A method for synthesizing halofuginone

Abstract

The application discloses a synthesis method of chlorinated nitidine, and belongs to the technical field of organic synthesis. The method is characterized in that 3,4-dimethoxyphenylacetamide is used as a starting material, and the starting material is sequentially subjected to acid catalysis cyclization, Vilsmeier formylation, Suzuki coupling, Wittig reaction, acid catalysis cyclization and quaternary ammonium ion exchange, so that high-purity chlorinated nitidine is prepared. The synthesis route is simple, the reaction condition is mild, the operation is simple, the single-step yield is high, the total yield reaches 45%-55%, the purity of the final product is greater than or equal to 99%, and the defects of the prior art, such as many side reactions, low yield and difficulty in industrial amplification, are effectively overcome.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for synthesizing chlorinated thorn alkali. Background Technology

[0002] Benzo[c]phenanthridine alkaloids are an important class of isoquinoline alkaloids. More than eighty compounds with this core skeleton have been identified and isolated from plants in the Rutaceae, Papaveraceae, and Corydalis families. Among them, thorn salts and their structural analogs have long been a research hotspot due to their rich and important biological activities.

[0003] The structure of nephrite chloride (with chloride ion as counter anion) is shown below: .

[0004] Zanthoxylum chloride has been shown to possess a variety of biological activities, including yeast respiration inhibition, cardiovascular activity, and anti-inflammatory and analgesic activities. Meanwhile, Zanthoxylum chloride and its derivatives are considered to be highly promising anti-tumor drug candidates due to their potent inhibitory effect on DNA topoisomerase I. This mechanism of action has also enabled it to exhibit significant anti-leukemia activity in L-1210 and P-388 leukemia cell models.

[0005] Since the yield of alkaloids naturally isolated from Zanthoxylum plants is only 0.003%-0.07%, this extremely low extraction efficiency greatly limits its subsequent research, development and application. Therefore, synthetic chemists have developed many methods to synthesize it.

[0006] The core methods for synthesizing thorn bases and their analogues all revolve around the construction of the benzo[c]phenanthrene core and the modification of characteristic functional groups. The mainstream strategies focus on catalytic coupling, cyclization, condensation, and addition reactions, encompassing metal catalytic systems such as palladium, nickel, ruthenium, and iridium, as well as metal-free strategies such as photocatalysis and oxidative cyclization. Specific core methods include: palladium-catalyzed coupling reaction of azabicyclic olefins with o-iodobenzene, followed by tandem cyclization; domino arylation of aryl trifluoromethanesulfonates; imine-toluene condensation reaction; cycloaddition reaction of lithium-lithiated toluene-benzonitrile; and the reaction of high-phthalate esters with imine-toluene condensation. Condensation reactions of amines; ruthenium-catalyzed CH-activated intermolecular cyclization of aryl Weinlebenzene with 7-azabenzonorbornene; nickel-catalyzed cyclization of o-bromobenzamide with alkynes; tandem reactions of Suzuki coupling and Bischler-Napieralski cyclization; nickel- or palladium-catalyzed cyclization of imines with alkynes; palladium-catalyzed cyclization of azabenzonorbornene with substituted phenylboronic acid after coupling; cyclization reactions mediated by high-pressure mercury lamp catalysis or high-valent iodine oxidation; coupling reactions of isoquinoline ring compounds formed by cross-coupling catalyzed by iridium with polysubstituted cyclic boric acids, etc.

[0007] These methods suffer from cumbersome operation, numerous side reactions, and low yields, making them unsuitable for industrial scale-up. Therefore, developing a novel synthetic method for chlorinated thorn alkali that is simple to operate, operates under mild conditions, yields high quantities, and is suitable for industrial production remains a pressing technical problem to be solved in this field. Summary of the Invention

[0008] The purpose of this invention is to provide: A method for synthesizing chlorobenzan alkali, and related technologies, to achieve the technical problems of simple steps, easy control of reaction conditions, and high overall yield in the synthesis of chlorobenzan alkali, or a combination thereof.

[0009] Terminology Explanation: Unless otherwise defined, all technical terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this subject matter pertains. Unless otherwise stated, all patents, patent inventions, and disclosures cited throughout this document are incorporated herein by reference in their entirety. Where multiple definitions exist for terms herein, the definitions provided in this chapter shall prevail.

[0010] It should be understood that the above brief description and the following detailed description are exemplary and for illustrative purposes only, and do not limit the subject matter of the invention in any way. In this invention, the singular is used in conjunction with the plural unless otherwise specifically stated. It should also be noted that, unless otherwise stated, the use of “or” or “or” means “and / or”. Furthermore, the use of the term “comprising” and other forms such as “including,” “containing,” and “contains” are not limiting.

[0011] Unless otherwise stated, conventional methods within the scope of the art, such as stirring, filtering, washing, extraction, drying, and concentration, shall be used.

[0012] Unless specifically defined herein, the use of all commercially available products herein employs standard techniques. For example, it may be carried out using the manufacturer's instructions for use with the kit, or in accordance with methods known in the art or the description of this invention. The techniques and methods described herein can generally be implemented according to conventional methods well known in the art, based on the descriptions in the various summary and more specific documents cited and discussed in this specification.

[0013] The terms “optional / arbitrary” or “optionally / arbitrarily” mean that the event or situation described below may or may not occur, including both the occurrence and non-occurrence of the event or situation.

