CN114315823A - Intermediate of berberine hydrochloride and analogue 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 as a formula II-1, II-2 or II-3 with alkali at-70 ℃ to-20 ℃ to obtain a reaction solution; (2) adding a compound shown as a formula IV-1, IV-2 or IV-3 into the reaction liquid 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 of high pressure axe, hydrogen and noble metal catalysis, 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 and sabelline, is a natural benzylisoquinoline alkaloid. The chemical name is as follows: 5, 6-dihydro-9, 10-dimethoxybenzo [ g)]-1, 3-benzodioxole [5, 6-alpha ]]Quinolizine hydrochloride dihydrate of formula C20H18ClNO5·2H2O, which was originally isolated from barberry bark in 1830 by Buchner et al (Buchner, J.A.; Herberger J.E.Reert.pharm.1830, 36, 1). At present, people can separate berberine from 4 plants of 10 species of the family, wherein berberis poiretii is one of the main plant sources for extracting and separating berberine (Chenyongmei, Chenrenhua, Shizhen national medicine, 2007,18 and 6).
Berberine shows good biological activity in diseases of central nervous system, cardiovascular system and motor system. The first 1969 s, the Amin group reported for the first time that berberine had varying degrees of inhibitory effect on G +, G-and fungi (Amin, a.h.; subciaah, t.v.; Abbasi, k.m. can.j.microbiol.1969,15,1067). Later, several groups of studies found that berberine showed different bacteriostatic activities against various bacteria or fungi, including methicillin-resistant staphylococcus aureus (MRSA), helicobacter pylori, mycobacterium tuberculosis, etc. The possible mechanism of inhibition is as follows: 1) berberine can combine with single-stranded or double-stranded DNA of thallus to form a compound, thereby inhibiting biosynthesis of protein and lipid and glycolysis of sugar; 2) berberine can inhibit the activity of topoisomerase and the like (Inoue, n.; terabayashi, t.; Takiguchi-Kawashima, Y.; scientific Reports 2021,11, 7718). Clinically, berberine is mainly used to treat bacterial infectious diseases such as bacillary dysentery and gastroenteritis (the best medical information in the world, 2019,19,231, from the Zijuan, He Meng Jing. The recent research shows that berberine is expected to be used for clinical treatment of cancers and frequently-occurring diseases such as 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 (Populus euphratica, Liuming, Guangzhou chemical, 2012,40,91.), and chemical synthesis are the main ways to obtain berberine. Among them, chemical synthesis is the most dominant and most direct source.
Since the first reports of total berberine synthesis by Kametani et al (Kametani, t.; Noguchi, i.; Saito, k.; Kaneda, s.j.chem.soc.c 1969,2036.) in the sixty years of the last century, 8 synthetic methods for berberine have been developed. These synthetic methods can be divided into three classes (Yan, x.f.; Zheng, j.f.; Li, Wei-Dong z.chi.j.org.chem.2021, 41,2217.) biomimetic synthetic strategy (C1 cyclization) (Cutter, p.s.; Miller, r.b.; Schore, n.e.tetrahedron 2002,58,1471.), intermolecular coupling strategy (C2 cyclization) (Chen, s.q.; Lin w.f.; Zang, j.h.; Liu j.h.; Qi, s.h.; Zhang, l.q.; Song, g.l.cn 1310, 2001.Tang c.g.1063171, 2017.Feng, x.; Chen l.o, c.a.cn.36, and other catalytic methods (e.g. 22, p.2014) and p.g. 2014.7. Industrially, piperonylethylamine and veratraldehyde are mostly used as raw materials (northeast pharmaceutical headquarters, journal of the Chinese pharmaceutical industry, 1972, (4),4.), and are firstly condensed to form an imine intermediate, and then the synthesis of berberine hydrochloride is completed through the steps of reduction, salification, cyclization, alkalization, acidification and the like.
At present, in the developed synthesis method or process of berberine hydrochloride and analogues thereof, the problems of high pressure kettle, highly toxic cyanide and 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 rich pharmacological activity and important application of the berberine hydrochloride and the analogues thereof in medicines, the development of a convenient and efficient chemical synthesis method of the compound has important commercial value.
