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【结 构 式】 
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【分子编号】21056 【品名】(R)-(-)-Valine; D-Valine; (R)-alpha-Aminoisovaleric acid 【CA登记号】640-68-6 |
【 分 子 式 】C5H11NO2 【 分 子 量 】117.14788 【元素组成】C 51.26% H 9.46% N 11.96% O 27.31% |
合成路线1
该中间体在本合成路线中的序号：(XXVII)The condensation of N-(benzyloxycarbonyl)-L-valine (XXIII) with intermediate heptanoate (VII) by means of NMM and Piv-Cl gives the dipeptide (XXIV), which is N-deprotected by means of H2 over Pd/C to yield the dipeptide (XXV). The condensation of (XXV) with N,N-dimethyl-L-valine (XXVI) (obtained by reductomethylation of L-valine (XXVII) with formaldehyde and H2 over Pd/C) by means of pentafluorophenyl trifluoroacetate and TFAA in pyridine affords the tripeptide (XXVIII), which is treated with TFA to cleave the tert-butyl group, yielding the tripeptide (XXIX). The condensation of (XXIX) with intermediate dipeptide (XXX) by means of DEPC provides the target pentapeptide dolastatin 10. The intermediate dipeptide (XXX) is obtained by condensation of intermediate (XV) with intermediate (XXII) by means of DEPC to give the dipeptide (XXXI), which is N-deprotected by treatment with TFA to afford the desired dipeptide (XXX).
| 【1】 Pettit, G.R.; Singh, S.B.; Williams, M.D.; Herald, D.L.; Hogan, F.; Burkett, D.D.; Clewlow, P.J.; The absolute configuration and synthesis of natural (-)-Dolastatin 10. J Am Chem Soc 1989, 111, Suppl. 3, 5463. |
| 【2】 Pettit, G.R.; Srirangam, J.K.; Singh, S.B.; Williams, M.D.; Herald, D.L.; Barkóczy, J.; Kantoci, D.; Hogan, F.; Dolastatins 24. Synthesis of (-)-dolastatin 10. X-Ray molecular structure of N,N-dimethylvalyl-valyl-dolaisoleucine tert-butyl ester. J Chem Soc Perkins Trans I 1996, 8, Suppl. 3, 859-63. |
| 【3】 Pettit, G.R.; Singh, S.B. (Arizona State University); Synthesis of dolastatin 10. US 4978744 . |
| 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) | 23514 | tert-butyl (3R,4S,5S)-3-methoxy-5-methyl-4-(methylamino)heptanoate | C14H29NO3 | 详情 | 详情 | |
| (XV) | 23520 | (2R,3R)-3-[(2S)-1-(tert-butoxycarbonyl)pyrrolidinyl]-3-methoxy-2-methylpropionic acid | C14H25NO5 | 详情 | 详情 | |
| (XXII) | 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 | |
| (XXIII) | 18092 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutyric acid | C13H17NO4 | 详情 | 详情 | |
| (XXIV) | 23516 | tert-butyl (3R,4S,5S)-4-[((2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoyl)(methyl)amino]-3-methoxy-5-methylheptanoate | C27H44N2O6 | 详情 | 详情 | |
| (XXV) | 23517 | tert-butyl (3R,4S,5S)-4-[[(2S)-2-amino-3-methylbutanoyl](methyl)amino]-3-methoxy-5-methylheptanoate | C19H38N2O4 | 详情 | 详情 | |
| (XXVI) | 23518 | (2S)-2-(dimethylamino)-3-methylbutyric acid | C7H15NO2 | 详情 | 详情 | |
| (XXVII) | 21056 | (R)-(-)-Valine; D-Valine; (R)-alpha-Aminoisovaleric acid | 640-68-6 | C5H11NO2 | 详情 | 详情 |
| (XXVIII) | 23519 | tert-butyl (3R,4S,5S)-4-[((2S)-2-[[(2S)-2-(dimethylamino)-3-methylbutanoyl]amino]-3-methylbutanoyl)(methyl)amino]-3-methoxy-5-methylheptanoate | C26H51N3O5 | 详情 | 详情 | |
| (XXIX) | 23505 | (3R,4S,5S)-4-[((2S)-2-[[(2S)-2-(dimethylamino)-3-methylbutanoyl]amino]-3-methylbutanoyl)(methyl)amino]-3-methoxy-5-methylheptanoic acid | C22H43N3O5 | 详情 | 详情 | |
