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【结 构 式】 
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【分子编号】59167 【品名】ethyl 5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-oxopentanoate 【CA登记号】 |
【 分 子 式 】C15H15NO5 【 分 子 量 】289.28784 【元素组成】C 62.28% H 5.23% N 4.84% O 27.65% |
合成路线1
该中间体在本合成路线中的序号：(XLI)The bromination of ethyl acetylsuccinate (XXXIV) produced initially the beta-bromo derivative (XXXV), which upon standing for further 12 hours in the presence of the HBr generated in the reaction underwent rearrangement to the delta-bromo isomer (XXXVI). Hydrolysis and decarboxylation of (XXXVI) in the presence of HCl produced the expected delta-bromolevulinic acid (XXXVII) along with the chloro analogue (XXXVIII). Esterification of this mixture of acids with ethanol and sulfuric acid led to the respective ethyl esters (XXXIX) and (XL). Condensation of halo esters (XXXIX) and (XL) with potassium phthalimide (XXVII) furnished ethyl delta-phthalimidolevulinate (XLI), which was finally converted to the title compound by acidic hydrolysis.
| 【1】 Lartillot, S.; Baron, C.; New route to delta-aminolevulinic and application to the synthesis of its alpha- and beta-methylated derivatives. Bull Soc Chim Fr 1966, 12, 3798. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXVII) | 27890 | Potassium phthalimide | 1074-82-4 | C8H4KNO2 | 详情 | 详情 |
| (XXXIV) | 59161 | Acetonyl succinic acid diethylester; Diethyl acetylsuccinate | 1115-30-6 | C10H16O5 | 详情 | 详情 |
| (XXXV) | 59162 | diethyl 2-acetyl-2-bromosuccinate | C10H15BrO5 | 详情 | 详情 | |
| (XXXVI) | 59163 | diethyl 2-(2-bromoacetyl)succinate | C10H15BrO5 | 详情 | 详情 | |
| (XXXVII) | 59164 | 5-bromo-4-oxopentanoic acid | C5H7BrO3 | 详情 | 详情 | |
| (XXXVIII) | 59168 | 5-chloro-4-oxopentanoic acid | C5H7ClO3 | 详情 | 详情 | |
| (XXXIX) | 59165 | ethyl 5-bromo-4-oxopentanoate | C7H11BrO3 | 详情 | 详情 | |
| (XL) | 59166 | ethyl 5-chloro-4-oxopentanoate | C7H11ClO3 | 详情 | 详情 | |
| (XLI) | 59167 | ethyl 5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-oxopentanoate | C15H15NO5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XLI)The organozinc reagent (LXXIX) was prepared by treatment of [(1-ethoxycyclopropyl)oxy]trimethylsilane (LXXVIII) with ZnCl2. Palladium-catalyzed coupling of (LXXIX) to phthalimidoacetyl chloride (VIII) furnished ethyl phthalimodolevulinate (XLI), which was finally hydrolyzed as in precedent methods.
| 【1】 Wang, J.; Scott, A.I.; An efficient synthesis of delta-aminolevulinic acid (ALA) and its isotopomers. Tetrahedron Lett 1997, 38, 5, 739. |
| 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) | 10278 | 2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl chloride | 6780-38-7 | C10H6ClNO3 | 详情 | 详情 |
| (XLI) | 59167 | ethyl 5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-oxopentanoate | C15H15NO5 | 详情 | 详情 | |
| (LXXVIII) | 52291 | Cyclopropanone ethyl trimethylsilyl acetal; (1-Ethoxycyclopropoxy)trimethylsilane | C8H18O2Si | 详情 | 详情 | |
| (LXXIX) | 59200 | bis(3-ethoxy-3-oxopropyl)zinc | C10H18O4Zn | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)The condensation of the labeled glycine (I) with phthalic anhydride (II) by heating at 160 C gives the labeled phthalimido acetic acid (III), which is treated with refluxing SOCl2 to yield the acyl chloride (IV). The condensation of (IV) with 3-iodopropionic acid ethyl ester (V) by means of the Zn/Cu couple and Pd(PPh3)4 in hot toluene affords the labeled 5-phthalimido-levulinate (VI), which is finally treated with refluxing 6N HCl to provide the target labeled aminolevulinic acid.