Disclosure of Invention
In view of the above, the present invention provides an intermediate of berberine hydrochloride and its analogues and a preparation method thereof (berberine hydrochloride and its analogues), which solves the problems of the existing preparation method, such as the use of autoclave, highly toxic cyanide and noble metal catalysis, difficult post-treatment, etc., and has important significance for exerting its wide medical research value and synthesizing other compounds as reaction substrates.
The structural formula of the intermediate of the berberine hydrochloride and the analogue 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 as a formula II-1, II-2 or II-3 with alkali at-70 ℃ to-20 ℃ to obtain a reaction solution; (2) adding a compound shown as a formula IV-1, IV-2 or IV-3 into the reaction liquid 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 the berberine hydrochloride and the analogue thereof is shown as V-1, the preparation method comprises the following steps: (1) reacting a compound shown as a formula II-1 with alkali at-70 to-20 ℃ to obtain a reaction solution; (2) adding a compound shown in a formula IV-1 into the reaction liquid for reaction;
specifically, when the structural formula of the intermediate of the berberine hydrochloride and the analogue thereof is shown as V-2, the preparation method comprises the following steps: (1) reacting a compound shown as a formula II-1 with alkali at-70 to-20 ℃ to obtain a reaction solution; (2) adding the reaction liquid into a compound shown as a formula IV-2 for reaction;
specifically, when the structural formula of the intermediate of the berberine hydrochloride and the analogue thereof is shown as V-3, the preparation method comprises the following steps: (1) reacting a compound shown as II-2 with alkali at-70 to-20 ℃ to obtain a reaction solution; (2) adding a compound shown in a formula IV-1 into the reaction liquid for reaction;
specifically, when the structural formula of the intermediate of the berberine hydrochloride and the analogue thereof is shown as V-4, the preparation method comprises the following steps: (1) reacting a compound shown as II-2 with alkali at-70 to-20 ℃ to obtain a reaction solution; (2) adding the reaction liquid into a compound shown as a formula IV-2 for reaction;
specifically, when the structural formula of the intermediate of the berberine hydrochloride and the analogue thereof is shown as V-5, the preparation method comprises the following steps: (1) reacting a compound shown as II-3 with alkali at-70 to-20 ℃ to obtain a reaction solution; (2) adding a compound shown in a formula IV-3 into the reaction liquid for reaction.
Further, the reaction solvent of the reaction in the step (1) and the step (2) is one or more of N, N-dimethylformamide and THF.
Further, the base is selected from one or more of NaH, sodium methoxide and potassium tert-butoxide, preferably 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) refluxing and reacting a compound shown as a 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/orThe preparation method of the compound shown in the formula IV-1, IV-2 or IV-3 comprises the following steps: dropping heavy-distilled SOCl into the compound shown as the formula III-1, III-2 or III-3 at-5-50 DEG C2Carrying out reaction to obtain a compound shown as a formula IV-1, IV-2 or IV-3; wherein, X is selected from H.
Specifically, the preparation method of the compound shown as the formula II-1 comprises the following steps: (1) carrying out reflux reaction on a compound shown as a formula I-1 and 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 as a formula II-1;
specifically, the preparation method of the compound shown as the formula II-2 comprises the following steps: (1) carrying out reflux reaction on a compound shown as a formula I-2 and 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 as a formula II-2;
specifically, the preparation method of the compound shown as the formula II-3 comprises the following steps: (1) carrying out reflux reaction on a compound shown as a formula I-3 and 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 as a formula II-3;
specifically, the preparation method of the compound shown in the formula IV-1 comprises the following steps: dropping heavy-distilled SOCl at-5-50 deg.C for the compound shown in formula III-12Carrying out reaction to obtain a compound shown as a formula IV-1;
specifically, the preparation method of the compound shown in the formula IV-2 comprises the following steps: dropping heavy-distilled SOCl at-5-50 deg.C for the compound shown in formula III-22Carrying out reaction to obtain a compound shown as a formula IV-2;
specifically, the preparation method of the compound shown in the formula IV-3 comprises the following steps: dropping heavy-distilled SOCl at-5-50 deg.C for the compound shown in formula III-32Carrying out reaction to obtain the compound shown as the formula IV-3.
