|
【结 构 式】 
|
【药物名称】UK-147535 【化学名称】3-[3-[2-(4-Chlorophenylsulfonamido)ethyl]-5-(4-fluorobenzyl)phenyl]propionic acid 【CA登记号】161777-76-0 【 分 子 式 】C24H23ClFNO4S 【 分 子 量 】475.97061 |
【开发单位】Pfizer (Originator) 【药理作用】Antiplatelet Therapy, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Prostanoid TP (Thromboxane A2) Antagonists |
合成路线1
The reaction of 1,3,5-tribromobenzene (I) with 4-fluorobenzaldehyde (II) by means of BuLi in ethyl ether gives the benzhydrol (III), which is condensed with ethyl acrylate (IV) by means of palladium acetate and tri o-tolylphosphine in refluxing acetonitrile yielding the phenylenebisacrylate (V). The acetylation of (V) with acetic anhydride and DMAP in dichloromethane affords the acetate (VI), which is hydrogenated with H2 over Pd/C in ethyl acetate providing the bispropanoate (VII). Selective hydrolysis of (VII) with NaOH in ethanol gives the monoacid (VIII), which is treated with oxalyl chloride in dichloromethane yielding the monoacyl chloride (IX). The reaction of (IX) with NH4OH affords the corresponding amide (X), which is treated with NaOCl and NaOH to perform degradation of the amide group and simultaneous hydrolysis of the ester group providing the amino acid (XI). Finally, this compound is sulfonated with 4-chlorophenylsulfonyl chloride (XII) and NaOH.
| 【1】 Dack, K.N.; Dickinson, R.P.; Long, C.J.; Steele, J.; Thromboxane modulating agents. 4. Design and synthesis of 3-(2-[((4-chlorophenyl)sulfonyl)amino]ethyl)benzenepropanoic acid derivatives as potent thromboxane receptor antagonists. Bioorg Med Chem Lett 1998, 8, 16, 2061. |
| 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) | 26991 | 1,3,5-tribromobenzene | 626-39-1 | C6H3Br3 | 详情 | 详情 |
| (II) | 12337 | 4-fluorobenzaldehyde | 459-57-4 | C7H5FO | 详情 | 详情 |
| (III) | 26992 | (3,5-dibromophenyl)(4-fluorophenyl)methanol | C13H9Br2FO | 详情 | 详情 | |
| (IV) | 10164 | ethyl acrylate | 140-88-5 | C5H8O2 | 详情 | 详情 |
| (V) | 26993 | ethyl (E)-3-[3-[(E)-3-ethoxy-3-oxo-1-propenyl]-5-[(4-fluorophenyl)(hydroxy)methyl]phenyl]-2-propenoate | C23H23FO5 | 详情 | 详情 | |
| (VI) | 26994 | ethyl (E)-3-[3-[(acetoxy)(4-fluorophenyl)methyl]-5-[(E)-3-ethoxy-3-oxo-1-propenyl]phenyl]-2-propenoate | C25H25FO6 | 详情 | 详情 | |
| (VII) | 26995 | ethyl 3-[3-(3-ethoxy-3-oxopropyl)-5-(4-fluorobenzyl)phenyl]propanoate | C23H27FO4 | 详情 | 详情 | |
| (VIII) | 26996 | 3-[3-(3-ethoxy-3-oxopropyl)-5-(4-fluorobenzyl)phenyl]propionic acid | C21H23FO4 | 详情 | 详情 | |
| (IX) | 26997 | ethyl 3-[3-(3-chloro-3-oxopropyl)-5-(4-fluorobenzyl)phenyl]propanoate | C21H22ClFO3 | 详情 | 详情 | |
| (X) | 26998 | ethyl 3-[3-(3-amino-3-oxopropyl)-5-(4-fluorobenzyl)phenyl]propanoate | C21H24FNO3 | 详情 | 详情 | |
| (XI) | 26999 | 3-[3-(2-aminoethyl)-5-(4-fluorobenzyl)phenyl]propionic acid | C18H20FNO2 | 详情 | 详情 | |
| (XII) | 15787 | 4-chlorobenzenesulfonyl chloride;4-chlorobenzene-1-sulfonyl chloride | 98-60-2 | C6H4Cl2O2S | 详情 | 详情 |
合成路线2
The reaction of monoacid (VIII) with diphenylphosphoryl azide and triethylamine in refluxing tert-butanol gives the tert-butoxycarbonyl aminoester (XIII), which is deprotected with trifluoroacetic acid to yield the aminoester (XIV). The sulfonation of (XIV) with 4-chlorophenylsulfonyl chloride (XII) and triethylamine in dichloromethane affords the sulfonamido ester (XV), which is finally hydrolyzed with NaOH in refluxing methanol.
