A kind of preparation method of 3-phenanthrenol
3-Phenanthrol is prepared by coupling 3-tert-butoxyphenylboronic acid with o-bromobenzaldehyde and Grignard reaction, which solves the problems of difficult isomer separation and high equipment requirements in the existing technology and achieves the preparation of 3-phenanthrol with high purity and high yield.
Patent Information
- Application Number
- CN202311482171.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2023-11-09
- Publication Date
- 2025-09-05
- Estimated Expiration
- 2043-11-09
AI Technical Summary
The existing 3-phenanthranol synthesis method is difficult to separate product isomers, has high equipment requirements, and the deprotection process is complicated, making it difficult to meet market demand.
3-tert-Butoxyphenylboronic acid is coupled with o-bromobenzaldehyde to generate 3'-tert-butoxy-[1,1'-biphenyl]-2-carboxaldehyde, which then reacts with a Grignard reagent to generate 3'-tert-butoxy-2-(2"-tert-butoxyvinyl)-1,1'-biphenyl. 3-Phenanthrol is obtained by ring closure with methanesulfonic acid and deprotection. The introduction of a tert-butyl group increases steric hindrance and simplifies the separation process.
The preparation of high-purity 3-phenanthranol is achieved, the isomer ratio is significantly reduced, the deprotection conditions are simple, no column chromatography is required, the equipment requirements are reduced, the yield is high, and the purity reaches more than 99.0%.
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Abstract
Description
Technical Field
[0001] The invention relates to a preparation method of 3-phenanthrenol, and belongs to the technical field of organic chemical synthesis. Background Art
[0002] 3-Phenanthrol (CAS 605-87-8) is a phenanthrene compound widely found in natural products. Due to its unique photoelectric and biological properties, it is used as a starting material for photosensitive components or as a pharmaceutical intermediate. 3-Phenanthrol can be used to synthesize a CE inhibitor, a prodrug for the CPT-11 anticancer drug, and can also serve as a phenanthrene nucleus or backbone to synthesize chiral ligands or catalysts, which have extensive applications in asymmetric synthesis.
[0003] To date, three main methods for synthesizing 3-phenanthrenol have been reported: First, the literature [Synthesis, 2021, vol. 53, #14, p. 2512-2516] reports the use of 3-methoxyphenylboronic acid and o-bromobenzaldehyde as raw materials, coupling to obtain 3'-methoxy-[1,1'-biphenyl]-2-carboxaldehyde, which is then nucleophilically substituted with (methoxymethyl)triphenylphosphonium chloride in potassium tert-butoxide to obtain 3'-methoxy-2-(2"-methoxyvinyl)-1,1'-biphenyl. This is followed by ring closure under the action of methanesulfonic acid and deprotection to obtain 3-phenanthrenol with an overall yield of 65.8%. This method uses a 4:1 ratio of 3-methoxyphenanthrene to 1-methoxyphenanthrene during ring closure, requiring column chromatography for separation. Deprotection requires ultra-low temperatures, which places high demands on equipment. The reaction equation is as follows:
[0004]
[0005] Secondly, the literature [European Journal of Medicinal Chemistry, 2018, vol. 149, p. 79-89] reports the coupling of 3-methoxyphenylboronic acid with 1-bromo-2-(2-methoxyvinyl)benzene to obtain 3'-methoxy-2-(2"-methoxyvinyl)-1,1'-biphenyl (enol ether), followed by ring closure under the action of methanesulfonic acid and final demethylation to obtain 3-phenanthrenol. However, the raw materials in this method are not easy to obtain, and there is still the problem of the ortho-para activity of the methoxy group, which means that 3-methoxyphenanthrene and 1-methoxyphenanthrene still need to be separated by column chromatography; the reaction equation is as follows:
[0006]
[0007] Third, the literature [Tetrahedron Letters, 2000, vol. 41, #42, pp. 8079-8082] reports the use of 2-nitronaphthalene and trans-1-methoxy-3-(trimethylsilyloxy)-1,3-butadiene to undergo a Diels-Alder reaction at high temperature to produce 3-phenanthrenol with an isolated yield of 21%, but the purification process is more difficult. The reaction equation is as follows:
[0008]
[0009] In the above-mentioned synthetic routes, there is the problem of difficulty in separating product isomers. Therefore, it is necessary to develop new directions for the synthetic process of 3-phenanthranol and provide better reaction routes to meet the growing market demand. Summary of the Invention
[0010] To overcome the above technical deficiencies, the present invention proposes a method for preparing 3-phenanthrenol. The method couples the compound 3-tert-butoxyphenylboronic acid and o-bromobenzaldehyde to obtain 3'-tert-butoxy-[1,1'-biphenyl]-2-carboxaldehyde. Subsequently, 2-(chloromethoxy)-2-methylpropane reacts with magnesium chips in tetrahydrofuran to generate a Grignard reagent. This is then replaced with 3'-tert-butoxy-[1,1'-biphenyl]-2-carboxaldehyde and eliminated by reflux and water separation with p-toluenesulfonic acid to obtain 3'-tert-butoxy-2-(2"-tert-butoxyvinyl)-1,1'-biphenyl. Finally, methanesulfonic acid is used for ring closure and de-tert-butyl protection to obtain 3-phenanthrenol. The present invention introduces tert-butyl protection, which not only increases steric hindrance and reduces isomers during ring closure, but also makes deprotection conditions easier, and the product can be obtained with a purity of more than 99.0% without the need for column chromatography.
