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【结 构 式】 
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【分子编号】69276 【品名】(1S,2S,4S)-methyl 2-(hex-5-en-1-yl(methyl)carbamoyl)-4-hydroxycyclopentanecarboxylate 【CA登记号】 |
【 分 子 式 】C15H25NO4 【 分 子 量 】283.36784 【元素组成】C 63.58% H 8.89% N 4.94% O 22.58% |
合成路线1
该中间体在本合成路线中的序号：(XV)Condensation of the cyclopentanol derivative (XV) with the quinolinol derivative (XI) under Mitsunobu conditions (PPh3, DIAD) in toluene affords adduct (XVI). Methyl ester (XVI) is hydrolyzed with LiOH.H2O in THF/H2O, giving the carboxylate lithium salt (XV), which upon coupling with ethyl 1(R)-amino-2(S)-vinylcyclopropanecarboxylate (IX) in the presence of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) in THF/H2O yields the desired intermediate (I) .
Intermediate (XVI) can also be prepared by condensation of quinolinol derivative (XI) with a different cyclopentanol derivative (XVIII) under Mitsunobu conditions (PPh3, DIAD) in toluene/THF. The benzyl ester in the resulting adduct (XIX) is converted to the corresponding carboxylic acid (XX) by treatment with triethylsilane and Pd(OAc)2 in refluxing THF or Me-THF. Finally, acid (XX) is amidated with N-methylhex-5-enamine (VII) in the presence of EEDQ in Me-THF or THF/Me-THF at 50 °C .
| 【1】 Horvath, A., Depre, D.P.M., Ormerod, D.J. (Tibotec Pharmaceuticals Ltd.). Processes and intermediates for preparing a macrocyclic protease inhibitor of HCV. WO 2008092955. |
| 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) | 69263 | (1S,2R)-ethyl 1-((1S,2S,4S)-2-(hex-5-en-1-yl(methyl)carbamoyl)-4-((2-(4-isopropylthiazol-2-yl)-7-methoxy-8-methylquinolin-4-yl)oxy)cyclopentanecarboxamido)-2-vinylcyclopropanecarboxylate | C39H50N4O6S | 详情 | 详情 | |
| (VII) | 69268 | N-methylhex-5-enamine;N-methylhex-5-en-1-amine | C7H15N | 详情 | 详情 | |
| (IX) | 69270 | (1R,2S)-ethyl 1-amino-2-vinylcyclopropanecarboxylate | 746657-36-3 | C8H13NO2 | 详情 | 详情 |
| (XI) | 69272 | 7-methoxy-8-methyl-2-[4-(1-methylethyl)-2-thiazolyl]-2-4-Quinolinol;(4-isopropylthiazol-2-yl)-7-methoxy-8-methylquinolin-4-ol | 923289-21-8 | C17H18N2O2S | 详情 | 详情 |
| (XV) | 69276 | (1S,2S,4S)-methyl 2-(hex-5-en-1-yl(methyl)carbamoyl)-4-hydroxycyclopentanecarboxylate | C15H25NO4 | 详情 | 详情 | |
| (XVI) | 69277 | (1S,2S,4S)-methyl 2-(hex-5-en-1-yl(methyl)carbamoyl)-4-((2-(4-isopropylthiazol-2-yl)-7-methoxy-8-methylquinolin-4-yl)oxy)cyclopentanecarboxylate | C32H41N3O5S | 详情 | 详情 | |
| (XVII) | 69278 | lithium (1S,2S,4S)-2-(hex-5-en-1-yl(methyl)carbamoyl)-4-((2-(4-isopropylthiazol-2-yl)-7-methoxy-8-methylquinolin-4-yl)oxy)cyclopentanecarboxylate | C31H38LiN3O5S | 详情 | 详情 | |
| (XVIII) | 69279 | (1S,2S,4S)-1-benzyl 2-methyl 4-hydroxycyclopentane-1,2-dicarboxylate | C15H18O5 | 详情 | 详情 | |
| (XIX) | 69280 | (1S,2S,4S)-1-benzyl 2-methyl 4-((2-(4-isopropylthiazol-2-yl)-7-methoxy-8-methylquinolin-4-yl)oxy)cyclopentane-1,2-dicarboxylate | C32H34N2O6S | 详情 | 详情 | |
