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【结 构 式】

【分子编号】13574

【品名】2,6-Dichloro-3-nitropyridine

【CA登记号】16013-85-7

【 分 子 式 】C5H2Cl2N2O2

【 分 子 量 】192.98856

【元素组成】C 31.12% H 1.04% Cl 36.74% N 14.52% O 16.58%
与该中间体有关的原料药合成路线共 9 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5合成路线6合成路线7合成路线8合成路线9

合成路线1

该中间体在本合成路线中的序号：(I)

The reaction of 2,6-dichloro-3-nitropyridine (I) with N-ethoxycarbonylpiperidine (II) by means of triethylamine in CHCl gives 6-chloro-2-(4-ethoxycarbonyl-1-piperazinyl)-3-nitropyridine (III), which is treated with ethanolic NH3 at 120 C in a sealed tube to afford 6-amino-2-(4-ethoxycarbonyl-1-piperazinyl)-3-nitropyridine (IV). The acetylation of (IV) with acetic anhydride - acetic acid at 90 C yields the corresponding 6-acetamido derivative (V), which is reduced with H2 over Pd/C in acetic acid giving 3-amino-6-acetamido-2-(4-ethoxycarbonyl-1-piperazinyl)pyridine (VI). The diazotation of (VI) with isoamyl nitrite (A) and tetrafluoroboric acid in ethanol affords 6-acetylamino-2-(4-ethoxycarbonylpiperazinyl)-3-pyridine diazonium tetrafluoroborate (VII), which by heat treatment at 120 C in toluene is converted into 6-acetylamino-2-(4-ethoxycarbonylpiperazinyl)-3-fluoropyridine (VIII). The hydrolysis of (VIII) with HCl in methanol yields the corresponding 6-aminopyridine derivative (IX), which is condensed with diethyl ethoxymethylenemalonate (X) by heating at 130 C to afford diethyl N-[2-(4-ethoxycarbonyl-1-piperazinyl)-3-fluoro-6-pyridinyl]aminomethylenemalonate (XI). The cyclization of (XI) by heating at 255 C yields ethyl 7-(4-ethoxycarbonyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (XII), which is N-alkylated by means of ethyl iodide and K2CO3 in hot DMF to afford ethyl 7-(4-ethoxycarbonyl-1-piperazinyl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (XIII). Finally, this compound is hydrolyzed by means of NaOH in refluxing ethanol.

参考文献 中间体
合成目标
【1】 Matsumoto, J.; et al. (Aventis Pharma SA; Dainippon Pharmaceutical Co., Ltd.); Novel naphthyridine derivatives, intermediates thereof, processes for preparation thereof and use thereof. EP 0009425; ES 483629; US 4359578 .
【2】 Blancafort, P.; Serradell, M.N.; Mealy, N.E.; Castaner, J.; Leeson, P.A.; AT-2266. Drugs Fut 1981, 6, 3, 129.
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) 32169 3-Methyl-1-nitrobutane; Isoamyl nitrite 543-87-3 C5H11NO2 详情 详情
(I) 13574 2,6-Dichloro-3-nitropyridine 16013-85-7 C5H2Cl2N2O2 详情 详情
(II) 24694 N-ethoxycarbonylpiperidine; Ethyl 1-piperazinecarboxylate; N-Ethoxycarbonyl piperazine; N-Carbethoxy piperazine 120-43-4 C7H14N2O2 详情 详情
(III) 32165 6-Chloro-2-(4-ethoxycarbonyl-1-piperazinyl)-3-nitropyridine; Ethyl 4-(6-chloro-3-nitro-2-pyridinyl)-1-piperazinecarboxylate C12H15ClN4O4 详情 详情
(IV) 32166 Ethyl 4-(6-amino-3-nitro-2-pyridinyl)-1-piperazinecarboxylate; 6-Amino-2-(4-ethoxycarbonyl-1-piperazinyl)-3-nitropyridine C12H17N5O4 详情 详情
(V) 32167 ethyl 4-[6-(acetamido)-3-nitro-2-pyridinyl]-1-piperazinecarboxylate C14H19N5O5 详情 详情
(VI) 32168 Ethyl 4-[6-(acetamido)-3-amino-2-pyridinyl]-1-piperazinecarboxylate; 3-Amino-6-acetamido-2-(4-ethoxycarbonyl-1-piperazinyl)pyridine C14H21N5O3 详情 详情
(VII) 32170 6-acetamido-2-(4-ethoxycarbonylpiperazinyl)-3-pyridine diazonium tetrafluoroborate; 6-Acetamido-2-[4-(ethoxycarbonyl)pipderazin-1-yl]pyridin-3-yldiazonium tetrafluoroborate C14H19BF4N6O3 详情 详情
(VIII) 32171 6-acetamido-2-(4-ethoxycarbonylpiperazinyl)-3-fluoropyridine; Ethyl 4-[6-(acetamido)-3-fluoro-2-pyridinyl]-1-piperazinecarboxylate C14H19FN4O3 详情 详情
(IX) 32172 ethyl 4-(6-amino-3-fluoro-2-pyridinyl)-1-piperazinecarboxylate C12H17FN4O2 详情 详情
(X) 14088 Diethyl ethoxymethylenemalonate; Diethyl 2-(ethoxymethylene)malonate 87-13-8 C10H16O5 详情 详情
(XI) 32173 N-[2-(4-EthoxycarbonyI-1-piperazinyl)-3-fluoro-6-pyridinyl]aminomethylenemalonate; Diethyl 2-[([6-[4-(ethoxycarbonyl)-1-piperazinyl]-5-fluoro-2-pyridinyl]amino)methylene]malonate C20H27FN4O6 详情 详情
(XII) 32174 Ethyl 7-(4-ethoxycarbonyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate; Ethyl 7-[4-(ethoxycarbonyl)-1-piperazinyl]-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylate C18H21FN4O5 详情 详情
(XIII) 32175 Ethyl 7-[4-(ethoxycarbonyl)-1-piperazinyl]-1-ethyl-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylate; Ethyl 7-(4-ethoxycarbonyl-1-piperazinyl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate C20H25FN4O5 详情 详情

