CN101245064B - Process for producing hydrochloric berberine - Google Patents
Process for producing hydrochloric berberine Download PDFInfo
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- CN101245064B CN101245064B CN2007100203326A CN200710020332A CN101245064B CN 101245064 B CN101245064 B CN 101245064B CN 2007100203326 A CN2007100203326 A CN 2007100203326A CN 200710020332 A CN200710020332 A CN 200710020332A CN 101245064 B CN101245064 B CN 101245064B
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Abstract
The invention relates to a preparation method of berberine hydrochloride which is a broad spectrum antibiotic. The method takes 2, 3-dimethoxy benzyl alcohol and homopiperony lamine as raw materials to prepare the berberine hydrochloride by six steps of reaction, namely, alkylation, chloromethylation, cyanidation, alcoholysis, condensation and cyclization. The synthetic technology has easily available materials, high yield but low cost, thus being suitable for industrial production.
Description
Technical field
The present invention relates to the preparation method of medical material medicine, be specifically related to a kind of preparation method of broad-spectrum antibiotics berberine hydrochloride.
Background technology
Berberine hydrochloride is a kind of widely used clinically antibacterials, has another name called Bererini Hydrochclorium.The has a broad antifungal spectrum of berberine hydrochloride; To multiple Gram-positive and the equal tool restraining effect of negative bacterium; Wherein dysentery bacterium, streptococcus pneumoniae, streptococcus aureus, suis, Corynebacterium diphtheriae, diphtheria corynebacterium, vibrio cholerae, Neisseria meningitidis, Shigella etc. are had strong restraining effect, ameba is also had certain effect.Be mainly used in bacillary dysentery bacillus and other intestinal tract infectionss clinically.Berberine can extract from plants such as the coptis and obtain, but because of receiving the restriction of plant resources, the research work of chemical complete synthesis Berberine has very high economic worth.Though the technology of the complete synthesis berberine hydrochloride of chemical method has got into suitability for industrialized production at present, operational path is long, production cost is higher.In order further to reduce the production cost of berberine hydrochloride, we are researching and developing the new synthesis technique of berberine hydrochloride always.
1912, Pictet and Gams just reported the complete synthesis route of Berberine, and this route is with homopiperony lamine and 3; The 4-dimethoxyphenylacetic acid is a raw material, obtains Berberine (Ber., 1912 through preparation acyl chlorides, condensation, dehydration condensation, reduction, cyclization and oxidation; 44,2480～2485.).Synthetic route is following:
The step that this route needs in becoming the ring process is longer, and in second annulation, selectivity is relatively poor.So this route total recovery is lower, cost is higher.
1980, " national bulk drug technology compilation " that medicine management general bureau of country publishes reported more sophisticated Berberine synthesis technique.Operational path is following:
This technology is raw material with the piperonyl cyclonene, and the route of Pictet and Gams is succinctly efficient.Dongbei Pharmaceutical General Factory has also been reported identical route (ZL01106089.1), but this technology has been used copper catalyst in becoming the ring process, cause need doing the decopper(ing) processing after the reaction, and operation inconvenience, and cost is higher.
Summary of the invention
The object of the present invention is to provide a new operational path of preparation berberine hydrochloride, be intended to overcome the shortcoming in the above synthesis technique, reduce cost, make it easy and simple to handle, be more suitable for suitability for industrialized production.
The present invention be be easy to get on the market 2,3-3,5-dimethoxybenzoic alcohol and homopiperony lamine are raw material, prepare berberine hydrochloride through six-step process altogether.The preparation method is following in detail:
(1) 1-(alkoxyl-methyl)-2; The preparation of 3-dimethoxy benzene (II): 2; 3-3,5-dimethoxybenzoic alcohol (I) is dissolved in the described solvent of claim 2; Add alkali (like sodium hydroxide, Pottasium Hydroxide, triethylamine, pyridine etc.) and alkylating reagent, under 30～100 ℃, reaction disappears until raw material point.After washing, the pickling, tell organic phase, solvent evaporated gets 1-(alkoxyl-methyl)-2, the 3-dimethoxy benzene.2, the mol ratio of 3-3,5-dimethoxybenzoic alcohol, alkali, alkylating reagent is 1:1.0～2.0:1.0～2.0.
(2) 2-(alkoxyl-methyl)-3, the preparation of 4-dimethoxy Benzyl Chloride (III): 1-(alkoxyl-methyl)-2,3-dimethoxy benzene (II) are dissolved in the described solvent of claim 3, under 0～50 ℃, drip the hydrochloric acid soln of trioxymethylene or Paraformaldehyde 96.After dropwising, keep solution, continue stirring reaction and disappear until raw material point at 0～50 ℃.After washing, the alkali cleaning, tell organic phase, solvent evaporated gets 2-(alkoxyl-methyl)-3,4-dimethoxy Benzyl Chloride.1-(alkoxyl-methyl)-2, the mol ratio of 3-dimethoxy benzene, formaldehyde, hydrochloric acid is 1:1.0～1.8:1.8～2.8.
