CN114315823B - Intermediate of berberine hydrochloride and analogues thereof and preparation method thereof - Google Patents
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Abstract
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to an intermediate of berberine hydrochloride and analogues thereof and a preparation method thereof. The preparation method of the intermediate comprises the following steps: (1) Reacting a compound shown in a formula II-1, II-2 or II-3 with alkali at a temperature of between 70 ℃ below zero and 20 ℃ below zero to obtain a reaction solution; (2) Adding the reaction liquid into a compound shown in the formula IV-1, IV-2 or IV-3 for reaction; then the intermediate is subjected to a series of reactions to prepare berberine hydrochloride and analogues thereof. The preparation method avoids the reaction catalyzed by high-pressure axe, hydrogen and noble metal, reduces the process cost, is suitable for industrial production, avoids the use of highly toxic cyanide, and increases the safety of synthesis.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to an intermediate of berberine hydrochloride and analogues thereof and a preparation method thereof.
Background
Berberine (Berberine), also known as Berberine, is a natural benzylisoquinoline alkaloid. The chemical name is: 5, 6-dihydro-9, 10-dimethoxybenzo [ g ]]-1, 3-benzodioxol [5, 6-alpha ]]Quinolizine hydrochloride dihydrate of formula C 20 H 18 ClNO 5 ·2H 2 O, which was originally isolated from Boschner et al at 1830 from Boschner's bark (Buchner, J.A.; herberger J.E. Repert. Pharm.1830,36, 1). At present, berberine can be separated from 4 plants of 10 species of the family, wherein berberine is one of main plant sources for extraction and separation of berberine (Chengmei, chen Renhua, shizhen national medicine, 2007,18,6).
Berberine has good biological activity in diseases of central nervous system, cardiovascular system and motor system. The Amin group reported for the first time, in 1969, that berberine has a different degree of inhibition on G+, G-and fungi (Amin, A.H.; subbaiah, T.V.; abbasi, K.M.can.J. Microbiol.1969,15,1067). Later, several groups have found that berberine exhibits different antibacterial activities against various bacteria or fungi, including methicillin-resistant staphylococcus aureus (MRSA), helicobacter pylori, mycobacterium tuberculosis, etc. Possible bacteriostatic mechanisms are as follows: 1) Berberine can combine with thallus single-chain or double-chain DNA to form complex, thereby inhibiting biosynthesis of protein and lipid and glycolysis of sugar; 2) Berberine can inhibit topoisomerase activity and the like (Inoue, n.; terabayashi, t.; takignuchi-Kawashima, Y.; scientific Reports 2021,11,7718). Clinically, berberine is mainly used for treating bacillary dysentery, gastroenteritis and other bacterial infectious diseases (Xing Juan, he Mengjing, abstract of the latest medical information in the world, 2019,19,231). The recent studies have found that berberine is promising for clinical treatment of frequently occurring diseases such as Cancer and Diabetes (Sun, Y.; xun, k.l.; wang, y.t.; chen, xp.anti-Cancer Drugs 2009,20,757.Lee,Yun S.; kim, woo s.; kim, kang h.; diabetes2006,55,2256.).
Plant extraction and isolation, tissue culture (Sato, f.; yamada, y. Phytochemistry 1984,23,281.), biological fermentation (Gao Yang, liu Ming, guangzhou chemical, 2012,40,91.) and chemical synthesis are the primary modes of obtaining berberine. Among these, chemical synthesis is the most dominant and most direct source.
Since the last sixty years, kametani et al reported the total synthesis of berberine (Kametani, t.; noguchi, i.; saito, k.; kaneda, s.j. Chem. Soc. C1969,2036.) a synthetic method of 8 berberine has been developed. These synthetic methods can be divided into three classes (Yan, x.f., zheng, j.f., li, wei-Dong z.child.j.org., chem.2021,41,2217.) biomimetic synthetic strategies (C1 cyclization method) (Cutter, p.s., miller, r.b., schore, n.e., tetrahedron 2002,58,1471.), intermolecular coupling strategies (C2 cyclization method) (Chen, s.q., lin w.f., zang, j.h., liu, j.h., qi, s.h., zhang, l.q., song, g.l.cn 1312250,2001.Tang C.G.CN 106543171,2017.Feng,X, fu, l., zhao, c.a., cn 107868072,2018) and other metal catalyzed synthetic methods (gaand, a.e., pimr, b.s., p.37pi., p.37, p.c., three-phase, p.37). Industrially, piperonylethylamine and veratraldehyde are mainly used as raw materials (northeast pharmaceutical general factory, journal of Chinese medicine industry, 1972, (4), 4.) to form an imine intermediate by condensation, and the synthesis of berberine hydrochloride is completed through the steps of reduction, salification, cyclization, alkalization, acidification and the like.
