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【结 构 式】 
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【分子编号】30256 【品名】6-chloronicotinoyl chloride 【CA登记号】58757-38-3 |
【 分 子 式 】C6H3Cl2NO 【 分 子 量 】176.00136 【元素组成】C 40.95% H 1.72% Cl 40.29% N 7.96% O 9.09% |
合成路线1
该中间体在本合成路线中的序号：(I)Friedel-Crafts acylation of benzene with 6-chloronicotinyl chloride (I) using AlCl3 afforded ketone (II). Subsequent displacement of the chlorine atom of (II) by means of ethanolic ammonia at 145 C in a pressure reactor led to the aminopyridine (III), which was converted to sulfonamide (IV) by means of tosyl chloride in pyridine. Alkylation of the pyridine N of (IV) with iodoacetamide gave (V), and further cyclization in the presence of trifluoroacetic anhydride produced the imidazopyridine (VI). Phosphonate (VIII) was prepared by treatment of triethyl phosphonoacetate (VII) with methylamine. Horner-Emmons condensation of this phosphonate with ketone (VI) yielded the E-propenamide (IX). Selective iodination of (IX) at position 3 using N-iodosuccinimide furnished iodide (X). This compound was first deprotonated with PhLi, then subjected to a halogen-metal exchange reaction with tert-butyllithium, and the resulting trianion was reacted with isopropyl isopropanethiolsulfonate to give sulfide (XI). Finally, smooth hydrolysis of the trifluoroacetamide group of (XI) employing MeOH-CH2Cl2 in the presence of silica gel provided the title compound.
| 【1】 Hamdouchi, C.; de Blas, J.; del Prado, M.; Gruber, J.; Heinz, B.A.; Vance, L.; 2-Amino-3-substituted-6-[(E)-1-phenyl-2-(N-methylcarbamoyl)vinyl]imidazo[1,2-a]pyridines as a novel class of inhibitors of human rhinovirus: Stereospecific synthesis and antiviral activity. J Med Chem 1999, 42, 1, 50. |
| 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) | 30256 | 6-chloronicotinoyl chloride | 58757-38-3 | C6H3Cl2NO | 详情 | 详情 |
| (II) | 30257 | (6-chloro-3-pyridinyl)(phenyl)methanone | C12H8ClNO | 详情 | 详情 | |
| (III) | 30258 | (6-amino-3-pyridinyl)(phenyl)methanone | C12H10N2O | 详情 | 详情 | |
| (IV) | 30259 | N-(5-benzoyl-2-pyridinyl)-4-methylbenzenesulfonamide | C19H16N2O3S | 详情 | 详情 | |
| (V) | 30260 | 2-(5-benzoyl-2-[[(4-methylphenyl)sulfonyl]imino]-1-pyridinyl)acetamide | C21H19N3O4S | 详情 | 详情 | |
| (VI) | 30261 | N-(6-benzoylimidazo[1,2-a]pyridin-2-yl)-2,2,2-trifluoroacetamide | C16H10F3N3O2 | 详情 | 详情 | |
| (VII) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (VIII) | 30262 | diethyl 2-(methylamino)-2-oxoethylphosphonate | C7H16NO4P | 详情 | 详情 | |
| (IX) | 30263 | (E)-N-methyl-3-phenyl-3-[2-[(2,2,2-trifluoroacetyl)amino]imidazo[1,2-a]pyridin-6-yl]-2-propenamide | C19H15F3N4O2 | 详情 | 详情 | |
| (X) | 30264 | (E)-3-[3-iodo-2-[(2,2,2-trifluoroacetyl)amino]imidazo[1,2-a]pyridin-6-yl]-N-methyl-3-phenyl-2-propenamide | C19H14F3IN4O2 | 详情 | 详情 | |
| (XI) | 30265 | (E)-3-[3-(isopropylsulfanyl)-2-[(2,2,2-trifluoroacetyl)amino]imidazo[1,2-a]pyridin-6-yl]-N-methyl-3-phenyl-2-propenamide | C22H21F3N4O2S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Ketone (III) was prepared by Friedel-Crafts acylation of benzene (II) with 6-chloronicotinyl chloride (I). Horner-Emmons reaction of (III) with diethyl (N-methylcarbamoylmethyl)phosphonate (IV) using potassium hexamethyl-disilazide produced a 3:1 mixture of E (V) and Z olefins (VI). The desired E isomer (V) was isolated by column chromatography and then treated with bromoketone (VII) to afford the betaine (VIII). Finally, the target imidazopyridine was obtained by condensation of (VIII) with cyanamide in the presence of K2CO3.
