518-34-3

Basic information

• Product Name: D-Tetrandrine
• Synonyms: [4aS-(4aR*,16aR*)]-3,4,4a,5,16a,17,18,19-Octahydro-12,21,22,26-tetramethoxy-4,17-dimethyl-16H-1,24:6,9-dietheno-11,15-metheno-2H-pyrido[2',3':17,18][1,11]dioxacycloeicosino[2,3,4-ij]isoquinoline;6’,7,12-tetramethoxy-2,2’-dimethyl-(1-beta)-berbama;fanchinine;sinomeninea;6,6',7,12-tetramethoxy-2,2'-dimethyl-1-beta-berbaman;6,6',7,12-TETRAMETHOXY-2,2'-DIMETHYLBERBAMAN;(1B)-6,6',7,12-TETRAMETHOXY-2,2'-DIMETHYLBERBAMAN;d-tetrandrine
• CAS NO: 518-34-3
• Molecular Formula: C₃₈H₄₂N₂O₆
• Molecular Weight: 622.75
• EINECS: 1806241-263-5
• Product Categories: Inhibitors;Alkaloids;reference substance;chemical reagent;pharmaceutical intermediate;phytochemical;reference standards from Chinese medicinal herbs (TCM).;standardized herbal extract
• Mol File: 518-34-3.mol
• Article Data: 10

Chemical Properties

• Melting Point: 219-222 °C(lit.)
• Boiling Point: 662.81°C (rough estimate)
• Flash Point: 175.8 °C
• Appearance: /solid
• Density: 1.1528 (rough estimate)
• Vapor Pressure: 4.88E-20mmHg at 25°C
• Refractive Index: 1.5300 (estimate)
• Storage Temp.: 2-8°C
• Solubility: Chloroform (Slightly), Methanol (Slightly, Heated)
• PKA: 7.70±0.20(Predicted)
• Merck: 14,9231
• CAS DataBase Reference: D-Tetrandrine(CAS DataBase Reference)
• NIST Chemistry Reference: D-Tetrandrine(518-34-3)
• EPA Substance Registry System: D-Tetrandrine(518-34-3)

Safety Data

• Hazard Codes: Xi
• Statements: 36/37/38
• Safety Statements: 22-24/25-36-26
• WGK Germany: 3
• RTECS: XE9350000
• Hazardous Substances Data: 518-34-3(Hazardous Substances Data)

Usage

Description

Different sources of media describe the Description of 518-34-3 differently. You can refer to the following data:
1. Recently it has been discovered that pronounced drug-dependence and related toxic effects occur in both dogs and rhesus monkeys with this alkaloid on intravenous injection with a dose of 10-150 mg/kg. When rapidly injected, the acute hypotensive effect is very marked and fatal at once. Following drug administration at toxic levels it is found that severe local tissue reaction heptaotoxicity and lymphoid necrosis occurs. At the highest dosage level there is a very definite nephrotoxicity in monkeys and some indications of this in dogs. The evidence available suggests that monkeys are less sensitive to hepatotoxicity with this drug than dogs.
2. Tetrandrine is a bis-benzylisoquinoline alkaloid that has been found in R. stephania roots and has diverse biological activities. It induces autophagy in HeLa, MCF-7, and human foreskin fibroblast (HFF) cells when used at a concentration of 5 μM, an effect that can be reversed by the autophagy inhibitor 3-methyladenine . Tetrandrine inhibits PAF-, thrombin-, collagen-, ADP-, or epinephrine-induced aggregation of isolated human platelets. Priming of mesenchymal stem cells (MSCs) with tetrandrine (5 and 10 μM) reduces TNF-α secretion by RAW 264.7 cells in co-culture. Ear skin transplantation of tetrandrine-primed MSCs decreases ear levels of TNF-α in a mouse model of ear skin inflammation. Tetrandrine (1 mg/kg) increases soleus muscle levels of glucose transporter 4 (Glut4) and decreases plasma glucose levels in a rat model of diabetes induced by streptozotocin .

