【结 构 式】 |
【分子编号】13501 【品名】Kojic acid; 5-Hydroxy-2-(hydroxymethyl)-4H-pyran-4-one 【CA登记号】501-30-4 |
【 分 子 式 】C6H6O4 【 分 子 量 】142.11124 【元素组成】C 50.71% H 4.26% O 45.03% |
合成路线1
该中间体在本合成路线中的序号:(I)The alkylation of 5-hydroxy-2-(hydroxymethyl)-4-pyrone (I) with diphenyldiazomethane in ethanol gives 5-(diphenylmethoxy)-2-(hydroxymethyl)-4-pyrone (II), which is treated with hydroxylamine in hot ethanol - water to afford 5-(diphenylmethoxy)-1-hydroxy-2-(hydroxymethyl)-4-pyridone (III). The alkylation of (III) with diphenylmethyl chloride, K2CO3 and NaI in DMSO yields 1,5-bis(diphenylmethoxy)-2-(hydroxymethyl)-4-pyridone (IV), which is condensed with N-hydroxyphthalimide (V) by means of triphenylphosphine in THF to give 1,5-bis(diphenylmethoxy)-2-(phthalimidooxymethyl)-4-pyridone (VI). The reaction of (VI) with hydrazine in ethanol affords the corresponding aminooxy derivative (VII), which is condensed with 2-[2-(triphenylmethylamino)thiazol-4-yl]glyoxylic acid (VIII) in CHCl3 - ethanol to yield 2(Z)-[1,5-bis(diphenylmethoxy)-4-oxo-1,4-dihydropyridin-2-ylmethoxyimino]-2-[2-(triphenylmethylamino)thiazol-4-yl]acetic acid (IX). The condensation of (IX) with (6R,7R)-7-amino-3-(chloromethyl)-3-cephem-4-carboxylic acid 4-methoxybenzyl ester (X) by means of NaHCO3, 1-hydroxybenzotriazole (HBT) and dicyclohexylcarbodiimide (DDC) in ethyl acetate - water gives the corresponding 7-acetamide derivative (XI), which by a new condensation with sodium 1,2,3-thiadiazole-5-thiolate (XII) in DMF - ethanol affords the fully protected final product (XIII). Finally, this compound is deprotected by a treatment with trifluoroacetic acid and anisole, the sodium salt being obtained by treatment with HaHCO3 in water.
【1】 Zama, Y.; Ishiyama, N.; Saita, T.; Naito, T.; Hirose, M.; Yokoyama, M.; Asano, T.; Senda, H.; Sekine, H.; Sanai, S. (Kaken Pharmaceutical Co., Ltd.); Cephalosporin cpds., processes for their preparation and antibacterial agents. EP 0251299; JP 1988146887; JP 1988152386; JP 1990288884; US 4822786; US 4883879 . |
【2】 Prous, J.; Castaner, J.; KP-736. Drugs Fut 1990, 15, 5, 457. |
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) | 13501 | Kojic acid; 5-Hydroxy-2-(hydroxymethyl)-4H-pyran-4-one | 501-30-4 | C6H6O4 | 详情 | 详情 |
(II) | 13502 | 5-(Benzhydryloxy)-2-(hydroxymethyl)-4H-pyran-4-one | C19H16O4 | 详情 | 详情 | |
(III) | 13503 | 5-(Benzhydryloxy)-1-hydroxy-2-(hydroxymethyl)-4(1H)-pyridinone | C19H17NO4 | 详情 | 详情 | |
(IV) | 13504 | 1,5-Bis(benzhydryloxy)-2-(hydroxymethyl)-4(1H)-pyridinone | C32H27NO4 | 详情 | 详情 | |
(V) | 13505 | N-Hydroxyphthalimide; 2-Hydroxy-1H-isoindole-1,3(2H)-dione | 524-38-9 | C8H5NO3 | 详情 | 详情 |
(VI) | 13506 | 2-[[1,5-Bis(benzhydryloxy)-4-oxo-1,4-dihydro-2-pyridinyl]methoxy]-1H-isoindole-1,3(2H)-dione | C40H30N2O6 | 详情 | 详情 | |
