A method for preparing 2-methyl-1H-ethylidene
By employing a two-step dehydration condensation reaction of acetic acid and 1,8-diaminonaphthalene in an aqueous phase, the problems of environmental pollution and complex synthesis in existing technologies have been solved, enabling the green synthesis and large-scale production of high-purity 2-methyl-1H-naphthalene.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- PUTIAN UNIV
- Filing Date
- 2026-03-23
- Publication Date
- 2026-05-26
AI Technical Summary
The existing synthesis process of 2-methyl-1H-isodidine relies on organic solvents and strong acids, which poses environmental pollution and safety hazards. In addition, the synthesis route is complex and the purity is low, making it difficult to achieve large-scale production.
2-Methyl-1H-carbidopaqueous amine was synthesized in an aqueous environment using a one-pot method with acetic acid and 1,8-diaminonaphthalene as raw materials. The carbidopaqueous amine ring was formed through a two-step dehydration condensation reaction, avoiding the use of catalysts and organic solvents. The purification process was simplified to filtration and column chromatography.
It achieves green synthesis, high-purity products, simplifies the operation process, reduces costs and environmental risks, and is suitable for large-scale production.
Smart Images
Figure CN122079901A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of chemical synthesis technology, specifically relating to a method for preparing 2-methyl-1H-isodidine. Background Technology
[0002] 2-Methyl-1H-carbidopa, as a core derivative of carbidopa compounds, is a key structural unit for constructing numerous functional molecules such as active pharmaceutical ingredients, organic optoelectronic materials, and high-performance chelating ligands. With its ever-expanding application potential, the market urgently demands an environmentally friendly, simple, and low-cost industrial synthesis route.
[0003] Currently, existing synthetic processes for 2-methyl-1H-carbidopaquediol heavily rely on the classic route, which has remained largely unchanged for decades: the condensation reaction of 1,8-diaminonaphthalene with acetaldehyde or acetamide in organic solvents or corrosive media. These existing technologies suffer from a significant lack of innovation, leading to a series of practical problems that hinder their development. Existing technologies generally use organic solvents such as toluene and xylene with stoichiometric or excess corrosive acid catalysts such as polyphosphoric acid and concentrated hydrochloric acid as the reaction system. This not only poses safety hazards but also generates serious environmental waste. Furthermore, existing technologies primarily use acetaldehyde to introduce a methyl group at the C2 position, failing to explore greener, more atom-economical pathways to construct the target molecule. Moreover, existing synthetic processes involve cumbersome post-processing steps and require complex purification methods, hindering their transformation into large-scale, continuous industrial production. Summary of the Invention
[0004] To address the aforementioned problems, this invention provides a method for preparing 2-methyl-1H-phenylenehydride. By using a one-pot method in an aqueous environment, 2-methyl-1H-phenylenehydride is synthesized without the need for catalysts, strong acids, or organic reagents. Furthermore, high-purity 2-methyl-1H-phenylenehydride can be obtained through filtration and column chromatography, effectively simplifying the preparation process.
[0005] To achieve the above objectives, the technical solution of the present invention is as follows: A method for preparing 2-methyl-1H-isodidine includes the following steps: Acetic acid and 1,8-diaminonaphthalene were used as reactants in a molar ratio of 2.5 to 5.5:1, and water was used as the reaction medium. One amino group of 1,8-diaminonaphthalene underwent a condensation reaction with the carboxyl group of acetic acid, removing one water molecule to obtain a product intermediate containing an amide bond. The other amino group on the intermediate underwent an intramolecular cyclization reaction with the carbonyl group in the amide bond, removing one water molecule to obtain the crude product. The crude product was purified to obtain the 2-methyl-1H-diphenyl ether.
[0006] This invention uses acetic acid and 1,8-diaminonaphthalene as reactants. The addition of excess acetic acid not only acts as a reactant but also increases the acidity of the reaction system and promotes the reaction. Water is used as the sole reaction medium, and a one-step cyclization condensation reaction is carried out in a reactor to finally obtain the target product.
[0007] The specific reaction between acetic acid and 1,8-diaminonaphthalene is as follows: One amino group of 1,8-diaminonaphthalene undergoes a condensation reaction with the carboxyl group of acetic acid, losing a water molecule to obtain a product intermediate containing an amide bond. In an acidic reaction system, the carbonyl group of the amide bond (—CO-NH—) in the intermediate changes from the keto form to the enol form, while the carbon-nitrogen single bond forms a carbon-nitrogen double bond. The other amino group on the intermediate undergoes an intramolecular cyclization reaction with the carbonyl group (enol form) in the amide bond, losing a water molecule to form a stable uridine ring structure.
