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【结 构 式】 
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【分子编号】21673 【品名】methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoate 【CA登记号】 |
【 分 子 式 】C15H21NO4 【 分 子 量 】279.33608 【元素组成】C 64.5% H 7.58% N 5.01% O 22.91% |
合成路线1
该中间体在本合成路线中的序号：(I)The reaction of N-(tert-butoxycarbonyl)-L-phenylalanine methyl ester (I) with trimethylphosphonate lithium salt (II) in THF gives the dimethyl L-phenylalanylmethylphosphonate (III), which is condensed with 2-phenylacetaldehyde (IV) by means of Na2CO3 in ethanol yielding the diphenylhexenone (V). The reduction of the carbonyl group of (V) with NaBH4 in methanol affords a diastereomeric mixture of alcohols (VI) and (VII) from which the desired major isomer (VII) is separated by column chromatography.. The epoxidation of the double bond of (VII) with MCPBA in dichloromethane gives the epoxide (VIII) (1), which is cleaved with Red-Al in THF providing the diol (IX). The reaction of (IX) with Ms-Cl and DIEA yields the intermediate dimesylate (X) which, without isolation, affords oxazolidinone (XI). The reaction of (XI) with sodium azide and 18-C-6 in DMSO gives the azide (XII), which is treated with NaH and Boc2O in THF in order to cleave the oxazolidine ring and furnish the protected aminoalcohol (XIII). Finally the azido group of (XIII) is hydrogenate with H2 over Pd/C in methanol to afford the monoprotected diaminoalcohol (XIV) the target compound.
| 【1】 Norbedo, S.; Benedetti, F.; Epoxyalcohol route to hydroxyethylene dipeptide isosteres: A new synthesis of the diaminoalcohol core of HIV-protease inhibitor ABT-538 (ritonavir). Chem Commun (London) 2001, 2, 203. |
| 【2】 Benedetti, F.; et al.; Versatile and stereoselective synthesis of diamino diol dipeptide isosteres, core units of pseudopeptide HIV protease inhibitors. J Org Chem 1997, 62, 26, 9348. |
| 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) | 21673 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoate | C15H21NO4 | 详情 | 详情 | |
| (II) | 29720 | [(dimethoxyphosphoryl)methyl]lithium | C3H8LiO3P | 详情 | 详情 | |
| (III) | 47117 | dimethyl (3S)-3-[(tert-butoxycarbonyl)amino]-2-oxo-4-phenylbutylphosphonate | C17H26NO6P | 详情 | 详情 | |
| (IV) | 18456 | 2-phenylacetaldehyde | 122-78-1 | C8H8O | 详情 | 详情 |
| (V) | 47118 | tert-butyl (1S,3E)-1-benzyl-2-oxo-5-phenyl-3-pentenylcarbamate | C23H27NO3 | 详情 | 详情 | |
| (VI) | 47119 | tert-butyl (1S,2S,3E)-1-benzyl-2-hydroxy-5-phenyl-3-pentenylcarbamate | C23H29NO3 | 详情 | 详情 | |
| (VII) | 47120 | tert-butyl (1S,2R,3E)-1-benzyl-2-hydroxy-5-phenyl-3-pentenylcarbamate | C23H29NO3 | 详情 | 详情 | |
| (VIII) | 47121 | tert-butyl (1S,2S)-1-benzyl-2-[(2R,3S)-3-benzyloxiranyl]-2-hydroxyethylcarbamate | C23H29NO4 | 详情 | 详情 | |
| (IX) | 47122 | tert-butyl (1S,2R,4R)-1-benzyl-2,4-dihydroxy-5-phenylpentylcarbamate | C23H31NO4 | 详情 | 详情 | |
| (X) | 47123 | (1R,3R)-1-[(1S)-1-[(3,3-dimethylbutanoyl)amino]-2-phenylethyl]-3-[(methylsulfonyl)oxy]-4-phenylbutyl methanesulfonate | C26H37NO7S2 | 详情 | 详情 | |
| (XI) | 47124 | (1R)-1-benzyl-2-[(4S,5S)-4-benzyl-2-oxo-1,3-oxazolidin-5-yl]ethyl methanesulfonate | C20H23NO5S | 详情 | 详情 | |
| (XII) | 47125 | (4S,5S)-5-[(2S)-2-azido-3-phenylpropyl]-4-benzyl-1,3-oxazolidin-2-one | C19H20N4O2 | 详情 | 详情 | |
| (XIII) | 47126 | tert-butyl (1S,2S,4S)-4-azido-1-benzyl-2-hydroxy-5-phenylpentylcarbamate | C23H30N4O3 | 详情 | 详情 | |
| (XIV) | 47127 | tert-butyl (1S,2S,4S)-4-amino-1-benzyl-2-hydroxy-5-phenylpentylcarbamate | C23H32N2O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Condensation of N-(tert-butoxycarbonyl)phenylalanine methyl ester (I) with pyrrolyl magnesium bromide (generated from pyrrole (II) and MeMgBr) furnished ketone (III). The N-Boc group of (III) was deprotected with HCl in dioxan to yield aminoketone (IV), which was then condensed with the succinate building block (V) in DMF to afford succinamide (VI). Further deprotection of the tert-butyl ester of (VI) by treatment with trifluoroacetic acid provided carboxylic acid (VII), which was coupled with O-tert-butyldimethylsilyl hydroxylamine (VIII) in the presence of EDC and HOBt to yield, after desilylation, the target hydroxamic acid.
