508233-74-7

Basic information

• Product Name: Vortioxetine
• Synonyms: Trintellix (vortioxetine);Vortioxetine(Lu AA21004);1-(2-((2,4-DIMETHYLPHENYL)THIO)PHENYL)PIPERAZINE-HCL;Vortioxetin;Vortioxetine, >=99%;1-[2-(2,4-Dimethylphenylsulfanyl)phenyl]piperazine;Lu AA 21004;Vortioxetine
• CAS NO: 508233-74-7
• Molecular Formula: C₁₈H₂₂N₂S
• Molecular Weight: 298.44568
• EINECS: 1308068-626-2
• Product Categories: Inhibitors;5-HT antagonist;Serotonin transporter inhibitor
• Mol File: 508233-74-7.mol

Chemical Properties

• Boiling Point: 424.833 °C at 760 mmHg
• Flash Point: 210.732 °C
• Appearance: /
• Density: 1.16
• Storage Temp.: -20°C Freezer
• Solubility: DMSO (Slightly), Methanol (Slightly)
• PKA: 8.85±0.10(Predicted)
• CAS DataBase Reference: Vortioxetine(CAS DataBase Reference)
• NIST Chemistry Reference: Vortioxetine(508233-74-7)
• EPA Substance Registry System: Vortioxetine(508233-74-7)

Safety Data

• Hazardous Substances Data: 508233-74-7(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Vortioxetine is used as an antidepressant for the treatment of major depressive disorder (MDD). It is particularly effective due to its multimodal action, which combines various mechanisms to improve mood and cognitive function in patients.
Used in Biological Studies:
Vortioxetine is also used in the biological study of the effectiveness of long-term treatment of patients with major depressive disorder. This helps researchers and medical professionals understand the long-term benefits and potential side effects of the drug, contributing to the development of better treatment strategies for MDD.

Curative for Major Depression Disorder

Vortioxetine is a new drug for treating depression, jointly developed and researched by the Danish Lundbeck (Lundbeck) and Japanese Takeda. ?In September 30, 2013, It is approved by the U.S. Food and Drug Administration (FDA) to enter into market with the brand name of Brintellix, for Major Depression Disorder (MDD) treatment. In October 2013, the European Medicines Agency (EMA)’s subordinate agency: Committee for Medicinal Products for Human Use (CHMP) recommended that vortioxetine for the treatment of severe depression should be licensed in the European market and be launched into ?the ?European market in January 2014. MDD features mood changes and a series of other symptoms, which have a great impact on the patient's ability to work, sleep, study, eat and enjoy the current happiness. Depressive symptoms can recur many times in life, but some patients may experience only once. Vortioxetine, mainly by increasing the concentration of serotonin (5-HT) in the central nervous system (CNS), exerts antidepressant effects. Compared with other selective serotonin reuptake inhibitors (SSRIS) or serotonin-norepinephrine reuptake inhibitors (SNRIS), vortioxetine almost has no effect on norepinephrine and dopamine neurons. A number of clinical trials have demonstrated the efficacy, safety and tolerability of vortioxetine in the treatment of MDD. Figure 1 shows the structure of vortioxetine.

Mechanism of Action

Vortioxetine is a small molecule piperazine sulfide. WHO w classifies it as antidepressants (N06A). The drug classification system of European Pharmaceutical Market Research Association (EPhMRA) classifies it as hypnotic / sedative drugs (N5B), antidepressants and mood stabilizers (N6A). Currently, depression is thought to be associated with a decrease in 5-HT activity, and decreased activity of norepinephrine (NE) and dopamine (DA) is thought to be associated with depression. Vortioxetine is a potent serotonin reuptake inhibitor. In human body it has high affinity with serotonin trans-porter (Ki=1.6 nmol - L - 1). But it almost has no affinity with norepinephrine transporter (Ki=113nmol - L-1) and dopamine transporter (Ki= 1000nmol - L - 1). At the same time, it is also a 5-HT1A receptor agonist and 5-HT1B receptor partial agonist, 5-HT1D, 5-HT3 and 5-HT7 receptor antagonist and 5-HT uptake inhibitor. Animal studies have shown that in rats, vinpocetine through interaction on these receptors, will increase depression related brain regions -- the level of the ventral hippocampus, prefrontal cortex extracellular serotonin , dopamine, norepinephrine, acetylcholine and histamine, at the same time it is also regulating the function of ?y -GABA (γ-aminobutyric acid) and glutamatergic neuron, thus exerting the effect of antidepressant.

