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【结 构 式】 
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【药物名称】CT-747 【化学名称】N-[5,5-Dimethyl-3-(4-methylphenylsulfonyl)thiazolidin-4(R)-ylcarbonyl]-4-O-[3-(dimethylamino)propyl]-L-tyrosine 【CA登记号】220397-12-6 【 分 子 式 】C27H37N3O6S2 【 分 子 量 】563.74044 |
【开发单位】Elan (Originator), Wyeth Pharmaceuticals (Originator) 【药理作用】Antiallergy/Antiasthmatic Drugs, Asthma Therapy, RESPIRATORY DRUGS, Integrin alpha4beta1 (VLA-4) Antagonists |
合成路线1
N-Boc-L-Tyrosine methyl ester (I) was alkylated with either 3-(dimethylamino)-1-propanol (II) under Mitsunobu conditions or with N,N-dimethyl-3-chloropropylamine (III) in the presence of K2CO3 to afford N-Boc-L-4-(3-dimethylaminopropoxy)phenylalanine methyl ester (IV). Subsequent acidic cleavage of the N-Boc protecting group of (IV) gave amino ester (V). N-Tosyl-L-5,5-dimethylthiaproline (VII) was obtained by treatment of L-5,5-dimethylthiaproline (VI) with p-toluenesulfonyl chloride in the presence of NaOH. Acid (VII) was then coupled to amino ester (V) using EDC and HOBt to furnish amide (VIII). Finally, basic hydrolysis of the methyl ester group of (VIII) yielded the title compound.
| 【1】 Grant, F.S.; Dressen, D.B.; Dappen, M.S.; et al.; CT747: A very potent and highly selective small molecule inhibitor of VLA4 that is metabolically stable. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 135. |
| 【2】 Ashwell, S.; Konradi, A.W.; Lombardo, L.J.; Dappen, M.S.; Baudy, R.B.; Kreft, A.; Grant, F.S.; Sarantakis, D.; Pleiss, M.A.; Semko, C.M.; Dressen, D.B.; Thorsett, E.D. (American Home Products Corp.; Athena Neurosciences, Inc.); Substd. phenylalanine type cpds. which inhibit leukocyte adhesion mediated by VLA-4. WO 9906431 . |
| 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) | 19875 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propanoate | 4326-36-7 | C15H21NO5 | 详情 | 详情 |
| (II) | 37173 | 3-(dimethylamino)-1-propanol | 3179-63-3 | C5H13NO | 详情 | 详情 |
| (III) | 24581 | 3-(Dimethylamino)propyl chloride; 3-Chloro-N,N-dimethyl-1-propanamine | 5407-04-5 | C5H12ClN | 详情 | 详情 |
| (IV) | 45680 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[4-[3-(dimethylamino)propoxy]phenyl]propanoate | C20H32N2O5 | 详情 | 详情 | |
| (V) | 45681 | methyl (2S)-2-amino-3-[4-[3-(dimethylamino)propoxy]phenyl]propanoate | C15H24N2O3 | 详情 | 详情 | |
| (VI) | 34776 | (4R)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid | 72778-00-8 | C6H11NO2S | 详情 | 详情 |
| (VII) | 45682 | (4R)-5,5-dimethyl-3-[(4-methylphenyl)sulfonyl]-1,3-thiazolidine-4-carboxylic acid | C13H17NO4S2 | 详情 | 详情 | |
| (VIII) | 45683 | methyl (2S)-3-[4-[3-(dimethylamino)propoxy]phenyl]-2-[([(4R)-5,5-dimethyl-3-[(4-methylphenyl)sulfonyl]-1,3-thiazolidin-4-yl]carbonyl)amino]propanoate | C28H39N3O6S2 | 详情 | 详情 |