise, and continuing to stir for 0.5-1.5h after the addition is complete.

10. The method according to claim 9, characterized in that, The separation and purification process includes the following steps: the quenched reaction solution is concentrated under reduced pressure and then extracted, the organic phases are combined, dried and concentrated under reduced pressure, and then purified by column chromatography to obtain methyl-substituted organic compounds.

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