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【结 构 式】 
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【分子编号】23663 【品名】(2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine 【CA登记号】 |
【 分 子 式 】C11H21NO4 【 分 子 量 】231.29208 【元素组成】C 57.12% H 9.15% N 6.06% O 27.67% |
合成路线1
该中间体在本合成路线中的序号：(XXVI)Protection of 2-hydroxyisovaleric acid (XIX) with tert-butyldimethylsilyl chloride and imidazole in DMF, followed by condensation with Meldrum's acid (XX) by use of diethyl phosphorocyanidate (DEPC) and Et3N in THF, furnishes derivative (XXI), which is then subjected to reaction with benzyl alcohol (XXII) in refluxing benzene to afford beta-keto ester (XXIII). Next, derivative (XXIII) is methylated with MeI and NaH and its benzyl group is removed by hydrogenation over Pd/C in THF to yield carboxylic acid (XXIV). Coupling between H-Pro-OBzl.HCl (XXV) and Boc-Leu-OH (XXVI) by means of DEPC and Et3N in DMF affords dipeptide (XXVII), which is then converted into fragment (XXVIII) by first condensation with carboxylic acid (XXIV) by means of DCC, HOBt and NMM in THF/DMF and treatment with tetrabutylammonium fluoride for TBDMS protecting group removal. Coupling of fragment (XXVIII) with fragment (XVIII) by means of DCC and DMAP in CH2Cl2 furnishes linear peptide (XXIX), which is hydrogenated over Pd/C in THF and then subjected to cyclization by means of BOPCl and Et3N in CH2Cl2 to give macrolide (XXX). Next, deprotection of (XXX) with TMSOTf affords intermediate (XXXI) (didemnin A).
| 【1】 Harris, B.D.; et al.; Synthetic studies of didemnins. II. Approaches to statine diastereomers. Tetrahedron Lett 1987, 28, 25, 2837. |
| 【2】 Hamada, Y.; Shioiri, T.; Anti-tumor active cyclic peptide derived from marine organism: Synthesis, conformation and bioactivity. Kagaku Zokan 1990, 118, 31. |
| 【3】 Hamada, Y.; et al.; Efficient total synthesis of didemnins A and B. J Am Chem Soc 1989, 111, 2, 669. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVIII) | 50786 | (5S,8R,9S,12R,13S)-13-[[tert-butyl(dimethyl)silyl]oxy]-5-(4-methoxybenzyl)-4,8-dimethyl-9-[[(2R)-4-methyl-2-(methylamino)pentanoyl]amino]-12-[(1S)-1-methylpropyl]-3,6,10-trioxo-1-phenyl-2,7-dioxa-4,11-diazapentadecan-15-oic acid | C44H70N4O10Si | 详情 | 详情 | |
| (XIX) | 37829 | (2S)-2-hydroxy-3-methylbutyric acid | C5H10O3 | 详情 | 详情 | |
| (XX) | 17938 | 8-chloro-11-(1-piperazinyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine | C18H20ClN3 | 详情 | 详情 | |
| (XXI) | 50789 | 5-((2S)-2-[[tert-butyl(dimethyl)silyl]oxy]-1-hydroxy-3-methylbutylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione | C17H30O6Si | 详情 | 详情 | |
| (XXII) | 18710 | Benzyl alcohol; Phenylmethanol | 100-51-6 | C7H8O | 详情 | 详情 |
| (XXIII) | 50790 | benzyl (4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-3-oxohexanoate | C20H32O4Si | 详情 | 详情 | |
| (XXIV) | 50791 | (2S,4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-2,5-dimethyl-3-oxohexanoic acid | C14H28O4Si | 详情 | 详情 | |
| (XXV) | 20930 | benzyl (2S)-2-pyrrolidinecarboxylate | 16652-71-4 | C12H15NO2 | 详情 | 详情 |
| (XXVI) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
| (XXVII) | 50792 | benzyl (2S)-1-[(2S)-2-amino-4-methylpentanoyl]-2-pyrrolidinecarboxylate | C18H26N2O3 | 详情 | 详情 | |
| (XXVIII) | 50793 | benzyl (2S)-1-((2S)-2-[[(2S,4S)-4-hydroxy-2,5-dimethyl-3-oxohexanoyl]amino]-4-methylpentanoyl)-2-pyrrolidinecarboxylate | C26H38N2O6 | 详情 | 详情 | |
| (XXIX) | 50794 | benzyl (2S)-1-[(2S,5S,7S,11S,12R,15S,16R,19S)-11-[[tert-butyl(dimethyl)silyl]oxy]-2-isobutyl-7-isopropyl-19-(4-methoxybenzyl)-5,16,20-trimethyl-15-[[(2R)-4-methyl-2-(methylamino)pentanoyl]amino]-12-[(1S)-1-methylpropyl]-4,6,9,14,18,21-hexaoxo-23-phenyl-8,17,22-trioxa-3,13,20-triazatricos-1-anoyl]-2-pyrrolidinecarboxylate | C70H106N6O15Si | 详情 | 详情 | |
| (XXX) | 50795 | (2R)-N-[(3S,6R,7S,10R,11S,15S,17S,20S,25aS)-11-[[tert-butyl(dimethyl)silyl]oxy]-20-isobutyl-15-isopropyl-3-(4-methoxybenzyl)-2,6,17-trimethyl-10-[(1S)-1-methylpropyl]-1,4,8,13,16,18,21-heptaoxodocosahydro-15H-pyrrolo[2,1-f][1,15,4,7,10,20]dioxatetraazacyclotricosin-7-yl]-4-methyl-2-(methylamino)pentanamide | C55H92N6O12Si | 详情 | 详情 | |
| (XXXI) | 50796 | (2R)-N-[(3S,6R,7S,10R,11S,15S,17S,20S,25aS)-11-hydroxy-20-isobutyl-15-isopropyl-3-(4-methoxybenzyl)-2,6,17-trimethyl-10-[(1S)-1-methylpropyl]-1,4,8,13,16,18,21-heptaoxodocosahydro-15H-pyrrolo[2,1-f][1,15,4,7,10,20]dioxatetraazacyclotricosin-7-yl]-4-methyl-2-(methylamino)pentanamide | C49H78N6O12 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)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).
| 【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3
该中间体在本合成路线中的序号：(V)Acylation of L-leucine benzyl ester (I) with bromoacetic acid (II) in the presence of DCC and DMAP gave bromoacetamide (III), which upon reaction with triphenyl phosphine was converted to phosphonium salt (IV). After treatment of (IV) with Et3N, the resulting ylide was condensed with N-Boc-L-leucine (V) to yield the acyl- phosphonate (VI). Acid deprotection of the N-Boc group of (VI) provided amine (VII), which was condensed with the depsipeptide (VIII) using EDC and HOBt yielding (IX). Removal of the N-Fmoc group from tetrapeptide (IX) was effected by treatment with piperidine in DMF, and the resulting amino compound was further condensed with protected L-asparagine (X) to furnish peptide (XI). After hydrogenolytic removal of the benzyl and carbobenzoxy groups of (XI), treatment with diphenyl phosphoryl azide and NaHCO3 produced the cyclic depsipeptide (XII).
