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【结 构 式】 
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【药物名称】Gadofosveset sodium, MS-32520, MS-325, AngioMARK 【化学名称】Trisodium [2(R)-[(4,4-diphenylcyclohexyloxy)(hydroxy)phosphoryloxymethyl]diethylenetriaminopentaacetato(6-)]gadolinate(3-) 【CA登记号】193901-90-5, 201688-00-8 (free acid, undefined isomer), 193901-91-6 (ligand) 【 分 子 式 】C33H38GdN3Na3O14P 【 分 子 量 】957.87571 |
【开发单位】Epix Medical (Originator), Mallinckrodt (Licensee), Schering AG (Licensee) 【药理作用】Diagnostic Agents, Magnetic Resonance Imaging Agents |
合成路线1
The amidation of L-serine methyl ester (I) with ethylenediamine (II) gives the amide (III), which is reduced with borane/THF to 2(R)-(hydroxymethyl)diethylenetriamine (IV). The reaction of (IV) with bromoacetic acid tert-butyl ester (V) by means of DIEA in DMF affords the penta tert-butyl acetate (VI), which is condensed with the chlorophosphoramidite (VII) by means of DIEA in dichloromethane giving the phosphoramidite intermediate (VIII). The condensation of (VIII) with 4,4-diphenylcyclohexanol (IX) (see scheme 23537901b) by means of tetrazole in acetonitile, with simultaneous oxidation with tert-butyl hydroperoxide yields the phosphate (X), which is selectively hydrolyzed at the 2-cyanoethyl ester group with ammonia in methanol affording the ammonium phosphate (XI). Finally, the hydrolysis of (XI) with HCl in ether/water eliminates the tert-butyl groups affording the desired chelating ligand (XII)
| 【1】 Scott, D.M.; Sajiki, H.; McMurray, T.J.; Lauffer, R.B. (Epix Medical, Inc.); Diagnostic imaging contrast agents with extended blood retention. WO 9623526 . |
| 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) | 20915 | methyl (2S)-2-amino-3-hydroxypropanoate | 5680-80-8 | C4H9NO3 | 详情 | 详情 |
| (II) | 14754 | ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine；1,2-Ethanediamine | 107-15-3 | C2H8N2 | 详情 | 详情 |
| (III) | 30315 | (2S)-2-amino-N-(2-aminoethyl)-3-hydroxypropanamide | C5H13N3O2 | 详情 | 详情 | |
| (IV) | 30316 | (2R)-2-amino-3-[(2-aminoethyl)amino]-1-propanol | C5H15N3O | 详情 | 详情 | |
| (V) | 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 |
| (VI) | 30317 | 3,6,9-Tris(tert-butoxycarbonylmethyl)-4(R)-(hydroxymethyl)-3,6,9-triazaundecanedioic acid di-tert-butyl ester | C35H65N3O11 | 详情 | 详情 | |
| (VII) | 22791 | 2-Cyanoethyl N,N-diisopropylphosphoramidochloridite | 89992-70-1 | C9H18ClN2OP | 详情 | 详情 |
| (VIII) | 30318 | 3,6,9-Tris(tert-butoxycarbonylmethyl)-4(R)-[2-cyanoethoxy(diisopropylamino)phosphinyloxymethyl]-3,6,9-triazaundecanedioic acid di-tert-butyl ester | C44H82N5O12P | 详情 | 详情 | |
| (IX) | 30319 | 4,4-diphenylcyclohexanol | C18H20O | 详情 | 详情 | |
| (X) | 30320 | 3,6,9-Tris(tert-butoxycarbonylmethyl)-4(R)-[2-cyanoethoxy(4,4-diphenylcyclohexyloxy)phosphoryloxymethyl]-3,6,9-triazaundecanedioic acid di-tert-butyl ester | C56H87N4O14P | 详情 | 详情 | |
| (XI) | 30321 | 3,6,9-Tris(tert-butoxycarbonylmethyl)-4(R)-[4,4-diphenylcyclohexyloxy(hydroxy)phosphoryloxymethyl]-3,6,9-triazaundecanedioic acid di-tert-butyl ester ammonium salt | C53H87N4O14P | 详情 | 详情 | |
| (XII) | 30322 | 3,6,9-Tris(carboxymethyl)-4(R)-[4,4-diphenylcyclohexyloxy(hydroxy)phosphoryloxymethyl]-3,6,9-triazaundecanedioic acid | C33H44N3O14P | 详情 | 详情 |
合成路线2
The reduction of benzoin (XIII) with NaBH4 in ethanol/water gives the diol (XIV), which by a pinacol rearrangement by means of H2SO4 in hot acetic acid yields the diphenylacetaldehyde (XXV). The cyclization of (XV) with methyl vinyl ketone (XVI) by means of KOH in ethanol affords the cyclohexenone (XVII), which is reduced first with H2 over Pd/C in THF and then with NaBH4 in ethanol/water giving the 4,4-diphenylcyclohexanol (IX). The reaction of (IX) with PCl3 in THF yields the dichlorophosphite (XVIII), which is treated with imidazole (XIX) in THF affording the bis imidophosphite (XX). The condensation of (XX) with the previously obtained penta tert-butyl acetate compound (VI) in THF/heptane gives the imidophosphite (XXI), which is oxidized with sodium periodate yielding the phosphoric acid diester (XXII). Finally, the hydrolysis of (XXII) with HCl in ether/water eliminates the tert-butyl groups affording the desired chelating ligand (XII).
