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【结 构 式】 
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【分子编号】21856 【品名】N,N-dipropylamine; N-propyl-1-propanamine 【CA登记号】142-84-7 |
【 分 子 式 】C6H15N 【 分 子 量 】101.19184 【元素组成】C 71.22% H 14.94% N 13.84% |
合成路线1
该中间体在本合成路线中的序号：(A)The benzoylation of tyrosine (I) with benzoyl chloride (II) in aqueous NaOH gives O,N-(di-benzoyl)-D,L-tyrosine (III), which by reaction with di-n-propylamine (A) by means of ethyl chlorocarbonate and triethylamine in acetone is converted into O,N-(di-benzoyl)-D,L-tyrosyl-di-n-propylamide (IV). Selective hydrolysis of (IV) with NaOH in methanol - water affords N-benzoyl-D,L-tyrosyl-di-n-propylamide (V), which is finally condensed with 2-(diethylamino)ethyl chloride (VI) by means of sodium methoxide in refluxing toluene.
| 【1】 Senin; et al.; Activity of derivatives of tyrosine on gastrointestinal motility. Gastrointestinal Motility in Health and Disease. Duthie, H.L. (Ed.); MTP Press Limited, Lancaster 1978, 417-427. |
| 【2】 Makovec, F.; Rovati, L.; Senini, P. (Rotta Research Laboratorium SpA); O-Tertiary amino-alkyl-N-benzoyl tyrosil amides. DE 2503992; FR 2259592; GB 1467927; JP 50116442; NL 167683C; US 4004008 . |
| 【3】 Serradell, M.N.; de Angelis, L.; Blancafort, P.; Castaner, J.; Tiropramide. Drugs Fut 1982, 7, 6, 413. |
| 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) | 21856 | N,N-dipropylamine; N-propyl-1-propanamine | 142-84-7 | C6H15N | 详情 | 详情 |
| (I) | 31970 | 4-Hydroxy-17O-phenylalanine; Hydroxy Phenyl Alanine; DL-tyrosine; 2-Amino-3-(4-hydroxyphenyl)propionic acid; 3-(4-Hydroxyphenyl)alanine; beta-(p-Hydroxyphenyl)alanine; tyrosine | 556-03-6 | C9H11NO3 | 详情 | 详情 |
| (II) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
| (III) | 31971 | N-benzoyl-4-(benzoyloxy)phenylalanine | C23H19NO5 | 详情 | 详情 | |
| (IV) | 31972 | 4-[2-(benzoylamino)-3-(dipropylamino)-3-oxopropyl]phenyl benzoate | C29H32N2O4 | 详情 | 详情 | |
| (V) | 31973 | N-[2-(dipropylamino)-1-(4-hydroxybenzyl)-2-oxoethyl]benzamide | C22H28N2O3 | 详情 | 详情 | |
| (VI) | 16194 | 2-chloro-N,N-diethyl-1-ethanamine; N-(2-chloroethyl)-N,N-diethylamine | 100-35-6 | C6H14ClN | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The condensation of 2-(2-methyl-3-nitrophenyl)acetic acid (I) with dipropylamine (II) by means of refluxing SOCl2 gives the corresponding amide (III), which is reduced with borane/THF yielding the tertiary amine (IV). The condensation of (IV) with diethyl oxalate by means of sodium ethoxide in refluxing ethanol affords the pyruvate ester (V), which is treated with NaOH and H2O2 yielding the acetic acid derivative (VI). Finally, this compound is cyclyzed by hydrogenation with H2 over Pd/C in ethanol.