(3) 2-(alkoxyl-methyl)-3; The preparation of 4-dimethoxybenzeneacetonitrile (IV): 2-(alkoxyl-methyl)-3,4-dimethoxy Benzyl Chloride (III) are dissolved in halohydrocarbon or (replacement) benzene solvent, add entry and sodium cyanide or Potssium Cyanide; And phase-transfer catalyst (like Tetrabutyl amonium bromide etc.); Under 30～100 ℃, stirring reaction disappears until raw material point.Tell water, organic phase water, dilute hydrochloric acid solution washing, the 2-that obtains behind the evaporate to dryness (alkoxyl-methyl)-3,4-dimethoxybenzeneacetonitrile.2-(alkoxyl-methyl)-3, the mol ratio of 4-dimethoxy Benzyl Chloride, sodium cyanide or Potssium Cyanide, phase-transfer catalyst is 1:1.0～2.0:0.05～0.2.
(4) 2-(alkoxyl-methyl)-3, the preparation of 4-dimethoxyphenylacetic acid ester (V): 2-(alkoxyl-methyl)-3,4-dimethoxybenzeneacetonitrile (IV) is dissolved in methyl alcohol or the ethanol, adds inorganic acid catalyst, and under the reflux conditions, reaction disappears until raw material point.Solvent evaporated, resistates dissolves with methylene dichloride, after washing, the alkali cleaning, tells organic phase, and solvent evaporated gets 2-(alkoxyl-methyl)-3,4-dimethoxyphenylacetic acid ester.2-(alkoxyl-methyl)-3,4-dimethoxybenzeneacetonitrile, inorganic acid catalyst, methyl alcohol or alcoholic acid mol ratio are 1:0.05～0.2:10～20.
(5) N-pepper ethyl-2-(alkoxyl-methyl)-3, the preparation of 4-dimethoxy BM (VI): 2-(alkoxyl-methyl)-3,4-dimethoxyphenylacetic acid ester (V) and homopiperony lamine directly mix; At 100～200 ℃ of following stirring reactions, until 2-(alkoxyl-methyl)-3,4-dimethoxyphenylacetic acid ester disappears; The decompressing and extracting product; With methyl alcohol or ethyl alcohol recrystallization, get N-pepper ethyl-2-(alkoxyl-methyl)-3,4-dimethoxy BM.2-(alkoxyl-methyl)-3, the mol ratio of 4-dimethoxyphenylacetic acid ester and homopiperony lamine is 1.0:1.0～1.2.
(6) preparation of berberine hydrochloride (VII): N-pepper ethyl-2-(alkoxyl-methyl)-3,4-dimethoxy BM (VI) are dissolved in the described solvent of claim 7, add phosphorus pentachloride, and under 30～80 ℃, stirring reaction several days disappears until raw material point.Solution with in the alkali and after, use chloroform extraction, drying, evaporate to dryness obtains the Berberine bullion.Bullion is dissolved in a spot of acetic acid, adds an amount of benzene and hydrochloric acid, is heated to 30～70 ℃, stirs 30 minutes, separates out the berberine hydrochloride product after the cooling.N-pepper ethyl-2-(alkoxyl-methyl)-3,4-dimethoxy BM and phosphorus pentachloride mol ratio be 1.0:2.0～5.0.
Embodiment
Following type reaction is used for illustrating the present invention, within the technical scheme that those skilled in the art all belong to the present invention to simple replacement that the present invention did or improvement etc. and protected.
Embodiment 1:1-(methoxyl methyl)-2, the preparation of 3-dimethoxy benzene (II)
2 of 168 grams, 3-3,5-dimethoxybenzoic alcohol (I) is dissolved in the 350mL methylene dichloride, adds 30% aqueous sodium hydroxide solution 150mL, under 80 ℃, drips methyl-sulfate 138 grams.After dropwising, continue to disappear until raw material point at 80 ℃ of following stirring reactions.Divide the phase of anhydrating, organic phase is used the water of 150mL and the 10% salt acid elution of 150mL respectively, and after the drying, solvent evaporated gets oily matter 1-(methoxyl methyl)-2,3-dimethoxy benzene 178 grams, yield 98%.This oily matter product directly is used for next step reaction.