Pharmacokinetics

The relative molecular weight of vortioxetine is small, and the plasma protein binding rate is 98 percent, which is not related to plasma concentration. It is widely distributed outside the cell and the apparent distribution volume is about 2600 L. Daily oral administration is 2.5 ~ 60mg, showing the linear pharmacokinetic characteristics in proportion to dosage of administration. Bioavailability is 75 percent and generally after 2 weeks of taking vortioxetine, its concentration will be stable in blood. Cmax is 7 to 11 hours. Vortioxetine is metabolized mainly by oxidation and glucuronidation . After a single oral administration of the radioisotope labeled vortioxetine, about 59 percent of it is excreted through the urine, and about 26 percent were excreted through the feces. There was almost no original vortioxetine 48 hours after administration of the drug. The complete metabolism in body requires about 66 hours. The oxidation is mainly completed through cytochrome P450 enzyme (CYP). The involved CYP includes CYP3A4/5, CYP2C19, CYP2C9, CYP2A6, CYP2C8, CYP2B6 and CYP2D6. Among them, CYP2D6 is the key enzyme which catalyzes and produces the main metabolite of duloxetine carboxylic acid. The drug concentration of CYP2D6 in the plasma with slow metabolism is twice higher than that of CYP2D6 in the plasma with the fast metabolism.

Drug Interaction

In the different experiment and researches using healthy volunteers as subjects, vortioxetine will be co-administered respectively with CYP2D6 inhibitor bupropion, CYP2C9/CYP2C19/CYP3A inhibitor fluconazole or CYP3A/ permeability glycoprotein (P-gp) inhibitor ketoconazole. The vortioxetine’s bioavailability will increase. Therefore when vortioxetine and strong CYP2D6 inhibitors (such as bupropion, fluoxetine, paroxetine and quinidine) are co-administered, the dosage should be halved. When vortioxetine and strong CYP inducers (rifampicin) are co-administered, its bioavailability will be reduced. Therefore when vortioxetine is co-administered with rifampicin or other strong CYP inducers (such as carbamazepine, Phenytoin sodium), the dosage should be increased, but the maximum dosage should not be three times higher than the normal dose. In addition, the use of 5-HT drugs itself is a risk factors of incurring abnormal bleeding. Therefore when vortioxetine is co-administered with aspirin, nonsteroidal anti-inflammatory drugs or other drugs affecting blood coagulation, special attention should be drawn to the abnormal bleeding of patients. Considering the functional mechanism of vortioxetine and potential toxicity of serotonin, so when it is co-administered with other drugs affecting 5-HT neurotransmitter systems (such as SSRIs, SNRIs, and triptans, buspirone, tramadol and tryptophan products), lt is likely to occur 5-HT syndrome. Therefore, close attention should be paid to the risk of 5-HT syndrome when it is used in combination with such drug. Once the 5-HT syndrome occurs, all such drugs should be discontinued immediately. Similar to the above reasons, monoamine oxidase inhibitors (MAOIs) are prohibited from being used in combination with MAOIs. MAOIs can not be administered within 21d after discontinuation of vortioxetine, and vortioxetine can not be administered within 14d after discontinuation of MAOIs. Because the combination of both will increase the risk of 5-HT syndrome in patients.

Synthesis

2,4-dimethyl-1- iodo-benzene reacts with 2- bromophenyl thiophenol and Bis(dibenzylidene acetone)palladium, under sodium tert-butoxide’s catalysis ?to generate vortioxetine 2,4- dimethyl thiophenol and 2- bromo benzene and piperazine(1-BOC-piperazine) react under the catalysis of Bis(dibenzylidene acetone)palladium , 1, 1'- linked naphthalene -2, 2'- bis diphenyl ?phosphine and sodium tert-butoxide to generate vortioxetine. Figure 1 is a chemical reaction diagram for the synthesis of vortioxetine.

