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【结 构 式】 
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【分子编号】13582 【品名】2-Pyridinylmethanamine; 2-Pyridinylmethylamine; 2-(Aminomethyl)pyridine 【CA登记号】3731-51-9 |
【 分 子 式 】C6H8N2 【 分 子 量 】108.143 【元素组成】C 66.64% H 7.46% N 25.9% |
合成路线1
该中间体在本合成路线中的序号：(II)The condensation of 2-aminomethylpyridine (II) with 2,2,2-trifluoroethyl-2,5-bis(2,2,2-trifluoroethoxy)benzoate (I) in refluxing glyme gives 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-pyridylmethyl)benzamide (III), which is then hydrogenated with H2 over Pd/C in acetic acid.
| 【1】 Bannitt, E.H.; Bronn, W.R.; Derivatives of pyrrolidine and piperidine. ES 435870; FR 2265366; GB 1508015; JP 58065268; US 3900481 . |
| 【2】 Hillier, K.; Castaner, J.; Flecainide acetate. Drugs Fut 1977, 2, 9, 586. |
| 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) | 33962 | 2-(benzyloxy)-2-oxoethyl 2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetate | C28H24ClNO6 | 详情 | 详情 | |
| (II) | 13582 | 2-Pyridinylmethanamine; 2-Pyridinylmethylamine; 2-(Aminomethyl)pyridine | 3731-51-9 | C6H8N2 | 详情 | 详情 |
| (III) | 33970 | N-(2-pyridinylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide | C17H14F6N2O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)The etherification of hydroquinone (I) with 2,2,2-trifluoroethyl trifluoromethanesulfonate (II) by means of K2CO3 in refluxing acetone gives the corresponding diether (III), which is submitted to a Friedel-Crafts condensation with Ac-Cl or Ac2O and AlCl3 in dichloromethane yielding the acetophenone (IV). The chlorination of (IV) with Cl2 in acetic acid at 55 C gives the alpha, alpha-dichloroacetophenone (V), which is further chlorinated with Cl2 and NaOAc in acetic acid at 100 C affording the corresponding trichloro derivative (VI). The reaction of (VI) with 2-(aminomethyl)pyridine (VII) in cyclohexane/toluene or isopropanol furnishes the benzamide (VIII), which is finally hydrogenated with H2 over Pt/C in isopropanol/acetic acid to give the target piperidine derivative.
| 【1】 Leir, C.M. (3M Pharmaceuticals); Process for the preparation of derivs. of pyrrolidine and piperidine. US 4642384 . |
| 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) | 13163 | p-Dihydrobenzene; Hydroquinone | 123-31-9 | C6H6O2 | 详情 | 详情 |
| (II) | 40675 | 2,2,2-trifluoroethyl trifluoromethanesulfonate | 6226-25-1 | C3H2F6O3S | 详情 | 详情 |
| (III) | 40737 | 1,4-bis(2,2,2-trifluoroethoxy)benzene; 4-(2,2,2-trifluoroethoxy)phenyl 2,2,2-trifluoroethyl ether | 66300-61-6 | C10H8F6O2 | 详情 | 详情 |
| (IV) | 40738 | 1-[2,5-bis(2,2,2-trifluoroethoxy)phenyl]-1-ethanone | 76784-40-2 | C12H10F6O3 | 详情 | 详情 |
| (V) | 40739 | 1-[2,5-bis(2,2,2-trifluoroethoxy)phenyl]-2,2-dichloro-1-ethanone | C12H8Cl2F6O3 | 详情 | 详情 | |
| (VI) | 40740 | 1-[2,5-bis(2,2,2-trifluoroethoxy)phenyl]-2,2,2-trichloro-1-ethanone | 76784-42-4 | C12H7Cl3F6O3 | 详情 | 详情 |
| (VII) | 13582 | 2-Pyridinylmethanamine; 2-Pyridinylmethylamine; 2-(Aminomethyl)pyridine | 3731-51-9 | C6H8N2 | 详情 | 详情 |
| (VIII) | 33970 | N-(2-pyridinylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide | C17H14F6N2O3 | 详情 | 详情 | |
| (IX) | 18983 | 1,4-dibromobenzene | 106-37-6 | C6H4Br2 | 详情 | 详情 |
| (X) | 19483 | 2,2,2-trifluoro-1-ethanol | 75-89-8 | C2H3F3O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)The racemic form of E-5880 is prepared as follows: The esterification of 2-methoxy-1,3-propanediol (I) with phenyl chlorocarbonate (II) in pyridine gives the diester (III), which is treated with 2-(aminomethyl)pyridine (IV) in refluxing chloroform, yielding the carbamate (V). The reaction of (V) with 4-hydroxypiperidine (VI) in refluxing chloroform affords the dicarbamate (VII), which by treatment with octadecyl isocyanate (VIII) gives the tricarbamate (X). Alternatively, (X) can be obtained by treatment of (VIII) with carbonate (II), yielding the intermediate (IX), which by treatment with octadecylamine (XI) at 100 C affords (X). The acylation of (X) with 2-methoxybenzoyl chloride (XII) in pyridine gives the precursor (XIII), which is finally treated with ethyl iodide in excess at reflux temperature and submitted to an ion exchange resin (Amberlite IRA-410 Cl- type). The optically active (R)-enantiomer is synthesized starting from L-mannitol.
