benzyl(bromo)magnesium; benzylmagnesium bromide -Drug Synthesis Database

【结构式】

【分子编号】28308

【品名】benzyl(bromo)magnesium; benzylmagnesium bromide

【CA登记号】1589-82-8

【分子式】C₇H₇BrMg

【分子量】195.34158

【元素组成】C 43.04% H 3.61% Br 40.9% Mg 12.44%

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 4-aminobenzophenone (I) with benzylmagnesium bromide (II) in ether gives the carbinol (III), which by reaction with acetic anhydride in hot pyridine yields the olefinic acetamide (IV). The chlorination of (IV) with Cl2 in CCl4 followed by refluxing in the same solvent affords the chlorovinyl acetamide (V), which is alkylated at the amidic nitrogen with 2-chloroethyl(diethyl)amine (VI) by means of KOH in refluxing acetone giving the disubstituted acetamide (VII). Finally, the deacetylation of (VII) with hot 10% HCl and salification with citric acid affords the target compound.

参考文献中间体

合成目标

【1】 Bitonti, A.J.; Baumann, R.J. (Merrell Pharmaceuticals, Inc.); Non-metabolizable clomiphene analogs for treatment of tamoxifen-resistant tumors. EP 0660821; JP 1997500863; WO 9406762 .

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)	28307	(4-aminophenyl)(phenyl)methanone	1137-41-3	C₁₃H₁₁NO	详情	详情
(II)	28308	benzyl(bromo)magnesium; benzylmagnesium bromide	1589-82-8	C₇H₇BrMg	详情	详情
(III)	28309	1-(4-aminophenyl)-1,2-diphenyl-1-ethanol		C₂₀H₁₉NO	详情	详情
(IV)	28310	N-[4-[(Z)-1,2-diphenylethenyl]phenyl]acetamide		C₂₂H₁₉NO	详情	详情
(V)	28311	N-[4-[(E)-2-chloro-1,2-diphenylethenyl]phenyl]acetamide		C₂₂H₁₈ClNO	详情	详情
(VI)	16194	2-chloro-N,N-diethyl-1-ethanamine; N-(2-chloroethyl)-N,N-diethylamine	100-35-6	C₆H₁₄ClN	详情	详情
(VII)	28312	N-[4-[(E)-2-chloro-1,2-diphenylethenyl]phenyl]-N-[2-(diethylamino)ethyl]acetamide		C₂₈H₃₁ClN₂O	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

This compound has been obtained by three related ways: 1.- The Grignard condensation of ethyl cyclohexanecarboxylate (I) with benzylmagnesium bromide (II) in THF gives 1-cyclohexyl-2-phenylethanone (III), which is condensed with bromoacetaldehyde diethyl acetal (IV) by means of potassium tert-butoxide in DMSO to yield 4-cyclohexyl-4-oxo-3-phenylbutyraldehyde diethylacetal (V). The methylation of (V) by means of methyl iodide and potassium tert-butoxide in the same solvent affords 4-cyclohexyl-3-methyl-4-oxo-3-phenylbutyraldehyde diethylacetal (VI), which is treated with HCl in acetone to give the corresponding aldehyde (VII). The reductocondensation of (VII) with 1-(2-methoxyphenyl)piperazine (VIII) by means of sodium triacetoxyborohydride in dichloromethane/acetic acid yields 1-cyclohexyl-4-[4-(2-methoxyphenyl)piperazin-1-yl]-2-methyl-2-phenyl-1-butanone (X) as a racemic mixture, which is resolved by chiral chromatography over a Chiralpak AD column. 2.- The Grignard condensation of 2-phenylpropionaldehyde (XI) with cyclohexylmagnesium chloride (XII) in ethyl ether/THF gives 1-cyclohexyl-2-phenyl-1-propanol (XIII), which is oxidized with DMSO and P2O5 in dichloromethane yielding the corresponding ketone (XIV). The condensation of (XIV) with allyl bromide by means of potassium tert-butoxide in THF affords 1-cyclohexyl-2-methyl-2-phenyl-4-penten-1-one (XV), which is ozonolyzed with O3 in methanol catalyzed by a small amount of Sudan III affording the previously reported aldehyde (VII). 3.- The condensation of aldehyde (VII) with 1-(2-methoxyphenyl)piperazine (VIII) can also be performed in isopropyl acetate giving 1-cyclohexyl-4-[4-(2-methoxyphenyl)piperazin-1-yl]-2-methyl-2-phenyl-3-buten-1-one (IX), which is hydrogenated with H2 over Pd/C in isopropanol to afford the previously reported racemic mixture (X).