[0008] In another preferred embodiment, the temperature of the condensation reaction is 100°C to 185°C.
[0009] In another preferred embodiment, the internal cyclization reaction is carried out at a temperature of 100°C to 185°C. The intermediate undergoes a condensation reaction at a high temperature of 100°C to 185°C, removing H2O, and finally cyclizing to form a stable uridine ring structure.
[0010] In another preferred embodiment, the total reaction time of the synthesis reaction and the internal cyclization reaction is 3h to 48h.
[0011] In another preferred embodiment, the crude product refers to the product obtained after vacuum concentration following the completion of the cyclization reaction.
[0012] In another preferred embodiment, the purification refers to purification using column chromatography.
[0013] In another preferred embodiment, the column chromatography refers to gradient elution using 200-300 mesh silica gel as the stationary phase and a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 1-5:1-5 as the mobile phase. Specifically, the 200-300 mesh silica gel is used as the stationary phase, and the petroleum ether / ethyl acetate mixed solvent is used as the mobile phase for gradient elution, with the volume ratios of petroleum ether and ethyl acetate in the eluent being 5:1, 3:1, 1:1, 1:3, and 1:5, respectively.
[0014] In another preferred embodiment, after gradient elution, the eluent with a volume ratio of petroleum ether to ethyl acetate of 1:5 is collected, concentrated, and dried to obtain the 2-methyl-1H-ethylhexidine.
[0015] Compared with the prior art, the present invention has the following beneficial effects: This invention employs a simple acetic acid-water reaction system, with acetic acid and 1,8-diaminonaphthalene reacting in an aqueous environment at a molar ratio of 2.5~5.5:1. Excess acetic acid serves as a reactant, increasing the acidity of the reaction system and promoting the reaction. This process completely eliminates toxic organic solvents and corrosive strong acids, using water as the sole reaction medium, thus eliminating the emission of toxic organic compounds (VOCs) and equipment corrosion at the source, achieving a green process. This invention is the first to successfully apply acetic acid to the synthesis of 2-methyl-1H-acetidine under heating conditions during the reaction process. The 2-methyl-1H-acetidine prepared using the method of this invention achieves a purity of up to 98%.
[0016] The preparation process of this invention presents a novel approach distinct from existing synthetic methods. Through a two-step dehydration condensation, intramolecular cyclization occurs simultaneously with the second dehydration reaction, providing a new approach and theoretical basis for the synthesis of 2-methyl-1H-ethylidene. This novel reaction pathway utilizes acetic acid under high-temperature hydrothermal conditions, via a two-step dehydration condensation reaction, to efficiently introduce a methyl group into the target product. This avoids the use of expensive pre-functionalized reagents, leading to higher reaction selectivity and fewer byproducts, thus reducing the burden on subsequent purification.
[0017] This invention employs a classic one-pot process, where the raw materials are mixed in water and reacted in a single step to obtain the target product. This process avoids the cumbersome steps required in traditional methods, such as azeotropic dehydration, catalyst neutralization, and multi-step extraction, greatly simplifying the operation and reducing yield losses and operational errors caused by numerous steps. The entire preparation process does not require strong acids / alkalis and does not generate waste liquid containing organic matter, thus avoiding the costs associated with treating waste gas, wastewater, and solid waste. The safety of the production environment is significantly improved, reducing occupational health risks and related management costs, and eliminating the need to invest in expensive explosion-proof equipment and corrosion-resistant reactors. The simplification of the process directly translates into optimized production efficiency and costs. More concentrated reaction time, reduced manpower, and lower energy consumption significantly reduce the overall production cost of the product, making it suitable for pilot-scale and large-scale production. Attached Figure Description
[0018] Figure 1 The image shows the proton NMR spectrum of 2-methyl-1H-ethylidene prepared in Example 1.
[0019] Figure 2 The image shows the carbon NMR spectrum of 2-methyl-1H-ethylidene prepared in Example 1. Detailed Implementation
[0020] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are for illustrative purposes only and are not intended to limit the invention.
[0021] Unless otherwise specified, the experimental methods described in the following embodiments are conventional methods; unless otherwise specified, the reagents and materials are commercially available.
