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【结 构 式】 
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【分子编号】59147 【品名】5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-oxopentanoic acid 【CA登记号】 |
【 分 子 式 】C13H11NO5 【 分 子 量 】261.23408 【元素组成】C 59.77% H 4.24% N 5.36% O 30.62% |
合成路线1
该中间体在本合成路线中的序号：(XI)In a different method, N-phthaloylglycine (VII) was obtained by melting a mixture of phthalic anhydride (V) and glycine (VI). Subsequent chlorination of (VII) using SOCl2 provided acid chloride (VIII). Condensation of (VIII) with the sodium derivative of the tricarboxylate compound (IX) gave the keto triester (X). Hydrogenolysis of the benzyl ester groups of (X), followed by decarboxylation in refluxing toluene, gave rise to delta-phthalimidolevulinic acid (XI). This was finally hydrolyzed to the title compound upon refluxing with 7 N HCl.
| 【1】 Neuberger, A.; Scott, J.J.; The synhtesis of delta-succinamidolaevulic acid and related compounds. J Chem Soc 1954, 1820. |
| 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) | 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 |
| (VI) | 20436 | glycine | 56-40-6 | C2H5NO2 | 详情 | 详情 |
| (VII) | 10284 | N-Phthaloylglycine; 2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)acetic acid | 4702-13-0 | C10H7NO4 | 详情 | 详情 |
| (VIII) | 10278 | 2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl chloride | 6780-38-7 | C10H6ClNO3 | 详情 | 详情 |
| (IX) | 59145 | tribenzyl 1,1,2-ethanetricarboxylate | C26H24O6 | 详情 | 详情 | |
| (X) | 59146 | tribenzyl 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-oxo-1,2,2-butanetricarboxylate | C36H29NO9 | 详情 | 详情 | |
| (XI) | 59147 | 5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-oxopentanoic acid | C13H11NO5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XI)Alkylation of potassium phthalimide (XXVII) with epichlorohydrin (XXVIII) provided N-glycidyl phthalimide (XXIX). Epoxide ring opening in (XXIX) with aqueous HBr led to bromohydrin (XXX), which was further oxidized to bromo ketone (XXXI) by means of CrO3. Coupling of bromo ketone (XXXI) with diethyl malonate (XXXII) to afford (XXXIII) was accomplished in the presence of NaOEt in EtOH/DMF as the solvent. Acid hydrolysis of the malonate ester (XXXIII), followed by thermal decarboxylation, gave rise to phthalimido levulinic acid (XI). The phthaloyl group of (XI) was finally hydrolyzed under acidic conditions to furnish delta-aminolevulinic acid.
| 【1】 Collins, A.; Tschudy, D.P.; Malonic ester synthesis of delta-aminolevulinic acid. The reaction of N-3-bromoacetonylphthalimide with malonic ester. J Org Chem 1959, 24, 556. |
| 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) | 59147 | 5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-oxopentanoic acid | C13H11NO5 | 详情 | 详情 | |
| (XXVII) | 27890 | Potassium phthalimide | 1074-82-4 | C8H4KNO2 | 详情 | 详情 |
| (XXVIII) | 10246 | N-Phenyl-2-[(triphenylstannyl)selanyl]benzamide | C31H25NOSeSn | 详情 | 详情 | |
| (XXIX) | 12335 | 2-(2-Oxiranylmethyl)-1H-isoindole-1,3(2H)-dione; N-(2,3-Epoxypropyl)phtalimide | 5455-98-1 | C11H9NO3 | 详情 | 详情 |
| (XXX) | 59158 | 2-(3-bromo-2-hydroxypropyl)-1H-isoindole-1,3(2H)-dione | C11H10BrNO3 | 详情 | 详情 | |
| (XXXI) | 59159 | 2-(3-Bromo-2-oxopropyl)isoindole-1,3-dione | C11H8BrNO3 | 详情 | 详情 | |
| (XXXII) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (XXXIII) | 59160 | diethyl 2-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-oxopropyl]malonate | C18H19NO7 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XI)Tetrahydrofurfurylamine (XLVII) was converted into the corresponding phthalimide (XLVIII) by reaction of phthalic anhydride (V) in boiling chloroform. Subsequent ruthenium-catalyzed oxidation of (XLVIII) produced keto acid (XI), along with a pentanolide by-product, which was removed by column chromatography. Finally, acid hydrolysis of (XI) led to the desired compound. A closely related strategy was based in the ruthenium oxidation of N-benzoyl tetrahydrofurfurylamine (LXX), prepared from amine (XLVII) and benzoyl chloride (XLIX), to afford 5-benzoylaminolevulinic acid (XXXV), which was then hydrolyzed in boiling 6 N HCl .
