Synthesis method and application of a sanguinarine intermediate compound bromide

Abstract

The present application relates to the field of medicine synthesis, and discloses a synthetic method of a sanguinarine intermediate compound bromide and application thereof. First, compared with the prior art, the synthetic method of the sanguinarine intermediate compound bromide can avoid using a difficult-to-prepare starting material, has short steps, mild reaction conditions, is easy to operate, has low cost, is environmentally friendly, has high yield and high product purity. Secondly, compared with the prior art, the sanguinarine hemisulfate synthesized by using the above bromide as a raw material can greatly reduce the amount of noble metal palladium catalyst, avoid using silver carbonate as an alkali (acid binding agent), and through conventional post-treatment operations such as extraction, beating and concentration, high-purity sanguinarine hemisulfate can be obtained without column chromatography separation.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical synthesis, and in particular to a method for synthesizing a brominated derivative of a sanguisorbin intermediate and its application. Background Technology

[0002] Aromatic benzo[c]phenanthrene alkaloids include sanguisorbin and celandine. The main active chemical components in *Botrytis cinerea* are sanguisorbin and celandine, with the highest content found in the fruit. *Botrytis cinerea* extract, obtained by extracting and purifying the fruit, can be used as a feed additive to replace antibiotics.

[0003] As shown below, the molecular skeleton of benzo[c]phenanthreneidine includes rings A, B, and C, and one benzene ring (ring D). Its chemical synthesis methods can be categorized according to the order in which the four rings A, B, and C are constructed. In existing technologies, constructing ring B or ring C last is most common. Traditional cyclization reactions using benzoyne, free radicals, or enamides as intermediates, and the rapidly developing palladium-catalyzed intramolecular coupling reactions in recent years, generally employ C10a-C11a bond linkages in the final step to construct the benzo[c]phenanthreneidine skeleton.

[0004] Brominated compound III is a key intermediate in the construction of sanguinarine and its salts. The synthetic route for sanguinarine hemisulfate is as follows:

[0005]

[0006] The existing synthetic methods for the above-mentioned brominated derivative III include the following:

[0007] Calder et al. (JOC2014) used a trichloroacetamide-substituted 1,4-dihydronaphthalene compound (JOC2014, 16c CAS1620902-92-2) as a starting material to prepare bromo derivative III (JOC2014, 22d, R1+R2=OCH2O, R3=H) in four steps. The yields of each step were 72% (column chromatography), 98%, 89%, and 98%, respectively. The synthetic route is shown below:

[0008] Scheme 4.Synthesis of Amides 22a-d

[0009]

[0010] The above-mentioned synthesis method has obvious drawbacks that limit its industrial application:

[0011] (1) Step 1 requires oxidation with manganese oxide, and the product needs to be separated by column chromatography; Step 2 requires a reaction time of up to 60 hours; Step 4 uses the genotoxic reagent MeI and the strong base NaH for methylation. Due to the long reaction time, column chromatography purification, and the use of genotoxic reagents, there are potential risks to the operation and product safety.

[0012] (2) The starting material, a 1,4-dihydronaphthalene compound substituted with trichloroacetamide (JOC2014, 16c), needs to be prepared in-house. Using bromopiperaldehyde (JOC2014, 5c) as the starting material, the preparation involves four steps with yields of 100%, 100%, 97%, and 81% respectively. Step 3, the reduction of ethyl arylacrylate to arylpropenol, requires a low temperature of -78℃ and column chromatography separation. Step 4, the ring-closure metathesis, requires a second-generation ruthenium-Grubbs catalyst. The reaction conditions involve ultra-low temperature, column chromatography purification, and a ruthenium catalyst, making the operation complex and the raw material costs high.

[0013] Therefore, developing a chemical synthesis method for preparing sanguinarine intermediate bromide with short steps, mild and easy-to-operate reaction conditions, low production cost, environmentally friendly process, high yield, and high product purity has become an urgent problem to be solved.

[0014] In addition, the following existing technologies have been reported regarding the preparation of oxidized sanguinarine and its analogues via bromide coupling routes:

[0015] In 2012, Cheng Pi et al. from Hunan Agricultural University reviewed the synthesis of benzo[a]phenanthridine alkaloids and their derivatives in the journal *Organic Chemistry*. They discussed a palladium-catalyzed aryl coupling route in the C10a-C11a cyclization of the benzo[a]phenanthridine basic skeleton, using palladium acetate as a catalyst to catalyze intramolecular aromatic coupling reactions of bromine- or iodine-substituted aromatic amide intermediates. They pointed out that intramolecular coupling reactions exhibit regioselectivity; different combinations of phosphine ligands / bases (acid-binding agents) may lead to the formation of C10a-C4 coupling products, affecting the yield of the target coupling product.

[0016] Harayama et al. (Chem pharm bull 1996, Synthesis 2001, Heterocycles 2005) used palladium acetate catalyst and screened the optimal system as P(o-Tol)3 / silver carbonate (for the preparation of oxidized sanguisorbin analogue oxidized chelidonine), with the stoichiometric ratio of bromide, palladium acetate catalyst, ligand, and base being 1:0.2:0.4:2, DMF solvent, reaction time 3 h, column chromatography separation, yield and purity unknown.

[0017] Cadler et al. (JOC2014) prepared oxidized sanguinarine using a Hermann-Beller cyclic palladium catalyst / silver carbonate system. Column chromatography separation was required. The stoichiometric ratio of bromide, cyclic palladium catalyst, and silver carbonate was 1:0.1:2. DMF solvent was used, and the reaction was carried out at 160℃ for 22 h. The yield was 90% (column chromatography separation), and the purity was unknown.

