tert-butyl 7-hydroxy-3,4-dihydro-2(1H)-isoquinolinecarboxylate -Drug Synthesis Database

【结构式】

【分子编号】28635

【品名】tert-butyl 7-hydroxy-3,4-dihydro-2(1H)-isoquinolinecarboxylate

【CA登记号】

【分子式】C₁₄H₁₉NO₃

【分子量】249.3098

【元素组成】C 67.45% H 7.68% N 5.62% O 19.25%

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：(II)

The reaction of 7-hydroxy-1,2,3,4-tetrahydroisoquinoline (I) with di-tert-butyl dicarbonate and triethylamine in dichloromethane gives 7-hydroxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (II), which is condensed with 2-(4-benzyloxyphenyl)-2-chloroacetic acid ethyl ester (III) (obtained by chlorination of 2-(4-benzyloxyphenyl)acetic acid ethyl ester (IV) with PCl5), by means of K2CO3 in refluxing acetonitrile yields the disubstituted acetate (V). The selective debenzylation of (V) with H2 over Pd/C in ethyl acetate affords the phenol (VI), which is alkylated with 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (VII) by means of diethyl azodicarboxylate (AZE) and triphenyl phosphine providing the protected intermediate (VIII). The deprotection of (VIII) with HCl in ethanol gives intermediate (IX) with two free NH groups, which is treated with pyrazole-1-carboxamidine (X) and diisopropylethylamine (DIEA) in DMF yielding the bis amidino derivative (XI), which is finally hydrolyzed with NaOH in ethanol/water.

参考文献中间体

合成目标

【1】 Kucznierz, R.; Von der Saal, W.; Leinert, H.; Grams, F.; Stegmeier, K. (Roche Diagnostics GmbH); New cyclic guanidines, process for preparing the same and medicaments. DE 19530996; EP 0846115; JP 1999511445; WO 9708165 .

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)	28634	1,2,3,4-tetrahydro-7-isoquinolinol		C₉H₁₁NO	详情	详情
(II)	28635	tert-butyl 7-hydroxy-3,4-dihydro-2(1H)-isoquinolinecarboxylate		C₁₄H₁₉NO₃	详情	详情
(III)	28636	ethyl 2-[4-(benzyloxy)phenyl]-2-chloroacetate		C₁₇H₁₇ClO₃	详情	详情
(IV)	28637	Ethyl 2-[4-(benzyloxy)phenyl]acetate; p-(Benzyloxy)phenylacetate		C₁₇H₁₈O₃	详情	详情
(V)	28638	tert-butyl 7-[1-[4-(benzyloxy)phenyl]-2-ethoxy-2-oxoethoxy]-3,4-dihydro-2(1H)-isoquinolinecarboxylate		C₃₁H₃₅NO₆	详情	详情
(VI)	28639	tert-butyl 7-[2-ethoxy-1-(4-hydroxyphenyl)-2-oxoethoxy]-3,4-dihydro-2(1H)-isoquinolinecarboxylate		C₂₄H₂₉NO₆	详情	详情
(VII)	18625	tert-butyl 4-hydroxy-1-piperidinecarboxylate		C₁₀H₁₉NO₃	详情	详情
(VIII)	28640	tert-butyl 7-[1-(4-[[1-(tert-butoxycarbonyl)-4-piperidinyl]oxy]phenyl)-2-ethoxy-2-oxoethoxy]-3,4-dihydro-2(1H)-isoquinolinecarboxylate		C₃₄H₄₆N₂O₈	详情	详情
(IX)	28641	ethyl 2-[4-(4-piperidinyloxy)phenyl]-2-(1,2,3,4-tetrahydro-7-isoquinolinyloxy)acetate		C₂₄H₃₀N₂O₄	详情	详情
(X)	15983	1H-pyrazole-1-carboximidamide	4023-00-1	C₄H₆N₄	详情	详情
(XI)	28642	ethyl 2-[4-([1-[amino(imino)methyl]-4-piperidinyl]oxy)phenyl]-2-([2-[amino(imino)methyl]-1,2,3,4-tetrahydro-7-isoquinolinyl]oxy)acetate		C₂₆H₃₄N₆O₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

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

Extended Information