A method for preparing tetrandrine and its analogues by alkylating jatrorrhizine

Abstract

The application discloses a method for preparing tetrandrine and its analogues by alkylating sinomontanine, which comprises the following steps: mixing and heating sinomontanine and alkyl carbonate, and / or making the sinomontanine and the alkyl carbonate to occur alkylating reaction under the condition of a catalyst to synthesize tetrandrine and 7-alkoxy sinomontanine and the like; the alkyl carbonate has the structure as shown in formula (I) or formula (II); the catalyst is any one or a combination of more of a base agent, an imidazolium ionic liquid and a pyridinium ionic liquid; the amount of the catalyst is 0.1% to 300% of the amount of the sinomontanine; the base agent is an inorganic base or an organic base; the imidazolium ionic liquid has the structure as shown in formula (III); and the pyridinium ionic liquid has the structure as shown in formula (IV) or formula (V). The application has the characteristics of simple synthesis method and high yield, and is favorable for the research and application of tetrandrine and its analogues.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemical synthesis technology, specifically relating to a method for preparing tetrandrine and its analogues by alkylation of tetrandrine. Background Technology

[0002] Tetrandrine A and fangchinorline (also known as tetrandrine B) are the main active ingredients of the traditional Chinese medicine *Stephania tetrandra* powder, belonging to the class of dibenzylisoquinoline alkaloids. They are very similar in chemical structure, the main difference being that tetrandrine A has a methoxy group at the 7-position, while fangchinorline has a phenolic hydroxyl group at the 7-position. In recent years, pharmacomechanical studies have shown that tetrandrine has antiarrhythmic, anti-myocardial ischemia, antihypertensive, anti-inflammatory, analgesic, anti-silicosis, and anticancer effects. In contrast, although fangchinorline also has some anti-inflammatory, analgesic, and antihypertensive effects, its anti-inflammatory and analgesic effects are weaker than those of tetrandrine, and its antihypertensive effect is also less potent and prolonged. Currently, injections, powders, and tablets made from tetrandrine are widely used clinically and marketed, while fangchinorline, due to its relatively low biological activity, is mainly limited to preclinical research.

[0003] Tetrandrine is primarily derived from traditional herbal extracts. The total alkaloid content in the root of the natural herb *Stephania tetrandra* ranges from 1.5% to 2.3%, with tetrandrine comprising approximately 1% and fangchinorline 0.5% to 1%. Due to the limited yield of *Stephania tetrandra* and its low alkaloid content, tetrandrine is in very short supply and far from meeting pharmaceutical demand. However, the fangchinorline content in the root of this herb is comparable to that of tetrandrine. If fangchinorline could be chemically converted into tetrandrine, which has higher biological activity, it would maximize the utilization of the plant and significantly increase the yield of tetrandrine. However, due to the strong nucleophilicity of the tertiary amino groups at the 2- and 2'-positions in its structure, the selective methylation reaction of tetrandrine with traditional methylating agents (such as iodomethane or dimethyl sulfate) presents significant challenges. Besides the methylation of the phenolic hydroxyl group at the C-7 position, the methylation of the 2- and 2'-position amino groups can lead to the formation of quaternary ammonium salts. Therefore, developing new techniques for the alkylation of tetrandrine to prepare tetrandrine and its analogues has significant research and application value. Summary of the Invention

[0004] To address the aforementioned shortcomings, this invention discloses a method for preparing tetrandrine and its analogues by alkylation of tetrandrine. The method uses tetrandrine as a raw material and synthesizes tetrandrine and its analogues through an alkylation reaction. The synthesis method is simple, has a high yield, and is beneficial for the research and application of tetrandrine and its analogues.

[0005] This invention is achieved using the following technical solution:

[0006] A method for preparing tetrandrine and its analogues by alkylation of tetrandrine, wherein tetrandrine and alkyl carbonate are mixed and reacted, wherein the alkyl carbonate has the structure described in formula (I) or formula (II).

