Yaozh News Star Club Edu TOP100 Customer Service APP
Iphone Download Android Download
  • English
  • 简体中文
Login Register
Search
Current Location： Home > Feedback Help Print

【结 构 式】

【分子编号】16734

【品名】(2S)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-L-proline; (2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid

【CA登记号】

【 分 子 式 】C10H17NO4

【 分 子 量 】215.24932

【元素组成】C 55.8% H 7.96% N 6.51% O 29.73%
与该中间体有关的原料药合成路线共 23 条
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6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15合成路线16合成路线17合成路线18合成路线19合成路线20合成路线21合成路线22合成路线23

合成路线1

该中间体在本合成路线中的序号：(XI)

Coupling of benzyloxy isovalery propionic acid (Bzl-Hip-OH) (I) with leucine trimethylsilylethyl ester (II) by means of HOBt and DCC followed by hydrogenation over Pd/C in isopropanol for benzyl protecting group removal provides dipeptide (III), which is then converted into compound (V) by first coupling to Boc-Sta(TBDMS)-OH (IV) by means of DMAP and DCC followed by removal of the TMSe group by means of TBAF. Coupling between Z-D-N-MeLeu-OH (VI) and H-Thr-OTMSe (VII) by means of N-hydroxysuccinimide (NHS) and EDC yields protected dipeptide (VIII), which is then condensed with dipeptide (IX) by means of DMAP and DCC and then treated with HCl in EtOAc for Boc removal to afford tetrapeptide (X) (in turn, dipeptide (IX) can be obtained by coupling between Boc-Pro-OH (XI) and Me2Tyr-ONb (XII) by means of EDC followed by p-nitrobenzyl removal by hydrogenation over Pd/C in HOAc). Coupling of tetrapeptide (X) with compound (V) by means of EDC, HOBt leads to formation of linear peptide (XIII), which is partially deprotected by treatment with TBAF and TFA and then cyclized by means of HOBt, EDC and NMM, providing macrolide (XIV).

参考文献 中间体
合成目标
【1】 Rinehart, K.L.; et al.; Total synthesis of didemnins A, B, and C. J Am Chem Soc 1987, 109, 22, 6846.
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) 50799 (2S,4S)-4-(benzyloxy)-2,5-dimethyl-3-oxohexanoic acid C15H20O4 详情 详情
(II) 50800 2-(trimethylsilyl)ethyl (2S)-2-amino-4-methylpentanoate C11H25NO2Si 详情 详情
(III) 50801 2-(trimethylsilyl)ethyl (2S)-2-[[(2S,4S)-4-hydroxy-2,5-dimethyl-3-oxohexanoyl]amino]-4-methylpentanoate C19H37NO5Si 详情 详情
(IV) 50802 (3S,4R,5S)-4-[(tert-butoxycarbonyl)amino]-3-[[tert-butyl(dimethyl)silyl]oxy]-5-methylheptanoic acid C19H39NO5Si 详情 详情
(V) 50803 (6R,7S,11S,13S,16S)-7-[[tert-butyl(dimethyl)silyl]oxy]-16-isobutyl-11-isopropyl-2,2,13-trimethyl-6-[(1S)-1-methylpropyl]-4,9,12,14-tetraoxo-3,10-dioxa-5,15-diazaheptadecan-17-oic acid C33H62N2O9Si 详情 详情
(VI) 50772 (2R)-2-[[(benzyloxy)carbonyl](methyl)amino]-4-methylpentanoic acid C15H21NO4 详情 详情
(VII) 50804 2-(trimethylsilyl)ethyl (2S,3R)-2-amino-3-hydroxybutanoate C9H21NO3Si 详情 详情
(VIII) 50805 2-(trimethylsilyl)ethyl (2S,3R)-2-([(2R)-2-[[(benzyloxy)carbonyl](methyl)amino]-4-methylpentanoyl]amino)-3-hydroxybutanoate C24H40N2O6Si 详情 详情
(IX) 50806 (2S)-2-[[[(2S)-1-(tert-butoxycarbonyl)pyrrolidinyl]carbonyl](methyl)amino]-3-(4-methoxyphenyl)propionic acid C21H30N2O6 详情 详情
(X) 50807 2-(trimethylsilyl)ethyl (2S,3R)-2-([(2R)-2-[[(benzyloxy)carbonyl](methyl)amino]-4-methylpentanoyl]amino)-3-[((2S)-3-(4-methoxyphenyl)-2-[methyl[(2S)pyrrolidinylcarbonyl]amino]propanoyl)oxy]butanoate C40H60N4O9Si 详情 详情
(XI) 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
(XII) 50808 　 C11H14NNbO3 详情 详情
(XIII) 50809 2-(trimethylsilyl)ethyl (2S,3R)-2-([(2R)-2-[[(benzyloxy)carbonyl](methyl)amino]-4-methylpentanoyl]amino)-3-[[(2S)-2-[[((2S)-1-[(2S,5S,7S,11S,12R)-11-[[tert-butyl(dimethyl)silyl]oxy]-2-isobutyl-7-isopropyl-5,16,16-trimethyl-12-[(1S)-1-methylpropyl]-4 C73H120N6O17Si2 详情 详情
(XIV) 50810 benzyl (1R)-1-[([(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 C57H84N6O14 详情 详情

合成路线2

该中间体在本合成路线中的序号：(IX)

The reaction of N-Boc-L-proline (IX) with O-methylhydroxylamine (II) gives the corresponding amide (X), which is reduced with LiAlH4 to N-Boc-L-prolinal (XI). The condensation of (XI) with boronate (XII) yields the carbinol (XIII) as the greater isomer, and it is methylated with Me-I and NaH to afford the methyl ether (XIV). Finally, the terminal double bond of (XIV) is oxidated by means of RuO4 to furnish the desired intermediate, the amino acid (XV).