[0018] The above-mentioned synthetic method for preparing oxysandroine and its analogues from brominated compounds has the disadvantages of having a palladium catalyst equivalent of more than 10%, requiring the use of expensive base (acid-binding agent) silver carbonate, long reaction time, needing column chromatography separation to obtain high-quality target products, low yield, and being unsuitable for industrial production. Summary of the Invention

[0019] To address the aforementioned technical problems, firstly, this invention provides a method for synthesizing the brominated intermediate of sanguisorbin. Compared with existing synthetic methods, this method avoids the use of difficult-to-prepare starting materials, and features shorter steps, milder and easier-to-operate reaction conditions, lower cost, environmental friendliness, higher yield, and higher product purity. Secondly, this invention further provides an application for preparing sanguisorbin hemisulfate from the aforementioned brominated compound. Compared with existing synthetic methods, this application significantly reduces the amount of palladium catalyst used, avoids the use of silver carbonate as a base (acid-binding agent), and eliminates the need for column chromatography separation. High-purity sanguisorbin hemisulfate can be obtained through conventional extraction, pulping, concentration, and other post-processing operations.

[0020] The specific technical solution of this invention is as follows:

[0021] In a first aspect, the present invention provides a method for synthesizing a brominated derivative of a sanguisorbin intermediate compound, which is obtained by a condensation reaction of compound I and compound II, as shown in the following synthetic route:

[0022]

[0023] As a preferred embodiment, the above-mentioned synthesis method specifically includes: compound II first reacts with thionyl chloride via a chlorination reaction to prepare an acyl chloride, and the obtained acyl chloride then reacts with compound I under alkaline catalytic conditions via a condensation reaction to obtain brominated compound III.

[0024] Preferably, the alkaline catalytic conditions are provided by an organic base and / or an inorganic base; the organic base is selected from one or more of triethylamine, diisopropylamine, and diisopropylethylamine; and the inorganic base is selected from one or more of sodium carbonate, sodium bicarbonate, and sodium hydroxide.

[0025] Preferably, in the chlorination reaction, the equivalence ratio of compound II to thionyl chloride is 1:1-1.5; and in the condensation reaction, the equivalence ratio of compound I, compound II, and the base is 1:1-1.3:1-2.0.

[0026] Preferably, in the chlorination reaction, the reaction solvent is selected from dichloromethane, acetonitrile, or toluene, and the reaction temperature is 40–50°C, preferably 40–45°C; in the condensation reaction, the reaction solvent is selected from dichloromethane, acetonitrile, or toluene, and the reaction temperature is 0–20°C, preferably 0–5°C.

[0027] Preferably, compound I is prepared using piperine as a starting material, and the synthetic route is as follows:

[0028]

[0029] Preferably, compound II is prepared using o-vanillin as the starting material, and the synthetic route is as follows:

[0030]

[0031] Secondly, this invention provides the application of the brominated derivative obtained by the above-mentioned synthetic method in the preparation of sanguisorbin hemisulfate. The brominated derivative is used to prepare sanguisorbin hemisulfate via an intramolecular aromatic coupling reaction and a reduction reaction. The synthetic route is shown below:

[0032]

[0033] Preferably, the intramolecular aromatic coupling reaction is carried out in the presence of a palladium catalyst, a ligand, a base (acid-binding agent), and a phase transfer catalyst.

[0034] Preferably, the palladium catalyst is selected from one or more of palladium acetate, palladium trifluoroacetate, palladium chloride, Pd(dba)2 and Pd(dppf)Cl2.

[0035] Preferably, the ligand is selected from one or more of triphenylphosphine, DPPP, DPPF, BINAP, and P(o-Tol)3.

[0036] Preferably, the alkali is selected from one or more of sodium carbonate, potassium phosphate, and potassium carbonate.

[0037] Preferably, the phase transfer catalyst is selected from one or more of tetrabutylammonium bromide and tetramethylammonium bromide.

[0038] Preferably, the equivalent ratio of the brominated derivative III, palladium catalyst, ligand, phase transfer catalyst and base is 1:0.005-0.02:0.04-0.08:0.05-0.2:1.5-5.0.

[0039] Preferably, the reaction solvent for the intramolecular aromatic coupling reaction is selected from one or more of toluene, NMP, DMF, and DMAC, and the reaction temperature is 120-200℃, more preferably 140-160℃.

[0040] Preferably, the reducing agent in the reduction reaction is selected from one or more of lithium aluminum hydride, red aluminum, DIBAL-H, borane, sodium borohydride, potassium borohydride, and lithium borohydride.

[0041] Preferably, the equivalent ratio of sanguisorbin to reducing agent is 1:1.0-3.0.

[0042] Preferably, the reaction solvent for the reduction reaction is selected from one or more of THF, dioxane, tert-butyl methyl ether, and toluene.

[0043] Preferably, the reaction temperature of the reduction reaction is -30 to 110°C, and more preferably -10 to 40°C.

[0044] Compared with the prior art, the present invention has the following technical effects:

[0045] (1) Compared with existing methods, the method for synthesizing the brominated intermediate of sanguinarine in this invention does not use genotoxic raw materials such as iodomethane, avoids conditions such as ultra-low temperature and column chromatography separation, shortens the reaction time, has strong process operability, and greatly improves labor safety. Furthermore, this invention has the advantages of mild reaction conditions, low production cost, environmental friendliness, high yield, and high product purity.

