Citalopram
カタログ番号:
B1669093
CAS番号:
59729-33-8
分子量:
324.4 g/mol
InChIキー:
WSEQXVZVJXJVFP-UHFFFAOYSA-N
注意:
研究専用です。人間または獣医用ではありません。
概要
説明
シタロプラムは、選択的セロトニン再取り込み阻害薬（SSRI）であり、抗うつ薬として広く使用されています。 主に、主要なうつ病、強迫性障害、パニック障害、社会不安障害の治療に処方されます . シタロプラムは、脳内の神経伝達物質であるセロトニンの再取り込みを阻害することにより、セロトニン作動性伝達を増強します .
準備方法
合成経路と反応条件
シタロプラムの合成には、いくつかの重要なステップが含まれます。
ベンゾフェノン誘導体の還元： プロセスは、プロトン性溶媒の存在下で、ナトリウムボロハイドライドを使用して、ベンゾフェノン誘導体の分離できないマグネシウム塩を還元することから始まります.
中間体の生成： 還元された化合物は、次に、非極性溶媒中で酸触媒と反応させて、中間体を取得します.
シアン化銅(I)との反応： 中間体は、極性溶媒媒体中でシアン化銅(I)と反応させ、次に極性および/またはアルコール性溶媒を使用して再結晶化して、シアノ化合物を取得します.
最終的な変換： 次に、シアノ化合物は、従来の方法でシタロプラムに変換されます.
工業生産方法
シタロプラムの工業生産は、同様の合成経路に従いますが、大規模製造向けに最適化されています。 プロセスには、最終生成物の高収率と純度を確保するために、反応条件を厳密に管理することが含まれます .
化学反応の分析
反応の種類
シタロプラムは、さまざまな化学反応を起こします。これには、以下が含まれます。
熱分解： シタロプラムは、189.3°Cで融解した後、単一ステップで分解し、臭化水素、ジメチルアミン、フルオロベンゼンを放出します.
酸化と還元： これらの反応はあまり一般的ではありませんが、特定の条件下で発生する可能性があります。
一般的な試薬と条件
ナトリウムボロハイドライド： 合成の還元段階で使用されます.
シアン化銅(I)： シアノ化合物の生成に使用されます.
酸触媒： 中間体の生成段階で使用されます.
生成される主な生成物
臭化水素： 熱分解中に放出されます.
ジメチルアミンとフルオロベンゼン： 熱分解の副生成物.
科学研究の応用
シタロプラムは、幅広い科学研究の応用を持っています。
科学的研究の応用
Therapeutic Applications
Citalopram is approved for several conditions, including:
- Major Depressive Disorder : The primary indication for this compound, showing significant efficacy in clinical trials.
- Anxiety Disorders : Effective in managing generalized anxiety disorder and panic disorder.
- Obsessive-Compulsive Disorder : Used off-label to alleviate symptoms.
- Eating Disorders : Prescribed for conditions such as bulimia nervosa and binge eating disorder.
- Alcohol Use Disorders : Investigated for its potential to reduce cravings and withdrawal symptoms.
Neuroprotective Effects
Recent studies have highlighted this compound's neuroprotective properties, particularly in neurodegenerative diseases like Alzheimer's Disease. Research indicates that this compound may mitigate mitochondrial dysfunction associated with Alzheimer's pathology.
Case Study Insights
-
Neuroprotection in Alzheimer's Disease :
- A study demonstrated that this compound treatment led to reduced levels of amyloid-beta (Aβ) and improved mitochondrial dynamics in mouse models expressing mutant amyloid precursor protein (APP). This suggests a potential role for this compound in protecting against synaptic dysfunction and enhancing cell survival rates in neurodegenerative contexts .
-
Impact on Neuronal Differentiation :
- Another investigation into human embryonic stem cells revealed that exposure to this compound during neuronal differentiation influenced gene expression patterns associated with neurodevelopment. This study utilized a multi-omics approach, indicating that this compound could have implications for developmental neuroscience .