参考文献 中间体
合成目标
【1】 Roux, F.; et al.; Synthesis of dolastatin-10 and [R-Doe]-dolastatin-10. Tetrahedron 1994, 50, 18, 5345.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(II) 46320 tert-butyl (2S)-2-[[methoxy(methyl)amino]carbonyl]-1-pyrrolidinecarboxylate C12H22N2O4 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) 13361 (Methoxyamino)methane; N,O-Dimethylhydroxylamine 1117-97-1 C2H7NO 详情 详情
(XI) 16724 tert-Butyl (2S)-2-formyltetrahydro-1H-pyrrole-1-carboxylate; tert-Butoxycarbonyl-L-prolinal 69610-41-9 C10H17NO3 详情 详情
(XII) 54600 2-[(Z)-2-butenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane C10H19BO2 详情 详情
(XIII) 54601 tert-butyl (2S)-2-[(1R,2S)-1-hydroxy-2-methyl-3-butenyl]-1-pyrrolidinecarboxylate C14H25NO3 详情 详情
(XIV) 54602 tert-butyl (2S)-2-[(1R,2S)-1-methoxy-2-methyl-3-butenyl]-1-pyrrolidinecarboxylate C15H27NO3 详情 详情
(XV) 23520 (2R,3R)-3-[(2S)-1-(tert-butoxycarbonyl)pyrrolidinyl]-3-methoxy-2-methylpropionic acid C14H25NO5 详情 详情

合成路线3

该中间体在本合成路线中的序号：(VII)

The reaction of N-Boc-L-prolinal (VII) with the boron enolate (VIII) in ethyl ether gives the chiral beta-hydroxythioester (IX), which is transesterified with K2CO3 and ethanol to afford the beta-hydroxypropionate (X). The methylation of the OH group of (X) with LiHMDS and Me-OTf as before provides the methoxyester (XI), which is finally hydrolyzed with LiOH in aq. ethanol to furnish the desired intermediate, the methoxy amino acid (XII).

参考文献 中间体
合成目标
【1】 Tomioka, K.; et al.; An expeditious synthesis of dolastatin 10. Tetrahedron 1991, 32, 21, 2395.
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) 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
(VIII) 54620 9-{[(E)-1-(phenylsulfanyl)-1-propenyl]oxy}-9-borabicyclo[3.3.1]nonane; (E)-1-(9-borabicyclo[3.3.1]non-9-yloxy)-1-propenyl phenyl sulfide C17H23BOS 详情 详情
(IX) 54621 tert-butyl (2S)-2-[(1R,2R)-1-hydroxy-2-methyl-3-oxo-3-(phenylsulfanyl)propyl]-1-pyrrolidinecarboxylate C19H27NO4S 详情 详情
(X) 54622 tert-butyl (2S)-2-[(1R,2R)-3-ethoxy-1-hydroxy-2-methyl-3-oxopropyl]-1-pyrrolidinecarboxylate C15H27NO5 详情 详情
(XI) 54623 tert-butyl (2S)-2-[(1R,2R)-3-ethoxy-1-methoxy-2-methyl-3-oxopropyl]-1-pyrrolidinecarboxylate C16H29NO5 详情 详情
(XII) 23520 (2R,3R)-3-[(2S)-1-(tert-butoxycarbonyl)pyrrolidinyl]-3-methoxy-2-methylpropionic acid C14H25NO5 详情 详情

合成路线4

该中间体在本合成路线中的序号：(I)

The enantioselective condensation of N-Boc-L-prolinal (I) with the chiral 2-bromopropionyloxazolidinone (II) by means of Co(PPh3)4 in THF gives the chiral beta-hydroxyamide (III), which is methylated by means of trimethyloxonium tetrafluoroborate in dichloromethane to yield the methyl ether (IV). Finally, elimination of the chiral auxiliary of (IV) by means of LiOH and H2O2 affords the target amino acid intermediate (V) (see scheme no. 14950701a , intermediate (XV)).

参考文献 中间体
合成目标
【1】 Pettit, G.R.; Grealish, M.P.; A cobalt-phosphine complex directed reformatsky approach to a stereospecific synthesis of the dolastatin 10 unit dolaproine (Dap). J Org Chem 2001, 66, 25, 8640.
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) 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
(II) 54635 (4R,5S)-3-(2-bromopropanoyl)-4-methyl-5-phenyl-1,3-oxazolidin-2-one C13H14BrNO3 详情 详情
(III) 54614 tert-butyl (2S)-2-{(1R,2R)-1-hydroxy-2-methyl-3-[(4R,5S)-4-methyl-2-oxo-5-phenyl-1,3-oxazolidin-3-yl]-3-oxopropyl}-1-pyrrolidinecarboxylate C23H32N2O6 详情 详情
(IV) 54636 tert-butyl (2S)-2-{(1R,2R)-1-methoxy-2-methyl-3-[(4R,5S)-4-methyl-2-oxo-5-phenyl-1,3-oxazolidin-3-yl]-3-oxopropyl}-1-pyrrolidinecarboxylate C24H34N2O6 详情 详情
(V) 23520 (2R,3R)-3-[(2S)-1-(tert-butoxycarbonyl)pyrrolidinyl]-3-methoxy-2-methylpropionic acid C14H25NO5 详情 详情

合成路线5

该中间体在本合成路线中的序号：(IV)

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
合成目标
【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6

该中间体在本合成路线中的序号：(XI)

2) The reaction of tert-butoxycarbonyl-L-proline (XI) with diazomethane and triethylamine in ether gives the diazoketone (XII), which by treatment with acetic acid at 100 C yields the acetoxyketone (XIII). The deprotection of (XIII) with trifluoroacetic acid affords the unprotected alpha-hydroxyketone (XIV), which is condensed with N-(benzylaminecarbonyl)-L-proline (VI) by means of 1-hydroxybenzotriazole (HOBT) giving the acetylated dipeptide analogue (XV). Finally, this compound is deacetylated with K2CO3 in methanol/water.

