Acyline, -Drug Synthesis Database

【结构式】

【药物名称】Acyline

【化学名称】Acetyl-2-naphthyl-D-alanyl-4-chloro-D-phenylalanyl-3-pyridyl-D-alanyl-L-seryl-4-acetamido-L-phenylalanyl-4-acetamido-D-phenylalanyl-L-leucyl-Nepsilon-isopropyl-L-lysyl-L-prolyl-D-alaninamide

【CA登记号】170157-13-8

【分子式】C₈₀H₁₀₂ClN₁₅O₁₄

【分子量】1533.25004

【开发单位】Salk Institute for Biological Studies (Originator), University of Washington (Originator)

【药理作用】Disorders of Sexual Function and Reproduction, Treatment of, ENDOCRINE DRUGS, Endometriosis Therapy, Female Infertility, Agents for, Gynecological Disorders, Treatment of , Hirsutism Therapy, GnRH (LHRH) Antagonists

合成路线1 合成路线2 合成路线3

合成路线1

The title compound was obtained by solid-phase peptide synthesis using a methylbenzhydrylamine resin. After attachment of N-Boc-D-alanine (I) to the resin by means of diisopropylcarbodiimide (DIC), the N-Boc protecting group was cleaved by treatment with a solution of trifluoroacetic in CH2Cl2 in the presence of 1,2-ethanedithiol, yielding the alanine-bound resin (II). To this were sequentially coupled the appropriate protected amino acids using DIC, each followed by the Boc group cleavage with trifluoroacetic acid. Coupling/deprotection cycles with N-Boc-L-proline (III), N-alpha-Boc-N-epsilon-benzyloxycarbonyl-N-epsilon-isopropyl-L-lysine (V), N-Boc-L-leucine (VII), N-alpha-Boc-N-4-Fmoc-L-4-aminophenylalanine (IX), N-alpha-Boc-N-4-Fmoc-D-4-aminophenylalanine (XI) and N-Boc-O-benzyl-L-serine (XIII), furnished the peptide resins (IV), (VI), (VIII), (X), (XII) and (XIV).

参考文献中间体

【1】 Rivier, J.E.; et al.; Gonadotropin-releasing hormone antagonists: Novel members of the azaline B family. J Med Chem 1995, 38, 14, 2649.
【2】 Rivier, J.E.F.; Porter, J.S.; Hoeger, C.A.; Jiang, G.; Rivier, C.L. (The Salk Institute for Biological Studies); GnRH antagonists. EP 0804471; JP 1998500397; US 5506207; WO 9525741 .

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)	15889	Ethyl 2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate;(Z)-ethyl 2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetate； ethyl 2-(2-amino-1,3-thiazol-4-yl)-2-(hydroxyimino)acetate	60845-81-0	C₇H₉N₃O₃S	详情	详情
(II)	46571	(1R,2R,3aS,9aS)-1-[(3S)-3-hydroxyoctyl]-5-methoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-ol		C₂₂H₃₄O₃	详情	详情
(III)	16734	(2S)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-L-proline; (2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid		C₁₀H₁₇NO₄	详情	详情
(IV)	46743	(2S)-N-[(1R)-2-amino-1-methyl-2-oxoethyl]-2-pyrrolidinecarboxamide		C₈H₁₅N₃O₂	详情	详情
(V)	46752	(2S)-6-[[(benzyloxy)carbonyl](isopropyl)amino]-2-[(tert-butoxycarbonyl)amino]hexanoic acid	125323-99-1	C₂₂H₃₄N₂O₆	详情	详情
(VI)	46744	benzyl (5S)-5-amino-6-[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]-6-oxohexyl(isopropyl)carbamate		C₂₅H₃₉N₅O₅	详情	详情
(VII)	23663	(2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine		C₁₁H₂₁NO₄	详情	详情
(VIII)	46745	benzyl (5S)-6-[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]-5-[[(2S)-2-amino-4-methylpentanoyl]amino]-6-oxohexyl(isopropyl)carbamate		C₃₁H₅₀N₆O₆	详情	详情
(IX)	46746	(2R)-2-[(tert-butoxycarbonyl)amino]-3-(4-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]phenyl)propionic acid	173054-11-0	C₂₉H₃₀N₂O₆	详情	详情
(X)	51379	9H-fluoren-9-ylmethyl 4-((2R,5S,8S)-2-amino-8-[[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]carbonyl]-5-isobutyl-13-isopropyl-3,6,14-trioxo-16-phenyl-15-oxa-4,7,13-triazahexadec-1-yl)phenylcarbamate		C₅₅H₇₀N₈O₉	详情	详情
(XI)	51387	(2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]phenyl)propionic acid		C₂₉H₃₀N₂O₆	详情	详情
(XII)	51380	9H-fluoren-9-ylmethyl 4-[(2S,5R,8S,11S)-2-amino-11-[[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]carbonyl]-5-(4-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]benzyl)-8-isobutyl-16-isopropyl-3,6,9,17-tetraoxo-19-phenyl-18-oxa-4,7,10,16-tetraazanonadec-1-yl]phenylcarbamate		C₇₉H₉₀N₁₀O₁₂	详情	详情
(XIII)	16886	(2S)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propionic acid; N-alpha-t-BOC-o-benzyl-L-serine	23680-31-1	C₁₅H₂₁NO₅	详情	详情
(XIV)	51381	benzyl (5S,8S,11R,14S,17S)-17-amino-5-[[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]carbonyl]-11,14-bis(4-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]benzyl)-8-isobutyl-7,10,13,16-tetraoxo-20-phenyl-19-oxa-6,9,12,15-tetraazaicos-1-yl(isopropyl)carbamate		C₈₉H₁₀₁N₁₁O₁₄	详情	详情

合成路线2

Coupling/deprotection cycles with N-Boc-D-(3-pyridyl)alanine (XV), N-Boc-D-4-chlorophenylalanine (XVII) and N-Boc-D-(2-naphthyl)alanine (XIX) furnished the peptide resins (XVI), (XVIII) and (XX).

