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【结 构 式】 
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【药物名称】 【化学名称】3-(4-Phenoxyphenylsulfonyl)-1-propanethiol 【CA登记号】202665-41-6 【 分 子 式 】C15H16O3S2 【 分 子 量 】308.42097 |
【开发单位】Pfizer (Originator) 【药理作用】Antiarthritic Drugs, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Matrix Metalloproteinase Inhibitors |
合成路线1
Alkylation of 4-fluorothiophenol (I) with 3-chloropropanol (II) in the presence of K2CO3 in DMF provided thioether (III), which was oxidized to sulfone (IV) using Oxone(R). Fluorine displacement in (IV) with phenol and K2CO3 gave phenoxy derivative (V). Subsequent Mitsunobu condensation of (V) with thioacetic acid afforded thioacetate ester (VI), which by further hydrolysis with NaOMe furnished the target thiol.
| 【1】 Freskos, J.N.; Abbas, Z.S.; Decrescenzo, G.A.; Getman, D.P.; Heintz, R.M.; Mischke, B.V.; McDonald, J.J. (Pharmacia Corp.); Thiol sulfone metalloprotease inhibitors. EP 0939628; WO 9803164 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 23540 | Phenol | 108-95-2 | C6H6O | 详情 | 详情 | |
| (I) | 22971 | 4-fluorobenzenethiol; 4-fluorophenylhydrosulfide; 4-Fluorothiophenol | 371-42-6 | C6H5FS | 详情 | 详情 |
| (II) | 19490 | 3-chloro-1-propanol | 627-30-5 | C3H7ClO | 详情 | 详情 |
| (III) | 27076 | 3-[(4-fluorophenyl)sulfanyl]-1-propanol | C9H11FOS | 详情 | 详情 | |
| (IV) | 27077 | 3-[(4-fluorophenyl)sulfonyl]-1-propanol | C9H11FO3S | 详情 | 详情 | |
| (V) | 27078 | 3-[(4-phenoxyphenyl)sulfonyl]-1-propanol | C15H16O4S | 详情 | 详情 | |
| (VI) | 27079 | S-[3-[(4-phenoxyphenyl)sulfonyl]propyl] ethanethioate | C17H18O4S2 | 详情 | 详情 |
合成路线2
The intermediate sulfone alcohol (V) has been obtained by an alternative procedure. 4-Phenoxyphenol (VII) was converted to thiophenol (IX) through the sequence of condensation with N,N-dimethylthiocarbamyl chloride, followed by thermal rearrangement of the resulting O-aryl thiocarbamate (VIII) to the S-aryl thiocarbamate, and then hydrolysis with KOH. Alkylation with 3-chloropropanol (II) provided thioether (X), which was then oxidized to the sulfone (V) with Oxone(R).
| 【1】 Inturrisi, C.E.; Collins, J.J.; Dunkel, I.J.; Portenoy, R.K.; Palmer, L.N.; Lapin, J.; Gupta, S.K.; Weinstein, S.M.; Transdermal fentanyl in children with cancer pain: Feasibility, tolerability, and pharmacokinetic correlates. J Pediatr 1999, 134, 3, 319. |
| 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) | 19490 | 3-chloro-1-propanol | 627-30-5 | C3H7ClO | 详情 | 详情 |
| (V) | 27078 | 3-[(4-phenoxyphenyl)sulfonyl]-1-propanol | C15H16O4S | 详情 | 详情 | |
| (VII) | 27080 | 4-Phenoxyphenol | 831-82-3 | C12H10O2 | 详情 | 详情 |
| (VIII) | 27081 | O-(4-phenoxyphenyl) dimethylcarbamothioate | C15H15NO2S | 详情 | 详情 | |
| (IX) | 26254 | 4-phenoxybenzenethiol; 4-phenoxyphenylhydrosulfide | C12H10OS | 详情 | 详情 | |
| (X) | 27082 | 3-[(4-phenoxyphenyl)sulfanyl]-1-propanol | C15H16O2S | 详情 | 详情 |