At present, in the developed synthetic method or process of berberine hydrochloride and analogues thereof, the problems of high pressure kettle, highly toxic cyanide, noble metal catalysis, difficult post-treatment and the like exist, and the production cost and the potential safety hazard are increased. Therefore, in view of the abundant pharmacological activity of berberine hydrochloride and analogues thereof and important application in medicines, a convenient and efficient chemical synthesis method for developing the compound has important commercial value.
Disclosure of Invention
In view of the above, the present invention aims to provide an intermediate of berberine hydrochloride and analogues thereof and a preparation method of berberine hydrochloride and analogues thereof, which solves the problems of high pressure kettle, highly toxic cyanide, noble metal catalysis, difficult post-treatment, etc. used in the existing preparation method, and has important significance for developing the wide medical research value and synthesizing other compounds as reaction substrates.
The structural formula of the intermediate of the berberine hydrochloride and the analogues thereof is shown as V-1, V-2, V-3, V-4 or V-5, and the preparation method comprises the following steps: (1) Reacting a compound shown in a formula II-1, II-2 or II-3 with alkali at a temperature of between 70 ℃ below zero and 20 ℃ below zero to obtain a reaction solution; (2) Adding the reaction liquid into a compound shown in the formula IV-1, IV-2 or IV-3 for reaction; wherein X in V-1, V-2, V-3, V-4, V-5, IV-1, IV-2 or IV-3 is selected from H or halogen.
Specifically, when the structural formula of the intermediate of berberine hydrochloride and analogues thereof is shown as V-1, the preparation method comprises the following steps: (1) Reacting a compound shown in a formula II-1 with alkali at a temperature of between 70 ℃ below zero and 20 ℃ below zero to obtain a reaction solution; (2) Adding the reaction solution into a compound shown in a formula IV-1 for reaction;
specifically, when the structural formula of the intermediate of berberine hydrochloride and analogues thereof is shown as V-2, the preparation method comprises the following steps: (1) Reacting a compound shown in a formula II-1 with alkali at a temperature of between 70 ℃ below zero and 20 ℃ below zero to obtain a reaction solution; (2) Adding the reaction solution into a compound shown in a formula IV-2 for reaction;
specifically, when the structural formula of the intermediate of berberine hydrochloride and analogues thereof is shown as V-3, the preparation method comprises the following steps: (1) Reacting the compound shown in II-2 with alkali at a temperature of between 70 ℃ below zero and 20 ℃ below zero to obtain a reaction solution; (2) Adding the reaction solution into a compound shown in a formula IV-1 for reaction;
specifically, when the structural formula of the intermediate of berberine hydrochloride and analogues thereof is shown as V-4, the preparation method comprises the following steps: (1) Reacting the compound shown in II-2 with alkali at a temperature of between 70 ℃ below zero and 20 ℃ below zero to obtain a reaction solution; (2) Adding the reaction solution into a compound shown in a formula IV-2 for reaction;
specifically, when the structural formula of the intermediate of berberine hydrochloride and analogues thereof is shown as V-5, the preparation method comprises the following steps: (1) Reacting the compound shown in II-3 with alkali at a temperature of between 70 ℃ below zero and 20 ℃ below zero to obtain a reaction solution; (2) And adding the reaction liquid into a compound shown in a formula IV-3 to react.
Further, the reaction solvent for the reaction in the step (1) and the step (2) is selected from one or more of N, N-dimethylformamide and THF.
Further, the base is selected from one or more of NaH, sodium methoxide, potassium tert-butoxide, preferably a mixture of one or more of potassium tert-butoxide.
Preferably, the base is selected from potassium tert-butoxide.
Preferably, the reaction temperature is-60, -30, -20 ℃, preferably-60 ℃.