| 【1】 Alvarez-Builla, J.; Ezquerra, J.; Vega, J.A.; Vaquero, J.J.; Hamdouchi, C.; Heinz, B.A.; Short synthesis and anti-rhinoviral activity of imidazo[1,2-a]pyridines: The effect of acyl groups at 3-position. Bioorg Med Chem Lett 1999, 9, 10, 1391. |
| 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) | 30256 | 6-chloronicotinoyl chloride | 58757-38-3 | C6H3Cl2NO | 详情 | 详情 |
| (II) | 13364 | Benzene | 71-43-2 | C6H6 | 详情 | 详情 |
| (III) | 30257 | (6-chloro-3-pyridinyl)(phenyl)methanone | C12H8ClNO | 详情 | 详情 | |
| (IV) | 30262 | diethyl 2-(methylamino)-2-oxoethylphosphonate | C7H16NO4P | 详情 | 详情 | |
| (V) | 30807 | (E)-3-(6-chloro-3-pyridinyl)-N-methyl-3-phenyl-2-propenamide | C15H13ClN2O | 详情 | 详情 | |
| (VI) | 30808 | (Z)-3-(6-chloro-3-pyridinyl)-N-methyl-3-phenyl-2-propenamide | C15H13ClN2O | 详情 | 详情 | |
| (VII) | 30809 | 1-bromo-3,3-dimethyl-2-butanone | 5469-26-1 | C6H11BrO | 详情 | 详情 |
| (VIII) | 30810 | 1-[2-Chloro-5-[2-(N-metylcarbamoyl)-1-phenylvinyl]pyridinium-1-yl]-3,3-dimethyl-2-oxo-1-butanide | C21H23ClN2O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)6-Chloronicotinic acid (I) was converted to the corresponding acid chloride (II) by treatment with oxalyl chloride. Condensation of acid chloride (II) with diethyl malonate in the presence of MgCl2 and Et3N produced the keto diester (III), which was further decarbethoxylated to ketone (IV) upon heating in moist DMSO. Displacement of the chloride group of (III) with 4-piperidone ethylene ketal (V) furnished the piperidinyl pyridine (VI). Knoevenagel condensation of malononitrile with 3-bromobenzaldehyde (VII) using glycine as the catalyst produced the benzylidene malononitrile (VIII). The dipyridyl derivative (IX) was obtained by condensation of ketone (VI) with dinitrile (VIII) in the presence of ammonium acetate. Cyclization of amino nitrile (IX) in hot formamide gave rise to the pyridopyrimidine system (X). Ketone (XI) was then obtained by acid hydrolysis of the ethylene ketal function of (X). Finally, condensation of ketone (XI) with 4-tetrahydropyranyloxyamine (XII) yielded the title oxime.