| 【1】 Wasserman, H.H.; et al.; The chemistry of vicinal tricarbonyls: Total syntheses of elastase inhibitors YM-47141 and YM-47142. Helv Chim Acta 2000, 83, 9, 2607. |
| 【2】 Wasserman, H.H.; et al.; Total syntheses of depsipeptide elastase inhibitor. J Am Chem Soc 1999, 121, 6, 1401. |
| 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) | 22252 | Benzyl (2S)-2-amino-4-methylpentanoate; Benzyl (S)-leucinate | C13H19NO2 | 详情 | 详情 | |
| (II) | 23660 | 2-Bromoacetic acid | 79-08-3 | C2H3BrO2 | 详情 | 详情 |
| (III) | 23661 | benzyl (2S)-2-[(2-bromoacetyl)amino]-4-methylpentanoate | C15H20BrNO3 | 详情 | 详情 | |
| (IV) | 23662 | benzyl (2S)-4-methyl-2-[[2-(triphenylphosphoranyl)acetyl]amino]pentanoate | C33H36NO3P | 详情 | 详情 | |
| (V) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
| (VI) | 23664 | benzyl (2S)-2-[[(4S)-4-[(tert-butoxycarbonyl)amino]-6-methyl-3-oxo-2-(triphenylphosphoranylidene)heptanoyl]amino]-4-methylpentanoate | C44H53N2O6P | 详情 | 详情 | |
| (VII) | 23665 | benzyl (2S)-2-[[(4S)-4-amino-6-methyl-3-oxo-2-(triphenylphosphoranylidene)heptanoyl]amino]-4-methylpentanoate | C39H45N2O4P | 详情 | 详情 | |
| (VIII) | 23666 | (2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-[((2R)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propanoyl)oxy]butyric acid | C27H32N2O8 | 详情 | 详情 | |
| (IX) | 23667 | benzyl (5R,8S,9S,12S,17S)-9-[(tert-butoxycarbonyl)amino]-1-(9H-fluoren-9-yl)-12,17-diisobutyl-5,8-dimethyl-3,6,10,13,15-pentaoxo-14-(triphenylphosphoranylidene)-2,7-dioxa-4,11,16-triazaoctadecan-18-oate | C66H75N4O11P | 详情 | 详情 | |
| (X) | 23668 | C13H16N2O5 | 详情 | 详情 | ||
| (XI) | 23669 | C64H79N6O13P | 详情 | 详情 | ||
| (XII) | 23670 | C49H65N6O10P | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(V)Acylation of L-leucine benzyl ester (I) with bromoacetic acid (II) in the presence of DCC and DMAP gave bromoacetamide (III), which upon reaction with triphenyl phosphine was converted to phosphonium salt (IV). After treatment of (IV) with Et3N, the resulting ylide was condensed with N-Boc-L-leucine (V) to yield the acyl- phosphonate (VI). Acid deprotection of the N-Boc group of (VI) provided amine (VII), which was condensed with the depsipeptide (VIII) using EDC and HOBt yielding (IX). Removal of the N-Fmoc group from tetrapeptide (IX) was effected by treatment with piperidine in DMF, and the resulting amino compound was further condensed with protected L-asparagine (X) to furnish peptide (XI). After hydrogenolytic removal of the benzyl and carbobenzoxy groups of (XI), treatment with diphenyl phosphoryl azide and NaHCO3 produced the cyclic depsipeptide (XII).
| 【1】 Wasserman, H.H.; et al.; The chemistry of vicinal tricarbonyls: Total syntheses of elastase inhibitors YM-47141 and YM-47142. Helv Chim Acta 2000, 83, 9, 2607. |
| 【2】 Wasserman, H.H.; et al.; Total syntheses of depsipeptide elastase inhibitor. J Am Chem Soc 1999, 121, 6, 1401. |
| 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) | 22252 | Benzyl (2S)-2-amino-4-methylpentanoate; Benzyl (S)-leucinate | C13H19NO2 | 详情 | 详情 | |
| (II) | 23660 | 2-Bromoacetic acid | 79-08-3 | C2H3BrO2 | 详情 | 详情 |
| (III) | 23661 | benzyl (2S)-2-[(2-bromoacetyl)amino]-4-methylpentanoate | C15H20BrNO3 | 详情 | 详情 | |
| (IV) | 23662 | benzyl (2S)-4-methyl-2-[[2-(triphenylphosphoranyl)acetyl]amino]pentanoate | C33H36NO3P | 详情 | 详情 | |
| (V) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
| (VI) | 23664 | benzyl (2S)-2-[[(4S)-4-[(tert-butoxycarbonyl)amino]-6-methyl-3-oxo-2-(triphenylphosphoranylidene)heptanoyl]amino]-4-methylpentanoate | C44H53N2O6P | 详情 | 详情 | |
| (VII) | 23665 | benzyl (2S)-2-[[(4S)-4-amino-6-methyl-3-oxo-2-(triphenylphosphoranylidene)heptanoyl]amino]-4-methylpentanoate | C39H45N2O4P | 详情 | 详情 | |
| (VIII) | 23666 | (2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-[((2R)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propanoyl)oxy]butyric acid | C27H32N2O8 | 详情 | 详情 | |
| (IX) | 23667 | benzyl (5R,8S,9S,12S,17S)-9-[(tert-butoxycarbonyl)amino]-1-(9H-fluoren-9-yl)-12,17-diisobutyl-5,8-dimethyl-3,6,10,13,15-pentaoxo-14-(triphenylphosphoranylidene)-2,7-dioxa-4,11,16-triazaoctadecan-18-oate | C66H75N4O11P | 详情 | 详情 | |
| (X) | 23668 | C13H16N2O5 | 详情 | 详情 | ||
| (XI) | 23669 | C64H79N6O13P | 详情 | 详情 | ||
| (XII) | 23670 | C49H65N6O10P | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XIII)The protected dipeptide (XIV) was prepared by coupling between L-proline benzyl ester (XII) and N-Boc-L-leucine (XIII) in the presence of DCC and HOBt. Acidic Boc group cleavage in (XIV) then gave amine (XV). The unstable keto acid (XVII) was obtained by hydrogenolysis of the epimeric benzyl esters (XVI), and subsequently coupled to the dipeptide ester (XV) by means of HBTU to afford the keto amide (XVIII) as a diastereomeric mixture. Desilylation of (XVIII) with tetrabutylammonium fluoride furnished the deprotected alcohol (XIX), which was further esterified with the protected isostatine (XI) leading to depsipeptide (XX). Then, removal of the O-silyl and N-Boc protecting groups of (XX) under acidic conditions provided intermediate (XXI)
| 【1】 Jou, G.; Gonzalez, I.; Albericio, F.; Lloyd-Williams, P.; Giralt, E.; Total synthesis of dehydrodidemnin B. Use of uronium and phosphonium salt coupling reagents in peptide synthesis in solution. J Org Chem 1997, 62, 2, 354. |
| 【2】 Giralt Lledo, E.; Albericio Palomera, F.; Lloyd-Williams, P.; Gonzalez Valcarcel, I.; Jou Prat, G.; Gomez Gonzalez, A.; Manzanares Secades, I. (PharmaMar, SA); Process for the preparation of didemnine A. ES 2102322 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 50793 | benzyl (2S)-1-((2S)-2-[[(2S,4S)-4-hydroxy-2,5-dimethyl-3-oxohexanoyl]amino]-4-methylpentanoyl)-2-pyrrolidinecarboxylate | C26H38N2O6 | 详情 | 详情 | |
| (XII) | 20930 | benzyl (2S)-2-pyrrolidinecarboxylate | 16652-71-4 | C12H15NO2 | 详情 | 详情 |
| (XIII) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
| (XIV) | 52728 | benzyl (2S)-1-{(2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoyl}-2-pyrrolidinecarboxylate | C23H34N2O5 | 详情 | 详情 | |
| (XV) | 50792 | benzyl (2S)-1-[(2S)-2-amino-4-methylpentanoyl]-2-pyrrolidinecarboxylate | C18H26N2O3 | 详情 | 详情 | |
| (XVI) | 52727 | benzyl (2S,4S)-4-{[tert-butyl(dimethyl)silyl]oxy}-2,5-dimethyl-3-oxohexanoate | C21H34O4Si | 详情 | 详情 | |
| (XVII) | 50791 | (2S,4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-2,5-dimethyl-3-oxohexanoic acid | C14H28O4Si | 详情 | 详情 | |
| (XVIII) | 52729 | benzyl (2S)-1-{(2S)-2-[((2S,4S)-4-{[tert-butyl(dimethyl)silyl]oxy}-2,5-dimethyl-3-oxohexanoyl)amino]-4-methylpentanoyl}-2-pyrrolidinecarboxylate | C32H52N2O6Si | 详情 | 详情 | |
| (XX) | 62535 | benzyl (2S)-1-{(2S,7S,11S,12R)-11-{[tert-butyl(dimethyl)silyl]oxy}-2-isobutyl-7-isopropyl-5,16,16-trimethyl-12-[(1S)-1-methylpropyl]-4,6,9,14-tetraoxo-8,15-dioxa-3,13-diazaheptadec-1-anoyl}-2-pyrrolidinecarboxylate | C45H75N3O10Si | 详情 | 详情 | |
| (XXI) | 62536 | benzyl (2S)-1-{(2S)-2-[((4S)-4-{[(3S,4R,5S)-4-amino-3-hydroxy-5-methylheptanoyl]oxy}-2,5-dimethyl-3-oxohexanoyl)amino]-4-methylpentanoyl}-2-pyrrolidinecarboxylate | C34H53N3O8 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(VII)Solid-phase peptide synthesis started with N-Boc-L-leucine linked to a PAM resin (VII). Deprotection of the Boc group was effected by treatment with trifluoroacetic acid in CH2Cl2 to give leucine-resin (VIII). Sequential couplings with the respective protected amino acids were mediated by DCC and HOBt, and trifluoroacetic acid in CH2Cl2 was used for deprotection of the Boc groups. The following protected amino acids were sequentially coupled: N-Boc-L-proline (IX), N-Boc-L-isoleucine (XI), N-Boc-L-proline (IX), N-Boc-L-glutamic acid omega-benzyl ester (XIV), N-Boc-L-phenylalanine (XVI) and N-Boc-L-aspartic acid omega-cyclohexyl ester (XVIII) to afford the peptide resins (X), (XII), (XIII), (XV), (XVII) and (XIX), respectively.
