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【结 构 式】

【分子编号】19733

【品名】(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid

【CA登记号】

【 分 子 式 】C10H19NO4

【 分 子 量 】217.2652

【元素组成】C 55.28% H 8.81% N 6.45% O 29.46%
与该中间体有关的原料药合成路线共 22 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1

该中间体在本合成路线中的序号：(B)

Coupling of Boc-Trp-OH (I) onto BHA resin by means of diisopropylcarbodiimide (DIPCDI) and HOBt in DMF followed by Boc removal by treatment with TFA in CH2Cl2 in the presence of mercaptoethanol provides on resin amino acid (II), which is converted into dipeptide (III) by coupling with Boc-Cys(Mbz)-OH by means of DIPCDI and HOBt followed by Boc removal by means of TFA in CH2Cl2. The same protocol of coupling and deprotection is followed for the incorporation of Boc-Val-OH and Boc-Lys(2-ClZ)-OH to furnish anchored tripeptide (IV), which is converted into protected octapeptide (V) by sequential amino acid couplings and deprotections by following the protocol described above. Simultaneous cleavage and protecting groups removal of resin (V) by treatment with HF in the presence of cresol and 1,2-ethanedithiol provides linear peptide (VI), which is finally oxidized by means of potassium ferrocyanide to furnish the desired product.

参考文献 中间体
合成目标
【1】 Schally, A.V.; Cai, R.Z.; Biologically active octapeptides. US 4650787 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(B) 19733 (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid C10H19NO4 详情 详情
(G) 22184 (2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropionic acid C14H19NO4 详情 详情
(E) 43774 6-chloro-5-(methylsulfanyl)-1H-indole; 6-chloro-1H-indol-5-yl methyl sulfide C9H8ClNS 详情 详情
(A),(F) 48335 Boc-Cys(pMeOBzl)-OH; Boc-S-(4-methoxybenzyl)-L-cysteine; Boc-Cys(4MeOBzl)-OH; Boc-L-Cysteine(4-Methoxybenzyl); N-alpha-t-Boc-S-(p-methoxybenzyl)-L-cysteine; Boc-Cys(4-Mob)-OH; Boc-S-(4-methoxybenzyl) Cysteine; Boc-S-4-methoxybenzyl-L-cysteine 18942-46-6 C16H23NO5S 详情 详情
(D) 48341 (2R)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propionic acid C16H20N2O4 详情 详情
(I) 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
(II) 48206 (2S)-2-amino-3-(1H-indol-3-yl)propanamide C11H13N3O 详情 详情
(III) 48337 (2R)-2-amino-N-[(1S)-2-amino-1-(1H-indol-3-ylmethyl)-2-oxoethyl]-3-[(4-methoxybenzyl)sulfanyl]propanamide C22H26N4O3S 详情 详情
(IV) 48338 2-chlorobenzyl (5S)-5-amino-6-[((1S)-1-[[((1R)-2-[[(1S)-2-amino-1-(1H-indol-3-ylmethyl)-2-oxoethyl]amino]-1-[[(4-methoxybenzyl)sulfanyl]methyl]-2-oxoethyl)amino]carbonyl]-2-methylpropyl)amino]-6-oxohexylcarbamate C41H52ClN7O7S 详情 详情
(V) 48339 4-((2S,5R,8S,11S,14R,17S)-18-amino-2-([(2R)-2-[[(2R)-2-amino-3-phenylpropanoyl]amino]-3-[(4-methoxybenzyl)sulfanyl]propanoyl]amino)-8-[4-([[(2-chlorobenzyl)oxy]carbonyl]amino)butyl]-5,17-bis(1H-indol-3-ylmethyl)-11-isopropyl-14-[[(4-methoxybenzyl)sulfanyl]methyl]-3,6,9,12,15,18-hexaoxo-4,7,10,13,16-pentaazaoctadec-1-yl)phenyl 2-bromobenzyl carbonate C89H98BrClN12O15S2 详情 详情
(VI) 48340 (2S,5R,8S,11S,14R,17S,20R,23R)-23-amino-11-(4-aminobutyl)-17-(4-hydroxybenzyl)-2,14-bis(1H-indol-3-ylmethyl)-8-isopropyl-4,7,10,13,16,19,22-heptaoxo-24-phenyl-5,20-bis(sulfanylmethyl)-3,6,9,12,15,18,21-heptaazatetracosan-1-amide C57H72N12O9S2 详情 详情
(C) 31374 (2S)-2-[(tert-butoxycarbonyl)amino]-6-([[(2-chlorobenzyl)oxy]carbonyl]amino)hexanoic acid C19H27ClN2O6 详情 详情

合成路线2

该中间体在本合成路线中的序号：(XII)

The enantioselective condensation of N-Boc-L-prolinal (I) with the chiral 3-propionyloxazolidinone (II) by means of Bu2B-OTf in dichloromethane gives the chiral beta-hydroxyamide (III), which is submitted to elimination of the chiral auxiliary by hydrolysis with LiOH and H2O2 in THF/water to yield the hydroxyacid (IV). The methylation of (IV) with Me-I and NaH in THF affords the methoxyacid (V). The condensation of intermediate (V) with 2-phenyl-1(S)-(2-thiazolyl)ethylamine (VI) by means of (EtO)2P(O)CN and DIEA gives the dipeptide (VII). The deprotection of (VII) by means of TFA yields dipeptide (VIII), which is condensed with the beta-methoxy-gamma-aminoacid (IX) as before to afford tripeptide (X). The deprotection of (X) by means of TFA yields tripeptide (XI), which is condensed with N-Boc-L-valine (XII) by means of BopCl and DIEA to afford tetrapeptide (XIII). The deprotection of (XIII) by means of TFA provides tetrapeptide (XIV), which is finally condensed with N,N-dimethyl-L-valine (XV) by means of (EtO)2P(O)CN and TEA to afford the target dolastatine.

参考文献 中间体
合成目标
【1】 Hayashi, K.; et al.; An efficient total synthesis of dolastatin 10, an antineoplastic pentapeptide of marine origin. Pept Chem 1990, Pub. 1991, 43.
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) 16724 tert-Butyl (2S)-2-formyltetrahydro-1H-pyrrole-1-carboxylate; tert-Butoxycarbonyl-L-prolinal 69610-41-9 C10H17NO3 详情 详情
(II) 46163 (4R,5S)-4-methyl-5-phenyl-3-propionyl-1,3-oxazolidin-2-one C13H15NO3 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) 54615 (2R,3R)-3-[(2S)-1-(tert-butoxycarbonyl)pyrrolidinyl]-3-hydroxy-2-methylpropanoic acid C13H23NO5 详情 详情
(V) 23520 (2R,3R)-3-[(2S)-1-(tert-butoxycarbonyl)pyrrolidinyl]-3-methoxy-2-methylpropionic acid C14H25NO5 详情 详情
(VI) 54607 (1S)-2-phenyl-1-(1,3-thiazol-2-yl)-1-ethanamine; (1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethylamine C11H12N2S 详情 详情
(VII) 54608 tert-butyl (2S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}propyl)-1-pyrrolidinecarboxylate C25H35N3O4S 详情 详情
(VIII) 54609 (2R,3R)-3-methoxy-2-methyl-N-[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]-3-[(2S)pyrrolidinyl]propanamide C20H27N3O2S 详情 详情
(IX) 54599 (3R,4S)-4-[(tert-butoxycarbonyl)(methyl)amino]-3-methoxy-5-methylheptanoic acid C15H29NO5 详情 详情
(X) 54610 tert-butyl (1S,2R)-2-methoxy-4-[(2S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}propyl)pyrrolidinyl]-1-[(1S)-1-methylpropyl]-4-oxobutyl(methyl)carbamate C35H54N4O6S 详情 详情
(XI) 54611 (2R,3R)-3-methoxy-3-{(2S)-1-[(3R,4S,5S)-3-methoxy-5-methyl-4-(methylamino)heptanoyl]pyrrolidinyl}-2-methyl-N-[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]propanamide C30H46N4O4S 详情 详情
(XII) 19733 (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid C10H19NO4 详情 详情
(XIII) 54616 tert-butyl (1S)-1-{[{(1S,2R)-2-methoxy-4-[(2S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}propyl)pyrrolidinyl]-1-[(1S)-1-methylpropyl]-4-oxobutyl}(methyl)amino]carbonyl}-2-methylpropylcarbamate C40H63N5O7S 详情 详情
(XIV) 23518 (2S)-2-(dimethylamino)-3-methylbutyric acid C7H15NO2 详情 详情
(XV) 54613 (2S)-2-amino-N-{(1S,2R)-2-methoxy-4-[(2S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}propyl)pyrrolidinyl]-1-[(1S)-1-methylpropyl]-4-oxobutyl}-N,3-dimethylbutanamide C35H55N5O5S 详情 详情

合成路线3

该中间体在本合成路线中的序号：(XXIV)

The condensation of intermediate (XIX) with intermediate (XII) by means of DEC and TEA gives the dipeptide (XX). The deprotection of (XX) by means of HCl yields dipeptide (XXI), which is condensed with intermediate (VI) by means of DEC and TEA to afford tripeptide (XXII). The deprotection of (XXII) by means of HBr yields tripeptide (XXIII), which is condensed with N-Boc-L-valine (XXIV) by means of BOPCl and TEA to afford tetrapeptide (XXV). The deprotection of (XXV) by means of HCl provides tetrapeptide (XXVI), which is finally condensed with N,N-dimethyl-L-valine (XXVII) by means of DEC and TEA to afford the target dolastatine.

