Degarelix acetate, FE-200486, -Drug Synthesis Database

【结构式】

【药物名称】Degarelix acetate, FE-200486

【化学名称】N-Acetyl-3-(2-naphthyl)-D-alanyl-4-chloro-D-phenylalanyl-3-(3-pyridyl)-D-alanyl-L-seryl-4-[2,6-dioxohexahydropyrimidin-4(S)-ylcarboxamido]-L-phenylalanyl-4-ureido-D-phenylalanyl-L-leucyl-N6-isopropyl-L-lysyl-L-prolyl-D-alaninamide acetate

【CA登记号】214766-78-6 (free base)

【分子式】C₈₄H₁₀₇ClN₁₈O₁₈

【分子量】1692.35219

【开发单位】Ferring (Originator)

【药理作用】Oncolytic Drugs, Prostate Cancer Therapy, GnRH (LHRH) Antagonists

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5

合成路线1

N-Boc-D-alanine (I) was coupled to the resin using diisopropyl carbodiimide and 1-hydroxybenzotriazole to afford resin (II). Subsequent cleavage of the Boc protecting group by means of trifluoroacetic acid provided the D-alanine-bound resin (III). Sequential coupling and deprotection cycles were carried out with the following protected amino acids: N-Boc-L-proline (IV), N-alpha-Boc-N6-isopropyl-N6-carbobenzoxy-L-lysine (VI) and N-Boc-L-leucine (VIII) to afford the respective peptide resins (V), (VII) and (IX). N-alpha-Boc-D-4-(Fmoc-amino)phenylalanine (X) was coupled to (IX), yielding resin (XI). Cleavage of the side-chain Fmoc protecting group with piperidine in DMF gave the aniline derivative (XII). After conversion to the corresponding urea by treatment with tert-butyl isocyanate, the Boc group was cleaved with trifluoroacetic acid to produce resin (XIII).

参考文献中间体

【1】 Stalewski, J.; Galyean, R.; Jiang, G.; et al.; GnRH antagonists: A new generation of long acting analogues incorporating p-ureido-phenylalanines at positions 5 and 6. J Med Chem 2001, 44, 3, 453.
【2】 Jiang, G.; Semple, G. (Ferring BV Group Holding); GnRH antagonists being modified in positions 5 and 6. WO 9846634 .

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)	15859	Boc-D-Alanine; (2R)-2-[(tert-butoxycarbonyl)amino]propionic acid	7764-95-6	C₈H₁₅NO₄	详情	详情
(II)	46750	tert-butyl (1R)-2-amino-1-methyl-2-oxoethylcarbamate		C₈H₁₆N₂O₃	详情	详情
(III)	46751	(2R)-2-aminopropanamide		C₃H₈N₂O	详情	详情
(IV)	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
(V)	46743	(2S)-N-[(1R)-2-amino-1-methyl-2-oxoethyl]-2-pyrrolidinecarboxamide		C₈H₁₅N₃O₂	详情	详情
(VI)	46752	(2S)-6-[[(benzyloxy)carbonyl](isopropyl)amino]-2-[(tert-butoxycarbonyl)amino]hexanoic acid	125323-99-1	C₂₂H₃₄N₂O₆	详情	详情
(VII)	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
(VIII)	23663	(2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine		C₁₁H₂₁NO₄	详情	详情
(IX)	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
(X)	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
(XI)	46747	9H-fluoren-9-ylmethyl 4-[(2R,5S,8S)-8-[[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]carbonyl]-2-[(tert-butoxycarbonyl)amino]-5-isobutyl-13-isopropyl-3,6,14-trioxo-16-phenyl-15-oxa-4,7,13-triazahexadec-1-yl]phenylcarbamate		C₆₀H₇₈N₈O₁₁	详情	详情
(XII)	46748	benzyl (5S,8S,11R)-11-(4-aminobenzyl)-5-[[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]carbonyl]-8-isobutyl-15,15-dimethyl-7,10,13-trioxo-14-oxa-6,9,12-triazahexadec-1-yl(isopropyl)carbamate		C₄₅H₆₈N₈O₉	详情	详情
(XIII)	46749	benzyl (5S)-5-[((2S)-2-[[(2R)-2-amino-3-(4-[[(tert-butylamino)carbonyl]amino]phenyl)propanoyl]amino]-4-methylpentanoyl)amino]-6-[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]-6-oxohexyl(isopropyl)carbamate		C₄₅H₆₉N₉O₈	详情	详情

