10097-84-4

Basic information

• Product Name: Tetrahydropalmatine
• Synonyms: AKOS 208-04;L-TETRAHYDROPALMATINE;L-TETRAHYDROPALMATINE HCL;DL-TETRAHYDROPALMATINE;TETRAHYDROPALMATINE;ROTUNDINE;ROTUNDIN HYDRATE;ROTUNDINUM
• CAS NO: 10097-84-4
• Molecular Formula: C₂₁H₂₅NO₄
• Molecular Weight: 355.43
• EINECS: 1592732-453-0
• Product Categories: Alkaloids;Miscellaneous Natural Products;Pharmaceutical intermediate;Plant extracts;chemical reagent;phytochemical;reference standards from Chinese medicinal herbs (TCM).;standardized herbal extract;Inhibitors
• Mol File: 10097-84-4.mol

Chemical Properties

• Boiling Point: 482.9 °C at 760 mmHg
• Flash Point: 138.7 °C
• Appearance: light yellow powder crystal
• Density: 1.23 g/cm³
• Vapor Pressure: 1.76E-09mmHg at 25°C
• Refractive Index: 1.608
• Storage Temp.: Hygroscopic, Refrigerator, under inert atmosphere
• Solubility: Chloroform (Slightly), Methanol (Slightly)
• CAS DataBase Reference: Tetrahydropalmatine(CAS DataBase Reference)
• NIST Chemistry Reference: Tetrahydropalmatine(10097-84-4)
• EPA Substance Registry System: Tetrahydropalmatine(10097-84-4)

Safety Data

• Safety Statements: 24/25
• Hazardous Substances Data: 10097-84-4(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Tetrahydropalmatine is used as an analgesic drug for treating heart disease and liver damage. It is particularly effective due to its ability to alleviate pain and its presence in traditional Chinese herbal medicine.
Used in Traditional Chinese Medicine:
Tetrahydropalmatine is used as an active constituent in various herbal preparations, providing relief from pain and anxiety, as well as addressing depression and parasitic infections.
Used in Sedative Applications:
Tetrahydropalmatine, specifically the levo isomer (l-THP), is used as a sedative for more than 40 years in China, where it is available as Rotundine or Rotundin.
Physical Properties:
Appearance: Off-white solid, odorless, tasteless, turns yellow under light and heat
Solubility: Usually dissolved in chloroform, slightly soluble in ethanol or ether, insoluble in water, and soluble in dilute sulfuric acid
Melting Point: 141–144°C
Specific Optical Rotation: -290 to -300°

References

1. https://en.wikipedia.org/wiki/Tetrahydropalmatine 2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3878639/ 3.https://www.worldseedsupply.com/product/corydalis-yanhusuo-tetrahydropalmatine-98-pure-thp-isolate/ 4. https://www.lktlabs.com/product/dl-tetrahydropalmatine/

References

Kondo, Matsuno., J. Pharm. Soc., Japan, 64, (9A), 28 (1944)

History

From the 1920s, many researchers have focused on the alkaloid compounds contained in the Yan Hu Suo and extracted more than 30 different kinds of alkaloids. Among them Rotundine is one of the most important active compounds and has been successfully applied in clinical practice.Tetrahydropalmatine (THP) was firstly discovered by Zhao Chenggu, a famous medicinal phytochemist in China. He isolated 13 kinds of alkaloids and identified the structure of 6 of them. In 1936, Huang Minglong, a famous organic chemist, proved THP is a racemate. From 1933, Wang Jingxi and Lu Zihui began to study the pharmacological effects of THP and found that THP could induce catalepsy in animals. Rotundine is a levo-THP and obtained from the resolution of DL-THP during 1959–1964. From 1956 to 1965, the famous Chinese neuropharmacologist, Jin Guozhang, identified Rotundine as the main effective component in Yan Hu Suo and further studied its underlying mechanisms. He also found that Stephania contains abundant L-THP, which could become the source of clinical medication.In 1965, Rotundine was recorded in the textbooks of pharmacology. After over 20?years of clinical practices, people have proved that Rotundine has reliable efficacy and low side effect. In 1977, Rotundine was recorded in the Chinese Pharmacopoeia. In 1979, THP achieved a full synthesis, and currently Rotundine is mainly produced by artificial synthesis. From 1980, the study on the mechanisms of Rotundine made great progress. The analgesic effect of Rotundine has nothing to do with opioid receptors or prostaglandins. Rotundine does not belong to narcotic analgesics and antipyretic analgesics. Further, Rotundine has been found to have no affinity with M-cholinergic receptor and GABA system in the brain. But it has affinity to dopamine receptors. The exact mechanisms and pharmacology effects of Rotundine still need more research.