[0014] This invention provides a method for synthesizing chlorinated thorn alkali, comprising the following steps: (1) 3,4-Dimethoxyphenylacetamide was reacted with hexamethylenetetramine in an acid solvent system to obtain 6,7-dimethoxy-3,4-dihydroisoquinoline-1(2H)-one; (2) 6,7-Dimethoxy-3,4-dihydroisoquinoline-1(2H)-one was dissolved in solvent A, mixed with Vilsmeier reagent, and reacted to give 2-chloro-3-formyl-6,7-dimethoxyisoquinoline; (3) In the presence of palladium catalyst and base a, 2-chloro-3-formyl-6,7-dimethoxyisoquinoline and 3,4-methylenedioxyphenylboronic acid were reacted in solvent B to give 2-(benzo[d][1,3]dioxacyclopenten-5-yl)-3-formyl-6,7-dimethoxyisoquinoline; (4) In the presence of base b, 2-(benzo[d][1,3]dioxacyclopenten-5-yl)-3-formyl-6,7-dimethoxyisoquinoline is reacted with (methoxymethyl)triphenylphosphonium chloride to give 2-(benzo[d][1,3]dioxacyclopenten-5-yl)-3-(2-methoxyvinyl)-6,7-dimethoxyisoquinoline; (5) 2-(benzo[d][1,3]dioxacyclopenten-5-yl)-3-(2-methoxyvinyl)-6,7-dimethoxyisoquinoline undergoes a cyclization reaction under acid catalysis to give 2,3-dimethoxy-8,9-methylenedioxybenzo[c]phenanthridine; (6) 2,3-Dimethoxy-8,9-methylenedioxybenzo[c]phenanthridine is reacted with methyl trifluoromethanesulfonate in an organic solvent to generate neem base trifluoromethanesulfonate, which is then subjected to base C treatment and hydrochloric acid ion exchange to obtain neem base chloride.

[0015] The synthetic route is shown below: .

[0016] in, Formula I: 3,4-Dimethoxyphenylacetamide.

[0017] Formula II: 6,7-Dimethoxy-3,4-dihydroisoquinoline-1(2H)-one.

[0018] Formula III: 2-chloro-3-formyl-6,7-dimethoxyisoquinoline.

[0019] Formula IV: 2-(benzo[d][1,3]dioxacyclopenten-5-yl)-3-formyl-6,7-dimethoxyisoquinoline.

[0020] Formula V: 2-(benzo[d][1,3]dioxacyclopenten-5-yl)-3-(2-methoxyvinyl)-6,7-dimethoxyisoquinoline (a mixture of E / Z isomers).

[0021] Formula VI: 2,3-Dimethoxy-8,9-methylenedioxybenzo[c]phenanthridine.

[0022] Formula VII: Chlorinated thorn base, namely 5-methyl-2,3-dimethoxy-8,9-methylenedioxybenzo[c]phenanthridine-5-onium chloride.

[0023] In step (1), the acid solvent system is a mixed solvent of glacial acetic acid and trifluoroacetic acid, wherein the volume ratio of glacial acetic acid to trifluoroacetic acid is 2-6:1, preferably 4:1; the total volume of the mixed solvent is 4-6 times the mass of 3,4-dimethoxyphenylacetamide.

[0024] In step (1), the molar ratio of 3,4-dimethoxyphenylacetamide to hexamethylenetetramine is 1:1.5-3, preferably 1:2; the reaction temperature is 110-130℃, preferably 120℃; and the reaction time is 0.5-2h, preferably 1h.

[0025] After the reaction in step (1) is completed, the process also includes cooling to 20-30℃, adding water to dilute, neutralizing with alkali solution to neutral, extracting with dichloromethane, combining the organic phases, drying and concentrating under reduced pressure to a viscous state, adding n-heptane, heating and refluxing to slurry for 0.5-3h, cooling to 0-10℃ and stirring for 0.5-2h, filtering and drying.

[0026] In step (2), the Vilsmeier reagent is prepared by N,N-dimethylformamide and phosphorus oxychloride in anhydrous tetrahydrofuran at -5 to 0°C, wherein the molar ratio of N,N-dimethylformamide to phosphorus oxychloride is 1-1.5:1.

[0027] In step (2), solvent A is tetrahydrofuran. The concentration of 6,7-dimethoxy-3,4-dihydroisoquinoline-1(2H)-one in the tetrahydrofuran solution of 6,7-dimethoxy-3,4-dihydroisoquinoline-1(2H)-one is 4-5 mol / L. The solution is added dropwise to the Vilsmeier reagent. The reaction temperature is -5~0℃ and the reaction time is 0.5-2h.

[0028] The reaction in step (2) includes quenching the reaction solution in a mixture of ice and sodium hydroxide aqueous solution, extracting with toluene, washing and concentrating the organic phase with water, oxidizing with sulfuric acid aqueous solution and potassium permanganate, drying and concentrating, and recrystallizing with ethyl acetate.

[0029] In step (3), the molar ratio of 2-chloro-3-formyl-6,7-dimethoxyisoquinoline to 3,4-methylenedioxyphenylboronic acid is 1:0.8-1.2, solvent B is 1,2-dimethoxyethane, and the molar volume ratio of 2-chloro-3-formyl-6,7-dimethoxyisoquinoline to solvent B is 0.8-0.9 mol:1 L.

