Berberine hydrochloride intermediate and preparation method of berberine hydrochloride

Abstract

The invention relates to the technical field of organic synthesis, in particular to a berberine hydrochloride intermediate and a preparation method of berberine hydrochloride. The preparation method of the berberine hydrochloride intermediate comprises the following steps: carrying out first reaction on 2, 3-dimethoxybenzylamine and a compound A in an optional first solvent to obtain a berberine hydrochloride intermediate B; the structural formulas of the compound A and the berberine hydrochloride intermediate B are as follows: # imgabs0 #, X is selected from at least one of O, Cl and Br, and a dotted line and double lines formed by dotted lines represent single bonds or double bonds. According to the invention, the compound A and the 2, 3-dimethoxybenzylamine are subjected to mixed reaction to synthesize the key intermediate of berberine hydrochloride, so that expensive materials such as o-veratraldehyde are not used, reaction steps are reduced, and the operation is simple and convenient. The berberine hydrochloride prepared by the method is stable in quality and can be directly used for pharmaceutical production.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a berberine hydrochloride intermediate and a preparation method of berberine hydrochloride. Background Art

[0002] Berberine hydrochloride is also known as berberine hydrochloride, and its structural formula is as follows:

[0003]

[0004] Berberine hydrochloride has long been used in clinical practice as a heat-clearing, detoxifying and antibacterial drug. It is often used to treat bacillary dysentery, acute gastroenteritis, chronic cholecystitis, conjunctivitis, suppurative otitis media and other diseases, and has significant therapeutic effects. Berberine hydrochloride is an isoquinoline alkaloid that exists in many plants of 10 genera in 4 families including Berberidaceae, such as Coptis chinensis, Phellodendron amurense, and Tripterygium wilfordii.

[0005] At present, there are two mainstream methods to obtain berberine hydrochloride. One is natural plant extraction, which is extracted from Chinese medicinal materials such as Phellodendron chinense; the other is chemical synthesis, usually starting from piperonyl ethylamine, condensing with resveratrol, and preparing it through hydrogenation reduction / sodium borohydride reduction, cyclization, purification and other processes.

[0006] There are three main existing synthetic routes for berberine hydrochloride, which are as follows:

[0007] (1) A patent application with the publication number CN1312250A reported by Northeast Pharmaceutical is representative. It uses high piperonal as raw material, synthesizes piperonyl ethylamine through two-step reaction, condenses with o-veratraldehyde, and is prepared through hydrogenation reduction, cyclization, purification and other processes. The synthetic route is as follows. This method is widely used in industrial production, but the synthesis steps are cumbersome and require two hydrogenations; the raw material o-veratraldehyde is expensive; ammonia is used in the reaction, and the reaction concentration is low and the wastewater treatment cost is extremely high.

[0008]

[0009] (2) Represented by the former Hangzhou No. 1 Pharmaceutical Factory, the piperonyl ring reacts with polyformaldehyde under acidic conditions to undergo chloromethylation, and then reacts with sodium cyanide to introduce a cyano group by a nucleophilic substitution reaction, and then hydrogenates under nickel catalysis to obtain piperonyl ethylamine, which is then cyclized to obtain the product. The synthetic route is as follows. This method has simple raw materials, but the yield of the synthetic route is low, only 11%, and sodium cyanide, a highly toxic drug, is required.

[0010]

[0011] (3) Represented by the former Nanning Pharmaceutical Factory, piperonal was used as the raw material, which reacted with nitromethane to undergo Henry reaction, and then was reduced to obtain piperonal ethylamine, which was then cyclized to obtain the product. The synthetic route is as follows.

[0012] This method uses a reducing agent, which has poor safety and uses highly toxic mercuric chloride, making it difficult to industrialize.

[0013]

[0014] The above three synthetic routes require the use of expensive raw materials and highly toxic substances, which are costly and long. Therefore, the development of a safe, environmentally friendly, and low-cost synthetic technology for berberine hydrochloride has important industrial value.

[0015] In view of this, the present invention is proposed. Summary of the invention

[0016] An object of the present invention is to provide a method for preparing a berberine hydrochloride intermediate, which avoids the use of expensive materials, has fewer reaction steps and is easy to operate.

[0017] Another object of the present invention is to provide a method for preparing berberine hydrochloride, which has low cost and is easy to operate.

[0018] In order to achieve the above-mentioned object of the present invention, the present invention provides a method for preparing a berberine hydrochloride intermediate, comprising the following steps:

[0019] 2,3-dimethoxybenzylamine and compound A are reacted in an optional first solvent to obtain berberine hydrochloride intermediate B;

[0020] The structural formula of the compound A is as follows:

[0021]

[0022] The structural formula of the berberine hydrochloride intermediate B is as follows:

[0023]

[0024] Wherein, X is selected from at least one of O, Cl and Br, and a double line consisting of a dotted line and a solid line represents a single bond or a double bond.

