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【结 构 式】 
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【药物名称】CP-195543 【化学名称】(+)-(3S,4R)-2-[3-Benzyl-4-hydroxy-3,4-dihydro-2H-benzopyran-7-yl]-4-(trifluoromethyl)benzoic acid 【CA登记号】204981-48-6, 205990-47-2 (trans-isomer), 179107-34-7 (undefined stereoch.) 【 分 子 式 】C24H19F3O4 【 分 子 量 】428.41183 |
【开发单位】Pfizer (Originator) 【药理作用】Antiallergy/Antiasthmatic Drugs, Antiarthritic Drugs, Asthma Therapy, RESPIRATORY DRUGS, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Leukotriene BLT (LTB4) Antagonists |
合成路线1
The reaction of 4(R)-benzyloxazolidin-2-one (I) with 3-phenylpropionyl chloride (II) by means of BuLi in THF gives 4(R)-benzyl-3-(3-phenylpropionyl)oxazolidin-2-one (III), which is condensed with 4-bromo-2-fluorobenzaldehyde (IV) by means of dibutylboron triflate or TiCl4 yielding the chiral intermediate (V). The reductive elimination of the oxazolidinone group affords (1R,2S)-2-benzyl-1-(4-bromo-2-fluorophenyl)propane-1,3-diol (VI), which is cyclized by means of sodium bis(trimethylsilyl)amide in hot DMSO to give the chiral dihydro-1-benzopyran (VII).The reaction of (VII) with the borane-THF complex and methyllithium in THF affords the boronic acid (VIII), which is condensed with 2-iodo-4-(trifluoromethyl)benzoic acid ethyl ester (IX) by means of KF and Pd/C in refluxing ethanol to provide the ethyl ester (X) of the target comopound. Finally, this compound is hydrolyzed with NaOH in refluxing isopropanol.
| 【1】 Piscopio, A.D.; Hawkins, J.M.; Caron, S.; Kelly, S.E.; Raggon, J.W.; Ruggeri, S.G.; Castaldi, M.J.; Dugger, R.W. (Pfizer Inc.); Processes and intermediates for preparing substd. chromanol derivs.. WO 9811085 . |
| 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) | 25351 | (4R)-4-benzyl-1,3-oxazolidin-2-one; (R)-(+)-4-benzyl-2-oxazolidinone | 102029-44-7 | C10H11NO2 | 详情 | 详情 |
| (II) | 16240 | 3-phenylpropanoyl chloride; Hydrocinnamoylchloride | 645-45-4 | C9H9ClO | 详情 | 详情 |
| (III) | 27829 | (4R)-4-benzyl-3-(3-phenylpropanoyl)-1,3-oxazolidin-2-one | C19H19NO3 | 详情 | 详情 | |
| (IV) | 27830 | 4-bromo-2-fluorobenzaldehyde | 57848-46-1 | C7H4BrFO | 详情 | 详情 |
| (V) | 27831 | (4R)-4-benzyl-3-[(2R,3R)-2-benzyl-3-(4-bromo-2-fluorophenyl)-3-hydroxypropanoyl]-1,3-oxazolidin-2-one | C26H23BrFNO4 | 详情 | 详情 | |
| (VI) | 27832 | (1R,2S)-2-benzyl-1-(4-bromo-2-fluorophenyl)-1,3-propanediol | C16H16BrFO2 | 详情 | 详情 | |
| (VII) | 27833 | (3S,4R)-3-benzyl-7-bromo-5-fluoro-3,4-dihydro-2H-chromen-4-ol | C16H14BrFO2 | 详情 | 详情 | |
| (VIII) | 27834 | (3S,4R)-3-benzyl-4-hydroxy-3,4-dihydro-2H-chromen-7-ylboronic acid | C16H17BO4 | 详情 | 详情 | |
| (IX) | 27835 | ethyl 2-iodo-4-(trifluoromethyl)benzoate | C10H8F3IO2 | 详情 | 详情 | |
| (X) | 27836 | ethyl 2-[(3S,4R)-3-benzyl-4-hydroxy-3,4-dihydro-2H-chromen-7-yl]-4-(trifluoromethyl)benzoate | C26H23F3O4 | 详情 | 详情 |