Chemical Properties

White powder

Physical properties

Appearance: Needle-like crystals (ether). Solubility: Hardly soluble in water and petroleum ether; soluble in ether and some organic solvents. Melting point: 219– 222?°C. Specific optical rotation: 285° (c?=?1, CHCl3); sensitive to light.

History

Recent studies have shown that tetrandrine has a variety of biological effects and very good applicational prospects in the treatment of fibrosis and portal vein and pulmonary hypertension, the regulation of immunologic function, as well as the prevention and treatment of tumor. As early as 1988, tetrandrine has been found having the effect on blocking the Ca2 + channel and was quickly applied into the pharmacological research in the field of cardiovascular and inflammatory diseases. Results from a large number of studies have shown that tetrandrine has good effects on antihypertension, arrhythmia, myocardial ischemia, inflammation, and so on. As a traditional Chinese calcium antagonist, tetrandrine has a broad prospects in clinical applications of cardiovascular and inflammatory diseases.In the early 1990s, the application of tetrandrine was extended. During that time, researchers conducted many studies about its protective effects on liver, lung, and mitochondria, which opened a new field for the treatment of liver disease. In 2002, it was found that tetrandrine can inhibit the synthesis of DNA and RNA in tumor cells, which provided a new method for the treatment of cancer. At present, the prevention and treatment effects of hypertension, fibrosis, digestive diseases, tumors, rheumatoid arthritis, and other autoimmune diseases of tetrandrine have been confirmed, as well as the function of reducing portal hypertension and pulmonary hypertension, while its other pharmacological effects are to be explored in further study.

Uses

Different sources of media describe the Uses of 518-34-3 differently. You can refer to the following data:
1. Tetrandrine is a lipopolysaccharide-induced microglial suppressor, effectively reducing the production of bacterial inflammatory mediators. Anti-inflammatory, anti-nociceptive. Tetrandrine is used in China to treat high blood pressure. This drug blocked the TPC2 calcium channel required for the Ebola infection process (Robert A. Davey et al., Science 2015, DOI: 10.1126/science.1258758).
2. analgesic, antineoplastic, antihypertensive, lymphotoxin

Indications

This product is included in national standards for chemical drugs (Volume 14), British Pharmacopoeia (2017), and European Pharmacopoeia (9.0th ed.). Tetrandrine is used for the treatment of mild to moderate hypertension and hypertensive crisis, rheumatism, silicosis, etc.

Pharmacology

Tetrandrine has analgesic, anti-inflammatory, and anti-allergic effects and has a wide range of usage on the cardiovascular system owing to its antihypertensive, anti-myocardial ischemia/reperfusion injury and antiarrhythmic effects. It can inhibit the platelet aggregation induced by ADP, collagen, and arachidonic acid in?vitro and can also restrain the platelet adhesion and thrombosis (in rabbits). Tetrandrine also has anticancer effects. Studies have shown that tetrandrine has a strong inhibitory effect on the DNA and RNA synthesis in L7712 and S180 (cancer cells), which can significantly suppress the growth of Wacker sarcoma W256. Besides that, tetrandrine has the ability to relax the striated muscle, and its methyl iodide or methyl bromide derivatives can also affect the muscles. Notably, tetrandrine can prevent silicosis and has a preferable outcome on the clinical treatment of such disease. In addition, tetrandrine also owns antipyretic, diuretic, and antiallergic shock effects.

Clinical Use

Tetrandrine is used for the treatment of hypertension, angina, termination of paroxysmal supraventricular tachycardia, pulmonary fibrosis, and other diseases in clinical application, and it also has strong antitumor effects. Tetrandrine was also approved for lowering blood glucose and free radical damage; its treatment effect on silicosis is significant and superior to conventional immunosuppressive and cytotoxic drugs.

