25614-03-3

Basic information

• Product Name: Bromocriptine
• Synonyms: (5’-alpha)-ropyl);,6’,18-trione;2-bromo-12’-hydroxy-2’-(1-methylethyl)-5’-alpha-(2-methylpropyl)ergotamin-3’;2-bromo-alpha-ergocryptine;2-bromo-alpha-ergokryptin;2-bromo-alpha-ergokryptine;2-bromo-ergocryptin;2-bromoergocryptine
• CAS NO: 25614-03-3
• Molecular Formula: C₃₂H₄₀BrN₅O₅
• Molecular Weight: 654.59
• EINECS: 247-128-5
• Product Categories: Organics
• Mol File: 25614-03-3.mol

Chemical Properties

• Melting Point: 215-218° (dec)
• Boiling Point: 891.3 °C at 760 mmHg
• Flash Point: 492.8 °C
• Appearance: white crystalline powder
• Density: 1.2734 (rough estimate)
• Refractive Index: 1.6400 (estimate)
• PKA: pKa 4.90±0.05(80% MCS t = RT) (Uncertain)
• Water Solubility: 2.07mg/L(temperature not stated)
• CAS DataBase Reference: Bromocriptine(CAS DataBase Reference)
• NIST Chemistry Reference: Bromocriptine(25614-03-3)
• EPA Substance Registry System: Bromocriptine(25614-03-3)

Safety Data

• Hazardous Substances Data: 25614-03-3(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Bromocriptine is used as a dopaminomimetic agent for treating all phases of idiopathic and postencephalic Parkinsonism. It exhibits antiparkinsonian activity by acting as a dopamine D2 receptor agonist, which helps alleviate the symptoms of Parkinson's disease.
Used in Endocrinology:
As an enzyme inhibitor, specifically for prolactin, Bromocriptine is used to inhibit prolactin secretion and release from the pituitary gland. This application is particularly relevant for conditions where excessive prolactin levels are present, such as hyperprolactinemia.
Used in Oncology:
Bromocriptine is also used in the field of oncology for its potential to retard tumor growth. Although the exact mechanisms are not fully understood, it is believed that its action as a dopamine D2 agonist may contribute to this effect.
Used in Drug Delivery Systems:
While not explicitly mentioned in the provided materials, Bromocriptine could potentially be incorporated into drug delivery systems to improve its bioavailability, targeting, and therapeutic outcomes in various medical applications.

World Health Organization (WHO)

Bromocriptine, a semisynthetic ergot alkaloid derivative and prolactin inhibitor was introduced into medicine in 1976. It is used in the prevention of lactation, but because of the risk of rebound effect and since only 10% of women benefit therapeutically from such intervention, the United States Food and Drug Administration has requested manufacturers to no longer indicate preparations containing bromocriptine for this purpose. The World Health Organization is not aware of similar action having been taken elsewhere.

Hazard

Poison; teratogen; developmental abnor- malities of the respiratory system,musculoskeletal system, rogenital system, craniofacial area, and body wall; teratogen; mutagen; questionable car- cinogen; tumorigen; causes nausea, vomiting, orthostatic hypotension; constipation, dyskinesias, psychoses, digital spasm, erythromelalgia.

Mechanism of action

Bromocriptine is absorbed after oral administration, but approximately 90% of a dose undergoes extensive first-pass hepatic metabolism, with the remainder hydrolyzed in the liver to inactive metabolites that are eliminated mostly in the bile. The half-life is relatively short (~3 hours).

Clinical Use

Bromocriptine is an ergot peptide derivative that is a partial agonist at D1-type and a full agonist at D2-type postsynaptic dopamine receptors, usually given in combination with levodopa therapy. It was the first direct dopamine receptor agonist used in treatment of Parkinson's disease after its development as an inhibitor of prolactin release (via activation of anterior pituitary D2 receptors). At low doses (typically 1–5 mg/day), bromocriptine is an effective prolactin inhibitor, and at higher doses (typically 10–20 mg/day), the antiparkinsonism and mood-elevating effects of bromocriptine become apparent.

Side effects

Bromocriptine has a number of undesirable side effects, even causing mental disturbances in long-term use.

