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【结 构 式】 
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【分子编号】11181 【品名】4-[4-(2-Pyrimidinyl)piperazino]butylamine; 4-[4-(2-Pyrimidinyl)piperazino]-1-butanamine 【CA登记号】33386-20-8 |
【 分 子 式 】C12H21N5 【 分 子 量 】235.33244 【元素组成】C 61.25% H 8.99% N 29.76% |
合成路线1
该中间体在本合成路线中的序号：(II)This compound has been obtained by two related ways: The reduction of 4-[4-(2-pyrimidinyl)piperazin-1-yl]butyronitrile (I) by means of RaNi and hydrazine in isopropanol gives 4-[4-(2-pyrimidinyl)piperazin-1-yl]butylamine (II), which is then condensed with 3,3-dimethylglutaric anhydride (III) in refluxing xylene or refluxing toluene to yield the target glutarimide derivative. Alternatively, the condensation of N-(4-bromobutyl)-3,3-dimethylglutarimide (IV) with 1-(2-pyrimidinyl)piperazine (V) by means of K2CO3 in refluxing acetonitrile also yields the target glutarimide derivative.
| 【1】 Yevich, J.P.; et al.; Buspirone analogues. 1. Structure-activity relationships in a series of N-aryl- and heteroarylpiperazine derivatives. J Med Chem 1983, 26, 2, 194. |
| 【2】 Temple, D.L. Jr. (Bristol-Myers Squibb Co.); 2-[4-[(4,4-Dialkyl-2,6-piperidinedion-1-yl)butyl]-1-piperazinyl]pyrimidines. BE 0895504; CH 656383; DE 3248160; FR 2518993; GB 2114122; JP 1983118582; JP 1994293753; US 4423049 . |
| 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) | 11180 | 4-[4-(2-Pyrimidinyl)piperazino]butanenitrile | C12H17N5 | 详情 | 详情 | |
| (II) | 11181 | 4-[4-(2-Pyrimidinyl)piperazino]butylamine; 4-[4-(2-Pyrimidinyl)piperazino]-1-butanamine | 33386-20-8 | C12H21N5 | 详情 | 详情 |
| (III) | 25549 | 4,4-dimethyldihydro-2H-pyran-2,6(3H)-dione | 4160-82-1 | C7H10O3 | 详情 | 详情 |
| (IV) | 56851 | 1-(4-bromobutyl)-4,4-dimethyl-2,6-piperidinedione | C11H18BrNO2 | 详情 | 详情 | |
| (V) | 11175 | 2-(1-Piperazinyl)pyrimidine; 2-Piperazinopyrimidine; N-(Pyrimidinyl)piperazine | 20980-22-7 | C8H12N4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XI)New syntheses of tandospirone have been described: 1) The hydrogenation of bicyclo[2.2.1]hept-5-ene-2,3-di-exo-carboxylic acid anhydride (I) with H2 over Pd/C in THF-water gives bicyclo[2.2.1]heptane-2,3-di-exo-carboxylic acid anhydride (II), which by reaction with ammonia in THF-water is converted into the imide (III). The reaction of (III) with 1,4-dibromobutane by means of K2CO3 in refluxing acetone yields N-(4-bromobutyl)bicyclo[2.2.1]heptane-2,3-di-exo-carboximide (IV), which is finally condensed with 1-(2-pyrimidinyl)piperazine (V) by means of K2CO3 and KI in hot DMF. 2) Imide (III) is condensed with propargyl bromide (VI) by means of K2CO3 in refluxing acetone affording N-propargylbicyclo[2.2.1]heptane-2,3-di-exo-carboximide (VII), which is allowed to react with piperazine (V) and formaldehyde by means of CuSO4 in dioxane to give N-[4-[4-(2-pyrimidinyl)piperazin-1-yl]-2-butynyl]bicyclo[2.2.1]heptane-2,3-di-exo-carboximide (VIII). Finally, this compound is reduced with H2 over Pd/C. 3) The condensation of piperazine (V) with 4-chlorobutyronitrile (IX) by means of NaOH in acetone gives 4-[4-(2-pyrimidinyl)piperazin-1-yl]butyronitrile (X), which is reduced with LiAlH4 in ether yielding 1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine (XI). Finally, this compound is condensed with anhydride (II) in refluxing pyridine.