[0046] (2) The synthetic route for preparing sanguinarine hemisulfate by using brominated derivatives in this invention can significantly reduce the amount of precious metal palladium catalyst used compared with existing methods, and avoids the use of silver carbonate as a base (acid-binding agent). High-purity sanguinarine hemisulfate can be obtained through conventional extraction, pulping, concentration and other post-processing operations without column chromatography separation. Attached Figure Description

[0047] Figure 1 The HPLC chromatogram of the brominated product obtained in step (3.1) of Example 1 is shown below.

[0048] Figure 2 The HPLC chromatogram of oxidized sanguinarine obtained in step (3.2) of Example 1 is shown.

[0049] Figure 3 The HPLC chromatogram of sanguinarine hemisulfate obtained in step (3.2) of Example 1 is shown. Detailed Implementation

[0050] The present invention will be further described below with reference to embodiments.

[0051] General Implementation Examples

[0052] A method for synthesizing a sanguisorbin intermediate bromide and sanguisorbin hemisulfate is shown below:

[0053]

[0054] The specific synthesis method is as follows:

[0055] (1) Preparation of brominated compound III: Compound II is first reacted with thionyl chloride via a chlorination reaction to prepare an acyl chloride. The resulting acyl chloride is then reacted with compound I under alkaline catalytic conditions via a condensation reaction to prepare compound III. The alkaline catalytic conditions are provided by an organic or inorganic base. Further, the organic base is selected from triethylamine, diisopropylamine, diisopropylethylamine, etc.; the inorganic base is selected from sodium carbonate, sodium bicarbonate, sodium hydroxide, etc.; in the chlorination reaction, the equivalence ratio of compound II to thionyl chloride is 1:1-1.5; in the condensation reaction, the equivalence ratio of compound I, compound II, and base is 1:1-1.3:1-2.0; the reaction solvent for the chlorination reaction is selected from dichloromethane, acetonitrile, toluene, etc., and the reaction temperature is 40-50℃, preferably 40-45℃; the reaction solvent for the condensation reaction is selected from dichloromethane, acetonitrile, toluene, etc., and the reaction temperature is 0-20℃, preferably 0-5℃.

[0056] (2) Preparation of oxidized sanguinarine: Oxidized sanguinarine was prepared by intramolecular aromatic coupling reaction of brominated derivative III via a palladium catalyst. The palladium catalyst was selected from palladium acetate, palladium trifluoroacetate, palladium chloride, Pd(dba)2, Pd(dppf)Cl2, etc.; the ligand was selected from triphenylphosphine, DPPP, DPPF, BINAP, P(o-Tol)3, etc.; the base / acid-binding agent was selected from sodium carbonate, potassium phosphate, potassium carbonate, etc.; the equivalence ratio of brominated derivative III, palladium catalyst, ligand, phase transfer catalyst, and base was 1:0.005-0.02:0.04-0.08:0.05-0.2:1.5-5.0; the reaction solvent was selected from toluene, NMP, DMF, DMAC, etc.; the reaction temperature was 120-200℃, preferably 140-160℃; the phase transfer catalyst was selected from tetrabutylammonium bromide, tetramethylammonium bromide, etc.

[0057] (3) Preparation of sanguinarine hemisulfate: Sanguinarine hemisulfate is prepared by reducing oxidized sanguinarine. The reducing agent is selected from lithium aluminum hydride, red aluminum, DIBAL-H, borane, sodium borohydride, potassium borohydride, lithium borohydride, etc. The equivalence ratio of oxidized sanguinarine to reducing agent is 1:1.0-3.0. The reaction solvent is selected from THF, dioxane, tert-butyl methyl ether, toluene, etc. The reaction temperature is -30 to 110℃, preferably -10 to 40℃.

[0058] Compound I was prepared using piperine as a starting material, and the synthetic route is as follows:

[0059]

[0060] The synthesis of compound I includes the following steps:

[0061] (1) Starting with piperine rings, compound B was obtained by FC acylation, followed by catalytic hydrogenation and hydrolysis to obtain compound C, and then compound D was prepared by cyclization reaction. Specifically:

[0062] FC acylation is carried out in a reaction solvent A (preferably dichloromethane, nitromethane, nitrobenzene, etc.) with a piperon ring and an acylation reagent (preferably butyric anhydride, succinic anhydride monoethyl ester chloride, succinic anhydride monomethyl ester chloride, etc.) at a reaction temperature of 0-40°C (preferably 10-30°C). The equivalent ratio of the piperon ring, the acylation reagent, and catalyst A is 1:1-1.5:1-1.5.

[0063] Catalytic hydrogenation to compound B and catalyst B (Pd / C) is carried out in reaction solvent B (preferably methanol, ethanol, isopropanol, etc.) at a reaction temperature of 50–80°C (preferably 60–80°C).

[0064] The cyclization reaction is carried out by compound C with an acidic catalyst C (preferably polyphosphoric acid, sulfuric acid, methanesulfonic acid, ferric chloride, aluminum trichloride, tin tetrachloride, acetic anhydride, boron trifluoride ether, trifluoroacetic acid, trifluoroacetic anhydride, and PPE, etc.) in a reaction solvent C (preferably dichloromethane, toluene, and chlorobenzene, etc.) at a reaction temperature of 20-110°C (preferably 20-40°C). The equivalence ratio of compound C to each acidic catalyst C is 1:0.5-1.5.

