Preparation method of biphenyl compound for synthesizing cephalotaxine
Through Suzuki coupling reaction and amidation reaction, the trisitine biphenyl compound is constructed using pepper ethylamine and ferulic acid, which solves the problems of expensive starting materials, complex operation and low yield in the prior art, and achieves high efficiency , an economical synthesis route provides the basis for the synthesis of trisapine.
Patent Information
- Application Number
- CN202411341648.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-25
- Publication Date
- 2024-12-31
AI Technical Summary
In the existing synthesis methods of trisitine biphenyl compound, the starting materials are expensive, complex in operation and low yield, making it difficult to use and simple operation of commercial reagents.
Using Suzuki coupling reaction and amidation reaction, using pepper ethylamine and ferulic acid as starting materials, C-C bonds and C-N bonds are constructed through multiple-step reactions to form a ten-membered macrocyclic compound intermediate, reducing the reaction cost and simplifying the operation process. .
It achieves a high yield and simplified experimental operation, reduces the reaction cost, and provides a feasible synthesis route for the biphenyl compound of triazine, laying the foundation for the synthesis of triazine.
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Figure CN119219613A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of catalytic synthesis, and in particular relates to a method for preparing a biphenyl compound for synthesizing cephalotaxine. Background Art
[0002] Biphenyl structures are widely present in natural products, such as cephalotaxine, isoginkgetin, and podophyllotoxin. Biphenyl compounds have certain physiological activities and drug effects. The ester-base compounds derived from the natural product cephalotaxine mentioned above can treat leukemia. Cephalotaxus alkaloids are a class of natural products isolated from Cephalotaxus plants. To date, nearly 100 cephalotaxine-type alkaloids have been isolated and identified, and some ester-base natural products have significant anti-tumor activity, such as homoharringtonine and cephalotaxine among ester-base derivatives. In the 1970s, there were research records of cephalotaxine for the treatment of leukemia-related diseases. At present, the ester-base derivative of cephalotaxine, homoharringtonine, has entered the market as a drug at home and abroad. The main way to obtain it is to extract it from plants or to obtain it through semi-synthesis of cephalotaxine. Cephalotaxine is also a natural product, extracted from Cephalotaxus plants. It is inactive by itself, but by changing the side chain groups, it can produce compounds such as homoharringtonine that have anti-tumor activity. At the same time, Cephalotaxine is the parent nucleus of Cephalotaxus alkaloids, with a unique structure: the core skeleton is a fused A / B / C / D tetracyclic system, in which the D ring has three adjacent chiral centers and multi-functional group substitutions, including an azaspirocyclic quaternary carbon center.
[0003] The intermediate of the biosynthetic route of Cephalotaxine proposed by Parry in 1980 is a biphenyl compound, so the synthesis of biphenyl compounds is of great significance. The previous synthesis routes have the problems of expensive starting materials, complicated operations, and low yields of the obtained products. Using commercial reagents can reduce experimental costs; simple operation experiments need to be implemented. Summary of the invention
[0004] The present invention provides a method for preparing a biphenyl compound for synthesizing cephalotaxine in order to solve the problems that the current method for preparing biphenyl compounds for synthesizing cephalotaxine has expensive starting materials, complicated operation and low yield of the obtained product.
[0005] The invention uses commercial reagents such as piperonyl ethylamine and ferulic acid as starting materials, and uses Suzuki coupling reaction as a key step to synthesize a biphenyl compound, and the compound can be used as a synthetic precursor of cephalotaxine. The route uses commercial reagents as raw materials, reduces reaction costs, and has relatively mild use conditions, simple experimental operations, and obtains biphenyl compounds with a good yield, and at the same time lays a certain foundation for the synthesis of cephalotaxine.
