ethyl 1-(4-pyridinyl)-4-piperidinecarboxylate -Drug Synthesis Database

【结构式】

【分子编号】44838

【品名】ethyl 1-(4-pyridinyl)-4-piperidinecarboxylate

【CA登记号】

【分子式】C₁₃H₁₈N₂O₂

【分子量】234.2982

【元素组成】C 66.64% H 7.74% N 11.96% O 13.66%

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：(V)

Treatment of protected hydroxy tetrahydroisoquinoline (I) with chloromethyl methyl sulfide (II) in DMF in the presence of NaH affords methylsulfanyl derivative (III), which is then converted into chloromethoxy compound (IV) by reaction with sulfuryl chloride in dichloromethane. Condensation of (IV) with piperidine derivative (V) by means of lithium diisopropylamide in THF provides compound (VI), whose Boc group is removed by means of TFA in CHCl3 to furnish deprotected tetrahydroisoquinolinic compound (VII). An amidinium group is then incorporated onto (VII) by reaction with 1H-pyrazole-1-carboxamidine hydrochloride (VIII) to give amidino derivative (IX), whose ethyl ester group is hydrolyzed by refluxing with HCl to afford carboxylic acid (X) as a dihydrochloride salt. Finally, the desired product is obtained by formation of the corresponding monomethanesulfonate trihydrate derivative by treatment with MsOH.

参考文献中间体

合成目标

【1】 Hayashi, M.; Yokota, K.; Katoh, S. (Japan Tobacco Inc.); Amidine cpds.. EP 1070714; JP 2000136190; WO 9952895 .

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)	28635	tert-butyl 7-hydroxy-3,4-dihydro-2(1H)-isoquinolinecarboxylate		C₁₄H₁₉NO₃	详情	详情
(II)	27701	chloro(methylsulfanyl)methane	2373-51-5	C₂H₅ClS	详情	详情
(III)	48929	tert-butyl 7-[(methylsulfanyl)methoxy]-3,4-dihydro-2(1H)-isoquinolinecarboxylate		C₁₆H₂₃NO₃S	详情	详情
(IV)	48930	tert-butyl 7-(chloromethoxy)-3,4-dihydro-2(1H)-isoquinolinecarboxylate		C₁₅H₂₀ClNO₃	详情	详情
(V)	44838	ethyl 1-(4-pyridinyl)-4-piperidinecarboxylate		C₁₃H₁₈N₂O₂	详情	详情
(VI)	48931	tert-butyl 7-[[4-(ethoxycarbonyl)-1-(4-pyridinyl)-4-piperidinyl]methoxy]-3,4-dihydro-2(1H)-isoquinolinecarboxylate		C₂₈H₃₇N₃O₅	详情	详情
(VII)	48932	ethyl 1-(4-pyridinyl)-4-[(1,2,3,4-tetrahydro-7-isoquinolinyloxy)methyl]-4-piperidinecarboxylate		C₂₃H₂₉N₃O₃	详情	详情
(VIII)	48933	1H-pyrrole-1-carboximidamide		C₅H₇N₃	详情	详情
(IX)	48934	ethyl 4-[([2-[amino(imino)methyl]-1,2,3,4-tetrahydro-7-isoquinolinyl]oxy)methyl]-1-(4-pyridinyl)-4-piperidinecarboxylate		C₂₄H₃₁N₅O₃	详情	详情
(X)	48935	4-[([2-[amino(imino)methyl]-1,2,3,4-tetrahydro-7-isoquinolinyl]oxy)methyl]-1-(4-pyridinyl)-4-piperidinecarboxylic acid		C₂₂H₂₇N₅O₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

Reduction of ethyl ester (I) with LiAlH4 provides primary carbinol (II), which is then converted into amine (III) by Mitsunobu reaction with phthalimide (A) in the presence of PPh3 and DEAD in THF, followed by an hydrazine mediated deprotection in EtOH. Reaction of amine (III) with 2-nitrophenyl isocyanate (IV) in CHCl3/THF or CH2Cl2, followed by reduction of the nitro group by hydrogenation over Pd/C in EtOH, affords aniline (V). Finally, aniline (V) is condensed with acid chloride (VI) in CHCl3 in the presence of pyridine to furnish the target compound.

参考文献中间体

合成目标

【1】 Tinsley, J.M.; Franciskoich, J.B.; Masters, J.J.; et al.; Non-amidine-containing 1,2-dibezamidobenzene inhibitors of human factor Xa with potent anticoagulant and antithrombotic activity. J Med Chem 2000, 43, 11, 2087.
【2】 Antithrombotic agents. WO 9900121 .

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)	12376	Phthalimide; 1H-Isoindole-1,3(2H)-dione; Isoindole-1,3-dione;Phthalic dicarboximide;Phenylimide;Isoindole-1,3-dione	85-41-6	C₈H₅NO₂	详情	详情
(I)	44838	ethyl 1-(4-pyridinyl)-4-piperidinecarboxylate		C₁₃H₁₈N₂O₂	详情	详情
(II)	44839	1-(4-pyridinyl)-4-piperidinyl hydroperoxide		C₁₀H₁₄N₂O₂	详情	详情
(III)	44840	O-[1-(4-pyridinyl)-4-piperidinyl]hydroxylamine; 4-(aminooxy)-1-(4-pyridinyl)piperidine		C₁₀H₁₅N₃O	详情	详情
(IV)	32771	1-isocyanato-2-nitrobenzene; 2-nitrophenyl isocyanate	3320-86-3	C₇H₄N₂O₃	详情	详情
(V)	44841	N-(2-aminophenyl)-N'-[[1-(4-pyridinyl)-4-piperidinyl]oxy]urea		C₁₇H₂₁N₅O₂	详情	详情
(VI)	10295	p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride	122-01-0	C₇H₄Cl₂O	详情	详情

Extended Information