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【结 构 式】 
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【分子编号】17984 【品名】6-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-3(2H)-pyridazinone 【CA登记号】 |
【 分 子 式 】C17H12N4O 【 分 子 量 】288.30864 【元素组成】C 70.82% H 4.2% N 19.43% O 5.55% |
合成路线1
该中间体在本合成路线中的序号：(VII)The Grignard condensation of phenylethynylmagnesium bromide with acetic anhydride in THF gives 4-phenyl-3-butyn-2-one (II), which is cyclized with 1-aminopyridinium iodide (III) by means of KOH in dichloromethane yielding the pyrazolopyridine (IV). The reaction of (IV) with 2-oxoacetic acid (V) by means of acetic acid in dimethoxyethane (DME) affords the butyric acid derivative (VI), which is cyclized with hydrazine in hot DMA to give the pyridazinone (VII). The condensation of (VII) with 4-bromobutyric acid ethyl ester (VIII) by means of benzyltriethylammonium chloride in hot DME/methanol provides the butyric ester intermediate (IX), which is finally hydrolyzed with NaOH.
| 【1】 Zanka, A.; et al.; Pilot-scale synthesis of a novel non-xanthine adenosine A1 receptor antagonist. 1,3-dipolar cycloaddition of pyridine N-immine to an acetylene. Org Process Res Dev 1998, 2, 5, 320. |
| 【2】 Zanka, A.; Efficient large-scale synthesis of 4-phenyl-3-butyn-2-one, a key intermediate for a novel potent adenosine antagonist. Org Process Res Dev 1998, 2, 1, 60. |
| 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) | 32758 | bromo(2-phenylethynyl)magnesium；phenylacetylenyl magnesium bromide;(phenylethynyl)magnesium bromide | C8H5BrMg | 详情 | 详情 | |
| (II) | 32759 | 4-phenyl-3-butyn-2-one | 1817-57-8 | C10H8O | 详情 | 详情 |
| (III) | 32760 | 1-aminopyridinium iodide | C5H7IN2 | 详情 | 详情 | |
| (IV) | 32760 | 1-aminopyridinium iodide | C5H7IN2 | 详情 | 详情 | |
| (V) | 15618 | 2-Oxoacetic acid; Glyoxylic Acid | 298-12-4 | C2H2O3 | 详情 | 详情 |
| (VI) | 32761 | 2-hydroxy-4-oxo-4-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)butyric acid | C17H14N2O4 | 详情 | 详情 | |
| (VII) | 17984 | 6-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-3(2H)-pyridazinone | C17H12N4O | 详情 | 详情 | |
| (VIII) | 11263 | ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate | 2969-81-5 | C6H11BrO2 | 详情 | 详情 |
| (IX) | 32762 | ethyl 4-[6-oxo-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-1(6H)-pyridazinyl]butanoate | C23H22N4O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)This compound was prepared by two ways starting from 3-(3-oxo-2,3-dihydropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine (I). Alkylation of (I) with 2-chlorocyclohexanone (II) in the presence of NaH in DMF gave diketone (V). Alternatively, condensation of (I) with epoxycyclohexane and NaH in DMF at 127 C yielded the ketoalcohol (IV) as a mixture of cis and trans isomers, which were separated by column chromatography. The major trans isomer was then oxidized with pyridinium dichromate to the diketone (V). Reaction of this diketone with the sodium salt of triethyl phosphonoacetate (VI) in toluene at 100 C afforded a mixture of unsaturated esters (VII) and (VIII), which were subsequently submitted to hydrolysis with NaOH. Then, column chromatography of the mixture provided the desired endocyclic unsaturated acid.
| 【1】 Tenda, Y.; Kinoshita, T.; Sakane, K.; Nishimura, S.; Akahane, A.; Durkin, K.; Kuroda, S.; Discovery of FR166124, a novel water-soluble pyrazolo-[1,5-a]pyridine adenosine A1 receptor antagonist. Bioorg Med Chem Lett 1999, 9, 14, 1979. |
| 【2】 Akahane, A.; Nishimura, S.; Itani, H.; Durkin, K.P.M. (Fujisawa Pharmaceutical Co., Ltd.); Pyrazolopyridine adenosine antagonists. EP 0737193; JP 1997507485; US 5773530; WO 9518128 . |
| 【3】 Zanka, A.; et al.; Process improvements in the production of a novel non-xanthine adenosine A1 receptopr antagonist. A "one-pot" horner-emmons isomerization reaction. Org Process Res Dev 1999, 3, 6, 394. |
| 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) | 17984 | 6-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-3(2H)-pyridazinone | C17H12N4O | 详情 | 详情 | |
| (II) | 17985 | 2-Chlorocyclohexanone | 822-87-7 | C6H9ClO | 详情 | 详情 |
| (III) | 17986 | 7-oxabicyclo[4.1.0]heptane; cyclohexene oxide | 286-20-4 | C6H10O | 详情 | 详情 |
| (IV) | 17987 | 2-(2-hydroxycyclohexyl)-6-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-3(2H)-pyridazinone | C23H22N4O2 | 详情 | 详情 | |
| (V) | 17988 | 2-(2-oxocyclohexyl)-6-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-3(2H)-pyridazinone | C23H20N4O2 | 详情 | 详情 | |
| (VI) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (VII) | 17990 | ethyl 2-[2-[6-oxo-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-1(6H)-pyridazinyl]cyclohexylidene]acetate | C27H26N4O3 | 详情 | 详情 | |
| (VIII) | 17991 | ethyl 2-[2-[6-oxo-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-1(6H)-pyridazinyl]-1-cyclohexen-1-yl]acetate | C27H26N4O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)The title compound was synthesized by alkylation of the previously described 6-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-3(2H)-pyridazinone (I) with 4-chloro-1-methylpiperidine (II) in the presence of NaH in hot DMF.
| 【1】 Akahane, A.; Kuroda, S.; Itani, H.; Shimizu, Y. (Fujisawa Pharmaceutical Co., Ltd.); Pyrazolopyridine cpd. and pharmaceutical use thereof. EP 0925299; JP 2000514821; US 6124456; WO 9803507 . |
合成路线4
该中间体在本合成路线中的序号：(I)An alternative procedure consisted in the Mitsunobu coupling of pyridazinone (I) with 4-hydroxy-1-methylpiperidine (III) in the presence of either diisopropyl- or diethyl azodicarboxylate and triphenylphosphine
| 【1】 Kuroda, S.; et al.; Design, synthesis and biological evaluation of a novel series of potent, orally active adenosine A1 receptor antagonists with high blood-brain barrier permeability. Chem Pharm Bull 2001, 49, 8, 988. |
| 【2】 Akahane, A.; Kuroda, S.; Itani, H.; Shimizu, Y. (Fujisawa Pharmaceutical Co., Ltd.); Pyrazolopyridine cpd. and pharmaceutical use thereof. EP 0925299; JP 2000514821; US 6124456; WO 9803507 . |