Preparation method of dendrophenol
By improving the dendrobium phenol synthesis process, the introduction of benzyl protection, negative hydrogen reducing agent reduction, bromine reaction, Wittig reaction and palladium catalytic hydrogenation under alkaline conditions has solved the problems of insufficient protection, high toxicity, difficulty in reducing ester bonds and cumbersome post-processing in the existing process, and the process is simplified, improved stability and reduced toxicity.
Patent Information
- Application Number
- CN202411806878.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-06
- Publication Date
- 2025-03-28
AI Technical Summary
In the existing dendrobium synthesis process, benzyl protection is not accurate enough, dimethyl sulfate is highly toxic, ester bond reduction is difficult, and the conditions are harsh, and post-processing is cumbersome.
Dendrobium phenol was prepared by introducing five-step reactions under alkaline conditions by introducing benzyl protection, negative hydrogen reducing agent reduction, bromine reaction, Wittig reaction and palladium catalytic hydrogenation.
The preparation process is shortened, the process controllability and stability is improved, the toxicity of the reagent is reduced, the harsh reaction conditions are avoided, and the post-processing is convenient and the yield is stable.
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Figure CN119707647A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the field of preparation of original drug compounds, and particularly relates to a method for preparing dendrobium phenol. Background Art
[0002] Gigantol (Dendrophenol), CAS: 83088-28-2, chemical name: 5-[2-(3-hydroxy-5-methoxyphenyl)ethyl]-2-methoxyphenol, chemical structure:
[0003]
[0004] Dendrobium phenol is derived from the extract of the traditional Chinese medicine Dendrobium officinale. It is a Wnt / β-catenin pathway inhibitor with significant tumor proliferation inhibition effects.
[0005] At present, the general process route of the synthesis of dendrobium phenol is as follows:
[0006]
[0007] Although this patented synthesis method can achieve the purpose of synthesizing dendrobium phenol, the shortcomings in the preparation process are: (1) the single protection of the benzyl group is difficult to control accurately; (2) dimethyl sulfate is highly toxic; (3) the reduction of the ester bond is relatively difficult, and the use of lithium aluminum tetrahydride as a reducing agent has strict requirements on the reaction conditions, and the post-processing is cumbersome due to the presence of aluminum salts. Summary of the invention
[0008] In view of the technical problems existing in the above-mentioned prior art, the present invention provides a synthesis process of dendrobium phenol. By improving its process route, the preparation process of dendrobium phenol is shortened, each step is more controllable, the stability of the preparation process is improved, the toxicity of the reagents used is lower, the reaction conditions are milder, the post-treatment is simpler, and the yield is stable.
[0009] This is specifically achieved through the following technical solutions:
[0010] Step 1: Under alkaline conditions, a benzyl group is introduced into the compound represented by formula I, i.e., 3-methoxy-4-hydroxybenzaldehyde (vanillin), to protect the phenolic hydroxyl group in its structure, thereby synthesizing 3-methoxy-4-benzyloxybenzaldehyde represented by formula II;
[0011] Step 2: Under the action of a negative hydrogen reducing agent, the aldehyde group in the structure of formula II is reduced to an alcohol hydroxyl group to synthesize 3-methoxy-4-benzyloxybenzyl alcohol as shown in formula III;
[0012] Step 3: Under the action of a brominating agent, 3-methoxy-4-benzyloxybenzyl alcohol shown in formula III undergoes a substitution reaction to synthesize a brominated benzyl derivative, such as 3-methoxy-4-benzyloxybenzyl bromide shown in formula IV;
[0013] Step 4: Under strong alkaline conditions, 3-methoxy-4-benzyloxybenzyl bromide shown in formula IV reacts with a trivalent phosphine reagent to generate a phosphorus ylide, and the generated phosphorus ylide reacts with 3-methoxy-5-benzyloxybenzaldehyde to undergo a Wittig reaction to generate a key intermediate V, including two cis and trans structures, as shown in formula V1 and formula V2;
[0014] Step 5: subjecting the intermediates shown in Formula V1 and Formula V2 to palladium carbon hydrogenation catalysis reaction, removing the benzyl protection reduction double bond, and synthesizing the dendrobium phenol shown in Formula VI.
