Resacetophenone; 1-(2,4-Dihydroxyphenyl)-1-ethanone -Drug Synthesis Database

【结构式】

【分子编号】13961

【品名】Resacetophenone; 1-(2,4-Dihydroxyphenyl)-1-ethanone

【CA登记号】89-84-9

【分子式】C₈H₈O₃

【分子量】152.14972

【元素组成】C 63.15% H 5.3% O 31.55%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(I)

2,4-Dihydroxyacetophenone (I) is formed by the Friedel-Crafts acetylation of resorcinol. This compound is condensed with diethyl oxalate in sodium ethoxide solution, affording (II). Disodium cromproxate (IV) is conveniently prepared from (II) by treatment with epichlorohydrine in aqueous ethanolic alkaline solution. It is recrystallized from hot water.

参考文献中间体

合成目标

【1】 Ruyun, J.; Disodium Cromproxate. Drugs Fut 1991, 16, 5, 422.
【2】 Liang, X.; Qi, J.; Lu, Y.; A simplified synthesis of 1,3-bis-(2-carboxychromone-7-oxy)-2-hydroxypropane disodium salt (78012). Acta Pharm Sin 1982, 17, 2, 143-5.

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
	10361	1,3-Dihydroxybenzene; m-Dihydroxybenzene; Resorcinol; Resorcin; 1,3-Benzenediol	108-46-3	C₆H₆O₂	详情	详情
(I)	13961	Resacetophenone; 1-(2,4-Dihydroxyphenyl)-1-ethanone	89-84-9	C₈H₈O₃	详情	详情
(II)	13962	ethyl 7-hydroxy-4-oxo-4H-chromene-2-carboxylate		C₁₂H₁₀O₅	详情	详情
(III)	13963	ethyl 7-(3-[[2-(ethoxycarbonyl)-4-oxo-4H-chromen-7-yl]oxy]-2-hydroxypropoxy)-4-oxo-4H-chromene-2-carboxylate		C₂₇H₂₄O₁₁	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

2',4'-Dihydroxyacetophenone (I) was selectively alkylated at position 4' with 1-bromo-3-chloropropane (II) in the presence of K2CO3 in refluxing acetone to yield the 4'-(3-chloropropyl)ether (III). Further condensation of (III) with Vilsmeier reagent, followed by aqueous work up, provided the 3-formylchromenone (IV), which was subsequently reduced with sodium borohydride in CHCl3-EtOH at 0 C to give the (hydroxymethyl)chromenone (V). Finally, alkylation of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (VI) with chloride (V) in the presence of K2CO3 and KI in refluxing acetonitrile yielded the title compound, which was isolated as the hydrochloride salt from methanol.

参考文献中间体

合成目标

【1】 Princep, M.; Guglietta, A.; Bolos, J.; Abaperidone Hydrochloride. Drugs Fut 2001, 26, 4, 335.
【2】 Bolos, J.; et al.; 7-[3-(1-Piperidinyl)propoxy]chromenones as potential atypical antipsychotics. J Med Chem 1996, 39, 15, 2962.
【3】 Bolós, J.; Anglada, L.; Gubert, S.; Planas, J.M.; Agut, J.; Princep, M.; De la Fuente, N.; Sacristan, A.; Ortiz, J.A.; 7-[3-(1-Piperidinyl)propoxy]chromenones as potential atypical antipsychotics. 2. Pharmacological profile of 7-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-piperidin-1-yl]propoxy]-3-(hydroxymethyl)chromen-4-one (abaperidone, FI-8602). J Med Chem 1998, 41, 27, 5402.
【4】 Foguet, R.; Anglada, L.; Bolós, J.; Ortiz, J.; Sacristán, A.; Castellò, J.M. (Ferrer Internacional SA); 4-(6-Fluoro-1, 2-benzisoxazolyl)-1-piperidinyl-propoxy-chromen-4-one derivs., their preparation and their use in the treatment of psychosis, schizophrenia and anxiety. EP 0765323; ES 2101646; ES 2103237; JP 1998501557; US 5736558; WO 9632389 .

