[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methyl 4-[4-(4-nitrophenyl)-1-piperazinyl]phenyl ether -Drug Synthesis Database

【结构式】

【分子编号】16347

【品名】[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methyl 4-[4-(4-nitrophenyl)-1-piperazinyl]phenyl ether

【CA登记号】

【分子式】C₃₀H₃₀F₂N₆O₄

【分子量】576.6030464

【元素组成】C 62.49% H 5.24% F 6.59% N 14.58% O 11.1%

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：(IV)

A new synthesis of Sch-51048 based on a known key intermediate has been described:The reaction of (I) (the final product in Tetrahedron Lett 1995, 36(11): 1787, or intermediate (II) in the synthesis published in the original monograph) with 4-[4-(4-nitrophenyl)piperazin-1-yl]phenol (II) (obtained from the corresponding anisole (III) with 48% HBr) by means of NaOH in DMSO yields the corresponding condensation product (IV). The reduction of the NO2 group of (IV) with H2 over Pd/C in ethanol affords the amine (V), which is acylated with phenyl chloroformate and pyridine to the corresponding carbamate (VI). The reaction of (VI) with hydrazine in dimethoxyethane affords the semicarbazide (VII), which is cyclized with formamidine acetate in 2-methoxyethanol to the triazolinone (VIII). Finally, this compound is alkylated with 3-bromopentane and NaOH in DMSO or DMF.

参考文献中间体

合成目标

【1】 Girijavallabhan, V.M.; Lovey, R.G.; Saksena, A.K.; et al.; SCH 51048, a novel broad-spectrum orally active antifungal agent: Synthesis and preliminary structure-activity profile. Bioorg Med Chem Lett 1995, 5, 2, 127.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	24543	vinyl acetate	108-05-4	C₄H₆O₂	详情	详情
(I)	16311	[(3S,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methyl 4-methylbenzenesulfonate		C₂₁H₂₁F₂N₃O₄S	详情	详情
(II)	16345	4-[4-(4-nitrophenyl)piperazino]phenol		C₁₆H₁₇N₃O₃	详情	详情
(III)	16314	methyl 4-[4-(4-nitrophenyl)piperazino]phenyl ether; 1-(4-methoxyphenyl)-4-(4-nitrophenyl)piperazine		C₁₇H₁₉N₃O₃	详情	详情
(IV)	16347	[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methyl 4-[4-(4-nitrophenyl)-1-piperazinyl]phenyl ether		C₃₀H₃₀F₂N₆O₄	详情	详情
(V)	16348	4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenylamine; [(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methyl 4-[4-(4-nitrophenyl)-1-piperazinyl]phenyl ether		C₃₀H₃₂F₂N₆O₂	详情	详情
(VI)	16349	phenyl 4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenylcarbamate		C₃₇H₃₆F₂N₆O₄	详情	详情
(VII)	16350	N-[4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenyl]-1-hydrazinecarboxamide		C₃₁H₃₄F₂N₈O₃	详情	详情
(VIII)	16351	4-[4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one		C₃₂H₃₂F₂N₈O₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XVI)

Synthesis of intermediate (XX): The reaction of 2-chloro-2',4'-difluoroacetophenone (I) with sodium acetate and NaI in DMF gives 2-acetoxy-2',4'-difluoroacetophenone (II), which by methylenation with methyltriphenylphosphonium bromide and sodium bis(trimethylsilyl)amide in THF yields 2-(2,4-difluorophenyl)-2-propen-1-ol acetate ester (III). The hydrolysis of (III) with KOH in dioxane/water affords the corresponding alcohol (IV), which is regioselectively epoxidized with titanium tetraisopropoxide and L-(+)-diethyl tartrate in dichloromethane to (S)-(-)-2-(2,4-difluorophenyl)oxirane-2-methanol (V). The reaction of (V) with 1,2,4-triazole (VI) in DMF affords (R)-2-(2,4-difluorophenyl)-3-(1,2,4-triazol-1-yl)propane-1,2-diol (VII), which is selectively mesylated with methanesulfonyl chloride and triethylamine to the monomesylate (VIII). The cyclization of (VIII) with NaH in DMF gives the oxirane (IX), which is condensed with diethyl malonate (X) by means of NaH in DMSO to yield a mixture of (5R-cis)- and (5R-trans)-5-(2,4-difluorophenyl)-2-oxo-5-(1,2,4-triazol-1-ylmethyl) tetrahydrofuran-3-carboxylic acid ethyl ester (XI). The reduction of (XI) with NaBH4 and LiCl in ethanol affords (R)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)-5-(1,2,4-triazol-1-yl) pentane-1,4-diol (XII), which is selectively tosylated with tosyl chloride and triethylamine in THF to the bistosylate (XIII). The cyclization of (XIII) by means of NaH in refluxing toluene gives (5R-cis)-5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl) tetrahydrofuran-3-methanol tosylate ester (XIV). The reaction of (XIV) with 1-(4-hydroxyphenyl)-4-(4-nitrophenyl)piperazine (XV) to obtain compound (XVI), and the following reaction sequence (XVI) to (XVII) to (XVIII) to (XIX) to (5R-cis)-4-[4-[4-[4-[5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl)tetrahydrofuran-3-ylmethoxy]phenyl]piperazin-1-yl]phenyl-3,4-dihydro-2H-1,2,4-triazol-3-one (XX) has been performed according to J Med Chem 1984, 27: 894-900.