[0015]
[0016] The introduction of benzyl group as described in step 1 is specifically performed by dissolving the compound 3-methoxy-4-hydroxybenzaldehyde represented by formula I and a base in a solvent, adding benzyl halide dropwise at room temperature, and controlling the reaction temperature to be 25-50° C. After the reaction is completed, pouring the reaction solution into a large amount of water while stirring, a large amount of solid precipitates, and filtering and washing with water to obtain product II.
[0017] Specifically, the base is selected from one of potassium carbonate, sodium carbonate, cesium carbonate, triethylamine or N,N-diisopropylethylamine;
[0018] Specifically, the benzyl halide is selected from benzyl bromide or benzyl chloride;
[0019] Specifically, the solvent is selected from a non-protonic solvent of the dosage form, and specifically can be selected from one of acetonitrile, tetrahydrofuran, N,N-dimethylformamide or N,N-dimethylacetamide.
[0020] The reaction of reducing the aldehyde group to the alcohol hydroxyl group described in step 2 is specifically performed by dissolving the compound 3-methoxy-4-benzyloxybenzaldehyde shown in formula II in a solvent, gradually adding a negative hydrogen reducing agent at -5 to 25°C, and after the addition is completed and the reaction is monitored, the reaction solution is poured into a large amount of water while stirring, a large amount of solid precipitates, and the product shown in formula II is obtained after filtration and washing with water.
[0021] Specifically, the negative hydrogen reducing agent is selected from one of potassium borohydride or sodium borohydride;
[0022] Specifically, the solvent is selected from polar solvents, and specifically one of methanol or ethanol can be selected.
[0023] The halogenation reaction in step 3 is specifically performed by adding a halogenating agent to a solvent to obtain the compound 3-methoxy-4-benzyloxybenzyl alcohol represented by formula III, and reacting at room temperature. After the reaction is completed, the reaction is quickly washed with a saturated sodium bicarbonate aqueous solution, and the organic phase is dried over anhydrous sodium sulfate, and the organic solvent is removed under reduced pressure to obtain the compound 3-methoxy-4-benzyloxybenzyl bromide represented by formula IV;
[0024] Specifically, the halogenating agent is selected from one of phosphorus tribromide, bromine, phosphorus trichloride or phosphorus pentachloride;
[0025] Specifically, the solvent is selected from dichloromethane or tetrahydrofuran.
[0026] The synthesis of phosphorus ylide and Wittig reaction described in step 4 is specifically performed by adding a tertiary phosphine reagent to the compound 3-methoxy-4-benzyloxybenzyl bromide shown in formula IV in a solvent to prepare phosphorus ylide. 3-methoxy-5-benzyloxybenzaldehyde and a base are added to the reaction solution, and the reaction is carried out at -5 to 25°C. After the reaction is monitored, the residue is extracted with dichloromethane and water, and the organic solvent is removed under reduced pressure to obtain a crude intermediate V. Intermediate V is dissolved in a mixed solvent of dichloromethane: petroleum ether in a volume ratio of 2 to 3:1, and the collected mobile phase is evaporated by rapid silica gel chromatography to obtain the cis and trans intermediate V products shown in formula V1 and formula V2;
[0027] Specifically, the tertiary phosphine reagent is selected from one of triphenylphosphine or tributylphosphine;
[0028] Specifically, the base is selected from one of sodium hydride, sodium methoxide or sodium hydroxide;
[0029] Specifically, the solvent is selected from aprotic inert solvents, and specifically can be selected from one of tetrahydrofuran and dichloromethane.
