Ganirelix acetate, Org-37462, RS-26306, Antagon, Orgalutran, -Drug Synthesis Database

【结构式】

【药物名称】Ganirelix acetate, Org-37462, RS-26306, Antagon, Orgalutran

【化学名称】N-Acetyl-3-(2-naphthyl)-D-alanyl-4-chloro-D-phenylalanyl-3-(3-pyridinyl)-D-alanyl-L-seryl-L-tyrosyl-N6-[(ethylamino)(ethylimino)methyl]-D-lysyl-L-leucyl-N6-[(ethylamino)(ethylimino)methyl]-L-lysyl-L-prolyl-D-alaninamide diacetate
　　　　　　N-Acetyl-3-(2-naphthyl)-D-alanyl-4-chloro-D-phenylalanyl-3-(3-pyridyl)-D-alanyl-L-seryl-L-tyrosyl-Nomega,N'omega-diethyl-D-homoarginyl-L-leucyl-Nomega,N'omega-diethyl-L-homoarginyl-L-prolyl-D-alaninamide diacetate

【CA登记号】129311-55-3, 124904-93-4 (free base)

【分子式】C₈₄H₁₂₁ClN₁₈O₁₇

【分子量】1690.46437

【开发单位】Roche (Originator), Organon (Licensee)

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

合成路线1 合成路线2 合成路线3

合成路线1

The synthesis of ganirelix was performed using usual solid-state peptide synthesis with a Beckman 990 or a 5.0 L Vega 296 automated solid-phase peptide synthesizer. The synthesis was initiated by condensation of chloromethylated polystyrene/divinylbenzene resin (Merrifieled resin) (II) with Boc-D-alanine (I) by means of cesium carbonate, giving Boc-D-ala-RESIN (III), which was submitted to successive cycles of deprotection with TFA or HCl and addition of a new protected amino acid by means of DCC or HOBt. The following amino acids were added successively: Boc-L-proline (IV), Nalpha-Boc-Nomega,N'omega-diethyl-L-homoarginine (VI), Boc-L-leucine (VIII), Nalpha-Boc-Nomega,N'omega-diethyl-D-homoarginine (X) and Boc-L-tyrosine (XII), yielding successively the peptide resins (V), (VII), (IX), (XI) and (XIII).

参考文献中间体

【1】 Robinson, J.3rd; Morgans, D.J.; Bingenheimer, W.; Arzeno, H.B.; Temporary serine protection in solid phase synthesis of LH-RH analogs. Int J Pept Protein Res 1993, 41, 4, 342.
【2】 Castaner, J.; Leeson, P.; Rabasseda, X.; Ganirelix Acetate. Drugs Fut 1999, 24, 4, 393.
【3】 Nestor, J.J. Jr.; McClure, N.L. (Syntex (USA), Inc.); Temporary minimal protection synthesis of LH-RH analogs. EP 0443532; JP 1992211096; US 5212288 .
【4】 Nestor, J.J. Jr.; Vickery, B.H. (Syntex (USA), Inc.); Nonapeptide and decapeptide analogs of LHRH as LHRH antagonists. EP 0277829; JP 1988201199; US 4801577 .
【5】 Vickery, B.H. (Syntex (USA), Inc.); LHRH antagonist analogs and 19-nor-progestational steroids for therapy. EP 0301850 .