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
(VI) 54599 (3R,4S)-4-[(tert-butoxycarbonyl)(methyl)amino]-3-methoxy-5-methylheptanoic acid C15H29NO5 详情 详情
(XII) 23520 (2R,3R)-3-[(2S)-1-(tert-butoxycarbonyl)pyrrolidinyl]-3-methoxy-2-methylpropionic acid C14H25NO5 详情 详情
(XIX) 54607 (1S)-2-phenyl-1-(1,3-thiazol-2-yl)-1-ethanamine; (1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethylamine C11H12N2S 详情 详情
(XX) 54608 tert-butyl (2S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}propyl)-1-pyrrolidinecarboxylate C25H35N3O4S 详情 详情
(XXI) 54609 (2R,3R)-3-methoxy-2-methyl-N-[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]-3-[(2S)pyrrolidinyl]propanamide C20H27N3O2S 详情 详情
(XXII) 54610 tert-butyl (1S,2R)-2-methoxy-4-[(2S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}propyl)pyrrolidinyl]-1-[(1S)-1-methylpropyl]-4-oxobutyl(methyl)carbamate C35H54N4O6S 详情 详情
(XXIII) 54611 (2R,3R)-3-methoxy-3-{(2S)-1-[(3R,4S,5S)-3-methoxy-5-methyl-4-(methylamino)heptanoyl]pyrrolidinyl}-2-methyl-N-[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]propanamide C30H46N4O4S 详情 详情
(XXIV) 19733 (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid C10H19NO4 详情 详情
(XXV) 54616 tert-butyl (1S)-1-{[{(1S,2R)-2-methoxy-4-[(2S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}propyl)pyrrolidinyl]-1-[(1S)-1-methylpropyl]-4-oxobutyl}(methyl)amino]carbonyl}-2-methylpropylcarbamate C40H63N5O7S 详情 详情
(XXVI) 54613 (2S)-2-amino-N-{(1S,2R)-2-methoxy-4-[(2S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}propyl)pyrrolidinyl]-1-[(1S)-1-methylpropyl]-4-oxobutyl}-N,3-dimethylbutanamide C35H55N5O5S 详情 详情
(XXVII) 23518 (2S)-2-(dimethylamino)-3-methylbutyric acid C7H15NO2 详情 详情

合成路线4

该中间体在本合成路线中的序号：(VII)

Reaction of the labeled chiral bromoacetylbornanesultam (I) with benzophenone imine (II) and DIEA in hot acetonitrile gives the imine (III), which is enantioselectively alkylated with isopropyl iodide and n-BuLi yielding the L-valine derivative (IV). Treatment of (IV) with HCl in THF in order to eliminate the diphenylmethylene group affords compound (V) with a free amino group that by protection with Boc2O in THF provides the L-valine derivative (VI). The hydrolysis of (VI) with LiOH in THF/water affords labeled N-(tert-butoxycarbonyl)-L-valine (VII), which is condensed with the decapeptide (VIII) by means of BOP and NMM in dichloromethane providing the linear undecapeptide (IX).

参考文献 中间体
合成目标
【1】 Metz, Y.; Kohler, B.; Burtscher, P.; Voges, R.; Wenger, R.; Synthesis of [S-[1-C-14]Val(7)]VALSPODAR application of (+)/(-)-[C-13,14(N)]BABS and (+)/(-)-[C-13,14(N)]DPMGBS, part 4. J Label Compd Radiopharm 2000, 43, 3, 205.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
19369 2-iodopropane 75-30-9 C3H7I 详情 详情
(I) 41048 (1R)-4-(2-bromoacetyl)-10,10-dimethyl-3lambda(6)-thiatricyclo[5.2.1.0(1,5)]decane-3,3-dione C13H19BrO3S 详情 详情
(I) 45254 (1R)-4-(2-bromoacetyl)-10,10-dimethyl-3lambda(6)-thiatricyclo[5.2.1.0(1,5)]decane-3,3-dione C13H19BrO3S 详情 详情
(II) 32024 diphenylmethanimine 1013-88-3 C13H11N 详情 详情
(III) 41049 (1R)-4-[2-[(dibenzylene)amino]acetyl]-10,10-dimethyl-3lambda(6)-thiatricyclo[5.2.1.0(1,5)]decane-3,3-dione C26H29NO3S 详情 详情
(III) 45255 (1R)-4-[2-[(dibenzylene)amino]acetyl]-10,10-dimethyl-3lambda(6)-thiatricyclo[5.2.1.0(1,5)]decane-3,3-dione C26H29NO3S 详情 详情
(IV) 41050 (1R)-4-[(2S)-2-[(dibenzylene)amino]-3-methylbutanoyl]-10,10-dimethyl-3lambda(6)-thiatricyclo[5.2.1.0(1,5)]decane-3,3-dione C29H35NO3S 详情 详情
(IV) 45256 (1R)-4-[(2S)-2-[(dibenzylene)amino]-3-methylbutanoyl]-10,10-dimethyl-3lambda(6)-thiatricyclo[5.2.1.0(1,5)]decane-3,3-dione C29H35NO3S 详情 详情
(V) 41051 (1R)-4-[(2S)-2-amino-3-methylbutanoyl]-10,10-dimethyl-3lambda(6)-thiatricyclo[5.2.1.0(1,5)]decane-3,3-dione C16H27NO3S 详情 详情
(V) 45257 (1R)-4-[(2S)-2-amino-3-methylbutanoyl]-10,10-dimethyl-3lambda(6)-thiatricyclo[5.2.1.0(1,5)]decane-3,3-dione C16H27NO3S 详情 详情
(VI) 41052 tert-butyl (1S)-1-[[(1R)-10,10-dimethyl-3,3-dioxo-3lambda(6)-thiatricyclo[5.2.1.0(1,5)]dec-4-yl]carbonyl]-2-methylpropylcarbamate C21H35NO5S 详情 详情
(VI) 45258 tert-butyl (1S)-1-[[(1R)-10,10-dimethyl-3,3-dioxo-3lambda(6)-thiatricyclo[5.2.1.0(1,5)]dec-4-yl]carbonyl]-2-methylpropylcarbamate C21H35NO5S 详情 详情
(VII) 19733 (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid C10H19NO4 详情 详情
(VII) 45259 (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid C10H19NO4 详情 详情
(VIII) 41053 　 C59H108N10O12 详情 详情
(IX) 41054 　 C69H125N11O15 详情 详情
(IX) 45260 methyl (6S,12S,15S,18S,21S,24R,27S,30S,33S,36S)-36-[(1R,2R,4E)-1-hydroxy-2-methyl-4-hexenyl]-12,18,27,30-tetraisobutyl-6,15,33-triisopropyl-2,2,8,11,17,21,24,26,29,32,35-undecamethyl-4,7,10,13,16,19,22,25,28,31,34-undecaoxo-3-oxa-5,8,11,14,17,20,23, C69H125N11O15 详情 详情

合成路线5

该中间体在本合成路线中的序号：(VIII)

The reaction of 14C labeled chiral bromoacetyl sultam (I) with benzophenoneimine (II) in hot acetonitrile gives the substituted benzophenoneimine (III), which is estereoselectively alkylated with isopropyl iodide (IV) and n-BuLi in THF yielding the labeled L-valine derivative (V). The hydrolysis of (V) with HCl in THF affords the valine derivative (VI) with a free amino group that is protected with Boc2O in THF providing the carbamate (VII). The basic hydrolysis of (VII) with LiOH in THF gives the labeled N-(tert-butoxycarbonyl)-L-valine (VIII), which is esterified with Bn-OH, EDC and DMAP in dichloromethane yielding the protected benzyl ester (IX). Treatment of (IX) with TFA in dichloromethane affords L-valine benzyl ester (X), which is condensed with the bromomethylbiphenyl (XI) by means of DIEA in hot DMF to give the N-alkylated valine ester (XII). The acylation of (XII) with pentanoyl chloride (XIII) by means of DIEA in toluene yields the N-disubstituted valine ester (XIV), which is finally deprotected by hydrogenation with H2 over Pd/C in EtOH.