[0030] The hydrogenation catalysis and benzyl removal reaction described in step 5 is specifically performed by adding a palladium catalyst to the compounds represented by formula V1 and formula V2 in a solvent under nitrogen protection, switching hydrogen, reacting at room temperature, monitoring the completion of the reaction, filtering out the catalyst, and removing the solvent under reduced pressure to obtain dendrobium phenol with a structure represented by formula VI, and no by-products are generated in the reaction;
[0031] Specifically, the palladium catalyst is palladium carbon;
[0032] Specifically, the solvent is selected from polar protic solvents, specifically one of methanol or ethanol;
[0033] Specifically, the final product is recrystallized from anhydrous ethanol to obtain a pure product.
[0034] Compared with the prior art, the present invention has the following beneficial effects:
[0035] The invention uses vanillin, which is widely available, low in price and non-toxic, as a raw material, and prepares dendrobium phenol through five steps of benzyl protection, reduction, bromination, Wittig reaction and hydrogenation. The reaction route is controllable, the reaction conditions are mild, and harsh reaction conditions such as high temperature, low temperature and high pressure are avoided. The post-treatment is convenient and the yield is stable. The invention is a novel, efficient and environmentally friendly preparation process of dendrobium phenol. BRIEF DESCRIPTION OF THE DRAWINGS
[0036] Figure 1 The H NMR spectrum of the intermediate II prepared in Example 2 3-methoxy-4-benzyloxybenzaldehyde ( 1 HNMR) spectra;
[0037] Figure 2 Preparation of Intermediate III 3-methoxy-4-benzyloxybenzyl alcohol for Example 4 1 H NMR spectra;
[0038] Figure 3 Preparation of Intermediate V1 and Intermediate V2 for Example 8 1 H NMR spectra;
[0039] Figure 4 Preparation of dendrobium phenol in Example 10 1 H NMR spectra. DETAILED DESCRIPTION
[0040] Synthesis of 3-Methoxy-4-Benzyloxybenzaldehyde (II)
[0041] Example 1
[0042] 10.0g of 3-methoxy-4-hydroxybenzaldehyde (vanillin) and 10.9g of potassium carbonate were dissolved in 100mL of N,N-dimethylformamide (DMF) and stirred at room temperature. 8.16mL of benzyl bromide was slowly dripped into the solution. The reaction temperature was controlled at 25-40°C. After the dripping was completed, the reaction was continued for about 3h. TLC monitored the reaction to be complete. The reaction solution was slowly poured into an ice-water bath while stirring. A large amount of white solid was precipitated. After stirring for 30 minutes, the white solid was filtered out and washed with a small amount of water to obtain 15.9g of the product 3-methoxy-4-benzyloxybenzaldehyde. The yield was about 100%. No purification was required. It was dried and used for later use.
[0043] Example 2
[0044] 10.0g of 3-methoxy-4-hydroxybenzaldehyde (vanillin) was dissolved in 100mL of tetrahydrofuran. Under ice bath conditions, 2.6g of sodium hydride was added to the reaction solution in batches. The reaction temperature was controlled to be less than 5°C. 7.9mL of benzyl chloride was slowly dripped into the solution. The temperature was controlled to be 35-50°C. After the dripping was completed, the reaction was continued for about 30 minutes. TLC monitored the reaction to be complete. The reaction solution was slowly poured into an ice water bath while stirring. A large amount of white solid was precipitated. After continuing to stir for 30 minutes, the white solid was filtered out and washed with a small amount of water to obtain the product 3-methoxy-4-benzyloxybenzaldehyde 15.9g, with a yield of about 100%. No purification was required. It was dried for use.
[0045] like Figure 1 The H NMR spectrum shown ( 1 H NMR): 1 H NMR: (400MHz, CDCl3) δ9.83(1H,s),7.45-7.36(6H,m),7.34-7.31(1H,m),6.98(1H,d,J=8.2Hz),5.24(2H,s),3.95(3H,s).
