[(6-cyano-1-ethyl-1H-indol-2-yl)methyl](triphenyl)phosphonium bromide -Drug Synthesis Database

【结构式】

【分子编号】50434

【品名】[(6-cyano-1-ethyl-1H-indol-2-yl)methyl](triphenyl)phosphonium bromide

【CA登记号】

【分子式】C₃₀H₂₆BrN₂P

【分子量】525.427682

【元素组成】C 68.58% H 4.99% Br 15.21% N 5.33% P 5.89%

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：(VIII)

Electrophilic nitration of p-tolunitrile (I) afforded the 3-nitro derivative (II), which was condensed with diethyl oxalate in the presence of sodium ethoxide to produce the sodium enolate of the alpha-keto ester (III). Compound (III) was then subjected to Reissert indole synthesis by means of Zn and HOAc to furnish ethyl 6-cyanoindole-2-carboxylate (IV). N-alkylation of indole (IV) with iodoethane and NaH in DMF gave (V), whose carboxylate group was reduced to alcohol (VI) employing in situ-generated calcium borohydride (obtained from NaBH4 and CaI2 in THF in the presence of NaHCO3). Treatment of alcohol (VI) with PBr3 in methylene chloride yielded the corresponding bromide (VII), which was then converted into the phosphonium salt (VIII) by means of triphenylphosphine in refluxing toluene.

参考文献中间体

合成目标

【1】 Koo, B.A.; Min, J.K.; Hong, W.S.; Ryu, E.J.; Nam, W.H.; Kim, J.M. (C & C Research Laboratories); Aromatic amidine derivs. useful as selective thrombin inhibitors. EP 0918768; JP 2000504030; US 6201006; WO 9745424 .

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)	15458	4-methylbenzonitrile; p-tolunitrile	104-85-8	C₈H₇N	详情	详情
(II)	50428	4-methyl-3-nitrobenzonitrile		C₈H₆N₂O₂	详情	详情
(III)	50429	sodium (Z)-1-(4-cyano-2-nitrophenyl)-3-ethoxy-3-oxo-1-propen-2-olate		C₁₂H₉N₂NaO₅	详情	详情
(IV)	50430	ethyl 6-cyano-1H-indole-2-carboxylate		C₁₂H₁₀N₂O₂	详情	详情
(V)	50431	ethyl 6-cyano-1-ethyl-1H-indole-2-carboxylate		C₁₄H₁₄N₂O₂	详情	详情
(VI)	50432	1-ethyl-2-(hydroxymethyl)-1H-indole-6-carbonitrile		C₁₂H₁₂N₂O	详情	详情
(VII)	50433	2-(bromomethyl)-1-ethyl-1H-indole-6-carbonitrile		C₁₂H₁₁BrN₂	详情	详情
(VIII)	50434	[(6-cyano-1-ethyl-1H-indol-2-yl)methyl](triphenyl)phosphonium bromide		C₃₀H₂₆BrN₂P	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VIII)

Fischer esterification of L-proline (IX) with MeOH and HCl gave (X). Treatment of (X) with di-tert-butyl dicarbonate provided N-Boc-proline methyl ester (XI). The ester function of (XI) was then reduced to aldehyde (XII) by employing DIBAL in toluene at -78 C. Wittig condensation between aldehyde (XII) and phosphonium bromide (VIII) in the presence of DBU yielded the (indolylvinyl)pyrrolidine (XIII), which was further hydrogenated to (XIV) in the presence of Pd/C. The N-Boc group of (XIV) was then cleaved by treatment with trifluoroacetic acid to furnish (XV).

参考文献中间体

合成目标

【1】 Koo, B.A.; Min, J.K.; Hong, W.S.; Ryu, E.J.; Nam, W.H.; Kim, J.M. (C & C Research Laboratories); Aromatic amidine derivs. useful as selective thrombin inhibitors. EP 0918768; JP 2000504030; US 6201006; WO 9745424 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIII)	50434	[(6-cyano-1-ethyl-1H-indol-2-yl)methyl](triphenyl)phosphonium bromide		C₃₀H₂₆BrN₂P	详情	详情
(IX)	16731	L-proline	147-85-3	C₅H₉NO₂	详情	详情
(X)	29552	methyl (2S)-2-pyrrolidinecarboxylate	2133-40-6	C₆H₁₁NO₂	详情	详情
(XI)	50435	1-(tert-butyl) 2-methyl (2S)-1,2-pyrrolidinedicarboxylate		C₁₁H₁₉NO₄	详情	详情
(XII)	16724	tert-Butyl (2S)-2-formyltetrahydro-1H-pyrrole-1-carboxylate; tert-Butoxycarbonyl-L-prolinal	69610-41-9	C₁₀H₁₇NO₃	详情	详情
(XIII)	50436	tert-butyl (2S)-2-[(E)-2-(6-cyano-1-ethyl-1H-indol-2-yl)ethenyl]-1-pyrrolidinecarboxylate		C₂₂H₂₇N₃O₂	详情	详情
(XIV)	50437	tert-butyl (2S)-2-[2-(6-cyano-1-ethyl-1H-indol-2-yl)ethyl]-1-pyrrolidinecarboxylate		C₂₂H₂₉N₃O₂	详情	详情
(XV)	50438	1-ethyl-2-[2-[(2S)pyrrolidinyl]ethyl]-1H-indole-6-carbonitrile		C₁₇H₂₁N₃	详情	详情

Extended Information