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【结 构 式】 
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【药物名称】Methylprednisolone suleptanate, U-67590A, Medrosol, Promedrol 【化学名称】8-Oxo-8-[N-(2-sulfoethyl)-N-methylamino]octanocic acid C-21 ester with 11beta,17,21-trihydroxy-6alpha-methylpregna-1,4-diene-3,20-dione,monosodium salt 【CA登记号】90350-40-6 【 分 子 式 】C33H48NNaO10S 【 分 子 量 】673.80501 |
【开发单位】Pfizer (Originator) 【药理作用】Antiallergy/Antiasthmatic Drugs, Asthma Therapy, Chemical Delivery Systems, DRUG DELIVERY, Drug Delivery Systems, IMMUNOMODULATING AGENTS, Immunosuppressants, Nephritis, Agents for, RENAL-UROLOGIC DRUGS, RESPIRATORY DRUGS, Systemic Lupus Erythematosus, Agents for, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Treatment of Other Autoimmune Disorders, Treatment of Renal Diseases, Corticosteroids, Glucocorticoids |
合成路线1
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
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
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4
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 |