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【结 构 式】 
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【分子编号】42794 【品名】Benzyl(triphenyl)phosphonium chloride 【CA登记号】1449-46-3 |
【 分 子 式 】C25H22ClP 【 分 子 量 】388.876142 【元素组成】C 77.22% H 5.7% Cl 9.12% P 7.96% |
合成路线1
该中间体在本合成路线中的序号：(II)The synthesis of GYKI-13504 is as follows: Trifluoroacetophenone (I) is reacted with triphenylbenzyl phosphonium chloride (II) in the presence of sodium methylate and this reaction yields stilbene (III). Stilbene (III) is then hydrogenized in the presence of charcoal palladium catalyzer and the yielded propane derivative (IV) is brominated with 1,2-dibromoethane. The brominated compound (V) is reacted with anizole (A) according to the Friedel Crafts' reaction. The yield (VI) is treated with pyridine hydrochloride and the phenol derivative (VII) is reacted with 2-chloroethanol tosylate (VIII) in the presence of potassium hydroxide. The chloroethoxy (IX) is treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and the (E)-isomer (X) is obtained with fractionated crystallization. This latter product is reacted with 2-aminoethanol (B) to obtain the end product GYKI-13504.
| 【1】 Abraham, G.; Horváth, T.; Toldy, L.; Borvendeg, J.; Csányl, E.; Kiss, E.; Szente, I.; Tory, K. (Egis Pharmaceuticals Ltd.); 1,1,2-Triphenylpropane and -propene derivatives. AT 368989; BE 0884716; DD 152536; ES 494286; GB 2058061; GR 69821; HU 18253 . |
| 【2】 Borvendeg, J.; GYKI-13504. Drugs Fut 1985, 10, 5, 395. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 10259 | Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol | 141-43-5 | C2H7NO | 详情 | 详情 |
| (A) | 23767 | Methoxybenzene; Methyl phenyl ether; Anisole | 100-66-3 | C7H8O | 详情 | 详情 |
| (I) | 29349 | 2,2,2-trifluoro-1-phenyl-1-ethanone; 4-Chloro-2-fluorotrifluoroacetophenone | 434-45-7 | C8H5F3O | 详情 | 详情 |
| (II) | 42794 | Benzyl(triphenyl)phosphonium chloride | 1449-46-3 | C25H22ClP | 详情 | 详情 |
| (III) | 29351 | 1-[(Z)-3,3,3-trifluoro-2-phenyl-1-propenyl]benzene | C15H11F3 | 详情 | 详情 | |
| (IV) | 29352 | 1-(3,3,3-trifluoro-2-phenylpropyl)benzene | C15H13F3 | 详情 | 详情 | |
| (V) | 29353 | 1-(1-bromo-3,3,3-trifluoro-2-phenylpropyl)benzene | C15H12BrF3 | 详情 | 详情 | |
| (VI) | 29354 | 1-methoxy-4-(3,3,3-trifluoro-1,2-diphenylpropyl)benzene | C22H19F3O | 详情 | 详情 | |
| (VII) | 29355 | 4-(3,3,3-trifluoro-1,2-diphenylpropyl)phenol | C21H17F3O | 详情 | 详情 | |
| (VIII) | 14632 | 2-chloroethyl 4-methylbenzenesulfonate; 2-Chloroethyl-p-toluenesulfonate | 80-41-1 | C9H11ClO3S | 详情 | 详情 |
| (IX) | 29356 | 1-(2-chloroethoxy)-4-(3,3,3-trifluoro-1,2-diphenylpropyl)benzene | C23H20ClF3O | 详情 | 详情 | |
| (X) | 29357 | 1-(2-chloroethoxy)-4-[(E)-3,3,3-trifluoro-1,2-diphenyl-1-propenyl]benzene | C23H18ClF3O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIX)Synthesis of 261501: The optical resolution of trans-3-penten-2-ol (IX) with porcine pancreatic lipase (PPL) and trifluoroethyl laurate in ethyl ether gives the (S)-trans-isomer (X), which is condensed with propargyl alcohol (XI) by means of tetrabutylammonium hyrogensulfate and NaOH in water, yielding the corresponding ether (XII). Rearrangement of (XII) by means of BuLi in THF affords (3R,4R,5E)-4-methylhept-5-en-1-yn-3-ol (XIII), which is silylated with Tbdms-Cl and imidazole to afford the corresponding silyl ether (XIV). The reaction of (XIV) with BH3 in THF provides the aldehyde (XV), which is condensed with phosphonate (XVI) by means of tetramethylguanidine (TMG) in THF to give the nonadienoic ester (XVII). Ozonolysis of (XVII), followed by reaction with Zn/HOAc yields the aldehyde (XVIII), which is condensed with benzyltriphenylphosphonium chloride (XIX) by means of BuLi in THF to afford the 8-phenyloctadienoic ester (XX). The hydrolysis of (XX) with LiOH in acetone/water furnishes the corresponding free acid (XXI), which is condensed with 3-chloro-4-methoxy-L-phenylalanine trichloroethyl ester (XXII) by means of pentafluorodiphenylphosphinate (FDPP) and DIEA in DMF to give the corresponding amide (XXIII). The desilylation of (XXIII) with aqueous HF in acetonitrile affords the hydroxyamide (XXIV), which is esterified with the intermediate 2(S)-[3-(tert-butoxycarbonylamino)-2,2-dimethylpropionyloxy]-4-methylpentanoic acid (VIII) by means of DCC and DMAP in dichloromethane gives the corresponding ester (XXV).
