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【结 构 式】 
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【分子编号】11179 【品名】4-Chlorobutanenitrile; 4-Chlorobutyronitrile 【CA登记号】628-20-6 |
【 分 子 式 】C4H6ClN 【 分 子 量 】103.55108 【元素组成】C 46.4% H 5.84% Cl 34.24% N 13.53% |
合成路线1
该中间体在本合成路线中的序号：(IX)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2
该中间体在本合成路线中的序号：(II)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3
该中间体在本合成路线中的序号：(IX)D-Alaninol (I) was protected as the tert-butyl carbamate (II) and then converted to mesylate (III). Displacement of the mesylate group of (III) with NaCN furnished nitrile (IV), which was hydrogenated over Raney Nickel to give diamine (V). Condensation of (V) with benzaldehyde (VI) in the presence of molecular sieves produced imine (VII) and subsequent reduction by means of NaBH4 gave rise to the benzyl amine (VIII). This amine was alkylated with 4-chlorobutyronitrile (IX) to afford nitrile (X), which was further converted to the triamino compound (XI) by hydrogenation over Raney Nickel. Reaction of (XI) with methyl 2-[(phenoxycarbonyl)oxy]acetate (XII) provided carbamate (XIII). The ester group of (XIII) was then hydrolyzed with NaOH to give carboxylic acid (XIV).
| 【1】 Lebreton, L.; et al.; Structure - Immunosuppressive activity relationships of new analogues of 15-deoxyspergualin. 2. Structural modifications of the spermidine moiety. J Med Chem 1999, 42, 23, 4749. |
| 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) | 21414 | (2R)-2-Amino-1-propanol; D-Alaninol; D-(-)-Alaninol | 35320-23-1 | C3H9NO | 详情 | 详情 |
| (II) | 31758 | tert-butyl (1R)-2-hydroxy-1-methylethylcarbamate | C8H17NO3 | 详情 | 详情 | |
| (III) | 31803 | (2R)-2-[(tert-butoxycarbonyl)amino]propyl methanesulfonate | C9H19NO5S | 详情 | 详情 | |
| (IV) | 31804 | tert-butyl (1R)-2-cyano-1-methylethylcarbamate | C9H16N2O2 | 详情 | 详情 | |
| (V) | 31805 | tert-butyl (1R)-3-amino-1-methylpropylcarbamate | C9H20N2O2 | 详情 | 详情 | |
| (VI) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (VII) | 31806 | tert-butyl (1R)-1-methyl-3-[[(E)-benzylidene]amino]propylcarbamate | C16H24N2O2 | 详情 | 详情 | |
| (VIII) | 31807 | tert-butyl (1R)-3-(benzylamino)-1-methylpropylcarbamate | C16H26N2O2 | 详情 | 详情 | |
| (IX) | 11179 | 4-Chlorobutanenitrile; 4-Chlorobutyronitrile | 628-20-6 | C4H6ClN | 详情 | 详情 |
| (X) | 31808 | tert-butyl (1R)-3-[benzyl(3-cyanopropyl)amino]-1-methylpropylcarbamate | C20H31N3O2 | 详情 | 详情 | |
| (XI) | 31809 | tert-butyl (1R)-3-[(4-aminobutyl)(benzyl)amino]-1-methylpropylcarbamate | C20H35N3O2 | 详情 | 详情 | |
| (XII) | 22341 | methyl 2-[(phenoxycarbonyl)oxy]acetate | C10H10O5 | 详情 | 详情 | |
| (XIII) | 31810 | methyl (6R)-9-benzyl-2,2,6-trimethyl-4,15-dioxo-3,16-dioxa-5,9,14-triazaoctadecan-18-oate | C24H39N3O6 | 详情 | 详情 | |
| (XIV) | 31811 | (6R)-9-benzyl-2,2,6-trimethyl-4,15-dioxo-3,16-dioxa-5,9,14-triazaoctadecan-18-oic acid | C23H37N3O6 | 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 1-(4-fluorophenyl)piperazine (I) with 4-chlorobutyronitrile (II) by means of Na2CO3 in refluxing acetonitrile gives 4-[4-(4-fluorophenyl) piperazin-1-yl]butyronitrile (III), which is reduced with LiAlH4 in THF yielding 1-(4-aminobutyl)-4-(4-fluorophenyl)piperazine (IV). Finally, this compound is condensed with 2-(diphenylmethylene)succinic anhydride (V) in refluxing acetic acid.
