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【结 构 式】 
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【分子编号】34873 【品名】1,3,5,7-tetraazatricyclo[3.3.1.1(3,7)]decane 【CA登记号】100-97-0 |
【 分 子 式 】C6H12N4 【 分 子 量 】140.18824 【元素组成】C 51.41% H 8.63% N 39.97% |
合成路线1
该中间体在本合成路线中的序号：(XIV)The reaction of 3,4-dihydro-1H-2-benzopyran (VII) with benzoyl chloride and ZnCl2 gives benzoic acid 2-[2-(chloromethyl)phenyl]ethyl ester (XIII), which is condensed with hexamethylenetetramine (XIV) yielding the amminium salt (XV). The hydrolysis of (XV) affords 2-(2-benzoyloxyethyl) benzaldehyde (XVI), which is condensed with nitromethane as before to give the nitrostyrene (XVII). The cyclization of (XVII) with FeCl3 and acetyl chloride as before yields 4-(2-benzoyloxyethyl)-3-chloroindolin-2-one (XVIII), which is dechlorinated with hydrazine and Pd/C to the indolinone (XIX). The hydrolysis of (XIX) with NaOH affords 4-(2-hydroxyethyl)indolin-2-one (XX), which is acylated with TsCl giving the tosylate (XXI). Finally, this compound is condensed with dipropylamine (II).
| 【1】 Hayler, J.D.; et al.; Development of large-scale syntheses or ropinirole in the pursuit of a manufacturing process. Org Process Res Dev 1998, 2, 1, 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 |
|---|---|---|---|---|---|---|
| 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 | |
| 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 | |
| 39563 | nitromethane | 75-52-5 | CH3NO2 | 详情 | 详情 | |
| (II) | 21856 | N,N-dipropylamine; N-propyl-1-propanamine | 142-84-7 | C6H15N | 详情 | 详情 |
| (VII) | 34866 | 3,4-dihydro-1H-isochromene | 493-05-0 | C9H10O | 详情 | 详情 |
| (XIII) | 34872 | 2-(chloromethyl)phenethyl benzoate | C16H15ClO2 | 详情 | 详情 | |
| (XIV) | 34873 | 1,3,5,7-tetraazatricyclo[3.3.1.1(3,7)]decane | 100-97-0 | C6H12N4 | 详情 | 详情 |
| (XV) | 34874 | 1-[2-[2-(benzoyloxy)ethyl]benzyl]-3,5,7-triaza-1-azoniatricyclo[3.3.1.1(3,7)]decane chloride | C22H27ClN4O2 | 详情 | 详情 | |
| (XVI) | 34875 | 2-formylphenethyl benzoate | C16H14O3 | 详情 | 详情 | |
| (XVII) | 34876 | 2-[(E)-2-nitroethenyl]phenethyl benzoate | C17H15NO4 | 详情 | 详情 | |
| (XVIII) | 34877 | 2-(3-chloro-2-oxo-2,3-dihydro-1H-indol-4-yl)ethyl benzoate | C17H14ClNO3 | 详情 | 详情 | |
| (XIX) | 34878 | 2-(2-oxo-2,3-dihydro-1H-indol-4-yl)ethyl benzoate | C17H15NO3 | 详情 | 详情 | |
| (XX) | 34879 | 4-(2-Hydroxyethyl)indolin-2-one | 139122-19-3 | C10H11NO2 | 详情 | 详情 |
| (XXI) | 34880 | 4-heptanol | 589-55-9 | C7H16O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)The reaction of ethyl 4-bromoacetoacetate (I) with 2-chloroethanol (II) by means of NaH in THF gives ethyl 4-(2-chloroethoxy)acetoacetate (III), which is treated with NaI in refluxing acetone to yield the corresponding 2-iodoethoxy derivative (IV). The condensation of (IV) with 2-chlorobenzaldehyde (V) by means of piperidine acetate in isopropanol affords ethyl 2-(2-chlorobenzylidene)-4-(2-iodoethoxy)acetoacetate (VI), which is cyclized with methyl 3-aminocrotonate (VII) in refluxing isopropanol to provide the dihydropyridine (VIII). The reaction of (VIII) with hexamethylenetetramine (IX) in hot acetonitrile gives the aminium salt (X), which is finally treated with benzenesulfonic acid in refluxing butanol (methanol)/water. Alternatively, the intermediate dihydropyridine (VIII) can be obtained as follows: The condensation of ethyl 4-(2-chloroethoxy)acetoacetate (III) with the aldehyde (V) by means of piperidine acetate in isopropanol gives ethyl 2-(2-chlorobenzylidene)-4-(2-chloroethoxy)acetoacetate (XI), which is cyclized with methyl 3-aminocrotonate (VII) in refluxing isopropanol to yield the corresponding dihydropyridine (XII). Finally, this compound is treated with NaI in refluxing isopropanol to afford the target intermediate dihydropyridine (VIII).
