diethyl 2-[(E)-4-methyl-2-pentenyl]malonate -Drug Synthesis Database

【结构式】

【分子编号】24607

【品名】diethyl 2-[(E)-4-methyl-2-pentenyl]malonate

【CA登记号】

【分子式】C₁₃H₂₂O₄

【分子量】242.31528

【元素组成】C 64.44% H 9.15% O 26.41%

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：(V)

Isobutyraldehyde (I) was condensed with vinylmagnesium bromide (II) to provide allylic alcohol (III). Condensation of (III) with diethyl malonate (IV) in the presence of titanium ethoxide, followed by Claisen rearrangement at 190 C gave malonate (V). Subsequent basic hydrolysis of (V) with concomitant decarboxylation yielded 6-methyl-4-heptenoic acid (VI). This was transformed to the corresponding acid chloride by means of SOCl2 and then coupled with (1R,2R)-(-)-pseudoephedrine (VII) to produce the chiral amide (VIII). Alkylation of the dianion of (VIII) with benzyl bromide (IX) in the presence of LiCl afforded the benzylated compound (X). Further treatment of (X) with N-bromosuccinimide and AcOH in THF generated the bromolactone (XI). The bromo group of (XI) was then displaced with NaN3, and the resulting azide (XII) was hydrogenated in the presence of di-tert-butyl dicarbonate to provide carbamate (XIII). Basic hydrolysis of the lactone (XII) gave hydroxyacid (XIV), which was oxidized to ketoacid (XV) by means of N-methylmorpholine-N-oxide and tetrapropyl ammonium perruthenate.

参考文献中间体

合成目标

【1】 Worland, S.T.; Ferre, R.A.; Patick, A.K.; Prins, T.J.; Meador, J.W. III; Zhou, R.; Dragovich, P.S.; Fuhrman, S.A.; Matthews, D.A.; Ford, C.E.; Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 3. Structure-activity studies of ketomethylene-containing peptidomimetics. J Med Chem 1999, 42, 7, 1203.

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)	13226	2-Methylpropanal; Isobutyraldehyde	78-84-2	C₄H₈O	详情	详情
(II)	16524	bromo(vinyl)magnesium	1826-67-1	C₂H₃BrMg	详情	详情
(III)	24605	4-methyl-1-penten-3-ol		C₆H₁₂O	详情	详情
(IV)	16829	Diethyl malonate	105-53-3	C₇H₁₂O₄	详情	详情
(V)	24607	diethyl 2-[(E)-4-methyl-2-pentenyl]malonate		C₁₃H₂₂O₄	详情	详情
(VI)	24608	(E)-6-methyl-4-heptenoic acid		C₈H₁₄O₂	详情	详情
(VII)	24609	(1R,2R)-2-(methylamino)-1-phenyl-1-propanol		C₁₀H₁₅NO	详情	详情
(VIII)	24610	(E)-N-[(1R,2R)-2-hydroxy-1-methyl-2-phenylethyl]-N,6-dimethyl-4-heptenamide		C₁₈H₂₇NO₂	详情	详情
(IX)	12912	1-(Bromomethyl)benzene; Alpha-bromotoluene	100-39-0	C₇H₇Br	详情	详情
(X)	24634	(2S,4E)-2-benzyl-N-[(1R,2R)-2-hydroxy-1-methyl-2-phenylethyl]-N,6-dimethyl-4-heptenamide		C₂₅H₃₃NO₂	详情	详情
(XI)	24635	(3R,5S)-3-benzyl-5-[(1R)-1-bromo-2-methylpropyl]dihydro-2(3H)-furanone		C₁₅H₁₉BrO₂	详情	详情
(XII)	24636	(3R,5S)-5-[(1S)-1-azido-2-methylpropyl]-3-benzyldihydro-2(3H)-furanone		C₁₅H₁₉N₃O₂	详情	详情
(XIII)	24637	tert-butyl (1S)-1-[(2S,4R)-4-benzyl-5-oxotetrahydro-2-furanyl]-2-methylpropylcarbamate		C₂₀H₂₉NO₄	详情	详情
(XIV)	24638	(2R,4S,5S)-2-benzyl-5-[(tert-butoxycarbonyl)amino]-4-hydroxy-6-methylheptanoic acid		C₂₀H₃₁NO₅	详情	详情
(XV)	24639	(2R,5S)-2-benzyl-5-[(tert-butoxycarbonyl)amino]-6-methyl-4-oxoheptanoic acid		C₂₀H₂₉NO₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(V)

