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【结 构 式】 
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【分子编号】38561 【品名】(3R,7aS)-3-phenyltetrahydro-5H-pyrrolo[1,2-c][1,3]oxazol-5-one 【CA登记号】103201-79-2 |
【 分 子 式 】C12H13NO2 【 分 子 量 】203.24076 【元素组成】C 70.92% H 6.45% N 6.89% O 15.74% |
合成路线1
该中间体在本合成路线中的序号：(IV)The reduction of L-pyroglutamic acid (I) with NaBH4 gives 5(S)-(hydroxymethyl)pyrrolidin-2-one (II), which is cyclized with benzaldehyde (III) by means of p-toluenesulfonic acid yielding the perhydropyrrolooxazolone (IV). The alkylation of (IV) with 2-cyclohexenyl bromide (V) and LDA in THF affords the corresponding cyclohexenyl derivative (VI), which is reduced with LiAlH4 in THF to give 1-benzyl-3(S)-(2-cyclohexenyl)-5(S)-(hydroxymethyl)pyrrolidine (VII). Elimination of the benzyl protecting group of (VII) with H2 over Pd/C yields the pyrrolidine (VIII), which is reprotected with benzyl chloroformate and K2CO3 to afford the carbamate (IX). The oxidation of the carbinol group of (IX) with Jones reagent or oxygen and platinum black gives the protected proline (X), which is finally deprotected with H2 over Pd/C providing the desired intermediate trans-4-cyclohexyl-L-proline (XI).
| 【1】 Thottathil, J.K.; et al.; Conversion of L-pyroglutamic acid to 4-alkyl substituted L-prolines. The synthesis of trans-4-cyclohexyl L-proline. J Org Chem 1986, 51, 16, 3140. |
| 【2】 Thottathil, J.K. (Bristol-Myers Squibb Co.); Process and intermediates for preparing trans-4-substd.-S-prolines. EP 0183390; US 4588819 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 | |
| (I) | 32046 | (3aR,4S,5R,6aS)-4-[(E,3R)-4-phenoxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-butenyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2H-cyclopenta[b]furan-2-one | C29H40O7 | 详情 | 详情 | |
| (II) | 38560 | (5S)-5-(hydroxymethyl)-2-pyrrolidinone | 17342-08-4 | C5H9NO2 | 详情 | 详情 |
| (III) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (IV) | 38561 | (3R,7aS)-3-phenyltetrahydro-5H-pyrrolo[1,2-c][1,3]oxazol-5-one | 103201-79-2 | C12H13NO2 | 详情 | 详情 |
| (V) | 30800 | 3-bromo-1-cyclohexene | 1521-51-3 | C6H9Br | 详情 | 详情 |
| (VI) | 38562 | (3R,6S,7aS)-6-[(1S)-2-cyclohexen-1-yl]-3-phenyltetrahydro-5H-pyrrolo[1,2-c][1,3]oxazol-5-one | C18H21NO2 | 详情 | 详情 | |
| (VII) | 38563 | [(2S,4S)-1-benzyl-4-[(1S)-2-cyclohexen-1-yl]pyrrolidinyl]methanol | C18H25NO | 详情 | 详情 | |
| (VIII) | 38564 | [(2S,4S)-4-cyclohexylpyrrolidinyl]methanol; trans-4-cyhexyl-L-Proline | 90657-55-9 | C11H21NO | 详情 | 详情 |
| (IX) | 38565 | benzyl (2S,4S)-4-cyclohexyl-2-(hydroxymethyl)-1-pyrrolidinecarboxylate | C19H27NO3 | 详情 | 详情 | |
| (X) | 38566 | (2S,4S)-1-[(benzyloxy)carbonyl]-4-cyclohexyl-2-pyrrolidinecarboxylic acid | C19H25NO4 | 详情 | 详情 | |
| (XI) | 38567 | (2S,4S)-4-cyclohexyl-2-pyrrolidinecarboxylic acid | C11H19NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)The reduction of L-pyroglutamic acid (I) with NaBH4 gives the chiral pyrrolidinone (II), which is cyclized with benzaldehyde (III) by means of Ts-OH in refluxing toluene to yield the N,O-acetal (IV). The reaction of (IV) with isobutyl chloroformate (V) and phenylselanyl chloride by means of LiHMDS in THF affords the selenoester (VI), which is treated directly with H2O2 in dichloromethane to provide the unsaturated bicyclic lactam (VII). The diastereoselective reaction of (VII) with lithium di(4-fuorophenyl)cuprate (VIII) gives the all-trans trisubstituted pyrrolidone (IX). The reduction of the carbonyl group (IX) with BH3 in THF that also causes the cleavage of the C-O bond of the oxazolidinone yields the pyrrolidine methanol derivative (X), which is submitted to ring expansion by treatment with MsCl, DCE and TEA to afford the expected trisubstituted 3-chloropiperidine (XI). The dechlorination of (XI) by means of Bu3SnH and AIBN in refluxing toluene provides the trans-1-benzyl-4-(4-fluorophenyl)piperidine-3-carboxylic acid isobutyl ester (XII), which is reduced with LiAlH4 in THF to furnish the carbinol (XIII). The reaction of (XIII) with Ms-Cl and TEA in dichloromethane gives the corresponding mesylate (XIV), which is condensed with 1,3-benzodioxol-5-ol (XV) by means of sodium isopropoxide in refluxing isopropanol to yield the aryl ether (XVI). Finally, this compound is deprotected by hydrogenation with H2 over Pd/C in methanol to afford the target trans-piperidine derivative.