| 【1】 Gallagher, G. Jr. (SmithKline Beecham Corp.); 4-Aminoalkyl-2(3H)-indolones. EP 0113964; ES 8600239; ES 8604143; US 4452808 . |
| 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) | 34861 | 2-(2-methyl-3-nitrophenyl)acetic acid | C9H9NO4 | 详情 | 详情 | |
| (II) | 21856 | N,N-dipropylamine; N-propyl-1-propanamine | 142-84-7 | C6H15N | 详情 | 详情 |
| (III) | 34862 | 2-(2-methyl-3-nitrophenyl)-N,N-dipropylacetamide | C15H22N2O3 | 详情 | 详情 | |
| (IV) | 34863 | N-(2-methyl-3-nitrophenethyl)-N,N-dipropylamine; N-(2-methyl-3-nitrophenethyl)-N-propyl-1-propanamine | C15H24N2O2 | 详情 | 详情 | |
| (V) | 17571 | Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate | 95-92-1 | C6H10O4 | 详情 | 详情 |
| (VI) | 34864 | ethyl 3-[2-[2-(dipropylamino)ethyl]-6-nitrophenyl]-2-oxopropanoate | C19H28N2O5 | 详情 | 详情 | |
| (VII) | 34865 | 2-[2-[2-(dipropylamino)ethyl]-6-nitrophenyl]acetic acid | C16H24N2O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The bromination of 3,4-dihydro-1H-2-benzopyran (VII) with Br2 gives the 1-bromo derivative (VIII), which, without isolation, is treated with hot HBr yielding 2-(2-bromoethyl)benzaldehyde (IX). The condensation of (IX) with nitromethane in acidic medium affords the nitrostyrene (X), which is cyclized with treatment with FeCl3 and acetyl chloride giving 4-(2-bromoethyl)-3-chloroindolin-2-one (XI). The dechlorination of (XI) with NaH2PO2 over Pd/C yields 4-(2-bromoethyl)indolin-2-one (XII), which is finally 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 |
|---|---|---|---|---|---|---|
| 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 |
| (VIII) | 34867 | 1-bromo-3,4-dihydro-1H-isochromene | C9H9BrO | 详情 | 详情 | |
| (IX) | 34868 | 2-(2-bromoethyl)benzaldehyde | C9H9BrO | 详情 | 详情 | |
| (X) | 34869 | 1-(2-bromoethyl)-2-[(E)-2-nitroethenyl]benzene | C10H10BrNO2 | 详情 | 详情 | |
| (XI) | 34870 | 4-(2-bromoethyl)-3-chloro-1,3-dihydro-2H-indol-2-one | C10H9BrClNO | 详情 | 详情 | |
| (XII) | 34871 | 4-(2-bromoethyl)-1,3-dihydro-2H-indol-2-one | C10H10BrNO | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)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5
该中间体在本合成路线中的序号：(2)1) 4-Chloro-2'-bromoacetophenone (I) is condensed with 2-amino 5-chloropyridine (II) to give 6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridine (III). 2) The above compound is reacted with formaldehyde and dimethylamine under Mannich conditions affording the 3-dimethylaminomethyl derivative (IV), which is subsequently quaternized with methyl iodide to afford the quaternary iodide (V). 3) Displacement of trimethylamine from salt (V) with cyanide ion leads to formation of the nitrile (VI), which on hydrolysis with hydrochloric acid in acetic acid gives the corresponding acid (VII). 4) In situ conversion of the acid to its acid chloride with phosphorus oxychloride followed by treatment with di-n-propylamine then leads to alpidem.
