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【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%

与该中间体有关的原料药合成路线共 3 条

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
Extended Information