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【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

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 .

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) .

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