Further, the preparation method of the compound shown in the formula II-1, II-2 or II-3 comprises the following steps: (1) Reflux-reacting a compound shown in the formula I-1, I-2 or I-3 with diethyl oxalate, cooling, recrystallizing and drying to obtain an intermediate; (2) Then heating the intermediate and a dehydration reagent to reflux for reaction to obtain a compound shown in the formula II-1, II-2 or II-3; the dehydration reagent is selected from one or more of phosphorus oxychloride and pyrophosphoryl chloride; and/or the preparation method of the compound shown in the formula IV-1, IV-2 or IV-3 comprises the following steps: dropwise adding a compound of formula III-1, III-2 or III-3 at-5-50deg.C to steam SOCl 2 Carrying out reaction to obtain a compound shown in a formula IV-1, IV-2 or IV-3; wherein X is selected from H.
Specifically, the preparation method of the compound shown in the formula II-1 comprises the following steps: (1) Reflux-reacting a compound shown in a formula I-1 with diethyl oxalate, cooling, recrystallizing and drying to obtain an intermediate; (2) Then heating the intermediate and a dehydration reagent to reflux for reaction to obtain a compound shown in the formula II-1;
specifically, the preparation method of the compound shown in the formula II-2 comprises the following steps: (1) Reflux-reacting the compound shown in the formula I-2 with diethyl oxalate, cooling, recrystallizing and drying to obtain an intermediate; (2) Then heating the intermediate and a dehydration reagent to reflux for reaction to obtain a compound shown in the formula II-2;
specifically, the preparation method of the compound shown in the formula II-3 comprises the following steps: (1) Reflux-reacting the compound shown in the formula I-3 with diethyl oxalate, cooling, recrystallizing and drying to obtain an intermediate; (2) Then heating the intermediate and a dehydration reagent to reflux for reaction to obtain a compound shown in the formula II-3;
specifically, the preparation method of the compound shown in the formula IV-1 comprises the following steps: dropwise adding a compound of formula III-1 at-5-50deg.C to evaporate SOCl 2 Carrying out a reaction to obtain a compound shown in a formula IV-1;
specifically, the preparation method of the compound shown in the formula IV-2 comprises the following steps: dropwise adding a compound of formula III-2 at-5-50deg.C to evaporate SOCl 2 Carrying out reaction to obtain a compound shown in a formula IV-2;
specifically, the preparation method of the compound shown in the formula IV-3 comprises the following steps: dropwise adding a compound of formula III-3 at-5-50deg.C to evaporate SOCl 2 The reaction is carried out to obtain the compound shown in the formula IV-3.
Further, after the compound shown in the formula V-1, V-2, V-3, V-4 or V-5 reacts with a reducing agent, adding alkali and ethanol to react at 50-70 ℃ to obtain the compound shown in the formula VI-1, VI-2, VI-3, VI-4 or VI-5; wherein X is selected from H or halogen, and R is selected from H;
the reducing agent is selected from sodium borohydride, sodium cyanoborohydride and sodium acetate borohydride.
Preferably, the reducing agent is selected from sodium borohydride.
Further, the reaction solvent of the reaction is selected from one or more of dichloromethane, acetic acid, formic acid, acetonitrile, tetrahydrofuran and trifluoroacetic acid, preferably formic acid-trifluoroacetic acid v/v=1:1.
Further the base may be selected from one or more of sodium hydroxide, potassium hydroxide, preferably sodium hydroxide; wherein the alkali concentration is 2N NaOH,3N NaOH,6N NaOH,10N NaOH, preferably 6N NaOH, and the temperature is 50deg.C, 60deg.C, 70deg.C, preferably 60deg.C.
Specifically, after a compound shown in a formula V-1 reacts with a reducing agent, adding alkali and ethanol to react at 50-70 ℃ to obtain the compound shown in the formula VI-1;
specifically, after a compound shown in a formula V-2 reacts with a reducing agent, adding alkali and ethanol to react at 50-70 ℃ to obtain the compound shown in the formula VI-2;
specifically, after a compound shown in a formula V-3 reacts with a reducing agent, adding alkali and ethanol to react at 50-70 ℃ to obtain the compound shown in the formula VI-3;
specifically, after a compound shown in a formula V-4 reacts with a reducing agent, adding alkali and ethanol to react at 50-70 ℃ to obtain the compound shown in the formula VI-4;
specifically, after the compound shown in the formula V-5 reacts with a reducing agent, alkali and ethanol are added to react at 50-70 ℃ to obtain the compound shown in the formula VI-5.