参考文献 中间体
合成目标
【1】 Moenius, T.; et al.; Carbon-14 labelling of Diovan(TM) in its valine-moiety. J Label Compd Radiopharm 2000, 43, 13, 1245.
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) 41945 (1S)-4-(2-bromoacetyl)-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione C12H18BrNO3S 详情 详情
(I) 45269 (1S)-4-(2-bromoacetyl)-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione C12H18BrNO3S 详情 详情
(II) 32024 diphenylmethanimine 1013-88-3 C13H11N 详情 详情
(III) 41946 (1S)-4-[2-[(dibenzylene)amino]acetyl]-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione C25H28N2O3S 详情 详情
(III) 45270 (1S)-4-[2-[(dibenzylene)amino]acetyl]-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione C25H28N2O3S 详情 详情
(IV) 19369 2-iodopropane 75-30-9 C3H7I 详情 详情
(V) 41940 (1S)-4-[(2S)-2-[(dibenzylene)amino]-3-methylbutanoyl]-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione C28H34N2O3S 详情 详情
(V) 45271 (1S)-4-[(2S)-2-[(dibenzylene)amino]-3-methylbutanoyl]-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione C28H34N2O3S 详情 详情
(VI) 41941 tert-butyl (1S)-1-[[(1S)-10,10-dimethyl-3,3-dioxo-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]dec-4-yl]carbonyl]-2-methylpropylcarbamate C20H34N2O5S 详情 详情
(VI) 45272 (1R)-4-[(2S)-2-amino-3-methylbutanoyl]-10,10-dimethyl-3lambda(6)-thiatricyclo[5.2.1.0(1,5)]decane-3,3-dione C16H27NO3S 详情 详情
(VII) 41947 tert-butyl (1S)-1-[[(1S)-10,10-dimethyl-3,3-dioxo-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]dec-4-yl]carbonyl]-2-methylpropylcarbamate C20H34N2O5S 详情 详情
(VII) 45273 tert-butyl (1S)-1-[[(1S)-10,10-dimethyl-3,3-dioxo-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]dec-4-yl]carbonyl]-2-methylpropylcarbamate C20H34N2O5S 详情 详情
(VIII) 19733 (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid C10H19NO4 详情 详情
(VIII) 45274 (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid C10H19NO4 详情 详情
(IX) 41942 benzyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoate C17H25NO4 详情 详情
(IX) 45275 benzyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoate C17H25NO4 详情 详情
(X) 41936 benzyl (2S)-2-amino-3-methylbutanoate C12H17NO2 详情 详情
(X) 45276 benzyl (2S)-2-amino-3-methylbutanoate C12H17NO2 详情 详情
(XI) 15538 5-[4'-(bromomethyl)[1,1'-biphenyl]-2-yl]-2-trityl-2H-1,2,3,4-tetraazole 124750-51-2 C33H25BrN4 详情 详情
(XII) 41943 benzyl (2S)-3-methyl-2-([[2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]amino)butanoate C45H41N5O2 详情 详情
(XII) 45277 benzyl (2S)-3-methyl-2-([[2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]amino)butanoate C45H41N5O2 详情 详情
(XIII) 15116 pentanoyl chloride; valeryl chloride 638-29-9 C5H9ClO 详情 详情
(XIV) 41944 benzyl (2S)-3-methyl-2-(pentanoyl[[2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]amino)butanoate C50H49N5O3 详情 详情
(XIV) 45278 benzyl (2S)-3-methyl-2-(pentanoyl[[2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]amino)butanoate C50H49N5O3 详情 详情

合成路线6

该中间体在本合成路线中的序号：(I)

N-tert-Butoxycarbonyl valine (I) was converted to amide (III) by coupling with pyrrolidine (II) by means of DCC and HOBT. Simultaneous reduction of both carbamoyl and amide functions of (III) using excess LiAlH4 in THF gave the chiral diamine (IV). Final acylation of (IV) with (3,4-dichlorophenyl)acetyl chloride (V) in CH2Cl2 yielded the target amide.

参考文献 中间体
合成目标
【1】 Costello, G.F.; et al.; 2-(3, 4-Dichlorophenyl)-N-methyl-N-[2-(1-pyrrolidinyl)-1-substituted-ethyl]-acetamides: The use of conformational analysis in the development of a novel series of potent opioid kappa agonists. J Med Chem 1991, 34, 1, 181-9.
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) 19733 (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid C10H19NO4 详情 详情
(II) 11376 Pyrrolidine 123-75-1 C4H9N 详情 详情
(III) 26112 tert-butyl (1S)-2-methyl-1-(1-pyrrolidinylcarbonyl)propylcarbamate C14H26N2O3 详情 详情
(IV) 26113 N-methyl-N-[(1S)-2-methyl-1-(1-pyrrolidinylmethyl)propyl]amine; (2S)-N,3-dimethyl-1-(1-pyrrolidinyl)-2-butanamine C10H22N2 详情 详情
(V) 26111 2-(3,4-dichlorophenyl)acetyl chloride C8H5Cl3O 详情 详情

合成路线7

该中间体在本合成路线中的序号：(VIII)

The reaction of tert-butoxycarbonyl-L-phenylalanine (I) with isobutyl chloroformate in THF gives the expected mixed anhydride which is treated with diazomethane and HCl yielding the corresponding chloromethyl ketone (II). The reduction of (II) with NaBH4 in THF affords the (S)-chlorohydrin (IV), which is treated with KOH in ethanol to obtain the chiral epoxide (V)(1,2). Ring opening of (V) with (±)(cis)-N-tert-butyl-4-(4-pyridylmethoxy)piperidine-2-carboxamide (VI) by a treatment with LiCl in refluxing ethanol gives a mixture of diastereomers that is separated by chromatography giving the pure isomer (VII). The reaction of (VII) with tert-butoxycarbonyl-L-valine (VIII) by treatment first with trifluoroacetic acid (TFA), and condesation by means of BOP ((benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate) and NMM (N-methylmorpholine) affords the expected condensation product (IX). Finally, this compound is condensed with quinoline-2-carboxylic acid (X) by means of BOP and NMM as before. 2) The piperidine (VI) has been obtained by condensation of (±)(cis)-N-(tert-butoxycarbonyl)-4-hydroxypiperidine-2-carboxamide (XI) with 4-(chloromethyl)pyridine (XII) by means of NaH in DMS, followed by hydrolysis with HCl.

参考文献 中间体
合成目标
【1】 Beaulieu, P.L.; et al.; Practical, stereoselective synthesis of palinavir, a potent HIV protease inhibitor. J Org Chem 1997, 62, 11, 3440.
【2】 Gillard, J.; et al.; Preparation of (2S,4R)-4-hydroxypipecolic acid and derivatives. J Org Chem 1996, 61, 6, 2226.
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) 12874 (2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine 13734-34-4 C14H19NO4 详情 详情
(II) 19727 tert-butyl (1S)-1-benzyl-3-diazo-2-oxopropylcarbamate C15H19N3O3 详情 详情
(III) 19728 tert-butyl (1S)-1-benzyl-3-chloro-2-oxopropylcarbamate C15H20ClNO3 详情 详情
(IV) 19729 (1S,2S)-[3-chloro-2-hydroxy-1-benzylpropyl]carbamic acid, 1,1-dimethylethyl ether; tert-butyl (1S,2S)-1-benzyl-3-chloro-2-hydroxypropylcarbamate 165727-45-7 C15H22ClNO3 详情 详情
(V) 19730 tert-butyl (1S)-1-[(2S)oxiranyl]-2-phenylethylcarbamate 98737-29-2 C15H21NO3 详情 详情
(VI) 19731 (2S,4R)-N-(tert-butyl)-4-(4-pyridinylmethoxy)-2-piperidinecarboxamide C16H25N3O2 详情 详情
(VII) 19732 tert-butyl (1S,2R)-1-benzyl-3-[(2S,4R)-2-[(tert-butylamino)carbonyl]-4-(4-pyridinylmethoxy)piperidinyl]-2-hydroxypropylcarbamate C31H46N4O5 详情 详情
(VIII) 19733 (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid C10H19NO4 详情 详情
(IX) 19734 tert-butyl (1S)-1-[([(1S,2R)-1-benzyl-3-[(2S,4R)-2-[(tert-butylamino)carbonyl]-4-(4-pyridinylmethoxy)piperidinyl]-2-hydroxypropyl]amino)carbonyl]-2-methylpropylcarbamate C36H55N5O6 详情 详情
(X) 14532 2-Quinolinecarboxylic acid; Quinaldic Acid 93-10-7 C10H7NO2 详情 详情
(XI) 19736 tert-butyl (2S,4R)-2-[(tert-butylamino)carbonyl]-4-hydroxy-1-piperidinecarboxylate C15H28N2O4 详情 详情
(XII) 10844 4-(Chloromethyl)pyridine 10445-91-7 C6H6ClN 详情 详情

合成路线8

该中间体在本合成路线中的序号：(X)

Removal of the Boc protecting group of (V) with trifluoroacetic acid was followed by coupling with N-Boc-D-leucine (VI) in the presence of HATU to provide (VII). The deprotection-coupling procedure was repeated using N-Boc-L-aspartic acid gamma-benzyl ester (VIII), N-Boc-L-valine (X), and N-Boc-D-Leucine yielding the depsipeptide resins (IX), (XI) and (XII), respectively.

