ethyl 2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)ethyl)phenyl)-2-methylpropanoate -Drug Synthesis Database

【结构式】

【分子编号】69008

【品名】ethyl 2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)ethyl)phenyl)-2-methylpropanoate

【CA登记号】　

【分子式】C₃₀H₄₁N₃O₃

【分子量】491.674

【元素组成】C 73.29% H 8.41% N 8.55% O 9.76%

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：(VIa)

In the first strategy, alkylation of 2-(4-piperidinyl)-1H-benzimidazole (I) with the tosylate ester (II) in the presence of Na2CO3 in DMF at 80 °C provides the N-substituted piperidine (III), which is subsequently alkylated with 2-chloroethyl ethyl ether (IV) by means of NaH in DMF, yielding the N-ethoxyethyl derivative (V) . Finally, oxazolidinone (V) is submitted to acidic hydrolysis .
In the other strategy, saponification of propanoate esters (VIa) or (VIb) with NaOH in EtOH at 50-55 °C is followed by acidification with aqueous AcOH .

参考文献中间体

合成目标

【1】 Orjales, A., Rubio, V., Bordell, M. (FAES FARMA, SA). Benzimidazole derivatives with antihistaminic activity. EP 0818454, ES 2124167, JP 1998059961, US 5877187.
【2】 Lee, C.-H., Khoo, J.-H., Kwon, K.-C., Ju, H. (Yuhan Corp.). Process for preparation of 2-methyl-2’-phenylpropionic acid derivatives and novel intermediate compounds. WO 2009102155.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIa)	69008	ethyl 2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)ethyl)phenyl)-2-methylpropanoate		C₃₀H₄₁N₃O₃	详情	详情
(VIb)	69009	methyl 2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)ethyl)phenyl)-2-methylpropanoate		C₂₉H₃₉N₃O₃	详情	详情
(I)	54965	2-(4-piperidinyl)-1H-benzimidazole；2-(Piperidin-4-yl)benzimidazole;4-(Benzimidazol-2-yl)piperidine；2-Piperidin-4-yl-1H-benzimidazole	38385-95-4	C₁₂H₁₅N₃	详情	详情
(II)	54966	4-[1-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-1-methylethyl]phenethyl 4-methylbenzenesulfonate		C₂₃H₂₉NO₄S	详情	详情
(III)	54967	2-(1-{4-[1-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-1-methylethyl]phenethyl}-4-piperidinyl)-1H-benzimidazole		C₂₈H₃₆N₄O	详情	详情
(IV)	29358	1-chloro-2-ethoxyethane	628-34-2	C₄H₉ClO	详情	详情
(V)	54968	2-[2-(1-{4-[1-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-1-methylethyl]phenethyl}-4-piperidinyl)-1H-benzimidazol-1-yl]ethyl ethyl ether; 2-(1-{4-[1-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-1-methylethyl]phenethyl}-4-piperidinyl)-1-(2-ethoxyethyl)-1H-benzimidazole		C₃₂H₄₄N₄O₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VIa)

Protection of 2-(4-piperidinyl)benzimidazole (I) with Boc2O in MeOH yields the N-Boc derivative (XI), which is then alkylated with 2-ethoxyethyl mesylate (XII) by means of KOH in toluene to afford the 1-(2-ethoxyethyl)benzimidazole (XIII). After deprotection of intermediate (XIII) with HCl in H2O, the resulting 1-(2-ethoxyethyl)-2-(4-piperidinyl)benzimidazole (X) is alkylated with mesylate (XIV) by means of Na2CO3 in refluxing MeOH, giving the ethyl ester (VIa).
Condensation of mesylate (XV) with 2-(4-piperidinyl)benzimidazole (I) by means of Na2CO3 in refluxing MeOH yields adduct (XVI), which is further alkylated with 2-ethoxyethyl mesylate (XII) in the presence of t-BuOK in DMF at 50 °C to afford the methyl ester (VIb) .

参考文献中间体

合成目标

【1】 Lee, C.-H., Khoo, J.-H., Kwon, K.-C., Ju, H. (Yuhan Corp.). Process for preparation of 2-methyl-2’-phenylpropionic acid derivatives and novel intermediate compounds. WO 2009102155.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIa)	69008	ethyl 2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)ethyl)phenyl)-2-methylpropanoate		C₃₀H₄₁N₃O₃	详情	详情
(VIb)	69009	methyl 2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)ethyl)phenyl)-2-methylpropanoate		C₂₉H₃₉N₃O₃	详情	详情
(I)	54965	2-(4-piperidinyl)-1H-benzimidazole；2-(Piperidin-4-yl)benzimidazole;4-(Benzimidazol-2-yl)piperidine；2-Piperidin-4-yl-1H-benzimidazole	38385-95-4	C₁₂H₁₅N₃	详情	详情
(X)	69012	1-(2-ethoxyethyl)-2-(4-piperidyl)benzimidazole;1-(2-ethoxyethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole		C₁₆H₂₃N₃O	详情	详情
(XI)	69013	tert-butyl 4-(1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate		C₁₇H₂₃N₃O₂	详情	详情
(XII)	69014	2-ethoxyethyl mesylate;2-ethoxyethyl methanesulfonate		C₅H₁₂O₄S	详情	详情
(XIII)	69015	tert-butyl 4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate		C₂₁H₃₁N₃O₃	详情	详情
(XIV)	69016	ethyl 2-methyl-2-(4-(2-((methylsulfonyl)oxy)ethyl)phenyl)propanoate		C₁₅H₂₂O₅S	详情	详情
(XV)	69018	methyl 2-methyl-2-(4-(2-((methylsulfonyl)oxy)ethyl)phenyl)propanoate		C₁₄H₂₀O₅S	详情	详情
(XVI)	69017	methyl 2-(4-(2-(4-(1H-benzo[d]imidazol-2-yl)piperidin-1-yl)ethyl)phenyl)-2-methylpropanoate		C₂₅H₃₁N₃O₂	详情	详情

Extended Information