N-alpha-(tert-butoxycarbonyl)-N-omega'-nitro-L-arginine -Drug Synthesis Database

【结构式】

【分子编号】29372

【品名】N-alpha-(tert-butoxycarbonyl)-N-omega'-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)

Solid-phase synthesis: Reduction of the carboxylic acid moiety of Boc-Arg(NO2)-OH (I) by first treatment with CDI followed by LiAlH4 affords aldehyde (II), which is then condensed with compound (III) in aqueous NaOAc and refluxing EtOH to yield semicarbazone linker (IV). Loading of (IV) onto aminomethyl polystyrene resin provides anchored arginine derivative (V), which is subjected to the following pathway to provide anchored peptide (VI): (i) Boc removal with TFA/CH2Cl2; (ii) incorporation of Boc-Gly-OH (A) by means of coupling agents HOBt, HBTU and DIEA in DMF; (iii) again Boc removal; and finally (iv) coupling of Boc-D-Arg(NO2)-OH (B) with HOBt, HBTU and DIEA in DMF. Deprotection of (VI) with TFA/CH2Cl2 and capping with benzylsulfonyl chloride (VII) and DIEA furnishes anchored derivative (VIII), which is cleaved by means of HOAc, aqueous formaldehyde and HCl in THF and finally hydrogenolyzed over Pd/C. The synthesis can also be performed in an analogous way by substitution of Boc-Arg(NO2)-OH for Boc-Arg(Cbz)2-OH.

参考文献中间体

合成目标

【1】 Marlowe, C.K.; Sinha, U.; Scarborough, R.M.; Gunn, A.C.; Design, synthesis and structure-activity relationship of a series of arginine aldehyde factor Xa inhibitors. Part 1: Structures based on the (D)-Arg-Gly-Arg tripeptide sequence. Bioorg Med Chem Lett 2000, 10, 1, 13.
【2】 Marlowe, C.K.; Scarborough, R.M.; Laibelman, A.M.; Sinha, U.; Zhu, B.-Y. (COR Therapeutics, Inc.); Inhibitors of factor Xa. US 5721214 .
【3】 Marlowe, C.K.; Scarborough, R.M.; Laibelman, A.M.; Sinha, U.; Zhu, B.-Y. (COR Therapeutics, Inc.); Inhibitors of factor Xa. EP 0846125; JP 1999507626; US 5919765; WO 9640743 .

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)	18066	N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid	4530-20-5	C₇H₁₃NO₄	详情	详情
(B)	39364	Omega-nitro-Boc-D-arginine	50913-12-7	C₁₁H₂₁N₅O₆	详情	详情
(I)	29372	N-alpha-(tert-butoxycarbonyl)-N-omega'-nitro-L-arginine		C₁₁H₂₁N₅O₆	详情	详情
(II)	43535			C₁₁H₂₁N₅O₅	详情	详情
(III)	43536	4-[[(hydrazinocarbonyl)amino]methyl]cyclohexanecarboxylic acid		C₉H₁₇N₃O₃	详情	详情
(IV)	43537			C₂₀H₃₆N₈O₇	详情	详情
(V)	43538			C₂₀H₃₇N₉O₆	详情	详情
(VI)	43539			C₂₈H₅₁N₁₅O₁₀	详情	详情
(VII)	25151	phenylmethanesulfonyl chloride	1939-99-7	C₇H₇ClO₂S	详情	详情
(VIII)	43540			C₃₀H₄₉N₁₅O₁₀S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

The title compound has been prepared by either solid-phase or solution-phase synthesis. In the first case, N(alpha)-Boc-N(omega)-nitro-L-arginine (I) was coupled with N,O-dimethylhydroxylamine, and the resulting N-methoxy-amide (II) was reduced with LiAlH4 to the corresponding aldehyde, isolated as the cyclic hemiaminal (III). Deprotection of the N-nitro group of (III) by hydrogenation over Pd/C afforded guanidine (IV), which was condensed with allyl chloroformate to give the allyl carbamate (V). Subsequent acid-catalyzed condensation with ethyl 6-hydroxyhexanoate (VI) at the aminal hydroxyl group provided ketal (VII). After hydrolysis of the ethyl ester of (VII), the resulting carboxylic acid (VIII) was coupled to amino-resin to produce the amide-resin (IX).