(VII) | 13507 | 2-[(Aminooxy)methyl]-1,5-bis(benzhydryloxy)-4(1H)-pyridinone | C32H28N2O4 | 详情 | 详情 | |
(VIII) | 13508 | 2-[2-(Benzhydrylamino)-1,3-thiazol-4-yl]-2-oxoacetic acid | C18H14N2O3S | 详情 | 详情 | |
(IX) | 13509 | 2-[2-(Benzhydrylamino)-1,3-thiazol-4-yl]-2-([[1,5-bis(benzhydryloxy)-4-oxo-1,4-dihydro-2-pyridinyl]methoxy]imino)acetic acid | C50H40N4O6S | 详情 | 详情 | |
(X) | 13510 | 4-methoxybenzyl (6R,7R)-7-amino-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C16H17ClN2O4S | 详情 | 详情 | |
(XI) | 13511 | 4-methoxybenzyl (6R,7R)-7-[[2-[2-(benzhydrylamino)-1,3-thiazol-4-yl]-2-([[1,5-bis(benzhydryloxy)-4-oxo-1,4-dihydro-2-pyridinyl]methoxy]imino)acetyl]amino]-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C66H55ClN6O9S2 | 详情 | 详情 | |
(XII) | 13512 | Sodium 1,2,3-thiadiazol-5-ylsulfide | 75849-83-1 | C2HN2NaS2 | 详情 | 详情 |
(XIII) | 13513 | 4-methoxybenzyl (6R,7R)-7-[[2-[2-(benzhydrylamino)-1,3-thiazol-4-yl]-2-([[1,5-bis(benzhydryloxy)-4-oxo-1,4-dihydro-2-pyridinyl]methoxy]imino)acetyl]amino]-8-oxo-3-[(1,2,3-thiadiazol-5-ylsulfanyl)methyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxyl | C68H56N8O9S4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(I)1) The reaction of 5-hydroxy-2-(hydroxymthyl)-4H-pyran-4-one (I) with benzyl chloride and NaOH gives 5-benzyloxy-2-(hydroxymethyl)-4H-pyran-4-one (II), which is oxidized with Jones reagent (CrO3/H2SO4)to the corresponding 2-carboxylic acid (III). The reaction of pyran (III) with ammonia at 90 C yields the expected pyridone (IV), which is methylated with trimethylsilyldiazomethane in methanol affording 5-benzyloxy-4-methoxypyridine-2-carboxylic acid methyl ester (V). The deprotection of (V) by hydrogenation with H2 overPd/C in methanol gives 5-hydroxy-4-methoxypyridine-2-carboxylic acid methyl ester (VI), which is submitted to radical acylation with acetaldehyde, tert-butyl peroxide and FeSO4 yielding 6-acetyl-5-hydroxy-4-methoxy-pyridine-2-carboxylic acid methyl ester (VII). The methyltaion of (VII) with trimethylsilyldiazomethane as before affords 6-acetyl-4,5-dimethoxypyridine-2-carboxylic acid methyl ester (VIII), which is brominated with pyridinium tribromide to the corresponding bromoacetyl derivative (IX). The cyclization of (IX) with 7-acetoxyoctanethiomide (X) in acetone at room temperature gives 6-[2-(6-acetoxyheptyl)thiazol-4-yl]-4,5-dimethoxypyridine-2-carboxylic acid methyl ester (XI), which is finally saponified with 0,5 N NaOH. 2) The 7-acetoxyoctanethioamide (X) has been obtained as follows: The reaction of 7-oxooctanoic acid (XIII) with ammonia and oxalyl chloride gives the corresponding amide (XIII), which is then treated with Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide) in pyridine to give the expected thioamide (X).
