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【结 构 式】 
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【分子编号】10321 【品名】2-Chloro-3-nitropyridine 【CA登记号】5470-18-8 |
【 分 子 式 】C5H3ClN2O2 【 分 子 量 】158.5438 【元素组成】C 37.88% H 1.91% Cl 22.36% N 17.67% O 20.18% |
合成路线1
该中间体在本合成路线中的序号：(I)2-Chloro-3-nitropyridine (I) is condensed with diethyl 2-(2-cyanoethyl)malonate (II) by means of NaH in refluxing THF fo give 1-cyano-3,3-bis(ethoxycarbonyl)-3-(3-nitro-2-pyridinyl)propane (III), which is hydrolyzed with NaOH io aqueous ethanol and decarboxylated in aqueous HCl to afford 2-(3-cyanopropyl)-3-nitropyridine (IV). Hydrogenation of (IV) over Pd/C in ethanol gives 3 amino-2-(3-cyanopropyl)pyridine (V), which is diazotized with NaNO2 in dilute H2SO4 and hydrolyzed to 2-(3-cyanopropyl)-3-hydroxypyridine (VI). Methylation of (VI) with MeI by means of NaH in Me2SO yields 2-(3-cyanopropyl)-3-methoxypyridine (VII), which is then reduced with LiAlH4 to provide 2-(4-amino-butyl)-3-methoxypyridine (VIII). The final stage is to condense (VIII) with 2-nitroamino-5-(6-methyl)-3-pyridinylmethyl)-4-pyrimidinone (XIII) in refluxing pyridine. Synthesis of the pyrimidinone (XIII) reagent commences with 2-methylpyridine-4-aldehyde (IX), which is condensed with malonic acid and decarboxylated in pyridine containing piperidine to afford 3-(6-methyl-3pyridinyl)acrylic acid (X). Esterification of (X) with ethanol-H2SO4, followed by reduction with H2 over Pd/C in ethanol gives ethyl (2-mcthyl-5-pyridinyl)ethanoate (XI), which with ethyl formate in the presence of NaH in glyme furnishes 1-(ethoxycarbonyl)-1-formyl-2-(2 methyl-5-pyridinyl)ethane (XII). Condensation of (XII) with nitroguanidine in ethanol in the presence of NaOEt provides the 4-pyrimidinone (XIII).
| 【1】 Durant, G.J.; Ganellin, C.R.; Sach, G.S. (SmithKline Beecham plc); Guanidines, thioureas and 1,1-diamino-2-nitroethyl. GB 1564502; US 4426526 . |
| 【2】 Durant, G.J.; Brown, T.H.; Ganellin, C.R. (SmithKline Beecham plc); Pyridylalkylpyrimidone cpds., process for preparin. EP 0017679 . |
| 【3】 Prous, J.; Castaner, J.; Icotidine trihydrochloride. Drugs Fut 1987, 12, 1, 24. |
| 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) | 12963 | Malonic acid | 141-82-2 | C3H4O4 | 详情 | 详情 |
| (I) | 10321 | 2-Chloro-3-nitropyridine | 5470-18-8 | C5H3ClN2O2 | 详情 | 详情 |
| (II) | 22941 | diethyl 2-(2-cyanoethyl)malonate | 17216-62-5 | C10H15NO4 | 详情 | 详情 |
| (III) | 22942 | diethyl 2-(2-cyanoethyl)-2-(3-nitro-2-pyridinyl)malonate | C15H17N3O6 | 详情 | 详情 | |
| (IV) | 22943 | 4-(3-nitro-2-pyridinyl)butanenitrile | C9H9N3O2 | 详情 | 详情 | |
| (V) | 22944 | 4-(3-amino-2-pyridinyl)butanenitrile | C9H11N3 | 详情 | 详情 | |
| (VI) | 22945 | 4-(3-hydroxy-2-pyridinyl)butanenitrile | C9H10N2O | 详情 | 详情 | |
| (VII) | 22946 | 4-(3-methoxy-2-pyridinyl)butanenitrile | C10H12N2O | 详情 | 详情 | |
| (VIII) | 22947 | 4-(3-methoxy-2-pyridinyl)-1-butanamine; 4-(3-methoxy-2-pyridinyl)butylamine | C10H16N2O | 详情 | 详情 | |
| (IX) | 22949 | 6-methylnicotinaldehyde | C7H7NO | 详情 | 详情 | |
| (X) | 22950 | (E)-3-(6-methyl-3-pyridinyl)-2-propenoic acid | C9H9NO2 | 详情 | 详情 | |
