Chemical Name: | (2R,4R)-4-Methyl-1-[N2-(3-methyl-1,2,3,4-tetrahydroquinolin-8-ylsulfonyl)-L-arginyl]piperidine-2-carboxylic acid monohydrate;(2R,4R)-1-[5-Guanidino-1-oxo-2(S)-(1,2,3,4-tetrahydro-3-methylquinolin-8-ylsulfonamido)pentyl]-4-methylpiperidine-2-carboxylic acid monohydrate | Generic Name: | 阿加曲班;Argatroban | Other Names: | Argipidine;Argatroban monohydrate;GN1600;DK-7419;MDI-805;OM-805;MCI-9038;MD-805;Argatroban Injection;Acova;Slonnon;Novastan | CAS: | 141396-28-3 | Related CAS: | 74863-84-6 (anhydrous) | Formula: | C23H38N6O6S | Mole Weight: | 526.65991 | structure: | | Company: | Mitsubishi Chemical (Originator), Encysive Pharmaceuticals (Licensee), Mitsubishi Pharma (Distributor), Daiichi Pharmaceutical (Codevelopment), GlaxoSmithKline (Codevelopment), Mitsubishi Pharma (Codevelopment), Sanofi-synthélabo (Codevelopment) | Usage: | Antithrombocytopenic, CARDIOVASCULAR DRUGS, Cerebrovascular Diseases, Treatment of, HEMATOLOGIC DRUGS, Hematopoiesis Disorders Therapy, Ischemic Stroke, Treatment of, NEUROLOGIC DRUGS, Peripheral Vascular Disease, Treatment of, Stroke, Treatment of, Treatment of Peripheral Obstructive Vascular Disease, Thrombin Inhibitors | | | |
Route 1 The condensation of N(G)-nitro-N2-(tert-butoxy-carbonyl)-L-arginine (I) with ethyl 4-methylpiperidine-2-carboxylate (II) by means of isobutyl chloroformate (A) and triethylamine in THF gives ethyl 1-[N(G)-nitro-N2-(tert-butoxycarbonyl)-L-arginyl]-4-methylpiperidine-2-carboxylate (III), which is protected with HCl in ethyl acetate yielding ethyl 1-(N(G)-nitro-L-arginyl)-4-methylpiperidine-2-carboxylate (IV). The condensation of (IV) with 3-methylquinoline-8-sulfonyl chloride (V) by means of triethylamine in chloroform affords ethyl 1-(N(G)-nitro-N2-(3-methyl-8-quinolinylsulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylate (VI), which is hydrolyzed with NaOH in ethanol-water giving 1-[N(G)-nitro-N2-(3-methyl-8-quinolinylsulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylic acid (VII). Finally, this compound is deprotected and reduced by hydrogenation with H2 over Pd/C in ethanol. | | Intermediates: | Serial No. | 3-(hydroxymethyl)pyrido[3,2-g]quinoline-5,10-dione | (A) | tert-butyl(dimethyl)silyl (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-10-undecenoate | (I) | tert-butyl(dimethyl)silyl (3S,6R,7S,8S,12Z,15S,16E)-15-(acetoxy)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoate | (II) | potassium acetate | (III) | potassium acetate | (IV) | methyl acetate | (V) | methyl acetate | (VI) | 1-Hydroxy-1-(methylsulfanyl)acetone | (VII) | | Reference 1: Kikumoto, R.; Tamao, Y.; Onkubo, K.; Tezuka, T.; Tonomura, S.; Hihikata, A.; Okamoto, S. (Mitsubishi Chemical Corp.); N2-Arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof. US 4201863 . Reference 2: Kikumoto, R.; Tamao, Y.; Onkubo, K.; Tezuka, T.; Tonomura, S.; Hihikata, A.; Okamoto, S. (Mitsubishi Chemical Corp.); N2-Arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof. EP 0008746; US 4258192 . Reference 3: Castaner, J.; Grau, M.; Blancafort, P.; Serradell, M.N.; MD-805. Drugs Fut 1982, 7, 11, 810. | Route 2 A new short synthesis of argatroban has been reported: The protection of 4-methylpiperidine (I) with (Boc)2O gives the carbamate (II), which is condensed with benzyl chloroformate by means of sec-butyl lithium and TMEDA in ethyl ether to yield (±)-trans-1-(tert-butoxycarbonyl)-4-methylpiperidine-2-carboxylic acid benzyl ester (III). Deprotection of the NH group of (III) with HCl in ethyl acetate affords (±)-trans-4-methylpiperidine-2-carboxylic acid benzyl ester (IV), which is condensed with the protected arginine derivative (V) by means of isobutyl chloroformate and TEA to provide the corresponding amide as a diastereomeric mixture. Resolution of this mixture by flash chromatography furnishes the desired diastereomer (VI), which is treated with HCl in ethyl acetate in order to remove the Boc-protecting group to yield compound (VII). Condensation of compound (VII) with 3-methylquinoline-8-sulfonyl chloride (VIII) by means of TEA in dichloromethane affords the expected sulfonamide (IX). Finally, this compound is submitted to hydrogenation with H2 over Pd/C in AcOH/ethanol in order to produce debenzylation, cleavage of the NO2 group and hydrogenation of the pyridine ring to yield argatroban. | | Intermediates: | Serial No. | 2-[4-[7-methoxy-3,4-dihydro-2(1H)-isoquinolinyl]butyl]-1H-isoindole-1,3(2H)-dione | (I) | tert-butyl(dimethyl)silyl (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-10-undecenoate | (V) | methyl acetate | (VIII) | (2S)-1-[4-(benzyloxy)phenyl]-2-(4-hydroxy-4-phenyl-1-piperidinyl)-1-propanone | (II) | 4-methyl-5-nitro-1H-imidazole | (III) | 5-nitro-4-[(E)-2-phenylethenyl]-1H-imidazole | (IV) | 1-benzyl-4-nitro-5-[(E)-2-phenylethenyl]-1H-imidazole | (VI) | 1-benzyl-5-nitro-4-[(E)-2-phenylethenyl]-1H-imidazole | (VII) | 1-benzyl-4-nitro-1H-imidazole-5-carboxylic acid | (IX) | | Reference 1: Belotti, D.; Cossy, J.; A short synthesis of argatroban: A potent selective thrombin inhibitor. Bioorg Med Chem Lett 2001, 11, 15, 1989. | | | |