| (XXX) | 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 | |
| (XXXI) | 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 |
合成路线2
该中间体在本合成路线中的序号：(XIII)The N-protection of 1-aminocyclopentane-1-carboxylic acid (I) with PhCH2-OCOCl and NaOH in tert-butyl methyl ether gives the carbamate (VII), which is condensed with L-tyrosine ethyl ester (VIII) by means isobutyl chloroformate and triethylamine in THF yielding the protected dipeptide (IX). The methylation of (IX) with dimethyl sulfate and K2CO3 in ethyl acetate affords the protected 4-O-methyl dipeptide (X). The deprotection of (X) with HCO2H and Pd/C in ethyl acetate affords the previously reported free dipeptide (V), which is condensed with 2(R)-bromo-3-methylbutyryl chloride (XI) by means of NMM in toluene giving the acylated dipeptide (XII). Finally, this compound is treated with thioacetic acid and K2CO3 in ethyl acetate. The intermediate 2(R)-bromo-3-methylbutyryl chloride (XI) has been obtained by reaction of D-valine (XIII) with NaNO2 and HBr giving the 2(R)-bromo-3-methylbutyric acid (XIV), which is then treated with SOCl2 and DMF to afford the target intermediate (XI).
| 【1】 Johnson, E.P.; et al.; Efficient large scale preparation of neutral endopeptidase/angiotensin-converting enzyme dual inhibitor CGS30440. Org Process Res Dev 1998, 2, 4, 238. |
| 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) | 33149 | 1-aminocyclopentanecarboxylic acid | 52-52-8 | C6H11NO2 | 详情 | 详情 |
| (V) | 33152 | ethyl (2S)-2-[[(1-aminocyclopentyl)carbonyl]amino]-3-(4-methoxyphenyl)propanoate | C18H26N2O4 | 详情 | 详情 | |
| (VII) | 33154 | 1-[[(benzyloxy)carbonyl]amino]cyclopentanecarboxylic acid | C14H17NO4 | 详情 | 详情 | |
| (VIII) | 33155 | ethyl (2S)-2-amino-3-(4-hydroxyphenyl)propanoate | 949-67-7 | C11H15NO3 | 详情 | 详情 |
| (IX) | 33156 | ethyl (2S)-2-[[(1-[[(benzyloxy)carbonyl]amino]cyclopentyl)carbonyl]amino]-3-(4-hydroxyphenyl)propanoate | C25H30N2O6 | 详情 | 详情 | |
| (X) | 33157 | ethyl (2S)-2-[[(1-[[(benzyloxy)carbonyl]amino]cyclopentyl)carbonyl]amino]-3-(4-methoxyphenyl)propanoate | C26H32N2O6 | 详情 | 详情 | |
| (XI) | 33159 | (2R)-2-bromo-3-methylbutanoyl chloride | C5H8BrClO | 详情 | 详情 | |
| (XII) | 33160 | ethyl (2S)-2-[[(1-[[(2R)-2-bromo-3-methylbutanoyl]amino]cyclopentyl)carbonyl]amino]-3-(4-methoxyphenyl)propanoate | C23H33BrN2O5 | 详情 | 详情 | |
| (XIII) | 21056 | (R)-(-)-Valine; D-Valine; (R)-alpha-Aminoisovaleric acid | 640-68-6 | C5H11NO2 | 详情 | 详情 |
| (XIV) | 33158 | (2R)-2-bromo-3-methylbutyric acid | 565-74-2 | C5H9BrO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXIV)Coupling of carbapenem phosphate (VIII) with thiol (XIII) using diisopropylethylamine gave rise to sulfide (XIX). Hydrogenolysis of the p-nitrobenzyl group of (XIX) with simultaneous azide reduction in the presence of Pd/C provided (XX). Treatment of p-nitrobenzyl chloroformate (XXI) with p-nitrophenol (XXII) afforded the nitrophenyl carbonate (XXIII), which was coupled with L-valine (XXIV), yielding carbamate (XXV). Activation of (XXV) with N-hydroxy succinimide and DCC then produced the succinimidyl ester (XXVI). Amine (XX) was coupled with succinimidyl ester (XXVI) to furnish amide (XXVII). The p-nitrobenzyl ester was finally removed by hydrogenation over Pd/C to provide the title compound.
