1,4,7,10-tetraazacyclododecane; Cyclen -Drug Synthesis Database

【结构式】

【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%

与该中间体有关的原料药合成路线共 7 条

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5 合成路线6 合成路线7

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.

参考文献中间体

合成目标

【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

参考文献中间体

合成目标

【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

参考文献中间体

合成目标

【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

参考文献中间体

合成目标

【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

参考文献中间体

合成目标

【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.

参考文献中间体

合成目标

【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 .

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)	49689	[4,7,10-tris(phosphonomethyl)-1,4,7,10-tetraazacyclododecan-1-yl]methylphosphonic acid		C₁₂H₃₂N₄O₁₂P₄	详情	详情

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).

参考文献中间体

合成目标

【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

Extended Information