[0046] Synthesis of 3-Methoxy-4-Benzyloxybenzyl alcohol
[0047] Example 3
[0048] 10.0 g of 3-methoxy-4-benzyloxybenzaldehyde was dissolved in 100 mL of methanol. Under ice bath conditions, 0.6 g of sodium borohydride was slowly added to the reaction solution in batches. The reaction temperature was controlled at -5 to 5 ° C. After the addition was completed, the reaction was continued for about 1 hour. TLC monitored the reaction to be complete. The reaction solution was slowly poured into an ice water bath while stirring. A large amount of white solid was precipitated. The pH was adjusted to about 4 to 5 with dilute hydrochloric acid. After stirring for 30 minutes, the white solid was filtered out and washed with a small amount of water to obtain the product 3-methoxy-4-benzyloxybenzyl alcohol 9.8 g, with a yield of 98%. No purification was required. It was dried for use.
[0049] Example 4
[0050] 10.0 g of 3-methoxy-4-benzyloxybenzaldehyde was dissolved in 100 mL of ethanol. Under ice bath conditions, 0.8 g of potassium borohydride was slowly added to the reaction solution in batches. The reaction temperature was controlled at -5 to 10 ° C. After the addition was completed, the reaction was continued for about 1 hour. TLC monitored the reaction to be complete. The reaction solution was slowly poured into an ice water bath while stirring. A large amount of white solid was precipitated. The pH was adjusted to about 4 to 5 with dilute hydrochloric acid. After stirring for 30 minutes, the white solid was filtered out and washed with a small amount of water to obtain the product 3-methoxy-4-benzyloxybenzyl alcohol 9.7 g, with a yield of 97%. No purification was required. It was dried for use.
[0051] like Figure 2 The H NMR spectrum shown (1 H NMR): 1 H NMR: (400MHz, CDCl3) δ7.45 (2H, d, J = 7.3Hz), 7.36 (2H, t, J = 7.6Hz), 7.30 (1H, t, J = 7.2Hz), 6.95 (1H, s), 6.82 (2H, q, J = 8.1Hz), 5.14 (2H, s), 4.61 (2H, s), 3.90 (3H, s).
[0052] Synthesis of 3-Benzyloxy-4-methoxybenzyl bromide
[0053] Example 5
[0054] 10.0 g of 3-methoxy-4-benzyloxybenzyl alcohol was dissolved in 100 mL of dichloromethane. Under ice bath conditions, 1.5 mL of phosphorus tribromide was slowly dripped into the reaction solution. The reaction temperature was controlled to be less than 10°C. After the dripping was completed, the ice bath was removed. The reaction was continued for about 12 hours at room temperature. TLC monitored the reaction to be complete. The reaction solution was slowly poured into a saturated sodium bicarbonate solution while stirring. After the addition was completed, stirring was continued for 10 minutes. The organic layer was separated, dried over anhydrous sodium sulfate, and dichloromethane was removed under reduced pressure to obtain 11.3 g of 3-benzyloxy-4-methoxybenzyl bromide. The yield was 90%. No purification was required and the next step of reaction was required as soon as possible.
[0055] Example 6
[0056] 10.0 g of 3-methoxy-4-benzyloxybenzyl alcohol was dissolved in 100 mL of tetrahydrofuran. Under ice bath condition, 1.5 mL of phosphorus pentachloride was slowly dripped into the reaction solution. The reaction temperature was controlled to be less than 10°C. After dripping, the ice bath was removed. The reaction was continued for about 12 hours at room temperature. TLC monitored the reaction to be complete. The tetrahydrofuran was removed under reduced pressure. The product was dissolved in dichloromethane. The reaction solution was slowly poured into a saturated sodium bicarbonate solution while stirring. After the addition was completed, the organic layer was separated, dried over anhydrous sodium sulfate, and dichloromethane was removed under reduced pressure to obtain 11.9 g of 3-benzyloxy-4-methoxybenzyl bromide. The yield was 95%. No purification was required and the next step of reaction was required as soon as possible.