References

Gralla, Coleman, Jonas, Cancer Chemother. Rep., Pt. 3, 5(1), 79 (1974)

InChI:InChI=1/C38H42N2O6/c1-39-15-13-25-20-32(42-4)34-22-28(25)29(39)17-23-7-10-27(11-8-23)45-33-19-24(9-12-31(33)41-3)18-30-36-26(14-16-40(30)2)21-35(43-5)37(44-6)38(36)46-34/h7-12,19-22,29-30H,13-18H2,1-6H3/t29?,30-/m0/s1

Synthetic route

diazomethane (186581-53-3, 908094-01-9) + (+)-penduline (26137-45-1) → Tetrandrin (518-34-3)

Conditions	Yield
With diethyl ether In methanol for 24h;	100%

C38H43BrN2O6 → Tetrandrin (518-34-3)

Conditions	Yield
With copper(l) iodide; caesium carbonate In toluene for 80h; Reagent/catalyst; Temperature; Ullmann Condensation; Reflux; Inert atmosphere;	56.5%

4-iodo-3-trifluoromethylbenzyl iodide + Tetrandrin (518-34-3) → C54H52F6I2N2O6(2+)*2I(1-)

Conditions	Yield
With tetraethylammonium bromide In water at 50℃; for 3h; Reagent/catalyst; Solvent; Temperature; Microwave irradiation;	96.64%
With sodium oxide In glycerol at 300℃; for 0.1h;	10.5g

1-(bromomethyl)-2- methoxy-4-(trifluoromethyl)benzene (886500-59-0) + Tetrandrin (518-34-3) → C56H58F6N2O8(2+)*2Br(1-)

Conditions	Yield
With triethyldodecylammonium hydroxide In water at 80℃; for 2h; Reagent/catalyst; Solvent; Temperature; Microwave irradiation;	96.05%
In dimethyl sulfoxide at -20℃; for 12h;	7.60g

2-methoxy-5-trifluoromethylbenzyl chloride + citric acid (77-92-9) + Tetrandrin (518-34-3) → C56H58F6N2O8(2+)*2Cl(1-)*C6H8O7

Conditions	Yield
Stage #1: 2-methoxy-5-trifluoromethylbenzyl chloride; Tetrandrin With 1-hexyl-1-methylpyrrolidin-1-ium bromide In water at 80℃; for 2h; Sonication; Stage #2: citric acid for 2h; pH=7.5; Reagent/catalyst; Solvent; Temperature; Heating;	96.05%

2-fluoro-3-trifluoromethylbenzyl iodide + Tetrandrin (518-34-3) → C54H52F8N2O6(2+)*2I(1-)

Conditions	Yield
With tetraethylammonium bromide In water at 50℃; for 4h; Reagent/catalyst; Solvent; Temperature; Microwave irradiation;	95.65%
With sodium oxide In glycerol at 300℃; for 0.1h;	10.15g

2-methoxy-4-trifluoromethylbenzyl iodide + Tetrandrin (518-34-3) → C56H58F6N2O8(2+)*2I(1-)

Conditions	Yield
With 1-butyl-methylpyrrolidinium bis(trifluoromethylsulfonyl)amide In water at 160℃; for 0.5h; Reagent/catalyst; Solvent; Temperature; Sonication;	95.62%
With potassium hydroxide In methanol at 50℃; for 72h;	7.60 g

2-methoxy-5-trifluoromethylbenzyl iodide + Tetrandrin (518-34-3) → C56H58F6N2O8(2+)*2I(1-)

Conditions	Yield
With tetraethylammonium chloride In water at 100℃; for 0.5h; Reagent/catalyst; Solvent; Temperature; Sonication;	95.51%
With triethylamine In butan-1-ol for 8h; Heating;	9.1g

3,5-difluorobenzyl iodide + Tetrandrin (518-34-3) → C52H52F4N2O6(2+)*2I(1-)

Conditions	Yield
With triethyldodecylammonium hydroxide In water at 60℃; for 6h; Reagent/catalyst; Solvent; Temperature; Microwave irradiation;	95.34%
With piperidine In 1,4-dioxane at 60℃; for 12h;	5.95 g

3,5-bis(trifluoromethyl)benzyl bromide (32247-96-4) + Tetrandrin (518-34-3) → C56H52F12N2O6(2+)*2Br(1-)

