Glycerine; Glycerin; Glycerol -Drug Synthesis Database

【结构式】

【分子编号】13289

【品名】Glycerine; Glycerin; Glycerol

【CA登记号】56-81-5

【分子式】C₃H₈O₃

【分子量】92.09472

【元素组成】C 39.13% H 8.76% O 52.12%

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：(II)

The cyclization of 2,4-dichlorophenacyl bromide (I) with glycerol (II) gives cis-2-(2,4-dichlorophenyl)-2-bromomethyl-4-hydroxymethyl-1,3-dioxolane (III), which is then benzoylated with benzoyl chloride (A) yielding cis-2-(2,4-dichlorophenyl)-2-bromomethyl-4-benzoyloxymethyl-1,3-dioxolane (IV). The condensation of (IV) with 1H-imidazole (V) affords cis-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-4-benzoyloxymethyl-1,3-dioxolane (VI), which is then debenzoylated in basic medium giving cis-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-4-hydroxymethyl-1,3-dioxolane (VII). The reaction of (VII) with methanesulfonyl chloride (B) yields cis-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethyl methanesulfonate (VIII). Finally, this compound is condensed with 1-acetyl-4-(4-hydroxyphenyl)piperazine (IX) by means of NaH in benzene - DMSO. Compound (IX) is obtained by reaction of 4-(1-piperazinyl)phenol dihydrobromide (X) with acetic anhydride by means of K2CO3 in refluxing acetic acid.

参考文献中间体

合成目标

【1】 Heeres, J.; et al.; DE 2804096 .
【2】 Blancafort, P.; Sweetman, A.J.; Castaner, J.; Serradell, M.N.; Ketoconazole. Drugs Fut 1979, 4, 7, 496.
【3】 Backx, L.J.J.; Mostmans, J.H.; Heeres, J. (Janssen Pharmaceutica NV); 1-(1,3-Dioxolan-2-ylmethyl)-1H-imidazoles. US 4335125 .

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)	10463	Benzoyl chloride	98-88-4	C₇H₅ClO	详情	详情
(B)	13467	Methanesulfonyl chloride;Mesyl chloride;Methylsulfonyl chloride;Methanesulfonic acid chloride;Methanesulfonyl chloride;Methanesulphonyl chloride	124-63-0	CH₃ClO₂S	详情	详情
(I)	36408	2-bromo-1-(2,4-dichlorophenyl)-1-ethanone		C₈H₅BrCl₂O	详情	详情
(II)	13289	Glycerine; Glycerin; Glycerol	56-81-5	C₃H₈O₃	详情	详情
(III)	39602	[(2S,4R)-2-(bromomethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl]methanol		C₁₁H₁₁BrCl₂O₃	详情	详情
(IV)	30485	[(2S,4S)-2-(bromomethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl]methyl benzoate; cis-2-(bromomethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl]methyl benzoate		C₁₈H₁₅BrCl₂O₄	详情	详情
(V)	10255	Imidazole; 1H-Imidazole	288-32-4	C₃H₄N₂	详情	详情
(VI)	39603	[(2S,4S)-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methyl benzoate		C₂₁H₁₈Cl₂N₂O₄	详情	详情
(VII)	39604	[(2S,4R)-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methanol	170210-50-1	C₁₄H₁₄Cl₂N₂O₃	详情	详情
(VIII)	39605	[(2S,4S)-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methyl methanesulfonate; cis-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methyl methanesulfonate		C₁₅H₁₆Cl₂N₂O₅S	详情	详情
(IX)	29119	1-Acetyl-4-(4-hydoxyphenyl)piperazine; 1-[4-(4-hydroxyphenyl)-1-piperazinyl]-1-ethanone; N-Acetyl-4-(4-hydoxyphenyl)piperazine	67914-60-7	C₁₂H₁₆N₂O₂	详情	详情
(X)	39606	4-(1-piperazinyl)phenol; 1-(4-Hydroxyphenyl)piperazine	56621-48-8	C₁₀H₁₄N₂O	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

The synthesis of erbulozole, starting from 1-(4-methoxyphenyl)-2-(1H-imidazol-1-yl)ethanone (I) is outlined. Ketalization of (I) with glycerin (II) was performed in n-heptane with p-toluenesulfonic acid as the catalyst and under azeotropic removal of H2O. The resulting dioxolane derivative (III), arising as a cis-trans mixture, was benzoylated to the ester (IV). Cis-trans isomers were separated by column chromatography over silica gel (Merck, Silica gel 60), using a mixture of trichloromethane and methanol (98:2 by volume) as the eluent. Saponification of the cis-benzoate (V) with sodium hydroxide in dioxane-water medium at room temperature afforded the alcohol (VI), which was converted to the methanesulfonate (VII) with methanesulfonylchloride in dry pyridine and methylenechloride (1:1 by volume). Under a nitrogen atmosphere, compound (VII) was coupled with (VIII) in acetone using K2CO3 as an acid acceptor to the target compound, erbulozole.

参考文献中间体

合成目标

【1】 Van Ginckel, R.; Geuens, G.; Heeres, J.; Tubulozole Hydrochloride. Drugs Fut 1984, 9, 12, 911.
【2】 Distelmans, R.; Van Ginckel, R.; Van Der Veken, L.J.E.; Heeres, J.; Erbulozole. Drugs Fut 1991, 16, 6, 507.

