3-methyl-2-butanone -Drug Synthesis Database

【结构式】

【分子编号】26143

【品名】3-methyl-2-butanone

【CA登记号】563-80-4

【分子式】C₅H₁₀O

【分子量】86.1338

【元素组成】C 69.72% H 11.7% O 18.58%

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：(XIII)

The resulting diol (VIII) was converted to the isopropylidene ketal (X) by means of dimethoxypropane (IX) and camphorsulfonic acid. Both pivaloyl groups of (X) were reductively removed with LiAlH4, and then selective protection of the primary hydroxyl group gave monopivalate (XI). The secondary hydroxyl group of (XI) was further oxidized to ketone (XII) with PCC. Aldol condensation of (XII) with 3-methyl-2-butanone (XIII) in the presence of LDA afforded (XIV) as a 3:7 diastereomeric mixture. Hydrolysis of pivalate ester of (XIV) with NaOMe was accompanied by intramolecular cyclization to the tetrahydrofuran (XV). This unstable intermediate was dehydrated with warm aqueous AcOH to produce furan (XVI) along with a minor amount of the ketal-hydrolyzed analogue. A trimethylsilyl group was introduced at position 5 of the furan ring of (XVI) through lithiation with n-BuLi, followed by treatment with trimethylsilyl chloride yielding (XVII).

参考文献中间体

合成目标

【1】 Shiraki, R.; et al.; Total synthesis of PI-091. Tetrahedron Lett 1995, 36, 31, 5551.
【2】 Shiraki, R.; et al.; Total synthesis of natural PI-091, a new platelet aggregation inhibitor of microbial origin. J Org Chem 1996, 61, 8, 2845.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIII)	26139	(2R,3R,4S)-2-[(2,2-dimethylpropanoyl)oxy]-3,4-dihydroxy-4-methyldecyl pivalate		C₂₁H₄₀O₆	详情	详情
(IX)	10722	1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane	77-76-9	C₅H₁₂O₂	详情	详情
(X)	26140	(1R)-2-[(2,2-dimethylpropanoyl)oxy]-1-[(4R,5S)-5-hexyl-2,2,5-trimethyl-1,3-dioxolan-4-yl]ethyl pivalate		C₂₄H₄₄O₆	详情	详情
(XI)	26141	(2R)-2-[(4R,5S)-5-hexyl-2,2,5-trimethyl-1,3-dioxolan-4-yl]-2-hydroxyethyl pivalate		C₁₉H₃₆O₅	详情	详情
(XII)	26142	2-[(4S,5S)-5-hexyl-2,2,5-trimethyl-1,3-dioxolan-4-yl]-2-oxoethyl pivalate		C₁₉H₃₄O₅	详情	详情
(XIII)	26143	3-methyl-2-butanone	563-80-4	C₅H₁₀O	详情	详情
(XIV)	26144	2-[(4R,5S)-5-hexyl-2,2,5-trimethyl-1,3-dioxolan-4-yl]-2-hydroxy-5-methyl-4-oxohexyl pivalate		C₂₄H₄₄O₆	详情	详情
(XV)	26145	4-[(4R,5S)-5-hexyl-2,2,5-trimethyl-1,3-dioxolan-4-yl]-2-isopropyltetrahydro-2,4-furandiol		C₁₉H₃₆O₅	详情	详情
(XVI)	26146	(4S,5R)-4-hexyl-5-(5-isopropyl-3-furyl)-2,2,4-trimethyl-1,3-dioxolane		C₁₉H₃₂O₃	详情	详情
(XVII)	26147	[3-[(4R,5S)-5-hexyl-2,2,5-trimethyl-1,3-dioxolan-4-yl]-5-isopropyl-2-furyl](trimethyl)silane		C₂₂H₄₀O₃Si	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

Condensation of 3-methyl-2-butanone (I) with methyl 2-methoxyacetate (II) by means of sodium in toluene gave diketone (III). Pyrazole (IV) was prepared by treatment of diketone (III) with hydrazine. Subsequent alkylation of pyrazole (IV) with isopropyl iodide in the presence of sodium hydride provided a mixture of N-alkylated regioisomers (V) and (VI). The desired minor isomer (V) was demethylated with BBr3 and the resulting alcohol (VII) was oxidized to aldehyde (VIII) using manganese dioxide. Addition of vinylmagnesium bromide to the formyl group of (VIII) produced allylic alcohol (IX), which was further oxidized to ketone (X) with MnO2. The benzoin-type condensation of unsaturated ketone (X) with aldehyde (XI) in the presence of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride furnished the 1,4-diketone (XII). Cyclization of (XII) to pyrrole (XIII) was carried out by treatment with ammonium acetate in refluxing MeOH. Finally, ester hydrolysis by means of NaOH gave rise to the corresponding carboxylic acid.

参考文献中间体

合成目标

【1】 Yamauchi, T.; Tokuhara, N.; Yoshimura, H.; Nagai, M.; Hida, T.; Tai, K.; Hibi, S.; Kikuchi, K.; Novel retinoic acid receptor alpha agonists: Syntheses and evaluation of pyrazole derivatives. Bioorg Med Chem Lett 2000, 10, 7, 619.

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)	26143	3-methyl-2-butanone	563-80-4	C₅H₁₀O	详情	详情
(II)	19100	methyl 2-methoxyacetate	6290-49-9	C₄H₈O₃	详情	详情
(III)	42297	1-methoxy-5-methyl-2,4-hexanedione		C₈H₁₄O₃	详情	详情
(IV)	42298	(3-isopropyl-1H-pyrazol-5-yl)methyl methyl ether; 3-isopropyl-5-(methoxymethyl)-1H-pyrazole		C₈H₁₄N₂O	详情	详情
(V)	42299	1,5-diisopropyl-3-(methoxymethyl)-1H-pyrazole; (1,5-diisopropyl-1H-pyrazol-3-yl)methyl methyl ether		C₁₁H₂₀N₂O	详情	详情
(VI)	42300	1,3-diisopropyl-5-(methoxymethyl)-1H-pyrazole; (1,3-diisopropyl-1H-pyrazol-5-yl)methyl methyl ether		C₁₁H₂₀N₂O	详情	详情
(VII)	42301	(1,5-diisopropyl-1H-pyrazol-3-yl)methanol		C₁₀H₁₈N₂O	详情	详情
(VIII)	42302	1,5-diisopropyl-1H-pyrazole-3-carbaldehyde		C₁₀H₁₆N₂O	详情	详情
(IX)	42303	1-(1,5-diisopropyl-1H-pyrazol-3-yl)-2-propen-1-ol		C₁₂H₂₀N₂O	详情	详情
(X)	42304	1-(1,5-diisopropyl-1H-pyrazol-3-yl)-2-propen-1-one		C₁₂H₁₈N₂O	详情	详情
(XI)	10170	methyl 4-formylbenzoate	1571-08-0	C₉H₈O₃	详情	详情
(XII)	42305	methyl 4-[4-(1,5-diisopropyl-1H-pyrazol-3-yl)-4-oxobutanoyl]benzoate		C₂₁H₂₆N₂O₄	详情	详情
(XIII)	42306	methyl 4-[5-(1,5-diisopropyl-1H-pyrazol-3-yl)-1H-pyrrol-2-yl]benzoate		C₂₁H₂₅N₃O₂	详情	详情

Extended Information