[0006] A method for preparing a biphenyl compound for synthesizing cephalotaxine is carried out according to the following steps:
[0007] 1. Put phthalic anhydride and xylene in a glass tube, stir and heat, and when the phthalic anhydride is completely dissolved and the xylene is refluxed, add piperonyl ethylamine. After the reaction is complete, remove the xylene by rotary evaporation to obtain compound 2;
[0008] 2. Add the obtained compound 2 and N-iodosuccinimide into a glass reaction bottle, then add acetonitrile, and after all are dissolved, add trifluoroacetic acid. After the reaction is complete, add H2O, and extract the obtained aqueous phase three times with ethyl acetate, then wash the extracted organic phase, and then remove the solvent of the organic phase by rotary evaporation to obtain a crude product. The crude product is separated and purified to obtain compound 3;
[0009] 3. Compound 3, bis(acetonitrile)palladium(II) chloride and 2-dicyclohexylphosphine-2',6'-dimethoxy-1,1'-biphenyl were weighed and placed in a glass tube, tetrahydrofuran, triethylamine and pinacol borane were added under a nitrogen atmosphere, and then heated to react. After the reaction was complete, ethyl acetate was used for extraction to obtain an organic solution containing a crude product. After removing EA by rotary evaporation under reduced pressure, a crude product was obtained, which was then separated and purified to obtain compound 4;
[0010] Fourth, compound 5 is prepared by first reducing ferulic acid with hydrogen under palladium-carbon catalysis to convert the double bond into a single bond, and then performing Fischer esterification with methanol as a solvent in a one-pot method to obtain an ester compound, which is then reacted with pivaloyl chloride and then iodinated with N-iodosuccinimide to obtain compound 5;
[0011] 5. Add compound 4, compound 5, potassium carbonate and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride into a glass tube, add 1,4-dioxane and water under nitrogen, heat, stir to dissolve, add water after the reaction is completed, extract three times with ethyl acetate, and remove the organic solvent by rotary evaporation to obtain a crude product. After separation and purification, a biphenyl compound for synthesizing cephalotaxine is obtained.
[0012] Reaction route of the present invention:
[0013]
[0014] Beneficial effects of the present invention:
[0015] The key strategy is to construct CC bonds through Suzuki coupling reaction and CN bonds through amidation reaction, synthesize linear compounds, and construct ten-membered macrocyclic compound intermediates. Compound 3 is obtained from commercial reagent piperonyl ethylamine through the addition of Pht protective group and iodination, and the total yield is 71% in 2 steps. Compound 3 is screened by reaction solvent and reaction catalyst to obtain compound 4 with a yield of 76%. Compound 5 is obtained by catalytic hydrogenation, Fischer esterification, Piv protective group, and iodination reaction with ferulic acid as raw material, and the reaction is 3 steps in total, and the yield is 97%. Compounds 4 and 5 undergo Suzuki coupling reaction to obtain compound 6, and the reaction yield is 60%. The synthesis route has a total of 5 steps, and the total yield is 32%. The present invention uses commercial reagents as raw materials, reduces the reaction cost, and the use conditions are relatively mild, the experimental operation is simple, and the biphenyl compound is obtained with a good yield, and at the same time, it lays a certain foundation for the synthesis of cephalotaxine. BRIEF DESCRIPTION OF THE DRAWINGS
[0016] Figure 1 is the H NMR spectrum of compound 5 obtained in Example 1;
[0017] Figure 2 is the C NMR spectrum of compound 5 obtained in Example 1;
[0018] Figure 3 is the H NMR spectrum of the biphenyl compound obtained in Example 1;
[0019] Figure 4 The C NMR spectrum of the biphenyl compound obtained in Example 1. DETAILED DESCRIPTION
[0020] Specific implementation method 1: This implementation method is a preparation method of a biphenyl compound for synthesizing Cephalotaxine, which is carried out according to the following steps:
[0021] 1. Put phthalic anhydride and xylene in a glass tube, stir and heat, and when the phthalic anhydride is completely dissolved and the xylene is refluxed, add piperonyl ethylamine. After the reaction is complete, remove the xylene by rotary evaporation to obtain compound 2;
[0022] 2. Add the obtained compound 2 and N-iodosuccinimide into a glass reaction bottle, then add acetonitrile, and after all are dissolved, add trifluoroacetic acid. After the reaction is complete, add H2O, and extract the obtained aqueous phase three times with ethyl acetate, then wash the extracted organic phase, and then remove the solvent of the organic phase by rotary evaporation to obtain a crude product. The crude product is separated and purified to obtain compound 3;
[0023] 3. Compound 3, bis(acetonitrile)palladium(II) chloride and 2-dicyclohexylphosphine-2',6'-dimethoxy-1,1'-biphenyl were placed in a glass tube, tetrahydrofuran, triethylamine and pinacol borane were added under a nitrogen atmosphere, and then heated to react. After the reaction was complete, ethyl acetate was used for extraction to obtain an organic solution containing a crude product. After removing EA by rotary evaporation under reduced pressure, a crude product was obtained, which was then separated and purified to obtain compound 4;
[0024] Fourth, compound 5 is prepared by firstly reducing ferulic acid with hydrogen under palladium-carbon catalysis to convert the double bond into a single bond, and then performing Fischer esterification with methanol as a solvent in a one-pot method to obtain an ester compound, and then reacting the compound with pivaloyl chloride, and then performing iodination reaction with N-iodosuccinimide to obtain compound 5;
[0025] 5. Add compound 4, compound 5, potassium carbonate and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride into a glass tube, add 1,4-dioxane and water under nitrogen, heat, stir to dissolve, add water after the reaction is completed, extract three times with ethyl acetate, and remove the organic solvent by rotary evaporation to obtain a crude product. After separation and purification, a biphenyl compound for synthesizing cephalotaxine is obtained.