Embodiment 2:2-(methoxyl methyl)-3, the preparation of 4-dimethoxy Benzyl Chloride (III)
The 1-(methoxyl methyl)-2 of 182 grams, 3-dimethoxy benzene (II) dissolve in the toluene of 400mL, under 30 ℃, drip the hydrochloric acid soln 200mL that is dissolved with 33 gram Paraformaldehyde 96s.After dropwising, keep solution, continue stirring reaction and disappear until raw material point at 30 ℃.Divide the phase of anhydrating, organic phase is washed with the water of 150mL and the saturated sodium bicarbonate solution of 150mL respectively, and after the drying, solvent evaporated gets oily matter 2-(methoxyl methyl)-3,4-dimethoxy Benzyl Chloride 210 grams, yield 91%.This oily matter product directly is used for next step reaction.
Embodiment 3:2-(methoxyl methyl)-3, the preparation of 4-dimethoxybenzeneacetonitrile (IV)
The 2-(methoxyl methyl)-3 of 230 grams, 4-dimethoxy Benzyl Chloride (III) is dissolved in the toluene of 500mL, adds the sodium cyanide of 200mL water and 75 grams, and the Tetrabutyl amonium bromide of 32 grams.Under 100 ℃, stirring reaction disappears until raw material point.Divide the phase of anhydrating, organic phase is washed with the water of 150mL and the saturated sodium bicarbonate solution of 150mL respectively, drying, and the bullion that obtains behind the evaporate to dryness is used ethyl alcohol recrystallization, gets 2-(methoxyl methyl)-3,4-dimethoxybenzeneacetonitrile 210 grams, 52～54 ℃ of fusing points, yield 95%.
Embodiment 4:2-(methoxyl methyl)-3, the preparation of 4-dimethoxyphenylacetic acid methyl esters (V)
The 2-(methoxyl methyl)-3 of 221 grams, 4-dimethoxybenzeneacetonitrile (IV) is dissolved among the methyl alcohol 500mL, adds the vitriol oil of 10 grams, reflux, reaction disappears until raw material point.Solvent evaporated, resistates with the 350mL methylene dichloride after, respectively with the saturated sodium bicarbonate solution washing of the water of 150mL and 150mL; Drying, the bullion that obtains behind the evaporate to dryness is used ethyl alcohol recrystallization, gets 2-(methoxyl methyl)-3; 4-dimethoxyphenylacetic acid methyl esters 244 grams, 65～67 ℃ of fusing points, yield 96%.
Embodiment 5:N-pepper ethyl-2-(methoxyl methyl)-3, the preparation of 4-dimethoxy BM (VI)
The 2-(methoxyl methyl)-3 of 254 grams, the homopiperony lamine of 4-dimethoxyphenylacetic acid methyl esters (V) and 165 grams directly mixes, at 170 ℃ of following stirring reactions; Until 2-(methoxyl methyl)-3,4-dimethoxyphenylacetic acid methyl esters disappears, and drains under the decompression; Residuum is used recrystallizing methanol, gets N-pepper ethyl-2-(methoxyl methyl)-3,4-dimethoxy BM 360 grams; 112～113 ℃ of fusing points, yield 93%.
Embodiment 6: the preparation of berberine hydrochloride (VII)
The N-pepper ethyl-2-(methoxyl methyl)-3 of 387 grams, 4-dimethoxy BM (VI) is dissolved in the 500mL methylene dichloride, adds the phosphorus pentachloride of 430 grams, under 40 ℃, stirring reaction, raw material point disappears after about 3 days.Solution is neutralized to pH=8 with 10% sodium hydroxide solution, tells organic phase, and water is used chloroform extraction (100 * 3) again, merges organic phase, and after the drying, solvent evaporated obtains the Berberine bullion.Bullion is dissolved in a spot of acetic acid, adds 150mL toluene and 50mL concentrated hydrochloric acid, is heated to 50 ℃, stirs 30 minutes, separates out berberine hydrochloride product 331 grams after the cooling, yield 89%.
Claims (7)
1. the preparation method of a broad-spectrum antibiotics berberine hydrochloride, these method concrete steps are following:
(1) 2,3-3,5-dimethoxybenzoic alcohol obtains 1-(alkoxyl-methyl)-2 through alkylated reaction, 3-dimethyl oxygen base benzene;
(2) 1-(alkoxyl-methyl)-2,3-dimethyl oxygen base obtains 2-(alkoxyl-methyl)-3 through chloromethylation, 4-dimethoxy Benzyl Chloride;
(3) 2-(alkoxyl-methyl)-3,4-dimethoxy Benzyl Chloride obtains 2-(alkoxyl-methyl)-3,4-dimethoxybenzeneacetonitrile through cyanogenation;
(4) 2-(alkoxyl-methyl)-3, the 4-dimethoxybenzeneacetonitrile obtains 2-(alkoxyl-methyl)-3 through alcoholysis, 4-dimethoxyphenylacetic acid ester;
(5) 2-(alkoxyl-methyl)-3,4-dimethoxyphenylacetic acid ester and homopiperony lamine condensation obtain N-pepper ethyl-2-(alkoxyl-methyl)-3,4-dimethoxy BM;
(6) N-pepper ethyl-2-(alkoxyl-methyl)-3,4-dimethoxy BM obtains berberine hydrochloride through ring-closure reaction.