Conditions	Yield
With dodecyltrimethylammonium hydroxide In water at 100℃; for 1h; Reagent/catalyst; Solvent; Temperature; Microwave irradiation;	95.21%
With sodium carbonate In N,N-dimethyl-formamide at 25 - 90℃;	91.5%
With diethylamine In dichloromethane at 60℃; for 12h;	10.45 g

succinic acid (110-15-6) + 1-bromomethyl-3,5-difluoro-benzene (141776-91-2) + Tetrandrin (518-34-3) → C52H52F4N2O6(2+)*2Br(1-)*C4H6O4

Conditions	Yield
Stage #1: 1-bromomethyl-3,5-difluoro-benzene; Tetrandrin With 1-butyl-3-methylimidazolium trifluoroacetate In water at 50℃; for 6h; Sonication; Stage #2: succinic acid for 2h; pH=7.5; Reagent/catalyst; Solvent; Temperature; Heating;	95.17%

2-methoxy-5-trifluoromethylbenzyl chloride + Tetrandrin (518-34-3) → C56H58F6N2O8(2+)*2Cl(1-)

Conditions	Yield
With N-benzyl-trimethylammonium hydroxide In water at 160℃; for 0.2h; Reagent/catalyst; Solvent; Temperature; Microwave irradiation;	94.4%
With potassium oxide In N,N-dimethyl-formamide at 140℃; for 0.5h;	9.15 g

4-bromomethyltrifluoromethylbenzene (402-49-3) + Tetrandrin (518-34-3) → C54H54F6N2O6(2+)*2Br(1-)

Conditions	Yield
With triethylhexadecylammonium chloride In water at 200℃; for 0.1h; Reagent/catalyst; Solvent; Temperature; Microwave irradiation;	94.14%

Tetrandrin (518-34-3) → 5-bromo-tetrandrine (62067-29-2)

Conditions	Yield
With bromine; acetic acid; trifluoroacetic acid In water at -15℃; for 4.5h;	94%
With bromine; acetic acid; trifluoroacetic acid In water at -20 - -15℃; for 4.5h;	93.4%
With bromine; acetic acid; trifluoroacetic acid In water for 0.0833333h; Heating;
With pyridinium hydrobromide perbromide; acetic acid at 20℃;

Tetrandrin (518-34-3) + methyl iodide (74-88-4) → N,N'-Dimethyl-tetrandrinium-diiodid (22445-73-4, 32434-18-7, 107800-34-0)

Conditions	Yield
In acetonitrile at 85℃;	94%

Tetrandrin (518-34-3) → 14-nitro-tetrandrine

Conditions	Yield
With nitric acid In dichloromethane; ethyl acetate at 0 - 20℃; Inert atmosphere;	94%
With nitric acid; acetic anhydride In dichloromethane at 0 - 20℃; Inert atmosphere;	94%
With nitric acid; acetic anhydride In dichloromethane at 0 - 20℃; for 4h; Inert atmosphere;	93%
With nitric acid; acetic anhydride In chloroform at -10 - 0℃; for 1.5h; Inert atmosphere;	92%

benzoyl chloride (98-88-4) + Tetrandrin (518-34-3) → 7-O-benzoyl-14-nitro-fangchinoline

Conditions	Yield
Stage #1: benzoyl chloride; Tetrandrin With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 8h; Inert atmosphere; Stage #2: With nitric acid; acetic anhydride In chloroform at -10 - 0℃; for 1.75h; Inert atmosphere;	94%

1-(Bromomethyl)-3-fluorobenzene (456-41-7) + Tetrandrin (518-34-3) → C52H54F2N2O6(2+)*2Br(1-)

Conditions	Yield
With N-benzyl-trimethylammonium hydroxide In water at 150℃; for 0.5h; Reagent/catalyst; Solvent; Temperature; Microwave irradiation;	93.94%
With sodium carbonate In N,N-dimethyl-formamide at 25 - 90℃;	89%
With sodium oxide In tetrahydrofuran for 4h; Heating;	7.94g