[0011] The preparation method of 3-phenanthrenol of the present invention comprises the following steps:
[0012] Step 1 (coupling reaction): 3-tert-butoxyphenylboronic acid, o-bromobenzaldehyde, potassium carbonate aqueous solution, and tetrakis(triphenylphosphine)palladium are coupled in an organic solvent to obtain 3'-tert-butoxy-[1,1'-biphenyl]-2-carbaldehyde; the reaction equation is as follows:
[0013]
[0014] Step 2 (Grignard reaction): 2-(chloromethoxy)-2-methylpropane is dissolved in tetrahydrofuran. About 10% of the tetrahydrofuran solution of 2-(chloromethoxy)-2-methylpropane is added dropwise to a reaction flask containing magnesium chips and iodine. The temperature is slowly raised to initiation, and the remaining tetrahydrofuran solution of 2-(chloromethoxy)-2-methylpropane is added dropwise to obtain a Grignard reagent. The reaction equation is shown below:
[0015]
[0016] Step 3 (Substitution and Elimination Reaction): Dissolve 3'-tert-butoxy-[1,1'-biphenyl]-2-carboxaldehyde in tetrahydrofuran, cool, and add the Grignard reagent from step 2. Quench with saturated ammonium chloride. Concentrate the organic phase under reduced pressure, replace the other organic solvents, add anhydrous p-toluenesulfonic acid, and heat to reflux under vacuum to remove water to obtain 3'-tert-butoxy-2-(2"-tert-butoxyvinyl)-1,1'-biphenyl. The reaction equation is as follows:
[0017]
[0018] Step 4 (ring closure and deprotection reaction): Mix 3'-tert-butoxy-2-(2"-tert-butoxyvinyl)-1,1'-biphenyl with dichloromethane, cool, add methanesulfonic acid to close the ring, then add anisole and methanesulfonic acid and heat to deprotect to obtain 3-phenanthrenol. The reaction equation is as follows:
[0019]
[0020] Furthermore, in the above technical solution, in the first step, the coupling temperature is selected from 80-100°C.
[0021] Furthermore, in the above technical solution, in the third step, the vacuum degree of the vacuum reflux water separation is selected from -0.02 to -0.04 MPa, and the temperature is selected from 60-85°C.
[0022] Furthermore, in the above technical solution, in the fourth step, the methanesulfonic acid ring closure is to first ring-close the enol ether with the tert-butoxy group in the para position at 0°C, wherein the molar ratio of 3'-tert-butoxy-2-(2"-tert-butoxyvinyl)-1,1'-biphenyl to methanesulfonic acid is 1:1.
[0023] Furthermore, in the above technical solution, in the fourth step, the deprotection is performed by adding methanesulfonic acid at elevated temperature to remove the tert-butoxy protection.
[0024] Advantageous Effects of the Invention
[0025] Compared with the existing technology, the equipment requirements are not high. The introduced tert-butyl group can increase the steric hindrance and is more inclined to close the ring in the para position with the tert-butoxy group. The isomers are greatly reduced. The final reaction liquid detection shows that the ratio of 3-phenanthranol to 1-phenanthranol is 50:1.
