Abstract
In this work, the synthesis of berberine was accomplished through three distinct routes. The key innovation lies in replacing the traditional intermediate piperonylamine with 2,3-dimethoxybenzylamine, thereby circumventing the lengthy and low-yielding steps of the intermediate. The newly developed routes are characterized by short synthetic sequences and by overall yields of 22.6–32.8% for berberine. Moreover, the starting materials are inexpensive, readily available, and derived from natural sources. Notably, in contrast to previously reported routes, route 2 can be carried out entirely at ambient temperature under atmospheric pressure. These attributes position the developed routes as candidates for industrial scale-up.
Introduction
Berberine is a natural isoquinoline alkaloid found in various plants from the Berberidaceae, − Ranunculaceae and Papaveraceae families. It exhibits a range of pharmacological activities, including antibacterial, anti-inflammatory, , antitumor, , cardiovascular disease treatment, diabetes management, and lipid regulation effects. However, plant extraction alone cannot meet the growing demand, , making the development of efficient and sustainable chemical synthesis methods crucial.
Berberine is commonly synthesized from 3,4-methylenedioxyphenethylamine 3 through amidation or cyclization to construct its core structure. , The Kametani group first achieved its total synthesis through a Mannich reaction ; however, this route suffered from long reaction times and low yield (Scheme a). Chen Zaixin’s team developed a six-step route using compound 3, which involved highly toxic cyanides (Scheme b). The Clift group reported a shorter four-step synthesis via Friedel–Crafts alkylation; however, this method proved costly, environmentally unfriendly, and unsuitable for large-scale production (Scheme c). Recently, the derivatization strategies for berberine have attracted widespread attention, , including enzyme cascade reactions, one-pot cyclization, , and asymmetric synthesis. Currently, the industrial synthesis of berberine relies on a method developed by Northeast Pharmaceutical Group, involving reduction and cyclization starting from compound 3 and 2,3-dimethoxybenzaldehyde (Scheme d). In 2016–2017, our group reported a Hoffmann elimination route and a convergent synthesis using NaBH4 instead of nickel–hydrogen to prepare the key intermediate compound 3 (Scheme e,f). ,
1. Previous and Our Synthetic Strategies to Berberine.
Despite these advances, strategies employing compound 3 as the key intermediate are inherently hampered by lengthy synthetic sequences, low overall yields, harsh reaction conditions, and high costs, which severely restrict their large-scale application. Notably, compound 3 requires a four-step linear synthetic route starting from commercially available catechol, further adding to the process complexity and total production costs. In sharp contrast, our key intermediate 6 can be facilely synthesized via a high-yield, one-step reaction using inexpensive 2,3-dimethoxybenzaldehyde 4 as the starting material, offering a much more concise and efficient synthetic pathway. Notably, although the skeleton structure of compound 6 is highly similar to that of compound 3, readily promote excessive alkylation due to its ortho-methoxy synergistic steric hindrance and electron donating effect, resulting in increased byproducts and poor selectivity. In addition, early compound 3 is more readily available on the market and the price is moderate. To the best of our knowledge, compound 6 has not been employed as a nitrogen source for compound 2 in previous studies on the synthesis of berberine.
Inspired by the above work, we conducted a retrosynthetic analysis of berberine and envisioned a fundamentally distinct convergent strategy. By replacing the conventional intermediate 3 with 2,3-dimethoxybenzylamine 6 (Scheme g), we established a streamlined synthetic route comprising only 5–6 steps. This protocol employs inexpensive, commercially available 1,3-benzodioxole as the starting material and avoids toxic cyanide reagents and high-pressure reaction conditions. Notably, Route 2 can be carried out entirely at ambient temperature and pressure, thereby offering milder reaction conditions and a more environmentally sustainable approach.
On the basis of a retrosynthetic analysis of berberine (Scheme ), we devised three synthetic routes to berberine. Starting from 1,3-benzodioxole 7, we prepared 3,4-methylenedioxy phenylacetic acid 5, 3,4-methylenedioxyphenethyl mesylate 12, and 3,4-methylenedioxyphenethyl bromide 15 respectively, and then each of these intermediates was reacted with the key intermediate 6 to afford compound 2 (Scheme ). The goal of this work is to develop a concise and cost-effective synthesis of berberine by circumventing the tedious multistep preparation of 3 in favor of a one-step access to 6. We evaluated the three alternative routes with emphasis on step economy, mildness of reaction conditions, and overall cost, aiming to identify the protocol most amenable to large-scale application.
