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【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%

与该中间体有关的原料药合成路线共 4 条

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
Extended Information