参考文献 中间体
合成目标
【1】 Wroblewski, T.; Silvestre, J.S.; Castañer, J.; JTP-4819. Drugs Fut 1998, 23, 4, 384.
【2】 Kobayashi, K.; Akamatsu, M.; Yata, S.; Abe, H.; Toide, K.; Kogayu, M.; Uchida, I. (Japan Tobacco Inc.; Welfide Corporation); Cpd. with prolyl endopeptidase inhibitor activity and pharmaceutical use thereof. EP 0670309; JP 1995512967; US 5536737; WO 9412474 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VI) 16729 (2S)-1-[(benzylamino)carbonyl]tetrahydro-1H-pyrrole-2-carboxylic acid C13H16N2O3 详情 详情
(XI) 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
(XII) 16735 tert-butyl (2S)-2-(2-diazoacetyl)tetrahydro-1H-pyrrole-1-carboxylate 101130-03-4 C11H17N3O3 详情 详情
(XIII) 16736 tert-butyl (2S)-2-[2-(acetoxy)acetyl]tetrahydro-1H-pyrrole-1-carboxylate C13H21NO5 详情 详情
(XIV) 16737 2-oxo-2-[(2S)tetrahydro-1H-pyrrol-2-yl]ethyl acetate C8H13NO3 详情 详情
(XV) 16738 2-[(2S)-1-([(2S)-1-[(benzylamino)carbonyl]tetrahydro-1H-pyrrol-2-yl]carbonyl)tetrahydro-1H-pyrrol-2-yl]-2-oxoethyl acetate C21H27N3O5 详情 详情

合成路线7

该中间体在本合成路线中的序号：(X)

The reaction of N-(tert-butoxycarbonyl [Boc])-4-O-methyl-L-tyrosine (I) with N,O-dimethylhydroxylamine (II) by means of dicyclohexylcarbodiimide (DCC) in THF gives the corresponding amide (III), which is reduced with LiAlH4 in ethyl ether yielding N-(tert-butoxycarbonyl)-4-O-methyl-L-tyrosinal (IV). The reductocondensation of (IV) with Nomega-tosyl-L-arginine (V) in methanol/acetic acid affords Nalpha-[2(S)-(tert-butoxycarbonylamino)-3-(4-methoxyphenyl)propyl]-Nomega-tosyl-L-arginine (VI), which is then attached to a polyestyrene resin (Merrifield resin) by means of DCC and dimethylaminopyridine (DMAP) to give the starting peptide-resin complex (IX). This resin (IX) is introduced into a Beckman 990 peptide synthesizer and submitted to successive amino acid coupling cycles (deprotection with TFA and coupling with (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate [BOP]) in order to introduce successively Boc-L-proline (X), Boc-L-serine (XII), Boc-L-(2-thienyl)alanine (XIV), Boc-glycine (XVI), Boc-L-(4-benzyloxy)proline (XVIII), Boc-L-proline (X), and Boc-L-(Nomega-tosyl)arginine (XXI) yielding resins (XI), (XIII), (XV), (XVII), (XIX), (XX), and the final resin (XXII), successively. The final peptide (RMP-7) is liberated from the resin (XXII) and simultaneously deprotected by a treatment with anhydrous HF with a 10% anisole and purified by HPLC over a C18 reverse phase column using trifluoroacetic acid/acetonitrile with a 0-25% gradient. Tritiated RMP-7 is obtained by bromination of RMP-7 with Br2 in acetic acid giving a monobrominated compound (XXIII) (basically the 5-position of the thiophene ring of thienylalanine is brominated), which is then tritiated with 3H2 and Pd/C in water.

参考文献 中间体
合成目标
【1】 Graul, A.; Leeson, P.; Castañer, J.; RMP-7. Drugs Fut 1998, 23, 1, 32.
【2】 Straub, J.A.; Musso, G.F.; Smart, J.L.; Lang, C.; Akiyama, A.; Bromination and subsequent catalytic tritiation of thienylalanine and 4-methyltyrosine residues in the bradykinin analog RMP-7. J Label Compd Radiopharm 1994, 34, 12, 1217-26.
【3】 Malfroy-Camine, B.; Smart, J.L. (Alkermes, Inc.); Method for increasing blood-brain barrier permeability. WO 9116355 .
【4】 Kozarich, J.W.; Musso, G.F.; Malfroy-Camine, B. (Alkermes, Inc.); Increasing blood-brain barrier permeability with permeabilizer peptides. WO 9218529 .
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) 16875 (2S)-2-[(tert-Butoxycarbonyl)amino]-3-(4-methoxyphenyl)propionic acid; N-t-BOC-O-Methyl-L-tyrosine 53267-93-9 C15H21NO5 详情 详情
(II) 13361 (Methoxyamino)methane; N,O-Dimethylhydroxylamine 1117-97-1 C2H7NO 详情 详情
(III) 16877 tert-butyl N-[(1S)-1-(4-methoxybenzyl)-2-[methoxy(methyl)amino]-2-oxoethyl]carbamate C17H26N2O5 详情 详情
(IV) 16878 tert-butyl N-[(1S)-1-formyl-2-(4-methoxyphenyl)ethyl]carbamate C15H21NO4 详情 详情
(V) 16879 (2S)-2-amino-5-[[imino(methylamino)methyl]amino]pentanoic acid C7H16N4O2 详情 详情
(VI) 16880 (2S)-2-[[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-methoxyphenyl)propyl]amino]-5-[[imino(methylamino)methyl]amino]pentanoic acid C22H37N5O5 详情 详情
(VII) 16881 (2S)-2-[benzyl[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-methoxyphenyl)propyl]amino]-5-[[imino(methylamino)methyl]amino]pentanoic acid C29H43N5O5 详情 详情
(IX) 16883 methyl (2S)-2-[benzyl[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-methoxyphenyl)propyl]amino]-5-[[imino(methylamino)methyl]amino]pentanoate C30H45N5O5 详情 详情
(X) 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
(XI) 16885 tert-butyl (2S)-2-[(3S,6S)-5-benzyl-11-imino-3-(4-methoxybenzyl)-6-(methoxycarbonyl)-2,5,10,12-tetraazatridec-1-anoyl]-1-pyrrolidinecarboxylate C35H52N6O6 详情 详情
(XII) 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) 16887 methyl (2S)-2-[benzyl[(2S)-2-[[((2S)-1-[(2S)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propanoyl]pyrrolidinyl)carbonyl]amino]-3-(4-methoxyphenyl)propyl]amino]-5-[[imino(methylamino)methyl]amino]pentanoate C45H63N7O8 详情 详情
(XIV) 16888 (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-thienyl)propionic acid；Boc-D-2-Thienylalanine 78452-55-8 C12H17NO4S 详情 详情
(XV) 16889 methyl (2S)-2-[benzyl[(2S)-2-([[(2S)-1-((2S)-3-(benzyloxy)-2-[[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-thienyl)propanoyl]amino]propanoyl)pyrrolidinyl]carbonyl]amino)-3-(4-methoxyphenyl)propyl]amino]-5-[[imino(methylamino)methyl]amino]pentanoate C52H70N8O9S 详情 详情

合成路线8

该中间体在本合成路线中的序号：(VI)

The enantioselective reduction of the oxazolidinone (I) with BH3/SMe2 and a chiral borinated catalyst gives the (S)-alcohol (II), which is condensed with the labeled imine (III) (prepared by reaction of 4-fluoroaniline (IV) and 13C-labeled 4-hydroxybenzaldehyde (V)) by means of TiCl4 in dichloromethane to yield the silylated adduct (VI) (previously the reactants are silylated with Tms-Cl and DIEA). Finally, adduct (VI) is resilylated with bis(trimethylsilyl)acetamide and cyclized and desilylated by treatment with TBAF in dichloromethane to afford the target 13C-labeled SCH-58235.

