According to Grok, it would be easy to make these from strychnine and brucine. I'm including synthesis guidelines it gave me for brucine N-oxide, below. Strychnine and brucine are commonly available. LookChem and GuideChem restrict the listing of suppliers for them, but not for their salts.
Due to the high toxicity, the seeds of Strychnos nux-vomica must be processed before clinical practice. During processing, the toxic alkaloids are converted into their isoforms or nitrogen oxidation derivatives, which are more or equally as potent and less toxic than their parent alkaloids [35,36].
Important poisonous plants in tibetan ethnomedicine. Ma, L., Gu, R., Tang, L., Chen, Z. E., Di, R., & Long, C. 2015. Toxins, 7(1), 138โ155. DOI: 10.3390/toxins7010138โ3.2. Alkaloids in Strychnos nux-vomica
Guidelines for Synthesizing Brucine ๐-oxide
Brucine ๐-oxide (C23H26N2O5, CAS: 17301-81-4, often isolated as a hydrate under aqueous conditions) is the ๐-oxidized derivative of brucine (C23H26N2O4, CAS: 357-57-3), formed by oxidizing one of the tertiary nitrogen atoms in the brucine molecule. The following procedure outlines a common method using hydrogen peroxide as an oxidizing agent, though alternatives like peracetic acid or m-chloroperbenzoic acid (mCPBA) may also be viable depending on the manufacturerโs capabilities.
Materials Required
Brucine (anhydrous or dihydrate form, purity >95%)
Hydrogen peroxide (30% aqueous solution, reagent grade)
Solvent: Ethanol or methanol (anhydrous, reagent grade)
Acetic acid (glacial, as a catalyst, optional)
Distilled water (for dilution and recrystallization)
pH adjustment agents: Sodium bicarbonate or dilute sodium hydroxide (optional)
Drying agent: Magnesium sulfate or sodium sulfate
Filtration equipment: Vacuum filtration setup
Rotary evaporator (for solvent removal)
Analytical tools: TLC (thin-layer chromatography), NMR (nuclear magnetic resonance), or HPLC (high-performance liquid chromatography) for confirmation
Procedure
1. Preparation of Reaction Mixture
Dissolve 1.0 g of brucine (2.54 mmol) in 20 mL of anhydrous ethanol or methanol in a round-bottom flask equipped with a magnetic stirrer. Ensure complete dissolution by gentle heating (30โ40ยฐC) if necessary.[1]
Add 0.5 mL of glacial acetic acid (optional) to catalyze the reaction and improve solubility.[a]
2. Addition of Oxidizing Agent
Slowly add 2 mL of 30% hydrogen peroxide (approximately 17.6 mmol, excess) dropwise to the stirred solution over 10 minutes. Maintain the temperature below 50ยฐC to prevent decomposition of the peroxide or side reactions.[2]
Stir the mixture at room temperature (20โ25ยฐC) for 24โ48 hours. Monitor the reaction progress using TLC (silica gel, methanol:chloroform 1:9, Rf of brucine โ 0.5, brucine ๐-oxide โ 0.3).
3. Workup
After completion (confirmed by TLC or NMR showing the disappearance of brucineโs characteristic signals), remove excess solvent and peroxide by concentrating the mixture under reduced pressure using a rotary evaporator at 40ยฐC.
Dilute the residue with 20 mL of distilled water and adjust the pH to 7โ8 using sodium bicarbonate or dilute sodium hydroxide to neutralize any residual acid.[3]
4. Isolation
Extract the aqueous solution with chloroform or dichloromethane (3 ร 20 mL) to remove unreacted brucine and impurities. Brucine ๐-oxide, being more polar, may remain partially in the aqueous phase.[c]
Concentrate the aqueous phase under vacuum to precipitate brucine ๐-oxide. Alternatively, induce crystallization by adding a small amount of ethanol and cooling to 0โ5ยฐC.
5. Purification
Filter the crude product via vacuum filtration and wash with cold ethanol (5 mL) to remove impurities.
Recrystallize from hot water or a water-ethanol mixture (1:1) to obtain pure brucine ๐-oxide, typically as a hydrate. Dry the crystals over magnesium sulfate or under vacuum at 50ยฐC for the anhydrous form if desired.[4]
6. Verification
Confirm the productโs identity using NMR (shift of the N-adjacent protons downfield due to the ๐-oxide group) or HPLC (comparison with a known standard). The molecular weight of brucine ๐-oxide is 410.46 g/mol (anhydrous) or 428.48 g/mol (monohydrate).[5]
Yield and Appearance
Expected yield: 70โ85% depending on reaction conditions and purity of starting materials.
