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【结 构 式】 
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【分子编号】11820 【品名】Suberic acid; Cork acid; Octanedioic acid 【CA登记号】505-48-6 |
【 分 子 式 】C8H14O4 【 分 子 量 】174.19676 【元素组成】C 55.16% H 8.1% O 36.74% |
合成路线1
该中间体在本合成路线中的序号：(I)Methylprednisolone suleptanate with and without radiolabeling can be prepared by two different ways: 1) The reaction of suberic acid (I) with pivaloyl chloride and triethylamine followed by condensation with N-methyltaurine sodium salt (II) gives 8-oxo-8-[N-(2-sulfoethyl)-N-methylamino]octanoic acid (III), which is treated with triethylamine and HCl, affording the corresponding triethylammonium salt (IV). The condensation of (IV) with methylprednisolone (V) by means of pivaloyl chloride and dimethylaminopyridine (DMAP) in dichloromethane yields the intermediate triethylammonium salt (VI), which is finally treated with sodium hydrogen sulfate in water. 2) The reaction of 21-deoxy-21-iodomethylprednisolone (VII) with suberic acid (I) by means of diisopropylethylamine (DEA) in DMF yields the corresponding 21-hemisuberate (VIII), which is then condensed with N-methyltaurine sodium salt (II) by means of isobutyl chloroformate and triethylamine in THF.
| 【1】 Anderson, B.D.; Conradi, R.A.; Knuth, K.E.; Strategies in the design of solution-stable, water-soluble prodrugs I: A physical-organic approach to pro-moiety selection for 21-esters of corticosteroids. J Pharm Sci 1985, 74, 365-74. |
| 【2】 Graul, A.; Leeson, J.; Castaner, J.; Methylprednisolone Suleptanate. Drugs Fut 1997, 22, 8, 833. |
| 【3】 Anderson, B.D.; Conradi, R.A. (Pharmacia Corp.); Sulfonate containing ester prodrugs of corticosteroids. JP 1984137500; US 4472392 . |
| 【4】 Pearlman, B.A. (Pharmacia Corp.); Amine salts of alkane-1,n-dicarboxylic acid mono-(2-sulfato-ethyl)amides. WO 8900558 . |
| 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) | 11820 | Suberic acid; Cork acid; Octanedioic acid | 505-48-6 | C8H14O4 | 详情 | 详情 |
| (II) | 11821 | sodium 2-(methylamino)-1-ethanesulfonate | 4316-74-9 | C3H8NNaO3S | 详情 | 详情 |
| (III) | 11822 | 7-[N-Methyl-N-(2-sulfoethyl)carbamoyl]heptanoic acid disodium salt | C11H19NNaO6S | 详情 | 详情 | |
| (IV) | 11823 | N,N-diethyl-1-ethanaminium 2-[(7-carboxyheptanoyl)(methyl)amino]-1-ethanesulfonate | C17H36N2O6S | 详情 | 详情 | |
| (V) | 10394 | Methylprednisolone | 83-43-2 | C22H30O5 | 详情 | 详情 |
| (VI) | 11825 | N,N-diethyl-1-ethanaminium 3-[(8-[2-[(6S,8S,9S,10R,11S,13S,14S,17R)-11,17-dihydroxy-6,10,13-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy]-8-oxooctanoyl)(methyl)amino]-1-propanesulfonate | C40H66N2O10S | 详情 | 详情 | |
| (VII) | 11826 | (6S,8S,9S,10R,11S,13S,14S,17R)-11,17-Dihydroxy-17-(2-iodoacetyl)-6,10,13-trimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one | C22H29IO4 | 详情 | 详情 | |
| (VIII) | 11827 | sodium 8-[2-[(6S,8S,9S,10R,11S,13S,14S,17R)-11,17-dihydroxy-6,10,13-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy]-8-oxooctanoate | C30H41NaO8 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)3) The title product labeled at 1, 2 and 4 positions is synthesized starting from [1,2,4-3H]-methylprednisolone and using the method described in the preceding paragraph to finally yield [1,2,4-3H]-methylprednisolone suleptanate. 4) The title product [14C]-labeled at the CO groups of the suberic acid is synthesized starting from methylprednisolone 21-O-mesylate (IX), which is condensed with [1,8-14C]-suberic acid (X) by means of diisopropyl ethylamine in DMF to yield the corresponding hemisuberate (XI). Finally, this compound is condensed with N-methyltaurine sodium salt (II) by means of isobutyl chloroformate as before.
