2,5-pyridinedicarboxylic acid -Drug Synthesis Database

【结构式】

【分子编号】14440

【品名】2,5-pyridinedicarboxylic acid

【CA登记号】100-26-5

【分子式】C₇H₅NO₄

【分子量】167.12104

【元素组成】C 50.31% H 3.02% N 8.38% O 38.29%

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：(III)

The protection of the chiral epoxy-alcohol (I) with Pmb-Cl, NaH and tetrabutylammonium iodide (TBAI) gives the protected compound (II), which is condensed with 2-amino-6-(2-methoxyethoxy)purine (III) in hot DMF to yield the adduct (IV). Elimination of the OH group of (IV) by means of a treatment with phenyl chlorothioformate, followed by a thermal elimination reaction with Bu3SnH and AIBN, affords the carbocyclic purine (V). The selective deprotection of (V) with DDQ in dichloromethane provides the cyclopentanol derivative (VI), which is treated with MsCl and DMAP to give the mesylate (VII).The reaction of (VII) with sodium 2-methoxyethanolate (A) in DMF yields the cyclopentene derivative (VIII), which is treated with AlI3 in hot acetonitrile to afford the carbocyclic guanine derivative (IX). The deprotection of (X) with BF3/Et2O and Ac2O provides the diacetyl derivative (X), which is finally deacetylated to the target chiral compound by means of NH3 in methanol.

参考文献中间体

合成目标

【1】 Jones, M.F.; et al.; Total synthesis of (-)-carbovir. J Chem Soc - Perkins Trans I 1991, 10, 2479.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	45380	sodium 2-methoxy-1-ethanolate	3139-99-9	C₃H₇NaO₂	详情	详情
(I)	29889	(1S,2R,3S,5R)-2-[(benzyloxy)methyl]-6-oxabicyclo[3.1.0]hexan-3-ol		C₁₃H₁₆O₃	详情	详情
(II)	45375	benzyl [(1S,2R,3S,5R)-3-[(4-methoxybenzyl)oxy]-6-oxabicyclo[3.1.0]hex-2-yl]methyl ether; (1S,2R,3S,5R)-2-[(benzyloxy)methyl]-3-[(4-methoxybenzyl)oxy]-6-oxabicyclo[3.1.0]hexane		C₂₁H₂₄O₄	详情	详情
(III)	14440	2,5-pyridinedicarboxylic acid	100-26-5	C₇H₅NO₄	详情	详情
(IV)	45376	(1S,2S,3S,5S)-5-[2-amino-6-(2-methoxyethoxy)-9H-purin-9-yl]-2-[(benzyloxy)methyl]-3-[(4-methoxybenzyl)oxy]cyclopentanol		C₂₉H₃₅N₅O₆	详情	详情
(V)	45377	9-[(1R,3R,4S)-3-[(benzyloxy)methyl]-4-[(4-methoxybenzyl)oxy]cyclopentyl]-6-(2-methoxyethoxy)-9H-purin-2-ylamine; 9-[(1R,3R,4S)-3-[(benzyloxy)methyl]-4-[(4-methoxybenzyl)oxy]cyclopentyl]-6-(2-methoxyethoxy)-9H-purin-2-amine		C₂₉H₃₅N₅O₅	详情	详情
(VI)	45378	(1S,2R,4R)-4-[2-amino-6-(2-methoxyethoxy)-9H-purin-9-yl]-2-[(benzyloxy)methyl]cyclopentanol		C₂₁H₂₇N₅O₄	详情	详情
(VII)	45379	9-((1R,3R,4S)-3-[(benzyloxy)methyl]-4-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]cyclopentyl)-6-(2-methoxyethoxy)-9H-purin-2-ylamine; 9-((1R,3R,4S)-3-[(benzyloxy)methyl]-4-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]cyclopentyl)-6-(2-methoxyethoxy)-9H-purin-2-amine		C₂₄H₃₃N₅O₄S	详情	详情
(VIII)	45381	9-[(1R,4S)-4-[(benzyloxy)methyl]-2-cyclopenten-1-yl]-6-(2-methoxyethoxy)-9H-purin-2-ylamine; 9-[(1R,4S)-4-[(benzyloxy)methyl]-2-cyclopenten-1-yl]-6-(2-methoxyethoxy)-9H-purin-2-amine		C₂₁H₂₅N₅O₃	详情	详情
(IX)	45382	2-amino-9-[(1R,4S)-4-[(benzyloxy)methyl]-2-cyclopenten-1-yl]-1,9-dihydro-6H-purin-6-one		C₁₈H₁₉N₅O₂	详情	详情
(X)	45383	[(1S,4R)-4-[2-(acetamido)-6-oxo-1,6-dihydro-9H-purin-9-yl]-2-cyclopenten-1-yl]methyl acetate		C₁₅H₁₇N₅O₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

