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【结 构 式】 
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【分子编号】20632 【品名】diphenyl[(2R)pyrrolidinyl]methanol 【CA登记号】 |
【 分 子 式 】C17H19NO 【 分 子 量 】253.344 【元素组成】C 80.6% H 7.56% N 5.53% O 6.32% |
合成路线1
该中间体在本合成路线中的序号：Reaction of 3-methoxybenzyl alcohol (XXIX) with TBDMS-Cl and imidazole in dichloromethane gives the silyl ether (XXX), which is condensed with allyl bromide (XXXI) by means of BuLi in hexane to yield the 2-allyl derivative (XXXII). Deprotection of (XXXII) by means of TBAF in THF affords the benzyl alcohol (XXXIII), which is oxidized with oxalyl chloride and TEA in DMSO/dichloromethane to provide 2-allyl-3-methoxybenzaldehyde (XXXIV). Condensation of compound (XXXIV) with the chiral 1-decyne (XXXV) by means of ethylmagnesium bromide in THF gives the secondary alcohol (XXXVI), which is oxidized with pyridinium chlorochromate (PCC) in dichloromethane yielding ketone (XXXVII). The enantioselective reduction of ketone (XXXVII) by means of trimethylboroxine (TMBO), BH3/Me2S and (R)-(2-pyrrolidinyl)diphenylmethanol in toluene affords the chiral secondary alcohol (XXXVIII) as a single diastereomer. Silylation of alcohol (XXXVIII) with TBDMS-Cl and imidazole yields the corresponding ether (XXXIX), which is submitted to cyclization catalyzed by Co2(CO)8 in refluxing acetonitrile affording the tricyclic ketone (XL). Hydrogenation of the conjugated double bond of (XL) with H2 over Pd/C in ethanol provides the saturated ketone (XLI), which is reduced with NaBH4 in ethanol to give the tricyclic alcohol (XLII). Elimination of the tetrahydropyranyl-protecting group of (XLII) with p-toluensulfonic acid in methanol provides diol (XXV) already described.
| 【1】 Sorbera, L.A.; Castaner, J.; Rabasseda, X.; UT-15. Drugs Fut 2001, 26, 4, 364. |
| 【2】 Rao, M.S.; Staszewski, J.P.; Guo, L.; Penmasta, R.; Moriarty, R.M. (United Therapeutics Corp.); Process for stereoselective synthesis of prostacyclin derivs.. WO 9921830 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 20632 | diphenyl[(2R)pyrrolidinyl]methanol | C17H19NO | 详情 | 详情 | ||
| (XXV) | 46571 | (1R,2R,3aS,9aS)-1-[(3S)-3-hydroxyoctyl]-5-methoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-ol | C22H34O3 | 详情 | 详情 | |
| (XXIX) | 46574 | 3-Anisylalcohol; (3-methoxyphenyl)methanol; m-Anisyl alcohol; m-methoxybenzyl alcohol; 3-Anisic alcohol; 3-Anise Alcohol; 3-methoxybenzyl alcohol; 3-methoxybenzene methanol | 6971-51-3 | C8H10O2 | 详情 | 详情 |
| (XXX) | 46575 | tert-butyl(dimethyl)silyl 3-methoxybenzyl ether; tert-butyl[(3-methoxybenzyl)oxy]dimethylsilane | C14H24O2Si | 详情 | 详情 | |
| (XXXI) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (XXXII) | 46576 | 2-allyl-3-([[tert-butyl(dimethyl)silyl]oxy]methyl)phenyl methyl ether; [(2-allyl-3-methoxybenzyl)oxy](tert-butyl)dimethylsilane | C17H28O2Si | 详情 | 详情 | |
| (XXXIII) | 46577 | (2-allyl-3-methoxyphenyl)methanol | C11H14O2 | 详情 | 详情 | |
| (XXXIV) | 46578 | 2-allyl-3-methoxybenzaldehyde | C11H12O2 | 详情 | 详情 | |
| (XXXV) | 46579 | (1S)-1-pentyl-4-pentynyl tetrahydro-2H-pyran-2-yl ether; 2-[[(1S)-1-pentyl-4-pentynyl]oxy]tetrahydro-2H-pyran | C15H26O2 | 详情 | 详情 | |
| (XXXVI) | 46580 | (6S)-1-(2-allyl-3-methoxyphenyl)-6-(tetrahydro-2H-pyran-2-yloxy)-2-undecyn-1-ol | C26H38O4 | 详情 | 详情 | |
| (XXXVII) | 46581 | (6S)-1-(2-allyl-3-methoxyphenyl)-6-(tetrahydro-2H-pyran-2-yloxy)-2-undecyn-1-one | C26H36O4 | 详情 | 详情 | |
| (XXXVIII) | 46582 | (1S,6S)-1-(2-allyl-3-methoxyphenyl)-6-(tetrahydro-2H-pyran-2-yloxy)-2-undecyn-1-ol | C26H38O4 | 详情 | 详情 | |
| (XXXIX) | 46583 | [[(1S,6S)-1-(2-allyl-3-methoxyphenyl)-6-(tetrahydro-2H-pyran-2-yloxy)-2-undecynyl]oxy](tert-butyl)dimethylsilane; 2-allyl-3-[(1S,6S)-1-[[tert-butyl(dimethyl)silyl]oxy]-6-(tetrahydro-2H-pyran-2-yloxy)-2-undecynyl]phenyl methyl ether | C32H52O4Si | 详情 | 详情 | |
| (XL) | 46584 | (4R,9aS)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-methoxy-3-[(3S)-3-(tetrahydro-2H-pyran-2-yloxy)octyl]-1,4,9,9a-tetrahydro-2H-cyclopenta[b]naphthalen-2-one | C33H52O5Si | 详情 | 详情 | |