| 【1】 Stolle, W.T.; Runge, T.A.; Hsi, R.S.P.; Synthesis of carbon-14 and tritium labeled methylprednisolone suleptanate. J Label Compd Radiopharm 1990, 28, 255-80. |
| 【2】 Graul, A.; Leeson, J.; Castaner, J.; Methylprednisolone Suleptanate. Drugs Fut 1997, 22, 8, 833. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 11821 | sodium 2-(methylamino)-1-ethanesulfonate | 4316-74-9 | C3H8NNaO3S | 详情 | 详情 |
| (IX) | 11828 | 2-[(6S,8S,9S,10R,11S,13S,14S,17R)-11,17-dihydroxy-6,10,13-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl methanesulfonate | C23H32O7S | 详情 | 详情 | |
| (X) | 11820 | Suberic acid; Cork acid; Octanedioic acid | 505-48-6 | C8H14O4 | 详情 | 详情 |
| (X) | 45087 | suberic acid | C8H14O4 | 详情 | 详情 | |
| (XI) | 11830 | 8-[2-[(6S,8S,9S,10R,11S,13S,14S,17R)-11,17-Dihydroxy-6,10,13-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy]-8-oxooctanoic acid | C30H42O8 | 详情 | 详情 | |
| (XI) | 45088 | 8-[2-[(6S,8S,9S,10R,11S,13S,14S,17R)-11,17-dihydroxy-6,10,13-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy]-8-oxooctanoic acid | C30H42O8 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XII)5. The condensation of diacid (XII) with aniline (II) by heating at 190 C gives the monoamide (VII), which is esterified by means of Dowex 50W-X2 in refluxing methanol to yield the monoamide monoester (XIII). Finally, this compound is treated with hydroxylamine and NaOMe in methanol to afford the target hydroxamic acid with overall yields of around 37%.
| 【1】 Stowell, J.C.; et al.; The synthesis of N-hydroxy-N'-phenyloctanediamide and its inhibitory effect on proliferation of AXC rat prostate cancer cells. J Med Chem 1995, 38, 8, 1411. |
合成路线4
该中间体在本合成路线中的序号：(XII)6. The reaction of acid (XII) with refluxing acetic anhydride gives the cyclic anhydride (XIV), which is treated with aniline (II) in THF to yield the monoamide (VII). The reaction of (VII) with ethyl chloroformate and TEA in THF affords the mixed anhydride (XV), which is finally treated with hydroxylamine in methanol to afford the target hydroxamic acid with overall yields of around 58%.
| 【1】 Mai, A.; et al.; A new facile and expeditious synthesis of N-hydroxy-N'-phenyloctanediamide, a potent inducer of terminal cytodifferentiation. Org Prep Proced Int 2001, 33, 4, 391. |
合成路线5
该中间体在本合成路线中的序号：(I)Mannich reaction of N-(2-methoxyphenyl)piperazine (I) with 3-acetylbenzothiophene (II) in the presence of paraformaldehyde and HCl in refluxing EtOH leads to the piperazinyl propanone (III). Subsequent keto group reduction with NaBH4 gives the target alcohol.
| 【2】 Bosch Rovira, A.; Roca Acin, J.; Monge Vega, A.; Del Rio Zambrana, J.; Palop Cubillo, J.A.; Lasheras Aldaz, B.; Del Castillo Nieto, J.C. (Laboratorios Vita, SA); Cpds. derived from thiophene and benzothiophene, and related utilisation and compsn.. EP 1008594; ES 2128266; JP 2002511883; US 6262056; WO 9902516 . |
| 【1】 Oficialdegui, A.-M.; Martínez-Esparza, J.; Pérez-Sailanes, S.; et al.; New 1-aryl-3-(4-arylpiperazin-1-yl)propane derivatives, with dual action at 5-HT1A serotonin receptors and serotonin transporter, as a new class of antidepressants. J Med Chem 2001, 44, 3, 418. |