2-cyclopenten-1-one -Drug Synthesis Database

【结构式】

【分子编号】25950

【品名】2-cyclopenten-1-one

【CA登记号】930-30-3

【分子式】C₅H₆O

【分子量】82.10204

【元素组成】C 73.15% H 7.37% O 19.49%

与该中间体有关的原料药合成路线共 5 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5

合成路线1

该中间体在本合成路线中的序号：(I)

The bromination of 2-cyclopentenone (I) gives 2-bromocyclopentenone (II), which is condensed with 3,5-difluorophenylboronic acid (III) by means of a Pd catalyst yielding 2-(3,5-difluorophenyl)-2-cyclopentenone (IV). The reaction of (IV) with the aryl lithium (V) affords the cyclopentenol derivative (VI), which is submitted to an oxidation with PDC with simultaneous allylic transposition to give 2-(3,5-difluorophenyl)-3-[4-(methylsulfanyl)phenyl]-2-cyclopenten-1-one (VII). Finally, this compound is oxidized with H 2O2 (Na2WO4) to the target sulfone. The preceding synthetic approach can also be performed with 2-iodo-2-cyclopentenone (obtained by iodination of (I) instead of its bromo analogue (II). The synthetic approaches can also be performed with the arylmagnesium analogue of lithium derivative (V).

参考文献中间体

合成目标

【1】 Black, C. (Merck Frosst Canada Inc.); 2-(3,5-Difluorophenyl)-3-(4-(methyl-sulfonyl)phenyl)-2-cyclopenten-1-one useful as an inhibitor of cyclooxygenase-2. EP 0863134; JP 1998251220 .

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)	25950	2-cyclopenten-1-one	930-30-3	C₅H₆O	详情	详情
(II)	25951	2-bromo-2-cyclopenten-1-one		C₅H₅BrO	详情	详情
(III)	25952	3,5-difluorophenylboronic acid	156545-07-2	C₆H₅BF₂O₂	详情	详情
(IV)	25953	2-(3,5-difluorophenyl)-2-cyclopenten-1-one		C₁₁H₈F₂O	详情	详情
(V)	18808	[4-(methylsulfanyl)phenyl]lithium		C₇H₇LiS	详情	详情
(VI)	25954	2-(3,5-difluorophenyl)-1-[4-(methylsulfanyl)phenyl]-2-cyclopenten-1-ol		C₁₈H₁₆F₂OS	详情	详情
(VII)	25955	2-(3,5-difluorophenyl)-3-[4-(methylsulfanyl)phenyl]-2-cyclopenten-1-one		C₁₈H₁₄F₂OS	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VI)

An alternative asymmetric procedure consisted in the LDA-promoted addition of cyclopentenone (VI) to the chiral dioxolanone (V), followed by catalytic hydrogenation to furnish (VII). The dioxolane group of (VII) was then cleaved by basic hydrolysis yielding the target (R)-hydroxyacid (IV).

参考文献中间体

合成目标

【1】 Tsuchiya, Y.; Nomoto, T.; Ohsawa, H.; Kawakami, K.; Ohwaki, K.; Nishikibe, M. (Banyu Pharmaceutical Co., Ltd.); 1,4-Disubstd. piperidine derivs.. EP 0823423; US 5750540; WO 9633973 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IV)	31466	(2R)-2-cyclopentyl-2-hydroxy-2-phenylethanoic acid		C₁₃H₁₆O₃	详情	详情
(V)	41599	(2S,5R)-2-(tert-butyl)-5-phenyl-1,3-dioxolan-4-one		C₁₃H₁₆O₃	详情	详情
(VI)	25950	2-cyclopenten-1-one	930-30-3	C₅H₆O	详情	详情
(VII)	41600	(2S,5R)-2-(tert-butyl)-5-cyclopentyl-5-phenyl-1,3-dioxolan-4-one		C₁₈H₂₄O₃	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 condensation of chiral dioxolane (I) with 2-cyclopentenone (II) by means of lithium diisopropylamide (LDA) in THF, followed by reaction with N-phenyl-trifluoromethanesulfonylimide gives the enol triflate (III), which is reduced with H2 over Pd/C in methanol yielding the chiral dioxolane (IV)(as major isomer (93:7)). The hydrolysis of (IV) with NaOH in methanol affords impure acid (V), which was purified through crystallization of its (-)-cinchonidine salt. Pure (V) is finally condensed with piperidine-4-amine (VI) by means of CDI and DIEA in DMF to afford the target amide.

参考文献中间体

合成目标

【1】 Mitsuya, M.; et al.; Stereoselective synthesis of a new muscarinic M3 receptor antagonist, J-104129. Bioorg Med Chem Lett 1999, 9, 14, 2037.