Synthesis

Bromocriptine, 2-bromoergocriptine (10.1.13), is a semisynthetic derivative of a natural ergot alkaloid, ergocriptin (a derivative of lysergic acid), which is synthesized by bromination of ergocriptin using N-bromosuccinimide [18,19].

Drug interactions

Potentially hazardous interactions with other drugs Increased risk of toxicity with bromocriptine and isometheptene.

Metabolism

Bromocriptine is extensively metabolised. It undergoes extensive first-pass biotransformation in the liver, reflected by complex metabolite profiles and by almost complete absence of parent drug in urine and faeces. In plasma the elimination half life is 3-4 hours for the parent drug and 50 hours for the inactive metabolites.The parent drug and its metabolites are also completely excreted via the liver with only 6% being eliminated via the kidney.

Synthetic route

α-ergocryptine (511-09-1) → Bromocriptine (25614-03-3)

Conditions	Yield
With bromodimethylsulfoxonium bromide In dimethyl sulfoxide for 0.166667h; Ambient temperature;	93%
With pyridazinium bromide; 3-bromo-6-chloro-2-methylimidazo In dichloromethane for 0.0333333h; Ambient temperature;	75%
With ammonium hydroxide; sodium hydroxide In dichloromethane; di-isopropyl ether; water; hydrogen bromide; dimethyl sulfoxide

α-ergocryptine (511-09-1) → (6aR,9R)-5a-Hydroxy-7-methyl-5-oxo-4,5,5a,6,6a,7,8,9-octahydro-indolo[4,3-fg]quinoline-9-carboxylic acid ((2R,5S,10aS,10bS)-10b-hydroxy-5-isobutyl-2-isopropyl-3,6-dioxo-octahydro-oxazolo[3,2-a]pyrrolo[2,1-c]pyrazin-2-yl)-amide + Bromocriptine (25614-03-3)

Conditions	Yield
With water; hydrogen bromide In dimethyl sulfoxide for 0.333333h; Product distribution; Ambient temperature; halogenation of indole alkaloids with various halogenated agents;	A 8% B 72%

trimethylsilyl bromide (2857-97-8) + α-ergocryptine (511-09-1) → Bromocriptine (25614-03-3)

Conditions	Yield
With ammonium hydroxide; sodium chloride In ice-water; dichloromethane; di-isopropyl ether; dimethyl sulfoxide; ethyl acetate

α-ergocryptine phosphate + α-ergocryptinine base + trimethylsilyl bromide (2857-97-8) + α-ergocryptine (511-09-1) → Bromocriptine (25614-03-3)

Conditions	Yield
	4.7 g (0.007243 mole, 85%)
	4.7 g (0.007243 mole, 85%)

α-ergocryptinine base + trimethylsilyl bromide (2857-97-8) + α-ergocryptine (511-09-1) → Bromocriptine (25614-03-3)

Conditions	Yield
With ammonium hydroxide; sodium chloride In ice-water; dimethyl sulfoxide; ethyl acetate	mole, 87%)
With ammonium hydroxide; sodium chloride In ice-water; dimethyl sulfoxide; ethyl acetate	6.3 g (0.00967 mole, 87%)

α-ergocryptine phosphate + trimethylsilyl bromide (2857-97-8) → Bromocriptine (25614-03-3)

Conditions	Yield
	0.9 g (0.001359 mole, 91.5%)
	0.9 g (0.001359 mole, 91.5%)

diispropyl ether + trimethylsilyl bromide (2857-97-8) + α-ergocryptine (511-09-1) → Bromocriptine (25614-03-3)

Conditions	Yield
With ammonium hydroxide; sodium chloride In ice-water; dichloromethane; dimethyl sulfoxide; ethyl acetate

Bromocriptine (25614-03-3) → Bromocriptinmesilat

Conditions	Yield
In butanone

N-ethyl-L-glutamine (3081-61-6, 5822-62-8, 17010-37-6, 34271-54-0) + Bromocriptine (25614-03-3) → L-theanine bromocriptine cocrystal

Conditions	Yield
In water; isopropyl alcohol

methanesulfonic acid (75-75-2) + Bromocriptine (25614-03-3) → Cycloset (22260-51-1)

Conditions	Yield
In methanol; water at 4℃; for 2.58333h; Solvent;