| 【1】 Liu, L.T.; Hong, P.-C.; Huang, H.-L.; Chen, S.-F.; Wang, C.-L. J.; Wen, Y.-S.; ASsymetric syntheses of trans-3,4-disubstituted 2-piperidinones and piperidines. Tetrahedron Asymmetry 2001, 12, Suppl. 3, 419-26. |
| 【2】 Cossy, J.; et al.; Ring expansion: Formal total synthesis of (-)-paroxetine. Tetrahedron Lett 2001, 42, 33, 5705. |
| 【3】 Thottathil, J.K.; et al.; Conversion of L-pyroglutamic acid to 4-alkyl substituted L-prolines. The synthesis of trans-4-cyclohexyl L-proline. J Org Chem 1986, 51, 16, 3140. |
| 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) | 12085 | (2R)-5-Oxotetrahydro-1H-pyrrole-2-carboxylic acid; 5-Oxo-D-proline; D-Pyroglutamic acid; (R)-(+)-2-Pyrrolidone-5-carboxylic acid | 4042-36-8 | C5H7NO3 | 详情 | 详情 |
| (II) | 56485 | (5S)-5-(hydroxymethyl)-2-pyrrolidinone | C5H9NO2 | 详情 | 详情 | |
| (III) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (IV) | 38561 | (3R,7aS)-3-phenyltetrahydro-5H-pyrrolo[1,2-c][1,3]oxazol-5-one | 103201-79-2 | C12H13NO2 | 详情 | 详情 |
| (V) | 13423 | 1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate | 543-27-1 | C5H9ClO2 | 详情 | 详情 |
| (VI) | 56478 | isobutyl (3R,7aS)-5-oxo-3-phenyl-6-(phenylselanyl)tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazole-6-carboxylate | C23H25NO4Se | 详情 | 详情 | |
| (VII) | 56479 | isobutyl (3R,7aS)-5-oxo-3-phenyl-5,7a-dihydro-1H-pyrrolo[1,2-c][1,3]oxazole-6-carboxylate | C17H19NO4 | 详情 | 详情 | |
| (VIII) | 56475 | C27H25CuF4Li | 详情 | 详情 | ||
| (IX) | 56480 | isobutyl (3R,6S,7R,7aS)-7-(4-fluorophenyl)-5-oxo-3-phenyltetrahydro-1H-pyrrolo[1,2-c][1,3]oxazole-6-carboxylate | C23H24FNO4 | 详情 | 详情 | |
| (X) | 56481 | isobutyl (3S,4R,5S)-1-benzyl-4-(4-fluorophenyl)-5-(hydroxymethyl)-3-pyrrolidinecarboxylate | C23H28FNO3 | 详情 | 详情 | |
| (XI) | 56482 | isobutyl (3S,4R,5R)-1-benzyl-5-chloro-4-(4-fluorophenyl)-3-piperidinecarboxylate | C23H27ClFNO2 | 详情 | 详情 | |
| (XII) | 56483 | isobutyl (3S,4R)-1-benzyl-4-(4-fluorophenyl)-3-piperidinecarboxylate | C23H28FNO2 | 详情 | 详情 | |
| (XIII) | 44020 | [(3S,4R)-1-benzyl-4-(4-fluorophenyl)piperidinyl]methanol | C19H22FNO | 详情 | 详情 | |
| (XIV) | 56484 | [(3S,4R)-1-benzyl-4-(4-fluorophenyl)piperidinyl]methyl methanesulfonate | C20H24FNO3S | 详情 | 详情 | |
| (XV) | 10985 | 1,3-Benzodioxol-5-ol; Sesamol | 533-31-3 | C7H6O3 | 详情 | 详情 |
| (XVI) | 44022 | (3S,4R)-3-[(1,3-benzodioxol-5-yloxy)methyl]-1-benzyl-4-(4-fluorophenyl)piperidine; 1,3-benzodioxol-5-yl [(3S,4R)-1-benzyl-4-(4-fluorophenyl)piperidinyl]methyl ether | C26H26FNO3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)(S)-5-(Hydroxymethyl)-2-pyrrolidinone (I) was condensed with benzaldehyde in the presence of p-toluenesulfonic acid, and the resulting oxazolidine (II) was hydrogenated over Pd/C to afford the N-benzyl pyrrolidinone (III). Treatment of alcohol (III) with I2 and triphenylphosphine gave iodide (IV), which was reduced to the methyl pyrrolidinone (V) employing NaBH4 in HMPT. An azido group was introduced at position 3 of pyrrolidinone (V) by treatment with 2,4,6-triisopropylbenzenesulfonyl azide in the presence of LDA, and the resulting trans-azide (VI) was subsequently epimerized to the cis-isomer (VII) by means of NaOEt in EtOH. Reduction of the azido group of (VII) to the corresponding amine (VIII) was carried out by catalytic hydrogenation over Pd/C, and further treatment with Boc2O provided the tert-butyl carbamate (IX). The N-benzyl group was then removed by means of lithium metal in liquid ammonia to afford (X).