参考文献 中间体
合成目标
【1】 Yanai, M.; Suguroi, T.; Solid-phase synthesis of cyclooctadepsipeptide N-4909 using a cyclization-cleavage method with oxime resin. J Antibiot 1999, 52, 9, 835.
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) 31816 (3S)-3-([(2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentanoyl]oxy)-13-methyltetradecanoic acid C26H49NO6 详情 详情
(VI) 31819 (2R)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid 16937-99-8 C11H21NO4 详情 详情
(VII) 31817 (6R,9S,12S)-6-isobutyl-2,2-dimethyl-9-[(1S)-1-methylpropyl]-12-(10-methylundecyl)-4,7,10-trioxo-3,11-dioxa-5,8-diazatetradecan-14-oic acid C32H60N2O7 详情 详情
(VIII) 25219 (2S)-4-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-4-oxobutyric acid 7536-58-5 C16H21NO6 详情 详情
(IX) 31821 (6S,9R,12S,15S)-6-[2-(benzyloxy)-2-oxoethyl]-9-isobutyl-2,2-dimethyl-12-[(1S)-1-methylpropyl]-15-(10-methylundecyl)-4,7,10,13-tetraoxo-3,14-dioxa-5,8,11-triazaheptadecan-17-oic acid C43H71N3O10 详情 详情
(X) 19733 (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid C10H19NO4 详情 详情
(XI) 31822 (6S,9S,12R,15S,18S)-9-[2-(benzyloxy)-2-oxoethyl]-12-isobutyl-6-isopropyl-2,2-dimethyl-15-[(1S)-1-methylpropyl]-18-(10-methylundecyl)-4,7,10,13,16-pentaoxo-3,17-dioxa-5,8,11,14-tetraazaicosan-20-oic acid C48H80N4O11 详情 详情
(XII) 31823 (6S,9S,12S,15R,18S,21S)-12-[2-(benzyloxy)-2-oxoethyl]-6,15-diisobutyl-9-isopropyl-2,2-dimethyl-18-[(1S)-1-methylpropyl]-21-(10-methylundecyl)-4,7,10,13,16,19-hexaoxo-3,20-dioxa-5,8,11,14,17-pentaazatricosan-23-oic acid C54H91N5O12 详情 详情

合成路线9

该中间体在本合成路线中的序号：(XV)

1-Butanesulfonyl chloride (XII) was reacted with ammonia in acetonitrile, and the resulting sulfonamide (XIII) was then converted to the N-trimethylsilyl derivative (XIV). This was coupled with acid fluoride (XVII), (obtained from Boc-valine (XV) and cyanuric fluoride (XVI)), to provide Boc-valinesulfonamide (XVIII). The Boc group of (XVIII) was then removed by acid treatment to give (XIX). Finally, coupling of this chiral intermediate with the previously obtained racemic acid (XI) furnished the title compound as a 7:3 mixture of diastereoisomers.

参考文献 中间体
合成目标
【1】 Sakaki, J.; Murata, T.; Yuumoto, Y.; Nakamura, I.; Frueh, T.; Pitterna, T.; Iwasaki, G.; Oda, K.; Yamamura, T.; Hayakawa, K.; Discovery of IRL 3461: A novel and potent endothelin antagonist with balanced ETA/ETB affinity. Bioorg Med Chem Lett 1998, 8, 16, 2241.
【2】 Fruh, T.; Pitterna, T.; Murata, T.; Svensson, L.D.; Yuumoto, Y.; Sakaki, J. (Novartis Japan KK); Antagonists of endothelin receptors. EP 0753004; JP 1997510720; US 5703106; WO 9526360 .
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) 26778 N-(3,5-dimethylbenzoyl)-4-(5-isoxazolyl)-N-methylphenylalanine C22H22N2O4 详情 详情
(XII) 26779 1-butanesulfonyl chloride 2386-60-9 C4H9ClO2S 详情 详情
(XIII) 26780 1-butanesulfonamide C4H11NO2S 详情 详情
(XIV) 26781 N-(trimethylsilyl)-1-butanesulfonamide C7H19NO2SSi 详情 详情
(XV) 19733 (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid C10H19NO4 详情 详情
(XVI) 26782 Cyanuric fluoride; 2,4,6-trifluoro-1,3,5-triazine 675-14-9 C3F3N3 详情 详情
(XVII) 26783 tert-butyl (1S)-1-(fluorocarbonyl)-2-methylpropylcarbamate C10H18FNO3 详情 详情
(XVIII) 26784 tert-butyl (1S)-1-[[(butylsulfonyl)amino]carbonyl]-2-methylpropylcarbamate C14H28N2O5S 详情 详情
(XIX) 26785 N-[(2S)-2-amino-3-methylbutanoyl]-1-butanesulfonamide C9H20N2O3S 详情 详情

合成路线10

该中间体在本合成路线中的序号：(VIII)

The reaction of ganciclovir (I) with trityl chloride in DMF in the presence of triethylamine and DMAP gives the N,O-bis(trityl) compound (VI), which is condensed with the activated L-valine derivative (III) by means of triethylamine in DMF/toluene to yield the expected valine ester (VII). Finally, the trityl groups of (VII) are removed with TFA in trifluoroethanol to afford the previously reported monoprotected compound (IV). The condensation of the tritylated ganciclovir (VI) with N-(tert-butoxycarbonyl)-L-valine (VIII) by means of DCC in dichloromethane gives the expected valine ester (IX), which is finally deprotected with TFA in dichloromethane. The valine ester (IX) can also be obtained by condensation of tritylated ganciclovir (VI) with N-(tert-butoxycarbonyl)-L-valine-N-carboxyanhydride (X) by means of triethylamine in DMF.

参考文献 中间体
合成目标
【1】 Sorbera, L.A.; Castañer, J.; Castañer, R.M.; Valganciclovir Hydrochloride. Drugs Fut 2000, 25, 5, 474.
【2】 Arzeno, H.B.; Humphreys, E.R. (F. Hoffmann-La Roche AG); Process for preparing purine derivs.. US 5756736; WO 9727196 .
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) 35312 2-amino-9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl]-1,9-dihydro-6H-purin-6-one C9H13N5O4 详情 详情
(III) 29555 benzyl (4S)-4-isopropyl-2,5-dioxo-1,3-oxazolidine-3-carboxylate 158257-41-1 C14H15NO5 详情 详情
(IV) 35314 2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]-3-hydroxypropyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoate C22H28N6O7 详情 详情
(VI) 35316 9-([2-hydroxy-1-[(trityloxy)methyl]ethoxy]methyl)-2-(tritylamino)-1,9-dihydro-6H-purin-6-one C47H41N5O4 详情 详情
(VII) 35319 2-[[6-oxo-2-(tritylamino)-1,6-dihydro-9H-purin-9-yl]methoxy]-3-(trityloxy)propyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoate C60H56N6O7 详情 详情
(VIII) 19733 (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid C10H19NO4 详情 详情
(IX) 35317 2-[[6-oxo-2-(tritylamino)-1,6-dihydro-9H-purin-9-yl]methoxy]-3-(trityloxy)propyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoate C57H58N6O7 详情 详情
(X) 35318 tert-butyl (4S)-4-isopropyl-2,5-dioxo-1,3-oxazolidine-3-carboxylate 141468-55-5 C11H17NO5 详情 详情

合成路线11

该中间体在本合成路线中的序号：(VI)

The Wittig condensation of decanal (I) with phosphorane (II) in benzene gives trans-2-dodecenoic acid methyl ester (III), which by thermal Michael addition of benzylamine yields the protected beta-aminoester (IV). The debenzylation of (IV) with H2 over Pd/C in methanol affords the free aminoester (V), which is condensed with N-(tert-butoxycarbonyl)-L-valine (VI) by means of 1-[3-(dimethylamino)propyl]-1-ethyl carbodiimide (WSC) in dichloromethane to give the dipeptide (VII) as a diastereomeric mixture, from which the desired isomer (VIII) is isolated by crystallization. The deprotection of the amino group of (VIII) with TFA in dichloromethane affords the peptide (IX), which is coupled with the conveniently protected glycyl-L-lysine dipeptide (X) by means of WSC as before to give the tetrapeptide (XI). The hydrolysis of the methyl ester group of (XI) with LiOH in THF/methanol/water yields the acidic tetrapeptide (XII). The intermediate glycyl-L-lysine dipeptide (X) has been obtained by coupling N-(tert-butoxycarbonyl)glycine (XV) with Nomega-(benzyloxycarbonyl)-L-lysine methyl ester (XVI) by means of WSC as before to give dipeptide (XVI), which is submitted to alkaline hydrolysis to provide the intermediate dipeptide (X).

