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【结 构 式】 
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【分子编号】25578 【品名】1-benzothiophene 【CA登记号】95-15-8 |
【 分 子 式 】C8H6S 【 分 子 量 】134.20164 【元素组成】C 71.6% H 4.51% S 23.89% |
合成路线1
该中间体在本合成路线中的序号：(I)3-(Chloromethyl)benzothiophene (II) was prepared by condensation of benzothiophene (I) with paraformaldehyde in the presence of HCl. Subsequent treatment of (II) with KCN produced nitrile (III). This was condensed with pyridine-4-carboxaldehyde (IV) to yield adduct (V). Oxidative photochemical cyclization of (V) furnished the benzothienoisoquinoline tetracyclic system (VI). Hydrolysis of the nitrile group of (VI) to carboxylic acid (VII) was achieved by treatment with KOH in hot glycerol. After conversion of (VII) to methyl ester (VIII), displacement by hydrazine gave rise to hydrazide (IX). Nitrosation of (IX), followed by rearrangement of the resulting acyl azide produced an intermediate isocyanate, that was further converted to ethyl carbamate (X) in boiling EtOH. Alternatively, Curtius rearrangement of carboxylic acid (VII) upon treatment with diphenylphosphoryl azide, and further reaction with tert-butanol furnished tert-butyl carbamate (XI). The title amine was then obtained by either hydrolysis of ethyl carbamate (X) with KOH or by trifluoroacetic acid promoted cleavage of carbamate (XI).
| 【1】 Reist, E.J. (SRI International); Novel benzothiophene analogs as antiviral agents. EP 0712404; JP 1997500386; US 5424315; WO 9504059 . |
| 【2】 Smee, D.F.; Zaveri, N.; Sidwell, R.W.; Reist, E.; Huffman, J.H.; Bradford, W.W.; Benzthieno[3,2-h]isoquinolines as novel nonnucleoside inhibitors of human cytomegalovirus. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 130. |
| 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) | 25578 | 1-benzothiophene | 95-15-8 | C8H6S | 详情 | 详情 |
| (II) | 40956 | 3-(chloromethyl)-1-benzothiophene | C9H7ClS | 详情 | 详情 | |
| (III) | 40957 | 2-(1-benzothiophen-3-yl)acetonitrile | 3216-48-6 | C10H7NS | 详情 | 详情 |
| (IV) | 17203 | 4-Pyridinecarboxaldehyde; isonicotinaldehyde | 872-85-5 | C6H5NO | 详情 | 详情 |
| (V) | 40958 | (E)-2-(1-benzothiophen-3-yl)-3-(4-pyridinyl)-2-propenenitrile | C16H10N2S | 详情 | 详情 | |
| (VI) | 40959 | [1]benzothieno[3,2-h]isoquinoline-6-carbonitrile | C16H8N2S | 详情 | 详情 | |
| (VII) | 40960 | [1]benzothieno[3,2-h]isoquinoline-6-carboxylic acid | C16H9NO2S | 详情 | 详情 | |
| (VIII) | 40961 | methyl [1]benzothieno[3,2-h]isoquinoline-6-carboxylate | C17H11NO2S | 详情 | 详情 | |
| (IX) | 40962 | [1]benzothieno[3,2-h]isoquinoline-6-carbohydrazide | C16H11N3OS | 详情 | 详情 | |
| (X) | 40963 | ethyl [1]benzothieno[3,2-h]isoquinolin-6-ylcarbamate | C18H14N2O2S | 详情 | 详情 | |
| (XI) | 40964 | tert-butyl [1]benzothieno[3,2-h]isoquinolin-6-ylcarbamate | C20H18N2O2S | 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-(Chloromethyl)benzothiophene (II) was prepared by condensation of benzothiophene (I) with paraformaldehyde in the presence of HCl. Subsequent treatment of (II) with KCN produced nitrile (III). This was condensed with pyridine-4-carboxaldehyde (IV) to yield adduct (V). Oxidative photochemical cyclization of (V) furnished the benzothienoisoquinoline tetracyclic system (VI). Hydrolysis of the nitrile grroup of (VI) to carboxylic acid (VII) was achieved by treatment with KOH in hot glycerol. After conversion of (VII) to methyl ester (VIII), displacement by hydrazine gave rise to hydrazide (IX). Nitrosation of (IX), followed by rearrangement of the resulting acyl azide produced an intermediate isocyanate, that was further converted to ethyl carbamate (X) in boiling EtOH. Alternatively, Curtius rearrangement of carboxylic acid (VII) upon treatment with diphenylphosphoryl azide, and further reaction with tert-butanol furnished tert-butyl carbamate (XI). Amine (XII) was obtained by either hydrolysis of ethyl carbamate (X) with KOH or by trifluoroacetic acid promoted cleavage of carbamate (XI). Finally, acylation of (XII) with trifluoroacetic anhydride furnished the title trifluoroacetamide.