[0065] (2) Compound D undergoes a condensation reaction to give intermediate compound E, which is then subjected to an aromatization reaction to give compound I. Specifically:

[0066] The condensation reaction is carried out by compound D and methylamine in reaction solvent D (preferably methanol, ethanol, isopropanol, etc.) at a reaction temperature of 40-80℃ (preferably 50-80℃), wherein the equivalent ratio of compound D to methylamine is 1:2.0-10.0.

[0067] The aromatization reaction is carried out with compound E and catalyst E (Pd / C) in reaction solvent E (preferably mesitylene, xylene, o-dichlorobenzene, m-dichlorobenzene, etc.) at a reaction temperature of 110-280℃ (preferably 150-250℃). The equivalent ratio of compound E, hydrogen acceptor E, and pH adjusting agent E is 1:0.5-2.0:0.5-2.0.

[0068] The method for synthesizing compound I of the present invention has the following advantages compared with conventional methods:

[0069] (1) In this invention, piperidine is used as a substitute for piperaldehyde, a controlled precursor chemical, as the starting material for the synthesis of two aromatic benzo[c]phenanthridine alkaloid intermediates (6,7-methylenedioxy-1-naphthylamine and N-methyl-6,7-(methylenedioxy)-1-naphthylamine). This invention has the advantages of readily available raw materials and low cost.

[0070] (2) The present invention uses pepper ring as the starting material and synthesizes α-tetrahydronaphthone intermediate compound through FC acylation, catalytic hydrogenation, hydrolysis and cyclization reaction. The cyclization reaction step is more mild in temperature than the traditional route, and the acid catalysts are all in equivalent quantity, resulting in less waste.

[0071] (3) In this invention, after obtaining compound D, compound I is further obtained through condensation and aromatization reactions. Compared with the prior art, it no longer requires the intermediate of 6,7-methylenedioxy-1-naphthylamine (which needs to be synthesized first, and then compound I is synthesized through multiple steps). The reaction steps are reduced by at least 2 steps, and the overall yield is improved. In addition, heterogeneous noble metal catalytic dehydrogenation conditions are used in the aromatization reaction. Under the combined action of hydrogen acceptor reagent and pH adjuster, the aromatization of tetrahydronaphthone imine substrate is successfully achieved, the product yield is further improved, and impurities are effectively controlled.

[0072] Compound II was prepared from o-vanillin using the following synthetic route:

[0073]

[0074] The synthesis of compound II includes the following steps:

[0075] Starting from o-vanillin, compound b was obtained through acetyl protection, compound c was obtained through bromination, compound d was obtained through deprotection and demethylation, compound e was obtained through cyclization, and finally compound II, a bromopiperidine ring carboxylic acid compound, was obtained through Pinnick oxidation. Specifically:

[0076] Acetyl protection is achieved by reacting o-vanillin with acetic anhydride and organic base a (preferably pyridine, triethylamine, diisopropylamine, etc.) in reaction solvent a (preferably the same organic base as organic base a, dichloromethane, toluene, etc.) at a reaction temperature of 0-40°C (preferably 10-30°C). The equivalent ratio of o-vanillin to acetic anhydride is 1:1-1.5.

[0077] The bromination reaction is carried out by compound b and bromine in catalyst b (preferably KBr) in reaction solvent b (preferably water, acetic acid, chloroform, etc.) at a reaction temperature of 10-40℃ (preferably 25-30℃). The equivalent ratio of compound b, bromine, and catalyst b is 1:1.1-1.3:3.0-3.5.

[0078] The deprotection and demethylation reactions are carried out by reacting compound c with Lewis acid catalyst c (preferably polyphosphoric acid, sulfuric acid, methanesulfonic acid, ferric chloride, aluminum trichloride, tin tetrachloride, acetic anhydride, boron trifluoride diethyl ether, trifluoroacetic acid, trifluoroacetic anhydride, and PPE, etc.) in reaction solvent c (preferably dichloroethane, toluene, and chlorobenzene, etc.) at a reaction temperature of 50-100°C (preferably 50-70°C). The equivalence ratio of compound c to Lewis acid catalyst c is 1:2.5-4.0.

[0079] The cyclization reaction is carried out in a reaction solvent d (preferably DMF, NMP, DMAC, etc.) with dibromomethane and catalyst d (preferably KF, potassium carbonate, CsF, etc.) at a reaction temperature of 100-160℃ (preferably 120-140℃). The equivalence ratio of compound d, dibromomethane, and catalyst d is 1:1.0-1.5:3.0-7.0.

[0080] The Pinnick oxidation reaction is carried out by compound e, oxidant sodium chlorite, buffer salt potassium dihydrogen phosphate or sodium dihydrogen phosphate, and hypochlorous acid scavenger e (preferably DMSO, H2O2, etc.) in reaction solvent e (preferably acetonitrile, water, tert-butanol, etc.) at a reaction temperature of 10-50°C (preferably 20-30°C). The equivalent ratio of compound e, oxidant sodium chlorite, buffer salt potassium dihydrogen phosphate or sodium dihydrogen phosphate, and hypochlorous acid scavenger e is 1:1.0-1.5:0.2-0.5:2.0-4.0.

[0081] Pinnick oxidation selectively oxidizes aldehydes to their corresponding carboxylic acids. This invention has found that Pinnick oxidation also exhibits good reactivity with sterically hindered substrates. When selecting the type of hypochlorous acid scavenger, the reactivity of the compound, side reactions, and its impact on the target reaction should be considered. Experiments in this invention have shown that, compared to other hypochlorous acid scavengers, only DMSO or hydrogen peroxide are effective as sodium hypochlorite scavengers in the reaction system of this invention. Furthermore, the amounts of NaH₂PO₄ and sodium chlorite also affect the purity and yield of the product. Sodium chlorite needs to be added in excess because it is susceptible to damage under light or the presence of impurities (such as Fe). 2+ and Fe 3+ It will decompose; furthermore, the present invention also found that sodium chlorite must be dissolved in water or in a buffer solution when added during the reaction process, otherwise the purity and yield of the product will not be ideal.

