chloro(cyclohexyl)magnesium -Drug Synthesis Database

【结构式】

【分子编号】31866

【品名】chloro(cyclohexyl)magnesium

【CA登记号】

【分子式】C₆H₁₁ClMg

【分子量】142.91104

【元素组成】C 50.43% H 7.76% Cl 24.81% Mg 17.01%

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：(XII)

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2

该中间体在本合成路线中的序号：(IV)

Alkylation of 3-benzoylpyridine (I) with methyl 2-bromopropionate (II) in refluxing acetone afforded pyridinium salt (III). The subsequent regiospecific copper-catalyzed condensation of (III) with cyclohexylmagesium chloride (IV) yielded dihydropyridine (V). Finally, ammonolysis of the methyl acetate ester of (V) provided the title amide.

参考文献中间体

合成目标

【1】 Agudoawu, S.A.; et al.; Synthesis and analgesic activity of 2-methyl-2-[1-(3-benzoyl-4-substituted-1,4-dihydropyridyl)]acetic acid methyl esters, acetic acids, and acetamides. Arch Pharm 1999, 332, 6, 213.

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)	27766	phenyl(3-pyridinyl)methanone	5424-19-1	C₁₂H₉NO	详情	详情
(II)	34941	methyl 2-bromopropanoate; 2-bromopropionic acid methyl ester	5445-17-0	C₄H₇BrO₂	详情	详情
(III)	34942	3-benzoyl-1-(2-methoxy-1-methyl-2-oxoethyl)pyridinium bromide		C₁₆H₁₆BrNO₃	详情	详情
(IV)	31866	chloro(cyclohexyl)magnesium		C₆H₁₁ClMg	详情	详情
(V)	34943	methyl 2-[3-benzoyl-4-cyclohexyl-1(4H)-pyridinyl]propanoate		C₂₂H₂₇NO₃	详情	详情

Extended Information