methyl 3-thioxo-2,3,6,11-tetrahydro-1H-indolizino[8,7-b]indole-11b(5H)-carboxylate -Drug Synthesis Database

【结构式】

【分子编号】63624

【品名】methyl 3-thioxo-2,3,6,11-tetrahydro-1H-indolizino[8,7-b]indole-11b(5H)-carboxylate

【CA登记号】

【分子式】C₁₆H₁₆N₂O₂S

【分子量】300.38132

【元素组成】C 63.98% H 5.37% N 9.33% O 10.65% S 10.68%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(I)

In a nonoxidative coupling sytrategy, the required tetracyclic precursor (X) has been prepared by two methods. Alkylation of thiolactam (I) with 2 (bromomethyl)-1-butene (II) gives the thioiminium salt (III), which undergoes thio-Claisen rearrangement in the presence of DBU in THF to produce (IV) as a mixture of cis and trans isomers. After conversion of thiolactams (IV) into the corresponding lactams with m-chloroperoxybenzoic acid (mCPBA), the desired isomer (V) is isolated employing preparative HPLC. Double bond dihydroxylation with N-methylmorpholine-N-oxide in the presence of a catalytic amount of OsO4 leads to diol (VI) as a diastereomeric mixture. Protection of diols (VI) with 1-methoxycyclohexene (VII) affords the corresponding mixture of cyclohexylidene ketals (VIII). After conversion of (VIII) to the respective thiolactams with Lawesson's reagent in hot toluene, separation of isomers employing preparative HPLC furnishes thiolactam (IX). Then, desulfuration of thiolactam (IX) by means of Raney nickel gives rise to intermediate (X) (7).

参考文献中间体

合成目标

【1】 Magnus, P.; Mendoza, J.S.; Stamford, A.; Ladlow, M.; Willis, P.; Nonoxidative coupling methodology for the synthesis of the antitumor bisindole alkaloid vinblastine and a lower-half analogue: Solvent effect on the stereochemistry of the crucial C-15/C-18' bond. J Am Chem Soc 1992, 114, 26, 10232.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	63624	methyl 3-thioxo-2,3,6,11-tetrahydro-1H-indolizino[8,7-b]indole-11b(5H)-carboxylate	C₁₆H₁₆N₂O₂S	详情	详情
(II)	63625		C₅H₉Br	详情	详情
(III)	63626	{11b-[(methyloxy)carbonyl]-1,2,5,6,11,11b-hexahydro-3H-indolizino[8,7-b]indol-3-ylidene}(2-ethyl-2-propenyl)sulfonium bromide	C₂₁H₂₅BrN₂O₂S	详情	详情
(IV)	63627	methyl 2-(2-ethyl-2-propenyl)-3-thioxo-2,3,6,11-tetrahydro-1H-indolizino[8,7-b]indole-11b(5H)-carboxylate	C₂₁H₂₄N₂O₂S	详情	详情
(V)	63628	methyl 2-(2-ethyl-2-propenyl)-3-oxo-2,3,6,11-tetrahydro-1H-indolizino[8,7-b]indole-11b(5H)-carboxylate	C₂₁H₂₄N₂O₃	详情	详情
(VI)	63629	methyl 2-[2-hydroxy-2-(hydroxymethyl)butyl]-3-oxo-2,3,6,11-tetrahydro-1H-indolizino[8,7-b]indole-11b(5H)-carboxylate	C₂₁H₂₆N₂O₅	详情	详情
(VII)	63630	1-(methyloxy)-1-cyclohexene; 1-cyclohexen-1-yl methyl ether	C₇H₁₂O	详情	详情
(VIII)	63631	methyl 2-[(2-ethyl-1,4-dioxaspiro[4.5]dec-2-yl)methyl]-3-oxo-2,3,6,11-tetrahydro-1H-indolizino[8,7-b]indole-11b(5H)-carboxylate	C₂₇H₃₄N₂O₅	详情	详情
(IX)	63632	methyl 2-[(2-ethyl-1,4-dioxaspiro[4.5]dec-2-yl)methyl]-3-thioxo-2,3,6,11-tetrahydro-1H-indolizino[8,7-b]indole-11b(5H)-carboxylate	C₂₇H₃₄N₂O₄S	详情	详情
(X)	63633	methyl 2-[(2-ethyl-1,4-dioxaspiro[4.5]dec-2-yl)methyl]-2,3,6,11-tetrahydro-1H-indolizino[8,7-b]indole-11b(5H)-carboxylate	C₂₇H₃₆N₂O₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