| 【1】 Okano, K.; Asano, O.; Shimomura, N.; Kawahara, T.; Abe, S.; Miyazawa, S.; Miyamoto, M.; Yoshimura, H.; Harada, K.; Nagaoka, J.; Kawata, T.; Yoshimura, T.; Suzuki, H.; Souda, S.; Machida, Y.; Katayama, K.; Yamatsu, I. (Eisai Co., Ltd.); Glycerin deriv. and its pharmacological use. AU 8937213; EP 0353474; JP 1990131467; JP 1996231508; US 5037827; US 5273985; US 5476863; US 5476864 . |
| 【2】 Okano, K.; Shimomura, N.; Asano, O.; et al.; Okano, K., Asano, O., Shimomura, N. et al. Structure-activity relationships of platelet activating factor (PAF) antagonists. 198th ACS Natl Meet (Sept 10-15, Miami Beach) 1989, Abst MEDI 55. |
| 【3】 Prous, J.; Castaner, J.; E-5880. Drugs Fut 1992, 17, 12, 1082. |
| 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) | 13579 | 2-Methoxy-1,3-propanediol | C4H10O3 | 详情 | 详情 | |
| (II) | 13580 | 1-[(Chlorocarbonyl)oxy]benzene; phenyl chloroformate | 1885-14-9 | C7H5ClO2 | 详情 | 详情 |
| (III) | 13581 | 2-methoxy-3-[(phenoxycarbonyl)oxy]propyl phenyl carbonate | C18H18O7 | 详情 | 详情 | |
| (IV) | 13582 | 2-Pyridinylmethanamine; 2-Pyridinylmethylamine; 2-(Aminomethyl)pyridine | 3731-51-9 | C6H8N2 | 详情 | 详情 |
| (V) | 13583 | (5-oxo-6-phenyl-1,4-dioxan-2-yl)methyl 2-pyridinylmethylcarbamate | C18H18N2O5 | 详情 | 详情 | |
| (VI) | 12076 | 4-Piperidinol; 4-Hydroxypiperidine | 5382-16-1 | C5H11NO | 详情 | 详情 |
| (VII) | 13585 | 2-methoxy-3-([[(2-pyridinylmethyl)amino]carbonyl]oxy)propyl 4-hydroxy-1-piperidinecarboxylate | C17H25N3O6 | 详情 | 详情 | |
| (VIII) | 13586 | 1-Isocyanatooctadecane; octadecyl isocyanate | 112-96-9 | C19H37NO | 详情 | 详情 |
| (IX) | 13587 | 2-methoxy-3-([[(2-pyridinylmethyl)amino]carbonyl]oxy)propyl 4-[(phenoxycarbonyl)oxy]-1-piperidinecarboxylate | C24H29N3O8 | 详情 | 详情 | |
| (X) | 13588 | 2-methoxy-3-([[(2-pyridinylmethyl)amino]carbonyl]oxy)propyl 4-[[(octadecylamino)carbonyl]oxy]-1-piperidinecarboxylate | C36H62N4O7 | 详情 | 详情 | |
| (XI) | 13589 | 1-Aminooctadecane; Octadecylamine; 1-Octadecanamine | 124-30-1 | C18H39N | 详情 | 详情 |
| (XII) | 13590 | 2-Methoxybenzoyl chloride; o-Anisoyl chloride; 2-Anisoyl chloride | 21615-34-9 | C8H7ClO2 | 详情 | 详情 |
| (XIII) | 13591 | 2-methoxy-3-([[(2-methoxybenzoyl)(2-pyridinylmethyl)amino]carbonyl]oxy)propyl 4-[[(octadecylamino)carbonyl]oxy]-1-piperidinecarboxylate | C44H68N4O9 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(III)The required chiral auxiliary hydroxyketone (II) was prepared from (S)-alpha-pinene (I) either by dihydroxylation with K2OsO4 and NMO, followed by Swern oxidation of the secondary alcohol, or by direct oxidation using KMnO4 under phase-transfer conditions. Condensation of (II) with 2-(aminomethyl)pyridine (III) in the presence of titanium isopropoxide or thionyl chloride as the dehydrating reagents provided the chiral imine (IV), which was estereoselectively alkylated with cyclohexylmethyl bromide (V) and n-BuLi, yielding (VI). Cleavage of the chiral auxiliary of (VI) was carried out by treatment with hydroxylamine hydrochloride. Enantiomeric enrichment of the resulting (S)-pyridylamine was achieved by recrystallization of the corresponding L-tartrate salt (VII). Finally, the amine was condensed with chlorobenzoxazole (VIII) in the presence of NaOAc and Na2CO3 in refluxing methylcyclohexane.
