Description
(S)-(+)-Clopidogrel is the functional enantiomer of clopidogrel (Item No.
13657) and a prodrug whose thiol metabolite antagonizes purine binding to the platelet purinergic receptor P2Y
12 (K
i = 316 nM in human platelets).
1 It is metabolized by the cytochrome P450 (CYP) isoform CYP2C19 in rat liver and inhibits ADP-induced platelet aggregation
ex vivo.
2 Formulations containing (S)-(+)-clopidogrel have been used in combination with aspirin to prevent vascular ischemic events in patients with acute coronary syndromes.
Uses
Clopidogrel Bisulfate is an oral, thienopyridine class antiplatelet agent used to inhibit blood clots in coronary artery disease, peripheral vascular disease, and cerebrovascular disease.
Manufacturing Process
Levo-rotatory ammonium camphor-10-sulfonate is dissolved in a minimum of
water and applied to the column of Amberlite IRN-77 resin. Elution is carried
out with water. The eluted fractions containing the levo-rotatory camphor-10-
sulfonic acid are lyophilized, melting point 198°C.
32 g (0.0994 mole) of racemic methyl-α-5-(4,5,6,7-tetrahydro-thieno(3,2-
c)pyridyl)(2-chlorophenyl)-acetate are dissolved in 150 ml of acetone. 9.95 g
(0.0397 mole) of levo-rotatory camphor-10-sulfonic acid monohydrate are
added. The clear solution is left to stand at room temperature. After 48 hours
the reaction mixture is concentrated to 50 ml and left to stand at room
temperature for 24 hours. The obtained camphor-10-sulfonic acid salt of
methyl-α-5-(4,5,6,7-tetrahydro-thieno(3,2-c)pyridyl)(2-chlorophenyl)-acetate
(SR 25990) are filtered off, washed with acetone and dried (yield: 55% on the
basis of the starting racemate), melting point 165°C, [α]D20=+24.67 (c=1.58
g/100 ml; methanol). The crystals obtained above are redissolved in the
minimum of boiling acetone (50 ml). The crystals obtained after cooling are
filtered off, washed with acetone and dried (yield: 88%), m.p. 165°C,
[α]D20=+24.75 (c=1.68 g/100 ml; methanol).
12 g (0.022 mole) of the pure camphor-10-sulfonic acid salt of methyl-α-5-
(4,5,6,7-tetrahydro-thieno(3,2-c)pyridyl)(2-chlorophenyl)-acetate are
dissolved in a minimum of water. After cooling to 5°C, the aqueous solution
obtained is made alkaline with a saturated aqueous solution of sodium
hydrogen carbonate. The alkaline aqueous phase is extracted with
dichloromethane. The organic extracts are dried over anhydrous sodium
sulfate. On evaporation of the solvent a colorless oil of dextro-rotatory
methyl-α-5-(4,5,6,7-tetrahydro-thieno(3,2-c)pyridyl)(2-chlorophenyl)-acetate
is obtained (quantitative yield). Oil, [α]D20=+51.52 (c=1.61 g/100 ml;
methanol).
800 ml of a saturated aqueous solution of sodium bicarbonate are added to a
suspension of 200 g of SR 25990 in 800 ml of dichloromethane. After vigorous
shaking, the organic phase is separated, dried over sodium sulfate and the
solvent is removed under reduced pressure. The residue is dissolved in 500 ml
of ice-cold acetone and 20.7 ml of concentrated sulfuric acid (93.64%) are
added drop-wise. The precipitate formed is isolated by filtration and washed
with 1 L of acetone, then dried in a vacuum oven at 50°C. 139 g of pure
white crystals of hydrogen sulfate of dextro-rotatory methyl-α-5-(4,5,6,7-
tetrahydro-thieno(3,2-c)pyridyl)(2-chlorophenyl)-acetate (SR 25990 C) are
thus obtained, m.p. 184°C, [α]D20=+55.10 (c=1.891 g/100 ml; methanol).
Synthesis
Clopidogrel bisulfate can be synthesized via a multistage process involving tosylation of thiophene ethanol, alkylation with (S)-2-chlorophenyl glycine methyl ester, and final cyclization, followed by addition of sulfuric acid in an acetone-water mixture to form the bisulfate salt[2]. Alternative synthetic routes include Strecker reactions, enzymatic resolution of racemic bromoester combined with tetrahydrothienopyridine hydrochloride, and substitution reactions using methyl amino(2-chlorophenyl)acetate as a nucleophile[3].
Veterinary Drugs and Treatments
Clopidogrel, a platelet aggregation inhibitor, may be useful for preventing
thrombi in susceptible cats. It may also improve pelvic limb
circulation in cats after a cardiogenic embolic event via a vasomodulating
effect secondary to inhibition of serotonin release from platelets.
Research is ongoing.