合成路线2

Further coupling with N-alpha-Boc-L-4-(Fmoc-amino)phenylalanine (XIV), followed by Fmoc deprotection with piperidine, furnished (XV). The aniline derivative (XV) was acylated with L-hydroorotic acid (XVI) to yield, after Boc group cleavage, resin (XVII). Coupling of (XVII) with N-Boc-L-serine(O-benzyl) (XVIII) and subsequent deprotection gave (XIX).

参考文献中间体

【1】 Stalewski, J.; Galyean, R.; Jiang, G.; et al.; GnRH antagonists: A new generation of long acting analogues incorporating p-ureido-phenylalanines at positions 5 and 6. J Med Chem 2001, 44, 3, 453.
【2】 Jiang, G.; Semple, G. (Ferring BV Group Holding); GnRH antagonists being modified in positions 5 and 6. WO 9846634 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XVIIII)	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
(XIII)	46749	benzyl (5S)-5-[((2S)-2-[[(2R)-2-amino-3-(4-[[(tert-butylamino)carbonyl]amino]phenyl)propanoyl]amino]-4-methylpentanoyl)amino]-6-[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]-6-oxohexyl(isopropyl)carbamate		C₄₅H₆₉N₉O₈	详情	详情
(XIV)	46753	(2S)-3-(4-aminophenyl)-2-[(tert-butoxycarbonyl)amino]propionic acid	55533-24-9	C₁₄H₂₀N₂O₄	详情	详情
(XV)	46754	benzyl (5S,8S,11R,14S)-14-(4-aminobenzyl)-5-[[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]carbonyl]-11-(4-[[(tert-butylamino)carbonyl]amino]benzyl)-8-isobutyl-18,18-dimethyl-7,10,13,16-tetraoxo-17-oxa-6,9,12,15-tetraazanonadec-1-yl(isopropyl)carbamate		C₅₉H₈₇N₁₁O₁₁	详情	详情
(XVI)	46755	(4R)-2,6-dioxohexahydro-4-pyrimidinecarboxylic acid		C₅H₆N₂O₄	详情	详情
(XVII)	46756	benzyl (5S)-5-[((2S)-2-[[(2R)-2-([(2S)-2-amino-3-[4-([[(4R)-2,6-dioxohexahydro-4-pyrimidinyl]carbonyl]amino)phenyl]propanoyl]amino)-3-(4-[[(tert-butylamino)carbonyl]amino]phenyl)propanoyl]amino]-4-methylpentanoyl)amino]-6-[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]-6-oxohexyl(isopropyl)carbamate		C₅₉H₈₃N₁₃O₁₂	详情	详情
(XIX)	46757	benzyl (5S,8S,11R,14S,17S)-17-amino-5-[[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]carbonyl]-11-(4-[[(tert-butylamino)carbonyl]amino]benzyl)-14-[4-([[(4R)-2,6-dioxohexahydro-4-pyrimidinyl]carbonyl]amino)benzyl]-8-isobutyl-7,10,13,16-tetraoxo-20-phenyl-19-oxa-6,9,12,15-tetraazaicos-1-yl(isopropyl)carbamate		C₆₉H₉₄N₁₄O₁₄	详情	详情

合成路线3

Peptide (XIX) was sequentially coupled with N-alpha-Boc-D-(3-pyridyl)alanine (XX) and N-Boc-D-(4-chlorophenyl)alanine (XXII) to furnish, after the corresponding deprotection cycles with TFA, the resins (XXI) and (XXIII), respectively.

