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【结 构 式】 
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【分子编号】27686 【品名】3-amino-2-thiophenecarboxylic acid methyl ester; methyl 3-amino-2-thiophenecarboxylate 【CA登记号】22288-78-4 |
【 分 子 式 】C6H7NO2S 【 分 子 量 】157.19312 【元素组成】C 45.85% H 4.49% N 8.91% O 20.36% S 20.4% |
合成路线1
该中间体在本合成路线中的序号：(VII)This compound can be obtained by several related ways: 1.- The cyclization of 3-aminothiophene-2-carboxamide (I) with pentanoyl anhydride (II) by means of DCC, DMAP and pyridine in DMF and NaOH gives 2-butylthieno[3,2-d]pyrimidin-4(3H)-one (III), which by reaction with POCl3 or SOCl2 affords 2-butyl-4-chlorothieno[3,2-d]pyrimidine (IV). Finally, this compound is condensed with cyclohexylamine (V) by means of triethylamine in in THF. 2.- The intermediate 2-butylthieno[3,2-d]pyrimidin-4-(3H)-one (III) can be obtained by other ways: a.- By cyclization of amide (I) with pentanoic acid (VI) by means of DCC, DMAP and pyridine in DMF and NaOH. b.- By cyclization of 3-aminothiophene-2-carboxylic acid methyl ester (VII) with pentanoic acid (VI) by means of DCC, DMAP and ammonia in dichloromethane. c.- By cyclization of 3-aminothiophene-2-carboxylic acid methyl ester (VII) with pentanoyl chloride (VIII) by means of pyridine and ammonia. d.- By cyclization of 3-aminothiophene-2-carboxylic acid (IX) with pentanoic anhydride (II) and ammonia.
| 【1】 Crespo, M. I.; Pages, L.; Vega, A.; Segarra, V.; Lopez, M.; Domenech, T.; Miralpeix, M.; Beleta, J.; Ryder, H.; Palacios, J.M.; Design, synthesis, and biological activities of new thieno[3,2-d]pyrimidines as selective type 4 phosphodiesterase inhibitors. J Med Chem 1998, 41, 21, 4021. |
| 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) | 27682 | 3-amino-2-thiophenecarboxamide | 147123-47-5 | C5H6N2OS | 详情 | 详情 |
| (II) | 27683 | pentanoic anhydride | 2082-59-9 | C10H18O3 | 详情 | 详情 |
| (III) | 27684 | 2-butylthieno[3,2-d]pyrimidin-4(3H)-one | C10H12N2OS | 详情 | 详情 | |
| (IV) | 27685 | 2-butyl-4-chlorothieno[3,2-d]pyrimidine | C10H11ClN2S | 详情 | 详情 | |
| (V) | 17966 | cyclohexanamine; cyclohexyl amine; cyclohexylamine | 108-91-8 | C6H13N | 详情 | 详情 |
| (VI) | 19682 | pentanoic acid | 109-52-4 | C5H10O2 | 详情 | 详情 |
| (VII) | 27686 | 3-amino-2-thiophenecarboxylic acid methyl ester; methyl 3-amino-2-thiophenecarboxylate | 22288-78-4 | C6H7NO2S | 详情 | 详情 |
| (VIII) | 15116 | pentanoyl chloride; valeryl chloride | 638-29-9 | C5H9ClO | 详情 | 详情 |
| (IX) | 27687 | 3-amino-2-thiophenecarboxylic acid | C5H5NO2S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Methyl 3-aminothiophene-2-carboxylate (I) is acylated by 3-chlorobenzenesulfonyl chloride (II) to produce sulfonamide (III). After alkaline hydrolysis of the methyl ester group of (III), the resultant carboxylic acid (IV) is chlorinated by means of oxalyl chloride to furnish acid chloride (V). Finally, coupling of acid chloride (V) with 6-amino-2-methylbenzothiazole (VI) yields the title carboxamide.
