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【结 构 式】 
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【分子编号】55933 【品名】2-Aminonicotinic acid; 2-Aminopyridine-3-carboxylic acid 【CA登记号】5345-47-1 |
【 分 子 式 】C6H6N2O2 【 分 子 量 】138.12592 【元素组成】C 52.17% H 4.38% N 20.28% O 23.17% |
合成路线1
该中间体在本合成路线中的序号：(XIX)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2
该中间体在本合成路线中的序号：(V)Reduction of 2-aminonicotinic acid (V) by means of LiAlH4 afforded amino alcohol (VI). Subsequent bromination of (VI) with N-bromosuccinimide gave 2-amino-5-bromo-3-(hydroxymethyl)pyridine (VII). Alcohol (VII) was then converted to the bromomethyl pyridine derivative (VIII) by treatment with concentrated hydrobromic acid. Condensation of bromo amine (VIII) with dimethyl malonate led to the naphthyridine carboxylate (IX). Basic hydrolysis of the methyl ester of (IX), followed by decarboxylation under acidic conditions, gave rise to naphthyridinone (X).
| 【1】 Seefeled, M.A.; et al.; Discovery and characterization of highly potent naphthyridine-based FabI inhibitors with in vivo activity. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1690. |
| 【2】 Uzinskas, I.N.; Miller, W.H.; Newlander, K.A.; Jakas, D.R.; Seefeld, M.A.; DeWolf, W.E. Jr. (GlaxoSmithKline Inc.); Fab I inhibitors. EP 1226138; WO 0127103 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 55933 | 2-Aminonicotinic acid; 2-Aminopyridine-3-carboxylic acid | 5345-47-1 | C6H6N2O2 | 详情 | 详情 |
| (VI) | 56112 | (2-amino-3-pyridinyl)methanol | 23612-57-9 | C6H8N2O | 详情 | 详情 |
| (VII) | 56113 | (2-amino-5-bromo-3-pyridinyl)methanol | C6H7BrN2O | 详情 | 详情 | |
| (VIII) | 56114 | 5-bromo-3-(bromomethyl)-2-pyridinamine; 5-bromo-3-(bromomethyl)-2-pyridinylamine | 335033-38-0 | C6H6Br2N2.HBr | 详情 | 详情 |
| (IX) | 56115 | methyl 6-bromo-2-oxo-1,2,3,4-tetrahydro[1,8]naphthyridine-3-carboxylate | 335031-10-2 | C10H9BrN2O3 | 详情 | 详情 |
| (X) | 56116 | 6-bromo-3,4-dihydro[1,8]naphthyridin-2(1H)-one | C8H7BrN2O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Fischer esterification of 2-aminonicotinic acid (I) leads to methyl ester (II). Subsequent treatment of ester (II) with a methanolic solution of guanidine (III) provides (2-aminonicotinoyl)guanidine (IV). Finally, bromination of (IV) employing Br2/HBr affords the title compound.
| 【1】 Cragoe, E.J. Jr. (Merck & Co., Inc.); Certain aminopyridinecarbonyl guanidines. DE 1963317; FR 2026469; US 3586688 . |
合成路线4
该中间体在本合成路线中的序号：(I)2-Aminonicotinic acid (I) is reduced to alcohol (II) employing LiAlH4 in refluxing THF. Subsequent bromination of (II) with N-bromosuccinimide affords 2-amino-5-bromo-3-(hydroxymethyl)pyridine (III). Heating of alcohol (III) with concentrated HBr leads to the bromomethyl pyridine (IV). This is further condensed with dimethyl malonate in the presence of NaOMe to produce the naphthyridinecarboxylate (V). Then, alkaline hydrolysis of ester (V), followed by acidic decarboxylation gives rise to 6-bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one (VI)
| 【1】 Uzinskas, I.N.; Miller, W.H.; Newlander, K.A.; Jakas, D.R.; Seefeld, M.A.; DeWolf, W.E. Jr. (GlaxoSmithKline Inc.); Fab I inhibitors. EP 1226138; WO 0127103 . |
| 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) | 55933 | 2-Aminonicotinic acid; 2-Aminopyridine-3-carboxylic acid | 5345-47-1 | C6H6N2O2 | 详情 | 详情 |
| (II) | 56112 | (2-amino-3-pyridinyl)methanol | 23612-57-9 | C6H8N2O | 详情 | 详情 |
| (III) | 56113 | (2-amino-5-bromo-3-pyridinyl)methanol | C6H7BrN2O | 详情 | 详情 | |
| (IV) | 56114 | 5-bromo-3-(bromomethyl)-2-pyridinamine; 5-bromo-3-(bromomethyl)-2-pyridinylamine | 335033-38-0 | C6H6Br2N2.HBr | 详情 | 详情 |
| (V) | 56115 | methyl 6-bromo-2-oxo-1,2,3,4-tetrahydro[1,8]naphthyridine-3-carboxylate | 335031-10-2 | C10H9BrN2O3 | 详情 | 详情 |
| (VI) | 56116 | 6-bromo-3,4-dihydro[1,8]naphthyridin-2(1H)-one | C8H7BrN2O | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)Reduction of 2-aminonicotinic acid (I) with LiAlH4 in THF gives (2-amino-3-pyridinyl)methanol (II), which by bromination with Br2 in AcOH yields (2-amino-5-bromo-3-pyridinyl)methanol hydrobromide (III). Substitution of alcohol (III) with aqueous HBr at reflux provides the corresponding bromide (IV), which by cyclocondensation with dimethyl malonate (V) in the presence of NaH in DMF/THF provides methyl 6-bromo-2-oxo-1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxylate (VI). Hydrolysis of ester (VI) with NaOH in refluxing MeOH, followed by decarboxylation in refluxing HCl leads to 6-bromo-3,4-dihydro-1,8-naphthyridin-2-one (VII) . Heck coupling of aryl bromide (VII) with t-butyl acrylate (VIII) in the presence of Pd(OAc)2, DIEA and P(o-tol)3 in propionitrile/DMF or acetonitrile/DMF affords the naphthyridinyl-acrylate (IX) , whose t-butyl ester group is then cleaved using TFA in CH2Cl2 to afford, after treatment with HCl in dioxane, (E)-3-(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (Xa) . Similarly, hydrolysis of t-butyl ester (IX) using HBr in AcOH yields 3-(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-3-yl)acrylic acid hydrobromide (Xb) . Finally, acrylic acids (Xa) or (Xb) are condensed with N-methyl-N-(3-methylbenzofuran-2-ylmethyl)-amine (XI) using EDC, HOBt and DIEA in DMF .
