ChemicalBook > Product Catalog > API > Blood System Drugs > Anticoagulant and Antiplatelet Drugs > Argatroban
Argatroban Chemical Properties
- Melting point:188-1890C
- Boiling point:777.2±70.0 °C(Predicted)
- Density 1.47±0.1 g/cm3(Predicted)
- storage temp. Store at +4°C
- form White to off-white powder.
- CAS DataBase Reference74863-84-6(CAS DataBase Reference)
Argatroban Usage And Synthesis
- DescriptionArgatroban is a new synthetic antithrombotic agent useful in maintenance anticoagulation them ischemic stroke and disseminated intravascular coagulation. In patients on hemodialysis, argatroban is su enor to heparin, generating a more stable antithrombin effect. Other potential uses include progressing ischemic stroke and disseminated intravascular coagulation.
- Chemical PropertiesWhite to Off-White Crystalline Solid
- OriginatorMitsubishi Kasei; Daiichi (Japan)
- UsesSynthetic thrombin inhibitor. Antithrombotic.
- Usesanticoagulant;direct thrombine inhibitor
- Manufacturing ProcessTo a stirred solution of 28.3 g of NG-nitro-N2-(tert-butoxycarbonyl)-L-arginine
in 450 ml of dry tetrahydrofuran were added in turn 9.0 g of triethylamine
and 12.2 g of isobutyl chloroformate while keeping the temperature at -20°C.
After 10 minutes, to this was added 15.2 g of ethyl 4-methyl-2-
piperidinecarboxylate and the mixture was stirred for 10 minutes at -20°C. At
the end of this period, the reaction mixture was warmed to room
temperature. The solvent was evaporated and the residue taken up in 400 ml
of ethyl acetate, and washed successively with 200 ml of water, 100 ml of 5%
sodium bicarbonate solution, 100 ml of 10% citric acid solution and 200 ml of
water. The ethyl acetate solution was dried over anhydrous sodium sulfate.
The solution was evaporated to give 31.5 g (75 %) of ethyl 1-[NG-nitro-N2-
(tert-butoxycarbonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylate in the form
of a syrup.
To a stirred solution of 30 g of ethyl 1-[NG-nitro-N2-(tert-butoxycarbonyl)-Larginyl]- 4-methyl-2-piperidinecarboxylate in 50 ml of ethyl acetate was added 80 ml of 10% dry HCl-ethyl acetate at 0°C. After 3 hours, to this solution was added 200 ml of dry ethyl ether to precipitate a viscous oily product. This was filtered and washed with dry ethyl ether to give ethyl 1-[NG-nitro-L-arginyl]-4- methyl-2-piperidinecarboxylate hydrochloride as an amorphous solid.
To a stirred solution of ethyl 1-(NG-nitro-L-arginyl)-4-methyl-2- piperidinecarboxylate hydrochloride in 200 ml of chloroform were added in turn 18.5 g of triethylamine, and 14.7 g of 3-methyl-8-quinolinesulfonyl chloride at 5°C, and stirring was continued for 3 hours at room temperature. At the end of this period, the solution was washed twice with 50 ml of water. The chloroform solution was dried over anhydrous sodium sulfate. Upon evaporation of the solvent, the residue was chromatographed on 50 g of silica gel packed in chloroform, washed with chloroform and eluted with 3% methanol-chloroform. The fraction eluted from 3% methanol-chloroform was evaporated to give 32.1 g (91%) of ethyl 1-[NG-nitro-N2-(3-methyl-8- quinolinesulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylate in the form of an amorphous solid.
A solution of 30 g the above product in 100 ml of ethanol and 100 ml of 1 N sodium hydroxide solution was stirred for 24 hrs at room temperature. At the end of this period, the solution was neutralized with 1 N hydrochloric acid and then concentrated to 70 ml. The solution was adjusted to pH=11 with 1 N sodium hydroxide solution, washed three times with 100 ml of ethyl acetate, acidified with 1 N hydrochloric acid and then extracted three times with 100 ml of chloroform. The combined chloroform solution was dried over anhydrous sodium sulfate and evaporated to give 28.0 g (97%) of 1-[NG-nitro-N2-(3- methyl-8-quinolinesulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylic acid as an amorphous solid. IR (KBr): 3,300, 1,720, 1,630 cm-1.
To a solution of 3.00 g of 1-[NG-nitro-N2-(3-methyl-8-quinolinesulfonyl)-Larginyl]- 4-methyl-2-piperidinecarboxylic acid in 50 ml of ethanol was added 0.5 g of palladium black and then the mixture was shaken under 10 kg/cm2 H2 pressure at 100°C for 8 hrs. At the end of this period, the ethanol solution was filtered to remove the catalyst and evaporated to give 2.50 g (90%) of 1- [N2-(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl]-4-methyl-2- piperidinecarboxylic acid as an amorphous solid. IR (KBr): 3,400, 1,620, 1,460, 1,380 cm-1.
- brand nameNovastan (Mitsubishi Chemical Corporation, Japan);Slonnon.
- Therapeutic FunctionAnticoagulant
- PharmacokineticsArgatroban is administered subcutaneously because of the low lipophilicity of the drug. The drug is bound to plasma protein and is metabolized via CYP3A4/5 to the aromatized metabolite and the two hydroxylated metabolites. The M-1 metabolite retains 20 to 30% of the antithrombotic activity. Coadministration of argatroban with inhibitors of CYP3A4 does not appear to produce clinically significant effects. Argatroban is eliminated via biliary secretion into the feces.
- Clinical UseArgatroban has been approved for the prophylaxis and treatment of thrombosis in patients with HIT (79). Argatroban is a peptidomimetic that binds selectively to the catalytic site of thrombin as a univalent competitive DTI. Argatroban is available as a mixture of 21-R and 21-S diastereomers (64:36), with the S-isomer approximately twice as potent as the R-isomer. The drug is a reversible inhibitor of both free thrombin as well as clot-bound thrombin.
Argatroban Preparation Products And Raw materials
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