[4-(methylsulfanyl)phenyl]lithium -Drug Synthesis Database

【结构式】

【分子编号】18808

【品名】[4-(methylsulfanyl)phenyl]lithium

【CA登记号】

【分子式】C₇H₇LiS

【分子量】130.13958

【元素组成】C 64.61% H 5.42% Li 5.33% S 24.64%

与该中间体有关的原料药合成路线共 4 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1

该中间体在本合成路线中的序号：(IV)

Alkylation of 2-(S)-tert-butyl-5-(S)-methyl-1,3-dioxolan-4-one (I) with 1,1,1-trifluoro-2-iodoethane (II) in the presence of LDA in THF at -72 C provided trifluoroethyl compound (III). Condensation of (III) with 4-(methylthio)phenyllithium (IV), prepared from 4-bromothioanisole and BuLi, gave (V), which was hydrolyzed with p-toluenesulfonic acid in boiling water to afford ketone (VI). Subsequent oxidation of sulfide group with KHSO5 (Oxone(R)) in the presence of Oct3NMeCl (Aliquat 336(R)) produced sulfone (VII). Esterification of (VII) with chloroacetic acid using 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide methyl-p-toluenesulfonate (CMC) as the condensing agent provided chloroacetate (VIII). Finally, condensation with 3,4-difluorophenol (IX) in the presence of DBU in acetonitrile gave the intermediate ether (X), which cyclized to produce the target furanone.

参考文献中间体

合成目标

【1】 Belley, M.; Gauthier, J.Y.; Grimm, E.; Leblanc, Y.; Li, C.-S.; Therien, M.; Lau, C.-K.; Prasit, P.; Roy, P. (Merck Frosst Canada Inc.); (Methylsulfonyl)phenyl-2-(5H)-furanones as COX-2 inhibitors. EP 0863891; JP 1999500146; US 5981576; WO 9714691 .

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)	18805	(2S,5S)-2-(tert-butyl)-5-methyl-1,3-dioxolan-4-one		C₈H₁₄O₃	详情	详情
(II)	18806	1,1,1-trifluoro-2-iodoethane	353-83-3	C₂H₂F₃I	详情	详情
(III)	18807	(2S,5R)-2-(tert-butyl)-5-methyl-5-(2,2,2-trifluoroethyl)-1,3-dioxolan-4-one		C₁₀H₁₅F₃O₃	详情	详情
(IV)	18808	[4-(methylsulfanyl)phenyl]lithium		C₇H₇LiS	详情	详情
(V)	18809	(2S,5R)-2-(tert-butyl)-5-methyl-4-[4-(methylsulfanyl)phenyl]-5-(2,2,2-trifluoroethyl)-1,3-dioxolan-4-ol		C₁₇H₂₃F₃O₃S	详情	详情
(VI)	18810	(2R)-4,4,4-trifluoro-2-hydroxy-2-methyl-1-[4-(methylsulfanyl)phenyl]-1-butanone		C₁₂H₁₃F₃O₂S	详情	详情
(VII)	18811	(2R)-4,4,4-trifluoro-2-hydroxy-2-methyl-1-[4-(methylsulfonyl)phenyl]-1-butanone		C₁₂H₁₃F₃O₄S	详情	详情
(VIII)	18812	(1R)-3,3,3-trifluoro-1-methyl-1-[4-(methylsulfonyl)benzoyl]propyl 2-chloroacetate		C₁₄H₁₄ClF₃O₅S	详情	详情
(IX)	16739	3,4-difluorophenol	2713-33-9	C₆H₄F₂O	详情	详情
(X)	18814	(1R)-3,3,3-trifluoro-1-methyl-1-[4-(methylsulfonyl)benzoyl]propyl 2-(3,4-difluorophenoxy)acetate		C₂₀H₁₇F₅O₆S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(V)

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3

该中间体在本合成路线中的序号：(V)

The condensation of 2-bromo-2-cyclopentenone (II) with the aryl lithium compound (V) gives the tertiary alcohol (VIII), which is submitted to an oxidation with PDC with simultaneous allylic transposition to provide 2-bromo-3-[4-(methylsulfanyl)phenyl]-2-cyclopenten-1-one (IX). The oxidation of (IX) with H2O2 (Na2WO4) or MCPBA yields the corresponding sulfone (X), which is finally condensed with boronic acid (III) by means of a Pd catalyst as before. 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
(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
(V)	18808	[4-(methylsulfanyl)phenyl]lithium		C₇H₇LiS	详情	详情
(VIII)	25956	2-bromo-1-[4-(methylsulfanyl)phenyl]-2-cyclopenten-1-ol		C₁₂H₁₃BrOS	详情	详情
(IX)	25957	2-bromo-3-[4-(methylsulfanyl)phenyl]-2-cyclopenten-1-one		C₁₂H₁₁BrOS	详情	详情
(X)	25958	2-bromo-3-[4-(methylsulfonyl)phenyl]-2-cyclopenten-1-one		C₁₂H₁₁BrO₃S	详情	详情

合成路线4

该中间体在本合成路线中的序号：(V)

The bromination of 3-ethoxy-2-cyclopentenone (XI) gives the 2-bromo derivative (XII), which is condensed with the aryl lithium (V) as before yielding the tertiary alcohol (XIII). Then (XIII) was submitted to an acid rearrangement to provide 2-bromo-3-[4-(sulfanylmethyl)phenyl]-2-cyclopentenone (IX), already obtained in the preceding approaches. 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】 Chan, C.-C.; Brideau, C.; Black, W.C.; et al.; 2,3-Diarylcyclopentenones as orally active, highly selective cyclooxygenase-2 inhibitors. J Med Chem 1999, 42, 7, 1274.
【2】 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	分子式	供应商	用于合成
(V)	18808	[4-(methylsulfanyl)phenyl]lithium	C₇H₇LiS	详情	详情
(IX)	25957	2-bromo-3-[4-(methylsulfanyl)phenyl]-2-cyclopenten-1-one	C₁₂H₁₁BrOS	详情	详情
(XI)	25959	3-ethoxy-2-cyclopenten-1-one	C₇H₁₀O₂	详情	详情
(XII)	25960	2-bromo-3-ethoxy-2-cyclopenten-1-one	C₇H₉BrO₂	详情	详情
(XIII)	25961	2-bromo-3-ethoxy-1-[4-(methylsulfanyl)phenyl]-2-cyclopenten-1-ol	C₁₄H₁₇BrO₂S	详情	详情

Extended Information