Further, reacting the compound shown in the formula VI-1, VI-2, VI-3, VI-4 or VI-5 with a decarbonylation reagent to obtain the compound shown in the formula VII-1, VII-2, VII-3, VII-4 or VII-5, wherein the decarbonylation reagent is one or more selected from phosphorus oxychloride, pyrophosphorylchloride, trichloroacetic anhydride, trifluoroacetic anhydride and difluoroacetic anhydride; wherein X is selected from H or halogen.
Specifically, reacting a compound shown in a formula VI-1 with a decarbonylation reagent to obtain a compound shown in a formula VII-1; reacting a compound shown in a formula VI-2 with a decarbonylation reagent to obtain a compound shown in a formula VII-2; reacting a compound shown in a formula VI-3 with a decarbonylation reagent to obtain a compound shown in a formula VII-3; reacting a compound shown in a formula VI-4 with a decarbonylation reagent to obtain a compound shown in a formula VII-4; reacting the compound shown in the formula VI-5 with a decarbonylation reagent to obtain the compound shown in the formula VII-5.
Further provided is a method for preparing berberine hydrochloride and analogues thereof, the method comprising: (1) Reacting a compound shown in a formula VII-1, a formula VII-2, a formula VII-3, a formula VII-4 or a formula VII-5 with a chlorinating agent to obtain a reaction solution; (2) Heating and refluxing the reaction liquid and zinc to react to obtain berberine hydrochloride and analogues thereof; the chlorinating agent is selected from one or more of phosphorus oxychloride, pyrophosphoryl chloride, phosphorus trichloride and phosphorus pentachloride; the structural formulas of the berberine hydrochloride and the analogues thereof are respectively shown as formulas VIII-1, VIII-2, VIII-3, VIII-4 and VIII-5, wherein X is selected from H or halogen in VII-1, VII-2, VII-3, VII-4, VII-5, VIII-1, VIII-2, VIII-3, VIII-4 and VIII-5.
Further, the equivalent ratio of the compound represented by the formula VII-1, VII-2, VII-3, VII-4 or VII-5 to the zinc is 1:0.5-10, preferably 1:1.5-3.
Further, in the step (1), the temperature is 70-90 ℃.
Further, in the step (1), the reaction solvent of the reaction is selected from one or more of formic acid and acetic acid.
Preferably, the chlorinating agent is selected from phosphorus oxychloride.
Preferably, the reaction time is selected from 2 to 8 hours, more preferably 2,5,8 hours, and even more preferably 2 hours.
Specifically, the structural formula of the berberine hydrochloride and the analogues thereof is shown as a formula VIII-1, and the preparation method comprises the following steps: (1) Reacting a compound shown in a formula VII-1 with a chloro reagent to obtain a reaction solution; (2) And heating and refluxing the reaction liquid and zinc to react to obtain berberine hydrochloride shown in the formula VIII-1 and analogues thereof.
Specifically, the structural formula of the berberine hydrochloride and the analogues thereof is shown as a formula VIII-2, and the preparation method comprises the following steps: (1) Reacting a compound shown in a formula VII-2 with a chloro reagent to obtain a reaction solution; (2) And heating and refluxing the reaction liquid and zinc to react to obtain berberine hydrochloride shown in the formula VIII-2 and analogues thereof.
Specifically, the structural formula of the berberine hydrochloride and the analogues thereof is shown as a formula VIII-3, and the preparation method comprises the following steps: (1) Reacting a compound shown in a formula VII-3 with a chloro reagent to obtain a reaction solution; (2) And heating and refluxing the reaction liquid and zinc to react to obtain berberine hydrochloride shown in the formula VIII-3 and analogues thereof.
Specifically, the structural formula of the berberine hydrochloride and the analogues thereof is shown as the formula VIII-4, and the preparation method comprises the following steps: (1) Reacting a compound shown in a formula VII-4 with a chloro reagent to obtain a reaction solution; (2) And heating and refluxing the reaction liquid and zinc to react to obtain berberine hydrochloride shown in the formula VIII-4 and analogues thereof.
Specifically, the structural formula of the berberine hydrochloride and the analogues thereof is shown as the formula VIII-5, and the preparation method comprises the following steps: (1) Reacting a compound shown in a formula VII-5 with a chloro reagent to obtain a reaction solution; (2) And heating and refluxing the reaction liquid and zinc to react to obtain berberine hydrochloride shown in the formula VIII-5 and analogues thereof.