| (XI) | 22951 | ethyl 3-(6-methyl-3-pyridinyl)propanoate | C11H15NO2 | 详情 | 详情 | |
| (XII) | 22952 | ethyl 2-formyl-3-(6-methyl-3-pyridinyl)propanoate | C12H15NO3 | 详情 | 详情 | |
| (XIII) | 22953 | 5-(6-Methylpyridin-3-ylmethyl)-2-(nitroamino)pyrimidin-4(1H)-one | C11H11N5O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)2) [14C]-Labeled: The condensation of 2-chloro-3-nitropyridine (I) with 1-methyl-3-phenylpiperazine (II) by means of KF at 140 C in DMF gives 4-methyl-1-(3-nitropyridin-2-yl)-2-phenylpiperazine (III), which is reduced with H2 over Pd/C in ethanol to the amine (IV). The reaction of (IV) with pentyl nitrite and bromoform at 100 C yields 1-(3-bromopyridin-2-yl)-4-methyl-2-phenylpiperazine (V), which by reaction with butyllithium and [14C]-labeled CO2 in ether is converted into 2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-carboxylic acid (VI). The reduction of (VI) with LiAlH4 in hot THF affords the corresponding alcohol (VII), which is finally cyclized in hot H2SO4.
| 【1】 Wieringa, J.H.; Kaspersen, F.M.; van Rooij, F.A.M.; Sperling, E.G.M.; The synthesis of ORG 3770 labelled with 3H, 13C and 14C. J Label Compd Radiopharm 1989, 27, 9, 1055. |
| 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) | 10321 | 2-Chloro-3-nitropyridine | 5470-18-8 | C5H3ClN2O2 | 详情 | 详情 |
| (II) | 10322 | 1-Methyl-3-phenylpiperazine | 5271-27-2 | C11H16N2 | 详情 | 详情 |
| (III) | 10323 | 4-Methyl-1-(3-nitro-2-pyridinyl)-2-phenylpiperazine | C16H18N4O2 | 详情 | 详情 | |
| (IV) | 10324 | 2-(4-Methyl-2-phenylpiperazino)-3-pyridinamine; 2-(4-Methyl-2-phenylpiperazino)-3-pyridinylamine | C16H20N4 | 详情 | 详情 | |
| (V) | 10325 | 1-(3-Bromo-2-pyridinyl)-4-methyl-2-phenylpiperazine | C16H18BrN3 | 详情 | 详情 | |
| (VI) | 10326 | 2-(4-Methyl-2-phenylpiperazino)nicotinic acid | C17H19N3O2 | 详情 | 详情 | |
| (VI) | 44646 | 2-(4-methyl-2-phenyl-1-piperazinyl)nicotinic acid | C17H19N3O2 | 详情 | 详情 | |
| (VII) | 10320 | [2-(4-Methyl-2-phenylpiperazino)-3-pyridinyl]methanol | 61337-89-1 | C17H21N3O | 详情 | 详情 |
| (VII) | 44647 | [2-(4-methyl-2-phenyl-1-piperazinyl)-3-pyridinyl]methanol | C17H21N3O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)Nucleophilic aromatic substitution of 2-chloro-3-nitropyridine (II) with excess piperazine (I) in acetonitrile at room temperature produces 1-(3-nitro-2-pyridyl)piperazine. Protection of the free piperazine nitrogen by treatment with di-tert-butyldicarbonate affords nitropyridine (III). Reduction of the nitro group to the amine is accomplished via hydrogenation (40 psi) over palladium on carbon. Treatment of the aminopyridine with acetaldehyde and sodium cyanoborohydride in methanol affords the (ethylamino)pyridine (IV). Removal of the BOC protecting group with trifluoroacetic acid and coupling of the resulting 1-[3-(ethylamino)pyridyl]piperazine with 5-methoxyindole-2-carboxylic acid using 1-ethyl-3-(dimethylaminopropyl)carbodiimide (EDC) or 1,1'-carbonyldiimidazole (CDI) affords U-87201 (V). Dissolution of (V) in methanol, treatment with 1 eq of methanesulfonic acid, and the addition of diethyl ether results in the precipitation of atevirdine mesylate.
