Glaspimod, HP-5 dimer, SK&F-107647, -Drug Synthesis Database

【结构式】

【药物名称】Glaspimod, HP-5 dimer, SK&F-107647

【化学名称】(2S,7S)-N2,N2'-[2,7-Bis(pyroglutamyl-glutamyl-aspartylamino)octanedioyl]bis(lysine)

【CA登记号】134143-28-5

【分子式】C₄₈H₇₄N₁₂O₂₂

【分子量】1171.19218

【开发单位】Amersham Health (Originator), GlaxoSmithKline (Originator)

【药理作用】HEMATOLOGIC DRUGS, Hematopoiesis Disorders Therapy, Hematopoietic Agents, IMMUNOMODULATING AGENTS, Immunomodulators

合成路线1 合成路线2 合成路线3

合成路线1

The Kolbe electrolysis of N-(tert-butoxycarbonyl)-L-glutamic acid 1-O-benzyl ester (I) gives 2(S),7(S)-bis(tert-butoxycarbonylamino)octanedioic acid dibenzyl ester (II), which is debenzylated with H2 over Pd/C in methanol yielding the free acid (III). The condensation of diacid (III) with N6-(benzyloxycarbonyl)-L-lysine benzyl ester (IV) affords the tripeptide (V), which is then treated with HCl in dioxane to eliminate the carbamate protecting groups so providing intermediate (VI).

参考文献中间体

【1】 Hiebl, J.; et al.; Large-scale synthesis of hematoregulatory nonapeptide SK&F 107647 by fragment coupling. J Pept Res 1999, 54, 1, 54.

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)	10136	(4R)-5-(Benzyloxy)-4-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid; N-t-BOC-D-glutamic acid alpha-benzyl ester	34404-30-3	C₁₇H₂₃NO₆	详情	详情
(II)	32394	dibenzyl (2S,7S)-2,7-bis[(tert-butoxycarbonyl)amino]octanedioate		C₃₂H₄₄N₂O₈	详情	详情
(III)	32395	(2S,7S)-2,7-bis[(tert-butoxycarbonyl)amino]octanedioic acid		C₁₈H₃₂N₂O₈	详情	详情
(IV)	32396	benzyl (2S)-2-amino-6-[[(benzyloxy)carbonyl]amino]hexanoate		C₂₁H₂₆N₂O₄	详情	详情
(V)	32397	dibenzyl (9S,12S,17S,20S)-12,17-bis[(tert-butoxycarbonyl)amino]-3,11,18,26-tetraoxo-1,28-diphenyl-2,27-dioxa-4,10,19,25-tetraazaoctacosane-9,20-dicarboxylate		C₆₀H₈₀N₆O₁₄	详情	详情
(VI)	32398	dibenzyl (9S,12S,17S,20S)-12,17-diamino-3,11,18,26-tetraoxo-1,28-diphenyl-2,27-dioxa-4,10,19,25-tetraazaoctacosane-9,20-dicarboxylate		C₅₀H₆₄N₆O₁₀	详情	详情

合成路线2

The esterification of N-(benzyloxycarbonyl)-L-aspartic acid 4-O-benzyl monoester (VII) with 2-(p-toluenesulfonyl)ethanol by means of DCC and pyridine gives the mixed diester (VIII), which is deprotected at the amino group with HCl in dioxane yielding compound (IX). The condensation of (IX) with protected glutamic acid (X) by means of HOBt, DIEA and WSC carbodiimide affords dipeptide (XI), which is deprotected with HCl as before giving (XII). The condensation of (XII) with pyroglutamic acid (XIII) as before yields tripeptide (XIV), which is deprotected at the terminal carboxy group by means of diazabicyclo[4.3.0]non-5-ene (DBN) providing tripeptide (XV).

