methyl 4-[(4-ethyl-2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-3-(phenylmethyl)-2,3,3a,4,5,7-hexahydro-1H-pyrrolo[2,3-d]carbazole-6-carboxylate -Drug Synthesis Database

【结构式】

【分子编号】63612

【品名】methyl 4-[(4-ethyl-2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-3-(phenylmethyl)-2,3,3a,4,5,7-hexahydro-1H-pyrrolo[2,3-d]carbazole-6-carboxylate

【CA登记号】

【分子式】C₃₁H₃₈N₂O₄

【分子量】502.6538

【元素组成】C 74.08% H 7.62% N 5.57% O 12.73%

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：(XI)

In an alternative synthesis, which does not utilize the alkaloid catharanthine, Sharpless asymmetric epoxidation of 2-ethyl-2-propenol (I) in the presence of ( )-diethyl tartrate provides (R)-2-ethyl-2,3-epoxypropanol (II). Subsequent addition of allylmagnesium chloride (III) to epoxide (II) leads to diol (IV), which is further protected as the corresponding acetonide (V) with 2,2 dimethoxypropane and p-TsOH. Ozonolysis of the terminal olefin (V) gives rise to aldehyde (VI). Condensation of aldehyde (VI) with the indoloazapine (VII) furnishes the bridged azepine (VIII) as a diastereomeric mixture. Without isolation, this mixture of amines is N-alkylated with benzyl bromide, and the resultant ammonium salts (IX) are subjected to rearrangement in boiling MeOH in the presence of Et3N to provide an equimolecular mixture of the tetracyclic diastereoisomers (X) and (XI) (5).

参考文献中间体

合成目标

【1】 Kuehne, M.E.; Matson, P.A..; Bornmann, W.G.; Enantioselective syntheses of vinblastine, leurosidine, vincovaline, and 20'-epi-vincovaline. J Org Chem 1991, 56, 2, 513.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	63603	2-ethyl-2-propen-1-ol	C₅H₁₀O	详情	详情
(II)	63604	(2-ethyl-2-oxiranyl)methanol	C₅H₁₀O₂	详情	详情
(III)	61128		C₄H₈	详情	详情
(IV)	63605	2-ethyl-5-hexene-1,2-diol	C₈H₁₆O₂	详情	详情
(V)	63606	4-(3-butenyl)-4-ethyl-2,2-dimethyl-1,3-dioxolane	C₁₁H₂₀O₂	详情	详情
(VI)	63607	3-(4-ethyl-2,2-dimethyl-1,3-dioxolan-4-yl)propanal	C₁₀H₁₈O₃	详情	详情
(VII)	63608	methyl 1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-5-carboxylate	C₁₄H₁₆N₂O₂	详情	详情
(VIII)	63609	methyl 15-{2-[(4S)-4-ethyl-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl}-8,12-diazatetracyclo[10.2.1.0~1,9~.0~2,7~]pentadeca-2,4,6,9-tetraene-10-carboxylate	C₂₄H₃₂N₂O₄	详情	详情
(IX)	63610	12-benzyl-15-{2-[(4S)-4-ethyl-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl}-10-(methoxycarbonyl)-8-aza-12-azoniatetracyclo[10.2.1.0~1,9~.0~2,7~]pentadeca-2,4,6,9-tetraene bromide	C₃₁H₃₉BrN₂O₄	详情	详情
(X)	63611	methyl 4-[(4-ethyl-2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-3-(phenylmethyl)-2,3,3a,4,5,7-hexahydro-1H-pyrrolo[2,3-d]carbazole-6-carboxylate	C₃₁H₃₈N₂O₄	详情	详情
(XI)	63612	methyl 4-[(4-ethyl-2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-3-(phenylmethyl)-2,3,3a,4,5,7-hexahydro-1H-pyrrolo[2,3-d]carbazole-6-carboxylate	C₃₁H₃₈N₂O₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XI)

Acidic hydrolysis of the mixture of diastereoisomeric acetonides (X) and (XI) leads to the respective diols, which are then separated by flash chromatography. After selective tosylation of the primary hydroxyl group of isomer (XII) with p-toluenesulfonic anhydride, the remaining tertiary hydroxyl is protected by silylation with trimethylsilyl triflate to furnish (XIII). Chlorination of (XIII) with tert-butyl hypochlorite leads to (XIV), which is then coupled to vindoline (XV) in the presence of AgBF4 to afford the bis-indolyl derivative (XVI) (5).