| 【1】 DiMaio, J. (National Research Council of Canada); Thrombin inhibitors based on the amino acid sequence of hirudin. JP 1999502203; WO 9629347 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
| (VIII) | 26057 | L-Leucine | 61-90-5 | C6H13NO2 | 详情 | 详情 |
| (IX) | 16374 | (1R,4S)-7-[(2,2-dimethylpropanoyl)oxy]-7-azabicyclo[2.2.1]heptan-2-one | C11H17NO3 | 详情 | 详情 | |
| (IX) | 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 | |
| (X) | 37334 | (2S)-4-methyl-2-[[(2S)pyrrolidinylcarbonyl]amino]pentanoic acid | 52899-07-7 | C11H20N2O3 | 详情 | 详情 |
| (XI) | 30009 | (2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentanoic acid | 13139-16-7 | C11H21NO4 | 详情 | 详情 |
| (XII) | 37335 | (2S)-2-[([(2S)-1-[(2S,3S)-2-amino-3-methylpentanoyl]pyrrolidinyl]carbonyl)amino]-4-methylpentanoic acid | C17H31N3O4 | 详情 | 详情 | |
| (XIII) | 37336 | (2S)-4-methyl-2-([[(2S)-1-((2S,3S)-3-methyl-2-[[(2S)pyrrolidinylcarbonyl]amino]pentanoyl)pyrrolidinyl]carbonyl]amino)pentanoic acid | C22H38N4O5 | 详情 | 详情 | |
| (XIV) | 25141 | (2S)-5-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid | 13574-13-5 | C17H23NO6 | 详情 | 详情 |
| (XV) | 37337 | (2S)-2-[[((2S)-1-[(2S,3S)-2-[([(2S)-1-[(2S)-2-amino-5-(benzyloxy)-5-oxopentanoyl]pyrrolidinyl]carbonyl)amino]-3-methylpentanoyl]pyrrolidinyl)carbonyl]amino]-4-methylpentanoic acid | C34H51N5O8 | 详情 | 详情 | |
| (XVI) | 12874 | (2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine | 13734-34-4 | C14H19NO4 | 详情 | 详情 |
| (XVII) | 37338 | (2S)-2-[[((2S)-1-[(2S,3S)-2-[([(2S)-1-[(2S)-2-[[(2S)-2-amino-3-phenylpropanoyl]amino]-5-(benzyloxy)-5-oxopentanoyl]pyrrolidinyl]carbonyl)amino]-3-methylpentanoyl]pyrrolidinyl)carbonyl]amino]-4-methylpentanoic acid | C43H60N6O9 | 详情 | 详情 | |
| (XVIII) | 37339 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-(cyclohexyloxy)-4-oxobutyric acid | 73821-95-1 | C15H25NO6 | 详情 | 详情 |
| (XIX) | 37340 | (2S)-2-[[((2S)-1-[(2S,3S)-2-[([(2S)-1-[(2S)-2-[((2S)-2-[[(2S)-2-amino-4-(cyclohexyloxy)-4-oxobutanoyl]amino]-3-phenylpropanoyl)amino]-5-(benzyloxy)-5-oxopentanoyl]pyrrolidinyl]carbonyl)amino]-3-methylpentanoyl]pyrrolidinyl)carbonyl]amino]-4-methylpentanoic acid | C53H75N7O12 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(XLII)Dipeptide (XLIV) was prepared by coupling N-Boc-L-leucine (XLII) with tryptophan derivative (XXII), followed by basic hydrolysis of the resulting dipeptide ester (XLIII). Dipeptides (XLIV) and (XLI) were then coupled in the presence of HATU to afford tetrapeptide (XLV), which was separated from minor amounts of a tryptophan-epimerized byproduct by semipreparative RP-HPLC. Tetrapeptide ester (XLV) was then hydrolyzed to acid (XLVI) with LiOH in aqueous tert-butanol.
| 【1】 Boger, D.L.; et al.; Total synthesis of HUN-7293. J Am Chem Soc 1999, 121, 26, 6197. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXII) | 26283 | methyl (2S)-3-(1-methoxy-1H-indol-3-yl)-2-(methylamino)propanoate | C14H18N2O3 | 详情 | 详情 | |
| (XLI) | 26302 | methyl (2S)-2-[[(2S,4R)-2-amino-4-methyloctanoyl](methyl)amino]propanoate | C14H28N2O3 | 详情 | 详情 | |
| (XLII) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
| (XLIII) | 26303 | methyl (2S)-2-[[(2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoyl](methyl)amino]-3-(1-methoxy-1H-indol-3-yl)propanoate | C25H37N3O6 | 详情 | 详情 | |
| (XLIV) | 26304 | (2S)-2-[[(2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoyl](methyl)amino]-3-(1-methoxy-1H-indol-3-yl)propionic acid | C24H35N3O6 | 详情 | 详情 | |
| (XLV) | 26305 | methyl (6S,9S,12S,15S)-6-isobutyl-9-[(1-methoxy-1H-indol-3-yl)methyl]-2,2,8,14,15-pentamethyl-12-[(2R)-2-methylhexyl]-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadecan-16-oate | C38H61N5O8 | 详情 | 详情 | |
| (XLVI) | 26308 | N-(Tert-butoxycarbonyl)-L-leucyl-(N-alpha-methyl-N-1-methoxy)-L-tryptophyl-L-(2-amino-4(R)-methyloctanoyl)-(N-methyl)-L-alanine; N-(Tert-butoxycarbonyl)-L-leucyl-(N-alpha-methyl-N-1-methoxy)-L-tryptophyl-L-(2-amino-4(R)-methyloctanoyl)-(N-methyl)-L-alanine | C37H59N5O8 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(V)The condensation of tert-butoxycarbonyl-L-leucinal (I) with 1-benzylimidazole (II) by means of BuLi in THF gives 1-benzyl-2-[2(S)-(tert-butoxycarbonylamino)-1-hydroxy-4-methylpentyl]imidazole (III), which is hydrolyzed with HCl in dioxane yielding 2-(2(S)-amino)-1-hydroxy-4-methylpentyl]-2-benzylimidazole (IV). The condensation of (IV) with tert-butoxycarbonyl-L-leucine (V) by means of dicyclohexylcarbodiimide (DCC) and hydroxybenzotriazole (HOBT) in TFA/dichloromethane affords the protected seudo-dipeptide (VI), which is debenzylated with H2 over Pd/C giving the expected seudo-peptide (VII): Finally, this compound is oxidizad with the Dess-Martin oxidant.
| 【1】 Tao, M.; et al.; Inhibition of calpain by peptidyl heterocycles. Bioorg Med Chem Lett 1996, 6, 24, 3009. |
| 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) | 27058 | tert-butyl (1S)-1-formyl-3-methylbutylcarbamate | C11H21NO3 | 详情 | 详情 | |
| (II) | 27059 | 1-benzyl-1H-imidazole | 4238-71-5 | C10H10N2 | 详情 | 详情 |
| (III) | 27060 | tert-butyl (1S)-1-[(1-benzyl-1H-imidazol-2-yl)(hydroxy)methyl]-3-methylbutylcarbamate | C21H31N3O3 | 详情 | 详情 | |
| (IV) | 27061 | (2S)-2-amino-1-(1-benzyl-1H-imidazol-2-yl)-4-methyl-1-pentanol | C16H23N3O | 详情 | 详情 | |
| (V) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
| (VI) | 27062 | tert-butyl (1S)-1-[([(1S)-1-[(1-benzyl-1H-imidazol-2-yl)(hydroxy)methyl]-3-methylbutyl]amino)carbonyl]-3-methylbutylcarbamate | C27H42N4O4 | 详情 | 详情 | |
| (VII) | 27063 | tert-butyl (1S)-1-[([(1S)-1-[hydroxy(1H-imidazol-2-yl)methyl]-3-methylbutyl]amino)carbonyl]-3-methylbutylcarbamate | C20H36N4O4 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(VIII)Reaction of 1-O-acetyl-2,3,5-tri-O-benzoyl-beta-D-ribofuranose (I) with trimethylsilyl cyanide in the presence of boron trifluoride gave nitrile (II), which was treated with liquid hydrogen sulfide and DMAP to yield thioamide (III). Condensation of this thioamide with bromoketone (IV) in acetonitrile afforded the thiazole derivative (V). Hydrolysis of the benzoate esters of (V) using sodium methoxide in methanol, followed by protection of the resulting 2,3-diol with acetone and triethyl orthoformate produced the corresponding isopropylidene ketal (VI). Treatment of the primary alcohol group of (VI) with sulfamoyl chloride gave rise to the sulfamate ester (VII). Further condensation of (VII) with N-Boc-L-leucine furnished (IX). The Boc and isopropylidene groups of (IX) were finally eliminated with trifluoroacetic acid to provide the title compound.
