【结 构 式】 |
【分子编号】14982 【品名】(2R,3R,7S,10R)-7-[(2S,3E,5E,7E,9S,11R)-11-(1,3-dithian-2-yl)-2-methoxy-3,9-dimethyl-3,5,7-dodecatrienyl]-2,3,10-trimethyl-1,4,6-trioxaspiro[4.5]decane; (1S,2E,4E,6E,8S,10R)-10-(1,3-dithian-2-yl)-2,8-dimethyl-1-[[(2R,3R,7S,10R)-2,3,10-trimethyl-1,4,6-trioxaspiro[4.5]dec-7-yl]methyl]-2,4,6-undecatrienyl methyl ether 【CA登记号】 |
【 分 子 式 】C29H48O4S2 【 分 子 量 】524.82972 【元素组成】C 66.37% H 9.22% O 12.19% S 12.22% |
合成路线1
该中间体在本合成路线中的序号:(XII)A partial synthesis of rapamycin has been reported: The reaction of 1-(trimethylsilyl)-1,3-pentadiyne (I) with a stannyl cuprate gives a mixture of (E)- and (Z)-stannyl derivatives (II) and (III) [the ratio (II)/(III) depends on the stannyl cuprate used]. Both compounds, after chromatographic separation, are condensed with the chiral aldehyde (IV) by means of butyllithium to afford the alcohols (V) and (VI), respectively. By chromatographic separation of the corresponding (S)-isomers, these are methylated and deprotected with methyl iodide and KOH, yielding the (E)- and (Z)-isomeric terminal acetylenes (VII) and (VIII). The reaction of either (VII) or (VIII) with tributylstannyl hydride and AIBN in refluxing toluene gives in both cases the (E,E)-dienylstannane (IX), which by reaction with I2 in dichloromethane affords the (E,E)-dienyl iodide (X). Finally, this compound is condensed with the vinyl iodide (XI) (see later) by means of PdCl2 in DMF to yield (XII), the protected C(10)-C(26) fragment of rapamycin [the C(20)-C(35)-C(1)-O(36) fragment based on the IUPAC nomenclature recommendations].
【1】 Maleczka, R.E.; Condon, S.M.; Leazer, J.L.; McCauley, J.A.; Smith, A.B.; Leahy, J.W.; Rapamycin synthetic studies. 2. Elaboration of the C(10)-C(26) perimeter. Tetrahedron Lett 1994, 35, 28, 4911. |
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) | 14971 | trimethyl(1,3-pentadiynyl)silane | C8H12Si | 详情 | 详情 | |
(II) | 14972 | trimethyl[(E)-4-(tributylstannyl)-3-penten-1-ynyl]silane | C20H40SiSn | 详情 | 详情 | |
(III) | 14973 | trimethyl[(Z)-4-(tributylstannyl)-3-penten-1-ynyl]silane | C20H40SiSn | 详情 | 详情 | |
(IV) | 14974 | 2-[(2R,3R,7S,10R)-2,3,10-trimethyl-1,4,6-trioxaspiro[4.5]dec-7-yl]acetaldehyde | C12H20O4 | 详情 | 详情 | |
(V) | 14975 | (E)-3-methyl-6-(trimethylsilyl)-1-[(2R,3R,7S,10R)-2,3,10-trimethyl-1,4,6-trioxaspiro[4.5]dec-7-yl]-3-hexen-5-yn-2-ol | C20H34O4Si | 详情 | 详情 | |
