2-(3,5-difluorophenyl)acetyl chloride -Drug Synthesis Database

【结构式】

【分子编号】28362

【品名】2-(3,5-difluorophenyl)acetyl chloride

【CA登记号】

【分子式】C₈H₅ClF₂O

【分子量】190.5766064

【元素组成】C 50.42% H 2.64% Cl 18.6% F 19.94% O 8.4%

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：(II)

The reaction of 3,5-difluorophenylacetic acid with SOCl2 gives the corresponding acyl chloride (II), which is cyclized with ethylene (III) by means of AlCl3 in dichloromethane yielding the tetralone (IV). The stereoselective reduction of (IV) with LiAlH4 catalyzed by (1R,2S)-N-methylephedrine affords 5,7-difluoro-1,2,3,4-tetrahydro-2(R)-naphthol (V). The reaction of (V) with methanesulfonyl chloride and triethylamine gives the expected mesylate (VI), which is treated with LiN3 in DMF yielding the 2(S)-azide (VII). The reduction of (VII) with H2 over Pd/C in ethyl acetate affords the corresponding amine (VIII), which is treated with formaldehyde and KCN to give the 2-aminoacetonitrile (IX). The acylation of (IX) with butyl formate in refluxing acetonitrile yields the formamide (X), with is treated with ethyl formate and potassium tert-butoxide in THF to afford the hydroxyvinyl derivative (XI). The cyclization of (XI) with potassium thiocyanate in hot ethanol gives 1-(5,7-difluoro-1,2,3,4-tetrahydro naphthalen-2(S)-yl)-2-thioxo-2,3-dihydro-1H-imidazole-5-carbonitrile (XII), which is finally reduced with LiAlH4 in THF.

参考文献中间体

合成目标

【1】 Martinez, G.R.; Repke, D.B.; Teitelbaum, P.J.; Walker, K.A.M.; Gooding, O.W.; Whiting, R.L.; Bansal, R.P.; Muehldorf, A.V. (Syntex (USA), Inc.); Benzocycloalkylazolethione derivs.. JP 1997512269; US 5438150; WO 9529165 .

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)	28361	2-(3,5-difluorophenyl)acetic acid	105184-38-1	C₈H₆F₂O₂	详情	详情
(II)	28362	2-(3,5-difluorophenyl)acetyl chloride		C₈H₅ClF₂O	详情	详情
(III)	28363	ethylene	9002-88-4	C₂H₄	详情	详情
(IV)	28364	5,7-difluoro-3,4-dihydro-2(1H)-naphthalenone		C₁₀H₈F₂O	详情	详情
(V)	28365	(2R)-5,7-difluoro-1,2,3,4-tetrahydro-2-naphthalenol		C₁₀H₁₀F₂O	详情	详情
(VI)	28366	(2R)-5,7-difluoro-1,2,3,4-tetrahydro-2-naphthalenyl methanesulfonate		C₁₁H₁₂F₂O₃S	详情	详情
(VII)	28367	(2S)-2-azido-5,7-difluoro-1,2,3,4-tetrahydronaphthalene		C₁₀H₉F₂N₃	详情	详情
(VIII)	18416	(2S)-5,7-difluoro-1,2,3,4-tetrahydro-2-naphthalenylamine; (2S)-5,7-difluoro-1,2,3,4-tetrahydro-2-naphthalenamine		C₁₀H₁₁F₂N	详情	详情
(IX)	28368	2-[[(2S)-5,7-difluoro-1,2,3,4-tetrahydro-2-naphthalenyl]amino]acetonitrile		C₁₂H₁₂F₂N₂	详情	详情
(X)	28369	cyanomethyl[(2S)-5,7-difluoro-1,2,3,4-tetrahydro-2-naphthalenyl]formamide		C₁₃H₁₂F₂N₂O	详情	详情
(XI)	28370	(Z)-1-cyano-2-hydroxyethenyl[(2S)-5,7-difluoro-1,2,3,4-tetrahydro-2-naphthalenyl]formamide		C₁₄H₁₂F₂N₂O₂	详情	详情
(XII)	28371	3-[(2S)-5,7-difluoro-1,2,3,4-tetrahydro-2-naphthalenyl]-2-thioxo-2,3-dihydro-1H-imidazole-4-carbonitrile		C₁₄H₁₁F₂N₃S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XI)