[0007] Equation (Ⅰ) is: Where R 1 R 2 R is any one of alkyl, substituted alkyl (such as hydroxyalkyl), benzyl, substituted benzyl and H. 1 It can be equal to or not equal to R 2 R 1 and R 2 They cannot both be H;

[0008] Equation (II) is: Where R 1 R 2 It can be any one of alkyl, substituted alkyl (such as hydroxyalkyl), benzyl, substituted benzyl and H, m = 0, 1, 2, 3, n = 1, 2, 3.

[0009] Furthermore, tetrandrine and alkyl carbonate are mixed and heated under a nitrogen atmosphere at a temperature of 60°C to 200°C to obtain tetrandrine and its analogues.

[0010] Furthermore, the heating reaction time is 2h to 48h.

[0011] Furthermore, fangchinorhinone, alkyl carbonate, and an auxiliary solvent are mixed and reacted to obtain tetrandrine and its analogues. The auxiliary solvent is any one or any combination of N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, toluene, acetonitrile, dimethyl sulfoxide, triethylene glycol dimethyl ether, and polyethylene glycol. Adding an auxiliary solvent can improve the solubility of fangchinorhinone, alkyl carbonate, and other raw materials, allowing the reaction to proceed at lower temperatures, reducing energy consumption, and facilitating the widespread application of the process.

[0012] Furthermore, the reaction of tetrandrine, alkyl carbonate and catalyst yields tetrandrine and its analogues, wherein the catalyst is any one or more combinations of alkali, imidazolium ionic liquid and pyridinium ionic liquid.

[0013] Furthermore, the amount of the catalyst used is 0.1% to 300% of the amount of fentanyl alkaloid used.

[0014] Furthermore, the alkali is an inorganic or organic alkali. The inorganic alkali is any one or more combinations of carbonates, bicarbonates, and oxides of Li, Na, K, Rb, Cs, Ca, Mg, and Al. The organic alkali is any one or more combinations of trimethylamine, triethylamine, N,N-diisopropylethylamine, imidazole and its derivatives, pyridine and its derivatives, tetraalkylurea, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5,7-triazidobicyclo(4.4.0)dec-5-ene, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), and triethylenediamine (DABCO).

[0015] Furthermore, the imidazolium ionic liquid has the structure described in formula (Ⅲ).

[0016] Equation (Ⅲ) is: Where R 1 R 2 It is any one of the following: straight alkyl, branched alkyl, alkyl containing any one or more heteroatoms of N, O, S, and P, benzyl, and substituted benzyl; Represented as anions, such as halide ions, carboxylate ions, and boron tetrafluoride ions (BF4). - ), phosphorus hexafluoride ions (PF6) - ), bis(trifluoromethanesulfonamide) ions (NTf2) - )wait.

[0017] Furthermore, the pyridinium ionic liquid has the structure described in formula (IV) or formula (V).

[0018] Equation (Ⅳ) is: Where R 1 It is any one of the following: straight-chain alkyl, branched alkyl, alkyl containing any one or more heteroatoms of N, O, S, and P, benzyl, and substituted benzyl; R 2 Substituents on the pyridine ring, such as alkoxy, acyloxy, acyl, ester, amino, amide, etc. Represented as anions, such as halide ions, carboxylate ions, and boron tetrafluoride ions (BF4). - ), phosphorus hexafluoride ions (PF6) - ), bis(trifluoromethanesulfonamide) ions (NTf2) - )wait;

[0019] Equation (V) is: R 1 It is any one of the following: a straight-chain alkyl group, a branched alkyl group, an alkyl group containing any one or more heteroatoms of N, O, S, and P, a benzyl group, and a substituted benzyl group; R 2 Substituents on the pyridine ring, such as alkoxy, acyloxy, acyl, ester, amino, and amide groups.

[0020] This invention involves reacting tetrandrine and alkyl carbonates to obtain tetrandrine and its analogues, as described in the following reaction... Figure 1 As shown.

