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【结 构 式】 
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【分子编号】15224 【品名】2-chloronicotinoyl chloride 【CA登记号】49609-84-9 |
【 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：(IV)In a different procedure, 2-chloronicotinic acid (III) was chlorinated to (IV) by means of boiling thionyl chloride. Condensation of acid chloride (IV) with 2-morpholinoethanol (V) gave rise to the morpholinoethyl chloronicotinate (VI). Finally, displacement of the 2-chloro with m-(trifluoromethyl)aniline (VII) in the presence of zinc oxide and iodine furnished the title compound.
| 【1】 Chiesi, P.; Servadio, V.; Pighi, R. (Chiesi Farmaceutici SpA); Processes for the preparation of morniflumate and analogous cpds.. EP 0349902 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 28824 | 2-Chloropyridine-3-carboxylic acid; 2-Chloronicotinic acid | 2942-59-8 | C6H4ClNO2 | 详情 | 详情 |
| (IV) | 15224 | 2-chloronicotinoyl chloride | 49609-84-9 | C6H3Cl2NO | 详情 | 详情 |
| (V) | 12856 | 4-(2-Hydroxyethyl)morpholine; 2-(4-Morpholinyl)-1-ethanol; N-(2-Hydroxyethyl)morpholine | 622-40-2 | C6H13NO2 | 详情 | 详情 |
| (VI) | 56318 | 2-(4-morpholinyl)ethyl 2-chloronicotinate | C12H15ClN2O3 | 详情 | 详情 | |
| (VII) | 26347 | 3-(trifluoromethyl)phenylamine; 3-(trifluoromethyl)aniline; 3-aminobenzotrifluoride | 98-16-8 | C7H6F3N | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)Alternatively, acid chloride (IV), prepared from 2-chloronicotinic acid (III), was treated with methanol and triethylamine to afford the methyl ester (VIII). Displacement of the 2-chloro with m-(trifluoromethyl)aniline (VII) yielded methyl niflumate (IX). Finally, transesterification of methyl ester (IX) with 2-morpholinoethanol (V) in the presence of sodium metal gave rise to the title compound.
| 【1】 Chiesi, P.; Servadio, V.; Pighi, R. (Chiesi Farmaceutici SpA); Processes for the preparation of morniflumate and analogous cpds.. EP 0349902 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 28824 | 2-Chloropyridine-3-carboxylic acid; 2-Chloronicotinic acid | 2942-59-8 | C6H4ClNO2 | 详情 | 详情 |
| (IV) | 15224 | 2-chloronicotinoyl chloride | 49609-84-9 | C6H3Cl2NO | 详情 | 详情 |
| (V) | 12856 | 4-(2-Hydroxyethyl)morpholine; 2-(4-Morpholinyl)-1-ethanol; N-(2-Hydroxyethyl)morpholine | 622-40-2 | C6H13NO2 | 详情 | 详情 |
| (VII) | 26347 | 3-(trifluoromethyl)phenylamine; 3-(trifluoromethyl)aniline; 3-aminobenzotrifluoride | 98-16-8 | C7H6F3N | 详情 | 详情 |
| (VIII) | 56319 | methyl 2-chloronicotinate | C7H6ClNO2 | 详情 | 详情 | |
| (IX) | 56320 | methyl 2-[3-(trifluoromethyl)anilino]nicotinate | C14H11F3N2O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：The diazonium salt from 2-amino-4-methylpyridine (I) is converted to 2-hydroxy-4-methylpyridine (II), which is nitrated to give 2-hydroxy-4-methyl-3-nitropyridine (III). Conversion to 2-chloro-4-methyl-3-nitropyridine (IV) is effected with phosphorous oxychloride and phosphorous pentachloride. Reduction of (IV) with hydrogen/Raney Nickel provides 3-amino-2-chloro-4-methylpyridine (V), which is condensed with 2-chloronicotinoyl chloride to give 2-chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridinecarboxamide (VI). Treatment with cyclopropylamine affords N-(2-chloro-4-methyl-3-pyridinyl)-2-(cyclopropylamino)-3-pyridinecarboxamide (VII), which is cyclized in the presence of sodium hydride to yield nevirapine.