| 【1】 George, P.; Kaplan, J.-P. (Sanofi-Synthelabo ); Imidazo[1,2-a] pyridine derivs. and their applicat. EP 0050563; US 4382938 . |
| 【2】 Friedmann, J.C.; Morselli, P.L.; Dimsdale, M.; Zivkovic, B.; Alpidem. Drugs Fut 1988, 13, 2, 106. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (2) | 21856 | N,N-dipropylamine; N-propyl-1-propanamine | 142-84-7 | C6H15N | 详情 | 详情 |
| (I) | 16720 | 2-bromo-1-(4-chlorophenyl)-1-ethanone; 2-Bromo-4'-chloroacetophenone | 536-38-9 | C8H6BrClO | 详情 | 详情 |
| (II) | 18559 | 5-Chloro-2-pyridinylamine; 5-Chloro-2-pyridinamine; 2-Amino-5-chloropyridine | 1072-98-6 | C5H5ClN2 | 详情 | 详情 |
| (III) | 21851 | 6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridine | C13H8Cl2N2 | 详情 | 详情 | |
| (IV) | 21852 | [6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]-N,N-dimethylmethanamine; N-[[6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl]-N,N-dimethylamine | C16H15Cl2N3 | 详情 | 详情 | |
| (V) | 21853 | [6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]-N,N,N-trimethylmethanaminium iodide | C17H18Cl2IN3 | 详情 | 详情 | |
| (VI) | 21854 | 2-[6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]acetonitrile | C15H9Cl2N3 | 详情 | 详情 | |
| (VII) | 21855 | 2-[6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]acetic acid | C15H10Cl2N2O2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IX)Isovanillin (I) was alkylated with phenethyl bromide (II) in the presence of K2CO3 to afford phenethyl ether (III). The aldehyde function of (III) was then reduced with NaBH4, and the resulting alcohol (IV) was converted to chloride (V) by means of SOCl2 in THF-DMF. Subsequent displacement of the chlorine atom of (V) by KCN afforded nitrile (VI), which was hydrolyzed to acid (VII) with KOH in aqueous EtOH. Further conversion of (VII) to acid chloride (VIII), followed by condensation with dipropyl amine (IX) in toluene provided amide (X). Finally, reduction with LiAlH4 gave the corresponding amine, that was isolated as the hydrochloride salt.
| 【1】 Nakazato, A.; et al.; Design, synthesis, structure-activity relationship. J Med Chem 1999, 42, 6, 1076. |
| 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) | 18455 | 3-hydroxy-4-methoxybenzaldehyde; Isovanillin | 621-59-0 | C8H8O3 | 详情 | 详情 |
| (II) | 20730 | 1-(2-bromoethyl)benzene；1-Bromo-2-phenylethane;(2-Bromoethyl)benzene;Phenethyl bromide | 103-63-9 | C8H9Br | 详情 | 详情 |
| (III) | 23679 | 4-methoxy-3-(phenethyloxy)benzaldehyde | C16H16O3 | 详情 | 详情 | |
| (IV) | 23680 | [4-methoxy-3-(phenethyloxy)phenyl]methanol | C16H18O3 | 详情 | 详情 | |
| (V) | 23681 | 4-(chloromethyl)-1-methoxy-2-(phenethyloxy)benzene; 5-(chloromethyl)-2-methoxyphenyl phenethyl ether | C16H17ClO2 | 详情 | 详情 | |
| (VI) | 23682 | 2-[4-methoxy-3-(phenethyloxy)phenyl]acetonitrile | C17H17NO2 | 详情 | 详情 | |
| (VII) | 23683 | 2-[4-methoxy-3-(phenethyloxy)phenyl]acetic acid | C17H18O4 | 详情 | 详情 | |
| (VIII) | 23685 | 2-[4-methoxy-3-(phenethyloxy)phenyl]acetyl chloride | C17H17ClO3 | 详情 | 详情 | |
| (IX) | 21856 | N,N-dipropylamine; N-propyl-1-propanamine | 142-84-7 | C6H15N | 详情 | 详情 |
| (X) | 23686 | 2-[4-methoxy-3-(phenethyloxy)phenyl]-N,N-dipropylacetamide | C23H31NO3 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(VIII)The condensation of 2-[6-(dimethylamino)pyridin-3-yl]acetonitrile (I) with ethyl acetate (II) by means of NaH in THF gives 2-[6-(dimethylamino)pyridin-3-yl]-3-oxobutyronitrile (III), which is treated with hydrazine in refluxing ethanol/water to yield the corresponding hydrazone (IV). The cyclization of (IV) with ethyl acetoacetate (V) in refluxing dioxane affords 3-[6-(dimethylamino)pyridin-3-yl]-2,5-dimethylpyrazolo[2,3-a]pyrimidin-7-ol (VI), which is treated with refluxing POCl3 to provide the expected 7-chloro derivative (VII). Finally, this compound is treated with dipropylamine (VIII) in refluxing acetonitrile to furnish the target dipropylamino derivative.