| 【1】 Wang, W.; Gallant, P.; Hill, J.M.; Yu, G.; Wendler, P.; Kluge, A.F.; Yu, X.Y.; Synthesis and structure-activity relationships of a series of novel thiazoles as inhibitors of aminoacyl-tRNA synthetases. Bioorg Med Chem Lett 1999, 9, 3, 375. |
| 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) | 20984 | methyl (Z)-7-[(1R,2S,3R,5S)-5-(acetoxy)-2-[(E)-3-oxo-3-(4-propylcyclohexyl)-1-propenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-5-heptenoate | C33H52O7 | 详情 | 详情 | |
| (II) | 29143 | (2S,3S,4R,5R)-4-(benzoyloxy)-5-[(benzoyloxy)methyl]-2-cyanotetrahydro-3-furanyl benzoate | C27H21NO7 | 详情 | 详情 | |
| (III) | 29144 | (2R,3S,4R,5R)-2-(aminocarbothioyl)-4-(benzoyloxy)-5-[(benzoyloxy)methyl]tetrahydro-3-furanyl benzoate | C27H23NO7S | 详情 | 详情 | |
| (IV) | 29211 | 1-bromo-4-phenyl-2-butanone | C10H11BrO | 详情 | 详情 | |
| (V) | 29212 | [(2R,3R,4S,5R)-3,4-bis(benzoyloxy)-5-(4-phenethyl-1,3-thiazol-2-yl)tetrahydro-2-furanyl]methyl benzoate | C37H31NO7S | 详情 | 详情 | |
| (VI) | 29213 | [(3aR,4R,6R,6aS)-2,2-dimethyl-6-(4-phenethyl-1,3-thiazol-2-yl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methanol | C19H23NO4S | 详情 | 详情 | |
| (VII) | 29214 | [(3aR,4R,6R,6aS)-2,2-dimethyl-6-(4-phenethyl-1,3-thiazol-2-yl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methylsulfamate | C19H24N2O6S2 | 详情 | 详情 | |
| (VIII) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
| (IX) | 29215 | tert-butyl (1S)-1-[[([[(3aR,4R,6R,6aS)-2,2-dimethyl-6-(4-phenethyl-1,3-thiazol-2-yl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methoxy]sulfonyl)amino]carbonyl]-3-methylbutylcarbamate | C30H43N3O9S2 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(VII)The reductocondensation of 4-benzyloxyaniline (I) with 1-(tert-butoxycarbonyl)piperidin-4-one (II) by means of NaBH(OAc)2 in dichloromethane gives N-(4-benzyloxyphenyl)-N-[1-(tert-butoxycarbonyl)piperidin-4-yl]amine (III), which is alkylated with 3-methyl-2-butenyl bromide (IV) by means of DIEA in THF yielding the tertiary amine (V). The deprotection of (V) with TFA in dichloromethane affords the piperidine (VI), which is condensed with N-(tert-butoxycarbonyl)-L-leucine (VII) by means of HBTU and DIEA in DMF to provide the intermediate (VIII). Finally, (VIII) is deprotected with TFA in dichloromethane.
| 【1】 Ryder, T.R.; Hu, L.-Y.; Rafferty, M.F.; et al.; Synthesis of a series of 4-benzyloxyaniline analogues as neuronal N-type calcium channel blockers with improved anticonvulsant and analgesic properties. J Med Chem 1999, 42, 20, 4239. |
| 【2】 Rafferty, M.F.; Ryder, T.R.; Hu, L.-Y. (Pfizer Inc.); Aniline derivs. as calcium channel blockers. WO 9907689 . |
| 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) | 22460 | 4-(benzyloxy)aniline; 4-(benzyloxy)phenylamine | C13H13NO | 详情 | 详情 | |
| (II) | 18620 | tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone | 79099-07-3 | C10H17NO3 | 详情 | 详情 |
| (III) | 38230 | tert-butyl 4-[4-(benzyloxy)anilino]-1-piperidinecarboxylate | C23H30N2O3 | 详情 | 详情 | |
| (IV) | 12989 | 4-Bromo-2-methyl-2-butene; 1-Bromo-3-methyl-2-butene | 870-63-3 | C5H9Br | 详情 | 详情 |
| (V) | 38231 | tert-butyl 4-[4-(benzyloxy)(3-methyl-2-butenyl)anilino]-1-piperidinecarboxylate | C28H38N2O3 | 详情 | 详情 | |
| (VI) | 38232 | N-[4-(benzyloxy)phenyl]-N-(3-methyl-2-butenyl)-N-(4-piperidinyl)amine; N-[4-(benzyloxy)phenyl]-N-(3-methyl-2-butenyl)-4-piperidinamine | C23H30N2O | 详情 | 详情 | |
| (VII) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
| (VIII) | 38233 | tert-butyl (1S)-1-([4-[4-(benzyloxy)(3-methyl-2-butenyl)anilino]-1-piperidinyl]carbonyl)-3-methylbutylcarbamate | C34H49N3O4 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(I)The reaction of N-(tert-butoxycarbonyl)-L-leucine (I) with N,O-dimethylhydroxylamine and HBTU in DMF gives the corresponding methoxyamide (II), which is reduced with LiAlH4 in ethyl ether yielding the aldehyde (III). The reductocondensation of (III) with the piperidine (IV) by means of sodium triacetoxyborohydride in dichloromethane affords the protected adduct (V), which is finally deprotected with TFA in dichloromethane. The intermediate piperidine (IV) has been obtained as follows: The reductocondensation of the piperidinone (VI) with 4-(benzyloxy)aniline (VII) by means of sodium triacetoxyborohydride in dichloromethane gives the secondary amine (VIII), which is alkylated with 3-methyl-2-butenyl bromide (IX) and DIPEA in THF yielding the protected piperidine (IX). Finally, this compound is deprotected with TFA in dichloromethane to afford the target intermediate (IV).
| 【1】 Siebers, K.M.; Hu, L.-Y.; Rafferty, M.F.; et al.; Neuronal N-type calcium channel blocker: Structure-activity relationship of a series of (S)-2-amino-1(4-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl)-4-methyl-pentan-1-one analogs. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 259. |
| 【2】 Rafferty, M.F.; Ryder, T.R.; Hu, L.-Y. (Pfizer Inc.); Aniline derivs. as calcium channel blockers. WO 9907689 . |
| 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) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
| (II) | 40395 | tert-butyl (1S)-1-[[methoxy(methyl)amino]carbonyl]-3-methylbutylcarbamate | C13H26N2O4 | 详情 | 详情 | |
| (III) | 27058 | tert-butyl (1S)-1-formyl-3-methylbutylcarbamate | C11H21NO3 | 详情 | 详情 | |
| (IV) | 38232 | N-[4-(benzyloxy)phenyl]-N-(3-methyl-2-butenyl)-N-(4-piperidinyl)amine; N-[4-(benzyloxy)phenyl]-N-(3-methyl-2-butenyl)-4-piperidinamine | C23H30N2O | 详情 | 详情 | |
| (V) | 40394 | tert-butyl (1S)-1-([4-[4-(benzyloxy)(3-methyl-2-butenyl)anilino]-1-piperidinyl]methyl)-3-methylbutylcarbamate | C34H51N3O3 | 详情 | 详情 | |
| (VI) | 18620 | tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone | 79099-07-3 | C10H17NO3 | 详情 | 详情 |
| (VII) | 22460 | 4-(benzyloxy)aniline; 4-(benzyloxy)phenylamine | C13H13NO | 详情 | 详情 | |
| (VIII) | 38230 | tert-butyl 4-[4-(benzyloxy)anilino]-1-piperidinecarboxylate | C23H30N2O3 | 详情 | 详情 | |
| (IX) | 12989 | 4-Bromo-2-methyl-2-butene; 1-Bromo-3-methyl-2-butene | 870-63-3 | C5H9Br | 详情 | 详情 |
| (X) | 38231 | tert-butyl 4-[4-(benzyloxy)(3-methyl-2-butenyl)anilino]-1-piperidinecarboxylate | C28H38N2O3 | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(VIII)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).
