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【结 构 式】

【分子编号】14694

【品名】(S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone

【CA登记号】90719-32-7

【 分 子 式 】C10H11NO2

【 分 子 量 】177.20288

【元素组成】C 67.78% H 6.26% N 7.9% O 18.06%
与该中间体有关的原料药合成路线共 21 条
合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15合成路线16合成路线17合成路线18合成路线19合成路线20合成路线21

合成路线1

该中间体在本合成路线中的序号：(XXVI)

4-Ethylpent-4-enoic acid (XXIV) is coupled to (R)-4-benzyl-2-oxazolidinone (XXV) via its mixed anhydride with pivaloyl chloride, producing the N-acyl oxazolidinone (XXVI). Diastereoselective cyanoethylation of (XXVI) with acrylonitrile leads to (XXVII). Reduction of imide (XXVII) with NaBH4, followed by protection of the resulting alcohol with t-butyldiphenylsilyl chloride furnishes the silyl ether (XXVIII). The nitrile function of (XXVIII) is then reduced by means of DIBAL to the aldehyde (XXIX), which is further treated with hydroxylamine to yield the corresponding oxime (XXX). Exposure of oxime (XXX) to NaOCl generates an intermediate nitrile oxide, which undergoes intramolecular 1,3-dipolar cycloaddition to the isoxazoline (XXXI). Subsequent reductive cleavage of the isoxazoline (XXXI) N-O bond with Zn/AcOH leads to compound (XXXII). Cyclohexanone (XXXII) is then converted to lactone (XXXIII) under Baeyer-Villiger conditions. Further methanolysis of lactone (XXXIII) gives rise to the open-chain dihydroxyester (XXXIV). Sequential protection of the primary hydroxyl group with triethylchlorosilane and the tertiary hydroxyl with trimethylchlorosilane furnishes the fully silylated triol (XXXV) (8). The lithium enolate of ester (XXXV) is then condensed with isothiocyanate (XXXVI) to produce thioanilide (XXXVII) (8, 9).

参考文献 中间体
合成目标
【1】 Yokoshima, S.; Ueda, T.; Kobayashi, S.; Sato, A.; Kuboyama, T.; Tokuyama, H.; Fukuyama, T.; Stereocontrolled total synthesis of (+)-vinblastine. J Am Chem Soc 2002, 124, 10, 2137.
【2】 Schneider, C.; First de novo synthesis of the bisindole alkaloid vinblastine. Angew Chem. Int Ed 2002, 41, 22, 4217.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXV) 63776 4-ethyl-4-pentenoic acid C7H12O2 详情 详情
(XXVI) 14694 (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone 90719-32-7 C10H11NO2 详情 详情
(XXVII) 63777 (4R)-4-benzyl-3-(4-ethyl-4-pentenoyl)-1,3-oxazolidin-2-one C17H21NO3 详情 详情
(XXVIII) 63778 (4R)-4-{[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}-6-ethyl-6-heptenenitrile C20H24N2O3 详情 详情
(XXIX) 63780 (4R)-4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-ethyl-6-heptenenitrile C26H35NOSi 详情 详情
(XXX) 63779 (4R)-4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-ethyl-6-heptenal C26H36O2Si 详情 详情
(XXXI) 63781 (4R)-4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-ethyl-6-heptenal oxime C26H37NO2Si 详情 详情
(XXXII) 63782 (3aR,5R)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-3a-ethyl-3,3a,4,5,6,7-hexahydro-2,1-benzisoxazole; [(3aR,5R)-3a-ethyl-3,3a,4,5,6,7-hexahydro-2,1-benzisoxazol-5-yl]methyl tert-butyl(diphenyl)silyl ether C26H35NO2Si 详情 详情
(XXXIII) 63783 (2S,4R)-4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-ethyl-2-(hydroxymethyl)cyclohexanone C26H36O3Si 详情 详情
(XXXIV) 63784 (5R,7S)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-7-ethyl-7-(hydroxymethyl)-2-oxepanone C26H36O4Si 详情 详情
(XXXV) 63785 methyl (4R,6S)-4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-hydroxy-6-(hydroxymethyl)octanoate C27H40O5Si 详情 详情
(XXXVI) 63788 methyl (4R,6S)-4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-{[(triethylsilyl)oxy]methyl}-6-[(trimethylsilyl)oxy]octanoate C36H62O5Si3 详情 详情
(XXXVII) 63789 2-[(Z)-3-(tetrahydro-2H-pyran-2-yloxy)-1-propenyl]phenyl isothiocyanate; 2-{[(Z)-3-(2-isothiocyanatophenyl)-2-propenyl]oxy}tetrahydro-2H-pyran C15H17NO2S 详情 详情
(XXXVIII) 63790 methyl (4R,6S)-4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-({2-[(Z)-3-(tetrahydro-2H-pyran-2-yloxy)-1-propenyl]anilino}carbothioyl)-6-{[(triethylsilyl)oxy]methyl}-6-[(trimethylsilyl)oxy]octanoate C51H79NO7SSi3 详情 详情

合成路线2

该中间体在本合成路线中的序号：(II)

The condensation of 3-(3-isopropoxy-4-methoxyphenyl)propionic acid (I) with the chiral adjuvant 4(S)-benzyloxazolidin-2-one (II) by means of n-BuLi in THF gives the amide (III), which is treated with triethylsilyl azide and KHMDS in THF to afford the chiral alpha-azido compound (IV). Elimination of the oxazolidin group methoxymagnesium bromide in methanol yields the methyl ester (V), which is reduced with H2 over Pd/C in methanol giving the alpha-aminoester (VI). The condensation of (VI) with N-(tert-butoxycarbonyl)-4-methoxy-3-nitro-L-phenylalanine (VII) by means of EDC and HOBT in dichloromethane provides the dipeptide (VIII), which is des-isopropylated with BCl3 in dichloromethane affording the phenolic compound (IX). The cyclization of (IX) with K2CO3 in DMSO gives the cyclic dipeptide (X), which is reduced with H2 over Pd/C in methanol and treated with H3PO2 and NaNO2 in order to eliminate the activating nitro group to give (XI). The methylation of (XI) with NaH and methyl iodide affords (XII), which is deprotected with TFA providing (XIII) with a free methylamino group.

参考文献 中间体
合成目标
【1】 Bigot, A.; et al.; Total synthesis of an antitumor agent RA-VII via an efficient preparation of cycloisodityrosine. J Org Chem 1999, 64, 17, 6283.
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) 26435 3-(3-isopropoxy-4-methoxyphenyl)propionic acid C13H18O4 详情 详情
(II) 14694 (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone 90719-32-7 C10H11NO2 详情 详情
(III) 26436 (4S)-4-benzyl-3-[3-(3-isopropoxy-4-methoxyphenyl)propanoyl]-1,3-oxazolidin-2-one C23H27NO5 详情 详情
(IV) 26437 (2S)-2-azido-1-[(4S)-4-benzyl-2-methylene-1,3-oxazolidin-3-yl]-3-(3-isopropoxy-4-methoxyphenyl)-1-propanone C24H28N4O4 详情 详情
(V) 26438 methyl (2S)-2-azido-3-(3-isopropoxy-4-methoxyphenyl)propanoate C14H19N3O4 详情 详情
(VI) 26439 methyl (2S)-2-amino-3-(3-isopropoxy-4-methoxyphenyl)propanoate C14H21NO4 详情 详情
(VII) 26440 (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-fluoro-3-nitrophenyl)propionic acid C14H17FN2O6 详情 详情
(VIII) 26441 methyl (2S)-2-[[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-fluoro-3-nitrophenyl)propanoyl]amino]-3-(3-isopropoxy-4-methoxyphenyl)propanoate C28H36FN3O9 详情 详情
(IX) 26442 methyl (2S)-2-[[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-fluoro-3-nitrophenyl)propanoyl]amino]-3-(3-hydroxy-4-methoxyphenyl)propanoate C25H30FN3O9 详情 详情
(X) 26443 methyl (9S,12S)-12-[(tert-butoxycarbonyl)amino]-4-methoxy-16-nitro-11-oxo-2-oxa-10-azatricyclo[12.2.2.1(3,7)]nonadeca-1(16),3(19),4,6,14,17-hexaene-9-carboxylate C25H29N3O9 详情 详情
(XI) 26444 methyl (9S,12S)-12-[(tert-butoxycarbonyl)amino]-4-methoxy-11-oxo-2-oxa-10-azatricyclo[12.2.2.1(3,7)]nonadeca-1(16),3(19),4,6,14,17-hexaene-9-carboxylate C25H30N2O7 详情 详情
(XII) 26445 methyl (9S,12S)-12-[(tert-butoxycarbonyl)(methyl)amino]-4-methoxy-11-oxo-2-oxa-10-azatricyclo[12.2.2.1(3,7)]nonadeca-1(16),3(19),4,6,14,17-hexaene-9-carboxylate C26H32N2O7 详情 详情
(XIII) 26446 methyl (9S,12S)-4-methoxy-12-(methylamino)-11-oxo-2-oxa-10-azatricyclo[12.2.2.1(3,7)]nonadeca-1(16),3(19),4,6,14,17-hexaene-9-carboxylate C21H24N2O5 详情 详情

