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【结 构 式】 
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【药物名称】BMS-229724 【化学名称】4-[4-[2-[2-[Bis(4-chlorophenyl)methoxy]ethylsulfonyl]ethoxy]phenyl]-1,1,1-trifluorobutan-2-one 【CA登记号】221914-85-8 【 分 子 式 】C27H25Cl2F3O5S 【 分 子 量 】589.4625 |
【开发单位】Bristol-Myers Squibb (Originator) 【药理作用】DERMATOLOGIC DRUGS, Topical Antiinflammatory Agents, Phospholipase A2 Inhibitors |
合成路线1
Condensation of 4,4'-dichlorobenzhydrol (I) with 2-bromoethanol (II) in the presence of sulfuric acid gave the bromopropyl ether (III), which was further condensed with 2-mercaptoethanol (IV), yielding thioether (V). Subsequent coupling of alcohol (V) with methyl 3-(4-hydroxyphenyl)propionate (VI) under Mitsunobu conditions furnished adduct (VII). Basic hydrolysis of the methyl ester function generated acid (VIII). After conversion of (VIII) to the corresponding acid chloride, its condensation with trifluoroacetic anhydride gave rise to the trifluoromethyl ketone (IX). The sulfide group of (X) was finally oxidized to the title sulfone using meta-chloroperbenzoic acid.
| 【1】 Banville, J.; Burke, J.R.; Gai, Y.; Johnson, G.; Zusi, F.C. (Bristol-Myers Squibb Co.); Selective cPLA2 inhibitors. EP 1140791; WO 9915129 . |
| 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) | 50505 | 4,4'-Dichlorobenzhydrol; Bis(4-chlorophenyl)carbinol | 90-97-1 | C13H10Cl2O | 详情 | 详情 |
| (II) | 10059 | Ethylene bromohydrin; 2-Bromo-1-ethanol | 540-51-2 | C2H5BrO | 详情 | 详情 |
| (III) | 50506 | 1-[(2-bromoethoxy)(4-chlorophenyl)methyl]-4-chlorobenzene; bis(4-chlorophenyl)methyl 2-bromoethyl ether | C15H13BrCl2O | 详情 | 详情 | |
| (IV) | 36375 | 2-Sulfanyl-1-ethanol; 2-Mercaptoethanol | 60-24-2 | C2H6OS | 详情 | 详情 |
| (V) | 50507 | 2-([2-[bis(4-chlorophenyl)methoxy]ethyl]sulfanyl)-1-ethanol | C17H18Cl2O2S | 详情 | 详情 | |
| (VI) | 30341 | methyl 3-(4-hydroxyphenyl)propanoate; 4-Hydroxyphenylpropionic acid methyl ester; 3-(4-Hydroxyphenyl)propionic acid methyl ester | 5597-50-2 | C10H12O3 | 详情 | 详情 |
| (VII) | 50508 | methyl 3-[4-[2-([2-[bis(4-chlorophenyl)methoxy]ethyl]sulfanyl)ethoxy]phenyl]propanoate | C27H28Cl2O4S | 详情 | 详情 | |
| (VIII) | 50509 | 3-[4-[2-([2-[bis(4-chlorophenyl)methoxy]ethyl]sulfanyl)ethoxy]phenyl]propionic acid | C26H26Cl2O4S | 详情 | 详情 | |
| (IX) | 50510 | 4-[4-[2-([2-[bis(4-chlorophenyl)methoxy]ethyl]sulfanyl)ethoxy]phenyl]-1,1,1-trifluoro-2-butanone | C27H25Cl2F3O3S | 详情 | 详情 |
合成路线2
The hydrolysis of the known thioacetate (I) with NaOH in THF gives the thiol (II), which is condensed with 14C-labelled bromoacetic acid (III) by means of NaOH in water to yield the sulfanyl-acetic acid (IV). The reduction of (IV) with LiAlH4 in THF affords the sulfanylethanol derivative (V); which is condensed with 3-(4-hydroxyphenyl)propionic acid methyl ester (VI) by means of DEAD and PPh3 in toluene to provide the labelled aryl ether (VII).The hydrolysis of the ester group of (VII) by means of KOH in ethanol/water gives the propionic acid (VIII), which is converted into the trifluoromethyl ketone (IX) by reaction with oxalyl chloride, trifluoroacetic anhydride and pyridine in toluene/dichloromethane. Finally, the oxidation of the sulfanyl group of (IX) with MCPBA in dichloromethane affords the target labelled sulfone.