| 【1】 Duggan, M.E.; Hartman, G.D.; Hoffman, W.F.; Meissner, R.S.; Perkins, J.J.; Askew, B.C.; Coleman, P.J.; Hutchinson, J.H.; Naylor-Olsen, A.M. (Merck & Co., Inc.); Integrin antagonists. EP 0934305; US 5981546; WO 9808840 . |
| 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) | 38560 | (5S)-5-(hydroxymethyl)-2-pyrrolidinone | 17342-08-4 | C5H9NO2 | 详情 | 详情 |
| (II) | 38561 | (3R,7aS)-3-phenyltetrahydro-5H-pyrrolo[1,2-c][1,3]oxazol-5-one | 103201-79-2 | C12H13NO2 | 详情 | 详情 |
| (III) | 45008 | (5S)-1-benzyl-5-(hydroxymethyl)-2-pyrrolidinone | 125629-91-6 | C12H15NO2 | 详情 | 详情 |
| (IV) | 45009 | (5S)-1-benzyl-5-(iodomethyl)-2-pyrrolidinone | C12H14INO | 详情 | 详情 | |
| (V) | 45010 | (5R)-1-benzyl-5-methyl-2-pyrrolidinone | C12H15NO | 详情 | 详情 | |
| (VI) | 45011 | (3R,5R)-3-azido-1-benzyl-5-methyl-2-pyrrolidinone | C12H14N4O | 详情 | 详情 | |
| (VII) | 45012 | (3S,5R)-3-azido-1-benzyl-5-methyl-2-pyrrolidinone | C12H14N4O | 详情 | 详情 | |
| (VIII) | 45013 | (3S,5R)-3-amino-1-benzyl-5-methyl-2-pyrrolidinone | C12H16N2O | 详情 | 详情 | |
| (IX) | 45014 | tert-butyl (3S,5R)-1-benzyl-5-methyl-2-oxopyrrolidinylcarbamate | C17H24N2O3 | 详情 | 详情 | |
| (X) | 45015 | tert-butyl (3S,5R)-5-methyl-2-oxopyrrolidinylcarbamate | C10H18N2O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)In a related procedure, the protected pyrrolidinone (II) was treated with 2,4,6-triisopropylbenzenesulfonyl azide and LDA to produce a 1:3.2 mixture of isomeric azides (XI) and (XII). After isolation of the major cis-isomer (XII), its catalytic hydrogenation over Pd/C yielded amine (XIII), which was subsequently protected as the N-Boc derivative (XIV). Reductive cleavage of the benzylidene group of (XIV) using Li in liquid ammonia provided the (hydroxymethyl)pyrrolidinone (XV). Reduction of the hydroxymethyl group to the methyl derivative (X) was effected via iodide (XVI) in a similar sequence as above.