合成路线3

该中间体在本合成路线中的序号：(I)

The condensation of the chiral oxazolidinone (I) with the pentenoic anhydride (II) by means of n-BuLi in THF gives the N-pentenoyloxazolidinone (III), which is condensed with acrolein (IV) catalyzed by TiCl4 and (-)-spartein in dichloromethane, yielding the chiral adduct (V). The ring-closing metathesis of (V) by means of a Ru catalyst in dichloromethane affords the chiral cyclopentenol derivative (VI), which is reduced to the (R,R)-5-(hydroxymethyl)-2-cyclopenten-1-ol (VII) by means of LiBH4 in THF. The reaction of diol (VII) with Ac2O; with methyl chloroformate, TEA and DMAP; or with ethyl chloroformate and pyridine gives the diacetate (VIII), the cyclic carbonate (IX) or the dicarbonate (X), respectively. The condensation of (VIII), (IX) or (X) with 2-amino-6-chloropurine (XI) by means of Pd(PPh3)4 yields the carbocyclic purines (XII), (XIII) or (XIV), respectively. Finally, these compounds are hydrolyzed with aqueous NaOH to the target carbocyclic guanine.

参考文献 中间体
合成目标
【1】 Crimmins, M.T.; et al.; An efficient, general asymmetric synthesis of carbocyclic nucleosides: Application of an asymmetric aldol/ring-closing metathesis strategy. J Org Chem 2000, 65, 25, 8499.
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) 14694 (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone 90719-32-7 C10H11NO2 详情 详情
(II) 17666 1,1-dimethylpropionic 4-pentenoic anhydride C10H16O3 详情 详情
(III) 17667 (4S)-4-benzyl-3-(4-pentenoyl)-1,3-oxazolidin-2-one C15H17NO3 详情 详情
(IV) 17668 acrylaldehyde; Acrolein 107-02-8 C3H4O 详情 详情
(V) 17669 (4S)-3-[(2S,3R)-2-allyl-3-hydroxy-4-pentenoyl]-4-benzyl-1,3-oxazolidin-2-one C18H21NO4 详情 详情
(VI) 17670 (4S)-4-benzyl-3-[[(1S,2R)-2-hydroxy-3-cyclopenten-1-yl]carbonyl]-1,3-oxazolidin-2-one C16H17NO4 详情 详情
(VII) 17671 (1R,5R)-5-(hydroxymethyl)-2-cyclopenten-1-ol C6H10O2 详情 详情
(VIII) 17674 [(1R,2R)-2-(acetoxy)-3-cyclopenten-1-yl]methyl acetate C10H14O4 详情 详情
(IX) 17673 (4aR,7aR)-4,4a,5,7a-tetrahydrocyclopenta[d][1,3]dioxin-2-one C7H8O3 详情 详情
(X) 17672 [(1R,2R)-2-[(methoxycarbonyl)oxy]-3-cyclopenten-1-yl]methyl methyl carbonate C10H14O6 详情 详情
(XI) 11664 4-Chloro-3-nitroquinoline C9H5ClN2O2 详情 详情
(XII) 45424 [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methyl acetate C13H14ClN5O2 详情 详情
(XIII) 17650 [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol C11H12ClN5O 详情 详情
(XIV) 45398 [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methyl methyl carbonate C13H14ClN5O3 详情 详情

合成路线4

该中间体在本合成路线中的序号：(XXXIV)

The condensation of propane-1,3-diol (XXV) with benzaldehyde by means of p-toluenesulfonic acid gives the corresponding cyclic acetal (XXVI), which is reduced with diisobutylaluminum hydride in toluene yielding 3-benzoyloxy-1-propanol (XXVII). The oxidation of (XXVII) with oxalyl chloride as before affords the corresponding aldehyde (XXVIII), which is submitted to a Wittig condensation with 2-(triphenylphosphoranylidene)acetic acid methyl ester (XXIX) giving (E)-5-benzyloxy-2-pentenoic acid methyl ester (XXX). The hydrolysis of (XXX) with NaOH in THF-water yields the corresponding acid (XXXI), which is condensed with pivaloyl chloride (XXXII) to afford the mixed anhydride (XXXIII). The condensation of (XXXIII) with 4(S)-benzyloxazolidin-2-one (XXXIV) by means of BuLi in THF gives 4(S)-benzyl-3-[5-benzyloxy-2(E)-pentenoyl]oxazolidin-2-one (XXXV), which is submitted to a Diels-Alder cycloaddition with cyclopentadiene (XXXVI) to yield 4-benzyl-3-[(3R,4R,5S,6S)-5-(2-benzyloxyethyl)bicyclo[2.2.1]hept-2-en-4-ylcarbonyl]oxazolidin-2-one (XXXVII). Hydrogenation of (XXXVII) with H2 over Pt in ethylacetate, followed by hydrolysis with H2O2 and LiOH affords (1R,2R,3S,4S)-3-(2-benzyloxyethyl)bicyclo[2.2.1]heptane-2-carboxylic acid (XXXVIII). The formation of the corresponding azide with ethyl chloroformate and sodium azide followed by degradation in refluxing toluene gives the amine (XXXIX), which is acylated with benzenesulfonyl chloride as before yielding the sulfonamide (XL). The deprotection of (XL) by hydrogenolysis with H2 over Pd/C in ethanol affords the substituted ethanol (XLI). Oxidation of (XLI) with oxalyl chloride as before gives the aldehyde (XLII), which is finally submitted to a Wittig condensation with 4-carboxybutyl triphenylphosphonium bromide and t-BuOK to yield acid (XIV) enantiomerically pure, already obtained.

参考文献 中间体
合成目标
【1】 Wong and F.F. Sun (Eds.), Raven Press, Ltd., New York 1989, 19, 659-62.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIV) 14674 (Z)-7-[(1R,2S,3S,4S)-3-[(phenylsulfonyl)amino]bicyclo[2.2.1]hept-2-yl]-5-heptenoic acid C20H27NO4S 详情 详情
(XXV) 14685 1,3-propanediol; Trimethylene Glycol 504-63-2 C3H8O2 详情 详情
(XXVI) 14686 2-phenyl-1,3-dioxane C10H12O2 详情 详情
(XXVII) 14687 3-(benzyloxy)-1-propanol; 3-(Benzyloxy)propanol 4799-68-2 C10H14O2 详情 详情
(XXVIII) 14688 3-(benzyloxy)propanal C10H12O2 详情 详情
(XXIX) 14689 Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate 2605-67-6 C21H19O2P 详情 详情
(XXX) 14690 Methyl (E)-5-(benzyloxy)-2-pentenoate C13H16O3 详情 详情
(XXXI) 14691 (E)-5-(Benzyloxy)-2-pentenoic acid C12H14O3 详情 详情
(XXXII) 13597 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride 3282-30-2 C5H9ClO 详情 详情
(XXXIII) 14693 (E)-4-(Benzyloxy)-2-pentenoic 1,1-Dimethylpropionic anhydride C17H22O4 详情 详情
(XXXIV) 14694 (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone 90719-32-7 C10H11NO2 详情 详情
(XXXV) 14695 (4S)-4-benzyl-3-[(E)-5-(benzyloxy)-2-pentenoyl]-1,3-oxazolan-2-one C22H23NO4 详情 详情
(XXXVI) 11183 1,3-Cyclopentadiene C5H6 详情 详情
(XXXVII) 14697 (4S)-4-benzyl-3-([(1R,2S,3S,4S)-3-[2-(benzyloxy)ethyl]bicyclo[2.2.1]hept-5-en-2-yl]carbonyl)-1,3-oxazolan-2-one C27H29NO4 详情 详情
(XXXVIII) 14698 (1S,2S,3S,4R)-3-[2-(benzyloxy)ethyl]bicyclo[2.2.1]heptane-2-carboxylic acid C17H22O3 详情 详情
(XXXIX) 14699 (1S,2S,3S,4R)-3-[2-(benzyloxy)ethyl]bicyclo[2.2.1]heptan-2-amine; (1S,2S,3S,4R)-3-[2-(benzyloxy)ethyl]bicyclo[2.2.1]hept-2-ylamine C16H23NO 详情 详情
(XL) 14700 N-[(1S,2S,3S,4R)-3-[2-(benzyloxy)ethyl]bicyclo[2.2.1]hept-2-yl]benzenesulfonamide C22H27NO3S 详情 详情
(XLI) 14701 N-[(1S,2S,3S,4R)-3-(2-hydroxyethyl)bicyclo[2.2.1]hept-2-yl]benzenesulfonamide C15H21NO3S 详情 详情
(XLII) 14673 N-[(1S,2S,3S,4R)-3-(2-oxoethyl)bicyclo[2.2.1]hept-2-yl]benzenesulfonamide C15H19NO3S 详情 详情