[0026] Figures in the specification
[0027] Figure 1 This is the HNMR spectrum of 3-phenanthrenol obtained in Example 6. Specific embodiments
[0028] Example 1
[0029]
[0030] 19.4 g (0.1 mol) of 3-tert-butoxyphenylboronic acid, 20 g (0.108 mol) of o-bromobenzaldehyde, 47 g (0.34 mol) of potassium carbonate, 1.39 g (1.2 mmol) of tetrakis(triphenylphosphine)palladium, 140 g of water and 240 g of acetonitrile were mixed in a reaction flask, replaced with nitrogen, heated to 80°C for reaction for 12 hours, cooled to 40°C, concentrated under reduced pressure to remove most of the acetonitrile, cooled to room temperature, extracted with isopropyl acetate, and the organic phase was washed with sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated to obtain 25.4 g of 3'-tert-butoxy-[1,1'-biphenyl]-2-carboxaldehyde as an oil with an HPLC index of 91.7%, which was used directly in the next step. 1 HNMR (400MHZ, CDCl3): δ10.09(s,1H),8.13(d,1H),8.01-7.76(m,2H),7.62-7.5 5(m,1H),7.50-7.43(m,1H),7.38-7.11(m,2H),7.09-6.95(m,1H),1.40(s,9H).
[0031] Example 2
[0032]
[0033] 19.4 g (0.1 mol) of 3-tert-butoxyphenylboronic acid, 20 g (0.108 mol) of o-bromobenzaldehyde, 47 g (0.34 mol) of potassium carbonate, 1.39 g (1.2 mmol) of tetrakis(triphenylphosphine)palladium, 140 g of water, and 300 g of 1,4-dioxane were mixed in a reaction flask, replaced with nitrogen, heated to 100°C for reaction for 7 hours, cooled to 60°C, concentrated under reduced pressure to remove most of the 1,4-dioxane, cooled to room temperature, extracted with isopropyl acetate, and the organic phase was washed with sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated to obtain 25.5 g of 3'-tert-butoxy-[1,1'-biphenyl]-2-carboxaldehyde as an oil, HPLC 92.2%, which was used directly in the next step.
[0034] Example 3
[0035]
[0036] Dissolve 14.7 g (0.12 mol) of 2-(chloromethoxy)-2-methylpropane in 150 mL of ultra-dry tetrahydrofuran. Add 3.5 g (0.144 mol) of magnesium turnings, one grain of iodine, and 10 mL of ultra-dry tetrahydrofuran to a reaction flask. Add the aforementioned approximately 10% 2-(chloromethoxy)-2-methylpropane solution in tetrahydrofuran dropwise. Slowly raise the temperature to initiation. Add the remaining 2-(chloromethoxy)-2-methylpropane solution in tetrahydrofuran dropwise. Raise the temperature to 60°C, react for 4 hours, and then cool to room temperature for later use.
[0037] Example 4
[0038]
[0039] 25.4 g (0.1 mol) of 3'-tert-butoxy-[1,1'-biphenyl]-2-carboxaldehyde was dissolved in 150 mL of tetrahydrofuran, cooled to -10 to -5°C, and 0.12 mol of the second step Grignard reagent was added dropwise at a temperature of 0 to 10°C. After the addition was complete, the mixture was reacted at 0-10°C for 3 hours, slowly heated to 20°C, quenched by adding saturated ammonium chloride, added with ethyl acetate, and allowed to stand for stratification. The aqueous phase was extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure and replaced with toluene until the KF was less than 0.05%. 1.0 g of anhydrous p-toluenesulfonic acid was added, and the mixture was heated to 60°C under vacuum and refluxed for 6 hours. The mixture was concentrated under reduced pressure to a residual volume of 3V, and isopropyl ether was added. The mixture was cooled to 0°C and slurried to obtain 26.3 g of 3'-tert-butoxy-2-(2"-tert-butoxyvinyl)-1,1'-biphenyl as an off-white solid with a yield of 81% and an HPLC index of 99.1%. 1 HNMR (400MHz, CDCl3): δ8.11(d,1H),7.56-7.25(m,5H),7.25-7.06(m,1H),7.05-6.86(m,1H),6.54(d,1H),5.41(d,1H),1.41(s,9H),1.35(s,9H).
[0040] Example 5
[0041]
[0042] 25.4 g (0.1 mol) of 3'-tert-butoxy-[1,1'-biphenyl]-2-carboxaldehyde was dissolved in 150 mL of tetrahydrofuran, cooled to -10 to -5°C, and 0.12 mol of the second step Grignard reagent was added dropwise at a temperature of 0 to 10°C. After the addition was complete, the mixture was reacted at 0-10°C for 3 hours, slowly heated to 20°C, quenched by the addition of saturated ammonium chloride, added with ethyl acetate, and allowed to stand for separation. The aqueous phase was extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The mixture was replaced with xylene until the KF was less than 0.05%. 1.0 g of anhydrous p-toluenesulfonic acid was added, and the mixture was heated to 85°C under vacuum and refluxed for 4 hours. The mixture was concentrated under reduced pressure to a residual volume of 4V, and isopropyl ether was added. The mixture was cooled to 0°C and beaten to obtain 27.8 g of 3'-tert-butoxy-2-(2"-tert-butoxyvinyl)-1,1'-biphenyl as an off-white solid with a yield of 85.6% and an HPLC index of 98.6%.
