LY-448212, -Drug Synthesis Database

【结构式】

【药物名称】LY-448212

【化学名称】N-3(R)-(Hydroxytetradecanoyl)-L-seryl-D-2,4-diaminobutyryl-3-(cyclopropylcarbamoyl)-L-alanyl-L-lysyl-L-2,4-diaminobutyryl-L-allothreonyl-(Z)-2,3-didehydro-2-aminobutyryl-3(S)-hydroxy-L-aspartyl-4-chloro-L-threonine C-1.9-O-3.1-lactone
　　　　　　3-(N-Cyclopropyl-L-asparagine)pseudomycin B

【CA登记号】319497-10-4

【分子式】C₅₄H₉₂ClN₁₃O₁₈

【分子量】1246.86464

【开发单位】Lilly (Originator)

【药理作用】Antifungal Agents, ANTIINFECTIVE THERAPY

合成路线1 合成路线2 合成路线3

合成路线1

The amino groups of pseudomycin B (I) were protected by treatment with N-(benzyloxycarbonyloxy)succinimide (II). The resulting pseudomycin B tribenzyl carbamate (III) was then coupled with cyclopropylamine (IV) by using TBTU to yield amide (V).

参考文献中间体

【1】 Sun, X.; Chen, S.-H.; Zhang, Y.-Z.; Current, W.L.; Rodriguez, M.; Sachs, R.K.; Gidda, J.; Zeckner, D.J.; Synthesis and antifungal activities of novel 3-amido bearing pseudomycin analogues. Bioorg Med Chem Lett 2001, 11, 7, 903.
【2】 Vasudevan, V.; Rodriguez, M.J.; Hellman, S.L.; Krstenansky, J.L.; Sun, X.D.; Chen, S.H.; Usyatinsky, A.Y.; Galka, C.S.; Zweifel, M.J. (Eli Lilly and Company); Pseudomycin amide and ester analogs. WO 0105817 .
【3】 Chen, S.H.; Sun, X.D.; Rodriguez, M.J. (Eli Lilly and Company); Pseudomycin prodrugs. WO 0105813 .

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)	50469	(2S)-2-((3S,6S,12S,15S,18S,21S,24R,27S)-18-(4-aminobutyl)-15,24-bis(2-aminoethyl)-21-(carboxymethyl)-3-[(1S)-2-chloro-1-hydroxyethyl]-9-[(Z)ethylidene]-12-[(1S)-1-hydroxyethyl]-27-[[(3R)-3-hydroxytetradecanoyl]amino]-2,5,8,11,14,17,20,23,26-nonaoxo-1-oxa-4,7,10,13,16,19,22,25-octaazacyclooctacosan-6-yl)-2-hydroxyethanoic acid		C₅₁H₈₇ClN₁₂O₁₉	详情	详情
(II)	30663	N-benzyloxycarbonyloxysuccinimide; 1-[[(Benzyloxy)carbonyl]oxy]-2,5-pyrrolidinedione	13139-17-8	C₁₂H₁₁NO₅	详情	详情
(III)	51197	(2S)-2-((3S,6S,12S,15S,18S,21S,24R,27S)-18-(4-[[(benzyloxy)carbonyl]amino]butyl)-15,24-bis(2-[[(benzyloxy)carbonyl]amino]ethyl)-21-(carboxymethyl)-3-[(1S)-2-chloro-1-hydroxyethyl]-9-[(Z)ethylidene]-12-[(1S)-1-hydroxyethyl]-27-[[(3R)-3-hydroxytetradecanoyl]amino]-2,5,8,11,14,17,20,23,26-nonaoxo-1-oxa-4,7,10,13,16,19,22,25-octaazacyclooctacosan-6-yl)-2-hydroxyethanoic acid		C₇₅H₁₀₅ClN₁₂O₂₅	详情	详情
(IV)	12263	Cyclopropylamine; Cyclopropanamine	765-30-0	C₃H₇N	详情	详情
(V)	51198	(2S)-2-((3S,6S,12S,15S,18S,21S,24R,27S)-18-(4-[[(benzyloxy)carbonyl]amino]butyl)-15,24-bis(2-[[(benzyloxy)carbonyl]amino]ethyl)-3-[(1S)-2-chloro-1-hydroxyethyl]-21-[2-(cyclopropylamino)-2-oxoethyl]-9-[(Z)ethylidene]-12-[(1S)-1-hydroxyethyl]-27-[[(3R)-3-hydroxytetradecanoyl]amino]-2,5,8,11,14,17,20,23,26-nonaoxo-1-oxa-4,7,10,13,16,19,22,25-octaazacyclooctacosan-6-yl)-2-hydroxyethanoic acid		C₇₈H₁₁₀ClN₁₃O₂₄	详情	详情

合成路线2

The N-benzyloxycarbonyl protecting groups of (V) were finally removed by catalytic hydrogenation over Pd/C.

