6-Hydroxy-2(1H)-quinolinone -Drug Synthesis Database

【结构式】

【分子编号】13913

【品名】6-Hydroxy-2(1H)-quinolinone

【CA登记号】

【分子式】C₉H₇NO₂

【分子量】161.16012

【元素组成】C 67.08% H 4.38% N 8.69% O 19.86%

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)

6-Hydroxy-2(1H)-quinolinone (I) is alkylated with epichlorohydrin in the presence of K2CO3 in MeOH to afford 6-(2,3-epoxypropoxy)-2(1H)-quinolinone (II). Ring opening of the epoxide (II) with 3,4-dimethoxybenzylamine gives OPC-18790. This compound is also obtained by the reductive alkylation of 6-(3-amino-2-hydroxypropoxy)-2(1H)-quinolinone (III) with 3,4-dimethoxybenzaldehyde.

参考文献中间体

合成目标

【1】 Sumida, T.; Fujioka, T.; Teramoto, S.; Tominaga, M.; Yabuuchi, Y.; Mori, T.; Hosokawa, T.; Novel positive inotropic agents; synthesis and biological activities of 6-(3-amino-2-hydroxypropoxy)-2(1H)-quinolinone derivatives. J Med Chem 1992, 35, 20, 3607-12.
【2】 Fujioka, T.; OPC-18790. Drugs Fut 1993, 18, 12, 1114.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	10146	Epichlorohydrin; 2-(Chloromethyl)oxirane	106-89-8	C₃H₅ClO	详情	详情
	13920	(3,4-Dimethoxyphenyl)methanamine; 3,4-Dimethoxybenzylamine; Veratrylamine	5763-61-1	C₉H₁₃NO₂	详情	详情
	18304	3,4-Dimethoxybenzaldehyde; Veratraldehyde	120-14-9	C₉H₁₀O₃	详情	详情
(I)	13913	6-Hydroxy-2(1H)-quinolinone		C₉H₇NO₂	详情	详情
(II)	13914	6-(2-Oxiranylmethoxy)-2(1H)-quinolinone		C₁₂H₁₁NO₃	详情	详情
(III)	13915	6-(3-Amino-2-hydroxypropoxy)-2(1H)-quinolinone		C₁₂H₁₄N₂O₃	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 synthesis of the (+)-(R)-isomer of OPC-18790 has been published: The condensation of 6-hydroxyquinolin-2(1H)-one (I) with (S)-(+)-epichlorohydrin (II) by means of triethylamine in methanol gives (S)-(+)-6-(3-chloro-2-hydroxypropoxy)quinolin-2(1H)-one (III), which by reaction with KOH in isopropanol/water yields the (R)-(-)-epoxide (IV). Finally, this compound is condensed with 3,4-dimethoxybenzylamine (V) by heating its mixture at 80 C. The (+)-(R)-isomer is about 10-fold more potent than the (-)-(S)-isomer.

参考文献中间体

合成目标

【1】 Fujioka, T.; Teramoto, S.; Tominaga, M.; Mori, T.; Sumida, T.; Yabuuchi, Y.; Tsujimi, S.; Takemoto, K.; Hosokawa, T.; Synthesis and biological activities of optically active 6-[3-(3,4-dimethox ybenzylamino)-2 hydroxypropoxy]-2(1H)-quinolinone (OPC-18790). Chem Pharm Bull 1996, 44, 8, 1596.

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)	13913	6-Hydroxy-2(1H)-quinolinone		C₉H₇NO₂	详情	详情
(II)	13917	(S)-Epichlorohydrin; (2S)-2-(Chloromethyl)oxirane;(S)-(+)-epichlorohydrin	67843-74-7	C₃H₅ClO	详情	详情
(III)	13918	6-[[(2S)-3-Chloro-2-hydroxypropyl]oxy]-2(1H)-quinolinone		C₁₂H₁₂ClNO₃	详情	详情
(IV)	13919	6-[(2R)Oxiranylmethoxy]-2(1H)-quinolinone		C₁₂H₁₁NO₃	详情	详情
(V)	13920	(3,4-Dimethoxyphenyl)methanamine; 3,4-Dimethoxybenzylamine; Veratrylamine	5763-61-1	C₉H₁₃NO₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

