Bupropion D9

Cat. No.: B3031121

CAS No.: 150988-80-0

M. Wt: 248.79 g/mol

InChI Key: SNPPWIUOZRMYNY-WVZRYRIDSA-N

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Overview

1. Description

9. Comparison with similar compounds

2. Scientific research applications

10. Properties

3. Mechanism of action

11. Synthesis routes and methods I

4. Safety and hazards

12. Synthesis routes and methods II

5. Future directions

13. Synthesis routes and methods III

6. Biochemical analysis

14. Synthesis routes and methods IV

7. Preparation methods

15. Retrosynthesis analysis

8. Chemical reactions analysis

16. Disclaimer

Description

Bupropion D9 is a deuterated form of bupropion, a norepinephrine and dopamine reuptake inhibitor commonly used in the treatment of major depressive disorder, seasonal affective disorder, and as an aid for smoking cessation . The deuterated form, this compound, is used primarily as an internal standard in analytical chemistry due to its stable isotopic labeling, which helps in the quantification of bupropion levels in biological matrices .

Scientific Research Applications

Bupropion D9 is extensively used in scientific research, particularly in:

Analytical Chemistry: As an internal standard for the quantification of bupropion in biological samples using techniques like liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS)

Pharmacokinetics: Studying the pharmacokinetics and metabolism of bupropion in different formulations and release kinetics.

Clinical Research: Investigating the efficacy and safety of bupropion in various therapeutic applications, including depression and smoking cessation

Mechanism of Action

Safety and Hazards

Bupropion, particularly the immediate release formulation, carries a higher risk of seizure than many other antidepressants, hence caution is recommended in patients with a history of seizure disorder. Common adverse effects of bupropion with the greatest difference from placebo are dry mouth, nausea, constipation, insomnia, anxiety, tremor, and excessive sweating.

Future Directions

Bupropion is sometimes used as an add-on agent to first-line treatments of depression such as selective serotonin reuptake inhibitor (SSRI) medications when there is a treatment-failure or only partial response. Bupropion is also used off-label for the management of Attention/Deficit-Hyperactivity Disorder (ADHD) in adults with comorbid bipolar depression to avoid mood destabilization caused by typical stimulant medications used for the treatment of ADHD.

Biochemical Analysis

Biochemical Properties

Bupropion D9 interacts with various enzymes and proteins within the body. It is primarily metabolized by the cytochrome P450 enzyme CYP2B6 into its primary active metabolite, hydroxybupropion . In vitro data suggest the existence of alternative hydroxylation pathways mediated by the highly polymorphic enzyme CYP2C19 .

Cellular Effects

This compound has been shown to have significant effects on various types of cells and cellular processes . It has been found to reduce negative biases in emotional processing but exacerbates impaired reward processing . It also has pro-inflammatory effects, particularly at doses of 50 μM and 100 μM .

Molecular Mechanism

This compound exerts its effects at the molecular level primarily by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft . This prolongs their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters .

Temporal Effects in Laboratory Settings

In laboratory settings, the effects of this compound have been observed to change over time . For instance, it was found that this compound initially further reduced the response bias for high-probability wins, but this effect reversed with six weeks’ treatment, normalizing reward processing .

Dosage Effects in Animal Models

The effects of this compound vary with different dosages in animal models . For instance, in isolation-induced aggression tests in mice, this compound increased time devoted to attack in long attack latency mice at doses of 10 mg/kg and 40 mg/kg .

Metabolic Pathways

This compound is involved in several metabolic pathways. It is primarily metabolized by the cytochrome P450 enzyme CYP2B6 into its primary active metabolite, hydroxybupropion . Cyp2c19 is also involved in this compound metabolism, primarily through alternate hydroxylation pathways .

Preparation Methods

Synthetic Routes and Reaction Conditions

The synthesis of Bupropion D9 involves the incorporation of deuterium atoms into the bupropion molecule. One common method is the hydrogen-deuterium exchange reaction, where hydrogen atoms in the bupropion molecule are replaced with deuterium atoms using deuterated reagents under specific conditions .

