【结 构 式】 |
【分子编号】54968 【品名】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 【CA登记号】 |
【 分 子 式 】C32H44N4O2 【 分 子 量 】516.72712 【元素组成】C 74.38% H 8.58% N 10.84% O 6.19% |
合成路线1
该中间体在本合成路线中的序号:(V)Alkylation of piperidinylbenzimidazole (I) with tosylate (II) provided the N-substituted piperidine (III). The imidazole N of (III) was subsequently alkylated with 2-chloroethyl ethyl ether (IV) in the presence of NaH, yielding the N-ethoxyethyl derivative (V). Finally, the two-step, acid and basic, hydrolysis of the oxazoline ring of (V) furnished the title carboxylic acid.
【1】 Orjales, A.; Rubio, V.; Bordell, M. (FAES); Benzimidazole derivs. with antihistaminic activity. EP 0818454; ES 2124167; JP 1998059961; US 5877187 . |
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) | 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:(V)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3
该中间体在本合成路线中的序号:(V)Oxazoline intermediate (V) can also be prepared by condensation of ethyl 2-[4-(2-hydroxyethyl)phenyl]-2-methylpropionate (VII) with 2-amino-2-methyl-1-propanol (VIII) by means of t-BuOK in CH2Cl2, followed by cyclization with SOCl2 in acetonitrile to give the oxazoline (IX), which is then condensed with 1-(2-ethoxyethyl)-2-(4-piperidyl)benzimidazole (X) in the presence of Na2CO3 in refluxing MeOH .
【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 |
---|---|---|---|---|---|---|
(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 | |
(VII) | 69010 | ethyl 2-[4-(2-hydroxyethyl)phenyl]-2-methylpropionate | C14H20O3 | 详情 | 详情 | |
(VIII) | 21513 | 2-amino-2-methyl-1-propanol;Karl Fischer;2-Amino-2-methyl-propan-1-ol;2-amino-2-methyl-1-propanol | 124-68-5 | C4H11NO | 详情 | 详情 |
(IX) | 69011 | 2-(2-(4-(2-chloroethyl)phenyl)propan-2-yl)-4,4-dimethyl-4,5-dihydrooxazole | C16H22ClNO | 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 |