| 【1】 Chen, C.; Webb, T.R.; McCarthy, J.R.; Moran, T.J.; Wilcoxen, K.M. (Janssen Pharmaceutica NV; Neurocrine Biosciences Inc.); Pyrazolopyrimidines as CRF receptor antagonists. EP 0880523; JP 2000503661; WO 9729109 . |
| 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) | 53973 | 2-[6-(dimethylamino)-3-pyridinyl]acetonitrile | n/a | C9H11N3 | 详情 | 详情 |
| (II) | 17491 | ethyl acetate | 141-78-6 | C4H8O2 | 详情 | 详情 |
| (III) | 53974 | 2-[6-(dimethylamino)-3-pyridinyl]-3-oxobutanenitrile | n/a | C11H13N3O | 详情 | 详情 |
| (IV) | 53975 | 2-[6-(dimethylamino)-3-pyridinyl]-3-[(Z)hydrazono]butanenitrile | n/a | C11H15N5 | 详情 | 详情 |
| (V) | 11819 | ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate | 141-97-9 | C6H10O3 | 详情 | 详情 |
| (VI) | 53976 | 3-[6-(dimethylamino)-3-pyridinyl]-2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-ol | n/a | C15H17N5O | 详情 | 详情 |
| (VII) | 53977 | N-[5-(7-chloro-2,5-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)-2-pyridinyl]-N,N-dimethylamine; 5-(7-chloro-2,5-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)-N,N-dimethyl-2-pyridinamine | n/a | C15H16ClN5 | 详情 | 详情 |
| (VIII) | 21856 | N,N-dipropylamine; N-propyl-1-propanamine | 142-84-7 | C6H15N | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(II)Condensation of carboxylic acid (I) with dipropylamine (II) in the presence of ethyl 1,2-dihydro-2-ethoxy-1-quinolinecarboxylate (EEDQ) yields amide (III), which is then brominated with Br2 in CCl4 to provide derivative (IV). Finally, bromoketoamide (IV) is cyclized with to 3-methyl-2-aminopyridine (V) in DMF to furnish the target product.
| 【1】 Biggio, G.; Carotti, A.; Trapani, G.; Liso, G.; Sanna, E.; Serra, M.; Ricciardi, L.; Franco, M.; latrofa, A.; Novel 2-phenylimidazo[1,2-a]pyridine derivatives as potent and selective ligands for peripheral benzodiazepine receptors: Synthesis, binding affinity, and in vivo studies. J Med Chem 1999, 42, 19, 3934. |
| 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) | 37461 | 4-(4-chlorophenyl)-4-oxobutyric acid | 3984-34-7 | C10H9ClO3 | 详情 | 详情 |
| (II) | 21856 | N,N-dipropylamine; N-propyl-1-propanamine | 142-84-7 | C6H15N | 详情 | 详情 |
| (III) | 47011 | 4-(4-chlorophenyl)-4-oxo-N,N-dipropylbutanamide | C16H22ClNO2 | 详情 | 详情 | |
| (IV) | 47012 | 3-bromo-4-(4-chlorophenyl)-4-oxo-N,N-dipropylbutanamide | C16H21BrClNO2 | 详情 | 详情 | |
| (V) | 13016 | 3-Methyl-2-pyridinylamine; 3-Methyl-2-pyridinamine; 2-Amino-3-picoline; 2-Amino-3-methylpyridine | 1603-40-3 | C6H8N2 | 详情 | 详情 |