合成路线2

该中间体在本合成路线中的序号：(I)

The reaction of 2,6-dichloro-3-nitropyridine (I) with ammonia yields 2-amino-3-nitro-chloropyridine (II). 4-Fluorobenzylamine (III) reacts in dioxane and in the presence of triethylamine with (II), resulting in the 2-amino-3-nitro-6-p-fluorobenzylamine derivative (IV). The latter is hydrated and in situ the 3-amino group is condensed with ethyl chloroformate leading to the stable 2-amino-3-carbethoxyamino-6-(p-fluorobenzylamino)pyridine (Flupirtine).

参考文献 中间体
合成目标
【1】 Thiele, K.; Steinmetz, G.; Bebenburg, W.v.; Chem Ztg 1979, 103, 10, 387.
【2】 Bebenburg, W.v.; Engel, J.; Sheldrick, W.S.; Thiele, K.; Chem Ztg 1981, 105, 10, 217.
【3】 Castaner, J.; Serradell, M.N.; Blancafort, P.; Flupirtine. Drugs Fut 1983, 8, 9, 773.
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) 13574 2,6-Dichloro-3-nitropyridine 16013-85-7 C5H2Cl2N2O2 详情 详情
(II) 13575 6-Chloro-3-nitro-2-pyridinamine; 2-Amino-6-chloro-3-nitropyridine; 6-Chloro-3-nitro-2-pyridinylamine 27048-04-0 C5H4ClN3O2 详情 详情
(III) 31095 4-fluorobenzylamine; (4-fluorophenyl)methanamine 140-75-0 C7H8FN 详情 详情
(IV) 13576 N(6)-(4-Fluorobenzyl)-3-nitro-2,6-pyridinediamine; N-(6-Amino-5-nitro-2-pyridinyl)-N-(4-fluorobenzyl)amine C12H11FN4O2 详情 详情
(V) 13577 N(6)-(4-Fluorobenzyl)-2,3,6-pyridinetriamine; 2-Amino-6-[(4-fluorobenzyl)amino]-3-pyridinylamine C12H13FN4 详情 详情

合成路线3

该中间体在本合成路线中的序号：(II)

D 7175 can be obtained in a 5-step synthesis starting from 2,e-dichloropyridine (I). Compound (I) is nitrated with HNO3/H2SO4 yielding 2,6-dichloro-3-nitropyridine (II). Subsequent reaction with ammonia and benzylamine leads to 2-amino-3-nitro-6-benzylaminopyridine (IV), which is hydrogenated using Raney Nickel as catalyst te the corresponding 3-amino derivative (V), which reacts without isolation with ethyl chloroformiate to D-7175.