[0026] Specific implementation method 2: This implementation method is different from the specific implementation method 1 in that: Step 1 is heated to 130° C. The rest is the same as the specific implementation method 1.
[0027] Specific implementation method 3: This implementation method is different from specific implementation method 1 or 2 in that the organic phase obtained by extraction in step 2 is washed twice with a saturated sodium thiosulfate solution. The rest is the same as specific implementation method 1 or 2.
[0028] Specific embodiment 4: This embodiment differs from specific embodiments 1 to 3 in that the glass tubes in steps 3 and 4 are both treated to be anhydrous and oxygen-free and filled with nitrogen. The rest is the same as specific embodiments 1 to 3.
[0029] Specific embodiment 5: This embodiment differs from specific embodiments 1 to 4 in that water and oxygen are removed under vacuum conditions by heating with a drying gun at 400° C. The rest is the same as specific embodiments 1 to 4.
[0030] Specific implementation method 6: This implementation method is different from the specific implementation methods 1 to 5 in that the step 3 is heated to 80° C. The rest is the same as the specific implementation methods 1 to 5.
[0031] Specific embodiment 7: This embodiment is different from the specific embodiments 1 to 6 in that: the specific preparation method of compound 5 in step 4 is:
[0032] a. Mix ferulic acid, Pd / C and methanol, add PhCl until the ferulic acid is completely dissolved, and then charge with hydrogen. After the reaction is completed, remove the methanol by vacuum rotary evaporation, and filter the obtained crude product, separate and purify it to obtain compound 5-2;
[0033] b. Add compound 5-2 and 4-dimethylaminopyridine to a flask, then add dichloromethane, add Et3N at room temperature, then drop pivaloyl chloride, after the reaction is completed, add saturated sodium bicarbonate solution to quench the reaction, then extract and filter to obtain compound 5-3;
[0034] c. Compound 5-3 and N-iodosuccinimide were added to a reaction flask, followed by acetonitrile. After compound 5-3 and N-iodosuccinimide were completely dissolved, trifluoroacetic acid was added dropwise. After the reaction was completed, H2O was added to quench the reaction, extracted three times with ethyl acetate, and the organic phase was washed twice with saturated sodium thiosulfate. The obtained organic phases were combined, the organic solvent was removed by rotary evaporation, and the compound 5 was obtained after separation and purification. The rest is the same as in the specific embodiments one to six.
[0035] Specific embodiment 8: This embodiment is different from specific embodiments 1 to 7 in that: step 5 is heated to 110° C. The rest is the same as specific embodiments 1 to 7.
[0036] Specific embodiment 9: This embodiment differs from specific embodiments 1 to 8 in that the separation and purification described in step 3 uses silica gel column chromatography. The rest is the same as specific embodiments 1 to 8.
[0037] Specific embodiment 10: This embodiment differs from specific embodiments 1 to 9 in that the solvent used for silica gel column chromatography is a mixture of petroleum ether and ethyl acetate. The rest is the same as specific embodiments 1 to 9.
[0038] The content of the present invention is not limited to the content of the above-mentioned embodiments. The combination of one or several specific embodiments can also achieve the purpose of the invention.