Further, in the compound IV, the method for preparing the compound IV (x=br) from the compound IV (x=h) is as follows: compound IV (x=h) was dissolved in dry acetonitrile, NBS solid (1.2 eq) was slowly added at 0 ℃, reflux reaction was carried out overnight at 80 ℃, TLC was monitored until the reaction of the starting materials was complete, stirring was stopped, cooled to room temperature, the remaining solvent was removed under reduced pressure, ethyl acetate was added, the solid was removed by filtration, extraction with ethyl acetate, saturated brine, dried over anhydrous sodium sulfate, filtration and concentration under reduced pressure to give crude product, and column chromatography gave the product as pale yellow liquid compound IV (x=br).
In certain embodiments, the method of preparing compound IV (x=cl) from compound IV (x=h) is specifically: compound IV (x=h) (25.8 g,100.0 mmol) was dissolved in dry acetonitrile (400.0 mL), NCS solid (1.2 eq) was slowly added at 0 ℃, reflux reacted overnight at 80 ℃, TLC monitored until the starting material was complete, stirring stopped, cooled to room temperature, ethyl acetate was added after removing the remaining solvent under reduced pressure, the solid was removed by filtration, ethyl acetate extraction (100.0 ml×3), saturated brine wash, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give crude product, column chromatography afforded the product pale yellow liquid compound IV (x=cl).
In the present invention, the structural formula of the related compound is shown in the following table 1:
TABLE 1 structural formula of Compounds according to the invention
The invention has the beneficial effects that
The intermediate of the berberine hydrochloride and the analogues thereof and the preparation method of the berberine hydrochloride and the analogues thereof avoid the reaction catalyzed by high-pressure axe, hydrogen and noble metal, reduce the process cost and are suitable for industrial production.
The intermediate of the berberine hydrochloride and the analogues thereof and the preparation method of the berberine hydrochloride and the analogues thereof avoid the use of the cyanide of the drastic drugs and increase the safety.
The intermediate of the berberine hydrochloride and the analogues thereof and the preparation method of the berberine hydrochloride and the analogues thereof have simple post-treatment process, and the product purity and the yield are improved.
Detailed Description
The examples are presented for better illustration of the invention, but the invention is not limited to the examples. Those skilled in the art will appreciate that various modifications and adaptations of the embodiments described above are possible in light of the above teachings and are intended to be within the scope of the invention.
In the embodiment of the invention, piperonylethylamine is used as an initial raw material for preparing berberine hydrochloride intermediates and berberine hydrochloride, and the synthetic route is as follows:
in the embodiment of the invention, the structural formula of the compound 2a is as follows:
EXAMPLE 1 Synthesis of Compound 3a
Piperonylethylamine 1a (181.7 g,1.1 mol) and diethyl oxalate (1.15 eq) were refluxed in toluene for 8 hours, cooled to room temperature,recrystallizing petroleum ether ethyl acetate, drying to obtain ethyl formyl piperonylethylamine, and directly carrying out the next step; ethyl formylpiperazine (265.0 g,1 mol) was dissolved in 1.0L acetonitrile in N 2 Under the protection of gas, 152.0mL (1.1 mol,1.1 eq) of pyrophosphoryl chloride was added, the mixture was heated to reflux, heated for 6h, and cooled to room temperature. Spin-evaporating to remove solvent, pouring into 1L ice water, and using K 2 CO 3 The solid was adjusted to pH 9, extracted with ethyl acetate (500.0 mL. Times.3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered off the drying agent, and the solvent was recovered by distillation to give compound 3a as a powdery solid (220.0 g, yield 90%, mp:79-80 ℃, purity greater than 95%).
EXAMPLE 2 Synthesis of Compound 4a
Meconnin 2a (97.0 g,500.0 mmol) was dissolved in absolute ethanol (400.0 mL) and slowly added dropwise to the distilled SOCl at 0deg.C 2 (135.0 mL), after the completion of the dropwise addition, the reaction is carried out at room temperature for 72h, stirring is stopped, ice water (200.0 mL) is poured for quenching, naOH solid powder (129.0 g) is added for multiple times, ethyl acetate is used for extraction (200.0 mL multiplied by 3), saturated saline is used for washing with water, anhydrous sodium sulfate is dried, filtration and reduced pressure concentration are carried out, colorless liquid 4a (93.0 g, yield 72%) is obtained, the crude product is not purified, and the crude product can be directly put into the next step, and is consistent with the data of the known literature. Wherein the alkali can be sodium hydroxide, sodium carbonate, potassium carbonate, preferably sodium hydroxide; wherein the temperature is 25 ℃,30 ℃,45 ℃, preferably 25 ℃.
