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【结 构 式】 
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【分子编号】10966 【品名】3-(Benzyloxy)-4-methoxybenzaldehyde; 3-Benzyloxy-4-methoxybenzaldehyde 【CA登记号】6346-05-0 |
【 分 子 式 】C15H14O3 【 分 子 量 】242.27436 【元素组成】C 74.36% H 5.82% O 19.81% |
合成路线1
该中间体在本合成路线中的序号：(I)The enantioselective synthesis of the (R)-enantiomer of rolipram, which is the most active, has been published: The reaction of 3-benzyloxy-4-methoxybenzaldehyde (I) with nitromethane by means of ammonium acetate in refluxing acetic acid gives 3-benzyloxy-4-methoxy-beta-nitrostyrene (II), which is condensed with the chiral oxazolidinone (R)-3-acetyl-4-benzyl-2-oxazolidinone (III) by means of sodium bis(trimethylsilyl)amine in THF yielding 4(R)-benzyl-3-[3(R)-(3-benzyloxy-4-methoxyphenyl)-4-nitrobutyryl]-2-oxa zolidinone (IV). Hydrogenation of (IV) with H2 over Raney Ni in ethanol - ethyl acetate affords 4(R)-(3-hydroxy-4-methoxyphenyl)-2-pyrrolidinone (VI) through the intermediate benzyl ether (V). Finally, compound (VI) is etherified with cyclopentyl bromide (VII) by means of NaH in refluxing THF.
| 【1】 Schmiechen, R.; Mulzer, J.; Zuhse, R.; Enantioselective synthesis of the antidepressant rolipram by Michael addition to a nitroolefin. Angew Chem. Int Ed Engl 1992, 31, 7, 870. |
| 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) | 10966 | 3-(Benzyloxy)-4-methoxybenzaldehyde; 3-Benzyloxy-4-methoxybenzaldehyde | 6346-05-0 | C15H14O3 | 详情 | 详情 |
| (II) | 10967 | trans-3-Benzyloxy-4-methoxy-beta-nitrostyrene; Benzyl 2-methoxy-5-[(E)-2-nitroethenyl]phenyl ether; 2-(Benzyloxy)-1-methoxy-4-[(E)-2-nitroethenyl]benzene | 63909-29-5 | C16H15NO4 | 详情 | 详情 |
| (III) | 10968 | (4R)-3-Acetyl-4-benzyl-1,3-oxazolidin-2-one; (R)-(-)-3-Acetyl-4-benzyl-2-oxazolidinone | 184363-65-3 | C12H13NO3 | 详情 | 详情 |
| (IV) | 10969 | (4R)-4-Benzyl-3-[(3S)-3-[3-(benzyloxy)-4-methoxyphenyl]-4-nitrobutanoyl]-1,3-oxazolidin-2-one | C28H28N2O7 | 详情 | 详情 | |
| (V) | 10970 | (4R)-4-[3-(Benzyloxy)-4-methoxyphenyl]-2-pyrrolidinone | C18H19NO3 | 详情 | 详情 | |
| (VI) | 10971 | (4R)-4-(3-Hydroxy-4-methoxyphenyl)tetrahydro-2H-pyrrol-2-one | C11H13NO3 | 详情 | 详情 | |
| (VII) | 10972 | 1-Bromocyclopentane; Cyclopentyl bromide | 137-43-9 | C5H9Br | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)3-Benzyloxy-4-methoxybenzaldehyde (I) was reduced to benzyl alcohol (II) with NaBH4, and then converted into bromide (III) using Me3SiBr. Alkylation of 4-(R)-benzyl-3-isovaleroyl-oxazolidinone (IV) with bromide (III) in the presence of lithium hexamethyldisilazide in THF at -70 C produced the (R,R) diastereoisomer (V). Then, hydrolysis of (V) with lithium hydroperoxide gave the (R)-acid (VI), which was reduced to alcohol (VII) by means of NaBH4 and I2. The reation of (VII) with NBS and PPh3 yielded bromide (VIII), which was condensed with dihydropyrazine (IX) in the presence of BuLi to give compound (X) as the major diastereoisomer. Subsequent acid hydrolysis of the dihydropyrazine (X) provided aminoester (XI), which was protected as the tert-butyl carbamate (XII) with Boc2O and DIEA. The carboxylate group of (XII) was reduced to aldehyde (XIII) with DIBAL-H in cold toluene. This aldehyde (XIII) was condensed with N-butyl methacrylamide (XIV) in the presence of butyllithium and chlorotitanium triisopropoxide at -75 C to give a mixture of diastereoisomeric aminoalcohols, from which the major threo compound (XV) was isolated by column chromatography.