[0021] Compared with existing technologies, this technical solution has the following advantages:

[0022] Traditional methods for synthesizing aryl methyl ethers primarily involve the methylation reaction of phenolic compounds with methyl halides or dimethyl sulfate. However, these methods not only utilize corrosive and toxic methylating agents but also require stoichiometric amounts of strong bases to neutralize acidic byproducts, leading to the formation of large amounts of inorganic salts. This process poses significant risks to human safety and the environment. Furthermore, due to the lack of chemoselectivity, some amino functional groups may undergo over-methylation. For example, in the methylation reaction of fangchinorline with iodomethane or dimethyl sulfate, besides the C-7 phenolic hydroxyl group undergoing methylation, the tertiary amino groups at the 2- and 2'-positions, due to their strong nucleophilicity, may lead to the formation of corresponding quaternary ammonium salts through over-methylation. This invention prepares tetrandrine and its analogues by alkylation reaction using tebufenozide and alkyl carbonate as raw materials. It can selectively reduce the alkylation reaction of the 2- and 2'-amino groups in the tebufenozide structure and promote the alkylation reaction of the phenolic hydroxyl group at the C-7 position, thereby facilitating the formation of tetrandrine and its analogues. On the other hand, alkyl carbonate compounds have the characteristics of low toxicity and good biodegradability compared with dimethyl sulfate and methyl halides. For example, dimethyl carbonate is non-toxic and biodegradable. Its main byproducts in the methylation reaction with phenolic compounds are carbon dioxide and methanol, which are particularly environmentally friendly. It can be used as a "green" methylation reagent to replace dimethyl sulfate and methyl halides.

[0023] This invention also extends the versatility of the reaction by adding an alkali, imidazolium ionic liquid or pyridinium ionic liquid as a catalyst, and auxiliary organic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, toluene, dimethyl sulfoxide, triethylene glycol dimethyl ether, and polyethylene glycol. This further promotes the alkylation of the phenolic hydroxyl group at the C-7 position of tetrandrine, thereby increasing the yield of tetrandrine and its analogues. The synthetic process described in this invention is simple, highly operable, and suitable for the large-scale production of tetrandrine and its analogues, which is beneficial to the research and application of tetrandrine and its analogues. Attached Figure Description

[0024] Figure 1 This is a schematic diagram illustrating the reaction of tebufenozide and alkyl carbonate in this invention.

[0025] Figure 2 This is a schematic diagram of the chemical structure of tetrandrine described in Example 1.

[0026] Figure 3 This is a schematic diagram of the chemical structure of 7-ethoxyfenozide described in Example 9.

[0027] Figure 4 This is a schematic diagram of the chemical structure of 7-β-hydroxyethoxyfenozide described in Example 10.

[0028] Figure 5 This is a schematic diagram of the chemical structure of 7-β-hydroxypropoxyfenozide described in Example 11.

[0029] Figure 6 This is a schematic diagram of the chemical structure of 7-benzyloxyfenozide described in Example 12. Detailed Implementation

[0030] The present invention is further illustrated by the following examples, but these are not intended to limit the invention. Specific experimental conditions and methods not specified in the following examples are generally conventional methods well known to those skilled in the art.

[0031] Example 1: Tetrandrine was prepared according to the method described in this application. Specifically, 500 mg of tetrandrine, 306 mg of DBN, and 20 mL of dimethyl carbonate were mixed and heated at 120 °C for 14 h under a nitrogen atmosphere to obtain a reaction solution. The reaction solution was then diluted with 20 mL of dichloromethane to obtain a diluted solution. The diluted solution was then washed twice with saturated brine. After separation, the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography to obtain 327 mg of a off-white solid (i.e., tetrandrine). The NMR analysis data of the off-white solid were as follows: 1HNMR (800MHz, CDCl3) δ7.34(d,J=8.1Hz,1H),7.13(dd,J=8.0,1.9Hz,1H),6.88(d,J=8.2Hz,1H),6.85(d,J=8.2Hz,1H),6.8 1(dd,J=8.2,2.3Hz,1H),6.55(s,1H),6.50(s,1H),6.32-6.28(m,2H),5.99(s,1H),3.92(s,3H),3.87(dd,J=11.0,5.6Hz,1H ),3.76-3.73(m,4H),3.54-3.48(m,1H),3.45-3.40(m,1H),3.37(s,3H),3.24(dd,J=12.3,5.5Hz,1H),3.18(s,3H),2.97-2 .84(m,4H),2.79(t,J=11.7Hz,1H),2.74-2.67(m,2H),2.61(s,3H),2.51(d,J=14.1Hz,1H),2.44-2.39(m,1H),2.32(s,3H). 13 C NMR (201MHz, CDCl3) δ153.76,151.47,149.46,148.68,148.53,147.10,143.82,13 7.92,135.33,135.02,132.74,130.25,128.20,128.13,128.03,123.01,122.80,1 22.09,122.01,120.25,116.23,112.77,111.56,105.79,63.97,61.49,60.40,56. 24,55.94,55.90,45.32,44.16,42.71,42.38,42.00,38.28,25.33,22.13.ESI-MS m / z:623.4(M+H).