合成路线5

该中间体在本合成路线中的序号：(XXIV)

4) The acylation of 4(S)-benzyloxazolidin-2-one (XXIV) with 4-pentenoyl pivaloyl anhydride (XXV) by means of NaH in THF gives 4(S)-benzyl-3-(4-pentenoyl)oxazolidin-2-one (XXVI), which is submitted to a diastereoselective syn aldol condensation with acrolein (XXVII), using dibutylboron triflate as catalyst, affording the aldol (XXVIII). The cyclization of (XXVIII) by means of the Grubbs catalyst in dichloromethane yields the cyclopentenol (XXIX), which is reduced with LiBH4 in THF/methanol to give the key intermediate 5(R)-(hydroxymethyl)-2-cyclopenten-1(R)-ol (XXX). The reaction of (XXX) with methyl chloroformate/pyridine/DMAP or methyl chloroformate/triethylamine/DMAP or acetic anhydride gives the diols (XXXI), (XXXII) and (XXXIII), respectively, each of which coupled with 2-amino-6-chloropurine (XXXIV) in the presence of NaH and palladium tetrakis(triphenylphosphine) in THF/DMSO, affords the purine intermediate (IX) already reported.

参考文献 中间体
合成目标
【1】 King, B.W.; Crimmins, M.T.; An efficient asymmetric approach to carbocyclic nucleosides: Asymmetric synthesis of 1592U89, a potent inhibitor of HIV reverse transcriptase. J Org Chem 1996, 61, 13, 4192-3.
【2】 Graul, A.; Castaner, J.; Leeson, P.A.; Abacavir Sulfate. Drugs Fut 1998, 23, 11, 1155-1167.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IX) 17650 [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol C11H12ClN5O 详情 详情
(XXIV) 14694 (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone 90719-32-7 C10H11NO2 详情 详情
(XXV) 17666 1,1-dimethylpropionic 4-pentenoic anhydride C10H16O3 详情 详情
(XXVI) 17667 (4S)-4-benzyl-3-(4-pentenoyl)-1,3-oxazolidin-2-one C15H17NO3 详情 详情
(XXVII) 17668 acrylaldehyde; Acrolein 107-02-8 C3H4O 详情 详情
(XXVIII) 17669 (4S)-3-[(2S,3R)-2-allyl-3-hydroxy-4-pentenoyl]-4-benzyl-1,3-oxazolidin-2-one C18H21NO4 详情 详情
(XXIX) 17670 (4S)-4-benzyl-3-[[(1S,2R)-2-hydroxy-3-cyclopenten-1-yl]carbonyl]-1,3-oxazolidin-2-one C16H17NO4 详情 详情
(XXX) 17671 (1R,5R)-5-(hydroxymethyl)-2-cyclopenten-1-ol C6H10O2 详情 详情
(XXXI) 17672 [(1R,2R)-2-[(methoxycarbonyl)oxy]-3-cyclopenten-1-yl]methyl methyl carbonate C10H14O6 详情 详情
(XXXII) 17673 (4aR,7aR)-4,4a,5,7a-tetrahydrocyclopenta[d][1,3]dioxin-2-one C7H8O3 详情 详情
(XXXIII) 17674 [(1R,2R)-2-(acetoxy)-3-cyclopenten-1-yl]methyl acetate C10H14O4 详情 详情
(XXXIV) 11644 6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine 10310-21-1 C5H4ClN5 详情 详情

合成路线6

该中间体在本合成路线中的序号：(I)

An efficient asymmetric synthesis of abacavir has been reported: Acylation of the chiral oxazolidinone (I) with the mixed anhydride (II) by means of BuLi in THF gives the N-pentenoyloxazolidinone (III), which by condensation with acrolein (IV) catalyzed by TiCl4 and (­)-spartein in dichloromethane yields the chiral adduct (V). The ring-closing metathesis of adduct (V) by means of the ruthenium catalyst (Cy3P)Cl2Ru=CHPh in dichloromethane affords the chiral cyclopentenol (VI), which is reduced to 5(R)-(hydroxymethyl)-2-cyclopenten-1(R)-ol (VII) by means of LiBH4 in THF. Reaction of diol (VII) with a) Ac2O, TEA and DMAP, b) methyl chloroformate, TEA and DMAP or c) methyl chloroformate, pyridine and DMAP gives a) the diacetate (VIII), b) the cyclic carbonate (IX) or c) the dicarbonate (X), respectively. The condensation of diacetate (VIII), cyclic carbonate (IX) or dicarbonate (X) with 2-amino-6-chloropurine (XI) by means of Pd(PPh3)4 yields the carbocyclic purines (XII), (XIII) or (XIV), respectively. Treatment of these chloro-purines (XII), (XIII) and (XIV) with cyclopropylamine (XV) in hot DMSO provides the corresponding cyclopropylaminopurine carbonate (XVI), abacavir or cyclopropylaminopurine acetate (XVII), respectively. Finally, the protecting groups of purines (XVI) and (XVII) are hydrolyzed with aqueous NaOH.

参考文献 中间体
合成目标
【1】 Crimmins, M.T.; et al.; An efficient, general asymmetric synthesis of carbocyclic nucleosides: Application of an asymmetric aldol/ring-closing metathesis strategy. J Org Chem 2000, 65, 25, 8499.
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) 14694 (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone 90719-32-7 C10H11NO2 详情 详情
(II) 17666 1,1-dimethylpropionic 4-pentenoic anhydride C10H16O3 详情 详情
(III) 17667 (4S)-4-benzyl-3-(4-pentenoyl)-1,3-oxazolidin-2-one C15H17NO3 详情 详情
(IV) 17668 acrylaldehyde; Acrolein 107-02-8 C3H4O 详情 详情
(V) 17669 (4S)-3-[(2S,3R)-2-allyl-3-hydroxy-4-pentenoyl]-4-benzyl-1,3-oxazolidin-2-one C18H21NO4 详情 详情
(VI) 17670 (4S)-4-benzyl-3-[[(1S,2R)-2-hydroxy-3-cyclopenten-1-yl]carbonyl]-1,3-oxazolidin-2-one C16H17NO4 详情 详情
(VII) 17671 (1R,5R)-5-(hydroxymethyl)-2-cyclopenten-1-ol C6H10O2 详情 详情
(VIII) 17674 [(1R,2R)-2-(acetoxy)-3-cyclopenten-1-yl]methyl acetate C10H14O4 详情 详情
(IX) 17673 (4aR,7aR)-4,4a,5,7a-tetrahydrocyclopenta[d][1,3]dioxin-2-one C7H8O3 详情 详情
(X) 17672 [(1R,2R)-2-[(methoxycarbonyl)oxy]-3-cyclopenten-1-yl]methyl methyl carbonate C10H14O6 详情 详情
(XI) 11644 6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine 10310-21-1 C5H4ClN5 详情 详情
(XII) 45424 [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methyl acetate C13H14ClN5O2 详情 详情
(XIII) 17650 [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol C11H12ClN5O 详情 详情
(XIV) 45398 [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methyl methyl carbonate C13H14ClN5O3 详情 详情
(XV) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情
(XVI) 49433 [(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopenten-1-yl]methyl acetate C16H20N6O2 详情 详情
(XVII) 49434 [(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopenten-1-yl]methyl methyl carbonate C16H20N6O3 详情 详情

合成路线7

该中间体在本合成路线中的序号：(IX)

The Michael reaction between 3,4-(methylenedioxy)-beta-nitrostyrene (I) and ethyl (4-methoxybenzoyl)acetate (II) in the presence of DBU gave adduct (III) as a mixture of isomers. Hydrogenation of this nitro ketone over Raney-Ni afforded, after spontaneous cyclization of the resulting amino ketone, the pyrroline (IV). Further reduction of the imine with NaBH3CN yielded a mixture of three pyrrolidine isomers. The desired trans-trans isomer (VI) could not be separated from the cis-trans isomer by column chromatography. However, the pure cis-cis compound (V) was isomerized to (VI) with NaOEt in refluxing EtOH. The protection of the amine as the tert-butyl carbamate with Boc2O, and saponification of the ester function provided the racemic acid (VII). Resolution of (VII) was achieved by conversion to the mixed anhydride (VIII) with pivaloyl chloride, followed by condensation with the lithium salt of (S)-4-benzyl-2-oxazolidinone (IX), and chromatographic separation of the resulting diastereomeric imides. Alternatively, racemic (VII) could be resolved by crystallization of its salt with (R)-a-methylbenzylamine. Removal of the Boc group from the appropriate isomer (X) with HCl in dioxan, followed by alkylation with N,N-dibutylbromoacetamide (XI) in the presence of i-Pr2NEt furnished the pyrrolidinylacetamide (XII). Finally, hydrolysis of the imide with lithium hydroperoxide provided the target acid.