参考文献 中间体
合成目标
【1】 Hesk, D.; et al.; Synthesis of 3H, 14C and 13C6 labelled Sch 58235. J Label Compd Radiopharm 2002, 45, 2, 145.
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) 53476 1-(4-fluorophenyl)-5-[(4S)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]-1,5-pentanedione n/a C20H18FNO4 详情 详情
(II) 53477 (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1,3-oxazolidin-2-one n/a C20H20FNO4 详情 详情
(III) 53478 　 n/a C13H10FNO 详情 详情
(III) 53481 4-{[(4-fluorophenyl)imino]methyl}phenol 3382-63-6 C13H10FNO 详情 详情
(IV) 37690 4-fluorophenylamine; 4-fluoroaniline 371-40-4 C6H6FN 详情 详情
(V) 13433 4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde 123-08-0 C7H6O2 详情 详情
(V) 53479 　 n/a C7H6O2 详情 详情
(VI) 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
(VI) 53480 　 n/a C37H40F2N2O7SSi 详情 详情

合成路线9

该中间体在本合成路线中的序号：(XXXII)

In a related semisynthetic strategy, didemnin A (XXIX) was first acylated by N-Boc-L-proline (XXXIII) yielding amide (XXXIV), which was further deprotected by treatment with HCl in EtOAc. The resultant prolyl didemnin A (XXXV) was then coupled with pyruvic acid (XXX) to furnish the title compound

参考文献 中间体
合成目标
【1】 Rinehart, K.L.; Katauskas, A.J. (University of Illinois); Semi-synthetic studies toward didemnin analogues. EP 0973518; JP 2001503746; WO 9817275 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXIX) 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
(XXX) 24060 3-chloro-N-(3-methoxyphenethyl)-N-methyl-1-propanamine C13H20ClNO 详情 详情
(XXXII) 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
(XXXIV) 62543 tert-butyl (2S)-2-{[{(1R)-1-[({(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]dioxatetraaz C59H93N7O15 详情 详情
(XXXV) 62544 (2S)-N-{(1R)-1-[({(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]dioxatetraazacyclotricosi C54H85N7O13 详情 详情

合成路线10

该中间体在本合成路线中的序号：(XXXIII)

In an alternative synthesis, the previously reported trichloroethyl ester (XXXVI) was deprotected by treatment with zinc dust in the presence of ammonium acetate yielding acid (XXXVII). This was then coupled to proline trichloroethyl ester (XXXVIII), prepared from N-Boc-L-proline (XXXIII), to furnish amide (XXXIX). Subsequent hydrogenolysis of the O-benzyl group of (XXXIX) provided intermediate (XL)

参考文献 中间体
合成目标
【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.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXXIII) 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
(XXXVI) 62545 2,2,2-trichloroethyl (2S)-2-{[(4S)-4-(benzyloxy)-2,5-dimethyl-3-oxohexanoyl]amino}-4-methylpentanoate C23H32Cl3NO5 详情 详情
(XXXVII) 62546 (2S)-2-{[(4S)-4-(benzyloxy)-2,5-dimethyl-3-oxohexanoyl]amino}-4-methylpentanoic acid C21H31NO5 详情 详情
(XXXVIII) 62547 2,2,2-trichloroethyl (2S)-2-pyrrolidinecarboxylate C7H10Cl3NO2 详情 详情
(XXXIX) 62548 2,2,2-trichloroethyl (2S)-1-((2S)-2-{[(4S)-4-(benzyloxy)-2,5-dimethyl-3-oxohexanoyl]amino}-4-methylpentanoyl)-2-pyrrolidinecarboxylate C28H39Cl3N2O6 详情 详情
(XL) 62549 2,2,2-trichloroethyl (2S)-1-((2S)-2-{[(4S)-4-hydroxy-2,5-dimethyl-3-oxohexanoyl]amino}-4-methylpentanoyl)-2-pyrrolidinecarboxylate C21H33Cl3N2O6 详情 详情

合成路线11

该中间体在本合成路线中的序号：(IX)

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.

参考文献 中间体
合成目标
【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12

该中间体在本合成路线中的序号：(XXVII)

Peptide resin (XX) was subjected to sequential coupling-deprotection cycles with the following amino acids: N-Boc-(2-thienyl)alanine (XXI), N-Boc-glycine (XXIII), N-Boc-4-hydroxyproline (XXV), N-Boc-proline (XXVII), Nalpha-Boc-Ngamma-tosyl-arginine (XXIX) and Nalpha-Boc-Ngamma-nitro-D-arginine (XXXI) to produce peptide resins (XXII), (XXIV), (XXVI), (XXVIII), (XXX) and (XXXII), respectively. The title peptide was finally obtained by deprotection and cleavage from the resin by means of treatment with HF.

