Napitane mesilate, ABT-200, A-75200, -Drug Synthesis Database

【结构式】

【药物名称】Napitane mesilate, ABT-200, A-75200

【化学名称】(±)-1-[5,6-(Methylenedioxy)-1,2,3,4-tetrahydronaphth-1(R*)-ylmethyl]-3(R*)-phenylpyrrolidine methanesulfonate
　　　　　　(±)-3(R*)-Phenyl-1-[6,7,8,9-tetrahydronaphtho[1,2-d]-1,3-dioxol-6(R*)-ylmethyl]pyrrolidine methanesulfonate

【CA登记号】149189-73-1, 148152-63-0 (free base), 125067-61-0 (undefined stereochem.)

【分子式】C₂₃H₂₉NO₅S

【分子量】431.55528

【开发单位】Abbott (Originator)

【药理作用】Antidepressants, Mood Disorders, Treatment of, PSYCHOPHARMACOLOGIC DRUGS, alpha2-Adrenoceptor Antagonists, Norepinephrine Reuptake Inhibitors

合成路线1 合成路线2

合成路线1

This compound has been obtained by several different ways: 1) The reaction of 6,7,8,9-tetrahydronaphtho[1,2-d][1,3]dioxol-6-one (I) with trimethylsilyl cyanide gives 8,9-dihydronaphtho[1,2-d][1,3]dioxole-6-carbonitrile (II), which is hydrogenated with NaBH4 and hydrolyzed with KOH yielding the carboxylic acid (III). The condensation of (III) with 3-phenylpyrrolidine (IV) by means of DCC in THF affords the acylated pyrrolidine (V), which is reduced with BH3 in THF giving intermediate (VI) as a mixture of the cis and trans racemic diastereomers. Finally, the reaction of this mixture with methanesulfonic acid yields the corresponding mixture of mesylates that is separated by crystallization to afford the target cis racemate. 2) The reduction of carbonitrile (II) with H2 over Raney-Ni gives the corresponding amine (VII), which is cyclized with 2-phenylsuccinic anhydride (VIII) to yield the succinamic acid derivative (IX). The cyclization of (IX) by means of acetyl chloride affords the succinimide (X) as a mixture of the cis and trans racemic diastereomers, which are separated by crystallization giving the cis racemate (cis)(X). Finally, this racemate is reduced with BH3.THF or BH3. Dimethyl sulfide and treated with methanesulfonic acid to afford the target compound. 3) The cyclization of amine (VII) with the dimesylate (XI) by means of DIEA in ethanol gives also the previously described mixture of the cis and trans racemic diastereomers (VI).

参考文献中间体

【1】 Buckner, S.A.; Zelle, R.E.; Basha, F.Z.; Meyer, M.D.; Tietje, K.; Hancock, A.A.; de Bernardis, J.F.; Synthesis and phamacological characterization of ABT-200: a putative novel antidepressant combining potent alpha-2 antagonism with moderate ne uotake inhibition. Bioorg Med Chem Lett 1994, 4, 11, 1319-22.
【2】 Deshpande, M.N.; et al.; A scalable process for the novel antidepressant ABT-200. Org Process Res Dev 1998, 2, 6, 351.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(cis)(X)	33723	(3R)-3-phenyl-1-[(6R)-6,7,8,9-tetrahydronaphtho[1,2-d][1,3]dioxol-6-ylmethyl]-2,5-pyrrolidinedione	C₂₂H₂₁NO₄	详情	详情
(I)	33715	8,9-dihydronaphtho[1,2-d][1,3]dioxol-6(7H)-one	C₁₁H₁₀O₃	详情	详情
(II)	33716	8,9-dihydronaphtho[1,2-d][1,3]dioxole-6-carbonitrile	C₁₂H₉NO₂	详情	详情
(III)	33717	6,7,8,9-tetrahydronaphtho[1,2-d][1,3]dioxole-6-carboxylic acid	C₁₂H₁₂O₄	详情	详情
(IV)	30991	3-phenylpyrrolidine	C₁₀H₁₃N	详情	详情
(V)	33718	(3-phenyl-1-pyrrolidinyl)(6,7,8,9-tetrahydronaphtho[1,2-d][1,3]dioxol-6-yl)methanone	C₂₂H₂₃NO₃	详情	详情
(VI)	33719	3-phenyl-1-(6,7,8,9-tetrahydronaphtho[1,2-d][1,3]dioxol-6-ylmethyl)pyrrolidine	C₂₂H₂₅NO₂	详情	详情
(VII)	33724	6,7,8,9-tetrahydronaphtho[1,2-d][1,3]dioxol-6-ylmethylamine; 6,7,8,9-tetrahydronaphtho[1,2-d][1,3]dioxol-6-ylmethanamine	C₁₂H₁₅NO₂	详情	详情
(VIII)	33720	3-phenyldihydro-2,5-furandione	C₁₀H₈O₃	详情	详情
(IX)	33721	4-oxo-3-phenyl-4-[(6,7,8,9-tetrahydronaphtho[1,2-d][1,3]dioxol-6-ylmethyl)amino]butyric acid	C₂₂H₂₃NO₅	详情	详情
(X)	33722	3-phenyl-1-(6,7,8,9-tetrahydronaphtho[1,2-d][1,3]dioxol-6-ylmethyl)-2,5-pyrrolidinedione	C₂₂H₂₁NO₄	详情	详情
(XI)	33725	2,9-dimethyl-2,9-dimethylene-5-phenyl-3,8-dioxa-2lambda(6),9lambda(6)-dithia-1,9-decadiene	C₁₆H₂₆O₂S₂	详情	详情

合成路线2

The reaction of 6,7,8,9-tetrahydronaphtho[1,2-d][1,3]dioxol-6-one (I) with nitromethane by means of butylamine in refluxing toluene/methylcyclohexane/acetic acid gives the nitromethyl derivative (XIII), which is reduced with H2 over Pd/C in methanol to yield the previously described amine (VII). Amine (VII) can be condensed with 2-phenylsuccinic acid by means of acetyl chloride in refluxing xylene yielding directly the previously reported succinimide (X) as a mixture of the cis and trans racemic diastereomers.

参考文献中间体

【1】 Deshpande, M.N.; et al.; A scalable process for the novel antidepressant ABT-200. Org Process Res Dev 1998, 2, 6, 351.

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)	33715	8,9-dihydronaphtho[1,2-d][1,3]dioxol-6(7H)-one		C₁₁H₁₀O₃	详情	详情
(VII)	33724	6,7,8,9-tetrahydronaphtho[1,2-d][1,3]dioxol-6-ylmethylamine; 6,7,8,9-tetrahydronaphtho[1,2-d][1,3]dioxol-6-ylmethanamine		C₁₂H₁₅NO₂	详情	详情
(X)	33722	3-phenyl-1-(6,7,8,9-tetrahydronaphtho[1,2-d][1,3]dioxol-6-ylmethyl)-2,5-pyrrolidinedione		C₂₂H₂₁NO₄	详情	详情
(XII)	33726	6-[(E)-nitromethylidene]-6,7,8,9-tetrahydronaphtho[1,2-d][1,3]dioxole		C₁₂H₁₁NO₄	详情	详情
(XIII)	33727	6-(nitromethyl)-8,9-dihydronaphtho[1,2-d][1,3]dioxole		C₁₂H₁₁NO₄	详情	详情
(XIV)	33728	2-phenylsuccinic acid	635-51-8	C₁₀H₁₀O₄	详情	详情

Extended Information