[0030] In step (3), the palladium catalyst is [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride, and its amount is 0.5%-2% of the molar amount of 2-chloro-3-formyl-6,7-dimethoxyisoquinoline; the base a is a saturated sodium bicarbonate aqueous solution, and the molar volume ratio of 2-chloro-3-formyl-6,7-dimethoxyisoquinoline to the saturated sodium bicarbonate aqueous solution is 2-3 mol:1 L; the reaction temperature is 70-80℃, and the reaction time is 1-3 h.

[0031] The reaction in step (3) includes cooling, dilution with water, extraction with ethyl acetate 2-3 times, washing the combined organic phases with saturated brine, drying with anhydrous sodium sulfate, filtering, concentrating, adding methyl tert-butyl ether and refluxing to form a slurry, cooling to crystallize, filtering, and drying.

[0032] In step (4), base b is potassium tert-butoxide, and the molar ratio of potassium tert-butoxide to (methoxymethyl)triphenylphosphonium chloride is 0.9-1.1:1; the molar ratio of 2-(benzo[d][1,3]dioxacyclopenten-5-yl)-3-formyl-6,7-dimethoxyisoquinoline to (methoxymethyl)triphenylphosphonium chloride is 1:0.8-1.2.

[0033] The reaction described in step (4) is carried out in anhydrous tetrahydrofuran, first at -5~0℃ for 0.5-1h, and then naturally heated to 20-30℃ for 2-5h.

[0034] The reaction in step (4) includes quenching with saturated ammonium chloride aqueous solution, extraction with ethyl acetate, drying of the organic phase, concentration, addition of n-heptane and silica gel, stirring and filtration, and concentration of the filtrate.

[0035] In step (5), the acid is methanesulfonic acid, and the molar ratio of methanesulfonic acid to 2-(benzo[d][1,3]dioxacyclopenten-5-yl)-3-(2-methoxyvinyl)-6,7-dimethoxyisoquinoline is 0.8-1.2:1; the cyclization reaction is carried out in dichloromethane, and the volume of dichloromethane used is 4-6 times the mass of 2-(benzo[d][1,3]dioxacyclopenten-5-yl)-3-(2-methoxyvinyl)-6,7-dimethoxyisoquinoline.

[0036] The reaction conditions in step (5) are as follows: first, the temperature is controlled at 0-5℃ for 0.5-2h, and then the temperature is naturally raised to 15-30℃ for 1-4h. After the reaction, the reaction also includes quenching with saturated sodium bicarbonate solution, separating the organic phase, extracting the aqueous phase with dichloromethane, combining the organic phases, drying, concentrating, adding ethanol to slurry for purification, cooling to crystallize, filtering, and drying.

[0037] In step (6), the molar ratio of 2,3-dimethoxy-8,9-methylenedioxybenzo[c]phenanthridine to methyl trifluoromethanesulfonate is 1:0.8-1.2. The reaction is carried out in toluene, and the volume of toluene used is 4-6 times the mass of 2,3-dimethoxy-8,9-methylenedioxybenzo[c]phenanthridine. The reaction temperature is 20-30℃, and the reaction time is 3-8h.

[0038] In step (6), the alkali c is a sodium hydroxide aqueous solution with a concentration of 0.1-0.5N, and the conditions for alkali c treatment are: stirring at 20-30℃ for 8-12h; the hydrochloric acid ion exchange is to use hydrochloric acid with a concentration of 1-6N and stir at 20-30℃ for 2-4h; after hydrochloric acid ion exchange, the steps of filtration, water washing and drying are also included.

[0039] Compared with the prior art, the present invention has the following beneficial effects: (1) The total synthesis of this invention involves only 6 reaction steps, avoiding the lengthy protection / deprotection operations and multiple column chromatography purification steps in the traditional route. The yield of each step is 85%-98%, and the total yield is 45%-55%.

[0040] (2) This invention creatively discovers that by using methanesulfonic acid as a catalyst and strictly limiting its amount, solvent and reaction conditions, a yield of up to 91% and a purity of 99.5% can be obtained. Compared with using Eaton reagent (optimal yield 82%) or trifluoromethanesulfonic acid (yield 49%), the yield is significantly improved and side reactions are effectively suppressed.

[0041] (3) The present invention has conducted detailed research and optimization on key parameters such as raw material ratio, solvent dosage, reaction temperature and time in each step of the reaction, and provided a clear operating window range, ensuring the stability and reproducibility of the synthesis process, which is conducive to industrial scale-up production. Detailed Implementation

[0042] The following non-limiting embodiments are intended to enable those skilled in the art to gain a more comprehensive understanding of the present invention, but do not limit the invention in any way. The following content is merely an exemplary description of the scope of protection claimed by the present invention, and those skilled in the art can make various changes and modifications to the present invention based on the disclosed content, and such changes should also fall within the scope of protection claimed by the present invention.

[0043] The present invention will be further described below by way of specific embodiments. Unless otherwise specified, all instruments, devices, equipment, reagents, products, etc., used in the embodiments of the present invention are obtained through conventional commercial means.

[0044] Example 1 A method for synthesizing chlorinated thorn alkali, the synthetic route of which is as follows: .