参考文献 中间体
合成目标
【1】 Winn, M.; et al.; 2,4-Diarylpyrrolidine-3-carboxylic acids-potent ETA selective endothelin receptor antagonists. 1. Discovery of A-127722. J Med Chem 1996, 39, 5, 1039.
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) 20675 5-[(E)-2-nitroethenyl]-1,3-benzodioxole 1485-00-3 C9H7NO4 详情 详情
(II) 20676 ethyl 3-(4-methoxyphenyl)-3-oxopropanoate C12H14O4 详情 详情
(III) 20677 ethyl 3-(1,3-benzodioxol-5-yl)-2-(4-methoxybenzoyl)-4-nitrobutanoate C21H21NO8 详情 详情
(IV) 20678 ethyl 3-(1,3-benzodioxol-5-yl)-5-(4-methoxyphenyl)-3,4-dihydro-2H-pyrrole-4-carboxylate C21H21NO5 详情 详情
(V) 20679 ethyl (2S,3R,4R)-4-(1,3-benzodioxol-5-yl)-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylate C21H23NO5 详情 详情
(VI) 20680 ethyl (2S,3S,4R)-4-(1,3-benzodioxol-5-yl)-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylate C21H23NO5 详情 详情
(VII) 20681 (2S,3S,4R)-4-(1,3-benzodioxol-5-yl)-1-(tert-butoxycarbonyl)-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylic acid C24H27NO7 详情 详情
(VIII) 20682 (2S,3S,4R)-4-(1,3-benzodioxol-5-yl)-1-(tert-butoxycarbonyl)-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylic 1,1-dimethylpropionic anhydride C29H35NO8 详情 详情
(IX) 14694 (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone 90719-32-7 C10H11NO2 详情 详情
(X) 20684 tert-butyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-3-[[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-2-(4-methoxyphenyl)-1-pyrrolidinecarboxylate C34H36N2O8 详情 详情
(XI) 20685 2-Bromo-N,N-dibutylacetamide; N,N-Dibutylbromoacetamide C10H20BrNO 详情 详情
(XII) 20686 2-[(2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-3-[[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-2-(4-methoxyphenyl)pyrrolidinyl]-N,N-dibutylacetamide C39H47N3O7 详情 详情

合成路线8

该中间体在本合成路线中的序号：(V)

The chiral compound was prepared by several alternative procedures. Acid hydrolysis of the known racemic ester (I) gave carboxylic acid (II), which was converted into acid chloride (III) by using oxalyl chloride in benzene. This was either condensed with (S)-2-phenylglycinol (V) or with (S)-4-benzyloxazolidine-2-one (VI) to provide the diastereomeric mixtures of amides (VI) or imides (VII), respectively. After chromatographic separation of the required (S,S)-diastereoisomers, the title compound was obtained by acid hydrolysis of the (S,S)-amide or by hydrolysis of the corresponding imide with NaOH.

参考文献 中间体
合成目标
【1】 Haigh, D.; Rami, H.K. (SmithKline Beecham plc); Benzoxazoles and pyridine derivs. useful in the treatment of type II diabetes. EP 0772605; JP 1998503508; WO 9604260; WO 9604261 .
【2】 Smith, S.A. (SmithKline Beecham plc); Use of an antagonist of PPAR-alpha and PPAR-gamma for the treatment of syndrom X. WO 9725042 .
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) 31288 methyl 3-(4-[2-[1,3-benzoxazol-2-yl(methyl)amino]ethoxy]phenyl)-2-(2,2,2-trifluoroethoxy)propanoate C22H23F3N2O5 详情 详情
(II) 31289 3-(4-[2-[1,3-benzoxazol-2-yl(methyl)amino]ethoxy]phenyl)-2-(2,2,2-trifluoroethoxy)propionic acid C21H21F3N2O5 详情 详情
(III) 31290 3-(4-[2-[1,3-benzoxazol-2-yl(methyl)amino]ethoxy]phenyl)-2-(2,2,2-trifluoroethoxy)propanoyl chloride C21H20ClF3N2O4 详情 详情
(IV) 10973 (2S)-2-Amino-2-phenyl-1-ethanol; (S)-2-Hydroxy-1-phenylethylamine; (S)-(+)-2-Phenylglycinol; (S)-2-Amino-2-phenyl-1-ethanol 20989-17-7 C8H11NO 详情 详情
(V) 14694 (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone 90719-32-7 C10H11NO2 详情 详情
(VI) 31291 3-(4-[2-[1,3-benzoxazol-2-yl(methyl)amino]ethoxy]phenyl)-N-[(1S)-2-hydroxy-1-phenylethyl]-2-(2,2,2-trifluoroethoxy)propanamide C29H30F3N3O5 详情 详情
(VII) 31292 (4S)-3-[3-(4-[2-[1,3-benzoxazol-2-yl(methyl)amino]ethoxy]phenyl)-2-(2,2,2-trifluoroethoxy)propanoyl]-4-benzyl-1,3-oxazolidin-2-one C31H30F3N3O6 详情 详情

合成路线9

该中间体在本合成路线中的序号：(V)

In an alternative procedure, (2,2,2-trifluoroethoxy)acetic acid (VIII) was converted into acid chloride (IX) by means of oxalyl chloride, and then coupled with (S)-4-benzyloxazolidine-2-one (V) in the presence of butyllithium to afford the chiral imide (X). The boron enolate obtained by treatment of (X) with di-n-butylboron triflate and triethylamine was then condensed with aldehyde (XI) to produce, after oxidative work-up with H2O2, a mixture of 3 diastereomeric aldol products (XII). The major [3(2S,3R),4S] isomer was isolated by column chromatography, and subsequently reduced with triethylsilane and trifluoroacetic acid to the (S,S) dehydroxylated compound (XIII). Basic hydrolysis of the imide (XIII) as above furnished the title carboxylic acid. Alternatively, treatment of the imide (XIII) with methanolic NaOMe produced the methyl ester (XIV), which was finally hydrolyzed to the target carboxylic acid employing HCl in aqueous dioxan.

参考文献 中间体
合成目标
【1】 Haigh, D.; Rami, H.K. (SmithKline Beecham plc); Benzoxazoles and pyridine derivs. useful in the treatment of type II diabetes. EP 0772605; JP 1998503508; WO 9604260; WO 9604261 .
【2】 Smith, S.A. (SmithKline Beecham plc); Use of an antagonist of PPAR-alpha and PPAR-gamma for the treatment of syndrom X. WO 9725042 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(V) 14694 (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone 90719-32-7 C10H11NO2 详情 详情
(VIII) 31293 2-(2,2,2-trifluoroethoxy)acetic acid C4H5F3O3 详情 详情
(IX) 31294 2-(2,2,2-trifluoroethoxy)acetyl chloride C4H4ClF3O2 详情 详情
(X) 31295 (4S)-4-benzyl-3-[2-(2,2,2-trifluoroethoxy)acetyl]-1,3-oxazolidin-2-one C14H14F3NO4 详情 详情
(XI) 31296 2-(4-[2-[1,3-benzoxazol-2-yl(methyl)amino]ethoxy]phenyl)acetaldehyde C18H18N2O3 详情 详情
(XII) 31297 (4S)-3-[3-(4-[2-[1,3-benzoxazol-2-yl(methyl)amino]ethoxy]phenyl)-3-hydroxy-2-(2,2,2-trifluoroethoxy)propanoyl]-4-benzyl-1,3-oxazolidin-2-one C31H30F3N3O7 详情 详情
(XIII) 31298 (4S)-3-[(2S)-3-(4-[2-[1,3-benzoxazol-2-yl(methyl)amino]ethoxy]phenyl)-2-(2,2,2-trifluoroethoxy)propanoyl]-4-benzyl-1,3-oxazolidin-2-one C31H30F3N3O6 详情 详情
(XIV) 31299 methyl (2S)-3-(4-[2-[1,3-benzoxazol-2-yl(methyl)amino]ethoxy]phenyl)-2-(2,2,2-trifluoroethoxy)propanoate C22H23F3N2O5 详情 详情

合成路线10

该中间体在本合成路线中的序号：(XII)

Synthesis of morpholine intermediate (I): Treatment of 4-fluorophenyl acetic acid (X) with trimethylacetyl chloride (XI) and Et3N in Et2O followed by reaction with 4-(S)-benzyl-2-oxazolidinone (XII) in THF and n-BuLi in hexane affords oxazolidinone derivative (XIII). Conversion of (XIII) into azido derivative (XV) is achieved by first treatment of (XIII) in THF with a potassium bis(trimethylsilyl)amide solution in toluene followed by treatment with 2,4,6-triisopropylphenylsulfonyl azide (XIV) in THF. Hydrolysis of azido-oxazolidinone derivative (XV) by means of LiOH in THF/H2O yields azido acetic acid derivative (XVI), which is then hydrogenated over Pd/C in H2O/HOAc to afford (S)-(4-fluorophenyl)glycine (XVII). Treatment of (S)-(4-fluorophenyl)glycine (XVII) with benzaldehyde (XVIII), NaOH and NaBH4 in MeOH yields N-benzyl (S)-(4-fluorophenyl)glycine (XIX), which is then cyclized with 1,2-dibromoethane (XX) in the presence of DIEA in DMF to furnish morpholine intermediate (I).

