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【结 构 式】 
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【分子编号】46503 【品名】methyl 7-amino-2-phenylthieno[2,3-b]pyrazine-6-carboxylate 【CA登记号】 |
【 分 子 式 】C14H11N3O2S 【 分 子 量 】285.32636 【元素组成】C 58.93% H 3.89% N 14.73% O 11.21% S 11.24% |
合成路线1
该中间体在本合成路线中的序号：(XIII)The mixture of 5- and 6-phenyl regioisomers of 2-hydroxy-3-carboxamidopyrazine (IX) and (X), prepared by a known method, was treated with POCl3 and Et3N to produce the corresponding chloro nitriles (XI) and (XII). Condensation of this mixture with methyl thioglycolate in the presence of NaOMe, followed by chromatographic separation of isomers furnished the desired thienopyrazine intermediate (XIII).
| 【1】 Meyer, M.D.; Altenbach, R.J.; Basha, F.; Carroll, W.A.; Drizin, I.; Kerwin, J.F.; Wendt, M.D.; Haight, A.R.; Zhang, W. (Abbott Laboratories Inc.); Benzopyranopyrrole and benzopyranopyridine alpha-1 adrenergic cpds.. EP 0942911; US 5891882; US 6046207; WO 9824791 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 46499 | 3-hydroxy-5-phenyl-2-pyrazinecarboxamide | C11H9N3O2 | 详情 | 详情 | |
| (X) | 46500 | 3-hydroxy-6-phenyl-2-pyrazinecarboxamide | C11H9N3O2 | 详情 | 详情 | |
| (XI) | 46501 | 3-chloro-5-phenyl-2-pyrazinecarbonitrile | C11H6ClN3 | 详情 | 详情 | |
| (XII) | 46502 | 3-chloro-6-phenyl-2-pyrazinecarbonitrile | C11H6ClN3 | 详情 | 详情 | |
| (XIII) | 46503 | methyl 7-amino-2-phenylthieno[2,3-b]pyrazine-6-carboxylate | C14H11N3O2S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIII)In a regioselective synthetic method, phenyl glyoxime (XIV) was condensed with aminomalononitrile to produce the pyrazine N-oxide (XV). Reduction of the N-oxide of (XV) with triethyl phosphite yielded (XVI). Diazotization of the amino group of (XVI), followed by diazo displacement with CuBr2, furnished bromo pyrazine (XVII). This was then cyclized with methyl thioglycolate as above to yield the desired thienopyrazine intermediate (XIII).
| 【1】 Meyer, M.D.; Altenbach, R.J.; Basha, F.; Carroll, W.A.; Drizin, I.; Kerwin, J.F.; Wendt, M.D.; Haight, A.R.; Zhang, W. (Abbott Laboratories Inc.); Benzopyranopyrrole and benzopyranopyridine alpha-1 adrenergic cpds.. EP 0942911; US 5891882; US 6046207; WO 9824791 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIII) | 46503 | methyl 7-amino-2-phenylthieno[2,3-b]pyrazine-6-carboxylate | C14H11N3O2S | 详情 | 详情 | |
| (XIV) | 46504 | 2-oxo-2-phenylacetaldehyde oxime | 532-54-7 | C8H7NO2 | 详情 | 详情 |
| (XV) | 46505 | 2-amino-3-cyano-5-phenylpyrazin-1-ium-1-olate | C11H8N4O | 详情 | 详情 | |
| (XVI) | 46506 | 3-amino-6-phenyl-2-pyrazinecarbonitrile | C11H8N4 | 详情 | 详情 | |
| (XVII) | 46507 | 3-bromo-6-phenyl-2-pyrazinecarbonitrile | C11H6BrN3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XIII)In an alternative synthesis, phenylacetaldehyde (XVIII) was condensed with pyrrolidine (XIX) to give enamine (XX). Nitrosation of malononitrile (XXI), followed by treatment with tosyl chloride, produced the O-tosyl oxime (XXII). This was condensed with enamine (XX), and to the intermediate adduct (XXIII) was added thiophenol producing the phenylthiopyrazine (XXIV). Subsequent oxidation of the sulfide group of (XXIV) to sulfone (XXV), followed by condensation with methyl thioglycolate, gave the desired thienopyrazine (XIII).
