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【结 构 式】

【药物名称】Bilastine;F-96221-BM

【化学名称】2-[4-[2-[4-[1-(2-Ethoxyethyl)benzimidazol-2-yl]piperidin-1-yl]ethyl]phenyl]-2-methylproionic acid

【CA登记号】202189-78-4

【 分 子 式 】C28H37N3O3

【 分 子 量 】463.62539

【开发单位】FAES (Originator)

【药理作用】Asthma Therapy, Drugs for Allergic Rhinitis, RESPIRATORY DRUGS, Treatment of Upper Respiratory Tract Disorders, Histamine H1 Receptor Antagonist;Treatment of Urticaria
合成路线1合成路线2合成路线3合成路线4合成路线5

合成路线1

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
【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

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 .

参考文献 中间体
【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

合成路线3

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
【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

合成路线4

Coupling of 2-(4-bromophenyl)ethanol (XVII) with dimethylketene ethyl trimethylsilyl acetal (XVIIIa) in the presence of Pd(dba)2, (t-Bu)3P and ZnF2 in DMF at 80 °C gives the 2-arylisobutyrate ester (XIXa). Subsequent hydroxyl group sulfonylation in (XIXa) with MsCl and Et3N in CH2Cl2 yields the mesylate ester (XIV).
Similarly, 2-(4-bromophenyl)ethanol (XVII) (optionally pretreated with HMDS and NH4Cl in MeCN) is coupled with dimethylketene methyl trimethylsilyl acetal (XVIIIb) in the presence of Pd(dba)2, (t-Bu)3P and ZnF2 in DMF at 80 °C, giving 2-arylisobutyrate ester (XIXb), which is then sulfonylated with MsCl in the presence of Et3N in CH2Cl2, affording synthon (XV) .

参考文献 中间体
【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
(XVIIIa) 44478 1-Ethoxy-2-methyl-1-trimethylsiloxypropene;1-Ethoxy-2-methyl-1-(trimethylsilyloxy)propene;1-Ethoxy-2-methyl-1-(trimethylsilyl)oxy-1-propene;1-ethoxy-2-methyl-1-propenyl trimethylsilyl ether; [(1-ethoxy-2-methyl-1-propenyl)oxy](trimethyl)silane ;dimethylketene ethyl trimethylsilyl acetal 31469-16-6 C9H20O2Si 详情 详情
(XVIIIb) 42016 1-Methoxy-2-methyl-1-(trimethylsiloxy)propene;1-Methoxy-2,2-dimethyl-1-(trimethylsiloxy)ethene;1-Methoxy-1-(trimethylsilyloxy)-2-methylpropene;[(1-methoxy-2-methyl-1-propenyl)oxy](trimethyl)silane; 1-methoxy-2-methyl-1-propenyl trimethylsilyl ether ;dimethylketene methyl trimethylsilyl acetal 31469-15-5 C8H18O2Si 详情 详情
(XIXa) 69019 ethyl 2-(4-(2-hydroxyethyl)phenyl)-2-methylpropanoate 　 C14H20O3 详情 详情
(XIXb) 69020 methyl 2-(4-(2-hydroxyethyl)phenyl)-2-methylpropanoate 　 C13H18O3 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
(XVII) 14248 2-(4-Bromophenyl)-1-ethanol; 4-Bromophenethyl alcohol；2-(4-bromophenyl)ethanol；2-(4-Bromophenyl)ethan-1-ol 4654-39-1 C8H9BrO 详情 详情

合成路线5

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.

参考文献 中间体
【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
Extended Information
Drug NewChemical Entity Original Patent(1)