(VI) | 14976 | (Z)-3-methyl-6-(trimethylsilyl)-1-[(2R,3R,7S,10R)-2,3,10-trimethyl-1,4,6-trioxaspiro[4.5]dec-7-yl]-3-hexen-5-yn-2-ol | C20H34O4Si | 详情 | 详情 | |
(VII) | 14977 | methyl (1S,2E)-2-methyl-1-[[(2R,3R,7S,10R)-2,3,10-trimethyl-1,4,6-trioxaspiro[4.5]dec-7-yl]methyl]-2-penten-4-ynyl ether; (2R,3R,7S,10R)-7-[(2S,3E)-2-methoxy-3-methyl-3-hexen-5-ynyl]-2,3,10-trimethyl-1,4,6-trioxaspiro[4.5]decane | C18H28O4 | 详情 | 详情 | |
(VIII) | 63930 | (2R,3R,7S,10R)-7-[(2S,3Z)-2-methoxy-3-methyl-3-hexen-5-ynyl]-2,3,10-trimethyl-1,4,6-trioxaspiro[4.5]decane; methyl (1S,2Z)-2-methyl-1-{[(2R,3R,7S,10R)-2,3,10-trimethyl-1,4,6-trioxaspiro[4.5]dec-7-yl]methyl}-2-penten-4-ynyl ether | C18H28O4 | 详情 | 详情 | |
(IX) | 14979 | tributyl[(1E,3E,5S)-5-methoxy-4-methyl-6-[(2R,3R,7S,10R)-2,3,10-trimethyl-1,4,6-trioxaspiro[4.5]dec-7-yl]-1,3-hexadienyl]stannane | C30H56O4Sn | 详情 | 详情 | |
(X) | 14980 | (1S,2E,4E)-5-iodo-2-methyl-1-[[(2R,3R,7S,10R)-2,3,10-trimethyl-1,4,6-trioxaspiro[4.5]dec-7-yl]methyl]-2,4-pentadienyl methyl ether; (2R,3R,7S,10R)-7-[(2S,3E,5E)-6-iodo-2-methoxy-3-methyl-3,5-hexadienyl]-2,3,10-trimethyl-1,4,6-trioxaspiro[4.5]decane | C18H29IO4 | 详情 | 详情 | |
(XI) | 14981 | tributyl[(E,3S,5R)-5-(1,3-dithian-2-yl)-3-methyl-1-hexenyl]stannane | C23H46S2Sn | 详情 | 详情 | |
(XII) | 14982 | (2R,3R,7S,10R)-7-[(2S,3E,5E,7E,9S,11R)-11-(1,3-dithian-2-yl)-2-methoxy-3,9-dimethyl-3,5,7-dodecatrienyl]-2,3,10-trimethyl-1,4,6-trioxaspiro[4.5]decane; (1S,2E,4E,6E,8S,10R)-10-(1,3-dithian-2-yl)-2,8-dimethyl-1-[[(2R,3R,7S,10R)-2,3,10-trimethyl-1,4,6-trioxaspiro[4.5]dec-7-yl]methyl]-2,4,6-undecatrienyl methyl ether | C29H48O4S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(VII)Title compound was prepared by two synthetic ways: 1) Treatment of hexafluorophenylpropanol (I) with KH and then with trifluoromethane- sulfonic anhydride gave triflate (II), which was converted into azide (III) by reaction with NaN3 in trifluoroacetic acid. Reduction of azide (III) with Raney-nickel in isopropanol afforded the corresponding amine, which was isolated as the hydrochloride salt (IV). Acid chloride (VI) was prepared from acid (V) by treatment with SOCl2. Then, condensation of (VI) with amine (IV) in the presence of pyridine provided the target amide.