| 【1】 Iida, K.; Kajiwara, M.; Synthesis of 13C and 15N multilabeled 5-aminolevulinic acid. J Label Compd Radiopharm 2002, 45, 2, 139. |
| 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) | 20436 | glycine | 56-40-6 | C2H5NO2 | 详情 | 详情 |
| (I) | 61588 | GLYCINE-13C2-15N | C2H5NO2 | 详情 | 详情 | |
| (II) | 11900 | 2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride | 85-44-9 | C8H4O3 | 详情 | 详情 |
| (III) | 10284 | N-Phthaloylglycine; 2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)acetic acid | 4702-13-0 | C10H7NO4 | 详情 | 详情 |
| (III) | 61589 | 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetic acid | C10H7NO4 | 详情 | 详情 | |
| (IV) | 10278 | 2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl chloride | 6780-38-7 | C10H6ClNO3 | 详情 | 详情 |
| (IV) | 61590 | 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl chloride | C10H6ClNO3 | 详情 | 详情 | |
| (V) | 61591 | ethyl 3-iodopropanoate | C5H9IO2 | 详情 | 详情 | |
| (VI) | 59167 | ethyl 5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-oxopentanoate | C15H15NO5 | 详情 | 详情 | |
| (VI) | 61592 | ethyl 5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-oxopentanoate | C15H15NO5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IX)The condensation of 13C-labelled methyl phenyl sulfone (I) with 2-(tert-butyldimethylsilyloxy)acetic acid ethyl ester (II) by means of BuLi in THF gives the labelled propanone derivative (III), which is condensed with ethyl 2-bromoacetate (IV) by means of NaH in THF to yield the gamma-oxo ester (V). Desulfurization of (V) by means of Al/Hg in THF/water affords the silylated 5-hydroxy-4-oxopentanoic acid ethyl ester (VI), which is desilylated by means of AcOH in THF/water to provide the free hydroxyester (VII). The condensation of (VII) with phthalimide (VIII) by means of DEAD and PPh3 in toluene gives the phthalimido derivative (IX), which is finally treated with refluxing 6N HCl to provide the target labelled aminolevulinic acid.
| 【1】 Kurumaya, K.; Okazaki, T.; Seido, N.; Akasaka, Y.; Kawajiri, Y.; Kajiwara, M.; Kondo, M.; Facile synthesis of delta-aminolevulinic acid (ALA) regioselectively labeled with 13C and direct observation of enzymatic transformation from ALA to porphobilinogen (PBG). J Label Compd Radiopharm 1989, 27, 2, 217. |
| 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) | 23622 | methyl phenyl sulfone; methyl(dioxo)phenyl-lambda(6)-sulfane | 3112-85-4 | C7H8O2S | 详情 | 详情 |
| (I) | 61635 | methyl phenyl sulfone; methyl(dioxo)phenyl-lambda~6~-sulfane | C7H8O2S | 详情 | 详情 | |
| (II) | 61636 | ethyl 2-{[tert-butyl(dimethyl)silyl]oxy}acetate | C10H22O3Si | 详情 | 详情 | |
| (III) | 61637 | 1-{[tert-butyl(dimethyl)silyl]oxy}-3-(phenylsulfonyl)acetone | C15H24O4SSi | 详情 | 详情 | |
| (III) | 64694 | 1-{[tert-butyl(dimethyl)silyl]oxy}-3-(phenylsulfonyl)acetone | C15H24O4SSi | 详情 | 详情 | |
| (IV) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (V) | 61639 | ethyl 5-{[tert-butyl(dimethyl)silyl]oxy}-4-oxo-3-(phenylsulfonyl)pentanoate | C19H30O6SSi | 详情 | 详情 | |
| (V) | 64691 | ethyl 5-{[tert-butyl(dimethyl)silyl]oxy}-4-oxo-3-(phenylsulfonyl)pentanoate | C19H30O6SSi | 详情 | 详情 | |
| (VI) | 61640 | ethyl 5-{[tert-butyl(dimethyl)silyl]oxy}-4-oxopentanoate | C13H26O4Si | 详情 | 详情 | |
| (VI) | 64692 | ethyl 5-{[tert-butyl(dimethyl)silyl]oxy}-4-oxopentanoate | C13H26O4Si | 详情 | 详情 | |
| (VII) | 61641 | ethyl 5-hydroxy-4-oxopentanoate | C7H12O4 | 详情 | 详情 | |
| (VII) | 64693 | ethyl 5-hydroxy-4-oxopentanoate | C7H12O4 | 详情 | 详情 | |
| (VIII) | 12376 | Phthalimide; 1H-Isoindole-1,3(2H)-dione; Isoindole-1,3-dione;Phthalic dicarboximide;Phenylimide;Isoindole-1,3-dione | 85-41-6 | C8H5NO2 | 详情 | 详情 |
| (IX) | 59167 | ethyl 5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-oxopentanoate | C15H15NO5 | 详情 | 详情 | |
| (IX) | 61642 | ethyl 5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-oxopentanoate | C15H15NO5 | 详情 | 详情 |