[0032] Example 2: Tetrandrine was prepared according to the method described in this application. Specifically, 500 mg of tetrandrine, 171 mg of 1-butyl-3-methylimidazolium chloride, and 20 mL of dimethyl carbonate were mixed and heated at 120 °C for 14 h under a nitrogen atmosphere to obtain a reaction solution. The reaction solution was then diluted with 20 mL of dichloromethane to obtain a diluted solution. The diluted solution was then washed twice with saturated brine. After separation, the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography to obtain 340 mg of off-white solid. The off-white solid was identified by NMR analysis as the same substance as the off-white solid obtained in Example 1, namely tetrandrine.

[0033] Example 3: Tetrandrine was prepared according to the method described in this application. Specifically, 500 mg of tetrandrine, 340 mg of potassium carbonate, and 20 mL of dimethyl carbonate were mixed and heated at 200 °C for 24 h under a nitrogen atmosphere to obtain a reaction solution. The reaction solution was then diluted with 40 mL of dichloromethane to obtain a diluted solution. The diluted solution was then washed twice with saturated brine. After separation, the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography to obtain 140 mg of a off-white solid. The off-white solid was identified by NMR analysis as the same substance as the off-white solid obtained in Example 1, namely tetrandrine.

[0034] Example 4: Tetrandrine was prepared according to the method described in this application. Specifically, 500 mg of tetrandrine, 323 mg of 4-dimethylaminopyridine (DMAP), and 20 mL of dimethyl carbonate were mixed and heated at 120 °C for 24 h under a nitrogen atmosphere to obtain a reaction solution. The reaction solution was then diluted with 40 mL of dichloromethane to obtain a diluted solution. The diluted solution was then washed twice with saturated brine. After separation, the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography to obtain 346 mg of a off-white solid. The off-white solid was identified by NMR analysis as the same substance as the off-white solid obtained in Example 1, namely tetrandrine.

[0035] Example 5: Tetrandrine was prepared according to the method described in this application. Specifically, 500 mg of tetrandrine, 148 mg of 4-dimethylamino-1-methylpyridinium-2-carboxylic acid, and 20 mL of dimethyl carbonate were mixed and heated at 120 °C for 24 h under a nitrogen atmosphere to obtain a reaction solution. The reaction solution was then diluted with 40 mL of dichloromethane to obtain a diluted solution. The diluted solution was then washed twice with saturated brine. After separation, the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography to obtain 342 mg of a off-white solid. The off-white solid was identified by NMR analysis as the same substance as the off-white solid obtained in Example 1, namely tetrandrine.

[0036] Example 6: Tetrandrine was prepared according to the method described in this application. Specifically, 500 mg of tetrandrine, 148 mg of 4-dimethylamino-1-methylpyridinium-2-carboxylic acid, and 20 mL of dimethyl carbonate were mixed and heated at 120 °C for 2 h under a nitrogen atmosphere to obtain a reaction solution. The reaction solution was then diluted with 40 mL of dichloromethane to obtain a diluted solution. The diluted solution was then washed twice with saturated brine. After separation, the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography to obtain 334 mg of a off-white solid. The off-white solid was identified by NMR analysis as the same substance as the off-white solid obtained in Example 1, namely tetrandrine.