| 【1】 Sheppard, G.S.; Florjancic, A.S.; Giesler, J.R.; Xu, L.; Guo, Y.; Davidsen, S.K.; Marcotte, P.A.; Elmore, I.; Albert, D.H.; Terrance, J.M.; Bouska, J.J.; Goodfellow, C.L.; Morgan, D.W.; Summers, J.B.; Aryl ketones as novel replacements for the C-terminal amide bond of succinyl hydroxamate MMP inhibitors. Bioorg Med Chem Lett 1998, 8, 22, 3251. |
| 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) | 21673 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoate | C15H21NO4 | 详情 | 详情 | |
| (II) | 21674 | 1H-pyrrole | 109-97-7 | C4H5N | 详情 | 详情 |
| (III) | 21675 | tert-butyl (1S)-1-benzyl-2-oxo-2-(1H-pyrrol-2-yl)ethylcarbamate | C18H22N2O3 | 详情 | 详情 | |
| (IV) | 21676 | (2S)-2-amino-3-phenyl-1-(1H-pyrrol-2-yl)-1-propanone hydrochloride | C13H15ClN2O | 详情 | 详情 | |
| (V) | 21641 | 1-(tert-butyl) 4-(2,3,4,5,6-pentafluorophenyl) (2S,3R)-2-allyl-3-isobutylbutanedioate | C21H25F5O4 | 详情 | 详情 | |
| (VI) | 21678 | tert-butyl (2S)-2-[(1R)-1-([[(1S)-1-benzyl-2-oxo-2-(1H-pyrrol-2-yl)ethyl]amino]carbonyl)-3-methylbutyl]-4-pentenoate | C28H38N2O4 | 详情 | 详情 | |
| (VII) | 21679 | (2S)-2-[(1R)-1-([[(1S)-1-benzyl-2-oxo-2-(1H-pyrrol-2-yl)ethyl]amino]carbonyl)-3-methylbutyl]-4-pentenoic acid | C24H30N2O4 | 详情 | 详情 | |
| (VIII) | 21644 | (Aminooxy)(tert-butyl)dimethylsilane; O-[tert-Butyl(dimethyl)silyl]hydroxylamine | 41879-39-4 | C6H17NOSi | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Condensation of N-(tert-butoxycarbonyl)phenylalanine methyl ester (I) with 2-thienyllithium (II) in THF at -78 C furnished racemized ketone (III). The N-Boc group of (III) was deprotected with HCl in dioxan to yield aminoketone (IV), which was then condensed with the succinate building block (V) in DMF to afford succinamide (VI). Further deprotection of the tert-butyl ester of (VI) by treatment with trifluoroacetic acid provided carboxylic acid (VII), which was coupled with O-tert-butyldimethylsilyl hydroxylamine (VIII) in the presence of EDC and HOBt to yield, after desilylation, the target hydroxamic acid.
