A method for highly selective synthesis of cis-1,4-cyclohexanediol

Abstract

The present invention belongs to the technical field of organic chemical synthesis, and particularly relates to a method for highly selectively synthesizing cis-1,4-cyclohexanediol. This method uses 1,4-cyclohexanedione as the raw material, employs a ruthenium-based catalyst with large steric hindrance to control the reaction selectivity, uses hydrogen as the hydrogen source, and directly synthesizes cis-1,4-cyclohexanediol in one step. This method has the advantages of high yield, few reaction steps, high selectivity, environmental friendliness, and easy large-scale preparation.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic chemical synthesis, and particularly relates to a method for highly selectively synthesizing cis-1,4-cyclohexanediol. Background Art

[0002] 1,4-cyclohexanediol is divided into trans-1,4-cyclohexanediol and cis-1,4-cyclohexanediol, as shown in the following figure. The melting point and boiling point of trans-1,4-cyclohexanediol are 416K and 423K respectively, soluble in ethanol and water, and is a plate-like solid at room temperature. The melting point of cis-1,4-cyclohexanediol is 386K, easily soluble in water, ethanol and acetone, and is in a rhombic crystal state at room temperature.

[0003]

[0004] Cis-1,4-cyclohexanediol is an important pharmaceutical intermediate, which can be used to synthesize new materials such as liquid crystal organic electrical materials, and has very important value and unique properties in chiral reagents and polymers. At present, the domestic production volume is small, especially the high-purity cis or trans form has a very small domestic production volume. In recent years, the research on the synthesis method of cis-1,4-cyclohexanediol has also received increasing attention. The main synthesis methods of cis-1,4-cyclohexanediol are as follows:

[0005] (1) In Journal of Organic Chemistry, 1989, 54(22), 5292-5302, the author used 2,3-dioxabicyclo[2.2.2]octane as the raw material, deuterated dichloromethane as the solvent, and synthesized cis-1,4-cyclohexanediol under the catalysis of RuCl2(PPh3)3. The raw materials of this method are not easily available, and the reaction yield is also low.

[0006]

[0007] (2) In patent CN 107759446 A, the author used 4-(hydroxyacetyloxy)cyclohexanone as the raw material, through a reduction reaction, synthesized diastereoisomers, and then after column chromatography to separate the cis intermediate, and finally obtained cis-1,4-cyclohexanediol through hydrolysis. This method has cumbersome steps, only 50% of the intermediate is utilized, the atom economy is low, and it is not suitable for large-scale preparation through column chromatography separation.

[0008]

[0009] (3) In Chemistry - A European Journal, 2009, 15(28), 6953 - 6963, the authors used hydroquinone as the raw material and Ru / C as the catalyst. Under a hydrogen atmosphere of 10 atmospheres, the reaction was carried out at 90 °C for 24 hours to prepare a mixture of 1,4 - cyclohexanediol. The cis - to - trans ratio in the product was 75:25. Although this method has a simple synthetic route, it cannot effectively prepare 1,4 - cyclohexanediol with a high cis - to - trans ratio.

[0010]

[0011] (4) In Bioorganic & Medicinal Chemistry Letters, 2015, 25(3), 695 - 700, the authors started with cyclohexanone protected by ethylene glycol at the carbonyl group. First, it was reduced to obtain the corresponding alcohol, and then the protecting group was removed in an aqueous hydrochloric acid solution to prepare a mixture of 1,4 - cyclohexanediol.

[0012]

[0013] (5) In Tetrahedron Letters, 2014, 55, 128 - 132, the authors synthesized 1,4 - cyclohexanediol by hydrogenation under the action of a ruthenium catalyst. Unfortunately, the obtained product was a mixture and a single - configuration product could not be obtained.

[0014]

[0015] In summary, the reported methods mentioned above mainly have the following disadvantages: complicated steps, long reaction time, high cost, difficult - to - obtain raw materials, and difficult separation of the obtained mixture, etc. Summary of the Invention

[0016] Aiming at the technical problems existing in the prior art, the purpose of the present invention is to provide a synthetic method of cis - 1,4 - cyclohexanediol with fewer reaction steps, easily - obtainable raw materials, high product purity, and suitable for large - scale production.