参考文献中间体

【1】 Stalewski, J.; Galyean, R.; Jiang, G.; et al.; GnRH antagonists: A new generation of long acting analogues incorporating p-ureido-phenylalanines at positions 5 and 6. J Med Chem 2001, 44, 3, 453.
【2】 Jiang, G.; Semple, G. (Ferring BV Group Holding); GnRH antagonists being modified in positions 5 and 6. WO 9846634 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XIX)	46757	benzyl (5S,8S,11R,14S,17S)-17-amino-5-[[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]carbonyl]-11-(4-[[(tert-butylamino)carbonyl]amino]benzyl)-14-[4-([[(4R)-2,6-dioxohexahydro-4-pyrimidinyl]carbonyl]amino)benzyl]-8-isobutyl-7,10,13,16-tetraoxo-20-phenyl-19-oxa-6,9,12,15-tetraazaicos-1-yl(isopropyl)carbamate	C₆₉H₉₄N₁₄O₁₄	详情	详情
(XX)	23494	(2R)-2-[(tert-butoxycarbonyl)amino]-3-(3-pyridinyl)propionic acid	C₁₃H₁₈N₂O₄	详情	详情
(XXI)	46760	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-(4-[[(tert-butylamino)carbonyl]amino]benzyl)-14-[4-([[(4R)-2,6-dioxohexahydro-4-pyrimidinyl]carbonyl]amino)benzyl]-8-isobutyl-7,10,13,16,19-pentaoxo-21-(3-pyridinyl)-6,9,12,15,18-pentaazahenicos-1-yl(isopropyl)carbamate	C₇₇H₁₀₂N₁₆O₁₅	详情	详情
(XXII)	23496	(2R)-2-[(tert-butoxycarbonyl)amino]-3-(4-chlorophenyl)propionic acid	C₁₄H₁₈ClNO₄	详情	详情
(XXIII)	46759	benzyl (5S,8S,11R,14S,17S,20R,23R)-23-amino-5-[[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]carbonyl]-17-[(benzyloxy)methyl]-11-(4-[[(tert-butylamino)carbonyl]amino]benzyl)-24-(4-chlorophenyl)-14-[4-([[(4R)-2,6-dioxohexahydro-4-pyrimidinyl]carbonyl]amino)benzyl]-8-isobutyl-7,10,13,16,19,22-hexaoxo-20-(3-pyridinylmethyl)-6,9,12,15,18,21-hexaazatetracos-1-yl(isopropyl)carbamate	C₈₆H₁₁₀ClN₁₇O₁₆	详情	详情

合成路线4

The coupling of resin (XXIII) with N-Boc-D-(2-naphthyl)alanine (XXIV) as before gave, after the corresponding deprotection cycle with trifluoroacetic acid, resin (XXV). The peptide resin (XXV) was acetylated with Ac2O and finally deprotected and cleaved from the resin by treatment with HF to provide the target peptide.

参考文献中间体

【1】 Stalewski, J.; Galyean, R.; Jiang, G.; et al.; GnRH antagonists: A new generation of long acting analogues incorporating p-ureido-phenylalanines at positions 5 and 6. J Med Chem 2001, 44, 3, 453.
【2】 Jiang, G.; Semple, G. (Ferring BV Group Holding); GnRH antagonists being modified in positions 5 and 6. WO 9846634 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XXIII)	46759	benzyl (5S,8S,11R,14S,17S,20R,23R)-23-amino-5-[[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]carbonyl]-17-[(benzyloxy)methyl]-11-(4-[[(tert-butylamino)carbonyl]amino]benzyl)-24-(4-chlorophenyl)-14-[4-([[(4R)-2,6-dioxohexahydro-4-pyrimidinyl]carbonyl]amino)benzyl]-8-isobutyl-7,10,13,16,19,22-hexaoxo-20-(3-pyridinylmethyl)-6,9,12,15,18,21-hexaazatetracos-1-yl(isopropyl)carbamate	C₈₆H₁₁₀ClN₁₇O₁₆	详情	详情
(XXIV)	23498	(2R)-2-[(tert-butoxycarbonyl)amino]-3-(2-naphthyl)propionic acid	C₁₈H₂₁NO₄	详情	详情
(XXV)	46758	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]-11-(4-[[(tert-butylamino)carbonyl]amino]benzyl)-23-(4-chlorobenzyl)-14-[4-([[(4R)-2,6-dioxohexahydro-4-pyrimidinyl]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	C₉₉H₁₂₁ClN₁₈O₁₇	详情	详情