[0039] Embodiment 1:
[0040] The preparation method of the biphenyl compound used for synthesizing Cephalotaxine in this embodiment is specifically carried out according to the following steps:
[0041] 1. Take phthalic anhydride (1.63 g, 11 mmol) and xylene (10 mL) in a 50 mL Schlenk glass tube, stir and heat to 130 ° C. When the phthalic anhydride is completely dissolved and the xylene is refluxed, compound 1 piperidine (1.35 mL, 10.0 mmol) is added to the reaction tube. After the piperidine is dissolved, the solution turns brown-yellow. The reaction progress is monitored by TLC, and the reaction is observed with an iodine color developer. After about 3 hours, the raw material piperidine is completely reacted, and the xylene is removed by rotary evaporation to obtain a crude product of compound 2, which is used in the next step.
[0042] The reaction route is:
[0043]
[0044] 2. Add the obtained compound 2 (0.29 g, 1.0 mmol) and NIS (0.23 g, 1.05 mmol) into a 20 mL glass reaction bottle, then add 1 mL of acetonitrile, and after the compound is completely dissolved, add trifluoroacetic acid (10 μL, 10 mol%). The solution is light brown. TLC monitors the reaction progress, and the reaction is complete after about 10 hours. After treatment, add H2O, extract the obtained aqueous phase with ethyl acetate three times, and then wash the obtained organic phase with saturated sodium thiosulfate solution twice, remove the organic phase solvent by rotary evaporation, and obtain a crude product. The crude product is further purified by silica gel column chromatography, and the eluent polarity is PE / EtOAc=4:1~EA. The target product 3 (0.35 g, 0.83 mmol, 83%) is obtained as a light yellow solid.
[0045] The reaction route is:
[0046]
[0047] The NMR data analysis of compound 3 is as follows:
[0048] Compound 3:R f =0.5(silica gel,PE / EtOAc=10:1,UV,I2)
[0049] 1 H NMR(400MHz,Chloroform-d)δ7.84(dq,J=4.8,2.2Hz,2H),7.71(dq,J=5.5,2.5Hz,2H),7 .22(s,1H),6.77(d,J=1.9Hz,1H),5.93(s,2H),3.97-3.78(m,2H),3.04(t,J=7.4Hz,2H).
[0050] 3. Compound 3 (0.2 g, 0.5 mmol), bis(acetonitrile)palladium(II) chloride (2.6 mg, 2 mol%), and SPhos (16 mg, 8 mol%) were weighed and placed in a 10 mL Schlenk glass tube with a piston. The reaction tube had been heated with a drying gun and water and oxygen were removed under vacuum. After the anhydrous and oxygen-free treatment was completed, nitrogen was filled into the system, and dry tetrahydrofuran (0.5 mL) was added with a syringe. Triethylamine (0.28 mL, 2.0 mmol) was added with a 500 μL micro syringe, and pinacol borane (0.22 mL, 1.5 mmol) was added with a 250 μL micro syringe. The solution was light yellow and then heated to 80°C. The reaction progress was monitored by TLC. After the reaction was allowed to proceed overnight, the solution turned black and the reaction was complete. After post-treatment, water was added to the reaction tube to quench the reaction, and EA was used for extraction to obtain an organic solution of the crude product. After removing EA by rotary evaporation under reduced pressure, the crude product was obtained. Then, the product was separated and purified by column chromatography, and the polarity of the eluent was PE / EtOAc=10:1 to obtain the target product 4, which was directly used in the next step because it contained by-products.
[0051] The reaction route is:
[0052]
[0053] 4. Add compound ferulic acid 5-1 (10.0 g, 51.0 mmol), Pd / C (0.1 g, 0.2 mol%), and methanol (50 mL) into a 250 mL round-bottom flask and mix. When ferulic acid 3-3 is completely dissolved, add PhCl (30 μL, 5 mol%) using a micro syringe, and then fill with hydrogen. The solution is gray and the reaction progress is monitored by TLC. After 18 hours of reaction, the solution changes from gray to black. TLC monitoring of the reaction reveals that the raw material disappears and the reaction is over. Post-treatment: First, vacuum evaporation is performed to remove methanol. The crude product is filtered with a suction funnel to remove the Pd / C catalyst. The eluent with a polarity of PE / EtOAc = 4:1 is used for elution, and then the eluent is removed by vacuum evaporation to obtain the target compound 5-2 (10.6 g, 50.0 mmol, 98%). The product is a white solid.
