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【结 构 式】 
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【分子编号】14855 【品名】1,4,7,10-tetraazacyclododecane; Cyclen 【CA登记号】294-90-6 |
【 分 子 式 】C8H20N4 【 分 子 量 】172.27376 【元素组成】C 55.78% H 11.7% N 32.52% |
合成路线1
该中间体在本合成路线中的序号：(I)The synthesis of gadoteridol is as follows: Compound (I) was reacted with DMF dimethylacetal to form the tricyclic intermediate (II). Following partial hydrolysis of (II), (III) was obtained and isolated in high quality and yield. (III) was reacted with tert-butyl bromoacetate in a basic media to obtain (IV), which was treated with aqueous sulfuric acid to effect removal of the tert-butyl and formyl protecting groups. (V) could be either crystallized or lyophilized. (V) was reacted with propylene oxide at pH 12 and excess propylene oxide was removed under vacuum upon completion of the reaction. (VI) was isolated by anion exchange chromatography with sulfate, and sulfate was then removed using a poly(4-vinylpyridine) resin. HP-DO3A was reacted with gadolinium oxide in water. Following concentration, excess gadolinium oxide was removed by filtration, and Gd(HP-DO3A)H2O was isolated by removing solvent. The product was then crystallized from methanol/acetone.
| 【1】 Emswiler, J.E.; Gaughan, G.T.; Delaney, E.J.; Prasad, J.S.; Tweedle, M.F.; Dischino, D.D.; Srivastava, S.K.; Synthesis of nonionic gadolinium chelates useful as contrast agents for magnetic resonance imaging: 1,4,7 Tris(carboxymethyl)-10-substituted-1,4,7,10-tetraazacyclodecanes and their corresponding gadolinium chelates. Inorg Chem 1991, 30, 6, 1265-9. |
| 【2】 Runge, V.M.; Tweedle, M.F.; Gadoteridol. Drugs Fut 1992, 17, 3, 187. |
| 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) | 14855 | 1,4,7,10-tetraazacyclododecane; Cyclen | 294-90-6 | C8H20N4 | 详情 | 详情 |
| (II) | 14856 | octahydro-5H-2a,4a,7,9a-tetraazacycloocta[cd]pentalene | C9H18N4 | 详情 | 详情 | |
| (III) | 14857 | 1,4,7,10-tetraazacyclododecane-1-carbaldehyde | C9H20N4O | 详情 | 详情 | |
| (IV) | 14858 | 2-[4,10-bis(2-hydroxy-2-oxoethyl)-7-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecan-1-yl]acetic acid | C17H32N4O7 | 详情 | 详情 | |
| (V) | 14859 | 2-[4,10-bis(2-hydroxy-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl]acetic acid | C14H26N4O6 | 详情 | 详情 | |
| (VI) | 14860 | tert-butyl 2-[4,10-bis[2-(tert-butoxy)-2-oxoethyl]-7-formyl-1,4,7,10-tetraazacyclododecan-1-yl]acetate | C27H50N4O7 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)1,4,7,10-Tetraazacyclododecane (I) was condensed with 2,3-epoxy-1,4-butanediol acetonide (II) in boiling n-butanol to afford adduct (III). Subsequent acetonide (III) hydrolysis in the presence of HCl led to triol (IV). Alkylation of (IV) with chloroacetic acid furnished the tetraaminotricarboxylic acid (V). Alternatively, compound (V) was prepared by alkylation of (III) with chloroacetic acid, followed by acidic ketal hydrolysis. The title gadolinium complex was finally prepared by treatment of the cyclic tetraamine (V) with gadolinium oxide
| 【1】 Gries, H.; Nickisch, K.; Platzek, J.; Börner, H.; Tilstam, U. (Schering AG); Process for producing N-beta-hydroxyalkyl-tri-N-carboxyalkyl-1,4,7,10-tetraazacyclododecane and N-beta-hydroxyalkyl-tri-N-carboxyalkyl-1,4,8,11-tetraazacyclotetradecane derivs. and their metal complexes. DE 4218744; WO 9324469 . |
| 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) | 14855 | 1,4,7,10-tetraazacyclododecane; Cyclen | 294-90-6 | C8H20N4 | 详情 | 详情 |
