methyl acetate -Drug Synthesis Database

【结构式】

【分子编号】44566

【品名】methyl acetate

【CA登记号】79-20-9

【分子式】C₃H₆O₂

【分子量】74.07944

【元素组成】C 48.64% H 8.16% O 43.2%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(II)

The synthesis of [14C]-mitoguazone has been reported: The methylation of [14C]-labeled potassium acetate (I) with dimethyl sulfate in HMPT gives the corresponding ester (II), which by reaction with the sodium salt of dimethylsulfoxide (III) in DMSO affords the hemithioketal (IV). Finally, this compound is condensed with aminoguanidine (V) in DMSO/water.

参考文献中间体

合成目标

【1】 Burgos, A.; Ellames, G.J.; Convenient synthesis of [2-C-14]-methylglyoxal bis(guanylhydrazone), [C-14]-mitoguazone. J Label Compd Radiopharm 1995, 36, 1, 93.

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)	44564	potassium acetate	127-08-2	C₂H₃KO₂	详情	详情
(I)	44565	potassium acetate		C₂H₃KO₂	详情	详情
(II)	44566	methyl acetate	79-20-9	C₃H₆O₂	详情	详情
(II)	44567	methyl acetate		C₃H₆O₂	详情	详情
(III)	44569	[(methoxysulfanyl)methyl]sodium		C₂H₅NaOS	详情	详情
(IV)	10014	1-Hydroxy-1-(methylsulfanyl)acetone	74178-33-9	C₄H₈O₂S	详情	详情
(IV)	44568	1-Hydroxy-1-(methylsulfanyl)acetone		C₄H₈O₂S	详情	详情
(V)	10015	1-Hydrazinecarboximidamide; Hydrazinecarboximidamide	79-17-4	CH₆N₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IV)

The intermediate (racemic)-2-(methoxycarbonylmethyl)-6,6-dimethyltetrahydropyran-2-carboxylic acid (VIII) has been obtained by several related methods: 1. The Grignard condensation of 4-methyl-3-pentenyl bromide (I) with diethyl oxalate (II) in HF gives the 2-oxoheptenoate (III), which is condensed with methyl acetate (IV) by means of LiHMDS in THF to yield 3-(ethoxycarbonyl)-3-hydroxy-7-methyl-6-octenoic acid methyl ester (V). The cyclization of (V) by means of Ts-OH in hot toluene or by means of hot aqueous formic acid affords 2-(methoxycarbonylmethyl)-6,6-dimethyltetrahydropyran-2-carboxylic acid ethyl ester (VI), which is hydrolyzed with KOH in boiling water to provide the corresponding dicarboxylic acid (VII). Finally, this compound is regioselectively monoesterified by means of BF3/MeOH in methanol to furnish the intermediate (racemic)-2-(methoxycarbonylmethyl)-6,6-dimethyltetrahydropyran-2-carboxylic acid (VIII). 2. The reaction of 3-(ethoxycarbonyl)-3-hydroxy-7-methyl-6-octenoic acid methyl ester (V) with HCl in hot methanol gives 3-(ethoxycarbonyl)-3,7-dihydroxy-7-methyloctanoic acid methyl ester (IX), which is then cyclized by means of ZnCl2 in hot dichloroethane to yield the previously described intermediate (VIII). 3. The hydrolysis of 3-(ethoxycarbonyl)-3-hydroxy-7-methyl-6-octenoic acid methyl ester (V) with KOH in refluxing methanol/water gives the corresponding diacid (X), which is regioselectively monoesterified by means of BF3/MeOH in methanol to yield 3-carboxy-3-hydroxy-7-methyl-6-octenoic acid methyl ester (XI). Finally, this compound is cyclized by means of Ts-OH in hot toluene to afford the previously described carboxylic intermediate (VIII). The racemic acid (VIII) is submitted to optical resolution by esterification with quinine (XII) by means of 2,4,6-trichlorobenzoyl chloride and TEA or DCC to give a diastereomeric mixture of esters (XIII) that is separated by preparative HPLC to obtain the desired diastereomer (XIV). The hydrolysis of (XIV) with KOH in refluxing ethanol/water gives the corresponding chiral dicarboxylic acid (XV), which is regioselectively monoesterified with BF3/MeOH in methanol to yield the chiral (R)-2-(methoxycarbonylmethyl)-6,6-dimethyltetrahydropyran-2-carboxylic acid (XVI). The esterification of (XVI) with cephalotaxine (XVII) by means of 2,4,6-trichlorobenzoyl chloride and TEA in toluene affords the corresponding ester (XVIII), which is treated with HBr in dichloromethane/HOAc, providing the bromoester (XIX). Finally, this compound is treated with NaHCO3, CaCO3 or BaCO3 in acetone/water to give the target hydroxyester.