[0025] In a specific embodiment of the present invention, when X is O, a double line composed of a dotted line and a real line represents a double bond; the preparation method further comprises: the berberine hydrochloride intermediate B is subjected to a reduction reaction with hydrogen in an optional second solvent in the presence of a catalyst to obtain a berberine hydrochloride intermediate C;

[0026] The structural formula of the berberine hydrochloride intermediate C is as follows:

[0027]

[0028] In a specific embodiment of the present invention, the catalyst includes at least one of palladium carbon, platinum carbon and Raney nickel.

[0029] In a specific embodiment of the present invention, the first solvent and the second solvent are each independently selected from at least one of water, methanol, ethanol, acetonitrile, toluene and glacial acetic acid.

[0030] In a specific embodiment of the present invention, when X is Cl or Br, a double line consisting of a dotted line and a solid line represents a single bond; the first reaction system further includes an optional acid binding agent. Further, the acid binding agent includes at least one of K2CO3, Na2CO3, NaOH, KOH, t-BuOK and triethylamine; the first solvent includes at least one of water, methanol, ethanol, acetonitrile, toluene and acetone.

[0031] In a specific embodiment of the present invention, the temperature of the first reaction is 10-110°C, preferably 60-80°C.

[0032] In a specific embodiment of the present invention, the molar ratio of the 2,3-dimethoxybenzylamine to the compound A is (1-1.5):1.

[0033] In a specific embodiment of the present invention, when X is Cl, the preparation of the compound A comprises: 1,2-methylenedioxybenzene and compound E undergo a Friedel-Crafts reaction under the action of a Lewis acid to obtain the compound A; the compound E comprises at least one of 1-bromo-2-chloroethane, 1-chloro-2-chloroethane and 2-chloro-ethanol.

[0034] In a specific embodiment of the present invention, the Lewis acid includes at least one of AlCl3, FeCl3, TiCl4 and ZnCl2.

[0035] In another specific embodiment of the present invention, when X is Cl or Br, the preparation of the compound A comprises: performing a reduction reaction on piperonyl acetaldehyde under the action of a reducing agent to obtain a compound D, and then performing a halogenation reaction with a halogenation agent to obtain a compound A;

[0036] The structural formula of the compound D is as follows:

[0037]

[0038] In a specific embodiment of the present invention, the reducing agent includes sodium borohydride and / or potassium borohydride; the halogenating agent includes at least one of HCl, SOCl2, PCl3, POCl3, PCl5, N-chlorosuccinimide, Cl2 and HBr.

[0039] In a specific embodiment of the present invention, the preparation of 2,3-dimethoxybenzylamine comprises:

[0040] 2,3-Dimethoxybenzaldehyde and ammonia undergo reductive amination reaction in the presence of a reducing agent to obtain 2,3-dimethoxybenzylamine.

[0041] In a specific embodiment of the present invention, the reducing agent includes at least one of hydrogen, formic acid, zinc powder and sodium cyanoborohydride.

[0042] Another aspect of the present invention provides a method for preparing berberine hydrochloride, comprising the following steps:

[0043] (a) using any one of the above methods for preparing berberine hydrochloride intermediates to prepare a berberine hydrochloride intermediate C as shown in the following formula;

[0044]

[0045] (b) The berberine hydrochloride intermediate C and glyoxal are subjected to a dehydration reaction in an optional third solvent under the action of a catalyst, and then the pH value is adjusted with hydrochloric acid, and the solid is collected.

[0046] Compared with the prior art, the present invention has the following beneficial effects:

[0047] The present invention synthesizes the key intermediate of berberine hydrochloride by mixing compound A with 2,3-dimethoxybenzylamine, avoids the use of expensive materials such as o-veratraldehyde, reduces the reaction steps, and is easy to operate. The berberine hydrochloride prepared by the method of the present invention has stable quality and can be directly used in drug production. DETAILED DESCRIPTION

[0048] The technical scheme of the present invention will be clearly and completely described below in conjunction with specific embodiments, but it will be appreciated by those skilled in the art that the following described embodiments are part of embodiments of the present invention, rather than all embodiments, and are only used to illustrate the present invention, and should not be considered as limiting the scope of the present invention. Based on the embodiments in the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative work, all belong to the scope of protection of the present invention. If specific conditions are not indicated in the embodiments, they are carried out according to normal conditions or conditions recommended by the manufacturer. If the manufacturer is not indicated in the reagents or instruments used, they are all conventional products that can be purchased commercially.