Industrial Production Methods

Industrial production of this compound typically involves large-scale hydrogen-deuterium exchange reactions. The process includes the use of deuterated solvents and catalysts to ensure the efficient incorporation of deuterium atoms. The reaction conditions are optimized to achieve high yields and purity of the deuterated product .

Chemical Reactions Analysis

Types of Reactions

Bupropion D9 undergoes similar chemical reactions as non-deuterated bupropion, including:

Oxidation: Bupropion can be oxidized to its metabolites, such as hydroxybupropion.

Reduction: Reduction reactions can convert bupropion to its reduced forms.

Substitution: Bupropion can undergo nucleophilic substitution reactions.

Common Reagents and Conditions

Oxidation: Common oxidizing agents include potassium permanganate and hydrogen peroxide.

Reduction: Reducing agents such as lithium aluminum hydride can be used.

Substitution: Nucleophilic reagents like sodium hydroxide are commonly used.

Major Products Formed

Oxidation: Hydroxybupropion and other oxidized metabolites.

Reduction: Reduced forms of bupropion.

Substitution: Various substituted derivatives depending on the nucleophile used

Comparison with Similar Compounds

Similar Compounds

Vortioxetine: Another antidepressant that affects serotonin receptors and inhibits serotonin reuptake.

Cariprazine: An atypical antipsychotic used for schizophrenia and bipolar disorder.

Uniqueness

Bupropion D9 is unique due to its deuterated nature, which provides stability and precision in analytical measurements. Unlike other antidepressants, bupropion does not have significant serotonergic effects, making it less likely to cause sexual side effects, sedation, or weight gain . Its dual action on norepinephrine and dopamine reuptake, along with its nicotinic acetylcholine receptor antagonism, sets it apart from other antidepressants and smoking cessation aids .

Properties

IUPAC Name	1-(3-chlorophenyl)-2-[[1,1,1,3,3,3-hexadeuterio-2-(trideuteriomethyl)propan-2-yl]amino]propan-1-one	Source
Details	Computed by Lexichem TK 2.7.0 (PubChem release 2021.05.07)
Source	PubChem
URL	https://pubchem.ncbi.nlm.nih.gov
Description	Data deposited in or computed by PubChem

InChI	InChI=1S/C13H18ClNO/c1-9(15-13(2,3)4)12(16)10-6-5-7-11(14)8-10/h5-9,15H,1-4H3/i2D3,3D3,4D3	Source
Details	Computed by InChI 1.0.6 (PubChem release 2021.05.07)
Source	PubChem
URL	https://pubchem.ncbi.nlm.nih.gov
Description	Data deposited in or computed by PubChem

InChI Key	SNPPWIUOZRMYNY-WVZRYRIDSA-N	Source
Details	Computed by InChI 1.0.6 (PubChem release 2021.05.07)
Source	PubChem
URL	https://pubchem.ncbi.nlm.nih.gov
Description	Data deposited in or computed by PubChem

Canonical SMILES	CC(C(=O)C1=CC(=CC=C1)Cl)NC(C)(C)C	Source
Details	Computed by OEChem 2.3.0 (PubChem release 2021.05.07)
Source	PubChem
URL	https://pubchem.ncbi.nlm.nih.gov
Description	Data deposited in or computed by PubChem

Isomeric SMILES	[2H]C([2H])([2H])C(C([2H])([2H])[2H])(C([2H])([2H])[2H])NC(C)C(=O)C1=CC(=CC=C1)Cl	Source
Details	Computed by OEChem 2.3.0 (PubChem release 2021.05.07)
Source	PubChem
URL	https://pubchem.ncbi.nlm.nih.gov
Description	Data deposited in or computed by PubChem

Molecular Formula	C13H18ClNO	Source
Details	Computed by PubChem 2.1 (PubChem release 2021.05.07)
Source	PubChem
URL	https://pubchem.ncbi.nlm.nih.gov
Description	Data deposited in or computed by PubChem

DSSTOX Substance ID	DTXSID70649420	Source
Record name	1-(3-Chlorophenyl)-2-{[2-(~2~H_3_)methyl(~2~H_6_)propan-2-yl]amino}propan-1-one
Source	EPA DSSTox
URL	https://comptox.epa.gov/dashboard/DTXSID70649420
Description	DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.