参考文献 中间体
合成目标
【1】 Sakai, K.; Yoshioka, T.; Agematu, H.; Chiba, H.; Dobashi, K.; Rhodopeptins, novel cyclic tetrapeptides with antifungal activities from Rhodococcus sp. III. Synthetic study of rhodopeptins. J Antibiot 1999, 52, 8, 710.
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) 31059 decanal 112-31-2 C10H20O 详情 详情
(II) 14686 2-phenyl-1,3-dioxane C10H12O2 详情 详情
(III) 31060 methyl (E)-2-dodecenoate C13H24O2 详情 详情
(IV) 31061 methyl 3-(benzylamino)dodecanoate C20H33NO2 详情 详情
(V) 31062 methyl 3-aminododecanoate C13H27NO2 详情 详情
(VI) 19733 (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid C10H19NO4 详情 详情
(VII) 31063 methyl 3-([(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoyl]amino)dodecanoate C23H44N2O5 详情 详情
(VIII) 31064 methyl (3R)-3-([(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoyl]amino)dodecanoate C23H44N2O5 详情 详情
(IX) 31065 methyl (3R)-3-[[(2S)-2-amino-3-methylbutanoyl]amino]dodecanoate C18H36N2O3 详情 详情
(X) 31066 (2S)-6-[[(benzyloxy)carbonyl]amino]-2-([2-[(tert-butoxycarbonyl)amino]acetyl]amino)hexanoic acid C21H31N3O7 详情 详情
(XI) 31067 methyl (9S,12S,15R)-9-(4-[[(benzyloxy)carbonyl]amino]butyl)-12-isopropyl-2,2-dimethyl-15-nonyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazaheptadecan-17-oate C39H65N5O9 详情 详情
(XII) 31068 (9S,12S,15R)-9-(4-[[(benzyloxy)carbonyl]amino]butyl)-12-isopropyl-2,2-dimethyl-15-nonyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazaheptadecan-17-oic acid C38H63N5O9 详情 详情
(XV) 18066 N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid 4530-20-5 C7H13NO4 详情 详情
(XVI) 31069 methyl (2S)-2-amino-6-[[(benzyloxy)carbonyl]amino]hexanoate C15H22N2O4 详情 详情
(XVII) 31070 methyl (2S)-6-[[(benzyloxy)carbonyl]amino]-2-([2-[(tert-butoxycarbonyl)amino]acetyl]amino)hexanoate C22H33N3O7 详情 详情

合成路线12

该中间体在本合成路线中的序号：(XXXIX)

The condensation of 3-hydroxybenzaldehyde (XXXIV) with phosphonate (XXXV) by means of DBU in dichloromethane gives the propenoic ester (XXXVI), which is enanthioselectively reduced catalyzed by (+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene(1,5-cyclooctadiene)rhodium (I) trifluoromethanesulfonate ((S,S)-DuP-Rh+OTf-) yielding the L-phenylalanine derivative (XXXVII). The deprotection of (XXXVII) by hydrogenation as usual affords the free amino acid (XXXVIII), which is condensed with Boc-L-valine (XXXIX) by means of EDC and HOAt to afford the dipeptide (XL). Hydrolysis of the ester group of (XXXIX) with LiOH in THF/water affords the N-protected amino acid (XLI), which is condensed with the perhydropyridazine (XLII) by means of EDC and HOAt to give the protected intermediate (XLIII). Finally, this compound is deprotected with TFA in dichloromethane to afford the desired intermediate the bis(iodovinyl) compound (XXXI). The intermediate perhydropyridazine (XLII) has been obtained as follows: The reaction of the iodoaldehyde (XLIV) with iodoform and CrCl2 in dioxane/THF gives the 1,6-diiodohexadiene (XLV), which, previous desilylation with TBAF, is condensed with the protected hexahydropyridazinecarboxylic acid (XLVI) by means of EDC, 4-Ppy and DIEA in dichloromethane to provide the protected diiodo ester (XLVII). Finally, this compound is deprotected with TFA in dichloromethane to yield the desired intermediate the perhydropyridazine (XLII).

参考文献 中间体
合成目标
【1】 Nicolaou, K.C.; et al.; Total synthesis of the novel immunosuppressant Sanglifehrin A. J Am Chem Soc 2000, 122, 16, 3830.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXXI) 32446 (1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl (3S)-1-[(2S)-2-[[(2S)-2-amino-3-methylbutanoyl]amino]-3-(3-hydroxyphenyl)propanoyl]hexahydro-3-pyridazinecarboxylate C26H36I2N4O5 详情 详情
(XXXIV) 28537 3-hydroxybenzaldehyde 100-83-4 C7H6O2 详情 详情
(XXXV) 35887 methyl 2-[[(benzyloxy)carbonyl]amino]-2-(diethoxyphosphoryl)acetate C15H22NO7P 详情 详情
(XXXVI) 35888 methyl (E)-2-[[(benzyloxy)carbonyl]amino]-3-(3-hydroxyphenyl)-2-propenoate C18H17NO5 详情 详情
(XXXVII) 35889 methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-(3-hydroxyphenyl)propanoate C18H19NO5 详情 详情
(XXXVIII) 35890 methyl (2S)-2-amino-3-(3-hydroxyphenyl)propanoate C10H13NO3 详情 详情
(XXXIX) 19733 (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid C10H19NO4 详情 详情
(XL) 35891 methyl (2S)-2-([(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoyl]amino)-3-(3-hydroxyphenyl)propanoate C20H30N2O6 详情 详情
(XLI) 32444 (2S)-2-([(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoyl]amino)-3-(3-hydroxyphenyl)propionic acid C19H28N2O6 详情 详情
(XLII) 32443 (1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl (3S)hexahydro-3-pyridazinecarboxylate C12H18I2N2O2 详情 详情
(XLIII) 32445 (1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl (3S)-1-[(2S)-2-([(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoyl]amino)-3-(3-hydroxyphenyl)propanoyl]hexahydro-3-pyridazinecarboxylate C31H44I2N4O7 详情 详情
(XLIV) 32438 (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-iodo-4-methyl-4-pentenal C12H23IO2Si 详情 详情
(XLV) 32439 tert-butyl([(1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl]oxy)dimethylsilane; tert-butyl(dimethyl)silyl (1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl ether C13H24I2OSi 详情 详情
(XLVI) 32441 (3S)-1,2-bis(tert-butoxycarbonyl)hexahydro-3-pyridazinecarboxylic acid C15H26N2O6 详情 详情
(XLVII) 32442 1,2-di(tert-butyl) 3-[(1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl] (3S)tetrahydro-1,2,3-pyridazinetricarboxylate C22H34I2N2O6 详情 详情

合成路线13

该中间体在本合成路线中的序号：(XV)

1-Butanesulfonyl chloride (XII) was reacted with ammonia in acetonitrile, and the resulting sulfonamide (XIII) was then converted to the N-trimethylsilyl derivative (XIV). This compound was coupled with acid fluoride (XVII), (obtained from Boc-valine (XV) and cyanuric fluoride (XVI)), to provide Boc-valinesulfonamide (XVIII). The Boc group of (XVIII) was then removed by acid treatment to give (XIX). Coupling of this chiral intermediate (XIX) with racemic acid (XI) in a biphasic solvent system, with partial isomerization of acid (XI), furnished the amide (XX) as a 12:1 diastereomeric mixture. The major D,L diastereoisomer was then isolated either by preparative HPLC or by recrystallization from isopropanol.

参考文献 中间体
合成目标
【1】 Sakaki, J.; Murata, T.; Yuumoto, Y.; Nakamura, I.; Hayakawa, K.; Stereoselective synthesis of a novel and bifunctional endothelin antagonist, IRL 3630. Bioorg Med Chem Lett 1998, 8, 16, 2247.
【2】 Sakaki, J.; Murata, T.; Yuumoto, Y.; Nakamura, I.; Okada, T. (Novartis Japan KK); Antagonists of endothelin receptors. JP 1999512702; WO 9711960 .
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) 26778 N-(3,5-dimethylbenzoyl)-4-(5-isoxazolyl)-N-methylphenylalanine C22H22N2O4 详情 详情
(XII) 26779 1-butanesulfonyl chloride 2386-60-9 C4H9ClO2S 详情 详情
(XIII) 26780 1-butanesulfonamide C4H11NO2S 详情 详情
(XIV) 26781 N-(trimethylsilyl)-1-butanesulfonamide C7H19NO2SSi 详情 详情
(XV) 19733 (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid C10H19NO4 详情 详情
(XVI) 26782 Cyanuric fluoride; 2,4,6-trifluoro-1,3,5-triazine 675-14-9 C3F3N3 详情 详情
(XVII) 26783 tert-butyl (1S)-1-(fluorocarbonyl)-2-methylpropylcarbamate C10H18FNO3 详情 详情
(XVIII) 26784 tert-butyl (1S)-1-[[(butylsulfonyl)amino]carbonyl]-2-methylpropylcarbamate C14H28N2O5S 详情 详情
(XIX) 26785 N-[(2S)-2-amino-3-methylbutanoyl]-1-butanesulfonamide C9H20N2O3S 详情 详情
(XX) 26786 N-[2-[((1S)-1-[[(butylsulfonyl)amino]carbonyl]-2-methylpropyl)amino]-1-[4-(5-isoxazolyl)benzyl]-2-oxoethyl]-N,3,5-trimethylbenzamide C31H40N4O6S 详情 详情