[0045] Step 1: Synthesis of Intermediate II (6,7-dimethoxy-3,4-dihydroisoquinoline-1(2H)-one) 3,4-Dimethoxyphenylacetamide (195.1 g, 1 mol) was dissolved in a mixture of glacial acetic acid (800 mL) and trifluoroacetic acid (200 mL). Hexamethylenetetramine (280.4 g, 2 mol) was added in portions at 25 °C. After the addition was complete, the mixture was heated to 120 °C and reacted for 1 hour. After the disappearance of starting material I by HPLC monitoring, the temperature was lowered to 25 °C, diluted with 5 L of water, and neutralized to neutral with sodium hydroxide. The mixture was extracted with dichloromethane (DCM) (3 × 4 L), the organic phases were combined, dried with anhydrous sodium sulfate, filtered, and the DCM was concentrated until the system became viscous. 2 L of n-heptane was added, and the mixture was heated to reflux and stirred for 2 hours to form a slurry. The temperature was lowered to 10 °C, and the mixture was stirred at 85 rpm for 1 hour. The solid was filtered off and dried in a vacuum oven at 45 °C to obtain 186.4 g of a pale yellow solid powder, with a yield of 90% and a purity of 98%.

[0046] LCMS (ESI) m / z calcd for: C 11 H 13 NO3(M+H) + :208; Found: 208. 1H NMR (400MHz, CDCl3): 3.89 (6H, s), 4.11 (2H, s), 4.44 (2H, s), 6.81 (1H, s), 6.84 (1H, s). Step 2: Synthesis of Intermediate III (2-chloro-3-formyl-6,7-dimethoxyisoquinoline) Under nitrogen protection, anhydrous DMF (265.7 g, 3.63 mol) was added to anhydrous tetrahydrofuran (500 mL), and the mixture was cooled to -2°C. POCl3 (322 mL, 3.5 mol) was slowly added dropwise over 40 min while maintaining an internal temperature of 2°C. The reaction mixture was then stirred at 0°C at 90 rpm for 30 min, cooled to -5°C, and stirred continuously. The Vilsmeier reagent was now prepared.

[0047] A tetrahydrofuran solution (200 mL) of intermediate II (186.4 g, 0.9 mol) was added dropwise to the prepared Vilsmeier reagent at an internal temperature of 2 °C, and the reaction was carried out at 2 °C for 1 hour. HPLC monitoring showed the disappearance of intermediate II, quenching the reaction by adding the reaction solution to a mixture of 2N sodium hydroxide aqueous solution (5 L) and ice (10 kg). The quenching process was carried out at 18 °C. After quenching, 2 L of toluene was added for extraction, followed by another extraction with 1 L of toluene on the aqueous phase. The combined organic phases were washed once with 1 L of water, and the organic phase was concentrated to 3 L at 25 °C. 3.6 L of 2N sulfuric acid aqueous solution was added, and the mixture was stirred vigorously while maintaining an internal temperature of 28 °C. Potassium permanganate (93 g, 0.59 mol) was added in batches. After the potassium permanganate was added, the mixture was stirred at 90 rpm for 7 hours at 28 °C. After the reaction was completed by HPLC monitoring, the organic phase was separated, dried with sodium sulfate, concentrated, dissolved in 500 mL of ethyl acetate by heating, stirred at 90 rpm for 1 h, cooled to 2 °C, filtered, and dried to obtain 194.3 g of yellow solid, with a yield of 86% and a purity of 97.8%.

[0048] LCMS (ESI) m / z calcd for: C 12 H 10 ClNO3(M+H) + :252; Found: 252. 1H NMR (400MHz, CDCl3): 3.45 (3H, s), 3.66 (3H, s), 6.92 (1H, s), 7.04 (1H, s), 9.25 (1H, s), 10.76 (1H, s). Step 3: Synthesis of intermediate IV (2-(benzo[d][1,3]dioxacyclopenten-5-yl)-3-formyl-6,7-dimethoxyisoquinoline) Intermediate III (194.3 g, 0.77 mol) and 3,4-methylenedioxyphenylboronic acid (129.4 g, 0.78 mol) were dissolved in 1,2-dimethoxyethane (900 mL), and saturated sodium bicarbonate aqueous solution (300 mL) was added. The mixture was purged three times with nitrogen. Under nitrogen protection, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride Pd(dppf)Cl2 (6.2 g, 8.5 mmol) was added, and the mixture was heated to 75 °C for 2 h. HPLC monitoring showed the starting material had disappeared. The reaction solution was then cooled to 25 °C. The reaction solution was diluted with 1.2 L of water, and then extracted twice with ethyl acetate (2 × 1 L). The organic phases were combined, washed with 1 L of saturated brine, separated, dried with anhydrous sodium sulfate, filtered, concentrated, and refluxed with 500 mL of TBME for 1 h. The mixture was then cooled to 2 °C, stirred at 70 rpm for 1 h, filtered, and dried to obtain 223.2 g of yellow solid, with a yield of 86% and a purity of 99.2%.

