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【结 构 式】 
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【分子编号】19395 【品名】1-chloro-4-iodobenzene 【CA登记号】637-87-6 |
【 分 子 式 】C6H4ClI 【 分 子 量 】238.45493 【元素组成】C 30.22% H 1.69% Cl 14.87% I 53.22% |
合成路线1
该中间体在本合成路线中的序号：(XI)Alternatively, the target compound can be obtained as follows: Condensation between 2,6-dichloro-4-methylbenzonitrile (X) and 4-chloroiodobenzene (XI) by means of Mg in refluxing ether gives methyleneimine derivative (XII), which is then converted into 4-(4-chlorobenzoyl)-3,5-dichlorotoluene (XIII) by refluxing in dioxane-aqueous phosphate buffer. (Alternatively, compound (XIII) can also be obtained either by condensation of 3,5-dichlorotoluene (XIV) with p-chlorobenzoyl chloride (IV) by means of BuLi in THF or by treatment of 2,6-dichloro-4-methylbenzoic acid (XV) with thionyl chloride (SOCl2) in refluxing DMF to give (XVI), which then reacts with chlorobenzene (XVII) by means of AlCl3 in refluxing CCl4). Bromination of (XIII) is then performed by reaction with N-bromosuccinimide and dibenzoyl peroxide in refluxing benzene to give 4-(4-chlorobenzoyl)-3,5-dichlorobenzyl bromide (XVIII). (Alternatively, (XVIII) can also be synthesized by treatment of the already reported benzophenone derivative (V) with HOAc in THF/H2O followed by reaction with phosphorus tribromide in diethyl ether.) Finally, (XVIII) is converted into the desired compound either by treatment with 5-amino-1,2,3-triazole-4-carboxamide (XIX) by means of NaH in refluxing EtOH or by first reaction of (XVIII) with KN3 in refluxing EtOH to furnish benzyl azide (VIII), followed by reaction with cyanoacetamide (IX) and NaOMe in refluxing EtOH.
| 【1】 Bochis, R.J.; Chabala, J.C.; Fisher, M.H. (Merck & Co., Inc.); 5-(Amino or substd.amino)-1,2,3-triazoles. EP 0151529; JP 1985188376; US 4590201 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 10295 | p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride | 122-01-0 | C7H4Cl2O | 详情 | 详情 |
| (V) | 49484 | [4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2,6-dichlorophenyl](4-chlorophenyl)methanone | C20H23Cl3O2Si | 详情 | 详情 | |
| (VIII) | 49487 | [4-(azidomethyl)-2,6-dichlorophenyl](4-chlorophenyl)methanone | C14H8Cl3N3O | 详情 | 详情 | |
| (IX) | 12122 | Cyanoacetamide; 2-Cyanoacetamide | 107-91-5 | C3H4N2O | 详情 | 详情 |
| (X) | 49488 | 2,6-dichloro-4-methylbenzonitrile | C8H5Cl2N | 详情 | 详情 | |
| (XI) | 19395 | 1-chloro-4-iodobenzene | 637-87-6 | C6H4ClI | 详情 | 详情 |
| (XII) | 49489 | (4-chlorophenyl)(2,6-dichloro-4-methylphenyl)methanimine | C14H10Cl3N | 详情 | 详情 | |
| (XIII) | 49490 | (4-chlorophenyl)(2,6-dichloro-4-methylphenyl)methanone | C14H9Cl3O | 详情 | 详情 | |
| (XIV) | 49491 | 1,3-dichloro-5-methylbenzene | C7H6Cl2 | 详情 | 详情 | |
| (XV) | 49492 | 2,6-dichloro-4-methylbenzoic acid | C8H6Cl2O2 | 详情 | 详情 | |
| (XVI) | 49493 | 2,6-dichloro-4-methylbenzoyl chloride | C8H5Cl3O | 详情 | 详情 | |
| (XVII) | 10190 | 1-Chlorobenzene | 108-90-7 | C6H5Cl | 详情 | 详情 |
| (XVIII) | 49494 | [4-(bromomethyl)-2,6-dichlorophenyl](4-chlorophenyl)methanone | C14H8BrCl3O | 详情 | 详情 | |
| (XIX) | 49495 | 5-amino-1H-1,2,3-triazole-4-carboxamide | C3H5N5O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Aryl lithium reagent (II) (prepared by halogen-metal exchange of 1-chloro-4-iodobenzene (I) with tert-butyllithium at -60 C), was added to 1,4-cyclohexanedione mono-ethylene ketal (III) to yield tertiary alcohol (IV). Then, mild acid hydrolysis of (IV) with pyridinium tosylate in aqueous acetone provided ketone (V). Deoxygenation of the benzylic alcohol of (V) with P2I4 in refluxing benzene produced the arylcyclohexanone (VI), which was further reduced to the trans cyclohexanol (VII) with NaBH4 in MeOH. Subsequent acylation of (VIII) with oxalyl chloride, followed by an aqueous quench furnished the oxalic acid monoester (VIII). The free-radical decarboxylative coupling of (VIII) with 2-chloronaphthoquinone (IX), promoted by ammonium persulfate and a trace of AgNO3 under phase-transfer conditions, provided the desired cyclohexylquinone (X) together with the cyclohexyl ester (XI) as mixtures of cis and trans isomers, which were separated by flash chromatography. Finally, conversion of the trans-(X) to the target hydroxylated compound was performed by treatment with KOH in boiling MeOH.