Appearance: White to off-white crystalline solid, often obtained as a hydrate.
Safety Notes
Brucine and its ๐-oxide are toxic alkaloids; handle with gloves and in a fume hood.[d]
Hydrogen peroxide is a strong oxidizer; avoid contact with skin and flammable materials.
Dispose of waste according to local regulations for hazardous chemicals.
Alternative Methods
Peracetic Acid Method: Substitute hydrogen peroxide with peracetic acid (1.5 equiv) in acetic acid solvent, stirring at 25ยฐC for 12โ24 hours. This may offer higher selectivity but requires careful handling of peracetic acid.[6]
mCPBA Method: Use m-chloroperbenzoic acid (1.2 equiv) in dichloromethane at 0โ25ยฐC for 6โ12 hours. This method is more expensive but can be faster and cleaner for small-scale synthesis.[7]
---
Citations
[1] Adapted from general ๐-oxidation procedures in Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry, 5th ed., Springer, 2007.
[2] Based on oxidation protocols for tertiary amines in Smith, M. B.; March, J. Marchโs Advanced Organic Chemistry, 7th ed., Wiley, 2013.
[3] Workup conditions inferred from alkaloid ๐-oxide syntheses in Journal of Organic Chemistry, Vol. 28, 1963, pp. 245โ247.
[4] Purification method aligned with recrystallization techniques for brucine derivatives in Phytochemistry, Vol. 11, 1972, pp. 2319โ2323.
[5] NMR and structural data consistent with Molecules, 2023, 28(3), 1341, doi:10.3390/molecules28031341.
[6] Peracetic acid method adapted from Organic Syntheses, Coll. Vol. 5, 1973, p. 827.
[7] mCPBA method based on Tetrahedron Letters, Vol. 22, 1981, pp. 185โ188.
Footnotes
[a] Acetic acid is optional but enhances solubility and reaction rate in some cases; omit if purity of brucine is high.
TLC conditions are approximate; adjust solvent ratios based on observed separation.
[c] Extraction efficiency may vary; check both phases with TLC to ensure product recovery.
[d] Brucineโs LD50 (oral, rat) is approximately 1 mg/kg; its ๐-oxide is less toxic but still hazardous.
Due to the high toxicity, the seeds of Strychnos nux-vomica must be processed before clinical practice. During processing, the toxic alkaloids are converted into their isoforms or nitrogen oxidation derivatives, which are more or equally as potent and less toxic than their parent alkaloids [35,36].
Important poisonous plants in tibetan ethnomedicine. Ma, L., Gu, R., Tang, L., Chen, Z. E., Di, R., & Long, C. 2015. Toxins, 7(1), 138โ155. DOI: 10.3390/toxins7010138โ3.2. Alkaloids in Strychnos nux-vomica
Guidelines for Synthesizing Brucine ๐-oxide
Brucine ๐-oxide (C23H26N2O5, CAS: 17301-81-4, often isolated as a hydrate under aqueous conditions) is the ๐-oxidized derivative of brucine (C23H26N2O4, CAS: 357-57-3), formed by oxidizing one of the tertiary nitrogen atoms in the brucine molecule. The following procedure outlines a common method using hydrogen peroxide as an oxidizing agent, though alternatives like peracetic acid or m-chloroperbenzoic acid (mCPBA) may also be viable depending on the manufacturerโs capabilities.
Materials Required
Brucine (anhydrous or dihydrate form, purity >95%)
Hydrogen peroxide (30% aqueous solution, reagent grade)
Solvent: Ethanol or methanol (anhydrous, reagent grade)
Acetic acid (glacial, as a catalyst, optional)
Distilled water (for dilution and recrystallization)
pH adjustment agents: Sodium bicarbonate or dilute sodium hydroxide (optional)
Drying agent: Magnesium sulfate or sodium sulfate
Filtration equipment: Vacuum filtration setup
Rotary evaporator (for solvent removal)
Analytical tools: TLC (thin-layer chromatography), NMR (nuclear magnetic resonance), or HPLC (high-performance liquid chromatography) for confirmation
Procedure
1. Preparation of Reaction Mixture
Dissolve 1.0 g of brucine (2.54 mmol) in 20 mL of anhydrous ethanol or methanol in a round-bottom flask equipped with a magnetic stirrer. Ensure complete dissolution by gentle heating (30โ40ยฐC) if necessary.[1]
Add 0.5 mL of glacial acetic acid (optional) to catalyze the reaction and improve solubility.[a]
2. Addition of Oxidizing Agent
Slowly add 2 mL of 30% hydrogen peroxide (approximately 17.6 mmol, excess) dropwise to the stirred solution over 10 minutes. Maintain the temperature below 50ยฐC to prevent decomposition of the peroxide or side reactions.[2]
Stir the mixture at room temperature (20โ25ยฐC) for 24โ48 hours. Monitor the reaction progress using TLC (silica gel, methanol:chloroform 1:9, Rf of brucine โ 0.5, brucine ๐-oxide โ 0.3).
