A process for the preparation of 1,6-hexanediol from dimethyl adipate

Abstract

This invention belongs to the field of organic synthesis and fine chemical technology, and specifically discloses a method for preparing 1,6-hexanediol from dimethyl adipate, comprising: (1) mixing dimethyl adipate, phenylboronic acid and pinacol borane directly or dissolving them in an organic solvent under an inert atmosphere, and reacting at room temperature to 60°C to generate a borate intermediate; (2) adding an alkaline aqueous solution directly to the reaction solution obtained in step (1), and hydrolyzing at 55-65°C for 6-10 hours to obtain the target product 1,6-hexanediol; (3) obtaining purified 1,6-hexanediol after extraction, drying and concentration. This invention provides a green, efficient and low-cost new route for the synthesis of 1,6-hexanediol, which is applicable to the fields of fine chemicals, bio-based materials and electronic chemicals. This invention further confirms that the reaction effect is better under solvent-free conditions, which is more suitable for industrial green production and has significant economic value and industrialization potential.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis and fine chemical technology, and specifically relates to a new method for reducing dimethyl adipate to 1,6-hexanediol using a non-metallic catalytic system under mild conditions. Background Technology

[0002] 1,6-Hexanediol is an important C6 diol widely used in the synthesis of polyurethane elastomers, unsaturated polyester resins, coating additives, and pharmaceutical intermediates. Currently, it is mainly produced industrially via the catalytic hydrogenation route of adipic acid or its esters (such as dimethyl adipate, or DMA).

[0003] However, the existing technology has significant drawbacks, which are precisely the technical problems that this invention aims to solve: (1) Dependence on precious metal catalysts: The mainstream process uses precious metal catalysts such as Ru and Pd. See CN109748778A and US06407294B1. The above patents disclose the process of preparing 1,6-hexanediol by hydrogenation of dimethyl adipate as raw material through precious metal catalysis. The process is costly and resource-limited.

[0004] (2) Harsh reaction conditions: It usually needs to be carried out at high temperature (>200℃) and high pressure hydrogen (>5MPa), see Li Xiaoyu, Luo Jingjie, Liang Changhai. Hydrogenation of adipic acid to 1,6-hexanediol by supported bimetallic iridium-rhenium catalyst. Catal. 2020, 490, 110976 (X. Li, J. Luo, C. Liang. Hydrogenation of adipic acid to 1,6-hexanediol by supported bimetallic Ir-Re catalyst. Mol.), which poses a severe challenge to the safety and energy consumption of the reaction equipment.

[0005] (3) Non-precious metal catalysts are highly complex: Bimetallic catalysts such as Cu-Zn and Cu-Ca developed to reduce costs need to be prepared by sol-gel method or coprecipitation method, see Zhao Yujun, Xu Yuxi, Wang Shengping, Ma Xinbin. Ternary Cu-ZnO-ZrO2 nanostructures prepared by surface-assisted coprecipitation for catalytic hydrogenation of dimethyl adipate to 1,6-hexanediol. ACS Applied Nano Materials, 2023, 6, 18890−18901 (Y. Zhao, Y. Xu, S. Wang, X. Ma. Ternary Cu-ZnO-ZrO2 Nanostructures Prepared by Surface-Assisted Coprecipitation for Catalytic Hydrogenation of Dimethyl Adipate to 1,6-Hexanediol.). Their activity is highly dependent on microscopic parameters such as pore structure and surface acidity / alkalinity, with poor batch reproducibility and easy deactivation.

[0006] Although some studies have attempted to use borane-based reducing agents (such as LiAlH4 and DIBAL-H), problems such as poor selectivity, weak functional group compatibility, and complex post-processing still exist, making them difficult to apply to long-chain diester molecules containing ester groups.

[0007] Therefore, there is an urgent need to develop a new route for the synthesis of 1,6-hexanediol that does not require transition metal catalysts, has mild conditions, and high selectivity. Summary of the Invention

[0008] The present invention aims to overcome the problems of strong dependence on metal catalysts, harsh reaction conditions, complex catalyst preparation and insufficient selectivity in the prior art, and provides a simple, mild, highly selective and high yield method for preparing 1,6-hexanediol.