参考文献 中间体
合成目标
【1】 Daffix, I.; Bergé, G.; Amblard, M.; et al.; Synthesis and characterization of bradykinin B2 receptor agonists containing constrained dipeptide mimics. J Med Chem 1999, 42, 20, 4193.
【2】 Dodey, P.; Luccarini, J.-M.; Martinez, J.; Amblard, M.; Daffix, I. (Fournier Industrie et Santé); Peptides agonists of bradykinine B2 receptor. FR 2756566; WO 9824809 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XX) 39383 (2S)-2-([2-[(3S)-3-[[(2S)-2-amino-3-(benzyloxy)propanoyl]amino]-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetyl]amino)-5-[(amino[[(4-methylphenyl)sulfonyl]imino]methyl)amino]pentanoic acid C35H43N7O8S2 详情 详情
(XXI) 16888 (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-thienyl)propionic acid；Boc-D-2-Thienylalanine 78452-55-8 C12H17NO4S 详情 详情
(XXII) 39385 (2S)-5-[(amino[[(4-methylphenyl)sulfonyl]imino]methyl)amino]-2-([2-[(3S)-3-[[(2S)-2-[[(2S)-2-amino-3-(2-thienyl)propanoyl]amino]-3-(benzyloxy)propanoyl]amino]-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetyl]amino)pentanoic acid C42H50N8O9S3 详情 详情
(XXIII) 18066 N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid 4530-20-5 C7H13NO4 详情 详情
(XXIV) 39386 　 C44H53N9O10S3 详情 详情
(XXV) 19043 (2R,4S)-1-(tert-butoxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acid C10H17NO5 详情 详情
(XXVI) 39387 　 C49H60N10O12S3 详情 详情
(XXVII) 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
(XXVIII) 39388 　 C54H67N11O13S3 详情 详情

合成路线13

该中间体在本合成路线中的序号：(VII)

The compound was originally isolated from Aspergillus fumigatus. The synthesis of this compound was further described. Treatment of N-phthaloyltryptophan methyl ester (I) with tert-butyl hypochlorite and triethylamine at -78 C led to the formation of the intermediate 3-chloroindolenine (II). Reaction of tributyl prenyl stannane (III) with boron trichloride generated in situ the transient boron reagent (IV), which after condensation with chloroindolenine (II) produced the 3-prenylindole (V). Subsequent removal of the phthalimide protecting group of (V) by hydrazinolysis provided aminoester (VI). Coupling of (VI) with acid fluoride (VIII), (generated from N-Boc-L-proline (VII) and cyanuric fluoride), gave rise to amide (IX). The Boc protecting group of (IX) was cleaved employing iodotrimethylsilane, and the resulting aminoester (X) was then cyclized with methanolic ammonia to produce the target diketopiperazine.

参考文献 中间体
合成目标
【1】 Schkeryantz, J.M.; et al.; Total synthesis of gypsetin, deoxybrevianamide E, brevianamide E, and tryprostatin B: Novel constructions of 2,3-disubstituted indoles. J Am Chem Soc 1999, 121, 51, 11964.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 26782 Cyanuric fluoride; 2,4,6-trifluoro-1,3,5-triazine 675-14-9 C3F3N3 详情 详情
(I) 31493 methyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-(1H-indol-3-yl)propanoate C20H16N2O4 详情 详情
(II) 31494 methyl (2S)-3-(3-chloro-3H-indol-3-yl)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoate C20H15ClN2O4 详情 详情
(III) 31502 tributyl(3-methyl-2-butenyl)stannane C17H36Sn 详情 详情
(IV) 31503 dichloro(1,1-dimethyl-2-propenyl)borane C5H9BCl2 详情 详情
(V) 31504 methyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-[2-(3-methyl-2-butenyl)-1H-indol-3-yl]propanoate C25H24N2O4 详情 详情
(VI) 31505 methyl (2S)-2-amino-3-[2-(3-methyl-2-butenyl)-1H-indol-3-yl]propanoate C17H22N2O2 详情 详情
(VII) 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
(VIII) 31506 tert-butyl (2S)-2-(fluorocarbonyl)-1-pyrrolidinecarboxylate C10H16FNO3 详情 详情
(IX) 31507 tert-butyl (2S)-2-[[((1S)-2-methoxy-1-[[2-(3-methyl-2-butenyl)-1H-indol-3-yl]methyl]-2-oxoethyl)amino]carbonyl]-1-pyrrolidinecarboxylate C27H37N3O5 详情 详情
(X) 31508 methyl (2S)-3-[2-(3-methyl-2-butenyl)-1H-indol-3-yl]-2-[[(2S)pyrrolidinylcarbonyl]amino]propanoate C22H29N3O3 详情 详情

合成路线14

该中间体在本合成路线中的序号：(VI)

The title compound was synthesized by stepwise solid-phase peptide synthesis, starting from the protected arginine linked to PAM resin (I). After deprotection of the Boc group of (I) with trifluoroacetic acid, coupling with (Boc)-tryptophan (II) in the presence of TBTU and diisopropylethylamine afforded the dipeptide resin (III). Sequential deprotection and coupling cycles with (Boc)-D-cyclohexylalanine (IV), (Boc)-proline (VI), (Boc)-ornithine (VIII), and (Fmoc)-phenylalanine (X) provided the resins (V), (VII), (IX) and (XI), respectively.

参考文献 中间体
合成目标
【1】 Wong, A.K.; Shields, I.A.; Taylor, S.M.; Short, A.; Fairlie, D.P.; Haaima, G.; Finch, A.M.; Effects of a new C5a receptor antagonist on C5a- and endotoxin-induced neutropenia in the rat. Br J Pharmacol 1999, 126, 3, 551.
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) 19064 (2S)-2-[(tert-butoxycarbonyl)amino]-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoic acid C18H28N4O6S 详情 详情
(II) 16114 N-alpha-t-BOC-L-tryptophan; (2S)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propionic acid 13139-14-5 C16H20N2O4 详情 详情
(III) 29340 (2S)-2-[[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoic acid C29H38N6O7S 详情 详情
(IV) 29348 (2R)-2-[(tert-butoxycarbonyl)amino]-3-cyclohexylpropionic acid C14H25NO4 详情 详情
(V) 29341 (6R,9S,12S)-6-(cyclohexylmethyl)-12-[3-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]propyl]-9-(1H-indol-3-ylmethyl)-2,2-dimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecan-13-oic acid C38H53N7O8S 详情 详情
(VI) 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
(VII) 29342 (2S)-2-[[(2S)-2-[[(2R)-2-([[(2S)-1-(tert-butoxycarbonyl)pyrrolidinyl]carbonyl]amino)-3-cyclohexylpropanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoic acid C43H60N8O9S 详情 详情
(VIII) 29343 (2S)-5-amino-2-[(tert-butoxycarbonyl)amino]pentanoic acid 21887-64-9 C10H20N2O4 详情 详情
(IX) 29344 (2S)-2-[[(2S)-2-[((2R)-2-[[((2S)-1-[(2S)-5-amino-2-[(tert-butoxycarbonyl)amino]pentanoyl]pyrrolidinyl)carbonyl]amino]-3-cyclohexylpropanoyl)amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoic acid C48H70N10O10S 详情 详情
(X) 19030 (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-phenylpropionic acid; N-((9H-fluoren-9-ylmethoxy)carbonyl)-phenylalanine 35661-40-6 C24H21NO4 详情 详情
(XI) 29345 Fluorenylmethoxycarbonyl-L-phenylalanyl-L-ornithyl-L-prolyl-D-cyclohexylalanyl-L-tryptophyl-L-(Nomega-tosyl)arginine C67H81N11O11S 详情 详情