| 【1】 Zheng, G.Z.; et al.; Pyridopyrimidine analogues as novel adenosine kinase inhibitors. Bioorg Med Chem Lett 2001, 11, 16, 2071. |
| 【2】 Stewart, A.O.; Perner, R.J.; McKie, J.A.; Zheng, G.Z.; Grillot, A.L.; Cowart, M.D.; Bhagwat, S.S.; Lee, C.-H. (Abbott Laboratories Inc.); 5,7-Disubstd.-4-aminopyrido[2,3-d]pyrimidine cpds.. WO 0023444 . |
| 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) | 12996 | 6-Chloronicotinic acid | 5326-23-8 | C6H4ClNO2 | 详情 | 详情 |
| (II) | 30256 | 6-chloronicotinoyl chloride | 58757-38-3 | C6H3Cl2NO | 详情 | 详情 |
| (III) | 49834 | dimethyl 2-[(6-chloro-3-pyridinyl)carbonyl]malonate | C11H10ClNO5 | 详情 | 详情 | |
| (IV) | 26555 | 1-(6-chloro-3-pyridinyl)-1-ethanone | C7H6ClNO | 详情 | 详情 | |
| (V) | 11338 | 1,4-Dioxa-8-azaspiro[4.5]decane; 4-Piperidone ethylene ketal | 177-11-7 | C7H13NO2 | 详情 | 详情 |
| (VI) | 49835 | 1-[6-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-3-pyridinyl]-1-ethanone | C14H18N2O3 | 详情 | 详情 | |
| (VII) | 10477 | 3-Bromobenzaldehyde; m-Bromobenzaldehyde | 3132-99-8 | C7H5BrO | 详情 | 详情 |
| (VIII) | 49836 | 2-(3-bromobenzylidene)malononitrile | C10H5BrN2 | 详情 | 详情 | |
| (IX) | 49837 | C24H22BrN5O2 | 详情 | 详情 | ||
| (X) | 49838 | 5-(3-bromophenyl)-7-[6-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-3-pyridinyl]pyrido[2,3-d]pyrimidin-4-amine; 5-(3-bromophenyl)-7-[6-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-3-pyridinyl]pyrido[2,3-d]pyrimidin-4-ylamine | C25H23BrN6O2 | 详情 | 详情 | |
| (XI) | 49839 | 1-[5-[4-amino-5-(3-bromophenyl)pyrido[2,3-d]pyrimidin-7-yl]-2-pyridinyl]-4-piperidinone | C23H19BrN6O | 详情 | 详情 | |
| (XII) | 49840 | O-tetrahydro-2H-pyran-4-ylhydroxylamine; 4-(aminooxy)tetrahydro-2H-pyran | C5H11NO2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)6-Chloronicotinic acid (I) is converted to the corresponding acid chloride (II) employing either SOCl2 or PCl5/POCl3. Treatment of acid chloride (II) with EtOH and Et3N, followed by reduction of the resultant ethyl ester with LiAlH4, furnishes 6-chloro-3-pyridylmethanol (III). Alcohol (III) is alternatively prepared by NaBH4 reduction of acid chloride (II). Chlorination of (III) by using SOCl2 gives the chloromethyl pyridine (IV), and further chloride displacement with KCN leads to nitrile (V). Substitution of the remaining chloride group of (V) upon heating with pyrrolidine (VI) furnishes the pyrrolidinyl pyridine (VII). Then hydrolysis of the nitrile function of (VII) under acidic conditions provides carboxylic acid (VIII). Bromination of 4-(methylsulfonyl)acetophenone (IX) in the presence of AlCl3 produces the phenacyl bromide (X). Finally, condensation between acid (VIII) and bromo ketone (X) under basic conditions gives rise to the title diaryl furanone
| 【1】 Almansa, C.; Alfon, J.; Cavalcanti, F.L.; Gomez, L.; Miralles, A.; Synthesis and SAR of 4-pyrrolidinylarylheterocycles as COX-2 selective inhibitors. Drugs Fut 2002, 27, Suppl. A. |