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
(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)	23483	(2R)-2-([[(2S)-1-(tert-butoxycarbonyl)pyrrolidinyl]carbonyl]amino)propionic acid		C₁₃H₂₂N₂O₅	详情	详情
(VI)	23484	(2S)-2-[(tert-butoxycarbonyl)amino]-6-[[(ethylamino)(ethylimino)methyl]amino]hexanoic acid		C₁₆H₃₂N₄O₄	详情	详情
(VII)	23485	(2R)-2-([[(2S)-1-((2S)-2-[(tert-butoxycarbonyl)amino]-6-[[(ethylamino)(ethylimino)methyl]amino]hexanoyl)pyrrolidinyl]carbonyl]amino)propionic acid		C₂₄H₄₄N₆O₆	详情	详情
(VIII)	23663	(2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine		C₁₁H₂₁NO₄	详情	详情
(IX)	23487	(2R)-2-([[(2S)-1-((2S)-2-([(2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoyl]amino)-6-[[(ethylamino)(ethylimino)methyl]amino]hexanoyl)pyrrolidinyl]carbonyl]amino)propionic acid		C₃₀H₅₅N₇O₇	详情	详情
(X)	23488	(2R)-2-[(tert-butoxycarbonyl)amino]-6-[[(ethylamino)(ethylimino)methyl]amino]hexanoic acid		C₁₆H₃₂N₄O₄	详情	详情
(XI)	23489	(2R)-2-[([(2S)-1-[(2S,5S,8R,14E)-8-[(tert-butoxycarbonyl)amino]-14-(ethylamino)-2-(4-[[(ethylamino)(ethylimino)methyl]amino]butyl)-5-isobutyl-4,7-dioxo-3,6,13,15-tetraaza-14-heptadecen-1-anoyl]pyrrolidinyl]carbonyl)amino]propionic acid		C₄₁H₇₇N₁₁O₈	详情	详情
(XII)	23490	(2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propionic acid		C₁₄H₁₉NO₅	详情	详情
(XIII)	23491	(2R)-2-[([(2S)-1-[(2S,5S,8R,11S)-2,8-bis(4-[[(ethylamino)(ethylimino)methyl]amino]butyl)-11-(4-hydroxybenzyl)-5-isobutyl-15,15-dimethyl-4,7,10,13-tetraoxo-14-oxa-3,6,9,12-tetraazahexadec-1-anoyl]pyrrolidinyl]carbonyl)amino]propionic acid		C₅₀H₈₆N₁₂O₁₀	详情	详情

合成路线2

The synthesis of ganirelix was performed using usual solid-state peptide synthesis with a The following amino acids were added successively to intermediate (XIII): N-Boc-O-benzyl-L-serine (XIV), Boc-(3-pyridyl)-D-alanine (XVI) and Boc-4-chloro-D-phenylalanine (XVIII), yielding successively the peptide resins (XV), (XVII) and (XIX).

参考文献中间体

【1】 Robinson, J.3rd; Morgans, D.J.; Bingenheimer, W.; Arzeno, H.B.; Temporary serine protection in solid phase synthesis of LH-RH analogs. Int J Pept Protein Res 1993, 41, 4, 342.
【2】 Castaner, J.; Leeson, P.; Rabasseda, X.; Ganirelix Acetate. Drugs Fut 1999, 24, 4, 393.
【3】 Nestor, J.J. Jr.; Vickery, B.H. (Syntex (USA), Inc.); Nonapeptide and decapeptide analogs of LHRH as LHRH antagonists. EP 0277829; JP 1988201199; US 4801577 .
【4】 Vickery, B.H. (Syntex (USA), Inc.); LHRH antagonist analogs and 19-nor-progestational steroids for therapy. EP 0301850 .
【5】 Nestor, J.J. Jr.; McClure, N.L. (Syntex (USA), Inc.); Temporary minimal protection synthesis of LH-RH analogs. EP 0443532; JP 1992211096; US 5212288 .