[0049] In the description of the present invention, it should be noted that the terms “first”, “second” and “third” are only used for descriptive purposes and cannot be understood as indicating or implying relative importance.

[0050] In one aspect, the present invention provides a method for preparing a berberine hydrochloride intermediate, comprising the following steps:

[0051] 2,3-dimethoxybenzylamine and compound A are reacted in an optional first solvent to obtain berberine hydrochloride intermediate B;

[0052] The structural formula of compound A is as follows:

[0053]

[0054] The structural formula of berberine hydrochloride intermediate B is as follows:

[0055]

[0056] Wherein, X is selected from at least one of O, Cl and Br, and a double line consisting of a dotted line and a solid line represents a single bond or a double bond.

[0057] The present invention synthesizes the key intermediate of berberine hydrochloride by mixing compound A with 2,3-dimethoxybenzylamine, avoids the use of expensive materials such as o-veratraldehyde, reduces the reaction steps, and is easy to operate. The berberine hydrochloride prepared by the method of the present invention has stable quality and can be directly used in drug production.

[0058] Wherein, compound A comprises at least one of the following structures:

[0059]

[0060] Berberine hydrochloride intermediate B includes at least one of the following structures:

[0061]

[0062] When compound A is compound A1, berberine hydrochloride intermediate B1 is obtained after the first reaction; when compound A is compound A2 or compound A3, berberine hydrochloride intermediate B2 (same as berberine hydrochloride intermediate C) is obtained after the first reaction. The specific synthetic routes are as follows:

[0063]

[0064] In a specific embodiment of the present invention, when X is O, that is, when compound A is compound A1, the first solvent includes at least one of water, methanol, ethanol, acetonitrile, toluene and glacial acetic acid. In actual operation, the mass of the first solvent can be 3 to 10 times the mass of 2,3-dimethoxybenzylamine, such as 3 times, 5 times, 8 times, 10 times or a range composed of any two thereof, but is not limited thereto, as long as the reaction system can be mixed uniformly.

[0065] In a specific embodiment of the present invention, when X is O, the molar ratio of 2,3-dimethoxybenzylamine to compound A (A1) is (1-1.5) : 1. For example, it can be 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1 or a range consisting of any two of them.

[0066] In a specific embodiment of the present invention, when X is O, the temperature of the first reaction is 10 to 110° C., preferably 60 to 80° C. For example, it can be 10° C., 20° C., 40° C., 60° C., 70° C., 80° C., or any two thereof. In actual operation, the time of the first reaction can be 0.5 to 2 h, but is not limited thereto, and the progress of the reaction can be monitored by TLC or the like, and the reaction time can be conventionally adjusted.

[0067] In a specific embodiment of the present invention, when X is O, the double line composed of a dotted line and a real line represents a double bond; the preparation method further comprises: berberine hydrochloride intermediate B (B1) is subjected to a reduction reaction with hydrogen in an optional second solvent in the presence of a catalyst to obtain berberine hydrochloride intermediate C;

[0068] The structural formula of berberine hydrochloride intermediate C is as follows:

[0069]

[0070] When X is O, that is, compound A is compound A1, berberine hydrochloride intermediate B1 is obtained after the first reaction, and further reduction reaction can be performed to obtain berberine hydrochloride intermediate C, that is, the aforementioned berberine hydrochloride intermediate B2. The specific synthetic routes are as follows:

[0071]

[0072] In a specific embodiment of the present invention, in the reduction reaction, the catalyst includes at least one of palladium carbon, platinum carbon and Raney nickel, preferably Raney nickel. In actual operation, the catalyst can be added according to the conventional amount of the catalyst, such as the amount of the catalyst can be 0.1wt% to 5wt% of the raw material, but is not limited thereto.

[0073] In a specific embodiment of the present invention, in the reduction reaction, in the reaction system, the pressure of hydrogen is 1 to 5 MPa, such as 1 MPa, 2 MPa, 3 MPa, 4 MPa, 5 MPa or any two of them, preferably 2 to 4 MPa. The temperature of the reduction reaction is 20 to 70°C, such as 20°C, 30°C, 40°C, 50°C, 60°C, 70°C or any two of them; the time of the reduction reaction is 1 to 4 h, such as 1 h, 2 h, 3 h, 4 h, etc., but not limited thereto, the progress of the reaction can be monitored by TLC and the reaction time can be conventionally adjusted.

[0074] In a specific embodiment of the present invention, the second solvent includes at least one of water, methanol, ethanol, acetonitrile, toluene, acetone and glacial acetic acid.

