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【结 构 式】

【分子编号】11442

【品名】(2S,4S)-1,2,3,4,5-Pentanepentol; D-Arabinol

【CA登记号】488-82-4

【 分 子 式 】C5H12O5

【 分 子 量 】152.14728

【元素组成】C 39.47% H 7.95% O 52.58%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(I)

The total synthesis of FK-506 is described: This synthesis was performed by previously constructing three building fragments (XX), (XXXII) and (XLVI), which later were coupled sequentially. First the synthesis of these fragments will be presented, and afterwards their sequential coupling will be described. 1) (2RS,4R,6S,7R,8S,10R)-2-(Bis(dimethylamino)phosphono)-7-(tert-butyldimethylsilyloxy)-6,8-dimethoxy-10-(1,3-dithian-2-yl)-4-methylundecane (XX). The reaction of L-arabitol (I) with 2-acetoxyisobutyryl chloride in acetonitrile gives the diacetoxycompound (II), which by treatment with sodium methoxide in THF yields (2S,4S)-1,2:4,5-diepoxy-3-pentanol (III). The protection of (III) with TBS-Cl in THF affords the protected compound (IV), which is condensed with ethoxyacetylene (V) by means of butyllithium and boron trifluoride ethearate in THF giving the diacetylenic alcohol (VI). Cyclization of (VI) by means of HgCl2 and p-toluenesulfonic acid in refluxing ethanol yields the dilactone (VII), which is methylated by means of methyl iodide and lithium diisopropylamide in THF affording the methylated dilactone (VIII). The deprotection of (VIII) with HF in acetonitrile gives the hydroxydilactone (IX), which is benzylated with benzyl trichloroacetimidate and trifluoromethanesulfonic acid in dichloromethane-cyclohexane yielding the benzyl protected dilactone (X). The methanolysis of (X), followed by methylation with NaH and methyl iodide in DMF affords the nonanedioic ester (XI), which is debenzylated by hydrogenolysis with H2 over Pd/C in ethyl acetate giving the hydroxy diester (XII). The lactonization of (XII) with pyridinium p-toluenesulfonate in dichloromethane yields the lactone-methyl ester (XIII), which is selectively reduced with L-Selectride in THF affording the lactol-methyl ester (XIV). The reaction of (XIV) with propane-1,3-dithiol and boron trifluoride ethearate in dichloromethane gives the 1,3-dithiane derivative (XV), which by reduction of its lactone group with LiAlH4 in THF yields (2R,4S,5R,6S,8R)-8-(1,3-dithian-2-yl)-4,6-dimethoxy-2-methylnonane-1,5-diol (XVI). The reaction of (XVI) with I2, pyridine and triphenylphosphine in benzene affords the 1-iodo derivative (XVII), which is protected with TBS trifluoromethanesulfonate and triethylamine in dichloromethane giving the protected iodide (XVIII). Finally, this compound is condensed with ethylphosphonic acid bis(dimethylamide) (XIX) by means of butyllithium in THF to afford the first building fragment (XX).