Pharmacological Profile
| Indication | Evidence Level | Patient Characteristics | Dosage Form |
|---|---|---|---|
| Major Depressive Disorder | High | Adults | Oral tablets |
| Generalized Anxiety Disorder | Moderate | Adults | Oral tablets |
| Obsessive-Compulsive Disorder | Moderate | Adults | Oral tablets |
| Bulimia Nervosa | Moderate | Adults | Oral tablets |
| Alcohol Use Disorders | Emerging | Adults | Oral tablets |
Adverse Effects and Considerations
While generally well-tolerated, this compound can cause side effects such as:
- Nausea
- Fatigue
- Sexual dysfunction
- Weight gain
Monitoring is essential, especially when used in combination with other medications due to potential drug-drug interactions.
作用機序
シタロプラムは、シナプス前ニューロンにおけるセロトニンの再取り込みを選択的に阻害することにより、シナプス間隙のセロトニン濃度を増加させることにより作用します . この作用は、セロトニン作動性伝達を増強し、うつ病や不安の症状を軽減します . シタロプラムは、ドーパミンおよびノルエピネフリン輸送体への影響は最小限であり、他の受容体サブタイプへの親和性はほとんどありません .
類似の化合物との比較
シタロプラムは、以下のような他の選択的セロトニン再取り込み阻害薬（SSRI）と比較されます。
エシタロプラム： 主要なうつ病の急性反応と寛解を達成する上で、シタロプラムよりも有効です.
フルオキセチン： 有効性は似ていますが、副作用のプロフィールが異なります.
パロキセチン： シタロプラムはより有効であり、副作用のプロフィールが良好です.
シタロプラムの独自性は、セロトニンの再取り込み阻害に対する高い選択性と、他の神経伝達物質系との最小限の相互作用にあります .
類似化合物との比較
Citalopram is compared with other selective serotonin reuptake inhibitors (SSRIs) such as:
Esthis compound: More efficacious than this compound in achieving acute response and remission in major depressive disorder.
Fluoxetine: Similar efficacy but different side effect profiles.
Paroxetine: This compound is more efficacious and has a better side effect profile.
This compound’s uniqueness lies in its high selectivity for serotonin reuptake inhibition and minimal interaction with other neurotransmitter systems .
生物活性
Citalopram is a widely used selective serotonin reuptake inhibitor (SSRI) primarily prescribed for the treatment of major depressive disorder (MDD) and anxiety disorders. Its biological activity is characterized by its mechanism of action, pharmacokinetics, efficacy in clinical settings, and its side effects profile.
This compound's primary mechanism involves the inhibition of serotonin reuptake in the central nervous system (CNS). This action enhances serotonergic neurotransmission, which is crucial for mood regulation. Unlike many tricyclic antidepressants, this compound exhibits a selective affinity for serotonin transporters (SLC6A4) and has minimal interactions with other neurotransmitter receptors such as norepinephrine, dopamine, and histamine receptors .
- Serotonin Reuptake Inhibition : this compound is at least eight times more potent than its metabolites in inhibiting serotonin reuptake, indicating that its antidepressant effects are primarily due to the parent compound rather than its metabolites .
- Receptor Affinity : this compound has low affinity for muscarinic acetylcholine receptors and does not significantly affect adrenergic or dopaminergic systems, which contributes to a favorable side effect profile compared to older antidepressants .
Pharmacokinetics
The pharmacokinetic profile of this compound includes:
- Bioavailability : Approximately 80%.
- Half-life : Ranges from 24 to 48 hours , with an average of about 35 hours. This half-life may be extended in populations with hepatic impairment or older age .
- Metabolism : Primarily metabolized by CYP450 enzymes (CYP3A4 and CYP2C19), leading to various metabolites, although the parent compound remains predominant in plasma .
Clinical Efficacy
Numerous clinical trials have demonstrated this compound's efficacy in treating depression:
- Children and Adolescents : A randomized controlled trial showed that this compound significantly improved depressive symptoms compared to placebo within one week. The mean dose was approximately 24 mg/day, with a notable effect size of 2.9 on the Children's Depression Rating Scale .
- Adults with MDD : In a study involving nearly 2,900 outpatients, the mean exit dose was 41.8 mg/day. The remission rates were reported at 28% using the Hamilton Depression Rating Scale (HAM-D) and 33% on the Quick Inventory of Depressive Symptomatology (QIDS-SR) .
- Preventive Efficacy : this compound has also been evaluated for preventing recurrent depression in elderly patients, showing significant efficacy in reducing recurrence rates during maintenance therapy .
Side Effects
While generally well tolerated, this compound can cause side effects including:
- Nausea
- Abdominal pain
- Rhinitis
- Discontinuation rates due to adverse events were comparable between this compound and placebo groups in various studies .