2. Retrosynthetic Analysis of Berberine.
3. Synthetic Routes of Berberine.
Results and Discussion
Starting from 1,3-benzodioxole 7, 3,4-methylenedioxybenzyl chloride 8 can be efficiently prepared via chloromethylation with paraformaldehyde and HCl (Scheme ). To avoid the disubstitution side reactions to which compound 7 is prone, Lewis acid catalysis was omitted in this work. Optimization studies revealed that the use of toluene as the solvent, low temperatures, and an 8:1 molar ratio of paraformaldehyde to 7 synergistically enhance the yield and suppress the formation of byproducts (Table ). A 90% yield was obtained after 9 h at 0 °C, whereas the yield dropped to only 60% at room temperature. This difference is attributed to the high electron density on the compound 7, which renders it highly reactive toward electrophilic substitution. Consequently, the competing formation of disubstituted products lowers the yield of the target monosubstituted product. Lowering the temperature to −15 °C gave only a marginal increase in yield at the expense of a significantly prolonged reaction time. Accordingly, the optimal conditions for preparing 8 were identified as toluene as the solvent, an 8:1 molar ratio of paraformaldehyde to 7, and a reaction temperature of 0 °C.
4. Condition Optimization of Blanc Reaction.
1. Optimization of Piperonyl Benzyl Chloride Synthesis Conditions.
| entry | (CH2O)n (eq) | solvent | time (h) | temp. (°C) | yield (%) |
|---|---|---|---|---|---|
| 1 | 8 | PhMe | 9 | 0 | 90 |
| 2 | 8 | PhMe | 15 | –15 | 91 |
| 3 | 8 | PhMe | 9 | 25 | 60 |
| 4 | 8 | CHCl3 | 9 | 0 | 78 |
| 5 | 8 | CHCl3 | 15 | –15 | 80 |
| 6 | 8 | CHCl3 | 9 | 25 | 56 |
Isolated yields.
The key intermediate 2,3-dimethoxybenzylamine 6 was synthesized through the reductive amination of 2,3-dimethoxybenzaldehyde 4 with ammonium formate under high-temperature conditions (Scheme ). Initially, a Leuckart reaction was attempted; although the aldehyde was fully converted, the product readily underwent further transformations to form compound 16 and 17, resulting in a low yield of the desired compound 6. Following the method described in the literature, a one-pot synthesis was employed. In this approach, compound 4 was first reacted with hydroxylamine hydrochloride to form compound 18, which was then reduced to compound 6 using Zn powder and concentrated hydrochloric acid, yielding a high final yield of 90%. This one-pot sequence effectively resolved the selectivity control issues encountered in the direct reductive amination.
5. Synthesis of 2, 3-Dimethoxybenzylamine.
The reduction of amides 9 is a key step in this synthetic route (Scheme ). This study systematically compared lithium aluminum hydride, borane, and the in situ generated borane system from NaBH4/I2 (Table ). The results showed that lithium aluminum hydride required excess amounts due to its coordination with the oxygen atom in the substrate, leading to a low yield of only 35% and facilitating the elimination of alkoxy groups. The NaBH4/I2 system exhibited lower reduction efficiency. In contrast, despite volatile losses of low-boiling borane under reflux, higher borane loadings deliver substantially enhanced reduction efficiency. Notably, the low yield under low borane loading (e.g., 3 equiv) originates primarily from incomplete reduction rather than severe side reactions. At this loading, the amount of borane is only sufficient to reduce the carbonyl group and quench the N–H proton of the secondary amide, leaving no excess borane to offset irreversible coordination consumption by the generated secondary amine or borane decomposition caused by trace water in THF. The free active borane is fully depleted at a conversion of 70%, terminating the reaction; the system mainly contains unreacted starting amide, with only trace aldehydes and benzyl alcohols formed via hydrolysis of hemiaminal intermediates. When the borane loading is increased to 6 equiv, the excess borane compensates for the aforementioned extra consumption, maintaining a high concentration of free active borane throughout the reaction to complete the two-step hydride transfer of the amide and achieve nearly full substrate conversion. The methoxy and benzodioxole moieties in the substrate remain intact without side reactions, and high-purity target secondary amine hydrochloride is obtained after salt formation with hydrochloric acid, with the yield elevated from 70% to 99%. Overall, the reduction efficiency was positively correlated with the amount of borane used. On the basis of overall reaction efficiency and economic considerations, borane was identified as the optimal reducing agent for reducing amide 10.
