Preparation method of cis-4-tert-butyl cyclohexanol
By using chiral ferrocene backbone ligand manganese complex catalyst and inorganic base for asymmetric hydrogenation reaction, the problem of high purity cis 4-tert-butyl cyclohexanol is solved, and a high selectivity and low cost preparation method is realized.
Patent Information
- Application Number
- CN202510430946.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-04-08
- Publication Date
- 2025-08-01
AI Technical Summary
In the prior art, the production cost of high purity cis 4-tert-butylcyclohexanol is relatively high, and the catalyst is mainly heterogeneous precious metals, resulting in high production costs.
4-tert-butylcyclohexanone is used as the raw material, chiral ferrocene backbone ligand manganese complex III is used as the catalyst, and inorganic base is an additive, and asymmetric hydrogenation reaction is carried out to prepare cis 4-tert-butylcyclohexanol.
The synthesis of cis 4-tert-butylcyclohexanol with high selectivity (cis/trans>95:5) is achieved, which significantly reduces the catalyst cost and has high application prospects.
Smart Images
Figure FT_1 
Figure SMS_3 
Figure SMS_4
Abstract
Description
Technical Field
[0001] The present invention belongs to the field of pharmaceutical technology, and particularly relates to a method for preparing cis-4-tert-butylcyclohexanol. Background Art
[0002] 4-tert-Butylcyclohexanol is an important intermediate in the synthesis of pharmaceuticals, pesticides, fragrances and liquid crystal materials. Especially in the fragrance field, because 4-tert-butylcyclohexanol ester derivatives are the main raw materials with a woody and patchouli-like aroma for the production of high-grade fragrances, soaps and shampoos, and are widely used. Modern research shows that the woody and patchouli-like aroma of 4-tert-butylcyclohexanol mainly comes from cis-4-tert-butylcyclohexanol, while trans-4-tert-butylcyclohexanol does not have this special aroma. Therefore, the higher the content of the cis isomer in 4-tert-butylcyclohexanol, the purer the aroma and the higher the price. In recent years, the demand for high-cis 4-tert-butylcyclohexanol intermediates in the fragrance industry, pesticides and pharmaceutical fields has gradually increased. However, at present, the technical routes for obtaining high-purity cis-4-tert-butylcyclohexanol through selective reactions generally have high costs, and the prices of products remain high.
[0003] At present, the synthesis methods of cis-4-tert-butylcyclohexanol are as follows:
[0004] 1. Catalytic hydrogenation is carried out with p-tert-butylphenol as the starting material, and the catalyst is mainly a heterogeneous noble metal catalyst, with a high cost;
[0005] 2. Catalytic hydrogenation is carried out with p-tert-butylcyclohexanone as the raw material, and the catalyst is also a heterogeneous and homogeneous noble metal catalyst, also facing the problem of high cost. Summary of the Invention
[0006] In order to overcome the above-mentioned deficiencies of the prior art, the purpose of the present invention is to provide a method for preparing cis-4-tert-butylcyclohexanol, which uses 4-tert-butylcyclohexanone as the raw material, chiral ferrocene skeleton ligand manganese complex III as the catalyst, and inorganic base as the additive, and performs an asymmetric hydrogenation reaction to obtain cis-4-tert-butylcyclohexanol I, which has high selectivity (cis / trans>95:5) and activity, and has high application prospects.
[0007] In order to achieve the above purpose, the technical solution adopted by the present invention is:
[0008] A method for preparing cis-4-tert-butylcyclohexanol, characterized in that 4-tert-butylcyclohexanone is used as the raw material, chiral ferrocene skeleton ligand manganese complex III is used as the catalyst, and inorganic base is used as the additive, and an asymmetric hydrogenation reaction is carried out to obtain cis-4-tert-butylcyclohexanol I, and the reaction formula is as follows:
[0009] 。
[0010] Furthermore, the reaction formula includes the following steps:
[0011] Step 1: In a solvent, a metal manganese precursor and a chiral ferrocene skeleton ligand IV are complexed at a molar ratio of 1:1 to 3 at room temperature to obtain a metal complex III. For the hydrogenation reaction, an in-situ complexed catalyst solution can be used, or the catalyst solution can be dried by rotation and the powder can be used;
[0012] Step 2: The metal catalyst III and 4-tert-butylcyclohexanone are mixed in a reaction solvent at a molar ratio of 1:100 to 10000, and then an alkali additive is added to the reaction mixture at a ratio of the additive to 4-tert-butylcyclohexanone of 1:10 to 100 in terms of molar ratio;
[0013] Step 3: After replacing the air in the high-pressure hydrogenation autoclave three times with hydrogen at 5-20 atm, the asymmetric hydrogenation reaction is carried out at a pressure of 1-100 atm and a temperature of -20-200 °C, and the hydrogenation time is 1-48 h;
[0014] Step 4: After the hydrogenation is completed, the hydrogen in the reaction kettle is slowly released. After most of the solvent is dried by rotation, it is filtered through a silica gel column. After washing with an eluent, the eluents are combined, and the solvent is dried by rotation to obtain cis-4-tert-butylcyclohexanol I.