| 【1】 Kojima, A.; Ishizumi, K.; Antoku, F.; Synthesis and anxiolytic activity of N-substituted cyclic imides (1R*,2S*,3R*,4S*)-N-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-2,3-bicyclo[2.2.1]heptanedicarboximide (tandospirone) and related compounds. Chem Pharm Bull 1991, 39, 9, 2288. |
| 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) | 11171 | (1R,2R,6S,7S)-4-Oxatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione | C9H8O3 | 详情 | 详情 | |
| (II) | 11172 | (1R,2S,6R,7S)-4-Oxatricyclo[5.2.1.0(2,6)]decane-3,5-dione | 6004-79-1 | C9H10O3 | 详情 | 详情 |
| (III) | 11173 | (1R,2S,6R,7S)-4-Azatricyclo[5.2.1.0(2,6)]decane-3,5-dione | C9H11NO2 | 详情 | 详情 | |
| (IV) | 11174 | (1R,2S,6R,7S)-4-(4-Bromobutyl)-4-azatricyclo[5.2.1.0(2,6)]decane-3,5-dione | C13H18BrNO2 | 详情 | 详情 | |
| (V) | 11175 | 2-(1-Piperazinyl)pyrimidine; 2-Piperazinopyrimidine; N-(Pyrimidinyl)piperazine | 20980-22-7 | C8H12N4 | 详情 | 详情 |
| (VI) | 11176 | 3-Bromopropyne; 3-Bromo-1-propyne | 106-96-7 | C3H3Br | 详情 | 详情 |
| (VII) | 11177 | (1R,2S,6R,7S)-4-(2-Propynyl)-4-azatricyclo[5.2.1.0(2,6)]decane-3,5-dione | C12H13NO2 | 详情 | 详情 | |
| (VIII) | 11178 | (1R,2S,6R,7S)-4-[4-[4-(2-Pyrimidinyl)piperazino]-2-butynyl]-4-azatricyclo[5.2.1.0(2,6)]decane-3,5-dione | C21H25N5O2 | 详情 | 详情 | |
| (IX) | 11179 | 4-Chlorobutanenitrile; 4-Chlorobutyronitrile | 628-20-6 | C4H6ClN | 详情 | 详情 |
| (X) | 11180 | 4-[4-(2-Pyrimidinyl)piperazino]butanenitrile | C12H17N5 | 详情 | 详情 | |
| (XI) | 11181 | 4-[4-(2-Pyrimidinyl)piperazino]butylamine; 4-[4-(2-Pyrimidinyl)piperazino]-1-butanamine | 33386-20-8 | C12H21N5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)By condensation of norbornane-2,3-di-endo-carboxylic anhydride (I) with 1-(4-aminobutyl)-4-(2 pyrimidinyl)piperazine (II) in refluxing pyridine.
| 【1】 Ishizumi, K.; Antoku, F.; Asami, Y. (Sumitomo Chemical Co., Ltd.); Succimide derivatives, compositions and method of use. CA 1184915; EP 0082402 . |
| 【2】 Castaner, J.; Prous, J.; SM-3997. Drugs Fut 1986, 11, 11, 949. |
合成路线4
该中间体在本合成路线中的序号：(IV)The condensation of 1-(2-pyrimidinyl)piperazine (I) with 3-chloro-1-cyanopropane (II) by means of Na2CO3 in n-butanol gives 4-(2-pyrimidinyl)-1-(3-cyanopropyl)piperazine (III). This product is reduced with LiAlH4 or with H2 and Raney-Ni yielding 4-(2-pyrimidinyl)-1-(4-aminobutyl)piperazine (IV), which is finally condensed with 8-oxaspiro[4.5]decane-7,9-dione-(3,3-tetramethylene-glutaric anhydride) (V) in pyridine.