[0043] Example 6
[0044]
[0045] 26 g (0.08 mol) of 3'-tert-butoxy-2-(2"-tert-butoxyvinyl)-1,1'-biphenyl and 600 mL of dichloromethane were added to a reaction flask and mixed. The mixture was cooled to -5-0°C, and 7.7 g (0.08 mol) of methanesulfonic acid was slowly added. The mixture was reacted at 0°C overnight. Sampling was performed to detect whether there was any residual raw material. Anisole and methanesulfonic acid were added, and the temperature was raised to 40-50°C for 6 hours to deprotect the mixture. The mixture was washed with aqueous sodium bicarbonate solution and aqueous sodium chloride solution, and concentrated under reduced pressure to remove most of the dichloromethane. The mixture was cooled to 0°C and allowed to stand for crystallization to obtain 14 g of 3-phenanthranol with a yield of 90.2% and an HPLC index of 99.4%. 1 HNMR (400MHz, DMSO-d6): δ10.05(s,1H),8.60(d,1H),8.06(d,1H),7.91(d,1H),7.82(d,1H),7.72(d,1H),7.59-7.66(m,3H),7.20(dd,1H).
[0046] The above description is only a preferred specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any technician familiar with the technical field, within the technical scope disclosed by the present invention, who makes equivalent replacements or changes based on the technical solution and inventive concept of the present invention, should be covered by the scope of protection of the present invention.
Claims
1. A method for preparing 3-phenanthrenol, characterized in that, The reaction route is as follows: The steps include: Step 1: 3-tert-butoxyphenylboronic acid, o-bromobenzaldehyde, potassium carbonate aqueous solution, and tetrakis(triphenylphosphine)palladium are coupled in an organic solvent to obtain 3'-tert-butoxy-[1,1'-biphenyl]-2-carbaldehyde; Step 2: Dissolve 2-(chloromethoxy)-2-methylpropane in tetrahydrofuran, add 10% of the 2-(chloromethoxy)-2-methylpropane tetrahydrofuran solution dropwise to a reaction flask containing magnesium chips and iodine, slowly raise the temperature to initiation, and add the remaining 2-(chloromethoxy)-2-methylpropane tetrahydrofuran solution dropwise to obtain a Grignard reagent; Step 3: Dissolve 3'-tert-butoxy-[1,1'-biphenyl]-2-carboxaldehyde in tetrahydrofuran, cool, add the Grignard reagent from step 2, quench with saturated ammonium chloride, concentrate the organic phase under reduced pressure, replace other organic solvents, add anhydrous p-toluenesulfonic acid, and heat to reflux under vacuum to remove water to obtain 3'-tert-butoxy-2-(2"-tert-butoxyvinyl)-1,1'-biphenyl; Step 4: Mix 3'-tert-butoxy-2-(2"-tert-butoxyvinyl)-1,1'-biphenyl with dichloromethane, cool, add methanesulfonic acid to close the ring, then add anisole and methanesulfonic acid and heat to deprotect to obtain 3-phenanthrenol.
2. The preparation method of 3-phenanthrenol according to claim 1, wherein: In the first step, the organic solvent is selected from acetonitrile or 1,4-dioxane.
3. The preparation method of 3-phenanthrenol according to claim 1, wherein: In the first step, the molar ratio of 3-tert-butoxyphenylboric acid, o-bromobenzaldehyde, potassium carbonate and tetrakis(triphenylphosphine)palladium is 1:1.05-1.10:3.0-3.5:0.01-0.
02.
4. The preparation method of 3-phenanthrenol according to claim 1, wherein: In the second step, the molar ratio of the 2-(chloromethoxy)-2-methylpropane, magnesium chips and iodine is 1:1.2:0.005-0.
01.
5. The preparation method of 3-phenanthrenol according to claim 1, wherein: In the third step, the organic solvent is selected from toluene or xylene.
6. The preparation method of 3-phenanthrenol according to claim 1, wherein: In the third step, the molar ratio of the 3'-tert-butoxy-[1,1'-biphenyl]-2-carbaldehyde to the Grignard reagent is 1:1.2.