参考文献中间体

合成目标

【1】 Fromtling, R.A.; Castañer, J.; SCH-56592. Drugs Fut 1996, 21, 2, 160.
【2】 Saksena, A.K.; Girijavallabhan, V.M.; Lovey, R.G.; Pike, R.E.; Wang, H.; Liu, Y.-T.; Ganguly, A.K.; Bennett, F. (Schering Corp.); Tetrahydrofuran antifungals. EP 0736030; JP 1997500658; US 5661151; US 5703079; WO 9517407 .

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)	16321	2-Chloro-2',4'-difluoroacetophenone; 2-Chloro-1-(2,4-difluorophenyl)-1-ethanone	51336-94-8	C₈H₅ClF₂O	详情	详情
(II)	16322	2-(2,4-Difluorophenyl)-2-oxoethyl acetate		C₁₀H₈F₂O₃	详情	详情
(III)	16323	2-(2,4-difluorophenyl)-2-propenyl acetate		C₁₁H₁₀F₂O₂	详情	详情
(IV)	15491	2-(2,4-difluorophenyl)-2-propen-1-ol		C₉H₈F₂O	详情	详情
(V)	17058	[(2S)-2-(2,4-difluorophenyl)oxiranyl]methanol		C₉H₈F₂O₂	详情	详情
(VI)	13135	1H-1,2,4-Triazole; 1,2,4-Triazole	288-88-0	C₂H₃N₃	详情	详情
(VII)	16327	(2R)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-1,2-propanediol		C₁₁H₁₁F₂N₃O₂	详情	详情
(VIII)	17061	(2R)-2-(2,4-difluorophenyl)-1-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-3-(1H-1,2,4-triazol-1-yl)-2-propanol		C₁₄H₁₇F₂N₃O₂S	详情	详情
(IX)	15477	1-[[(2R)-2-(2,4-difluorophenyl)oxiranyl]methyl]-1H-1,2,4-triazole		C₁₁H₉F₂N₃O	详情	详情
(X)	16829	Diethyl malonate	105-53-3	C₇H₁₂O₄	详情	详情
(XI)	16331	ethyl (5R)-5-(2,4-difluorophenyl)-2-oxo-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furancarboxylate		C₁₆H₁₅F₂N₃O₄	详情	详情
(XII)	16332	(4R)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)-5-(1H-1,2,4-triazol-1-yl)-1,4-pentanediol		C₁₄H₁₇F₂N₃O₃	详情	详情
(XIII)	17066	(4R)-4-(2,4-difluorophenyl)-4-hydroxy-2-([[(4-methylphenyl)sulfonyl]oxy]methyl)-5-(1H-1,2,4-triazol-1-yl)pentyl 4-methylbenzenesulfonate		C₂₈H₂₉F₂N₃O₇S₂	详情	详情
(XIV)	16311	[(3S,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methyl 4-methylbenzenesulfonate		C₂₁H₂₁F₂N₃O₄S	详情	详情
(XV)	16345	4-[4-(4-nitrophenyl)piperazino]phenol		C₁₆H₁₇N₃O₃	详情	详情
(XVI)	16347	[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methyl 4-[4-(4-nitrophenyl)-1-piperazinyl]phenyl ether		C₃₀H₃₀F₂N₆O₄	详情	详情
(XVII)	17070	4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenylamine		C₃₀H₃₂F₂N₆O₂	详情	详情
(XVIII)	17071	N-[4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenyl]-N-(1-phenoxyvinyl)amine		C₃₈H₃₈F₂N₆O₃	详情	详情
(XIX)	16350	N-[4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenyl]-1-hydrazinecarboxamide		C₃₁H₃₄F₂N₈O₃	详情	详情
(XX)	16351	4-[4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one		C₃₂H₃₂F₂N₈O₃	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XXI)

Coupling of tosylate (XIII) with the sodium salt of phenol (XX) produced ether (XXI). The nitro group of (XXI) was then reduced to amine (XXII) by hydrogenation over Pt/C. Subsequent condensation of (XXII) with phenyl chloroformate in pyridine afforded the phenyl carbamate (XXIII), which was reacted with hydrazine to yield the semicarbazide derivative (XXIV). Ring closure of (XXIV) with formamidine acetate then provided triazolone (XXV).

参考文献中间体

合成目标

【1】 Saksena, A.K.; Girijavallabhan, V.M.; Lovey, R.G.; Pike, R.E.; Wang, H.; Liu, Y.-T.; Ganguly, A.K.; Bennett, F. (Schering Corp.); Tetrahydrofuran antifungals. EP 0773941; WO 9638443 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	13580	1-[(Chlorocarbonyl)oxy]benzene; phenyl chloroformate	1885-14-9	C₇H₅ClO₂	详情	详情
	15369	Iminoformamide; Methanimidamide	463-52-5	CH₄N₂	详情	详情
(XIII)	16311	[(3S,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methyl 4-methylbenzenesulfonate		C₂₁H₂₁F₂N₃O₄S	详情	详情
(XX)	16345	4-[4-(4-nitrophenyl)piperazino]phenol		C₁₆H₁₇N₃O₃	详情	详情
(XXI)	16347	[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methyl 4-[4-(4-nitrophenyl)-1-piperazinyl]phenyl ether		C₃₀H₃₀F₂N₆O₄	详情	详情
(XXII)	16348	4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenylamine; [(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methyl 4-[4-(4-nitrophenyl)-1-piperazinyl]phenyl ether		C₃₀H₃₂F₂N₆O₂	详情	详情
(XXIII)	16349	phenyl 4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenylcarbamate		C₃₇H₃₆F₂N₆O₄	详情	详情
(XXIV)	16350	N-[4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenyl]-1-hydrazinecarboxamide		C₃₁H₃₄F₂N₈O₃	详情	详情
(XXV)	16351	4-[4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one		C₃₂H₃₂F₂N₈O₃	详情	详情

Extended Information