4093-35-0

Hazards Identification

Pictogram(s):

Signal:

Warning

GHS Hazard Statements:

H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]
H312 (100%): Harmful in contact with skin [Warning Acute toxicity, dermal]
H332 (100%): Harmful if inhaled [Warning Acute toxicity, inhalation]

Precautionary Statement Codes:

P261, P264, P270, P271, P280, P301+P317, P302+P352, P304+P340, P317, P321, P330, P362+P364, and P501

Hazard Classes and Categories:

Acute Tox. 4 (100%)

Usage

Uses

Used in Pharmaceutical Industry:
Bromopride is used as an antiemetic agent for the treatment of nausea and vomiting. Its dopamine D2 receptor antagonist properties contribute to its effectiveness in managing these symptoms.
Used in Neuropharmacology Research:
Bromopride is utilized in methods and systems for analyzing the neuropharmacology of drugs. Its ability to interact with dopamine D2 receptors and inhibit cholinesterase activity makes it a valuable tool for studying the effects of drugs on the central nervous system and for developing new therapeutic agents.

Originator

Praiden,Italchemi,Italy,1977

Manufacturing Process

To 119 g (0.45 mol) of N-(2-diethylaminoethyl)-2-methoxy-4-aminobenzamide dissolved in 200 cc of acetic acid are added in the cold in small portions 69 g of acetic anhydride (0.45 mol + 50% excess). The starting material is made by esterifying 4-aminosalicylic acid with methanol, then acetylating with acetic anhydride and then methylating with dimethyl sulfate. The solution obtained is heated for 2 hours on a water bath and then boiled for 15 minutes. It is cooled at 25°C. While agitating constantly and maintaining the temperature between 25° and 30°C, there is added to the solution drop by drop 72 g of bromine dissolved in 60 cc of acetic acid. It is agitated for one hour. The mixture obtained is added to one liter of water and the base is precipitated by the addition of 30% soda, The precipitated base is extracted with 40 cc of methylene chloride. After evaporation of the solvent, the residue is boiled for two hours with 390 g of concentrated hydrochloric acid in 780 cc of water. It is cooled, diluted with one liter of water, 12 g of charcoal are added, and the mixture filtered. The base is precipitated with 30% soda. The N-(2- diethylaminoethyl)-2-methoxy-4-amino-5-bromobenzamide formed crystallizes, is centrifuged and washed with water. A yield of 85 g of base having a melting point of 129°-130°C is obtained. To produce the dihydrochloride, the free base is dissolved in 110 cc of absolute alcohol, 9.6 g of dry hydrochloric acid dissolved in 35 cc of alcohol are added, followed by 2.8 cc of water. The dihydrochloride precipitates, is centrifuged, washed, and dried at 40°C. It was a solid white material having a melting point of 134°-135°C.

Therapeutic Function

Antiemetic

InChI:InChI=1/C14H22BrN3O2/c1-4-18(5-2)7-6-17-14(19)10-8-11(15)12(16)9-13(10)20-3/h8-9H,4-7,16H2,1-3H3,(H,17,19)

Synthetic route

carbon monoxide (201230-82-2) + 2-bromo-4-iodo-5-methoxyaniline (1285695-16-0) + N,N-diethylethylenediamine (100-36-7) → bromopride (4093-35-0)

Conditions	Yield
With triethylamine; triphenylphosphine; bis(dibenzylideneacetone)-palladium(0) In 1,4-dioxane at 80℃; Inert atmosphere; Sealed chamber;	74.7 mg

4-bromo-3-nitroanizole (5344-78-5) → bromopride (4093-35-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrogenchloride; iron / ethanol; water / 3 h / Reflux 2: tetramethylammonium dichloroiodate(I) / ethyl acetate / 96 h 3: triethylamine; triphenylphosphine; bis(dibenzylideneacetone)-palladium(0) / 1,4-dioxane / 80 °C / Inert atmosphere; Sealed chamber View Scheme

2-bromo-5-methoxyaniline (59557-92-5) → bromopride (4093-35-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: tetramethylammonium dichloroiodate(I) / ethyl acetate / 96 h 2: triethylamine; triphenylphosphine; bis(dibenzylideneacetone)-palladium(0) / 1,4-dioxane / 80 °C / Inert atmosphere; Sealed chamber View Scheme

