483-14-7

Basic information

• Product Name: rotundine
• Synonyms: 6H-Dibenzo[a,g]quinolizine, 5,8,13,13a-tetrahydro-2,3,9,10-tetramethoxy-, (13aS)-;ROTUNDINE 98+%;(-)-Gindarine;(13aS)-2,3,9,10-Tetramethoxy-5,6,13,13a-tetrahydro-8H-dibenzo[a,g]quinolizine;(S)-Tetrahydropalmitine;[13aS,(-)]-5,8,13,13a-Tetrahydro-2,3,9,10-tetramethoxy-6H-dibenzo[a,g]quinolizine;Gindarine;(13aS)-2,3,9,10-tetramethoxy-6,8,13,13a-tetrahydro-5H-isoquinolino[2,1-b]isoquinoline
• CAS NO: 483-14-7
• Molecular Formula: C₂₁H₂₅NO₄
• Molecular Weight: 355.43
• Product Categories: Inhibitors;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 483-14-7.mol

Chemical Properties

• Melting Point: 141-143°C
• Boiling Point: 482.9 °C at 760 mmHg
• Flash Point: 138.7 °C
• Appearance: Off-white solid
• Density: 1.23 g/cm³
• Storage Temp.: Refrigerator
• Solubility: insoluble in H2O; ≥16 mg/mL in DMSO; ≥2.95 mg/mL in EtOH with gentle warming and ultrasonic
• PKA: 6.53±0.20(Predicted)
• Water Solubility: Soluble in chloroform
• CAS DataBase Reference: rotundine(CAS DataBase Reference)
• NIST Chemistry Reference: rotundine(483-14-7)
• EPA Substance Registry System: rotundine(483-14-7)

Safety Data

• RTECS: HQ1792500
• Hazardous Substances Data: 483-14-7(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Applications:
Rotundine is used as an analgesic drug for the treatment of various health conditions, including heart disease and liver damage. Its natural origin and potent therapeutic effects contribute to its popularity in traditional Chinese medicine.
Used in Heart Disease Treatment:
Rotundine is used as a therapeutic agent for heart disease, where it helps alleviate pain and discomfort associated with the condition. Its analgesic properties make it a valuable addition to the treatment regimen for heart disease patients.
Used in Liver Damage Treatment:
Rotundine is also used as a treatment for liver damage, where it aids in the recovery and repair of liver tissues. Its ability to provide relief from pain and inflammation makes it an essential component in the management of liver-related health issues.

Biological Activity

levo-tetrahydropalmatine (l-thp) is an active herbal constituent of preparations containing plant species of the genera stephania and corydalis. in china, it has been approved and used for a number of clinical indications under the drug name rotundine.

in vitro

in contrast to other thpb derivatives, l-thp is an antagonist at both of d1 and d2 receptors. the ki values for l-thp at d1 and d2 dopamine receptors are approximately 124 nm (d1) and 388 nm (d2), while the ic50 values are 166 nm and 1.4 μm for d1 and d2, respectively. the relatively high affinity of l-thp at d1 vs. d2 receptors, distinguishes it from other available dopamine receptor antagonist drugs (e.g., haloperidol) [1].

in vivo

it has been found that l-thp produces dose-dependent reductions in locomotor activity and operant responding for non-drug reinforcers in rats [1].

references

[1] wang jb, mantsch jr. l-tetrahydropalamatine: a potential new medication for the treatment of cocaine addiction. future med chem. 2012 feb;4(2):177-86.

Upstream product

• 2934-97-6 (+/-)-tetrahydropalmatine 
• 186581-53-3 diazomethane 
• 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 
• 1356336-72-5 (S)-1-(chloromethyl)-3,4-dimethoxy-2-(p-tolylsulfinyl)benzene 
• 1356336-70-3 (S)-1,2-dimethoxy-4-methyl-3-(p-tolylsulfinyl)benzene 
• 65495-21-8 N,N-dimethyl-3,4-dimethoxybenzylamine 
• 102321-59-5 N-(2,3-dimethoxybenzyl)-2-(3,4-dimethoxyphenyl)ethan-1-aminium chloride 
• 47355-66-8 N-(2,3-dimethoxybenzyl)-2-(3,4-dimethoxyphenyl)ethan-1-amine 
• 120-20-7 2-(3,4-dimethoxyphenyl)-ethylamine 
• 86-51-1 2,3-dimethyoxybenzaldehyde 
• 26067-60-7 2,3,9,10-tetramethoxy-5,8-dihydro-6H-isoquinolino[3,2-α]isoquinoline 

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

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.

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.

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.