参考文献中间体

合成目标

【1】 Robin, J.-P.; et al.; The first semi-synthesis of enantiopure homoharringtonine via anhydrohomoharringtonine from a preformed chiral acyl moiety. Tetrahedron Lett 1999, 40, 2931.
【2】 Robin, J.; Robin, J.-P.; Cavoleau, S.; Chauviat, L.; Charbonnel, S.; Dhal, R.; Dujardin, G.; Fournier, F.; Gilet, C.; Girodier, L.; Mevelec, L.; Poutot, S.; Rouaud, S. (OncoPharm Corp.); Novel cephalotaxane derivs. and process for their preparation. EP 1064285; FR 2776292; WO 9948894 .

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)	31462	5-bromo-2-methyl-2-pentene		C₆H₁₁Br	详情	详情
(II)	17571	Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate	95-92-1	C₆H₁₀O₄	详情	详情
(III)	52779	ethyl 3,6-dimethyl-2-oxo-5-heptenoate		C₁₁H₁₈O₃	详情	详情
(IV)	44566	methyl acetate	79-20-9	C₃H₆O₂	详情	详情
(V)	52780	1-ethyl 4-methyl 2-hydroxy-2-(4-methyl-3-pentenyl)succinate		C₁₃H₂₂O₅	详情	详情
(VI)	52781	ethyl 2-(2-methoxy-2-oxoethyl)-6,6-dimethyltetrahydro-2H-pyran-2-carboxylate		C₁₃H₂₂O₅	详情	详情
(VII)	52782	2-(carboxymethyl)-6,6-dimethyltetrahydro-2H-pyran-2-carboxylic acid		C₁₀H₁₆O₅	详情	详情
(VIII)	52783	2-(2-methoxy-2-oxoethyl)-6,6-dimethyltetrahydro-2H-pyran-2-carboxylic acid		C₁₁H₁₈O₅	详情	详情
(IX)	52784	1-ethyl 4-methyl 2-hydroxy-2-(4-hydroxy-4-methylpentyl)succinate		C₁₃H₂₄O₆	详情	详情
(X)	52785	2-hydroxy-2-(4-methyl-3-pentenyl)succinic acid		C₁₀H₁₆O₅	详情	详情
(XI)	52786	2-hydroxy-2-(2-methoxy-2-oxoethyl)-6-methyl-5-heptenoic acid		C₁₁H₁₈O₅	详情	详情
(XII)	52787	(R)-(6-methoxy-4-quinolinyl)[(2S,4S,5R)-5-vinyl-1-azabicyclo[2.2.2]oct-2-yl]methanol		C₂₀H₂₄N₂O₂	详情	详情
(XIII)	52788	(R)-(6-methoxy-4-quinolinyl)[(2S,4S,5R)-5-vinyl-1-azabicyclo[2.2.2]oct-2-yl]methyl 2-(2-methoxy-2-oxoethyl)-6,6-dimethyltetrahydro-2H-pyran-2-carboxylate		C₃₁H₄₀N₂O₆	详情	详情
(XIV)	52789	(R)-(6-methoxy-4-quinolinyl)[(2S,4S,5R)-5-vinyl-1-azabicyclo[2.2.2]oct-2-yl]methyl (2R)-2-(2-methoxy-2-oxoethyl)-6,6-dimethyltetrahydro-2H-pyran-2-carboxylate		C₃₁H₄₀N₂O₆	详情	详情
(XV)	52790	(2R)-2-(carboxymethyl)-6,6-dimethyltetrahydro-2H-pyran-2-carboxylic acid		C₁₀H₁₆O₅	详情	详情
(XVI)	52791	(2R)-2-(2-methoxy-2-oxoethyl)-6,6-dimethyltetrahydro-2H-pyran-2-carboxylic acid		C₁₁H₁₈O₅	详情	详情
(XVII)	52792	(1S,3aR,14bS)-2-methoxy-1,5,6,8,9,14b-hexahydro-4H-cyclopenta[a][1,3]dioxolo[4,5-h]pyrrolo[2,1-b][3]benzazepin-1-ol		C₁₈H₂₁NO₄	详情	详情
(XVIII)	52793	(1S,3aR,14bS)-2-methoxy-1,5,6,8,9,14b-hexahydro-4H-cyclopenta[a][1,3]dioxolo[4,5-h]pyrrolo[2,1-b][3]benzazepin-1-yl (2R)-2-(2-methoxy-2-oxoethyl)-6,6-dimethyltetrahydro-2H-pyran-2-carboxylate		C₂₉H₃₇NO₈	详情	详情
(XIX)	52794	1-[(1S,3aR,14bS)-2-methoxy-1,5,6,8,9,14b-hexahydro-4H-cyclopenta[a][1,3]dioxolo[4,5-h]pyrrolo[2,1-b][3]benzazepin-1-yl] 4-methyl (2R)-2-(4-bromo-4-methylpentyl)-2-hydroxybutanedioate		C₂₉H₃₈BrNO₈	详情	详情

Extended Information