合成路线14

该中间体在本合成路线中的序号：(VII)

The precursor (R)-9-[4-hydroxy-2-(hydroxymethyl)]guanine (VI) was prepared by conjugate addition of dimethyl itaconate (II) to 2-amino-6-chloropurine (I), followed by reduction of the resultant diester (III) with LiBH4 to yield (IV). Subsequent displacement of the 6-chloro group of (IV) with ammonia under pressure furnished the racemic 2,6-diaminopurine (V). Then, enantioselective deamination of (V) in the presence of adenosine deaminase provided the target (R)-guanine derivative (VI). Esterification of the 4-hydroxy group of (VI) with N-Boc-L-valine (VII) by means of DCC gave the valine ester (VIII). The remaining free hydroxyl group of (VIII) was further esterified with stearoyl chloride (IX) in pyridine, yielding stearate (X). Finally, acid-promoted N-Boc group cleavage in (IX) furnished the title compound.

参考文献 中间体
合成目标
【1】 Engelhardt, P.; Hoberg, M.; Zhou, X.-X.; Lindborg, B.; Johansson, N.G. (Medivir AB); Acyclic nucleoside derivs.. EP 0888348; JP 2000504720; JP 2000504721; US 5869493; WO 9730051; WO 9730052 .
【2】 Synthesis of acyclic nucleoside derivs.. WO 9834917 .
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) 11644 6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine 10310-21-1 C5H4ClN5 详情 详情
(II) 21416 dimethyl 2-methylenesuccinate 617-52-7 C7H10O4 详情 详情
(III) 52956 dimethyl 2-[(2-amino-6-chloro-9H-purin-9-yl)methyl]succinate C12H14ClN5O4 详情 详情
(IV) 52957 2-[(2-amino-6-chloro-9H-purin-9-yl)methyl]-1,4-butanediol C10H14ClN5O2 详情 详情
(V) 52958 2-[(2,6-diamino-9H-purin-9-yl)methyl]-1,4-butanediol C10H16N6O2 详情 详情
(VI) 52959 2-amino-9-[(2R)-4-hydroxy-2-(hydroxymethyl)butyl]-1,9-dihydro-6H-purin-6-one C10H15N5O3 详情 详情
(VII) 19733 (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid C10H19NO4 详情 详情
(VIII) 52960 (3R)-4-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-3-(hydroxymethyl)butyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoate C20H32N6O6 详情 详情
(IX) 52961 n-Octadecanoyl chloride; Octadecanoyl Chloride; Stearic acid chloride; Stearoyl chloride 112-76-5 C18H35ClO 详情 详情
(X) 52962 (2R)-2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]-4-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoyl}oxy)butyl stearate C38H66N6O7 详情 详情

合成路线15

该中间体在本合成路线中的序号：(VII)

In an alternative method, (R)-9-[4-hydroxy-2-(hydroxymethyl)]guanine (VI) was selectively silylated at the 4-hydroxyl by means of tert-butyldiphenylsilyl chloride. The resultant mono-silylated compound (XIV) was acylated with stearoyl chloride (IX), producing stearate ester (XV). Desilylation of (XV) with tetrabutylammonium fluoride, followed by coupling with either N-Boc-L-valine (VII) or N-Cbz-L-valine (XVI), furnished the respective N-protected valyl esters (X) and (XIII). The title compound was then obtained by N-deprotection of (X) and (XIII) under acidic conditions or by catalytic hydrogenation, respectively.

参考文献 中间体
合成目标
【1】 Engelhardt, P.; Hoberg, M.; Zhou, X.-X.; Lindborg, B.; Johansson, N.G. (Medivir AB); Acyclic nucleoside derivs.. EP 0888348; JP 2000504720; JP 2000504721; US 5869493; WO 9730051; WO 9730052 .
【2】 Synthesis of acyclic nucleoside derivs.. WO 9834917 .
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) 52959 2-amino-9-[(2R)-4-hydroxy-2-(hydroxymethyl)butyl]-1,9-dihydro-6H-purin-6-one C10H15N5O3 详情 详情
(VII) 19733 (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid C10H19NO4 详情 详情
(IX) 52961 n-Octadecanoyl chloride; Octadecanoyl Chloride; Stearic acid chloride; Stearoyl chloride 112-76-5 C18H35ClO 详情 详情
(X) 52962 (2R)-2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]-4-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoyl}oxy)butyl stearate C38H66N6O7 详情 详情
(XIII) 52965 (2R)-2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]-4-[((2S)-2-{[(benzyloxy)carbonyl]amino}-3-methylbutanoyl)oxy]butyl stearate C41H64N6O7 详情 详情
(XIV) 52966 2-amino-9-[(2R)-4-{[tert-butyl(diphenyl)silyl]oxy}-2-(hydroxymethyl)butyl]-1,9-dihydro-6H-purin-6-one C26H33N5O3Si 详情 详情
(XV) 52967 (2R)-2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]-4-{[tert-butyl(diphenyl)silyl]oxy}butyl stearate C44H67N5O4Si 详情 详情
(XVI) 18092 (2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutyric acid C13H17NO4 详情 详情

合成路线16

该中间体在本合成路线中的序号：(I)

By deprotection of tripeptide (V) (hydrogenolysis of the benzyl group with H2 over Pd/C) followed by condensation with amino acid ester (XI) by means of diethyl cyanophosphonate (DECP) in DMF. The intermediates (V) and (XI) have been obtained as follows: 1.- The condensation of N-(tert-butoxycarbonyl)-L-valine (I) with L-leucine benzyl ester (II) by means of DCC, NMM and NHS gives the dipeptide (III), which is condensed with L-phenylalanine benzyl ester (IV) by first debenzylation and condensation as before yielding the desired tripeptide (V). 2.- The cyclization of N-(tert-butoxycarbonyl)-L-glutamine (VI) by means of DCC and NHS gives the glutarimide (VII), which is partially reduced with NaBH4 to the cyclic Boc-glutaminal (VIII). The condensation of (VIII) with the phosphonate (IX) by means of NaH in THF affords the unsaturated protected aminoester (X), which is finally deprotected with trifluoroacetic acid in dichloromethane providing the desired amino acid ester (XI).

参考文献 中间体
合成目标
【1】 Shepherd, T.A.; Furness, K.; Venkatraman, S.; Wang, Q.M.; Aubé, J.; Nimkar, S.; Kong, J.; Hanzlik, R.P.; Synthesis and evaluation of peptidyl Michael acceptors that inactivate human rhinovirus 3C protease and inhibit virus replication. J Med Chem 1998, 41, 14, 2579.
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) 19733 (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid C10H19NO4 详情 详情
(II) 27691 benzyl (2S)-2-amino-5-methylhexanoate C14H21NO2 详情 详情
(III) 27692 benzyl (2S)-2-([(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoyl]amino)-5-methylhexanoate C24H38N2O5 详情 详情
(IV) 27693 benzyl (2S)-2-amino-3-phenylpropanoate；L-phenylalanine benzyl ester C16H17NO2 详情 详情
(V) 27694 benzyl (6S,9S,12S)-12-benzyl-9-isopentyl-6-isopropyl-2,2-dimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecan-13-oate C33H47N3O6 详情 详情
(VI) 27695 (2S)-6-amino-2-[(tert-butoxycarbonyl)amino]-6-oxohexanoic acid C11H20N2O5 详情 详情
(VII) 27696 tert-butyl (3S)-2,6-dioxopiperidinylcarbamate C10H16N2O4 详情 详情
(VIII) 27697 tert-butyl (3S)-2-hydroxy-6-oxopiperidinylcarbamate C10H18N2O4 详情 详情
(IX) 27698 methyl 2-(diethoxyphosphoryl)acetate 1067-74-9 C7H15O5P 详情 详情
(X) 27699 methyl (E,4S)-8-amino-4-[(tert-butoxycarbonyl)amino]-8-oxo-2-octenoate C14H24N2O5 详情 详情
(XI) 27700 methyl (E,4S)-4,8-diamino-8-oxo-2-octenoate C9H16N2O3 详情 详情

合成路线17

该中间体在本合成路线中的序号：(VIII)

Coupling of carboxylic acid (I) with tert-butylamine (II) by means of EDC-HOBt in CH2Cl2 affords carboxamide (III), whose Boc group is removed by treatment with HCl/dioxane to provide compound (IV). Coupling of thiazolidine (IV) to Boc-protected allophenylnorstatine (V) by means of DCC and HOBt in EtOAc provides derivative (VI), whose is deprotected by treatment with HCl/dioxane to yield (VII), which is then coupled to Boc-Val-OH (VIII) with EDC-HOBt in DMF to furnish compound (IX). On the other hand, aminophenol derivative (XI) is condensed with benzyl chloroacetate (XII) in DMF in the presence of K2CO3 to furnish derivative (XIII), which is then debenzylated by hydrogenation over Pd/C in MeOH to yield acetic acid derivative (XIV). Finally, the Boc group of (IX) is removed with HCl/dioxane and the resulting amine (X) is coupled to carboxylic acid (XIV) by first treatment with N-hydroxy-5-norbornene-2,3-dicarboximide (HONB) and DCC in CH2Cl2 followed by treatment with Et3N in DMF. Alternatively, the coupling can be performed by means of EDC and HOBt in DMF.

