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【结 构 式】 
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【分子编号】11303 【品名】(E)-3-Phenyl-2-propenoyl chloride; 3-Phenyl-2-propenoyl chloride 【CA登记号】102-92-1 |
【 分 子 式 】C9H7ClO 【 分 子 量 】166.60668 【元素组成】C 64.88% H 4.23% Cl 21.28% O 9.6% |
合成路线1
该中间体在本合成路线中的序号：(IX)This compound can be prepared by two similar ways: 1) The monoacylation of ethylene glycol (I) with chloroacetyl chloride (II) and triethylamine gives 2-hydroxyethyl chloroacetate (III), which is condensed with saccharine (IV) by means of NaOH in ethylene glycol yielding 2-hydroxyethyl 3-oxo-1,2-benzisothiazoline-2-acetate 1,1-dioxide (V). Isomerization of (V) by means of potassium tert-butoxide in DMSO affords2-hydroxyethyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (VI), which is methylated with NaOH and methyl iodide in aqueous ethanol giving the corresponding N-methyl derivative (VII). Hydrolysis of (VII) with NaOH in ethanol - water yields the corresponding free acid (VIII), which is acylated with cinnamoyl chloride (IX) by means of triethylamine in dichloromethane to afford the biscinnamoyl derivative (X). Finally, this compound is treated with 2-aminopyridine (XI) in dichloromethane. 2) The preceding sequence can also be carried out with cyclohexanol (XII) instead of ethylene glycol (I), then producing compounds (XIII), (XIV), (XV) and (XVI), which by hydrolysis affords the free acid (VIII).
| 【1】 Bruzzese, T.; Dell'Acqua, E.; Ottonni, F.; Van den Heuvel, H.H. (SPA (Societa Prodotti Antibiotici)); Process for preparing benzothiazine compds. EP 0146102 . |
| 【2】 Prous, J.; Castaner, J.; CINNOXICAM. Drugs Fut 1990, 15, 2, 119. |
| 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) | 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 |
| (II) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (III) | 11297 | 2-hydroxyethyl 2-chloroacetate | C4H7ClO3 | 详情 | 详情 | |
| (IV) | 11298 | 1H-1,2-Benzisothiazole-1,1,3(2H)-trione; Saccharin | 81-07-2 | C7H5NO3S | 详情 | 详情 |
| (V) | 11299 | 2-hydroxyethyl 2-(1,1,3-trioxo-1,3-dihydro-2H-1,2-benzisothiazol-2-yl)acetate | C11H11NO6S | 详情 | 详情 | |
| (VI) | 11300 | 2-hydroxyethyl 4-hydroxy-1,1-dioxo-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate | C11H11NO6S | 详情 | 详情 | |
| (VII) | 11301 | 2-hydroxyethyl 4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate | C12H13NO6S | 详情 | 详情 | |
| (VIII) | 11302 | 4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylic acid | C10H9NO5S | 详情 | 详情 | |
| (IX) | 11303 | (E)-3-Phenyl-2-propenoyl chloride; 3-Phenyl-2-propenoyl chloride | 102-92-1 | C9H7ClO | 详情 | 详情 |
| (X) | 11304 | 2-Methyl-1,1-dioxo-4-[[(E)-3-phenyl-2-propenoyl]oxy]-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylic (E)-2-phenyl-2-propenoic anhydride | C28H21NO7S | 详情 | 详情 | |
| (XI) | 11305 | 2-Pyridinamine; 2-Pyridinylamine; 2-Aminopyridine | 504-29-0 | C5H6N2 | 详情 | 详情 |
| (XII) | 11306 | Cyclohexanol | 108-93-0 | C6H12O | 详情 | 详情 |
| (XIII) | 11307 | cyclohexyl 2-chloroacetate | C8H13ClO2 | 详情 | 详情 | |
| (XIV) | 11308 | cyclohexyl 2-(1,1,3-trioxo-1,3-dihydro-2H-1,2-benzisothiazol-2-yl)acetate | C15H17NO5S | 详情 | 详情 | |
| (XV) | 11309 | cyclohexyl 4-hydroxy-1,1-dioxo-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate | C15H17NO5S | 详情 | 详情 | |
| (XVI) | 11310 | cyclohexyl 4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate | C16H19NO5S | 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 condensation of sodium saccharin (I) with tert-butyl chloroacetate (II) in hot DMF gives the benzoisothiazolin-acetic ester (III), which is rearranged by means of potassium tert-butoxide in THF to yield 4-hydroxy-2H-1,2-benzothiazine-3-carboxylic acid tert-butyl ester 1,1-dioxide (IV). The methylation of (IV) with dimethyl sulfate and NaOH in water affords the 2-methyl derivative (V), which is acylated with cinnamoyl chloride (VI) and TEA in DMF to provide the 4-cinnamoyloxy derivative (VII). The cleavage of the tert-butyl group of (VII) by means of Tms-Cl, NaI and sodium thiosulfate gives the expected free acid (VIII), which is finally condensed with 2-aminopyridine (IX), previous activation with Cl2SO or ethyl chloroformate, and TEA in chloroform or dichloromethane to give rise to the target amide.
