Argipidine, Argatroban monohydrate, GN1600, DK-7419, MDI-805, OM-805, MCI-9038, MD-805, Argatroban Injection, Acova, Slonnon, Novastan, -Drug Synthesis Database

【结构式】

【药物名称】Argipidine, Argatroban monohydrate, GN1600, DK-7419, MDI-805, OM-805, MCI-9038, MD-805, Argatroban Injection, Acova, Slonnon, Novastan

【化学名称】(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

【CA登记号】141396-28-3, 74863-84-6 (anhydrous)

【分子式】C₂₃H₃₈N₆O₆S

【分子量】526.65991

【开发单位】Mitsubishi Chemical (Originator), Encysive Pharmaceuticals (Licensee), Mitsubishi Pharma (Distributor), Daiichi Pharmaceutical (Codevelopment), GlaxoSmithKline (Codevelopment), Mitsubishi Pharma (Codevelopment), Sanofi-synthélabo (Codevelopment)

【药理作用】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

合成路线1 合成路线2

合成路线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.

参考文献中间体

【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 .
【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 .
【3】 Castaner, J.; Grau, M.; Blancafort, P.; Serradell, M.N.; MD-805. Drugs Fut 1982, 7, 11, 810.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	13423	1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate	543-27-1	C₅H₉ClO₂	详情	详情
(I)	32085	N(G)-nitro-N2-(tert-butoxy-carbonyl)-L-arginine; Nalpha-(tert-butoxycarbonyl)-Nomega-nitro-L-arginine		C₁₁H₂₁N₅O₆	详情	详情
(II)	32086	Ethyl (2R,4R)-4-methyl-2-piperidinecarboxylate		C₉H₁₇NO₂	详情	详情
(III)	32087	Ethyl 1-[N(G)-nitro-N2-(tert-butoxycarbonyl)-L-arginyl]-4-methylpiperidine-2-carboxylate; [Nalpha-(tert-butoxycarbonyl)-Nomega-nitro-L-arginyl]-4(R)-methylpiperidine-2(R)-carboxylic acid ethyl ester		C₂₀H₃₆N₆O₇	详情	详情
(IV)	32088	1-(N-omega-nitro-L-arginyl)-4(R)-methylpiperidine-2(R)-carboxylic acid ethyl ester; Ethyl 1-(N(G)-nitro-L-arginyl)-4-methylpiperidine-2-carboxylate		C₁₅H₂₈N₆O₅	详情	详情
(V)	32089	3-methylquinoline-8-suIfonyl chloride; 3-methyl-8-quinolinesulfonyl chloride		C₁₀H₈ClNO₂S	详情	详情
(VI)	32090	Ethyl 1-(N(G)-nitro-N2-(3-methyl-8-quinolinylsulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylate; [Nalpha-(3-Methylquinolin-8-ylsulfonyl)-Nomega-nitro-L-arginyl]-4(R)-methylpiperidine-2(R)-carboxylic acid ethyl ester		C₂₅H₃₅N₇O₇S	详情	详情
(VII)	32091	[Nalpha-(3-Methylquinolin-8-ylsulfonyl)-Nomega-nitro-L-arginyl]-4(R)-methylpiperidine-2(R)-carboxylic acid; 1-[N(G)-Nitro-N2-(3-methyl-8-quinolinylsulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylic acid		C₂₃H₃₁N₇O₇S	详情	详情

合成路线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.

参考文献中间体

【1】 Belotti, D.; Cossy, J.; A short synthesis of argatroban: A potent selective thrombin inhibitor. Bioorg Med Chem Lett 2001, 11, 15, 1989.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	10192	4-Methylpiperidine; gamma-Pipecoline	626-58-4	C₆H₁₃N	详情	详情
(II)	49427	tert-butyl 4-methyl-1-piperidinecarboxylate		C₁₁H₂₁NO₂	详情	详情
(III)	49428	2-benzyl 1-(tert-butyl) (2R,4R)-4-methyl-1,2-piperidinedicarboxylate		C₁₉H₂₇NO₄	详情	详情
(IV)	49429	benzyl (2R,4R)-4-methyl-2-piperidinecarboxylate		C₁₄H₁₉NO₂	详情	详情
(V)	32085	N(G)-nitro-N2-(tert-butoxy-carbonyl)-L-arginine; Nalpha-(tert-butoxycarbonyl)-Nomega-nitro-L-arginine		C₁₁H₂₁N₅O₆	详情	详情
(VI)	49430			C₂₅H₃₈N₆O₇	详情	详情
(VII)	49431			C₂₀H₃₀N₆O₅	详情	详情
(VIII)	32089	3-methylquinoline-8-suIfonyl chloride; 3-methyl-8-quinolinesulfonyl chloride		C₁₀H₈ClNO₂S	详情	详情
(IX)	49432			C₃₀H₃₇N₇O₇S	详情	详情

Extended Information