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)	31681	(2R,5R)-2-(tert-butyl)-5-phenyl-1,3-dioxolan-4-one		C₁₃H₁₆O₃	详情	详情
(II)	25950	2-cyclopenten-1-one	930-30-3	C₅H₆O	详情	详情
(III)	31682	(3S)-3-[(2R,4R)-2-(tert-butyl)-5-oxo-4-phenyl-1,3-dioxolan-4-yl]-1-cyclopenten-1-yl trifluoromethanesulfonate		C₁₉H₂₁F₃O₆S	详情	详情
(IV)	31683	(2R,5R)-2-(tert-butyl)-5-cyclopentyl-5-phenyl-1,3-dioxolan-4-one		C₁₈H₂₄O₃	详情	详情
(V)	31466	(2R)-2-cyclopentyl-2-hydroxy-2-phenylethanoic acid		C₁₃H₁₆O₃	详情	详情
(VI)	31463	1-(4-methyl-3-pentenyl)-4-piperidinamine; 1-(4-methyl-3-pentenyl)-4-piperidinylamine		C₁₁H₂₂N₂	详情	详情

合成路线4

该中间体在本合成路线中的序号：(VI)

参考文献中间体

合成目标

【1】 Tsuchiya, Y.; Nomoto, T.; Ohsawa, H.; Kawakami, K.; Ohwaki, K.; Nishikibe, M. (Banyu Pharmaceutical Co., Ltd.); 1,4-Disubstd. piperidine derivs.. EP 0823423; US 5750540; WO 9633973 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IV)	31466	(2R)-2-cyclopentyl-2-hydroxy-2-phenylethanoic acid		C₁₃H₁₆O₃	详情	详情
(V)	41599	(2S,5R)-2-(tert-butyl)-5-phenyl-1,3-dioxolan-4-one		C₁₃H₁₆O₃	详情	详情
(VI)	25950	2-cyclopenten-1-one	930-30-3	C₅H₆O	详情	详情
(VII)	41600	(2S,5R)-2-(tert-butyl)-5-cyclopentyl-5-phenyl-1,3-dioxolan-4-one		C₁₈H₂₄O₃	详情	详情

合成路线5

该中间体在本合成路线中的序号：(III)

Condensation of ethyl bromoacetate (I) with dimethyl sulfide gave the sulfonium salt (II). Addition of the sulfur ylide resulting from (II) and DBU to cyclopentenone (III) produced the bicyclic compound (IV). This was converted into the silyl enolate (V), which was subsequently oxidized to the unsaturated ketone (VI) by means of palladium diacetate. Alternatively, (IV) was directly oxidized to (VI) using allyl methyl carbonate and palladium diacetate. Treatment of enone (VI) with tert-butyl hydroperoxide and DBU produced epoxide (VII), which was further converted into hydroxy ketone (VIII) by reaction with diphenyl diselenide in the presence of N-acetyl-cysteine and sodium borate. Bucherer-Bergs reaction of ketone (VIII) with potassium cyanide and ammonium carbamate produced a mixture of diastereomeric hydantoins (IX). After N-alkylation of the hydantoin ring of (IX) with benzyl bromide, the desired isomer (X) was isolated by preparative HPLC. Finally, alcohol oxidation, with concomitant hydantoin hydrolysis, by treatment with Jones reagent furnished the title compound.

参考文献中间体

合成目标

【1】 Massey, S.M.; Monn, J.A.; Valli, M.J. (Eli Lilly and Company); Excitatory amino acid receptor modulators. EP 0878463; US 5958960 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IXa)	44097			C₁₁H₁₄N₂O₅	详情	详情
(IXb)	44098			C₁₁H₁₄N₂O₅	详情	详情
(I)	16640	Ethyl 2-bromoacetate; Ethyl bromoacetate	105-36-2	C₄H₇BrO₂	详情	详情
(II)	11947	(2-Ethoxy-2-oxoethyl)(dimethyl)sulfonium bromide	5187-82-6	C₆H₁₃BrO₂S	详情	详情
(III)	25950	2-cyclopenten-1-one	930-30-3	C₅H₆O	详情	详情
(IV)	44092	ethyl (1S,5R,6S)-2-oxobicyclo[3.1.0]hexane-6-carboxylate		C₉H₁₂O₃	详情	详情
(V)	44093	ethyl (1S,5R,6S)-2-[(trimethylsilyl)oxy]bicyclo[3.1.0]hex-2-ene-6-carboxylate		C₁₂H₂₀O₃Si	详情	详情
(VI)	44094	ethyl (1R,5S,6S)-4-oxobicyclo[3.1.0]hex-2-ene-6-carboxylate		C₉H₁₀O₃	详情	详情
(VII)	44095	ethyl (1R,2R,4R,6S,7S)-5-oxo-3-oxatricyclo[4.1.0.0(2,4)]heptane-7-carboxylate		C₉H₁₀O₄	详情	详情
(VIII)	44096	ethyl (1R,2S,5S,6S)-2-hydroxy-4-oxobicyclo[3.1.0]hexane-6-carboxylate		C₉H₁₂O₄	详情	详情
(X)	44099			C₁₈H₂₀N₂O₅	详情	详情

Extended Information