dimethyl 4-(4-morpholinyl)-2,6-pyridinedicarboxylate -Drug Synthesis Database

【结构式】

【分子编号】58801

【品名】dimethyl 4-(4-morpholinyl)-2,6-pyridinedicarboxylate

【CA登记号】

【分子式】C₁₃H₁₆N₂O₅

【分子量】280.28052

【元素组成】C 55.71% H 5.75% N 9.99% O 28.54%

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)

The condensation of 4-chloro-2,6-pyridinedicarboxylic acid (I) with morpholine (II) afforded the morpholinopyridinedicarboxylic acid (III), which was further esterified with MeOH and HCl to produce diester (IV). Reduction of (IV) with NaBH4 and CaCl2 gave hydroxy ester (V). After protection of the hydroxyl group of (V) as the trimethylsilylethoxymethyl derivative (VII), the ester group was hydrolyzed under basic conditions yielding acid (VIII). This was then subjected to a Curtius rearrangement with DPPA in the presence of tert-butanol to generate the tert-butyl carbamate (IX). Alkylation of carbamate (IX) with 3-methoxy-5-nitrobenzyl bromide (X) and NaH furnished the N-benzyl carbamate derivative (XI). The nitro group of (XI) was then reduced to amine (XII) by catalytic hydrogenation over Pd/C.

参考文献中间体

合成目标

【1】 Fukami, T.; Mase, T.; Tsuchiya, Y.; Kanatani, A.; Fukuroda, T. (Banyu Pharmaceutical Co., Ltd.); Aminopyridine derivs.. EP 0889034; US 6011039; WO 9734873 .

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)	58799	4-chloro-2,6-pyridinedicarboxylic acid		C₇H₄ClNO₄	详情	详情
(II)	10388	Morpholine	110-91-8	C₄H₉NO	详情	详情
(III)	58800	4-(4-morpholinyl)-2,6-pyridinedicarboxylic acid		C₁₁H₁₂N₂O₅	详情	详情
(IV)	58801	dimethyl 4-(4-morpholinyl)-2,6-pyridinedicarboxylate		C₁₃H₁₆N₂O₅	详情	详情
(V)	58802	ethyl 6-(hydroxymethyl)-4-(4-morpholinyl)-2-pyridinecarboxylate		C₁₃H₁₈N₂O₄	详情	详情
(VI)	27243	[2-(chloromethoxy)ethyl](trimethyl)silane	76513-69-4	C₆H₁₅ClOSi	详情	详情
(VII)	58803	ethyl 4-(4-morpholinyl)-6-({[2-(trimethylsilyl)ethoxy]methoxy}methyl)-2-pyridinecarboxylate		C₁₉H₃₂N₂O₅Si	详情	详情
(VIII)	58804	4-(4-morpholinyl)-6-({[2-(trimethylsilyl)ethoxy]methoxy}methyl)-2-pyridinecarboxylic acid		C₁₇H₂₈N₂O₅Si	详情	详情
(IX)	58805	tert-butyl 4-(4-morpholinyl)-6-({[2-(trimethylsilyl)ethoxy]methoxy}methyl)-2-pyridinylcarbamate		C₂₁H₃₇N₃O₅Si	详情	详情
(X)	58806	3-(bromomethyl)-5-nitrophenyl methyl ether; 1-(bromomethyl)-3-methoxy-5-nitrobenzene		C₈H₈BrNO₃	详情	详情
(XI)	58807	tert-butyl 3-methoxy-5-nitrobenzyl[4-(4-morpholinyl)-6-({[2-(trimethylsilyl)ethoxy]methoxy}methyl)-2-pyridinyl]carbamate		C₂₉H₄₄N₄O₈Si	详情	详情
(XII)	58808	tert-butyl 3-amino-5-methoxybenzyl[4-(4-morpholinyl)-6-({[2-(trimethylsilyl)ethoxy]methoxy}methyl)-2-pyridinyl]carbamate		C₂₉H₄₆N₄O₆Si	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IV)

A similar method, but using a different protection strategy, has been reported. 4-Hydroxy-2,6-pyridinedicarboxylic acid (XVIII) was condensed with morpholine (II) to provide, after Fischer esterification, the morpholinopyridine diester (IV). Reduction of (IV) with calcium borohydride furnished hydroxy ester (V). Protection of (V) as the corresponding tetrahydropyranyl ether, followed by ester group saponification, afforded (XIX). Curtius rearrangement of acid (XIX) in the same conditions as above gave carbamate (XX), which was alkylated with benzyl chloride (XXI) yielding (XXII). After reduction of the nitroderivative (XXII) with iron and ammonium chloride, the resultant amine (XXIII) was acylated by allyl chloroformate to produce carbamate (XXIV). Then, acidic treatment removed the tetrahydropyranyl-protecting group to afford alcohol (XIV), which was finally processed as in the above method.

参考文献中间体

合成目标

【1】 Haga, Y.; Tsuchiya, Y.; Mase, T.; et al.; Potent and selective aminopyridine NPY Y1 receptor antagonists. 21st Symp Med Chem (Nov 28 2001, Kyoto) 2001, Abst 2P-38.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(II)	10388	Morpholine	110-91-8	C₄H₉NO	详情	详情
(IV)	58801	dimethyl 4-(4-morpholinyl)-2,6-pyridinedicarboxylate		C₁₃H₁₆N₂O₅	详情	详情
(V)	58802	ethyl 6-(hydroxymethyl)-4-(4-morpholinyl)-2-pyridinecarboxylate		C₁₃H₁₈N₂O₄	详情	详情
(XIV)	58810	allyl 3-({(tert-butoxycarbonyl)[6-(hydroxymethyl)-4-(4-morpholinyl)-2-pyridinyl]amino}methyl)-5-methoxyphenylcarbamate		C₂₇H₃₆N₄O₇	详情	详情
(XVIII)	58814	4-hydroxy-2,6-pyridinedicarboxylic acid		C₇H₅NO₅	详情	详情
(XIX)	58815	4-(4-morpholinyl)-6-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-pyridinecarboxylic acid		C₁₆H₂₂N₂O₅	详情	详情
(XX)	58816	tert-butyl 4-(4-morpholinyl)-6-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-pyridinylcarbamate		C₂₀H₃₁N₃O₅	详情	详情
(XXI)	58817	3-(chloromethyl)-5-nitrophenyl methyl ether; 1-(chloromethyl)-3-methoxy-5-nitrobenzene		C₈H₈ClNO₃	详情	详情
(XXII)	58818	tert-butyl 3-methoxy-5-nitrobenzyl{4-(4-morpholinyl)-6-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-pyridinyl}carbamate		C₂₈H₃₈N₄O₈	详情	详情
(XXIII)	58819	tert-butyl 3-amino-5-methoxybenzyl{4-(4-morpholinyl)-6-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-pyridinyl}carbamate		C₂₈H₄₀N₄O₆	详情	详情
(XXIV)	58820	allyl 3-[((tert-butoxycarbonyl){4-(4-morpholinyl)-6-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-pyridinyl}amino)methyl]-5-methoxyphenylcarbamate		C₃₂H₄₄N₄O₈	详情	详情

Extended Information