| (II) | 60022 | 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane | C7H12O3 | 详情 | 详情 | |
| (III) | 60023 | (5S,6R)-2,2-dimethyl-6-(1,4,7,10-tetraazacyclododecan-1-yl)-1,3-dioxepan-5-ol | C15H32N4O3 | 详情 | 详情 | |
| (IV) | 60024 | (2S,3R)-3-(1,4,7,10-tetraazacyclododecan-1-yl)-1,2,4-butanetriol | C12H28N4O3 | 详情 | 详情 | |
| (V) | 60025 | 2-[4-[(1R,2S)-2,3-dihydroxy-1-(hydroxymethyl)propyl]-7,10-bis(2-hydroxy-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl]acetic acid | C18H34N4O9 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)In a similar procedure, condensation of (I) with epoxide (II) in isopropanol in the presence of LiCl furnished the corresponding adduct as a complex with LiCl (VI) (2). Condensation of (VI) with chloroacetic acid, followed by acidic hydrolysis provided the lithium complex (VII). Finally, treatment of (VII) with Gd2O3 and HCl afforded the title gadolinium compound
| 【1】 Blaszkiewicz, P.; Platzek, J.; Hoffmann, H.; Petrov, O. (Schering AG); Lithium complexes of N-(1-hydroxymethyl-2,3-dihydroxypropyl)-1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane, production and use thereof. DE 10064467; WO 0248119 . |
| 【2】 Blaszkiewicz, P.; Petrov, O. (Schering AG); Production of mono and 1,7-bis-N-hydroxyalkyl-cyclene and lithium salt complexes. DE 19724186; US 5994536; WO 9855467 . |
| 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) | 14855 | 1,4,7,10-tetraazacyclododecane; Cyclen | 294-90-6 | C8H20N4 | 详情 | 详情 |
| (II) | 60022 | 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane | C7H12O3 | 详情 | 详情 | |
| (VI) | 60026 | lithium chloride (5S,6R)-2,2-dimethyl-6-(1,4,7,10-tetraazacyclododecan-1-yl)-1,3-dioxepan-5-ol | C15H32ClLiN4O3 | 详情 | 详情 | |
| (VII) | 60027 | lithium chloride 2-[4-[(1R,2S)-2,3-dihydroxy-1-(hydroxymethyl)propyl]-7,10-bis(2-hydroxy-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl]acetic acid | C18H34ClLiN4O9 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)The macrocyclic tetraamine (I) was protected as the triaminomethane derivative (VIII) by treatment with either triethyl orthoformate (4) or with dimethylformamide dimethylacetal (5). Alkylation of (VIII) with bromoacetic acid gave rise to the N-formyl N',N'',N'''-tris(carboxymethyl) compound (IX). After basic hydrolysis of the formamide function of (IX), the resultant N-deprotected amine (X) was condensed with epoxide (II) to yield (XI). Further complexation with GdCl3 and ketal group hydrolysis led to the target compound
| 【1】 Murru, M.; Ripa, G.; Scala, A.; Viscardi, C.F.; Ausonio, M.; Scotti, C.; Cossuta, P. (Bracco SpA; Dibra SpA); A process for the preparation of macrocyclic chelants and the chelates thereof with paramagnetic metal ions. WO 9856775 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 23660 | 2-Bromoacetic acid | 79-08-3 | C2H3BrO2 | 详情 | 详情 |
| (I) | 14855 | 1,4,7,10-tetraazacyclododecane; Cyclen | 294-90-6 | C8H20N4 | 详情 | 详情 |
| (II) | 60022 | 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane | C7H12O3 | 详情 | 详情 | |
| (VIII) | 60028 | octahydro-5H-2a,4a,7,9a-tetraazacycloocta[cd]pentalene | C9H18N4 | 详情 | 详情 | |
| (IX) | 60029 | 2-[4-formyl-7,10-bis(2-hydroxy-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl]acetic acid | C15H26N4O7 | 详情 | 详情 | |
| (X) | 60030 | trisodium 2-[4,10-bis(2-oxido-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl]acetate | C14H23N4Na3O6 | 详情 | 详情 | |
