Chemical Properties
White to off-white crystalline powder
Originator
Cuprimine,MSD,US,1963
Uses
As a Penicillin metabolite, D-(-)-Penicillamin can be used in the treatment of Wilson’s disease, Cystinuria, Scleroderma and arsenic poisoning.
Uses
chelating agent (Cu), antirheumatic
Uses
D-(-)-Penicillamin is used as an antirheumatic and as a chelating agent in Wilson′s disease. It is used as a copper chelator to form mixed disulfides with cysteine or other sulfide media components. It is used to inactivate protein-1 DNA binding and to inhibit the growth of asynchronous cultures of rabbit articular chondrocytes.
Definition
ChEBI: An optically active form of penicillamine having D-configuration. Pharmaceutical form (L-form is toxic) of chelating agent used to treat heavy metal poisoning.
Manufacturing Process
(a) Preparation of mercuric chloride complex of penicillamine: To a solution of 372 g (1 mol) of potassium benzyl-penicillin in 940 ml of distilled water at room temperature is added a solution of 40 g (1 mol) of sodium hydroxide in 180 ml of distilled water over a period of one-half hour. The solution is then stirred for two hours at room temperature. While maintaining room temperature, 67 ml of concentrated hydrochloric acid is added at a slow rate. This solution is then added, over a period of time of one-half hour, to a solution of 271 g (1 mol) of HgCl2 in 3.52 liters of distilled water in the presence of 50 g of Hyflo and 5 ml of octyl alcohol. After one hour of agitation, the resulting mixture is treated with 185 ml of concentrated hydrochloric acid and filtered.
(b) Removal of benzylpenilloaldehyde: To the filtrate obtained in step (a), warmed to 50°C is slowly added 108 g (1 mol) of phenyl hydrazine. The mixture is cooled to room temperature and 84 ml of concentrated hydrochloric acid are added. The mixture is agitated briefly and the precipitated benzylpenilloaldehyde phenyl hydrazone is filtered off.
(c) Preparation of isopropylidene penicillamine hydrochloride: To the filtrate obtained in step (b) is added at 20°C to 25°C a total of 85 g of hydrogen sulfide. The precipitated HgS is filtered off and the filtrate is concentrated under reduced pressure to a volume of 200 to 500 ml. Following a polish filtration, the product-rich concentrate is mixed with 1.5 liters of isobutyl acetate. The mixture is refluxed at about 40°C under reduced pressure in equipment fitted with a water separation device. When no further water separates, the batch is cooled to 30°C and filtered. The reactor is washed with 1 liter of acetone, which is used also to wash the cake. The cake is further washed with 200 ml of acetone. The acetone washes are added to the isobutyl acetate filtrate and the mixture is refluxed for 20 to 30 minutes. After a holding period of one hour at 5°C. the crystals of isopropylidene penicillamine hydrochloride are filtered and washed with 200 ml of acetone. On drying for twelve hours at 25°C this product, containing 1 mol of water, weighs about 178 g (73%).
(d) Preparation of penicillamine hydrochloride: The 178 g of isopropylidene penicillamine hydrochloride obtained in step (c) is dissolved in 350 ml of distilled water. The solution is heated at 90°C to 95°C for one to one and onehalf hours, removing acetone by distillation through an efficient column. There is then added 2.6 liters of isobutyl acetate. The mixture is refluxed at a temperature of about 40°C under reduced pressure in equipment fitted with a water separation device. When no further water separates, the pressure is adjusted so that the mixture distills at a vapor temperature of 83°C to 88°C. A total of 650 ml of distillate is collected. The batch is allowed to cool to 50°C and then filtered. The crystals are washed with isobutyl acetate and then dried at 35°C for 24 hours. The virtually anhydrous penicillamine hydrochloride obtained weighs about 128 g (69% from potassium benzyl-penicillin).
Brand name
Cuprimine(Merck); Depen (Medpointe).
Therapeutic Function
Antiarthritic
General Description
D-Penicillamine contains a β-lactam chemical structure.
Clinical Use
Rheumatoid arthritis, Wilson’s disease, cystinuria, lead
poisoning, chronic active hepatitis
Synthesis
d-penicillamine can be synthesized in a multistep process that begins with
heating isobutyraldehyde, pyridine, sulfur, and
ammonia in benzene to form 5,5-dimethyl-2-
isopropyl-?3-thiazoline. Treatment with hydrogen cyanide gives 4-cyano-5,5-dimethyl-
2-isopropylthiazolidine, which on acid hydrolysis gives d,l-penicillamine hydrochloride. Resolution is accomplished by
conversion of the racemate to d,l-3-formyl-
2,2,5,5-tetramethylthiazolidine-4-carboxylic
acid by treatment first with acetone, then
with acetic formic anhydride. The enantiomers are separated in the usual manner,
using, for example, l-lysine or d-(?)-
threo-1-(4-nitrophenyl)-2-aminopropane-1,3-
diol. Acidification liberates d-3-formyl-
2,2,5,5-tetramethylthiazolidine-4-carboxylic
acid, which is hydrolyzed with hydrochloric
acid to yield d-penicillamine hydrochloride.
Neutralization with ethanolic triethylamine affords d-penicillamine.
Drug interactions
Potentially hazardous interactions with other drugs
Antipsychotics: avoid with clozapine (increased risk
of agranulocytosis).
Sodium aurothiomalate: increased risk of
haematological toxicity
Metabolism
Penicillamine undergoes limited metabolism in the liver,
to S-methyl penicillamine.
It is mainly excreted in the urine as disulfides, along with
some S-methyl penicillamine and unchanged drug; a small
amount may be excreted in the faeces
Purification Methods
The melting point of D-(-)-penicillamine depends on the rate of heating (m 202-206o is obtained by starting at 195o and heating at 2o/minute). It is soluble in H2O and alcohols but insoluble in Et2O, CHCl3, CCl4 and hydrocarbon solvents. Purify it by dissolving it in MeOH and adding Et2O slowly. Dry it in vacuo and store it under N2. [Weight et al. Angew Chem, Int Ed (English) 14 330 1975, Cornforth in The Chemistry of Penicillin (Clarke, Johnson and Robinson eds) Princeton Univ Press, 455 1949, Review: Chain et al. Antibiotics (Oxford University Press) 2 1949, Polymorphism: Vidler J Pharm Pharmacol 28 663 1976]. The D-S-benzyl derivative has m 197-198o (from H2O), [] D 17 -20o (c 1, N NaOH), -70o (N HCl). [Beilstein 4 IV 3228.]
