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【结 构 式】 
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【药物名称】 【化学名称】2-[4-[2-[2(R)-2-Hydroxy-2-(4-hydroxyphenyl)-1(S)-methylethylamino]ethyl]phenoxy]-2-methylpropionic acid 【CA登记号】247073-88-7 【 分 子 式 】C21H27NO5 【 分 子 量 】373.45304 |
【开发单位】Kissei (Originator) 【药理作用】RENAL-UROLOGIC DRUGS, Urinary Incontinence Therapy, beta3-Adrenoceptor Agonists |
合成路线1
2-(4-Hydroxyphenyl)ethanol (I) was protected at the aliphatic hydroxyl group by the following sequence. Reaction of (I) with methoxymethyl chloride and NaH blocked the phenolic hydroxyl as the methoxymethyl ether (II), which was subsequently treated with benzyl bromide to produce the fully protected compound (III). Further hydrolysis of the methoxymethyl ether using trifluoroacetic acid gave rise to 4-(2-benzyloxyethyl)phenol (IV). Condensation of phenol (IV) with 1,1,1-trichloro-2-methyl-2-propanol (V) under basic conditions generated the 2-(aryloxy)isobutyric acid (VI). After esterification of (VI) with SOCl2 in EtOH to give (VII), its O-benzyl protecting group was removed by catalytic hydrogenation to produce (VIII). Alcohol (VIII) was then converted into alkyl bromide (IX) by using CBr4 and PPh3. Alkylation of (-)-4'-hydroxynorephedrine (X) with bromide (IX) in hot DMF afforded the secondary amine (XI). The ethyl ester group of (XI) was finally hydrolyzed with NaOH to the title carboxylic acid.
| 【1】 Hirabayashi, A.; Tamai, T.; Muranaka, H.; Tanaka, N.; Ishikawa, T.; Mukaiyama, H.; Akahane, M.; Akahane, S.; beta(3)- Adrenoceptor agonists for the treatment of frequent urination and urinary incontinence: 2-[4-(2-[[1S,2R)-2- hydroxy-2-(4- hydroxyphenyl)-1-methylethyl]ethyl) phenoxy]-2-methylpropionic acid. Bioorg Med Chem 2001, 9, 12, 3265. |
| 【2】 Sato, M.; Tanaka, N.; Akahane, M.; Tamai, T.; Muranaka, H.; Mukaiyama, H.; Hiribayashi, A. (Kissei Pharmaceutical Co., Ltd.); 2-Methylpropionic acid derivs. and medicinal compsns. containing the same. EP 1072583; WO 9952856 . |
| 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) | 47355 | 4-(2-hydroxyethyl)phenol | 501-94-0 | C8H10O2 | 详情 | 详情 |
| (II) | 56061 | sodium 2-[4-(methoxymethoxy)phenyl]-1-ethanolate | C10H13NaO3 | 详情 | 详情 | |
| (III) | 56062 | benzyl 4-(methoxymethoxy)phenethyl ether; 1-[2-(benzyloxy)ethyl]-4-(methoxymethoxy)benzene | C17H20O3 | 详情 | 详情 | |
| (IV) | 56063 | 4-[2-(benzyloxy)ethyl]phenol | C15H16O2 | 详情 | 详情 | |
| (V) | 25975 | 1,1,1-trichloro-2-methyl-2-propanol | 57-15-8 | C4H7Cl3O | 详情 | 详情 |
| (VI) | 56064 | 2-{4-[2-(benzyloxy)ethyl]phenoxy}-2-methylpropanoic acid | C19H22O4 | 详情 | 详情 | |
| (VII) | 56065 | ethyl 2-{4-[2-(benzyloxy)ethyl]phenoxy}-2-methylpropanoate | C21H26O4 | 详情 | 详情 | |
| (VIII) | 56066 | ethyl 2-[4-(2-hydroxyethyl)phenoxy]-2-methylpropanoate | C14H20O4 | 详情 | 详情 | |
| (IX) | 56067 | ethyl 2-[4-(2-bromoethyl)phenoxy]-2-methylpropanoate | C14H19BrO3 | 详情 | 详情 | |
| (X) | 46836 | 4-[(1R,2S)-2-amino-1-hydroxypropyl]phenol | C9H13NO2 | 详情 | 详情 | |
| (XI) | 56068 | ethyl 2-[4-(2-{[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino}ethyl)phenoxy]-2-methylpropanoate | C23H31NO5 | 详情 | 详情 |
合成路线2
An alternative route to the intermediate bromide (IX) has been reported. Condensation of phenol (XII) with 1,1,1-trichloro-2-methyl-2-propanol (V) led to 2-phenoxyisobutyric acid (XIII), which was further esterified by treatment with SOCl2 in EtOH to yield (XIV). Friedel-Crafts acylation of (XIV) with bromoacetyl bromide (XV) in the presence of AlCl3 provided the phenacyl bromide (XVI). The corresponding phenethyl bromide (IX) was then obtained by reduction of ketone (XVI) with triethylsilane in trifluoroacetic acid.
| 【1】 Hirabayashi, A.; Tamai, T.; Muranaka, H.; Tanaka, N.; Ishikawa, T.; Mukaiyama, H.; Akahane, M.; Akahane, S.; beta(3)- Adrenoceptor agonists for the treatment of frequent urination and urinary incontinence: 2-[4-(2-[[1S,2R)-2- hydroxy-2-(4- hydroxyphenyl)-1-methylethyl]ethyl) phenoxy]-2-methylpropionic acid. Bioorg Med Chem 2001, 9, 12, 3265. |
| 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) | 25975 | 1,1,1-trichloro-2-methyl-2-propanol | 57-15-8 | C4H7Cl3O | 详情 | 详情 |
| (IX) | 56067 | ethyl 2-[4-(2-bromoethyl)phenoxy]-2-methylpropanoate | C14H19BrO3 | 详情 | 详情 | |
| (XII) | 23540 | Phenol | 108-95-2 | C6H6O | 详情 | 详情 |
| (XIII) | 56069 | 2-methyl-2-phenoxypropanoic acid | C10H12O3 | 详情 | 详情 | |
| (XIV) | 56070 | ethyl 2-methyl-2-phenoxypropanoate | C12H16O3 | 详情 | 详情 | |
| (XV) | 14005 | 2-Bromoacetyl bromide; Bromoacetyl bromide | 598-21-0 | C2H2Br2O | 详情 | 详情 |
| (XVI) | 56071 | ethyl 2-[4-(2-bromoacetyl)phenoxy]-2-methylpropanoate | C14H17BrO4 | 详情 | 详情 |