Pharmacology

1. Effects on the central nervous system: Rotundine has significant analgesic, sedative, and hypnotic effects, and its mechanism has nothing to do with opioid receptors. It has no obvious addiction effect. Using Rotundine combined with pethidine can enhance the analgesic effect, reduce the amount of pethidine, and further reduce the occurrence of drug dependence. The present study suggests that Rotundine is a central dopamine receptor blocker that inhibits the transmission of peripheral pain information by blocking the D2 receptor of the striatum and nucleus accumbens and the PAG-RgpI-spinal dorsal horn nerve pathway. In addition, Rotundine also has a suppression of the strengthening of the motor response induced by drug abuse, that is, inhibition of behavioral sensitization.2. Effects on the cardio-cerebrovascular system: Rotundine has inhibitory effect on the injuries caused by cerebral ischemia and reperfusion and myocardial ischemia and reperfusion. It also could lower the blood pressure. The pharmacological mechanism of Rotundine on the cardiovascular and cerebrovascular aspects is quite complex and may relate to the regulation of inflammation and inhibition of apoptosis. It is also found that Rotundine acts on α-receptors and has a noncompetitive antagonistic effect on calcium.3. Rotundine can reverse the drug resistance of tumor cells; the mechanism may be through the downregulating of the expression of P-glycoprotein (P-gp) and the upregulating of the expression of topo II in tumor cells.4. Rotundine has an excitatory effect on the endocrine system, such as the pituitaryadrenal system, and also has a protective effect on the liver.5. Drug metabolisms: The absorption of Rotundine by oral administration is complete. At 15?min it can be absorbed by 40–50%. It begins to work at 10–30?min, and the effect can last 2–5?h. In vivo distribution is through fat and the lung, liver, and kidney. If administered by subcutaneous injection, after 12?h, Rotundine will be discharged by 80% with the urine.

Clinical Use

1. Pain induced by gastrointestinal and hepatobiliary disorders, menstrual pain, and pain after childbirth.2. Mild trauma and postoperative pain3. Headache insomnia and spasmodic cough.4. There is a report about the usage of Rotundine in arrhythmia caused by I–III hypertension and other diseases.5. The hypnotic effect of Rotundine happens in 15?min after administration and then appears after 2?h. Because the analgesic effect happens at the same time, Rotundine is particularly suitable for insomnia patients with pain.6. Side effects: drowsiness, dizziness, fatigue, and nausea. Large dose of Rotundine can inhibit the respiratory center and may cause extrapyramidal symptoms.

Purification Methods

Crystallise it from MeOH or EtOH by addition of water [see Kametani & Ihara J Chem Soc (C) 530 1967, Bradsher & Dutta J Org Chem 26 2231 1961]. When crystallised from Me2CO/Et2O, it has m 142o. The hydrate has m 115o(effervescence). The picrate has m 188o(dec) (from aqueous EtOH). [Bradsher & Datta J Org Chem 26 2231 1961, Beilstein 21 II 196, 21 III/IV 2769.]

InChI:InChI=1/C21H25NO4/c1-23-18-6-5-13-9-17-15-11-20(25-3)19(24-2)10-14(15)7-8-22(17)12-16(13)21(18)26-4/h5-6,10-11,17H,7-9,12H2,1-4H3/t17-/m0/s1

Upstream product

• 186581-53-3 diazomethane 
• 6487-33-8 (-)-isocorypalmine 
• 6018-39-9 corypalmine 
• 2934-97-6 (+/-)-tetrahydropalmatine 
• 870282-81-8 (13aS)-2,3,9,10-tetramethoxy-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizin-5-ol 
• 870282-72-7 (13aS)-2,3,9,10-tetramethoxy-5-phenylsulfanyl-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine 
• 870282-77-2 [1-(3,4-dimethoxyphenyl)-meth-(1E)-ylidene]-((2R)-2-methoxymethylpyrrolidin-1-yl)-amine 
• 870282-79-4 (3S)-3-(3,4-dimethoxyphenyl)-7,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline 
• 870282-78-3 (3S)-3-(3,4-dimethoxyphenyl)-7,8-dimethoxy-2-((2R)-2-methoxymethylpyrrolidin-1-yl)-3,4-dihydro-2H-isoquinolin-1-one 
• 70945-99-2 N,N-diethyl-2,3-dimethoxy-6-methyl-benzamide 
• 50-00-0 formaldehyd 
• 1356336-76-9 (1S)-1-[3,4-dimethoxy-2-(S)-p-tolylsulfinyl]benzyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline 
• 1356336-74-7 (1S)-1-[3,4-dimethoxy-2-(S)-p-tolylsulfinyl]benzyl-6,7-dimethoxy-2-(S)-p-tolylsulfinyl-1,2,3,4-tetrahydroisoquinoline 
• 1356336-71-4 (S)-1-[3,4-dimethoxy-2-(p-tolylsulfinyl)phenyl]-N,N-dimethylmethanamine 

