bromo[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]magnesium -Drug Synthesis Database

【结构式】

【分子编号】29184

【品名】bromo[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]magnesium

【CA登记号】

【分子式】C₁₂H₁₆BrMgNO

【分子量】294.47418

【元素组成】C 48.95% H 5.48% Br 27.13% Mg 8.25% N 4.76% O 5.43%

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：(XI)

Condensation of 4-(benzyloxy)benzaldehyde (VII) with N,N-dimethyl thioformamide (A) in the presence of LDA at -78 C generated the alpha-hydroxythioamide (VIII), which was cyclized by means of methanesulfonic acid to afford benzothiophene (IX). Friedel-Crafts acylation of (IX) with acid chloride (VI) upon heating in chlorobenzene yielded the 3-acyl benzothiophene (X). Subsequent displacement of the dimethylamino group of (X) by Grignard reagent (XI) produced the 2-aryl benzothiophene (XII). Deoxygenation of the keto group of (XII) was accomplished by the sequence of reduction to alcohol (XIII) with LiAlH4, followed by treatment with Et3SiH in trifluoroacetic acid to give (XIV). The benzyl ether of (XIV) was finally deprotected by hydrogenation over Pd/C to furnish the title compound.

参考文献中间体

合成目标

【1】 McCowan, J.R.; Sall, D.J.; Gifford-Moore, D.S.; Takeuchi, K.; Denney, M.L.; Kohn, T.J.; Smith, G.F.; Dibasic benzo[b]thiophene derivatives as a novel class of active site directed thrombin inhibitors: 4. SAR studies on the conformationally restricted C3-side chain of hydroxybenzo[b]thiophenes. Bioorg Med Chem Lett 1999, 9, 5, 759.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	29180	dimethylthioformamide	758-16-7	C₃H₇NS	详情	详情
(VI)	29178	3-methoxy-4-[[(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl]oxy]benzoyl chloride		C₁₈H₂₄ClNO₃	详情	详情
(VII)	29179	4-(Benzyloxy)benzaldehyde	4397-53-9	C₁₄H₁₂O₂	详情	详情
(VIII)	29181	2-[4-(benzyloxy)phenyl]-2-hydroxy-N,N-dimethylethanethioamide		C₁₇H₁₉NO₂S	详情	详情
(IX)	29182	6-(benzyloxy)-N,N-dimethyl-1-benzothiophen-2-amine		C₁₇H₁₇NOS	详情	详情
(X)	29183	[6-(benzyloxy)-2-(dimethylamino)-1-benzothiophen-3-yl](3-methoxy-4-[[(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl]oxy]phenyl)methanone		C₃₅H₄₀N₂O₄S	详情	详情
(XI)	29184	bromo[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]magnesium		C₁₂H₁₆BrMgNO	详情	详情
(XII)	29185	(6-(benzyloxy)-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-1-benzothiophen-3-yl)(3-methoxy-4-[[(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl]oxy]phenyl)methanone		C₄₅H₅₀N₂O₅S	详情	详情
(XIII)	29186	(6-(benzyloxy)-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-1-benzothiophen-3-yl)(3-methoxy-4-[[(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl]oxy]phenyl)methanol		C₄₅H₅₂N₂O₅S	详情	详情
(XIV)	29187	1-(2-[4-[6-(benzyloxy)-3-(3-methoxy-4-[[(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl]oxy]benzyl)-1-benzothiophen-2-yl]phenoxy]ethyl)pyrrolidine		C₄₅H₅₂N₂O₄S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VIII)

The condensation of 3-methoxyacetophenone (I) with benzaldehyde (II) by means of NaOH in ethanol - water gives 3'-methoxychalcone (III), which by addition of HCN (KCN) in ethanol-acetic acid is transformed into 2-phenyl-4-(3-methoxyphenyl)-4-oxobutyronitrile (IV). The hydrolysis of (IV) with aqueous H2SO4 at 100 C affords the corresponding ketoacid (V), which is reduced with amalgamated zinc and 2N HCl yielding 2-phenyl-4-(3-methoxyphenyl)butyric acid (VI). The cyclization of (VI) by means of liquid HF yields 2-phenyl-6-methoxy-1,2,3,4-tetrahydro-1-naphthalenone (VII), which is finally condensed with 4-(2-pyrrolidinoethoxy)phenylmagnesium bromide in refluxing THF.

参考文献中间体

合成目标

【1】 Thorpe, P.; Castañer, J.; Nafoxidine. Drugs Fut 1978, 3, 3, 211.
【2】 Duncan, G.W.; Lednicer, D.; US 3483293 .
【3】 Lednicer, D.; US 3274213 .

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)	18792	3-methoxyacetophenone; 1-(3-methoxyphenyl)-1-ethanone	586-37-8	C₉H₁₀O₂	详情	详情
(II)	10498	Benzaldehyde;Benzoic aldehyde;Phenylmethanal	100-52-7	C₇H₆O	详情	详情
(III)	39791	(E)-1-(3-methoxyphenyl)-3-phenyl-2-propen-1-one		C₁₆H₁₄O₂	详情	详情
(IV)	39792	4-(3-methoxyphenyl)-4-oxo-2-phenylbutanenitrile		C₁₇H₁₅NO₂	详情	详情
(V)	39793	4-(3-methoxyphenyl)-4-oxo-2-phenylbutyric acid		C₁₇H₁₆O₄	详情	详情
(VI)	39794	4-(3-methoxyphenyl)-2-phenylbutyric acid		C₁₇H₁₈O₃	详情	详情
(VII)	39795	6-methoxy-2-phenyl-3,4-dihydro-1(2H)-naphthalenone		C₁₇H₁₆O₂	详情	详情
(VIII)	29184	bromo[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]magnesium		C₁₂H₁₆BrMgNO	详情	详情

Extended Information