Chlorination of 3-methylbenzofuran-2-carboxylic acid (XII) with (COCl)2 and catalytic DMF, followed by condensation with CH3NH2 in CH2Cl2 yields the corresponding benzofuran-2-carboxamide (XIII), which is finally reduced with LiAlH4 in THF .Alternatively, 3-methylbenzofuran-2-carbaldehyde (XIV) is condensed with CH3NH2 in MeOH and subsequently reduced with NaBH4 in EtOH .
| 【1】 Burgess, W.J., Huffman, W.F., Miller, W.H., Uzinskas, I.N., Jakas, D., Newlander, K.A., Seefeld, M.A. (Affinium Pharmaceuticals, Inc.). CA 2447597, EP 1560584, JP 2005519984, US 2004147580, US 7049310, US 8153652, WO 2003088897. |
| 【2】 Schmid, M.B., Mendlein, J.D., Berman, J.M., Kaplan, N. (Affinium Pharmaceuticals, Inc.). EP 1608377, JP 2006523207, US 2006142265, US 7879872, US 2012010127, WO 2004082586. |
| 【3】 Pauls, H., Ramnauth, J. (Affinium Pharmaceuticals, Inc.). EP 2125802, US 8263613, US 2013150400, WO 2008098374. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (Xa) | 67798 | (E)-3-(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-3-yl)acrylic acid hydrochloride | C11H10N2O3.HCl | 详情 | 详情 | |
| (Xb) | 67799 | 3-(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-3-yl)acrylic acid hydrobromide | C11H10N2O3.HBr | 详情 | 详情 | |
| (I) | 55933 | 2-Aminonicotinic acid; 2-Aminopyridine-3-carboxylic acid | 5345-47-1 | C6H6N2O2 | 详情 | 详情 |
| (II) | 56112 | (2-amino-3-pyridinyl)methanol | 23612-57-9 | C6H8N2O | 详情 | 详情 |
| (III) | 67797 | (2-amino-5-bromo-3-pyridinyl)methanol hydrobromide | 443956-55-6 | C6H72N2O.HBr | 详情 | 详情 |
| (IV) | 56114 | 5-bromo-3-(bromomethyl)-2-pyridinamine; 5-bromo-3-(bromomethyl)-2-pyridinylamine | 335033-38-0 | C6H6Br2N2.HBr | 详情 | 详情 |
| (V) | 19373 | dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester | 108-59-8 | C5H8O4 | 详情 | 详情 |
| (VI) | 56115 | methyl 6-bromo-2-oxo-1,2,3,4-tetrahydro[1,8]naphthyridine-3-carboxylate | 335031-10-2 | C10H9BrN2O3 | 详情 | 详情 |
| (VII) | 56116 | 6-bromo-3,4-dihydro[1,8]naphthyridin-2(1H)-one | C8H7BrN2O | 详情 | 详情 | |
| (VIII) | 12760 | tert-butyl acrylate | 1663-39-4 | C7H12O2 | 详情 | 详情 |
| (IX) | 56117 | tert-butyl (E)-3-(7-oxo-5,6,7,8-tetrahydro[1,8]naphthyridin-3-yl)-2-propenoate | C15H18N2O3 | 详情 | 详情 | |
| (XI) | 67800 | N-methyl-N-(3-methylbenzofuran-2-ylmethyl)-amine | C11H13NO | 详情 | 详情 | |
| (XII) | 67801 | 3-methylbenzofuran-2-carboxylic acid | C10H8O3 | 详情 | 详情 | |
| (XIII) | 67802 | N,3-dimethylbenzofuran-2-carboxamide | C11H11NO2 | 详情 | 详情 | |
| (XIV) | 67803 | 3-methylbenzofuran-2-carbaldehyde | C10H8O2 | 详情 | 详情 |