[0015] Furthermore, in the composition of the eluent in Step 4, ethyl acetate: petroleum ether = 1-20:100.
[0016] Furthermore, the additive used in the asymmetric hydrogenation reaction is an inorganic base.
[0017] Furthermore, the inorganic base is one of lithium hydroxide, lithium carbonate, lithium tert-butoxide, sodium hydroxide, sodium carbonate, sodium tert-butoxide, sodium isopropoxide, potassium carbonate, potassium hydroxide, potassium tert-butoxide, and cesium carbonate.
[0018] Furthermore, the solvent can be a protic alcohol solvent or an aprotic solvent, and the inorganic base is one of dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, toluene, and ethyl acetate.
[0019] Furthermore, the chiral ferrocene skeleton ligand manganese complex III used in the asymmetric hydrogenation reaction in Step 3 can be directly formed by in-situ complexation of a bisphosphine ligand IV and a metal manganese precursor in a solvent to generate a catalyst solution.
[0020] Furthermore, the structural formula of the chiral ferrocene skeleton ligand IV used in the asymmetric hydrogenation reaction is as follows:
[0021] ,
[0022] In the formula: Ar is an aryl group or a substituted aryl group; the above general formula includes its stereoisomers.
[0023] Further, the metal manganese precursor used in the asymmetric hydrogenation reaction includes one of the precursors such as manganese pentacarbonyl bromide, dimanganese decacarbonyl, manganese acetate or manganese phthalocyanine.
[0024] The beneficial effects of the present invention are as follows: Compared with the precious metal (ruthenium, iridium and rhodium) catalysts reported in previous literatures, the present invention synthesizes cis-4-tert-butylcyclohexanol through the asymmetric hydrogenation reaction of 4-tert-butylcyclohexanone catalyzed by the abundant metal manganese, which can significantly reduce the catalyst cost. The costs of precious metals ruthenium, iridium and rhodium are hundreds or even thousands of times that of the abundant metal manganese. At the same time, the ligand used in the present invention is simple to synthesize, the raw materials are easy to obtain and the cost is low. Therefore, the complex catalyst has a significant cost advantage. Description of the Drawings
[0025] Figure 1 For the hydrogenation product obtained in Example 1 1 1H NMR spectrum. Detailed Embodiments
[0026] The present invention will be further described below in conjunction with the drawings and embodiments, but the present invention is not limited to the following embodiments.
[0027] Example 1:
[0028]
[0029] In a glove box, Mn(CO)5Br (1.8 mg, 0.006 mmol), ligand L4 (5.59 mg, 0.006 mmol) and 1 mL of ethanol were placed in an ampoule and stirred at room temperature for 30 min. The catalyst solution was transferred to a hydrogenation reaction tube, and 2.59 mg of lithium tert-butoxide and 100 mg of the substrate were added in sequence, and then 1 mL of ethanol was added. The mixture was purged with hydrogen three times and reacted at room temperature and 50 atm H2 for 20 h. After the reaction was completed, the solvent was evaporated to dryness. The residue was dissolved in 10 mL of dichloromethane, washed successively with water and brine, dried over anhydrous sodium sulfate, and then evaporated to dryness. The target product alcohol I was obtained by column chromatography on a short silica gel column. 1 The reaction conversion rate detected by 1H NMR > 99%, cis / trans > 95:5. 1 1H NMR (400 MHz, Chloroform-d) δ 4.03 (s,1H), 1.90 – 1.76 (m, 2H), 1.60 – 1.43 (m, 4H), 1.42 – 1.28 (m, 3H), 1.07 –0.94 (m, 1H), 0.86 (s, 9H).
[0030] Example 2:
[0031]
[0032] In the glove box, Mn(CO)5Br (1.8 mg, 0.006 mmol), ligand L1 (4.13 mg, 0.006 mmol) and 1 mL of ethanol were placed in an ampoule. The reaction was stirred at room temperature for 30 min. The catalyst solution was transferred to a hydrogenation reaction tube. 100 mg of the substrate and 2.59 mg of lithium tert-butoxide were added successively, and then 1 mL of ethanol was added. The mixture was purged with hydrogen three times and reacted at room temperature and 50 atm H2 for 20 h. After the reaction, the solvent was evaporated. The residue was dissolved in 10 mL of dichloromethane, washed successively with water and brine, dried over anhydrous sodium sulfate, and then the solvent was evaporated. The target product alcohol I was obtained by column chromatography on a short silica gel column. 1 The reaction conversion rate detected by 1H NMR > 99%, cis / trans > 90:10.
[0033] Example 3:
[0034]
[0035] In the glove box, Mn2(CO) 10 (1.2 mg, 0.003 mmol), ligand L4 (5.59 mg, 0.006 mmol) and 1 mL of ethanol were placed in an ampoule. The reaction was stirred at room temperature for 30 min. The catalyst solution was transferred to a hydrogenation reaction tube. 2.59 mg of lithium tert-butoxide and 100 mg of the substrate were added successively, and then 1 mL of ethanol was added. The mixture was purged with hydrogen three times and reacted at room temperature and 50 atm H2 for 20 h. After the reaction, the solvent was evaporated. The residue was dissolved in 10 mL of dichloromethane, washed successively with water and brine, dried over anhydrous sodium sulfate, and then the solvent was evaporated. The target product alcohol I was obtained by column chromatography on a short silica gel column. 1 The reaction conversion rate detected by 1H NMR > 99%, cis / trans > 90:10.
