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【结 构 式】 
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【分子编号】40932 【品名】3-(cyanomethyl)-2-pyridinecarbonitrile 【CA登记号】 |
【 分 子 式 】C8H5N3 【 分 子 量 】143.14792 【元素组成】C 67.12% H 3.52% N 29.35% |
合成路线1
该中间体在本合成路线中的序号：(II)Reaction of 3-(cyanomethyl)pyridine-N-oxide (I) with cyanotrimethylsilane and dimethylcarbamoyl chloride provided dinitrile (II). Subsequent cyclization of (II) in the presence of HBr gave rise to 6-amino-8-bromo-1,7-naphthyridine (III). Attachment of a 3-nitrophenyl group to (III) to afford (V) was carried out by Suzuki coupling of (III) with 3-nitrophenylboronic acid (IV) in the presence of bis(dibenzylideneacetone)palladium and triphenylphosphine. The required triflate (VI) was then obtained by nitrosation of aminonaphthyridine (V) in trifluromethanesulfonic acid/DMF. Finally, a second Suzuki coupling of (VI) with 4-carboxyphenylboronic acid (VII) provided the title 6,8-diarylnaphthyridine.
| 【1】 Bray-French, K.; Hersperger, R.; Müller, T.; Mazzoni, L.; Palladium-catalyzed cross-coupling reactions for the synthesis of 6,8-disubstituted 1,7-naphthyridines: A novel class of potent and selective phosphodiesterase type 4D inhibitors. J Med Chem 2000, 43, 4, 675. |
| 【2】 Hersperger, R. (Novartis AG); Naphtyridine derivs.. EP 0934320; US 6136821; WO 9818796 . |
| 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) | 40931 | 3-(cyanomethyl)-1-pyridiniumolate | C7H6N2O | 详情 | 详情 | |
| (II) | 40932 | 3-(cyanomethyl)-2-pyridinecarbonitrile | C8H5N3 | 详情 | 详情 | |
| (III) | 40933 | 8-bromo[1,7]naphthyridin-6-ylamine; 8-bromo[1,7]naphthyridin-6-amine | C8H6BrN3 | 详情 | 详情 | |
| (IV) | 40934 | 3-nitrophenylboronic acid | 13331-27-6 | C6H6BNO4 | 详情 | 详情 |
| (V) | 40935 | 8-(3-nitrophenyl)[1,7]naphthyridin-6-ylamine; 8-(3-nitrophenyl)[1,7]naphthyridin-6-amine | C14H10N4O2 | 详情 | 详情 | |
| (VI) | 40936 | 8-(3-nitrophenyl)[1,7]naphthyridin-6-yl trifluoromethanesulfonate | C15H8F3N3O5S | 详情 | 详情 | |
| (VII) | 32841 | 4-(dihydroxyboryl)benzoic acid；4-Boronobenzoic acid；4-carboxyphenylboronic acid;4-(Dihydroxyboryl)benzoic acid | 14047-29-1 | C7H7BO4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)3-(Cyanomethyl)pyridine-N-oxide (VI) was converted to the pyridine dinitrile (VII) by treatment with cyanotrimethylsilane and dimethylcarbamoyl chloride. Cyclization of dinitrile (VII) in the presence of HBr gave rise to 6-amino-8-bromo-1,7-naphthyridine (VIII). Attachment of the benzofurazanyl moiety to (VIII) was performed by Suzuki coupling with boronic acid (V) in the presence of bis(dibenzylideneacetone)palladium and tri(o-tolyl)phosphine. The resultant 6 amino-8-aryl naphthyridine (IX) was subjected to diazotization in the presence of trifluoromethanesulfonic acid to furnish triflate (X). Further Suzuki coupling of triflate (X) with 4-carboxyphenylboronic acid (XI) led to the title compound.