[0075] In actual operation, after the first reaction, no additional post-treatment is required. It is only necessary to cool the system after the first reaction to room temperature, introduce hydrogen and adjust the hydrogen pressure, and then carry out the reduction reaction.

[0076] In a specific embodiment of the present invention, after the reduction reaction, the catalyst is removed and the product is concentrated to obtain a crude product of berberine hydrochloride intermediate C.

[0077] In a specific embodiment of the present invention, when X is Cl or Br, the double line composed of a dotted line and a solid line represents a single bond; the system of the first reaction further includes an optional acid binding agent. Further, the acid binding agent includes at least one of K2CO3, Na2CO3, NaOH, KOH, t-BuOK and triethylamine.

[0078] In a specific embodiment of the present invention, the molar ratio of the amount of the acid binding agent to the compound A (A2) is (1-3):1, such as 1:1, 2:1, 3:1, etc., but is not limited thereto.

[0079] In a specific embodiment of the present invention, when X is Cl or Br, the first solvent includes at least one of water, methanol, ethanol, acetonitrile, toluene and acetone. In actual operation, the mass of the first solvent can be 3 to 10 times the mass of 2,3-dimethoxybenzylamine, such as 3 times, 5 times, 8 times, 10 times or any two thereof, but is not limited thereto, as long as the reaction system can be mixed uniformly.

[0080] In a specific embodiment of the present invention, when X is Cl or Br, the temperature of the first reaction is 40 to 100° C., preferably 60 to 80° C.; the time of the first reaction is 2 to 48 hours.

[0081] In a specific embodiment of the present invention, when X is Cl or Br, the molar ratio of 2,3-dimethoxybenzylamine to compound A (A2 / A3) is (1-1.5) : 1. For example, it can be 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1 or a range consisting of any two of them.

[0082] In a specific embodiment of the present invention, when X is Cl or Br, the first reaction comprises: filtering to remove the catalyst, and then concentrating.

[0083] In a specific embodiment of the present invention, when X is Cl or Br, the preparation of compound A (A2 / A3) includes: piperonyl acetaldehyde undergoes a reduction reaction under the action of a reducing agent to obtain compound D, and then undergoes a halogenation reaction to obtain compound A (A2 / A3);

[0084] The structural formula of compound D is as follows:

[0085]

[0086] The synthetic route of compound A is as follows:

[0087]

[0088] In a specific embodiment of the present invention, the reducing agent includes sodium borohydride and / or potassium borohydride; the halogenating agent includes at least one of HCl, SOCl2, PCl3, POCl3, PCl5, N-chlorosuccinimide, Cl2 and HBr.

[0089] Wherein, in the preparation of compound A (A2 / A3), piperonyl acetaldehyde is reduced under sodium borohydride or potassium borohydride to obtain compound D, and compound D is halogenated with a halogenating agent to obtain the corresponding compound A (A2 / A3); the molar ratio of the reducing agent to piperonyl acetaldehyde can be (1-8):1, but is not limited thereto; the solvent used in the reduction reaction includes at least one of methanol and ethanol; the solvent used in the halogenation reaction includes dichloromethane. In actual operation, the mass of the solvent used in the reduction reaction can be 3-10 times the mass of piperonyl acetaldehyde, such as 3 times, 5 times, 8 times, 10 times or a range consisting of any two thereof, but is not limited thereto, as long as the reaction system can be mixed evenly. The mass of the solvent used in the halogenation reaction can be 3-10 times the mass of the crude product after the reduction reaction, such as 3 times, 5 times, 8 times, 10 times or a range consisting of any two thereof, but is not limited thereto, as long as the reaction system can be mixed evenly.

[0090] In a specific embodiment of the present invention, in the preparation of compound A (A2 / A3), the temperature of the reduction reaction is 30-50° C. In actual operation, after the reduction reaction is completed, water is added for quenching, and then an organic solvent is used for extraction, and the organic phase is collected and concentrated to obtain the product.

[0091] In a specific embodiment of the present invention, the molar ratio of the halogenating agent to the compound D is (0.8-1.5) : 1. For example, it can be 0.8:1, 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1 or any two thereof.

[0092] In a specific embodiment of the present invention, in the preparation of compound A (A2 / A3), the temperature of the halogenation reaction is 25 to 40° C. In actual operation, after the halogenation reaction is completed, the solvent is removed to obtain the product.

[0093] In a specific embodiment of the present invention, when X is Cl, the preparation of compound A (A2) includes: 1,2-methylenedioxybenzene and compound E undergo Friedel-Crafts reaction under the action of Lewis acid to obtain compound A (A2); compound E includes at least one of 1-bromo-2-chloroethane, 1-chloro-2-chloroethane and 2-chloro-ethanol.