| 【1】 Nakanishi, T.; Otsuka, T.; Hashimoto, S.; Okamoto, M.; Muramatsu, Y.; Hino, M.; Hatanaka, H.; WF14865A and B, new cathepsins B and L inhibitors produed by Aphanoascus fulvescens. I. Taxomy, production, purification and biological properties. J Antibiot 2000, 53, 5, 449. |
| 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) | 38561 | (3R,7aS)-3-phenyltetrahydro-5H-pyrrolo[1,2-c][1,3]oxazol-5-one | 103201-79-2 | C12H13NO2 | 详情 | 详情 |
| (X) | 45015 | tert-butyl (3S,5R)-5-methyl-2-oxopyrrolidinylcarbamate | C10H18N2O3 | 详情 | 详情 | |
| (XI) | 45016 | (3R,6R,7aS)-6-azido-3-phenyltetrahydro-5H-pyrrolo[1,2-c][1,3]oxazol-5-one | C12H12N4O2 | 详情 | 详情 | |
| (XII) | 45017 | (3R,6S,7aS)-6-azido-3-phenyltetrahydro-5H-pyrrolo[1,2-c][1,3]oxazol-5-one | C12H12N4O2 | 详情 | 详情 | |
| (XIII) | 45018 | (3R,6S,7aS)-6-amino-3-phenyltetrahydro-5H-pyrrolo[1,2-c][1,3]oxazol-5-one | C12H14N2O2 | 详情 | 详情 | |
| (XIV) | 45019 | tert-butyl (3R,6S,7aS)-5-oxo-3-phenyltetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-6-ylcarbamate | C17H22N2O4 | 详情 | 详情 | |
| (XV) | 45020 | tert-butyl (3S,5S)-5-(hydroxymethyl)-2-oxopyrrolidinylcarbamate | C10H18N2O4 | 详情 | 详情 | |
| (XVI) | 45021 | tert-butyl (3S,5S)-5-(iodomethyl)-2-oxopyrrolidinylcarbamate | C10H17IN2O3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XXXVII)Dehydrogenation of 2(R)-phenylperhydropyrrolo[1,2-c]oxazol-4-one (XXXVII) by α-selenylation with PhSeCl in the presence of KHMDS and TMSCl in THF, followed by oxidation with H2O2 in pyridine or EtOAc and elimination of the selenoxide intermediate produces the unsaturated analogue (XXXVIII) , which by cyclopropanation by means of isopropyl trimethylphosphonium bromide and BuLi in THF affords the tricyclic compound (XXXIX). Reductive ring opening of intermediate (XXXIX) by means of LiAlH4 in refluxing THF produces the N-benzylprolinol (XL), which is debenzylated to the prolinol (XLI) by catalytic hydrogenation over Pd/C in AcOH/EtOAc. After protection of amine (XLI) with Boc2O in CH2Cl2, the resulting N-Boccyclopropaprolinol (XLII) is subjected to Jones oxidation to furnish carboxylic acid (XLIII). Subsequent esterification of acid (XLIII) with (trimethylsilyl)diazomethane in toluene/MeOH affords the N-Boccyclopropaproline methyl ester (XLIV), which is finally deprotected with HCl in dioxane .
| 【1】 Venkatraman, S., Bogen, S.L., Arasappan, A. et al. Discovery of (1R,5S)-N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[2(S)-[[[(1,1-dimethylethyl)amino]carbonyl] amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S) carboxamide (SCH 503034), a selective, potent, orally bioavailable hepatitis C virus NS3 protease inhibitor: A potential therapeutic agent for the treatment of hepatitis C infection. J Med Chem 2006, 49(20): 6074-86. |
| 【2】 Zhang, R., Mamai, A., Madalengoitia, J.S. Cyclopropanation reactions of pyroglutamic acid-derived synthons with alkylidene transfer reagents. J Org Chem 1999, 64(2): 547-55. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 69339 | methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate HCl salt | 565456-77-1 | C9H15NO2.HCl | 详情 | 详情 |
| (XXXVII) | 38561 | (3R,7aS)-3-phenyltetrahydro-5H-pyrrolo[1,2-c][1,3]oxazol-5-one | 103201-79-2 | C12H13NO2 | 详情 | 详情 |
| (XXXVIII) | 69362 | (3R,7aS)-3-phenyl-1,7a-dihydropyrrolo[1,2-c]oxazol-5(3H)-one | C12H11NO2 | 详情 | 详情 | |
| (XXXIX) | 69363 | (1R,2S,5S,6bS)-6,6-dimethyl-3-phenyltetrahydro-1H-cyclopropa[3,4]pyrrolo[1,2-c]oxazol-5(3H)-one | C15H17NO2 | 详情 | 详情 | |
| (XL) | 69364 | (1R,2S,5S)-(3-benzyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-yl)methanol | C15H21NO | 详情 | 详情 | |
| (XLI) | 69365 | ((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-yl)methanol | C8H15NO | 详情 | 详情 | |
| (XLII) | 69366 | (1R,2S,5S)-tert-butyl 2-(hydroxymethyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate | C13H23NO3 | 详情 | 详情 | |
| (XLIII) | 69367 | (1R,2S,5S)-3-(tert-butoxycarbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid | C13H21NO4 | 详情 | 详情 | |
| (XLIV) | 69368 | (1R,2S,5S)-3-tert-butyl 2-methyl 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate | C14H23NO4 | 详情 | 详情 |