参考文献 中间体
合成目标
【1】 Castaner, J.; Silvestre, J.S.; Bayes, M.; Sorbera, L.A.; Aprepitant and L-758298. Drugs Fut 2002, 27, 3, 211.
【2】 Dorn, C.P.; Hale, J.J.; Maccoss, M.; Mills, S.G. (Merck & Co., Inc.); Prodrugs of morpholine tachykinin receptor antagonists. EP 0748320; JP 1997509935; US 5691336; WO 9523798 .
【3】 Dorn, C.P.; Hale, J.J.; Maccoss, M.; Mills, S.G.; Ladduwahetty, T.; Shah, S.K. (Merck & Co., Inc.); Morpholine and thiomorpholine tachykinin receptor antagonists. EP 0577394; JP 1994172178; US 5719147; WO 9400440; WO 9516679 .
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) 18288 (3S)-4-benzyl-3-(4-fluorophenyl)-2-morpholinone C17H16FNO2 详情 详情
(X) 18999 4-Fluorophenylacetic acid; 2-(4-Fluorophenyl)acetic acid 405-50-5 C8H7FO2 详情 详情
(XI) 13597 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride 3282-30-2 C5H9ClO 详情 详情
(XII) 14694 (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone 90719-32-7 C10H11NO2 详情 详情
(XIII) 44186 (4S)-4-benzyl-3-[2-(4-fluorophenyl)acetyl]-1,3-oxazolidin-2-one C18H16FNO3 详情 详情
(XIV) 44187 2,4,6-triisopropylbenzenesulfonyl azide C15H23N3O2S 详情 详情
(XV) 44188 (4S)-3-[(2S)-2-azido-2-(4-fluorophenyl)ethanoyl]-4-benzyl-1,3-oxazolidin-2-one C18H15FN4O3 详情 详情
(XVI) 44189 (2S)-2-azido-2-(4-fluorophenyl)ethanoic acid C8H6FN3O2 详情 详情
(XVII) 43098 (2R)-2-amino-2-(4-fluorophenyl)ethanoic acid 7292-73-1 C8H8FNO2 详情 详情
(XVIII) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(XIX) 44190 (2S)-2-(benzylamino)-2-(4-fluorophenyl)ethanoic acid C15H14FNO2 详情 详情
(XX) 10252 1,2-Dibromoethane; Ethylene dibromide 106-93-4 C2H4Br2 详情 详情

合成路线11

该中间体在本合成路线中的序号：(VII)

The reaction of 2,5-dimethoxytetrahydrofuran-3-carbaldehyde (I) with 2-(trimethylsilyl)-1,3-dithiane (II) by means of BuLi in THF gives the expected condensation product (III), which is treated with HgCl2 and methanol in THF/water yielding 2-(2,5-dimethoxytetrahydrofuran-3-yl)acetic acid methyl ester (IV). The cyclization of (IV) with 4'-aminobiphenyl-4-carbonitrile (V) by means of CDE in hot trifluorocetic acid affords the biphenylylpyrrole (VI), which is hydrolyzed with LiOH and condensed with the chiral auxiliary 4(S)- benzyloxazolidin-2-one (VII) by means of pivaloyl chloride, BuLi and TEA in THF giving the acylated thiazolidine (VIII). The stereocontrolled reaction of (VIII) with benzyl bromoacetate (IX) by means of sodium hexamethyldisylazane (NaHMDS) in THF yields the succinamic ester (X), which is hydrolyzed with LiOH in THF/water to afford the succinic acid monoester (XI). The amidation of (XI) with 3(S)-amino-4,4-dimethyltetrahydrofuran-2-one (XII) by means of TBTU and NMM in DMF provides the succinamic ester derivative (XIII), which is debenzylated by hydrogenation with H2 over Pd/C in methanol.

参考文献 中间体
合成目标
【1】 Deal, J.G.; Bender, S.L.; Chong, W.K.M.; et al.; Preparation of various P1'-heterocyclic succinamide inhibitors of matrix metalloproteases (MMP's). 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 197.
【2】 Bender, S.L.; Castelhano, A.L.; Chong, W.K.M.; Abreo, M.A.; Billedeau, R.J.; Chen, J.J.; Deal, J.G. (Agouron Pharmaceuticals, Inc.; Syntex (USA), Inc.); Heteroaryl succinamides and their use as metalloproteinase inhibitors. EP 0937042; JP 2000511201; US 6008243; WO 9817643 .
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) 26664 2,5-dimethoxytetrahydro-3-furancarbaldehyde C7H12O4 详情 详情
(II) 16517 1,3-dithian-2-yl(trimethyl)silane; 2-Trimethylsilyl-1,3-dithiane 13411-42-2 C7H16S2Si 详情 详情
(III) 26665 3-(1,3-dithian-2-ylidenemethyl)-2,5-dimethoxytetrahydrofuran C11H18O3S2 详情 详情
(IV) 26666 methyl 2-(2,5-dimethoxytetrahydro-3-furanyl)acetate C9H16O5 详情 详情
(V) 26667 4'-amino[1,1'-biphenyl]-4-carbonitrile 4854-84-6 C13H10N2 详情 详情
(VI) 26668 methyl 2-[1-(4'-cyano[1,1'-biphenyl]-4-yl)-1H-pyrrol-3-yl]acetate C20H16N2O2 详情 详情
(VII) 14694 (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone 90719-32-7 C10H11NO2 详情 详情
(VIII) 26669 4'-(3-[2-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-2-oxoethyl]-1H-pyrrol-1-yl)[1,1'-biphenyl]-4-carbonitrile C29H23N3O3 详情 详情
(IX) 26670 benzyl (3S)-4-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-[1-(4'-cyano[1,1'-biphenyl]-4-yl)-1H-pyrrol-3-yl]-4-oxobutanoate C38H31N3O5 详情 详情
(X) 12869 benzyl 2-bromoacetate 5437-45-6 C9H9BrO2 详情 详情
(XI) 26671 (2S)-4-(benzyloxy)-2-[1-(4'-cyano[1,1'-biphenyl]-4-yl)-1H-pyrrol-3-yl]-4-oxobutyric acid C28H22N2O4 详情 详情
(XII) 26672 (3S)-3-amino-4,4-dimethyldihydro-2(3H)-furanone C6H11NO2 详情 详情
(XIII) 26673 benzyl (3S)-3-[1-(4'-cyano[1,1'-biphenyl]-4-yl)-1H-pyrrol-3-yl]-4-[[(3S)-4,4-dimethyl-2-oxotetrahydro-3-furanyl]amino]-4-oxobutanoate C34H31N3O5 详情 详情

合成路线12

该中间体在本合成路线中的序号：(I)

The intermediate (R)-formyl amide (IX) was synthesized as follows. Acylation of the lithium anion of (S)-4-benzyl-2-oxazolidinone (I) with valeryl chloride (II) provided acyl oxazolidinone (III). Subsequent diastereoselective benzyloxymethylation of (III) with chloride (IV) and TiCl4 gave benzyl ether (V). Hydrolysis of (V) with lithium peroxide, followed by coupling of the resulting carboxylic acid (VI) with diethylamine in the presence of TBTU yielded diethylamide (VII). Hydrogenolysis of the benzyl group of (VII) using Pearlman's catalyst afforded alcohol (VIII), which was oxidized to aldehyde (IX) by means of Dess-Martin periodinane or NaOCl in the presence of 2,2,6,6-tetramethyl-1-piperidinyloxy radical (TEMPO) to give (IX).