| (XLI) | 46570 | (1R,3aS,9aS)-5-methoxy-1-[(3S)-3-(tetrahydro-2H-pyran-2-yloxy)octyl]-1,3,3a,4,9,9a-hexahydro-2H-cyclopenta[b]naphthalen-2-one | C27H40O4 | 详情 | 详情 | |
| (XLII) | 46585 | (1R,2R,3aS,9aS)-5-methoxy-1-[(3S)-3-(tetrahydro-2H-pyran-2-yloxy)octyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-ol | C27H42O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)Nitration of 4-hydroxyacetophenone with KNO3 in cold H2SO4 gave the 3-nitro derivative (II), which was protected as the benzyl ether (III) with benzyl bromide in DMF. Hydrogenation of the nitro group of (III) over PtO2 afforded aniline (IV), and further treatment of (IV) with methanesulfonyl chloride in pyridine provided sulfonamide (V). Subsequent alpha-bromination of the acetophenone (V) was achieved using CuBr2 in a refluxing mixture of EtOAc and CHCl3. Asymmetric reduction of the ketone with borane in the presence of the chiral oxazaborolidine (VII), (prepared in situ from (R)-a,a-diphenyl-2-pyrrolidinemethanol (VIII) and trimethylboroxine (IX) in boiling toluene), provided the (R)-alcohol (X). The bromo group of (X) was then substituted for a iodo group upon treatment with NaI in acetone, and the resulting (IX) was protected as the triethylsilyl ether (XII) with Et3SiCl in the presence of imidazole and dimethylaminopyridine. Reaction of 4,4'-dihydroxybenzophenone (XIII) with chlorodifluoromethane and t-BuOK yielded the bis(difluoromethyl) ether (XIV). The benzhydryl amine (XV) was then obtained by reductive amination with ammonium formate at 160 C, followed by acid hydrolysis of the intermediate formamide. Condensation of iodide (XII) with benzhydryl amine (XV) in the presence of diisopropyl ethylamine in THF at 110 C in a sealed flask provided the secondary amine (XVI). Finally, the target compound was obtained by desilylation with tetrabutylammonium fluoride, followed by hydrogenolysis of the benzyl protecting group.
| 【1】 Washburn, W.N.; Girotra, R.N.; Sher, P.M.; Mikkilineni, A.B.; Poss, K.M.; Mathur, A.; Gavai, A.; Bisacchi, G.S. (Bristol-Myers Squibb Co.); Catecholamine surrogates useful as B3 agonists. CA 2138675; EP 0659737; JP 1995206806; US 5776983 . |
| 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) | 18123 | 1-(4-hydroxyphenyl)-1-ethanone; 4'-Hydroxyacetophenone | 99-93-4 | C8H8O2 | 详情 | 详情 |
| (II) | 20626 | 1-(4-hydroxy-3-nitrophenyl)-1-ethanone | 6322-56-1 | C8H7NO4 | 详情 | 详情 |
| (III) | 20627 | 1-[4-(benzyloxy)-3-nitrophenyl]-1-ethanone | C15H13NO4 | 详情 | 详情 | |
| (IV) | 20628 | 1-[3-amino-4-(benzyloxy)phenyl]-1-ethanone | C15H15NO2 | 详情 | 详情 | |
| (V) | 20629 | N-[5-acetyl-2-(benzyloxy)phenyl]methanesulfonamide | C16H17NO4S | 详情 | 详情 | |
| (VI) | 20630 | N-[2-(benzyloxy)-5-(2-bromoacetyl)phenyl]methanesulfonamide | C16H16BrNO4S | 详情 | 详情 | |
| (VII) | 20631 | (R)-Methyl oxazaborolidine; (3aR)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole | 112022-83-0 | C18H20BNO | 详情 | 详情 |
| (VIII) | 20632 | diphenyl[(2R)pyrrolidinyl]methanol | C17H19NO | 详情 | 详情 | |
| (IX) | 20633 | 2,4,6-trimethylboroxin | 823-96-1 | C3H9B3O3 | 详情 | 详情 |
| (X) | 20634 | N-[2-(benzyloxy)-5-[(1R)-2-bromo-1-hydroxyethyl]phenyl]methanesulfonamide | C16H18BrNO4S | 详情 | 详情 | |
| (XI) | 20635 | N-[2-(benzyloxy)-5-[(1R)-1-hydroxy-2-iodoethyl]phenyl]methanesulfonamide | C16H18INO4S | 详情 | 详情 | |
| (XII) | 20636 | N-(2-(benzyloxy)-5-[(1R)-2-iodo-1-[(triethylsilyl)oxy]ethyl]phenyl)methanesulfonamide | C22H32INO4SSi | 详情 | 详情 | |
| (XIII) | 20637 | bis(4-hydroxyphenyl)methanone | 611-99-4 | C13H10O3 | 详情 | 详情 |
| (XIV) | 20638 | bis[4-(difluoromethoxy)phenyl]methanone | C15H10F4O3 | 详情 | 详情 | |
| (XV) | 20639 | bis[4-(difluoromethoxy)phenyl]methylamine; bis[4-(difluoromethoxy)phenyl]methanamine | C15H13F4NO2 | 详情 | 详情 | |
| (XVI) | 20640 | N-(2-(benzyloxy)-5-[(1R)-2-([bis[4-(difluoromethoxy)phenyl]methyl]amino)-1-[(triethylsilyl)oxy]ethyl]phenyl)methanesulfonamide | C37H44F4N2O6SSi | 详情 | 详情 |