| 【1】 Sheppard, G.S.; Florjancic, A.S.; Giesler, J.R.; Xu, L.; Guo, Y.; Davidsen, S.K.; Marcotte, P.A.; Elmore, I.; Albert, D.H.; Terrance, J.M.; Bouska, J.J.; Goodfellow, C.L.; Morgan, D.W.; Summers, J.B.; Aryl ketones as novel replacements for the C-terminal amide bond of succinyl hydroxamate MMP inhibitors. Bioorg Med Chem Lett 1998, 8, 22, 3251. |
| 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) | 21673 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoate | C15H21NO4 | 详情 | 详情 | |
| (II) | 21682 | 2-thienyllithium | 2786-07-4 | C4H3LiS | 详情 | 详情 |
| (III) | 21683 | tert-butyl 1-benzyl-2-oxo-2-(2-thienyl)ethylcarbamate | C18H21NO3S | 详情 | 详情 | |
| (IV) | 21684 | 2-amino-3-phenyl-1-(2-thienyl)-1-propanone hydrochloride | C13H14ClNOS | 详情 | 详情 | |
| (V) | 21641 | 1-(tert-butyl) 4-(2,3,4,5,6-pentafluorophenyl) (2S,3R)-2-allyl-3-isobutylbutanedioate | C21H25F5O4 | 详情 | 详情 | |
| (VI) | 21686 | tert-butyl (2S)-2-[(1R)-1-([[1-benzyl-2-oxo-2-(2-thienyl)ethyl]amino]carbonyl)-3-methylbutyl]-4-pentenoate | C28H37NO4S | 详情 | 详情 | |
| (VII) | 21687 | (2S)-2-[(1R)-1-([[1-benzyl-2-oxo-2-(2-thienyl)ethyl]amino]carbonyl)-3-methylbutyl]-4-pentenoic acid | C24H29NO4S | 详情 | 详情 | |
| (VIII) | 21644 | (Aminooxy)(tert-butyl)dimethylsilane; O-[tert-Butyl(dimethyl)silyl]hydroxylamine | 41879-39-4 | C6H17NOSi | 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 N-(tert-butoxycarbonyl)phenylalanine methyl ester (I) with 2-oxazolyllithium (II) in THF at -78 C furnished racemized ketone (III). The N-Boc group of (III) was deprotected with HCl in dioxan to yield aminoketone (IV), which was then condensed with the succinate building block (V) in DMF to afford succinamide (VI). Further deprotection of the tert-butyl ester of (VI) by treatment with trifluoroacetic acid provided carboxylic acid (VII), which was coupled with O-tert-butyldimethylsilyl hydroxylamine (VIII) in the presence of EDC and HOBt to yield, after desilylation, the target hydroxamic acid.
| 【1】 Sheppard, G.S.; Florjancic, A.S.; Giesler, J.R.; Xu, L.; Guo, Y.; Davidsen, S.K.; Marcotte, P.A.; Elmore, I.; Albert, D.H.; Terrance, J.M.; Bouska, J.J.; Goodfellow, C.L.; Morgan, D.W.; Summers, J.B.; Aryl ketones as novel replacements for the C-terminal amide bond of succinyl hydroxamate MMP inhibitors. Bioorg Med Chem Lett 1998, 8, 22, 3251. |
| 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) | 21673 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoate | C15H21NO4 | 详情 | 详情 | |
| (II) | 21690 | 1,3-oxazol-2-yllithium | C3H2LiNO | 详情 | 详情 | |
| (III) | 21691 | tert-butyl 1-benzyl-2-(1,3-oxazol-2-yl)-2-oxoethylcarbamate | C17H20N2O4 | 详情 | 详情 | |
| (IV) | 21692 | 2-amino-1-(1,3-oxazol-2-yl)-3-phenyl-1-propanone hydrochloride | C12H13ClN2O2 | 详情 | 详情 | |
| (V) | 21641 | 1-(tert-butyl) 4-(2,3,4,5,6-pentafluorophenyl) (2S,3R)-2-allyl-3-isobutylbutanedioate | C21H25F5O4 | 详情 | 详情 | |
| (VI) | 21694 | tert-butyl (2S)-2-[(1R)-1-([[1-benzyl-2-(1,3-oxazol-2-yl)-2-oxoethyl]amino]carbonyl)-3-methylbutyl]-4-pentenoate | C27H36N2O5 | 详情 | 详情 | |
| (VII) | 21695 | (2S)-2-[(1R)-1-([[1-benzyl-2-(1,3-oxazol-2-yl)-2-oxoethyl]amino]carbonyl)-3-methylbutyl]-4-pentenoic acid | C23H28N2O5 | 详情 | 详情 | |
| (VIII) | 21644 | (Aminooxy)(tert-butyl)dimethylsilane; O-[tert-Butyl(dimethyl)silyl]hydroxylamine | 41879-39-4 | C6H17NOSi | 详情 | 详情 |