[0022] In existing technologies, 2-methyl-1H-phenylenehydride is synthesized by condensation reaction of 1,8-diaminonaphthalene and acetaldehyde or acetamide in an organic solvent such as toluene or xylene under reflux, or by heating in a strong acid medium such as polyphosphoric acid. However, the following inherent drawbacks exist:
[0023] (1) Regarding the reaction medium and environmental impact, existing technologies rely on organic solvents or strong acids, resulting in environmental unfriendliness and high treatment costs. Existing solutions use volatile organic solvents or highly corrosive polyphosphoric acid as reaction media. These substances are inherently toxic and environmentally harmful, and their use inevitably generates waste liquids and gases containing toxic substances. To treat these three wastes, production enterprises must invest in high end-of-pipe treatment costs. The root cause of its shortcomings lies in the fact that the design of existing technical routes is based on traditional, non-green chemical systems, failing to take process greening as the core consideration of the solution, thus transferring enormous environmental pressure to the production process.
[0024] (2) Regarding reaction strategies and atom economy, the existing technologies employ complex synthetic routes, resulting in cumbersome synthetic strategies and insufficient exploration of atom economy. Existing schemes all use acetaldehyde or acetamide as the source for directly introducing methyl groups into the target product molecule, and their reaction processes are limited to strong acid environments or catalyst conditions. The drawback of existing schemes is that strategies dependent on strong acid environments or catalyst conditions have long been dominant, and have suppressed the exploration of other potentially more atom-economical reaction routes to efficiently construct target molecules, causing the synthetic methodology in this field to stagnate for many years and lack fundamental innovation.
[0025] (3) Regarding the process flow and industrialization potential, existing technologies suffer from complex reaction systems and low product purity, leading to cumbersome post-processing and difficulty in scaling up production. When organic solvents are used, the reaction usually requires a long azeotropic dehydration process to ensure equilibrium shift, resulting in high energy consumption and low efficiency. When polyphosphoric acid or other media are used, multiple cumbersome steps such as neutralization and water washing are required after the reaction to separate the crude product. More importantly, the crude products obtained from these two routes are often complex in composition and have poor purity. The fundamental reason is the insufficient selectivity of the reaction and the introduction of complex media systems, which makes the purification stage heavily reliant on complex purification techniques that are difficult to scale up industrially. This greatly limits the practical application value and large-scale production potential of existing technologies.
[0026] This invention provides a method for obtaining high-purity 2-methyl-1H-phenyleneidine in an aqueous environment using acetic acid and 1,8-diaminonaphthalene as reactants in a one-pot process. The specific process is as follows: S1. Dissolve high-purity acetic acid (≥99.8%) in deionized water and stir to form a homogeneous acetic acid solution.
[0027] S2. Add 1,8-diaminonaphthalene to the above acetic acid solution and mix and disperse it thoroughly by shaking or stirring to form a reaction slurry. The molar ratio of acetic acid to 1,8-diaminonaphthalene is 2.5~5.5:1, which is much higher than the stoichiometric ratio. The excess acetic acid not only acts as a reactant but also plays a role in adjusting the pH of the reaction system and promoting the reaction.
[0028] S3. Transfer the reaction slurry to a reaction vessel lined with polytetrafluoroethylene, seal it, and place it in a heating device. React at a temperature range of 100℃ to 185℃ for 3 to 48 hours.
[0029] Experimental verification showed that the yield of 2-methyl-1H-isodamine gradually increased with increasing reaction temperature when the reaction was carried out at 100℃, 120℃, 140℃, 160℃, 170℃, 175℃, and 180℃. Analysis of the products obtained by silica gel thin-layer chromatography and column chromatography purification confirmed that the yield of 2-methyl-1H-isodamine gradually increased with increasing reaction temperature. When the reaction temperature reached 185℃, the yield of 2-methyl-1H-isodamine no longer increased, but the content of byproducts increased significantly. Therefore, in this invention, the optimal reaction temperature is 180℃.