Molecular Weight	248.79 g/mol	Source
Details	Computed by PubChem 2.1 (PubChem release 2021.05.07)
Source	PubChem
URL	https://pubchem.ncbi.nlm.nih.gov
Description	Data deposited in or computed by PubChem

CAS No.	150988-80-0	Source
Record name	1-(3-Chlorophenyl)-2-{[2-(~2~H_3_)methyl(~2~H_6_)propan-2-yl]amino}propan-1-one
Source	EPA DSSTox
URL	https://comptox.epa.gov/dashboard/DTXSID70649420
Description	DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.

Synthesis routes and methods I

Procedure details

t-Butylamine was added to m-chloro-α-bromopropiophenone obtained above and the reaction mixture was refluxed for 3 hours. Excessive t-butylamine was removed by evaporation below 80° C. The concentrated solution was cooled down to room temperature and then extracted with 800 ml of ethyl acetate and 280 ml of water. The organic phase was dried with anhydrous magnesium sulfate (15 g) to obtain a solution of bupropion free base. A solution of HCl in ethyl acetate was added at room temperature to the organic phase. Crude product of bupropion hydrochloride was obtained after filtration. The crude product of bupropion hydrochloride was dissolved in 1200 ml of methanol and 120 ml of water at 80° C., decolorized with activated carbon (5 g) for 20 minutes and filtered. The filtrate was cooled and filtered to obtain wet product of bupropion hydrochloride. The wet product was dried in vacuum (−0.04˜−0.09 MPa, 80° C.) for 3 hours to obtain pure product. Total yield was 70% based on m-chloropropiophenone, and the HPLC's purify was higher than or equal to 99.9%.

Name

t-Butylamine

Quantity

0 (± 1) mol

Type

reactant

Reaction Step One

Name

m-chloro-α-bromopropiophenone

Quantity

0 (± 1) mol

Type

reactant

Reaction Step One

Name

bupropion

Details

Synthesis routes and methods II

Procedure details

Bupropion HCl was replaced with HBr and adjusted to obtain same amount Bupropion base.

Name

Bupropion HCl

Quantity

0 (± 1) mol

Type

reactant

Reaction Step One

Name

HBr

Quantity

0 (± 1) mol

Type

reactant

Reaction Step Two

Name

Bupropion

Details

Synthesis routes and methods III

Procedure details

The dissolution of bupropion HBr formulations according to the invention were assessed in three USP-3 media, i.e., SGF pH 1.2, Acetate Buffer pH 4.5 and Phosphate Buffer pH 6.8 over a period of 16 hours. These results are contained in FIG. 66. Particularly Bupropion HBr XL 348 mg tablets (final), Lot # Bup-HBr-XL-012-5; Wellbutrin XL 300 mg tablets (final), Lot # 05A116; Bupropion HBr XL 348 mg tablets ECl Lot # Bup-HBr-XL-012-5 (EC 32 mg wg) and Wellbutrin XL 300 mg tablets (EC10-Lot # 05D047 were assessed in SGF media pH 1.2 for 2 hours, Acetate Buffer pH 4.5 for 2 hours, and Phosphate Buffer SIF pH 6.8 for a total of 10 hours. The results are contained in the FIG. 66-68.