EXAMPLE 3 Synthesis of Compound 5a
Compound 3a (22.3 g,90.0 mmol) was dissolved in DMF (120.0 mL) and cooled to-60℃N 2 Under protection, the mixture was dissolved in DMF (100.0 mL) t BuOK (20.2 g,180.0 mmol) was slowly added to the reaction system, which turned to dark green immediately, stirred at-60℃for 1h, then DMF (80.0 mL) dissolved compound 4a (30.4 g,117.0 mmol) was added dropwise, stirred for another 4h, after stopping stirring, saturated NaHCO was added at room temperature 3 Quenching (60.0 mL), extracting with ethyl acetate (50.0 mL. Times.3), saturated saline washing, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain yellow solid crude product, recrystallizing with ethyl acetate-petroleum ether to obtain pale yellow solid 5a (yield 72%, purity greater than 95%).
EXAMPLE 4 Synthesis of Compound 6a
Compound 5a (35.0 g,81.7 mmol) was dissolved in trifluoroacetic acid-formic acid (100.0 mL, v/v=1:1) and NaBH was added in portions at room temperature 4 (18.5 g,489.0 mmol), maintaining the internal temperature at 60deg.C, removing residual solvent under reduced pressure, and adding saturated Na 2 CO 3 Quenching the solution, extracting with dichloromethane, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain crude product, and recrystallizing with ethyl acetate-petroleum ether to obtain white solid compound 6a (yield 82%, purity more than 95%).
EXAMPLE 5 Synthesis of Compound 7a
Compound 6a (27.0 g,68.0 mmol) was dissolved in ethanol (100.0 mL), 6N NaOH (100.0 mL) was added, heated at 60 ℃ for 3h, cooled to room temperature, the remaining ethanol was removed under reduced pressure, ph=2 was adjusted by adding 3M hydrochloric acid solution, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give crude product, and recrystallized from methanol-water to give colorless solid powder 7a (yield 96%, purity greater than 95%).
Wherein compound 7a can be directly prepared from 5a by a one-pot method: experimental procedures are the same as the synthesis of the compound 6a, naOH(s) is used for quenching reaction, ethanol is used for heating at 60 ℃ for 3 hours, cooling is carried out to room temperature, the subsequent operation is the same as the synthesis of the compound 7a, and the compound 7a can be obtained through methanol-water recrystallization. The preparation of 7a by a one-pot method is simple in post-treatment operation, production time is saved, and production efficiency is improved.
EXAMPLE 6 Synthesis of Compound 8a
Compound 7a (17.0 g,42.8 mmol) was placed in a two-necked flask, N 2 Trifluoroacetic anhydride (18.0 mL) was added thereto at 0deg.C, stirred at room temperature for 10h, and the remaining trifluoroacetic anhydride was distilled off under reduced pressure to saturate NaHCO 3 Quenching, extraction with ethyl acetate (20.0 mL. Times.3), saturated saline washing, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain crude product, and recrystallizing with ethyl acetate-petroleum ether to obtain pale yellow compound 8a (yield 83%, purity more than 95%).
EXAMPLE 7 Synthesis of Compound 9a
Compound 8a (10.5 g,30.0 mmol) was placed in a round bottom flask and POCl was added at room temperature 3 (32.0 mL), heating and refluxing at 80 ℃ for 2h, and subtracting after the raw materials react completelyExcess phosphorus oxychloride was removed by pressure distillation, the color changed from yellow to orange, and the crude product was used directly in the next step;
zinc powder (2.3 g,36.0 mmol) is added into the crude product reaction bottle, glacial acetic acid (80.0 mL) is added and mixed, heating and refluxing are carried out for 1.5h, the reaction liquid is cooled to 0 ℃, 0.4mL of concentrated hydrochloric acid is added dropwise to adjust the pH value to be 1-2, after filtration, water (250.0 mL) is added into a filter cake to dissolve, the temperature is kept at 80 ℃ for 30min, caO (4.0 g) is added to adjust the pH value to be 8-8.5, filtration is carried out while the filter cake is hot, concentrated hydrochloric acid is added into the filtrate to adjust the pH value to be 1-2, crystallization is carried out below 5 ℃, berberine hydrochloride and analogues crude product 9a can be obtained, 70% ethanol is crystallized twice, and refined berberine hydrochloride and analogues 9a (yield is 60%, purity is more than 97%) can be obtained). Finally, it is noted that the above embodiments are only for illustrating the technical solution of the present invention and not for limiting the same, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications and equivalents may be made thereto without departing from the spirit and scope of the technical solution of the present invention, which is intended to be covered by the scope of the claims of the present invention.