Synthesis

The sequence involves iterative palladium-catalyzed carbon– heteroatom bond formations, the first establishing the thioethereal bond between commercially available thiol (213) and o-iodobromobenzene (214) employing conditions described by Schopfer and Schlapbach. Next, Buchwald–Hartwig conditions were employed to establish the piperazine linkage, and this was followed by subjection to warm hydrobromic acid to furnish vortioxetine hydrobromide (XXVI) in 75% yield across the entire three-step sequence.

in vitro

vortioxetine (lu aa21004) was the lead compound, displaying high affinity for recombinant human 5-ht1a (ki = 15 nm), 5-ht1b (ki = 33 nm), 5-ht3a (ki = 3.7 nm), 5-ht7 (ki = 19 nm), and noradrenergic β1 (ki = 46 nm) receptors, and sert (ki = 1.6 nm). vortioxetine displayed antagonistic properties at 5-ht3a and 5-ht7 receptors, partial agonist properties at 5-ht1b receptors, agonistic properties at 5-ht1a receptors, and potent inhibition of sert [1].

in vivo

in conscious rats, vortioxetine significantly increased extracellular 5-ht levels in the brain after acute and 3 days of treatment. following the 3-day treatment (5 or 10 mg/kg/day) sert occupancies were only 43% and 57%, respectively [1].

Drug interactions

Potentially hazardous interactions with other drugs Antibacterials: avoid with linezolid; concentration reduced by rifampicin - consider increasing vortioxetine dose. Antidepressants: possible increased risk of convulsions with SSRIs and, tricyclics; avoid with moclobemide; increased risk of hypertension and CNS excitation with MAOIs - avoid. Antiepileptics: concentration possibly reduced by carbamazepine, fosphenytoin and phenytoin - consider increasing vortioxetine dose. Antimalarials: possible increased risk of convulsions with mefloquine; avoid with artemether with lumefantrine and artenimol with piperaquine. Antipsychotics: possible increased risk of convulsions with butyrophenones, phenothiazines and thioxanthenes. Dopaminergics: risk of CNS excitation and hypertension with rasagiline and selegiline.

Metabolism

Vortioxetine is extensively metabolised in the liver, mainly by oxidation catalysed by CYP2D6 and to a minor extent CYP3A4/5 and CYP2C9, and subsequent glucuronic acid conjugation. The major metabolite of vortioxetine is pharmacologically inactive. Approximately two thirds of the inactive vortioxetine metabolites are excreted in the urine and approximately one third in the faeces. Only negligible amounts of vortioxetine are excreted in the faeces.

references

[1] bang-andersen b, ruhland t, j?rgensen m, smith g, frederiksen k, jensen kg, zhong h, nielsen sm, hogg s, m?rk a, stensb?l tb. discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (lu aa21004): a novel multimodal compound for the treatment of major depressive disorder. j med chem. 2011;54(9):3206-21. [2] theunissen el, street d, h?jer am, vermeeren a, van oers a, ramaekers jg. a randomized trial on the acute and steady-state effects of a new antidepressant, vortioxetine (lu aa21004), on actual driving and cognition. clin pharmacol ther. 2013;93(6):493-501.

InChI:InChI=1S/C18H22N2S/c1-14-7-8-17(15(2)13-14)21-18-6-4-3-5-16(18)20-11-9-19-10-12-20/h3-8,13,19H,9-12H2,1-2H3

Upstream product

• 110-85-0 piperazine 
• 4214-28-2 1-iodo-2,4-dimethylbenzene 
• 6320-02-1 o-bromothiophenol 
• 960203-27-4 Vortioxetine hydrobromide 
• 63-42-3 D-(+)-lactose 
• 1541160-62-6 1-((2-bromo)-phenylthio)pyrrolidine-2,5-dione 
• 1609659-20-2 tert-butyl 4-(2-iodophenyl)piperazine-1-carboxylate 
• 1019453-85-0 2-(2,4-dimethylphenylsulphanyl)benzeneamine 
• 960203-41-2 (2′-bromophenyl)(2,4-dimethylphenyl)sulfane 
• 57260-71-6 1-t-Butoxycarbonylpiperazine 
• 583-70-0 1-bromo-2,4-dimethylbenzene 
• 136-95-8 2-amino-benzthiazole 
• 149-30-4 2-Mercaptobenzothiazole 
• 50606-33-2 piperazine-1-carboxylic acid phenyl ester 

Downstream Products

• 960203-27-4 Vortioxetine hydrobromide 
• 960203-28-5 Vortioxetine hydrochloride 
• 960203-29-6 Vortioxetine mesylate 
• 960203-35-4 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine sulfate 
• 960203-36-5 Vortioxetine phosphate 
• 960203-37-6 Vortioxetine nitrate 
• 960203-39-8 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrobromide ethyl acetate solvate 
• 960203-40-1 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydrochloride monohydrate 