参考文献 中间体
合成目标
【1】 Soucy, F.; et al.; A novel and efficient synthesis of a highly active analogue clasto-lactacystin beta-lactone. J Am Chem Soc 1999, 121, 43, 9967.
【2】 Plamondon, L.; Soucy, F.; Behnke, M.; Roush, W.; Synthesis of clasto-lactacystin beta-lactone and analogs thereof. WO 9909006 .
【3】 Plamondon, L.; Adams, J.; Elliot, P. (ProScript, Inc.); Proteasome inhibitors, ubiquitin pathway inhibitors or agents that interfere with the activation of NF-kappaB via the ubiquitin proteasome pathway to treat inflammatory and autoimmune diseases. WO 9915183 .
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) 14694 (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone 90719-32-7 C10H11NO2 详情 详情
(II) 15116 pentanoyl chloride; valeryl chloride 638-29-9 C5H9ClO 详情 详情
(III) 29431 (4S)-4-benzyl-3-pentanoyl-1,3-oxazolidin-2-one C15H19NO3 详情 详情
(IV) 14560 Benzyl chloromethyl ether; 1-[(chloromethoxy)methyl]benzene 3587-60-8 C8H9ClO 详情 详情
(V) 37794 (4S)-4-benzyl-3-[(2R)-2-[(benzyloxy)methyl]pentanoyl]-1,3-oxazolidin-2-one C23H27NO4 详情 详情
(VI) 37795 (2R)-2-[(benzyloxy)methyl]pentanoic acid C13H18O3 详情 详情
(VII) 37796 (2R)-2-[(benzyloxy)methyl]-N,N-diethylpentanamide C17H27NO2 详情 详情
(VIII) 37797 (2R)-N,N-diethyl-2-(hydroxymethyl)pentanamide C10H21NO2 详情 详情
(IX) 37798 (2R)-N,N-diethyl-2-formylpentanamide C10H19NO2 详情 详情

合成路线13

该中间体在本合成路线中的序号：(XVI)

Pyrrolidinone (XXVI): The selective hydrolysis of the known methyl ester (XIV) with NaOH in methanol/water gives the corresponding carboxylic acid (XV), which is coupled with the chiral oxazolidinone (XVI) by means of pivaloyl chloride and Et3N in THF to yield the amide (XVII). The regiocontrolled alkylation of (XVII) with allyl iodide and NaN(SiMe3)2 in THF affords the allyl derivative (XVIII), which is submitted to ozonolysis in dichloromethane to provide the aldehyde (XIX). The condensation of (XIX) with 2,4-dimethoxybenzylamine (XX) yields imine (XXI), which by a reductive cyclization with NaBH3CN in THF/EtOH affords pyrrolidinone (XXII). Cleavage of the oxazolidine ring of (XXII) with TsOH in hot methanol gives the amino alcohol (XXIII), which is oxidized with oxalyl chloride in DMSO to the aldehyde (XXIV). Finally, this compound is condensed with triethyl phosphonoacetate (XXV) by means of NaN(SiMe3)2 in THF to provide the desired pyrrolidinone (XXVI).

参考文献 中间体
合成目标
【1】 Dragovich, P.S.; Prins, T.J.; Zhou, R.; et al.; Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 4. Incorporation of P1 lactam moieties as L-glutamine replacements. J Med Chem 1999, 42, 7, 1213.
【2】 Graul, A.; Castañer, J.; AG-7088. Drugs Fut 2000, 25, 1, 9.
【3】 Meyer, M.D.; Daanen, J.F.; Ehrlich, P.P.; Ralston, J.W. (Abbott Laboratories Inc.); 3-Phenylpyrrole alpha-1 adrenergic cpds.. WO 9957122 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
32112 3-iodo-1-propene;3-iodo-propen;allyl iodide 556-56-9 C3H5I 详情 详情
(XIV) 32109 tert-butyl (4S)-4-(3-methoxy-3-oxopropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate C14H25NO5 详情 详情
(XV) 32110 3-[(4S)-3-(tert-butoxycarbonyl)-2,2-dimethyl-1,3-oxazolidin-4-yl]propionic acid C13H23NO5 详情 详情
(XVI) 14694 (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone 90719-32-7 C10H11NO2 详情 详情
(XVII) 32111 tert-butyl (4S)-4-[3-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-oxopropyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate C23H32N2O6 详情 详情
(XVIII) 32113 tert-butyl (4S)-4-((2S)-2-[[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-4-pentenyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate C26H36N2O6 详情 详情
(XIX) 32114 tert-butyl (4S)-4-((2R)-2-[[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-4-oxobutyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate C25H34N2O7 详情 详情
(XX) 32115 (2,4-dimethoxyphenyl)methanamine; 2,4-dimethoxybenzylamine 20781-21-9 C9H13NO2 详情 详情
(XXI) 32116 tert-butyl (4S)-4-[(2R)-2-[[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-4-[(2,4-dimethoxybenzyl)imino]butyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate C34H45N3O8 详情 详情
(XXII) 32117 tert-butyl (4S)-4-[[(3S)-1-(2,4-dimethoxybenzyl)-2-oxopyrrolidinyl]methyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate C24H36N2O6 详情 详情
(XXIII) 32118 tert-butyl (1S)-2-[(3S)-1-(2,4-dimethoxybenzyl)-2-oxopyrrolidinyl]-1-(hydroxymethyl)ethylcarbamate C21H32N2O6 详情 详情
(XXIV) 32119 tert-butyl (1S)-2-[(3S)-1-(2,4-dimethoxybenzyl)-2-oxopyrrolidinyl]-1-formylethylcarbamate C21H30N2O6 详情 详情
(XXV) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(XXVI) 32105 ethyl (E,4S)-4-[(tert-butoxycarbonyl)amino]-5-[(3S)-1-(2,4-dimethoxybenzyl)-2-oxopyrrolidinyl]-2-pentenoate C25H36N2O7 详情 详情

合成路线14

该中间体在本合成路线中的序号：(II)

Condensation of pentanoyl chloride (I) with (S)-4-benzyl-2-oxazolidinone (II) in the presence of n-butyllithium afforded the chiral N-acyl oxazolidinone (III). Subsequent asymetric alkylation of (III) with 1-bromo-2-butyne (IV) using LDA as the base produced the alkylated diastereoisomer (V). The chiral auxiliary oxazolidinone was finally removed by hydrolysis with lithium hydroperoxide to afford the required (R)-carboxylic acid.

参考文献 中间体
合成目标
【1】 Hauck, R.-S.; Elmazar, M.M.E.; Nau, H.; Bojic, U.; VPA-analogous antiepileptics. DE 4231085; US 5786380; WO 9406743 .
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) 15116 pentanoyl chloride; valeryl chloride 638-29-9 C5H9ClO 详情 详情
(II) 14694 (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone 90719-32-7 C10H11NO2 详情 详情
(III) 29431 (4S)-4-benzyl-3-pentanoyl-1,3-oxazolidin-2-one C15H19NO3 详情 详情
(IV) 29428 1-bromo-2-butyne 3355-28-0 C4H5Br 详情 详情
(V) 29432 (4S)-4-benzyl-3-[(2R)-2-propyl-4-hexynoyl]-1,3-oxazolidin-2-one C19H23NO3 详情 详情

合成路线15

该中间体在本合成路线中的序号：(II)

Condensation of 4-methylpentanoyl chloride (I) with (S)-4-benzyl-2-oxazolidinone using n-BuLi afforded the N-acyloxazolidinone (III). Asymmetric alkylation of (III) with tert-butyl bromoacetate and LDA gave (IV), and subsequent removal of the chiral auxiliary by hydrolysis with lithium peroxide yielded (R)-2-isobutylsuccinic acid mono tert-butyl ester (V). This was further alkylated with allyl bromide (VI) and LDA to provide the (R,R)-2,3-disubstituted succinate (VII). Epimerization of (VII) to the required (2R,3S)-isomer (VIII) was accomplished by treatment with LDA and Et2AlCl. Benzyl ester (IX) was then prepared by reaction of (VIII) with benzyl bromide and DBU. Hydroboration of the olefinic double bond of (IX) by means of 9-borabicyclononane, followed by oxidative treatment with H2O2 gave rise to the primary alcohol (X). This was converted to carbonate (XI) upon reaction with p-nitrophenyl chloroformate and N-methylmorpholine (NMM). Coupling of (XI) with lysine derivative (XII) then yielded carbamate (XIII).