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)	13961	Resacetophenone; 1-(2,4-Dihydroxyphenyl)-1-ethanone	89-84-9	C₈H₈O₃	详情	详情
(II)	10358	1-Bromo-3-chloropropane	109-70-6	C₃H₆BrCl	详情	详情
(III)	26820	1-[4-(3-chloropropoxy)-2-hydroxyphenyl]-1-ethanone		C₁₁H₁₃ClO₃	详情	详情
(IV)	26821	7-(3-chloropropoxy)-4-oxo-4H-chromene-3-carbaldehyde		C₁₃H₁₁ClO₄	详情	详情
(V)	26822	7-(3-chloropropoxy)-3-(hydroxymethyl)-4H-chromen-4-one		C₁₃H₁₃ClO₄	详情	详情
(VI)	17910	6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole		C₁₂H₁₃FN₂O	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VII)

Regioselective Mitsunobu condensation of 2',4'-dihydroxyacetophenone (VII) with N-Boc-4-piperidinol (VIII) afforded ether (IX). The 2'-hydroxyl group of (IX) was then alkylated with 2,2,2-trifluoroethyl trifluoromethanesulfonate in the presence of Cs2CO3 to give (X). Oxidative rearrangement of the acetophenone (X) employing thallium trinitrate and trimethyl orthoformate generated the phenylacetic ester (XI), which was hydrolyzed to acid (XII) with NaOH in aqueous MeOH. Subsequent EDC-mediated coupling of (XII) with piperidine intermediate (VI) yielded amide (XIII). The N-Boc group of (XIII) was cleaved using HCl in EtOAc, and the secondary amine (XIV) was acylated with acetic anhydride in the presence of diisopropyl ethylamine to afford the target acetamide.

参考文献中间体

合成目标

【1】 Bock, M.G.; Evans, B.E.; Williams, P.D.; et al.; Nonpeptide oxytocin antagonists: Analogs of L-371,257 with improved potency. Bioorg Med Chem Lett 1999, 9, 9, 1311.
【2】 Freidinger, R.M.; Stauffer, K.; Perlow, D.S.; Sparks, M.A.; Williams, P.D.; Bell, I.M. (Merck & Co., Inc.); Tocolytic oxytocin receptor antagonists. GB 2326410; US 6090805 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	40675	2,2,2-trifluoroethyl trifluoromethanesulfonate	6226-25-1	C₃H₂F₆O₃S	详情	详情
(VI)	19420	1-(4-piperidinyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one		C₁₃H₁₆N₂O₂	详情	详情
(VII)	13961	Resacetophenone; 1-(2,4-Dihydroxyphenyl)-1-ethanone	89-84-9	C₈H₈O₃	详情	详情
(VIII)	18625	tert-butyl 4-hydroxy-1-piperidinecarboxylate		C₁₀H₁₉NO₃	详情	详情
(X)	27110	tert-butyl 4-[4-acetyl-3-(2,2,2-trifluoroethoxy)phenoxy]-1-piperidinecarboxylate		C₂₀H₂₆F₃NO₅	详情	详情
(XI)	27111	tert-butyl 4-[4-(2-methoxy-2-oxoethyl)-3-(2,2,2-trifluoroethoxy)phenoxy]-1-piperidinecarboxylate		C₂₁H₂₈F₃NO₆	详情	详情
(XII)	27112	2-[4-[[1-(tert-butoxycarbonyl)-4-piperidinyl]oxy]-2-(2,2,2-trifluoroethoxy)phenyl]acetic acid		C₂₀H₂₆F₃NO₆	详情	详情
(XIII)	27113	tert-butyl 4-[4-(2-oxo-2-[4-[2-oxo-2H-3,1-benzoxazin-1(4H)-yl]-1-piperidinyl]ethyl)-3-(2,2,2-trifluoroethoxy)phenoxy]-1-piperidinecarboxylate		C₃₃H₄₀F₃N₃O₇	详情	详情
(XIV)	27114	phenyl(1-[2-[4-(4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenyl]acetyl]-4-piperidinyl)formamide		C₂₇H₃₂F₃N₃O₄	详情	详情

Extended Information