3,4-bis(trifluoromethyl)benzyl bromide + Tetrandrin (518-34-3) → C56H52F12N2O6(2+)*2Br(1-)

Conditions	Yield
With cetyltrimethylammonium chloride In water at 180℃; for 0.1h; Reagent/catalyst; Solvent; Temperature; Microwave irradiation;	93.1%

4-(bromomethyl)-2-fluoropyridine (64992-03-6) + toluene-4-sulfonic acid (104-15-4) + Tetrandrin (518-34-3) → C50H52F2N4O6(2+)*2Br(1-)*C7H8O3S

Conditions	Yield
Stage #1: 4-(bromomethyl)-2-fluoropyridine; Tetrandrin In water at 80℃; for 2h; Sonication; Stage #2: toluene-4-sulfonic acid for 1.5h; pH=7.5; Reagent/catalyst; Solvent; Temperature; Heating;	92.74%

4-Fluorobenzyl bromide (459-46-1) + Tetrandrin (518-34-3) → C52H54F2N2O6(2+)*2Br(1-)

Conditions	Yield
With N-benzyl-N,N,N-triethylammonium chloride In water at 90℃; for 4h; Reagent/catalyst; Solvent; Temperature; Sonication;	92.5%

(2E)-but-2-enedioic acid (110-17-8) + 2-(bromomethyl)-1,4-difluorobenzene (85117-99-3) + Tetrandrin (518-34-3) → C52H52F4N2O6(2+)*2Br(1-)*C4H4O4

Conditions	Yield
Stage #1: 2-(bromomethyl)-1,4-difluorobenzene; Tetrandrin With tetrabutylammomium bromide In water at 100℃; for 6h; Stage #2: (2E)-but-2-enedioic acid for 8h; pH=7.5; Reagent/catalyst; Solvent; Temperature; Heating;	92.33%

2,5-difluorobenzyl chloride (495-07-8) + Tetrandrin (518-34-3) → C52H52F4N2O6(2+)*2Cl(1-)

Conditions	Yield
With trimethyloctadecylammonium chloride In water at 120℃; for 6h; Reagent/catalyst; Solvent; Temperature; Microwave irradiation;	92.19%

2-fluorobenzyl chloride (345-35-7) + Tetrandrin (518-34-3) → C52H54F2N2O6(2+)*2Cl(1-)

Conditions	Yield
With tetrabutylammomium bromide In water at 60℃; for 12h; Reagent/catalyst; Solvent; Temperature;	90.91%
With potassium hydride In methanol at 65℃; for 8h;	80%

Tetrandrin (518-34-3) → C38H42N2O9S

Conditions	Yield
With sulfuric acid; sodium sulfate In dichloromethane at 20℃; for 11.25h;	90%

oxirane (75-21-8) + Tetrandrin (518-34-3) → N,N’-dihydroxyethyl-tetrandrine chloride

Conditions	Yield
With hydrogenchloride In water at 0 - 20℃;	89%

o-trifluoromethylbenzyl bromide (395-44-8) + Tetrandrin (518-34-3) → C54H54F6N2O6(2+)*2Br(1-)

Conditions	Yield
With sodium carbonate In N,N-dimethyl-formamide at 25 - 90℃;	87.5%

1-bromomethyl-3-chlorobenzene (766-80-3) + Tetrandrin (518-34-3) → C52H54Cl2N2O6(2+)*2Br(1-)

Conditions	Yield
With sodium carbonate In N,N-dimethyl-formamide at 25 - 90℃;	85.3%

benzyl bromide (100-39-0) + Tetrandrin (518-34-3) → (S,S)-N,N'-dibenzyltetrandrine dibromide

Conditions	Yield
In acetone for 15h; Heating;	84%

1-bromomethyl-3-methyl-benzene (620-13-3) + Tetrandrin (518-34-3) → C54H60N2O6(2+)*2Br(1-)