| 【1】 Hargrave, K.D.; Grozinger, K.G.; Proudfoot, J.R.; et al.; Novel non-nucleoside inhibitors of HIV-1 reverse transcriptase. 1. Tricyclic pyridobenzo- and dipyridodiazepinones. J Med Chem 1991, 34, 7, 2231-41. |
| 【2】 Riska, P.S.; Johnstone, J.N.; Silverstein, H.H.; Hattox, S.E.; Norris, S.H.; St. George, R.; Grob, P.M.; Hargrave, K.D.; Nevirapine. Drugs Fut 1992, 17, 10, 887. |
| 【3】 Hargrave, K.D.; Merluzzi, V.J.; Labadia, M.; et al.; Inhibition of HIV-1 replication by a non-nucleoside reverse transcriptase inhibitor. Science 1990, 250, 4986, 1411-3. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 15224 | 2-chloronicotinoyl chloride | 49609-84-9 | C6H3Cl2NO | 详情 | 详情 | |
| (I) | 14614 | 2-Amino-4-picoline; 4-Methyl-2-pyridinamine; 4-Methyl-2-pyridinylamine; 2-Amino-4-methylpyridine | 695-34-1 | C6H8N2 | 详情 | 详情 |
| (II) | 14615 | 4-methyl-2-pyridinol | C6H7NO | 详情 | 详情 | |
| (III) | 14616 | 4-Methyl-3-nitro-pyridin-2-ol; 4-Methyl-3-nitro-2-pyridinol | 21901-18-8 | C6H6N2O3 | 详情 | 详情 |
| (IV) | 14617 | 2-chloro-4-methyl-3-nitropyridine | 23056-39-5 | C6H5ClN2O2 | 详情 | 详情 |
| (V) | 14618 | 2-chloro-4-methyl-3-pyridinamine; 2-chloro-4-methyl-3-pyridinylamine | 133627-45-9 | C6H7ClN2 | 详情 | 详情 |
| (VI) | 14619 | 2-chloro-N-(2-chloro-4-methyl-3-pyridinyl)nicotinamide | C12H9Cl2N3O | 详情 | 详情 | |
| (VII) | 14620 | N-(2-chloro-4-methyl-3-pyridinyl)-2-(cyclopropylamino)nicotinamide; N-(2-chloro-4-methyl-3-pyridinyl)-2-(cyclopropylamino)-3-pyridinecarboxamide | 133627-47-1 | C15H15ClN4O | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)The synthesis of MD-39-AM (V) was carried out as follows: From 2-chloronicotinic acid (as its acyl chloride) (I) and thiourea in triethylamine (1:1:2), compound (II) was obtained. However, in order to avoid the substitution of 2-Cl by sulfur, 2-methylisothiourea was used. By boiling a solution of (II) in dimethylformamide (DMF) for 15 min, (III) (87%) was obtained. Reaction of (III) with phosphorous oxychloride gave 4-chloro-2-(methylthio)pyrido[2,3-d]pyrimidine (IV) (90%). By reacting (IV) with aniline in ethanol, MD-39-AM was obtained.
