2-methyl-1,3-cyclopentanedione -Drug Synthesis Database

【结构式】

【分子编号】24232

【品名】2-methyl-1,3-cyclopentanedione

【CA登记号】765-69-5

【分子式】C₆H₈O₂

【分子量】112.12832

【元素组成】C 64.27% H 7.19% O 28.54%

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 cyclization of methyl 5-oxo-6-heptenoate (I) with 2-methylcyclopentane-1-3-dione (II) by means of pyridine in refluxing toluene gives methyl 3-(1,5-dioxo-7a-methyl 5,6,7,7a-tetrahydroindan-4-yl)propionate (III), which is hydrolyzed with 5N HCl to the corresponding free acid (IV). Separation of the optical isomers with ephedrine affords the 3-(1,5-dioxo-7a-methyl-5,6,7,7a-tetrahydroindan 4-yl)propionic acid (V), which is reduced with NaBH4 in water to the 1beta-hydroxyacid (VI). Reduction of the double bond of (VI) with H2 over Pd/C in acetic acid gives the saturated ketoacid (VII), which is acetylated with acetic anhydride to the acetoxy Iactone (VIII). The Grignard reaction of (VIII) with propylmagnesium bromide (IX) and treatment with methanolic KOH affords 6-ethyl-3-hydroxy-3a-methyl-1,2,3,3a,4,5,8,9,9a,9b decahydro 7H benz[e]inden-7-one (X), which is finally acetylated with acetic anhydride as before.

参考文献中间体

合成目标

【1】 Joly, R.; Warnant, J.; Goffinet, B.; Nouveaux composés tricycliques et procédé de préparation. FR 1359675 .
【2】 Amiard, G.; Torelli, V.; Nomine, G.; Sur l'hydrogenation catalytique de structures tetrahydroindaniques, intermediaries de syntheses totales steroides. Bull Soc Chim France 1968, 9, 2, 3664.
【3】 Cerede, J.; Amiard, G.; Velluz, L.; Nomine, G.; Torelli, V.; Pogres en synthese totale steroide. CR Hebd Seances Acad Sci 1963, 257, 3086.
【4】 Morales-Alanis, H.; et al.; Antiandrogenic activity of a series of des-A-steroid derivatives. J Med Chem 1985, 28, 12, 1796.
【5】 Bouton, M.-M.; Jacques, J.; Pierdet, A. (Aventis Pharma SA); Certain decahydro-7H-benz(e)-inden-7-ones, compositions containing same and method of use. EP 0059146; FR 2500441; JP 2243646; JP 57156430; US 4466971; US 4607054; US 4849454; US 4927975; US 5158981 .
【6】 Castaner, J.; Prous, J.; RU-38882. Drugs Fut 1986, 11, 10, 856.

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)	24231	methyl 5-oxo-6-heptenoate		C₈H₁₂O₃	详情	详情
(II)	24232	2-methyl-1,3-cyclopentanedione	765-69-5	C₆H₈O₂	详情	详情
(III)	24233	methyl 3-(7a-methyl-1,5-dioxo-2,3,5,6,7,7a-hexahydro-1H-inden-4-yl)propanoate		C₁₄H₁₈O₄	详情	详情
(IV)	24234	3-(7a-methyl-1,5-dioxo-2,3,5,6,7,7a-hexahydro-1H-inden-4-yl)propionic acid		C₁₃H₁₆O₄	详情	详情
(V)	24235	3-[(7aS)-7a-methyl-1,5-dioxo-2,3,5,6,7,7a-hexahydro-1H-inden-4-yl]propionic acid		C₁₃H₁₆O₄	详情	详情
(VI)	24236	3-[(1S,7aS)-1-hydroxy-7a-methyl-5-oxo-2,3,5,6,7,7a-hexahydro-1H-inden-4-yl]propionic acid		C₁₃H₁₈O₄	详情	详情
(VII)	24237	3-[(1S,3aS,4S,7aS)-1-hydroxy-7a-methyl-5-oxooctahydro-1H-inden-4-yl]propionic acid		C₁₃H₂₀O₄	详情	详情
(VIII)	24238	(6aS,7S,9aS,9bS)-6a-methyl-3-oxododecahydrocyclopenta[f]chromen-7-yl acetate		C₁₅H₂₂O₄	详情	详情
(IX)	24239	bromo(ethyl)magnesium；ethylmagnesium bromide	925-90-6	C₂H₅BrMg	详情	详情
(X)	24240	(3S,3aS,9aS,9bS)-6-ethyl-3-hydroxy-3a-methyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-cyclopenta[a]naphthalen-7-one		C₁₆H₂₄O₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