Conditions	Yield
With sodium carbonate In N,N-dimethyl-formamide at 25 - 90℃;	82.3%

2-(bromomethyl)-1-fluoro-4-(trifluoromethyl)benzene + Tetrandrin (518-34-3) → C54H52F8N2O6(2+)*2Br(1-)

Conditions	Yield
With sodium carbonate In N,N-dimethyl-formamide at 25 - 90℃;	80.4%

Upstream product

• 186581-53-3 diazomethane 
• 26137-45-1 (+)-penduline 
• 67-56-1 methanol 
• 38769-07-2 fangchinoline 
• 436-77-1 demethyltetrandrine 
• 66277-16-5 didehydro-N-methylcoclaurinium iodide 
• 17934-80-4 (+/-)-1-(4-hydroxybenzyl)-7-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride 
• 1472-62-4 N-methylcoclaurine 
• 2973-76-4 5-bromo-4-hydroxy-3-methoxybenzaldehyde 
• 38849-59-1 5-(8-bromo-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)-2-methoxy-phenol 
• 1131-94-8 homoisovanillic acid 
• 56139-04-9 2-(3-bromo-4,5-dimethoxyphenyl)ethanamine 
• 54291-90-6 5-bromo-3,4-dimethoxy-1-(2-nitrovinyl)benzene 
• 6948-30-7 5-bromoveratralaldehyde 

Downstream Products

• 477-57-6 tetrandrine 
• 3423-07-2 (S)-N-methylcoclaurine 
• 3423-02-7 (R)-(-)-O-methylarmepavine 
• 3423-05-0 (R)-7-methoxy-1-(4-methoxy-benzyl)-2-methyl-1,2,3,4-tetrahydro-isoquinolin-6-ol 
• 5701-00-8 (R)-O-methylarmepavine 
• 5096-70-8 (-)-(R)-(N)-methylcoclaurine 
• 24724-87-6 aristelegin-C 
• 93-51-6 2-Methoxy-4-methylphenol 
• 75-50-3 trimethylamine 
• 18251-36-0 thalidezine 
• 6681-13-6 Hernandezine 

Relevant articles and documents

Total synthesis method of optically pure Tetrandrine

The invention discloses a total synthesis method of optically pure tetrandrine, and belongs to the technical field of drug synthesis. The method comprises the following steps: (1) under the action ofa catalyst (1), carrying out intermolecular Ullmann reaction on a compound (1) and a compound (2) under alkaline and high-temperature conditions to synthesize a compound 3; (2) removing a hydroxyl protecting group from the compound (3) under an acidic condition to synthesize a compound (4); (3) carrying out intramolecular Ullmann reaction on the compound (4) under the action of a catalyst (2) under alkaline and high-temperature conditions to synthesize a compound (5), namely the optically pure tetrandrine. A convergent synthesis strategy is adopted, and only three steps are needed from the compound (1) to the synthesis of optically pure tetrandrine so that the reaction steps are greatly reduced, and the time and the material cost are saved; the yield can be as high as 28.7%-38.9%, and theyield is increased by dozens of times; the target product can be obtained on the gram scale, 1.3 g-1. 5 g of final optically pure product is synthesized, and the method has better industrialization potential.

Anti-inflammatory effects of the partially purified extract of radix stephaniae tetrandrae

This invention relates to inflammatory responses in isolated peripheral human neutrophils that studied in the presence or absence of specially processed Radix Stephaniae tetrandrae (SPRST). We conclude that SPRST exerts anti-inflammatory effects by interf

ALKALOIDS OF DEHAASIA TRIANDRA

Separation of the basic fraction from Dehaasia triandra afforded two new bisbenzylisoquinoline alkaloids, dehatridine and dehatrine, along with six known alkaloids, isocorydine, corytuberine, atheroline, nantenine, obaberine and a quaternary aporphine alkaloid, xanthoplanine (5). - Keywords: Dehaasia triandra; Lauraceae; Iau-Guoo-Nan; bisbenzylisoquinoline alkaloids; dehatridine; dehatrine.