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)	13288	2-(1H-Imidazol-1-yl)-1-(4-methoxyphenyl)-1-ethanone		C₁₂H₁₂N₂O₂	详情	详情
(II)	13289	Glycerine; Glycerin; Glycerol	56-81-5	C₃H₈O₃	详情	详情
(III)	13290	[2-(1H-Imidazol-1-ylmethyl)-2-(4-methoxyphenyl)-1,3-dioxolan-4-yl]methanol		C₁₅H₁₈N₂O₄	详情	详情
(IV)	13291	[2-(1H-imidazol-1-ylmethyl)-2-(4-methoxyphenyl)-1,3-dioxolan-4-yl]methyl benzoate		C₂₂H₂₂N₂O₅	详情	详情
(V)	13292	[(2R,4R)-2-(1H-imidazol-1-ylmethyl)-2-(4-methoxyphenyl)-1,3-dioxolan-4-yl]methyl benzoate		C₂₂H₂₂N₂O₅	详情	详情
(VI)	13293	[(2R,4S)-2-(1H-Imidazol-1-ylmethyl)-2-(4-methoxyphenyl)-1,3-dioxolan-4-yl]methanol		C₁₅H₁₈N₂O₄	详情	详情
(VII)	13294	[(2R,4R)-2-(1H-imidazol-1-ylmethyl)-2-(4-methoxyphenyl)-1,3-dioxolan-4-yl]methyl methanesulfonate		C₁₆H₂₀N₂O₆S	详情	详情
(VIII)	13295	ethyl 4-sulfanylphenylcarbamate		C₉H₁₁NO₂S	详情	详情

合成路线3

该中间体在本合成路线中的序号：(II)

8-Methoxyquinoline-5-carboxylic acid (III) was prepared by Skraup synthesis from 3-amino-4-methoxybenzoic acid (I) and glycerol (II) in sulfuric acid at 180 C. Subsequent treatment of (III) with oxalyl chloride using a catalytic amount of DMF gave the corresponding acid chloride (IV), which was finally coupled with 4-amino-3,5-dichloropyridine (V) in the presence of NaH in DMF to provide the target amide.

参考文献中间体

合成目标

【1】 Buckley, G.M.; et al.; 8-Methoxyquinoline-5-carboxamides as PDE4 inhibitors: A potential treatment for asthma. Bioorg Med Chem Lett 2002, 12, 12, 1613.
【2】 Dyke, H.J.; Montana, J.G.; Lowe, C.; Kendall, H.J.; Sabin, V.M. (Celltech Group plc); Quinoline carboxamides as TNF inhibitors and as PDE-IV inhibitors. EP 0952832; JP 2000510865; US 5804588; WO 9744036 .

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)	30419	3-amino-4-methoxybenzoic acid	2840-26-8	C₈H₉NO₃	详情	详情
(II)	13289	Glycerine; Glycerin; Glycerol	56-81-5	C₃H₈O₃	详情	详情
(III)	30420	8-methoxy-5-quinolinecarboxylic acid		C₁₁H₉NO₃	详情	详情
(IV)	30421	8-methoxy-5-quinolinecarbonyl chloride		C₁₁H₈ClNO₂	详情	详情
(V)	25135	3,5-dichloro-4-pyridinamine; 4-amino-3,5-dichloropyridine	22889-78-7	C₅H₄Cl₂N₂	详情	详情

合成路线4

该中间体在本合成路线中的序号：(II)

Bromoacetophenone (I) was converted into a cis/trans mixture of ketals (III) by treatment with glycerin (II) and p-toluenesulfonic acid. Subsequent reaction of (III) with 2-naphthalenesulfonyl chloride gave the corresponding mixture of sulfonate esters. After separation of the desired cis-isomer (IV), its condensation with the phenol derivative (V) produced ether (VI). Finally, displacement of the bromine atom of (VI) with 3-mercapto-4-methyl-1,2,4-triazole (VII) using Na2CO3 in DMF gave rise to the title thioether.

参考文献中间体

合成目标

【1】 Backx, L.; Meerpoel, L.; Heeres, J.; et al.; Structure-activity relationship of a novel chemical family of MTP inhibitors with lipid-lowering properties. 16th Int Symp Med Chem (Sept 18 2000, Bologna) 2000, Abst PA-142.

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)	16720	2-bromo-1-(4-chlorophenyl)-1-ethanone; 2-Bromo-4'-chloroacetophenone	536-38-9	C₈H₆BrClO	详情	详情
(II)	13289	Glycerine; Glycerin; Glycerol	56-81-5	C₃H₈O₃	详情	详情
(III)	44994	[2-(bromomethyl)-2-(4-chlorophenyl)-1,3-dioxolan-4-yl]methanol		C₁₁H₁₂BrClO₃	详情	详情
(IV)	44990	[(2S,4S)-2-(bromomethyl)-2-(4-chlorophenyl)-1,3-dioxolan-4-yl]methyl 2-naphthalenesulfonate		C₂₁H₁₈BrClO₅S	详情	详情
(V)	44991	4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2-[(1R)-1-methylpropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one		C₂₂H₂₇N₅O₂	详情	详情
(VI)	44992	4-[4-[4-(4-[[(2S,4R)-2-(bromomethyl)-2-(4-chlorophenyl)-1,3-dioxolan-4-yl]methoxy]phenyl)-1-piperazinyl]phenyl]-2-[(1R)-1-methylpropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one		C₃₃H₃₇BrClN₅O₄	详情	详情
(VII)	44993	4-methyl-4H-1,2,4-triazole-3-thiol; 4-methyl-4H-1,2,4-triazol-3-ylhydrosulfide		C₃H₅N₃S	详情	详情

Extended Information