| 【1】 Rasetti, V.; Wood, J.; Grütter, M.; Maibaum, J.; Goeschke, R.; Cohen, N.C.; Fuhrer, W.; Rahuel, J.; Stutz, S.; Novel 2,7-dialkyl substituted 5(S)-amino-4(S)-hydr. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.229. |
| 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) | 10966 | 3-(Benzyloxy)-4-methoxybenzaldehyde; 3-Benzyloxy-4-methoxybenzaldehyde | 6346-05-0 | C15H14O3 | 详情 | 详情 |
| (II) | 23283 | [3-(benzyloxy)-4-methoxyphenyl]methanol | C15H16O3 | 详情 | 详情 | |
| (III) | 23284 | 2-(benzyloxy)-4-(bromomethyl)-1-methoxybenzene; benzyl 5-(bromomethyl)-2-methoxyphenyl ether | C15H15BrO2 | 详情 | 详情 | |
| (IV) | 23285 | (4R)-4-benzyl-3-(3-methylbutanoyl)-1,3-oxazolidin-2-one | C15H19NO3 | 详情 | 详情 | |
| (V) | 23286 | (4R)-4-benzyl-3-[(2R)-2-[3-(benzyloxy)-4-methoxybenzyl]-3-methylbutanoyl]-1,3-oxazolidin-2-one | C30H33NO5 | 详情 | 详情 | |
| (VI) | 23287 | (2R)-2-[3-(benzyloxy)-4-methoxybenzyl]-3-methylbutyric acid | C20H24O4 | 详情 | 详情 | |
| (VII) | 23288 | (2R)-2-[3-(benzyloxy)-4-methoxybenzyl]-3-methyl-1-butanol | C20H26O3 | 详情 | 详情 | |
| (VIII) | 23289 | benzyl 5-[(2R)-2-(bromomethyl)-3-methylbutyl]-2-methoxyphenyl ether; 2-(benzyloxy)-4-[(2R)-2-(bromomethyl)-3-methylbutyl]-1-methoxybenzene | C20H25BrO2 | 详情 | 详情 | |
| (IX) | 10291 | (S)-2,5-Dihydro-3,6-dimethoxy-2-isopropylpyrazine; (2S)-2-Isopropyl-3,6-dimethoxy-2,5-dihydropyrazine; (3S)-3-Isopropyl-5-methoxy-3,6-dihydro-2-pyrazinyl methyl ether | 78342-42-4 | C9H16N2O2 | 详情 | 详情 |
| (X) | 23291 | benzyl 5-((2S)-2-[[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydro-2-pyrazinyl]methyl]-3-methylbutyl)-2-methoxyphenyl ether; (2S,5R)-2-[(2S)-2-[3-(benzyloxy)-4-methoxybenzyl]-3-methylbutyl]-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine | C29H40N2O4 | 详情 | 详情 | |
| (XI) | 23292 | methyl (2S,4S)-2-amino-4-[3-(benzyloxy)-4-methoxybenzyl]-5-methylhexanoate | C23H31NO4 | 详情 | 详情 | |
| (XII) | 23293 | methyl (2S,4S)-4-[3-(benzyloxy)-4-methoxybenzyl]-2-[(tert-butoxycarbonyl)amino]-5-methylhexanoate | C28H39NO6 | 详情 | 详情 | |
| (XIII) | 23294 | tert-butyl (1S,3S)-3-[3-(benzyloxy)-4-methoxybenzyl]-1-formyl-4-methylpentylcarbamate | C27H37NO5 | 详情 | 详情 | |
| (XIV) | 23295 | N-butyl-2-methylacrylamide | C8H15NO | 详情 | 详情 | |