Further, after reacting the compound shown in the formula V-1, V-2, V-3, V-4 or V-5 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, 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 one or more selected from dichloromethane, acetic acid, formic acid, acetonitrile, tetrahydrofuran and trifluoroacetic acid, and preferably formic acid-trifluoroacetic acid v/v ═ 1: 1.
Further, the alkali can be one or more of sodium hydroxide, potassium hydroxide and preferably sodium hydroxide; wherein the alkali concentration can be selected from 2N NaOH,3N NaOH,6N NaOH,10N NaOH, preferably 6N NaOH, and the temperature can be selected from 50 deg.C, 60 deg.C, 70 deg.C, preferably 60 deg.C.
Specifically, after reacting a compound shown as a formula V-1 with a reducing agent, adding alkali and ethanol, and reacting at 50-70 ℃ to obtain a compound shown as a formula VI-1;
specifically, after reacting a compound shown as a formula V-2 with a reducing agent, adding alkali and ethanol, and reacting at 50-70 ℃ to obtain a compound shown as a formula VI-2;
specifically, after reacting a compound shown as a formula V-3 with a reducing agent, adding alkali and ethanol, and reacting at 50-70 ℃ to obtain a compound shown as a formula VI-3;
specifically, after reacting a compound shown as a formula V-4 with a reducing agent, adding alkali and ethanol, and reacting at 50-70 ℃ to obtain a compound shown as a formula VI-4;
specifically, after reacting the compound shown as the formula V-5 with a reducing agent, adding alkali and ethanol, and reacting at 50-70 ℃ to obtain the compound shown as 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 a mixture of more of phosphorus oxychloride, pyrophosphoryl chloride, trichloroacetic anhydride, trifluoroacetic anhydride and difluoroacetic anhydride; wherein, X is selected from H or halogen.
Specifically, the compound shown as the formula VI-1 and a decarbonylation reagent are reacted to obtain the compound shown as the formula VII-1; reacting a compound shown as a formula VI-2 with a decarbonylation reagent to obtain a compound shown as a formula VII-2; reacting a compound shown as a formula VI-3 with a decarbonylation reagent to obtain a compound shown as a formula VII-3; reacting a compound shown as a formula VI-4 with a decarbonylation reagent to obtain a compound shown as a formula VII-4; and (3) reacting the compound shown as the formula VI-5 with a decarbonylation reagent to obtain the compound shown as the formula VII-5.
Further provides a preparation method of berberine hydrochloride and analogues thereof, which comprises the following steps: (1) reacting a compound shown as a formula VII-1, VII-2, VII-3, VII-4 or VII-5 with a chlorinated reagent to obtain a reaction solution; (2) heating and refluxing the reaction liquid and zinc to react to obtain the berberine hydrochloride and analogues thereof; the chlorinated reagent 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 in VII-1, VII-2, VII-3, VII-4, VII-5, VIII-1, VIII-2, VIII-3, VIII-4 and VIII-5, X is selected from H or halogen.
Further, the equivalent ratio of the compound shown as the formula VII-1, VII-2, VII-3, VII-4 or VII-5 to the zinc is 1: 0.5 to 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 one or more of formic acid and acetic acid.
Preferably, the chlorinating agent is selected from phosphorus oxychloride.
Preferably, the reaction time may be selected from 2 to 8 hours, more preferably 2,5, 8 hours, more preferably 2 hours.