参考文献 中间体
合成目标
【1】 Xue, C.-B.; Cherney, R.J.; DeCicco, C.P.; Degrado, W.F.; He, X.; Hodge, C.N.; Jacobson, I.C.; Magolda, R.L.; Arner, E.C.; Duan, J.; Nelson, D.J. (DuPont Pharmaceuticals Co.); Novel macrocyclic cpds. as metalloprotease inhibitors. EP 0863885; JP 2000502050; WO 9718207 .
【2】 Nelson, D.; Magolda, R.L.; Jacobson, I.C.; He, X.; Arner, E.; Cherney, R.J.; Duan, J.; Xue, C.-B.; Decicco, C.P.; Degrado, W.F. (DuPont Pharmaceuticals Co.); Novel macrocyclic cpds. as metalloprotease inhibitors. EP 0981521; WO 9851665 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情
17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(I) 25390 4-methylpentanoyl chloride 38136-29-7 C6H11ClO 详情 详情
(II) 14694 (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone 90719-32-7 C10H11NO2 详情 详情
(III) 25391 (4S)-4-benzyl-3-(4-methylpentanoyl)-1,3-oxazolidin-2-one C16H21NO3 详情 详情
(IV) 25392 tert-butyl (3R)-3-[[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-5-methylhexanoate C22H31NO5 详情 详情
(V) 25393 (2R)-2-[2-(tert-butoxy)-2-oxoethyl]-4-methylpentanoic acid C12H22O4 详情 详情
(VI) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(VII) 35082 (2R,3R)-3-(tert-butoxycarbonyl)-2-isobutyl-5-hexenoic acid C15H26O4 详情 详情
(VIII) 35083 (2R,3S)-3-(tert-butoxycarbonyl)-2-isobutyl-5-hexenoic acid C15H26O4 详情 详情
(IX) 35084 4-benzyl 1-(tert-butyl) (2S,3R)-2-allyl-3-isobutylbutanedioate C22H32O4 详情 详情
(X) 35085 4-benzyl 1-(tert-butyl) (2S,3R)-2-(3-hydroxypropyl)-3-isobutylbutanedioate C22H34O5 详情 详情
(XI) 35086 1-benzyl 4-(tert-butyl) (2R,3S)-2-isobutyl-3-(3-[[(4-nitrophenoxy)carbonyl]oxy]propyl)butanedioate C29H37NO9 详情 详情
(XII) 35087 methyl (2S)-6-amino-2-[[(benzyloxy)carbonyl]amino]hexanoate C15H22N2O4 详情 详情
(XIII) 35088 17-benzyl 16-(tert-butyl) 5-methyl (5S,16S,17R)-19-methyl-3,11-dioxo-1-phenyl-2,12-dioxa-4,10-diazaicosane-5,16,17-tricarboxylate C38H54N2O10 详情 详情

合成路线16

该中间体在本合成路线中的序号：(I)

Treatment of S-4-benzyl-2-oxazolidinone (II) with n-butyllithium, followed by acylation with valeroyl chloride (I) afforded the N-valeroyloxazolidinone (III). Subsequent alkylation of (III) with isopropyl triflate (V), prepared from isopropyl alcohol (IV) and trifluoromethanesulfonic anhydride, in the presence of LDA produced the (4S,2'R)-2-isopropylvaleroyl derivative (VI). Hydrolysis of (VI) using lithium peroxide yielded the chiral carboxylic acid (VII), which was converted to the corresponding acid chloride (VIII) by treatment with oxalyl chloride. Finally, reaction of (VIII) with ammonia furnished the title amide.

参考文献 中间体
合成目标
【1】 Yagen, B.; Bialer, M.; Spigelstein, O. (Yissum Research Development Co.); Propylisopropyl acetic acid and propylisopropyl acetamide stereoisomers, a method for their synthesis and pharmaceutical compsns. containing them. WO 9954282 .
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) 14694 (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone 90719-32-7 C10H11NO2 详情 详情
(II) 15116 pentanoyl chloride; valeryl chloride 638-29-9 C5H9ClO 详情 详情
(III) 29431 (4S)-4-benzyl-3-pentanoyl-1,3-oxazolidin-2-one C15H19NO3 详情 详情
(IV) 19250 2-propanol 67-63-0 C3H8O 详情 详情
(V) 35062 isopropyl trifluoromethanesulfonate C4H7F3O3S 详情 详情
(VI) 35063 (4S)-4-benzyl-3-[(2R)-2-isopropylpentanoyl]-1,3-oxazolidin-2-one C18H25NO3 详情 详情
(VII) 35064 (2R)-2-isopropylpentanoic acid C8H16O2 详情 详情
(VIII) 35065 (2R)-2-isopropylpentanoyl chloride C8H15ClO 详情 详情

合成路线17

该中间体在本合成路线中的序号：(IV)

Esterification of 3-(4-hydroxyphenyl)propionic acid (I), followed by alkylation of the phenolic hydroxyl, provided methyl 3-(4-benzyloxyphenyl)propionate (II), which was hydrolyzed to the corresponding carboxylic acid (III) by means of LiOH. Coupling of carboxylic acid (III) with the chiral auxiliary (S)-4-benzyl-2-oxazolidinone (IV) gave the oxazolide (V), which was subjected to diastereoselective alkylation with tert-butyl bromoacetate (VI), yielding (VII). Subsequent removal of the chiral auxiliary group of (VII) using lithium hydroperoxide afforded the (R)-acid (VIII). Alkylation of the dianion of acid (VIII) with allyl bromide (IX) and further epimerization in the presence of LDA and Et2AlCl furnished the anti-dialkylated succinate (X). The carboxyl group of (X) was then alkylated using benzyl bromide and DBU to produce the corresponding benzyl ester (XI). Olefin (XI) hydroboration followed by oxidative work-up gave rise to the primary alcohol (XII). This was acylated with 4-nitrophenyl chloroformate (XIII) to provide the activated carbonate (XIV).

参考文献 中间体
合成目标
【1】 Xue, C.-B.; et al.; Discovery of macrocyclic hydroxamic acids containing biphenylmethyl derivatives at P1', a series of selective TNF-alpha converting enzyme inhibitors with potent cellular activity in the inhibition of TNF-alpha release. J Med Chem 2001, 44, 21, 3351.
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) 25691 3-(4-hydroxyphenyl)propionic acid 501-97-3 C9H10O3 详情 详情
(II) 53167 methyl 3-[4-(benzyloxy)phenyl]propanoate n/a C17H18O3 详情 详情
(III) 53168 3-[4-(benzyloxy)phenyl]propanoic acid 50463-48-4 C16H16O3 详情 详情
(IV) 14694 (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone 90719-32-7 C10H11NO2 详情 详情
(V) 53169 (4S)-4-benzyl-3-{3-[4-(benzyloxy)phenyl]propanoyl}-1,3-oxazolidin-2-one n/a C26H25NO4 详情 详情
(VI) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(VII) 53170 tert-butyl (3R)-4-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-[4-(benzyloxy)benzyl]-4-oxobutanoate n/a C32H35NO6 详情 详情
(VIII) 53171 (2R)-2-[4-(benzyloxy)benzyl]-4-(tert-butoxy)-4-oxobutanoic acid n/a C22H26O5 详情 详情
(IX) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(X) 53172 (2R,3S)-2-[4-(benzyloxy)benzyl]-3-(tert-butoxycarbonyl)-5-hexenoic acid n/a C25H30O5 详情 详情
(XI) 53173 4-benzyl 1-(tert-butyl) (2S,3R)-2-allyl-3-[4-(benzyloxy)benzyl]butanedioate n/a C32H36O5 详情 详情
(XII) 53174 1-benzyl 4-(tert-butyl) (2R,3S)-2-[4-(benzyloxy)benzyl]-3-(3-hydroxypropyl)butanedioate n/a C32H38O6 详情 详情
(XIII) 16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情
(XIV) 53175 1-benzyl 4-(tert-butyl) (2R,3S)-2-[4-(benzyloxy)benzyl]-3-(3-{[(4-nitrophenoxy)carbonyl]oxy}propyl)butanedioate n/a C39H41NO10 详情 详情

合成路线18

该中间体在本合成路线中的序号：(II)

The first method required the chiral building block (S)-(4-fluorophenyl)glycine (VI), which was prepared from 4-fluorophenyl acetic acid (I) by two routes. Condensation of (I) with (S)-4-benzyl-2-oxazolidinone (II), via activation as the corresponding mixed anhydride with pivaloyl chloride, furnished the N-acyl oxazolidinone (III). The potassium enolate of (III) was then reacted with 2,4,6-triisopropylphenylsulfonyl azide, producing stereoselectively azide (IV). Hydrolytic removal of the chiral auxiliary of (IV) gave (S)-azido-(4-fluorophenyl)acetic acid (V), which was then reduced to the desired amino acid (VI) by catalytic hydrogenation over Pd/C. Alternatively, 4-fluorophenyl acetic acid (I) was converted to the corresponding acid chloride (VII) with SOCl2. Bromination of (VII) under Hell-Volhard-Zelinskii conditions, followed by quenching with MeOH, afforded the racemic alpha-bromo ester (VIII). Displacement of the bromide of (VIII) with NaN3 using a phase-transfer catalyst produced the azido ester (IX). Catalytic hydrogenation of the azido group of (IX) gave the racemic amino ester, which was resolved via formation of the diastereomeric salts with (+)-dibenzoyltartaric acid. The desired (S)-amino ester (X) was then hydrolyzed to (VI) under acidic conditions.