Name

bupropion HBr

Quantity

0 (± 1) mol

Type

reactant

Reaction Step One

Name

Acetate

Quantity

0 (± 1) mol

Type

reactant

Reaction Step Two

Name

Phosphate

Quantity

0 (± 1) mol

Type

reactant

Reaction Step Three

Name

Acetate

Quantity

0 (± 1) mol

Type

reactant

Reaction Step Four

Name

Phosphate

Quantity

0 (± 1) mol

Type

reactant

Reaction Step Four

[Compound]

Name

Bupropion HBr XL 348

Quantity

0 (± 1) mol

Type

reactant

Reaction Step Five

[Compound]

Name

Bup-HBr XL-012-5

Quantity

0 (± 1) mol

Type

reactant

Reaction Step Six

Name

Wellbutrin XL

Quantity

300 mg

Type

reactant

Reaction Step Seven

[Compound]

Name

Bupropion HBr XL 348

Quantity

0 (± 1) mol

Type

reactant

Reaction Step Eight

[Compound]

Name

Bup-HBr XL-012-5

Quantity

32 mg

Type

reactant

Reaction Step Eight

Name

Wellbutrin XL

Quantity

300 mg

Type

reactant

Reaction Step Eight

Name

Bupropion

Details

Synthesis routes and methods IV

Procedure details

1.0 g of bupropion hydrochloride salt was dissolved in the minimum amount of water in 250 ml flask. The contents of the flask were transferred to a separatory funnel, to which 20 ml of 10% aqueous sodium carbonate was added, and the mixture was extracted with methylene chloride (3×50 ml). The combined methylene chloride extracts were washed with water (3×50 ml), then brine solution (50 ml), dried over anhydrous K2CO3, filtered and the filtrate stripped down under reduced pressure on a rotary evaporator to give the desired product as a yellow oil (7.9 g, 90% yield). 1H NMR (CDCl3, 400 MHz): δ 7.90 (s, 1H), 7.81 (d, j=7.8 Hz, 1H), 7.48 (d, j=7.8 Hz, 1H), 7.37 (dd, j1=j2=7.8 Hz, 1H), 4.24 (qt, J=7.2 Hz, 1H), 1.19 (d, j=7.2 Hz, 3H), 0.97 (s, 9H) ppm. ppm; MS m/z 240 (M+). LC-MS m/z 240 (M+) single peak at Rt=8.40 min.

Name

bupropion hydrochloride

Quantity

1 g

Type

reactant

Reaction Step One

Name

water

Quantity

0 (± 1) mol

Type

solvent

Reaction Step One

Name

sodium carbonate

Quantity

20 mL

Type

reactant

Reaction Step Two

Name

desired product

Yield

90%

Details

Retrosynthesis Analysis

AI-Powered Synthesis Planning: Our tool employs the Template_relevance Pistachio, Template_relevance Bkms_metabolic, Template_relevance Pistachio_ringbreaker, Template_relevance Reaxys, Template_relevance Reaxys_biocatalysis model, leveraging a vast database of chemical reactions to predict feasible synthetic routes.

One-Step Synthesis Focus: Specifically designed for one-step synthesis, it provides concise and direct routes for your target compounds, streamlining the synthesis process.

Accurate Predictions: Utilizing the extensive PISTACHIO, BKMS_METABOLIC, PISTACHIO_RINGBREAKER, REAXYS, REAXYS_BIOCATALYSIS database, our tool offers high-accuracy predictions, reflecting the latest in chemical research and data.

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

Bupropion D9

Reactant of Route 2

Bupropion D9

Reactant of Route 3

Bupropion D9

Reactant of Route 4

Bupropion D9

Reactant of Route 5

Bupropion D9

Reactant of Route 6

Bupropion D9

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Please be aware that all articles and product information presented on BenchChem are intended solely for informational purposes. The products available for purchase on BenchChem are specifically designed for in-vitro studies, which are conducted outside of living organisms. In-vitro studies, derived from the Latin term "in glass," involve experiments performed in controlled laboratory settings using cells or tissues. It is important to note that these products are not categorized as medicines or drugs, and they have not received approval from the FDA for the prevention, treatment, or cure of any medical condition, ailment, or disease. We must emphasize that any form of bodily introduction of these products into humans or animals is strictly prohibited by law. It is essential to adhere to these guidelines to ensure compliance with legal and ethical standards in research and experimentation.

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