| 【1】 Reist, E.J. (SRI International); Novel benzothiophene analogs as antiviral agents. EP 0712404; JP 1997500386; US 5424315; WO 9504059 . |
| 【2】 Smee, D.F.; Zaveri, N.; Sidwell, R.W.; Reist, E.; Huffman, J.H.; Bradford, W.W.; Benzthieno[3,2-h]isoquinolines as novel nonnucleoside inhibitors of human cytomegalovirus. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 130. |
| 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) | 25578 | 1-benzothiophene | 95-15-8 | C8H6S | 详情 | 详情 |
| (II) | 40956 | 3-(chloromethyl)-1-benzothiophene | C9H7ClS | 详情 | 详情 | |
| (III) | 40957 | 2-(1-benzothiophen-3-yl)acetonitrile | 3216-48-6 | C10H7NS | 详情 | 详情 |
| (IV) | 17203 | 4-Pyridinecarboxaldehyde; isonicotinaldehyde | 872-85-5 | C6H5NO | 详情 | 详情 |
| (V) | 40958 | (E)-2-(1-benzothiophen-3-yl)-3-(4-pyridinyl)-2-propenenitrile | C16H10N2S | 详情 | 详情 | |
| (VI) | 40959 | [1]benzothieno[3,2-h]isoquinoline-6-carbonitrile | C16H8N2S | 详情 | 详情 | |
| (VII) | 40960 | [1]benzothieno[3,2-h]isoquinoline-6-carboxylic acid | C16H9NO2S | 详情 | 详情 | |
| (VIII) | 40961 | methyl [1]benzothieno[3,2-h]isoquinoline-6-carboxylate | C17H11NO2S | 详情 | 详情 | |
| (IX) | 40962 | [1]benzothieno[3,2-h]isoquinoline-6-carbohydrazide | C16H11N3OS | 详情 | 详情 | |
| (X) | 40963 | ethyl [1]benzothieno[3,2-h]isoquinolin-6-ylcarbamate | C18H14N2O2S | 详情 | 详情 | |
| (XI) | 40964 | tert-butyl [1]benzothieno[3,2-h]isoquinolin-6-ylcarbamate | C20H18N2O2S | 详情 | 详情 | |
| (XII) | 40965 | [1]benzothieno[3,2-h]isoquinolin-6-ylamine; [1]benzothieno[3,2-h]isoquinolin-6-amine | C15H10N2S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)The reaction of benzo[b]thiophene (I) with triethyl borate by means of butyllithium gives benzo[b]thiophene-2-boronic acid diethyl ester (II), which is hydrolyzed to the target compound in acidic medium.
合成路线4
该中间体在本合成路线中的序号：(III)Oxidation of 2,3-dimethylfuran (I) under Vilsmeier conditions with POCl3 in DMF affords aldehyde (II), which is then condensed with benzothiophene (III) by means of n-BuLi in THF to provide secondary alcohol (IV). Reduction of (IV) under Nutaitis conditions with NaBH4 and TFA in THF yields methylene congener (V), which is then treated with p-anisoyl chloride (VI) under Friedel-Crafts conditions with SnCl4 in CS2 to give 1-oxa-9-thiacyclopenta[b]fluorene heterocycle (VII). Demethylation of methyl ether (VII) with BBr3 in CH2Cl2 affords phenol (VIII), which is then bis-iodinated with molecular iodine and NaOH in MeOH to yield di-iodo phenol (IX). Compound (IX) is then condensed with (S)-2-hydroxy-3-phenylpropionic acid (X) under Mitsunobu conditions with DEAD and PPh3 in benzene to furnish (R)-2-benzyl-acetic acid derivative (XI), which is finally hydrolyzed by treatment with KOH in H2O/dioxane to provide the desired product.
| 【1】 Sredy, j.; Seesteller, L.; Li, Z.; Sawicki, D.R.; Wrobel, J.; Sullivan, D.; Synthesis and PTP1B inhibition of novel 4-aryl-1-oxa-9-thiacyclopenta[b]fluorenes. Bioorg Med Chem Lett 2000, 10, 14, 1535. |
| 【2】 Li, Z.; Wrobel, J.E. (American Home Products Corp.); 4-Aryl-1-oxa-9-thia-cyclopenta[b]fluorenes. US 6057316 . |
| 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) | 48451 | 2,3-Dimethylfuran | 14920-89-9 | C6H8O | 详情 | 详情 |
| (II) | 48452 | 4,5-Dimethyl-2-furaldehyde; 4,5-Dimethylfurfural | C7H8O2 | 详情 | 详情 | |
| (III) | 25578 | 1-benzothiophene | 95-15-8 | C8H6S | 详情 | 详情 |
| (IV) | 48453 | 1-benzothiophen-2-yl(4,5-dimethyl-2-furyl)methanol | C15H14O2S | 详情 | 详情 | |
| (V) | 48454 | 5-(1-benzothiophen-2-ylmethyl)-2,3-dimethylfuran | C15H14OS | 详情 | 详情 | |
| (VI) | 22671 | 4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride | 100-07-2 | C8H7ClO2 | 详情 | 详情 |
| (VII) | 48455 | 4-(2,3-dimethyl[1]benzothieno[3,2-f][1]benzofuran-4-yl)phenyl methyl ether; 4-(4-methoxyphenyl)-2,3-dimethyl[1]benzothieno[3,2-f][1]benzofuran | C23H18O2S | 详情 | 详情 | |
| (VIII) | 48456 | 4-(2,3-dimethyl[1]benzothieno[3,2-f][1]benzofuran-4-yl)phenol | C22H16O2S | 详情 | 详情 | |
| (IX) | 48457 | 4-(2,3-dimethyl[1]benzothieno[3,2-f][1]benzofuran-4-yl)-2,6-diiodophenol | C22H14I2O2S | 详情 | 详情 | |
| (X) | 39252 | methyl (2S)-2-hydroxy-3-phenylpropanoate | C10H12O3 | 详情 | 详情 | |
| (XI) | 48458 | methyl (2R)-2-[4-(2,3-dimethyl[1]benzothieno[3,2-f][1]benzofuran-4-yl)-2,6-diiodophenoxy]-3-phenylpropanoate | C32H24I2O4S | 详情 | 详情 |