Specifically, the structural formula of the berberine hydrochloride and the analogue thereof is shown as a formula VIII-1, and the preparation method comprises the following steps: (1) reacting a compound shown as a formula VII-1 with a chlorinated reagent to obtain a reaction solution; (2) 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 analogue thereof is shown as a formula VIII-2, and the preparation method comprises the following steps: (1) reacting a compound shown as a formula VII-2 with a chlorinated reagent to obtain a reaction solution; (2) 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 analogue thereof is shown as a formula VIII-3, and the preparation method comprises the following steps: (1) reacting a compound shown as a formula VII-3 with a chlorinated reagent to obtain a reaction solution; (2) 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 analogue thereof is shown as a formula VIII-4, and the preparation method comprises the following steps: (1) reacting a compound shown as a formula VII-4 with a chlorinated reagent to obtain a reaction solution; (2) 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 analogue thereof is shown as a formula VIII-5, and the preparation method comprises the following steps: (1) reacting a compound shown as a formula VII-5 with a chlorinated reagent to obtain a reaction solution; (2) 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 ═ R) from the compound IV (X ═ H) is as follows: dissolving a compound IV (X ═ H) in dry acetonitrile, slowly adding NBS (or NCS) solid (1.2eq) at 0 ℃, refluxing at 80 ℃ for reaction overnight, monitoring by TLC until the raw material is completely reacted, stopping stirring, cooling to room temperature, removing residual solvent under reduced pressure, adding ethyl acetate, filtering to remove the solid, extracting by ethyl acetate, washing by saturated salt water, drying by anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain a crude product, and performing column chromatography to obtain a product, namely a light yellow liquid compound IV (X ═ Br).
In certain embodiments, the method for preparing compound IV (X ═ R) from compound IV (X ═ H) is specifically: dissolving compound IV (X ═ H) (25.8g,100.0mmol) in dry acetonitrile (400.0mL), slowly adding NBS (or NCS) solid (1.2eq) at 0 ℃, refluxing at 80 ℃ overnight, monitoring by TLC until the reaction of the starting material is complete, stopping stirring, cooling to room temperature, removing the remaining solvent under reduced pressure, adding ethyl acetate, filtering to remove the solid, extracting with ethyl acetate (100.0mL × 3), washing with saturated brine, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain a crude product, and performing column chromatography to obtain a light yellow liquid compound IV (X ═ Cl).
In the present invention, the structural formula of the related compounds is shown in the following table 1:
TABLE 1 structural formula of compound related to the present invention
The invention has the beneficial effects that
The intermediate of the berberine hydrochloride and the analogue thereof and the preparation method of the berberine hydrochloride and the analogue thereof avoid the reaction catalyzed by a 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 analogue thereof and the preparation method of the berberine hydrochloride and the analogue thereof avoid the use of highly toxic cyanide and increase the safety.
The intermediate of the berberine hydrochloride and the analogue thereof and the post-treatment process of the preparation method of the berberine hydrochloride and the analogue thereof provided by the invention have the advantages of simple process, high product purity and high yield.
Detailed Description
The examples are given for the purpose of better illustration of the invention, but the invention is not limited to the examples. Therefore, those skilled in the art should make insubstantial modifications and adaptations to the embodiments of the present invention in light of the above teachings and remain within the scope of the invention.
In the embodiment of the invention, piperonylethylamine is used as an initial raw material to prepare a berberine hydrochloride intermediate and berberine hydrochloride, and the synthetic route is as follows:
in the examples of the present invention, the structural formula of compound 2a is:
EXAMPLE 1 Synthesis of Compound 3a
Refluxing piperonylethylamine 1a (181.7g,1.1mol) and diethyl oxalate (1.15eq) in toluene solution for 8h, cooling to room temperature, recrystallizing with petroleum ether ethyl acetate, and drying to obtain ethylcarbamyl piperonylethylamine which can be directly used for the next step; ethylesterformylpiperonylethylamine (265.0g,1mol) was dissolved in 1.0L acetonitrile in N2Under the protection of gas, 152.0mL (1.1mol, 1.1eq) of pyrophosphoryl chloride is added, the mixture is heated to reflux and heated for 6h, and then cooled to room temperature. Removing the solvent by rotary evaporation, pouring into 1L ice water, and adding K2CO3The solid was adjusted to pH 9, extracted with ethyl acetate (500.0 mL. times.3), washed with saturated brine, dried over anhydrous sodium sulfate of the organic phase, filtered off the drying agent, and the solvent was recovered by distillation to give compound 3a as a powdery solid (220.0g, yield 90%, mp:79-80 ℃ C., purity > 95%).