| 【1】 Lin, Y.-I.; et al.; Peptidic prodrugs of novel aminomethyl-THF 1beta-methylcarbapenems. Bioorg Med Chem Lett 1997, 7, 13, 1665. |
| 【2】 Lin, Y.-I.; Bitha, P.; Sakya, S.; Strohmeyer, T.W.; Bush, K. (American Cyanamid Co.); Novel 2-thiosubstd. carbapenems. CA 2118961; EP 0617036; JP 1994321948; US 5602118 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 13224 | 4-nitrobenzyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | 90776-59-3 | C29H27N2O10P | 详情 | 详情 |
| (XIII) | 33047 | (2R,3R)-2-(azidomethyl)tetrahydro-3-furanthiol; (2R,3R)-2-(azidomethyl)tetrahydro-3-furanylhydrosulfide | C5H9N3OS | 详情 | 详情 | |
| (XIX) | 33053 | 4-nitrobenzyl (4R,5S,6S)-3-[[(2R,3R)-2-(azidomethyl)tetrahydro-3-furanyl]sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C22H25N5O7S | 详情 | 详情 | |
| (XX) | 33054 | (4R,5S,6S)-3-[[(2R,3R)-2-(aminomethyl)tetrahydro-3-furanyl]sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid | C15H22N2O5S | 详情 | 详情 | |
| (XXI) | 33055 | 1-[[(chlorocarbonyl)oxy]methyl]-4-nitrobenzene | 4457-32-3 | C8H6ClNO4 | 详情 | 详情 |
| (XXII) | 11236 | 4-Nitrophenol; p-Nitrophenol | 100-02-7 | C6H5NO3 | 详情 | 详情 |
| (XXIII) | 33056 | 4-nitrobenzyl 4-nitrophenyl carbonate | C14H10N2O7 | 详情 | 详情 | |
| (XXIV) | 21056 | (R)-(-)-Valine; D-Valine; (R)-alpha-Aminoisovaleric acid | 640-68-6 | C5H11NO2 | 详情 | 详情 |
| (XXV) | 33057 | (2S)-3-methyl-2-([[(4-nitrobenzyl)oxy]carbonyl]amino)butyric acid | C13H16N2O6 | 详情 | 详情 | |
| (XXVI) | 33058 | 4-nitrobenzyl (1S)-1-[[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]-2-methylpropylcarbamate | C17H19N3O8 | 详情 | 详情 | |
| (XXVII) | 33059 | (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-[[(2R,3R)-2-([[(2S)-3-methyl-2-([[(4-nitrobenzyl)oxy]carbonyl]amino)butanoyl]amino]methyl)tetrahydro-3-furanyl]sulfanyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid | C28H36N4O10S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)Condensation of D-valine (I) with 4-methoxybenzenesulfonyl chloride (II) in the presence of Et3N afforded sulfonyl derivative (III), which was subsequently converted to tert-butyl ester (V) upon treatment with dimethylformamide di-tert-butyl acetal (IV). Alkylation of (V) with 2-picolyl chloride-HCl (VI) and K2CO3 in DMF provided the N-(2-picolyl) compound (VII). Then, the tert-butyl ester of (VII) was deprotected with HCl in CH2Cl2, and the resulting carboxylic acid (VIII) was condensed with O-tert-butyl hydroxylamine using N-(3-dimethylaminopropyl)-N'-ethylcarbo-diimide-HCl (EDC) and 1-hydroxybenzotriazole (HOBt) to give the tert-butyl hydroxamate (IX). The target hydroxamic acid was then obtained by deprotection of (IX) with HCl in dichloroethane containing one equivalent of EtOH.