参考文献中间体

【1】 Sun, X.; Chen, S.-H.; Zhang, Y.-Z.; Current, W.L.; Rodriguez, M.; Sachs, R.K.; Gidda, J.; Zeckner, D.J.; Synthesis and antifungal activities of novel 3-amido bearing pseudomycin analogues. Bioorg Med Chem Lett 2001, 11, 7, 903.
【2】 Chen, S.H.; Sun, X.D.; Rodriguez, M.J. (Eli Lilly and Company); Pseudomycin prodrugs. WO 0105813 .
【3】 Vasudevan, V.; Rodriguez, M.J.; Hellman, S.L.; Krstenansky, J.L.; Sun, X.D.; Chen, S.H.; Usyatinsky, A.Y.; Galka, C.S.; Zweifel, M.J. (Eli Lilly and Company); Pseudomycin amide and ester analogs. WO 0105817 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(V)	51198	(2S)-2-((3S,6S,12S,15S,18S,21S,24R,27S)-18-(4-[[(benzyloxy)carbonyl]amino]butyl)-15,24-bis(2-[[(benzyloxy)carbonyl]amino]ethyl)-3-[(1S)-2-chloro-1-hydroxyethyl]-21-[2-(cyclopropylamino)-2-oxoethyl]-9-[(Z)ethylidene]-12-[(1S)-1-hydroxyethyl]-27-[[(3R)-3-hydroxytetradecanoyl]amino]-2,5,8,11,14,17,20,23,26-nonaoxo-1-oxa-4,7,10,13,16,19,22,25-octaazacyclooctacosan-6-yl)-2-hydroxyethanoic acid		C₇₈H₁₁₀ClN₁₃O₂₄	详情	详情

合成路线3

In a closely related method, pseudomycin B (I) was protected as the corresponding allyl carbamate (VII) by treatment with diallyl pyrocarbonate (VI). After coupling of (VII) with cyclopropylamine (IV), the allyloxycarbonyl groups were deprotected by means of tributyltin hydride and palladium chloride.

参考文献中间体

【1】 Sun, X.; Chen, S.-H.; Zhang, Y.-Z.; Current, W.L.; Rodriguez, M.; Sachs, R.K.; Gidda, J.; Zeckner, D.J.; Synthesis and antifungal activities of novel 3-amido bearing pseudomycin analogues. Bioorg Med Chem Lett 2001, 11, 7, 903.
【2】 Chen, S.H.; Sun, X.D.; Rodriguez, M.J. (Eli Lilly and Company); Pseudomycin prodrugs. WO 0105813 .

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)	50469	(2S)-2-((3S,6S,12S,15S,18S,21S,24R,27S)-18-(4-aminobutyl)-15,24-bis(2-aminoethyl)-21-(carboxymethyl)-3-[(1S)-2-chloro-1-hydroxyethyl]-9-[(Z)ethylidene]-12-[(1S)-1-hydroxyethyl]-27-[[(3R)-3-hydroxytetradecanoyl]amino]-2,5,8,11,14,17,20,23,26-nonaoxo-1-oxa-4,7,10,13,16,19,22,25-octaazacyclooctacosan-6-yl)-2-hydroxyethanoic acid		C₅₁H₈₇ClN₁₂O₁₉	详情	详情
(IV)	12263	Cyclopropylamine; Cyclopropanamine	765-30-0	C₃H₇N	详情	详情
(VI)	51199			C₈H₁₀O₅	详情	详情
(VII)	51200	(2S)-2-((3S,6S,12S,15S,18S,21S,24R,27S)-18-(4-[[(allyloxy)carbonyl]amino]butyl)-15,24-bis(2-[[(allyloxy)carbonyl]amino]ethyl)-21-(carboxymethyl)-3-[(1S)-2-chloro-1-hydroxyethyl]-9-[(Z)ethylidene]-12-[(1S)-1-hydroxyethyl]-27-[[(3R)-3-hydroxytetradecanoyl]amino]-2,5,8,11,14,17,20,23,26-nonaoxo-1-oxa-4,7,10,13,16,19,22,25-octaazacyclooctacosan-6-yl)-2-hydroxyethanoic acid		C₆₃H₉₉ClN₁₂O₂₅	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)