[0037] Example 7: Tetrandrine was prepared according to the method described in this application. Specifically, 500 mg of tetrandrine, 1.5 mg of 4-dimethylamino-1-methylpyridinium-2-carboxylic acid, and 20 mL of dimethyl carbonate were mixed and heated at 120 °C for 48 h under a nitrogen atmosphere to obtain a reaction solution. The reaction solution was then diluted with 40 mL of dichloromethane to obtain a diluted solution. The diluted solution was then washed twice with saturated brine. After separation, the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography to obtain 340 mg of a off-white solid. The off-white solid was identified by NMR analysis as the same substance as the off-white solid obtained in Example 1, namely tetrandrine.

[0038] Example 8: Tetrandrine was prepared according to the method described in this application. Specifically, 500 mg of tetrandrine, 14.8 mg of 4-dimethylamino-1-methylpyridinium-2-carboxylic acid, 83 mg of triethylamine, 20 mL of dimethyl carbonate, and 4 mL of N,N-dimethylformamide were mixed and heated at 60°C for 48 h under a nitrogen atmosphere to obtain a reaction solution. The reaction solution was then diluted with 40 mL of dichloromethane to obtain a diluted solution. The diluted solution was then washed twice with saturated brine. After separation, the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography to obtain 335 mg of a off-white solid. The off-white solid was identified by NMR analysis as the same substance as the off-white solid obtained in Example 1, namely tetrandrine.

[0039] Example 9: 7-Ethoxyfenoxanorline was prepared according to the method described in this application. Specifically, 183 mg of fenoxanorline, 83 mg of triethylamine, 5.4 mg of 4-dimethylamino-1-methylpyridinium-2-carboxylic acid, and 10 mL of diethyl carbonate were heated at 120°C for 24 h under a nitrogen atmosphere to obtain a reaction solution. The reaction solution was then diluted with 20 mL of dichloromethane to obtain a diluted solution. The diluted solution was then washed twice with saturated brine. After separation, the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography to obtain 75 mg of a white solid (7-ethoxyfenoxanorline). The NMR analysis data of the white solid were as follows: 1 H NMR (800MHz, CDCl3) δ7.36(dd,J=8.1,1.8Hz,1H),7.13(dd,J=8.1,2.4Hz,1H),6.88(dd,J=8.2,1.4Hz,1H),6.85(d,J=8.2Hz,1H),6.82(dd,J=8 .2,2.4Hz,1H),6.53(d,J=1.5Hz,1H),6.50(s,1H),6.31(dd,J=8.2,1.9Hz,1H),6.30(s,1H),5.95(s,1H),3.92(s,3H),3.83(dd,J=11.2,5.6Hz, 1H),3.76(d,J=10.1Hz,1H),3.73(s,3H),3.58-3.49(m,3H),3.41(dq,J =14.2,7.0Hz,1H),3.36(s,3H),3.30(dd,J=12.4,5.5Hz,1H),2.96-2.8 5(m,4H),2.82(t,J=11.8Hz,1H),2.75-2.68(m,2H),2.59(s,3H),2.53( d,J=14.0Hz,1H),2.48-2.43(m,1H),2.33(s,3H),0.79(t,J=7.0Hz,3H). 13CNMR(201MHz,CDCl3)δ153.79,151.64,149.45,148.83,148.52,147.14,143.82,13 6.72,135.00,134.64,132.72,130.30,128.02,127.81,127.19,122.88,122.61,122 .10,122.03,120.16,116.04,112.74,111.55,105.69,68.33,64.33,61.58,56.19,5 5.86,55.81,45.32,44.31,42.49,42.41,41.84,40.43,24.20,22.25,14.91.ESI-MS m / z:637.4(M+H).