参考文献中间体

合成目标

【1】 Xu, Y.C.; et al.; Synthesis and pharmacology of LY426965: A potent, selective orally active, and long-lasting 5-HT1A receptor antagonist. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 107.
【2】 Kohlman, D.T.; O'Toole, J.C.; Godfrey, A.G.; Xu, Y.-C.; Zhang, T.Y. (Eli Lilly and Company); Arylpiperazines having activity at the serotonin 1A receptor. EP 0924205; WO 9931077 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	11463	3-Bromo-1-propene; 3-Bromopropene；allyl bromide	106-95-6	C₃H₅Br	详情	详情
(I)	31858	ethyl cyclohexanecarboxylate	3289-28-9	C₉H₁₆O₂	详情	详情
(II)	28308	benzyl(bromo)magnesium; benzylmagnesium bromide	1589-82-8	C₇H₇BrMg	详情	详情
(III)	31859	1-cyclohexyl-2-phenyl-1-ethanone		C₁₄H₁₈O	详情	详情
(IV)	12113	2-Bromo-1-ethoxyethyl ethyl ether; 2-Bromo-1,1-diethoxyethane; Bromoacetaldehyde diethylacetal	2032-35-1	C₆H₁₃BrO₂	详情	详情
(V)	31860	1-cyclohexyl-4,4-diethoxy-2-phenyl-1-butanone		C₂₀H₃₀O₃	详情	详情
(VI)	31861	1-cyclohexyl-4,4-diethoxy-2-methyl-2-phenyl-1-butanone		C₂₁H₃₂O₃	详情	详情
(VII)	31862	4-cyclohexyl-3-methyl-4-oxo-3-phenylbutanal		C₁₇H₂₂O₂	详情	详情
(VIII)	11882	1-(2-Methoxyphenyl)piperazine; Methyl 2-piperazinophenyl ether; 1-(2-Methoxyphenyl)-piperazine	35386-24-4	C₁₁H₁₆N₂O	详情	详情
(IX)	31863	(E)-1-cyclohexyl-4-[4-(2-methoxyphenyl)-1-piperazinyl]-2-methyl-2-phenyl-3-buten-1-one		C₂₈H₃₆N₂O₂	详情	详情
(X)	31864	1-cyclohexyl-4-[4-(2-methoxyphenyl)-1-piperazinyl]-2-methyl-2-phenyl-1-butanone		C₂₈H₃₈N₂O₂	详情	详情
(XI)	31865	hydratropaldehyde	93-53-8	C₉H₁₀O	详情	详情
(XII)	31866	chloro(cyclohexyl)magnesium		C₆H₁₁ClMg	详情	详情
(XIII)	31867	1-cyclohexyl-2-phenyl-1-propanol		C₁₅H₂₂O	详情	详情
(XIV)	31868	1-cyclohexyl-2-phenyl-1-propanone		C₁₅H₂₀O	详情	详情
(XV)	31869	1-cyclohexyl-2-methyl-2-phenyl-4-penten-1-one		C₁₈H₂₄O	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

Addition of benzylmagnesium bromide to 4-chlorobutyronitrile (II) gives rise to the chloro ketone adduct (III). Subsequent chloride displacement with ethylenediamine (IV) furnishes the target diamino ketone.

参考文献中间体

合成目标

【1】 Andreadou, I.; Rekka, E.A.; Demopoulos, V.J.; Bijloo, G.J.; Kourounakis, P.N.; Synthesis, antioxidant and anti-inflammatory activity of novel substituted ethylenediamines and ethanolamines. A preliminary quantitative structure-activity relationship study. Arzneim-Forsch Drug Res 1997, 47, 5, 643.

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)	28308	benzyl(bromo)magnesium; benzylmagnesium bromide	1589-82-8	C₇H₇BrMg	详情	详情
(II)	11179	4-Chlorobutanenitrile; 4-Chlorobutyronitrile	628-20-6	C₄H₆ClN	详情	详情
(III)	64973	5-chloro-1-phenyl-2-pentanone		C₁₁H₁₃ClO	详情	详情
(IV)	14754	ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine；1,2-Ethanediamine	107-15-3	C₂H₈N₂	详情	详情

Extended Information