1,2,3,4-Tetrahydroisoquinoline -Drug Synthesis Database

【结构式】

【分子编号】14124

【品名】1,2,3,4-Tetrahydroisoquinoline

【CA登记号】91-21-4

【分子式】C₉H₁₁N

【分子量】133.19308

【元素组成】C 81.16% H 8.32% N 10.52%

与该中间体有关的原料药合成路线共 4 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1

该中间体在本合成路线中的序号：(I)

The acetylation of 1,2,3,4-tetrahydroisoquinoline (I) with acetic anhydride gives 2-acetyl-1,2,3,4-tetrahydroisoquinoline (II), which is sulfonated with chloro sulfonic acid in methylene chloride yielding 2-acetyl-7-chlorosulfonyl-1,2,3,4-tetrahydroisoquinoline (III). The reaction of (III) with 3-chloroaniline (IV) and triethylamine in refluxing acetone affords 2-acetyl-7-(3-chlorophenylamino sulfonyl)-1,2,3,4-tetrahydroisoquinoline (V), which is deacetylated by a treatment with HCl in refluxing butanol to 7-(3-chlorophenylaminosulfonyl)-1,2,3,4-tetrahydroisoquinoline (VI). Finally, this compound is condensed with bis(chlorosulfonyl)imide (VII) [prepared with chlorosulfonic acid (VIII) and chlorosulfonyl isocyanate (IX)] in acetonitrile containing triethylamine.

参考文献中间体

合成目标

【1】 Ali Fadia E. (SmithKline Beecham Corp.); N,N'-Bis[substituted-1,2,3,4-tetrahydroisoquinolino]disulfonylimides and antiallergic compositions and method of use. DD 158240; EP 0038177; US 4135935 .
【2】 Serradell, M.N.; Chu, S.S.; Castaner, J.; SKF-88046. Drugs Fut 1985, 10, 1, 42.

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)	14124	1,2,3,4-Tetrahydroisoquinoline	91-21-4	C₉H₁₁N	详情	详情
(II)	29003	1-[3,4-dihydro-2(1H)-isoquinolinyl]-1-ethanone		C₁₁H₁₃NO	详情	详情
(III)	29004	2-acetyl-1,2,3,4-tetrahydro-7-isoquinolinesulfonyl chloride		C₁₁H₁₂ClNO₃S	详情	详情
(IV)	25239	3-chloroaniline; 3-chlorophenylamine	108-42-9	C₆H₆ClN	详情	详情
(V)	29005	2-acetyl-N-(3-chlorophenyl)-1,2,3,4-tetrahydro-7-isoquinolinesulfonamide		C₁₇H₁₇ClN₂O₃S	详情	详情
(VI)	29006	N-(3-chlorophenyl)-1,2,3,4-tetrahydro-7-isoquinolinesulfonamide		C₁₅H₁₅ClN₂O₂S	详情	详情
(VII)	29007	Bis(chlorosulfonyl)imide		HCl₂NO₄S₂	详情	详情
(VIII)	29008	Chlorosulfonic acid	7790-94-5	HClO₃S	详情	详情
(IX)	14101	Chlorosulfonyl isocyanate	1189-71-5	CClNO₃S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

Protection of the amino group of 2-aminoethanol (I) with di-tert-butyldicarbonate, followed by reaction with phenylchlorocarbonate, gives 2-(tert-butoxycarbonylamino)ethylphenylcarbonate (II), which on reaction in refluxing 1,2,3,4-tetrahydroisoquinoline (III) yields 1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid 2-(tert-butoxycarbonylamino)ethyl ester (IV). Compound (IV) is deprotected with HCl in methanol to give 1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid 2-aminoethyl ester (V), which is coupled with 3-(N-tert-butoxycarbonyl-N-phenylamino)propanoic acid (VI) in the presence of dicyclohexylcarbodiimide to afford N-[2-(1,2,3,4-tetrahydroisoquinolin-2-ylcarbonyloxy)ethyl]-3-(N'-tert-butoxycarbonyl-N'-phenylamino)propanamide (VII). Deprotection of (VII) with HCl in methanol gives N-[2-(1,2,3,4-tetrahydroisoquinolin-2-ylcarbonyloxy)ethyl]-3-(phenylamino)propanamide (VIII), which is acylated with 5-bromonicotinoyl chloride hydrochloride (IX) in the presence of triethylamine to yield 3-bromo-5-[N-phenyl-N-[2-[2-(1,2,3,4-tetrahydroisoquinolin-2-ylcarbonyloxy)ethylcarbamoyl]ethyl]carbamoyl]pyridine (X). Compound (X) is finally reacted with iodopropane and iodide anion exchanged by nitrate with IRA-410 (NO3-).