| 【1】 Richman, D.D.; Fischl, M.A.; Grieco, M.H.; et al.; The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex: A double-blind, placebo-controlled trial. New Engl J Med 1987, 317, 4, 192-7. |
| 【2】 Tan, C.-K.; Busso, M.; Romero, D.L.; et al.; Nonnucleoside reverse transcriptase inhibitors that potently and specifically block human immunodeficiency virus type 1 replication. Proc Natl Acad Sci USA 1991, 88, 19, 8806-10. |
| 【3】 Romero, D.L.; Atevirdine Mesylate. Drugs Fut 1994, 19, 1, 9. |
| 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) | 10355 | Diethylenediamine; Piperazine | 110-85-0 | C4H10N2 | 详情 | 详情 |
| (II) | 10321 | 2-Chloro-3-nitropyridine | 5470-18-8 | C5H3ClN2O2 | 详情 | 详情 |
| (III) | 16159 | tert-butyl 4-(3-nitro-2-pyridinyl)tetrahydro-1(2H)-pyrazinecarboxylate | C14H20N4O4 | 详情 | 详情 | |
| (IV) | 14880 | tert-butyl 4-[3-(ethylamino)-2-pyridinyl]tetrahydro-1(2H)-pyrazinecarboxylate | C16H26N4O2 | 详情 | 详情 | |
| (V) | 63849 | {4-[3-(ethylamino)-2-pyridinyl]-1-piperazinyl}(1H-indol-2-yl)methanone | C20H23N5O | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)The condensation of 4-aminophenol (I) with 2-chloro-3-nitropyridine (II) in DMF at 100 C gives 4-(3-nitropyridin-2-ylamino)phenol (III), which is reduced with H2 over Pd/C in THF-methanol to afford 4-(3-aminopyridin-2-ylamino)phenol (IV). Finally, this compound is condensed with 4-methoxybenzenesulfonylchloride (V) by means of pyridine in THF.
| 【1】 Yoshino, H.; Ueda, N.; Sugumi, H.; Niijima, J.; Kotake, Y.; Okada, T.; Koyanagi, N.; Watanabe, T.; Asada, M.; Yoshimatsu, K.; Iijima, A.; Nagasu, T.; Tsukahara, K.; Kitoh, K. (Eisai Co., Ltd.); Sulfonamide derivs. EP 0472053; JP 1993039256; US 5250549; US 5292758; US 5332751; US 5434172 . |
| 【2】 Niijima, J.; Yoshino, H.; Ueda, N.; et al.; Novel sulfonamides as potential, systemically active antitumor agents. J Med Chem 1992, 35, 13, 2496-7. |
| 【3】 Hoshi, A.; Castaner, J.; E-7010. Drugs Fut 1993, 18, 11, 995. |
| 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) | 15715 | 4-Aminophenol | 123-30-8 | C6H7NO | 详情 | 详情 |
| (II) | 10321 | 2-Chloro-3-nitropyridine | 5470-18-8 | C5H3ClN2O2 | 详情 | 详情 |
| (III) | 15717 | 4-[(3-nitro-2-pyridinyl)amino]phenol | C11H9N3O3 | 详情 | 详情 | |
| (IV) | 15718 | 4-[(3-amino-2-pyridinyl)amino]phenol | C11H11N3O | 详情 | 详情 | |
| (V) | 15719 | 4-methoxybenzenesulfonyl chloride | 98-68-0 | C7H7ClO3S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)The synthesis of delavirdine mesylate is depicted in Scheme 19654001a: The first three chemical steps are the same as those used for the synthesis of atevirdine mesylate (ATV, U-87201E) (2, 3). Nucleophilic aromatic substitution of 2-chloro-3-nitropyridine (II) with excess piperazine in acetonitrile at room temperature