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【结 构 式】 
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【分子编号】24142 【品名】4-bromo-2-thiophenecarbaldehyde 【CA登记号】18791-75-8 |
【 分 子 式 】C5H3BrOS 【 分 子 量 】191.04822 【元素组成】C 31.43% H 1.58% Br 41.82% O 8.37% S 16.78% |
合成路线1
该中间体在本合成路线中的序号：(I)The reaction of 4-bromo-2-thiophienecarboxaldehyde (I) with imidazole yields 4-(1H-imidazol-1-yl)-2 thiophenecarboxaldehyde (II), which by cyanide-catalyzed conjugate addition to 2-butenenitrile (III) in DMF is converted to 4-[4-(1H-imidazol-1-yl)-2-thienyl]-3-methyl-4-oxobutyronitrile (IV). Hydrolysis of (IV) in refluxing 4N HCl gives 4-[4-(1H imidazol-1-yl)-2-thienyl-4 oxobutanoic acid (V), which is finally cyclized with hydrazine in refluxing water to afford motapizone.
| 【1】 Borbe, H.; Doppelfeld, I.-S.; Hilboll, G.; Lohr, J.P.; Prop, G. (A. Nattermann & Cie. GmbH); Imidazolylalkylthienyl tetrahydropyridazines and processes for their use. DE 3241102; EP 0112987; US 4644998 . |
| 【2】 Prop, G.; Hilboll, G.; Borbe, H.O.; Motapizone. Drugs Fut 1986, 11, 1, 24. |
| 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) | 24142 | 4-bromo-2-thiophenecarbaldehyde | 18791-75-8 | C5H3BrOS | 详情 | 详情 |
| (II) | 24143 | 4-(1H-Imidazol-1-yl)-2-thiophenecarbaldehyde; 4-(1H-Imidazol-1-yl)-2 thiophenecarboxaldehyde | C8H6N2OS | 详情 | 详情 | |
| (III) | 24144 | (E)-2-butenenitrile | 4786-20-3 | C4H5N | 详情 | 详情 |
| (IV) | 24145 | 4-[4-(1H-imidazol-1-yl)-2-thienyl]-3-methyl-4-oxobutanenitrile | C12H11N3OS | 详情 | 详情 | |
| (V) | 24146 | 4-[4-(1H-imidazol-1-yl)-2-thienyl]-3-methyl-4-oxobutyric acid | C12H12N2O3S | 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-bromothiophene-2-carbaldehyde (I) with triethyl orthoformate gives the corresponding acetal (II), which is treated with NaOMe, CuO and KI in hot methanol yielding 5-methoxythiophene-2-carbaldehyde diethylacetal (III). The hydrolysis of (III) with HCl in methanol affords the carbaldehyde (IV), which is condensed with the phosphonate (V) by means of NaH in THF to provide the ethyl acrylate (VI). The hydrolysis of (VI) with KOH in methanol gives the acrylic acid (VII), which is esterified with 4-nitrophenol, TEA and 2-chloro-1-methylpyridinium iodide in dichloromethane yielding the activate ester (VIII). The condensation of (VIII) with the tetracyclic ketone (IX) (obtained by treatment of the dimeric ketonic compound (X) with NaOMe in methanol) affords the adduct (XI), which is treated with HBr in acetonitrile to open the cyclopropane ring and provide the bromomethyl compound (XII). The aromatization of (XII) with p-nitrophenyl chloroformate (XIII) and TEA in dichloromethane affords the activated carbonate ester (XIV), which is finally treated with 1-methylpiperazine (XV) to furnish the target carbamate.