参考文献 中间体
合成目标
【1】 Bebengurg, W.; Engek, J.; Heese, J.; Thiele, K. (Degussa AG); 2-Amino-3-acylamino-6-benzylaminopyridine derivatives having antiepileptic action. DE 3337593 .
【2】 Molliere, M.; Engel, J.; Emig, P.; D-7175. Drugs Fut 1988, 13, 1, 22.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
15147 Benzylamine; Phenylmethanamine 100-46-9 C7H9N 详情 详情
(I) 13573 2,6-Dichloropyridine 2402-78-0 C5H3Cl2N 详情 详情
(II) 13574 2,6-Dichloro-3-nitropyridine 16013-85-7 C5H2Cl2N2O2 详情 详情
(III) 13575 6-Chloro-3-nitro-2-pyridinamine; 2-Amino-6-chloro-3-nitropyridine; 6-Chloro-3-nitro-2-pyridinylamine 27048-04-0 C5H4ClN3O2 详情 详情
(IV) 21572 N(6)-benzyl-3-nitro-2,6-pyridinediamine C12H12N4O2 详情 详情
(V) 21573 2-amino-6-(benzylamino)-3-pyridinylamine C12H14N4 详情 详情

合成路线4

该中间体在本合成路线中的序号：(I)

2,6-Dichloro-3-nitropyridine (I) reacts with ammonia and p-chlorobenzylamine (III) yielding 2-amino-3-nitro-6-(4-chlorobenzyl)aminopyridine (IV). D-9389 is obtained after hydrogenation and reaction with ethylchloroformate.

参考文献 中间体
合成目标
【1】 Bebengurg, W.; Engek, J.; Heese, J.; Thiele, K. (Degussa AG); 2-Amino-3-acylamino-6-benzylaminopyridine derivatives having antiepileptic action. DE 3337593 .
【2】 Molliere, M.; Emig, P.; Szelenyi, I.; Engel, J.; D-9389. Drugs Fut 1988, 13, 8, 717.
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) 13574 2,6-Dichloro-3-nitropyridine 16013-85-7 C5H2Cl2N2O2 详情 详情
(II) 13575 6-Chloro-3-nitro-2-pyridinamine; 2-Amino-6-chloro-3-nitropyridine; 6-Chloro-3-nitro-2-pyridinylamine 27048-04-0 C5H4ClN3O2 详情 详情
(III) 23378 (4-chlorophenyl)methanamine; 4-chlorobenzylamine 104-86-9 C7H8ClN 详情 详情
(IV) 23379 N-(6-amino-5-nitro-2-pyridinyl)-N-(4-chlorobenzyl)amine; N(6)-(4-chlorobenzyl)-3-nitro-2,6-pyridinediamine C12H11ClN4O2 详情 详情
(V) 23380 2-amino-6-[(4-chlorobenzyl)amino]-3-pyridinylamine; N(6)-(4-chlorobenzyl)-2,3,6-pyridinetriamine C12H13ClN4 详情 详情

合成路线5

该中间体在本合成路线中的序号：(I)

D-11208 is obtained in a five step synthesis: 2,6-Dichloro-3-nitropyridine (I) reacts with ammonia to give 2-amino-3-nitro-6-chloropyridine (II). Subsequent condensation with 4-trifluoromethyl benzylamine (III) yields 2-amino-3-nitro-6-(4-trifluoromethyl)aminopyridine (IV). Hydrogenation with Raney Nickel as catalyst and reaction with ethyl chloroformiate yields D-11208.

参考文献 中间体
合成目标
【1】 Bebengurg, W.; Engek, J.; Heese, J.; Thiele, K. (Degussa AG); 2-Amino-3-acylamino-6-benzylaminopyridine derivatives having antiepileptic action. DE 3337593 .
【2】 Engel, J.; Molliere, M.; Emig, P.; Szelenyi, I.; D-11208. Drugs Fut 1988, 13, 9, 817.
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) 13574 2,6-Dichloro-3-nitropyridine 16013-85-7 C5H2Cl2N2O2 详情 详情
(II) 13575 6-Chloro-3-nitro-2-pyridinamine; 2-Amino-6-chloro-3-nitropyridine; 6-Chloro-3-nitro-2-pyridinylamine 27048-04-0 C5H4ClN3O2 详情 详情
(III) 21925 [4-(trifluoromethyl)phenyl]methanamine; 4-(trifluoromethyl)benzylamine 3300-51-4 C8H8F3N 详情 详情
(IV) 23270 N-(6-amino-5-nitro-2-pyridinyl)-N-[4-(trifluoromethyl)benzyl]amine; 3-nitro-N(6)-[4-(trifluoromethyl)benzyl]-2,6-pyridinediamine C13H11F3N4O2 详情 详情
(V) 23271 2-amino-6-[[4-(trifluoromethyl)benzyl]amino]-3-pyridinylamine; N(6)-[4-(trifluoromethyl)benzyl]-2,3,6-pyridinetriamine C13H13F3N4 详情 详情

合成路线6

该中间体在本合成路线中的序号：(II)

D-19050 can be obtained in a 5-step synthesis starting from 2,6-dichloropyridine (I): Compound (I) is nitrated with HNO3/H2SO4 yielding 2,6-dichloro-3-nitropyridine (II). Subsequent reaction with ammonia and 4-fluorobenzylamine leads to 2-amino-3-nitro-6-(4-fluorobenzylamino)pyridine (IV), which is hydrogenated using Raney Nickel as catalyst to the corresponding 3-amino derivative (V). This is not isolated, but reacted with (prop-1-en-3-yl)chloroformate to give D-19050.

