-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】Cyclo[D-alanyl-L-tyrosyl-L-valyl-4(R)-hydroxy-L-prolyl-D-allothreonyl-L-threonyl-3(S)-hydroxy-L-prolyl-3(R)-hydroxy-L-glutaminylglycyl-D-allothreonyl-L-ornithyl-3(S)-aminohexadecanoyl-D-allothreonyl] hydrochloride

【CA登记号】289616-10-0

【分子式】C₇₁H₁₁₈ClN₁₅O₂₂

【分子量】1569.27241

【开发单位】Fujisawa (Originator)

【药理作用】Antifungal Agents, ANTIINFECTIVE THERAPY

合成路线1 合成路线2

合成路线1

Wittig reaction between aldehyde (I) and methyl(triphenylphosphoranylidene triphenyl)-acetate (II) in refluxing toluene provides E-olefin (III), which is then subjected to reaction with lithium derivative (IV) in THF to afford adduct (V). Benzyl groups of (V) are removed by hydrogenation over Pd(OH)2 in HOAc:MeOH:EtOAc to furnish amine (VI), which is then coupled to Z-Orn(Boc)-OH using 1-ethyl-3-dimethylaminopropylcarbodiimide (WSCD.HCl) and HOBt in CH2Cl2 to give beta-amino acid derivative (VIII). Saponification of the methyl ester group in (VIII) by means of LiOH, followed by condensation with HOBt by means of WSCD.HCl, yields activated ester (IX).

参考文献中间体

【1】 Hashimoto, S.; Hashimoto, M.; Tanaka, A.; Fujie, A.; Shigematsu, N.; Barrett, D.; An expedient synthesis of the amide analog of the potent antifungal lipopeptidolactone FR901469. Tetrahedron Lett 2001, 42, 4, 703.

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)	50186	Myristaldehyde; Myristyl aldehyde; Tetradecanal; Myristic aldehyde trimer; Tetradecyl aldehyde	124-25-4	C₁₄H₂₈O	详情	详情
(II)	14689	Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate	2605-67-6	C₂₁H₁₉O₂P	详情	详情
(III)	50187	methyl (E)-2-hexadecenoate		C₁₇H₃₂O₂	详情	详情
(IV)	30864	N-Benzyl-N-(1(R)-phenylethyl)amide lithium salt		C₁₅H₁₆LiN	详情	详情
(V)	50188	methyl (3R)-3-[benzyl[(1R)-1-phenylethyl]amino]hexadecanoate		C₃₂H₄₉NO₂	详情	详情
(VI)	50189	methyl (3R)-3-aminohexadecanoate		C₁₇H₃₅NO₂	详情	详情
(VII)	50190	(2S)-2-[[(benzyloxy)carbonyl]amino]-5-[(tert-butoxycarbonyl)amino]pentanoic acid		C₁₈H₂₆N₂O₆	详情	详情
(VIII)	50191	methyl (3R)-3-([(2S)-2-[[(benzyloxy)carbonyl]amino]-5-[(tert-butoxycarbonyl)amino]pentanoyl]amino)hexadecanoate		C₃₅H₅₉N₃O₇	详情	详情
(IX)	50192	tert-butyl (4S)-5-([(1R)-1-[2-(1H-1,2,3-benzotriazol-1-yloxy)-2-oxoethyl]tetradecyl]amino)-4-[[(benzyloxy)carbonyl]amino]-5-oxopentylcarbamate		C₄₀H₆₀N₆O₇	详情	详情

合成路线2

Natural peptide FR901469 (X) is incubated with Actinoplanes utahensis IFO-13244 in PBS to afford linear peptide (XI), which is then converted into precursor (XII) by coupling with activated intermediate (IX) by means of DIEA in DMF followed by removal of the Z protecting group by hydrogenation over Pd/C. Finally, the target product is obtained by macrocyclization of (XII) by means of HOBt and WSCD.HCl followed by Boc removal with neat TFA.

参考文献中间体

【1】 Hashimoto, S.; Hashimoto, M.; Tanaka, A.; Fujie, A.; Shigematsu, N.; Barrett, D.; An expedient synthesis of the amide analog of the potent antifungal lipopeptidolactone FR901469. Tetrahedron Lett 2001, 42, 4, 703.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(IX)	50192	tert-butyl (4S)-5-([(1R)-1-[2-(1H-1,2,3-benzotriazol-1-yloxy)-2-oxoethyl]tetradecyl]amino)-4-[[(benzyloxy)carbonyl]amino]-5-oxopentylcarbamate	C₄₀H₆₀N₆O₇	详情	详情
(X)	50193	(3R)-3-[(2R,6S,9S,12R,15R,19R,22S,25R,31S,33aS,34S,39S,42R,44aS)-22-(3-aminopropyl)-2,34-dihydroxy-9-(4-hydroxybenzyl)-15,25,39,42-tetrakis[(1R)-1-hydroxyethyl]-6-isopropyl-12-methyl-5,8,11,14,17,21,24,27,30,33,38,41,44-tridecaoxo-19-tridecylnonatriacontahydro-1H,5H,21H-dipyrrolo[2,1-o:2,1-x][1,4,7,10,13,16,19,22,25,28,31,34,37]oxadodecaazacyclotetracontin-31-yl]-3-hydroxypropanamide	C₇₁H₁₁₆N₁₄O₂₃	详情	详情
(XI)	50194	(2R,3R)-2-[(2-[[(2S,3R)-5-amino-2-([[(2S,3S)-1-((2S,3R)-2-[[(2R,3R)-2-([[(2S,4R)-1-((2S)-2-[[(2S)-2-[((2R)-2-[[(2R,3R)-2-amino-3-hydroxybutanoyl]amino]propanoyl)amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-methylbutanoyl)-4-hydroxypyrrolidinyl]carbonyl]amino)-3-hydroxybutanoyl]amino]-3-hydroxybutanoyl)-3-hydroxypyrrolidinyl]carbonyl]amino)-3-hydroxy-5-oxopentanoyl]amino]acetyl)amino]-3-hydroxybutyric acid	C₅₀H₇₈N₁₂O₂₁	详情	详情
(XII)	50195		C₇₆H₁₂₇N₁₅O₂₅	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)