参考文献中间体

合成目标

【1】 Cohen, C.R.; Weinhouse, M.I.; Roberts, C.; et al.; Synthesis and biological activity of transition-state urokinase inhibitors. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 090.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	38115	3-[(chlorocarbonyl)oxy]-1-propene	2937-50-0	C₄H₅ClO₂	详情	详情
(I)	29372	N-alpha-(tert-butoxycarbonyl)-N-omega'-nitro-L-arginine		C₁₁H₂₁N₅O₆	详情	详情
(II)	29373	N-alpha-(tert-butoxycarbonyl)-N1-methoxy-N1-methyl-N-omega'-nitro-L-argininamide		C₁₃H₂₆N₆O₆	详情	详情
(III)	29374	3(S)-(Tert-butoxycarbonylamino)-2-hydroxy-N2-nitropiperidine-1-carboxamidine		C₁₁H₂₁N₅O₅	详情	详情
(IV)	29375	tert-butyl (3S)-1-[amino(imino)methyl]-2-hydroxypiperidinylcarbamate		C₁₁H₂₂N₄O₃	详情	详情
(V)	29376	allyl (E)-amino[(3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxypiperidinyl]methylidenecarbamate		C₁₅H₂₆N₄O₅	详情	详情
(VI)	29377	ethyl 6-hydroxyhexanoate		C₈H₁₆O₃	详情	详情
(VII)	29378	ethyl 6-([(3S)-1-[[[(allyloxy)carbonyl]imino](amino)methyl]-3-[(tert-butoxycarbonyl)amino]piperidinyl]oxy)hexanoate		C₂₃H₄₀N₄O₇	详情	详情
(VIII)	29379	6-([(3S)-1-[[[(allyloxy)carbonyl]imino](amino)methyl]-3-[(tert-butoxycarbonyl)amino]piperidinyl]oxy)hexanoic acid		C₂₁H₃₆N₄O₇	详情	详情
(IX)	29380	allyl (E)-amino[(3S)-2-[(6-amino-6-oxohexyl)oxy]-3-[(tert-butoxycarbonyl)amino]piperidinyl]methylidenecarbamate		C₂₁H₃₇N₅O₆	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XII)

Coupling of N(alpha)-Boc-N(G)-nitro-L-arginine (XII) with 2-aminothiazole (XIII) gave amide (XIV). After cleavage of the Boc group of (XIV) with HCl, the resulting amine (XV) was coupled with the intermediate carboxylic acid (XI) using diethyl cyanophosphonate to afford adduct (XVI). The terahydropyranyl group of (XVI) was finally deprotected by treatment with aqueous acetic acid.

参考文献中间体

合成目标

【1】 Wiethe, R.W.; Andrews, R.C.; Rabinowitz, M.H.; Musso, D.L.; Chan, J.H.; McDougald, D.L.; Gaul, M.D.; Cowan, D.J.; Stanford, J.B.; Babacz, D.G.; Andersen, M.W. (Glaxo Group Ltd.); Formamide cpds. as therapeutic agents. US 6191150; WO 0012466 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XII)	29372	N-alpha-(tert-butoxycarbonyl)-N-omega'-nitro-L-arginine		C₁₁H₂₁N₅O₆	详情	详情
(XIII)	19795	2-Thiazolamine; 1,3-thiazol-2-amine; 1,3-thiazol-2-ylamine	96-50-4	C₃H₄N₂S	详情	详情
(XIV)	44125			C₁₄H₂₃N₇O₅S	详情	详情
(XV)	44126			C₉H₁₅N₇O₃S	详情	详情
(XVI)	44124	(2R,3S)-3-[formyl(tetrahydro-2H-pyran-2-yloxy)amino]-2-isobutylhexanoic acid		C₁₆H₂₉NO₅	详情	详情
(XVII)	44127			C₂₅H₄₂N₈O₇S	详情	详情

