34911-55-2

Usage

Uses

Used in Pharmaceutical Industry:
Bupropion is used as an antidepressant for treating major depressive disorders. It works by blocking the reuptake of dopamine, leading to an increase in the levels of dopamine in the brain, which contributes to its antidepressant effects.
Used in Sleep Disorder Treatment:
Bupropion is used as a treatment for sleep disorders associated with pain. Its mechanism of action helps alleviate pain and improve sleep quality in patients suffering from such conditions.
Used in Vasoconstriction:
Bupropion is used as a vasoconstrictor, functioning as a non-selective agonist of all adrenergic receptors. This application is particularly useful in medical procedures where constriction of blood vessels is required.
Used in Drug Interaction Studies:
Due to the presence of active metabolites, such as hydroxybupropion, threohydrobupropion, and erythrohydrobupropion, Bupropion is used in studying drug interactions, especially those involving cytochrome P450 2D6 (CYP2D6). Understanding these interactions is crucial for optimizing treatment regimens and minimizing potential adverse effects.

Originator

Burroughs Wellcome (United Kingdom)

Manufacturing Process

To ethyl magnesium bromide (2 L, 3 M) was added over 45 min with stirring and cooling m-chlorobenzonitrile (688.0 g, 5 mole) in ether (2.5 L). The resultant solution was heated under gentle reflux for 5 h. The reaction mixture was hydrolyzed with cold dilute hydrochloric acid, the ether was distilled off, and the aqueous solution was heated at 90°C for 1 h. The flask was then cooled. The solid ketone that separated was washed with cold water and recrystallized from methanol. The recrystallized m-chloropropiophenone, melting point 39°-40°C, weighed 750.0 g. In methylene chloride (3 L) was dissolved m-chloropropiophenone (698.0 g; 4.15 mole). The solution was stirred with charcoal (Darco) and magnesium sulfate for 2 h and filtered. To it was added with stirring (662.0 g) of bromine in methylene chloride (1 L). When the bromine color had faded completely, the solvent was evaporated in vacuum and m-chloro-α-bromopropiophenone was obtained as oil. The m-chloro-α-bromopropiophenone was dissolved in acetonitrile (1300 ml). To this, t-butylamine (733.0 g) in acetonitrile (1300 ml) was added while keeping the temperature below 32°C. The reaction mixture was allowed to stand over night. It was then partitioned between water (4200 ml) and ether (2700 ml). The aqueous layer was extracted with a further portion of ether (1300 ml). The combined ethereal layers were then washed with water (4200 ml) to which hydrochloric acid was added until the pH of the aqueous layer was 9. The aqueous layer was separated and washed with ether (500 ml) and then discarded. The combined ethereal layers were then stirred with ice (560.0 g) and concentrated hydrochloric acid (324 ml). The ethereal layer was separated and again washed with water (200 ml) and concentrated hydrochloric acid (50 ml). These last two acid layers were combined and concentrated in vacuum until crystals appeared. The solution was then chilled to 5°C and filtered. The product was sucked dry, washed with acetone and recrystallized from a mixture of isopropanol (3 L) and absolute ethanol (800 ml). The DL-m-chloro-α-t-butylaminopropiophenone hydrochloride so was obtained, melting point 233°-234°C. The DL-m-chloro-α-t-butylaminopropiophenone was obtained by treatment of DL-m-chloro-α-t-butylaminopropiophenone hydrochloride with sodium hydroxide.

Biological Functions

Bupropion (Wellbutrin) is a pharmacologically unique antidepressant, since it is a weak inhibitor of both dopamine and norepinephrine neuronal reuptake. However, its actual antidepressant activity is not well understood. Bupropion is generally well tolerated and does not block muscarinic, histaminergic, or adrenergic receptors. Unlike the SSRIs and venlafaxine, bupropion does not cause sexual side effects. However, it can cause CNS stimulation, including restlessness and insomnia. High doses of bupropion, given as its original formulation, were associated with a risk of seizures in 0.4% of patients. However, this risk is lower with slow-release bupropion (Wellbutrin SR). This formulation still requires dosing twice a day, and bupropion is contraindicated in patients with a history of seizures. Bupropion inhibits the cytochrome P450 2D6 isoenzyme and may elevate blood levels of drugs metabolized by this route.

