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【结 构 式】

【分子编号】13280

【品名】2-Phenylpyrazolo[1,5-a]pyridine

【CA登记号】

【 分 子 式 】C13H10N2

【 分 子 量 】194.23588

【元素组成】C 80.39% H 5.19% N 14.42%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(IV)

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:(VIII)

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
Extended Information