[0017] To achieve the above - mentioned purpose, the technical solution adopted by the present invention is as follows:

[0018] A method for highly selectively synthesizing cis - 1,4 - cyclohexanediol, and the synthetic route is as follows:

[0019]

[0020] The synthesis steps are as follows: In a reaction kettle, after adding 1,4 - cyclohexanedione, a catalyst, a base, and a solvent, displace with nitrogen three times, and finally fill with hydrogen to a certain pressure. Stir and react at 50 - 110 °C for 10 - 40 h. After the reaction is completed, cool to room temperature, slowly release hydrogen, filter with diatomite and then concentrate, remove the organic solvent, and cis - 1,4 - cyclohexanediol is obtained.

[0021] Preferably, the catalyst is a sterically hindered ruthenium - based catalyst, and its structural formula is one of the formulas L1 - L12:

[0022]

[0023] Preferably, the molar ratio of 1,4 - cyclohexanedione to the catalyst is 100 - 900:1.

[0024] Preferably, the base is sodium tert - butoxide, potassium tert - butoxide, lithium tert - butoxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, potassium ethoxide, butyllithium, tert - butyllithium, or lithium diisopropylamide.

[0025] Preferably, the molar ratio of 1,4 - cyclohexanedione to the base is 1:5 - 20.

[0026] Preferably, the solvent is dichloromethane, chloroform, toluene, xylene, tetrahydrofuran, 2 - methyltetrahydrofuran, N,N - dimethylformamide, methanol, ethanol, or dimethyl sulfoxide.

[0027] Preferably, the concentration of 1,4 - cyclohexanedione in the solvent is 0.1 - 5 mol / L (abbreviated as M).

[0028] Preferably, the pressure is 10 - 80 atmospheres.

[0029] Beneficial effects: The present invention uses a sterically hindered ruthenium - based catalyst to control the reaction selectivity, and cis - 1,4 - cyclohexanediol is obtained by one - step synthesis with a high cis - trans ratio. This method has the advantages of high yield, few reaction steps, high selectivity, environmental friendliness, and easy large - scale preparation. Description of the Drawings

[0030] Figure 1 It is the nuclear magnetic resonance hydrogen spectrum of the target product cis - 1,4 - cyclohexanediol obtained in Example 1 of the present invention.

[0031] Figure 2 It is the nuclear magnetic resonance carbon spectrum of the target product cis - 1,4 - cyclohexanediol obtained in Example 1 of the present invention. Detailed Embodiments

[0032] The following describes the present invention in detail with reference to the embodiments, but the protection scope of the present invention is not limited to the following embodiments.

[0033] Example 1

[0034] A method for highly selective synthesis of cis-1,4-cyclohexanediol: In a reaction kettle, after adding 1,4-cyclohexanedione (molar equivalent 1), catalyst L1 (molar equivalent 0.01), sodium tert-butoxide as the base (molar equivalent 20) and dichloromethane as the solvent (0.2M), displace with nitrogen 3 times, and finally fill with hydrogen to 10 atmospheres. Stir and react at 50 °C for 40 h. After the reaction is completed, cool to room temperature, slowly release hydrogen, filter with diatomaceous earth and concentrate, and remove the organic solvent to obtain cis-1,4-cyclohexanediol with a yield of 90%.

[0035] The target product was characterized by NMR, and the results were as follows:

[0036] 1 HNMR(400MHz,[D6]DMSO):δ4.29(s,2H),3.51(m,2H),1.59 - 1.36(m,8H);

[0037] 13 CNMR(400MHz,[D6]DMSO):δ65.89,30.37。

[0038] The melting point of the target product is 98 - 100 °C, and the density is 1.156 g / cm 3 。

[0039] Example 2

[0040] A method for highly selective synthesis of cis-1,4-cyclohexanediol: In a reaction kettle, after adding 1,4-cyclohexanedione (molar equivalent 1), catalyst L4 (molar equivalent 0.01), potassium tert-butoxide as the base (molar equivalent 10) and toluene as the solvent (0.5M), displace with nitrogen 3 times, and finally fill with hydrogen to 20 atmospheres. Stir and react at 100 °C for 30 h. After the reaction is completed, cool to room temperature, slowly release hydrogen, filter with diatomaceous earth and concentrate, and remove the organic solvent to obtain cis-1,4-cyclohexanediol with a yield of 89%.

[0041] The NMR data, melting point and density of the target product in this example are the same as those in Example 1.

