【结 构 式】 ![]() |
【分子编号】23940 【品名】2-Chloro-4-pyridinecarbonitrile; 2-chloroisonicotinonitrile 【CA登记号】33252-30-1 |
【 分 子 式 】C6H3ClN2 【 分 子 量 】138.556 【元素组成】C 52.01% H 2.18% Cl 25.59% N 20.22% |
合成路线1
该中间体在本合成路线中的序号:(I)The reaction of 2-chloro-4-cyanopyridine (I) with sodium methoxide in refluxing methanol gives 2-methoxy-4-cyanopyridine (II), which by reduction with H2 over Raney-Ni and semicarbazide HCl in water-ethanol is converted to 2-methoxypyridine-4-carboxyaldehyde (III). The condensation of (III) with malonic acid (IV) by means of piperidine in hot pyridine yields 3-(2-methoxy-4-pyridyl)acrylic acid (V), which is esterified with ethanol and H2SO4 to the ethyl ester (VI). The reduction of (VII) with H2 over Pd/C in ethanol affords the corresponding propionate (VII). Formylation of (VII) with ethyl formate and NaH gives ethyl 2-formyl-3-(2-methoxy-4-pyridyl)propionate (VIII), which is cyclized with nitroguanidine (IX) by means of sodium methoxide in refluxing methanol yielding 2-nitroamino-5-12-methoxy-4-pyridylmethylpyrimidin-4(1H)-one (X). The reaction of (X) with 2-[5-(dimethylaminomethyl)-2 furylmethylthio]ethylamine in refluxing ethanol gives the O-methyl derivative of SK&F 93574 (XII), whicn is finally deprotected with HCl in refluxing ethanol.
【1】 Brown, T.H.; Ife, R.J. (SmithKline Beecham plc); Pyrimidine compounds. DD 140252; EP 0003677; ES 477667; US 4234588; US 4649141 . |
【2】 Adger, B.M.; Lewis, N.J. (SmithKline Beecham plc); Chemical process. EP 0141560 . |
【3】 Prous, J.; Castaner, J.; SK&F-93574. Drugs Fut 1986, 11, 8, 671. |
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) | 23944 | 1-Hydrazinecarboxamide | 563-41-7 | CH5N3O | 详情 | 详情 |
(I) | 23940 | 2-Chloro-4-pyridinecarbonitrile; 2-chloroisonicotinonitrile | 33252-30-1 | C6H3ClN2 | 详情 | 详情 |
(II) | 23943 | 2-methoxyisonicotinonitrile | C7H6N2O | 详情 | 详情 | |
(III) | 23941 | 2-methoxyisonicotinaldehyde | C7H7NO2 | 详情 | 详情 | |
(IV) | 12963 | Malonic acid | 141-82-2 | C3H4O4 | 详情 | 详情 |
(V) | 23945 | (Z)-3-(2-methoxy-4-pyridinyl)-2-propenoic acid | C9H9NO3 | 详情 | 详情 | |
(VI) | 23946 | ethyl (Z)-3-(2-methoxy-4-pyridinyl)-2-propenoate | C11H13NO3 | 详情 | 详情 | |
(VII) | 23947 | ethyl 3-(2-methoxy-4-pyridinyl)propanoate | C11H15NO3 | 详情 | 详情 | |
(VIII) | 23948 | ethyl 2-formyl-3-(2-methoxy-4-pyridinyl)propanoate | C12H15NO4 | 详情 | 详情 | |
(IX) | 23949 | N2-Nitroguanidine | CH4N4O2 | 详情 | 详情 | |
(X) | 23950 | 5-(2-Methoxypyridin-4-yl)-2-(nitroamino)pyrimidin-4(1H)-one | C11H11N5O4 | 详情 | 详情 | |
(XI) | 13851 | 2-[([5-[(Dimethylamino)methyl]-2-furyl]methyl)sulfanyl]-1-ethanamine; N-[(5-[[(2-Aminoethyl)sulfanyl]methyl]-2-furyl)methyl]-N,N-dimethylamine | C10H18N2OS | 详情 | 详情 | |
(XII) | 23951 | 2-([2-[([5-[(dimethylamino)methyl]-2-furyl]methyl)sulfanyl]ethyl]amino)-5-[(2-methoxy-4-pyridinyl)methyl]-4(1H)-pyrimidinone | C21H27N5O3S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(XI)Treatment of 4-cyanopyridine N-oxide (X) with phosphorus oxychloride and phosphorus pentachloride under reflux produced a mixture of 2-chloro (XI) and 3-chloropyridines (XII), which were separated by column chromatography. The 3-chloro isomer (XII) was further treated with sodium ethoxide in DMF to produce the ethoxypyridine (XIII). The pyrazolopyrimidine nucleus (XIV) was then obtained by condensation of cyanopyridine (XIII) with aminopyrazole (IX) in the presence of NaH. Finally, diazotization of (XIV) in 50% sulfuric acid converted the aminopyrimidine group into the required pyrimidinone.
【1】 Bacon, E.R.; Singh, B.; Lesher, G.Y.; Lesher, L.E. (Sanofi-Synthelabo); 6-Heterocyclyl pyrazolo[3,4-d]pyrimidin-4-ones and compsns. and method of use. US 5294612 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(IX) | 26911 | 5-amino-1-cyclopentyl-3-ethyl-1H-pyrazole-4-carboxamide | C11H18N4O | 详情 | 详情 | |
(X) | 26912 | 4-cyano-1-pyridiniumolate | 14906-59-3 | C6H4N2O | 详情 | 详情 |
(XI) | 23940 | 2-Chloro-4-pyridinecarbonitrile; 2-chloroisonicotinonitrile | 33252-30-1 | C6H3ClN2 | 详情 | 详情 |
(XII) | 26913 | 3-chloroisonicotinonitrile | C6H3ClN2 | 详情 | 详情 | |
(XIII) | 26914 | 3-ethoxyisonicotinonitrile | C8H8N2O | 详情 | 详情 | |
(XIV) | 26915 | 1-cyclopentyl-6-(3-ethoxy-4-pyridinyl)-3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine | C19H24N6O | 详情 | 详情 |