Pharmacology

Bupropion is an α-aminoketone that is structurally related to amphetamines, and it exhibits unique activity comparable to that of other antidepressants. It is believed that bupropion restores the total amount of norepinephrine in the body. Bupropion is a poor reuptake inhibitor of dopamine, and does not exhibit anticholinergic activity or inhibit MAO. Its efficacy as an antidepressant is comparable to that of tricyclic antidepressants, and as a serotonin uptake inhibitor it is comparable to fluoxetine.

Synthesis

The synthesis of bupropion, 1-3(-chlorophenyl)-2-[(1,1-dimethylethyl)amino]- 1-propanone (7.3.5), begins with the reaction of 3-chlorobenzonitrile, with ethylmagnesium bromide to give 3-chloropropiophenone (7.3.3). Brominating this with bromine gives 3-chloro-α-bromopropiophenone (7.3.4), which on reaction with tert-butylamine gives bupropion (7.3.5) [54–58].

InChI:InChI=1/C13H18ClNO/c1-9(15-13(2,3)4)12(16)10-6-5-7-11(14)8-10/h5-9,15H,1-4H3

Upstream product

• 34841-35-5 3'-chloro-propiophenone 
• 75-64-9 tert-butylamine 
• 34911-51-8 2-bromo-3'-chloropropiophenone 
• 31677-93-7 BUPROPION HYDROCHLORIDE 
• 152943-33-4 (+/-)-1-(3-chlorophenyl)-2-hydroxypropan-1-one 
• 1038432-24-4 (±)-methyl 2-{[(tert-butyldimethylsilyl)oxy](3-chlorophenyl)methyl}prop-2-enoate 
• 1038432-31-3 (+/-)-2-{[(tert-butyldimethylsilyl)oxy](3-chlorophenyl)methyl}prop-2-enoic acid 
• 1038432-36-8 (+/-)-1-[(tert-butyldimethylsilyl)oxy]-1-(3-chlorophenyl)propan-2-one 
• 26293-11-8 β-methyl-3-chlorostyrene 
• 364364-56-7 methyl α-methylene-β-[(p-toluenesulfonyl)amino]-3-(3-chlorophenyl)propionate 
• 587-04-2 m-Chlorobenzaldehyde 
• 535-80-8 3-chlorobenzoate 
• 766-84-7 3-chloro-benzonitrile 

Downstream Products

• 92264-82-9 Threohydrobupropion 
• 92264-82-9 Erythrohydrobupropion 
• 913728-76-4 3-tert-butyl-5-(3-chlorophenyl)-4-methyloxazolin-2-one 
• 905818-69-1 bupropion hydrobromide 
• 92264-82-9 (S,S)-2-(tert-butylamino)-1-(3-chlorophenyl)propanol 
• 92264-82-9 erythrohydrobupropion 
• 1132091-22-5 rac-1-(m-chlorophenyl)-2-(tert-butylamino)-(2-²H)-propan-1-one 
• 357399-43-0 (2R,3R)-2-(-3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol 
• 1296138-81-2 hydroxybupropion 

Relevant academic research and scientific papers

Across-the-World Automated Optimization and Continuous-Flow Synthesis of Pharmaceutical Agents Operating Through a Cloud-Based Server

The power of the Cloud has been harnessed for pharmaceutical compound production with remote servers based in Tokyo, Japan being left to autonomously find optimal synthesis conditions for three active pharmaceutical ingredients (APIs) in laboratories in Cambridge, UK. A researcher located in Los Angeles, USA controlled the entire process via an internet connection. The constituent synthetic steps for Tramadol, Lidocaine, and Bupropion were thus optimized with minimal intervention from operators within hours, yielding conditions satisfying customizable evaluation functions for all examples.

Preparation method of bupropion hydrochloride

The invention discloses a preparation method of bupropion hydrochloride. M-chlorophenylacetone is used as a raw material to take bromination reaction with sodium bromide, sulfuric acid and hydrogen peroxide in a water-halohydrocarbon solvent to prepare a brominated intermediate; then the prepared bromide reacts with tert-butylamine to prepare amfebutamone, after the reaction for preparing amfebutamone is completely reacted, the water is directly added, after a reaction solution is layered, the layered organic layer is cleaned and distilled to obtain amfebutamone, and obtained amfebutamone is acidified by virtue of isopropanol hydrochloride to obtain bupropion hydrochloride; and the peparation process of amfebutamone, the alkalinity of a water layer obtained after the layering of the reaction solution is adjusted by using sodium hydroxide, after tert-butylamine is recovered in a distillation manner, the water layer comprising bromine ions is concentrated, the pH value is adjusted to beneutral by using sulfuric acid, the obtained aqueous solution comprising sodium bromide is used for taking the bromination reaction again so as to be circularly utilized. By adopting the preparation method, the environment-friendly circular utilization of bromine is realized, and the production cost is reduced.