[0030] Under high temperature conditions, with water as the reaction medium, acetic acid reacts with 1,8-diaminonaphthalene in the following chemical reaction process: Dehydration condensation: One amino group of 1,8-diaminonaphthalene undergoes a condensation reaction with the carboxyl group of acetic acid, removing one water molecule to obtain a product intermediate containing an amide bond; Keto-enol resonance tautomerism: In an acidic reaction system, the carbonyl group of the amide bond (—CO-NH—) in the intermediate changes from the keto form to the enol form, while the carbon-nitrogen single bond forms a carbon-nitrogen double bond; Cyclization and dehydration condensation: Another amino group on the intermediate undergoes an intramolecular cyclization reaction with the carbonyl group (enol form) in the amide bond, removing a water molecule to form a stable uridine ring structure. The entire reaction process is completed in one step in the reactor.
[0031] S4. After the reaction is complete, cool and purify to obtain the 2-methyl-1H-isodidine.
[0032] The following is a detailed description of a method for preparing 2-methyl-1H-isodidine.
[0033] High-grade pure acetic acid (≥99.8%) and 1,8-diaminonaphthalene (≥97%) were both purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.
[0034] Example 1 A method for preparing 2-methyl-1H-isodidine includes the following steps: S1. Accurately measure 2.0 mL (34.59 mmol) of acetic acid and accurately weigh 1.0 g (6.32 mmol) of 1,8-diaminonaphthalene, and prepare 18 mL of deionized water.
[0035] Add the measured acetic acid to 18 ml of deionized water and stir well to obtain 20 ml of acetic acid solution. Then add the weighed 1,8-diaminonaphthalene to the solution and gently shake the beaker to fully disperse the solid powder in the solution to form a suspension slurry.
[0036] S2. Transfer all of the above mixed slurry into a 50 ml reaction vessel lined with polytetrafluoroethylene. After sealing, place the reaction vessel in an oven preheated to 180°C and react at this temperature for 3 hours.
[0037] S3. After the reaction is complete, remove the reaction vessel from the oven and allow it to cool naturally to room temperature. Open the reaction vessel to obtain a brownish-yellow mixed solution containing the target product. Then, concentrate this mixed solution under reduced pressure to remove most of the water, obtaining the crude product. Finally, use column chromatography to separate and purify the crude product, collecting the eluent containing the target product. The specific purification process is as follows:
[0038] Gradient elution was performed using 300-mesh silica gel as the stationary phase and a petroleum ether / ethyl acetate mixed solvent as the mobile phase. The volume ratios of petroleum ether to ethyl acetate in the eluent were 5:1, 3:1, 1:1, 1:3, and 1:5, respectively. The eluent with a petroleum ether / ethyl acetate volume ratio of 1:5 was collected, concentrated, and dried to obtain a yellow-green solid, 2-methyl-1H-ethylhexidine, with the structural formula shown in formula (1). The yield was 75%, and the purity was 98%. Its proton NMR spectrum is shown below. Figure 1 As shown, the carbon spectrum is as follows Figure 2 As shown.
[0039] Equation (1).
[0040] Yellowish-green solid; 1 H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H), 7.12 (t, J = 7.6 Hz, 1H), 7.06 (t, J = 7.3 Hz, 1H), 6.98 (d, J = 8.1 Hz, 2H), 6.51 (d, J =7.2 Hz, 1H), 6.25 (d, J = 7.2 Hz, 1H), 2.01 (s, 3H). 13 C NMR (101 MHz D, MSO-d6) δ 154.69, 145.68, 138.67, 135.53, 129.37, 128.34, 121.65, 119.00, 117.86, 113.18, 101.95, 21.74.
[0041] Example 2 A method for preparing 2-methyl-1H-isodidine includes the following steps: S1. Accurately measure 1.5 mL (25.94 mmol) of acetic acid and accurately weigh 1.0 g (6.32 mmol) of 1,8-diaminonaphthalene, and prepare 18.5 mL of deionized water.
[0042] Add the measured acetic acid to 18.5 mL of deionized water and stir until well mixed to obtain 20 mL of acetic acid solution. Then add the weighed 1,8-diaminonaphthalene to the solution and gently shake the beaker to fully disperse the solid powder in the solution to form a suspension slurry.
[0043] S2. Transfer all of the above mixed slurry into a 50 ml reaction vessel lined with polytetrafluoroethylene. After sealing, place the reaction vessel in an oven preheated to 180°C and react at this temperature for 3 hours.