[0082] The method for synthesizing compound II of the present invention has the following advantages compared with conventional methods:

[0083] (1) This invention uses 6-bromopiperaldehyde intermediate instead of bromopiperidine ring intermediate, and does not require low-temperature lithiation reaction with active reagent LDA, which greatly improves the safety of operation and is suitable for industrial scale-up production.

[0084] (2) In the deprotection and demethylation steps of the present invention (from compound c to compound d), the deprotection and demethylation reactions are carried out in a one-pot process, avoiding the use of reagents such as boron tribromide; in the cyclization reaction, potassium fluoride is used instead of potassium carbonate or cesium carbonate, which not only makes the raw materials readily available, but also greatly increases the yield to more than 90%; in the final step of aldehyde to acid oxidation, Pinnick oxidation is used, which uses economical and environmentally friendly oxidizing reagents, with a yield of more than 70%, while avoiding the use of expensive reagents such as silver nitrate and silver oxide in the silver mirror reaction, eliminating the need for additional silver salt separation and recovery operations, and avoiding the use of oxidizing reagents such as potassium permanganate, which not only provides mild conditions, but also eliminates the risk of heavy metal pollution.

[0085] (3) The synthetic route of the present invention has the advantages of readily available raw materials, short steps, mild reaction conditions, low production cost, environmental protection, high yield and high purity. Specific Implementation

[0087] Example 1

[0088] (1) Synthesis of Compound I

[0089] (1.1) Compound B was prepared by DF-C acylation of the piperonyl compound: 100g of piperonyl, 500mL of dichloromethane, and 148g of monoethyl succinate chloride were added to a 2L four-necked flask. The temperature was lowered to 10℃, and 146g of anhydrous ferric chloride was added in batches. GC was monitored until the reaction of the starting material was completed. 110g of hydrochloric acid aqueous solution was added to the reaction flask, and the mixture was stirred at low temperature for 1h. Then 1L of water was added, and the temperature was raised to 25℃ and stirred for 2h. The mixture was separated into layers. The aqueous phase was extracted with dichloromethane, and the organic phases were combined. After vacuum distillation, 210.8g of brown viscous liquid was obtained. The GC purity was 87.96%, and the crude yield was 102.8%. This liquid was directly used in the next step of the reaction.

[0090] Catalytic hydrogenation and hydrolysis were used to prepare compound C: 210.8 g of the prepared compound B, 1000 ml of ethanol, and 10.5 g of 5% Pd / C were added to a 2 L autoclave. The autoclave was closed, and hydrogen gas was purged five times. Hydrogen gas was then introduced again to 1.2 MPa, and the mixture was heated to 75 °C and kept at that temperature for 24 h. GC was used to monitor the reaction until the reactants were completely reacted. The catalyst was filtered, and some ethanol was removed by rotary evaporation of the filtrate. 500 mL of water was added to the reaction mixture, and 300 g of 20% sodium hydroxide aqueous solution was added dropwise. The mixture was heated to 50 °C and stirred for 2 h. GC was used to monitor the hydrolysis until it was complete (from Et to H). Most of the ethanol was removed by vacuum distillation, and the remaining aqueous phase was extracted with dichloromethane. Hydrochloric acid was added dropwise to the aqueous phase under ice water to adjust the pH to about 1, resulting in the precipitation of a large amount of solid. Filtering yielded 154 g of compound C with a GC purity of 99.39%. The overall yield of the first and second steps was 90.3%.

[0091] Preparation of compound D by cyclization reaction: 500 g of compound C and 2500 mL of dichloromethane were added to a 5 L four-necked flask. 356 g of boron trifluoride diethyl ether solution was added dropwise, followed by 343 g of acetic anhydride. After the addition was complete, the mixture was stirred at room temperature for 2 h. GC was monitored until the starting material was completely converted. 1000 mL of water was added, and stirring continued for 5 h. The mixture was separated into layers. The organic layer was washed with water and separated again. The concentrated organic layer was poured into 2.5 L of water and stirred for 1 h. After filtration and drying, 420 g of compound D was obtained. The GC purity was 99.23%, and the yield was 91.95%. Compound D was also prepared from the piperine ring, with a combined yield of 83%.

[0092] (1.2) Synthesis of compound I from compound D

[0093] Preparation of compound E by condensation reaction: 10g of crude compound D and 21.8g of 30% methylamine methanol solution were added to a thick-walled pressure-resistant bottle. After sealing, the bottle was placed in an oil bath, heated to 50℃, and stirred for 16h. The temperature was then lowered to -10℃ and stirred for 3h. The mixture was filtered, and the filter cake was washed twice with 15ml of methanol. The mother liquor and methanol concentrate were recycled (the reaction can be repeated by adding new compound D and methylamine methanol solution). 7.3g of solid was dried, with a GC purity of 94.20% and a yield of 68.3% (the mother liquor was recycled once, and the total yield was >88%).