6. Condition Optimization of Reductive Amination Reaction.
2. Screening of Reducing Agent.
| entry | reductant | solvent | temp. (°C) | time (h) | yield (%) |
|---|---|---|---|---|---|
| 1 | LiAlH4 (2 equiv) | THF | 70 | 6 | 15 |
| 2 | LiAlH4 (5 equiv) | THF | 70 | 6 | 24 |
| 3 | LiAlH4 (10 equiv) | THF | 70 | 6 | 35 |
| 4 | BH3 (1.1 equiv) | THF | 70 | 4 | 52 |
| 5 | BH3 (3 equiv) | THF | 70 | 4 | 70 |
| 6 | BH3 (6 equiv) | THF | 70 | 4 | 99 |
| 7 | NaBH4/I2 | THF | 70 | 6 | 32 |
Isolated yields.
Given the harsh conditions of high-temperature condensation and reduction in Route 1, we devised a milder Route 2 that employs Grignard reagents for the nucleophilic addition to ethylene oxide to synthesize compound 11 (Scheme ). The effects of reaction temperature and the molar ratio of ethylene oxide on the yield were investigated. At 0 °C, the yield was only 12%. However, at 25 °C, the yield significantly increased to 65%. In contrast, at 65 °C, the yield dropped sharply to 23% due to decomposition of ethylene oxide via spontaneous ring-opening (Table ). The molar ratio of ethylene oxide to halide also significantly impacted the reaction yield. A 1:1 ratio resulted in a marked decrease in yield, while a 5:1 ratio only improved the yield by 2% compared to a 2.5:1 ratio. Considering cost-effectiveness, the optimal reaction conditions were determined to be a 2:1 molar ratio of ethylene oxide to halide at 25 °C.
7. Condition Optimization of Gregnard Reaction.
3. Exploration of Grignard Reaction Conditions.
| entry | Mg (eq) | THF (mL) | ethylene oxide (eq) | time (h) | temp. (°C) | yield (%) |
|---|---|---|---|---|---|---|
| 1 | 1.5 | 10 | 2.5 | 3 | 0 | 12 |
| 2 | 1.5 | 10 | 2.5 | 3 | 25 | 65 |
| 3 | 1.5 | 10 | 2.5 | 3 | 65 | 23 |
| 4 | 1.5 | 10 | 1 | 3 | 25 | 30 |
| 5 | 1.5 | 10 | 5 | 3 | 25 | 67 |
Isolated yields.
To avoid high-temperature amidation and strong reduction reactions while enhancing functional group compatibility, this study first converted hydroxyl groups into mesylates. The compound 12 underwent nucleophilic substitution with compound 6 to form compound 2 (Scheme ). Experiments indicated that the choice of solvent and the equivalents of amine significantly affected yield and selectivity (Table ). Acetonitrile or isopropanol provided moderate yields, while tetrahydrofuran led to decreased yields. Although ethanol achieved complete conversion, it also increased the formation of byproducts. Analysis of these byproducts revealed that they were primarily tertiary amines generated from overalkylation, indicating that the target secondary amine retained its nucleophilicity and further reacted with compound 12, thus reducing selectivity. To suppress side reactions, we optimized the molar ratio of 2,3-dimethoxybenzylamine 6. As the equivalents of amine increased, the reaction yield gradually improved. A molar ratio of 3:1 of 6 to 12 achieved a yield of 74%, with no significant yield increase upon further increasing the ratio. Considering reaction efficiency and side reaction control, the optimal conditions were determined to be a 3:1 molar ratio of compound 6 to 12, with Et3N as the base and acetonitrile as the solvent, under reflux. Although modification of leaving groups, protecting group strategies, or stepwise synthetic approaches can theoretically suppress tertiary amine byproduct formation, these manipulations inevitably prolong synthetic sequences and raise overall production costs; scalable low-cost optimizations of these routes will be explored in future work.
