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【结 构 式】 
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【药物名称】 【化学名称】N-[4-Cyano-3-(trifluoromethyl)phenyl]-2(R)-hydroxy-2-methyl-3-[4-(isothiocyanato)phenylsulfanyl]propionamide 【CA登记号】247090-55-7, 247090-62-6 (S) 【 分 子 式 】C19H14F3N3O2S2 【 分 子 量 】437.46553 |
【开发单位】University of Tennessee, Memphis (Originator) 【药理作用】PHARMACOLOGICAL TOOLS |
合成路线1
Coupling of the chiral auxiliary (R)-proline (I) with methacryloyl chloride (II) under Schotten-Baumann conditions provided amide (III). This was converted to bromolactone (IV) by asymmetric bromolactonization in the presence of N-bromosuccinimide. Subsequent acid hydrolysis yielded the chiral (R)-bromoacid (V), that was converted to acid chloride (VI) and then coupled with 4-amino-2-trifluoromethylbenzonitrile (VII) in DMA at low temperature to afford anilide (VIII). Coupling with 4-aminothiophenol (IX) using NaH in THF produced sulfide (X). Finally, conversion of the aniline precursor (X) to the target isothiocyanate was achieved by reaction with thiophosgene in the presence of NaHCO3.
| 【1】 Mukherjee, A.; et al.; Affinity labeling of the androgen receptor with nosteroidal chemoaffinity ligands. Biochem Pharmacol 1999, 58, 8, 1259. |
| 【2】 Dalton, J.T.; Miller, D.D.; Kirkovsky, L.; Mukherjee, A.; Yin, D.; Chiral nonsteroidal affinity ligands for the androgen receptor. 1. Bicalutamide analogues bearing electrophilic groups in the B aromatic ring. J Med Chem 2000, 43, 4, 581. |
| 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) | 28284 | D-proline | 344-25-2 | C5H9NO2 | 详情 | 详情 |
| (II) | 33553 | 2-methylacryloyl chloride | 920-46-7 | C4H5ClO | 详情 | 详情 |
| (III) | 40972 | (2R)-1-methacryloyl-2-pyrrolidinecarboxylic acid | C9H13NO3 | 详情 | 详情 | |
| (IV) | 40967 | (3R,8aR)-3-(bromomethyl)-3-methyltetrahydro-1H-pyrrolo[2,1-c][1,4]oxazine-1,4(3H)-dione | C9H12BrNO3 | 详情 | 详情 | |
| (V) | 40968 | (2R)-3-bromo-2-hydroxy-2-methylpropionic acid | C4H7BrO3 | 详情 | 详情 | |
| (VI) | 40969 | (2R)-3-bromo-2-hydroxy-2-methylpropanoyl chloride | C4H6BrClO2 | 详情 | 详情 | |
| (VII) | 18743 | 4-amino-2-(trifluoromethyl)benzonitrile；5-Amino-2-cyanobenzotrifluoride | 654-70-6 | C8H5F3N2 | 详情 | 详情 |
| (VIII) | 40970 | (2R)-3-bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide | C12H10BrF3N2O2 | 详情 | 详情 | |
| (IX) | 16490 | 4-aminophenylhydrosulfide; 4-aminothiophenol; 4-aminobenzenethiol | 1193-02-8 | C6H7NS | 详情 | 详情 |
| (X) | 40971 | (2R)-3-[(4-aminophenyl)sulfanyl]-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide | C18H16F3N3O2S | 详情 | 详情 |