[0009] Specifically, the present invention provides a method for preparing 1,6-hexanediol from dimethyl adipate, comprising the following sequential steps: (1) Hydroboration reduction step: Under an inert atmosphere (such as nitrogen or argon), dimethyl adipate, phenylboronic acid, and pinacolborane (HBpin) are directly mixed or dissolved in an organic solvent and reacted at room temperature to 60°C to generate borate intermediate 1b. The reaction principle is: phenylboronic acid, as a Lewis acid, activates the oxygen atom of the ester group, which enhances the electrophilicity of the carbonyl carbon, making it more susceptible to addition reaction by the nucleophile HBpin. Subsequently, the CO bond breaks to generate the product borate intermediate 1b and the byproduct methylpinacolborane CH3OBpin.

[0010]

[0011] (2) Hydrolysis step: No intermediate separation is required. Add an alkaline aqueous solution directly to the reaction solution obtained in step (1), and hydrolyze at 55-65℃ for 6-10 hours to obtain the target product, 1,6-hexanediol. The reaction principle is: boron atoms are electron-deficient, OH... - As a nucleophile, boron is attacked, transforming from a planar structure into a tetrahedral negatively charged intermediate. Electron rearrangement occurs in the intermediate, the OB bond breaks, and the alkoxy group (RO⁻) is released. The alkoxy group abstracts a proton from water, producing the product 1,6-hexanediol and the byproduct pinacolborate (pinBOH). Methylpinacolborate (CH₃OBpin) hydrolyzes to form low-boiling methanol and pinBOH.

[0012]

[0013] (3) Post-processing steps: After extraction, drying and concentration, high-purity 1,6-hexanediol is obtained.

[0014] Preferably, the molar amount of phenylboronic acid is 3-8% of the molar amount of dimethyl adipate, more preferably 5%.

[0015] Preferably, the molar amount of pinacol borane is 4 to 6 times the molar amount of dimethyl adipate, more preferably 5 times.

[0016] Preferably, the organic solvent is anhydrous tetrahydrofuran (THF), toluene, or 1,4-dioxane.

[0017] Preferably, the alkaline aqueous solution is an 8-12 wt% NaOH aqueous solution or a KOH aqueous solution, more preferably a 10 wt% NaOH aqueous solution.

[0018] Preferably, the hydrolysis temperature in step (2) is 60°C and the hydrolysis time is 8 hours.

[0019] Compared with the prior art, the beneficial effects of the present invention are as follows: (1) Non-metallic catalytic system: For the first time, phenylboronic acid was used as an organic small molecule catalyst to activate HBpin, completely avoiding precious metals or complex heterogeneous catalysts. The raw materials are cheap, readily available, and environmentally friendly.

[0020] (2) The reaction conditions are extremely mild: the entire preparation process of this invention is carried out under normal pressure and ≤80℃ conditions, without the need for high-pressure hydrogen or high-temperature equipment, which greatly reduces safety risks and investment costs.

[0021] (3) High selectivity and high purity: The reaction path of this invention is specific, and the target 1,6-hexanediol is generated in a high yield.

[0022] (4) The continuity of the "one-pot" process: the borate ester intermediate is hydrolyzed in situ, and the whole process can be completed in one pot, avoiding separation loss and operational complexity, significantly improving efficiency and atom economy, and is suitable for continuous production.

[0023]

[0024] (5) Solvent-free reaction is better and green environmental protection is further improved: This invention further verifies that the reaction can be carried out smoothly under the condition of no organic solvent. Compared with the organic solvent system, the solvent-free system has a faster reaction rate, a higher yield of the target product 1,6-hexanediol, and simpler post-processing. It avoids the energy consumption of solvent use and recycling, and further improves the greenness and economy of the process.

[0025] (6) The process has excellent scalability: After multiple batches of small-scale and gram-scale experiments, the yield of 1,6-hexanediol in the small-scale experiment (1 mmol dimethyl adipate) reached up to 89%, and the yield of 1,6-hexanediol in the gram-scale experiment (50 mmol dimethyl adipate) was stable at over 85%. The process has strong stability and has a clear prospect for industrialization. Attached Figure Description

[0026] Figure 1 The 1H NMR spectrum of borate intermediate 1b from Example 1; Figure 2 The image shows the 1H NMR spectrum of the target product 1,6-hexanediol prepared in Example 1. Detailed Implementation

