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【结 构 式】 
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【分子编号】12016 【品名】methyl 2-anilinonicotinate 【CA登记号】 |
【 分 子 式 】C13H12N2O2 【 分 子 量 】228.25056 【元素组成】C 68.41% H 5.3% N 12.27% O 14.02% |
合成路线1
该中间体在本合成路线中的序号：(IIa)The first synthesis of Sch 37224 began with methyl or ethyl 2-phenylamino-3-pyridine carboxylate (IIa or b). Either one was condensed with tert-butyl acetate in the presence of a base such as potassium tert-butoxide to form the 1,8-naphthyridinone ring system (III). Bromination of (III), or preferably of its sodium or potassium salt, led to the 3-bromonaphthyridinone (IV). Displacement of the bromine by amines in hot DMF then led to a series of zwitterionic naphthyridinones, including Sch 37224 (I). The resulting crude product was purified by chromatography on silica gel using 2,2,2-trifluoroethanol as eluant, or by recrystallization from mixtures of trifluoroethanol/methanol or trifluoroethanol/water. The above synthesis was well suited for the preparation of analogues of Sch 37224. However, a scale-up of the above method to prepare multikilogram quantities of (I) needed for extended studies revealed the following drawbacks: (i) The yields for the conversion of (III) to (IV) and for (IV) to (I) were moderate. (ii) Displacement of the bromine in (IV) with pyrrolidine was inconsistent, and required refluxing of the reaction mixture for a prolonged period of time. This resulted in formation of the structurally similar impurity (V) in varying amounts (5). The removal of (V) from (I) was difficult and, after repeated crystallizations, (I) free of (V) could not be obtained. (iii) Refluxing DMF and pyrrolidine formed many volatile products, which needed containment for the large-scale synthesis.
| 【1】 Kanji, N.; Nakagawa, A.; Miyata, S.; Ide, H. (Hisamitsu Pharmaceutical Co., Ltd.); Naphthyridine derivatives. JP 77116495 . |
| 【2】 Blythin, D.J.; Shue, H. (Schering Corp.); Zwitterionic 1,8-naphthyridine and pyrazino[2,3-b]pyridine containing compounds useful as anti-allergic, anti-inflammatory and cytoprotective agents. EP 0232328; JP 1988500453; US 4684727; WO 8700752 . |
| 【3】 Hill, D.A.; Turner, G.L. (Glaxo Wellcome plc); Neuromuscular blocking agents. CH 683427; EP 0539470; FR 2665791; GB 2260763; JP 1993508648; JP 1998139763; US 5453510; WO 9200965 . |
| 【4】 Blythin, D.J.; Gala, D.; Pirodomast < Prop INN >. Drugs Fut 1991, 16, 12, 1099. |
| 【5】 Shue, H.-J.; Spitler, J.M.; Carlon, F.E.; Kreutner, W.; Sherwood, J.; Bythin, D.J.; Rizzo, C.; Anti-allergy agents. 2. Zwitterionic 1,8-naphthyridin-2(1H)-ones. Potent, orally active inhibitors of the release of leukotrienes and other bronchospastic agents. Med Chem Res 1991, 1, 2, 151-4. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IIa) | 12016 | methyl 2-anilinonicotinate | C13H12N2O2 | 详情 | 详情 | |
| (IIb) | 12017 | ethyl 2-anilinonicotinate | C14H14N2O2 | 详情 | 详情 | |
| (I) | 12015 | 2-oxo-1-phenyl-3-tetrahydro-1H-pyrrolium-1-yl-1,2-dihydro[1,8]naphthyridin-4-olate | C18H17N3O2 | 详情 | 详情 | |
| (III) | 12018 | 4-Hydroxy-1-phenyl[1,8]naphthyridin-2(1H)-one | C14H10N2O2 | 详情 | 详情 | |
| (IV) | 12019 | 3-Bromo-4-hydroxy-1-phenyl[1,8]naphthyridin-2(1H)-one | C14H9BrN2O2 | 详情 | 详情 | |
| (V) | 12020 | 3-(dimethylammonio)-2-oxo-1-phenyl-1,2-dihydro[1,8]naphthyridin-4-olate | C16H15N3O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IIa)To overcome problems for the previous synthesis, a more efficient, economical and environmentally sound process for the preparation of Sch 37224 was needed. Research toward this goal led to the new synthesis of (I). Salient features of this synthesis are summarized below. Since N-acylation of (II) is reported to be very difficult, a novel, mild, high yielding N-acylation procedure, utilizing propylene oxide as a neutral, irreversible acid scavenger during the N-acylation step, was developed for the conversion of (II) to (VI). The displacement of chlorine from (VI) led to (VII), which proved to be moderately unstable. Hence, mild conditions were developed for an efficient conversion of crude (VII) to (I). The merits of this synthesis are discussed in the literature. This synthesis was used successfully to prepare tens of kilos of (I).
| 【1】 Andresen, O.R.; Pedersen, E.B.; Phosphorus pentoxide in organic synthesis, III. New synthesis of pyrido[2,3-d]pyrimidin-4(3H)-ones. Liebigs Ann Chem 1982, 1012. |
| 【2】 Nyce, P.L.; Steinman, M.; Gala, D.; An efficient synthesis of 1,8-napthyridin-2(1H)-ones: Synthesis of leukotriene inhibitor Sch 37224. Synthesis 1991, 7, 571-4. |
| 【3】 Blythin, D.J.; Gala, D.; Pirodomast < Prop INN >. Drugs Fut 1991, 16, 12, 1099. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IIa) | 12016 | methyl 2-anilinonicotinate | C13H12N2O2 | 详情 | 详情 | |
| (I) | 12015 | 2-oxo-1-phenyl-3-tetrahydro-1H-pyrrolium-1-yl-1,2-dihydro[1,8]naphthyridin-4-olate | C18H17N3O2 | 详情 | 详情 | |
| (VI) | 12023 | methyl 2-[(2-chloroacetyl)anilino]nicotinate | C15H13ClN2O3 | 详情 | 详情 | |
| (VII) | 12024 | methyl 2-[[2-(1-pyrrolidinyl)acetyl]anilino]nicotinate | C19H21N3O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IIa)The preparation of radiolabeled (I), needed for biological and pharmacological studies, was accomplished by yet another synthesis. Here, the high yielding synthesis of (IIa) was utilized to prepare labeled (IIa) from chloronicotinic acid and U-14C aniline. This was then condensed with (VIII) to produce radiolabeled (I). This process minimized the handling and workup of radiolabeled materials. The mechanistic aspects for the development of this synthesis have been described recently.
| 【1】 Blythin, D.J.; Gala, D.; Pirodomast < Prop INN >. Drugs Fut 1991, 16, 12, 1099. |
| 【2】 Gala, D.; Duelfer, T.; A short synthesis and its application to the preparation of radiolabelled leukotriene inhibitor Sch 37224. J Label Compd Radiopharm 1991, 29, 6, 651-6. |