| 【1】 Saito, H.; Kobayashi, E.; Gomi, K.; Okamoto, A.; Nagamura, S.; Amishiro, N.; Synthesis and antitumor activity of duocarmycin derivatives: A-ring pyrrole compounds bearing 5-membered heteroarylacryloyl groups. Chem Pharm Bull 1999, 47, 10, 1393. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11236 | 4-Nitrophenol; p-Nitrophenol | 100-02-7 | C6H5NO3 | 详情 | 详情 | |
| (I) | 24142 | 4-bromo-2-thiophenecarbaldehyde | 18791-75-8 | C5H3BrOS | 详情 | 详情 |
| (II) | 38358 | (4-bromo-2-thienyl)(ethoxy)methyl ethyl ether; 4-bromo-2-(diethoxymethyl)thiophene | C9H13BrO2S | 详情 | 详情 | |
| (III) | 38359 | 5-(diethoxymethyl)-3-thienyl methyl ether; 2-(diethoxymethyl)-4-methoxythiophene | C10H16O3S | 详情 | 详情 | |
| (IV) | 35360 | C47H75N3O14 | 详情 | 详情 | ||
| (V) | 38361 | ethyl 2-(dimethoxyphosphoryl)acetate | C6H13O5P | 详情 | 详情 | |
| (VI) | 38362 | ethyl (E)-3-(4-methoxy-2-thienyl)-2-propenoate | C10H12O3S | 详情 | 详情 | |
| (VII) | 38363 | (E)-3-(4-methoxy-2-thienyl)-2-propenoic acid | C8H8O3S | 详情 | 详情 | |
| (VIII) | 38364 | 4-nitrophenyl (E)-3-(4-methoxy-2-thienyl)-2-propenoate | C14H11NO5S | 详情 | 详情 | |
| (IX) | 38365 | methyl (3bR,4aS)-2-methyl-8-oxo-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate | C14H14N2O3 | 详情 | 详情 | |
| (X) | 38366 | methyl (2R,3bR,4aS)-2-methyl-3,8-dioxo-6-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-1,2,3,4,4a,5,6,8-octahydrocyclopropa[c]pyrrolo[3,2-e]indole-2-carboxylate | C26H25N3O8 | 详情 | 详情 | |
| (XI) | 38367 | methyl (3bR,4aS)-6-[(E)-3-(4-methoxy-2-thienyl)-2-propenoyl]-2-methyl-8-oxo-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate | C22H20N2O5S | 详情 | 详情 | |
| (XII) | 38368 | methyl (8S)-8-(bromomethyl)-6-[(E)-3-(4-methoxy-2-thienyl)-2-propenoyl]-2-methyl-4-oxo-3,4,6,7,8,8a-hexahydropyrrolo[3,2-e]indole-1-carboxylate | C22H21BrN2O5S | 详情 | 详情 | |
| (XIII) | 16605 | 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene | 7693-46-1 | C7H4ClNO4 | 详情 | 详情 |
| (XIV) | 38369 | methyl (8S)-8-(bromomethyl)-6-[(E)-3-(4-methoxy-2-thienyl)-2-propenoyl]-2-methyl-4-[[(4-nitrophenoxy)carbonyl]oxy]-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate | C29H24BrN3O9S | 详情 | 详情 | |
| (XV) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Jones oxidation of 4-bromothiophene-2-carbaldehyde (I) leads to acid (II), which is further esterified with H2SO4/MeOH to furnish methyl 4-bromothiophene-2-carboxylate (III). Subsequent Heck coupling of aryl bromide (III) with cyclohexylammonium acrylate (IV) gives rise to the thienylacrylic acid (V). Cyclization of (V) with SOCl2 in the presence of pyridine produces the thienothiophene derivative (VI). Acid chloride (VI) is then coupled to N-(dimethylaminopropyl)aniline (VII) under Schotten-Baumann conditions, yielding amide (VIII). Finally, photochemical cyclization of (VIII) affords the target tetracyclic compound.
| 【1】 DoganKoruznjak, J.; Slade, N.; Zamola, B.; Pavelic, K.; Karminski-Zamola, G.; Synthesis, photochemical synthesis and antitumor evaluation of novel derivatives of thieno[3',2':4,5]thieno[2,3-c]quinolones. Chem Pharm Bull 2002, 50, 5, 656. |
| 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) | 24142 | 4-bromo-2-thiophenecarbaldehyde | 18791-75-8 | C5H3BrOS | 详情 | 详情 |
| (II) | 64296 | 4-bromo-2-thiophenecarboxylic acid | C5H3BrO2S | 详情 | 详情 | |
| (III) | 64297 | methyl 4-bromo-2-thiophenecarboxylate | C6H5BrO2S | 详情 | 详情 | |
| (IV) | 19139 | acrylic acid | 79-10-7 | C3H4O2 | 详情 | 详情 |
| (V) | 64298 | (E)-3-[5-(methoxycarbonyl)-3-thienyl]-2-propenoic acid | C9H8O4S | 详情 | 详情 | |
| (VI) | 64299 | methyl 4-chloro-5-(chlorocarbonyl)thieno[2,3-b]thiophene-2-carboxylate | C9H4Cl2O3S2 | 详情 | 详情 | |
| (VII) | 64300 | N-(3-anilinopropyl)-N,N-dimethylamine; N~1~,N~1~-dimethyl-N~3~-phenyl-1,3-propanediamine | C11H18N2 | 详情 | 详情 | |
| (VIII) | 64301 | methyl 4-chloro-5-({[3-(dimethylamino)propyl]anilino}carbonyl)thieno[2,3-b]thiophene-2-carboxylate | C20H21ClN2O3S2 | 详情 | 详情 |