[0054] Compound 5-2 (10.6 g, 50.0 mmol) and DMAP (0.30 g, 5 mol%) were added to a 200 mL round-bottom flask, and dichloromethane (50 mL) was added to dissolve the compound. Et3N (11 mL, 80.0 mmol) was added by syringe at room temperature, and then pivaloyl chloride (6.3 mL, 55 mmol) was slowly added dropwise. At this time, white substance appeared in the solution. The reaction progress was monitored by TLC spot plate, and the developing agent polarity PE / EtOAc = 4:1. After 6 hours of reaction, the solution turned slightly yellow, and the raw material disappeared and the reaction was completed. After treatment, saturated sodium bicarbonate solution was added to quench the reaction, and the dichloromethane was extracted. The solvent was removed by evaporation under reduced pressure, and the crude product was filtered with dichloromethane to obtain compound 5-3;
[0055] Compound 5-3 (1.8 g, 6.3 mmol) and NIS (1.4 g, 6.3 mmol) were added to a 20 mL reaction bottle, followed by 10 mL of acetonitrile. After the compound was completely dissolved, TFA (15 μL, 10 mol%) was added dropwise, and the solution turned dark red. TLC and NMR monitored the reaction structure. After 24 h of reaction, the reaction was completed. After treatment, H2O was added to quench the reaction, ethyl acetate was extracted three times, and the organic phase was washed twice with saturated sodium thiosulfate. The obtained organic phases were combined and the organic solvent was removed by rotary evaporation to obtain a crude reaction product. Subsequently, the target compound 5 (2.5 g, 5.8 mmol, 93%) was obtained as a white solid by separation and purification on a silica gel column, using a polarity-size PE / EtOAc=10:1 eluent for elution.
[0056] 1 H NMR (400MHz, Chloroform-d) δ7.39(s,1H),6.87(s,1H),3.77(s,3H),3.69(s,3H),3.02(t,J=8.7,6.9Hz,2H),2.62(t,J=7.8Hz,2H),1.34(s,9H).
[0057] 13 C NMR (101MHz, Chloroform-d) δ176.51,172.98,151.60,141.41,139.15,132.86,113.45,86.98,56.04,51.82,39.11,35.83,34.34,27.22.
[0058]
[0059] 5. Add compound 4 (146 mg, 0.35 mmol), 5 (105 mg, 0.25 mmol), potassium carbonate (103 mg, 0.75 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (9 mg, 5 mol%) into a 10 mL Schlenk glass tube with a piston. After the anhydrous and oxygen-free treatment is completed, nitrogen is filled into the system. Add dry 1,4-dioxane (0.5 mL) and water (50 μL) dropwise through a syringe, then heat to 110°C, stir and dissolve. The solution is orange-red. The reaction is monitored by TLC. After about 4 hours, the solution turns black and the reaction is complete. H2O was added to the reaction tube, extracted with ethyl acetate three times, and the organic solvent was removed by rotary evaporation to obtain a crude product, which was separated and purified by column chromatography. The polarity of the eluent was PE / EtOAc = 10:1 to 4:1 to obtain the target product 6 (88 mg, 0.15 mmol, 60%) as a light yellow solid, which was the biphenyl compound used to synthesize cephalotaxine.
[0060] The reaction route is:
[0061]
[0062] Its NMR data analysis is: Compound 6:R f =0.5(silica gel,PE / EtOAc=10:1,UV,I2)
[0063] 1 H NMR (400MHz, Chloroform-d) δ7.82-7.73(m,2H),7.73-7.62(m,2H),6.85(d,J=7.0Hz,2H),6.71(s,1H),6.61(s,1H),5.93(d,J= 13.3,2H),3.83(s,3H),3.70(t,J=7.3Hz,2H),3.61(s,13H),2.92-2.55(m,2H),2.43(t,J=7.9Hz,2H),1.34(s,9H),1.24(s,6H).
[0064] The invention successfully prepares a biphenyl compound, which can be used in a biogenic synthesis route for synthesizing cephalotaxine.