【1】 Panzeri, A.; Nesi, M.; Di Salle, E. (Pharmacia & Upjohn AB); Phenylsubstd. 4-azasteroid fluoroderivs.. EP 0793671; JP 1998509188; US 5922728; WO 9710257 . |
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) | 18970 | 1,1,1,3,3,3-hexafluoro-2-phenyl-2-propanol | 718-64-9 | C9H6F6O | 详情 | 详情 |
(II) | 18971 | 2,2,2-trifluoro-1-phenyl-1-(trifluoromethyl)ethyl trifluoromethanesulfonate | C10H5F9O3S | 详情 | 详情 | |
(III) | 18972 | 1-[1-azido-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]benzene; 2,2,2-trifluoro-1-phenyl-1-(trifluoromethyl)ethyl azide | C9H5F6N3 | 详情 | 详情 | |
(IV) | 18973 | 1,1,1,3,3,3-hexafluoro-2-phenyl-2-propanamine hydrochloride | C9H8ClF6N | 详情 | 详情 | |
(V) | 13533 | (4aS,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-Dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxylic acid | C19H27NO3 | 详情 | 详情 | |
(VI) | 18975 | (4aS,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carbonyl chloride | C19H26ClNO2 | 详情 | 详情 | |
(VII) | 14982 | (2R,3R,7S,10R)-7-[(2S,3E,5E,7E,9S,11R)-11-(1,3-dithian-2-yl)-2-methoxy-3,9-dimethyl-3,5,7-dodecatrienyl]-2,3,10-trimethyl-1,4,6-trioxaspiro[4.5]decane; (1S,2E,4E,6E,8S,10R)-10-(1,3-dithian-2-yl)-2,8-dimethyl-1-[[(2R,3R,7S,10R)-2,3,10-trimethyl-1,4,6-trioxaspiro[4.5]dec-7-yl]methyl]-2,4,6-undecatrienyl methyl ether | C29H48O4S2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(VII)2) Alternatively, oxoandrostenecarboxylic acid (VII) was converted into acid chloride (VIII) by treatment with oxalyl chloride and a trace of DMF in CH2Cl2. Subsequent condensation of (VIII) with amine (IV), prepared as before, yielded the corresponding amide (IX). The oxidative cleavage of (IX) with NaIO4 and KmnO4 afforded ketoacid (X), which was cyclized with ammonia in ethylene glycol at 180 C providing the azasteroid (XI). Catalytic hydrogenation of the double bond over PtO2 gave (XII), which was finally oxidized with phenylseleninic anhydride (XIII) in boiling chlorobenzene to furnish the 1,2-unsaturated compound.
【1】 Panzeri, A.; Nesi, M.; Di Salle, E. (Pharmacia & Upjohn AB); Phenylsubstd. 4-azasteroid fluoroderivs.. EP 0793671; JP 1998509188; US 5922728; WO 9710257 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(VII) | 14982 | (2R,3R,7S,10R)-7-[(2S,3E,5E,7E,9S,11R)-11-(1,3-dithian-2-yl)-2-methoxy-3,9-dimethyl-3,5,7-dodecatrienyl]-2,3,10-trimethyl-1,4,6-trioxaspiro[4.5]decane; (1S,2E,4E,6E,8S,10R)-10-(1,3-dithian-2-yl)-2,8-dimethyl-1-[[(2R,3R,7S,10R)-2,3,10-trimethyl-1,4,6-trioxaspiro[4.5]dec-7-yl]methyl]-2,4,6-undecatrienyl methyl ether | C29H48O4S2 | 详情 | 详情 | |
(VIII) | 18977 | (8S,9S,10R,13S,14S,17S)-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-carbonyl chloride | C20H27ClO2 | 详情 | 详情 | |
(IX) | 18978 | (8S,9S,10R,13S,14S,17S)-10,13-dimethyl-3-oxo-N-[2,2,2-trifluoro-1-phenyl-1-(trifluoromethyl)ethyl]-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-carboxamide | C29H33F6NO2 | 详情 | 详情 | |
(X) | 18979 | 3-[(3S,3aS,5aS,6R,9aS,9bS)-3a,6-dimethyl-7-oxo-3-([[2,2,2-trifluoro-1-phenyl-1-(trifluoromethyl)ethyl]amino]carbonyl)dodecahydro-1H-cyclopenta[a]naphthalen-6-yl]propionic acid | C28H33F6NO4 | 详情 | 详情 | |
(XI) | 18980 | (4aR,4bS,6aS,7S,9aS,9bS)-4a,6a-dimethyl-2-oxo-N-[2,2,2-trifluoro-1-phenyl-1-(trifluoromethyl)ethyl]-2,3,4,4a,4b,5,6,6a,7,8,9,9a,9b,10-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide | C28H32F6N2O2 | 详情 | 详情 | |
(XII) | 18981 | (4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-N-[2,2,2-trifluoro-1-phenyl-1-(trifluoromethyl)ethyl]hexadecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide | C28H34F6N2O2 | 详情 | 详情 | |
(XIII) | 18982 | 3-Oxo-1,3-diphenyl-1lambda(4),3lambda(4)-diselenoxan-1-one; Benzeneseleninic anhydride | 17697-12-0 | C12H10O3Se2 | 详情 | 详情 |