[0040] Example 10: 7-β-hydroxyethoxyfenoxanorline was prepared according to the method described in this application. Specifically, 183 mg of fenoxanorline, 40 mg of ethylene carbonate (CAS 96-49-1), and 5.4 mg of 4-dimethylamino-1-methylpyridinium-2-carboxylic acid were dissolved in 10 mL of a 20% N,N-dimethylformamide solution in triethylene glycol dimethyl ether. The solution was then refluxed at 120°C under a nitrogen atmosphere for 24 h to obtain a reaction solution. The reaction solution was then diluted with 20 mL of dichloromethane to obtain a diluted solution. The diluted solution was washed twice with saturated brine. After separation, the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography to obtain 152 mg of a white solid (i.e., 7-β-hydroxyethoxyfenoxanorline). The NMR analysis data of the white solid were as follows: 1H NMR(800MHz,CDCl3)δ7.35(dd,J=8.1,1.7Hz,1H),7.14(dd,J=8.1,2.4Hz,1H),6.87(d,J=8.4Hz,1H),6.85(d,J=8.2Hz,1H),6.81(dd,J=8.2,2.4Hz,1H),6.53(s,1H),6.51(s,1H),6.33-6.30(m,2H),5.97(s,1H),3.92(s,3H),3.86(dd,J=11.2,5.4Hz,1H),3.75(s,3H),3.73(d,J=10.2Hz,1H),3.60-3.57(m,1H),3.53-3.49(m,2H),3.48-3.44(m,1H),3.43-3.39(m,1H),3.37(s,3H),3.36-3.34(m,1H),3.29(dd,J=12.4,5.4Hz,1H),2.97-2.87(m,4H),2.78(t,J=11.8Hz,1H),2.76-2.69(m,2H),2.62(s,3H),2.51(d,J=14.0Hz,1H),2.48-2.43(m,1H),2.31(s,3H). 13 C NMR(201MHz,CDCl3)δ153.84,151.10,149.45,148.77,148.31,147.14,143.57,136.37,134.91,134.57,132.67,130.32,128.62,128.09,127.71,123.19,122.89,122.12,122.11,119.76,115.99,113.02,111.60,105.83,74.84,64.06,61.59,61.54,56.20,56.04,55.92,45.30,44.23,42.54,42.43,41.91,38.93,24.88,22.21.ESI-MS m / z:653.4(M+H)。

[0041] Example 11: 7-β-hydroxypropoxyfenoxanorline was prepared according to the method described in this application. Specifically, 183 mg of fenoxanorline, 46 mg of propylene carbonate, and 5.4 mg of 4-dimethylamino-1-methylpyridinium-2-carboxylic acid were dissolved in 10 mL of a 20% N,N-dimethylformamide solution in triethylene glycol dimethyl ether. The mixture was then refluxed at 90°C under a nitrogen atmosphere for 24 h to obtain a reaction solution. The reaction solution was then diluted with 20 mL of dichloromethane to obtain a diluted solution. The diluted solution was washed twice with saturated brine. After separation, the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography to obtain 132 mg of solid (i.e., 7-β-hydroxypropoxyfenoxanorline). The NMR analysis data of the solid were as follows: 1 HNMR (800MHz, CDCl3) δ7.36 (dt, J=7.9, 4.4Hz, 1H), 7.14 (dt, J=8.0, 2.7Hz, 1H), 6.87-6.83 (m, 2H), 6.81 (td, J=8.3, 2.4Hz, 1H), 6.53 (d, J=4. 2Hz,1H),6.50(d,J=6.7Hz,1H),6.33-6.29(m,2H),5.95(d,J=25.8Hz,1H),3.91(s,3H),3.84(ddd,J=37.5,11.2,5.4Hz,1H),3.74(s,3H),3.7 1(dd,J=10.1,2.4Hz,1H),3.61-3.38(m,4H),3.35(d,J=5.4Hz,3H),3. 30-3.26(m,1H),3.24-3.18(m,1H),2.96-2.85(m,4H),2.78(td,J=11.7 ,8.5Hz,1H),2.74-2.67(m,2H),2.61(d,J=11.8Hz,3H),2.51(d,J=14.2Hz,1H),2.46-2.41(m,1H),2.29(s,3H),0.91(dd,J=17.9,6.5Hz,3H). 13CNMR(201MHz,CDCl3)δ153.75,151.09,150.60,149.41,148.79,148.59,148 .19,148.07,147.07,147.05,143.55,143.42,137.08,136.14,134.96,134. 93,134.53,132.64,132.61,130.32,130.30,128.60,128.44,128.10,128.07,127.87,127.71,124.50,124.01,123.24,122.94,122.84,122.11,122.10 ,122.05,119.72,119.56,115.89,115.86,113.10,113.01,111.53,105.80,105.77,79.71,78.56,66.46,65.66,64.17,63.96,61.54,61.51,56.15,56. 09,56.02,55.88,55.84,45.27,45.21,44.13,44.12,42.48,42.44,42.39,42.38,41.84,41.78,39.32,39.05,24.84,24.66,22.19,22.16,17.91,17.76.