4-methoxy-2-nitroaniline (96-96-8) → bromopride (4093-35-0)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: sulfuric acid; acetic acid; sodium nitrite / water / 15 - 20 °C 1.2: 20 - 80 °C 2.1: hydrogenchloride; iron / ethanol; water / 3 h / Reflux 3.1: tetramethylammonium dichloroiodate(I) / ethyl acetate / 96 h 4.1: triethylamine; triphenylphosphine; bis(dibenzylideneacetone)-palladium(0) / 1,4-dioxane / 80 °C / Inert atmosphere; Sealed chamber View Scheme

bromopride (4093-35-0) → Bromoprid-N-oxid

Conditions	Yield
With dihydrogen peroxide In ethanol Ambient temperature;	11%

bromopride (4093-35-0) → 4-amino-5-bromo-N-(2-diethylamino-ethyl)-3-iodo-2-methoxy-benzamide

Conditions	Yield
Stage #1: bromopride With trifluoroacetic acid; thallium(III) trifluoroacetate at 20℃; for 0.5h; thallation; Stage #2: With trifluoroacetic acid; sodium iodide at 20℃; for 5h; Iodination; Further stages.;

bromopride (4093-35-0) → [131I]-iodo-Bromopride

Conditions	Yield
Stage #1: bromopride With trifluoroacetic acid; thallium(III) trifluoroacetate for 0.166667h; thallation; Stage #2: With [131I]-sodium iodide; trifluoroacetic acid for 0.0833333h; Iodination; Further stages.;

bromopride (4093-35-0) + p-dimethylaminocinnamaldehyde (6203-18-5) → C25H34BrN4O2(1+)

Conditions	Yield
With hydrogenchloride; sodium dodecyl-sulfate In water Reagent/catalyst; Flow reactor;

Upstream product

• 96-96-8 4-methoxy-2-nitroaniline 
• 59557-92-5 2-bromo-5-methoxyaniline 
• 5344-78-5 4-bromo-3-nitroanizole 
• 201230-82-2 carbon monoxide 
• 1285695-16-0 2-bromo-4-iodo-5-methoxyaniline 
• 100-36-7 N,N-diethylethylenediamine 

Relevant academic research and scientific papers

SYSTEM PROVIDING CONTROLLED DELIVERY OF GASEOUS CO FOR CARBONYLATION REACTIONS

A carbonylation system comprising at least one carbon monoxide producing chamber and at least one carbon monoxide consuming chamber forming an interconnected multi-chamber system, said interconnection allowing carbon monoxide to pass from the at least one carbon monoxide producing chamber to the at least one carbon monoxide consuming chamber, said at least one carbon monoxide producing chamber containing a reaction mixture comprising a carbon monoxide precursor and a catalyst, said at least one carbon monoxide consuming chamber being suitable for carbonylation reactions, said interconnected multi- chamber system being sealable from the surrounding atmosphere during carbonylation.

Ex situ generation of stoichiometric and substoichiometric 12CO and 13CO and its efficient incorporation in palladium catalyzed aminocarbonylations

A new technique for the ex situ generation of carbon monoxide (CO) and its efficient incorporation in palladium catalyzed carbonylation reactions was achieved using a simple sealed two-chamber system. The ex situ generation of CO was derived by a palladium catalyzed decarbonylation of tertiary acid chlorides using a catalyst originating from Pd(dba)2 and P(tBu)3. Preliminary studies using pivaloyl chloride as the CO-precursor provided an alternative approach for the aminocarbonylation of 2-pyridyl tosylate derivatives using only 1.5 equiv of CO. Further design of the acid chloride CO-precursor led to the development of a new solid, stable, and easy to handle source of CO for chemical transformations. The synthesis of this CO-precursor also provided an entry point for the late installment of an isotopically carbon-labeled acid chloride for the subsequent release of gaseous [ 13C]CO. In combination with studies aimed toward application of CO as the limiting reagent, this method provided highly efficient palladium catalyzed aminocarbonylations with CO-incorporations up to 96%. The ex situ generated CO and the two-chamber system were tested in the synthesis of several compounds of pharmaceutical interest and all of them were labeled as their [ 13C]carbonyl counterparts in good to excellent yields based on limiting CO. Finally, palladium catalyzed decarbonylation at room temperature also allowed for a successful double carbonylation. This new protocol provides a facile and clean source of gaseous CO, which is safely handled and stored. Furthermore, since the CO is generated ex situ, excellent functional group tolerance is secured in the carbonylation chamber. Finally, CO is only generated and released in minute amounts, hence, eliminating the need for specialized equipment such as CO-detectors and equipment for running high pressure reactions.