38821-49-7

White or yellowish-white powder.

Sinemet,Merck Sharp and Dohme,Italy,1974

Inhibitor (decarboxylase).

ChEBI: The hydrate of 3-(3,4-dihydroxyphenyl)propanoic acid in which the hydrogens alpha- to the carboxyl group are substituted by hydrazinyl and methyl groups (S-configuration). Carbidopa is a dopa decarboxylase inhibitor, so pr vents conversion of levodopa to dopamine. It has no antiparkinson activity by itself, but is used in the management of Parkinson's disease to reduce peripheral adverse effects of levodopa.

To a solution of vanillin in toluene is added nitroethane, butylamine and glacial acetic acid. The mixture is refluxed and the water of reaction is steadily azeotropically removed by distillation. After the theoretical amount of water is distilled out, distillation is continued to remove excess reactants. The last trace of excess reactants is then removed at room temperature under a vacuum. The product is then triturated with a hydrocarbon solvent such as Skellysolve B and is thus obtained in a crystalline state. In general, however, it is preferred to dissolve the residue directly in toluene for use in the next step, without isolating the 1-(2-nitropropen-1-yl)-4-hydroxy-3- methoxybenzene.
A mixture of iron, ferric chloride and water is added to the toluene solution. The mixture is heated to reflux and concentrated hydrochloric acid is added dropwise at a rate calculated to keep the mixture refluxing vigorously. After the hydrochloric acid is all added, the refluxing is continued by the application of heat for several hours. A siliceous filter aid is then added to the cooled reaction mixture and the material is removed by filtration. The filter cake is washed four times, each time with 90 ml of benzene. The organic layer is then separated from the filtrate. The water layer is acidified to a pH of 2 and extracted three times with 90 ml portions of benzene.
These extracts are then combined with the organic solvent layer and the combined organic phase is extracted four times with 100 ml portions of water. It is then stirred for an hour with 230 ml of 10% sodium bisulfite solution. The organic solvent phase is then separated, washed seven times with 100 ml portions of water and dried over magnesium sulfate. Evaporation of the solvent gives 1-(4-hydroxy-3-methoxyphenyl)-2-propanone in the form of an oil.
A mixture of 59.5 g of that oily product, 1.85 liters of benzene and 1 kg of potassium bisulfite in 200 liters of water is stirred at room temperature for two hours. The precipitated bisulfite addition product of the ketone is isolated by filtration and washed with isopropanol and then with ether. Five hundred grams of the adduct is mixed with 119.5 g of potassium cyanide, 292 ml of 85% hydrazine hydrate and 910 ml of water. The mixture is stirred overnight at room temperature after which the product is isolated by filtration. The product is washed 3 times with 250 ml portions of water and then 3 times with 230 ml portions of ether. It is then air dried and vacuum dried at room temperature.
Fifty cubic centimeters of concentrated hydrochloric acid is saturated with hydrogen chloride gas at -10°C. To the solution is then added 2.5 g of the intermediate product, of the formula shown above, slowly with vigorous stirring. The mixture is allowed to stir overnight while warming at room temperature gradually. It is then concentrated in vacuo to a syrup. To the residual syrup is added 100 ml of 48% hydrobromic acid. The reaction vessel is purged with nitrogen and the reaction mixture is then refluxed for 3 hours after which it is concentrated in vacuo to a mixture of a syrup and a solid. The residue is taken up in sufficient water to form a clear solution. Activated charcoal is added and the mixture is heated to boiling and filtered.
The filtrate is concentrated to dryness in vacuo and the residue is taken up in 25 cc of ethanol. The residual ammonium bromide is removed by filtration and to the filtrate there is added sufficient diethylamine to change the pH to 6.4. The mixture is warmed to 60°C and then cooled to room temperature. It is then allowed to stand overnight to effect complete crystallization. It is then cooled to 0°C and the product is isolated by filtration, washed with methanol and air dried. The product (α-hydrazino-α-methyl-β-(3,4-dihydroxyphenyl)- propionic acid) is recrystallized once from water using a proportion of 15 cc water per gram of product.

Lodosyn (Bristol-Myers Squibb).

Muscle relaxant, Antiparkinsonian

Carbidopa, (S)-3-(3,4-dihydroxyphenyl)-2-hydrazinyl-2-methylpropanoic acid, is a whitecrystalline powder, slightly soluble in water (pK_a＝7.8).Carbidopa is absorbed slower than levodopa and is 36%plasma protein bound.Carbidopa is metabolized to twomain metabolites (α-methyl-3-methoxy-4-hydroxyphenylpropionicacid and α-methyl-3,4-dihydroxyphenylpropionicacid). These two metabolites are primarily eliminated in theurine unchanged or as glucuronide conjugates. Unchangedcarbidopa accounts for 30% of the total urinary excretion.No drug interactions have been described.