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【结 构 式】 
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【药物名称】Befloxatone, MD-370503 【化学名称】5(R)-(Methoxymethyl)-3-[4-[4,4,4-trifluoro-3(R)-hydroxybutoxy]phenyl]oxazolidin-2-one 【CA登记号】134564-82-2 【 分 子 式 】C15H18F3NO5 【 分 子 量 】349.30961 |
【开发单位】Sanofi-synthélabo (Originator) 【药理作用】Antidepressants, Mood Disorders, Treatment of, PSYCHOPHARMACOLOGIC DRUGS, Smoking Cessation, Aid to, TREATMENT OF POISONING, DRUG ABUSE & DEPENDENCY, Treatment of Substance Dependency, MAO-A Inhibitors |
合成路线1
Befloxatone is obtained by condensation of 1,1,1-trifluoro-4-(tosyloxy)-2(R)-butanol (I) with 3-(4-hydroxyphenyl)-5(R)-(methoxymethyl)oxazolidin-2-one (II) by means of K2CO3 in hot DMF.
| 【1】 Castaner, J.; Sorbera, L.A.; Rabasseda, X.; Befloxatone. Drugs Fut 1999, 24, 10, 1057. |
| 【2】 Koenig, J.-J.; Schoofs, A.; Jarreau, F.-X.; Rovei, V. (Laboratoires Delalande); 3-Aryl oxazolidinones, process for their preparation and their therapeutical use. EP 0424243; EP 0424244; EP 0428421; JP 1992502333; JP 1992502334; JP 1992502335; US 5036090; US 5036091; US 5171747; US 5196543; WO 9105775 . |
| 【3】 Jarreau, F.-X.; Koenig, J.-J.; Rovei, V. (Laboratoires Delalande); 3-Aryl-oxazolidinone derivs., process for their preparation and their use in therapeutics. EP 0511031; FR 2675504; JP 1993112542; US 5264443 . |
合成路线2
1) Synthesis of Butanol (I): 1a) The reduction of 4,4,4-trifluoro-2-oxobutyric acid ethyl ester (III) with NaBH4 in dichloromethane gives 4,4,4-trifluoro-2-hydroxybutyric acid ethyl ester (IV), which is hydrolyzed with NaOH in ethanol, yielding the corresponding acid (V). The optical resolution of (V) with 1(S)-phenylethylamine in hot ethanol affords the 3(R)-hydroxy enantiomer (VI) (1,3), which is reduced with NaBH4 and BF3 ethearate in THF to provide 4,4,4-trifluorobutane-1,3(R)-diol (VII). Finally, this compound is monotosylated by means of tosyl chloride and DMAP in pyridine to afford intermediate (I). 1b) The digestion of 4,4,4-trifluoro-3-hydroxybutyric acid ethyl ester (IV) with Novozym in a phosphate buffer gives the corresponding (R)-enantiomer (VIII), which is reduced with NaBH4 in ethanol, yielding 4,4,4-trifluorobutane-1,3(R)-diol (VII) (4). Finally, this compound is monotosylated by means of tosyl chloride as before to give butanol (I).
| 【1】 Castaner, J.; Sorbera, L.A.; Rabasseda, X.; Befloxatone. Drugs Fut 1999, 24, 10, 1057. |
| 【2】 Koenig, J.-J.; Schoofs, A.; Jarreau, F.-X.; Rovei, V. (Laboratoires Delalande); 3-Aryl oxazolidinones, process for their preparation and their therapeutical use. EP 0424243; EP 0424244; EP 0428421; JP 1992502333; JP 1992502334; JP 1992502335; US 5036090; US 5036091; US 5171747; US 5196543; WO 9105775 . |
| 【3】 Jarreau, F.-X.; Koenig, J.-J.; Rovei, V. (Laboratoires Delalande); 3-Aryl-oxazolidinone derivs., process for their preparation and their use in therapeutics. EP 0511031; FR 2675504; JP 1993112542; US 5264443 . |
| 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) | 28681 | (3R)-4,4,4-trifluoro-3-hydroxybutyl 4-methylbenzenesulfonate | C11H13F3O4S | 详情 | 详情 | |
| (III) | 25432 | ethyl 4,4,4-trifluoro-3-oxobutanoate | 372-31-6 | C6H7F3O3 | 详情 | 详情 |
| (IV) | 28683 | ethyl 4,4,4-trifluoro-3-hydroxybutanoate | 372-30-5 | C6H9F3O3 | 详情 | 详情 |
| (V) | 28684 | 4,4,4-trifluoro-3-hydroxybutyric acid | C4H5F3O3 | 详情 | 详情 | |