The alkylation of dimethyl malonate (IX) with 4-(methylsulfonyl)phenacyl bromide (VIII) by means of K2CO3 in hot acetone gives the substituted malonic ester (X), which is condensed with 2-(3,5-difluorophenyl)acetyl chloride (XI) by means of MgBr2 and pyridine in acetonitrile yielding the disubstituted malonic ester (XII). The cyclization of (XII) by means of triethylamine affords the cylopentenone dicarboxylic ester (XIII), which is finally decarboxylated with H2SO4 in hot acetic acid to provide the target compound.

参考文献中间体

合成目标

【1】 Grabowski, E.J.J.; Zhaol, D.L.; Prasit, P.; Xu, F.; Ouimet, N.; Tillyer, R.D.; Black, C.; Chen, C.Y.; Reider, P.J.; Efficient syntheses of 2-(3 ',5 '-difluorophenyl)-3-(4 '-methylsulfonylphenyl)-cyclopent-2-enone, a potent COX-2 inhibitor. Tetrahedron 1999, 55, 19, 6001.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIII)	19624	(4R,5S,6S,7R)-4,7-dibenzyl-1,3-bis(3-iodobenzyl)-5,6-bis(methoxymethoxy)-1,3-diazepan-2-one		C₃₇H₄₀I₂N₂O₅	详情	详情
(IX)	19373	dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester	108-59-8	C₅H₈O₄	详情	详情
(X)	31626	dimethyl 2-[2-[4-(methylsulfonyl)phenyl]-2-oxoethyl]malonate		C₁₄H₁₆O₇S	详情	详情
(XI)	28362	2-(3,5-difluorophenyl)acetyl chloride		C₈H₅ClF₂O	详情	详情
(XII)	31624	dimethyl 2-[2-(3,5-difluorophenyl)acetyl]-2-[2-[4-(methylsulfonyl)phenyl]-2-oxoethyl]malonate		C₂₂H₂₀F₂O₈S	详情	详情
(XIII)	31625	dimethyl 3-(3,5-difluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-oxo-3-cyclopentene-1,1-dicarboxylate		C₂₂H₁₈F₂O₇S	详情	详情

合成路线3

该中间体在本合成路线中的序号：(II)

The reaction of 3,5-difluorophenylacetic acid (I) with oxalyl chloride and DMF in dichloromethane gives the corresponding acyl chloride (II), which is condensed with L-alanine (III) by means of aqueous NaOH, yielding N-(3,5-difluorophenylacetyl)-L-alanine (IV). Finally, this compound is condensed with L-phenylglycine tert-butyl ester (V) by means of 2-ethoxy-1,2-dihydroquinoline-1-carboxylic acid ethyl ester (EEDQ) and NMM in THF.

参考文献中间体

合成目标

【1】 Methods and cpds. for inhibiting beta-amyloid peptide release and/or its synthesis. JP 2001503782; WO 9822494 .

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)	28361	2-(3,5-difluorophenyl)acetic acid	105184-38-1	C₈H₆F₂O₂	详情	详情
(II)	28362	2-(3,5-difluorophenyl)acetyl chloride		C₈H₅ClF₂O	详情	详情
(III)	10141	D-Alanine; D-2-Aminopropionic Acid	338-69-2	C₃H₇NO₂	详情	详情
(IV)	46287	(2S)-2-[[2-(3,5-difluorophenyl)acetyl]amino]propionic acid		C₁₁H₁₁F₂NO₃	详情	详情
(V)	46288	tert-butyl (2S)-2-amino-2-phenylethanoate		C₁₂H₁₇NO₂	详情	详情

Extended Information