[0094] The synthetic route of compound A (A2) is as follows:

[0095]

[0096] In the preparation of compound A (A2), the temperature of the Friedel-Crafts reaction is -5 to 15°C and the time is 1 to 5 hours.

[0097] In a specific embodiment of the present invention, the Lewis acid includes but is not limited to at least one of AlCl3, FeCl3, TiCl4 and ZnCl2, and the amount of Lewis acid used is a conventional catalyst amount, and the molar ratio of Lewis acid to 1,2-methylenedioxybenzene can be (1-3) : 1, such as 1:1, 1.5:1, 2:1, 3:1.

[0098] In actual operation, the solvent of the Friedel-Crafts reaction may include chlorobenzene, but is not limited thereto. The mass of chlorobenzene may be 3 to 15 times the mass of 1,2-methylenedioxybenzene, such as 3 times, 8 times, 10 times, 15 times or a range consisting of any two of them, but is not limited thereto, as long as the reaction system can be mixed uniformly. After the Friedel-Crafts reaction is completed, water is added to quench, an organic solvent is used for extraction, the organic phase is collected, and the product is concentrated.

[0099] In a specific embodiment of the present invention, the preparation of 2,3-dimethoxybenzylamine comprises:

[0100] 2,3-dimethoxybenzaldehyde and ammonia gas or ammonia water are subjected to a reductive amination reaction in the presence of a reducing agent to obtain 2,3-dimethoxybenzylamine. The reducing agent includes at least one of hydrogen gas, formic acid, zinc powder and sodium cyanoborohydride. The solvent used includes at least one of water, methanol, ethanol and toluene.

[0101] In a specific embodiment of the present invention, the molar ratio of ammonia gas or ammonia water, calculated as NH3, to 2,3-dimethoxybenzaldehyde is (1-5) : 1, such as 1:1, 2:1, 3:1, 4:1, 5:1, etc., but is not limited thereto.

[0102] In actual operation, the reductive amination reaction is carried out under the action of a catalyst, which may include a palladium-carbon catalyst. The amount of the catalyst used is the conventional amount of the catalyst.

[0103] In a specific embodiment of the present invention, the temperature of the reductive amination reaction is 70-100°C.

[0104] Another aspect of the present invention provides a method for preparing berberine hydrochloride, comprising the following steps:

[0105] (a) using any one of the above methods for preparing berberine hydrochloride intermediates to prepare a berberine hydrochloride intermediate C as shown in the following formula;

[0106]

[0107] (b) The berberine hydrochloride intermediate C is subjected to a dehydration reaction with glyoxal in an optional third solvent in the presence of a catalyst, and then the pH value is adjusted with hydrochloric acid, and the solid is collected.

[0108] The specific synthetic route is as follows:

[0109]

[0110] In actual operation, after the berberine hydrochloride intermediate C is prepared according to the aforementioned method, the crude product can be directly used for step (b) without purification.

[0111] In a specific embodiment of the present invention, in step (b), the molar ratio of berberine hydrochloride intermediate C to glyoxal is 1:(0.5-2), preferably 1:(0.8-1.2).

[0112] In actual operation, glyoxal is added in the form of an aqueous solution. The mass fraction of the glyoxal aqueous solution is not limited, for example, it can be 30% to 50%, but is not limited thereto.

[0113] In a specific embodiment of the present invention, the third solvent includes at least one of methanol, ethanol, acetonitrile, formic acid and glacial acetic acid, preferably formic acid. Further, the amount of the third solvent can be 1 to 5 times the mass of the berberine hydrochloride intermediate C, such as 2 to 3 times, but is not limited thereto.

[0114] In a specific embodiment of the present invention, in step (b), the catalyst comprises a copper salt. Further, the copper salt comprises copper sulfate. The molar ratio of the amount of the catalyst to the berberine hydrochloride intermediate C is (0.8-5):1.

[0115] In a specific embodiment of the present invention, in step (b), the temperature of the dehydration reaction is 40 to 70°C, and the time of the dehydration reaction is 2 to 8 hours. For example, in different embodiments, the temperature of the dehydration reaction can be 40°C, 50°C, 60°C, 70°C, or a range consisting of any two thereof, and the time of the dehydration reaction can be 2 hours, 4 hours, 6 hours, 8 hours, etc., but is not limited thereto, and the progress of the reaction can be monitored by TLC or the like, and the reaction time can be conventionally adjusted.

[0116] In a specific embodiment of the present invention, hydrochloric acid is used to adjust the pH value to 3-6.

[0117] In a specific embodiment of the present invention, in step (b), collecting the solid comprises: cooling the pH-adjusted material to 0-10°C, standing for more than 0.5h, and filtering. Furthermore, the filtered and collected solid can be recrystallized at least once using ethanol.