| 【1】 MacPherson, L.J.; et al.; Discovery of CGS 27023A, a non-peptidic, potent, and orally active stromelysin inhibitor that blocks cartilage degradation in rabbits. J Med Chem 1997, 40, 16, 2525. |
| 【2】 MacPherson, L.J.; Parker, D.T.; Jeng, A.Y. (Novartis Corp.); Arylsulfonamido-substd. hydroxamic acids. US 5506242; US 5552419 . |
| 【3】 MacPherson, L.J.; Parker, D.T. (Novartis Corp.); Arylsulfonamido-substd. hydroxamic acids. US 5646167 . |
| 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) | 21056 | (R)-(-)-Valine; D-Valine; (R)-alpha-Aminoisovaleric acid | 640-68-6 | C5H11NO2 | 详情 | 详情 |
| (II) | 15719 | 4-methoxybenzenesulfonyl chloride | 98-68-0 | C7H7ClO3S | 详情 | 详情 |
| (III) | 21058 | (2R)-2-[[(4-methoxyphenyl)sulfonyl]amino]-3-methylbutyric acid | C12H17NO5S | 详情 | 详情 | |
| (IV) | 21059 | N-[di(tert-butoxy)methyl]-N,N-dimethylamine; di(tert-butoxy)-N,N-dimethylmethanamine | 36805-97-7 | C11H25NO2 | 详情 | 详情 |
| (V) | 21060 | tert-butyl (2R)-2-[[(4-methoxyphenyl)sulfonyl]amino]-3-methylbutanoate | C16H25NO5S | 详情 | 详情 | |
| (VI) | 21061 | 2-(chloromethyl)pyridine hydrochloride | 6959-47-3 | C6H7Cl2N | 详情 | 详情 |
| (VII) | 21062 | tert-butyl (2R)-2-[[(4-methoxyphenyl)sulfonyl](2-pyridinylmethyl)amino]-3-methylbutanoate | C22H30N2O5S | 详情 | 详情 | |
| (VIII) | 21063 | (2R)-2-[[(4-methoxyphenyl)sulfonyl](2-pyridinylmethyl)amino]-3-methylbutyric acid hydrochloride | C18H23ClN2O5S | 详情 | 详情 | |
| (IX) | 21064 | (2R)-N-(tert-butoxy)-2-[[(4-methoxyphenyl)sulfonyl](2-pyridinylmethyl)amino]-3-methylbutanamide | C22H31N3O5S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)The title compound was obtained by the solid-phase method using a peptide synthesizer. Starting from Fmoc-valine linked to Wang resin (I), cleavage of the Fmoc group with piperidine in DMF provided the deprotected valine-resin (II), which was then coupled with Fmoc-leucine (III) by means of 1-hydroxybenzotriazole and diisopropylcarbodiimide. The resulting dipeptide resin (IV) was deprotected with piperidine in DMF to give (V), and further coupling with protected serine (VI) yielded (VII). After Fmoc-deprotection, the tripeptide-resin (VIII) was coupled with phenyl isocyanate (IX), affording urea (X). Cleavage from the resin with simultaneous deprotection using trifluoroacetic acid furnished the tripeptide urea (XI). This was finally esterified by treatment with ethanolic HCl to provide the target ethyl ester.
| 【1】 Sawa, E.; et al.; Structural modification of Fas C-terminal tripeptide and its effects on the inhibitory activity of Fas/FAP-1 binding. J Med Chem 1999, 42, 17, 3289. |
| 【2】 Kataoka, S.; Nishitoba, T.; Takahashi, M.; Sawa, E.; Kamishohara, M. (Kirin Brewery Co., Ltd.); Novel peptide cpds. and medicinal compsns. thereof. JP 1999171896; WO 9711091 . |
| 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) | 19932 | (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-methylbutyric acid | C20H21NO4 | 详情 | 详情 | |
| (II) | 21056 | (R)-(-)-Valine; D-Valine; (R)-alpha-Aminoisovaleric acid | 640-68-6 | C5H11NO2 | 详情 | 详情 |
| (III) | 19934 | (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-methylpentanoic acid | C21H23NO4 | 详情 | 详情 | |
| (IV) | 33117 | (2S)-2-[((2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-methylpentanoyl)amino]-3-methylbutyric acid | C26H32N2O5 | 详情 | 详情 | |