The esterification of pyridine-2,5-dicarboxylic acid (I) with thionyl chloride/methanol gives the corresponding dimethyl ester (II), which is hydrogenated with H2 over PtO2 in acetic acid yielding piperidine-2,5-dicarboxylic acid dimethyl ester (III), as a mixture of the cis- and trans-isomers. The condensation of (III) with 2-chloroacetonitrile (IV) by means of Na2CO3 in refluxing isobutyl methyl ketone affords the expected 1-(cyanomethyl) derivative (V), which is cyclized by hydrogenation with H2 over RaNi in methanol/ethyl acetate giving racemic cis-1-oxo-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine-7-carboxylic acid methyl ester (VI). The reduction of (VI) with LiAlH4 in refluxing THF yields the corresponding hydroxymethyl derivative (VII), which is condensed with 2-chloropyrimidine by means of Na2CO3 in refluxing water affording racemic cis-7-(hydroxymethyl)-2-(2-pyrimidinyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (IX). The reaction of (IX) with methanesulfonyl chloride and triethylamine gives the expected mesylate (X), which is treated with sodium azide in DMF to afford the corresponding azido derivative (XI). The reaction of (XI) with hydrazine in refluxing ethanol gives the racemic cis-7-(aminomethyl)-2-(2-pyrimidinyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (XII), which is submitted to optical resolution by formation of the corresponding salt with (-)-mandelic acid, separation of the diastereomers by crystallization, and decomposition of the desired salt with NaOH to yield (7R,9aS)-7-(aminomethyl)-2-(2-pyrimidinyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (XIII). Finally, this compound is condensed with succinic anhydride (XIV) in refluxing xylene.

参考文献中间体

合成目标

【1】 Castaner, J.; Graul, J.; Silvestre, J.S.; Sunepitron Hydrochloride. Drugs Fut 1998, 23, 2, 161.
【2】 Desai, K.A.; Bright, G.M. (Pfizer Inc.); Bis-aza-bicyclic anxiolytic agents and antidepressants. EP 0380217; JP 1990233681; US 5122525; WO 9008144; WO 9008148 .

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)	14440	2,5-pyridinedicarboxylic acid	100-26-5	C₇H₅NO₄	详情	详情
(II)	14441	dimethyl 2,5-pyridinedicarboxylate	881-86-7	C₉H₉NO₄	详情	详情
(III)	14442	dimethyl 2,5-piperidinedicarboxylate		C₉H₁₅NO₄	详情	详情
(IV)	14443	2-chloroacetonitrile; chloroacetonitrile	107-14-2	C₂H₂ClN	详情	详情
(V)	14444	dimethyl 1-(cyanomethyl)-2,5-piperidinedicarboxylate		C₁₁H₁₆N₂O₄	详情	详情
(VI)	14445	methyl (7S,9aS)-1-oxooctahydro-2H-pyrido[1,2-a]pyrazine-7-carboxylate		C₁₀H₁₆N₂O₃	详情	详情
(VII)	14446	(7S,9aS)octahydro-2H-pyrido[1,2-a]pyrazin-7-ylmethanol		C₉H₁₈N₂O	详情	详情
(VIII)	11191	2-Chloropyrimidine	1722-12-9	C₄H₃ClN₂	详情	详情
(IX)	14448	[(7S,9aS)-2-(2-pyrimidinyl)octahydro-2H-pyrido[1,2-a]pyrazin-7-yl]methanol		C₁₃H₂₀N₄O	详情	详情
(X)	14449	[(7S,9aS)-2-(2-pyrimidinyl)octahydro-2H-pyrido[1,2-a]pyrazin-7-yl]methyl methanesulfonate		C₁₄H₂₂N₄O₃S	详情	详情
(XI)	14450	[(7S,9aS)-2-(2-pyrimidinyl)octahydro-2H-pyrido[1,2-a]pyrazin-7-yl]methyl azide; (7S,9aS)-7-(azidomethyl)-2-(2-pyrimidinyl)octahydro-2H-pyrido[1,2-a]pyrazine		C₁₃H₁₉N₇	详情	详情
(XII)	63830	[(7S,9aS)-2-(2-pyrimidinyl)octahydro-2H-pyrido[1,2-a]pyrazin-7-yl]methylamine; [(7S,9aS)-2-(2-pyrimidinyl)octahydro-2H-pyrido[1,2-a]pyrazin-7-yl]methanamine		C₁₃H₂₁N₅	详情	详情
(XIII)	14451	[(7R,9aS)-2-(2-pyrimidinyl)octahydro-2H-pyrido[1,2-a]pyrazin-7-yl]methylamine; [(7R,9aS)-2-(2-pyrimidinyl)octahydro-2H-pyrido[1,2-a]pyrazin-7-yl]methanamine		C₁₃H₂₁N₅	详情	详情
(XIV)	11291	Dihydro-2,5-furandione; Succinic anhydride	108-30-5	C₄H₄O₃	详情	详情

Extended Information