Summary Table of Key Findings
| Parameter | Details |
|---|---|
| Mechanism of Action | Selective serotonin reuptake inhibitor |
| Bioavailability | ~80% |
| Half-life | 24 to 48 hours (average ~35 hours) |
| Metabolism | Primarily via CYP3A4 and CYP2C19 |
| Efficacy in Adults | Remission rates: 28% (HAM-D), 33% (QIDS-SR) |
| Efficacy in Children | Significant improvement within one week |
| Common Side Effects | Nausea, abdominal pain, rhinitis |
Case Studies
Several case studies illustrate this compound's effectiveness:
- A study on patients undergoing treatment for head and neck cancer indicated that this compound could prevent major depression during treatment phases, showcasing its utility beyond traditional psychiatric settings .
- Another longitudinal study highlighted that this compound maintained efficacy over extended periods, confirming its role in long-term management strategies for depression .
Q & A
Basic Research Questions
Q. What experimental designs are most robust for isolating citalopram's neuropharmacological effects from confounding variables in clinical trials?
Methodological Answer:
- Use double-blind, randomized controlled trials (RCTs) with placebo arms to minimize bias.
- Control physiological variables (e.g., heart rate, anxiety levels) through pre-screening and stratified randomization .
- Incorporate crossover designs to reduce inter-individual variability, ensuring washout periods account for this compound’s half-life (~35 hours) .
- Validate outcomes using standardized scales (e.g., Hamilton Depression Rating Scale) to quantify symptom severity objectively .
Q. How can researchers ensure reproducibility when studying this compound’s molecular mechanisms in vitro?
Methodological Answer:
- Standardize cell lines (e.g., HEK-293 for serotonin transporter expression) and culture conditions (e.g., serum concentration, incubation time) .
- Replicate dose-response curves (e.g., 50–200 µM for apoptosis assays) across multiple replicates, using statistical methods like one-way ANOVA with post-hoc Tukey tests to confirm significance .
- Report raw data and analytical protocols (e.g., flow cytometry for apoptosis detection) in compliance with FAIR (Findable, Accessible, Interoperable, Reusable) principles .
Advanced Research Questions
Q. How do conflicting findings on this compound’s efficacy in comorbid depression and chronic illness (e.g., HIV/HCV) inform hypothesis refinement?
Methodological Answer:
- Conduct meta-analyses of trials (e.g., CTN-194 study) to identify heterogeneity sources, such as patient subgroups or drug interactions with interferon/ribavirin .
- Apply PICOT framework to refine hypotheses: Population (HIV/HCV co-infected), Intervention (this compound), Comparison (placebo), Outcome (depression incidence), Time (6–12 months) .
- Use sensitivity analyses to test robustness, excluding outliers or adjusting for covariates like baseline cytokine levels .
Q. What methodologies resolve contradictions in this compound’s impact on interoceptive awareness versus anxiety reduction?
Methodological Answer:
- Employ multimodal imaging (fMRI/EEG) paired with behavioral tasks (e.g., heartbeat detection) to disentangle interoceptive vs. anxiolytic effects .
- Apply mixed-effects models to longitudinal data, separating acute (single-dose) and chronic (4–8 weeks) administration effects .
- Control for serotonin-independent pathways (e.g., vagal nerve activity) via pharmacological blockade or heart rate variability metrics .
Q. How can researchers investigate this compound’s pro-apoptotic effects in cancer cells while addressing variability in dose-response relationships?
Methodological Answer:
- Use high-throughput screening (e.g., MTT assays) to establish IC50 values across cancer cell lines (e.g., HEP-2, MCF-7) .
- Validate apoptosis via dual staining (Annexin V-FITC/PI) and caspase-3 activation assays, with triplicate technical and biological replicates .
- Apply systems biology models to simulate dose-dependent effects on cell cycle arrest (G0/G1 phase) and mitochondrial membrane potential .
Q. Data Analysis & Contradiction Resolution
Q. What statistical approaches are optimal for reconciling discrepancies in this compound’s efficacy across demographic subgroups (e.g., age, sex)?
Methodological Answer:
- Perform subgroup analyses with Bonferroni correction to avoid Type I errors, reporting confidence intervals for effect sizes (e.g., Cohen’s d) .