| 【1】 Montserrat Vidal, C.; Serra Masia, J. (Laboratorios Salvat SA); 4-Cinnamoyloxy-2-methyl-N-(2-pyridyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide, process for obtaining it and intermediates for its preparation. ES 2053395 . |
| 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) | 33704 | 1,1-Dioxide-1,2-benzisothiazol-3(2H)-one, sodium salt; 1,2-Benzisothiazol-3(2H)-one, 1,1-dioxide, sodium salt (1:1) | 38279-26-4 | C7H4NNaO3S | 详情 | 详情 |
| (II) | 40664 | tert-butyl 2-chloroacetate | 107-59-5 | C6H11ClO2 | 详情 | 详情 |
| (III) | 50875 | tert-butyl 2-(1,1,3-trioxo-1,3-dihydro-2H-1,2-benzisothiazol-2-yl)acetate | C13H15NO5S | 详情 | 详情 | |
| (IV) | 50876 | tert-butyl 4-hydroxy-1,1-dioxo-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate | C13H15NO5S | 详情 | 详情 | |
| (V) | 50877 | tert-butyl 4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate | C14H17NO5S | 详情 | 详情 | |
| (VI) | 11303 | (E)-3-Phenyl-2-propenoyl chloride; 3-Phenyl-2-propenoyl chloride | 102-92-1 | C9H7ClO | 详情 | 详情 |
| (VII) | 50878 | tert-butyl 2-methyl-1,1-dioxo-4-[[(E)-3-phenyl-2-propenoyl]oxy]-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate | C23H23NO6S | 详情 | 详情 | |
| (VIII) | 50879 | 2-methyl-1,1-dioxo-4-[[(E)-3-phenyl-2-propenoyl]oxy]-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylic acid | C19H15NO6S | 详情 | 详情 | |
| (IX) | 11305 | 2-Pyridinamine; 2-Pyridinylamine; 2-Aminopyridine | 504-29-0 | C5H6N2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)The N-arylpyrrole (III) was prepared by the Clauson-Kaas reaction of 2-nitroaniline (I) with 2,5-dimethoxytetrahydrofuran (II) in AcOH under microwave irradiation. Subsequent reduction of the nitro group of (III) using BiCl3 and NaBH4 provided aniline (IV), which was condensed with cinnamoyl chloride (V) in the presence of pyridine to give the corresponding amide (VI). Cyclization of (VI) using POCl3 and pyridine produced the pyrroloquinoxaline (VII), and further Vilsmeier-Haack formylation gave aldehyde (VIII). This was condensed with boiling 3-(dimethylamino)propylamine (IX), and the resulting imine (X) was finally reduced to the target amine with NaBH4 in MeOH. The title compound was finally converted to the trioxalate salt upon treatment with oxalic acid in isopropanol.
| 【1】 Guillon, J.; Rault, S.; Kervran, A.; Renard, P.; Manechez, D.; Pfeiffer, B.; Dallemagne, P.; Synthesis of new pyrrolo[1,2-a]quinoxalines: Potential non-peptide glucagon receptor antagonists. Eur J Med Chem 1998, 33, 4, 293. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 15713 | Oxalic acid | 144-62-7 | C2H2O4 | 详情 | 详情 | |
| (I) | 11608 | o-Nitroaniline; 2-Nitroaniline; 2-Nitrophenylamine | 88-74-4 | C6H6N2O2 | 详情 | 详情 |
| (II) | 12132 | 2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether | 696-59-3 | C6H12O3 | 详情 | 详情 |
| (III) | 31487 | 1-(2-nitrophenyl)-1H-pyrrole | 33265-60-0 | C10H8N2O2 | 详情 | 详情 |
| (IV) | 31488 | 2-(1H-pyrrol-1-yl)aniline; 2-(1H-pyrrol-1-yl)phenylamine | 6025-60-1 | C10H10N2 | 详情 | 详情 |
| (V) | 11303 | (E)-3-Phenyl-2-propenoyl chloride; 3-Phenyl-2-propenoyl chloride | 102-92-1 | C9H7ClO | 详情 | 详情 |
| (VI) | 31489 | (E)-3-phenyl-N-[2-(1H-pyrrol-1-yl)phenyl]-2-propenamide | C19H16N2O | 详情 | 详情 | |
| (VII) | 31490 | 4-[(E)-2-phenylethenyl]pyrrolo[1,2-a]quinoxaline | C19H14N2 | 详情 | 详情 | |
| (VIII) | 31491 | 4-[(E)-2-phenylethenyl]pyrrolo[1,2-a]quinoxaline-1-carbaldehyde | C20H14N2O | 详情 | 详情 | |
| (IX) | 25248 | N-(3-aminopropyl)-N,N-dimethylamine; N(1),N(1)-dimethyl-1,3-propanediamine | 109-55-7 | C5H14N2 | 详情 | 详情 |
| (X) | 31492 | N-[3-(dimethylamino)propyl]-N-((E)-[4-[(E)-2-phenylethenyl]pyrrolo[1,2-a]quinoxalin-1-yl]methylidene)amine; N(1),N(1)-dimethyl-N(3)-((E)-[4-[(E)-2-phenylethenyl]pyrrolo[1,2-a]quinoxalin-1-yl]methylidene)-1,3-propanediamine | C25H26N4 | 详情 | 详情 |