合成路线5

Alternatively, after coupling of the peptide resin (XIII) with alpha-Boc-L-4-(Fmoc-amino)phenylalanine (XIV), the Fmoc protecting group was not removed, yielding resin (XXVI). Subsequent coupling cycles with amino acids (XVIII), (XX), (XXII) and (XXIV) as above finally produced resin (XXVII). The Fmoc group was then deprotected by treatment with piperidine, and the resulting aniline was acylated with L-hydroorotic acid (XVI) to provide resin (XXVIII), which was finally cleaved and deprotected by treatment with HF.

参考文献中间体

【1】 Stalewski, J.; Galyean, R.; Jiang, G.; et al.; GnRH antagonists: A new generation of long acting analogues incorporating p-ureido-phenylalanines at positions 5 and 6. J Med Chem 2001, 44, 3, 453.
【2】 Jiang, G.; Semple, G. (Ferring BV Group Holding); GnRH antagonists being modified in positions 5 and 6. WO 9846634 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIII)	46749	benzyl (5S)-5-[((2S)-2-[[(2R)-2-amino-3-(4-[[(tert-butylamino)carbonyl]amino]phenyl)propanoyl]amino]-4-methylpentanoyl)amino]-6-[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]-6-oxohexyl(isopropyl)carbamate		C₄₅H₆₉N₉O₈	详情	详情
(XIV)	46753	(2S)-3-(4-aminophenyl)-2-[(tert-butoxycarbonyl)amino]propionic acid	55533-24-9	C₁₄H₂₀N₂O₄	详情	详情
(XVI)	46755	(4R)-2,6-dioxohexahydro-4-pyrimidinecarboxylic acid		C₅H₆N₂O₄	详情	详情
(XXVI)	46761	9H-fluoren-9-ylmethyl 4-[(2S,5R,8S,11S)-11-[[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]carbonyl]-2-[(tert-butoxycarbonyl)amino]-5-(4-[[(tert-butylamino)carbonyl]amino]benzyl)-8-isobutyl-16-isopropyl-3,6,9,17-tetraoxo-19-phenyl-18-oxa-4,7,10,16-tetraazanonadec-1-yl]phenylcarbamate		C₇₄H₉₇N₁₁O₁₃	详情	详情
(XXVII)	46762	benzyl (5S,8S,11R,14S,17S,20R,23R,26R)-5-[[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]carbonyl]-17-[(benzyloxy)methyl]-11-(4-[[(tert-butylamino)carbonyl]amino]benzyl)-23-(4-chlorobenzyl)-14-(4-[[(9H-fluoren-9-ylmethoxy)ca		C₁₁₁H₁₂₉ClN₁₆O₁₇	详情	详情
(XXVIII)	46763	benzyl (5S,8S,11R,14S,17S,20R,23R,26R)-5-[[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]carbonyl]-17-[(benzyloxy)methyl]-11-(4-[[(tert-butylamino)carbonyl]amino]benzyl)-23-(4-chlorobenzyl)-14-[4-([[(4R)-2,6-dioxohexahydro-4		C₁₀₁H₁₂₃ClN₁₈O₁₈	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(2)