- Use machine learning (e.g., random forests) to identify predictors of treatment response (e.g., genetic polymorphisms in CYP2C19) .
- Publish negative results and raw datasets in open repositories to enable re-analysis and reduce publication bias .
Q. How should researchers address variability in this compound’s pharmacokinetics when designing cross-species studies?
Methodological Answer:
- Normalize doses using allometric scaling (body surface area) for rodent-to-human translation .
- Measure plasma concentrations via LC-MS/MS to correlate exposure levels with behavioral outcomes (e.g., forced swim test immobility) .
- Account for species-specific metabolism (e.g., CYP2D6 in humans vs. CYP2D2 in rats) using in vitro microsomal assays .
Q. Ethical & Methodological Considerations
Q. What protocols ensure ethical rigor in trials involving vulnerable populations (e.g., adolescents, elderly) receiving this compound?
Methodological Answer:
- Adhere to ICH-GCP guidelines , obtaining informed consent with simplified language for cognitive impairment cohorts .
- Monitor adverse events (e.g., QT prolongation) via ECG and serum electrolytes, with independent Data Safety Monitoring Boards (DSMBs) .
- Use adaptive designs to halt trials early if harm or futility is detected .
特性
IUPAC Name |
1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-3H-2-benzofuran-5-carbonitrile |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C20H21FN2O/c1-23(2)11-3-10-20(17-5-7-18(21)8-6-17)19-9-4-15(13-22)12-16(19)14-24-20/h4-9,12H,3,10-11,14H2,1-2H3 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
WSEQXVZVJXJVFP-UHFFFAOYSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
CN(C)CCCC1(C2=C(CO1)C=C(C=C2)C#N)C3=CC=C(C=C3)F |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C20H21FN2O |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID8022826 |
Source
|
| Record name | Citalopram | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID8022826 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
324.4 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Physical Description |
Solid |
Source
|
| Record name | Citalopram | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0005038 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Boiling Point |
347-358, BP: 175-181 °C at 0.03 mm Hg /Citalopram/ |
Source
|
| Record name | Citalopram | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00215 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | Citalopram | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/7042 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
Solubility |
Sparingly soluble, log Kow = 1.39 at 22 °C.Solubility in water = 15,460 mg/L at 22 °C /Citalopram hydrobromide/, ... Sparingly soluble in water and soluble in ethanol. |
Source
|
| Record name | Citalopram | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00215 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | Citalopram | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/7042 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
Mechanism of Action |
The mechanism of action of citalopram results from its inhibition of CNS neuronal reuptake of serotonin (5-HT). The molecular target for citalopram is the serotonin transporter (solute carrier family 6 member 4, _SLC6A4_), inhibiting its serotonin reuptake in the synaptic cleft. Citalopram binds with significantly less affinity to histamine, acetylcholine, and norepinephrine receptors than tricyclic antidepressant drugs. This drug has no or neglible affinity for _5-HT1A_, _5-HT2A_, _dopamine D_1 and _D2_, _α1-_, _α2_-, and_ β adrenergic_, _histamine H1_, _gamma-aminobutyric acid_ (GABA), _muscarinic_, _cholinergic_, and _benzodiazepine_ receptors. Antagonism of _muscarinic_, _histaminergic_, and _adrenergic receptors_ is thought to be associated with several anticholinergic, sedative, and cardiovascular effects of other psychotropic drugs., /In/ whole-cell patch clamp recording of heterologous HERG-mediated currents in transfected mammalian cells ... citalopram blocks HERG with an IC(50) of 3.97 uM. This is slightly less potent than fluoxetine in /the same/ system (IC(50) of 1.50 uM). In isolated guinea pig ventricular cardiomyocytes, citalopram inhibited L-type calcium current (I(Ca,L)). The voltage dependence of I(Ca,L) inactivation in the presence of 100 uM citalopram was shifted significantly leftward. As a result, the I(Ca,L) 'window' in citalopram was found to be smaller & leftward-shifted compared to control. /These/ effects ... may help to explain citalopram's good cardiac safety profile, given its propensity to block HERG at excessive dosages. /Salt not specified/, The study was aimed to investigate the effects of the minimal effective doses of acute citalopram (5 mg/kg), (+/-)-8-hydroxydipropylaminotetralin HBr (8-OH-DPAT; 0.1 mg/kg), & their combined treatment on the rat open field & forced swimming behaviour & post-mortem monoamine content. The animals were prospectively divided into the vehicle- and para-chlorophenylalanine (p-CPA)-pretreated (350 mg/kg) groups. Acute citalopram (5 mg/kg), 8-OH-DPAT (0.1 mg/kg), or their combined treatment had no major effect on the rat open field & forced swimming behaviour. The post-mortem catecholamine content in four brain regions studied was unchanged in all treatment groups. The combined 8-OH-DPAT (0.1 mg/kg) & citalopram (5 mg/kg) treatment partially reversed the p-CPA-induced decr of serotonin (5-HT) and 5-hydroxy-indolacetic acid (5-HIAA) content. The present experiments demonstrate that the 5-HT1A receptors mediate some of the selective serotonin reuptake inhibitor-induced biochemical phenomena. |
