3-methylquinoline-8-suIfonyl chloride; 3-methyl-8-quinolinesulfonyl chloride -Drug Synthesis Database

【结构式】

【分子编号】32089

【品名】3-methylquinoline-8-suIfonyl chloride; 3-methyl-8-quinolinesulfonyl chloride

【CA登记号】

【分子式】C₁₀H₈ClNO₂S

【分子量】241.69776

【元素组成】C 49.69% H 3.34% Cl 14.67% N 5.8% O 13.24% S 13.27%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(V)

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

合成目标

【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

该中间体在本合成路线中的序号：(VIII)

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

合成目标

【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