2-Phenylpyrazolo[1,5-a]pyridine -Drug Synthesis Database

【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 合成路线2

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.

参考文献中间体

合成目标

【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.

参考文献中间体

合成目标

【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