| 【1】 López-Rodríguez, M.L.; Morcillo, M.J.; Rovat, T.K.; Fernández, E.; Sanz, A.M.; Orensanz, L.; 1-[omega-(4-Arylpiperazin-1-yl)alkyl]-3-diphenylmethylene-2,5-pyrrolidinediones as 5-HT1A receptor ligands: Study of the steric requirements of the terminal amide fragment on 5-HT1A affinity/selectivity. Bioorg Med Chem Lett 1998, 8, 6, 581. |
| 【2】 López-Rodríguez, M.L.; Morcillo, M.J.; Rovat, T.K.; Fernandez, E.; Vicente, B.; Sanz, A.M.; Hernandez, M.; Orensanz, L.; Synthesis and structure-activity relationships of a new model of arylpiperazines. 4. 1-[omega-(4-Arylpiperazin-1-yl)alkyl]-3-(diphenylmethylene)-2,5-pyrrolidinediones and -3-(9H-fluoren-9-ylidene)-2,5-pyrrolidinediones: Study of the steric requirements of. J Med Chem 1999, 42, 1, 36. |
| 【3】 K. Rovat, T.; Oesanz Muno, L.M.; Fernandez Velando, E.; Lopez Rodriguez, M.L.; Rosado Samitier, M.L.; Morcillo Ortega, M.J. (Universidad Complutense de Madrid); New imidapiperazine derivs.. ES 2094690 . |
| 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) | 12143 | 1-(4-Fluorophenyl)piperazine | 2252-63-3 | C10H13FN2 | 详情 | 详情 |
| (II) | 11179 | 4-Chlorobutanenitrile; 4-Chlorobutyronitrile | 628-20-6 | C4H6ClN | 详情 | 详情 |
| (III) | 28670 | 4-[4-(4-fluorophenyl)-1-piperazinyl]butanenitrile | C14H18FN3 | 详情 | 详情 | |
| (IV) | 28671 | 4-[4-(4-fluorophenyl)-1-piperazinyl]-1-butanamine | C14H22FN3 | 详情 | 详情 | |
| (V) | 28672 | 3-(dibenzylene)dihydro-2,5-furandione | C17H12O3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)Addition of benzylmagnesium bromide to 4-chlorobutyronitrile (II) gives rise to the chloro ketone adduct (III). Subsequent chloride displacement with ethylenediamine (IV) furnishes the target diamino ketone.
| 【1】 Andreadou, I.; Rekka, E.A.; Demopoulos, V.J.; Bijloo, G.J.; Kourounakis, P.N.; Synthesis, antioxidant and anti-inflammatory activity of novel substituted ethylenediamines and ethanolamines. A preliminary quantitative structure-activity relationship study. Arzneim-Forsch Drug Res 1997, 47, 5, 643. |
| 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) | 28308 | benzyl(bromo)magnesium; benzylmagnesium bromide | 1589-82-8 | C7H7BrMg | 详情 | 详情 |
| (II) | 11179 | 4-Chlorobutanenitrile; 4-Chlorobutyronitrile | 628-20-6 | C4H6ClN | 详情 | 详情 |
| (III) | 64973 | 5-chloro-1-phenyl-2-pentanone | C11H13ClO | 详情 | 详情 | |
| (IV) | 14754 | ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine；1,2-Ethanediamine | 107-15-3 | C2H8N2 | 详情 | 详情 |