1,3-Dibromo-5,5-dimethylhydantoin (DBH) mediated one-pot syntheses of α-bromo/amino ketones from alkenes in water

α-Bromo ketones are versatile intermediates of high practical utility. Traditional approaches to these compounds are restricted to a relatively hazardous/complex reagent combination, a long reaction time, the use of non-environmentally friendly solvents, or a limited substrate scope. Herein, we describe the development of a new methodology for the preparation of α-bromo ketones from alkenes using 1,3-dibromo-5,5-dimethylhydantoin (DBH) as a bromine source and an oxidant simultaneously. This easy to carry out two-step one-pot protocol proceeds in water and provides high yield of a great variety of α-bromo ketones. Addition of an amine to the intermediate α-bromo ketone further enables the preparation of α-amino ketones in a one-pot sequence.

Method for preparing bupropion hydrochloride

The invention discloses a novel method for preparing bupropion hydrochloride. According to the invention, m-chlorophenylacetone is taken as an initiator, then is brominated in a hydrobromic acid-hydrogen peroxide system, 3'-chlorine-alpha-bromophenyl ethyl ketone is synthesized; then through replacement by tert-butylamine and acidification by HCl-absolute ethyl alcohol, bupropion hydrochloride is obtained. The preparation method of bupropion hydrochloride replaces traditional bromine bromination, pollution can be effectively reduced, damage due to bromine volatilization on the operators can be greatly mitigated, and the method has the advantages of simple operation, low cost, high yield, and less side reaction, and is very suitable for industrial production.

Hyphenating the curtius rearrangement with morita-baylis-hillman adducts: Synthesis of biologically active acyloins and vicinal aminoalcohols

Using Morita-Baylis-Hillman adducts as substrates, the Curtius rearrangement was performed in a sequence that allowed the synthesis of several hydroxy-ketones (acyloins) with great structural diversity and in good overall yields. These acyloins in turn were easily transformed into 1,2-anti aminoalcohols through a highly diastereoselective reductive amination step. The synthetic utility of these approaches was exemplified by performing the syntheses of (±)-bupropion, a drug used to treat the abstinence syndrome of smoker and (±)-spisulosine, a potent anti-tumoral compound originally isolated form a marine source.

BUPROPION HYDROBROMIDE POLYMORPHS

Polymorphous and amorphous forms of bupropion hydrobromide are described.

Process for preparing bupropion hydrochloride

This invention described a synthesis method of bupropion hydrochloride. m-chloropropiophenone was brominated directly with bromine, then aminated with t-butylamine and finally reacted with HCl to obtain crude product of bupropion hydrochloride. Pure product was obtained after recrystallization. This method is convenient and suitable for commercial manufacturing because of low cost of production, high yield, less byproducts and being environmental friendly.

Enhancing transdermal delivery of opiod antagonists and agonistis using codrugs links to bupropion or hydroxybupropion

The present invention is directed to novel codrugs comprising bupropion or hydroxybupropion and an opioid antagonist or an opioid agonist joined together by chemical bonding. The codrugs provide a significant increase in the transdermal flux across human skin, as compared to the basic opioid antagonist or opioid agonist.

Acyloins from Morita-Baylis-Hillman adducts: an alternative approach to the racemic total synthesis of bupropion

In this Letter, we describe an easy and straightforward strategy for the preparation of acyloins (α-hydroxyketones) from Morita-Baylis-Hillman adducts, based on a Curtius rearrangement. Different acyloins were obtained with good overall yield (>40% for three steps). To exemplify the synthetic usefulness of this strategy, total synthesis of (±)-bupropion, a dopamine, and nor-epinefrine reuptake inhibitor has been accomplished in eight steps with an overall yield of 25%.

AN IMPROVED PROCESS FOR PREPARING BUPROPION HYDROCHLORIDE

The present invention relates to an improved process for preparing Bupropion Hydrochloride of formula (I). The present invention also provides a process for purification of Bupropion hydrochloride.