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【结 构 式】 
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【药物名称】 【化学名称】2-[2,6-Dichloro-4-[2-[2(R)-hydroxy-2-(4-hydroxyphenyl)-1(S)-methylethylamino]ethyl]phenylamino]acetic acid hydrate 【CA登记号】227467-90-5 (anhydrous) 【 分 子 式 】C19H24Cl2N2O5 【 分 子 量 】431.31953 |
【开发单位】Kissei (Originator) 【药理作用】RENAL-UROLOGIC DRUGS, Urinary Incontinence Therapy, beta3-Adrenoceptor Agonists |
合成路线1
The condensation of 2-(4-aminophenyl)ethanol (I) with ethyl 2-bromoacetate (II) by means of K2CO3 in DMF gives 2-[4-(2-hydroxyethyl)phenylamino]acetic acid ethyl ester (III), which is chlorinated with t-butyl hypochlorite in dichloromethane to yield the 2,6-dichlorophenyl derivative (IV). The bromination of (IV) by means of PPh3 and CBr4 in dichloromethane affords the 2-bromoethyl derivative (V), which is condensed with (1R,2S)-2-amino-1-(4-hydroxyphenyl)-1-propanol (VI) by means of DIEA in hot DMF to provide the ethyl ester precursor (VII). Finally, this compound is hydrolyzed with aq. 1N NaOH to give the target N-phenylglycine derivative.
| 【1】 Tanaka, N.; Mukaiyama, H.; Akahane, M.; Miyata, H.; Akahane, S.; Muranaka, H.; Hirabayashi, A.; Tamai, T.; Discovery of novel N-phenylglycine derivatives as potent and selective beta3-adrenoceptor agonists for the treatment of frequent urination and urinary incontinence. J Med Chem 2001, 44, 9, 1436. |
| 【2】 Sato, M.; Tanaka, N.; Akahane, M.; Tamai, T.; Muranaka, H.; Mukaiyama, H.; Hirabayashi, A. (Kissei Pharmaceutical Co., Ltd.); Phenylaminoalkylcarboxylic acid derivs. and medicinal compsns. containing the same. EP 1043308; WO 9931045 . |
| 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) | 14019 | p-Aminophenylethanol; 2-(4-Aminophenyl)-1-ethanol | 104-10-9 | C8H11NO | 详情 | 详情 |
| (II) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (III) | 55795 | ethyl 2-[4-(2-hydroxyethyl)anilino]acetate | C12H17NO3 | 详情 | 详情 | |
| (IV) | 55796 | ethyl 2-[2,6-dichloro-4-(2-hydroxyethyl)anilino]acetate | C12H15Cl2NO3 | 详情 | 详情 | |
| (V) | 55797 | ethyl 2-[4-(2-bromoethyl)-2,6-dichloroanilino]acetate | C12H14BrCl2NO2 | 详情 | 详情 | |
| (VI) | 46836 | 4-[(1R,2S)-2-amino-1-hydroxypropyl]phenol | C9H13NO2 | 详情 | 详情 | |
| (VII) | 55798 | ethyl 2-[2,6-dichloro-4-(2-{[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino}ethyl)anilino]acetate | C21H26Cl2N2O4 | 详情 | 详情 |