[0049] LCMS (ESI) m / z calcd for: C 19 H 15 NO5(M+H) + :338; Found: 338. 1H NMR (400MHz, CDCl3): 3.71 (3H, s), 3.79 (3H, s), 5.92 (2H, s), 6.53(1H, d), 6.64 (1H, s), 6.77 (1H, d), 6.98 (1H, s), 7.15 (1H, s), 9.13( 1H, s), 10.58( 1H, s). Step 4: Synthesis of intermediate V (2-(benzo[d][1,3]dioxacyclopenten-5-yl)-3-(2-methoxyvinyl)-6,7-dimethoxyisoquinoline) Under nitrogen protection, (methoxymethyl)triphenylphosphonium chloride (233.1 g, 0.68 mol) was added to anhydrous tetrahydrofuran (1 L), and potassium tert-butoxide (76.3 g, 0.68 mol) was added in portions at -2 °C. After the addition was complete, the mixture was stirred at -2 °C and 90 rpm for 30 min to prepare phosphorus ylide. While maintaining the temperature, under nitrogen protection, a tetrahydrofuran solution (600 mL) of intermediate IV (223.2 g, 0.66 mol) was added dropwise. After the addition was complete, the mixture was naturally heated to 25 °C and stirred for 3 h. The reaction was stopped when the starting material disappeared as monitored by HPLC. The reaction was quenched by adding a saturated ammonium chloride aqueous solution (1 L) at 28 °C. The mixture was extracted three times with ethyl acetate (600 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. After concentration to dryness, the crude product was mixed with n-heptane (1 L) and silica gel (200 g), stirred at 90 rpm for 30 min, filtered through silica gel, and the silica gel was washed with 200 mL of n-heptane. The n-heptane mixtures were combined and concentrated to dryness to obtain a yellow solid (237.3 g, 0.65 mol). This solid was an E:Z mixture (E:Z = 4:1), with a total yield of 98% and a total purity of 98.9%.

[0050] LCMS (ESI) m / z calcd for: C 21 H 19 NO5(M+H) + :366; Found: 366. 1H NMR (400MHz, CDCl3): E: 3.51(3H, s), 3.61 (3H, s), 3.64 (3H, s), 5.82 (1H, d), 5.96 (2H, s), 6.41 (1H, d), 6.62 (1H, s), 6.85 (1H, d), 7.01(1H, d), 7.05 (1H, s), 7.14 (1H, s), 9.32(1H, s). 1H NMR (400MHz, CDCl3): Z: 3.78 (3H, s), 3.68 (3H, s), 3.84 (3H, s), 5.26 (1H, d), 5.77 (2H, s), 6.11 (1H, d), 6.60 (1H, s), 6.75 (1H, d), 7.03(1H, d), 7.12 (1H, s), 7.19 (1H, s), 9.46(1H, s). Step 5: Synthesis of intermediate VI (2,3-dimethoxy-8,9-methylenedioxybenzo[c]phenanthridine) Under nitrogen protection, intermediate V (237.3 g, 0.65 mol) was dissolved in dichloromethane (1 L) and cooled to 0 °C. Methanesulfonic acid (62.5 g, 0.65 mol) was added dropwise at an internal temperature of 2 °C. After the addition was complete, the reaction was maintained at 2 °C for 1 h, then naturally heated to room temperature for another 2 h. The reaction was stopped when the starting material disappeared as monitored by HPLC. 1 L of saturated sodium bicarbonate solution was added to quench the reaction, and the DCM phase was separated. The aqueous phase was further extracted twice with DCM (500 mL × 2). The organic phases were combined, dried with anhydrous sodium sulfate, filtered, concentrated, and then slurried with 500 mL of ethanol at 28 °C at a stirring speed of 100 rpm. The mixture was cooled to 2 °C, filtered, and dried to obtain a pale yellow solid (197 g, 0.59 mol), with a yield of 91% and a purity of 99.5%.

[0051] LCMS (ESI) m / z calcd for: C 20 H 15 NO4(M+H) + :334; Found: 334. 1H NMR (400 MHz, CDCl3): δ 4.10 (s, 3H), 4.17 (s, 3H), 6.13 (s, 2H), 7.28 (s, 1H), 7.41 (s, 1H), 7.84 (d, 1H), 7.91 (s, 1H), 8.30 (d, 1H), 8.73(s,1H), 9.26 (s, 1H). Step 6: Synthesis of Product VII (Nephrolepisole Chloride) Intermediate VI (197 g, 0.59 mol) was dissolved in toluene (1 L), and methyl trifluoromethanesulfonate (96.8 g, 0.59 mol) was added dropwise while maintaining an internal temperature of 28 °C. After the addition was complete, the mixture was stirred at 28 °C for 5 h. HPLC monitoring showed that the starting material disappeared. The mixture was then cooled to 2 °C and stirred for 1 h. After filtration, the filter cake was washed with toluene. This compound was identified as thorn alkaloid trifluoromethanesulfonate. The filter cake was added to ethanol (2.5 L), and 0.2 N sodium hydroxide (3.1 L) was added. The mixture was stirred at 28 °C for 9 h. HPLC monitoring showed that the thorn alkaloid trifluoromethanesulfonate disappeared. The mixture was then cooled to 2 °C and stirred for 1 h. After filtration, the filter cake was washed with ethanol:water in a 1:1 ratio. The obtained filter cake was dispersed in 1L of water, and 300mL of 4N hydrochloric acid was added. The mixture was stirred at 28℃ for 3h, cooled to 2℃ and stirred for 1h. The stirring speed was 110rpm. The mixture was filtered, and the filter cake was washed with ice water and dried to obtain a light yellow solid chlorinated alkali (191.5g, 0.5mol), with a yield of 85% and a purity of 99.3%.