参考文献中间体

合成目标

【1】 Kuehne, M.E.; Matson, P.A..; Bornmann, W.G.; Enantioselective syntheses of vinblastine, leurosidine, vincovaline, and 20'-epi-vincovaline. J Org Chem 1991, 56, 2, 513.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(X)	63611	methyl 4-[(4-ethyl-2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-3-(phenylmethyl)-2,3,3a,4,5,7-hexahydro-1H-pyrrolo[2,3-d]carbazole-6-carboxylate	C₃₁H₃₈N₂O₄	详情	详情
(XI)	63612	methyl 4-[(4-ethyl-2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-3-(phenylmethyl)-2,3,3a,4,5,7-hexahydro-1H-pyrrolo[2,3-d]carbazole-6-carboxylate	C₃₁H₃₈N₂O₄	详情	详情
(XII)	63613	methyl 4-[2-hydroxy-2-(hydroxymethyl)butyl]-3-(phenylmethyl)-2,3,3a,4,5,7-hexahydro-1H-pyrrolo[2,3-d]carbazole-6-carboxylate	C₂₈H₃₄N₂O₄	详情	详情
(XIII)	63614	methyl 4-{2-({[(4-methylphenyl)sulfonyl]oxy}methyl)-2-[(trimethylsilyl)oxy]butyl}-3-(phenylmethyl)-2,3,3a,4,5,7-hexahydro-1H-pyrrolo[2,3-d]carbazole-6-carboxylate	C₃₈H₄₈N₂O₆SSi	详情	详情
(XIV)	63615	methyl 6-chloro-4-{2-({[(4-methylphenyl)sulfonyl]oxy}methyl)-2-[(trimethylsilyl)oxy]butyl}-3-(phenylmethyl)-2,3,3a,4,5,6-hexahydro-1H-pyrrolo[2,3-d]carbazole-6-carboxylate	C₃₈H₄₇ClN₂O₆SSi	详情	详情
(XV)	63596	methyl 4-(acetyloxy)-3a-ethyl-5-hydroxy-6-methyl-8-(methyloxy)-3a,4,5,5a,6,11,12,13a-octahydro-1H-indolizino[8,1-cd]carbazole-5-carboxylate	C₂₅H₃₂N₂O₆	详情	详情
(XVI)	63616	methyl 4-(acetyloxy)-3a-ethyl-5-hydroxy-6-methyl-8-(methyloxy)-9-[6-[(methyloxy)carbonyl]-4-{2-({[(4-methylphenyl)sulfonyl]oxy}methyl)-2-[(trimethylsilyl)oxy]butyl}-3-(phenylmethyl)-2,3,3a,4,5,6-hexahydro-1H-pyrrolo[2,3-d]carbazol-6-yl]-3a,4,5,5a,6,	C₆₃H₇₈N₄O₁₂SSi	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XI)

In an improved method for the preparation of intermediate (XI), indolodiazepine (I) is condensed with the chiral ferrocenylethyl acetate (II) to produce the N-alkylated compound (III) as an inseparable mixture of diastereoisomers. Subsequent condensation of (III) with aldehyde (IV) and rearrangement in refluxing benzene gives rise to the tetracyclic compound (V) as a single diastereoisomer. Acetolysis of (V) provides amine (VI) along with minor amounts of a partly epimerized compound, which can be removed by chromatography. Then, alkylation of (VI) with benzyl bromide yields the key synthetic intermediate (XI) (6).

参考文献中间体

合成目标

【1】 Kuehne, M.E.; Bandarage, U.K.; An alternative enantioselective generation of intermediates in the total synthesis of vinblastine: Enantioselection in secodine-type reactions induced by alpha-ferrocenylethyl N-substituents. J Org Chem 1996, 61, 3, 1175.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	63608	methyl 1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-5-carboxylate	C₁₄H₁₆N₂O₂	详情	详情
(II)	63620		C₂₆H₂₅FeO₂P	详情	详情
(III)	63621		C₃₉H₄₁N₂O₂P	详情	详情
(IV)	63607	3-(4-ethyl-2,2-dimethyl-1,3-dioxolan-4-yl)propanal	C₁₀H₁₈O₃	详情	详情
(V)	63622		C₄₈H₅₅FeN₂O₄P	详情	详情
(VI)	63623	methyl 4-[(4-ethyl-2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2,3,3a,4,5,7-hexahydro-1H-pyrrolo[2,3-d]carbazole-6-carboxylate	C₂₄H₃₂N₂O₄	详情	详情
(XI)	63612	methyl 4-[(4-ethyl-2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-3-(phenylmethyl)-2,3,3a,4,5,7-hexahydro-1H-pyrrolo[2,3-d]carbazole-6-carboxylate	C₃₁H₃₈N₂O₄	详情	详情

Extended Information