参考文献 中间体
合成目标
【1】 Engel, J.; Emig, P.; Szelenyi, I.; Nickel, B.; Weischer, K.H.; D-19050. Drugs Fut 1989, 14, 6, 511.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
31095 4-fluorobenzylamine; (4-fluorophenyl)methanamine 140-75-0 C7H8FN 详情 详情
(I) 13573 2,6-Dichloropyridine 2402-78-0 C5H3Cl2N 详情 详情
(II) 13574 2,6-Dichloro-3-nitropyridine 16013-85-7 C5H2Cl2N2O2 详情 详情
(III) 13575 6-Chloro-3-nitro-2-pyridinamine; 2-Amino-6-chloro-3-nitropyridine; 6-Chloro-3-nitro-2-pyridinylamine 27048-04-0 C5H4ClN3O2 详情 详情
(IV) 13576 N(6)-(4-Fluorobenzyl)-3-nitro-2,6-pyridinediamine; N-(6-Amino-5-nitro-2-pyridinyl)-N-(4-fluorobenzyl)amine C12H11FN4O2 详情 详情
(V) 13577 N(6)-(4-Fluorobenzyl)-2,3,6-pyridinetriamine; 2-Amino-6-[(4-fluorobenzyl)amino]-3-pyridinylamine C12H13FN4 详情 详情

合成路线7

该中间体在本合成路线中的序号：(II)

D-19274 can be obtained in a 6-step synthesis starting from 2,6-dichloropyridine (I). Compound (I) is nitrated with HNO3/H2SO4 yielding 2,6-dichloro-3-nitropyridine (II). Subsequent reaction with ammonia and 4-fluorobenzylamine leads to 2-amino-3-nitro-6-(4-fluorobenzylamino)pyridine (IV), which is hydrogenated using Raney Nickel as catalyst to the corresponding 3-amino derivative (V), which reacts with 2-bromoethyl chloroformate to 2-bromoethyl [N-(2-amino-6-(4-fluorobenzylamino)pyridin-3-yl)]carbamate hydrochloride (VI). (VI) is then treated with excess NaOH at 35 C, followed by treatment with isopropanol HCl to give the desired D-19274.

参考文献 中间体
合成目标
【1】 Engel, J.; Emig, P.; Nickel, B.; Szelenyi, I. (Asta Medica AG); 3-(N-heterocyclyl)-2,6-diaminopyridines and N-oxides, their preparation and their use as medicines. DE 3915184; EP 0343429; JP 1990017186; US 4923858 .
【2】 Emig, P.; Engel, J.; Nickel, B.; Szelenyi, I.; Werner, U.; D-19274. Drugs Fut 1990, 15, 3, 223.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
31095 4-fluorobenzylamine; (4-fluorophenyl)methanamine 140-75-0 C7H8FN 详情 详情
63775 1-bromo-2-[(chlorocarbonyl)oxy]ethane C3H4BrClO2 详情 详情
(I) 13573 2,6-Dichloropyridine 2402-78-0 C5H3Cl2N 详情 详情
(II) 13574 2,6-Dichloro-3-nitropyridine 16013-85-7 C5H2Cl2N2O2 详情 详情
(III) 13575 6-Chloro-3-nitro-2-pyridinamine; 2-Amino-6-chloro-3-nitropyridine; 6-Chloro-3-nitro-2-pyridinylamine 27048-04-0 C5H4ClN3O2 详情 详情
(IV) 13576 N(6)-(4-Fluorobenzyl)-3-nitro-2,6-pyridinediamine; N-(6-Amino-5-nitro-2-pyridinyl)-N-(4-fluorobenzyl)amine C12H11FN4O2 详情 详情
(V) 13577 N(6)-(4-Fluorobenzyl)-2,3,6-pyridinetriamine; 2-Amino-6-[(4-fluorobenzyl)amino]-3-pyridinylamine C12H13FN4 详情 详情
(VI) 13578 2-bromoethyl 2-amino-6-[(4-fluorobenzyl)amino]-3-pyridinylcarbamate C15H16BrFN4O2 详情 详情