[0052] LCMS (ESI) m / z calcd for: C 21 H18 NO4 + Cl - (M) + : 348; Found: 348. 1H NMR (400 MHz, DMSO-d6) δ 4.03 (s, 3H), 4.22 (s, 3H), 4.89 (s, 3H), 6.33 (s, 2H), 7.76 (s, 1H), 7.91 (s, 1H), 8.27 (d, J = 9.0 Hz, 1H), 8.30 (s,1H), 8.35 (s, 1H), 8.89 (d, J = 9.0 Hz, 1H), 9.87 (s, 1H). Example 2 A method for synthesizing chlorinated thorn alkali, differing from Example 1 only in step 5, is as follows: Synthesis of intermediate VI (2,3-dimethoxy-8,9-methylenedioxybenzo[c]phenanthridine) Under nitrogen protection, intermediate V (237.3 g, 0.65 mol) was dissolved in dichloromethane (950 mL) and cooled to 0 °C. Methanesulfonic acid (50 g, 0.52 mol) was added dropwise at an internal temperature of 2 °C. After the addition was complete, the reaction was maintained at 0 °C for 2 h, then naturally heated to 30 °C and reacted for 1 h. The reaction was stopped when the starting material disappeared as monitored by HPLC. 1 L of saturated sodium bicarbonate solution was added to quench the reaction, and the DCM phase was separated. The aqueous phase was further extracted twice with DCM (500 mL × 2). The organic phases were combined, dried with anhydrous sodium sulfate, filtered, concentrated, and then slurried with 500 mL of ethanol at 28 °C. The mixture was cooled to 2 °C, filtered, and dried to obtain a pale yellow solid (190 g, 0.57 mol), with a yield of 88% and a purity of 99%.

[0053] Example 3 A method for synthesizing chlorinated thorn alkali, differing from Example 1 only in step 5, is as follows: Synthesis of intermediate VI (2,3-dimethoxy-8,9-methylenedioxybenzo[c]phenanthridine) Under nitrogen protection, intermediate V (237.3 g, 0.65 mol) was dissolved in dichloromethane (1.4 L) and cooled to 0 °C. Methanesulfonic acid (75 g, 0.78 mol) was added dropwise at an internal temperature of 2 °C. After the addition was complete, the reaction was maintained at 5 °C for 0.5 h, then naturally heated to 15 °C and reacted for 4 h. The reaction was stopped when the starting material disappeared as monitored by HPLC. 1 L of saturated sodium bicarbonate solution was added to quench the reaction, and the DCM phase was separated. The aqueous phase was further extracted twice with DCM (500 mL × 2). The organic phases were combined, dried with anhydrous sodium sulfate, filtered, concentrated, and then slurried with 500 mL of ethanol at 28 °C. The mixture was cooled to 2 °C, filtered, and dried to obtain a pale yellow solid (184 g, 0.55 mol), with a yield of 85% and a purity of 98.2%.

[0054] Comparative Example 1 The only difference between this comparative example and Example 1 is the acid catalyst used in step 5, as detailed below: Under nitrogen protection, intermediate V (237.3 g, 0.65 mol) was dissolved in dichloromethane (1 L) and cooled to 0 °C. 250 mL of Eaton reagent was added dropwise while maintaining an internal temperature of 2 °C. After addition, the reaction was maintained at 2 °C for 1 h, then naturally warmed to room temperature for another 2 h. The reaction was stopped when the starting material disappeared as monitored by HPLC. 1 L of saturated sodium bicarbonate solution was added to quench the reaction, and the DCM phase was separated. The aqueous phase was further extracted twice with DCM (500 mL × 2). The organic phases were combined, dried with anhydrous sodium sulfate, filtered, concentrated, and then slurried with 500 mL of ethanol at 28 °C at a stirring speed of 100 rpm. The mixture was cooled to 2 °C, filtered, and dried to obtain a pale yellow solid (143 g, 0.43 mol), with a yield of 66% and a purity of 97.1%.

[0055] Comparative Example 2 The only difference between this comparative example and Example 1 is the acid catalyst used in step 5, as detailed below: Under nitrogen protection, intermediate V (237.3 g, 0.65 mol) was dissolved in 600 mL of dichloromethane and cooled to 0 °C. 600 mL of Eaton reagent was added dropwise while maintaining an internal temperature of 2 °C. After addition, the reaction was maintained at 2 °C for 1 h, then naturally warmed to room temperature for another 2 h. The reaction was stopped when the starting material disappeared as monitored by HPLC. 1 L of saturated sodium bicarbonate solution was added to quench the reaction, and the DCM phase was separated. The aqueous phase was further extracted twice with DCM (500 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and then slurried with 500 mL of ethanol at 28 °C with stirring at 100 rpm. The mixture was cooled to 2 °C, filtered, and dried to obtain a pale yellow solid (176 g, 0.53 mol), with a yield of 82% and a purity of 97.8%.

[0056] Comparative Example 3 The only difference between this comparative example and Example 1 is the acid catalyst used in step 5, as detailed below: Under nitrogen protection, intermediate V (237.3 g, 0.65 mol) was dissolved in dichloromethane (1 L) and cooled to 0 °C. Trifluoromethanesulfonic acid (97.5 g, 0.65 mol) was added dropwise at an internal temperature of 2 °C. After the addition was complete, the reaction was maintained at 2 °C for 1 h, and then naturally heated to room temperature for 2 h. The reaction was stopped when the starting material disappeared as monitored by HPLC. The reaction was quenched by adding 1 L of saturated sodium bicarbonate solution, and the DCM phase was separated. The aqueous phase was extracted twice with DCM (500 mL × 2). The organic phases were combined, dried with anhydrous sodium sulfate, filtered, concentrated, and 500 mL of ethanol was added. The mixture was stirred at 28 °C at 100 rpm, cooled to 2 °C, filtered, and dried to obtain a pale yellow solid (106 g, 0.32 mol), with a yield of 49% and a purity of 96.6%.