合成路线4

该中间体在本合成路线中的序号：(XI)

The alkylation of 3(R)-hydroxyhexanoic acid methyl ester (I) with isobutyl bromide (II) and LDA in THF gives 3(R)-hydroxy-2(R)-isobutylhexanoic acid methyl ester (III), which is hydrolyzed with LiOH in THF/MeOH/water to yield the corresponding lithium salt (IV). The condensation of (IV) with O-tetrahydropyranyl-hydroxylamine (V) by means of DCC in ethyl acetate affords the protected hydroxamic acid (VI), which is treated with Ms-Cl and pyridine to provide the mesylate (VII). The cyclization of (VII) by means of K2CO3 in refluxing acetone gives the chiral azetidinone (VIII), which is opened by means of NaOH in dioxane/water, yielding the carboxylic acid (IX). The formylation of the NH group of (IX) with acetic formic anhydride and pyridine in dichloromethane affords the intermediate (X). The condensation of the N-protected nitro arginine (XI) with 2-aminothiazole (XII) by means of EDC in DMF gives the argininamide (XIII), which is deprotected by means of HCl in dioxane to yield the intermediate (XIV). Condensation of (XIV) with (X) by means of diethyl phosphorylcyanide (DEPC) and NMM in DMF gives the protected dipeptide (XV), which is treated with AcOH in warm water to yield the target dipeptide.

参考文献中间体

合成目标

【1】 Rabinowitz, M.H.; Andrews, R.C.; Becherer, J.D.; et al.; Design of selective and soluble inhibitors of tumor necrosis factor-alpha converting enzyme (TACE). J Med Chem 2001, 44, 24, 4252.

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)	44116	methyl (3R)-3-hydroxyhexanoate		C₇H₁₄O₃	详情	详情
(II)	24599	1-bromo-2-methylpropane	78-77-3	C₄H₉Br	详情	详情
(III)	44118	methyl (2R,3R)-3-hydroxy-2-isobutylhexanoate		C₁₁H₂₂O₃	详情	详情
(IV)	62871			C₁₀H₁₉LiO₃	详情	详情
(V)	52106	2-(aminooxy)tetrahydro-2H-pyran; O-tetrahydro-2H-pyran-2-ylhydroxylamine		C₅H₁₁NO₂	详情	详情
(VI)	44120	(2R,3R)-3-hydroxy-2-isobutyl-N-(tetrahydro-2H-pyran-2-yloxy)hexanamide		C₁₅H₂₉NO₄	详情	详情
(VII)	44121	(1R,2R)-4-methyl-1-propyl-2-[[(tetrahydro-2H-pyran-2-yloxy)amino]carbonyl]pentyl methanesulfonate		C₁₆H₃₁NO₆S	详情	详情
(VIII)	44122	(3R,4S)-3-isobutyl-4-propyl-1-(tetrahydro-2H-pyran-2-yloxy)-2-azetidinone		C₁₅H₂₇NO₃	详情	详情
(IX)	44123	(2R,3S)-2-isobutyl-3-[(tetrahydro-2H-pyran-2-yloxy)amino]hexanoic acid		C₁₅H₂₉NO₄	详情	详情
(X)	44124	(2R,3S)-3-[formyl(tetrahydro-2H-pyran-2-yloxy)amino]-2-isobutylhexanoic acid		C₁₆H₂₉NO₅	详情	详情
(XI)	29372	N-alpha-(tert-butoxycarbonyl)-N-omega'-nitro-L-arginine		C₁₁H₂₁N₅O₆	详情	详情
(XII)	19795	2-Thiazolamine; 1,3-thiazol-2-amine; 1,3-thiazol-2-ylamine	96-50-4	C₃H₄N₂S	详情	详情
(XIII)	44125			C₁₄H₂₃N₇O₅S	详情	详情
(XIV)	44126			C₉H₁₅N₇O₃S	详情	详情
(XV)	44127			C₂₅H₄₂N₈O₇S	详情	详情

Extended Information