| 【1】 Dischino, D.D.; Banville, J.; Remillard, R.; Synthesis of carbon-14 labeled 4-[4-[2-[2-[bis(4-chlorophenyl)methoxy]ethylsulfonyl][1-14C]ethoxy]phenyl]-1,1,1-trifluoro-2-butanone. J Label Compd Radiopharm 2003, 46, 2, 167. |
| 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) | 64511 | S-{2-[bis(4-chlorophenyl)methoxy]ethyl} ethanethioate | C17H16Cl2O2S | 详情 | 详情 | |
| (II) | 64512 | 2-[bis(4-chlorophenyl)methoxy]ethylhydrosulfide; 2-[bis(4-chlorophenyl)methoxy]-1-ethanethiol | C15H14Cl2OS | 详情 | 详情 | |
| (III) | 23660 | 2-Bromoacetic acid | 79-08-3 | C2H3BrO2 | 详情 | 详情 |
| (III) | 64514 | 2-bromoacetic acid | C2H3BrO2 | 详情 | 详情 | |
| (IV) | 64513 | 2-({2-[bis(4-chlorophenyl)methoxy]ethyl}sulfanyl)acetic acid | C17H16Cl2O3S | 详情 | 详情 | |
| (IV) | 64515 | 2-({2-[bis(4-chlorophenyl)methoxy]ethyl}sulfanyl)acetic acid | C17H16Cl2O3S | 详情 | 详情 | |
| (V) | 50507 | 2-([2-[bis(4-chlorophenyl)methoxy]ethyl]sulfanyl)-1-ethanol | C17H18Cl2O2S | 详情 | 详情 | |
| (V) | 64516 | 2-({2-[bis(4-chlorophenyl)methoxy]ethyl}sulfanyl)-1-ethanol | C17H18Cl2O2S | 详情 | 详情 | |
| (VI) | 30341 | methyl 3-(4-hydroxyphenyl)propanoate; 4-Hydroxyphenylpropionic acid methyl ester; 3-(4-Hydroxyphenyl)propionic acid methyl ester | 5597-50-2 | C10H12O3 | 详情 | 详情 |
| (VII) | 50508 | methyl 3-[4-[2-([2-[bis(4-chlorophenyl)methoxy]ethyl]sulfanyl)ethoxy]phenyl]propanoate | C27H28Cl2O4S | 详情 | 详情 | |
| (VII) | 64517 | methyl 3-{4-[2-({2-[bis(4-chlorophenyl)methoxy]ethyl}sulfanyl)ethoxy]phenyl}propanoate | C27H28Cl2O4S | 详情 | 详情 | |
| (VIII) | 50509 | 3-[4-[2-([2-[bis(4-chlorophenyl)methoxy]ethyl]sulfanyl)ethoxy]phenyl]propionic acid | C26H26Cl2O4S | 详情 | 详情 | |
| (VIII) | 64518 | 3-{4-[2-({2-[bis(4-chlorophenyl)methoxy]ethyl}sulfanyl)ethoxy]phenyl}propanoic acid | C26H26Cl2O4S | 详情 | 详情 | |
| (IX) | 50510 | 4-[4-[2-([2-[bis(4-chlorophenyl)methoxy]ethyl]sulfanyl)ethoxy]phenyl]-1,1,1-trifluoro-2-butanone | C27H25Cl2F3O3S | 详情 | 详情 | |
| (IX) | 64519 | 4-{4-[2-({2-[bis(4-chlorophenyl)methoxy]ethyl}sulfanyl)ethoxy]phenyl}-1,1,1-trifluoro-2-butanone | C27H25Cl2F3O3S | 详情 | 详情 |