[0094] Aromatization preparation of compound I: 1 g of 5% Pd / C, 4.7 g of naphthalene, 6 g of sodium carbonate, and 150 ml of mesitylene were added to a 500 mL four-necked flask. The mixture was heated to 150 °C and stirred. 15 g of a mesitylene solution of crude compound E was slowly added. The reaction was carried out at 150 °C for 5 h. The mixture was then cooled, filtered, and the filtrate was transferred to a 500 mL four-necked flask. 100 ml of 10% sulfuric acid aqueous solution was added dropwise. The mixture was heated to 50 °C and stirred for 1 h. The aqueous phases were separated and combined. The pH of the aqueous phase was adjusted to 11-12, and a solid precipitated. The solid was extracted with dichloromethane. The organic phases were combined and rotary evaporated to obtain 10.4 g of a brown solid with a purity of 96.88% and a yield of 70%.

[0095] (2) Synthesis of Compound II

[0096] (2.1) Preparation of compound d

[0097]

[0098] Acetyl protection: 265 mL of pyridine, 500 g of o-vanillin, and 340 g of acetic anhydride were added to a reaction flask. The reaction was carried out at 25 °C for 3 h. HPLC showed no residual starting material. The mixture was directly filtered, and 400 mL of HCl solution was added to the mother liquor. The mixture was filtered again, and the filter cakes were combined and dried to obtain 595 g of white solid compound b. The HPLC purity was 99.63%, and the yield was 93.2%.

[0099] Bromination reaction: 500 mL of H2O and 98 g of KBr were added to the reaction flask and stirred to dissolve. 49.4 g of bromine was added and stirred for 10 min to dissolve. 50 g of b was added at room temperature. There was no obvious temperature rise. The reaction was carried out at 25 °C for 8 h. The product was directly filtered and dried to obtain 68.2 g of orange solid powder compound c. The HPLC purity was 97.60% and the yield was 97.0%.

[0100] Deprotection and demethylation: In a reaction flask, 50g of compound c and 300mL of dichloroethane were added sequentially and stirred until dissolved. 61g of AlCl3 was added in portions, maintaining a temperature T < 35℃. The mixture was stirred at room temperature for 1 hour until the system turned dark green. The temperature was then raised to 70℃ and reacted for 30 hours. For direct post-treatment, 200mL of water was added dropwise to the reaction system, maintaining a temperature T < 35℃. The mixture was concentrated under vacuum to remove dichloroethane. 500mL of ethyl acetate was added, and the mixture was filtered and separated into layers. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were refluxed with activated carbon for decolorization. The mixture was filtered, concentrated to dry vacuum, and dried to obtain 38.4g of a yellow-green solid compound d, with an HPLC purity of 95.12% and a yield of 96.6%.

[0101] (2.2) Preparation of compound e

[0102]

[0103] Cyclization reaction: 60 g of compound d and 350 mL of DMF were added sequentially to a reaction flask and stirred until dissolved. Then, 80.4 g of KF and 62.6 g of dibromomethane were added, and the mixture was heated to 130 °C and reacted for 6 h. HPLC monitoring was maintained until no starting material remained. Direct post-processing was performed: 1 L of water was added dropwise to the reaction system, and the mixture was filtered and dried to obtain 59.8 g of black solid compound e, with an HPLC purity of 96.89% and a yield of 94.4%.

[0104] (2.3) Preparation of compound II (bromopiperidine carboxylic acid)

[0105]

[0106] Oxidation reaction: In a reaction flask, 50g of compound e, 150mL of acetonitrile, 150mL of H2O, 34.1g of DMSO, and 7.8g of NaH2PO4 were added sequentially with mechanical stirring. The flask was placed in an ice-water bath, and NaClO2 aqueous solution (32.2g of 80% sodium chlorite added to 500mL of water) was added dropwise, maintaining a temperature of T < 25℃. After the addition was complete, the reaction was carried out at 20℃ for 5h, and HPLC monitoring was performed until no raw material remained. Direct post-processing: 50mL of 10% dilute hydrochloric acid was added, and the mixture was stirred for 1h. 400mL of ethyl acetate was added, and the mixture was filtered and separated. The aqueous layer was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, decolorized with activated carbon, and concentrated to obtain a deep yellow solid, compound II, 39.6g, with an HPLC purity of 96.91% and a yield of 74.0%.

[0107] (3) Synthesis of sanguinarine hemisulfate

[0108]

[0109] (3.1) Preparation of brominated compound III: Compound II (5 g, 1.25 eq) and 20 mL of dichloromethane were added to reactor 1, followed by the dropwise addition of sulfoxide (2.9 g, 1.5 eq). The mixture was heated to reflux and the reaction was monitored by TLC until no raw material remained. The solvent and excess sulfoxide were removed by concentration under reduced pressure, and the mixture was diluted with 20 mL of dichloromethane. Compound I (3.28 g, 1 eq), 20 mL of dichloromethane, and triethylamine (2.48 g, 1.5 eq) were added to reactor 2. The reaction mixture from reactor 1 was added dropwise to reactor 2 at 10 °C, and the mixture was allowed to rise naturally to room temperature. The reaction was monitored by TLC until no raw material remained. 5% H2SO4 was added for extraction and separation. The organic layer was washed twice with water, and the mixture was decolorized and concentrated to obtain a white solid brominated compound III (5.2 g, as shown in the figure). Figure 1 As shown, the HPLC purity was 99.74%, and the yield was 74.5%.