| 【2】 Almansa Rosales, C.; Gonzalez Gonzalez, C.; Torres Barreda, M.C. (J. Uriach & Cia., SA); Novel heterocyclic cpds. with anti-inflammatory activity. EP 1281709; ES 2166710; WO 0183475 . |
| 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) | 12996 | 6-Chloronicotinic acid | 5326-23-8 | C6H4ClNO2 | 详情 | 详情 |
| (II) | 30256 | 6-chloronicotinoyl chloride | 58757-38-3 | C6H3Cl2NO | 详情 | 详情 |
| (III) | 60372 | (6-chloro-3-pyridinyl)methanol | C6H6ClNO | 详情 | 详情 | |
| (IV) | 60373 | 2-chloro-5-(chloromethyl)pyridine | C6H5Cl2N | 详情 | 详情 | |
| (V) | 60374 | 2-(6-chloro-3-pyridinyl)acetonitrile | C7H5ClN2 | 详情 | 详情 | |
| (VI) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (VII) | 60375 | 2-[6-(1-pyrrolidinyl)-3-pyridinyl]acetonitrile | C11H13N3 | 详情 | 详情 | |
| (VIII) | 60376 | 2-[6-(1-pyrrolidinyl)-3-pyridinyl]acetic acid | C11H14N2O2 | 详情 | 详情 | |
| (IX) | 19263 | 1-[4-(methylsulfonyl)phenyl]-1-ethanone; 4-methylsulfonylacetophenone | 10297-73-1 | C9H10O3S | 详情 | 详情 |
| (X) | 19264 | 2-bromo-1-[4-(methylsulfonyl)phenyl]-1-ethanone | C9H9BrO3S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IV)Wittig reaction of 1-methylpyrrole-2-carboxaldehyde (I) with (ethoxycarbonylmethylene)triphenylphosphorane furnishes the pyrrolylacrylate ester (II), which is subsequently hydrogenated over Pd/C to the pyrrolylpropionate (III). Friedel-Crafts acylation of pyrrole (III) with 6-chloronicotinoyl chloride (IV) gives rise to the pyrrolyl ketone (V). After alkaline hydrolysis of the ethyl ester group of (V), the resultant carboxylic acid (VI) is converted into the corresponding acid chloride (VII) employing oxalyl chloride and DMF. Finally, coupling of acid chloride (VII) with the known aniline derivative (VIII) leads to the desired amide.
| 【1】 Youngman, M.A.; Carson, J.R.; Lee, J.S.; Dax, S.L.; Zhang, S.-P.; Colburn, R.W.; Stone, D.J.; Codd, E.E.; Jetter, M.C.; Synthesis and structure-activity relationships of aroylpyrrole alkylamide bradykinin (B2) antagonists. Bioorg Med Chem Lett 2003, 13, 7, 1341. |
| 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) | 64337 | 1-methyl-1H-pyrrole-2-carbaldehyde | C6H7NO | 详情 | 详情 | |
| (II) | 64338 | ethyl 3-(1-methyl-1H-pyrrol-2-yl)-2-propenoate | C10H13NO2 | 详情 | 详情 | |
| (III) | 64339 | ethyl 3-(1-methyl-1H-pyrrol-2-yl)propanoate | C10H15NO2 | 详情 | 详情 | |
| (IV) | 30256 | 6-chloronicotinoyl chloride | 58757-38-3 | C6H3Cl2NO | 详情 | 详情 |
| (V) | 64340 | ethyl 3-{5-[(6-chloro-3-pyridinyl)carbonyl]-1-methyl-1H-pyrrol-2-yl}propanoate | C16H17ClN2O3 | 详情 | 详情 | |
| (VI) | 64341 | 3-{5-[(6-chloro-3-pyridinyl)carbonyl]-1-methyl-1H-pyrrol-2-yl}propanoic acid | C14H13ClN2O3 | 详情 | 详情 | |
| (VII) | 64342 | 3-{5-[(6-chloro-3-pyridinyl)carbonyl]-1-methyl-1H-pyrrol-2-yl}propanoyl chloride | C14H12Cl2N2O2 | 详情 | 详情 | |
| (VIII) | 64343 | 2,4-dichloro-N-methyl-3-{[(2-methyl-8-quinolinyl)oxy]methyl}aniline; N-(2,4-dichloro-3-{[(2-methyl-8-quinolinyl)oxy]methyl}phenyl)-N-methylamine | C18H16Cl2N2O | 详情 | 详情 |