-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】4(S)-[2(R)-Benzyl-5(S)-(cyclopentylsulfanylcarboxamido)-6-methyl-4-oxoheptanamido]-6-carbamoyl-2(E)-hexenoic acid ethyl ester

【CA登记号】

【分子式】C₃₀H₄₃N₃O₆S

【分子量】573.75771

【开发单位】Agouron (Originator)

【药理作用】ANTIINFECTIVE THERAPY, Antiviral Drugs

合成路线1 合成路线2

合成路线1

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

【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

Acid (XV) was coupled with protected amino acid (XVI) to give amide (XVII), and the Boc protecting group of (XVII) was then removed under acidic conditions. The resulting amine (XVIII) was condensed with cyclopentyl chlorothioformate (XIX) to provide thiocarbamate (XX). Finally, the title compound was obtained by trifluoroacetic acid-promoted cleavage of the trityl protecting group of (XIX).

参考文献中间体

【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	分子式	供应商	用于合成
(XV)	24639	(2R,5S)-2-benzyl-5-[(tert-butoxycarbonyl)amino]-6-methyl-4-oxoheptanoic acid	C₂₀H₂₉NO₅	详情	详情
(XVI)	24618	ethyl (E,4S)-4-amino-7-oxo-7-(tritylamino)-2-heptenoate	C₂₈H₃₀N₂O₃	详情	详情
(XVII)	24640	ethyl (E,4S)-4-([(2R,5S)-2-benzyl-5-[(tert-butoxycarbonyl)amino]-6-methyl-4-oxoheptanoyl]amino)-7-oxo-7-(tritylamino)-2-heptenoate	C₄₈H₅₇N₃O₇	详情	详情
(XVIII)	24641	ethyl (E,4S)-4-[[(2R,5S)-5-amino-2-benzyl-6-methyl-4-oxoheptanoyl]amino]-7-oxo-7-(tritylamino)-2-heptenoate	C₄₃H₄₉N₃O₅	详情	详情
(XIX)	24621	1-[(chlorocarbonyl)sulfanyl]cyclopentane	C₆H₉ClOS	详情	详情
(XX)	24642	ethyl (E,4S)-4-[((2R,5S)-2-benzyl-5-[[(cyclopentylsulfanyl)carbonyl]amino]-6-methyl-4-oxoheptanoyl)amino]-7-oxo-7-(tritylamino)-2-heptenoate	C₄₉H₅₇N₃O₆S	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)