[0118] Example 1

[0119] This example provides a method for preparing berberine hydrochloride intermediate B2 and berberine hydrochloride, and the synthetic route is as follows:

[0120]

[0121] The specific steps include:

[0122] (1) Add 250 g of methanol, 29.5 g (0.18 mol) of piperonyl acetaldehyde and 30 g (0.18 mol) of 2,3-dimethoxybenzylamine into an autoclave, stir evenly, heat to 64° C., and stir to react for 1 h.

[0123] (2) The material after the reaction in step (1) was cooled to 25° C., 1 g of Raney nickel was added, hydrogen was introduced into the reaction system, the autoclave was sealed, and hydrogen was replaced three times, the pressure was maintained at 3 MPa, and then the temperature was raised to 60° C. and the reaction was carried out for 2 h. After the reaction was completed, the temperature was cooled to room temperature, the catalyst was filtered out, and the mixture was concentrated to obtain a crude product of berberine hydrochloride intermediate B2.

[0124] (3) To the crude product obtained in step (2), 150 g of formic acid, 25 g (0.16 mol) of copper sulfate, and 25 g of a 40% aqueous solution of glyoxal were added, and then the temperature was raised to 55° C. for dehydration reaction. After stirring for 4 h, hydrochloric acid was added to adjust the pH value to 3, the heating was stopped, the temperature was lowered to 5° C., the mixture was allowed to stand for 1 h, filtered, and washed with water to obtain a crude product. The crude product was then recrystallized twice from ethanol, centrifuged, and dried to obtain berberine hydrochloride with a yield of 79% (total of three steps) and an HPLC content of 99.8%.

[0125] Example 2

[0126] This example provides a method for preparing berberine hydrochloride intermediate B2 and berberine hydrochloride, and the synthetic route is as follows:

[0127]

[0128] The specific steps include:

[0129] (1) Add 151 g (1.1 mol) of potassium carbonate, 184 g (1.0 mol) of 5-(2-chloroethyl)-1,3-benzodioxetane and 167 g (1.0 mol) of 2,3-dimethoxybenzylamine to a three-necked flask, stir evenly, heat to 100°C, and react with stirring for 5 hours. Filter and separate the organic layer, extract with dichloromethane, wash with water 3 times, combine the organic layers, and concentrate under reduced pressure to obtain 310 g of a light yellow oil, with a crude yield of 98%.

[0130] (2) To the crude product obtained in step (1), 915 g of formic acid, 152.5 g (1 mol) of copper sulfate, and 150 g of a 40% aqueous solution of glyoxal were added, and then the temperature was raised to 55° C. for dehydration reaction. After stirring for 4 h, hydrochloric acid was added to adjust the pH value to 3, the heating was stopped, the temperature was lowered to 5° C., the mixture was allowed to stand for 1 h, filtered, and washed with water to obtain a crude product. The crude product was then recrystallized twice from ethanol, centrifuged, and dried to obtain berberine hydrochloride with a yield of 85% (total of two steps) and an HPLC content of 99.7%.

[0131] Among them, the preparation method of compound A2, the synthetic route is as follows:

[0132]

[0133] The specific steps include:

[0134] (1) Add 200 g of ethanol, 30 g (0.18 mol) of piperonyl acetaldehyde and 11.3 g (1.0 mol) of sodium borohydride into a three-necked flask, stir evenly, heat to 40°C, and stir to react for 2 h. Add 100 g of water to quench, extract with dichloromethane, wash with water 3 times, combine the organic layers, and concentrate under reduced pressure to obtain 29.7 g of a light yellow oil, with a crude yield of 99%.

[0135] (2) To the crude product obtained in step (1), 100 g of dichloromethane and 18.9 g (0.16 mol) of dichlorothionyl were added, and the temperature was raised to 30° C. for chlorination reaction. After stirring for 2 h, heating was stopped and the solvent was removed under reduced pressure to obtain 27.6 g of an oily substance with a yield of 83% (total of two steps), which was directly used for the preparation of berberine hydrochloride intermediate B2.

[0136] Example 3

[0137] This example refers to the preparation method of berberine hydrochloride intermediate B2 and berberine hydrochloride in Example 2, with the only difference being that the preparation method of compound A2 is different.

[0138] The overall yield of this example is 82% (two steps combined), and the HPLC purity is 97.8%.