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)	23491	(2R)-2-[([(2S)-1-[(2S,5S,8R,11S)-2,8-bis(4-[[(ethylamino)(ethylimino)methyl]amino]butyl)-11-(4-hydroxybenzyl)-5-isobutyl-15,15-dimethyl-4,7,10,13-tetraoxo-14-oxa-3,6,9,12-tetraazahexadec-1-anoyl]pyrrolidinyl]carbonyl)amino]propionic acid		C₅₀H₈₆N₁₂O₁₀	详情	详情
(XIV)	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
(XV)	23493	(2R)-2-[([(2S)-1-[(2S,5S,8R,11S,14S)-14-[(benzyloxy)methyl]-2,8-bis(4-[[(ethylamino)(ethylimino)methyl]amino]butyl)-11-(4-hydroxybenzyl)-5-isobutyl-18,18-dimethyl-4,7,10,13,16-pentaoxo-17-oxa-3,6,9,12,15-pentaazanonadec-1-anoyl]pyrrolidinyl]carbonyl		C₆₀H₉₇N₁₃O₁₂	详情	详情
(XVI)	23494	(2R)-2-[(tert-butoxycarbonyl)amino]-3-(3-pyridinyl)propionic acid		C₁₃H₁₈N₂O₄	详情	详情
(XVII)	23495	(2R)-2-[([(2S)-1-[(2S,5S,8R,11S,14S,17R)-2,8-bis(4-[[(ethylamino)(ethylimino)methyl]amino]butyl)-11-(4-hydroxybenzyl)-14-(hydroxymethyl)-5-isobutyl-21,21-dimethyl-4,7,10,13,16,19-hexaoxo-17-(3-pyridinylmethyl)-20-oxa-3,6,9,12,15,18-hexaazadocos-1-an		C₆₁H₉₉N₁₅O₁₃	详情	详情
(XVIII)	23496	(2R)-2-[(tert-butoxycarbonyl)amino]-3-(4-chlorophenyl)propionic acid		C₁₄H₁₈ClNO₄	详情	详情
(XIX)	23497	(2R)-2-[([(2S)-1-[(2S,5S,8R,11S,14S,17R,20R)-20-(4-chlorobenzyl)-2,8-bis(4-[[(ethylamino)(ethylimino)methyl]amino]butyl)-11-(4-hydroxybenzyl)-14-(hydroxymethyl)-5-isobutyl-24,24-dimethyl-4,7,10,13,16,19,22-heptaoxo-17-(3-pyridinylmethyl)-23-oxa-3,6,		C₇₀H₁₀₇ClN₁₆O₁₄	详情	详情

合成路线3

The amino acid Boc-(2-naphthyl)-D-alanine (XX) were added to intermediate (XIX), yielding the peptide resin (XXI). When the integration of amino acids was completed, the peptide resin (XXI) was deprotected with TFA, acetylated with acetic anhydride and finally treated with ammonia in methanol in order to eliminate the resin matrix and form the final amide group.

参考文献中间体

【1】 Robinson, J.3rd; Morgans, D.J.; Bingenheimer, W.; Arzeno, H.B.; Temporary serine protection in solid phase synthesis of LH-RH analogs. Int J Pept Protein Res 1993, 41, 4, 342.
【2】 Castaner, J.; Leeson, P.; Rabasseda, X.; Ganirelix Acetate. Drugs Fut 1999, 24, 4, 393.
【3】 Nestor, J.J. Jr.; McClure, N.L. (Syntex (USA), Inc.); Temporary minimal protection synthesis of LH-RH analogs. EP 0443532; JP 1992211096; US 5212288 .
【4】 Vickery, B.H. (Syntex (USA), Inc.); LHRH antagonist analogs and 19-nor-progestational steroids for therapy. EP 0301850 .
【5】 Nestor, J.J. Jr.; Vickery, B.H. (Syntex (USA), Inc.); Nonapeptide and decapeptide analogs of LHRH as LHRH antagonists. EP 0277829; JP 1988201199; US 4801577 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XIX)	23497	(2R)-2-[([(2S)-1-[(2S,5S,8R,11S,14S,17R,20R)-20-(4-chlorobenzyl)-2,8-bis(4-[[(ethylamino)(ethylimino)methyl]amino]butyl)-11-(4-hydroxybenzyl)-14-(hydroxymethyl)-5-isobutyl-24,24-dimethyl-4,7,10,13,16,19,22-heptaoxo-17-(3-pyridinylmethyl)-23-oxa-3,6,	C₇₀H₁₀₇ClN₁₆O₁₄	详情	详情
(XX)	23498	(2R)-2-[(tert-butoxycarbonyl)amino]-3-(2-naphthyl)propionic acid	C₁₈H₂₁NO₄	详情	详情
(XXI)	23499	(2R)-2-[([(2S)-1-[(2S,5S,8R,11S,14S,17R,20R,23R)-20-(4-chlorobenzyl)-2,8-bis(4-[[(ethylamino)(ethylimino)methyl]amino]butyl)-11-(4-hydroxybenzyl)-14-(hydroxymethyl)-5-isobutyl-27,27-dimethyl-23-(2-naphthylmethyl)-4,7,10,13,16,19,22,25-octaoxo-17-(3-	C₈₃H₁₁₈ClN₁₇O₁₅	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)