[0036] The present invention uses 4-tert-butylcyclohexanone as a raw material to carry out an asymmetric hydrogenation reaction to obtain cis-4-tert-butylcyclohexanol. The key is the chiral ferrocene skeleton ligand manganese complex catalyst. The ferrocene skeleton ligand is simple to synthesize, the raw materials are easy to obtain and the cost is low. The metal manganese precursor can be Mn(CO)5Br or Mn2(CO) 10 and other commercial products. The ratio of the cis product to the trans product is greater than 90:10. Compared with the precious metal-catalyzed hydrogenation synthesis method reported in the previous literature, the present invention has obvious cost advantages and greater industrialization prospects.
[0037] Such as Figure 1As shown, for the hydrogenated product obtained in Example 1 1 1H NMR spectrum. Cis-4-tert-butylcyclohexanol and trans-4-tert-butylcyclohexanol are diastereoisomers, and the chemical shifts of the hydrogens on the carbon atom directly connected to the hydroxyl group in the molecular structures of the two are different. It can be known from the integration that the ratio of the cis isomer to the trans isomer is approximately 95:5.
Claims
1. A method for preparing cis-4-tert-butylcyclohexanol, characterized in that, Using 4-tert-butylcyclohexanone as the raw material, chiral ferrocene framework ligand manganese complex III as the catalyst, and inorganic base as the additive, an asymmetric hydrogenation reaction is carried out to obtain cis-4-tert-butylcyclohexanol I. The reaction formula is as follows: 。 2. The preparation method of cis-4-tert-butylcyclohexanol according to claim 1, wherein, According to the reaction formula, it includes the following steps: Step 1: In a solvent, a metal manganese precursor and chiral ferrocene framework ligand IV are complexed at a molar ratio of 1:1 to 3 at room temperature to obtain metal complex III. For the hydrogenation reaction, an in-situ complexed catalyst solution can be used, or the catalyst solution can be dried by rotation to obtain a powder for use; Step 2: According to the molar ratio of metal catalyst III to 4-tert-butylcyclohexanone of 1:100 to 10000, they are mixed in a reaction solvent, and then an alkali additive is added to the reaction mixture according to the molar ratio of the additive to 4-tert-butylcyclohexanone of 1:10 to 100; Step 3: After replacing the air in the high-pressure hydrogenation autoclave three times with 5-20 atm of hydrogen, the asymmetric hydrogenation reaction is carried out at 1-100 atm and a temperature of -20 to 200 °C, and the hydrogenation time is 1-48 h; Step 4: After the hydrogenation is completed, the hydrogen in the reaction kettle is slowly released. After most of the solvent is dried by rotation, it is filtered through a silica gel column. After washing with an eluent, the eluents are combined, and the solvent is dried by rotation to obtain cis-4-tert-butylcyclohexanol I.
3. The preparation method of cis-4-tert-butylcyclohexanol according to claim 2, characterized in that, In the composition of the eluent in Step 4, ethyl acetate: petroleum ether = 1-20:
100.
4. The preparation method of cis-4-tert-butylcyclohexanol according to claim 2, characterized in that, The additive used in the asymmetric hydrogenation reaction is an inorganic base.
5. The preparation method of cis-4-tert-butylcyclohexanol according to claim 2, characterized in that, The inorganic base is one of lithium hydroxide, lithium carbonate, lithium tert-butoxide, sodium hydroxide, sodium carbonate, sodium tert-butoxide, sodium isopropoxide, potassium carbonate, potassium hydroxide, potassium tert-butoxide, cesium carbonate.
6. The preparation method of cis-4-tert-butylcyclohexanol according to claim 2, wherein The solvent can be a protic alcohol solvent or an aprotic solvent, and the inorganic base is one of dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, toluene, and ethyl acetate.
7. The preparation method of cis-4-tert-butylcyclohexanol according to claim 2, wherein, In the asymmetric hydrogenation reaction in Step 3, the chiral ferrocene framework ligand manganese complex III can be directly formed by in-situ complexation of a bisphosphine ligand IV and a metal manganese precursor in a solvent to form a catalyst solution.
8. The preparation method of cis-4-tert-butylcyclohexanol according to claim 2, characterized in that, The structural formula of the chiral ferrocene framework ligand IV used in the asymmetric hydrogenation reaction is shown as follows: ， In the formula: Ar is an aryl group or a substituted aryl group; the above general formula includes its stereoisomers.
9. The preparation method of cis-4-tert-butylcyclohexanol according to claim 2, characterized in that, The metal manganese precursor used in the asymmetric hydrogenation reaction includes one of manganese pentacarbonyl bromide, dimanganese decacarbonyl, manganese acetate, or manganese phthalocyanine.