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【结 构 式】 
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【分子编号】15998 【品名】methyl 2-[(2R)-1-[(E)-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2-propenoyl]hexahydro-2-pyridinyl]acetate 【CA登记号】 |
【 分 子 式 】C24H25N3O3 【 分 子 量 】403.48092 【元素组成】C 71.44% H 6.25% N 10.41% O 11.9% |
合成路线1
该中间体在本合成路线中的序号：(VII)FK-352 can be obtained by two related ways: 1) The Wittig condensation of 2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde (I) with trimethyl phosphonoacetate (II) by means of NaH in hot toluene gives 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2(E)-propenoic acid methyl ester (III), which by hydrolysis with aqueous NaOH yields the expected free acid (IV) (1). The reaction of (IV) with SOCl2 and DMF in dichloromethane affords the corresponding acyl chloride (V), which is condensed with 2-[2(R)-piperidinyl]acetic acid ethyl ester (VI) by means of triethylamine in dichloromethane affording the acylated piperidine (VII). Finally, this compound is hydrolyzed with NaOH in refluxing methanol. 2) The free acid precursor (IV) can also be obtained by condensation of 2-phenylpyrazolo[1,5-a]pyridine (VIII) with 3-(dimethylamino)acrylic acid ethyl ester (IX) by means of AlCl3 in methylene chloride giving the ethyl ester (X), which is hydrolyzed to the free acid (IV) by treatment with aqueous NaOH.
| 【1】 Ireland, C.; Castaner, J.; FK-352. Drugs Fut 1997, 22, 4, 350. |
| 【2】 Shiokawa, Y.; Akahane, A.; Katayama, H.; Mitsunaga, T. (Fujisawa Pharmaceutical Co., Ltd.); Pyrazolopyridine cpds. and processes for preparation thereof. AU 8817602; EP 0299209; JP 1989045385; US 4925849; US 4994453; US 5087629; US 5102878; US 5179103; US 5296490 . |
| 【3】 Shiokawa, Y.; Akahane, A.; Katayama, H.; Mitsunaga, T. (Fujisawa Pharmaceutical Co., Ltd.); Use of adenosine antagonists in the prevention and treatment of pancreatitis and ulcer. EP 0497258; JP 1992244084; JP 1993058913; US 5338743 . |
| 【4】 Kohno, Y.; Nagatomi, I.; Hanaoka, K. (Fujisawa Pharmaceutical Co., Ltd.); Pyrazolopyridine cpds. for the treatment of anemia. EP 0644762; WO 9325205 . |
| 【5】 Shiokawa, Y.; Akahane, A.; Katayama, H.; Mitsunaga, T. (Fujisawa Pharmaceutical Co., Ltd.); Pyrazolopyridine cpd. and process for preparation thereof. EP 0516941; JP 1993112566; JP 1996208650; US 5234930 . |
| 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) | 13271 | 2-Phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde | C14H10N2O | 详情 | 详情 | |
| (II) | 15993 | Trimethyl phosphonoformate; Methyl dimethoxy(oxo)phosphoranecarboxylate | 31142-23-1 | C4H9O5P | 详情 | 详情 |
| (III) | 13273 | methyl (E)-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2-propenoate | C17H14N2O2 | 详情 | 详情 | |
| (IV) | 13274 | (E)-3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)-2-propenoic acid | C16H12N2O2 | 详情 | 详情 | |
| (V) | 13275 | (E)-3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)-2-propenoyl chloride | C16H11ClN2O | 详情 | 详情 | |
| (VI) | 15997 | methyl 2-[(2R)hexahydro-2-pyridinyl]acetate | C8H15NO2 | 详情 | 详情 | |
| (VII) | 15998 | methyl 2-[(2R)-1-[(E)-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2-propenoyl]hexahydro-2-pyridinyl]acetate | C24H25N3O3 | 详情 | 详情 | |
| (VIII) | 13280 | 2-Phenylpyrazolo[1,5-a]pyridine | C13H10N2 | 详情 | 详情 | |
| (IX) | 16000 | ethyl (E)-3-(dimethylamino)-2-propenoate; Ethyl trans-3-dimethylaminoacrylate | 1117-37-9 | C7H13NO2 | 详情 | 详情 |
| (X) | 13283 | ethyl (E)-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2-propenoate | C18H16N2O2 | 详情 | 详情 |