合成路线15

该中间体在本合成路线中的序号：(IV)

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
合成目标
【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16

该中间体在本合成路线中的序号：(VIII)

This compound has been obtained by two related ways: 1) The reaction of 1-(tert-butoxycarbonylamino)cyclopentane-1-carboxylic acid (I) with ammonia, EDC and HOBT gives the amide (II), which is deprotected with 4N HCl and condensed with N-(tert-butoxycarbonyl)-D-methionine (III) by means of EDC and HOBT yielding the dipeptide (IV). The cyclization of (IV) with methyl iodide and NaH affords the pyrrolidinone (V), which is deprotected with HCl and condensed with 1-(benzyloxycarbonyl)-L-proline (VI) by means of EDC and HOBT giving the protected seudopeptide (VII). Finally, this compound is deprotected by hydrogenation with H2 over Pd/C. 2) The deprotection of (V) with HCl and its condensation with 1-(tert-butoxycarbonyl)-L-proline (VIII) by means of EDC and HOBT gives the protected seudopeptide (IX), which is finally deprotected with 4N HCl.

参考文献 中间体
合成目标
【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) 30890 1-[(tert-butoxycarbonyl)amino]cyclopentanecarboxylic acid C11H19NO4 详情 详情
(II) 30891 tert-butyl 1-(aminocarbonyl)cyclopentylcarbamate C11H20N2O3 详情 详情
(III) 26710 (2R)-2-[(tert-butoxycarbonyl)amino]-4-(methylsulfanyl)butyric acid 5241-66-7 C10H19NO4S 详情 详情
(IV) 30892 tert-butyl (1R)-1-([[1-(aminocarbonyl)cyclopentyl]amino]carbonyl)-3-(methylsulfanyl)propylcarbamate C16H29N3O4S 详情 详情
(V) 30893 tert-butyl (3R)-1-[1-(aminocarbonyl)cyclopentyl]-2-oxopyrrolidinylcarbamate C15H25N3O4 详情 详情
(VI) 19113 (2S)-1-[(benzyloxy)carbonyl]-2-pyrrolidinecarboxylic acid 1148-11-4 C13H15NO4 详情 详情
(VII) 30894 benzyl (2S)-2-[([(3R)-1-[1-(aminocarbonyl)cyclopentyl]-2-oxopyrrolidinyl]amino)carbonyl]-1-pyrrolidinecarboxylate C23H30N4O5 详情 详情
(VIII) 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
(IX) 30895 tert-butyl (2S)-2-[([(3R)-1-[1-(aminocarbonyl)cyclopentyl]-2-oxopyrrolidinyl]amino)carbonyl]-1-pyrrolidinecarboxylate C20H32N4O5 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 compound was prepared by solid-phase peptide synthesis on a PAM-resin. Starting from a N(alpha)-Boc-N(gamma)-Tos-L-arginine resin (I), cleavage of the Boc protecting group by means of trifluoroacetic acid provided Arg(Tos)-resin (II). Coupling of (II) with N(alpha)-Boc-L-tryptophan (III) using O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) and diisopropylethylamine, followed by acid cleavage of the Boc group gave dipeptide resin (IV). This was in turn coupled and deprotected with the following amino acids N-Boc-D-cyclohexylalanine (V), N--Boc-L-proline (VII) and N(alpha)-Boc-N(delta)-Tos-L-ornithine (IX) to furnish the peptide resins (VI), (VIII), (X) and (XII), respectively.

参考文献 中间体
合成目标
【1】 Wong, A.K.; Finch, A.M.; Pierens, G.K.; Craik, D.J.; Taylor, S.M.; Fairlie, D.P.; Small molecular probes for G-protein-coupled C5a receptors: Conformationally constrained antagonists derived from the C terminus of the human plasma protein C5a. J Med Chem 1998, 41, 18, 3417.
【2】 Wong, A.K.; Fairlie, D.P.; Finch, A.M.; Wadi, S.K.; Craik, D.J.; Taylor, S.M.; Paczkowski, N.J.; Low-molecular-weight peptidic and cyclic antagonists of the receptor for the complement factor C5a. J Med Chem 1999, 42, 11, 1965.
【3】 Fairlie, D.; Wong, A.; Finch, A.M.; Taylor, S.M. (University of Queensland); Cyclic agonists and antagonists of C5a receptors and G protein-coupled receptors. EP 1017713; WO 9900406 .
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) 19064 (2S)-2-[(tert-butoxycarbonyl)amino]-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoic acid C18H28N4O6S 详情 详情
(II) 34498 (2S)-2-amino-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoic acid C13H20N4O4S 详情 详情
(III) 16114 N-alpha-t-BOC-L-tryptophan; (2S)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propionic acid 13139-14-5 C16H20N2O4 详情 详情
(IV) 34499 (2S)-2-[[(2S)-2-amino-3-(1H-indol-3-yl)propanoyl]amino]-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoic acid C24H30N6O5S 详情 详情
(V) 29348 (2R)-2-[(tert-butoxycarbonyl)amino]-3-cyclohexylpropionic acid C14H25NO4 详情 详情
(VI) 34500 (2S)-2-[[(2S)-2-[[(2R)-2-amino-3-cyclohexylpropanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoic acid C33H45N7O6S 详情 详情
(VII) 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
(VIII) 34505 (2S)-2-[[(2S)-2-[((2R)-3-cyclohexyl-2-[[(2S)pyrrolidinylcarbonyl]amino]propanoyl)amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoic acid C38H52N8O7S 详情 详情
(IX) 34501 (2S)-2-[(tert-butoxycarbonyl)amino]-5-[[(4-methylphenyl)sulfonyl]amino]pentanoic acid C17H26N2O6S 详情 详情
(X) 34502 　 C50H68N10O10S2 详情 详情

合成路线18

该中间体在本合成路线中的序号：(IV)

The compound was prepared by solid phase peptide synthesis on a p-methylbenzhydrylamine resin. Attachment of Boc-L-alanine (I) afforded resin (II). Subsequent deprotection of the Boc group of (II) gave the alanine-linked resin (III). Coupling of (III) with Boc-L-proline (IV), followed by Boc group cleavage yielded the dipeptide resin (V). Further coupling of (V) with N-Boc-(2S,3R)-3-amino-2-hydroxy-5-methylhexanoic acid (VI) furnished the tripeptide resin (VI). Finally, deprotection of the Boc group of (VI) and simultaneous cleavage from the resin by treatment with HF provided the title tripeptide amide.