In an alternative, stereospecific synthesis of (X), Sharpless asymmetric epoxidation of 2-ethyl-2-propen-1-ol (XI) in the presence of (-)-diethyl tartrate provides the (R)-epoxide (XII). Ring opening of (XII) with sodium thiophenoxide produces diol (XIII), which is further protected with 1-methoxycyclohexene (VII), yielding ketal (XIV). Sulfide (XIV) is then oxidized with mCPBA to afford sulfoxide (XV) as a mixture of diastereoisomers. Pummerer rearrangement of sulfoxides (XV) in boiling Ac2O, followed by alkaline hydrolysis of the intermediate alpha-acetoxy sulfides furnishes aldehyde (XVI). Then, aldol condensation of aldehyde (XVI) with thiolactam (I) employing stannous triflate and N-ethylpiperidine gives adduct (XVII). Dehydration of alcohol (XVII) to the alpha,beta-unsaturated thiolactam (XVIII) is accomplished by tosylation with p-toluenesulfonic anhydride, followed by tosylate elimination in the presence of DBU. Desulfuration of thiolactam (XVIII) with deactivated Ra-Ni leads to (XIX). Then, hydrogenation of olefin (XIX) produces a mixture of epimers, from which the target isomer (X) can be isolated by column chromatography (7).

参考文献中间体

合成目标

【1】 Magnus, P.; Mendoza, J.S.; Stamford, A.; Ladlow, M.; Willis, P.; Nonoxidative coupling methodology for the synthesis of the antitumor bisindole alkaloid vinblastine and a lower-half analogue: Solvent effect on the stereochemistry of the crucial C-15/C-18' bond. J Am Chem Soc 1992, 114, 26, 10232.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	63624	methyl 3-thioxo-2,3,6,11-tetrahydro-1H-indolizino[8,7-b]indole-11b(5H)-carboxylate	C₁₆H₁₆N₂O₂S	详情	详情
(VII)	63630	1-(methyloxy)-1-cyclohexene; 1-cyclohexen-1-yl methyl ether	C₇H₁₂O	详情	详情
(X)	63633	methyl 2-[(2-ethyl-1,4-dioxaspiro[4.5]dec-2-yl)methyl]-2,3,6,11-tetrahydro-1H-indolizino[8,7-b]indole-11b(5H)-carboxylate	C₂₇H₃₆N₂O₄	详情	详情
(XI)	63603	2-ethyl-2-propen-1-ol	C₅H₁₀O	详情	详情
(XII)	63604	(2-ethyl-2-oxiranyl)methanol	C₅H₁₀O₂	详情	详情
(XIII)	63634	2-[(phenylsulfanyl)methyl]-1,2-butanediol	C₁₁H₁₆O₂S	详情	详情
(XIV)	63635	2-ethyl-2-[(phenylsulfanyl)methyl]-1,4-dioxaspiro[4.5]decane; (2-ethyl-1,4-dioxaspiro[4.5]dec-2-yl)methyl phenyl sulfide	C₁₇H₂₄O₂S	详情	详情
(XV)	63636	(2-ethyl-1,4-dioxaspiro[4.5]dec-2-yl)methyl phenyl sulfoxide; 2-ethyl-2-[(phenylsulfinyl)methyl]-1,4-dioxaspiro[4.5]decane	C₁₇H₂₄O₃S	详情	详情
(XVI)	63637		C₁₁H₁₈O₃	详情	详情
(XVII)	63638	methyl 2-[(2-ethyl-1,4-dioxaspiro[4.5]dec-2-yl)(hydroxy)methyl]-3-thioxo-2,3,6,11-tetrahydro-1H-indolizino[8,7-b]indole-11b(5H)-carboxylate	C₂₇H₃₄N₂O₅S	详情	详情
(XVIII)	63639	methyl 2-[(2-ethyl-1,4-dioxaspiro[4.5]dec-2-yl)methylidene]-3-thioxo-2,3,6,11-tetrahydro-1H-indolizino[8,7-b]indole-11b(5H)-carboxylate	C₂₇H₃₂N₂O₄S	详情	详情
(XIX)	63640	methyl 2-[(2-ethyl-1,4-dioxaspiro[4.5]dec-2-yl)methylidene]-2,3,6,11-tetrahydro-1H-indolizino[8,7-b]indole-11b(5H)-carboxylate	C₂₇H₃₄N₂O₄	详情	详情

Extended Information