OP C-33509 has been obtained by coupling imidazolecarboxamide (VI) with amine (IX) in refluxing CHCl3. The intermediates (VI) and (IX) have been obtained as follows: 1) Alkylation of 6-hydroxycarbostyril (I) with N-(3-bromopropyl)- phthalimide (II) in the presence of K2CO3 in DMF furnished the phthalimidopropyl ether (III). Subsequent hydrazinolysis of the phthalimide in refluxing EtOH provided the primary amine (IV). Then, the imidazolecarboxamide (VI) was obtained by treating amine (IV) with 1,1'-carbonyldiimidazole (V) and two equivalents of imidazole in DMSO. 2) Ring opening of 1,2 epoxycyclohexane (VII) with cyclopropylamine (VIII) gave the racemic trans aminoalcohol. Resolution of enantiomers (IX) and (X) was accomplished by esterification with (S)-mandelic acid (XI), followed by chromatographic separation of the diastereomeric esters. Hydrolysis of the desired ester (XII) then provided optically pure aminoalcohol (IX). Finally, the target urea derivative was obtained by coupling imidazolyl urea (VI) with amine (IX) in refluxing chloroform.

参考文献中间体

合成目标

【1】 Koga, Y.; Kihara, Y.; Okada, M.; Inoue, Y.; Tochizawa, S.; Toga, K.; Tachibana, K.; Kimura, Y.; Nishi, T.; Hidaka, H.; 2(1H)- Quinoline derivatives as novel anti-arteriostenotic agents showing anti-thrombotic and anti-hyperplastic activities. Bioorg Med Chem Lett 1998, 8, 12, 1471.

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)	13913	6-Hydroxy-2(1H)-quinolinone		C₉H₇NO₂	详情	详情
(II)	15216	N-(3-Bromopropyl)phthalimide; 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione	5460-29-7	C₁₁H₁₀BrNO₂	详情	详情
(III)	18912	2-[3-[(2-oxo-1,2-dihydro-6-quinolinyl)oxy]propyl]-1H-isoindole-1,3(2H)-dione		C₂₀H₁₆N₂O₄	详情	详情
(IV)	18913	6-(3-aminopropoxy)-2(1H)-quinolinone		C₁₂H₁₄N₂O₂	详情	详情
(V)	11353	1,1'-Carbonyldiimidazole; Di(1H-imidazol-1-yl)methanone; N,N-Carbonyldiimidazole; 1,1'-Carbonylbis(1H-imidazole)	530-62-1	C₇H₆N₄O	详情	详情
(VI)	18915	N-[3-[(2-oxo-1,2-dihydro-6-quinolinyl)oxy]propyl]-1H-imidazole-1-carboxamide		C₁₆H₁₆N₄O₃	详情	详情
(VII)	17986	7-oxabicyclo[4.1.0]heptane; cyclohexene oxide	286-20-4	C₆H₁₀O	详情	详情
(VIII)	12263	Cyclopropylamine; Cyclopropanamine	765-30-0	C₃H₇N	详情	详情
(IX)	18918	(1R,2R)-2-(cyclopropylamino)cyclohexanol		C₉H₁₇NO	详情	详情
(X)	18919	(1S,2S)-2-(cyclopropylamino)cyclohexanol		C₉H₁₇NO	详情	详情
(XI)	12563	(2S)-2-Hydroxy-2-phenylethanoic acid; S-(+)-Mandelic acid	17199-29-0	C₈H₈O₃	详情	详情
(XII)	18921	(1R,2R)-2-(cyclopropylamino)cyclohexyl (2S)-2-hydroxy-2-phenylethanoate		C₁₇H₂₃NO₃	详情	详情

合成路线4

该中间体在本合成路线中的序号：(I)

6-Hydroxyquinolin-2-one (I) was O-alkylated with 2-bromoacetophenone (II) by means of K2CO3 to give the phenacyl ether (III). Then, a Reformatsky-type condensation of (III) with ethyl 2-(bromomethyl)acrylate (IV) and Zn, with concomitant cyclization, yielded the target methylenebutyrolactone.

参考文献中间体

合成目标

【1】 Wang, T.-C.; et al.; alpha-Methylidene-gamma-butyrolactones: Synthesis and evaluation of quinolin-2(1H)-one derivatives. Helv Chim Acta 1998, 81, 6, 1038.

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)	13913	6-Hydroxy-2(1H)-quinolinone		C₉H₇NO₂	详情	详情
(II)	10315	2-Bromo-1-phenyl-ethanone; 2-Bromo-1-phenyl-1-ethanone	70-11-1	C₈H₇BrO	详情	详情
(III)	21429	6-(2-oxo-2-phenylethoxy)-2(1H)-quinolinone		C₁₇H₁₃NO₃	详情	详情
(IV)	11328	ethyl 2-(bromomethyl)acrylate	17435-72-2	C₆H₉BrO₂	详情	详情

Extended Information