参考文献 中间体
合成目标
【1】 Takaku, H.; Hattori, N.; Mimoto, T.; et al.; Structure-activity relationship of orally potent tripeptide-based HIV protease inhibitors containing hydroxymethylcarbonyl isostere. Chem Pharm Bull 2000, 48, 9, 1310.
【2】 Terashima, K.; Mimoto, T.; Takaku, H.; Nojima, S.; Kiso, Y. (Japan Energy Corp.); Novel tripeptide cpds. and anti-AIDS drugs. EP 0900566; WO 9829118 .
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) 34777 (4R)-3-(tert-butoxycarbonyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid C11H19NO4S 详情 详情
(II) 17895 2-Amino-2-methylpropane; tert-butylamine; 2-methyl-2-propanamine 75-64-9 C4H11N 详情 详情
(III) 45695 tert-butyl (4R)-4-[(tert-butylamino)carbonyl]-5,5-dimethyl-1,3-thiazolidine-3-carboxylate C15H28N2O3S 详情 详情
(IV) 15836 N-t-BOC-(2R,3R)-3-Amino-2-hydroxy-4-phenylbutyric acid; (2S,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyric acid 116661-86-0 C15H21NO5 详情 详情
(V) 45697 tert-butyl (1S,2S)-1-benzyl-3-[(4R)-4-[(tert-butylamino)carbonyl]-5,5-dimethyl-1,3-thiazolidin-3-yl]-2-hydroxy-3-oxopropylcarbamate C25H39N3O5S 详情 详情
(VI) 45698 tert-butyl (1S)-1-[[((1S,2S)-1-benzyl-3-[(4R)-4-[(tert-butylamino)carbonyl]-5,5-dimethyl-1,3-thiazolidin-3-yl]-2-hydroxy-3-oxopropyl)amino]carbonyl]-2-methylpropylcarbamate 1638-63-7 C30H48N4O6S 详情 详情
(VII) 29294 (4R)-3-[(2S,3S)-3-amino-2-hydroxy-4-phenylbutanoyl]-N-(tert-butyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxamide C20H31N3O3S 详情 详情
(VIII) 19733 (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid C10H19NO4 详情 详情
(IX) 45698 tert-butyl (1S)-1-[[((1S,2S)-1-benzyl-3-[(4R)-4-[(tert-butylamino)carbonyl]-5,5-dimethyl-1,3-thiazolidin-3-yl]-2-hydroxy-3-oxopropyl)amino]carbonyl]-2-methylpropylcarbamate 1638-63-7 C30H48N4O6S 详情 详情
(X) 45699 (4R)-3-((2S,3S)-3-[[(2S)-2-amino-3-methylbutanoyl]amino]-2-hydroxy-4-phenylbutanoyl)-N-(tert-butyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxamide C25H40N4O4S 详情 详情
(XI) 45700 N,N-Dimethyl-3-aminophenol; 3-Dimethylaminophenol; m-Dimethylaminophenol 99-07-0 C8H11NO 详情 详情
(XII) 45701 benzyl 2-chloroacetate 140-18-1 C9H9ClO2 详情 详情
(XIII) 45702 benzyl 2-[3-(dimethylamino)phenoxy]acetate C17H19NO3 详情 详情
(XIV) 45703 2-[3-(dimethylamino)phenoxy]acetic acid C10H13NO3 详情 详情

合成路线18

该中间体在本合成路线中的序号：(II)

Coupling of (3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (I) with N-Boc-L-valine (II) using benzotriazolyloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) provided amide (III). After deprotection of the Boc group of (III) with trifluoroacetic acid, the resulting valyl amide (IV) was reduced with BH3-Me2S to afford diamine (V). Finally, coupling of (V) with 3-(4-hydroxyphenyl)propionic acid (VI) in the presence of BOP yielded the target compound.

参考文献 中间体
合成目标
【1】 Thomas, J.B.; Fall, M.J.; Cooper, J.B.; Rothman, R.B.; Mascarella, S.W.; Xu, H.; Partilla, J.S.; Dersch, C.M.; McCullough, K.B.; Cantrell, B.E.; Zimmerman, D.M.; Carroll, F.I.; Identification of an opioid kappa receptor subtype-selective N-substituent for (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine. J Med Chem 1998, 41, 26, 5188.
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) 16620 3-[(3R,4R)-3,4-dimethylhexahydro-4-pyridinyl]phenol 119193-19-0 C13H19NO 详情 详情
(II) 19733 (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid C10H19NO4 详情 详情
(III) 25688 tert-butyl (1S)-1-[[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidinyl]carbonyl]-2-methylpropylcarbamate C23H36N2O4 详情 详情
(IV) 25689 (2S)-2-amino-1-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidinyl]-3-methyl-1-butanone C18H28N2O2 详情 详情
(V) 25690 3-[(3R,4R)-1-[(2S)-2-amino-3-methylbutyl]-3,4-dimethylpiperidinyl]phenol C18H30N2O 详情 详情
(VI) 25691 3-(4-hydroxyphenyl)propionic acid 501-97-3 C9H10O3 详情 详情

合成路线19

该中间体在本合成路线中的序号：(VIII)

After Boc group deprotection in (VII) by means of HCl in dioxan, coupling with N-Boc-valine (VIII) provided tripeptide (IX). Further deprotection and coupling cycles with N-Boc-cyclohexylglycine (X) and N-Boc-glutamic acid benzyl ester (XII) furnished peptides (XI) and (XIII), respectively.

参考文献 中间体
合成目标
【1】 Rancourt, J.; Tsantrizos, Y.; Simoneau, B.; Wernic, D.; Poupart, M.-A.; Llinas-Brunet, M. (Boehringer Ingelheim (Canada) Ltd.); Hepatitis C inhibitor peptides. EP 1003775; WO 9907733 .
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) 35617 tert-butyl (2S,4R)-2-[([(1S)-1-[(benzyloxy)carbonyl]butyl]amino)carbonyl]-4-(2-naphthylmethoxy)-1-pyrrolidinecarboxylate C33H40N2O6 详情 详情
(VIII) 19733 (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid C10H19NO4 详情 详情
(IX) 35618 benzyl (2S)-2-([[(2S,4R)-1-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoyl]-4-(2-naphthylmethoxy)pyrrolidinyl]carbonyl]amino)pentanoate C38H49N3O7 详情 详情
(X) 35619 (2S)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoic acid C13H23NO4 详情 详情
(XI) 35620 benzyl (2S)-2-([[(2S,4R)-1-[(2S)-2-([(2S)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoyl]amino)-3-methylbutanoyl]-4-(2-naphthylmethoxy)pyrrolidinyl]carbonyl]amino)pentanoate C46H62N4O8 详情 详情
(XII) 25141 (2S)-5-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid 13574-13-5 C17H23NO6 详情 详情
(XIII) 35621 benzyl (4R)-5-([(1S)-2-[((1S)-1-[[(2S,4R)-2-[([(1S)-1-[(benzyloxy)carbonyl]butyl]amino)carbonyl]-4-(2-naphthylmethoxy)pyrrolidinyl]carbonyl]-2-methylpropyl)amino]-1-cyclohexyl-2-oxoethyl]amino)-4-[(tert-butoxycarbonyl)amino]-5-oxopentanoate C58H75N5O11 详情 详情

合成路线20

该中间体在本合成路线中的序号：(I)

Coupling on N-Boc-L-valine (I) with 3-bromopropylamine (II) by means of HBTU afforded amide (III). After Boc group cleavage in (III) using trifluoroacetic acid, the resultant amine (IV) was coupled with N-Boc-L-tyrosine (V) to yield the dipeptide amide (VI). Intramolecular cyclization of (VI) to produce the macrocycle (VII) was achieved by treatment with cesium carbonate in the presence of tetrabutylammonium iodide. Subsequent acid cleavage of the Boc protecting group of (VII) furnished the intermediate amine (VIII).