produces 1-(3-nitro-2-pyridyl)piperazine. Protection of the free piperazine nitrogen by treatment with di-tert-butyldicarbonate affords nitropyridine (III). Reduction of the nitro group to the amine is accomplished via hydrogenation (40 psi) over palladium on carbon. Treatment of the aminopyridine with acetone and sodium cyanoborohydride in methanol affords the 3-(1-methylethylamino)pyridine (IV). Removal of the BOC protecting group with trifluoroacetic acid and coupling of the resulting 1-[3-(1-methylethylamino)pyridyl]piperazine with 5-nitroindole-2-carboxylic acid using 1-ethyl-3-(dimethylaminopropyl)carbodiimide (EDC) or 1,1'-carbonyldiimidazole (CDI) affords (V). Catalytic reduction of the nitro group and treatment of the resulting amine with methanesulfonyl chloride provides U-90152. Dissolution of U-90152 in acetonitrile and treatment with 1 eq of methanesulfonic acid results in the precipitation of delavirdine mesylate.
| 【1】 Romero, D.L.; Atevirdine mesylate (U-87201E). Drugs Fut 1994, 19, 1, 7-12. |
| 【2】 Aristoff, P.A.; Romero, D.L.; Palmer, J.R.; Thomas, R.C.; Smith, H.W. (Pharmacia Corp.); Diaromatic substd. cpds. as anti-HIV-1 agents. US 5563142 . |
| 【3】 Busso, M.; Romero, D.L.; Biles, C.; Genin, M.J.; Tarpley, W.G.; Morge, R.A.; Reusser, F.; Althaus, I.W.; Thomas, R.C.; Resnick, L.; Bis(heteroaryl)piperazine (BHAP) reverse transcriptase inhibitors: Structure-activity relationships of novel substituted indole analogues and the identification oF (U-90152S), a second-generation clinical candidate. J Med Chem 1993, 36, 10, 1505-8. |
| 【4】 Romero, D.L.; Delavirdine Mesylate. Drugs Fut 1994, 19, 3, 238. |
| 【5】 Tan, C.-K.; Busso, M.; Romero, D.L.; et al.; Nonnucleoside reverse transcriptase inhibitors that potently and specifically block human immunodeficiency virus type 1 replication. Proc Natl Acad Sci USA 1991, 88, 19, 8806-10. |
| 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) | 10355 | Diethylenediamine; Piperazine | 110-85-0 | C4H10N2 | 详情 | 详情 |
| (II) | 10321 | 2-Chloro-3-nitropyridine | 5470-18-8 | C5H3ClN2O2 | 详情 | 详情 |
| (III) | 16159 | tert-butyl 4-(3-nitro-2-pyridinyl)tetrahydro-1(2H)-pyrazinecarboxylate | C14H20N4O4 | 详情 | 详情 | |
| (IV) | 16160 | tert-butyl 4-[3-(isopropylamino)-2-pyridinyl]tetrahydro-1(2H)-pyrazinecarboxylate | C17H28N4O2 | 详情 | 详情 | |
| (V) | 16161 | [4-[3-(isopropylamino)-2-pyridinyl]piperazino](5-nitro-1H-indol-2-yl)methanone | C21H24N6O3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)The title compound has been obtained by several related ways: The reaction of 2-chloro-3-nitropyridine (I) with methylboronic acid by means of Pd(PPh3)4 and K2CO3 in hot dioxane gives 2-methyl-3-nitropyridine (III), which is condensed with dimethylformamide dimethylacetal (IV) to yield 2-[2-(dimethylamino)vinyl]-3-nitropyridine (V). The oxidation of (V) by means of NaIO4 affords 3-nitropyridine-2-carbaldehyde (VI), which is condensed with semicarbazide (VII) to provide the corresponding semicarbazone (VIII). Finally, the nitro group of (VIII) is reduced with SnCl2 or Na2S to furnish the target 3-aminopyridine-2-carbaldehyde semicarbazone. 