[0057] Synthesis of Intermediate V
[0058] Example 7
[0059] 10.0 g of 3-methoxy-4-benzyloxybenzyl bromide was dissolved in 100 mL of tetrahydrofuran. At room temperature, 8.5 g of triphenylphosphine was added to the reaction solution. The reaction was continued for about 4 hours, and a large amount of white solid was precipitated. After the temperature of the reaction solution was lowered to room temperature, 2.6 g of sodium hydride was added in batches under ice bath conditions. After the addition, the mixture was stirred for 1 hour. 7.9 g of 3-methoxy-5-benzyloxybenzaldehyde (prepared from 3-methoxy-5-hydroxybenzaldehyde by the method of Example 1 or 2) was dissolved in tetrahydrofuran. The solution was added dropwise to the reaction solution. After stirring at room temperature for 12 hours, the reaction was monitored by TLC to be complete. Tetrahydrofuran was removed under reduced pressure, and the product was dispersed with a small amount of DCM and washed with water. The dried crude product was dispersed in a mixed solution of dichloromethane: petroleum ether in a volume ratio of 3:1, and quickly passed through a silica gel column chromatography. The mobile phase was collected and eluted with an appropriate amount of mobile phase in the same proportion. After reduced pressure evaporation, the products with structures shown in Formula V1 and Formula V2 were obtained.
[0060]
[0061] Example 8
[0062] 10.0 g of 3-methoxy-4-benzyloxybenzyl bromide was dissolved in 100 mL of dichloromethane. At room temperature, 8.5 g of tributylphosphine was added to the reaction solution. The reaction was continued for about 4 hours to precipitate a large amount of white solid. After the reaction solution temperature was lowered to room temperature, 3.5 g of sodium methoxide was added in batches under ice bath conditions. After addition, the mixture was stirred for 1 hour. 7.9 g of 3-methoxy-5-benzyloxybenzaldehyde (prepared from 3-methoxy-5-hydroxybenzaldehyde by the method of Example 1 or 2) was dissolved in DMF. The solution was added dropwise to the reaction solution. After stirring at room temperature for 12 hours, the reaction was monitored by TLC to be complete. The reaction solution was poured into a large amount of ice water while stirring. A large amount of solid was precipitated. The solid was filtered out, washed with a small amount of water, and dried to obtain a crude intermediate V. The dried crude product is dispersed in a mixed solution of dichloromethane and petroleum ether in a volume ratio of 2:1, quickly passed through a silica gel column chromatography, the mobile phase is collected and eluted with an appropriate amount of the mobile phase in the same proportion, and evaporated to dryness under reduced pressure to obtain products with structures shown in Formula V1 and Formula V2.
[0063] like Figure 3 The H NMR spectrum shown is 1 H NMR): 1 H NMR: (400MHz, CDCl3) δ7.50-6.40 (Multi H, Ar), 5.13-4.97 (Double bond H, Benzyl H), 3.84-3.56 (-OMe, H).
[0064] Synthesis of Dendrobium phenol
[0065] Example 9
[0066] 5.0 g of intermediate V was dissolved in 100 mL of methanol. Under nitrogen protection, 0.5 g of palladium carbon (10% palladium, 55% water) was added to the reaction solution. The hydrogen was switched to react for about 12 hours. The reaction was monitored by TLC to be complete. The palladium carbon was filtered off under reduced pressure and washed with a small amount of methanol. The crude product of dendrobium phenol was obtained after the solvent was recovered under reduced pressure. The pure product 2.9 g was obtained by recrystallization from anhydrous ethanol with a yield of 98%.
[0067] Example 10
[0068] 5.0 g of intermediate V was dissolved in 100 mL of ethanol. Under nitrogen protection, 0.5 g of tetrakis(triphenylphosphine)palladium was added to the reaction solution, a catalytic amount of acetic acid was added dropwise, and hydrogen was switched to react for about 12 hours. TLC monitored the reaction to be complete. The palladium carbon was filtered off under reduced pressure and washed with a small amount of ethanol. The crude product of dendrobium phenol was obtained after the solvent was recovered under reduced pressure. 3.0 g of the pure product was obtained by recrystallization from anhydrous ethanol, with a yield of 100%.