| 【1】 Weinstock, J.; Franz, R.G. (GlaxoSmithKline Inc.); Phosphate transport inhibitors. WO 0228353 . |
| 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) | 27686 | 3-amino-2-thiophenecarboxylic acid methyl ester; methyl 3-amino-2-thiophenecarboxylate | 22288-78-4 | C6H7NO2S | 详情 | 详情 |
| (II) | 63966 | 3-chlorobenzenesulfonyl chloride | C6H4Cl2O2S | 详情 | 详情 | |
| (III) | 63967 | methyl 3-{[(3-chlorophenyl)sulfonyl]amino}-2-thiophenecarboxylate | C12H10ClNO4S2 | 详情 | 详情 | |
| (IV) | 63968 | 3-{[(3-chlorophenyl)sulfonyl]amino}-2-thiophenecarboxylic acid | C11H8ClNO4S2 | 详情 | 详情 | |
| (V) | 63969 | 3-{[(3-chlorophenyl)sulfonyl]amino}-2-thiophenecarbonyl chloride | C11H7Cl2NO3S2 | 详情 | 详情 | |
| (VI) | 63970 | 2-methyl-1,3-benzothiazol-6-amine; 2-methyl-1,3-benzothiazol-6-ylamine | C8H8N2S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Decarboxylation of methyl 3-aminothiophene-2-carboxylate (I) in 2 N NaOH leads to 3-aminothiophene (II). Meldrum's acid (III) is condensed with triethyl orthoformate to produce the ethoxymethylene derivative (IV). Subsequent reaction of enol ether (IV) with 3-aminothiophene (II) gives rise to enamine (V), which is further cyclized to thienopyridinone (VI) upon heating in dowtherm A at 260 C. This is then chlorinated by means of oxalyl chloride to furnish 4-chlorothieno[3,2-b]pyridine (VII). Metalation of (VII) with butyllithium in cold THF, followed by treatment with I2 affords the aryl iodide (VIII). Palladium-catalyzed coupling of (VIII) with the lithiated derivative of 1-methylimidazole (IX) yields (X). Finally, displacement of the chloride group of (X) with 5-amino-2-methylindole (XI) provides the title compound.
| 【1】 Munchhof, M.J.; Adams, M.A.; Atherton, J.A.; et al.; Development of thienopyridines as VEGFR-2 kinase inhibitors. 225th ACS Natl Meet (March 23 2003, New Orleans) 2003, Abst MEDI 129. |
| 【2】 Sobolov-Jaynes, S.B.; Munchhof, M.J. (Pfizer Products Inc.); Thienopyrimidine and thienopyridine derivs. useful as anticancer agents. EP 1028964; JP 2001522853; WO 9924440 . |
| 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) | 27686 | 3-amino-2-thiophenecarboxylic acid methyl ester; methyl 3-amino-2-thiophenecarboxylate | 22288-78-4 | C6H7NO2S | 详情 | 详情 |
| (II) | 63448 | 3-thiophenylamine; 3-thiophenamine | C4H5NS | 详情 | 详情 | |
| (III) | 14738 | Meldrum's acid; 2,2-dimethyl-1,3-dioxane-4,6-dione；Malonic acid cyclic isopropylidene ester | 2033-24-1 | C6H8O4 | 详情 | 详情 |
| (IV) | 63449 | 5-[(ethyloxy)methylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione | C9H12O5 | 详情 | 详情 | |
| (V) | 63450 | 2,2-dimethyl-5-[(3-thiophenylamino)methylidene]-1,3-dioxane-4,6-dione | C11H11NO4S | 详情 | 详情 | |
| (VI) | 63451 | thieno[3,2-b]pyridin-7(4H)-one | C7H5NOS | 详情 | 详情 | |
| (VII) | 63452 | 7-chlorothieno[3,2-b]pyridine | C7H4ClNS | 详情 | 详情 | |
| (VIII) | 63453 | 7-chloro-2-iodothieno[3,2-b]pyridine | C7H3ClINS | 详情 | 详情 | |
| (IX) | 38630 | 1-methyl-1H-imidazole | 616-47-7 | C4H6N2 | 详情 | 详情 |
| (X) | 63454 | 7-chloro-2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridine | C11H8ClN3S | 详情 | 详情 | |
| (XI) | 63455 | 2-methyl-1H-indol-5-ylamine; 2-methyl-1H-indol-5-amine | C9H10N2 | 详情 | 详情 |