Relevant articles and documents

Preparation method of novel severe depression treatment drug

The invention provides a preparation method of novel medicament for treating severe depression, and belongs to the field of drug synthesis. A specific scheme of the invention is as follows: 2,4 - dimethyl thiophenol is used. 2 - Bromoiodobenzene, piperazine is a starting material, cuprous iodide is used as a catalyst, one-pot method is used for preparing the, and an organic base is added in the reaction system. To the preparation process, the reaction can be effectively carried out in a homogeneous phase, so that the reaction speed is obviously increased, and the product yield is greatly improved. The problem that in the prior art, homogeneous phase cannot be formed in a reaction system, the reaction time is over 40 hours, and the cost is not greatly reduced in industrial production is solved. Due to the adoption of triethylamine, N, N - diisopropylethylamine and other organic amines, the reaction can be carried out in a homogeneous phase, so that the secondary reaction is reduced, the yield and the purity are greatly improved. The piperazine does not need to be simultaneously added with the starting materials, the feeding step is optimized, the side reaction is reduced, the processes such as filtering are not increased, the procedures in industrialization are not increased, and the investment of equipment and the like is increased.

Study of the isomeric Maillard degradants, glycosylamine and Amadori rearrangement products, and their differentiation via MS2 fingerprinting from collision-induced decomposition of protonated ions

Rationale: The focus of this work was to study glycosylamine and Amadori rearrangement products (ARPs), the two major degradants in the Maillard reactions of pharmaceutical interest, and utilize their MS2 fingerprints by liquid chromatography/high-resolution tandem mass spectrometry (LC/HRMS2) to quickly distinguish the two isomeric degradants. These two types of degradants are frequently encountered in the compatibility and stability studies of drug products containing primary or secondary amine active pharmaceutical ingredients (APIs), which are formulated with excipients consisting of reducing sugar functionalities. Methods: Vortioxetine was employed as the primary model compound to react with lactose to obtain the glycosylamine and ARP degradants of the Maillard reaction, and their MS2 spectra (MS2 fingerprints) were obtained by LC/MS2. Subsequently, the two degradants were isolated via preparative HPLC and their structures were confirmed by one- and two-dimensional (1D and 2D) nuclear magnetic resonance (NMR) determination. Results: The MS2 fingerprints of the two degradants display significantly different profiles, despite the fact that many common fragments are observed. Specifically, protonated glycosylamine shows a prominent characteristic fragment of [Mvort + C2H3O]+ at m/z 341 (Mvort is the vortioxetine core), while protonated ARP shows a prominent characteristic fragment of [Mvort + CH]+ at m/z 311. Further study of the Maillard reactions between several other structurally diverse primary/secondary amines and lactose produced similar patterns. Conclusions: The study suggests that the characteristic MS2 fragment peaks and their ratios may be used to differentiate the glycosylamine and ARP degradants, the two isomeric degradants of the Maillard reaction, which are commonly encountered in finished dosage forms of pharmaceutical products containing primary and secondary amine APIs.

Regioselective C-H Thioarylation of Electron-Rich Arenes by Iron(III) Triflimide Catalysis

A mild and regioselective method for the preparation of unsymmetrical biaryl sulfides using iron(III) catalysis is described. Activation of N-(arylthio)succinimides using the powerful Lewis acid iron(III) triflimide allowed the efficient thiolation of a range of arenes, including anisoles, phenols, acetanilides, and N-heterocycles. The method was applicable for the late-stage thiolation of tyrosine and tryptophan derivatives and was used as the key step for the synthesis of pharmaceutically relevant biaryl sulfur-containing compounds such as the antibiotic dapsone and the antidepressant vortioxetine. Kinetic studies revealed that while N-(arylthio)succinimides bearing electron-deficient arenes underwent thioarylation catalyzed entirely by iron(III) triflimide, N-(arylthio)succinimides with electron-rich arenes displayed an autocatalytic mechanism promoted by the Lewis basic product.

Redox-active benzimidazolium sulfonamides as cationic thiolating reagents for reductive cross-coupling of organic halides

Redox-active benzimidazolium sulfonamides as thiolating reagents have been developed for reductive C-S bond coupling. The IMDN-SO2R reagent provides a bench-stable cationic precursor to generate a portfolio of highly active N-S intermediates, which can be successfully applied in cross-electrophilic coupling with various organic halides. The employment of an electrophilic sulfur source solved the problem of catalyst deactivation and avoided odorous thiols, featuring practical conditions, broad substrate scope, and excellent tolerance.

