Flesinoxan hydrochloride, DU-29373, -Drug Synthesis Database

【结构式】

【药物名称】Flesinoxan hydrochloride, DU-29373

【化学名称】(+)-(S)-4-Fluoro-N-[2-[4-[2-(hydroxymethyl)-1,4-benzodioxan-5-yl]-1-piperazinyl]ethyl]benzamide monohydrochloride

【CA登记号】98205-89-1, 98206-10-1 (free base)

【分子式】C₂₂H₂₇ClFN₃O₄

【分子量】451.92959

【开发单位】Duphar (Originator), Solvay (Originator)

【药理作用】Antidepressants, Anxiolytics, Generalized Anxiety Disorder (GAD), Treatment of, Mood Disorders, Treatment of, PSYCHOPHARMACOLOGIC DRUGS, 5-HT1A Receptor Agonists

合成路线1 合成路线2

合成路线1

A synthesis of (+)-(R)-flesinoxan has been described: The nitration of pyrocatechol (I) with nitric acid gives 3-nitrocatechol (II), which is cyclized with epichlorohydrin (III) and acylated with acetic anhydride, yielding 2-(acetoxymethyl)-5-nitro-1,4-benzodioxan (IV). The reduction of (IV) with H2 over Pd/C in ethanol affords the corresponding amine (V), which is cyclized with bis(2-chloroethyl)amine in refluxing chlorobenzene to afford the piperazine (VI). The reaction of (VI) with N-(4-fluorobenzoyl)aziridine (VII) by means of triethylamine in refluxing acetone gives racemic flesinoxan (VIII), which is then submitted to a carefully controlled enzymatic acetylation with Amano P-30 lipase, which acetylates the (R)-isomer selectively. After separation of the nonesterified compound, the acetate is hydrolyzed to give an enriched product, which is submitted to a new enzymatic esterification to improve the optical purity.

参考文献中间体

【1】 Ghazal, N.B.; Ennis, M.D.; The synthesis of (+)- and (-)-flesinoxan: Application of enzymatic resolution methodology. Tetrahedron Lett 1992, 33, 42, 6287.

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)	11599	o-Dihydroxybenzene; Catechol; Pyrocatechol	120-80-9	C₆H₆O₂	详情	详情
(II)	11600	3-Nitro-1,2-benzenediol		C₆H₅NO₄	详情	详情
(III)	10146	Epichlorohydrin; 2-(Chloromethyl)oxirane	106-89-8	C₃H₅ClO	详情	详情
(IV)	11602	(5-nitro-2,3-dihydro-1,4-benzodioxin-2-yl)methyl acetate		C₁₁H₁₁NO₆	详情	详情
(V)	11603	(5-amino-2,3-dihydro-1,4-benzodioxin-2-yl)methyl acetate		C₁₁H₁₃NO₄	详情	详情
(VI)	11604	(5-piperazino-2,3-dihydro-1,4-benzodioxin-2-yl)methyl acetate		C₁₅H₂₀N₂O₄	详情	详情
(VII)	11605	1-Aziranyl(4-fluorophenyl)methanone		C₉H₈FNO	详情	详情
(VIII)	11606	4-fluoro-N-(2-[4-[2-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-5-yl]piperazino]ethyl)benzamide		C₂₂H₂₆FN₃O₄	详情	详情

合成路线2

Flesinoxan hydrochloride is obtained in a multiple-step synthesis, including the resolution of one of the racemic intermediates (VIII), starting with the monobenzyl ether of catechol (I). Treatment of (I) with sulfuryl chloride in methylene chloride gives (II). This chloro compound is nitrated with nitric acid resulting in the mononitro derivative (III). In a one-pot procedure compound (III) is converted to the racemic benzodioxan structure (V) by condensation with epichlorohydrin, followed by treatment of the intermediate (IV) with hydrochloric acid and with potassium hydroxide, respectively. After conversion of the hydroxymethyl derivative to the benzoic ester (VI), compound (VII) can be obtained by catalytic hydrogenation of (VI). Treatment of (VII) with bischloroethylamine results in the racemic piperazine analogue (VIII). In this phase the resolution of the piperazine is carried out with (+)-camphorsulfonic acid. After several recrystallizations, the optically pure (+)-enantiomer is obtained. Reaction of this (+)-N-[2-(hydroxymethyl)-1,4-benzodioxan-5-yl]piperazine (VIII) with N-(4-fluorobenzoyl)aziridine, saponification of the benzoate ester and treatment with hydrochloric acid gives flesinoxan monohydrochloride.

参考文献中间体

【1】 Hartog, J.; Wouters, W.; FLESINOXAN HYDROCHLORIDE < Rec INN >. Drugs Fut 1988, 13, 1, 31.

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)	15209	Phenol, 2-(phenylmethoxy)-; 2-(benzyloxy)phenol	6272-38-4	C₁₃H₁₂O₂	详情	详情
(II)	21575	2-(benzyloxy)-4-chlorophenol		C₁₃H₁₁ClO₂	详情	详情
(III)	21576	2-(benzyloxy)-4-chloro-6-nitrophenol		C₁₃H₁₀ClNO₄	详情	详情
(IV)	21577	2-[[2-(benzyloxy)-4-chloro-6-nitrophenoxy]methyl]oxirane; benzyl 5-chloro-3-nitro-2-(2-oxiranylmethoxy)phenyl ether		C₁₆H₁₄ClNO₅	详情	详情
(V)	21578	(7-chloro-5-nitro-2,3-dihydro-1,4-benzodioxin-2-yl)methanol		C₉H₈ClNO₅	详情	详情
(VI)	21579	(7-chloro-5-nitro-2,3-dihydro-1,4-benzodioxin-2-yl)methyl benzoate		C₁₆H₁₂ClNO₆	详情	详情
(VII)	21580	(5-amino-2,3-dihydro-1,4-benzodioxin-2-yl)methyl benzoate		C₁₆H₁₅NO₄	详情	详情
(VIII)	21581	[5-(1-piperazinyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl benzoate		C₂₀H₂₂N₂O₄	详情	详情
(IX)	10146	Epichlorohydrin; 2-(Chloromethyl)oxirane	106-89-8	C₃H₅ClO	详情	详情
(X)	21583	2-chloro-N-(2-chloroethyl)-1-ethanamine; Bis(2-chloroethyl)amine; 1,1'-iminobis(2-chloroethane); N,N-bis(2-chloroethyl)amine	821-48-7	C₄H₉Cl₂N	详情	详情

Extended Information