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【结 构 式】 
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【分子编号】24927 【品名】tert-butyl (2R,3aR,7aR,10aR)-8-(dimethoxymethyl)-5-(5-hexenyl)-10-oxo-2-vinyl-2,3,5,6,7,7a,10,10a-octahydropyrrolo[2,3-i]isoquinoline-1(4H)-carboxylate 【CA登记号】 |
【 分 子 式 】C27H42N2O5 【 分 子 量 】474.64096 【元素组成】C 68.32% H 8.92% N 5.9% O 16.85% |
合成路线1
该中间体在本合成路线中的序号：(Ia)Antineoplaston AS2-5 (AS2-5) can be obtained in the following way (1,2): N-Phenylacetyl-L-glutamine sodium is synthesized in two steps. In the first step, phenylacetic acid (I) is treated with N-hydroxysuccinimide (B) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (A) in acetonitrile to give intermediate (Ia). In the second step, (Ia) is reacted without purification with L-glutamine (II) in the presence of NaHCO3 in 1:1 acetonitrile-water mixture to afford N-phenylacetyl-L-glutamine (III) in 87% yield. Compound (III) is then converted to sodium salt in aqueous solution by treatment with aqueous sodium hydroxide solution (pH 7). In a large scale preparation reaction of phenylacetyl chloride with L-glutamine in aqueous solution containing NaHCO3 affords N-phenyiacetyl L-glutamine sodium.
| 【1】 Burzynski, S.R. (Burzynski Research Institute); Purified antineoplaston fractions and methods of treating neoplastic disease. US 4558057 . |
| 【2】 Berman, E.M.; Gregor, V.E.; Showalter, H.H.D. (Pfizer Inc.); Benzoselenino[4,3,2-cd]indazole compound, compositions comprising the compounds and processes for producing the compounds. AU 8544154; EP 0170412; ES 8704956 . |
| 【3】 Khalid, M.; Burzynski, S.R.; Antineoplaston AS2-5. Drugs Fut 1986, 11, 5, 364. |
| 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) | 10264 | 1-Hydroxydihydro-1H-pyrrole-2,5-dione; N-Hydroxysuccinimide; 1-Hydroxy-2,5-pyrrolidinedione | 6066-82-6 | C4H5NO3 | 详情 | 详情 |
| (Ia) | 24927 | tert-butyl (2R,3aR,7aR,10aR)-8-(dimethoxymethyl)-5-(5-hexenyl)-10-oxo-2-vinyl-2,3,5,6,7,7a,10,10a-octahydropyrrolo[2,3-i]isoquinoline-1(4H)-carboxylate | C27H42N2O5 | 详情 | 详情 | |
| (A) | 24945 | N-[3-(dimethylamino)propyl]-N'-ethylcarbodiimide | 25952-53-8 | C8H17N3 | 详情 | 详情 |
| (I) | 16148 | Benzeneacetic acid; 2-Phenylacetic acid; Phenyl Acetic Acid | 103-82-2 | C8H8O2 | 详情 | 详情 |
| (II) | 24948 | L-glutamine | 56-85-9 | C5H10N2O3 | 详情 | 详情 |
| (III) | 24949 | (2S)-5-amino-5-oxo-2-[(2-phenylacetyl)amino]pentanoic acid | C13H16N2O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVIII)The ketalization of (XVII) with methyl orthoformate in methanol gives the dinethylketal (XVIII), which is condensed with 3-butenyllithium (XIX) to afford the tetracyclic compound (XX). A new cyclization of (XX) by means of a ruthenium catalyst closes the macrocycle of (XXI), which is condensed with 5-hexenoyl chloride (XXII) and triethylamine affording the precursor (XXIII) of the cyclooctane ring found in the target compound. The cyclization of (XXIII) with the same ruthenium catalyst gives the intermediate (XXIV) with the ring system of the target compound, which is finally reduced with DIBAL in order to eliminate the extra oxygen of (XXIV), and oxidized again with Dess Martin periodinane (DMP) to regenerate the formyl group reduced by the DIBAL to yield the target ircinal A.
| 【1】 Martin, S.F.; et al.; Enantioselective total synthesis of ircinal A and related manzamine alkaloids. J Am Chem Soc 1999, 121, 4, 866. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVII) | 24926 | tert-butyl (2R,3aR,7aR,10aR)-8-formyl-5-(5-hexenyl)-10-oxo-2-vinyl-2,3,5,6,7,7a,10,10a-octahydropyrrolo[2,3-i]isoquinoline-1(4H)-carboxylate | C25H36N2O4 | 详情 | 详情 | |
| (XVIII) | 24927 | tert-butyl (2R,3aR,7aR,10aR)-8-(dimethoxymethyl)-5-(5-hexenyl)-10-oxo-2-vinyl-2,3,5,6,7,7a,10,10a-octahydropyrrolo[2,3-i]isoquinoline-1(4H)-carboxylate | C27H42N2O5 | 详情 | 详情 | |
| (XIX) | 24928 | 4-pentenyllithium | C5H9Li | 详情 | 详情 | |
| (XX) | 24929 | (4aR,6aS,10R,11aR,11bR)-6a-(3-butenyl)-5-(dimethoxymethyl)-2-(5-hexenyl)-10-vinyl-2,3,4,4a,6a,10,11,11b-octahydro-1H-[1,3]oxazolo[5,4,3-hi]pyrido[3,4-d]indol-8-one | C27H40N2O4 | 详情 | 详情 | |
| (XXI) | 24930 | (1S,13R,14R,16R,23R)-21-(dimethoxymethyl)-16-vinyl-19-oxa-10,17-diazapentacyclo[11.6.2.1(1,14).1(10,14).0(17,23)]tricosa-4,20-dien-18-one | C25H36N2O4 | 详情 | 详情 | |
| (XXII) | 24931 | 5-hexenoyl chloride | C6H9ClO | 详情 | 详情 | |
| (XXIII) | 24932 | 1-[(1R,13S,14R,16R,18R)-19-(dimethoxymethyl)-13-hydroxy-16-vinyl-4,15-diazatetracyclo[11.5.2.1(4,18).0(14,18)]henicosa-9,19-dien-15-yl]-5-hexen-1-one | C30H46N2O4 | 详情 | 详情 | |
| (XXIV) | 24933 | (1R,2R,4R,12R,13S)-13-hydroxy-10-oxo-11,22-diazapentacyclo[11.11.2.1(2,22).0(2,12).0(4,11)]heptacosa-5,16,25-triene-25-carbaldehyde | C26H36N2O3 | 详情 | 详情 | |
| (XXV) | 24934 | (1R,2R,4R,12R,13S)-25-(hydroxymethyl)-11,22-diazapentacyclo[11.11.2.1(2,22).0(2,12).0(4,11)]heptacosa-5,16,25-trien-13-ol | C26H40N2O2 | 详情 | 详情 |