| 【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13
该中间体在本合成路线中的序号：(III)This compound has been obtained by two different ways: 1) The reaction of 2-(tert-butoxycarbonyl)-2-ethylbutyric acid (I) with ammonia, EDC and HOBT gives the amide (II), which is deprotected with 4N HCl and condensed with N-(tert-butoxycarbonyl)-L-leucine (III) by means of EDC and HOBT yielding the dipeptide (IV). The deprotection of (IV) with HCl and condensation with 1-(tert-butoxycarbonyl)-L-proline pentafluorophenyl ester (V) affords the protected tripeptide (VI), which is finally deprotected with 4N HCl. 2) The deprotection of amide (II) with HCl followed by condensation with N-(benzyloxcarbonyl)-L-prolyl-L-leucine (VII) gives the protected tripeptide (VIII), which is deprotected by hydrogenation with H2 over Pd/C.
| 【1】 Evans, M.C.; et al.; Synthesis and dopamine receptor modulating activity of novel peptidomimetics of L-prolyl-L-leucyl-glycinamide featuring alpha,alpha-disubstituted amino acids. J Med Chem 1999, 42, 8, 1441. |
| 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) | 30883 | 2-[(tert-butoxycarbonyl)amino]-2-ethylbutyric acid | C11H21NO4 | 详情 | 详情 | |
| (II) | 30884 | tert-butyl 1-(aminocarbonyl)-1-ethylpropylcarbamate | C11H22N2O3 | 详情 | 详情 | |
| (III) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
| (IV) | 30885 | tert-butyl (1S)-1-([[1-(aminocarbonyl)-1-ethylpropyl]amino]carbonyl)-3-methylbutylcarbamate | C17H33N3O4 | 详情 | 详情 | |
| (V) | 30886 | 1-(tert-butyl) 2-(2,3,4,5,6-pentafluorophenyl) (2S)-1,2-pyrrolidinedicarboxylate | C16H16F5NO4 | 详情 | 详情 | |
| (VI) | 30887 | tert-butyl (2S)-2-([[(1S)-1-([[1-(aminocarbonyl)-1-ethylpropyl]amino]carbonyl)-3-methylbutyl]amino]carbonyl)-1-pyrrolidinecarboxylate | C22H40N4O5 | 详情 | 详情 | |
| (VII) | 30888 | (2S)-2-[([(2S)-1-[(benzyloxy)carbonyl]pyrrolidinyl]carbonyl)amino]-4-methylpentanoic acid | 61596-47-2 | C19H26N2O5 | 详情 | 详情 |
| (VIII) | 30889 | benzyl (2S)-2-([[(1S)-1-([[1-(aminocarbonyl)-1-ethylpropyl]amino]carbonyl)-3-methylbutyl]amino]carbonyl)-1-pyrrolidinecarboxylate | C25H38N4O5 | 详情 | 详情 |
合成路线14
该中间体在本合成路线中的序号：(I)Boc-Leucine (I) was converted to Weinreb amide (II) by activation with isobutyl chloroformate and N-methylpiperidine, followed by treatment of the resulting mixed anhydride with N,O-dimethylhydroxylamine. Reduction of (II) with LiAlH4 provided the aldehyde (III), which was condensed with the lithium anion of ethyl propiolate (IV) to furnish the acetylenic alcohol (Va-b) as an inseparable mixture of diastereomers. Catalytic hydrogenation of the triple bond of (Va-b) over Pd/BaSO4, followed by acid-catalyzed lactonization of the resulting hydroxy ester provided the diastereomeric mixture of gamma-lactones (VIa-b). After separation by column chromatography, alkylation of the desired isomer employing iodomethane and lithium hexamethyldisilazide at -78 C provided the desired alpha-methyl lactone (VII), along with a small amount of the corresponding epimer. Lactone (VII) hydrolysis using LiOH gave hydroxy acid (VIII), which was further protected as the silyl ether (IX) with tert-butyldimethylsilyl chloride and imidazole. The Boc protecting group of (IX) was selectively removed by treatment with trifluoroacetic acid in CH2Cl2 at 0 C, and the resulting amine (X) was treated with Fmoc-succinimide to provide the Fmoc-protected intermediate (XI).
| 【1】 Lin, X.; Shin, D.; Downs, D.; Tang, J.; Koelsch, G.; Ghosh, A.K.; Ermolieff, J.; Design of potent inhibitors for human brain memapsin 2 (beta-secretase). J Am Chem Soc 2000, 122, 14, 3522. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (Va) | 40625 | ethyl (4R,5S)-5-[(tert-butoxycarbonyl)amino]-4-hydroxy-7-methyl-2-octynoate | C16H27NO5 | 详情 | 详情 | |
| (Vb) | 40626 | ethyl (4S,5S)-5-[(tert-butoxycarbonyl)amino]-4-hydroxy-7-methyl-2-octynoate | C16H27NO5 | 详情 | 详情 | |
| (VIa) | 40627 | tert-butyl (1S)-3-methyl-1-[(2R)-5-oxotetrahydro-2-furanyl]butylcarbamate | C14H25NO4 | 详情 | 详情 | |
| (VIb) | 40628 | tert-butyl (1S)-3-methyl-1-[(2S)-5-oxotetrahydro-2-furanyl]butylcarbamate | C14H25NO4 | 详情 | 详情 | |
| (I) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
| (II) | 40395 | tert-butyl (1S)-1-[[methoxy(methyl)amino]carbonyl]-3-methylbutylcarbamate | C13H26N2O4 | 详情 | 详情 | |
| (III) | 27058 | tert-butyl (1S)-1-formyl-3-methylbutylcarbamate | C11H21NO3 | 详情 | 详情 | |
| (IV) | 35333 | ethyl propiolate | 623-47-2 | C5H6O2 | 详情 | 详情 |
| (VII) | 40629 | tert-butyl (1S)-3-methyl-1-[(2S,4R)-4-methyl-5-oxotetrahydro-2-furanyl]butylcarbamate | C15H27NO4 | 详情 | 详情 | |
| (VIII) | 40630 | (2R,4S,5S)-5-[(tert-butoxycarbonyl)amino]-4-hydroxy-2,7-dimethyloctanoic acid | C15H29NO5 | 详情 | 详情 | |
| (IX) | 40631 | (2R,4S,5S)-5-[(tert-butoxycarbonyl)amino]-4-[[tert-butyl(dimethyl)silyl]oxy]-2,7-dimethyloctanoic acid | C21H43NO5Si | 详情 | 详情 | |
| (X) | 40632 | (2R,4S,5S)-5-amino-4-[[tert-butyl(dimethyl)silyl]oxy]-2,7-dimethyloctanoic acid | C16H35NO3Si | 详情 | 详情 | |
| (XI) | 40633 | (2R,4S,5S)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-2,7-dimethyloctanoic acid | C31H45NO5Si | 详情 | 详情 |
合成路线15
该中间体在本合成路线中的序号：(I)Boc-Leucine (I) was converted to Weinreb amide (II) by activation with isobutyl chloroformate and N-methylpiperidine, followed by treatment of the resulting mixed anhydride with N,O-dimethylhydroxylamine. Reduction of (II) with LiAlH4 provided the aldehyde (III), which was condensed with the lithium anion of ethyl propiolate (IV) to furnish the acetylenic alcohol (Va-b) as an inseparable mixture of diastereomers. Catalytic hydrogenation of the triple bond of (Va-b) over Pd/BaSO4, followed by acid-catalyzed lactonization of the resulting hydroxy ester provided the diastereomeric mixture of gamma-lactones (VIa-b). After separation by column chromatography, alkylation of the desired isomer employing iodomethane and lithium hexamethyldisilazide at -78 C provided the desired alpha-methyl lactone (VII), along with a small amount of the corresponding epimer. Lactone (VII) hydrolysis using LiOH gave hydroxy acid (VIII), which was further protected as the silyl ether (IX) with tert-butyldimethylsilyl chloride and imidazole. The Boc protecting group of (IX) was selectively removed by treatment with trifluoroacetic acid in CH2Cl2 at 0 C, and the resulting amine (X) was treated with Fmoc-succinimide to provide the Fmoc-protected intermediate (XI).