[0139] In this embodiment, the synthetic route of compound A2 is as follows:

[0140]

[0141] The specific steps include:

[0142] Add 200g of chlorobenzene, 22g (0.18mol) of 1,2-methylenedioxybenzene and 47.9g (0.36mol) of aluminum chloride to a three-necked flask, stir evenly, cool to -5-0°C, add 25.6g (0.18mol) of 1-bromo-2-chloroethane dropwise, and stir to react for 2h. Add 100g of water to quench, extract with dichloromethane, wash with water 3 times, combine the organic layers, and concentrate under reduced pressure to obtain 29.4g of light yellow oil, with a crude yield of 89%. The obtained crude product is directly used for the preparation of berberine hydrochloride intermediate B2.

[0143] Example 4

[0144] This example refers to the preparation method of berberine hydrochloride intermediate B2 and berberine hydrochloride in Example 1, with the only difference being that this example also includes a preparation method of 2,3-dimethoxybenzylamine.

[0145] In this embodiment, the synthetic route of the compound 2,3-dimethoxybenzylamine is as follows:

[0146]

[0147] The specific steps include:

[0148] Add 200mL methanol, 50g 40% ammonia water, 29.5g 2,3-dimethoxybenzaldehyde (0.18mol) and 0.5g 5% Pt / C into the autoclave; replace with nitrogen, then replace with hydrogen, 40kg pressure, 90℃ for 24h, after the reaction is complete, cool to room temperature. Filter, combine the organic layers, and concentrate under reduced pressure to obtain 28.6g of light yellow solid, with a crude yield of 95%.

[0149] Example 5

[0150] This example is based on the preparation method of Example 1, with the only difference being that in step (1), the reaction temperature and reaction time are different.

[0151] In step (1) of this embodiment, the reaction temperature is 25° C. and the reaction time is 24 h. The overall yield of this embodiment is 75% and the HPLC purity is 99.2%.

[0152] Example 6

[0153] This example is based on the preparation method of Example 1, with the only difference being that in step (1), the reaction temperature and reaction time are different, and the solvent is toluene.

[0154] In step (1) of this embodiment, the reaction temperature is 110° C. and the reaction time is 1 h. The overall yield of this embodiment is 88% and the HPLC purity is 99.5%.

[0155] Example 7

[0156] This example is based on the preparation method of Example 1, with the only difference being that in step (1), the type of solvent is different.

[0157] In step (1) of this embodiment, the solvent is glacial acetic acid. The overall yield of this embodiment is 90%, and the HPLC purity is 98.8%.

[0158] Example 8

[0159] This example is based on the preparation method of Example 1, with the only difference being that in step (2), the type of catalyst is different.

[0160] In step (2) of this embodiment, an equal weight of palladium on carbon (5% Pt / C) is used to replace Raney nickel. The overall yield of the three steps of this embodiment is 75%, and the HPLC purity is 99.5%.

[0161] Example 9

[0162] This example is based on the preparation method of Example 1, with the only difference being that in step (1), the amount of piperonyl acetaldehyde used is different.

[0163] In step (1) of this embodiment, the amount of piperonyl acetaldehyde used is 44 g. The overall yield of this embodiment is 92%, and the HPLC purity is 99.1%.

[0164] Example 10

[0165] This example is prepared by referring to the preparation method of Example 2, except that an equimolar amount of Compound A3 is used to replace Compound A2.

[0166] The overall yield of this example is 93%, and the HPLC purity is 99.6%.

[0167] The preparation method of compound A3 in this example, the synthetic route is as follows:

[0168]

[0169] The specific steps include:

[0170] (1) Add 200 g of ethanol, 30 g (0.18 mol) of piperonyl acetaldehyde and 11.3 g (1.0 mol) of sodium borohydride into a three-necked flask, stir evenly, heat to 40°C, and stir to react for 2 h. Add 100 g of water to quench, extract with dichloromethane, wash with water 3 times, combine the organic layers, and concentrate under reduced pressure to obtain 29.7 g of a light yellow oil, with a crude yield of 99%.

[0171] (2) Add 100 g of dichloromethane and 25.2 g (0.16 mol) of bromine to the crude product obtained in step (1), then heat to 27°C for bromination reaction, stir for 3 h, and then stop heating. Add water to quench the reaction, extract twice, combine the organic layers, and remove the solvent under reduced pressure to obtain 33.9 g of an oily substance with a yield of 93% (total of two steps), which is directly used for the preparation of berberine hydrochloride intermediate B2.

[0172] Embodiment 11

[0173] This example is based on the preparation method of Example 2, with the only difference being that in step (1), the acid binding agent added is sodium carbonate.

[0174] The overall yield of this example is 82%, and the HPLC purity is 99.5%.

[0175] Example 12

[0176] This example refers to the preparation method of Example 3, except that 1-bromo-2-chloroethane is replaced with 1-chloro-2-chloroethane in an equal molar amount. The yield of the crude compound A2 is 87%.