| 【1】 Kawakami, H.; et al.; A new synthesis of 5-aminolevulinic acid. Agric Biol Chem 1991, 55, 6, 1687. |
| 【2】 Matsumoto, K.; Kawakami, H.; Koseki, K.; Ebata, T.; Matsushita, H. (Japan Tobacco Inc.); Method of preparing an acid additional salt of delta-aminolevulinic acid. US 5284973 . |
| 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) | 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 |
| (XI) | 59147 | 5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-oxopentanoic acid | C13H11NO5 | 详情 | 详情 | |
| (XXXV) | 59156 | 5-(benzoylamino)-4-oxopentanoic acid | C12H13NO4 | 详情 | 详情 | |
| (LXVII) | 27335 | Tetrahydro-2-furanylmethanamine; Tetrahydrofurfurylamine | 4795-29-3 | C5H11NO | 详情 | 详情 |
| (LXVIII) | 59191 | 2-(tetrahydro-2-furanylmethyl)-1H-isoindole-1,3(2H)-dione | C13H13NO3 | 详情 | 详情 | |
| (LXIX) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
| (LXX) | 59192 | N-(tetrahydro-2-furanylmethyl)benzamide | C12H15NO2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XI)A related method was based on the oxidation of N-furfuryl phthalimide (LXXI) under irradiation by light in the presence of oxigen gas and a sensitizer, such as Rose Bengal, to afford the 2,5-dihydrofuranone (LXXII) along with its ring-opened isomer (LXXIII). Subsequent catalytic hydrogenation provided phthalimidolevulinic acid (XI), which was then subjected to acidic hydrolysis. Butenolide (LXXII) was also obtained by the photooxygenation of 5-phthalimidomethyl)furfural (LXXIV). Reduction of (LXXII) to phthalimidolevulinic acid (XI) was accomplished using zinc dust in HOAc under sonication.
| 【1】 Cottier, L.; et al.; Syntheses of gamma-oxo acids or gamma-oxo esters by photooxygenation of furanic compounds and reduction under ultrasound: Application to the synthesis of 5-aminolevulinic acid hydrochloride. Synthesis (Stuttgart) 1995, 3, 303. |
| 【2】 Shimizu, T.; Takeya, H.; Ueki, H.; Process for preparing 5-aminolevulinic acid. US 5380935 . |
| 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) | 59147 | 5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-oxopentanoic acid | C13H11NO5 | 详情 | 详情 | |
| (LXXI) | 59193 | 2-(2-furylmethyl)-1H-isoindole-1,3(2H)-dione | C13H9NO3 | 详情 | 详情 | |
| (LXXII) | 59194 | 2-[(2-hydroxy-5-oxo-2,5-dihydro-2-furanyl)methyl]-1H-isoindole-1,3(2H)-dione | C13H9NO5 | 详情 | 详情 | |
| (LXXIII) | 59195 | (Z)-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-oxo-2-pentenoic acid | C13H9NO5 | 详情 | 详情 | |
| (LXXIV) | 59196 | 5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-2-furaldehyde | C14H9NO4 | 详情 | 详情 |