1 Smith, D.B.; Schreiber, S.L.; Ragan, J.A.; Uehling, D.E.; Nakatsuka, M.; Sammakia, T.; Total synthesis of FK506 and an FKBP probe reagent, (C8,C9-13C2)-FK5. J Am Chem Soc 1990, 112, 14, 5583.
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) 11442 (2S,4S)-1,2,3,4,5-Pentanepentol; D-Arabinol 488-82-4 C5H12O5 详情 详情
(II) 11439 [(3aR,5R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-3aH-di[1,3]dioxolo[4,5-b:4,5-d]pyran-5-yl]methyl 4-methylbenzenesulfonate C19H26O8S 详情 详情
(III) 11444 Di[(2S)oxiranyl]methanol C5H8O3 详情 详情
(IV) 11445 tert-Butyl(dimethyl)silyl di[(2S)oxiranyl]methyl ether; tert-Butyl[di[(2S)oxiranyl]methoxy]dimethylsilane C11H22O3Si 详情 详情
(V) 11446 1-Ethoxyacetylene; Ethyl ethynyl ether.; Ethoxyethyne 927-80-0 C4H6O 详情 详情
(VI) 11447 (4S,6S)-5-[[tert-Butyl(dimethyl)silyl]oxy]-1,9-diethoxy-1,8-nonadiyne-4,6-diol C19H34O5Si 详情 详情
(VII) 11448 (5S)-5-[[[tert-Butyl(dimethyl)silyl]oxy][(2S)-5-oxotetrahydro-2-furanyl]methyl]dihydro-2(3H)-furanone C15H26O5Si 详情 详情
(VIII) 11449 (3R,5S)-5-[[[tert-Butyl(dimethyl)silyl]oxy][(2S,4R)-4-methyl-5-oxotetrahydro-2-furanyl]methyl]-3-methyldihydro-2(3H)-furanone C17H30O5Si 详情 详情
(IX) 11450 (3R,5S)-5-[Hydroxy[(2S,4R)-4-methyl-5-oxotetrahydro-2-furanyl]methyl]-3-methyldihydro-2(3H)-furanone C11H16O5 详情 详情
(X) 11451 5-(2-Bromophenyl)-1-(4-nitrophenyl)-1H-1,2,3,4-tetraazole C13H8BrN5O2 详情 详情
(XI) 11452 dimethyl (2R,4S,6S,8R)-5-(benzyloxy)-4,6-dimethoxy-2,8-dimethylnonanedioate C22H34O7 详情 详情
(XII) 11453 dimethyl (2R,4S,6S,8R)-5-hydroxy-4,6-dimethoxy-2,8-dimethylnonanedioate C15H28O7 详情 详情
(XIII) 11454 methyl (2R,4S)-4-methoxy-4-[(2S,3S,5R)-3-methoxy-5-methyl-6-oxotetrahydro-2H-pyran-2-yl]-2-methylbutanoate C14H24O6 详情 详情
(XIV) 11455 methyl (2R,4S)-4-[(2S,3S,5R)-6-hydroxy-3-methoxy-5-methyltetrahydro-2H-pyran-2-yl]-4-methoxy-2-methylbutanoate C14H26O6 详情 详情
(XV) 11456 (3R,5S,6R)-6-[(1S,3R)-3-(1,3-Dithian-2-yl)-1-methoxybutyl]-5-methoxy-3-methyltetrahydro-2H-pyran-2-one C16H28O4S2 详情 详情
(XVI) 11457 (2R,4S,5R,6S,8R)-8-(1,3-Dithian-2-yl)-4,6-dimethoxy-2-methyl-1,5-nonanediol C16H32O4S2 详情 详情
(XVII) 11458 (2R,4S,5S,6S,8R)-8-(1,3-Dithian-2-yl)-1-iodo-4,6-dimethoxy-2-methyl-5-nonanol C16H31IO3S2 详情 详情
(XVIII) 11459 tert-Butyl([(1S,2S,4R)-1-[(1S,3R)-3-(1,3-dithian-2-yl)-1-methoxybutyl]-5-iodo-2-methoxy-4-methylpentyl]oxy)dimethylsilane; tert-Butyl(dimethyl)silyl (1S,2S,4R)-1-[(1S,3R)-3-(1,3-dithian-2-yl)-1-methoxybutyl]-5-iodo-2-methoxy-4-methylpentyl ether C22H45IO3S2Si 详情 详情
(XIX) 11460 Ethyl-N,N,N',N'-tetramethylphosphonic diamide C6H17N2OP 详情 详情
(XX) 11491 (3R,5S,6R,7S,9R)-6-[[tert-Butyl(dimethyl)silyl]oxy]-9-(1,3-dithian-2-yl)-5,7-dimethoxy-1,3-dimethyldecyl-N,N,N',N'-tetramethylphosphonic diamide C28H61N2O4PS2Si 详情 详情

合成路线2

该中间体在本合成路线中的序号:(XIX)