8. Condition Optimization on the Synthesis of Secondary Amine Compound 2.
4. Screening of Feed Ratios and Solvent Types in the Synthesis of Secondary Amine Compounds.
| entry | 2, 3-dimethoxyaniline (eq) | base | solvent | time (h) | yield (%) |
|---|---|---|---|---|---|
| 1 | 1.1 | Et3N | MeCN | 17 | 49 |
| 2 | 1.1 | Et3N | IPA | 17 | 48 |
| 3 | 1.1 | Et3N | THF | 20 | 32 |
| 4 | 1.1 | Et3N | EtOH | 20 | trace |
| 5 | 1.5 | Et3N | MeCN | 17 | 60 |
| 6 | 2 | Et3N | MeCN | 17 | 65 |
| 7 | 3 | Et3N | MeCN | 17 | 74 |
| 8 | 6 | Et3N | MeCN | 17 | 74 |
Isolated yields.
To simplify the procedure and enhance the scalability of the synthesis, we developed a more efficient Route 3 for the preparation of compound 2. This route can be achieved through two pathways (Scheme ). The first pathway involves nucleophilic substitution followed by carbonyl reduction; however, the intermediate is highly unstable and prone to decomposition, making purification impossible. Therefore, we chose the second pathway, which entails reduction of 19 to 15; the latter then reacts with compound 6 in the presence of a base to efficiently yield compound 2.
9. Synthetic Pathways for Secondary Amine Compounds.
The copper-catalyzed cyclization of berberine 1 in formic acid is a key step. The loading of copper sulfate was found to exert a significant influence on the yield (Table ). With 1 equiv, the yield is only 22%, while increasing it to 3.6 equiv raises the yield to 60%. However, no further significant improvement was observed when the loading was increased to 7.2 equiv. Extending the reaction time to 24 h results in only a 1% increase in yield, suggesting that there are selectivity issues in the current cyclization reaction. Consequently, optimizing the reaction conditions is necessary to enhance both product selectivity and yield.
5. Investigation of Berberine Cyclization Reaction Conditions.
| entry | Glyoxal (eq) | CuSO4 (eq) | solvent | time (h) | yield (%) |
|---|---|---|---|---|---|
| 1 | 2 | 1 | HCOOH | 5 | 22 |
| 2 | 2 | 1.8 | HCOOH | 5 | 45 |
| 3 | 2 | 3.6 | HCOOH | 5 | 60 |
| 4 | 2 | 7.2 | HCOOH | 5 | 60 |
| 5 | 2 | 3.6 | HCOOH | 24 | 61 |
Isolated yields.
Based on literature precedents, ,, we propose the following speculative mechanism for the berberine cyclization (Scheme ). Cu2+ acts as an oxidant and preferentially coordinates to glyoxal to facilitate its activation, followed by condensation with a secondary amine to form intermediate A. Subsequent coordination of Cu2+ directs the molecule to fold into a transient seven-membered ring intermediate, which then undergoes two sequential intramolecular electrophilic aromatic substitutions to construct the two six-membered rings. The then cuprous oxysalt is unstable and readily reacts with HCl to form stable cuprous chloride or its complexes, precipitating as insoluble cuprous dichloroberberine. Basification of the reaction mixture to basic conditions decomposes this precipitate, releasing the berberine cation. We note that this mechanism is only a tentative proposal and warrants further validation.
10. Proposed Reaction Mechanism.
To further evaluate the practical advantages of our synthetic design, we systematically compared our routes with the mainstream industrial route (Northeast Pharmaceutical Group) and the state-of-the-art laboratory route reported by Clift’s group, in terms of step count, raw material accessibility, reaction conditions, atom economy, and industrial scalability. The detailed comparison is summarized in Table .