合成路线8

该中间体在本合成路线中的序号：(II)

2,6-Dichloropyridine (I) was nitrated with HNO3 and H2SO4 to give nitropyridine (II). Substitution of the 2-chloro atom of (II) with cuprous cyanide at 180 C afforded nitrile (III). The remaining 6-chloro atom of (III) was then substituted with N-methyl-3,4-dimethoxyaniline (IV) in monoethyl glycol in the presence of pyridine to provide diaryl amine (V). The nitro group of (V) was further reduced with iron powder and HCl yielding the 3-amino derivative (VI). Finally, cyclization of (VI) with chloroformamidine hydrochloride (VII) in dimethylsulfone at 140 C produced the target pyridopyrimidine.

参考文献 中间体
合成目标
【1】 Gangjee, A.; Zhu, Y.; Queener, S.F.; 6-Substituted 2,4-diaminopyrido[3,2-d]pyrimidine analogues of piritrexim as inhibitors of dihydrofolate reductase from rat liver, Pneumocystis carinii, and Toxoplasma gondii and as antitumor agents. J Med Chem 1998, 41, 23, 4533.
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) 13573 2,6-Dichloropyridine 2402-78-0 C5H3Cl2N 详情 详情
(II) 13574 2,6-Dichloro-3-nitropyridine 16013-85-7 C5H2Cl2N2O2 详情 详情
(III) 29206 6-chloro-3-nitro-2-pyridinecarbonitrile C6H2ClN3O2 详情 详情
(IV) 29207 3,4-dimethoxy-N-methylaniline C9H13NO2 详情 详情
(V) 29208 6-[3,4-dimethoxy(methyl)anilino]-3-nitro-2-pyridinecarbonitrile C15H14N4O4 详情 详情
(VI) 29209 3-amino-6-[3,4-dimethoxy(methyl)anilino]-2-pyridinecarbonitrile C15H16N4O2 详情 详情
(VII) 29210 chloroformamidine CH3ClN2 详情 详情

合成路线9

该中间体在本合成路线中的序号：(I)

Selective substitution of the 2-chloro group of 2,6-dichloro-3-nitropyridine (I) by methylamine gave 6-chloro-2-(methylamino)-3-nitropyridine (II). The 6-chloro group of (II) was then displaced by sodium methoxide to afford methyl ether (III). The nitro group of (III) was reduced by catalytic hydrogenation, and the resulting diamine (IV) was cyclized with glycolic acid to furnish the imidazopyridine (V). Mitsunobu coupling of alcohol (V) with 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione (VI) produced the corresponding ether (VII). The title compound was then obtained by acid deprotection of the trityl group of (VII), followed by conversion to the hydrochloride salt.

参考文献 中间体
合成目标
【2】 Wada, K.; Oguchi, M.; Honma, H.; et al.; Molecular design, synthesis, and hypoglycemic activity of a series of thiazolidine-2,4-diones. J Med Chem 2000, 43, 16, 3052.
【1】 Fujita, T.; Fujimoto, K.; Yoshioka, T.; Yanagisawa, H.; Fujiwara, T.; Horikoshi, H.; Oguchi, M.; Wada, K. (Sankyo Co., Ltd.); Heterocyclic cpds. having antidiabetic activity, their preparation and their use. CA 2146701; EP 0676398; JP 1995330728; US 5624935; US 5834501; US 5962470; US 6117893 .
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) 13574 2,6-Dichloro-3-nitropyridine 16013-85-7 C5H2Cl2N2O2 详情 详情
(II) 44762 N-(6-chloro-3-nitro-2-pyridinyl)-N-methylamine; 6-chloro-N-methyl-3-nitro-2-pyridinamine C6H6ClN3O2 详情 详情
(III) 44763 6-methoxy-N-methyl-3-nitro-2-pyridinamine; N-(6-methoxy-3-nitro-2-pyridinyl)-N-methylamine C7H9N3O3 详情 详情
(IV) 44764 N-(3-amino-6-methoxy-2-pyridinyl)-N-methylamine; 6-methoxy-N(2)-methyl-2,3-pyridinediamine C7H11N3O 详情 详情
(V) 44765 (5-methoxy-3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)methanol C9H11N3O2 详情 详情
(VI) 18803 5-(4-hydroxybenzyl)-3-trityl-1,3-thiazolidine-2,4-dione C29H23NO3S 详情 详情
(VII) 44767 5-[4-[(5-methoxy-3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)methoxy]benzyl]-3-trityl-1,3-thiazolidine-2,4-dione C38H32N4O4S 详情 详情
Extended Information