[0027] The technical solution of the present invention will be further described below with reference to specific embodiments. Unless otherwise specified, the preparation methods and usage conditions used in the following embodiments are conventional methods; unless otherwise specified, the reagents and materials used in the following embodiments can be obtained commercially. Example 1: Small-scale process optimization

[0028] Under a nitrogen inert atmosphere, 1.0 mmol of dimethyl adipate (98% purity), 0.05 mmol of phenylboronic acid (98% purity), and 20 mL of anhydrous tetrahydrofuran (98% purity, dehydrated and deoxygenated) were added to a 100 mL Schlenk flask. Under ice bath cooling, 5.0 mmol of pinacol borane (98% purity) was slowly added dropwise. After the addition was complete, the ice bath was removed, and the reaction was stirred at room temperature for 60 hours (the dimethyl adipate was completely eliminated by thin-layer chromatography (TLC)). Subsequently, 5 mL of a 10 wt% NaOH aqueous solution was added directly to the reaction solution, and the temperature was raised to 60 °C and stirred for 8 hours for hydrolysis. After the hydrolysis reaction was completed, the mixture was cooled to room temperature, and the reaction solution was extracted three times with 15 mL of dichloromethane. All organic phases were combined, dried over anhydrous Na₂SO₄, and finally concentrated under reduced pressure to obtain purified 1,6-hexanediol.

[0029] Using tetraethylsilane as an internal standard, quantitative analysis by ¹H NMR (CDCl3, 400MHz) showed that the yield of 1,6-hexanediol in this example was 89%; the purity of the product was 98% as detected by gas chromatography.

[0030] like Figure 1 As shown, the borate ester intermediate 1b was characterized by proton NMR spectroscopy using deuterated chloroform as solvent, and the results are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 3.74 (td, J = 6.5, 1.5 Hz,4H), 1.52 – 1.45 (m, 4H), 1.29 – 1.25 (m, 4H), 1.17 – 1.16 (m, 24H). like Figure 2 As shown, the 1H NMR spectrum of the 1,6-hexanediol product was characterized using deuterated chloroform as solvent and measured at 400 MHz. The results are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 3.56 (t, J = 6.6 Hz, 4H), 2.89 (s, 1H), 2.67 (s, 1H), 1.52 (t, J = 6.7 Hz, 4H), 1.34 (t, J = 3.8 Hz, 4H), 0.88 (t, J = 8.0 Hz, 16H), 0.49 – 0.43 (m, 10H). Example 2: Gram-scale verification

[0031] 1,6-Hexanediol was prepared using the exact same reaction steps, reagents, and process parameters as in Example 1, except that the amounts of reactants were scaled up proportionally. 50 mmol of dimethyl adipate (98% purity), 2.5 mmol of phenylboronic acid, 250 mmol of pinacol borane, 100 mL of anhydrous THF, and 25 mL of 10 wt% NaOH aqueous solution were added. After extraction, drying, and vacuum concentration, 4.13 g of 1,6-hexanediol product was obtained, with a yield of 85%. Gas chromatography analysis showed the product purity to be 98%, demonstrating the robustness of the preparation process and its feasibility for industrial scale-up. Example 3

[0032] 1,6-hexanediol was prepared using the same method as in Example 1, except that the amount of phenylboronic acid used in this example was 0.03 mmol, the yield of 1,6-hexanediol was 77%, and the purity of the product was 98% as determined by gas chromatography. Example 4

[0033] 1,6-hexanediol was prepared using the same method as in Example 1, except that the amount of phenylboronic acid used in this example was 0.08 mmol, the yield of 1,6-hexanediol was 87%, and the purity of the product was 97% as determined by gas chromatography. Example 5

[0034] 1,6-hexanediol was prepared using the same method as in Example 1, except that the amount of pinacol borane used in this example was 4.0 mmol, the yield of 1,6-hexanediol was 73%, and the purity of the product was 98% as determined by gas chromatography. Example 6

[0035] 1,6-hexanediol was prepared using the same method as in Example 1, except that the amount of pinacol borane used in this example was 6.0 mmol, the yield of 1,6-hexanediol was 85%, and the purity of the product was 98% as determined by gas chromatography. Example 7

[0036] 1,6-hexanediol was prepared using the same method as in Example 1, except that: in this example, an 8 wt% NaOH aqueous solution was used as the alkaline aqueous solution, the yield of 1,6-hexanediol was 71%, and the purity of the product was 98% as determined by gas chromatography. Example 8