Asymmetric Robinson annulation of 2-methylcyclopentane-1,3-dione (II) with (phenylsulfanyl)methyl vinyl ketone (I) using R-(+)-phenylalanine as the catalyst afforded the chiral bicyclic dione (III). Oxidation of the sulfide group of (III) by means of m-chloroperbenzoic acid gave sulfone (IV). This was reduced with LiAlH4 to the trans-hydrindane derivative (V), which was further oxidized to ketone (VI) with Jones reagent. The indaneacetic ester (VII) was obtained by Horner-Emmons condensation of ketone (VI) with triethyl phosphonoacetate, followed by catalytic hydrogenation. Treatment of (VII) with bromide (VIII) in the presence of LDA provided an inseparable mixture (IX and X) of alkylated compounds at the alpha position of the ester and sulfone functions, respectively. Ester reduction of this mixture by means of DIBAL afforded the mixture of alcohols (XI) and (XII), which were separated by chromatography. The desired alcohol (XI) was reduced to the methyl derivative (XIII) via conversion to the corresponding mesylate, which was then reduced by treatment with lithium triethyl borohydride.

参考文献中间体

合成目标

【1】 Marczak, S.; et al.; Synthesis and biological activity of the 1alpha,25-dihydroxyvitamin D3 diastereomer with unnatural configuration at the rings C/D side-chain moiety. Bioorg Med Chem Lett 2001, 11, 1, 63.

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)	47713	1-(phenylsulfanyl)-3-buten-2-one		C₁₀H₁₀OS	详情	详情
(II)	24232	2-methyl-1,3-cyclopentanedione	765-69-5	C₆H₈O₂	详情	详情
(III)	47714	(7aR)-7a-methyl-4-(phenylsulfanyl)-2,3,7,7a-tetrahydro-1H-indene-1,5(6H)-dione		C₁₆H₁₆O₂S	详情	详情
(IV)	47715	(7aR)-7a-methyl-4-(phenylsulfonyl)-2,3,7,7a-tetrahydro-1H-indene-1,5(6H)-dione		C₁₆H₁₆O₄S	详情	详情
(V)	47716	(3aS,4S,7aR)-7a-methyl-4-(phenylsulfonyl)octahydro-1H-inden-1-ol		C₁₆H₂₂O₃S	详情	详情
(VI)	47717	(3aS,4S,7aR)-7a-methyl-4-(phenylsulfonyl)octahydro-1H-inden-1-one		C₁₆H₂₀O₃S	详情	详情
(VII)	47718	ethyl 2-[(1S,3aS,4S,7aS)-7a-methyl-4-(phenylsulfonyl)octahydro-1H-inden-1-yl]acetate		C₂₀H₂₈O₄S	详情	详情
(VIII)	47719	(4-bromo-1,1-dimethylbutoxy)(triethyl)silane; 4-bromo-1,1-dimethylbutyl triethylsilyl ether		C₁₂H₂₇BrOSi	详情	详情
(IX)	47720	ethyl (2S)-2-[(1S,3aS,4S,7aS)-7a-methyl-4-(phenylsulfonyl)octahydro-1H-inden-1-yl]-6-methyl-6-[(triethylsilyl)oxy]heptanoate		C₃₂H₅₄O₅SSi	详情	详情
(X)	47721	ethyl 2-[(1S,3aS,7aS)-7a-methyl-4-[4-methyl-4-[(triethylsilyl)oxy]pentyl]-4-(phenylsulfonyl)octahydro-1H-inden-1-yl]acetate		C₃₂H₅₄O₅SSi	详情	详情
(XI)	47729	(2S)-2-[(1S,3aS,4S,7aS)-7a-methyl-4-(phenylsulfonyl)octahydro-1H-inden-1-yl]-6-methyl-6-[(triethylsilyl)oxy]-1-heptanol		C₃₀H₅₂O₄SSi	详情	详情
(XII)	47722	2-[(1S,3aS,7aS)-7a-methyl-4-[4-methyl-4-[(triethylsilyl)oxy]pentyl]-4-(phenylsulfonyl)octahydro-1H-inden-1-yl]-1-ethanol		C₃₀H₅₂O₄SSi	详情	详情
(XIII)	47723	(1S,3aS,4S,7aS)-1-[(1S)-1,5-dimethyl-5-[(triethylsilyl)oxy]hexyl]-7a-methyloctahydro-1H-inden-4-yl phenyl sulfone; ([(5S)-5-[(1S,3aS,4S,7aS)-7a-methyl-4-(phenylsulfonyl)octahydro-1H-inden-1-yl]-1,1-dimethylhexyl]oxy)(triethyl)silane		C₃₀H₅₂O₃SSi	详情	详情

Extended Information