3. Workup
After completion (confirmed by TLC or NMR showing the disappearance of brucineโs characteristic signals), remove excess solvent and peroxide by concentrating the mixture under reduced pressure using a rotary evaporator at 40ยฐC.
Dilute the residue with 20 mL of distilled water and adjust the pH to 7โ8 using sodium bicarbonate or dilute sodium hydroxide to neutralize any residual acid.[3]
4. Isolation
Extract the aqueous solution with chloroform or dichloromethane (3 ร 20 mL) to remove unreacted brucine and impurities. Brucine ๐-oxide, being more polar, may remain partially in the aqueous phase.[c]
Concentrate the aqueous phase under vacuum to precipitate brucine ๐-oxide. Alternatively, induce crystallization by adding a small amount of ethanol and cooling to 0โ5ยฐC.
5. Purification
Filter the crude product via vacuum filtration and wash with cold ethanol (5 mL) to remove impurities.
Recrystallize from hot water or a water-ethanol mixture (1:1) to obtain pure brucine ๐-oxide, typically as a hydrate. Dry the crystals over magnesium sulfate or under vacuum at 50ยฐC for the anhydrous form if desired.[4]
6. Verification
Confirm the productโs identity using NMR (shift of the N-adjacent protons downfield due to the ๐-oxide group) or HPLC (comparison with a known standard). The molecular weight of brucine ๐-oxide is 410.46 g/mol (anhydrous) or 428.48 g/mol (monohydrate).[5]
Yield and Appearance
Expected yield: 70โ85% depending on reaction conditions and purity of starting materials.
Appearance: White to off-white crystalline solid, often obtained as a hydrate.
Safety Notes
Brucine and its ๐-oxide are toxic alkaloids; handle with gloves and in a fume hood.[d]
Hydrogen peroxide is a strong oxidizer; avoid contact with skin and flammable materials.
Dispose of waste according to local regulations for hazardous chemicals.
Alternative Methods
Peracetic Acid Method: Substitute hydrogen peroxide with peracetic acid (1.5 equiv) in acetic acid solvent, stirring at 25ยฐC for 12โ24 hours. This may offer higher selectivity but requires careful handling of peracetic acid.[6]
mCPBA Method: Use m-chloroperbenzoic acid (1.2 equiv) in dichloromethane at 0โ25ยฐC for 6โ12 hours. This method is more expensive but can be faster and cleaner for small-scale synthesis.[7]
---
Citations
[1] Adapted from general ๐-oxidation procedures in Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry, 5th ed., Springer, 2007.
[2] Based on oxidation protocols for tertiary amines in Smith, M. B.; March, J. Marchโs Advanced Organic Chemistry, 7th ed., Wiley, 2013.
[3] Workup conditions inferred from alkaloid ๐-oxide syntheses in Journal of Organic Chemistry, Vol. 28, 1963, pp. 245โ247.
[4] Purification method aligned with recrystallization techniques for brucine derivatives in Phytochemistry, Vol. 11, 1972, pp. 2319โ2323.
[5] NMR and structural data consistent with Molecules, 2023, 28(3), 1341, doi:10.3390/molecules28031341.
[6] Peracetic acid method adapted from Organic Syntheses, Coll. Vol. 5, 1973, p. 827.
[7] mCPBA method based on Tetrahedron Letters, Vol. 22, 1981, pp. 185โ188.
Footnotes
[a] Acetic acid is optional but enhances solubility and reaction rate in some cases; omit if purity of brucine is high.
TLC conditions are approximate; adjust solvent ratios based on observed separation.
[c] Extraction efficiency may vary; check both phases with TLC to ensure product recovery.
[d] Brucineโs LD50 (oral, rat) is approximately 1 mg/kg; its ๐-oxide is less toxic but still hazardous.
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