| (XI) | 60031 | trisodium 2-[4-[(5R,6S)-6-hydroxy-2,2-dimethyl-1,3-dioxepan-5-yl]-7,10-bis(2-oxido-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl]acetate | C21H35N4Na3O9 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VIII)Alternatively, the protected tetraamine (VIII) was condensed with epoxide (II) to afford (XII), which was further hydrolyzed to the mono-substituted tetraazacyclododecane (III) under basic conditions. Alkylation of (III) with chloracetic acid, followed by acidic ketal hydrolysis furnished the precursor (V), which was finally complexed with gadolinium oxide as above
| 【1】 Gries, H.; Platzek, J. (Schering AG); Process for the production of metal complexes of N-beta-hydroxyalkyl-tri-N-carboxyalkyl-1,4,7,10-tetraazacyclododecane and derivs. thereof. DE 4237943; EP 0596586 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 60022 | 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane | C7H12O3 | 详情 | 详情 | |
| (III) | 60023 | (5S,6R)-2,2-dimethyl-6-(1,4,7,10-tetraazacyclododecan-1-yl)-1,3-dioxepan-5-ol | C15H32N4O3 | 详情 | 详情 | |
| (V) | 60025 | 2-[4-[(1R,2S)-2,3-dihydroxy-1-(hydroxymethyl)propyl]-7,10-bis(2-hydroxy-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl]acetic acid | C18H34N4O9 | 详情 | 详情 | |
| (VIII) | 14855 | 1,4,7,10-tetraazacyclododecane; Cyclen | 294-90-6 | C8H20N4 | 详情 | 详情 |
| (XII) | 60028 | octahydro-5H-2a,4a,7,9a-tetraazacycloocta[cd]pentalene | C9H18N4 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)The reaction of 1,4,7,10-tetraazacyclododecane (I) with formaldehyde and phosphoric acid in refluxing aqueous HCl gives the tetraphosphonic acid (II), which is then treated with aqueous 166HoCl3 to obtain the target chelate.
| 【1】 Simon, J.; Garlich, J.R.; Wilson, D.A.; McMillan, K. (Marion Merrell Dow, Inc.); Bone marrow suppressing agents. EP 0374501; JP 1990237936; US 4882142 . |
合成路线7
该中间体在本合成路线中的序号：(I)Alkylation of tetraazacyclodecane (I) with ethyl 2-bromobutyrate (II) afforded the tetrasubstituted macrocycle (III) as a mixture of diastereoisomers. Subsequent hydrolysis of the ethyl ester groups of (III) using ethanolic NaOH gave the octacarboxylic acid (IV). Complexation of (IV) with either Gd2O3 or GdCl3 and NaOH generated the corresponding gadolinium chelate. The mixture of diastereoisomeric chelates was then isomerized under acidic conditions to furnish the racemic pair of R,R,R,R and S,S,S,S isomers (V).
| 【1】 Port, M.; et al.; P792: A rapid clearance blood pool agent for magnetic resonance imaging: Preliminary results. MAGMA Magn Reson Mater Phys Biol Med 2001, 12, 2-3, 121. |
| 【2】 Rousseaux, O.; Simonot, C. (Guerbet SA); Gadolinium complex tetramides and use in medical imaging. EP 1178975; FR 2793795; WO 0071526 . |
| 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) | 14855 | 1,4,7,10-tetraazacyclododecane; Cyclen | 294-90-6 | C8H20N4 | 详情 | 详情 |
| (II) | 56041 | diethyl 2-bromopentanedioate | C9H15BrO4 | 详情 | 详情 | |
| (III) | 56042 | diethyl 2-{4,7,10-tris[4-ethoxy-1-(ethoxycarbonyl)-4-oxobutyl]-1,4,7,10-tetraazacyclododecan-1-yl}pentanedioate | C44H76N4O16 | 详情 | 详情 | |
| (IV) | 56043 | 2-[4,10-bis(1-carboxy-4-hydroxy-4-oxobutyl)-7-(1,3-dicarboxypropyl)-1,4,7,10-tetraazacyclododecan-1-yl]pentanedioic acid | C28H44N4O16 | 详情 | 详情 | |
| (V) | 56044 | gadolinium (2R)-2-{4,10-bis[(1R)-3-carboxy-1-carboxylatopropyl]-7-[(1R)-1-carboxy-4-hydroxy-4-oxobutyl]-1,4,7,10-tetraazacyclododecan-1-yl}-4-carboxybutanoate | C28H41GdN4O16 | 详情 | 详情 |