| 【1】 Martinez-Merino, V.; Ochoa, M.C.; Fernandez, F.J.; Artigas, P.; Monge, A.; Bellver, C.; Sanmartin, C.; Fernandez-Alvarez, E.; 2-Arylamino-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidines: Synthesis and diuretic activity. Eur J Med Chem 1989, 24, 209. |
| 【2】 Martinez-Merino, V.; Monge, A.; Sanmartin, C.; MD-39-AM. Drugs Fut 1992, 17, 2, 107. |
| 【3】 Ochoa, M.C.; Fernández, F.J.; Sanmartín, C.; Monge, A.; Martínez-Merino, V.; Bellver, C.; Artigas, P.; Diuretic and hypotensive activities of 4-anilino derivatives of 2-methylthiopyrido[2,3-d]pyrimidines. Arzneim-Forsch Drug Res 1990, 40, 11, 1230-3. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10272 | [[Amino(imino)methyl]sulfanyl]methane | 2986-19-8 | C2H6N2S | 详情 | 详情 | |
| (I) | 15224 | 2-chloronicotinoyl chloride | 49609-84-9 | C6H3Cl2NO | 详情 | 详情 |
| (II) | 15225 | 2-chloro-3-([[imino(methylsulfanyl)methyl]amino]carbonyl)pyridine | C8H8ClN3OS | 详情 | 详情 | |
| (III) | 15226 | 2-(methylsulfanyl)pyrido[2,3-d]pyrimidin-4-ol | C8H7N3OS | 详情 | 详情 | |
| (IV) | 15227 | 4-chloropyrido[2,3-d]pyrimidin-2-yl methyl sulfide; 4-chloro-2-(methylsulfanyl)pyrido[2,3-d]pyrimidine | C8H6ClN3S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XV)The intermediate amino alcohol (XVIII) was prepared by two ways. 2-Chloronicotinic acid (XIV) was converted to the corresponding acid chloride (XV) by treatment with oxalyl chloride, and then reacted with potassium tert-butoxide to afford the tert-butyl ester (XVI). Displacement of the chloride group of (XVI) with methanolic methylamine gave rise to the 2-(methylamino)nicotinic ester (XVII), which was then reduced to alcohol (XVIII) employing LiAlH4. Alternatively, 2-aminonicotinic acid (XIX) was esterified to (XX) by means of 2-chloro-1,3-dimethylimidazolinium chloride in MeOH. The amino group of (XX) was acylated with formic acetic anhydride to give formamide (XXI). Amino alcohol (XVIII) was then obtained by reduction of amido ester (XXI) in the presence of LiAlH4. Condensation of (XVIII) with 1-chloroethyl chloroformate produced the carbamate alcohol (XXII), which was subsequently esterified with N-Boc-sarcosine (XXIII) by means of EDC yielding (XXIV) (2). Quaternization of the triazole compound (XIII) with the chloroethyl carbamate (XXIV) in the presence of NaI furnished the corresponding triazolium salt, which was finally subjected to acidic Boc group cleavage to produce the title compound.
| 【1】 Ohwada, J.; Tsukazaki, M.; Hayase, T.; et al.; Design, synthesis and antifungal activity of a novel water soluble prodrug of antifungal triazole. Bioorg Med Chem Lett 2003, 13, 2, 191. |
| 【2】 Hayase, T.; Tsukazaki, M.; Ohwada, J.; et al.; Development of novel water antifungal, RO0098557. 21st Symp Med Chem (Nov 28 2001, Kyoto) 2001, Abst 1P-06. |
| 【3】 Ohwada, J.; et al.; RO0098557, a novel water soluble azole prodrug for parenteral and oral administration (I). Design, synthesis, physicochemical properties and bioconversion. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-820. |