Source
|
| Record name | Citalopram | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00215 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | Citalopram | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/7042 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
Color/Form |
Fine white to off-white powder | |
CAS No. |
59729-33-8 |
Source
|
| Record name | Citalopram | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=59729-33-8 | |
| Description | CAS Common Chemistry is an open community resource for accessing chemical information. Nearly 500,000 chemical substances from CAS REGISTRY cover areas of community interest, including common and frequently regulated chemicals, and those relevant to high school and undergraduate chemistry classes. This chemical information, curated by our expert scientists, is provided in alignment with our mission as a division of the American Chemical Society. | |
| Explanation | The data from CAS Common Chemistry is provided under a CC-BY-NC 4.0 license, unless otherwise stated. | |
| Record name | Citalopram [USP:INN:BAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0059729338 | |
| Description | ChemIDplus is a free, web search system that provides access to the structure and nomenclature authority files used for the identification of chemical substances cited in National Library of Medicine (NLM) databases, including the TOXNET system. | |
| Record name | Citalopram | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00215 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | Citalopram | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID8022826 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | Citalopram | |
| Source | European Chemicals Agency (ECHA) | |
| URL | https://echa.europa.eu/substance-information/-/substanceinfo/100.056.247 | |
| Description | The European Chemicals Agency (ECHA) is an agency of the European Union which is the driving force among regulatory authorities in implementing the EU's groundbreaking chemicals legislation for the benefit of human health and the environment as well as for innovation and competitiveness. | |
| Explanation | Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page. | |
| Record name | CITALOPRAM | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/0DHU5B8D6V | |
| Description | The FDA Global Substance Registration System (GSRS) enables the efficient and accurate exchange of information on what substances are in regulated products. Instead of relying on names, which vary across regulatory domains, countries, and regions, the GSRS knowledge base makes it possible for substances to be defined by standardized, scientific descriptions. | |
| Explanation | Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required. | |
| Record name | Citalopram | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/7042 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
| Record name | Citalopram | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0005038 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Melting Point |
182-188, Crystals from isopropanol. MP: 182-183. Freely soluble in water, ethanol, chloroform /Citolapram hydrobromide/, 178 °C |
Source
|
| Record name | Citalopram | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00215 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | Citalopram | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/7042 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
| Record name | Citalopram | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0005038 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Synthesis routes and methods I
Procedure details
A solution of freshly prepared 3-dimethylaminopropylmagnesium chloride (0.6M in THF, 7.6 ml) was added to a cooled solution of 3-chloromethyl-4-(4-fluoro-benzoyl)-benzonitrile (0.5 g) in ethylene glycol dimethyl ether (4 ml) so that the temperature did not raise above −4° C. The mixture was stirred for 30 minutes at −15° C. and 100 minutes at room temperature before 0.5N hydrobromic acid was added to adjust the pH to 10. The phases were separated and the aqueous phase was extracted twice with toluene (25 ml). The combined organic phases were dried over sodium sulfate, filtered and dried in vacuo to give a viscous oil (0.44 g, 75%). Spectral and analytical data were in accordance with the literature.
Quantity
0.5 g
Type
reactant
Reaction Step One
Synthesis routes and methods II
Procedure details
A solution of 3-dimethylaminopropylmagnesium chloride (1.2M in THF, 84 ml) was added to a cooled solution of 3-chloromethyl-4-(4-fluoro-benzoyl)-benzonitrile (25.0 g) in a mixture of toluene (175 ml) and THF (50 ml) so that the temperature did not raise above −5° C. The mixture was stirred for 2 hours at 0° C. before water (100 ml) and saturated NH4Cl solution were added to adjust the pH to 9. The phases were separated and the aqueous phase was extracted twice with toluene (200 ml). The combined organic phases were washed with water (200 ml) and concentrated in vacuo to give a viscous oil (28.0 g, 95%). Spectral and analytical data were in accordance with the literature.
