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【结 构 式】 
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【药物名称】Tolevamer Potassium Sodium, GT267-004, GT160-246 (sodium salt), Exodif 【化学名称】4-Ethenylbenzenesulfonic acid potassium salt polymer with 4-ethenylbenzenesulfonic acid sodium salt 【CA登记号】81998-90-5, 28038-50-8 (sodium salt), 28210-41-5 (free acid) 【 分 子 式 】 【 分 子 量 】 |
【开发单位】Genzyme Corp. (US). 【药理作用】Toxin-Binding Polymer，Treatment of C. difficile-Associated Diarrhea |
合成路线1
Polymerization of p-bromostyrene (I) in refluxing benzene in the presence of benzoyl peroxide affords poly(p-bromostyrene) (II) (1), which undergoes metalation to the polystyryl lithium (III) by treatment with butyl lithium in THF or benzene (1, 2). Exposure of (III) to sulfur dioxide atmosphere generates an intermediate polysulfinic acid (IV), which spontaneously oxidizes to the sulfonic acid tolevamer (3). Tolevamer is reported to dissolve in basic solutions to form the corresponding salts (3). Scheme 1.
| 【1】 Trefouel, M.J. Sur une préparation de polyparabutylstyrène. Compt Rend 1959, 248: 800-2. |
| 【2】 Trefouel, M.J. Sur la conversion partielle du polyparabromostyrène en acide polystyrèneparacarboxylique. Compt Rend 1960, 250: 2209-10. |
| 【3】 Trefouel, M.J. Sur une préparation d’acide polystyrèneparasulfonique. Compt Rend 1960, 250: 3839-40. |
合成路线2
In a different procedure, the potassium salt of tolevamer can be synthesized as follows. Chlorosulfonation of phenethyl bromide (V) with ClSO3H gives 4-(2-bromoethyl)benzenesulfonyl chloride (VI), which undergoes simultaneous elimination of HBr and sulfonyl chloride hydrolysis in boiling ethanolic KOH to furnish potassium 4-vinylbenzenesulfonate (VII). Subsequent polymerization of (VII) in DMF solution in the presence of tert-butyl peracetate as initiator gives rise to tolevamer potassium (4). Scheme 2.
| 【4】 Wiley, R.H., Reed, S.F., Jr. Sulfostyrenes. Polymers and copolymers of potassium p-vinylbenzenesulfonate. J Am Chem Soc 1956, 78(10): 2171-3. |