Downstream Products

• 6487-33-8 (-)-isocorypalmine 
• 605-34-5 (S)-scoulerine 
• 2506-20-9 2,3,9,10-tetramethoxy-13aα-berbine; hydrochloride 
• 77519-57-4 (S)-(-)-8-oxoxylopinine 

Relevant articles and documents

BIOSYNTHESIS OF (+)-, (-)- AND (+/-)-TETRAHYDROPALMATINES

Specific incorporation of didehydroreticuline and reticuline into (+/-)-, (+)-, and (-)-tetrahydropalmatines in Cocculus laurifolius and of (R)- and (S)-reticulines into (R)- and (S)-tetrahydropalmatines respectively has been demonstrated.Feeding of 3H,4'-methoxy-14C>reticuline suggested that reticuline was not converted in the plants into didehydroreticuline and racemisation of optically active forms of tetrahydropalmatine did not take place via dehydrotetrahydropalmatine.

Total Synthesis of (-)-Canadine, (-)-Rotundine, (-)-Sinactine, and (-)-Xylopinine Using a Last-Step Enantioselective Ir-Catalyzed Hydrogenation

A concise asymmetric total synthesis of a group of tetrahydroprotoberberine alkaloids, (-)-canadine, (-)-rotundine, (-)-sinactine, and (-)-xylopinine, has been accomplished in three steps from the commercially available corresponding disubstituted phenylethylamine and disubstituted benzaldehyde. Our synthesis toward these four alkaloids took advantage of the following strategy: In the first step, we achieved an efficient and sustainable synthesis of secondary amine hydrochlorides via a fully continuous flow; in the second step, we developed a Pictet-Spengler reaction/Friedel-Crafts hydroxyalkylation/dehydration cascade for the construction of the dihydroprotoberberine core structure (ABCD-ring); and in the last step, Ir-catalyzed enantioselective hydrogenation was employed for the introduction of the desired stereochemistry at the C-14 position in the tetrahydroprotoberberine alkaloids. This work significantly expedites the asymmetric synthesis of the entire tetrahydroprotoberberine alkaloid family as well as a more diverse set of structurally related non-natural analogues.

Method for synthesizing tetrahydroberberine and derivatives thereof

The invention provides a method for synthesizing tetrahydroberberine and derivatives thereof. Specifically, in the presence of an iridium metal catalyst precursor, a chiral diphosphine ligand, an acid and a halogen-containing additive, in a hydrogen atmosphere, a compound (II) is subjected to an asymmetric catalytic hydrogenation reaction in an organic solvent so as to prepare the compound (I).

Asymmetric total synthesis and identification of tetrahydroprotoberberine derivatives as new antipsychotic agents possessing a dopamine D1, D2 and serotonin 5-HT1A multi-action profile

An effective and rapid method for the microwave-assisted preparation of the key intermediate for the total synthesis of tetrahydroprotoberberines (THPBs) including l-stepholidine (l-SPD) was developed. Thirty-one THPB derivatives with diverse substituents on A and D ring were synthesized, and their binding affinity to dopamine D1, D2 and serotonin 5-HT 1A and 5-HT2A receptors were determined. Compounds 18k and 18m were identified as partial agonists at the D1 receptor with Ki values of 50 and 6.3 nM, while both compounds act as D2 receptor antagonists (Ki = 305 and 145 nM, respectively) and 5-HT1A receptor full agonists (Ki = 149 and 908 nM, respectively). These two THPBs compounds exerted antipsychotic actions in animal models. Further electrophysiological studies employing single-unit recording in intact animals demonstrated that 18k-excited dopaminergic (DA) neurons are associated with its 5-HT1A receptor agonistic activity. These results suggest that these two compounds targeted to multiple neurotransmitter receptors may present novel lead drugs with new pharmacological profiles for the treatment of schizophrenia.

Asymmetric synthesis of (S)-(-)-tetrahydropalmatine and (S)-(-)-canadine via a sulfinyl-directed Pictet-Spengler cyclization

(S)-(-)-Tetrahydropalmatine 2 and (S)-(-)-canadine 4 were synthesized in three steps from (S)-6, in 33% and 34% overall yield, respectively. Thus, condensation of the (S)-(E)-sulfinylimines 10 and 11 with the carbanion derived from (S)-6 gave the tetrahydroisoquinolines 12 and 13, respectively, which upon TFA induced N-desulfinylation, and subsequent microwave assisted Pictet-Spengler cyclization effected both cyclization and C-desulfinylation producing (S)-(-)-tetrahydropalmatine 2 and (S)-(-)-canadine 4 in optically pure form.

