4-ethyl-3,5-dimethoxybenzaldehyde -Drug Synthesis Database

【结构式】

【分子编号】20754

【品名】4-ethyl-3,5-dimethoxybenzaldehyde

【CA登记号】

【分子式】C₁₁H₁₄O₃

【分子量】194.23036

【元素组成】C 68.02% H 7.27% O 24.71%

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：(I)

The reaction of benzaldehyde (I) with the sulfoxide (II) by means of benzyltrimethylammonium hydroxide in methanol gives the styrene derivative (III), which is hydrolyzed with HCl in methanol to the phenylacetate (IV). The condensation of (IV) with dimethyl oxalate by means of NaH in THF yields the succinate (V), which by reaction with formaldehyde and K2CO3 is converted into the acrylate (VI). The condensation of (VI) with ethyl 3-(methylamino)propionate gives intermediate (VII), which is cyclized by means of NaH in refluxing toluene yielding the piperidinone (IX). The condensation of (IX) with trimethyl phosphonoacetate (X) by means of NaH in THF affords the expected piperidinyleneacetate (XI), which is reduced with H2 over Pd/C in methanol giving the piperidinylacetate (XII). The cyclization of (XII) by means of polyphosphoric acid (PPA) in refluxing toluene yields the benzoisoquinoline (XIII), which is finally selectively demethylated with BBr3 in methylene chloride to the target compound.

参考文献中间体

合成目标

【1】 Stadler, H.; Bos, M.; Wichmann, J. (F. Hoffmann-La Roche AG); Tricyclic benzo[e]isoindoles and benzo[h]isoquinolines . EP 0958285; JP 2000507965; WO 9830546 .

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)	20754	4-ethyl-3,5-dimethoxybenzaldehyde		C₁₁H₁₄O₃	详情	详情
(II)	20766	methyl (methylsulfanyl)methyl sulfoxide; methyl[(methylsulfanyl)methyl]oxo-lambda(4)-sulfane	33577-16-1	C₃H₈OS₂	详情	详情
(III)	20767	methyl (Z)-2-(4-ethyl-3,5-dimethoxyphenyl)-1-(methylsulfanyl)-1-ethenesulfenate		C₁₄H₂₀O₃S₂	详情	详情
(IV)	20768	methyl 2-(4-ethyl-3,5-dimethoxyphenyl)acetate		C₁₃H₁₈O₄	详情	详情
(V)	20769	dimethyl 2-(4-ethyl-3,5-dimethoxyphenyl)-3-oxosuccinate		C₁₆H₂₀O₇	详情	详情
(VI)	20770	methyl 2-(4-ethyl-3,5-dimethoxyphenyl)acrylate		C₁₄H₁₈O₄	详情	详情
(VII)	20771	ethyl 3-(methylamino)propanoate		C₆H₁₃NO₂	详情	详情
(VIII)	20772	methyl 3-[(3-ethoxy-3-oxopropyl)(methyl)amino]-2-(4-ethyl-3,5-dimethoxyphenyl)propanoate		C₂₀H₃₁NO₆	详情	详情
(IX)	20773	3-(4-ethyl-3,5-dimethoxyphenyl)-1-methyl-4-piperidinone		C₁₆H₂₃NO₃	详情	详情
(X)	13272	Methyl 2-(dimethoxyphosphoryl)acetate; Trimethyl phosphoroacetate	5927-18-4	C₅H₁₁O₅P	详情	详情
(XI)	20775	methyl 2-[3-(4-ethyl-3,5-dimethoxyphenyl)-1-methyl-4-piperidinylidene]acetate		C₁₉H₂₇NO₄	详情	详情
(XII)	20776	methyl 2-[3-(4-ethyl-3,5-dimethoxyphenyl)-1-methyl-4-piperidinyl]acetate		C₁₉H₂₉NO₄	详情	详情
(XIII)	20777	(4aR,10bS)-8-ethyl-7,9-dimethoxy-2-methyl-1,3,4,4a,5,10b-hexahydrobenzo[h]isoquinolin-6(2H)-one		C₁₈H₂₅NO₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

The reaction of 4-ethyl-3,5-dimethoxybenzaldehyde (I) with (ethoxycarbonylmethyl)triphenylphosphonium bromide (II) by means o butyllithium in THF gives the acrylate (III), which is allowed to react with nitromethane/triton B in hot methanol yielding the 4-nitrobutyrate (IV). The reduction of (IV) with H2 over RaNi in ethanol affords the 4-aminobutyrate (V), which is cyclized to the pyrrolidinone (VI) by means of p-toluenesulfonic acid in refluxing ethanol. The methylation of (VI) with NaH/methyl iodide in THF gives the corresponding N-methylpyrrolidinone (VII), which is condensed with tert-butyl bromoacetate (VIII) by means of butyllithium/diisopropylamine in THF yielding the intermediate (IX). The reduction of the ketonic grupof (IX) with the complex borane/THF in THF affords the pyrrolidineacetate ester (X), which is cyclized by means of polyphosphoric acid (PPA) at 120 C giving the benzisoindole (XI). Finally, this compound is selectively demethylate by menas of BBr3 in dichloromethane.

参考文献中间体

合成目标

【1】 Stadler, H.; Bos, M.; Wichmann, J. (F. Hoffmann-La Roche AG); Tricyclic benzo[e]isoindoles and benzo[h]isoquinolines . EP 0958285; JP 2000507965; WO 9830546 .

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)	20754	4-ethyl-3,5-dimethoxybenzaldehyde		C₁₁H₁₄O₃	详情	详情
(II)	20755	(2-ethoxy-2-oxoethyl)(triphenyl)phosphonium bromide	1530-45-6	C₂₂H₂₂BrO₂P	详情	详情
(III)	20756	ethyl (E)-3-(4-ethyl-3,5-dimethoxyphenyl)-2-propenoate		C₁₅H₂₀O₄	详情	详情
(IV)	20757	ethyl 3-(4-ethyl-3,5-dimethoxyphenyl)-4-nitrobutanoate		C₁₆H₂₃NO₆	详情	详情
(V)	20758	ethyl 4-amino-3-(4-ethyl-3,5-dimethoxyphenyl)butanoate		C₁₆H₂₅NO₄	详情	详情
(VI)	20759	4-(4-ethyl-3,5-dimethoxyphenyl)-2-pyrrolidinone		C₁₄H₁₉NO₃	详情	详情
(VII)	20760	4-(4-ethyl-3,5-dimethoxyphenyl)-1-methyl-2-pyrrolidinone		C₁₅H₂₁NO₃	详情	详情
(VIII)	17430	2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate	5292-43-3	C₆H₁₁BrO₂	详情	详情
(IX)	20762	tert-butyl 2-[4-(4-ethyl-3,5-dimethoxyphenyl)-1-methyl-2-oxo-3-pyrrolidinyl]acetate		C₂₁H₃₁NO₅	详情	详情
(X)	20763	tert-butyl 2-[4-(4-ethyl-3,5-dimethoxyphenyl)-1-methyl-3-pyrrolidinyl]acetate		C₂₁H₃₃NO₄	详情	详情
(XI)	20764	(3aS,9bS)-7-ethyl-6,8-dimethoxy-2-methyl-1,2,3,3a,4,9b-hexahydro-5H-benzo[e]isoindol-5-one		C₁₇H₂₃NO₃	详情	详情

Extended Information