| 【1】 WO 9640184 . |
| 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) | 18904 | (2S)-2-([3-[(tert-butoxycarbonyl)amino]-2,2-dimethylpropanoyl]oxy)-4-methylpentanoic acid | C16H29NO6 | 详情 | 详情 | |
| (IX) | 42786 | (E)-3-penten-2-ol | C5H10O | 详情 | 详情 | |
| (X) | 42787 | (2S,3E)-3-penten-2-ol | C5H10O | 详情 | 详情 | |
| (XI) | 16664 | Propargyl Alcohol; 2-propyn-1-ol | 107-19-7 | C3H4O | 详情 | 详情 |
| (XII) | 42788 | (1S,2E)-1-methyl-2-butenyl 2-propynyl ether; (E,4S)-4-(2-propynyloxy)-2-pentene | C8H12O | 详情 | 详情 | |
| (XIII) | 42789 | (3R,4R,5E)-4-methyl-5-hepten-1-yn-3-ol | C8H12O | 详情 | 详情 | |
| (XIV) | 42790 | tert-butyl(dimethyl)silyl (1R,2R,3E)-1-ethynyl-2-methyl-3-pentenyl ether; tert-butyl[[(1R,2R,3E)-1-ethynyl-2-methyl-3-pentenyl]oxy]dimethylsilane | C14H26OSi | 详情 | 详情 | |
| (XV) | 42791 | (3S,4R,5E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-heptenal | C14H28O2Si | 详情 | 详情 | |
| (XVI) | 27698 | methyl 2-(diethoxyphosphoryl)acetate | 1067-74-9 | C7H15O5P | 详情 | 详情 |
| (XVII) | 42792 | methyl (2E,5S,6R,7E)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-2,7-nonadienoate | C17H32O3Si | 详情 | 详情 | |
| (XVIII) | 42793 | methyl (E,5S,6S)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-7-oxo-2-heptenoate | C15H28O4Si | 详情 | 详情 | |
| (XIX) | 42794 | Benzyl(triphenyl)phosphonium chloride | 1449-46-3 | C25H22ClP | 详情 | 详情 |
| (XX) | 34373 | methyl (2E,5S,6R,7E)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-8-phenyl-2,7-octadienoate | C22H34O3Si | 详情 | 详情 | |
| (XXI) | 34374 | (2E,5S,6R,7E)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-8-phenyl-2,7-octadienoic acid | C21H32O3Si | 详情 | 详情 | |
| (XXII) | 42795 | 2,2,2-trichloroethyl (2R)-2-amino-3-(3-chloro-4-methoxyphenyl)propanoate | C12H13Cl4NO3 | 详情 | 详情 | |
| (XXIII) | 42796 | 2,2,2-trichloroethyl (2R)-2-[((2E,5S,6R,7E)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-8-phenyl-2,7-octadienoyl)amino]-3-(3-chloro-4-methoxyphenyl)propanoate | C33H43Cl4NO5Si | 详情 | 详情 | |
| (XXIV) | 18905 | 2,2,2-trichloroethyl (2R)-3-(3-chloro-4-methoxyphenyl)-2-[[(2E,5S,6R,7E)-5-hydroxy-6-methyl-8-phenyl-2,7-octadienoyl]amino]propanoate | C27H29Cl4NO5 | 详情 | 详情 | |
| (XXV) | 18906 | 2,2,2-trichloroethyl (10S,13S,15E,19R)-19-(3-chloro-4-methoxybenzyl)-10-isobutyl-2,2,7,7-tetramethyl-13-[(1R,2E)-1-methyl-3-phenyl-2-propenyl]-4,8,11,17-tetraoxo-3,9,12-trioxa-5,18-diaza-15-icosen-20-oate | C43H56Cl4N2O10 | 详情 | 详情 |