[0037] 1,6-hexanediol was prepared using the same method as in Example 1, except that: in this example, the alkaline aqueous solution was selected as a 12wt% KOH aqueous solution, the yield of 1,6-hexanediol was 73%, and the purity of the product was 98% as determined by gas chromatography. Example 9

[0038] 1,6-hexanediol was prepared using the same method as in Example 1, except that the hydrolysis temperature in this example was 65°C with constant stirring for 6 hours, the yield of 1,6-hexanediol was 77%, and the purity of the product was 98% as determined by gas chromatography. Example 10

[0039] 1,6-hexanediol was prepared using the same method as in Example 1, except that the hydrolysis temperature in this example was 55°C and the hydrolysis was carried out under constant temperature stirring for 10 hours. The yield of 1,6-hexanediol was 83%, and the purity of the product was 98% as determined by gas chromatography. Example 11

[0040] 1,6-hexanediol was prepared using the same method as in Example 1, except that the reaction temperature for generating the borate intermediate was different in this example. The ice bath was removed, and the reaction was heated to 40°C until the dimethyl adipate in the raw material was completely eliminated by thin-layer chromatography (TLC). The yield of 1,6-hexanediol was 84%, and the purity of the product was 98% as determined by gas chromatography. Example 12

[0041] 1,6-hexanediol was prepared using the same method as in Example 1, except that the reaction temperature for generating the borate intermediate was different in this example. The ice bath was removed, and the reaction was heated to 60°C until the dimethyl adipate in the raw material was completely eliminated by thin-layer chromatography (TLC). The yield of 1,6-hexanediol was 79%, and the purity of the product was 98% as determined by gas chromatography. Example 13

[0042] 1,6-Hexanediol was prepared using the same method as in Example 1, with the only difference being that no organic solvent was added during the reaction process in this example. Dimethyl adipate, phenylboronic acid, and pinacol borane were directly mixed and reacted. The yield of 1,6-hexanediol was found to be as high as 91%, and the purity of the product was 98% as determined by gas chromatography. The results indicate that the reaction is more efficient under solvent-free conditions, with a higher yield of 1,6-hexanediol compared to the organic solvent system. Comparative Example 1: The reaction temperature for generating the intermediate was 80℃.

[0043] 1,6-hexanediol was prepared using the same method as in Example 1, except that the reaction temperature for generating the borate intermediate was different in this comparative example. The ice bath was removed, and the reaction was heated to 80°C until the dimethyl adipate in the raw material was completely eliminated by thin-layer chromatography (TLC). The yield of 1,6-hexanediol was too low, only 55%. Comparative Example 2: NaOH aqueous solution concentration 7wt%

[0044] 1,6-Hexanediol was prepared using the same method as in Example 1, except that the concentration of the NaOH aqueous solution used for hydrolysis in this comparative example was 7 wt%. Testing revealed a low yield of 1,6-hexanediol, only 70%, and the ¹H NMR spectrum showed obvious residual feedstock and byproduct characteristic peaks, indicating a significant decrease in product purity and incomplete hydrolysis. These results demonstrate that the process efficiency deteriorates significantly when the NaOH aqueous solution concentration is below 8 wt%. Comparative Example 3: NaOH aqueous solution concentration 13wt%

[0045] 1,6-Hexanediol was prepared using the same method as in Example 1, except that the concentration of the NaOH aqueous solution used for hydrolysis was replaced with 13 wt%. Analysis showed that the yield of 1,6-hexanediol in this comparative example decreased to 78%, and the ¹H NMR spectrum showed characteristic signals of enolization byproducts (δ 5.8~6.2 ppm). Quantification using the internal standard method revealed a product purity of only 82%, indicating that excessively high concentrations of strong base can trigger β-elimination side reactions, leading to a decrease in the yield and purity of the target product. Comparative Example 4: NaOH aqueous solution concentration 15wt%

[0046] 1,6-hexanediol was prepared using the same method as in Example 1, except that the concentration of the NaOH aqueous solution used for hydrolysis was replaced with 15 wt%. Testing showed that the yield of 1,6-hexanediol in this comparative example decreased to 71%, and the byproduct signal was significantly enhanced, further validating the rationality of the 8-12 wt% alkali concentration range of this invention. Comparative Example 5: Hydrolysis time 5.5 hours