| 【1】 Lin, X.; Shin, D.; Downs, D.; Tang, J.; Koelsch, G.; Ghosh, A.K.; Ermolieff, J.; Design of potent inhibitors for human brain memapsin 2 (beta-secretase). J Am Chem Soc 2000, 122, 14, 3522. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (Va) | 40625 | ethyl (4R,5S)-5-[(tert-butoxycarbonyl)amino]-4-hydroxy-7-methyl-2-octynoate | C16H27NO5 | 详情 | 详情 | |
| (Vb) | 40626 | ethyl (4S,5S)-5-[(tert-butoxycarbonyl)amino]-4-hydroxy-7-methyl-2-octynoate | C16H27NO5 | 详情 | 详情 | |
| (VIa) | 40627 | tert-butyl (1S)-3-methyl-1-[(2R)-5-oxotetrahydro-2-furanyl]butylcarbamate | C14H25NO4 | 详情 | 详情 | |
| (VIb) | 40628 | tert-butyl (1S)-3-methyl-1-[(2S)-5-oxotetrahydro-2-furanyl]butylcarbamate | C14H25NO4 | 详情 | 详情 | |
| (I) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
| (II) | 40395 | tert-butyl (1S)-1-[[methoxy(methyl)amino]carbonyl]-3-methylbutylcarbamate | C13H26N2O4 | 详情 | 详情 | |
| (III) | 27058 | tert-butyl (1S)-1-formyl-3-methylbutylcarbamate | C11H21NO3 | 详情 | 详情 | |
| (IV) | 35333 | ethyl propiolate | 623-47-2 | C5H6O2 | 详情 | 详情 |
| (VII) | 40629 | tert-butyl (1S)-3-methyl-1-[(2S,4R)-4-methyl-5-oxotetrahydro-2-furanyl]butylcarbamate | C15H27NO4 | 详情 | 详情 | |
| (VIII) | 40630 | (2R,4S,5S)-5-[(tert-butoxycarbonyl)amino]-4-hydroxy-2,7-dimethyloctanoic acid | C15H29NO5 | 详情 | 详情 | |
| (IX) | 40631 | (2R,4S,5S)-5-[(tert-butoxycarbonyl)amino]-4-[[tert-butyl(dimethyl)silyl]oxy]-2,7-dimethyloctanoic acid | C21H43NO5Si | 详情 | 详情 | |
| (X) | 40632 | (2R,4S,5S)-5-amino-4-[[tert-butyl(dimethyl)silyl]oxy]-2,7-dimethyloctanoic acid | C16H35NO3Si | 详情 | 详情 | |
| (XI) | 40633 | (2R,4S,5S)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-2,7-dimethyloctanoic acid | C31H45NO5Si | 详情 | 详情 |
合成路线16
该中间体在本合成路线中的序号：(I)The peptide moiety (XVII) was prepared by solid-phase synthesis in a peptide synthesizer starting from Boc-Leu-PAM resin (I). Removal of the Boc protecting group of (I) was effected by treatment with trifluoroacetic acid in CH2Cl2. To the deprotected Leu-resin (II) were sequentially incorporated the following amino acids: N-Fmoc-L-serine(O-t-Bu) (III), N-Fmoc-L-glutamine(Trt) (V), N-Fmoc-L-cyclohexylglycine (VII), again Fmoc-L-serine(O-t-Bu) (III), and N-Fmoc-L-alanine (X) using DCC and HOBt activation in N-methyl-2-pyrrolidinone, each followed by an Fmoc deprotection cycle with piperidine in DMF. The peptide resins (IV), (VI), (VIII), (IX) and (XI) were in turn obtained.
| 【2】 Garsky, V.M.; Feng, D.-M.; DeFeo-Jones, D. (Merck & Co., Inc.); Conjugates useful in the treatment of prostate cancer. JP 2000509407; WO 9818493 . |
| 【3】 Oliff, A.I.; Jones, R.E.; Defeo-Jones, D. (Merck & Co., Inc.); A method of treating cancer. WO 0059930 . |
| 【1】 Feng, D.-M.; Wai, J.; Ramjit, H.G.; Sardana, M.K.; Lumma, P.K.; DeFeo-Jones, D.; Jones, R.E.; Freidinger, R.M.; Oliff, A.; Garsky, V.M.; The synthesis of a prodrug of doxorubicin designed to provide reduced systemic toxicity and greater target efficacy. J Med Chem 2001, 44, 24, 4216. |
| 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) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
| (II) | 26057 | L-Leucine | 61-90-5 | C6H13NO2 | 详情 | 详情 |
| (III) | 33118 | (2S)-3-(tert-butoxy)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid | 71989-33-8 | C22H25NO5 | 详情 | 详情 |
| (IV) | 53663 | (2S)-2-{[(2S)-2-amino-3-(tert-butoxy)propanoyl]amino}-4-methylpentanoic acid | n/a | C13H26N2O4 | 详情 | 详情 |
| (V) | 53664 | (2S)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-5-oxo-5-(tritylamino)pentanoic acid | n/a | C39H34N2O5 | 详情 | 详情 |
| (VI) | 53665 | (2S)-2-{[(2S)-2-{[(2S)-2-amino-5-oxo-5-(tritylamino)pentanoyl]amino}-3-(tert-butoxy)propanoyl]amino}-4-methylpentanoic acid | n/a | C37H48N4O6 | 详情 | 详情 |
| (VII) | 53666 | (2S)-2-cyclohexyl-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}ethanoic acid | n/a | C23H25NO4 | 详情 | 详情 |
| (VIII) | 53667 | (2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-amino-2-cyclohexylethanoyl]amino}-5-oxo-5-(tritylamino)pentanoyl]amino}-3-(tert-butoxy)propanoyl]amino}-4-methylpentanoic acid | n/a | C45H61N5O7 | 详情 | 详情 |
| (IX) | 53668 | (2S,5S,8S,11S,14S)-14-amino-5-(tert-butoxymethyl)-11-cyclohexyl-2-isobutyl-17,17-dimethyl-4,7,10,13-tetraoxo-8-[3-oxo-3-(tritylamino)propyl]-16-oxa-3,6,9,12-tetraazaoctadecan-1-oic acid | n/a | C52H74N6O9 | 详情 | 详情 |
| (X) | 19926 | (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid | C18H17NO4 | 详情 | 详情 | |
| (XI) | 53669 | (2S,5S,8S,11S,14S)-14-{[(2S)-2-aminopropanoyl]amino}-5-(tert-butoxymethyl)-11-cyclohexyl-2-isobutyl-17,17-dimethyl-4,7,10,13-tetraoxo-8-[3-oxo-3-(tritylamino)propyl]-16-oxa-3,6,9,12-tetraazaoctadecan-1-oic acid | n/a | C55H79N7O10 | 详情 | 详情 |
合成路线17
该中间体在本合成路线中的序号：(VII)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).
| 【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18
该中间体在本合成路线中的序号：(VIII)N-Alkylation of benzyl N-allylcarbamate (I) with 5-bromo-1-pentene (II) by means of NaH in DMF provides olefin metathesis substrate (III), which is then converted into azepine (IV) by means of catalytic bis(tricyclohexylphosphine)benzylideneruthenium (IV) dichloride (Grubbs catalyst) in refluxing CH2Cl2. Epoxidation of (IV) with m-CPBA in CH2Cl2 affords oxirane (V), which is then treated with NaN3 and NH4Cl in H2O/MeOH to provide a mixture of regioisomers from which (VI) is chromatographically isolated. Reduction of azide (VI) with 1,3-propanedithiol and Et3N in MeOH furnishes amino alcohol derivative (VII), which is then acylated with Boc-Leu-OH by means of EDC and HOBt to provide protected derivative (IX). Removal of the Z protecting group by hydrogenolysis over Pd/C in MeOH gives amine (X), which is then condensed with 2-pyridylsulfonyl chloride (XI) by means of Et3N in CH2Cl2 to yield compound (XII). Boc removal from (XII) by treatment with HCl in MeOH/AcOEt affords amine (XIII), which is then acylated with benzofuran-2-carboxylic acid (XIV) by means of EDC and HOBt to give derivative (XV). Finally, the desired product is obtained by oxidation of (XV) with pyridine sulfur trioxide complex and Et3N in DMSO followed by diastereomer separation by HPLC.