EXAMPLE 2 Synthesis of Compound 4a
Meconnin 2a (97.0g,500.0mmol) was dissolved in absolute ethanol (400.0mL) and slowly added dropwise to heavily evaporate SOCl at 0 deg.C2(135.0mL), after the dropwise addition, the reaction was carried out at room temperature for 72 hours, the stirring was stopped, the reaction mixture was quenched by pouring ice water (200.0mL), and NaOH solid powder (129.0g) was added in portions, extracted with ethyl acetate (200.0 mL. times.3), washed with saturated brine, and then dried with anhydrous sulfurSodium acid drying, filtration, reduced pressure concentration to colorless liquid 4a (93.0g, yield 72%), crude product without purification, can be directly put into the next step, and known literature data comparison is consistent. Wherein the alkali can be selected from sodium hydroxide, sodium carbonate, potassium carbonate, preferably sodium hydroxide; wherein the temperature can be 25 deg.C, 30 deg.C, 45 deg.C, preferably 25 deg.C.
EXAMPLE 3 Synthesis of Compound 5a
Dissolve Compound 3a (22.3g,90.0mmol) in DMF (120.0mL), cool to-60 deg.C, N2Under protection, the solution is dissolved in DMF (100.0mL)tBuOK (20.2g,180.0mmol) was slowly added to the reaction, which immediately turned dark green, -60 ℃ stirred for 1h, followed by dropwise addition of Compound 4a (30.4g,117.0mmol) dissolved in DMF (80.0mL), stirring for 4h, after the stirring was stopped, to room temperature saturated NaHCO was added3Quenching (60.0mL), extracting with ethyl acetate (50.0mL × 3), washing with saturated brine, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain a yellow solid crude product, and recrystallizing with ethyl acetate-petroleum ether to obtain a pale yellow solid 5a (yield 72%, purity greater than 95%).
EXAMPLE 4 Synthesis of Compound 6a
Compound 5a (35.0g,81.7mmol) was dissolved in trifluoroacetic acid-formic acid (100.0mL, v/v ═ 1:1) and NaBH was added portionwise at room temperature4(18.5g,489.0mmol), maintaining the internal temperature at 60 deg.C until the starting materials react completely, removing the remaining solvent under reduced pressure, and adding saturated Na2CO3Quenching the solution, extracting with dichloromethane, washing with saturated salt water, 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 greater than 95%).
EXAMPLE 5 Synthesis of Compound 7a
Dissolving compound 6a (27.0g,68.0mmol) in ethanol (100.0mL), adding 6N NaOH (100.0mL), heating at 60 ℃ for 3h, cooling to room temperature, removing the remaining ethanol under reduced pressure, adding 3M hydrochloric acid solution to adjust pH to 2, extracting with dichloromethane, washing with saturated brine, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain crude product, and recrystallizing with methanol-water to obtain colorless solid powder 7a (yield 96%, purity greater than 95%).
Wherein the compound 7a can be directly prepared by a 5a one-pot method: the experimental operation was carried out with the synthesis of compound 6a, quenching reaction was carried out with NaOH(s), ethanol, heating at 60 ℃ for 3h, cooling to room temperature, the subsequent operation was the same as the synthesis of 7a, and methanol-water recrystallization gave 7 a. Namely, the 7a can be prepared by a one-pot method, namely, the post-treatment operation is simple, the production time is saved, and the production efficiency is improved.
EXAMPLE 6 Synthesis of Compound 8a
Compound 7a (17.0g,42.8mmol) was placed in a two-necked flask, N2Trifluoroacetic anhydride (18.0mL) was added at 0 ℃ and stirred at room temperature for 10h, and the remaining trifluoroacetic anhydride, saturated NaHCO, was removed by distillation under reduced pressure3Quenching, ethyl acetate extraction (20.0mL × 3), washing with saturated brine, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain crude product, and recrystallizing with ethyl acetate-petroleum ether to obtain light yellow compound 8a (yield 83%, purity greater than 95%).
