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【结 构 式】 
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【药物名称】SB-219994 【化学名称】3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2(S)-(2,2,2-trifluoroethoxy)propionic acid 【CA登记号】177785-17-0 【 分 子 式 】C21H21F3N2O5 【 分 子 量 】438.40712 |
【开发单位】GlaxoSmithKline (Originator) 【药理作用】Antidiabetic Drugs, ENDOCRINE DRUGS, Insulin Sensitizers, PPARgamma Agonists |
合成路线1
The chiral compound was prepared by several alternative procedures. Acid hydrolysis of the known racemic ester (I) gave carboxylic acid (II), which was converted into acid chloride (III) by using oxalyl chloride in benzene. This was either condensed with (S)-2-phenylglycinol (V) or with (S)-4-benzyloxazolidine-2-one (VI) to provide the diastereomeric mixtures of amides (VI) or imides (VII), respectively. After chromatographic separation of the required (S,S)-diastereoisomers, the title compound was obtained by acid hydrolysis of the (S,S)-amide or by hydrolysis of the corresponding imide with NaOH.
| 【1】 Haigh, D.; Rami, H.K. (SmithKline Beecham plc); Benzoxazoles and pyridine derivs. useful in the treatment of type II diabetes. EP 0772605; JP 1998503508; WO 9604260; WO 9604261 . |
| 【2】 Smith, S.A. (SmithKline Beecham plc); Use of an antagonist of PPAR-alpha and PPAR-gamma for the treatment of syndrom X. WO 9725042 . |
| 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) | 31288 | methyl 3-(4-[2-[1,3-benzoxazol-2-yl(methyl)amino]ethoxy]phenyl)-2-(2,2,2-trifluoroethoxy)propanoate | C22H23F3N2O5 | 详情 | 详情 | |
| (II) | 31289 | 3-(4-[2-[1,3-benzoxazol-2-yl(methyl)amino]ethoxy]phenyl)-2-(2,2,2-trifluoroethoxy)propionic acid | C21H21F3N2O5 | 详情 | 详情 | |
| (III) | 31290 | 3-(4-[2-[1,3-benzoxazol-2-yl(methyl)amino]ethoxy]phenyl)-2-(2,2,2-trifluoroethoxy)propanoyl chloride | C21H20ClF3N2O4 | 详情 | 详情 | |
| (IV) | 10973 | (2S)-2-Amino-2-phenyl-1-ethanol; (S)-2-Hydroxy-1-phenylethylamine; (S)-(+)-2-Phenylglycinol; (S)-2-Amino-2-phenyl-1-ethanol | 20989-17-7 | C8H11NO | 详情 | 详情 |
| (V) | 14694 | (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone | 90719-32-7 | C10H11NO2 | 详情 | 详情 |
| (VI) | 31291 | 3-(4-[2-[1,3-benzoxazol-2-yl(methyl)amino]ethoxy]phenyl)-N-[(1S)-2-hydroxy-1-phenylethyl]-2-(2,2,2-trifluoroethoxy)propanamide | C29H30F3N3O5 | 详情 | 详情 | |
| (VII) | 31292 | (4S)-3-[3-(4-[2-[1,3-benzoxazol-2-yl(methyl)amino]ethoxy]phenyl)-2-(2,2,2-trifluoroethoxy)propanoyl]-4-benzyl-1,3-oxazolidin-2-one | C31H30F3N3O6 | 详情 | 详情 |
合成路线2
In an alternative procedure, (2,2,2-trifluoroethoxy)acetic acid (VIII) was converted into acid chloride (IX) by means of oxalyl chloride, and then coupled with (S)-4-benzyloxazolidine-2-one (V) in the presence of butyllithium to afford the chiral imide (X). The boron enolate obtained by treatment of (X) with di-n-butylboron triflate and triethylamine was then condensed with aldehyde (XI) to produce, after oxidative work-up with H2O2, a mixture of 3 diastereomeric aldol products (XII). The major [3(2S,3R),4S] isomer was isolated by column chromatography, and subsequently reduced with triethylsilane and trifluoroacetic acid to the (S,S) dehydroxylated compound (XIII). Basic hydrolysis of the imide (XIII) as above furnished the title carboxylic acid. Alternatively, treatment of the imide (XIII) with methanolic NaOMe produced the methyl ester (XIV), which was finally hydrolyzed to the target carboxylic acid employing HCl in aqueous dioxan.
| 【1】 Haigh, D.; Rami, H.K. (SmithKline Beecham plc); Benzoxazoles and pyridine derivs. useful in the treatment of type II diabetes. EP 0772605; JP 1998503508; WO 9604260; WO 9604261 . |
| 【2】 Smith, S.A. (SmithKline Beecham plc); Use of an antagonist of PPAR-alpha and PPAR-gamma for the treatment of syndrom X. WO 9725042 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 14694 | (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone | 90719-32-7 | C10H11NO2 | 详情 | 详情 |
| (VIII) | 31293 | 2-(2,2,2-trifluoroethoxy)acetic acid | C4H5F3O3 | 详情 | 详情 | |
| (IX) | 31294 | 2-(2,2,2-trifluoroethoxy)acetyl chloride | C4H4ClF3O2 | 详情 | 详情 | |
| (X) | 31295 | (4S)-4-benzyl-3-[2-(2,2,2-trifluoroethoxy)acetyl]-1,3-oxazolidin-2-one | C14H14F3NO4 | 详情 | 详情 | |
| (XI) | 31296 | 2-(4-[2-[1,3-benzoxazol-2-yl(methyl)amino]ethoxy]phenyl)acetaldehyde | C18H18N2O3 | 详情 | 详情 | |
| (XII) | 31297 | (4S)-3-[3-(4-[2-[1,3-benzoxazol-2-yl(methyl)amino]ethoxy]phenyl)-3-hydroxy-2-(2,2,2-trifluoroethoxy)propanoyl]-4-benzyl-1,3-oxazolidin-2-one | C31H30F3N3O7 | 详情 | 详情 | |
| (XIII) | 31298 | (4S)-3-[(2S)-3-(4-[2-[1,3-benzoxazol-2-yl(methyl)amino]ethoxy]phenyl)-2-(2,2,2-trifluoroethoxy)propanoyl]-4-benzyl-1,3-oxazolidin-2-one | C31H30F3N3O6 | 详情 | 详情 | |
| (XIV) | 31299 | methyl (2S)-3-(4-[2-[1,3-benzoxazol-2-yl(methyl)amino]ethoxy]phenyl)-2-(2,2,2-trifluoroethoxy)propanoate | C22H23F3N2O5 | 详情 | 详情 |