| 【1】 Roth, G.P.; et al.; Optimization and scale-up of an asymetric route to the LTB4 inhibitor ontazolast. Org Process Res Dev 1997, 1, 5, 331. |
| 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) | 16643 | Poly-alpha-pinene; (1S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-2-ene | 7785-26-4 | C10H16 | 详情 | 详情 |
| (II) | 31762 | (1S,2R,5S)-2-hydroxy-2,6,6-trimethylbicyclo[3.1.1]heptan-3-one | C10H16O2 | 详情 | 详情 | |
| (III) | 13582 | 2-Pyridinylmethanamine; 2-Pyridinylmethylamine; 2-(Aminomethyl)pyridine | 3731-51-9 | C6H8N2 | 详情 | 详情 |
| (IV) | 31763 | (1S,2R,5S)-2,6,6-trimethyl-3-[(2-pyridinylmethyl)imino]bicyclo[3.1.1]heptan-2-ol | C16H22N2O | 详情 | 详情 | |
| (V) | 31767 | 1-(bromomethyl)cyclohexane | 2550-36-9 | C7H13Br | 详情 | 详情 |
| (VI) | 31764 | (1S,2R,5S)-3-[[(1S)-2-cyclohexyl-1-(2-pyridinyl)ethyl]imino]-2,6,6-trimethylbicyclo[3.1.1]heptan-2-ol | C23H34N2O | 详情 | 详情 | |
| (VII) | 31765 | (1S)-2-cyclohexyl-1-(2-pyridinyl)ethylamine; (1S)-2-cyclohexyl-1-(2-pyridinyl)-1-ethanamine | C13H20N2 | 详情 | 详情 | |
| (VIII) | 31766 | 2-chloro-5-methyl-1,3-benzoxazole | C8H6ClNO | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XII)The intermediate benzyl chloride (VII) is obtained as follows: The reduction of 4-(bromomethyl)benzoic acid methyl ester (IX) with DIBAL in dichloromethane gives 4-(bromomethyl)benzyl alcohol (X), which is condensed with sulfamide (XI) (obtained by sulfonation of 2-(aminomethyl)pyridine (XII) with sulfonyl chloride (II) and TEA), by means of K2CO3 in dichloromethane, yielding the disubstituted sulfamide (XIII). Finally, the hydroxymethyl group of (XIII) is treated with MsCl and TEA in refluxing dichloromethane to afford the target benzyl chloride (VII).
| 【1】 Bogucki, D.E.; Boehringer, E.M.; Wang, Z.; Bridger, G.J.; Schols, D.; Skerlj, R.T. (AnorMED Inc.); Antiviral macrocyclic cpds.. EP 1095031; WO 0002870 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 32624 | 2-Nitrobenzenesulfonyl chloride | 1694-92-4 | C6H4ClNO4S | 详情 | 详情 |
| (VII) | 46251 | N-[4-(chloromethyl)benzyl]-2-nitro-N-(2-pyridinylmethyl)benzenesulfonamide | C20H18ClN3O4S | 详情 | 详情 | |
| (IX) | 14565 | methyl 4-(bromomethyl)benzoate | 2417-72-3 | C9H9BrO2 | 详情 | 详情 |
| (X) | 46253 | [4-(bromomethyl)phenyl]methanol | C8H9BrO | 详情 | 详情 | |
| (XI) | 46254 | 2-nitro-N-(2-pyridinylmethyl)benzenesulfonamide | C12H11N3O4S | 详情 | 详情 | |
| (XII) | 13582 | 2-Pyridinylmethanamine; 2-Pyridinylmethylamine; 2-(Aminomethyl)pyridine | 3731-51-9 | C6H8N2 | 详情 | 详情 |
| (XIII) | 46255 | N-[4-(hydroxymethyl)benzyl]-2-nitro-N-(2-pyridinylmethyl)benzenesulfonamide | C20H19N3O5S | 详情 | 详情 |