2-Methyl-3-nitropyridine (III) can also be obtained by condensation of 2-chloro-3-nitropyridine (I) with diethyl malonate (II) by means of Na, followed by decarboxylative hydrolysis with H2SO4 at 125 C. The direct oxidation of 2-methyl-3-nitropyridine (III) with SeO2 in dioxane gives carbaldehyde (VI), which is treated with ethyleneglycol (IX) and Ts-OH to yield the cyclic acetal (X). The reduction of (X) with H2 over Pd/C in ethanol affords 3-aminopyridine-2-carbaldehyde ethylene ketal (XI), which is treated with semicarbazide (VI) and HCl to afford the target 3-aminopyridine-2-carbaldehyde semicarbazone. The condensation of 2-chloro-3-nitropyridine (I) with tributyl vinyl tin (XII) Pd(PPh3)4 and PPH3 in refluxing toluene gives 3-nitro-2-vinylpyridine (XIII), which is oxidized with O3 and Me2S in methanol to yield 3-nitropyridine-2-carbaldehyde (VI). This compound is condensed with semicarbazide (VII) and reduced to the target compound as already described.
| 【1】 Li, J.; et al.; Syntheses and antitumor activities of potent inhibitors of ribonucleotide reductase: 3-Amino-4-methylpyridine-2-carboxaldehyde-thiosemicarbazone (3-AMP), 3-amino-pyridine-2-carboxaldehyde-thiosemicarbazone (3-AP) and its water-soluble prodrugs. Curr Med Chem 2001, 8, 2, 121. |
| 【2】 Niu, C.; et al.; Synthesis of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP). Tetrahedron 1998, 54, 23, 6311. |
| 【3】 Liu, M-C.; et al.; Synthesis and antitumor activity of amino derivatives of pyridine-2-carboxaldehyde thiosemicarbazone. J Med Chem 1992, 35, 20, 3672. |
| 【4】 Sartorelli, A.C.; Lin, T.-S. (Yale University); 2-Formylpyridine thiosemicarbazone derivs., their preparation and their use as antitumor agents. EP 0570294; JP 1994128230; US 5281715; US 5721259 . |
| 【5】 Doyle, T.W.; Li, J.; Chen, S.-H.; Li, X.; Niu, C.-S. (Vion Pharmaceuticals, Inc.); Process for the synthesis of ribonucleotide reductase inhibitors 3-AP and 3-AMP. US 5869676; WO 9851670 . |
| 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) | 10321 | 2-Chloro-3-nitropyridine | 5470-18-8 | C5H3ClN2O2 | 详情 | 详情 |
| (II) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (III) | 54410 | 2-methyl-3-nitropyridine | 18699-87-1 | C6H6N2O2 | 详情 | 详情 |
| (IV) | 11984 | N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal | 4637-24-5 | C5H13NO2 | 详情 | 详情 |