[0110] (3.2) Preparation of oxidized sanguinarine: 40 mL of NMP, bromide III (2 g, 1 eq), palladium acetate (0.0105 g, 0.01 eq), P(Tol)3 (0.0879 g, 0.06 eq), and tetrabutylammonium bromide (0.1552 g, 0.1 eq) were added to a reactor and stirred at 25 °C for 1 h. Potassium phosphate (2.97 g, 3 eq) was added, and the reaction was continued at 80 °C for 1 h. TLC was monitored until no raw material remained. The mixture was cooled to room temperature, 20 mL of water was added, and the mixture was stirred for 2 h. The mixture was filtered, and the filter cake was washed with 20 mL of ethanol and dried under vacuum at 50 °C to obtain 1.46 g of a pale yellow solid powder (1.52 g, as shown in the figure). Figure 2 As shown, the HPLC purity was 99.92%, and the yield was 93.1%.

[0111] (3.3) Preparation of sanguinarine hemisulfate: In reactor 1, oxidized sanguinarine (10 g, 1 eq) and THF (50 mL) were added under nitrogen protection. Lithium aluminum hydride (1.64 g, 1.5 eq) was added in portions at 0 °C, and the reaction was allowed to proceed naturally to room temperature. TLC was monitored until no raw material remained. Water (10 mL) was slowly added, and ethyl acetate (50 mL) was used for extraction three times. The organic layers were combined. The organic layer was placed in reactor 2, and 30% sulfuric acid (56.4 g, 6 eq) was added dropwise. 80 mL of ethanol was added, and the mixture was stirred for 2 h. After filtration, the filter cake was washed with 20 mL of ethanol and dried under vacuum at 50 °C to obtain an orange-yellow solid powder (10.4 g, as shown in the image). Figure 3 As shown, the HPLC purity was 99.18%, and the yield was 84.1%.

[0112] Example 2

[0113] (1) Synthesis of compound I: Same as in Example 1.

[0114] (2) Synthesis of compound II: Same as in Example 1.

[0115] (3) Synthesis of sanguinarine hemisulfate

[0116]

[0117] (3.1) Preparation of brominated compound III: Compound II (4.8 g, 1.2 eq) and 20 mL of dichloromethane were added to reactor 1, and sulfoxide (2.91 g, 1.5 eq) was added dropwise. The reaction was heated to 40 °C and monitored by TLC until no raw material remained. The solvent and excess sulfoxide were removed by concentration under reduced pressure and diluted with 20 mL of dichloromethane. Compound I (3.28 g, 1 eq) and 20 mL of dichloromethane and diisopropylamine (2.15 g, 1.3 eq) were added to reactor 2. The reaction solution in reactor 1 was added dropwise to reactor 2 at 5 °C and reacted at 10 °C. The reaction was monitored by TLC until no raw material remained. 5% H2SO4 was added for extraction and separation. The organic layer was washed twice with water and decolorized and concentrated to obtain a white solid brominated compound III (4.86 g, HPLC purity 98.21%, yield 69.6%).

[0118] (3.2) Preparation of oxidized sanguinarine: 40 mL of L-MAC, bromide III (2 g, 1 eq), palladium chloride (0.0167 g, 0.02 eq), BINAP (0.234 g, 0.08 eq), and tetrabutylammonium bromide (0.2343 g, 0.15 eq) were added to a reactor and stirred at 25 °C for 1 h. Potassium carbonate (3.248 g, 5 eq) was added and the reaction was carried out at 100 °C for 1 h. The reaction was monitored by TLC until no raw material remained. The mixture was cooled to room temperature and 20 mL of water was added. The mixture was stirred for 2 h and filtered. The filter cake was washed with 20 mL of ethanol and dried under vacuum at 50 °C to obtain a pale yellow solid powder (1.55 g, HPLC purity 99.78%, yield 95.0%).

[0119] (3.3) Preparation of sanguinarine hemisulfate: Oxysanguinarine (10 g, 1 eq) and toluene (80 mL) were added to reactor 1 under nitrogen protection. DIBAL-H (8.2 g, 2.0 eq) was added in portions at room temperature and the mixture was refluxed. TLC was monitored until no raw material remained. Water (10 mL) was slowly added and ethyl acetate (50 mL) was extracted three times. The organic layers were combined. The organic layer was placed in reactor 2, and 30% sulfuric acid (56.4 g, 6 eq) was added dropwise. 80 mL of ethanol was added, and the mixture was stirred for 2 h. The mixture was filtered, and the filter cake was washed with 20 mL of ethanol and dried under vacuum at 50 °C to obtain an orange-yellow solid powder (9.8 g, HPLC purity 98.43%, yield 79.2%).

[0120] Example 3

[0121] (1) Synthesis of compound I: Same as in Example 1.

[0122] (2) Synthesis of compound II: Same as in Example 1.

[0123] (3) Synthesis of sanguinarine hemisulfate

[0124]

[0125] (3.1) Preparation of brominated compound III: Compound II (4.39 g, 1.1 eq) and 20 mL toluene were added to reactor 1, and thionyl chloride (3.19 g, 1.64 eq) was added dropwise. The temperature was raised to 50 °C and the reaction was monitored by TLC until no raw material remained. The solvent and excess thionyl chloride were removed by concentration under reduced pressure and diluted with 20 mL toluene. Compound I (3.28 g, 1 eq) and 20 mL toluene and sodium bicarbonate (2.74 g, 2.0 eq) were added to reactor 2. The reaction solution in reactor 1 was added dropwise to reactor 2 at 10 °C and the temperature was raised to 20 °C by natural temperature monitoring. The reaction was monitored by TLC until no raw material remained. 5% H2SO4 was added for extraction and separation. The organic layer was washed twice with water and decolorized and concentrated to obtain a white solid brominated compound III (4.98 g, HPLC purity 99.06%, yield 71.4%).

