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【结 构 式】 
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【分子编号】69268 【品名】N-methylhex-5-enamine;N-methylhex-5-en-1-amine 【CA登记号】 |
【 分 子 式 】C7H15N 【 分 子 量 】113.20284 【元素组成】C 74.27% H 13.36% N 12.37% |
合成路线1
该中间体在本合成路线中的序号：(VII)Lactone acid (VI) is amidated with N-methylhex-5-enamine (VII) in the presence of O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HATU) and DIEA in DMF at 0 °C. The resulting lactone amide (VIII) is opened with LiOH in THF/methanol/H2O and the intermediate carboxylic acid is then condensed with the hydrochloride of amine (IX) by means of DIAD and HATU in DMF, producing hydroxyamide (X) . Finally, alcohol (X) and quinolinol derivative (XI) are coupled under Mitsunobu conditions (PPh3, DIAD) in THF .
Alternatively, lactone acid (VI) is esterified with di-tert-butyl dicarbonate (Boc2O) in the presence of DMAP in CH2Cl2, providing the tert-butyl-protected lactone (XII), which is then opened by treatment with LiOH in dioxane/H2O at 0 °C. Amidation of the in situ-generated acid with the vinylcyclopropyl amino acid ester (IX) (in its hydrochloride form) in DMF at 0 °C gives amino acid (XIII), which is coupled with the quinoline moiety (XI) by a Mitsunobu reaction (PPh3, DIAD) in THF at 0 °C, affording adduct (XIV), with the proper configuration of the chiral center at position 3 of the cyclopentane. Subsequent deprotection of the tert-butyl ester (XIV) with triethylsilane and TFA in CH2Cl2 followed by condensation of the resulting acid with alkenylamine (VII) by means of DIAD and HATU in DMF at 0 °C yields the desired noncyclic diene (I) .
| 【1】 Raboisson, P., De Kock, H., Rosenquist, A. et al. Structure-activity relationship study on a novel series of cyclopentane-containing macrocyclic inhibitors of the hepatitis C virus NS3/4A protease leading to the discovery of TMC435350. Bioorg Med Chem Lett 2008, 18(17): 4853-8. |
| 【2】 Stokbroekx, S.C.M., Leys, C., Swinney, K.A., Wuyts, S., Horvath, A. (Tibotec Pharmaceuticals Ltd.). Polymorphic forms of a macrocyclic inhibitor of HCV. WO 2008092954. |
| 【3】 Raboisson, P.J.-M.B., De Kock, H.A., Hu, L. et al. (Tibotec Pharmaceuticals Ltd.; Medivir AB). Macrocyclic inhibitors of hepatitis C virus. CA 2616580, EP 1912999, JP 2009502889, WO 2007014926. |
| 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 | |
| (VI) | 69267 | (1S,4S,5S)-3-oxo-2-oxabicyclo[2.2.1]heptane-5-carboxylic acid | C7H8O4 | 详情 | 详情 | |
| (VII) | 69268 | N-methylhex-5-enamine;N-methylhex-5-en-1-amine | C7H15N | 详情 | 详情 | |
| (VIII) | 69269 | (1R,4S)-N-(hex-5-en-1-yl)-N-methyl-3-oxo-2-oxabicyclo[2.2.1]heptane-5-carboxamide | C14H21NO3 | 详情 | 详情 | |
| (IX) | 69270 | (1R,2S)-ethyl 1-amino-2-vinylcyclopropanecarboxylate | 746657-36-3 | C8H13NO2 | 详情 | 详情 |
| (X) | 69271 | (1R,2S)-ethyl 1-((1S,2S,4R)-2-(hex-5-en-1-yl(methyl)carbamoyl)-4-hydroxycyclopentanecarboxamido)-2-vinylcyclopropanecarboxylate | C22H34N2O5 | 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 |
| (XII) | 69273 | (1S,4S,5S)-tert-butyl 3-oxo-2-oxabicyclo[2.2.1]heptane-5-carboxylate | C11H16O4 | 详情 | 详情 | |
| (XIII) | 69274 | (1S,2S,4S)-tert-butyl 2-(((1S,2S)-1-(ethoxycarbonyl)-2-vinylcyclopropyl)carbamoyl)-4-hydroxycyclopentanecarboxylate | C19H29NO6 | 详情 | 详情 | |
| (XIV) | 69275 | (1S,2S,4S)-tert-butyl 2-(((1S,2S)-1-(ethoxycarbonyl)-2-vinylcyclopropyl)carbamoyl)-4-((2-(4-isopropylthiazol-2-yl)-7-methoxy-8-methylquinolin-4-yl)oxy)cyclopentanecarboxylate | C36H45N3O7S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)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3
该中间体在本合成路线中的序号：(VII)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 |