| 【1】 Frank, A.; Karn, H.; Spanig, H. (Abbott GmbH & Co. KG); Production of 1-hydroxyalkyl-5-nitroimidazoles. DE 2359625; FR 2253019; GB 1481349 . |
| 【2】 Frank, A.; Dockner, T.; Karn, H. (Abbott GmbH & Co. KG); Process for the preparation of 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole of high purity. EP 0150407 . |
| 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) | 19395 | 1-chloro-4-iodobenzene | 637-87-6 | C6H4ClI | 详情 | 详情 |
| (II) | 19396 | (4-chlorophenyl)lithium | C6H4ClLi | 详情 | 详情 | |
| (III) | 11377 | 1,4-Dioxaspiro[4.5]decan-8-one | 4746-97-8 | C8H12O3 | 详情 | 详情 |
| (IV) | 19398 | 8-(4-chlorophenyl)-1,4-dioxaspiro[4.5]decan-8-ol | C14H17ClO3 | 详情 | 详情 | |
| (V) | 19399 | 4-(4-chlorophenyl)-4-hydroxycyclohexanone | C12H13ClO2 | 详情 | 详情 | |
| (VI) | 19400 | 4-(4-chlorophenyl)cyclohexanone | C12H13ClO | 详情 | 详情 | |
| (VII) | 19401 | 4-(4-chlorophenyl)cyclohexanol | C12H15ClO | 详情 | 详情 | |
| (VIII) | 19402 | 2-[[4-(4-chlorophenyl)cyclohexyl]oxy]-2-oxoacetic acid | C14H15ClO4 | 详情 | 详情 | |
| (IX) | 19403 | 2-chloronaphthoquinone | 1010-60-2 | C10H5ClO2 | 详情 | 详情 |
| (X) | 19404 | 2-chloro-3-[4-(4-chlorophenyl)cyclohexyl]naphthoquinone | C22H18Cl2O2 | 详情 | 详情 | |
| (XI) | 19405 | 4-(4-chlorophenyl)cyclohexyl 3-chloro-1,4-dioxo-1,4-dihydro-2-naphthalenecarboxylate | C23H18Cl2O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)An improved procedure, amenable to the industrial synthesis of the precursor (I) was further developed. Heck coupling of p-chloroiodobenzene (III) with allyl alcohol (IV) in the presence of tetramethylammonium chloride and a catalytic amount of palladium acetate provided 3-(p-chlorophenyl)propanal (V) along with minor amounts of its branched isomer (VI). Further reduction of this mixture with NaBH4 led to the respective alcohols (VII) and (VIII). Only the desired alcohol (VII) underwent bromination to the desired bromide (IX) in the presence of PBr3 in hot toluene, whereas the branched alcohol (VIII) was dehydrohalogenated to olefin (X). Subsequent alkylation of pyridazinedione (XI) with the above reaction mixture afforded the pure intermediate
| 【1】 Matsumoto, H.; Kamikawaji, M.; Horiuchi, T. (Nissan Chemical Industry, Ltd.); Processes for the preparation of (p-chlorophenyl)propanol derivs.. EP 1138660; WO 0035843 . |
| 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) | 60514 | 4,5-dibromo-6-[3-(4-chlorophenyl)propoxy]-3(2H)-pyridazinone | C13H11Br2ClN2O2 | 详情 | 详情 | |
| (III) | 19395 | 1-chloro-4-iodobenzene | 637-87-6 | C6H4ClI | 详情 | 详情 |
| (IV) | 12234 | 2-Propen-1-ol; Allyl alcohol | 107-18-6 | C3H6O | 详情 | 详情 |
| (V) | 60515 | 3-(4-chlorophenyl)propanal | C9H9ClO | 详情 | 详情 | |
| (VI) | 60516 | 2-(4-chlorophenyl)propanal | C9H9ClO | 详情 | 详情 | |
| (VII) | 60517 | 3-(4-chlorophenyl)-1-propanol | C9H11ClO | 详情 | 详情 | |
| (VIII) | 60518 | 2-(4-chlorophenyl)-1-propanol | C9H11ClO | 详情 | 详情 | |
| (IX) | 60520 | 1-(3-bromopropyl)-4-chlorobenzene | C9H10BrCl | 详情 | 详情 | |
| (X) | 60519 | 1-chloro-4-isopropenylbenzene | C9H9Cl | 详情 | 详情 | |
| (XI) | 63949 | 4,5-dibromo-1,2-dihydro-3,6-pyridazinedione | C4H2Br2N2O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VI)Treatment of carboxylic acid (I) with refluxing cyclohexanone (II) and H2SO4 affords derivative (III), which is then condensed with propargyl bromide (IV) by means of NaH in DMF to yield propargyl ether (V). Treatment of (V) with Et3N in toluene followed by condensation with 4-cloro-iodobenzene (VI) by means of PdCl2, PPh3 and CuI provides propinyloxy derivative (VII), which is then converted into propenyloxy derivative (VIII) by hydrogenation over Pd/ BaSO4 in pyridine. Opening of the lactone ring of (VIII) by means of NaH in MeOH and THF affords methyl ester (IX), which is then condensed with benzoyl chloride (X) by means of DMAP and Et3N in CH2Cl2 to give benzoate (XI). Treatment of (XI) with Et2Zn and chloroiodomethane in dichloroethane (or alternatively in CH2Cl2 or THF) followed by recrystallization from isopropanol furnishes cyclopropane derivative (XII), which is then hydrolyzed by treatment with NaOH in dioxane to yield alcohol (XIII). Finally, (XIII) is condensed with intermediate (XIV) by means of NaH in DMF and then deprotected by treatment with HCl in dioxane to afford the target compound.