| 【1】 Wu, Y.H.; et al.; N-(Heteroarcyclic)piperazizylalkylazaspiroalkanediones. DE 2057845; FR 2073406; GB 1332194; US 3717634 . |
| 【2】 Wu, Y.H.; et al.; Psychosedative agents. 2. 8-(4-substituted-1-piperazinylalkyl)-8-azaspiro-[4,5]decane-7,9-diones. J Med Chem 1972, 15, 5, 477-479. |
| 【3】 Castaner, J.; Thorpe, P.; Buspirone. Drugs Fut 1976, 1, 9, 409. |
| 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) | 11175 | 2-(1-Piperazinyl)pyrimidine; 2-Piperazinopyrimidine; N-(Pyrimidinyl)piperazine | 20980-22-7 | C8H12N4 | 详情 | 详情 |
| (II) | 11179 | 4-Chlorobutanenitrile; 4-Chlorobutyronitrile | 628-20-6 | C4H6ClN | 详情 | 详情 |
| (III) | 11180 | 4-[4-(2-Pyrimidinyl)piperazino]butanenitrile | C12H17N5 | 详情 | 详情 | |
| (IV) | 11181 | 4-[4-(2-Pyrimidinyl)piperazino]butylamine; 4-[4-(2-Pyrimidinyl)piperazino]-1-butanamine | 33386-20-8 | C12H21N5 | 详情 | 详情 |
| (V) | 34125 | 8-oxaspiro[4.5]decane-7,9-dione | 5662-95-3 | C9H12O3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IX)Reaction of 1,3,5,7-cyclooctatetraene (I) with maleimide (Step a, b), or maleic anhydride (Step c), in refluxing toluene affords the imide (II) or the anhydride (III) in 78 and 85% yields, respectively. Reaction of imide intermediate (II) with 1,4-dibromobutane gives the omega-haloalkylimide, which subsequently is reacted with 1-(2-pyrimidinyl)piperazine to yield Wy-47846 (Method A). Alternatively, Wy-47846 can be prepared via the reaction of (III) with 1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine in refluxing pyridine (Method B), as shown in scheme. Wy-47846 is achiral.
| 【2】 Abou-Gharbia, M.; Moyer, J.A.; Haskins, J.T.; WY-47846. Drugs Fut 1989, 14, 5, 442. |
| 【1】 Abou-Gharbia, M.; et al.; Polycyclic aryl- and heteroarylpiperazyl imides as 5-HT1A receptor ligands and potential anxiolytic agents: synthesis and structure-activity relationship studies. J Med Chem 1988, 31, 7, 1382. |
| 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) | 20923 | 1,3,5,7-cyclooctatetraene | 629-20-9 | C8H8 | 详情 | 详情 |
| (II) | 20924 | bicyclo[4.2.0]octa-2,4-diene | C8H10 | 详情 | 详情 | |
| (III) | 20925 | (2R,6S,8R,11S)-4-azatetracyclo[5.4.2.0(2,6).0(8,11)]trideca-9,12-diene-3,5-dione | C12H11NO2 | 详情 | 详情 | |
| (IV) | 20926 | (2R,6S,8R,11S)-4-oxatetracyclo[5.4.2.0(2,6).0(8,11)]trideca-9,12-diene-3,5-dione | C12H10O3 | 详情 | 详情 | |
| (V) | 19711 | 1H-pyrrole-2,5-dione | 541-59-3 | C4H3NO2 | 详情 | 详情 |
| (VI) | 11182 | 2,5-Furandione; Maleic anhydride | 108-31-6 | C4H2O3 | 详情 | 详情 |
| (VII) | 11883 | 1,4-Dibromobutane; 1,4-Butylene bromide | 110-52-1 | C4H8Br2 | 详情 | 详情 |
| (VIII) | 11175 | 2-(1-Piperazinyl)pyrimidine; 2-Piperazinopyrimidine; N-(Pyrimidinyl)piperazine | 20980-22-7 | C8H12N4 | 详情 | 详情 |
| (IX) | 11181 | 4-[4-(2-Pyrimidinyl)piperazino]butylamine; 4-[4-(2-Pyrimidinyl)piperazino]-1-butanamine | 33386-20-8 | C12H21N5 | 详情 | 详情 |