N(G)-nitro-N2-(tert-butoxy-carbonyl)-L-arginine; Nalpha-(tert-butoxycarbonyl)-Nomega-nitro-L-arginine -Drug Synthesis Database

【结构式】

【分子编号】32085

【品名】N(G)-nitro-N2-(tert-butoxy-carbonyl)-L-arginine; Nalpha-(tert-butoxycarbonyl)-Nomega-nitro-L-arginine

【CA登记号】

【分子式】C₁₁H₂₁N₅O₆

【分子量】319.31784

【元素组成】C 41.38% H 6.63% N 21.93% O 30.06%

与该中间体有关的原料药合成路线共 4 条

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

该中间体在本合成路线中的序号：(I)

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：(V)

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

合成路线3

该中间体在本合成路线中的序号：(XXXI)

Peptide resin (XX) was subjected to sequential coupling-deprotection cycles with the following amino acids: N-Boc-(2-thienyl)alanine (XXI), N-Boc-glycine (XXIII), N-Boc-4-hydroxyproline (XXV), N-Boc-proline (XXVII), Nalpha-Boc-NG-tosyl-arginine (XXIX) and Nalpha-Boc-NG-nitro-D-arginine (XXXI) to produce peptide resins (XXII), (XXIV), (XXVI), (XXVIII), (XXX) and (XXXII), respectively. The title peptide was finally obtained by deprotection and cleavage from the resin by means of treatment with HF.

参考文献中间体

合成目标

【1】 Daffix, I.; Bergé, G.; Amblard, M.; et al.; Synthesis and characterization of bradykinin B2 receptor agonists containing constrained dipeptide mimics. J Med Chem 1999, 42, 20, 4193.
【2】 Dodey, P.; Luccarini, J.-M.; Martinez, J.; Amblard, M.; Daffix, I. (Fournier Industrie et Santé); Peptides agonists of bradykinine B2 receptor. FR 2756566; WO 9824809 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XXVIII)	39388		C₅₄H₆₇N₁₁O₁₃S₃	详情	详情
(XXIX)	39391	(2S)-2-[(tert-butoxycarbonyl)amino]-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoic acid	C₁₈H₂₈N₄O₆S	详情	详情
(XXX)	39389		C₆₇H₈₅N₁₅O₁₆S₄	详情	详情
(XXXI)	32085	N(G)-nitro-N2-(tert-butoxy-carbonyl)-L-arginine; Nalpha-(tert-butoxycarbonyl)-Nomega-nitro-L-arginine	C₁₁H₂₁N₅O₆	详情	详情
(XXXII)	39390		C₇₃H₉₆N₂₀O₁₉S₄	详情	详情

合成路线4

该中间体在本合成路线中的序号：(I)

Boc-Nitroarginine (I) was activated as the mixed anhydride (II), which was further converted to the Weinreb amide (III) upon treatment with N,O-dimethylhydroxylamine. Reduction of (III) with LiAlH4 furnished N-Boc-nitroargininal (IV). This was reductively condensed with the mono-Boc-protected ethylenediamine (V) in the presence of sodium triacetoxyborohydride, yielding amine (VI). The Boc protecting groups of (VI) were finally removed by treatment with trifluoroacetic acid to provide the title compound.

参考文献中间体

合成目标

【1】 Hah, J.-M.; et al.; Reduced amide bond peptidomimetics. (4S)-N-(4-Amino-5-(aminoalkyl]aminopentyl)-N'-nitroguanidines, potent and highly selective inhibitors of neuronal nitric oxide synthase. J Med Chem 2001, 44, 16, 2667.

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)	32085	N(G)-nitro-N2-(tert-butoxy-carbonyl)-L-arginine; Nalpha-(tert-butoxycarbonyl)-Nomega-nitro-L-arginine		C₁₁H₂₁N₅O₆	详情	详情
(II)	53139		n/a	C₁₆H₂₉N₅O₈	详情	详情
(III)	53140		n/a	C₁₃H₂₆N₆O₆	详情	详情
(IV)	53141		n/a	C₁₁H₂₁N₅O₅	详情	详情
(V)	13241	N-Boc-ethylenediamine;tert-butyl (2-aminoethyl)carbamate；tert-butyl 2-aminoethylcarbamate; tert-Butyl n-(2-aminoethyl)carbamate	57260-73-8	C₇H₁₆N₂O₂	详情	详情
(VI)	53142		n/a	C₁₈H₃₇N₇O₆	详情	详情

Extended Information