参考文献 中间体
合成目标
【1】 Baker, R.; Harrison, T.; Mcleod, A.M.; Owens, A.P.; Seward, E.M.; Swain, C.J.; Teall, M.R. (Merck Sharp & Dohme Ltd.); Substd. morpholine derivs. and their use as therapeutic agents. EP 0737192; EP 1099702; JP 1997507484; JP 2000219629; US 5612337; WO 9518124 .
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) 18999 4-Fluorophenylacetic acid; 2-(4-Fluorophenyl)acetic acid 405-50-5 C8H7FO2 详情 详情
(II) 14694 (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone 90719-32-7 C10H11NO2 详情 详情
(III) 44186 (4S)-4-benzyl-3-[2-(4-fluorophenyl)acetyl]-1,3-oxazolidin-2-one C18H16FNO3 详情 详情
(IV) 44188 (4S)-3-[(2S)-2-azido-2-(4-fluorophenyl)ethanoyl]-4-benzyl-1,3-oxazolidin-2-one C18H15FN4O3 详情 详情
(V) 44189 (2S)-2-azido-2-(4-fluorophenyl)ethanoic acid C8H6FN3O2 详情 详情
(VI) 37104 (8R,9S,10R,13S,14S,17S)-17-hydroxy-2-[(Z)-hydroxymethylidene]-4,10,13,17-tetramethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-one C22H32O3 详情 详情
(VII) 44191 methyl 2-bromo-2-(4-fluorophenyl)acetate C9H8BrFO2 详情 详情
(VIII) 53260 (1R,3S,5R)-3-{[tert-butyl(dimethyl)silyl]oxy}tricyclo[3.2.0.0~2,7~]heptan-6-one n/a C13H22O2Si 详情 详情
(IX) 53261 bicyclo[3.2.0]hept-2-en-6-one 13173-09-6 C7H8O 详情 详情
(X) 43098 (2R)-2-amino-2-(4-fluorophenyl)ethanoic acid 7292-73-1 C8H8FNO2 详情 详情

合成路线19

该中间体在本合成路线中的序号：

The title enantiomer has been obtained by resolution of the racemic acid (I). Acid (I) is activated as the mixed anhydride (II) with pivalic acid and triethylamine. Subsequent coupling of anhydride (II) with the potassium anion of (S)-4-benzyl-2-oxazolidinone leads to a mixture of the diastereoisomeric imides (III) and (IV), which can be separated by column chromatography and recrystallization. Then, removal of the chiral auxiliary from the target isomer (III) by hydrolysis with lithium peroxide furnishes the desired (S)-enantiomer.

参考文献 中间体
合成目标
【1】 Miyachi, H.; Nomura, M.; Tanase, T.; Suzuki, M.; Murakami, K.; Awano, K.; Enantio-dependent binding and transactivation of optically active phenylpropanoic acid derivatives at human peroxisome proliferator-activated receptor alpha. Bioorg Med Chem Lett 2002, 12, 3, 333.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
14694 (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone 90719-32-7 C10H11NO2 详情 详情
(I) 61870 2-[4-methoxy-3-({[4-(trifluoromethyl)benzyl]amino}carbonyl)benzyl]butanoic acid C21H22F3NO4 详情 详情
(II) 61871 1,1-dimethylpropanoic 1-[4-methoxy-3-({[4-(trifluoromethyl)benzyl]amino}carbonyl)benzyl]butanoic anhydride C26H30F3NO5 详情 详情
(III) 61872 5-((2S)-2-{[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}butyl)-2-methoxy-N-[4-(trifluoromethyl)benzyl]benzamide C31H31F3N2O5 详情 详情
(IV) 61873 5-((2R)-2-{[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}butyl)-2-methoxy-N-[4-(trifluoromethyl)benzyl]benzamide C31H31F3N2O5 详情 详情

合成路线20

该中间体在本合成路线中的序号：(I)

Preparation of the 15-methylerythromycin A precursor (XI) is accomplished by a chemobiosynthetic approach, utilizing the diketide surrogate (IX). Synthesis of (IX) is carried out as follows. Acylation of (S)-4-benzyl-2-oxazolidinone (I) with propionyl chloride (II) affords the N-propionyl oxazolidinone (III). Diastereoselective aldol condensation of (III) with butyraldehyde (IV) employing dibutylboron triflate leads to adduct (V). Deacetylation of cysteamine hydrochloride (VI) with Ac2O provides (VII). Then, selective hydrolysis of the thioester function of (VII) under alkaline conditions provides thiol (VIII). Condensation of the acyl oxazolidinone (V) with thiol (VIII) in the presence of AlMe3 gives rise to the thioester substrate (IX) (1). Incubation of a recombinant Streptomyces coelicolor strain with the diketide surrogate (IX) leads to the production of 6-deoxy-15-methylerythronolide B (X). Subsequent bioconversion of the aglycone (X) in a Saccharopolyspora erythraea strain affords the desired 15-methylerythromycin A (XI).

参考文献 中间体
合成目标
【1】 Macielag, M.; Abbanat, D.; Ashley, G.; Foleno, B.; Fu, H.; Li, Y.; Wira, E.; Bush, K.; Structure-activity studies of 15-methyl ketolides: Optimization of the heterocyclic substituent. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-1662.
【2】 Hlasta, D.; Khosla, C.; Chu, D.T.W.; Ashley, G.; Henninger, T.C.; Grant, E.B. (Ortho-McNeil Pharmaceutical, Inc.); Ketolide antibacterials. WO 0232918 .
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) 14694 (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone 90719-32-7 C10H11NO2 详情 详情
(II) 15967 propanoyl chloride; propionyl chloride 79-03-8 C3H5ClO 详情 详情
(III) 25713 (4S)-4-benzyl-3-propionyl-1,3-oxazolidin-2-one C13H15NO3 详情 详情
(IV) 23694 butyraldehyde 123-72-8 C4H8O 详情 详情
(V) 62287 (4S)-4-benzyl-3-[(2S,3R)-3-hydroxy-2-methylhexanoyl]-1,3-oxazolidin-2-one C17H23NO4 详情 详情
(VI) 13186 2-Aminoethanethiol; 2-Amino-1-ethanethiol; 2-Aminoethylhydrosulfide; Cysteamine 60-23-1 C2H7NS 详情 详情
(VII) 62288 Ethanethioic acid, S-[2-(acetylamino)ethyl] ester; N,S-DIACETYLCYSTEAMINE; (TM)S-(2-(ACETYLAMINO)ETHYL) ETHANETHIOATE}; N,S-DIACETYL-BETA-MERCAPTOETHYLAMINE; N,s-Diacetylcysteamine; N-2-Mercaptoethylacetamide-acetate; {S-[2-(ACETYLAMINO)ETHYL] ETHANETHIOATE}; N,S-DIACETYLCYSTEAMINE*; N,S-Diacetyl-.beta.-mercaptoethylamine 1420-88-8 C6H11NO2S 详情 详情
(VIII) 20034 N-(2-sulfanylethyl)acetamide 1190-73-4 C4H9NOS 详情 详情
(IX) 62289 S-[2-(acetylamino)ethyl] (2S,3R)-3-hydroxy-2-methylhexanethioate C11H21NO3S 详情 详情
(X) 62290 (3R,4S,5R,6S,7S,9R,11R,12S,13R,14R)-4,6,12-trihydroxy-3,5,7,9,11,13-hexamethyl-14-propyl-2,10-oxacyclotetradecanedione C22H40O6 详情 详情
(XI) 62291 (3R,4S,5R,6R,7S,9R,11R,12R,13S,14R)-6-{[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-7,12,13-trihydroxy-4-{[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-14-pr C38H69NO13 详情 详情

合成路线21

该中间体在本合成路线中的序号：(II)

The title N-acyloxazolidinone is synthesized by condensation of E-crotonyl chloride (I) with the lithium derivative of (S)-4-benzyl-2-oxazolidinone (II) in cold THF.

参考文献 中间体
合成目标
【1】 McHenry, K.T.; Ankala, S.V.; Ghosh, A.K.; Fenteany, G.; A non-antibacterial oxazolidinone derivative that inhibits epithelial cell sheet migration. ChemBioChem 2002, 3, 11, 1105.
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) 40178 (E)-2-Butenoyl chloride; (E)-Crotonyl chloride 625-35-4 C4H5ClO 详情 详情
(II) 14694 (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone 90719-32-7 C10H11NO2 详情 详情
Extended Information