[0042] Example 12: 7-Benzyloxyfenanoline was prepared according to the method described in this application. Specifically, 183 mg of fenanoline, 109 mg of dibenzyl carbonate, and 5.4 mg of 4-dimethylamino-1-methylpyridinium-2-carboxylic acid were dissolved in 10 mL of a 20% N,N-dimethylformamide solution in triethylene glycol dimethyl ether. The solution was then heated at 120°C under a nitrogen atmosphere for 24 h to obtain a reaction solution. The reaction solution was then diluted with 20 mL of dichloromethane to obtain a diluted solution. The diluted solution was washed twice with saturated brine. After separation, the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography to obtain 100 mg of a white solid (i.e., 7-benzyloxyfenanoline). The NMR analysis data of the white solid were as follows: 1HNMR(800MHz,CDCl3)δ7.33(dd,J=8.1,2.0Hz,1H),7.24-7.19(m,3H),7.14(dd,J=8.1,2.5Hz,1H),7.00(dd,J=7.2,1.8Hz,2H),6.89(dd,J=8.2,1.3Hz,1H),6.87(d,J=8.2Hz,1H),6.80(dd,J=8.2,2.5Hz,1H),6.53(d,J=1.6Hz,1H),6.51(s,1H),6.34(s,1H),6.31(dd,J=8.2,2.0Hz,1H),5.86(s,1H),4.62(d,J=10.6Hz,1H),4.26(d,J=10.6Hz,1H),3.93(s,3H),3.77(d,J=10.1Hz,1H),3.74(dd,J=11.1,5.7Hz,1H),3.73(s,3H),3.57-3.52(m,1H),3.50-3.45(m,1H),3.37(s,3H),3.29(dd,J=12.4,5.6Hz,1H),2.98-2.91(m,2H),2.89-2.81(m,2H),2.78(t,J=11.8Hz,1H),2.75-2.69(m,2H),2.54(d,J=14.0Hz,1H),2.50(s,3H),2.49-2.44(m,1H),2.35(s,3H). 13 C NMR(201MHz,CDCl3)δ153.86,151.51,149.44,148.91,148.63,147.17,144.12,137.52,136.90,134.97,134.75,132.70,130.26,128.36,128.21,128.07,127.61,127.53,123.09,122.86,122.00,121.96,120.45,116.22,112.93,111.60,106.11,74.47,64.21,61.59,56.22,55.98,55.92,45.72,44.35,42.54,42.47,42.04,40.23,24.83,22.24.ESI-MS m / z:699.5(M+H)。

[0043] Furthermore, it should be understood that although this specification describes embodiments, not every embodiment contains only one independent technical solution. This narrative style is merely for clarity. Those skilled in the art should consider the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

1. A method for preparing tetrandrine, characterized by: Mixing 500 mg of tetrandrine, 148 mg of 4-dimethylamino-1-methylpyridinium-2-carboxylic acid and 20 mL of dimethyl carbonate in a nitrogen atmosphere and heating the reaction at 120°C for 2 h to obtain a reaction solution, then diluting the reaction solution with 40 mL of dichloromethane to obtain a diluted solution, then washing the diluted solution with saturated brine twice, separating the layers, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating the organic phase under reduced pressure to obtain a residue, and then purifying the residue by silica gel column chromatography to obtain 334 mg of a white solid, which is Hanfangji A.

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