| (V) | 33123 | (2S)-2-[[(2S)-2-amino-4-methylpentanoyl]amino]-3-methylbutyric acid | 35436-83-0 | C11H22N2O3 | 详情 | 详情 |
| (VI) | 33118 | (2S)-3-(tert-butoxy)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid | 71989-33-8 | C22H25NO5 | 详情 | 详情 |
| (VII) | 33119 | (5S,8S,11S)-5-(tert-butoxymethyl)-1-(9H-fluoren-9-yl)-8-isobutyl-11-isopropyl-3,6,9-trioxo-2-oxa-4,7,10-triazadodecan-12-oic acid | C33H45N3O7 | 详情 | 详情 | |
| (VIII) | 33120 | (2S)-2-[((2S)-2-[[(2S)-2-amino-3-(tert-butoxy)propanoyl]amino]-4-methylpentanoyl)amino]-3-methylbutyric acid | C18H35N3O5 | 详情 | 详情 | |
| (IX) | 11289 | 1-Isocyanatobenzene; phenyl isocyanate; Phenylisocyanate | 103-71-9 | C7H5NO | 详情 | 详情 |
| (X) | 33121 | (2S)-2-[((2S)-2-[[(2S)-2-[(anilinocarbonyl)amino]-3-(tert-butoxy)propanoyl]amino]-4-methylpentanoyl)amino]-3-methylbutyric acid | C25H40N4O6 | 详情 | 详情 | |
| (XI) | 33122 | (2S)-2-[[(2S)-2-([(2S)-2-[(anilinocarbonyl)amino]-3-hydroxypropanoyl]amino)-4-methylpentanoyl]amino]-3-methylbutyric acid | C21H32N4O6 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)The synthesis of the carboxylic acid intermediate (VIII) has been performed as follows: The reaction of D-valine (I) with benzyl chloroformate and NaHCO3 gives the protected valine (II), which is esterified with pentafluorophenol and EDAC to yield the activated ester (III). The condensation of (III) with the lithium enolate of methyl acetate (IV) affords the beta ketoester (V), which is stereoselectively reduced with KBH4 and crystallized to afford the desired enantiomeric beta hydroxyester (VI). The silylation of (VI) with Tips-OTf and lutidine provides the silyl ether (VII), which is hydrolyzed with NaOH to give the desired carboxylic acid intermediate (VIII). The synthesis of the activated ester intermediate (XV) has been performed as follows: The reaction of L-valine (IX) with NaNO2 and H2SO4 gives the hydroxyacid (X), which is esterified with allyl bromide (XI) and K2CO3 to yield the allyl ester (XII). The condensation of (XII) with the intermediate (VIII) by means of EDAC and DMAP affords the adduct (XIII), which is treated with Pd(PPh3)4 to provide the carboxylic acid (XIV). Finally, this compound is esterified with C6F5-OTf to give the activated ester intermediate (XV).
| 【1】 Liang, B.; et al.; Total syntheses and biological investigations of tamandarins A and B and tamandarin A analogs. J Am Chem Soc 2001, 123, 19, 4469. |
| 【2】 Joullie, M.M.; et al.; Total synthesis of (-)-tamandarin B. Tetrahedron Lett 2000, 41, 49, 9373. |
| 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) | 21056 | (R)-(-)-Valine; D-Valine; (R)-alpha-Aminoisovaleric acid | 640-68-6 | C5H11NO2 | 详情 | 详情 |
| (II) | 49332 | (2R)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutyric acid | C13H17NO4 | 详情 | 详情 | |
| (III) | 49323 | 2,3,4,5,6-pentafluorophenyl (2R)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoate | C19H16F5NO4 | 详情 | 详情 | |
| (IV) | 49324 | C3H5LiO2 | 详情 | 详情 | ||
| (V) | 49325 | methyl (4R)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-oxohexanoate | C16H21NO5 | 详情 | 详情 | |
| (VI) | 49326 | methyl (3S,4R)-4-[[(benzyloxy)carbonyl]amino]-3-hydroxy-5-methylhexanoate | C16H23NO5 | 详情 | 详情 | |
| (VII) | 49327 | methyl (3S,4R)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-[(triisopropylsilyl)oxy]hexanoate | C25H43NO5Si | 详情 | 详情 | |