| 【1】 Németh, N.; Vereczkey, G.D.; Krasznai, G.; Koványi, G.; Német, G.; Blask, G.; Tömpe, P.; Nagy, K.; Bozsing, D.; Simig, G. (Egis Pharmaceuticals Ltd.); A process and intermediate cpds. for the preparation of amlodipine benzene sulphonate. EP 0902016 . |
| 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) | 36651 | Ethyl (bromoacetyl)acetate;ethyl 4-bromo-3-oxobutanoate | 13176-46-0 | C6H9BrO3 | 详情 | 详情 |
| (II) | 10384 | 2-Chloro-1-ethanol; Ethylene chlorohydrin | 107-07-3 | C2H5ClO | 详情 | 详情 |
| (III) | 48269 | ethyl 4-(2-chloroethoxy)-3-oxobutanoate | C8H13ClO4 | 详情 | 详情 | |
| (IV) | 48270 | ethyl 4-(2-iodoethoxy)-3-oxobutanoate | C8H13IO4 | 详情 | 详情 | |
| (V) | 24114 | 2-chlorobenzaldehyde | 89-98-5 | C7H5ClO | 详情 | 详情 |
| (VI) | 48271 | ethyl (Z)-3-(2-chlorophenyl)-2-[2-(2-iodoethoxy)acetyl]-2-propenoate | C15H16ClIO4 | 详情 | 详情 | |
| (VII) | 11372 | Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate | C5H9NO2 | 详情 | 详情 | |
| (VIII) | 48272 | 3-ethyl 5-methyl 4-(2-chlorophenyl)-2-[(2-iodoethoxy)methyl]-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate | C20H23ClINO5 | 详情 | 详情 | |
| (IX) | 34873 | 1,3,5,7-tetraazatricyclo[3.3.1.1(3,7)]decane | 100-97-0 | C6H12N4 | 详情 | 详情 |
| (X) | 48273 | 1-(2-[[4-(2-chlorophenyl)-3-(ethoxycarbonyl)-5-(methoxycarbonyl)-6-methyl-1,4-dihydro-2-pyridinyl]methoxy]ethyl)-3,5,7-triaza-1-azoniatricyclo[3.3.1.1(3,7)]decane iodide | C26H35ClIN5O5 | 详情 | 详情 | |
| (XI) | 48274 | ethyl (Z)-2-[2-(2-chloroethoxy)acetyl]-3-(2-chlorophenyl)-2-propenoate | C15H16Cl2O4 | 详情 | 详情 | |
| (XII) | 48275 | 3-ethyl 5-methyl 2-[(2-chloroethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate | C20H23Cl2NO5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：2-Aminoacetophenone.HCl (IV) is prepared from acetophenone (I) via 2-bromoacetophenone (II) and the quaternary urotropine salt (III). Acetylation of (IV) with acetic anhydride in water in the presence of sodium hydrogen carbonate yields 2-acetamidoacetophenone (V), which is converted to 2-acetamido-3-hydroxypropiophenone.HCl (VI) with formaldehyde in water. After removing the acetyl group with hydrochloric acid in ethanol, 2-amino-3-hydroxypropiophenone.HCl (VII) is formed, which is reduced with hydrogen over Pd/C in methanol to rac-erythro-2-amino-1-phenyl-1,3-propanediol.HCl (VIII). Reductive condensation of the corresponding base (IX) with phenoxyacetone (X) and hydrogen over PtO2 affords a mixture of aminodiols epimeric at C-1' (XI). (XI) is finally converted to the corresponding hydrochloride salts, from which the salt of the less soluble [1R*,2S*(S*)]-stereoisomer, i.e., solpecainol is isolated by crystallization. Structure and purity of solpecainol have been confirmed by x-ray crystallography and HPLC-MS.
| 【1】 Central Res. Inst. Chem. Hung. Acad. Sci. Report (27.10.1983) 1983. |
| 【2】 Levai, L.; Fazekas, G.; Petocz, L.; Grasser, K. (Egis Pharmaceuticals Ltd.); Novel N-alkyl derivs. of 1-phenyl-2-amino-1,3-propandiol and process for preparing same. DE 2810482; GB 1560470; JP 1978112827; US 4259257 . |
| 【3】 Vida, L.; Szepesy, L.; Lakszner, K.; Comparison and evaluation of derivatization methods for gas chromatographic determination of various propanediols. Chromatographia 1984, 19, 304. |
| 【4】 Berényi, E.; Petócz, L.; Blaskó, G.; Nógrádi, M.; Solpecainol Hydrochloride. Drugs Fut 1991, 16, 6, 514. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 34873 | 1,3,5,7-tetraazatricyclo[3.3.1.1(3,7)]decane | 100-97-0 | C6H12N4 | 详情 | 详情 | |
| (I) | 10317 | Acetophenone | 98-86-2 | C8H8O | 详情 | 详情 |
| (II) | 10315 | 2-Bromo-1-phenyl-ethanone; 2-Bromo-1-phenyl-1-ethanone | 70-11-1 | C8H7BrO | 详情 | 详情 |
| (III) | 14599 | 2-(1-bromo-1lambda(5),3,5,7-tetraazatricyclo[3.3.1.1(3,7)]dec-1-yl)-1-phenyl-1-ethanone | C14H19BrN4O | 详情 | 详情 | |
| (IV) | 14600 | 2-(chloroamino)-1-phenylethanone | C8H8ClNO | 详情 | 详情 | |
| (V) | 14601 | N-(2-oxo-2-phenylethyl)acetamide | C10H11NO2 | 详情 | 详情 | |
| (VI) | 14602 | N-[1-(hydroxymethyl)-2-oxo-2-phenylethyl]acetamide | C11H13NO3 | 详情 | 详情 | |
| (VII) | 14603 | 2-(Cloroamino)-3-hydroxy-1-phenyl-1-propanone | C9H10ClNO2 | 详情 | 详情 | |
| (VIII) | 14604 | (1R,2S)-2-(Chloroamino)-1-phenylpropane-1,3-diol | C9H12ClNO2 | 详情 | 详情 | |
| (IX) | 14605 | (1R,2S)-2-amino-1-phenyl-1,3-propanediol | C9H13NO2 | 详情 | 详情 | |
| (X) | 10875 | 1-Phenoxyacetone; 1-Phenoxy-2-propanone | 621-87-4 | C9H10O2 | 详情 | 详情 |
| (XI) | 14607 | (1R,2S)-2-[(1-methyl-2-phenoxyethyl)amino]-1-phenyl-1,3-propanediol | C18H23NO3 | 详情 | 详情 |