[0177] The overall yield of this example is 85%, and the HPLC purity is 99.0%.

[0178] The invention synthesizes the key intermediate of berberine hydrochloride by mixing and reacting the compound homopiperonal or 5-(2-chloroethyl)-1,3-benzodioxetane or 5-(2-bromoethyl)-1,3-benzodioxetane with 2,3-dimethoxybenzylamine, thereby avoiding the use of expensive materials such as o-veratraldehyde, reducing the reaction steps, and being easy to operate. The berberine hydrochloride prepared by the method of the invention has stable quality and can be directly used in drug production.

[0179] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing a berberine hydrochloride intermediate, characterized in that: The method comprises the following steps: 2,3-dimethoxybenzylamine and compound A are subjected to a first reaction in an optional first solvent to obtain a berberine hydrochloride intermediate B; The structural formula of the compound A is as follows: The structural formula of the berberine hydrochloride intermediate B is as follows: Wherein, X is selected from at least one of O, Cl and Br, and a double line consisting of a dotted line and a solid line represents a single bond or a double bond.

2. The method for preparing a berberine hydrochloride intermediate according to claim 1, characterized in that: When X is O, a double line composed of a dotted line and a real line represents a double bond; the preparation method further comprises: the berberine hydrochloride intermediate B is subjected to a reduction reaction with hydrogen in an optional second solvent in the presence of a catalyst to obtain a berberine hydrochloride intermediate C; The structural formula of the berberine hydrochloride intermediate C is as follows:

3. The method for preparing a berberine hydrochloride intermediate according to claim 2, characterized in that: The catalyst includes at least one of palladium carbon, platinum carbon and Raney nickel.

4. The method for preparing a berberine hydrochloride intermediate according to claim 2, characterized in that: The first solvent and the second solvent are each independently selected from at least one of water, methanol, ethanol, acetonitrile, toluene and glacial acetic acid.

5. The method for preparing a berberine hydrochloride intermediate according to claim 1, characterized in that: When X is Cl or Br, the double line composed of a dotted line and a solid line represents a single bond; the system of the first reaction further includes an optional acid binding agent; Preferably, the acid binding agent comprises at least one of K2CO3, Na2CO3, NaOH, KOH, t-BuOK and triethylamine; Preferably, the first solvent includes at least one of water, methanol, ethanol, acetonitrile, toluene and acetone.

6. The method for preparing a berberine hydrochloride intermediate according to claim 1, characterized in that: The temperature of the first reaction is 10 to 110°C; Preferably, the temperature of the first reaction is 60-80°C.

7. The method for preparing a berberine hydrochloride intermediate according to claim 1, characterized in that: The molar ratio of the 2,3-dimethoxybenzylamine to the compound A is (1-1.5):

1.

8. The method for preparing a berberine hydrochloride intermediate according to claim 1, characterized in that: When X is Cl, the preparation of the compound A comprises: 1,2-methylenedioxybenzene and compound E undergo Friedel-Crafts reaction under the action of Lewis acid to obtain the compound A; The compound E includes at least one of 1-bromo-2-chloroethane, 1-chloro-2-chloroethane and 2-chloro-ethanol; Preferably, the Lewis acid comprises at least one of AlCl3, FeCl3, TiCl4 and ZnCl2; Alternatively, when X is Cl or Br, the preparation of the compound A comprises: performing a reduction reaction on piperonyl acetaldehyde under the action of a reducing agent to obtain a compound D, and then performing a halogenation reaction with a halogenation agent to obtain a compound A; The structural formula of the compound D is as follows: Preferably, the reducing agent comprises sodium borohydride and / or potassium borohydride; Preferably, the halogenating agent comprises at least one of HCl, SOCl2, PCl3, POCl3, PCl5, N-chlorosuccinimide, Cl2 and HBr.

9. The method for preparing a berberine hydrochloride intermediate according to claim 1, characterized in that: The preparation of 2,3-dimethoxybenzylamine comprises: 2,3-dimethoxybenzaldehyde and ammonia are subjected to a reductive amination reaction in the presence of a reducing agent to obtain 2,3-dimethoxybenzylamine; Preferably, the reducing agent comprises at least one of hydrogen, formic acid, zinc powder and sodium cyanoborohydride.

10. A method for preparing berberine hydrochloride, characterized in that: The steps include: (a) using the method for preparing a berberine hydrochloride intermediate according to any one of claims 1 to 9 to prepare a berberine hydrochloride intermediate C as shown in the following formula; (b) The berberine hydrochloride intermediate C and glyoxal are subjected to a dehydration reaction in an optional third solvent under the action of a catalyst, and then the pH value is adjusted with hydrochloric acid, and the solid is collected.

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