[0042] Example 3

[0043] A method for highly selective synthesis of cis-1,4-cyclohexanediol: In a reaction kettle, add 1,4-cyclohexanedione (molar equivalent 1), catalyst L7 (molar equivalent 0.005), sodium methoxide as the base (molar equivalent 5) and the solvent xylene (2M), displace with nitrogen 3 times, and finally fill with hydrogen to 40 atmospheres. Stir and react at 80 °C for 20 h. After the reaction is completed, cool to room temperature, slowly release hydrogen, filter through diatomaceous earth and concentrate, remove the organic solvent, and obtain cis-1,4-cyclohexanediol with a yield of 92%.

[0044] The NMR data, melting point and density of the target product in this example are the same as those in Example 1.

[0045] Example 4

[0046] A method for highly selective synthesis of cis-1,4-cyclohexanediol: In a reaction kettle, add 1,4-cyclohexanedione (molar equivalent 1), catalyst L9 (molar equivalent 0.007), potassium hydroxide as the base (molar equivalent 15) and the solvent tetrahydrofuran (0.1M), displace with nitrogen 3 times, and finally fill with hydrogen to 50 atmospheres. Stir and react at 60 °C for 10 h. After the reaction is completed, cool to room temperature, slowly release hydrogen, filter through diatomaceous earth and concentrate, remove the organic solvent, and obtain cis-1,4-cyclohexanediol with a yield of 95%.

[0047] The NMR data, melting point and density of the target product in this example are the same as those in Example 1.

[0048] Example 5

[0049] A method for highly selective synthesis of cis-1,4-cyclohexanediol: In a reaction kettle, add 1,4-cyclohexanedione (molar equivalent 1), catalyst L11 (molar equivalent 0.006), cesium carbonate as the base (molar equivalent 10) and the solvent N,N-dimethylformamide (5M), displace with nitrogen 3 times, and finally fill with hydrogen to 60 atmospheres. Stir and react at 110 °C for 24 h. After the reaction is completed, cool to room temperature, slowly release hydrogen, filter through diatomaceous earth and concentrate, remove the organic solvent, and obtain cis-1,4-cyclohexanediol with a yield of 78%.

[0050] The NMR data, melting point and density of the target product in this example are the same as those in Example 1.

[0051] Example 6

[0052] A method for highly selectively synthesizing cis-1,4-cyclohexanediol: In a reaction kettle, after adding 1,4-cyclohexanedione (molar equivalent 1), catalyst L12 (molar equivalent 0.009), potassium bicarbonate as the base (molar equivalent 18), and the solvent chloroform (1 M), it is purged with nitrogen three times, and finally hydrogen is charged to 80 atmospheres. The reaction is stirred at 50 °C for 36 h. After the reaction is completed, it is cooled to room temperature, the hydrogen is slowly released, filtered through diatomaceous earth and concentrated, and the organic solvent is removed to obtain cis-1,4-cyclohexanediol with a yield of 95%.

[0053] The NMR data, melting point, and density of the target product in this example are the same as those in Example 1.

Claims

1. A method for highly selectively synthesizing cis-1,4-cyclohexanediol, characterized in that: In a reaction kettle, after adding 1,4-cyclohexanedione, a catalyst, a base and a solvent, it is purged with nitrogen three times, and finally hydrogen is filled to a certain pressure. The reaction is stirred at 50-110 °C for 10-40 h. After the reaction is completed, it is cooled to room temperature, hydrogen is slowly released, and after filtration through diatomite, it is concentrated to remove the organic solvent, thus obtaining cis-1,4-cyclohexanediol; Among them, the catalyst is a sterically hindered ruthenium-based catalyst, and its structural formula is one of the formulas L1-L8: The base is sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, potassium ethoxide, butyllithium, tert-butyllithium or lithium diisopropylamide; The pressure is 10-80 atmospheres.

2. The method for highly selectively synthesizing cis-1,4-cyclohexanediol according to claim 1, characterized in that: The molar ratio of 1,4-cyclohexanedione to the catalyst is 100-900:

1.

3. The method for highly selectively synthesizing cis-1,4-cyclohexanediol according to claim 1, characterized in that: The molar ratio of 1,4-cyclohexanedione to the base is 1:5-20.

4. The method for highly selectively synthesizing cis-1,4-cyclohexanediol according to claim 1, wherein: The solvent is dichloromethane, chloroform, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, methanol, ethanol or dimethyl sulfoxide.

5. The method for highly selectively synthesizing cis-1,4-cyclohexanediol according to claim 1 or 4, characterized in that: The concentration of 1,4-cyclohexanedione in the solvent is 0.1-5 mol / L.

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