2. the preparation method of berberine hydrochloride according to claim 1 is characterized in that, in the reactions step (1); 2, the 3-3,5-dimethoxybenzoic alcohol is in the presence of alkali; Obtain 1-(alkoxyl-methyl)-2 through alkylation, 3-dimethyl oxygen base benzene, alkylating reagent is selected from haloalkane, diazomethane, diazoethane, methyl-sulfate; Alkylating catalyzer is selected from mineral alkali or organic bases; React used solvent and be selected from halohydrocarbon, benzene and substituted benzene, 1-(alkoxyl-methyl)-2, the alkyl in the 3-dimethyl oxygen base benzene is selected from methyl or ethyl.
3. the preparation method of berberine hydrochloride according to claim 1; It is characterized in that, in the reactions step (2), 1-(alkoxyl-methyl)-2; 3-dimethyl oxygen base obtains 2-(alkoxyl-methyl)-3 through chloromethylation; 4-dimethoxy Benzyl Chloride, chloromethylation reagent is selected from trioxymethylene, Paraformaldehyde 96, formaldehyde solution and hydrogen chloride gas, concentrated hydrochloric acid, phosphorus trichloride, and the solvent of chloromethylation is selected from halohydrocarbon, benzene and substituted benzene; 2-(alkoxyl-methyl)-3, the alkyl in the 4-dimethoxy Benzyl Chloride is selected from methyl or ethyl.
4. the preparation method of berberine hydrochloride according to claim 1 is characterized in that, in the reactions step (3); 2-(alkoxyl-methyl)-3,4-dimethoxy Benzyl Chloride is in the presence of phase-transfer catalyst; Obtain 2-(alkoxyl-methyl)-3 through cyanogenation, 4-dimethoxybenzeneacetonitrile, organic solvent are selected from halohydrocarbon, benzene and substituted benzene; Cyanating reagent is selected from sodium cyanide, Potssium Cyanide; Phase-transfer catalyst is selected from quaternary amine, season phosphonium salt, 2-(alkoxyl-methyl)-3, and the alkyl in the 4-dimethoxybenzeneacetonitrile is selected from methyl or ethyl.
5. the preparation method of berberine hydrochloride according to claim 1; It is characterized in that, in the reactions step (4), 2-(alkoxyl-methyl)-3; The 4-dimethoxybenzeneacetonitrile should obtain 2-(alkoxyl-methyl)-3 through alcohol liberation; 4-dimethoxyphenylacetic acid ester, 2-(alkoxyl-methyl)-3 wherein, the alkyl in the 4-dimethoxyphenylacetic acid ester is selected from methyl or ethyl.
6. the preparation method of berberine hydrochloride according to claim 1; It is characterized in that, in the reactions step (5), 2-(alkoxyl-methyl)-3; The direct condensation of 4-dimethoxyphenylacetic acid ester and homopiperony lamine obtains N-pepper ethyl-2-(alkoxyl-methyl)-3; 4-dimethoxy BM, N-pepper ethyl-2-(alkoxyl-methyl)-3 wherein, the alkyl in the 4-dimethoxy BM is selected from methyl or ethyl.
7. the preparation method of berberine hydrochloride according to claim 1 is characterized in that, in the reactions step (5); N-pepper ethyl-2-(alkoxyl-methyl)-3,4-dimethoxy BM is in organic solvent; Under the muriatic effect of inorganic phosphorus; A direct step cyclization obtains berberine hydrochloride, and organic solvent is selected from halohydrocarbon, benzene and substituted benzene, acetonitrile, and the inorganic phosphorus muriate is selected from phosphorus trichloride, phosphorus pentachloride, ulcer phosphorus chloride.
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| CN102964268A (en) * | 2012-10-27 | 2013-03-13 | 安徽丰乐香料有限责任公司 | Synthesis method of menthyl amide cooling agent |
| CN104529994B (en) * | 2014-12-12 | 2018-05-04 | 西南民族大学 | A kind of preparation method of the key intermediate of berberine |
| CN107880012A (en) * | 2017-11-09 | 2018-04-06 | 华中药业股份有限公司 | The synthetic method of the veratryl homopiperony lamine hydrochlorides of N 2 ', 3 ' |
| CN109232556A (en) * | 2018-10-08 | 2019-01-18 | 佑华制药（乐山）有限公司 | A kind of Berberine hydrochloride production technology |
| CN113735847B (en) * | 2021-09-10 | 2022-06-07 | 四川大学 | Synthetic preparation method of berberine hydrochloride |
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| CN1312250A (en) * | 2001-01-19 | 2001-09-12 | 东北制药总厂 | Preparation of berberine and its salts |
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