| 【1】 Marquis, R.W.; et al.; Azepanone-based inhibitors of human and rat cathepsin K. J Med Chem 2001, 44, 9, 1380. |
| 【2】 Cummings, M.D.; Veber, D.F.; Yamashita, D.; Ru, Y.; Marquis, R.W. Jr.; Thompson, S.K. (SmithKline Beecham Corp.); Protease inhibitors. EP 1158986; WO 0038687 . |
| 【3】 Veber, D.F.; Marquis, R.W. Jr.; Thompson, S.K.; Ru, Y.; Cummings, M.D.; Yamashita, D. (GlaxoSmithKline Inc.); Protease inhibitors. WO 0195911 . |
| 【4】 Veber, D.F.; Marquis, R.W. Jr.; Thompson, S.K.; Yamashita, D.S.; Ru, Y.; Cummings, M.D. (GlaxoSmithKline Inc.); Methods of treatment. WO 0178734 . |
| 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) | 49723 | benzyl allylcarbamate | C11H13NO2 | 详情 | 详情 | |
| (II) | 49724 | 1-Bromo-4-Pentene; 5-Bromo-1-pentene; 4-Penten-1-yl Bromide | 1119-51-3 | C5H9Br | 详情 | 详情 |
| (III) | 49725 | benzyl allyl(4-pentenyl)carbamate | C16H21NO2 | 详情 | 详情 | |
| (IV) | 49726 | benzyl 2,3,4,7-tetrahydro-1H-azepine-1-carboxylate | C14H17NO2 | 详情 | 详情 | |
| (V) | 49727 | benzyl 8-oxa-3-azabicyclo[5.1.0]octane-3-carboxylate | C14H17NO3 | 详情 | 详情 | |
| (VI) | 49728 | benzyl 4-azido-3-hydroxy-1-azepanecarboxylate | C14H18N4O3 | 详情 | 详情 | |
| (VII) | 49729 | benzyl 4-amino-3-hydroxy-1-azepanecarboxylate | C14H20N2O3 | 详情 | 详情 | |
| (VIII) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
| (IX) | 49730 | benzyl 4-([(2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoyl]amino)-3-hydroxy-1-azepanecarboxylate | C25H39N3O6 | 详情 | 详情 | |
| (X) | 49731 | tert-butyl (1S)-1-[[(3-hydroxy-4-azepanyl)amino]carbonyl]-3-methylbutylcarbamate | C17H33N3O4 | 详情 | 详情 | |
| (XI) | 49732 | 2-pyridinesulfonyl chloride | C5H4ClNO2S | 详情 | 详情 | |
| (XII) | 49733 | tert-butyl (1S)-1-([[3-hydroxy-1-(2-pyridinylsulfonyl)-4-azepanyl]amino]carbonyl)-3-methylbutylcarbamate | C22H36N4O6S | 详情 | 详情 | |
| (XIII) | 49734 | (2S)-2-amino-N-[3-hydroxy-1-(2-pyridinylsulfonyl)-4-azepanyl]-4-methylpentanamide | C17H28N4O4S | 详情 | 详情 | |
| (XIV) | 35339 | (2S,6S,9S)-8-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4,4,7,13,14,14-hexamethyl-3,5-dioxatetracyclo[8.3.1.0(1,9).0(2,6)]tetradeca-7,12-dien-9-ol | C25H42O4Si | 详情 | 详情 | |
| (XV) | 49735 | N-[(1S)-1-([[3-hydroxy-1-(2-pyridinylsulfonyl)-4-azepanyl]amino]carbonyl)-3-methylbutyl]-1-benzofuran-2-carboxamide | C26H32N4O6S | 详情 | 详情 |
合成路线19
该中间体在本合成路线中的序号：(VIII)Palladium-catalyzed coupling of methyl (3-bromophenyl)acetate (I) with 2-pyridyl triflate (II) furnished the pyridylphenylacetate ester (III), which was further hydrolyzed with LiOH to the corresponding carboxylic acid (IV). Coupling of acid (IV) with (3S)-3N-Boc-1,3-diamino-2-butanol (V) using HBTU produced amide (VI). After acid cleavage of the Boc protecting group of (VI), the resulting amine (VII) was coupled with N-Boc-leucine (VIII), yielding adduct (IX). Subsequent acidic deprotection of (IX) provided the intermediate amine (X).
| 【1】 Bondinell, W.E.; Desjarlais, R.L.; Yamashita, D.S.; Veber, D.F. (GlaxoSmithKline Inc.); Protease inhibitors. WO 9959526 . |
| 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) | 50901 | methyl 2-(3-bromophenyl)acetate | 150529-73-0 | C9H9BrO2 | 详情 | 详情 |
| (II) | 50902 | 2-Pyridyl trifluoromethanesulfonate; 2-Pyridyl triflate | C6H4F3NO3S | 详情 | 详情 | |
| (III) | 50903 | methyl 2-[3-(2-pyridinyl)phenyl]acetate | C14H13NO2 | 详情 | 详情 | |
| (IV) | 50904 | 2-[3-(2-pyridinyl)phenyl]acetic acid | C13H11NO2 | 详情 | 详情 | |
| (V) | 50905 | tert-butyl (1S)-3-amino-2-hydroxy-1-methylpropylcarbamate | C9H20N2O3 | 详情 | 详情 | |
| (VI) | 50906 | tert-butyl (1S)-2-hydroxy-1-methyl-3-([2-[3-(2-pyridinyl)phenyl]acetyl]amino)propylcarbamate | C22H29N3O4 | 详情 | 详情 | |
| (VII) | 50907 | N-[(3S)-3-amino-2-hydroxybutyl]-2-[3-(2-pyridinyl)phenyl]acetamide | C17H21N3O2 | 详情 | 详情 | |
| (VIII) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
| (IX) | 50908 | tert-butyl (1S)-1-([[(1S)-2-hydroxy-1-methyl-3-([2-[3-(2-pyridinyl)phenyl]acetyl]amino)propyl]amino]carbonyl)-3-methylbutylcarbamate | C28H40N4O5 | 详情 | 详情 | |
| (X) | 50909 | (2S)-2-amino-N-[(1S)-2-hydroxy-1-methyl-3-([2-[3-(2-pyridinyl)phenyl]acetyl]amino)propyl]-4-methylpentanamide | C23H32N4O3 | 详情 | 详情 |
合成路线20
该中间体在本合成路线中的序号：(XVII)Coupling of N-Boc-L-leucine (XVII) with glycine benzyl ester (XVIII), followed by acidic N-Boc group cleavage, affords the dipeptide benzyl ester (XIX), which is submitted to coupling with N-Boc-L-isoleucine (XX) and further benzyl ester hydrogenolysis to give rise to the N-Boc tripeptide (XXI). Then, assembly between (XXI) and pentapeptide (XVI) is accomplished by means of EDC/HOBt, providing the protected peptide (XXII). Hydrogenolysis of the benzyl groups of (XXII), followed by Boc group cleavage with trifluoroacetic acid, leads to the fully deprotected octapeptide (XXIII).
| 【1】 Rawale, S.; Hrihorczuk, L.M.; Wei, W.-Z.; Zemlicka, J.; Synthesis and biological activity of the prodrug of class I major histocompatibility peptide GILGFVFTL activated by Beta-glucuronidase. J Med Chem 2002, 45, 4, 937. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVI) | 65161 | benzyl (2S,5S,8S,11S,14S)-14-amino-8-benzyl-5-[(1R)-1-(benzyloxy)ethyl]-2-isobutyl-11-isopropyl-4,7,10,13-tetraoxo-15-phenyl-3,6,9,12-tetraazapentadecan-1-oate | C47H59N5O7 | 详情 | 详情 | |
| (XVII) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
| (XVIII) | 13601 | benzyl 2-aminoacetate; Glycine benzyl ester hydrochloride | 1738-68-7 | C9H11NO2 | 详情 | 详情 |
| (XIX) | 65167 | benzyl 2-{[(2S)-2-amino-4-methylpentanoyl]amino}acetate | C15H22N2O3 | 详情 | 详情 | |
| (XX) | 30009 | (2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentanoic acid | 13139-16-7 | C11H21NO4 | 详情 | 详情 |
| (XXI) | 65166 | (6S,9S)-9-isobutyl-2,2-dimethyl-6-[(1S)-1-methylpropyl]-4,7,10-trioxo-3-oxa-5,8,11-triazatridecan-13-oic acid | C19H35N3O6 | 详情 | 详情 | |
| (XXII) | 65165 | benzyl (6S,9S,15S,18S,21S,24S,27S)-15,21-dibenzyl-24-[(1R)-1-(benzyloxy)ethyl]-9,27-diisobutyl-18-isopropyl-2,2-dimethyl-6-[(1S)-1-methylpropyl]-4,7,10,13,16,19,22,25-octaoxo-3-oxa-5,8,11,14,17,20,23,26-octaazaoctacosan-28-oate | C66H92N8O12 | 详情 | 详情 | |
| (XXIII) | 65164 | (2S,5S,8S,11S,14S,20S,23S,24S)-23-amino-8,14-dibenzyl-5-[(1R)-1-hydroxyethyl]-2,20-diisobutyl-11-isopropyl-24-methyl-4,7,10,13,16,19,22-heptaoxo-3,6,9,12,15,18,21-heptaazahexacosan-1-oic acid | C47H72N8O10 | 详情 | 详情 |
合成路线21
该中间体在本合成路线中的序号：(X)Condensation of N-Boc-L-leucine (X) with L-phenylalanine methyl ester (XI) in the presence of DIEA, HOBt and BOP in DMF gives the protected dipeptide (XII). Dipeptide (XII) is then deprotected by means of TFA in CH2Cl2 to yield L-Leu-L-Phe-OMe trifluoroacetate salt (XIII), which without isolation is then condensed with N-Boc-Lhomophenylalanine (XIV) in the presence of DIEA, HOBt and BOP in acetonitrile to yield the protected tripeptide (XV) . Then, N-deprotection of peptide (XV) by means of TFA in CH2Cl2 gives tripeptide (XVI), which is finally coupled with chloroacetyl chloride (XVII) in the presence of DIEA in DMF .