| (VI) | 28685 | (3R)-4,4,4-trifluoro-3-hydroxybutyric acid | C4H5F3O3 | 详情 | 详情 | |
| (VII) | 28686 | (3R)-4,4,4-trifluoro-1,3-butanediol | C4H7F3O2 | 详情 | 详情 | |
| (VIII) | 28687 | (3R)-4,4,4-Trifluoro-3-hydroxybutanoic acid ethyl ester | 85571-85-3 | C6H9F3O3 | 详情 | 详情 |
合成路线3
2) Synthesis of Oxazolidinone (II): 2a) The reaction of 4-benzyloxyaniline (IX) with 1,4-dioxaspiro[4.5]decan-2(S)-ylmethyl methanesulfonate (X) by means of TEA at 140 C gives 3-(4-benzyloxyphenylamino)propane-1,2(R)-diol (XI), which is cyclized with diethyl carbonate and sodium methoxide in refluxing toluene, yielding 3-(4-benzyloxyphenyl)-5(R)-(hydroxymethyl)oxazolidin-2-one (XII). The methylation of (XII) with dimethyl sulfate, NaOH and tetrabutylammonium bisulfate in hot toluene/water affords the corresponding methoxymethyl derivative (XIII). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in ethanol/dichloromethane to give oxazolidinone (II). 2b) The methylation of 4(S)-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolane (XIV) with dimethyl sulfate and NaOH gives 4(S)-(methoxymethyl)-2,2-dimethyl-1,3-dioxolane (XV), which is hydrolyzed with hot aqueous HCl to 3-methoxypropane-1,2(R)-diol (XVI). The cyclization of (XVI) with diethyl carbonate by means of NaH affords 4(S)-(methoxymethyl)-1,3-dioxolan-2-one (XVII) (2, 5). The condensation of (XVII) with N-(4-benzyloxyphenyl)carbamic acid methyl ester (XVIII) (obtained by reaction of 4-benzyloxyaniline (IX) with methyl chloroformate) by means of K2CO3 at 160 C provides the protected oxazolidinone (XIII), which is finally debenzylated as before to give oxazolidinone (II).
| 【1】 Castaner, J.; Sorbera, L.A.; Rabasseda, X.; Befloxatone. Drugs Fut 1999, 24, 10, 1057. |
| 【2】 Koenig, J.-J.; Schoofs, A.; Jarreau, F.-X.; Rovei, V. (Laboratoires Delalande); 3-Aryl oxazolidinones, process for their preparation and their therapeutical use. EP 0424243; EP 0424244; EP 0428421; JP 1992502333; JP 1992502334; JP 1992502335; US 5036090; US 5036091; US 5171747; US 5196543; WO 9105775 . |
| 【3】 Jarreau, F.-X.; Koenig, J.-J.; Rovei, V. (Laboratoires Delalande); 3-Aryl-oxazolidinone derivs., process for their preparation and their use in therapeutics. EP 0511031; FR 2675504; JP 1993112542; US 5264443 . |
| 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) | 28682 | (5R)-3-(4-hydroxyphenyl)-5-(methoxymethyl)-1,3-oxazolidin-2-one | C11H13NO4 | 详情 | 详情 | |
| (IX) | 22460 | 4-(benzyloxy)aniline; 4-(benzyloxy)phenylamine | C13H13NO | 详情 | 详情 | |
| (X) | 28688 | (2R)-1,4-dioxaspiro[4.5]dec-2-ylmethyl methanesulfonate | C10H18O5S | 详情 | 详情 | |
| (XI) | 28689 | (2R)-3-[4-(benzyloxy)anilino]-1,2-propanediol | C16H19NO3 | 详情 | 详情 | |
| (XII) | 28695 | (5R)-3-[4-(benzyloxy)phenyl]-5-(hydroxymethyl)-1,3-oxazolidin-2-one | C17H17NO4 | 详情 | 详情 | |
| (XIII) | 28690 | (5R)-3-[4-(benzyloxy)phenyl]-5-(methoxymethyl)-1,3-oxazolidin-2-one | C18H19NO4 | 详情 | 详情 | |
| (XIV) | 12709 | [(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]methanol | 22323-82-6 | C6H12O3 | 详情 | 详情 |
| (XV) | 28691 | (4S)-4-(methoxymethyl)-2,2-dimethyl-1,3-dioxolane | C7H14O3 | 详情 | 详情 | |
| (XVI) | 28692 | (2R)-3-methoxy-1,2-propanediol | C4H10O3 | 详情 | 详情 | |
| (XVII) | 28693 | (4S)-4-(methoxymethyl)-1,3-dioxolan-2-one | C5H8O4 | 详情 | 详情 | |
| (XVIII) | 28694 | methyl 4-(benzyloxy)phenylcarbamate | C15H15NO3 | 详情 | 详情 |