(1R,2S,6R,7S)-4-Azatricyclo[5.2.1.0(2,6)]decane-3,5-dione -Drug Synthesis Database

【结构式】

【分子编号】11173

【品名】(1R,2S,6R,7S)-4-Azatricyclo[5.2.1.0(2,6)]decane-3,5-dione

【CA登记号】

【分子式】C₉H₁₁NO₂

【分子量】165.19188

【元素组成】C 65.44% H 6.71% N 8.48% O 19.37%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(III)

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

合成目标

【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：(V)

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

合成目标

【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

该中间体在本合成路线中的序号：(IV)

Lurasidone hydrochloride can be synthesized as follows. The condensation of 1-(1,2-benzoisothiazol-3-yl)piperazine (I) with (R,R)-1,2-bis(methanesulfonyloxymethyl)cyclohexane (II) in the presence of potassium carbonate and tetrabutylammonium bisulfate in boiling toluene gives the spiropiperazinium salt (III) (1-3), which is further reacted with bicyclo[2.2.1]heptane-2,3-dicarboximide (IV) by means of potassium carbonate in hot xylene or toluene to yield lurasidone (1-4). Lurasidone base is finally converted to the corresponding hydrochloride salt by treatment with HCl in acetone (5). Scheme 1.

参考文献中间体

合成目标

【1】 Yujiro, K., Hisashi, B. (Sumitomo Chem. Co., Ltd.; Sumitomo Pharm. Co., Ltd.). Production method of imido derivative. JP 2003160583.
【2】 Nobuyuki, A., Hisashi, B. (Sumitomo Chem. Co., Ltd.; Dainippon Sumitomo Pharma Co., Ltd.). Method for producing quaternary ammonium salt. JP 2006169154.
【3】 Nobuyuki, A., Hisashi, B. (Sumitomo Chem. Co., Ltd.; Dainippon Sumitomo Pharma Co., Ltd.). Method for producing quaternary ammonium salt. JP 2006169155.
【4】 Saji, I., Muto, M., Tanno, N., Yoshigi, M. (Dainippon Sumitomo Pharma Co., Ltd.). Imide derivatives and their production and use. EP 0464846, JP 5017440, US 5532372, US 5780632.
【5】 Kakiya, Y., Oda, M. (Sumitomo Pharm. Co., Ltd.). Process for producing imide compound. WO 2005009999.

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)	16280	3-piperazino-1,2-benzisothiazole; 1,2-Benzisothiazole-3-(1-piperazinyl)	87691-87-0	C₁₁H₁₃N₃S	详情	详情
(II)	65627	(R,R)-1,2-Bis(methanesulfonyloxymethyl)cyclohexane; (1R-trans)-1,2-Cyclohexanedimethanol dimethanesulfonate,; (1R,2R)-1,2-Bis(methanesulfonyloxymethyl)cyclohexane	186204-35-3	C₁₀H₂₀O₆S₂	详情	详情
(III)	65628	(3aR,7aR)-4'-(1,2-Benzisothiazol-3-yl)octahydrospiro[2H-isoindole-2,1'-piperazinium] methanesulfonate	186204-37-5	C₁₉H₂₆N₃S.CH₃O₃S	详情	详情
(IV)	11173	(1R,2S,6R,7S)-4-Azatricyclo[5.2.1.0(2,6)]decane-3,5-dione		C₉H₁₁NO₂	详情	详情

Extended Information