参考文献中间体

【1】 Rivier, J.E.; et al.; Gonadotropin-releasing hormone antagonists: Novel members of the azaline B family. J Med Chem 1995, 38, 14, 2649.
【2】 Rivier, J.E.F.; Porter, J.S.; Hoeger, C.A.; Jiang, G.; Rivier, C.L. (The Salk Institute for Biological Studies); GnRH antagonists. EP 0804471; JP 1998500397; US 5506207; WO 9525741 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XIV)	51381	benzyl (5S,8S,11R,14S,17S)-17-amino-5-[[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]carbonyl]-11,14-bis(4-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]benzyl)-8-isobutyl-7,10,13,16-tetraoxo-20-phenyl-19-oxa-6,9,12,15-tetraazaicos-1-yl(isopropyl)carbamate	C₈₉H₁₀₁N₁₁O₁₄	详情	详情
(XV)	23494	(2R)-2-[(tert-butoxycarbonyl)amino]-3-(3-pyridinyl)propionic acid	C₁₃H₁₈N₂O₄	详情	详情
(XVI)	51382	benzyl (5S,8S,11R,14S,17S,20R)-20-amino-5-[[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]carbonyl]-17-[(benzyloxy)methyl]-11,14-bis(4-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]benzyl)-8-isobutyl-7,10,13,16,19-pentaoxo-21-(3-pyridinyl)-6,9,12,15,18-pentaazahenicos-1-yl(isopropyl)carbamate	C₉₇H₁₀₉N₁₃O₁₅	详情	详情
(XVII)	23496	(2R)-2-[(tert-butoxycarbonyl)amino]-3-(4-chlorophenyl)propionic acid	C₁₄H₁₈ClNO₄	详情	详情
(XVIII)	51583	4-(2-ethyl-5-nitro-2,3-dihydro-1H-inden-2-yl)-1H-imidazole	C₁₄H₁₅N₃O₂	详情	详情
(XIX)	23498	(2R)-2-[(tert-butoxycarbonyl)amino]-3-(2-naphthyl)propionic acid	C₁₈H₂₁NO₄	详情	详情
(XX)	51384	benzyl (5S,8S,11R,14S,17S,20R,23R,26R)-26-amino-5-[[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]carbonyl]-17-[(benzyloxy)methyl]-23-(4-chlorobenzyl)-11,14-bis(4-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]benzyl)-8-isobutyl-27-(2-naphthyl)-7,10,13,16,19,22,25-heptaoxo-20-(3-pyridinylmethyl)-6,9,12,15,18,21,24-heptaazaheptacos-1-yl(isopropyl)carbamate	C₁₁₉H₁₂₈ClN₁₅O₁₇	详情	详情

合成路线3

The side-chain Fmoc protecting groups of (XX) were then cleaved by treatment with piperidine in DMF, and the resulting compound (XXI) was acetylated with acetic anhydride to give (XXII). Finally, removal of the remaining protecting groups and cleavage from the resin was achieved by treatment with liquid HF and anisole.

参考文献中间体

【1】 Rivier, J.E.; et al.; Gonadotropin-releasing hormone antagonists: Novel members of the azaline B family. J Med Chem 1995, 38, 14, 2649.
【2】 Rivier, J.E.F.; Porter, J.S.; Hoeger, C.A.; Jiang, G.; Rivier, C.L. (The Salk Institute for Biological Studies); GnRH antagonists. EP 0804471; JP 1998500397; US 5506207; WO 9525741 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XX)	51384	benzyl (5S,8S,11R,14S,17S,20R,23R,26R)-26-amino-5-[[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]carbonyl]-17-[(benzyloxy)methyl]-23-(4-chlorobenzyl)-11,14-bis(4-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]benzyl)-8-isobutyl-27-(2-naphthyl)-7,10,13,16,19,22,25-heptaoxo-20-(3-pyridinylmethyl)-6,9,12,15,18,21,24-heptaazaheptacos-1-yl(isopropyl)carbamate	C₁₁₉H₁₂₈ClN₁₅O₁₇	详情	详情
(XXI)	51385	benzyl (5S,8S,11R,14S,17S,20R,23R,26R)-26-amino-11,14-bis(4-aminobenzyl)-5-[[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]carbonyl]-17-[(benzyloxy)methyl]-23-(4-chlorobenzyl)-8-isobutyl-27-(2-naphthyl)-7,10,13,16,19,22,25-heptaoxo-20-(3-pyridinylmethyl)-6,9,12,15,18,21,24-heptaazaheptacos-1-yl(isopropyl)carbamate	C₈₉H₁₀₈ClN₁₅O₁₃	详情	详情
(XXII)	51386	benzyl (5S,8S,11R,14S,17S,20R,23R,26R)-11,14-bis[4-(acetamido)benzyl]-5-[[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]carbonyl]-17-[(benzyloxy)methyl]-23-(4-chlorobenzyl)-8-isobutyl-26-(2-naphthylmethyl)-7,10,13,16,19,22,25,28-octaoxo-20-(3-pyridinylmethyl)-6,9,12,15,18,21,24,27-octaazanonacos-1-yl(isopropyl)carbamate	C₉₅H₁₁₄ClN₁₅O₁₆	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1) FDA Approved Drug Products(1)