| 【4】 Shimma, N.; Fukuda, H.; Umeda, I.; Ohwada, J.; Sakaitani, M.; Oikawa, N.; Hayase, T.; Tsukazaki, M.; Mizuguchi, E. (F. Hoffmann-La Roche AG); N-Substd. carbamoyloxyalkyl-azolium derivs.. WO 0132652 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIII) | 55929 | 4-{2-[(1R,2R)-2-(2,5-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-1,3-thiazol-4-yl}benzonitrile | C22H17F2N5OS | 详情 | 详情 | |
| (XIV) | 28824 | 2-Chloropyridine-3-carboxylic acid; 2-Chloronicotinic acid | 2942-59-8 | C6H4ClNO2 | 详情 | 详情 |
| (XV) | 15224 | 2-chloronicotinoyl chloride | 49609-84-9 | C6H3Cl2NO | 详情 | 详情 |
| (XVI) | 55930 | tert-butyl 2-chloronicotinate | C10H12ClNO2 | 详情 | 详情 | |
| (XVII) | 55931 | tert-butyl 2-(methylamino)nicotinate | C11H16N2O2 | 详情 | 详情 | |
| (XVIII) | 55932 | [2-(methylamino)-3-pyridinyl]methanol | C7H10N2O | 详情 | 详情 | |
| (XIX) | 55933 | 2-Aminonicotinic acid; 2-Aminopyridine-3-carboxylic acid | 5345-47-1 | C6H6N2O2 | 详情 | 详情 |
| (XX) | 55934 | methyl 2-aminonicotinate | 14667-47-1 | C7H8N2O2 | 详情 | 详情 |
| (XXI) | 55935 | methyl 2-(formylamino)nicotinate | C8H8N2O3 | 详情 | 详情 | |
| (XXII) | 55936 | 1-chloroethyl 3-(hydroxymethyl)-2-pyridinyl(methyl)carbamate | C10H13ClN2O3 | 详情 | 详情 | |
| (XXIII) | 55937 | Boc-L-sarcosine; Boc-N-Methylglycine; Boc-sarcosine; N-tert-Butoxycarbonylsarcosine | 13734-36-6 | C8H15NO4 | 详情 | 详情 |
| (XXIV) | 55938 | {2-[[(1-chloroethoxy)carbonyl](methyl)amino]-3-pyridinyl}methyl 2-[(tert-butoxycarbonyl)(methyl)amino]acetate | C18H26ClN3O6 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)The intermediate 2-chloropyridin-3-ylmethylamine (VI) has been obtained as follows. The reaction of 2-chloropyridine-3-carboxylic acid (I) with refluxing SOCl2 gives the corresponding acyl chloride (II), which is reduced by means of NaBH4 in water to yield the carbinol (III). The reaction of (III) with SOCl2 in toluene affords the chloromethyl derivative (IV), which is treated with esther NaN3 in DMF or LiN3 ijn DMSO to provide the azidomethyl derivative (V). Finally, this compound is reduced with PPh3 in THF/water or H2, Pd/C in EtOH to furnish the desired 2-chloropyridin-3-ylmethylamine intermediate (VI).
| 【1】 Design and synthesis of 8-hydroxy-[1,6]naphthyridines as novel inhibitors of HIV-1 integrase in vitro and in infected cells. J Med Chem 2003, 46, 4, 453. |
| 【2】 Young, S.D.; Guare, J.P.; Wai, J.S.; Payne, L.S.; Fisher, T.E.; Zhuang, L.; Embrey, M. (Merck & Co., Inc.); Aza- and polyaza-naphthalenyl ketones useful as HIV integrase inhibitors. WO 0236734 . |
| 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) | 28824 | 2-Chloropyridine-3-carboxylic acid; 2-Chloronicotinic acid | 2942-59-8 | C6H4ClNO2 | 详情 | 详情 |
| (II) | 15224 | 2-chloronicotinoyl chloride | 49609-84-9 | C6H3Cl2NO | 详情 | 详情 |
| (III) | 61829 | (2-chloro-3-pyridinyl)methanol | C6H6ClNO | 详情 | 详情 | |
| (IV) | 61830 | 2-Chloronicotinyl chloride; 2-CHLORONICOTINOYL CHLORIDE; 2-Chloropyridine-3-carbonyl chloride | 49609-84-9 | C6H5Cl2N | 详情 | 详情 |
| (V) | 61831 | (2-chloro-3-pyridinyl)methyl azide; 3-(azidomethyl)-2-chloropyridine | C6H5ClN4 | 详情 | 详情 | |
| (VI) | 61832 | (2-chloro-3-pyridinyl)methanamine; (2-chloro-3-pyridinyl)methylamine | C6H7ClN2 | 详情 | 详情 |