[0126] (3.2) Preparation of oxidized sanguinarine: 20 mL of NMP, bromide III (2 g, 1 eq), palladium trifluoroacetate (0.025 g, 0.016 eq), DPPP (0.078 g, 0.04 eq), and tetramethylammonium bromide (0.116 g, 0.16 eq) were added to a reactor and stirred at 25 °C for 1 h. Potassium phosphate (1.5 g, 1.5 eq) was added and the reaction was carried out at 80 °C for 1 h. The reaction was monitored by TLC until no raw material remained. The mixture was cooled to room temperature and 20 mL of water was added. The mixture was stirred for 2 h and filtered. The filter cake was washed with 20 mL of ethanol and dried under vacuum at 50 °C to obtain a pale yellow solid powder (1.49 g, HPLC purity 99.66%, yield 91.3%).

[0127] (3.3) Preparation of sanguinarine hemisulfate: In reactor 1, oxidized sanguinarine (10 g, 1 eq) and dioxane (40 mL) were added under nitrogen protection. Lithium aluminum hydride (3.28 g, 3 eq) was added in batches at 0 °C. The mixture was allowed to naturally warm to room temperature, and the reaction was monitored by TLC until no raw material remained. Water (10 mL) was slowly added, and the mixture was extracted three times with ethyl acetate (50 mL). The organic layers were combined. The organic layer was placed in reactor 2, and 30% sulfuric acid (56.4 g, 6 eq) was added dropwise. 80 mL of ethanol was added, and the mixture was stirred for 2 h. The mixture was filtered, and the filter cake was washed with 20 mL of ethanol and dried under vacuum at 50 °C to obtain an orange-yellow solid powder (10.1 g, HPLC purity 98.74%, yield 81.7%).

[0128] Data Comparison:

[0129] The differences in reaction conditions for each step in Examples 1-3, as well as the product purity and yield data, are shown in the table below:

[0130]

[0131]

[0132] Unless otherwise specified, the raw materials and equipment used in this invention are all commonly used in the field; unless otherwise specified, the methods used in this invention are all conventional methods in the field.

[0133] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Any simple modifications, alterations, and equivalent transformations made to the above embodiments based on the technical essence of the present invention shall still fall within the protection scope of the present invention.

Claims

1. A method for synthesizing sanguinarine hemisulfate, characterized in that: The synthetic route for preparing oxidized sanguinarine via intramolecular aromatic coupling reaction in the presence of palladium catalyst, ligand, base, and phase transfer catalyst, followed by reduction reaction, is as follows: In intramolecular aromatic coupling reactions: The palladium catalyst, ligand, base, phase transfer catalyst, and solvent are selected from one of the following combinations: Palladium acetate, P(o-Tol)3, potassium phosphate, tetrabutylammonium bromide and NMP; Palladium chloride, BINAP, potassium carbonate, tetrabutylammonium bromide, and DMAC; Palladium trifluoroacetate, DPPP, potassium phosphate, tetramethylammonium bromide, and NMP; The equivalence ratio of bromide III, palladium catalyst, ligand, phase transfer catalyst, and base is 1:0.005-0.02:0.04-0.08:0.05-0.2:1.5-5.0; bromide III is synthesized from compound I and compound II via a condensation reaction, and the synthetic route is as follows:

2. The synthesis method according to claim 1, characterized in that: Compound II is first reacted with thionyl chloride via a chlorination reaction to prepare an acyl chloride. The resulting acyl chloride is then reacted with compound I under alkaline catalytic conditions via a condensation reaction to obtain brominated compound III.

3. The synthesis method as described in claim 2, characterized in that: The alkaline catalytic conditions are provided by organic and / or inorganic bases; The organic base is selected from one or more of triethylamine, diisopropylamine, and diisopropylethylamine; The inorganic base is selected from one or more of sodium carbonate, sodium bicarbonate, and sodium hydroxide; In the chlorination reaction, the equivalence ratio of compound II to thionyl chloride is 1:1-1.5; in the condensation reaction, the equivalence ratio of compound I, compound II and the base is 1:1-1.3:1-2.

0.

4. The synthesis method according to claim 1 or 2, characterized in that: In the chlorination reaction, the reaction solvent is selected from dichloromethane, acetonitrile, or toluene; the reaction temperature is 40–50 °C.

5. The synthesis method according to claim 1 or 2, characterized in that: In the condensation reaction, the reaction solvent is selected from dichloromethane, acetonitrile, or toluene, and the reaction temperature is 0–20°C.

6. The synthesis method according to claim 1 or 2, characterized in that: Compound I was prepared using piperine as a starting material, and the synthetic route is as follows:

7. The synthesis method according to claim 1 or 2, characterized in that: Compound II was prepared from o-vanillin using the following synthetic route:

8. The synthesis method according to claim 1, characterized in that: The reducing agent in the reduction reaction is selected from one or more of lithium aluminum hydride, red aluminum, DIBAL-H, borane, sodium borohydride, potassium borohydride, and lithium borohydride.

9. The synthesis method according to claim 1, characterized in that: The equivalent ratio of sanguinarine to reducing agent is 1:1.0-3.

0.

10. The synthesis method according to claim 1, characterized in that: The reaction solvent for the reduction reaction is selected from one or more of THF, dioxane, tert-butyl methyl ether, and toluene.

11. The synthesis method according to claim 1, characterized in that: The reduction reaction is carried out at a temperature of -30 to 110°C.

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