| (V) | 54411 | (E)-N,N-dimethyl-2-(3-nitro-2-pyridinyl)-1-ethenamine; N,N-dimethyl-N-[(E)-2-(3-nitro-2-pyridinyl)ethenyl]amine | C9H11N3O2 | 详情 | 详情 | |
| (VI) | 54414 | 3-nitro-2-pyridinecarbaldehyde | 10261-94-6 | C6H4N2O3 | 详情 | 详情 |
| (VII) | 12954 | 1-Hydrazinecarbothioamide; Thiosemicarbazide | 79-19-6 | CH5N3S | 详情 | 详情 |
| (VIII) | 54415 | 2-[(E)-(3-nitro-2-pyridinyl)methylidene]-1-hydrazinecarbothioamide | C7H7N5O2S | 详情 | 详情 | |
| (IX) | 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 |
| (X) | 54413 | 2-(1,3-dioxolan-2-yl)-3-nitropyridine | C8H8N2O4 | 详情 | 详情 | |
| (XI) | 54412 | 2-(1,3-dioxolan-2-yl)-3-pyridinylamine; 2-(1,3-dioxolan-2-yl)-3-pyridinamine | C8H10N2O2 | 详情 | 详情 | |
| (XII) | 54417 | 3,3-dibutyl-1-heptene | C15H30 | 详情 | 详情 | |
| (XIII) | 54416 | 3-nitro-2-vinylpyridine | C7H6N2O2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(IX)The acylation of 4-benzyloxyaniline (I) with trifluoroacetyl chloride and triethylamine in dichloromethane gives the corresponding amide (II), which is treated with resin-supported triphenylphosphine and CCl4 to yield the iminochloride (III). The cyclization of (III) with sodium azide in hot acetic acid affords the tetrazole (IV), which is debenzylated with H2 over Pd/C in ethanol/THF, giving the phenol (V). The reaction of (V) with hexamethylenetetramine (HMT) in hot trifluoroacetic acid yields the benzaldehyde (VI), which by methylation with methyl iodide/K2CO3 in acetone affords 2-methoxy-5-[5-(trifluoromethyl)tetrazol-1-yl]benzaldehyde (VII). Finally, this compound is reductocondensed with (2S,3S)-2-phenylpiperidin-3-amine (VIII) by means of sodium triacetoxyborohydride/acetic acid in dichloromethane. The chiral (2S,3S)-2-phenylpiperidin-3-amine (VIII) has been obtained as follows: The condensation of 2-chloro-3-nitropyridine (IX) with phenylboronic acid (X) by means of palladium tetrakis(triphenylphosphine) and Na2CO3 in dimethoxyethane gives 3-nitro-2-phenylpyridine (XI), which is hydrogenated with H2 over Pd/C in ethanol/HCl, yielding (?-cis-2-phenylpiperidin-3-amine (XII). Finally, this compound is submitted to optical resolution by means of di-p-toluoyl-L-tartaric acid in ethanol/water.
| 【1】 Congreve, M.; Chung, K.M.L.; Armour, D.R.; et al.; Tetrazole NK1 receptor antagonists: The identifica. Bioorg Med Chem Lett 1996, 6, 9, 1015. |
| 【2】 Silvestre, J.S.; Castañer, J.; Sorbera, L.A.; GR-205171. Drugs Fut 1999, 24, 3, 254. |
| 【3】 Armour, D.R.; Evans, B.; Giblin, G.M.P.; Hann, M.M.; Hubbard, T.; Lewell, X.; Middlemiss, D.; Naylor, A.; Pegg, N.A.; Vinader, M.V.; Watson, S.P. (Glaxo Wellcome plc); 3-(5-Tetrazolyl-benzyl)amino-piperidine derivs. an. EP 0720609; JP 1999106341; US 5703240; US 5843966; WO 9508549 . |
| 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) | 22460 | 4-(benzyloxy)aniline; 4-(benzyloxy)phenylamine | C13H13NO | 详情 | 详情 | |