【1】 Massa, M.A.; et al.; The total synthesis of the natural product endothelin converting enzyme (ECE) inhibitor, WS75624 B. 213th ACS Natl Meet (April 13-17, San Francisco) 1997, Abst MEDI 196. |
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) | 13501 | Kojic acid; 5-Hydroxy-2-(hydroxymethyl)-4H-pyran-4-one | 501-30-4 | C6H6O4 | 详情 | 详情 |
(II) | 19852 | 5-(benzyloxy)-2-(hydroxymethyl)-4H-pyran-4-one | C13H12O4 | 详情 | 详情 | |
(III) | 19853 | 5-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid | C13H10O5 | 详情 | 详情 | |
(IV) | 19854 | 5-(benzyloxy)-4-oxo-1,4-dihydro-2-pyridinecarboxylic acid | C13H11NO4 | 详情 | 详情 | |
(V) | 19855 | methyl 5-(benzyloxy)-4-methoxy-2-pyridinecarboxylate | C15H15NO4 | 详情 | 详情 | |
(VI) | 19856 | methyl 5-hydroxy-4-methoxy-2-pyridinecarboxylate | C8H9NO4 | 详情 | 详情 | |
(VII) | 19857 | methyl 6-acetyl-5-hydroxy-4-methoxy-2-pyridinecarboxylate | C10H11NO5 | 详情 | 详情 | |
(VIII) | 19858 | methyl 6-acetyl-4,5-dimethoxy-2-pyridinecarboxylate | C11H13NO5 | 详情 | 详情 | |
(IX) | 19859 | methyl 6-(2-bromoacetyl)-4,5-dimethoxy-2-pyridinecarboxylate | C11H12BrNO5 | 详情 | 详情 | |
(X) | 19860 | 7-amino-1-methyl-7-thioxoheptyl acetate | C10H19NO2S | 详情 | 详情 | |
(XI) | 19861 | methyl 6-[2-[6-(acetoxy)heptyl]-1,3-thiazol-4-yl]-4,5-dimethoxy-2-pyridinecarboxylate | C21H28N2O6S | 详情 | 详情 | |
(XII) | 19862 | 7-oxooctanoic acid | C8H14O3 | 详情 | 详情 | |
(XIII) | 19863 | 7-oxooctanamide | C8H15NO2 | 详情 | 详情 | |
(XIV) | 19864 | 7-hydroxyoctanamide | C8H17NO2 | 详情 | 详情 | |
(XV) | 19865 | 7-amino-1-methyl-7-oxoheptyl acetate | C10H19NO3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(I)Kojic acid (I) was chlorinated with neat thionyl chloride, and the resultant chloride (II) was further reduced to the methyl derivative (III) employing Zn and HCl. The hydroxymethylation of (III) with formaldehyde in the presence NaOH provided alcohol (IV). After protection of the 3-hydroxyl group of (IV) as the benzyl ether (V), the primary alcohol of (V) was oxidized to aldehyde (VI) using SO3-pyridine complex and DMSO. Further oxidation of aldehyde (VI) with sodium chlorite furnished the carboxylic acid (VII). Activation of acid (VII) was achieved by coupling with 2-mercaptothiazoline (VIII) using DCC and DMAP. The resulting thiazolidine amide (IX) was then reacted with methylamine in CH2Cl2 under mild conditions to give the N-methyl amide (X). Further treatment of (X) with a methanolic solution of methylamine in a sealed tube at 70 C converted the pyranone ring to the pyridone (XI). The benzyl protecting group of (XI) was then removed by catalytic hydrogenation, and the title compound was finally isolated as the hydrochloride salt.
【1】 Liu, Z.D.; et al.; Synthesis of 2-amino-3-hydroxypyridin-4(1H)-ones: Novel iron chelators with enhanced pFe3+ values. Bioorg Med Chem 2001, 9, 3, 563. |
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) | 13501 | Kojic acid; 5-Hydroxy-2-(hydroxymethyl)-4H-pyran-4-one | 501-30-4 | C6H6O4 | 详情 | 详情 |
(II) | 48642 | (2-Chloromethyl)-5-hydroxy-4H-pyran-4-one | C6H5ClO3 | 详情 | 详情 | |
(III) | 45934 | 5-hydroxy-2-methyl-4H-pyran-4-one | C6H6O3 | 详情 | 详情 | |
(IV) | 48643 | 3-hydroxy-2-(hydroxymethyl)-6-methyl-4H-pyran-4-one | C7H8O4 | 详情 | 详情 | |
