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【结 构 式】 
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【分子编号】11822 【品名】7-[N-Methyl-N-(2-sulfoethyl)carbamoyl]heptanoic acid disodium salt 【CA登记号】 |
【 分 子 式 】C11H19NNaO6S 【 分 子 量 】316.330768 【元素组成】C 41.77% H 6.05% N 4.43% Na 7.27% O 30.35% S 10.14% |
合成路线1
该中间体在本合成路线中的序号：(III)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：(III)5) The title product [3H]- or [2H]-labeled at C7 of the steroid nucleus is synthesized starting from 21-acetoxy-11beta,17alpha-dihydroxy-6-methylpregna-4,6-diene-3,20-dione (XII), which is hydrogenated with tritium or deuterium over Pd/C in methanol yielding a mixture of the two isomeric dihydro compounds (XIII) and (XIV). The treatment of this mixture with 6N HCl affords compound (XV) labeled at C7, which is dehydrogenated with SeO2 in refluxing tert-butanol and deacetylated with KOH in methanol, yielding methylprednisolone labeled with 3H or 2H at C7 (XVI). Finally, this compound is condensed with 8-oxo-8-[N-(2-sulfoethyl)-N-methylamino]octanoic acid (III) by means of tert-butoxycarbonyl chloride 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 |
|---|---|---|---|---|---|---|
| (III) | 11822 | 7-[N-Methyl-N-(2-sulfoethyl)carbamoyl]heptanoic acid disodium salt | C11H19NNaO6S | 详情 | 详情 | |
| (XII) | 11831 | 2-[(8S,9S,10R,11S,13S,14S,17R)-11,17-dihydroxy-6,10,13-trimethyl-3-oxo-2,3,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl acetate | C24H32O6 | 详情 | 详情 | |
| (XIII) | 11832 | 2-[(8S,9S,10R,11S,13S,14S,17R)-11,17-dihydroxy-6,10,13-trimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl acetate | C24H34O6 | 详情 | 详情 | |
| (XIII) | 45093 | 2-[(8S,9S,10R,11S,13S,14S,17R)-11,17-dihydroxy-6,10,13-trimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl acetate | C24H34O6 | 详情 | 详情 | |
| (XIII) | 45094 | 2-[(8S,9S,10R,11S,13S,14S,17R)-11,17-dihydroxy-6,10,13-trimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl acetate | C24H34O6 | 详情 | 详情 | |
| (XIV) | 11833 | 2-[(8S,9S,10R,11S,13S,14S,17R)-11,17-dihydroxy-6,10,13-trimethyl-3-oxo-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl acetate | C24H34O6 | 详情 | 详情 | |
| (XIV) | 45095 | 2-[(8S,9S,10R,11S,13S,14S,17R)-11,17-dihydroxy-6,10,13-trimethyl-3-oxo-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl acetate | C24H34O6 | 详情 | 详情 | |
| (XIV) | 45096 | 2-[(8S,9S,10R,11S,13S,14S,17R)-11,17-dihydroxy-6,10,13-trimethyl-3-oxo-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl acetate | C24H34O6 | 详情 | 详情 | |
| (XV) | 11834 | 2-[(6S,8S,9S,10R,11S,13S,14S,17R)-11,17-dihydroxy-6,10,13-trimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl acetate | C24H34O6 | 详情 | 详情 | |
| (XV) | 45099 | 2-[(6S,8S,9S,10R,11S,13S,14S,17R)-11,17-dihydroxy-6,10,13-trimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl acetate | C24H34O6 | 详情 | 详情 | |
| (XV) | 45100 | 2-[(6S,8S,9S,10R,11S,13S,14S,17R)-11,17-dihydroxy-6,10,13-trimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl acetate | C24H34O6 | 详情 | 详情 | |
| (XVI) | 10394 | Methylprednisolone | 83-43-2 | C22H30O5 | 详情 | 详情 |
| (XVI) | 45097 | (6S,8S,9S,10R,11S,13S,14S,17R)-17-glycoloyl-11,17-dihydroxy-6,10,13-trimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one | C22H30O5 | 详情 | 详情 | |
| (XVI) | 45098 | (6S,8S,9S,10R,11S,13S,14S,17R)-17-glycoloyl-11,17-dihydroxy-6,10,13-trimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one | C22H30O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)6) The title product [14C]-labeled at C8 of the suberic acid moiety is synthesized starting from 7-bromoheptanoic acid (XVII), which is reduced with borane/dimethylsulfide complex in THF to 7-bromoheptanol (XVIII). The protection of (XVIII) with dihydropyran and p-toluenesulfonic acid affords the tetrahydropyranyl ether (XIX), which is condensed with [14C]-sodium cyanide to give 8-(tetrahydropyranyloxy)octanenitrile (XX). The hydrolysis of (XX) with 6N NaOH yields the corresponding protected acid (XXI), which is condensed with N-methyltaurine sodium salt (III) by means of carbonyldiimidazole (CDI) and deprotected in acidic medium to afford [1-14C]-8-hydroxy-N-methyl-N-(2-sulfoethyl)octanamide sodium salt (XXII). The oxidation of (XXII) with KMnO4 in water gives [8-14C]-8-oxo-8-[N-(2-sulfoethyl)-N-methylamino]octanoic acid (XXIII), which is finally condensed with methylprednisolone 21-O-mesylate (IX) in the usual way.
| 【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 |
|---|---|---|---|---|---|---|
| (III) | 11822 | 7-[N-Methyl-N-(2-sulfoethyl)carbamoyl]heptanoic acid disodium salt | C11H19NNaO6S | 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 | |
| (XVII) | 11836 | 7-Bromoheptanoic acid | 30515-28-7 | C7H13BrO2 | 详情 | 详情 |
| (XVIII) | 11837 | 7-Bromo-1-heptanol | 10160-24-4 | C7H15BrO | 详情 | 详情 |
| (XIX) | 11838 | 1-Bromo-8-tetrahydropyranyloxyoctane; 8-Bromooctyl tetrahydro-2H-pyran-2-yl ether; 2-[(8-Bromooctyl)oxy]tetrahydro-2H-pyran | 50816-20-1 | C13H25BrO2 | 详情 | 详情 |
| (XX) | 11839 | 9-(Tetrahydro-2H-pyran-2-yloxy)nonanenitrile | C14H25NO2 | 详情 | 详情 | |
| (XX) | 45089 | 9-(tetrahydro-2H-pyran-2-yloxy)nonanenitrile | C14H25NO2 | 详情 | 详情 | |
| (XXI) | 11840 | 9-(Tetrahydro-2H-pyran-2-yloxy)nonanoic acid | C14H26O4 | 详情 | 详情 | |
| (XXI) | 45090 | 9-(tetrahydro-2H-pyran-2-yloxy)nonanoic acid | C14H26O4 | 详情 | 详情 | |
| (XXII) | 11841 | sodium 2-[(8-hydroxyoctanoyl)(methyl)amino]-1-ethanesulfonate | C11H22NNaO5S | 详情 | 详情 | |
| (XXII) | 45091 | sodium 2-[(8-hydroxyoctanoyl)(methyl)amino]-1-ethanesulfonate | C11H22NNaO5S | 详情 | 详情 | |
| (XXIII) | 11842 | sodium 2-[(7-carboxyheptanoyl)(methyl)amino]-1-ethanesulfonate | C11H20NNaO6S | 详情 | 详情 | |
| (XXIII) | 45092 | sodium 2-[(7-carboxyheptanoyl)(methyl)amino]-1-ethanesulfonate | C11H20NNaO6S | 详情 | 详情 |