| 【1】 Hemmerle, H.; Schindler, P.; Herling, A. (Aventis SA); Derivs. of substd. cyclohexane, their process of preparation and their application for the treatment of diseases. EP 0587088; JP 1994211736; US 5463062 . |
| 【2】 Hemmerle, H.; Schubert, G.; Burger, H.-J.; Herling, A.; Efendic, S. (Aventis SA); Cyclohexane derivs., processes for their preparation and their use as glucose-6-phosphatase inhibitors. CA 2149007; CA 4416433; EP 0682024; JP 1995330767; US 5739147 . |
| 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) | 44864 | Quinic acid; 1,3,4,5-tetrahydroxycyclohexanecarboxylic acid | C7H12O6 | 详情 | 详情 | |
| (II) | 11059 | Cyclohexanone | 108-94-1 | C6H10O | 详情 | 详情 |
| (III) | 44855 | C13H18O5 | 详情 | 详情 | ||
| (IV) | 11176 | 3-Bromopropyne; 3-Bromo-1-propyne | 106-96-7 | C3H3Br | 详情 | 详情 |
| (V) | 44856 | C16H20O5 | 详情 | 详情 | ||
| (VI) | 19395 | 1-chloro-4-iodobenzene | 637-87-6 | C6H4ClI | 详情 | 详情 |
| (VII) | 44857 | C22H23ClO5 | 详情 | 详情 | ||
| (VIII) | 44858 | C22H25ClO5 | 详情 | 详情 | ||
| (IX) | 44859 | C23H29ClO6 | 详情 | 详情 | ||
| (X) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
| (XI) | 44860 | C30H33ClO7 | 详情 | 详情 | ||
| (XII) | 44861 | C31H35ClO7 | 详情 | 详情 | ||
| (XIII) | 44862 | C23H29ClO6 | 详情 | 详情 | ||
| (XIV) | 44863 | C17H12N6O | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)The oxidation of p-chloroiodobenzene (I) with peracetic acid (II) in acetic acid affords 4-chloroiodosobenzene diacetate (III), which is then condensed with thiophene (IV) by means of acetic anhydride and trifluoroacetic acid yielding (p-chlorophenyl)-2-thienyliodonium trifluoroacetate (V). Finally this salt is treated with HCl in aqueous formic acid. (1-4)
| 【1】 Moyle, C.L. (Dow Chem. Co.); US 3885036 . |
| 【2】 Castaner, J.; Blancafort, P.; Tiodonium chloride. Drugs Fut 1977, 7, 6, 407. |
| 【3】 Moyle, C.L. (Dow Chem. Co.); DE 2145733; GB 1351531 . |
| 【4】 Moyle, C.L. (Dow Chem. Co.); US 3763187 . |
| 【5】 Moyle, C.L. (Dow Chem. Co.); FR 2153532 . |
| 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) | 19395 | 1-chloro-4-iodobenzene | 637-87-6 | C6H4ClI | 详情 | 详情 |
| (II) | 54916 | Peracetic acid; Peroxyacetic acid | 79-21-0 | C2H4O3 | 详情 | 详情 |
| (III) | 60922 | bis(acetyloxy)(4-chlorophenyl)-lambda~3~-iodane | C10H10ClIO4 | 详情 | 详情 | |
| (IV) | 13297 | Thiophene | 110-02-1 | C4H4S | 详情 | 详情 |
| (V) | 60923 | (4-chlorophenyl)(2-thienyl)iodonium | C12H7ClF3IO2S | 详情 | 详情 |