[0057] Comparative Example 4 The only difference between this comparative example and Example 1 is the palladium catalyst used in step 3, as detailed below: Intermediate III (194.3 g, 0.77 mol) and 3,4-methylenedioxyphenylboronic acid (129.4 g, 0.78 mol) were dissolved in 1,2-dimethoxyethane (900 mL), and saturated sodium bicarbonate aqueous solution (300 mL) was added. The mixture was purged three times with nitrogen. Under nitrogen protection, tetrakis(triphenylphosphine)palladium Pd(PPh3)4 (9.8 g, 8.5 mmol) was added, and the mixture was heated to 75 °C for 2 h. HPLC monitoring showed the starting material had disappeared. The reaction solution was cooled to 25 °C. 1.2 L of water was added to dilute the reaction solution, followed by extraction twice with ethyl acetate (2 × 1 L). The organic phases were combined, washed with 1 L of saturated brine, separated, dried with anhydrous sodium sulfate, filtered, concentrated, and refluxed with TBME (500 mL) for 1 h. The mixture was cooled to 2 °C, stirred at 70 rpm for 1 h, filtered, and dried to obtain 182 g of yellow solid, yield 70%, purity 98.9%.

[0058] Comparative Example 5 The only difference between this comparative example and Example 1 is the palladium catalyst used in step 3, as detailed below: Intermediate III (194.3 g, 0.77 mol) and 3,4-methylenedioxyphenylboronic acid (129.4 g, 0.78 mol) were dissolved in 1,2-dimethoxyethane (900 mL), and saturated sodium bicarbonate aqueous solution (300 mL) was added. The mixture was purged three times with nitrogen. Under nitrogen protection, tris(dibenzylacetone)dipalladium Pd2(dba)3 (7.8 g, 8.5 mmol) was added, and the mixture was heated to 75 °C for 2 h. HPLC monitoring showed the starting material had disappeared. The reaction solution was cooled to 25 °C. 1.2 L of water was added to dilute the reaction solution, followed by extraction twice with ethyl acetate (2 × 1 L). The organic phases were combined, washed with 1 L of saturated brine, separated, dried with anhydrous sodium sulfate, filtered, concentrated, and refluxed with TBME (500 mL) for 1 h. The mixture was cooled to 2 °C, stirred at 70 rpm for 1 h, filtered, and dried to obtain 171 g of a yellow solid, yield 66%, purity 98.5%.

[0059] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A method for synthesizing chlorinated thorn alkali, characterized in that, Includes the following steps: (1) 3,4-Dimethoxyphenylacetamide was reacted with hexamethylenetetramine in an acid solvent system to obtain 6,7-dimethoxy-3,4-dihydroisoquinoline-1(2H)-one; (2) 6,7-Dimethoxy-3,4-dihydroisoquinoline-1(2H)-one was dissolved in solvent A, mixed with Vilsmeier reagent, and reacted to give 2-chloro-3-formyl-6,7-dimethoxyisoquinoline; (3) In the presence of palladium catalyst and base a, 2-chloro-3-formyl-6,7-dimethoxyisoquinoline and 3,4-methylenedioxyphenylboronic acid were reacted in solvent B to give 2-(benzo[d][1,3]dioxacyclopenten-5-yl)-3-formyl-6,7-dimethoxyisoquinoline; (4) In the presence of base b, 2-(benzo[d][1,3]dioxacyclopenten-5-yl)-3-formyl-6,7-dimethoxyisoquinoline is reacted with (methoxymethyl)triphenylphosphonium chloride to give 2-(benzo[d][1,3]dioxacyclopenten-5-yl)-3-(2-methoxyvinyl)-6,7-dimethoxyisoquinoline; (5) 2-(benzo[d][1,3]dioxacyclopenten-5-yl)-3-(2-methoxyvinyl)-6,7-dimethoxyisoquinoline undergoes a cyclization reaction under acid catalysis to give 2,3-dimethoxy-8,9-methylenedioxybenzo[c]phenanthridine; (6) 2,3-Dimethoxy-8,9-methylenedioxybenzo[c]phenanthridine is reacted with methyl trifluoromethanesulfonate in an organic solvent to generate neem base trifluoromethanesulfonate, which is then subjected to base C treatment and hydrochloric acid ion exchange to obtain neem base chloride.

2. The synthesis method according to claim 1, characterized in that, The acid solvent system in step (1) is a mixed solvent of glacial acetic acid and trifluoroacetic acid, wherein the volume ratio of glacial acetic acid to trifluoroacetic acid is 2-6:1; the total volume of the mixed solvent is 4-6 times the mass of 3,4-dimethoxyphenylacetamide; the molar ratio of 3,4-dimethoxyphenylacetamide to hexamethylenetetramine is 1:1.5-3; the reaction temperature is 110-130℃; and the reaction time is 0.5-2h.

3. The synthesis method according to claim 2, characterized in that, After the reaction in step (1) is completed, the process also includes cooling to 20-30℃, adding water to dilute, neutralizing with alkali solution to neutral, extracting with dichloromethane, combining the organic phases, drying and concentrating under reduced pressure to a viscous state, adding n-heptane, heating and refluxing to slurry for 0.5-3 h, cooling to 0-10℃ and stirring for 0.5-2 h, filtering and drying.