| 【1】 Phiasivongsa, P., Sehl, L.C., Fuller, W.D., Laidig, G.J. (Proteolix, Inc.). Crystalline peptide epoxy ketone protease inhibitors and the synthesis of amino acid keto-epoxides. WO 2009045497. |
| 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) | 69390 | (R)-methyl 2-((S)-2-((R)-2-(2-chloroacetamido)-4-phenylbutanamido)-4-methylpentanamido)-3-phenylpropanoate | C28H36ClN3O5 | 详情 | 详情 | |
| (X) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
| (XI) | 12324 | methyl (2R)-2-amino-3-phenylpropanoate | 21685-51-8 | C10H13NO2 | 详情 | 详情 |
| (XII) | 69398 | L-Phenylalanine,N-[(1,1-dimethylethoxy)carbonyl]-L-leucyl-, methyl ester;tert-butyloxycarbonyl-leucylphenylalanine methyl ester;(R)-methyl 2-((S)-2-((tert-butoxycarbonyl)amino)-4-methylpentanamido)-3-phenylpropanoate | 5874-73-7 | C21H32N2O5 | 详情 | 详情 |
| (XIII) | 69399 | (R)-methyl 2-((S)-2-amino-4-methylpentanamido)-3-phenylpropanoate 2,2,2-trifluoroacetate;L-Leu-L-Phe-OMe trifluoroacetate salt | C16H24N2O3.C2HF3O2 | 详情 | 详情 | |
| (XIV) | 12874 | (2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine | 13734-34-4 | C14H19NO4 | 详情 | 详情 |
| (XV) | 69400 | (6S,9S,12R)-methyl 12-benzyl-9-isobutyl-2,2-dimethyl-4,7,10-trioxo-6-phenethyl-3-oxa-5,8,11-triazatridecan-13-oate | C31H43N3O6 | 详情 | 详情 | |
| (XVI) | 69401 | (R)-methyl 2-((S)-2-((R)-2-amino-4-phenylbutanamido)-4-methylpentanamido)-3-phenylpropanoate 2,2,2-trifluoroacetate | C26H35N3O4.C2HF3O2 | 详情 | 详情 | |
| (XVII) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
合成路线22
该中间体在本合成路线中的序号：(X)The tripeptide benzyl ester precursor (IV) is prepared by the following procedure. Condensation of N-Boc-L-leucine (X) with L-phenylalanine benzyl ester (XVIII) in the presence of DIEA, HOBt and PyBOP in acetonitrile gives the protected dipeptide (XIX), which upon deprotection by means of TFA in CH2Cl2 yields dipeptide (XX). Without isolation, intermediate (XX) is then condensed with N-Boc-L-homophenylalanine (XIV) in the presence of DEEA (diethyl-aminoethanol), HOBt and PyBOP in acetonitrile to provide protected tripeptide (XXI) , which is finally N-deprotected by means of TFA in CH2Cl2 .
| 【1】 Smyth, M.S., Laidig, G.J. (Proteolix, Inc.). Compounds for proteasome enzyme inhibition. CA 2589765, EP 1781688, JP 2008509166, US 2009131421, WO 2006017842. |
| 【2】 Smyth, M.S., Laidig, G.J., Borchardt, R.T. et al. (Proteolix, Inc.). Compounds for proteasome enzyme inhibition. EP 1745064, JP 2008501637, US 2005245435, US 2008200398, US 7232818, WO 2005105827. |
| 【3】 Smyth, M.S., Laidig, G.J. (Proteolix, Inc.). Compounds for enzyme inhibition. US 2006030533, US 7417042. |
| 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) | 69393 | (R)-benzyl 2-((S)-2-((R)-2-amino-4-phenylbutanamido)-4-methylpentanamido)-3-phenylpropanoate 2,2,2-trifluoroacetate | C32H39N3O4.C2HF3O2 | 详情 | 详情 | |
| (X) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
| (XIV) | 12874 | (2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine | 13734-34-4 | C14H19NO4 | 详情 | 详情 |
| (XVIII) | 27693 | benzyl (2S)-2-amino-3-phenylpropanoate；L-phenylalanine benzyl ester | C16H17NO2 | 详情 | 详情 | |
| (XIX) | 69402 | (R)-benzyl 2-((S)-2-((tert-butoxycarbonyl)amino)-4-methylpentanamido)-3-phenylpropanoate | C27H36N2O5 | 详情 | 详情 | |
| (XX) | 69403 | (R)-benzyl 2-((S)-2-amino-4-methylpentanamido)-3-phenylpropanoate 2,2,2-trifluoroacetate | C22H28N2O3.C2HF3O2 | 详情 | 详情 | |
| (XXI) | 69404 | (6S,9S,12R)-benzyl 12-benzyl-9-isobutyl-2,2-dimethyl-4,7,10-trioxo-6-phenethyl-3-oxa-5,8,11-triazatridecan-13-oate | C37H47N3O6 | 详情 | 详情 |
合成路线23
该中间体在本合成路线中的序号：(X)Condensation of N-Boc-leucine (X) with N,O-dimethylhydroxylamine hydrochloride by means of i-BuOCOCl, NMM and Et3N in CH2Cl2 gives N-Boc-L-leucine Weinreb amide (XXVII) , which is then coupled with isopropenyl magnesium bromide (XXVIII) in THF (1) or 2-bromopropene (XXIX) in the presence of BuLi in Et2O at –78 °C to yield the heptenone derivative (XXX) . Reduction of heptenone (XXX) with NaBH4 and CeCl3·7H2O in MeOH results in a diastereomeric mixture of allylic alcohols (XXXIa) and (XXXIb), which is then epoxidized by treatment with mCPBA in CH2Cl2 to afford a mixture of oxiranes (XXXIIa) and (XXXIIb). Finally, this mixture is oxidized with Dess Martin periodinane in acetonitrile, followed by chromatographic separation . Compound (XXVI) can also be prepared by epoxidation of heptenone derivative (XXX) with H2O2 in the presence of PhCN and DIEA in MeOH or NaOCl in pyridine or Ca(OCl)2 in NMP , followed by separation by means of column chromatography .
| 【2】 Sin, N., Kim, K.B., Elofsson, M., Meng, L., Auth, H., Kwok, B.H.B., Crews, C.M. Total synthesis of the potent proteasome inhibitor epoximicin: A useful tool for understanding proteosome biology. Bioorg Med Chem Lett 1999, 9(15): 2283-8. |
| 【1】 Phiasivongsa, P., Sehl, L.C., Fuller, W.D., Laidig, G.J. (Proteolix, Inc.). Crystalline peptide epoxy ketone protease inhibitors and the synthesis of amino acid keto-epoxides. WO 2009045497. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXIa) | 69411 | tert-butyl ((3S,4R)-3-hydroxy-2,6-dimethylhept-1-en-4-yl)carbamate | C14H27NO3 | 详情 | 详情 | |
| (XXXIb) | 69412 | tert-butyl ((3R,4R)-3-hydroxy-2,6-dimethylhept-1-en-4-yl)carbamate | C14H27NO3 | 详情 | 详情 | |
| (XXXIIa) | 69413 | tert-butyl ((1R,2S)-1-hydroxy-4-methyl-1-(2-methyloxiran-2-yl)pentan-2-yl)carbamate | C14H27NO4 | 详情 | 详情 | |
| (XXXIIb) | 69414 | tert-butyl ((1S,2S)-1-hydroxy-4-methyl-1-(2-methyloxiran-2-yl)pentan-2-yl)carbamate | C14H27NO4 | 详情 | 详情 | |
| (X) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
| (XXVI) | 43028 | tert-butyl ((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)carbamate；tert-butyl (1S)-3-methyl-1-[[(2R)-2-methyloxiranyl]carbonyl]butylcarbamate | C14H25NO4 | 详情 | 详情 | |
| (XXVII) | 40395 | tert-butyl (1S)-1-[[methoxy(methyl)amino]carbonyl]-3-methylbutylcarbamate | C13H26N2O4 | 详情 | 详情 | |
| (XXVIII) | 43649 | bromo(isopropenyl)magnesium；isopropenyl magnesium bromide；1-Methylvinylmagnesiumbromide;1-Propen-2-ylmagnesium bromide;a-Methylvinylmagnesium bromide | 13291-18-4 | C3H5BrMg | 详情 | 详情 |
| (XXIX) | 42375 | 2-bromo-1-propene；2-bromopropene;Isopropenyl bromide;a-Methylvinyl bromide | 557-93-7 | C3H5Br | 详情 | 详情 |
| (XXX) | 43027 | tert-butyl (1S)-1-isobutyl-3-methyl-2-oxo-3-butenylcarbamate | C14H25NO3 | 详情 | 详情 |