参考文献中间体

【1】 Hiebl, J.; et al.; Large-scale synthesis of hematoregulatory nonapeptide SK&F 107647 by fragment coupling. J Pept Res 1999, 54, 1, 54.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	40676	2-[(4-Methylphenyl)sulfonyl]ethanol; 2-[(4-methylphenyl)sulfonyl]-1-ethanol	22381-54-0	C₉H₁₂O₃S	详情	详情
(VII)	25219	(2S)-4-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-4-oxobutyric acid	7536-58-5	C₁₆H₂₁NO₆	详情	详情
(VIII)	32399	4-benzyl 1-[2-[(4-methylphenyl)sulfonyl]ethyl] (2S)-2-[(tert-butoxycarbonyl)amino]butanedioate		C₂₅H₃₁NO₈S	详情	详情
(IX)	32400	4-benzyl 1-[2-[(4-methylphenyl)sulfonyl]ethyl] (2S)-2-aminobutanedioate		C₂₀H₂₃NO₆S	详情	详情
(X)	25141	(2S)-5-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid	13574-13-5	C₁₇H₂₃NO₆	详情	详情
(XI)	32401	4-benzyl 1-[2-[(4-methylphenyl)sulfonyl]ethyl] (2S)-2-([(2S)-5-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoyl]amino)butanedioate		C₃₇H₄₄N₂O₁₁S	详情	详情
(XII)	32402	4-benzyl 1-[2-[(4-methylphenyl)sulfonyl]ethyl] (2S)-2-[[(2S)-2-amino-5-(benzyloxy)-5-oxopentanoyl]amino]butanedioate		C₃₂H₃₆N₂O₉S	详情	详情
(XIII)	32406	(2S)-5-oxo-2-pyrrolidinecarboxylic acid	98-79-3	C₅H₇NO₃	详情	详情
(XIV)	32403	4-benzyl 1-[2-[(4-methylphenyl)sulfonyl]ethyl] (2S)-2-[[(2S)-5-(benzyloxy)-5-oxo-2-([[(2S)-5-oxopyrrolidinyl]carbonyl]amino)pentanoyl]amino]butanedioate		C₃₇H₄₁N₃O₁₁S	详情	详情
(XV)	32404	(2S)-4-(benzyloxy)-2-[[(2S)-5-(benzyloxy)-5-oxo-2-([[(2S)-5-oxopyrrolidinyl]carbonyl]amino)pentanoyl]amino]-4-oxobutyric acid		C₂₈H₃₁N₃O₉	详情	详情

合成路线3

The condensation of tripeptide (XV) with intermediate tripeptide (VI) by means of TDBTU and DIEA in DMF gives the fully benzylated target compound, which is finally deprotected with H2 over Pd/C in DMF/AcOH.

参考文献中间体

【1】 Hiebl, J.; et al.; Large-scale synthesis of hematoregulatory nonapeptide SK&F 107647 by fragment coupling. J Pept Res 1999, 54, 1, 54.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VI)	32398	dibenzyl (9S,12S,17S,20S)-12,17-diamino-3,11,18,26-tetraoxo-1,28-diphenyl-2,27-dioxa-4,10,19,25-tetraazaoctacosane-9,20-dicarboxylate	C₅₀H₆₄N₆O₁₀	详情	详情
(XV)	32404	(2S)-4-(benzyloxy)-2-[[(2S)-5-(benzyloxy)-5-oxo-2-([[(2S)-5-oxopyrrolidinyl]carbonyl]amino)pentanoyl]amino]-4-oxobutyric acid	C₂₈H₃₁N₃O₉	详情	详情
(XVI)	32405	dibenzyl (4S,7S,10S,15S,18S,21S)-10,15-bis{[((1S)-1-[(benzyloxy)carbonyl]-5-{[(benzyloxy)carbonyl]amino}pentyl)amino]carbonyl}-7,18-bis[2-(benzyloxy)-2-oxoethyl]-5,8,17,20-tetraoxo-4,21-bis({[(2S)-5-oxopyrrolidinyl]carbonyl}amino)-6,9,16,19-tetraazatetracosane-1,24-dioate	C₁₀₆H₁₂₂N₁₂O₂₆	详情	详情

Extended Information