[0069] like Figure 4 The H NMR spectrum shown ( 1 H NMR): (400MHz, CDCl3) δ6.83 (1H, d, J = 8.0Hz), 6.68 (1H, dd, J = 8.0, 1.7Hz), 6.63 (1H, d, J = 1.7Hz), 6.31 (1H, bro.s),6.26-6.21(2H,m),5.50(1H,s),4.97(1H,s),3.84(3H,s),3.75(3H,s),2.80(4H,dt,J=7.8,3.4Hz).
Claims
1. A method for preparing dendrobium phenol, characterized in that: The following steps are involved: A benzyl group is introduced into the hydroxyl group of 3-methoxy-4-hydroxybenzaldehyde to synthesize 3-methoxy-4-benzyloxybenzaldehyde; the aldehyde group in the structure of 3-methoxy-4-benzyloxybenzaldehyde is reduced to an alcoholic hydroxyl group to synthesize 3-methoxy-4-benzyloxybenzyl alcohol; 3-methoxy-4-benzyloxybenzyl alcohol undergoes a substitution reaction under the action of a brominating agent to synthesize 3-methoxy-4-benzyloxybenzyl bromide; 3-methoxy-4-benzyloxybenzyl bromide reacts with a tertiary phosphine reagent to prepare a phosphorus ylide, and the phosphorus ylide undergoes a Wittig reaction with 3-methoxy-5-benzyloxybenzaldehyde to synthesize intermediates shown in formulas V1 and V2; the intermediates shown in formulas V1 and V2 are debenzylated and the double bonds are reduced to obtain dendrobium phenol.
2. The method for preparing dendrobium phenol according to claim 1, characterized in that: The reaction of introducing the benzyl group is as follows: 3-methoxy-4-hydroxybenzaldehyde, a base and a solvent are mixed, and benzyl halide is added dropwise. After the reaction is completed, the reaction solution is poured into water, and the precipitated solid is 3-methoxy-4-benzyloxybenzaldehyde.
3. The method for preparing dendrobium phenol according to claim 2, characterized in that: The base is selected from potassium carbonate, sodium carbonate, cesium carbonate, triethylamine or N,N-diisopropylethylamine.
4. The method for preparing dendrobium phenol according to claim 1, characterized in that: The reaction of reducing the aldehyde group to the alcohol hydroxyl group is as follows: adding a negative hydrogen reducing agent to 3-methoxy-4-benzyloxybenzaldehyde dissolved in a solvent, and after the reaction is completed, pouring the reaction solution into water, and precipitating a solid, namely 3-methoxy-4-benzyloxybenzyl alcohol.
5. The method for preparing dendrobium phenol according to claim 4, characterized in that: The negative hydrogen reducing agent is selected from potassium borohydride or sodium borohydride.
6. The method for preparing dendrobium phenol according to claim 1, characterized in that: The substitution reaction is to add a halogenating agent to 3-methoxy-4-benzyloxybenzyl alcohol dissolved in a solvent to carry out a reaction, and then remove the organic solvent after the reaction to obtain 3-methoxy-4-benzyloxybenzyl bromide.
7. The method for preparing dendrobium phenol according to claim 6, characterized in that: The halogenating agent is selected from phosphorus tribromide, bromine, phosphorus trichloride or phosphorus pentachloride.
8. The method for preparing dendrobium phenol according to claim 1, characterized in that: The Wittig reaction is to add 3-methoxy-5-benzyloxybenzaldehyde and a base to the phosphorus ylide to react, extract and remove the solvent to obtain a mixture of intermediate formula V1 and formula V2.
9. The method for preparing dendrobium phenol according to claim 8, characterized in that: The mixture of the intermediate formula V1 and the intermediate formula V2 is dissolved in a mixed solvent of dichloromethane: petroleum ether in a volume ratio of 2-3:1, and the mobile phase is collected and the solvent is removed by rapid silica gel chromatography to obtain the intermediate formula V1 and the intermediate formula V2.
10. The method for preparing dendrobium phenol according to claim 1, characterized in that: The reaction of removing the benzyl group and reducing the double bond is as follows: under the protection of an inert gas, a palladium catalyst is added to the intermediate dissolved in a solvent, and hydrogen is introduced to react to obtain dendrobium phenol.