参考文献 中间体
合成目标
【1】 Maggiora, L.L.; Simmons, W.H.; Orawski, A.T.; Apstatin analogue inhibitors of aminopeptidase P, a bradykinin-degrading enzyme. J Med Chem 1999, 42, 13, 2394.
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) 26450 Boc-L-Alanine;(S)-2-((tert-butoxycarbonyl)amino)propanoic acid;N-Boc-L-alanine; (2S)-2-[(tert-butoxycarbonyl)amino]propionic acid 15761-38-3 C8H15NO4 详情 详情
(II) 35168 tert-butyl (1S)-2-amino-1-methyl-2-oxoethylcarbamate C8H16N2O3 详情 详情
(III) 35169 (2S)-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) 35170 (2S)-N-[(1S)-2-amino-1-methyl-2-oxoethyl]-2-pyrrolidinecarboxamide C8H15N3O2 详情 详情
(VI) 35171 (2S,3R)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-5-methylhexanoic acid C12H23NO5 详情 详情
(VII) 35172 tert-butyl (1R)-1-[(1S)-2-[(2S)-2-([[(1S)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]-1-hydroxy-2-oxoethyl]-3-methylbutylcarbamate C20H36N4O6 详情 详情

合成路线19

该中间体在本合成路线中的序号：(XXI)

Simultaneous coupling of five N-Boc-arginin (XIX) residues to the free amino groups of the peptide template (XVIII), followed by acid deprotection of the Boc groups, furnished (XX). To this were assembled five N-Boc-proline residues (XXI) to provide, after acid deprotection, resin (XXII). Then, reductive condensation with Boc-protected lysinal (XXIII) furnished the protected pseudopeptide adduct (XXIV). Finally, simultaneous cleavage from the resin and removal of protecting groups was effected by treatment with anhydrous hydrogen fluoride.

参考文献 中间体
合成目标
【1】 Callebaut, C.; et al.; Inhibition of HIV infection by pseudopeptides blocking viral envelope glycoprotein-mediated membrane fusion and cell death. Virology 1996, 218, 1, 181.
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) 42143 (3S,6S,9R,15R)-3,9-bis(4-aminobutyl)-1-[(2S)-1-((5S,8S)-5-(4-aminobutyl)-16-(4-chlorophenyl)-8-[[(2S)-2,6-diaminohexanoyl]amino]-4,7,14-trioxo-15-oxa-3,6,13-triazahexadec-1-anoyl)pyrrolidinyl]-6-[3-(cyclohexyloxy)-3-oxopropyl]-15-[[(4-methylbenzyl)s C70H111ClN14O15S 详情 详情
(XIX) 14073 (2S)-5-[[Amino(imino)methyl]amino]-2-[(tert-butoxycarbonyl)amino]pentanoic acid 13726-76-6 C11H22N4O4 详情 详情
(XX) 42144 　 C100H171ClN34O24S 详情 详情
(XXI) 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
(XXII) 42145 　 C81H126ClN19O17SArg4Pro4 详情 详情
(XXIII) 42146 tert-butyl (1S)-5-[(tert-butoxycarbonyl)amino]-1-formylpentylcarbamate C16H30N2O5 详情 详情
(XXIV) 42147 　 C205H350ClN53O50S 详情 详情

合成路线20

该中间体在本合成路线中的序号：(III)

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
合成目标
【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21

该中间体在本合成路线中的序号：(I)

The condensation of tert-butoxycarbonylproline (I) with methylamine (II), isovaleraldehyde (III) and ethyl isocyanoacetate (IV) in methanol gives Boc-Pro-Me-Leu-Gly-OEt (V), which is separated from its diastereoisomer by chromatography over silica gel. The reaction of (V) with ammonia in cold methanol yields the corresponding amide (VI). Finally this compound is deprotected by treatment with dry HCl in ethyl acetate

参考文献 中间体
合成目标
【1】 Blancafort, P.; Serradell, M.N.; Castaner, J.; Owen, R.T.; Pareptide. Drugs Fut 1979, 4, 11, 821.
【2】 Failli, A.; et al.; Synthetic MIF analoges. Part I:synthesis by four component condensation (4CC) and classical methods. Arzneim-Forsch 1977, 27, 12, 2286.
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) 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
(II) 11021 Methanamine; Methylamine 74-89-5 CH5N 详情 详情
(III) 26052 3-methylbutanal 590-86-3 C5H10O 详情 详情
(IV) 11877 Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate 105-56-6 C5H7NO2 详情 详情
(V) 60946 tert-butyl (2S)-2-{[((1R)-1-{[(2-ethoxy-2-oxoethyl)amino]carbonyl}-3-methylbutyl)(methyl)amino]carbonyl}-1-pyrrolidinecarboxylate C21H37N3O6 详情 详情
(VI) 60947 tert-butyl (2S)-2-{[((1R)-1-{[(2-amino-2-oxoethyl)amino]carbonyl}-3-methylbutyl)(methyl)amino]carbonyl}-1-pyrrolidinecarboxylate C19H34N4O5 详情 详情

合成路线22

该中间体在本合成路线中的序号：(II)

L-Proline (I) is protected as its N-Boc derivative (II) with Boc2O/NaOH in a two-phase system. N-Boc-Proline (II) is further converted into diazo ketone (III) via activation with ethyl chloroformate, followed by condensation with diazomethane. Subsequent treatment of diazo ketone (III) with AcOH leads to the acetoxy ketone (IV). Then, acidic N-Boc group cleavage in (IV) furnishes amine (V). On the other side, L-proline (I) is acylated by 4-phenylbutyryl chloride to produce the corresponding amide (VI). Coupling between 2-(acetoxyacetyl)pyrrolidine (V) and N-(phenylbutyryl)proline (VI) via activation with pivaloyl chloride leads to the amide adduct (VII). Finally, methanolysis of the acetate ester group of (VII) provides the target hydroxyacetyl compound.