参考文献 中间体
合成目标
【1】 Mak, C.C.; Le, V.-D.; Wong, C.-H.; Elder, J.H.; Lin, Y.-C.; Design, synthesis, and biological evaluation of HIV/FIV protease inhibitors incorporating a conformationally constrained macrocycle with a small P3' residue. Bioorg Med Chem Lett 2001, 11, 2, 219.
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) 19733 (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid C10H19NO4 详情 详情
(II) 25449 3-bromo-1-propanamine; 3-bromopropylamine 18370-81-5 C3H8BrN 详情 详情
(III) 47889 tert-butyl (1S)-1-[[(3-bromopropyl)amino]carbonyl]-2-methylpropylcarbamate C13H25BrN2O3 详情 详情
(IV) 47890 (2S)-2-amino-N-(3-bromopropyl)-3-methylbutanamide C8H17BrN2O 详情 详情
(V) 25395 (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propionic acid 3978-80-1 C14H19NO5 详情 详情
(VI) 47891 tert-butyl (1S)-2-[((1S)-1-[[(3-bromopropyl)amino]carbonyl]-2-methylpropyl)amino]-1-(4-hydroxybenzyl)-2-oxoethylcarbamate C22H34BrN3O5 详情 详情
(VII) 47892 tert-butyl (8S,11S)-8-isopropyl-7,10-dioxo-2-oxa-6,9-diazabicyclo[11.2.2]heptadeca-1(15),13,16-trien-11-ylcarbamate C22H33N3O5 详情 详情
(VIII) 47893 (8S,11S)-11-amino-8-isopropyl-2-oxa-6,9-diazabicyclo[11.2.2]heptadeca-1(15),13,16-triene-7,10-dione C17H25N3O3 详情 详情

合成路线21

该中间体在本合成路线中的序号：(IX)

Metalation of N-Boc-pyrrole (I) with the lithium amide of tetramethylpiperidine, followed by boronation with triethyl borate and acidic work-up leads to the pyrroleboronic acid (II). Subsequent catalytic hydrogenation over Pt/C provides the racemic pyrrolidineboronic acid (III). Alternatively, protection of pyrrolidine (IV) with Boc2O affords (V). After metalation of N-Boc-pyrrolidine (V) with s-butyllithium, treatment with triethyl borate gives rise to the boronic acid (III). Condensation of the racemic boronic acid (III) with (+)-pinanediol (VI) furnishes the corresponding mixture of diastereoisomeric pinanediol boronates, from which the desired isomer (VII) can be isolated by column chromatography. Further removal of the N-Boc protecting group under acidic conditions yields the pyrrolidineboronic ester (VIII). Coupling of pyrrolidine (VIII) with N-Boc-L-valine (IX) produces amide (X). The N-Boc group is then cleaved with HCl in Et2O to afford the deprotected amine (XI). Finally, removal of the pinanediol moiety by transesterification of the boronic ester (XI) with phenylboronic acid provides the desired boronic dipeptide

参考文献 中间体
合成目标
【1】 Gibson, F.S.; Singh, A.K.; Soumeillant, M.C.; Manchand, P.S.; Humora, M.; Kronenthal, D.R.; A practical synthesis of L-valyl-pyrrolidine-(2R)-boronic acid: Efficient recycling of the costly chiral auxiliary (+)-pinanediol. Org Process Res Dev 2002, 6, 6, 814.
【2】 Coutts, S.J.; Kelly, T.A.; Snow, R.J.; Kennedy, C.A.; Barton, R.W.; Adams, J.; Krolikowski, D.A.; Freeman, D.M.; Campbell, S.J.; Ksiazek, J.F.; Bachovchin, W.W.; Structure-activity relationships of boronic acid inhibitors of dipeptidyl peptidase IV. 1. Variation of the P2 position of Xaa-boroPro dipeptides. J Med Chem 1996, 39, 10, 2087.
【3】 Wallner, B.P. (Point Therapeutics, Inc.); Cyclic boroproline cpds.. JP 2002517401; WO 9962914 .
【4】 Hoshi, H.; Okumura, J.; Naito, T.; Abe, Y.; Abukari, S. (Bristol-Myers Squibb Co.); Substituted vinyl cephalosporins. DE 3402642; US 4520022 .
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) 16432 tert-Butyl pyrrole-1-carboxylate; tert-Butyl-1H-pyrrole-1-carboxylate; tert-Butyl-1-pyrrolecarboxylate 5176-27-2 C9H13NO2 详情 详情
(II) 63008 1-{[(1,1-dimethylethyl)oxy]carbonyl}-1H-pyrrol-2-ylboronic acid; 1-(tert-butoxycarbonyl)-1H-pyrrol-2-ylboronic acid C9H14BNO4 详情 详情
(III) 63002 1-{[(1,1-dimethylethyl)oxy]carbonyl}-2-pyrrolidinylboronic acid; 1-(tert-butoxycarbonyl)-2-pyrrolidinylboronic acid 149682-75-7 C9H18BNO4 详情 详情
(IV) 11376 Pyrrolidine 123-75-1 C4H9N 详情 详情
(V) 16439 tert-butyl 1-pyrrolidinecarboxylate 86953-79-9 C9H17NO2 详情 详情
(VI) 63005 (1S,2S,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptane-2,3-diol; (+)-Pinanediol 18680-27-8 C10H18O2 详情 详情
(VII) 63006 tert-butyl (2R)-2-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0~2,6~]dec-4-yl]-1-pyrrolidinecarboxylate C19H32BNO4 详情 详情
(VIII) 63007 (2R)-2-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0~2,6~]dec-4-yl]pyrrolidine 205116-75-2 C14H24BNO2 详情 详情
(IX) 19733 (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid C10H19NO4 详情 详情
(X) 63011 tert-butyl (1S)-2-methyl-1-({(2R)-2-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0~2,6~]dec-4-yl]pyrrolidinyl}carbonyl)propylcarbamate C24H41BN2O5 详情 详情
(XI) 63012 (2S)-2-amino-3-methyl-1-{(2R)-2-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0~2,6~]dec-4-yl]pyrrolidinyl}-1-butanone C19H33BN2O3 详情 详情

合成路线22

该中间体在本合成路线中的序号：(VI)

Coupling between epoxide (I) and amine (II) affords amino alcohol (III). The amino group of (III) is then protected with benzyl chloroformate to provide carbamate (IV). Removal of the N-Boc group of (IV) with trifluoroacetic acid yields amine (V), which is subsequently coupled with N-Boc-L-valine (VI) by means of TBTU to furnish amide (VII). After acidic Boc group cleavage in (VII), the resultant amine (VIII) is acylated by picolinic acid (IX) producing amide (X).

参考文献 中间体
合成目标
【1】 Noteberg, D.; et al.; New antimalarials: Design and synthesis of protease inhibitors with effect in cultured parasite-infected human erythrocytes. Drugs Fut 2002, 27, Suppl. A.
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) 23444 tert-butyl (1S)-1-[(2R)oxiranyl]-2-phenylethylcarbamate C15H21NO3 详情 详情
(II) 58402 (2S)-2-amino-3-(4-bromophenyl)propanamide C9H11BrN2O 详情 详情
(III) 58396 tert-butyl (1S,2S)-3-{[(1S)-2-amino-1-(4-bromobenzyl)-2-oxoethyl]amino}-1-benzyl-2-hydroxypropylcarbamate C24H32BrN3O4 详情 详情
(IV) 58397 benzyl (1S)-2-amino-1-(4-bromobenzyl)-2-oxoethyl{(2S,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl}carbamate C32H38BrN3O6 详情 详情
(V) 58398 benzyl (1S)-2-amino-1-(4-bromobenzyl)-2-oxoethyl[(2S,3S)-3-amino-2-hydroxy-4-phenylbutyl]carbamate C27H30BrN3O4 详情 详情
(VI) 19733 (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid C10H19NO4 详情 详情
(VII) 58399 benzyl (1S)-2-amino-1-(4-bromobenzyl)-2-oxoethyl[(2S,3S)-3-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoyl}amino)-2-hydroxy-4-phenylbutyl]carbamate C37H47BrN4O7 详情 详情
(VIII) 58400 benzyl (1S)-2-amino-1-(4-bromobenzyl)-2-oxoethyl((2S,3S)-3-{[(2S)-2-amino-3-methylbutanoyl]amino}-2-hydroxy-4-phenylbutyl)carbamate C32H39BrN4O5 详情 详情
(IX) 59950 (chloromethyl)(dimethyl)silyl isopropyl ether; (chloromethyl)(isopropoxy)dimethylsilane C6H15ClOSi 详情 详情
(X) 58401 benzyl (1S)-2-amino-1-(4-bromobenzyl)-2-oxoethyl[(2S,3S)-2-hydroxy-3-({(2S)-3-methyl-2-[(2-pyridinylcarbonyl)amino]butanoyl}amino)-4-phenylbutyl]carbamate C38H42BrN5O6 详情 详情
Extended Information