| (XX) | 69281 | (1S,2S,4S)-4-((2-(4-isopropylthiazol-2-yl)-7-methoxy-8-methylquinolin-4-yl)oxy)-2-(methoxycarbonyl)cyclopentanecarboxylic acid | C25H28N2O6S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XV)Esterification of 1,2,3,4-butanetetracarboxylic acid (XXXVI) with EtOH in the presence of H2SO4 in refluxing toluene yields the corresponding tetraethyl ester (XXXVII), which upon treatment with NaOMe in MeOH followed by HCl in refluxing H2O yields trans-4-oxocyclopentane-1,2-dicarboxylic acid (rac-[XXXVIII]). Reduction of intermediate (XXXVIII) with H2 over Rh/C in the presence of NaOH in H2O followed by treatment with H2SO4 in acetone furnishes meso-4-hydroxycyclopentane-1,2-dicarboxylic acid (rac-[XXXIX]), which upon treatment with ethyl chloroformate in the presence of Et3N in THF affords lactone acid (rac-[VI]). Acid rac-(VI) is esterified with benzyl alcohol in the presence of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) and DMAP in EtOAc. Benzyl ester (rac-[XL]) is treated with Amberlyst-15 or MsOH in MeOH, affording racemic cyclopentanol (rac-[XVIII]). Finally, racemate rac-(XVIII) is resolved by chiral HPLC, yielding the desired (R,R,R)-isomer intermediate (XVIII) .
Intermediate (XV) is prepared from intermediate (XVIII) by hydrogenolysis with H2 over Pd/C in THF or DMF and subsequent amidation of the resulting carboxylic acid (XLI) with N-methylhex-5-enamine (VII) in the presence of DIEA, HATU or O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HBTU) in DMF or acetonitrile, or EDC in the presence or absence of DMAP in THF or CH2Cl2, or EEDQ in refluxing THF .
| 【1】 Llinas-Brunet, M., Bailey, M.D., Cameron, D. et al. (Boehringer Ingelheim [Canada] Ltd.). Hepatitis C inhibitor tri-peptides. CA 2338946, EP 1105413, EP 2028186, JP 2002522554, US 6323180, WO 2000009543. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| rac-(VI) | 69297 | racemic 3-oxo-2-oxabicyclo[2.2.1]heptane-5-carboxylic acid | C7H8O4 | 详情 | 详情 | |
| rac-(XL) | 69300 | racemic benzyl 3-oxo-2-oxabicyclo[2.2.1]heptane-5-carboxylate | C14H14O4 | 详情 | 详情 | |
| rac-(XVIII) | 69298 | racemic 1-benzyl 2-methyl 4-hydroxycyclopentane-1,2-dicarboxylate | C15H18O5 | 详情 | 详情 | |
| (VII) | 69268 | N-methylhex-5-enamine;N-methylhex-5-en-1-amine | C7H15N | 详情 | 详情 | |
| (XV) | 69276 | (1S,2S,4S)-methyl 2-(hex-5-en-1-yl(methyl)carbamoyl)-4-hydroxycyclopentanecarboxylate | C15H25NO4 | 详情 | 详情 | |
| (XVIII) | 69299 | (1S,2S,4S)-1-benzyl 2-methyl 4-hydroxycyclopentane-1,2-dicarboxylate | C15H18O5 | 详情 | 详情 | |
| (XXXVI) | 56634 | 1,2,3,4-butanetetracarboxylic acid;1,2,3,4-Tetracarboxybutane | 1703-58-8 | C8H10O8 | 详情 | 详情 |
| (XXXVII) | 69294 | tetraethyl butane-1,2,3,4-tetracarboxylate | C16H26O8 | 详情 | 详情 | |
| (XXXVIII) | 69295 | racemic 4-oxocyclopentane-1,2-dicarboxylic acid | C7H8O5 | 详情 | 详情 | |
| (XXXIX) | 69296 | racemic 4-hydroxycyclopentane-1,2-dicarboxylic acid | C7H10O5 | 详情 | 详情 | |
| (XLI) | 69301 | (1S,2S,4S)-4-hydroxy-2-(methoxycarbonyl)cyclopentanecarboxylic acid | C8H12O5 | 详情 | 详情 |