| 【1】 Amedio, J.C. Jr.; et al.; A practical preparation of 4,4-diphenylcyclohexanol: A key intermediate in the synthesis of MS-325. Synth Commun 1998, 28, 20, 3895. |
| 【2】 Dunham, S.O.; Lauffer, R.B. (Epix Medical, Inc.); Contrast-enhanced diagnostic imaging method for monitoring interventional therapies. WO 9917809 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 30317 | 3,6,9-Tris(tert-butoxycarbonylmethyl)-4(R)-(hydroxymethyl)-3,6,9-triazaundecanedioic acid di-tert-butyl ester | C35H65N3O11 | 详情 | 详情 | |
| (IX) | 30319 | 4,4-diphenylcyclohexanol | C18H20O | 详情 | 详情 | |
| (XII) | 30322 | 3,6,9-Tris(carboxymethyl)-4(R)-[4,4-diphenylcyclohexyloxy(hydroxy)phosphoryloxymethyl]-3,6,9-triazaundecanedioic acid | C33H44N3O14P | 详情 | 详情 | |
| (XIII) | 24135 | 2-hydroxy-1,2-diphenyl-1-ethanone; benzoin | 579-44-2 | C14H12O2 | 详情 | 详情 |
| (XIV) | 30331 | Hydrobenzoin; 1,2-diphenyl-1,2-ethanediol | 655-48-1 | C14H14O2 | 详情 | 详情 |
| (XV) | 30323 | 2,2-diphenylacetaldehyde | 947-91-1 | C14H12O | 详情 | 详情 |
| (XVI) | 30324 | 3-buten-2-one; methyl vinyl ketone | 78-94-4 | C4H6O | 详情 | 详情 |
| (XVII) | 30325 | 4,4-diphenyl-2-cyclohexen-1-one | C18H16O | 详情 | 详情 | |
| (XVIII) | 30326 | Dichlorophosphorous acid 4,4-diphenylcyclohexyl ester | C18H19Cl2OP | 详情 | 详情 | |
| (XIX) | 10255 | Imidazole; 1H-Imidazole | 288-32-4 | C3H4N2 | 详情 | 详情 |
| (XX) | 30327 | 4,4-diphenylcyclohexyl di(1H-imidazol-1-yl)phosphinite | C24H25N4OP | 详情 | 详情 | |
| (XXI) | 30328 | 3,6,9-Tris(tert-butoxycarbonylmethyl)-4(R)-[4,4-diphenylcyclohexyloxy(1-imidazolyl)phosphoryloxymethyl]-3,6,9-triazaundecanedioic acid di-tert-butyl ester | C56H86N5O12P | 详情 | 详情 | |
| (XXII) | 30329 | 3,6,9-Tris(tert-butoxycarbonylmethyl)-4(R)-[4,4-diphenylcyclohexyloxy(hydroxy)phosphoryloxymethyl]-3,6,9-triazaundecanedioic acid di-tert-butyl ester | C53H84N3O14P | 详情 | 详情 |
合成路线3
Finally, the target gadolinium complex has been obtained by reaction of the ligand (XIII) with Gd2O3 and N-methylglucamine in hot water.
| 【1】 Scott, D.M.; Sajiki, H.; McMurray, T.J.; Lauffer, R.B. (Epix Medical, Inc.); Diagnostic imaging contrast agents with extended blood retention. WO 9623526 . |