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【结 构 式】

【药物名称】Tandospirone citrate, SM-3997, Sediel

【化学名称】3aalpha,4alpha,5,6,7alpha,7aalpha-Hexahydro-2-[4- [4-(2-pyrimidinyl)-1-piperazinyl]butyl]-4,7-methano-1H-isoindole-1,3(2H)-dione dihydrogen citrate
　　　　　　(1R*,2S*,3R*,4S*)-N-[4-[4-(2-Pyrimidinyl)-1-piperazinyl]butyl]-2,3-norbornanedicarboximide citrate

【CA登记号】112457-95-1, 87760-53-0 (free base)

【 分 子 式 】C27H37N5O9

【 分 子 量 】575.62404

【开发单位】Sumitomo Pharmaceuticals (Originator), Pfizer (Licensee)

【药理作用】Antidepressants, Antipsychotic Drugs, Anxiolytics, Generalized Anxiety Disorder (GAD), Treatment of, Mood Disorders, Treatment of, PSYCHOPHARMACOLOGIC DRUGS, 5-HT1A Receptor Agonists

合成路线1合成路线2合成路线3合成路线4

合成路线1

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.

参考文献 中间体
【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

The synthesis of SM-3997 labeled in the carbonyl groups or the pyrimidine ring has been reported: The Diels-Alder condensation of cyclopentadiene (II) with [14C]-labeled maleic anhydride (I) gives bicyclo[2.2.1]hept-5-ene-2,3-endo-di[14C]-carboxylic anhydride (III), which by treatment with ammonia in THF is converted to the corresponding imide (IV endo). Heating of (IV endo) at 190 C in diphenylether affords the corresponding exo isomer (IV exo), which is hydrogenated with H2 over Pd/C in ethanol - THF to give the saturated exo-imide (V). The condensation of (V) with 1,4-dibromobutane (VI) by means of K2CO3 in refluxing acetone yields the N-(4-bromobutyl)imide (VII), which is finally condensed with 1-(2-pyrimidinyl)piperazine (VIII) by means of K2CO3 and KI in hot DMF to afford SM-399 [14C]-labeled at the carbonyl groups.

参考文献 中间体
【1】 Kanamaru, H.; Nishioka, K.; 14C-labeling of a novel anxiolytic agent tandospirone. J Label Compd Radiopharm 1992, 31, 6, 427.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IV endo) 11185 (1R,2S,6R,7S)-4-Azatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione C9H9NO2 详情 详情
(IV exo) 11186 (1R,2R,6S,7S)-4-Azatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione C9H9NO2 详情 详情
(IV endo) 45052 (1R,2R,6S,7S)-4-azatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione C9H9NO2 详情 详情
(IV exo) 45053 (1R,2S,6R,7S)-4-azatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione C9H9NO2 详情 详情
(I) 11182 2,5-Furandione; Maleic anhydride 108-31-6 C4H2O3 详情 详情
(I) 45050 2,5-furandione C4H2O3 详情 详情
(II) 11183 1,3-Cyclopentadiene C5H6 详情 详情
(III) 11184 (1R,2S,6R,7S)-4-Oxatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione C9H8O3 详情 详情
(III) 45051 (1R,2R,6S,7S)-4-oxatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione C9H8O3 详情 详情
(V) 11173 (1R,2S,6R,7S)-4-Azatricyclo[5.2.1.0(2,6)]decane-3,5-dione C9H11NO2 详情 详情
(V) 45054 (1R,2R,6S,7S)-4-azatricyclo[5.2.1.0(2,6)]decane-3,5-dione C9H11NO2 详情 详情
(VII) 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
(VII) 45055 (1R,2R,6S,7S)-4-(4-bromobutyl)-4-azatricyclo[5.2.1.0(2,6)]decane-3,5-dione C13H18BrNO2 详情 详情
(VIII) 11175 2-(1-Piperazinyl)pyrimidine; 2-Piperazinopyrimidine; N-(Pyrimidinyl)piperazine 20980-22-7 C8H12N4 详情 详情

合成路线3

The condensation of piperazine (I) with [14C]-labeled 2-chloropyrimidine (II) in refluxing ethanol gives the labeled 1-(2-pyrimidinyl)piperazine (III), which is then condensed with the N-(4-bromobutyl)imide (IV) by means of K2CO3 and KI as before, affording SM-3997 labeled at the pyrimidine ring.

参考文献 中间体
【1】 Kanamaru, H.; Nishioka, K.; 14C-labeling of a novel anxiolytic agent tandospirone. J Label Compd Radiopharm 1992, 31, 6, 427.
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) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(II) 11191 2-Chloropyrimidine 1722-12-9 C4H3ClN2 详情 详情
(II) 45056 2-chloropyrimidine C4H3ClN2 详情 详情
(III) 11175 2-(1-Piperazinyl)pyrimidine; 2-Piperazinopyrimidine; N-(Pyrimidinyl)piperazine 20980-22-7 C8H12N4 详情 详情
(III) 45057 2-(1-piperazinyl)pyrimidine C8H12N4 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

合成路线4

By condensation of norbornane-2,3-di-endo-carboxylic anhydride (I) with 1-(4-aminobutyl)-4-(2 pyrimidinyl)piperazine (II) in refluxing pyridine.

参考文献 中间体
【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.
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) 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
(II) 11181 4-[4-(2-Pyrimidinyl)piperazino]butylamine; 4-[4-(2-Pyrimidinyl)piperazino]-1-butanamine 33386-20-8 C12H21N5 详情 详情
Extended Information