Name
Yield
95%
Synthesis routes and methods III
Procedure details
A solution of 4-fluoro phenylmagnesium bromide (0.7M in THF, 16 ml) was added to a cooled solution of 2-chloromethyl-4-cyano-benzoyl chloride (1.75 g) in toluene (20 ml) so that the temperature did not rise above 0° C. After 40 minutes a solution of 3-dimethylaminopropylmagnesium chloride (0.85M in THF, 10 ml) was added so that the temperature did not rise above 2° C. The mixture was stirred for 30 minutes, and water (30 ml) was added. The pH of the mixture was adjusted to 4.5, and the phases were separated. The pH of the aqueous phase was adjusted to 8 and extracted with toluene (30 ml) and 2-propanol (10 ml). The organic phase was concentrated in vacuo to give a viscous oil (1.5 g, 56%). Spectral and analytical data were in accordance with the literature.
Name
Yield
56%
Synthesis routes and methods IV
Procedure details
60% Sodium hydride (0.92 g) was dispersed in THF (30 ml). To the obtained suspension was added dropwise a solution of 1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (4.80 g) in THF (10 ml) at 40-50° C. The mixture was stirred at the same temperature for 30 min, and a solution of 3-dimethylaminopropyl chloride (3.2 g) in toluene (20 ml) was added dropwise, which was followed by stirring for 10 min. Then, dimethyl sulfoxide (30 ml) was further added dropwise and the mixture was stirred at 65-70° C. for 3 hr. The reaction mixture was poured into ice water (200 ml) and extracted 3 times with toluene (60 ml). The organic layer was extracted twice with 20% aqueous acetic acid (60 ml). The aqueous layer was neutralized, extracted twice with toluene (60 ml) and washed with water. Anhydrous potassium carbonate (2 g) and silica gel (2 g) were added and the mixture was stirred and filtered. The solvent was evaporated to give 1-(3′-dimethylaminopropyl)-1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (citalopram base) as a viscous oil (3.37 g, 51.6%).
Quantity
4.8 g
Type
reactant
Reaction Step Two
[Compound]
Name
ice water
Quantity
200 mL
Type
reactant
Reaction Step Five
Synthesis routes and methods V
Procedure details
To a stirred solution of 5-aminomethyl-1-(3-dimethylamino-propyl)-1-(4-fluoro-phenyl)-1,3-dihydro-isobenzofuran (0.5 g, 1.5 mmol) in dichloromethane (10 mL) was added an aqueous solution of potassium bisulfate and sodium hydroxide (19 mL; 0.2 M in K2S2O8, 3.8 mmol; 0.4 M in NaOH, 7.6 mmol), followed by an aqueous solution of nickel sulfate (1.5 mL, 40 mM, 61 μmol). The mixture was stirred vigorously for 4 days, and was then filtered through celite. The filtrate was partitioned between aqueous sulfuric acid (2 M) and toluene. The aqueous layer was separated, and the pH of the mixture was adjusted to >9 by the addition of aqueous ammonia solution (25% w/v). The solution was extracted with toluene, and this latter toluene extract was dried over magnesium sulfate and evaporated to give the free base of citalopram as a very pale yellow oil (0.35 g, 70%).
Name
5-aminomethyl-1-(3-dimethylamino-propyl)-1-(4-fluoro-phenyl)-1,3-dihydro-isobenzofuran
Quantity
0.5 g
Type
reactant
Reaction Step One
Name
Name
Yield
70%
Retrosynthesis Analysis
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Strategy Settings
| Precursor scoring | Relevance Heuristic |
|---|---|
| Min. plausibility | 0.01 |
| Model | Template_relevance |
| Template Set | Pistachio/Bkms_metabolic/Pistachio_ringbreaker/Reaxys/Reaxys_biocatalysis |
| Top-N result to add to graph | 6 |
Feasible Synthetic Routes
Reactant of Route 1
Citalopram
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Citalopram
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Citalopram
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Citalopram
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