4. The synthesis method according to claim 1, characterized in that, The Vilsmeier reagent mentioned in step (2) is prepared by N,N-dimethylformamide and phosphorus oxychloride in anhydrous tetrahydrofuran at -5~0℃, wherein the molar ratio of N,N-dimethylformamide to phosphorus oxychloride is 1-1.5:

1.

5. The synthesis method according to claim 1, characterized in that, In step (2), solvent A is tetrahydrofuran. The concentration of 6,7-dimethoxy-3,4-dihydroisoquinoline-1(2H)-one in the tetrahydrofuran solution of 6,7-dimethoxy-3,4-dihydroisoquinoline-1(2H)-one is 4-5 mol / L. The reaction temperature is -5~0℃ and the reaction time is 0.5-2h.

6. The synthesis method according to claim 5, characterized in that, Step (2) after the reaction also includes quenching the reaction solution in a mixture of ice and sodium hydroxide aqueous solution, extracting with toluene, washing and concentrating the organic phase with water, oxidizing with sulfuric acid aqueous solution and potassium permanganate, drying and concentrating, and recrystallizing with ethyl acetate.

7. The synthesis method according to claim 1, characterized in that, In step (3), the molar ratio of 2-chloro-3-formyl-6,7-dimethoxyisoquinoline to 3,4-methylenedioxyphenylboronic acid is 1:0.8-1.2, the solvent B is 1,2-dimethoxyethane, and the molar volume ratio of 2-chloro-3-formyl-6,7-dimethoxyisoquinoline to solvent B is 0.8-0.9 mol:1 L.

8. The synthesis method according to claim 7, characterized in that, The palladium catalyst in step (3) is [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride, and its amount is 0.5%-2% of the molar amount of 2-chloro-3-formyl-6,7-dimethoxyisoquinoline; the base a is a saturated sodium bicarbonate aqueous solution, and the molar volume ratio of 2-chloro-3-formyl-6,7-dimethoxyisoquinoline to the saturated sodium bicarbonate aqueous solution is 2-3 mol:1 L; the reaction temperature is 70-80℃, and the reaction time is 1-3 h.

9. The synthesis method according to claim 8, characterized in that, Step (3) after the reaction also includes cooling, dilution with water, extraction with ethyl acetate 2-3 times, combining the organic phases, washing with saturated brine, drying with anhydrous sodium sulfate, filtering, concentrating, adding methyl tert-butyl ether, refluxing and slurrying, cooling to crystallize, filtering, and drying.

10. The synthesis method according to claim 1, characterized in that, In step (4), base b is potassium tert-butoxide, and the molar ratio of potassium tert-butoxide to (methoxymethyl)triphenylphosphonium chloride is 0.9-1.1:1; the molar ratio of 2-(benzo[d][1,3]dioxacyclopenten-5-yl)-3-formyl-6,7-dimethoxyisoquinoline to (methoxymethyl)triphenylphosphonium chloride is 1:0.8-1.

2.

11. The synthesis method according to claim 10, characterized in that, The reaction described in step (4) is carried out in anhydrous tetrahydrofuran, first at -5~0℃ for 0.5-1h, and then naturally heated to 20-30℃ for 2-5h.

12. The synthesis method according to claim 11, characterized in that, Step (4) includes quenching with saturated ammonium chloride aqueous solution, extraction with ethyl acetate, drying the organic phase, concentrating, adding n-heptane and silica gel, stirring and filtering, and concentrating the filtrate.

13. The synthesis method according to claim 1, characterized in that, The acid catalyst in step (5) is methanesulfonic acid, and the molar ratio of methanesulfonic acid to 2-(benzo[d][1,3]dioxacyclopenten-5-yl)-3-(2-methoxyvinyl)-6,7-dimethoxyisoquinoline is 0.8-1.2:1; the cyclization reaction is carried out in dichloromethane, and the volume of dichloromethane used is 4-6 times the mass of 2-(benzo[d][1,3]dioxacyclopenten-5-yl)-3-(2-methoxyvinyl)-6,7-dimethoxyisoquinoline.

14. The synthesis method according to claim 13, characterized in that, The reaction conditions in step (5) are as follows: first, the temperature is controlled at 0-5℃ for 0.5-2h, and then the temperature is naturally raised to 15-30℃ for 1-4h. After the reaction, the reaction also includes quenching with saturated sodium bicarbonate solution, separating the organic phase, extracting the aqueous phase with dichloromethane, combining the organic phases, drying, concentrating, adding ethanol to slurry for purification, cooling to crystallize, filtering, and drying.

15. The synthesis method according to claim 1, characterized in that, In step (6), the molar ratio of 2,3-dimethoxy-8,9-methylenedioxybenzo[c]phenanthridine to methyl trifluoromethanesulfonate is 1:0.8-1.

2. The reaction is carried out in toluene, and the volume of toluene used is 4-6 times the mass of 2,3-dimethoxy-8,9-methylenedioxybenzo[c]phenanthridine. The reaction temperature is 20-30℃ and the reaction time is 3-8h.

16. The synthesis method according to claim 15, characterized in that, The alkali c mentioned in step (6) is a sodium hydroxide aqueous solution with a concentration of 0.1-0.5N. The conditions for alkali c treatment are: stirring at 20-30℃ for 8-12 hours; the hydrochloric acid ion exchange is to use hydrochloric acid with a concentration of 1-6N and stir at 20-30℃ for 2-4 hours; after hydrochloric acid ion exchange, the steps of filtration, water washing and drying are also included.