[0047] 1,6-Hexanediol was prepared using the same method as in Example 1, except that the hydrolysis reaction time was shortened to 5.5 hours in this comparative example. The yield of 1,6-Hexanediol in this comparative example was 72%, and thin-layer chromatography (TLC) showed that unhydrolyzed borate intermediates remained in the reaction solution. Comparative Example 6: Hydrolysis time 5 hours

[0048] 1,6-Hexanediol was prepared using the same method as in Example 1, except that the hydrolysis reaction time was shortened to 5 hours in this comparative example. Testing revealed that the yield of 1,6-hexanediol in this comparative example was only 65%, and thin-layer chromatography (TLC) showed that a large amount of unhydrolyzed borate intermediates remained in the reaction solution. Comparative Example 7: Hydrolysis time 11 hours

[0049] 1,6-Hexanediol was prepared using the same method as in Example 1, except that the hydrolysis reaction time was extended to 11 hours in this comparative example. The yield of 1,6-Hexanediol in this comparative example was 82%, with no borate ester intermediate remaining. However, the ¹H NMR spectrum showed characteristic peaks of olefinic hydrogens at δ 5.8-6.2 ppm, indicating the formation of a small amount of unsaturated alcohol (β-elimination byproduct), accompanied by a small amount of intermolecular dehydration ether byproducts, confirming that excessively long hydrolysis time can trigger side reactions. Comparative Example 8: Without phenylboronic acid catalysis

[0050] 1,6-Hexanediol was prepared using the same method as in Example 1, except that phenylboronic acid catalyst was not added in this comparative example. After 60 hours of reaction, a large amount of dimethyl adipate remained as a raw material, and the final yield of 1,6-hexanediol was only 12%, demonstrating that the catalytic effect of phenylboronic acid is key to the efficient reaction of this invention. Comparative Example 9: Traditional Hydrogenation Process

[0051] The method disclosed in existing technology CN109748778A, using dimethyl adipate as a raw material and Ru / C as a catalyst, prepares 1,6-hexanediol by hydrogenation at 220℃ and 6MPa H2 conditions. Testing showed a product yield of 85%, but this method requires high-temperature and high-pressure equipment, and the catalyst cost is more than ten times that of this invention, highlighting the cost and safety advantages of this invention.

Claims

1. A method for preparing 1,6-hexanediol from dimethyl adipate, characterized in that, Includes the following steps: (1) Under an inert atmosphere, dimethyl adipate, phenylboronic acid and pinacol borane are directly mixed or dissolved in an organic solvent and reacted at room temperature to 60°C to generate a borate intermediate; (2) Add an alkaline aqueous solution directly to the reaction solution obtained in step (1) and hydrolyze at 55-65℃ for 6-10 hours to obtain the target product 1,6-hexanediol; (3) After extraction, drying and concentration, purified 1,6-hexanediol is obtained.

2. The method for preparing 1,6-hexanediol from dimethyl adipate according to claim 1, characterized in that: The molar amount of phenylboronic acid is 3-8% of the molar amount of dimethyl adipate.

3. The method for preparing 1,6-hexanediol from dimethyl adipate according to claim 1, characterized in that: The molar amount of pinacol borane is 4 to 6 times the molar amount of dimethyl adipate.

4. The method for preparing 1,6-hexanediol from dimethyl adipate according to claim 1, characterized in that: The organic solvent is anhydrous tetrahydrofuran, toluene, or 1,4-dioxane.

5. The method for preparing 1,6-hexanediol from dimethyl adipate according to claim 1, characterized in that: The alkaline aqueous solution is an 8-12 wt% NaOH or KOH aqueous solution.

6. The method for preparing 1,6-hexanediol from dimethyl adipate according to claim 1, characterized in that: The alkaline aqueous solution is a 10wt% NaOH aqueous solution.

7. The method for preparing 1,6-hexanediol from dimethyl adipate according to claim 1, characterized in that: In step (2), the hydrolysis reaction is carried out at 60°C for 8 hours.

8. Chemically pure 1,6-hexanediol is prepared by the method for preparing 1,6-hexanediol from dimethyl adipate as described in any one of claims 1-7.

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