| 【1】 Hersperger, R.; Dawson, J.; Mueller, T.; Synthesis of 4-(8-benzo[1,2,5]oxadiazol-5-yl-[1,7]naphthyridine-6-yl)-benzoic acid: A potent and selective phosphodiesterase type 4D inhibitor. Bioorg Med Chem Lett 2002, 12, 2, 233. |
| 【2】 Hersperger, R. (Novartis AG); Naphtyridine derivs.. EP 0934320; US 6136821; WO 9818796 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 59799 | 2,1,3-benzoxadiazol-5-ylboronic acid | C6H5BN2O3 | 详情 | 详情 | |
| (VI) | 40931 | 3-(cyanomethyl)-1-pyridiniumolate | C7H6N2O | 详情 | 详情 | |
| (VII) | 40932 | 3-(cyanomethyl)-2-pyridinecarbonitrile | C8H5N3 | 详情 | 详情 | |
| (VIII) | 40933 | 8-bromo[1,7]naphthyridin-6-ylamine; 8-bromo[1,7]naphthyridin-6-amine | C8H6BrN3 | 详情 | 详情 | |
| (IX) | 59906 | 8-(2,1,3-benzoxadiazol-5-yl)[1,7]naphthyridin-6-amine; 8-(2,1,3-benzoxadiazol-5-yl)[1,7]naphthyridin-6-ylamine | C14H9N5O | 详情 | 详情 | |
| (X) | 59907 | 8-(2,1,3-benzoxadiazol-5-yl)[1,7]naphthyridin-6-yl trifluoromethanesulfonate | C15H7F3N4O4S | 详情 | 详情 | |
| (XI) | 32841 | 4-(dihydroxyboryl)benzoic acid；4-Boronobenzoic acid；4-carboxyphenylboronic acid;4-(Dihydroxyboryl)benzoic acid | 14047-29-1 | C7H7BO4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VII)In an alternative synthetic procedure, dinitrile (VII) was cyclized in the presence of sodium methoxide to produce 6-amino-8-methoxy-1,7-naphthyridine (XII). This was converted to triflate (XIII) by diazotization in the presence of trifluoromethanesulfonic acid. Suzuki coupling of triflate (XIII) with 4 carboxyphenylboronic acid (XI) yielded adduct (XIV). The 8-methoxy group of (XIV) was then displaced with PBr3 to produce bromide (XV), which was subjected to further Suzuki coupling with the benzofurazan boronic acid (V) to provide the title compound.
| 【1】 Hersperger, R.; Dawson, J.; Mueller, T.; Synthesis of 4-(8-benzo[1,2,5]oxadiazol-5-yl-[1,7]naphthyridine-6-yl)-benzoic acid: A potent and selective phosphodiesterase type 4D inhibitor. Bioorg Med Chem Lett 2002, 12, 2, 233. |
| 【2】 Hersperger, R. (Novartis AG); Naphtyridine derivs.. EP 0934320; US 6136821; WO 9818796 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 59799 | 2,1,3-benzoxadiazol-5-ylboronic acid | C6H5BN2O3 | 详情 | 详情 | |
| (VII) | 40932 | 3-(cyanomethyl)-2-pyridinecarbonitrile | C8H5N3 | 详情 | 详情 | |
| (XI) | 32841 | 4-(dihydroxyboryl)benzoic acid；4-Boronobenzoic acid；4-carboxyphenylboronic acid;4-(Dihydroxyboryl)benzoic acid | 14047-29-1 | C7H7BO4 | 详情 | 详情 |
| (XII) | 59909 | 8-methoxy[1,7]naphthyridin-6-amine; 8-methoxy[1,7]naphthyridin-6-ylamine | C9H9N3O | 详情 | 详情 | |
| (XIII) | 59910 | 8-methoxy[1,7]naphthyridin-6-yl trifluoromethanesulfonate | C10H7F3N2O4S | 详情 | 详情 | |
| (XIV) | 59911 | 4-(8-methoxy[1,7]naphthyridin-6-yl)benzoic acid | C16H12N2O3 | 详情 | 详情 | |
| (XV) | 59912 | 4-(8-bromo[1,7]naphthyridin-6-yl)benzoic acid | C15H9BrN2O2 | 详情 | 详情 |