(V) | 48644 | 3-(benzyloxy)-2-(hydroxymethyl)-6-methyl-4H-pyran-4-one | C14H14O4 | 详情 | 详情 | |
(VI) | 48645 | 3-(benzyloxy)-6-methyl-4-oxo-4H-pyran-2-carbaldehyde | C14H12O4 | 详情 | 详情 | |
(VII) | 48646 | 3-(benzyloxy)-6-methyl-4-oxo-4H-pyran-2-carboxylic acid | C14H12O5 | 详情 | 详情 | |
(VIII) | 28895 | 4,5-dihydro-1,3-thiazol-2-ylhydrosulfide | 96-53-7 | C3H5NS2 | 详情 | 详情 |
(IX) | 48647 | 3-(benzyloxy)-6-methyl-2-[(2-thioxo-1,3-thiazolidin-3-yl)carbonyl]-4H-pyran-4-one | C17H15NO4S2 | 详情 | 详情 | |
(X) | 48648 | 3-(benzyloxy)-N,6-dimethyl-4-oxo-4H-pyran-2-carboxamide | C15H15NO4 | 详情 | 详情 | |
(XI) | 48649 | 3-(benzyloxy)-N,1,6-trimethyl-4-oxo-1,4-dihydro-2-pyridinecarboxamide | C16H18N2O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号:(I)The reaction of 5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one (I) with SOCl2, followed by dechlorination with Zn/HCl, gives 5-hydroxy-2-methyl-4H-pyran-4-one (II), which is condensed with formaldehyde to yield 3-hydroxy-2-(hydroxymethyl)-6-methyl-4H-pyran-4-one (III). The protection of the aromatic OH group of (III) with Bn-Br affords the benzyl ether (IV), which is treated with methylamine to provide the corresponding 4-pyridone (V). The reaction of the OH group of (V) with phthalimide (VI) by means of DEAD and PPh3 gives the expected phthalimido derivative (VII), which is cleaved with hydrazine to yield the aminomethyl derivative (VIII). The condensation of the amino group of (VIII) with the activated amide (IX) (obtained by condensation of N-propylsuccinamic acid (X) with 2-thiazolidinone (XI) by means of DCC and DMAP) affords the adduct (XII), which is finally debenzylated by hydrogenation with H2 over Pd/C to provide the target succinamide derivative.
【1】 Liu, Z.D.; et al.; Design, synthesis, and evaluation of novel 2-substituted 3-hydroxypyridin-4-ones: Structure-activity investigation of metalloenzyme inhibition by iron chelators. J Med Chem 2002, 45, 3, 631. |
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) | 13501 | Kojic acid; 5-Hydroxy-2-(hydroxymethyl)-4H-pyran-4-one | 501-30-4 | C6H6O4 | 详情 | 详情 |
(II) | 45934 | 5-hydroxy-2-methyl-4H-pyran-4-one | C6H6O3 | 详情 | 详情 | |
(III) | 48643 | 3-hydroxy-2-(hydroxymethyl)-6-methyl-4H-pyran-4-one | C7H8O4 | 详情 | 详情 | |
(IV) | 48644 | 3-(benzyloxy)-2-(hydroxymethyl)-6-methyl-4H-pyran-4-one | C14H14O4 | 详情 | 详情 | |
(V) | 54747 | 3-(benzyloxy)-2-(hydroxymethyl)-1,6-dimethyl-4(1H)-pyridinone | C15H17NO3 | 详情 | 详情 | |
(VI) | 12376 | Phthalimide; 1H-Isoindole-1,3(2H)-dione; Isoindole-1,3-dione;Phthalic dicarboximide;Phenylimide;Isoindole-1,3-dione | 85-41-6 | C8H5NO2 | 详情 | 详情 |
(VII) | 54748 | 2-{[3-(benzyloxy)-1,6-dimethyl-4-oxo-1,4-dihydro-2-pyridinyl]methyl}-1H-isoindole-1,3(2H)-dione | C23H20N2O4 | 详情 | 详情 | |
(VIII) | 54749 | 2-(aminomethyl)-3-(benzyloxy)-1,6-dimethyl-4(1H)-pyridinone | C15H18N2O2 | 详情 | 详情 | |
(IX) | 54750 | 4-oxo-N-propyl-4-(2-thioxo-1,3-thiazolidin-3-yl)butanamide | C10H16N2O2S2 | 详情 | 详情 | |
(X) | 54752 | 4-oxo-4-(propylamino)butanoic acid | C7H13NO3 | 详情 | 详情 | |
(XI) | 54751 | Thiazolidine-2-thione | C3H5NS2 | 详情 | 详情 | |
(XII) | 54753 | N~1~-{[3-(benzyloxy)-1,6-dimethyl-4-oxo-1,4-dihydro-2-pyridinyl]methyl}-N~4~-propylsuccinamide | C22H29N3O4 | 详情 | 详情 |