(E)-3-(methylanilino)-2-propenal -Drug Synthesis Database

【结构式】

【分子编号】27906

【品名】(E)-3-(methylanilino)-2-propenal

【CA登记号】

【分子式】C₁₀H₁₁NO

【分子量】161.20348

【元素组成】C 74.51% H 6.88% N 8.69% O 9.92%

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：(VII)

A synthesis of [14C]-labeled fluvastatin has been described: The acylation of fluorobenzene (I) with [14C]-bromoacetyl chloride (II) by means of AlCl3 gives the expected phenacyl bromide (III), which is condensed with N-isopropylaniline (IV) in hot ethanol yielding the tertiary amine (V). The cyclization of (V) by means of anhydrous ZnCl2 in refluxing ethanol affords the indole (VI), which is alkylated with 3-(N-methyl-N-phenylamino)acroleine (VII) by means of POCl3 in refluxing acetonitrile giving 3-[3-(4-fluorophenyl)-1-isopropylindol-2-yl]acroleine (VIII). The reductocondensation of (VIII) with tert-butyl acetoacetate (IX) by means of NaH and BuLi in THF yields 7-[3-(4-fluorophenyl)-1-isopropylindol-2-yl)-5-hydroxy-3-oxo-6-heptenoic acid tert-butyl ester (X), which is further reduced with NaBH4 and diethyl(methoxy)borane in THF to the dihydroxy compound (XI) as a mixture of the two syn-enantiomers (XI). Finally, this compound is hydrolyzed with NaOH in methanol to the expected sodium salt.

参考文献中间体

合成目标

【1】 Jones, L.; Tang, Y.S.; Sunay, U.B.; Synthesis of carbon-14 labeled fluvastatin (Lescol(R)). J Label Compd Radiopharm 1998, 41, 1, 1.

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)	17466	Fluorobenzene	462-06-6	C₆H₅F	详情	详情
(II)	27903	2-Bromoacetyl chloride	22118-09-8	C₂H₂BrClO	详情	详情
(II)	45080	2-bromoacetyl chloride		C₂H₂BrClO	详情	详情
(III)	27904	2-bromo-1-(4-fluorophenyl)-1-ethanone	403-29-2	C₈H₆BrFO	详情	详情
(III)	45081	2-bromo-1-(4-fluorophenyl)-1-ethanone		C₈H₆BrFO	详情	详情
(IV)	27905	N-isopropyl-N-phenylamine	768-52-5	C₉H₁₃N	详情	详情
(V)	11787	1-(4-Fluorophenyl)-2-(isopropylanilino)-1-ethanone		C₁₇H₁₈FNO	详情	详情
(V)	45082	1-(4-fluorophenyl)-2-(isopropylanilino)-1-ethanone		C₁₇H₁₈FNO	详情	详情
(VI)	11788	3-(4-Fluorophenyl)-1-isopropyl-1H-indole	93957-49-4	C₁₇H₁₆FN	详情	详情
(VI)	45083	3-(4-fluorophenyl)-1-isopropyl-1H-indole		C₁₇H₁₆FN	详情	详情
(VII)	27906	(E)-3-(methylanilino)-2-propenal		C₁₀H₁₁NO	详情	详情
(VIII)	11790	(E)-3-[3-(4-Fluorophenyl)-1-isopropyl-1H-indol-2-yl]-2-propenal		C₂₀H₁₈FNO	详情	详情
(VIII)	45084	(E)-3-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-2-propenal		C₂₀H₁₈FNO	详情	详情
(IX)	27907	Acetoacetic acid tert-butyl ester;3-Oxo-butanoic acid 1,1-dimethylethyl estertert-butyl 3-oxobutanoate	1694-31-1	C₈H₁₄O₃	详情	详情
(X)	27908	tert-butyl (E)-7-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-5-hydroxy-3-oxo-6-heptenoate		C₂₈H₃₂FNO₄	详情	详情
(X)	45085	tert-butyl (E)-7-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-5-hydroxy-3-oxo-6-heptenoate		C₂₈H₃₂FNO₄	详情	详情
(XI)	27909	tert-butyl (3R,5S,6E)-7-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-3,5-dihydroxy-6-heptenoate		C₂₈H₃₄FNO₄	详情	详情
(XI)	45086	tert-butyl (3R,5S,6E)-7-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-3,5-dihydroxy-6-heptenoate		C₂₈H₃₄FNO₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VI)

The Friedel-Crafts condensation of fluorobenzene (I) with chloroacetyl chloride (II) by means of AlCl3 gives the phenacyl chloride (III), which is cyclized with N-isopropylaniline (IV) by means of ZnCl2 to yield 3-(4-fluorophenyl)-1-isopropyl-1H-indole (V). The condensation of (V) with 3-(N-methyl-N-phenylamino)acrolein (VI) by means of POCl3 in acetonitrile affords 3-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]acrolein (VII), which is further condensed with tert-butyl acetoacetate (VIII) by means of BuLi and NaH in THF to provide 7-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-5-hydroxy-3-oxo-6(E)-heptenoic acid tert-butyl ester (IX). The reduction of the ketonic group of (IX) with NaBH4 catalyzed by Et2B-OMe as chelating agent gives the diol (X) with a syn configuration. Finally, the tert-butyl ester group of (X) is hydrolyzed with NaOH in ethanol/water to afford the target fluvastatin sodium.

参考文献中间体

合成目标

【1】 Repic, O.; et al.; The story of Lescol: From research to production. Org Process Res Dev 2001, 5, 5, 519.

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)	17466	Fluorobenzene	462-06-6	C₆H₅F	详情	详情
(II)	11296	2-Chloroacetyl chloride; Chloroacetic chloride	79-04-9	C₂H₂Cl₂O	详情	详情
(III)	11786	2-Chloro-1-(4-fluorophenyl)-1-ethanone; 2-Chloro-4'-fluoroacetophenone	456-04-2	C₈H₆ClFO	详情	详情
(IV)	27905	N-isopropyl-N-phenylamine	768-52-5	C₉H₁₃N	详情	详情
(V)	11788	3-(4-Fluorophenyl)-1-isopropyl-1H-indole	93957-49-4	C₁₇H₁₆FN	详情	详情
(VI)	27906	(E)-3-(methylanilino)-2-propenal		C₁₀H₁₁NO	详情	详情
(VII)	11790	(E)-3-[3-(4-Fluorophenyl)-1-isopropyl-1H-indol-2-yl]-2-propenal		C₂₀H₁₈FNO	详情	详情
(VIII)	27907	Acetoacetic acid tert-butyl ester;3-Oxo-butanoic acid 1,1-dimethylethyl estertert-butyl 3-oxobutanoate	1694-31-1	C₈H₁₄O₃	详情	详情
(IX)	27908	tert-butyl (E)-7-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-5-hydroxy-3-oxo-6-heptenoate		C₂₈H₃₂FNO₄	详情	详情
(X)	27909	tert-butyl (3R,5S,6E)-7-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-3,5-dihydroxy-6-heptenoate		C₂₈H₃₄FNO₄	详情	详情

Extended Information