Romurtide, Muroctasin, DJ-7041, MDP-Lys(L18), Nopia, -Drug Synthesis Database

【结构式】

【药物名称】Romurtide, Muroctasin, DJ-7041, MDP-Lys(L18), Nopia

【化学名称】Nalpha-(N-Acetylmuramoyl-L-alanyl-D-isoglutaminyl)-Nepsilon-stearoyl-L-lysine
　　　　　　N2-[N2-[N-(N-Acetylmuramoyl)-L-alanyl]-D-alpha-glutaminyl]-N6-(1-octadecanoyl)-L-lysine
　　　　　　2-Acetamido-3-O-[(R)-1-[[(S)-1-[[(R)-1-carbamoyl-3-[[(S)-1-carboxy-5-stearamidopentyl]carbamoyl]propyl]carbamoyl]ethyl]carbamoyl]ethyl]-2-deoxy-D-glucopyranose

【CA登记号】78113-36-7

【分子式】C₄₃H₇₈N₆O₁₃

【分子量】887.13351

【开发单位】Daiichi Pharmaceutical (Originator)

【药理作用】IMMUNOMODULATING AGENTS, Immunostimulants

合成路线1 合成路线2 合成路线3

合成路线1

The condensation of tert-butoxycarbonyl-L-alanine (I) with benzyl D-isoglutaminate (II) by means of N-hydroxysuccinimide (NOHS) and dicyclohexylcarbodiimide (DCC) gives the protected dipeptide (III), which is hydrogenated with H2 over Pd/C in methanol yielding tert-butoxycarbonyl-D-isoglutaminyl-L-alanine (IV). The condensation of (IV) with Nepsilon-(benzyloxycarbonyl)-L-lysine benzyl ester (V) by means of ethyl chloroformate and triethylamine affords the protected tripeptide (VI), which is treated with trifluoroacetic acid (TFA) to afford L-alanyl-D-isoglutaminyl-(Nepsilon-benzyloxycarbonyl)-L-lysine benzyl ester (VII).

参考文献中间体

【1】 Shiba, T.; Yamamura, Y.; Nagase, O.; Kotani, S.; Ogawa, H. (Daiichi Seiyaku Co.; Ltd.); Muramyldipeptide derivatives, process for preparing said compounds and pharmaceutical compositions containing said compounds. EP 0021367 .
【2】 Robinson, C.P.; MUROCTASIN. Drugs Fut 1989, 14, 5, 432.
【3】 Shiba, T.; Kusumoto, S.; Tarumi, Y.; Ikenaka, K.; Chemical synthesis of N-acetylmuramyl peptides with partial structures of bacterial cell wall and their analogs in relation to immunoadjuvant activities. 1976, 49(2): 533-9. Bull Chem Soc Jpn 1976, 49, 2, 533.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	20337	N-(tert-butoxycarbonyl)alanine	C₈H₁₅NO₄	详情	详情
(II)	20868	benzyl 4,5-diamino-5-oxopentanoate	C₁₂H₁₆N₂O₃	详情	详情
(III)	20869	benzyl 5-amino-4-([2-[(tert-butoxycarbonyl)amino]propanoyl]amino)-5-oxopentanoate	C₂₀H₂₉N₃O₆	详情	详情
(IV)	20870	5-amino-4-([2-[(tert-butoxycarbonyl)amino]propanoyl]amino)-5-oxopentanoic acid	C₁₃H₂₃N₃O₆	详情	详情
(V)	20871	benzyl 2-amino-6-[[(benzyloxy)carbonyl]amino]hexanoate	C₂₁H₂₆N₂O₄	详情	详情
(VI)	20872	benzyl 9-(aminocarbonyl)-14-(4-[[(benzyloxy)carbonyl]amino]butyl)-2,2,6-trimethyl-4,7,12-trioxo-3-oxa-5,8,13-triazapentadecan-15-oate	C₃₄H₄₇N₅O₉	详情	详情
(VII)	20873	benzyl 2-([5-amino-4-[(2-aminopropanoyl)amino]-5-oxopentanoyl]amino)-6-[[(benzyloxy)carbonyl]amino]hexanoate	C₂₉H₃₉N₅O₇	详情	详情

合成路线2

The condensation of (VII) with 1-O-benzyl-4,6-O-benzylidene-N-acetylmuramic acid (VIII) by means of NOHS and DCC as before gives the protected muramyl tripeptide (IX) , which is treated with acetic acid yielding the partially protected compound (X).