6. Comprehensive Comparison of Different Synthetic Routes Toward Berberine .
| comparison items | northeast pharmaceutical group | clift’s group | our work |
|---|---|---|---|
| Synthetic steps | 6 | 4 | 6 |
| Nature of starting materials | Cheap and available | Synthetic intermediates, no bulk-scale industrial availability | Cheap and available |
| Reaction conditions | High temperature and high pressure, highly toxic NaCN system | Strongly corrosive triflic acid catalysis, iodine oxidation; no highly toxic reagents | All routes operated at atmospheric pressure; Route 2 proceeds at ambient temperature |
| Note: Amide reduction in Route 1 employs borane | |||
| Number of synthetic steps for key intermediate | 4 | / | 1 |
| Overall full-process atom economy | 56% | 48% | 63% |
| Industrial scalability | Moderate | Low | High |
(1) Total linear steps are counted uniformly from bulk commercial basic chemicals, excluding workup, purification, and salification auxiliary procedures. (2) Overall atom economy is calculated based on all core reagents involved in the main reactions, excluding solvents, catalysts, and post-treatment reagents. (3) The “four-step” description of Clift’s route refers to the synthetic sequence starting from prefunctionalized advanced intermediates.
Conclusion
In summary, we have developed three synthetic routes to berberine, starting from 1,3-benzodioxole 7 and 2,3-dimethoxybenzaldehydeas 4. Route 1 involves a six-step reaction sequence, including amide reduction, to synthesize berberine 1 under atmospheric pressure, achieving a total yield of 28.8%. Route 2 adopts mesylate-mediated nucleophilic substitution under ambient temperature and atmospheric pressure, which avoids highly toxic chemical reagents, delivers an overall yield of 22.6%, and markedly enhances functional group tolerance. Route 3 utilizes an efficient acylation-bromination-reduction strategy, yielding 32.8% and demonstrating improved synthetic efficiency and industrial applicability.
Experimental Section
General Methods
All reagents and solvents were commercially available and used without further purification unless otherwise stated. The spots were visualized under UV light (254 nm). Nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz (1H NMR) and 101 MHz (13C NMR) in CDCl3 or DMSO-d 6, with chemical shifts (δ) reported in parts per million (ppm) relative to tetramethylsilane (TMS) as the internal standard. Column chromatography was carried out on silica gel (200–300 mesh). All reactions involving air- or moisture-sensitive reagents were performed under a nitrogen atmosphere with dry solvents. General synthetic procedures for all compounds are described herein. Full experimental details, including detailed stepwise experimental procedures and characterization data of all other derivatives and raw spectral data, are provided in the Supporting Information.
General Synthetic Procedure for Compounds
General Procedure for the Preparation of Compound 8
Concentrated HCl (155 mL) was added dropwise to the mixture of the substrate and paraformaldehyde at 0–5 °C, and the mixture was stirred for 9 h until TLC indicated completion. After workup and vacuum distillation (142–150 °C, 9.3 kPa), the product was obtained as a colorless liquid.
General Procedure for the Preparation of Compound 5
Activated Mg (0.21 g, 8.8 mmol) in anhydrous THF (5 mL) was treated with 3,4-methylenedioxybenzyl chloride (1.0 g, 5.9 mmol) in THF (5 mL) and a trace of 1,2-dibromoethane to generate the Grignard reagent, which was then reacted with dry CO2. After aqueous workup and chromatographic purification, the product was obtained as white crystals.
General Procedure for the Preparation of Compound 9
A mixture of piperonylic acid (1.50 g, 8.3 mmol) and 2,3-dimethoxybenzylamine (2.10 g, 12.5 mmol) was stirred at 180 °C for 1.5 h until TLC indicated complete consumption of piperonylic acid. After workup, the product was obtained as a light brown solid.
General Procedure for the Preparation of Compound 10
A mixture of piperonyl cyclohexane (10.00 g, 0.082 mol) and NBS (15.30 g, 0.861 mol) in CHCl3 (50 mL) was heated at 70 °C for 2 h until TLC indicated completion. After workup and chromatographic purification, the product was obtained as a pale yellow liquid.
General Procedure for the Preparation of Compound 11
Activated Mg (0.18 g, 7.5 mmol) in anhydrous THF (5 mL) was treated with 1-bromo-3,4-methylenedioxybenzene (1.00 g, 5 mmol) in THF (5 mL) and a catalytic amount of 1,2-dibromoethane (1 mol %) to generate the Grignard reagent, which was then reacted with ethylene oxide in THF (3 M, 4.2 mL, 12.5 mmol) at 25 °C for 3 h. After workup and column chromatography (PE/EA = 5:1), the product was obtained as a colorless oil.