Claims
1. A method for preparing a biphenyl compound for synthesizing cephalotaxine, characterized in that The method is specifically carried out in the following steps:
1. Put phthalic anhydride and xylene in a glass tube, stir and heat, and when the phthalic anhydride is completely dissolved and the xylene is refluxed, add piperonyl ethylamine. After the reaction is complete, remove the xylene by rotary evaporation to obtain compound 2; 2. Add the obtained compound 2 and N-iodosuccinimide into a glass reaction bottle, then add acetonitrile, and after dissolving, add trifluoroacetic acid. After the reaction is complete, add H2O, and extract the obtained aqueous phase three times with ethyl acetate, then wash the extracted organic phase, and then remove the solvent of the organic phase by rotary evaporation to obtain a crude product. The crude product is separated and purified to obtain compound 3; 3. Compound 3, bis(acetonitrile)palladium(II) chloride, and 2-dicyclohexylphosphine-2',6'-dimethoxy-1,1'-biphenyl are placed in a glass tube, and tetrahydrofuran, triethylamine, and pinacol borane are added under a nitrogen atmosphere, followed by heating for reaction, and after the reaction is complete, extraction is performed using ethyl acetate to obtain an organic solution containing a crude product, and after removing ethyl acetate by rotary evaporation under reduced pressure, a crude product is obtained, which is then separated and purified to obtain compound 4; Fourth, compound 5 is prepared by firstly reducing ferulic acid with hydrogen under palladium-carbon catalysis to convert the double bond into a single bond, and then reacting with methanol as a solvent to undergo Fischer esterification to obtain an ester compound, which is then reacted with pivaloyl chloride and then iodinated with N-iodosuccinimide to obtain compound 5; 5. Add compound 4, compound 5, potassium carbonate and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride into a glass tube, add 1,4-dioxane and water under nitrogen, heat, stir to dissolve, add water after the reaction is completed, extract three times with ethyl acetate, and remove the organic solvent by rotary evaporation to obtain a crude product. After separation and purification, a biphenyl compound for synthesizing cephalotaxine is obtained.
2. The method for preparing a biphenyl compound for synthesizing cephalotaxine according to claim 1, characterized in that Step 1: Heat to 130°C.
3. The method for preparing a biphenyl compound for synthesizing cephalotaxine according to claim 1, characterized in that The organic phase obtained by extraction in step 2 was washed twice with saturated sodium thiosulfate solution.
4. The method for preparing a biphenyl compound for synthesizing cephalotaxine according to claim 1, characterized in that The glass tubes in step 3 and step 4 are both treated to be anhydrous and oxygen-free and filled with nitrogen.
5. The method for preparing a biphenyl compound for synthesizing cephalotaxine according to claim 4, characterized in that The anhydrous and oxygen-free treatment method is to use a drying gun to heat at 400°C to remove water and oxygen under vacuum conditions.
6. The method for preparing a biphenyl compound for synthesizing cephalotaxine according to claim 1, characterized in that Step 3: Heat to 80°C.
7. The method for preparing a biphenyl compound for synthesizing Cephalotaxine according to claim 1, characterized in that The specific preparation method of compound 5 in step 4 is: a. Mix ferulic acid, Pd / C and methanol, add PhCl until the ferulic acid is completely dissolved, and then charge with hydrogen. After the reaction is completed, remove the methanol by vacuum rotary evaporation, and filter the obtained crude product, separate and purify it to obtain compound 5-2; b. Add compound 5-2 and 4-dimethylaminopyridine to a flask, then add dichloromethane, add Et3N at room temperature, then drop pivaloyl chloride, after the reaction is completed, add saturated sodium bicarbonate solution to quench the reaction, then extract and filter to obtain compound 5-3; c. Compound 5-3 and N-iodosuccinimide were added to a reaction flask, followed by acetonitrile. After compound 5-3 and N-iodosuccinimide were completely dissolved, trifluoroacetic acid was added dropwise. After the reaction was completed, H2O was added to quench the reaction. The mixture was extracted three times with ethyl acetate, and the organic phase was washed twice with saturated sodium thiosulfate. The organic phases were combined, and the organic solvent was removed by rotary evaporation. Compound 5 was obtained by separation and purification.
8. The method for preparing a biphenyl compound for synthesizing Cephalotaxine according to claim 1, characterized in that Step 5: Heat to 110°C.
9. The method for preparing a biphenyl compound for synthesizing cephalotaxine according to claim 1, characterized in that The separation and purification described in step 3 is carried out by silica gel column chromatography.
10. The method for preparing a biphenyl compound for synthesizing cephalotaxine according to claim 9, characterized in that Step 3: The solvent used for silica gel column chromatography is a mixture of petroleum ether and ethyl acetate.