Asymmetric synthesis of tetrahydropalmatine via tandem 1,2-addition/ cyclization

The enantioselective synthesis of both enantiomers of tetrahydropalmatine (2) (ee = 98%), a natural alkaloid belonging to the tetrahydroprotoberberine family, is described. The key step of this total synthesis is based on our tandem 1,2-addition/ring-closure methodology employing lithiated methylbenzamide and benzaldehyde SAMP or RAMP hydrazones as substrates. An initial route was investigated for the formation of N- and 3-substituted dihydroisoquinolones starting from 2-substituted benzaldehyde SAMP hydrazones, but although high diastereoselectivity was achieved, only disappointing yields were obtained. In our subsequent synthetic strategy, 2,3-dimethoxy-6-methylbenzamide 6 and 3,4-dimethoxybenzaldehyde SAMP or RAMP hydrazone 19 gave the dihydroisoquinolones 20 in high diastereomeric purity (de ≥ 96%) and reasonable yield (54-55%), taking into account the complex functionalities established in one step. Cleavage of the N-N bond of the chiral auxiliary and reduction of the carbonyl group of the amide moiety were performed in the same step, and the resulting tetrahydroisoquinolines 22 (ee = 99%) were N-functionalized by treatment with various electrophiles to investigate the ring closure by Pummerer, Friedel-Crafts, and Pomeranz-Fritsch reactions. The Pummerer cyclization led to the formation of (S)-(-)-2 with slight racemization (ee = 89%), whereas the Friedel-Crafts reaction proved to be unsuccessful. Finally, Pomeranz-Fritsch-type cyclization afforded the desired title compound (R)-(+)-2 in excellent enantioselectivity in 9% overall yield over seven steps and after optimization of the last step (S)-(-)-2 in 17% overall yield.

Aberrant Biosynthesis of (±)-, (+)- and (-)-12-Bromotetrahydropalmatines

The incorporation of 2′-bromodidehydro[N-14CH3]reticulinium iodide (1) into (±)-12-bromotetrahydropalmatine (4), (+)-12-bromotetrahydropalmatine (9) and (-)-12-bromotetrahydropalmatine (7) in Cocculus laurifolius DC (Menispermaceae) has been studied and stereospecific reduction of 1 into (+)-9 and (-)-7 and (±)-(4), 12-bromotetrahydropalmatines demonstrated.

Total synthesis of (-)-tetrahydropalmatine via chiral formamidine carbanions: Unexpected behavior with certain ortho-substituted electrophiles

A method has been developed by alkylation of chiral lithioformamidines to construct protoberberine alkaloids with a C(9) and C(10) D-ring substitution pattern. This ring pattern was established using an ortho-substituted hydroxymethylbenzene electrophile protected as a silyl ether to ultimately provide (-)-tetrahydropalmatine in 88% ee. Additionally, we have discovered limitations with ortho-substituted electrophiles in the asymmetric formamidine alkylation. These electrophiles have the potential to disrupt the lithium formamidine chelate and cause the selectivity in the alkylation to be uncharacteristically low. The total synthesis of (±)-canadine and (-)-tetrahydropalmatine along with the limitations to the formamidine alkylation technology are delineated herein.

THE ALKALOIDS OF Hydrastis canadensis L. (RANUNCULACEAE). TWO NEW ALKALOIDS: HYDRASTIDINE AND ISOHYDRASTIDINE

Ten alkaloids have been isolated from rhizomes and roots of Hydrastis canadensis L.Four of them, viz. berberine, 1, β-hydrastine, 2, canadine, 3, and canadaline, 4, had been previously isolated.Two are new phthalideisoquinoline alkaloids, viz. 3'-O-demethyl-β-hydrastine, named hydrastidine, 5, and 4'-O-demethyl-β-hydrastine, named isohydrastidine, 6.Two are (-)-(S)-corypalmine, 7, and (-)-(S)-isocorypalmine, 8, known mono-O-demethyl derivatives of (-)-(S)-tetrahydropalmatine, 9.One, 10, is a bis-O,O'-demethyl derivative of 9, whose hydroxy groups were not located, whereas the structure of the tenth alkaloid is still unknown. 1H NMR data for 1-8 and 10, and 13C NMR data for 5, 6, and 8 are reported.