| (VIII) | 49328 | (3S,4R)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-[(triisopropylsilyl)oxy]hexanoic acid | C24H41NO5Si | 详情 | 详情 | |
| (IX) | 37828 | L-2-Amino-3-methylbutyric acid; L-2-Aminoisovaleric acid; 2-Aminoisovaleric acid; L-2-Amino-3-methylbutyric acid; L-alpha-Aminoisovaleric acid; L-valine; (S)-(+)-Valine; (S)-alpha-Aminoisovaleric acid | 72-18-4 | C5H11NO2 | 详情 | 详情 |
| (X) | 37829 | (2S)-2-hydroxy-3-methylbutyric acid | C5H10O3 | 详情 | 详情 | |
| (XI) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (XII) | 37830 | allyl (2S)-2-hydroxy-3-methylbutanoate | C8H14O3 | 详情 | 详情 | |
| (XIII) | 49329 | (1S)-1-[(allyloxy)carbonyl]-2-methylpropyl (3S,4R)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-[(triisopropylsilyl)oxy]hexanoate | C32H53NO7Si | 详情 | 详情 | |
| (XIV) | 49330 | (2S)-2-([(3S,4R)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-[(triisopropylsilyl)oxy]hexanoyl]oxy)-3-methylbutyric acid | C29H49NO7Si | 详情 | 详情 | |
| (XV) | 49331 | (1S)-2-methyl-1-[(2,3,4,5,6-pentafluorophenoxy)carbonyl]propyl (3S,4R)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-[(triisopropylsilyl)oxy]hexanoate | C35H48F5NO7Si | 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 protected 4-pyrimidinylphenylalanine (III) was prepared by palladium-catalyzed coupling of the boronophenylalanine (I) with the 5-halopyrimidine (II). After acidic cleavage of the N-Boc protecting group of (III), the resultant amino ester (IV) was coupled with N-Boc-cycloleucine (V) to provide dipeptide (VI). Further acidic treatment of (VI) removed the N-Boc group to yield amine (VII). The chiral bromo acid (IX) was obtained by diazotization of D-valine (VIII) in the presence of HBr and KBr. Acylation of the racemic amine (VII) with bromo acid (IX) furnished the corresponding amide (X) as an epimeric mixture. The bromo group of (X) was finally displaced with potassium thioacetate to give the title thioacetate ester.
| 【1】 Gude, C.; Chan, K.; Firooznia, F.; et al.; Synthesis and biological activity of novel potent endothelin-converting enzyme-1 inhibitors. Bioorg Med Chem Lett 2001, 11, 3, 375. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 47701 | methyl 2-[(tert-butoxycarbonyl)amino]-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate | C21H32BNO6 | 详情 | 详情 | |
| (II) | 38987 | 5-bromopyrimidine | 4595-59-9 | C4H3BrN2 | 详情 | 详情 |
| (III) | 47702 | methyl 2-[(tert-butoxycarbonyl)amino]-3-[4-(5-pyrimidinyl)phenyl]propanoate | C19H23N3O4 | 详情 | 详情 | |
| (IV) | 47703 | methyl 2-amino-3-[4-(5-pyrimidinyl)phenyl]propanoate | C14H15N3O2 | 详情 | 详情 | |
| (V) | 30890 | 1-[(tert-butoxycarbonyl)amino]cyclopentanecarboxylic acid | C11H19NO4 | 详情 | 详情 | |
| (VI) | 47704 | methyl 2-[([1-[(tert-butoxycarbonyl)amino]cyclopentyl]carbonyl)amino]-3-[4-(5-pyrimidinyl)phenyl]propanoate | C25H32N4O5 | 详情 | 详情 | |
| (VII) | 47705 | methyl 2-[[(1-aminocyclopentyl)carbonyl]amino]-3-[4-(5-pyrimidinyl)phenyl]propanoate | C20H24N4O3 | 详情 | 详情 | |
| (VIII) | 21056 | (R)-(-)-Valine; D-Valine; (R)-alpha-Aminoisovaleric acid | 640-68-6 | C5H11NO2 | 详情 | 详情 |
| (IX) | 33158 | (2R)-2-bromo-3-methylbutyric acid | 565-74-2 | C5H9BrO2 | 详情 | 详情 |
| (X) | 47706 | methyl 2-[[(1-[[(2R)-2-bromo-3-methylbutanoyl]amino]cyclopentyl)carbonyl]amino]-3-[4-(5-pyrimidinyl)phenyl]propanoate | C25H31BrN4O4 | 详情 | 详情 |