General Procedure for the Preparation of Compound 12
A solution of 3,4-methylenedioxyphenethyl alcohol (1.48 g, 8.9 mmol) and Et3N (4.50 g, 44.5 mmol) in DCM (20 mL) was treated dropwise with methanesulfonyl chloride (4.08 g, 35.6 mmol) at 0 °C over 30 min, then warmed to 25 °C and stirred for 2 h until TLC indicated complete consumption of the starting material. After workup and column chromatography (PE/EA = 5:1), the product was obtained as a colorless oil.
General Procedure for the Preparation of Compound 13
A mixture of 3,4-methylenedioxyphenethylmethanesulfonate (1.00 g, 4.1 mmol), 2,3-dimethoxybenzylamine (2.05 g, 12.3 mmol), and Et3N (1.24 g, 12.3 mmol) in i-PrOH (20 mL) was heated at 80 °C for 17 h until TLC indicated complete consumption of the mesylate. After workup, column chromatography (PE/EA = 1:1), and salt formation with conc. HCl, the product was obtained as a white solid.
General Procedure for the Preparation of Compound 14
A mixture of 3,4-methylenedioxyacetophenone (0.9 g, 5.5 mmol), NBS (1.00 g, 5.6 mmol), and p-TsOH·H2O (1.56 g, 8.2 mmol) in MeCN (20 mL) was heated at 80 °C for 2 h until TLC indicated completion. After workup and column chromatography (PE/DCM = 2:1), the product was obtained as white crystals.
General Procedure for the Preparation of Compound 15
A mixture of 2-bromo-1-(3,4-methylenedioxyphenyl)ethan-1-one (0.50 g, 2.1 mmol) and TFA (1.65 mL, 10.5 mmol) was treated dropwise with triethylsilane (1.17 g, 10.5 mmol) at 0 °C, then stirred at 25 °C for 6 h until TLC indicated complete consumption of the starting material. After workup and column chromatography, the product was obtained as a colorless liquid.
Synthesis of 2,3-Dimethoxybenzylamine 6
2,3-Dimethoxybenzaldehyde (1.00 g, 6.0 mmol) in EtOH (10 mL) was treated with hydroxylamine hydrochloride (0.50 g, 7.2 mmol) at 25 °C for 1 h, followed by the sequential addition of Zn powder (0.98 g, 15.0 mmol) and HCl at 0 °C, and the mixture was then stirred at room temperature for 3 h. After workup and column chromatography, the product was obtained as a colorless liquid.
General Procedure for the Preparation of Compound 2
The amide (0.50 g, 1.5 mmol) in THF (10 mL) was treated dropwise with borane (1 M, 9.1 mL, 9.0 mmol) at room temperature, and the mixture was heated at 70 °C for 3 h until TLC indicated complete consumption of the starting amide. After acidic workup and trituration, the product was obtained as a white solid.
Synthesis of Berberine 1
A mixture of compound 2 (1.00 g, 2.8 mmol) and CuSO4 (1.75 g, 10 mmol) in 98% formic acid (10 mL) was stirred at 100 °C for 30 min, then treated slowly with aqueous glyoxal (40% in H2O, 0.88 g) and stirred at 100 °C for 5 h, with additional conc. HCl (0.8 equiv and 0.6 equiv) added at 2 and 4 h, respectively. After hot filtration, the resulting copper complex was subjected to basic workup (pH 10) with CaO, followed by acidification (pH 2) with 10% HCl to afford berberine as a yellow solid.
Supplementary Material
Acknowledgments
We are grateful to the Financial support from the National Science Foundation of China (No. 21602183). We thank the Fundamental Research Funds for the Central Universities, Southwest Minzu University (No. ZYN2026116.). We also thank Dr. Xinying Li and Dr. Zhichuan Shi of Southwest Minzu University for their valuable assistance with NMR measurements.
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.6c06067.
Experimental section with characterization data and copies of spectra (PDF)
This work was supported by Project supported by the National Science Foundation of China (No. 21602183), and the Fundamental Research Funds for the Central Universities, Southwest Minzu University (No. ZYN2026116).
The authors declare no competing financial interest.
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