参考文献 中间体
合成目标
【1】 Wallén, E.A.; Christiaans, J.A.M.; Saario, S.M.; Forsberg, M.M.; Venalainen, J.I.; Paso, H.M.; Mannisto, P.T.; Gynther, J.; 4-Phenylbutanoyl-2(S)-acylpyrrolidines and 4-phenylbutanoyl-L-prolyl-2(S)-acylpyrrolidines as prolyl oligopeptidase inhibitors. Bioorg Med Chem 2002, 10, 7, 2199.
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) 16131 methyl 4-(butyrylamino)-3-methylbenzoate C13H17NO3 详情 详情
(II) 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
(III) 64266 (L)-2-Diazoacetyl-pyrrolidine-1-carboxylic acid tertiary-butyl ester (L)-2-Diazoacetyl-pyrrolidine-1-carboxylic acid tertiary-butyl ester (L)-2-Diazoacetyl-pyrrolidine-1-carboxylic acid tertiary-butyl ester 101130-03-4 C11H17N3O3 详情 详情
(IV) 16736 tert-butyl (2S)-2-[2-(acetoxy)acetyl]tetrahydro-1H-pyrrole-1-carboxylate C13H21NO5 详情 详情
(V) 16737 2-oxo-2-[(2S)tetrahydro-1H-pyrrol-2-yl]ethyl acetate C8H13NO3 详情 详情
(VI) 64267 (2S)-1-(4-phenylbutanoyl)-2-pyrrolidinecarboxylic acid C15H19NO3 详情 详情
(VII) 64268 2-oxo-2-((2S)-1-{[(2S)-1-(4-phenylbutanoyl)pyrrolidinyl]carbonyl}pyrrolidinyl)ethyl acetate C23H30N2O5 详情 详情

合成路线23

该中间体在本合成路线中的序号：(III)

Daclatasvir can be prepared by two alternative methods:
Bromination of 4,4’-diacetylbiphenyl (I) with Br2 in CH2Cl2 generates 4,4’-bis(bromoacetyl)biphenyl (II), which is then condensed with NBoc-L-proline (III) in the presence of DIEA in acetonitrile to give the diester (IV). Subsequent cyclization of the keto ester (IV) with NH4OAc in toluene at 95-100 °C affords the bis(imidazole) precursor (V) . In an alternative method, coupling of N-Boc-L-proline (III) with 2-amino-4’-bromoacetophenone (VI) by means of HATU and DIEA in DMF provides the keto amide (VII), which undergoes cyclization to the imidazolyl-pyrrolidine (VIII) upon heating to 140 °C with NH4OAc in xylenes in a sealed tube. Treatment of the aryl bromide (VIII) with bis(pinacolato)diboron in the presence of Pd(PPh3)4 and KOAc in dioxane at 80 °C gives rise to the boronate ester (IX). Then, Suzuki coupling between bromide (VIII) and boronate (IX) using Pd(PPh3)4 and NaHCO3 in DME/H2O at 80 °C also affords the bis(imidazolyl)biphenyl precursor (V) . Deprotection of compound (V) with either TFA in CH2Cl2 or HCl in MeOH or i-PrOH/H2O at 50 °C provides the N-unsubstituted-bis(pyrrolidine) compound (X), which is then acylated with N-(methoxycarbonyl)-L-valine (XI) by means of EDC, HOBt·H2O and DIEA in acetonitrile, followed by treatment with HCl in EtOH .

参考文献 中间体
合成目标
【1】 Bachand, C., Belema, M., Deon, D.H. et al. (Bristol-Myers Squibb Co.). Hepatitis C virus inhibitors. EP 2049522, JP 201050013, WO 2008021927.
【2】 Pack, S.K., Geng, P., Smith, M.J., Hamm, J. (Bristol-Myers Squibb Co.). Process for synthesizing compounds useful for treating hepatitis C. CN 101778841, EP 2178863, JP 2010535784, US 2009043107, US 7728027, WO 2009020825.
【3】 Kim, S., Gao, Q., Yang, F. (Bristol-Myers Squibb Co.). Crystalline form of methyl ((1S)-1-(((2S)-2-(5-(4’-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenylyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate dihydrochloride salt. CN 101778840, EP 2183244, JP 2010535785, US 2009041716, WO 2009020828.
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) 68845 4,4'-Diacetylbiphenyl;1,1'-([1,1'-biphenyl]-4,4'-diyl)diethanone；1-(4'-Acetyl[1,1'-biphenyl]-4-yl)ethan-1-one 787-69-9 C16H14O2 详情 详情
(II) 68846 4,4’-bis(bromoacetyl)biphenyl;4,4'-Bis(2-bromoacetyl)biphenyl;1,1'-([1,1'-biphenyl]-4,4'-diyl)bis(2-bromoethanone);1,1'-(1,1'-Biphenyl)-4,4'-diylbis(2-bromoethan-1-one);2-Bromo-1-[4-[4-(2-bromoacetyl)phenyl]phenyl]ethanone;4,4'-Bis(2-bromoacetyl)biphenyl 4072-67-7 C16H12Br2O2 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) 68849 　 　 C36H44N2O10 详情 详情
(V) 68848 　 　 C36H44N6O4 详情 详情
(VI) 68851 2-amino-1-(4-bromophenyl)ethanone hydrochloride 　 C8H8BrNO.HCl 详情 详情
(VII) 68850 tert-butyl 2（S）-((2-(4-bromophenyl)-2-oxoethyl)carbamoyl)pyrrolidine-1-carboxylate 　 C18H23BrN2O4 详情 详情
(VIII) 68852 tert-butyl 2（S）-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate 　 C18H22BrN3O2 详情 详情
(IX) 68853 tert-butyl 2（S）-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate 　 C24H34BN3O4 详情 详情
(X) 68847 (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid 　 C22H32N6.4HCl 详情 详情
(XI) 68854 (S)-2-((methoxycarbonyl)amino)-3-methylbutanoic acid 　 C7H13NO4 详情 详情
Extended Information