参考文献中间体

合成目标

【1】 Tsushima, S.; Takatani, M.; Nishikawa, K. (Takeda Chemical Industries, Ltd.); Pyridinium nitrate, its production and use. EP 0382380; JP 1990275876; US 4981860 .
【2】 Mealy, N.; Prous, J.; Castaner, J.; TCV-309. Drugs Fut 1993, 18, 8, 721.

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)	10259	Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol	141-43-5	C₂H₇NO	详情	详情
(II)	14123	2-[(tert-butoxycarbonyl)amino]ethyl phenyl carbonate		C₁₄H₁₉NO₅	详情	详情
(III)	14124	1,2,3,4-Tetrahydroisoquinoline	91-21-4	C₉H₁₁N	详情	详情
(IV)	14125	2-[(tert-butoxycarbonyl)amino]ethyl 3,4-dihydro-2(1H)-isoquinolinecarboxylate		C₁₇H₂₄N₂O₄	详情	详情
(V)	14126	2-aminoethyl 3,4-dihydro-2(1H)-isoquinolinecarboxylate		C₁₂H₁₆N₂O₂	详情	详情
(VI)	14127	3-[(tert-Butoxycarbonyl)anilino]propionic acid		C₁₄H₁₉NO₄	详情	详情
(VII)	14128	2-([3-[(tert-butoxycarbonyl)anilino]propanoyl]amino)ethyl 3,4-dihydro-2(1H)-isoquinolinecarboxylate		C₂₆H₃₃N₃O₅	详情	详情
(VIII)	14129	2-[(3-anilinopropanoyl)amino]ethyl 3,4-dihydro-2(1H)-isoquinolinecarboxylate		C₂₁H₂₅N₃O₃	详情	详情
(IX)	14130	5-Bromonicotinoyl chloride	39620-02-5	C₆H₃BrClNO	详情	详情
(X)	14131	2-[(3-[[(5-bromo-3-pyridinyl)carbonyl]anilino]propanoyl)amino]ethyl 3,4-dihydro-2(1H)-isoquinolinecarboxylate		C₂₇H₂₇BrN₄O₄	详情	详情

合成路线3

该中间体在本合成路线中的序号：(II)

Regioselective substitution of the 2-chloro group of 2,4-dichloroquinoline (I) with 1,2,3,4-tetrahydroisoquinoline (II) in refluxing toluene provides the 2-(tetrahydroisoquinolinyl)quinoline (III). Then, displacement of the remaining 4-chloro group by heating with ethanolamine (IV) furnishes the title compound

参考文献中间体

合成目标

【1】 Pinard, E.; Alanine, A.; Bourson, A.; Buttelman, B.; Heitz, M.-P.; Mutel, V.; Gill, R.; Trube, G.; Wyler, R.; 4-Aminoquinolines as a novel class of NR1/2B subtype selective NMDA receptor antagonists. Bioorg Med. Chem. Lett 2002, 12, 18, 2615.

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)	61332	2,4-Dichloroquinoline		C₉H₅Cl₂N	详情	详情
(II)	14124	1,2,3,4-Tetrahydroisoquinoline	91-21-4	C₉H₁₁N	详情	详情
(III)	61333	4-chloro-2-[3,4-dihydro-2(1H)-isoquinolinyl]quinoline		C₁₈H₁₅ClN₂	详情	详情
(IV)	10259	Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol	141-43-5	C₂H₇NO	详情	详情

合成路线4

该中间体在本合成路线中的序号：(II)

The title compound is prepared by condensation of 4-amino-2-bromopyridine (I) with an excess of tetrahydroisoquinoline (II) at 130 C

参考文献中间体

合成目标

【1】 Büttelman, B.; Alanine, A.; Bourson, A.; Gill, R.; Heitz, M.-P.; Mutel, V.; Pinard, E.; Trube, G.; Wyler, R.; 2-(3,4-Dihydro-1H-isoquinolin-2yl)-pyridines as a novel class of NR1/2B subtype selective NMDA receptor antagonists. Bioorg Med Chem Lett 2003, 13, 5, 829.

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)	63474	2-bromo-4-pyridinamine; 2-bromo-4-pyridinylamine		C₅H₅BrN₂	详情	详情
(II)	14124	1,2,3,4-Tetrahydroisoquinoline	91-21-4	C₉H₁₁N	详情	详情

Extended Information