| (XV) | 23296 | tert-butyl (1S,2S)-1-[(2S)-2-[3-(benzyloxy)-4-methoxybenzyl]-3-methylbutyl]-4-[(butylamino)carbonyl]-2-hydroxy-4-pentenylcarbamate | C35H52N2O6 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XII)In an alternative procedure, isovanillin (XI) was protected by O-benzylation, giving (XII), and its aldehyde group was subsequently reduced to alcohol (XIII) with NaBH4. The benzylic alcohol (XIII) was chlorinated to (XIV), which was converted to nitrile (XV) by chloride displacement with tetraethylammonium cyanide. Nitrile (XV) was subjected to Claisen condensation with ethyl formate, yielding (XVI), followed by sulfonylation with benzenesulfonyl chloride to afford (XVII), which was cyclized to the amino thiophene (XVIII) by treatment with ethyl thioglycolate (IV) as above. Condensation of (XVIII) with 2,5-dimethoxytetrahydrofuran (VI) produced the corresponding pyrrole derivative (XIX). After conversion of the ester group of (XIX) to amide (XX) upon heating with pyrrolidine (VIII), its cyclization with POCl3 furnished the thienopyrrolizinone (XXI). The O-benzyl protecting group of (XXI) was finally cleaved by treatment with HBr in HOAc.
| 【1】 Lisowski, V.; et al.; Design, synthesis and antiproliferative activity of tripentones: A new series of antitubulin agents. Bioorg Med Chem Lett 2001, 11, 16, 2205. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 18838 | methyl 2-sulfanylacetate | 2365-48-2 | C3H6O2S | 详情 | 详情 |
| (VI) | 12121 | (Z)-4-(Dimethylamino)-3-imidazo[1,2-a]pyridin-6-yl-3-buten-2-one | C13H15N3O | 详情 | 详情 | |
| (VIII) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (XI) | 18455 | 3-hydroxy-4-methoxybenzaldehyde; Isovanillin | 621-59-0 | C8H8O3 | 详情 | 详情 |
| (XII) | 10966 | 3-(Benzyloxy)-4-methoxybenzaldehyde; 3-Benzyloxy-4-methoxybenzaldehyde | 6346-05-0 | C15H14O3 | 详情 | 详情 |
| (XIII) | 23823 | 5-[4-hydroxy-2-(3-hydroxybutyl)-3,5,6-trimethylphenoxy]-2,2-dimethylpentanoic acid | C20H32O5 | 详情 | 详情 | |
| (XIV) | 52232 | benzyl 5-(chloromethyl)-2-methoxyphenyl ether; 2-(benzyloxy)-4-(chloromethyl)-1-methoxybenzene | C15H15ClO2 | 详情 | 详情 | |
| (XV) | 52233 | (3-Benzyloxy-4-methoxyphenyl)acetonitrile | C16H15NO2 | 详情 | 详情 | |
| (XVI) | 52234 | sodium (Z)-2-[3-(benzyloxy)-4-methoxyphenyl]-2-cyano-1-ethenolate | C17H14NNaO3 | 详情 | 详情 | |
| (XVII) | 52235 | (Z)-2-[3-(benzyloxy)-4-methoxyphenyl]-2-cyanoethenyl benzenesulfonate | C23H19NO5S | 详情 | 详情 | |
| (XVIII) | 52236 | methyl 3-amino-4-[3-(benzyloxy)-4-methoxyphenyl]-2-thiophenecarboxylate | C20H19NO4S | 详情 | 详情 | |
| (XIX) | 52234 | sodium (Z)-2-[3-(benzyloxy)-4-methoxyphenyl]-2-cyano-1-ethenolate | C17H14NNaO3 | 详情 | 详情 | |
| (XX) | 52238 | [4-[3-(benzyloxy)-4-methoxyphenyl]-3-(1H-pyrrol-1-yl)-2-thienyl](1-pyrrolidinyl)methanone | C27H26N2O3S | 详情 | 详情 | |
| (XXI) | 52239 | 3-[3-(benzyloxy)-4-methoxyphenyl]-8H-thieno[2,3-b]pyrrolizin-8-one | C23H17NO3S | 详情 | 详情 |