| (II) | 22461 | N-[4-(benzyloxy)phenyl]-2,2,2-trifluoroacetamide | C15H12F3NO2 | 详情 | 详情 | |
| (III) | 22462 | N-[4-(benzyloxy)phenyl]-2,2,2-trifluoroethanimidoyl chloride | C15H11ClF3NO | 详情 | 详情 | |
| (IV) | 22463 | 1-[4-(benzyloxy)phenyl]-5-(trifluoromethyl)-1H-1,2,3,4-tetraazole; benzyl 4-[5-(trifluoromethyl)-1H-1,2,3,4-tetraazol-1-yl]phenyl ether | C15H11F3N4O | 详情 | 详情 | |
| (V) | 22464 | 4-[5-(trifluoromethyl)-1H-1,2,3,4-tetraazol-1-yl]phenol | C8H5F3N4O | 详情 | 详情 | |
| (VI) | 22465 | 2-hydroxy-5-[5-(trifluoromethyl)-1H-1,2,3,4-tetraazol-1-yl]benzaldehyde | C9H5F3N4O2 | 详情 | 详情 | |
| (VII) | 22466 | 2-methoxy-5-[5-(trifluoromethyl)-1H-1,2,3,4-tetraazol-1-yl]benzaldehyde | C10H7F3N4O2 | 详情 | 详情 | |
| (VIII) | 22467 | (2S,3S)-2-phenylpiperidinylamine; (2S,3S)-2-phenyl-3-piperidinamine | C11H16N2 | 详情 | 详情 | |
| (IX) | 10321 | 2-Chloro-3-nitropyridine | 5470-18-8 | C5H3ClN2O2 | 详情 | 详情 |
| (IX) | 16593 | Phenylboronic acid；Benzeneboronic acid;Phenylboron dihydroxide | 98-80-6 | C6H7BO2 | 详情 | 详情 |
| (XI) | 22470 | 3-nitro-2-phenylpyridine | C11H8N2O2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(I)The reaction of 2-chloro-3-nitropyridine (I) with piperidine (II) in dichloromethane gives 3-nitro-2-(1-piperidinyl)pyridine (III), which is cyclized by means of anhydrous ZnCl2 in refluxing acetic acid yielding the acetoxy dipyridoimidazole (IV). The deacetylation of (IV) with NaOH in methanol affords the alcohol (V), which is oxidized with oxalyl chloride and DMSO in dichloromethane to give the ketone (VI). The bromination of (VI) with Br2 in hot aqueous HBr yields the alpha-bromoketone (VII), which is finally cyclized with N,N-dimethylthiourea (VIII) in refluxing ethanol.
| 【1】 Chang, M.S.; Chung, K.J.; Park, S.H.; Kim, Y.H.; Kim, K.B.; Choi, W.S.; Kim, S.G.; Lee, J.M.; Seo, K.H.; Yoo, H.Y.; Paek, J.H.; Kang, D.P. (Yung-Jin Pharmaceutical Co., Ltd.); Benz- or pyrido-imidazole derivs.. WO 9703077 . |
| 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) | 10321 | 2-Chloro-3-nitropyridine | 5470-18-8 | C5H3ClN2O2 | 详情 | 详情 |
| (II) | 10158 | Piperidine | 110-89-4 | C5H11N | 详情 | 详情 |
| (III) | 35469 | 3-nitro-2-(1-piperidinyl)pyridine | C10H13N3O2 | 详情 | 详情 | |
| (IV) | 35470 | 6,7,8,9-tetrahydropyrido[3',2':4,5]imidazo[1,2-a]pyridin-6-yl acetate | C12H13N3O2 | 详情 | 详情 | |
| (V) | 35471 | 6,7,8,9-tetrahydropyrido[3',2':4,5]imidazo[1,2-a]pyridin-6-ol | C10H11N3O | 详情 | 详情 | |
| (VI) | 35472 | 8,9-dihydropyrido[3',2':4,5]imidazo[1,2-a]pyridin-6(7H)-one | C10H9N3O | 详情 | 详情 | |
| (VII) | 35473 | 7-bromo-8,9-dihydropyrido[3',2':4,5]imidazo[1,2-a]pyridin-6(7H)-one | C10H8BrN3O | 详情 | 详情 | |
| (VIII) | 35474 | N,N-dimethylthiourea | C3H8N2S | 详情 | 详情 |