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【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%

与该中间体有关的原料药合成路线共 2 条

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
Extended Information