Isobutyraldehyde (I) was condensed with vinylmagnesium bromide (II) to provide allylic alcohol (III).Transesterification with diethyl malonate (IV) in the presence of titanium ethoxide, followed by Claisen rearrangement at 190 C gave malonate (V). Subsequent basic hydrolysis of (V) with concomitant decarboxylation yielded 6-methyl-4-heptenoic acid (VI). This was transformed to the corresponding acid chloride by means of SOCl2 and then coupled with (1R,2R)-(-)-pseudoephedrine (VII) to produce the chiral amide (VIII). Alkylation of the dianion of (VIII) with 4-flourobenzyl bromide (IX) in the presence of LiCl afforded the benzylated compound (X). Further treatment of (X) with N-bromosuccinimide and AcOH in THF generated the bromolactone (XI). The bromo group of (XI) was then displaced with NaN3, and the resulting azide (XII) was hydrogenated in the presence of di-tert-butyl dicarbonate to provide carbamate (XIII). Basic hydrolysis of the lactone (XIII) gave hydroxyacid (XIV), which was oxidized to ketoacid (XV) by means of N-methylmorpholine-N-oxide and tetrapropyl ammonium perruthenate.

参考文献中间体

合成目标

【1】 Worland, S.T.; Ferre, R.A.; Patick, A.K.; Prins, T.J.; Meador, J.W. III; Zhou, R.; Dragovich, P.S.; Fuhrman, S.A.; Matthews, D.A.; Ford, C.E.; Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 3. Structure-activity studies of ketomethylene-containing peptidomimetics. J Med Chem 1999, 42, 7, 1203.

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)	13226	2-Methylpropanal; Isobutyraldehyde	78-84-2	C₄H₈O	详情	详情
(II)	16524	bromo(vinyl)magnesium	1826-67-1	C₂H₃BrMg	详情	详情
(III)	24605	4-methyl-1-penten-3-ol		C₆H₁₂O	详情	详情
(IV)	16829	Diethyl malonate	105-53-3	C₇H₁₂O₄	详情	详情
(V)	24607	diethyl 2-[(E)-4-methyl-2-pentenyl]malonate		C₁₃H₂₂O₄	详情	详情
(VI)	24608	(E)-6-methyl-4-heptenoic acid		C₈H₁₄O₂	详情	详情
(VII)	24609	(1R,2R)-2-(methylamino)-1-phenyl-1-propanol		C₁₀H₁₅NO	详情	详情
(VIII)	24610	(E)-N-[(1R,2R)-2-hydroxy-1-methyl-2-phenylethyl]-N,6-dimethyl-4-heptenamide		C₁₈H₂₇NO₂	详情	详情
(IX)	24611	1-(bromomethyl)-4-fluorobenzene	459-46-1	C₇H₆BrF	详情	详情
(X)	24612	(2S,4E)-2-(4-fluorobenzyl)-N-[(1R,2R)-2-hydroxy-1-methyl-2-phenylethyl]-N,6-dimethyl-4-heptenamide		C₂₅H₃₂FNO₂	详情	详情
(XI)	24613	(3R,5S)-5-[(1R)-1-bromo-2-methylpropyl]-3-(4-fluorobenzyl)dihydro-2(3H)-furanone		C₁₅H₁₈BrFO₂	详情	详情
(XII)	24614	(3R,5S)-5-[(1S)-1-azido-2-methylpropyl]-3-(4-fluorobenzyl)dihydro-2(3H)-furanone		C₁₅H₁₈FN₃O₂	详情	详情
(XIII)	24615	tert-butyl (1S)-1-[(2S,4R)-4-(4-fluorobenzyl)-5-oxotetrahydro-2-furanyl]-2-methylpropylcarbamate		C₂₀H₂₈FNO₄	详情	详情
(XIV)	24616	(2R,4S,5S)-5-[(tert-butoxycarbonyl)amino]-2-(4-fluorobenzyl)-4-hydroxy-6-methylheptanoic acid		C₂₀H₃₀FNO₅	详情	详情
(XV)	24617	(2R,5S)-5-[(tert-butoxycarbonyl)amino]-2-(4-fluorobenzyl)-6-methyl-4-oxoheptanoic acid		C₂₀H₂₈FNO₅	详情	详情

Extended Information