1-aminopyridinium iodide -Drug Synthesis Database

【结构式】

【分子编号】32760

【品名】1-aminopyridinium iodide

【CA登记号】

【分子式】C₅H₇IN₂

【分子量】222.02853

【元素组成】C 27.05% H 3.18% I 57.16% N 12.62%

与该中间体有关的原料药合成路线共 5 条

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5

合成路线1

该中间体在本合成路线中的序号：(I)

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：(IX)

A new practical synthesis of FK-453, suitable for large scale manufacture is described: Bromination of cinnamic aldehyde (I) with Br2 in HOAc gives the dibromoderivative (II), which is treated with NaHSO3 and triethylamine yielding alpha-bromocinnamic aldehyde (III). The reaction of (III) with triethyl orthoformate affords the corresponding acetal (IV), which is treated with KOH in hot ethanol to give the acetylenic acetal (V). Acidic hydrolysis of the acetal (V) with sulfuric acid in refluxing water affords phenylpropargyl aldehyde (VI), which by a Horner-Emmons condensation with the phosphonate (VII) by means of KOH in DMSO gives 5-phenylpent-2(E)-en-4-ynoic acid ethyl ester (VIII). The 1,3-dipolar cycloaddition of (VIII) with 1-aminopyridinium iodide (IX) by means of KOH and K2CO3 in the same solvent yields 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2(E)-propenoic acid ethyl ester (X), which is hydrolyzed with NaOH in hot methanol affording the corresponding free acid (XI). Reaction of (XI) with SOCl2 and DMF gives the activated acyl chloride (XII), which is condensed with the silylated chiral piperidineethanol (XIII) [obtained by silylation of the chiral piperidineethanol (XIV) with N,N'-bis(trimethylsilyl)urea (BSU)] by means of Et3N and DMAP in CH2Cl2, yielding the silylated target compound (XV). Finally, this compound is desilylated by means of K2CO3 in methanol.

参考文献中间体

合成目标

【1】 Morinaga, Y.; Zanka, A.; Uematsu, R.; Yamazaki, H.; Yasuda, H.; Process development of a novel-xanthine adenosine A1 receptor antagonist. Org Process Res Dev 1999, 3, 6, 389.

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)	41712	(E)-3-phenyl-2-propenal	14371-10-9	C₉H₈O	详情	详情
(II)	41735	2,3-dibromo-3-phenylpropanal		C₉H₈Br₂O	详情	详情
(III)	41736	(Z)-2-bromo-3-phenyl-2-propenal	5443-49-2	C₉H₇BrO	详情	详情
(IV)	41737	(Z)-2-bromo-1-ethoxy-3-phenyl-2-propenyl ethyl ether; 1-[(Z)-2-bromo-3,3-diethoxy-1-propenyl]benzene		C₁₃H₁₇BrO₂	详情	详情
(V)	41738	1-(3,3-diethoxy-1-propynyl)benzene; 1-ethoxy-3-phenyl-2-propynyl ethyl ether	6142-95-6	C₁₃H₁₆O₂	详情	详情
(VI)	41739	3-phenyl-2-propynal	2579-22-8	C₉H₆O	详情	详情
(VII)	10019	Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate	867-13-0	C₈H₁₇O₅P	详情	详情
(VIII)	41740	ethyl (E)-5-phenyl-2-penten-4-ynoate		C₁₃H₁₂O₂	详情	详情
(IX)	32760	1-aminopyridinium iodide		C₅H₇IN₂	详情	详情
(X)	13273	methyl (E)-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2-propenoate		C₁₇H₁₄N₂O₂	详情	详情
(XI)	13274	(E)-3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)-2-propenoic acid		C₁₆H₁₂N₂O₂	详情	详情
(XII)	13275	(E)-3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)-2-propenoyl chloride		C₁₆H₁₁ClN₂O	详情	详情
(XIII)	41741	(2R)-2-[2-[(trimethylsilyl)oxy]ethyl]piperidine; 2-[(2R)piperidinyl]ethyl trimethylsilyl ether		C₁₀H₂₃NOSi	详情	详情
(XIV)	13276	2-[(2R)Piperidinyl]-1-ethanol		C₇H₁₅NO	详情	详情
(XV)	41742	(E)-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-1-((2R)-2-[2-[(trimethylsilyl)oxy]ethyl]piperidinyl)-2-propen-1-one		C₂₆H₃₃N₃O₂Si	详情	详情

合成路线3

该中间体在本合成路线中的序号：(IV)

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.

参考文献中间体

合成目标

【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4

该中间体在本合成路线中的序号：(III)

参考文献中间体

合成目标

【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5

该中间体在本合成路线中的序号：(I)

The 1,3-dipolar cycloaddition of N-aminopyridinium iodide (I) to dimethyl acetylenedicarboxylate (II) afforded the pyrazolopyridine system (III). Ester groups hydrolysis and regioselective decarboxylation of (III) with hot 50% sulfuric acid gave the mono-carboxylic acid (IV), which was further esterified with ethanol and sulfuric acid. Finally, reductive amination of the ethyl ester (V) with (p-chlorophenyl)piperazine (VI) in the presence of LiAlH4 provided the target compound.

参考文献中间体

合成目标

【1】 Lober, S.; et al.; Rationally based efficacy tuning of selective dopamine D4 receptor ligands leading to the complete antagonist 2-[4-(4-chlorophenyl) piperazin-1-ylmethyl]pyrazolo[1,5-a]pyridine (FAUC 213). J Med Chem 2001, 44, 17, 2691.

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)	24551	Dimethyl acetylenedicarboxylate; Dimethyl 2-butynedioate;Acetylenedicarboxylic acid dimethyl ester	762-42-5	C₆H₆O₄	详情	详情
(III)	51036	dimethyl pyrazolo[1,5-a]pyridine-2,3-dicarboxylate		C₁₁H₁₀N₂O₄	详情	详情
(IV)	51037	pyrazolo[1,5-a]pyridine-2-carboxylic acid		C₈H₆N₂O₂	详情	详情
(V)	51038	ethyl pyrazolo[1,5-a]pyridine-2-carboxylate		C₁₀H₁₀N₂O₂	详情	详情
(VI)	33593	1-(4-chlorophenyl)piperazine	38869-46-4	C₁₀H₁₃ClN₂	详情	详情

Extended Information