[0044] S3. After the reaction is complete, remove the reaction vessel from the oven and allow it to cool naturally to room temperature. Open the reaction vessel to obtain a brownish-yellow mixed solution containing the target product. Then, concentrate this mixed solution under reduced pressure to remove most of the water, obtaining the crude product. Finally, use column chromatography to separate and purify the crude product, collecting the eluent containing the target product. The specific purification process is as follows:
[0045] Gradient elution was performed using 200-mesh silica gel as the stationary phase and a petroleum ether / ethyl acetate mixed solvent as the mobile phase. The volume ratios of petroleum ether to ethyl acetate in the eluent were 5:1, 3:1, 1:1, 1:3, and 1:5, respectively. The eluent with a petroleum ether / ethyl acetate volume ratio of 1:5 was collected, concentrated, and dried to obtain a yellow-green solid, 2-methyl-1H-ethyl idine, with a yield of 75% and a purity of 98%.
[0046] Example 3 A method for preparing 2-methyl-1H-isodidine includes the following steps: S1. Accurately measure 0.9 mL (15.56 mmol) of acetic acid and accurately weigh 1.0 g (6.32 mmol) of 1,8-diaminonaphthalene, and prepare 19.1 mL of deionized water.
[0047] Add the measured acetic acid to 18 ml of deionized water and stir well to obtain 20 ml of acetic acid solution. Then add the weighed 1,8-diaminonaphthalene to the solution and gently shake the beaker to fully disperse the solid powder in the solution to form a suspension slurry.
[0048] S2. Transfer all of the above mixed slurry into a 50 ml reaction vessel lined with polytetrafluoroethylene. After sealing, place the reaction vessel in an oven preheated to 180°C and react at this temperature for 3 hours.
[0049] S3. After the reaction is complete, remove the reaction vessel from the oven and allow it to cool naturally to room temperature. Open the reaction vessel to obtain a brownish-yellow mixed solution containing the target product. Then, concentrate this mixed solution under reduced pressure to remove most of the water, obtaining the crude product. Finally, use column chromatography to separate and purify the crude product, collecting the eluent containing the target product. The specific purification process is as follows:
[0050] Gradient elution was performed using 200-mesh silica gel as the stationary phase and a petroleum ether / ethyl acetate mixed solvent as the mobile phase. The volume ratios of petroleum ether to ethyl acetate in the eluent were 5:1, 3:1, 1:1, 1:3, and 1:5, respectively. The eluent with a petroleum ether / ethyl acetate volume ratio of 1:5 was collected, concentrated, and dried to obtain a yellow-green solid, 2-methyl-1H-ethyl idine, with a yield of 75% and a purity of 98%.
[0051] The above are merely preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.
Claims
1. A method for preparing 2-methyl-1H-phenyleneidine, characterized in that, Includes the following steps: Acetic acid and 1,8-diaminonaphthalene in a molar ratio of 2.5 to 5.5:1 were used as reactants, and water was used as the reaction medium. One amino group of 1,8-diaminonaphthalene underwent a condensation reaction with the carboxyl group of acetic acid, removing one water molecule to obtain a product intermediate containing an amide bond. The other amino group on the intermediate underwent an intramolecular cyclization reaction with the carbonyl group in the amide bond, removing one water molecule to obtain the crude product. The crude product was purified to obtain the 2-methyl-1H-isodidine.
2. The method for preparing 2-methyl-1H-phenylenevinylene according to claim 1, characterized in that, The condensation reaction is carried out at a temperature of 100℃~185℃.
3. The method for preparing 2-methyl-1H-phenylenevinylene according to claim 2, characterized in that, The temperature for the cyclization reaction is 100℃~185℃.
4. The method for preparing 2-methyl-1H-phenylenevinylene according to claim 1, characterized in that, The total reaction time for the condensation reaction and the internal cyclization reaction is 3h to 48h.
5. The method for preparing 2-methyl-1H-phenylenevinylene according to claim 1, characterized in that, The crude product refers to the product obtained after vacuum concentration following the completion of the internal cyclization reaction.
6. The method for preparing 2-methyl-1H-phenylenevinylene according to claim 1, characterized in that, The purification mentioned refers to purification using column chromatography.
7. The method for preparing 2-methyl-1H-phenylenevinylene according to claim 6, characterized in that, The column chromatography refers to gradient elution using 200-300 mesh silica gel as the stationary phase and a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 1-5:1-5 as the mobile phase.
8. The method for preparing 2-methyl-1H-phenylenevinylene according to claim 7, characterized in that, After gradient elution, the eluent with a volume ratio of petroleum ether to ethyl acetate of 1:5 is collected, concentrated, and dried to obtain the 2-methyl-1H-ethylhexidine.