Gadobutrol, SH-L-562, Gadovist, -Drug Synthesis Database

【结构式】

【药物名称】Gadobutrol, SH-L-562, Gadovist

【化学名称】[10-[(1RS,2SR)-2,3-Dihydroxy-1-(hydroxymethyl)propyl]-1,4,7,10-tetraazacyclodecane-1,4,7-triacetato(3-)]gadolinium

【CA登记号】138071-82-6

【分子式】C₁₈H₃₁GdN₄O₉

【分子量】604.71917

【开发单位】Schering AG (Originator)

【药理作用】Diagnostic Agents, Magnetic Resonance Imaging Agents

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1

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

【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2

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

【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3

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

【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4

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

【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5

In a related method for obtaining the precursor (V), epoxide (II) was condensed with the tosyl-protected tetraamine (XIII) in an autoclave at 170 C to give (XIV). The N-tosyl groups of (XIV) were then removed by treatment with lithium metal in liquid ammonia, yielding intermediate (III), which was then subjected to alkylation with bromoacetic acid, followed by acid hydrolysis

参考文献中间体

【1】 Platzek, J.; Gries, H.; Weinmann, H.-J.; Schuhmann-Giampieri, G.; Press, W.-R. (Schering AG); 1,4,7,10-Tetraazacyclododecane-butyl-triols, process for their preparation, and pharmaceutical agents containing these cpds.. DE 4009119; EP 0448191; US 2002176823; US 6399043 .

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
(II)	30022	1-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-propen-1-ol		C₁₅H₂₀O₃	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
(XIII)	60032	1,4,7-tris[(4-methylphenyl)sulfonyl]-1,4,7,10-tetraazacyclododecane		C₂₉H₃₈N₄O₆S₃	详情	详情
(XIV)	60033	(5S,6R)-2,2-dimethyl-6-{4,7,10-tris[(4-methylphenyl)sulfonyl]-1,4,7,10-tetraazacyclododecan-1-yl}-1,3-dioxepan-5-ol		C₃₆H₅₀N₄O₉S₃	详情	详情

合成路线6

A different synthesis started from the previously reported tetraaza cyclopentaacenaphthylene (XV). Treatment of (XV) with a solution of piperazine at pH 6 gave rise to the bicyclic lactam (XVI). Alkylation of (XVI) with bromoacetic acid, followed by basic lactam hydrolysis furnished the tris(carboxymethyl) derivative (X), which was processed as in Scheme 3.

参考文献中间体

【1】 Argese, M.; Ripa, G. (Bracco SpA; Dibra SpA); 1,4,7,10-Tetraazabicyclo[8.2.2]tetradecan-2-one, a process for the preparation thereof and the use thereof for the preparation of tetraazamacrocycles. EP 0998476; JP 2002511884; WO 9905145 .

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
(X)	60030	trisodium 2-[4,10-bis(2-oxido-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl]acetate		C₁₄H₂₃N₄Na₃O₆	详情	详情
(XV)	60034	1,4,7,10-tetraazatricyclo[8.2.2.2~4,7~]hexadecane		C₁₂H₂₄N₄	详情	详情
(XVI)	60035	1,4,7,10-tetraazabicyclo[8.2.2]tetradecan-11-one		C₁₀H₂₀N₄O	详情	详情
(XVII)	60036	2-[7-(2-hydroxy-2-oxoethyl)-11-oxo-1,4,7,10-tetraazabicyclo[8.2.2]tetradec-4-yl]acetic acid		C₁₄H₂₄N₄O₅	详情	详情

Extended Information