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【结 构 式】 
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【分子编号】13283 【品名】ethyl (E)-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2-propenoate 【CA登记号】 |
【 分 子 式 】C18H16N2O2 【 分 子 量 】292.33732 【元素组成】C 73.95% H 5.52% N 9.58% O 10.95% |
合成路线1
该中间体在本合成路线中的序号：(VII)A new synthesis of FK-453 has been published: The cyclization of 1-aminopyridinium iodide (I) with 3-phenylpropynoic acid ethyl ester (II) by means of KOH in DMF gives 2-phenylpyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester (III), which is decarboxylated with 47% aqueous HBr yielding 2-phenylpyrazolo[1,5-a]pyridine (IV). The Vilsmayer formylation of (IV) with POCl3 and DMF affords 2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde (V), which by a Horner-Emmonds condensation with 2-(diethoxyphosphoryl)acetic acid ethyl ester and NaH in THF is converted into 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2(E)-propenoic acid ethyl ester (VII). The hydrolysis of (VII) with NaOH in methanol gives the free acid (VIII), which by reaction with SOCl2 in dichloromethane yields the corresponding acyl chloride (IX). The condensation of (IX) with 2-(2-hydroxyethyl)piperidine (X) by means of triethylamine in dichloromethane affords FK-453 as a racemic mixture (XI), which is finally submitted to optical resolution.
| 【1】 Kita, Y.; Akahane, A.; Kusunoki, T.; Terai, T.; Yoshida, K.; Shiokawa, Y.; Mitsunaga, T.; Katayama, H.; Discovery of FK453, a novel non-xanthine adenosine A1 receptor antagonist. Bioorg Med Chem Lett 1996, 6, 17, 2059. |
| 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) | 32760 | 1-aminopyridinium iodide | C5H7IN2 | 详情 | 详情 | |
| (II) | 13278 | ethyl phenylpropiolate; ethyl 3-phenyl-2-propynoate | 2216-94-6 | C11H10O2 | 详情 | 详情 |
| (III) | 13279 | ethyl 2-phenylpyrazolo[1,5-a]pyridine-3-carboxylate | C16H14N2O2 | 详情 | 详情 | |
| (IV) | 13280 | 2-Phenylpyrazolo[1,5-a]pyridine | C13H10N2 | 详情 | 详情 | |
| (V) | 13271 | 2-Phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde | C14H10N2O | 详情 | 详情 | |
| (VI) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (VII) | 13283 | ethyl (E)-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2-propenoate | C18H16N2O2 | 详情 | 详情 | |
| (VIII) | 13274 | (E)-3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)-2-propenoic acid | C16H12N2O2 | 详情 | 详情 | |
| (IX) | 13275 | (E)-3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)-2-propenoyl chloride | C16H11ClN2O | 详情 | 详情 | |
| (X) | 17614 | 2-(2-piperidinyl)-1-ethanol; 2-Piperidineethanol | 1484-84-0 | C7H15NO | 详情 | 详情 |
| (XI) | 13287 | (E)-1-[2-(2-Hydroxyethyl)-1-piperidinyl]-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2-propen-1-one | C23H25N3O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)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 |