参考文献中间体

【1】 Shiba, T.; Yamamura, Y.; Nagase, O.; Kotani, S.; Ogawa, H. (Daiichi Seiyaku Co.; Ltd.); Muramyldipeptide derivatives, process for preparing said compounds and pharmaceutical compositions containing said compounds. EP 0021367 .
【2】 Robinson, C.P.; MUROCTASIN. Drugs Fut 1989, 14, 5, 432.
【3】 Shiba, T.; Kusumoto, S.; Tarumi, Y.; Ikenaka, K.; Chemical synthesis of N-acetylmuramyl peptides with partial structures of bacterial cell wall and their analogs in relation to immunoadjuvant activities. 1976, 49(2): 533-9. Bull Chem Soc Jpn 1976, 49, 2, 533.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VII)	20873	benzyl 2-([5-amino-4-[(2-aminopropanoyl)amino]-5-oxopentanoyl]amino)-6-[[(benzyloxy)carbonyl]amino]hexanoate	C₂₉H₃₉N₅O₇	详情	详情
(VIII)	20874	2-[[7-(acetamido)-6-(benzyloxy)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-8-yl]oxy]propionic acid	C₂₅H₂₉NO₈	详情	详情
(IX)	20875	benzyl 2-[[4-([2-[(2-[[7-(acetamido)-6-(benzyloxy)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-8-yl]oxy]propanoyl)amino]propanoyl]amino)-5-amino-5-oxopentanoyl]amino]-6-[[(benzyloxy)carbonyl]amino]hexanoate	C₅₄H₆₆N₆O₁₄	详情	详情
(X)	20876	benzyl 2-[[4-([2-[(2-[[3-(acetamido)-2-(benzyloxy)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]oxy]propanoyl)amino]propanoyl]amino)-5-amino-5-oxopentanoyl]amino]-6-[[(benzyloxy)carbonyl]amino]hexanoate	C₄₇H₆₂N₆O₁₄	详情	详情

合成路线3

Hydrogenation of (X) with H2 over Pd/C in acetic acid affords Nalpha-(N-acetylmuramoyl-L-alanyl-D-isoglutaminyl)-L-lysine (XI), which is finally condensed with N-hydroxynorbornene-2,3-dicarboxyimide ester of stearic acid (XII) by means of N-methylmorpholine in DMF.

参考文献中间体

【1】 Shiba, T.; Yamamura, Y.; Nagase, O.; Kotani, S.; Ogawa, H. (Daiichi Seiyaku Co.; Ltd.); Muramyldipeptide derivatives, process for preparing said compounds and pharmaceutical compositions containing said compounds. EP 0021367 .
【2】 Robinson, C.P.; MUROCTASIN. Drugs Fut 1989, 14, 5, 432.
【3】 Shiba, T.; Kusumoto, S.; Tarumi, Y.; Ikenaka, K.; Chemical synthesis of N-acetylmuramyl peptides with partial structures of bacterial cell wall and their analogs in relation to immunoadjuvant activities. 1976, 49(2): 533-9. Bull Chem Soc Jpn 1976, 49, 2, 533.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	28928	4-methylmorpholine	109-02-4	C₅H₁₁NO	详情	详情
(X)	20876	benzyl 2-[[4-([2-[(2-[[3-(acetamido)-2-(benzyloxy)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]oxy]propanoyl)amino]propanoyl]amino)-5-amino-5-oxopentanoyl]amino]-6-[[(benzyloxy)carbonyl]amino]hexanoate		C₄₇H₆₂N₆O₁₄	详情	详情
(XI)	20877	N(2)-[4-([2-[(2-[[3-(acetamido)-2,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]oxy]propanoyl)amino]propanoyl]amino)-5-amino-5-oxopentanoyl]lysine		C₂₅H₄₄N₆O₁₂	详情	详情
(XII)	20878	4-(stearoyloxy)-4-azatricyclo[5.2.1.0(2,6)]dec-2(6)-ene-3,5-dione		C₂₇H₄₃NO₄	详情	详情

Extended Information