Claims (9)
1. The preparation method of berberine hydrochloride and analogues thereof is characterized by comprising the following steps: (1) Reacting a compound shown in a formula VII-1, a formula VII-2, a formula VII-3, a formula VII-4 or a formula VII-5 with a chlorinating agent to obtain a reaction solution; (2) Heating and refluxing the reaction liquid with zinc and acetic acid for reaction, and then acidifying and crystallizing by hydrochloric acid to obtain berberine hydrochloride and analogues thereof; the chlorinating agent is selected from one or more of phosphorus oxychloride, pyrophosphoryl chloride, phosphorus trichloride and phosphorus pentachloride; the structural formulas of the berberine hydrochloride and the analogues thereof are respectively shown as formulas VIII-1, VIII-2, VIII-3, VIII-4 and VIII-5,
the structural formulas of the compounds shown in the formulas VII-1, VII-2, VII-3, VII-4 and VII-5 are respectively shown as follows:
wherein X is selected from H or halogen.
2. The process of claim 1, wherein the equivalent ratio of the compound of formula VII-1, VII-2, VII-3, VII-4 or VII-5 to the zinc is 1:0.5-10.
3. The process according to claim 1, wherein in step (1), the temperature of the reaction is from 70 ℃ to 90 ℃.
4. The process according to claim 1, wherein in the step (1), the process for producing the compound of formula VII-1, VII-2, VII-3, VII-4 or VII-5 comprises: reacting a compound shown in a formula VI-1, VI-2, VI-3, VI-4 or VI-5 with a decarbonylation reagent to obtain a compound shown in a formula VII-1, VII-2, VII-3, VII-4 or VII-5, wherein the decarbonylation reagent is selected from one or more of phosphorus oxychloride, pyrophosphorylchloride, trichloroacetic anhydride, trifluoroacetic anhydride and difluoroacetic anhydride;
wherein X is selected from H or halogen, and R is selected from H.
5. The process of claim 4, wherein the process for preparing the compound of VI-1, VI-2, VI-3, VI-4 or VI-5 comprises: mixing a compound represented by the formula V-1, V-2, V-3, V-4 or V-5 with NaBH 4 After the reaction, adding alkali and ethanol to react at 50-70 ℃ to obtain the compound shown in the formulas VI-1, VI-2, VI-3, VI-4 or VI-5;
wherein X is selected from H or halogen.
6. The method of claim 5, wherein the method for preparing the compound of V-1, V-2, V-3, V-4, V-5 comprises: (1) Reacting a compound shown in a formula II-1, II-2 or II-3 with alkali at a temperature of between 70 ℃ below zero and 20 ℃ below zero to obtain a reaction solution; (2) Adding the reaction liquid into a compound shown in the formula IV-1, IV-2 or IV-3 for reaction;
wherein X is selected from H or halogen.
7. The process according to claim 6, wherein the reaction solvent for the reaction in the step (1) and the step (2) is one or more selected from the group consisting of N, N-dimethylformamide and THF.
8. The method according to claim 6, wherein the base is one or more selected from NaH, sodium methoxide and potassium tert-butoxide.
9. The process according to claim 6, wherein the process for producing the compound of formula II-1, II-2 or II-3 comprises: (1) Reflux-reacting a compound shown in the formula I-1, I-2 or I-3 with diethyl oxalate, cooling, recrystallizing and drying to obtain an intermediate; (2) Then heating the intermediate and a dehydration reagent to reflux for reaction to obtain a compound shown in the formula II-1, II-2 or II-3; the dehydration reagent is selected from one or more of phosphorus oxychloride and pyrophosphoryl chloride; and/or the preparation method of the compound shown in the formula IV-1, IV-2 or IV-3 comprises the following steps: dropwise adding a compound of formula III-1, III-2 or III-3 at-5-50deg.C to steam SOCl 2 Carrying out reaction to obtain a compound shown in a formula IV-1, IV-2 or IV-3;
wherein X is selected from H.
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