Dipivefrine

Dipivefrine Basic information
Product Name:Dipivefrine
Synonyms:dipiverfrin;DIPIVEFRIN;dipivefrine;Propanoic acid, 2,2-dimethyl-, 4-[1-hydroxy-2-(methylamino)ethyl]-1,2-phenylene ester;Propanoic acid, 2,2-dimethyl-, 4-[1-hydroxy-2-(methylamino)ethyl]-1,2-phenylene ester, (+-)-;[2-(2,2-dimethylpropanoyloxy)-5-[1-hydroxy-2-(methylamino)ethyl]phenyl] 2,2-dimethylpropanoate;2,2-dimethylpropionic acid [5-[1-hydroxy-2-(methylamino)ethyl]-2-pivaloyloxy-phenyl] ester;[2-(2,2-dimethylpropanoyloxy)-4-(1-hydroxy-2-methylamino-ethyl)- phenyl] 2,2-dimethylpropanoate
CAS:52365-63-6
MF:C19H29NO5
MW:351.44
EINECS:
Product Categories:
Mol File:52365-63-6.mol
Dipivefrine Structure
Dipivefrine Chemical Properties
Melting point 146-147°
pkapKa 8.40(RT) (Uncertain)
Safety Information
MSDS Information
Dipivefrine Usage And Synthesis
OriginatorPropine,Allergan,W. Germany,1978
UsesAdrenergic (ophthalmic).
DefinitionChEBI: Dipivefrin is the dipivalate ester of (+-)-epinephrine (racepinephrine). A pro-drug of epinephrine, the hydrochloride is used topically as eye drops to reduce intra-ocular pressure in the treatment of open-angle glaucoma or ocular hypertension. It has a role as a prodrug, an adrenergic agonist, a sympathomimetic agent, an antiglaucoma drug and an ophthalmology drug. It is a member of ethanolamines and a pivalate ester. It is functionally related to an adrenaline. It is a conjugate base of a dipivefrin(1+).
Manufacturing ProcessFirst, 0.27 mol of α-chloro-3',4'-dihydroxyacetophenone are dissolved in 200 ml methanol with warming. Next, 100 ml of a 40% aqueous solution of methylamine is slowly added and the mixture stirred at 50°C to 55°C for 2 hours. The reaction mixture is then stirred an additional 24 hours at room temperature.
The crude product separates as a solid from the reaction medium and is recovered by filtration, and it is then washed thoroughly with ether and dissolved in 350 ml 1 N HCl. Then, approximately 250 ml of the aqueous solvent is removed with a rotary evaporator and the evaporation residue combined with 125 ml methanol and filtered through decolorizing charcoal. The product is precipitated as the HCl salt by the addition of 7 parts of acetone. The resulting crystalline material is removed by filtration dried at 40°C with vacuum, and has a melting point of about 242°C and is used without further purification.
Next, 25.3 g, 0.125 mol, of the above product are dissolved in 250 ml ethyl acetate and 0.125 mol perchloric acid as a 70% aqueous solution is slowly added thereto with continuous stirring. Then, an excess of pivaloyl chloride, 280 ml, is added and the mixture slowly warmed to reflux temperature. The reaction mixture is refluxed for about 5 hours and allowed to cool to room temperature with continuous stirring. The product is precipitated as the perchlorate salt by the addition of perchloric acid, HClO4, in 500 ml ether. The product is isolated and purified by dissolving in 75 ml acetone and precipitating it with 150 to 200 ml of water.
To 20 g of the above compound dissolved in 300 ml 95% ethanol in a Parr reaction vessel is added 1.5 g Adams catalyst, platinum dioxide, and the mixture shaken under hydrogen at 50 psi for 1 hour at ambient temperature. The mixture is then filtered and the ethanol removed on a standard rotary evaporator. The resulting oil is dissolved in 200 ml ether and slowly added to 1,200 ml ether with continuous stirring. The product separates as crystals which are removed after 15 to 30 minutes by filtration. The compound melts at 146°C to 147°C and needs no further purification.


Therapeutic FunctionAdrenergic (ophthalmic)
General DescriptionToovercome several of the pharmacokinetic and pharmaceuticalshortcomings of E as an ophthalmic agent, the prodrugapproach has been successfully applied. Dipivefrin is a prodrugof E that is formed by the esterification of the catecholOH groups of E with pivalic acid. Most of the advantages ofthis prodrug over E stem from improved bioavailability. Thegreatly increased lipophilicity allows much greater penetrabilityinto the eye through the corneal epithelial andendothelial layer. The stroma in between requires hydrophilicityfor penetration. Dipivefrin has that, too, due tothe 1-OH group and cationic nitrogen (the eyedrops containthe hydrochloride [HCl] salt). This dual solubility permitsmuch greater penetrability into the eye than the very hydrophilicE hydrochloride. Increased DOA is also achievedbecause the drug is resistant to the metabolism by COMT.In addition to its increased in vivo stability, it is also lesseasily oxidized by air due to the protection of the catecholOH groups. This high bioavailability and in vivo and in vitrostability translate into increased potency such that the 0.1%ophthalmic solution is approximately equivalent to a 2% Esolution. After its absorption, it is converted to E by esterasesslowly in the cornea and anterior chamber.Dipivefrin also offers the advantage of being less irritatingto the eye than E.
Dipivefrine Preparation Products And Raw materials
Raw materials2-hydroxy-1-(4-hydroxyphenyl)ethanone-->Hydrogen-->Pivaloyl chloride-->Methylamine-->2-Chloro-3',4'-dihydroxyacetophenone
tert-Butylhydroquinone 4-tert-Butylcatechol Ethanol ibopamine 4-ETHOXY-3-METHOXYPHENETHYLAMINE Ethylparaben Resorcinol PHENYL VALERATE ISOXADIFEN-ETHYL Dipivefrine Hydroquinone Ethyl acetate Catechol P-TOLYL ISOBUTYRATE Ethyl acrylate CHLOROPHOSPHONAZO III Phenylacetic acid Ethyl cyanoacetate

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