Upstream product

• 511-09-1 α-ergocryptine 
• 2857-97-8 trimethylsilyl bromide 
• 6045-63-2 α-ergocryptine phosphate 
• 511-09-1 α-ergocryptine 
• 511-09-1 α-ergocryptine 

Downstream Products

• 22260-51-1 Cycloset 

Relevant articles and documents

SIDE REACTIONS IN BROMINATION OF α-ERGOCRYPTINE

2,3-Dihydro-2-oxo-α-ergocryptine (III) and 2,3-dihydro-2-oxo-3-hydroxy-α-ergocryptine (IV) were found as the side reaction products in bromination of α-ergocryptine (I) with bromine in the presence of water. 2,3-Dihydro-2-oxo-3-ethoxy-α-ergocryptine (V) was formed in the presence of ethanol.

Process for the preparation of 2-bromo-8-ergolinyl compounds

2-bromo-8-ergolinyl compounds of the formula STR1 wherein R8 is NH2, NH--CONEt2, CONH2, STR2 and STR3 wherein R1 =C1-4 -alkyl and R2 =C1-4 -alkyl and benzyl, R9 and R10 each mean hydrogen or, together, a bond, and the substituent R8 can be in the α- or β- position, and their acid addition salts, can be prepared from corresponding 8-ergolinyl compounds and their acid addition salts by bromination with elemental bromine in the presence of hydrogen bromide in a halogenated hydrocarbon.

Process for the preparation of 2-halogenated ergoline derivatives

The invention relates to a novel process for the halogenation in 2-position of ergot alkaloids. The process is characterized by that as a halogenating agent a system consisting of dimethylsulfoxide, a trialkylhalosilane or triarylhalosilane and optionally a hydrogen halide is used.

HALOGENATION OF INDOLE ALKALOIDS WITH HALODIMETHYLSULFONIUM HALOGENIDS AND HALODIMETHYLSULFOXONIUM HALOGENIDS

A new field of application of halodimethylsulfonium halogenids and halodimethylsulfoxonium halogenids had been studied.The formers were used for the halogenation of indole alkaloids, compounds of ergoline or aspidospermidine structure, and vincamine.

Process for the preparation of 2-halogenated ergoline derivatives

The invention relates to a novel process for the halogenation in 2-position of ergot alkaloids. The process is characterized by that as a halogenating agent a system consisting of dimethylsulfoxide, a trialkylhalosilane or triaryl-halosilane and optionally a hydrogen halide is used.

Process for the preparation of 2-bromo-α-ergocryptine

The invention relates to a novel process for the preparation of 2-bromo-α-ergocryptine and its acid addition salt by brominating α-ergocryptine in such a way that the bromination is carried out at room temperature by using a dimethylsulphoxide-hydrogen bromide mixture containing no more 0.02% of water and, if desired, converting the thus-obtained 2-bromo-α-ergocryptine to an acid addition salt in a known manner.

Process for brominating ergot alkaloids

The present invention provides an improved process for the production of a compound of formula I STR1 wherein R1 is carboxyl, alkoxy(C1-5)carbonyl, amido, alkyl(C1-5)amido, di(alkyl(C1-5)amido or an amido radical of formula II STR2 wherein Ra is alkyl(C1-4), Rb is alkyl(C1-4) or benzyl, and R2 is hydrogen or alkyl(C1-4), and either R3 is hydrogen and R4 is hydrogen or alkoxy(C1-4) or R3 and R4 together are a single bond, characterized in that a compound of formula III STR3 wherein R1 to R4 are as defined above, is brominated with a bromine complex of 3-bromo-6-chloro-2-methyl-imidazo[1,2-b]pyridazine.

BROMINATION OF α-ERGOCRYPTINE AND OTHER ERGOT ALKALOIDS WITH 3-BROMO-6-CHLORO-2-METHYLIMIDAZO/1,2-b/PYRIDAZINE-BROMINE COMPLEX AS A NEW BROMINATING AGENT

A new and improved bromination of α-ergocryptine and some other ergot alkaloids of the type 1, 2 and 3 using 3-bromo-6-chloro-2-methylimidazo/1,2-b/pyridazine-bromine complex (5) as a new brominating agent, to give purified 2-bromo derivatives in yields up to 81percent, is described.