The intermediate chiral phosphonamide (XXXII) has been obtained as follows: The treatment of arabitol (XIX) with the Moffat reagent (alpha-acetoxy-isobutyric acyl chloride) (XX) gives the intermediate (XXI), which, without isolation, by treatment with NaOMe and with Tbdms-Cl yields the silylated diepoxide (XXII). The condensation of (XXII) with ethoxyethynyl lithium (XXIII) by means of BF3/Et2O, HgCl2 and Ts-OH affords the bis(lactone) (XXIV), which is methylated by means of methyl iodide and LDA to provide the dimethyl analogue (XXV). The hydrolysis and desilylation of (XXV) by means of HF, followed by reprotection with benzyl trichloroacetimidate, and exhaustive methylation with NaH and methyl iodide gives the chiral nonanedioic dimethyl ester (XXVI). The reductive cleavage of the benzyl ether group with H2 over Pd(OH)2, followed by cyclization by means of PPTS yields the lactone (XXVII). The reduction of (XXVII) with L-selectride, followed by protection with propane-1,3-dithiol and BF3/Et2O affords the 1,3-dithiane (XXVIII). The reduction of the lactone group of (XXVIII) with LiAlH4, followed by reaction with PPh3 and I2 provides the chiral nonyl iodide (XXIX). The protection of the OH group of (XXIX) by means of Tbdms-OTf gives the silyl ether (XXX), which is finally condensed with lithium derived ethylphosphonamide (XXXI) to yield the intermediate chiral phosphonamide (XXXII).

1 Ragan, J.A.; The total synthesis of FK506 and an FKBP probe reagent, (C8,C9-13C2)-FK506. Diss Abstr Int B - Sci Eng 1991, 51, 8, 3849.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIX) 11442 (2S,4S)-1,2,3,4,5-Pentanepentol; D-Arabinol 488-82-4 C5H12O5 详情 详情
(XX) 32808 2-chloro-1,1-dimethyl-2-oxoethyl acetate 40635-66-3 C6H9ClO3 详情 详情
(XXI) 57258 (1R,3R)-3-(acetyloxy)-4-chloro-1-(chloromethyl)-2-hydroxybutyl acetate C9H14Cl2O5 详情 详情
(XXII) 11445 tert-Butyl(dimethyl)silyl di[(2S)oxiranyl]methyl ether; tert-Butyl[di[(2S)oxiranyl]methoxy]dimethylsilane C11H22O3Si 详情 详情
(XXIII) 55241 (2-ethoxyethynyl)lithium C4H5LiO 详情 详情
(XXIV) 11448 (5S)-5-[[[tert-Butyl(dimethyl)silyl]oxy][(2S)-5-oxotetrahydro-2-furanyl]methyl]dihydro-2(3H)-furanone C15H26O5Si 详情 详情
(XXV) 11449 (3R,5S)-5-[[[tert-Butyl(dimethyl)silyl]oxy][(2S,4R)-4-methyl-5-oxotetrahydro-2-furanyl]methyl]-3-methyldihydro-2(3H)-furanone C17H30O5Si 详情 详情
(XXVI) 11452 dimethyl (2R,4S,6S,8R)-5-(benzyloxy)-4,6-dimethoxy-2,8-dimethylnonanedioate C22H34O7 详情 详情
(XXVII) 11454 methyl (2R,4S)-4-methoxy-4-[(2S,3S,5R)-3-methoxy-5-methyl-6-oxotetrahydro-2H-pyran-2-yl]-2-methylbutanoate C14H24O6 详情 详情
(XXVIII) 11456 (3R,5S,6R)-6-[(1S,3R)-3-(1,3-Dithian-2-yl)-1-methoxybutyl]-5-methoxy-3-methyltetrahydro-2H-pyran-2-one C16H28O4S2 详情 详情
(XXIX) 11458 (2R,4S,5S,6S,8R)-8-(1,3-Dithian-2-yl)-1-iodo-4,6-dimethoxy-2-methyl-5-nonanol C16H31IO3S2 详情 详情
(XXX) 11459 tert-Butyl([(1S,2S,4R)-1-[(1S,3R)-3-(1,3-dithian-2-yl)-1-methoxybutyl]-5-iodo-2-methoxy-4-methylpentyl]oxy)dimethylsilane; tert-Butyl(dimethyl)silyl (1S,2S,4R)-1-[(1S,3R)-3-(1,3-dithian-2-yl)-1-methoxybutyl]-5-iodo-2-methoxy-4-methylpentyl ether C22H45IO3S2Si 详情 详情
(XXXI) 57259 {1-[bis(dimethylamino)phosphoryl]ethyl}lithium C6H16LiN2OP 详情 详情
(XXXII) 11491 (3R,5S,6R,7S,9R)-6-[[tert-Butyl(dimethyl)silyl]oxy]-9-(1,3-dithian-2-yl)-5,7-dimethoxy-1,3-dimethyldecyl-N,N,N',N'-tetramethylphosphonic diamide C28H61N2O4PS2Si 详情 详情
Extended Information