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【结 构 式】 
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【分子编号】13980 【品名】methyl nicotinate; Nicotinic acid, methyl ester 【CA登记号】93-60-7 |
【 分 子 式 】C7H7NO2 【 分 子 量 】137.13812 【元素组成】C 61.31% H 5.14% N 10.21% O 23.33% |
合成路线1
该中间体在本合成路线中的序号：(III)This compound can be obtained by three different ways: 1) By condensation of nicotinoyl chloride (I) with 1,2-diaminopropane (IV) by means of triethylamine in pyridine. 2) By reaction of nicotinic acid (II) with 1,2-diaminopropane (IV) by means of ethyl chloroformate and triethylamine in THF. 3) By heating at 120 C a mixture of methyl nicotinate (III) with 1,2-diaminopropane (IV).
| 【1】 Mori, T.; Takaku, S.; Matsuura, F.; Murakami, Y.; Noda, Y.; Yamazaki, T.; Neichi, T.; Nakakimura, H.; Kataoka, S (Chugai Pharmaceutical Co. Ltd.); Nicotinamide derivative, process dor preparing the same and pharmaceutical composition containing the same. EP 0029602; JP 56075474 . |
| 【2】 Grau, M.; Serradell, M.N.; Castaner, J.; Blancafort, P.; AVS. Drugs Fut 1983, 8, 6, 485. |
合成路线2
该中间体在本合成路线中的序号：(II)The esteritication of nicotinic acid (I) with methanol and HCl or H2SO4 yields the corresponding methyl ester (II), which is treated with ethanolamine (A) to afford N-(beta-hydroxyethyl)nicotinamide (III). Finally, this compound is transformed into the nitrate ester by the usual methods.
| 【1】 Masayoshi, S.; Solubilizing agents. V. Pyridinecarboxamides. Yakugaku Zasshi 1960, 80, 1706-12. |
| 【2】 Thorpe, P.J.; Castaner, J.; SG-75. Drugs Fut 1979, 4, 2, 134. |
| 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) | 10259 | Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol | 141-43-5 | C2H7NO | 详情 | 详情 |
| (I) | 10752 | Nicotinic acid; Niacin | 59-67-6 | C6H5NO2 | 详情 | 详情 |
| (II) | 13980 | methyl nicotinate; Nicotinic acid, methyl ester | 93-60-7 | C7H7NO2 | 详情 | 详情 |
| (III) | 13982 | N-(2-Hydroxyethyl)nicotinamide | C8H10N2O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)The starting products are prepared as follows: The reaction of pyridine-3-carboxylic acid methyl ester (I) with ethanolamine (II) gives the 2-hydroxyethylamide (III), which by reaction with diketene in THF yields the corresponding acetoacetic ester (V). The reaction of (V) with ammonia in THF affords the expected 3-aminocrotonate ester (VI).
| 【1】 Ogawa, T.; Hatayama, K.; Maeda, H.; Kita, Y.; Mild and facile cleavage of 2-cyanoethyl ester using sodium sulfide or tetrabutylammonium fluoride. Synthesis of 1,4-dihydropyridine monocarboxylic acids and unsymmetrical 1,4-dihydropyridine dicarboxylates. Chem Pharm Bull 1994, 42, 8, 1579-89. |
| 【2】 Mealy, N.; Martel, A.M.; Castaner, J.; CD-832.HCl. Drugs Fut 1996, 21, 12, 1221. |
| 【3】 Kelly, R.C.; Martin, D.G.; Aristoff, P.A. (Pharmacia Corp.); Novel CC-1065 analogs. AU 8812290; EP 0340243; WO 8804659 . |
| 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) | 13980 | methyl nicotinate; Nicotinic acid, methyl ester | 93-60-7 | C7H7NO2 | 详情 | 详情 |
| (II) | 10259 | Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol | 141-43-5 | C2H7NO | 详情 | 详情 |
| (III) | 13982 | N-(2-Hydroxyethyl)nicotinamide | C8H10N2O2 | 详情 | 详情 | |
| (IV) | 11367 | 4-Methylene-2-oxetanone; Acetyl ketene | 674-82-8 | C4H4O2 | 详情 | 详情 |
| (V) | 13984 | 2-[(3-pyridinylcarbonyl)amino]ethyl 3-oxobutanoate | C12H14N2O4 | 详情 | 详情 | |
| (VI) | 13985 | 2-[(3-pyridinylcarbonyl)amino]ethyl (E)-3-amino-2-butenoate | C12H15N3O3 | 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 selective reduction of methyl nicotinate (I) with simultaneous protection of the resulting NH group with phenyl chloroformate gives the 1,2-dihydropyridine derivative (II), which is treated with MCPBA (III) to afford the hydroxyester (IV). The reduction of (IV) with Tms-OTf and borane/THF complex affords the allylic alcohol (V), which is oxidized with CrO3 in acetone to provide the ketone (VI). The asymmetric reduction of (VI) with LiAlH4 catalyzed by (-)-N-methyl-ephedrine gives the chiral alcohol (VII), which is treated with refluxing 1N HCl to yield the carboxylic acid (VIII).The reduction of (VIII) with borane/THF complex and H2O2 affords the chiral carbinol (IX), which is finally deprotected by treatment with LiOH to provide the target isofagomine.
| 【1】 Zhao, G.; et al.; Selective fowler reductions: Asymmetric total synthesis of isofagomine and other 1-azasugars from methyl nicotinate. Org Lett 2001, 3, 2, 201. |
| 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) | 13980 | methyl nicotinate; Nicotinic acid, methyl ester | 93-60-7 | C7H7NO2 | 详情 | 详情 |
| (II) | 52903 | 3-methyl 1-phenyl 1,3(2H)-pyridinedicarboxylate | C14H13NO4 | 详情 | 详情 | |
| (III) | 17888 | m-Chloroperbenzoic acid; 3-Chlorobenzenecarboperoxoic acid | 937-14-4 | C7H5ClO3 | 详情 | 详情 |
| (IV) | 52904 | 3-methyl 1-phenyl 5-[(3-chlorobenzoyl)oxy]-6-hydroxy-5,6-dihydro-1,3(2H)-pyridinedicarboxylate | C21H18ClNO7 | 详情 | 详情 | |
| (V) | 52905 | 3-methyl 1-phenyl 5-hydroxy-5,6-dihydro-1,3(2H)-pyridinedicarboxylate | C14H15NO5 | 详情 | 详情 | |
| (VI) | 52906 | 3-methyl 1-phenyl 5-oxo-5,6-dihydro-1,3(2H)-pyridinedicarboxylate | C14H13NO5 | 详情 | 详情 | |
| (VII) | 52907 | 3-methyl 1-phenyl (5S)-5-hydroxy-5,6-dihydro-1,3(2H)-pyridinedicarboxylate | C14H15NO5 | 详情 | 详情 | |
| (VIII) | 52908 | (5S)-5-hydroxy-1-(phenoxycarbonyl)-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid | C13H13NO5 | 详情 | 详情 | |
| (IX) | 52909 | phenyl (3R,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)-1-piperidinecarboxylate | C13H17NO5 | 详情 | 详情 |