EXAMPLE 7 Synthesis of Compound 9a
Compound 8a (10.5g,30.0mmol) was placed in a round bottom flask and POCl was added at room temperature3(32.0mL), heating and refluxing for 2h at 80 ℃, after the raw materials react completely, removing excessive phosphorus oxychloride by reduced pressure distillation, wherein the color changes from yellow to orange, and the crude product is directly used in the next step;
adding zinc powder (2.3g,36.0mmol) into the crude product reaction bottle, adding glacial acetic acid (80.0mL), mixing, heating and refluxing for 1.5h, cooling the reaction solution to 0 ℃, dropwise adding 0.4mL of concentrated hydrochloric acid to adjust the pH value to 1-2, filtering, adding water (250.0mL) into a filter cake to dissolve, keeping the temperature at 80 ℃ for 30min, adding CaO (4.0g) to adjust the pH value to 8-8.5, filtering while hot, adding concentrated hydrochloric acid into the filtrate to adjust the pH value to 1-2, cooling to below 5 ℃ to crystallize, thus obtaining crude berberine hydrochloride and analogues 9a, crystallizing with 70% ethanol twice to obtain refined berberine hydrochloride and analogues 9a (yield 60%, purity is more than 97%). Finally, the above embodiments are only intended to illustrate the technical solution of the present invention and not to limit the same, and although the present invention has been described in detail with reference to the preferred embodiments, it will be understood by those skilled in the art that modifications or equivalent substitutions may be made to the technical solution of the present invention without departing from the spirit and scope of the technical solution of the present invention, which shall be covered by the claims of the present invention.
Claims (10)
1. A preparation method of an intermediate of berberine hydrochloride and analogues thereof, wherein the structural formula of the intermediate is shown as V-1, V-2, V-3, V-4 and V-5, and is characterized in that the preparation method comprises the following steps: (1) reacting a compound shown as a formula II-1, II-2 or II-3 with alkali at-70 ℃ to-20 ℃ to obtain a reaction solution; (2) adding a compound shown as a formula IV-1, IV-2 or IV-3 into the reaction liquid for reaction;
wherein, X is selected from H or halogen.
2. The preparation method according to claim 1, wherein the reaction solvent for the reaction in step (1) and step (2) is one or more selected from the group consisting of N, N-dimethylformamide and THF.
3. The preparation method according to claim 1, wherein the base is one or more selected from NaH, sodium methoxide and potassium tert-butoxide.
4. The method according to claim 1, wherein the compound of formula II-1, II-2 or II-3 is prepared by a method comprising: (1) refluxing and reacting a compound shown as a 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: dropping the compound shown in formula III-1, III-2 or III-3 at-5-50 deg.C to evaporateSOCl2Carrying out reaction to obtain a compound shown as a formula IV-1, IV-2 or IV-3;
wherein, X is selected from H.
5. The process according to claim 1, wherein the compound of formula V-1, V-2, V-3, V-4 or V-5 is reacted with NaBH4After the reaction, 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, R is selected from H.
6. The preparation method of claim 5, wherein the compound represented by formula VI-1, VI-2, VI-3, VI-4 or VI-5 is reacted with decarbonylation reagent to obtain the compound represented by 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, pyrophosphoryl chloride, trichloroacetic anhydride, trifluoroacetic anhydride and difluoroacetic anhydride;
wherein, X is selected from H or halogen.
7. The preparation method of the berberine hydrochloride and the analogues thereof is characterized by comprising the following steps: (1) reacting a compound shown as a formula VII-1, VII-2, VII-3, VII-4 or VII-5 with a chlorinated reagent to obtain a reaction solution; (2) heating and refluxing the reaction liquid and zinc to react to obtain the berberine hydrochloride and analogues thereof; the chlorinated reagent 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 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.
8. The method according to claim 7, wherein the equivalent ratio of the compound represented by formula VII-1, VII-2, VII-3, VII-4 or VII-5 to the zinc is 1: 0.5-10.
9. The method according to claim 7, wherein the temperature in the step (1) is 70 to 90 ℃.
10. The preparation method according to claim 7, wherein in the step (1), the reaction solvent for the reaction is one or more selected from formic acid and acetic acid.
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