| 【1】 Meyer, M.D.; Altenbach, R.J.; Basha, F.; Carroll, W.A.; Drizin, I.; Kerwin, J.F.; Wendt, M.D.; Haight, A.R.; Zhang, W. (Abbott Laboratories Inc.); Benzopyranopyrrole and benzopyranopyridine alpha-1 adrenergic cpds.. EP 0942911; US 5891882; US 6046207; WO 9824791 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIII) | 46503 | methyl 7-amino-2-phenylthieno[2,3-b]pyrazine-6-carboxylate | C14H11N3O2S | 详情 | 详情 | |
| (XVIII) | 18456 | 2-phenylacetaldehyde | 122-78-1 | C8H8O | 详情 | 详情 |
| (XIX) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (XX) | 46508 | 1-[(E)-2-phenylethenyl]pyrrolidine | C12H15N | 详情 | 详情 | |
| (XXI) | 12061 | Malononitrile | 109-77-3 | C3H2N2 | 详情 | 详情 |
| (XXII) | 46509 | 2-([[(4-methylphenyl)sulfonyl]oxy]imino)malononitrile | C10H7N3O3S | 详情 | 详情 | |
| (XXIII) | 46510 | 2-[[(E)-1-phenyl-2-(1-pyrrolidinyl)ethenyl]imino]malononitrile | C15H14N4 | 详情 | 详情 | |
| (XXIV) | 46511 | 6-phenyl-3-(phenylsulfanyl)-2-pyrazinecarbonitrile | C17H11N3S | 详情 | 详情 | |
| (XXV) | 46512 | 6-phenyl-3-(phenylsulfonyl)-2-pyrazinecarbonitrile | C17H11N3O2S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XIII)The amino ester intermediate (XIII) was treated with phosgene and Et3N, and to the resulting isocyanate (XXVI) was added the primary amine (VIII), producing urea (XXVII). Then, cyclization of (XXVII) in refluxing toluene generated the desired compound, which was isolated as the hydrochloride salt.
| 【1】 Meyer, M.D.; Altenbach, R.J.; Basha, F.; Carroll, W.A.; Drizin, I.; Kerwin, J.F.; Wendt, M.D.; Haight, A.R.; Zhang, W. (Abbott Laboratories Inc.); Benzopyranopyrrole and benzopyranopyridine alpha-1 adrenergic cpds.. EP 0942911; US 5891882; US 6046207; WO 9824791 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 46498 | 4-[(3aR,9bR)-9-methoxy-1,3a,4,9b-tetrahydrochromeno[3,4-c]pyrrol-2(3H)-yl]-1-butanamine; 4-[(3aR,9bR)-9-methoxy-1,3a,4,9b-tetrahydrochromeno[3,4-c]pyrrol-2(3H)-yl]butylamine | C16H24N2O2 | 详情 | 详情 | |
| (XIII) | 46503 | methyl 7-amino-2-phenylthieno[2,3-b]pyrazine-6-carboxylate | C14H11N3O2S | 详情 | 详情 | |
| (XXVI) | 46513 | methyl 7-isocyanato-2-phenylthieno[2,3-b]pyrazine-6-carboxylate | C15H9N3O3S | 详情 | 详情 | |
| (XXVII) | 46514 | methyl 7-[[([4-[(3aR,9bR)-9-methoxy-1,3a,4,9b-tetrahydrochromeno[3,4-c]pyrrol-2(3H)-yl]butyl]amino)carbonyl]amino]-2-phenylthieno[2,3-b]pyrazine-6-carboxylate | C31H33N5O5S | 详情 | 详情 |