| 【1】 Dickinson, R.P.; Dack, K.N.; Steele, J. (Pfizer Inc.); Benzenealkanoic acids for cardiovascular diseases. EP 0662950; JP 1996502046; US 5618941; WO 9406761 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 26996 | 3-[3-(3-ethoxy-3-oxopropyl)-5-(4-fluorobenzyl)phenyl]propionic acid | C21H23FO4 | 详情 | 详情 | |
| (XII) | 15787 | 4-chlorobenzenesulfonyl chloride;4-chlorobenzene-1-sulfonyl chloride | 98-60-2 | C6H4Cl2O2S | 详情 | 详情 |
| (XIII) | 27000 | ethyl 3-[3-[2-[(tert-butoxycarbonyl)amino]ethyl]-5-(4-fluorobenzyl)phenyl]propanoate | C25H32FNO4 | 详情 | 详情 | |
| (XIV) | 27001 | ethyl 3-[3-(2-aminoethyl)-5-(4-fluorobenzyl)phenyl]propanoate | C20H24FNO2 | 详情 | 详情 | |
| (XV) | 27002 | ethyl 3-[3-(2-[[(4-chlorophenyl)sulfonyl]amino]ethyl)-5-(4-fluorobenzyl)phenyl]propanoate | C26H27ClFNO4S | 详情 | 详情 |
合成路线3
The reaction of 3-bromo-5-iodobenzoic acid (I) with SOCl2 gives the corresponding acyl chloride (II), which by a Friedel-Crafts condensation with fluorobenzene (II) by means of AlCl3 in refluxing dichloromethane yields the benzophenone (IV). The condensation of (IV) with ethyl acrylate (V) by means of palladium acetate and triethylamine in refluxing acetonitrile affords the cinnamic acid derivative (VI), which is condensed with N-vinylphthalimide (VII) by means of palladium acetate and diisopropylamine in refluxing xylene to provide the unsaturated adduct (VIII). The reduction of the carbonyl group of (VIII) with triethylsilane and TFA gives the diphenylmethane derivative (IX), which is hydrogenated with H2 over Pd/C in ethyl acetate to yield the saturated diphenylmethane derivative (X). Elimination of the phthalimido group of (X) with hydrazine affords (XI) with a primary amino group. that is sulfonated with 4-chlorophenylsulfonyl chloride (XII) and triethylamine in THF to provide the sulfonamide (XIII). Finally, the ester group of (XIII) is hydrolyzed with aqueous NaOH.
| 【1】 Waite, D.C.; Mason, C.P.; A scalable synthesis of the thromboxane receptor antagonist 3-(3-[2-(4-chlorobenzenesulfonamido)ethyl]-5-(4-fluorobenzyl)phenyl]propionic acid via a regioselective heck cross-coupling strategy. Org Process Res Dev 1998, 2, 2, 116. |
| 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) | 32745 | 3-bromo-5-iodobenzoic acid | 188815-32-9 | C7H4BrIO2 | 详情 | 详情 |
| (II) | 32746 | 3-bromo-5-iodobenzoyl chloride | C7H3BrClIO | 详情 | 详情 | |
| (III) | 17466 | Fluorobenzene | 462-06-6 | C6H5F | 详情 | 详情 |
| (IV) | 32747 | (3-bromo-5-iodophenyl)(4-fluorophenyl)methanone | C13H7BrFIO | 详情 | 详情 | |
| (V) | 10164 | ethyl acrylate | 140-88-5 | C5H8O2 | 详情 | 详情 |
| (VI) | 32748 | ethyl (E)-3-[3-bromo-5-(4-fluorobenzoyl)phenyl]-2-propenoate | C18H14BrFO3 | 详情 | 详情 | |
| (VII) | 32749 | 2-vinyl-1H-isoindole-1,3(2H)-dione | 3485-84-5 | C10H7NO2 | 详情 | 详情 |
| (VIII) | 32750 | ethyl (E)-3-[3-[(E)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethenyl]-5-(4-fluorobenzoyl)phenyl]-2-propenoate | C28H20FNO5 | 详情 | 详情 | |
| (IX) | 32751 | ethyl (E)-3-[3-[(E)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethenyl]-5-(4-fluorobenzyl)phenyl]-2-propenoate | C28H22FNO4 | 详情 | 详情 | |
| (X) | 32752 | ethyl 3-[3-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-(4-fluorobenzyl)phenyl]propanoate | C28H26FNO4 | 详情 | 详情 | |
| (XI) | 27001 | ethyl 3-[3-(2-aminoethyl)-5-(4-fluorobenzyl)phenyl]propanoate | C20H24FNO2 | 详情 | 详情 | |
| (XII) | 15787 | 4-chlorobenzenesulfonyl chloride;4-chlorobenzene-1-sulfonyl chloride | 98-60-2 | C6H4Cl2O2S | 详情 | 详情 |
| (XIII) | 27002 | ethyl 3-[3-(2-[[(4-chlorophenyl)sulfonyl]amino]ethyl)-5-(4-fluorobenzyl)phenyl]propanoate | C26H27ClFNO4S | 详情 | 详情 |