(4-methylphenyl)lithium -Drug Synthesis Database

【结构式】

【分子编号】29629

【品名】(4-methylphenyl)lithium

【CA登记号】

【分子式】C₇H₇Li

【分子量】98.07358

【元素组成】C 85.73% H 7.19% Li 7.08%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(IV)

Condensation of 4-bromothiophenol (I) with 3,3-dimethylacrylic acid in the presence of piperidine gave acid (II), which was converted to the corresponding acid chloride with (COCl)2 and then cyclized by treatment with SnCl4 to the thiochromanone (III). Addition of 4-tolyllithium (IV) to ketone (III) and further dehydration of the resulting tertiary alcohol (V) upon treatment with p-toluenesulfonic acid produced the benzothiochromene (VI). After lithiation by means of BuLi, quenching with DMF produced aldehyde (VII). Subsequent Horner-Emmons condensation of (VII) with phosphonate (VIII) in the presence of BuLi yielded a mixture of E and Z olefins from which the required isomer (IX) was isolated by chromatography. Cyclization of ketal (IX) by means of SnCl4 produced the naphthothiopyran (X). The ethyl ester group of (X) was finally hydrolyzed with LiOH to yield the title carboxylic acid.

参考文献中间体

合成目标

【1】 Escobar, M.; Vuligonda, V.; Standeven, A.M.; Chandraratna, R.A.S.; A new class of potent RAR antagonists: Dihydroanthracenyl, benzochromenyl and benzothiochromenyl retinoids. Bioorg Med Chem Lett 1999, 9, 5, 743.
【2】 Johnson, A.T.; Chandraratna, R.A.; Vuligonda, V. (Allergan, Inc.); Benzo[1,2-g]-chrom-3-ene and benzo[1,2-g]-thiochrom-3-ene derivatives. EP 0948478; WO 9825875 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	34677	3-methyl-2-butenoic acid	541-47-9	C₅H₈O₂	详情	详情
(I)	29626	4-bromophenylhydrosulfide; 4-bromobenzenethiol	106-53-6	C₆H₅BrS	详情	详情
(II)	29627	3-[(4-bromophenyl)sulfanyl]-3-methylbutyric acid		C₁₁H₁₃BrO₂S	详情	详情
(III)	29628	6-bromo-2,2-dimethyl-2,3-dihydro-4H-thiochromen-4-one		C₁₁H₁₁BrOS	详情	详情
(IV)	29629	(4-methylphenyl)lithium		C₇H₇Li	详情	详情
(V)	29630	6-bromo-2,2-dimethyl-4-(4-methylphenyl)-4-thiochromanol		C₁₈H₁₉BrOS	详情	详情
(VI)	29631	6-bromo-2,2-dimethyl-4-(4-methylphenyl)-2H-thiochromene		C₁₈H₁₇BrS	详情	详情
(VII)	29632	2,2-dimethyl-4-(4-methylphenyl)-2H-thiochromene-6-carbaldehyde		C₁₉H₁₈OS	详情	详情
(VIII)	29633	ethyl 4-[1-(diethoxyphosphoryl)-3,3-dimethoxypropyl]benzoate		C₁₈H₂₉O₇P	详情	详情
(IX)	29634	ethyl 4-[(E)-1-(2,2-dimethoxyethyl)-2-[2,2-dimethyl-4-(4-methylphenyl)-2H-thiochromen-6-yl]ethenyl]benzoate		C₃₃H₃₆O₄S	详情	详情
(X)	29635	ethyl 4-[2,2-dimethyl-4-(4-methylphenyl)-2H-benzo[g]thiochromen-7-yl]benzoate		C₃₁H₂₈O₂S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

Treatment of azabicyclo[3.2.1]octene derivative (I) with lithiated compound (II) in THF followed by quenching with trifluoroacetic acid yields tropane (III), whose oxadiazole group is converted into a methyl ester by treatment with nickel boride (Ni2B) and HCl in refluxing methanol to provide the 2-beta,3-alpha stereoisomer (IV). Finally, the desired nortropane compound is obtained by refluxing tropane (IV) with alpha-chloroethyl chloroformate (ACE-Cl) in dichloromethane followed by solvolysis with methanol.

参考文献中间体

合成目标

【1】 Kuhar, M.J.; Blough, B.E.; Holmquist, C.R.; Carroll, F.I.; Abraham, P.; 3alpha-(4-Substituted phenyl) mortropane-2beta-carboxylic acid methyl esters show selective binding at the norepinephrine transporter. Bioorg Med Chem Lett 2000, 10, 21, 2445.
【2】 Holmquist, C.R.; et al.; 3alpha-(4'-Substituted phenyl)tropane-2beta-carboxylic acid methyl esters: Novel ligands with high affinity and selectivity at the dopamine transporter. J Med Chem 1996, 39, 21, 4139.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	47190	(1R,5S)-8-methyl-2-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]oct-2-ene	C₁₁H₁₅N₃O	详情	详情
(II)	29629	(4-methylphenyl)lithium	C₇H₇Li	详情	详情
(III)	47191	(1R,2R,3R,5S)-8-methyl-2-(3-methyl-1,2,4-oxadiazol-5-yl)-3-(4-methylphenyl)-8-azabicyclo[3.2.1]octane	C₁₈H₂₃N₃O	详情	详情
(IV)	47192	methyl (1R,2S,3R,5S)-8-methyl-3-(4-methylphenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate	C₁₇H₂₃NO₂	详情	详情

Extended Information