5-hydroxy-2-methyl-4H-pyran-4-one -Drug Synthesis Database

【结构式】

【分子编号】45934

【品名】5-hydroxy-2-methyl-4H-pyran-4-one

【CA登记号】

【分子式】C₆H₆O₃

【分子量】126.11184

【元素组成】C 57.14% H 4.8% O 38.06%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(I)

Treatment of allomaltol (I) with acetaldehyde (II) and NaOH in H2O affords pyranone derivative (III), which is benzylated by means of benzyl bromide (IV) and NaOH in refluxing H2O/MeOH to provide compound (V). O-Methylation of (V) by reaction with NaH and MeI in DMF furnishes methoxyethyl derivative (VI), which is then heated with methylamine and NaOH in EtOH/H2O to yield pyridinone derivative (VII). Finally, the benzyl group of (VII) is removed by hydrogenation over Pd/C in MeOH to give the desired product.

参考文献中间体

合成目标

【1】 Tilbrook, G.S.; Hider, R.C.; Liu, Z. (BTG International Ltd.); Novel orally active iron (III) chelators. WO 9854138 .

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)	45934	5-hydroxy-2-methyl-4H-pyran-4-one		C₆H₆O₃	详情	详情
(II)	11974	Acetaldehyde	75-07-0	C₂H₄O	详情	详情
(III)	45935	3-hydroxy-2-(1-hydroxyethyl)-6-methyl-4H-pyran-4-one		C₈H₁₀O₄	详情	详情
(IV)	12912	1-(Bromomethyl)benzene; Alpha-bromotoluene	100-39-0	C₇H₇Br	详情	详情
(V)	45936	3-(benzyloxy)-2-(1-hydroxyethyl)-6-methyl-4H-pyran-4-one		C₁₅H₁₆O₄	详情	详情
(VI)	45937	3-(benzyloxy)-2-(1-methoxyethyl)-6-methyl-4H-pyran-4-one		C₁₆H₁₈O₄	详情	详情
(VII)	45938	3-(benzyloxy)-2-(1-methoxyethyl)-1,6-dimethyl-4(1H)-pyridinone		C₁₇H₂₁NO₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

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.

参考文献中间体

合成目标

【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3

该中间体在本合成路线中的序号：(II)

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.

参考文献中间体

合成目标

【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