Preparation method of novel severe depression treatment drug

The invention provides a preparation method of novel medicament for treating severe depression, and belongs to the field of drug synthesis. A specific scheme of the invention is as follows: 2,4 - dimethyl thiophenol is used. 2 - Bromoiodobenzene, piperazine is a starting material, cuprous iodide is used as a catalyst, one-pot method is used for preparing the, and an organic base is added in the reaction system. To the preparation process, the reaction can be effectively carried out in a homogeneous phase, so that the reaction speed is obviously increased, and the product yield is greatly improved. The problem that in the prior art, homogeneous phase cannot be formed in a reaction system, the reaction time is over 40 hours, and the cost is not greatly reduced in industrial production is solved. Due to the adoption of triethylamine, N, N - diisopropylethylamine and other organic amines, the reaction can be carried out in a homogeneous phase, so that the secondary reaction is reduced, the yield and the purity are greatly improved. The piperazine does not need to be simultaneously added with the starting materials, the feeding step is optimized, the side reaction is reduced, the processes such as filtering are not increased, the procedures in industrialization are not increased, and the investment of equipment and the like is increased.

THERAPEUTIC USES OF COMPOUNDS HAVING COMBINED SERT, 5-HT3 AND 5-HT1A ACTIVITY

New pharmaceutical uses of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine and pharmaceutically acceptable salts thereof are provided.

Preparation method of 1-[2-(2, 4-dimethylthiophenyl)-phenyl]piperazine

The invention relates to a preparation method of 1-[2-(2,4-dimethylthiophenyl)-phenyl]piperazine. The method comprises the steps that 2,4-dimethylthiophenol and 1-halogen-2-nitrobenzene carry out a substitution reaction to prepare 2-(2,4-dimethylthiophenyl) nitrobenzene, 2-(2,4-dimethylthiophenyl) nitrobenzene is reduced to prepare 2-(2,4-dimethylthiophenyl)aniline, and 2-(2,4-dimethylthiophenyl)aniline and bis(2-chloroethyl)amine hydrochloride carry out a cyclization reaction to prepare 1-[2-(2,4-dimethylthiophenyl)-phenyl]piperazine. According to the preparation method, 2,4-dimethylthiophenol and 1-halogen-2-nitrobenzene are used as starting materials, and a substitution reaction, a reduction reaction and a cyclization reaction are carried out to prepare the target compound. The three-step reaction is low in cost, high in yield and easy to purify and industrialize.

Dechalcogenization of Aryl Dichalcogenides to Synthesize Aryl Chalcogenides via Copper Catalysis

An application for dechalcogenization of aryl dichalcogenides via copper catalysis to synthesize aryl chalcogenides is disclosed. This approach is highlighted by the practical conditions, broad substrate scope, and good functional group tolerance with several sensitive groups such as aldehyde, ketone, ester, amide, cyanide, alkene, nitro, and methylsulfonyl. Furthermore, the robustness of this methodology is depicted by the late-stage modification of estrone and synthesis of vortioxetine. Remarkably, synthesis of more challenging organic materials with large ring tension under milder conditions and synthesis of some halogen contained diaryl sulfides which could not be synthesized using metal-catalyzed coupling reactions of aryl halogen are successfully accomplished with this protocol.

Vortioxetine impurity 1-[3-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine and use thereof

The invention relates to the field of pharmaceutical synthesis, and discloses a vortioxetine impurity 1-[3-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine and a use thereof. During the experiment process of synthesizing vortioxetine, the inventors accidentally find an important impurity I of vortioxetine, namely 1-[3-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine, a preparation method of the impurity I is determined, the structure analysis of the impurity I is performed, and the impurity I is not reported before. The impurity is used as a vortioxetine intermediate, and a reference substance ofthe quality research of the raw medicine and preparations thereof, and a solid foundation for the quality research of vortioxetine is further laid.

Preparation method of vortioxetine

The invention relates to the field of organic synthetic route design, in particular to a preparation method of vortioxetine. The preparation method comprises the steps that 2-bromoiodobenzene (formulaII), 2,4-dimethyl benzenethio (formula III), N-phenoxycarbonyl piperazine (formula IV) and tert butyl alcohol (formula V) are taken as raw materials, in an aprotic solvent and under an alkaline condition, a palladium catalyst and a phosphine ligand are added for catalysis, heating is performed, and an intermediate 1 is formed orientedly; in an acidic condition, N-Boc-vortioxetine (formula VI) inthe intermediate 1 is subjected to Boc protecting group removal, and then a crude vortioxetine product (formula I) is formed through alkaline dissociation. The method has the advantages that the raw materials are simple and easy to obtain, the reaction condition of the process is mild, the product has high yield and high purity, and the method is suitable for industrial production.