Gadomelitol, P-792, Vistarem, -Drug Synthesis Database

【结构式】

【药物名称】Gadomelitol, P-792, Vistarem

【化学名称】Hydrogen [2,2',2'',2'''-[1,4,7,10-tetraazacyclododecane-1,4,7,10-triyl]tetrakis[5-[[2-[[4- [[4-[[2-[[3,5-bis[bis[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl-2,4,6-tribromo]carbamoyl]phenyl]amino]-2-oxoethyl]carbamoyl]phenyl]carbamoyl]phenyl]amino]-2-oxoethyl]amino]-5-oxopentanoato](4-)]gadolinate(1-)
　　　　　　Hydrogen [[1,1',1'',1''',1'''',1''''',1'''''',1''''''',1'''''''',1''''''''',1'''''''''',1''''''''''',1'''''''''''',1''''''''''''',1'''''''''''''',1'''''''''''''''-[(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl-kappaN1,kappaN4,kappaN7,kappaN10)tetrakis[[4-(carboxy-kappaO)-1-oxo-4,1-butanediyl]imino(1-oxo-2,1-ethanediyl)imino-4,1-phenylenecarbonylimino-4,1-phenylenecarbonylimino(1-oxo-2,1-ethanediyl)imino(2,4,6-tribromo-5,1,3-benzenetriyl)bis(carbonylnitrilo)]]hexadecakis[1-deoxy-D-glucitolato]](4-)]gadolinate(1-)

【CA登记号】227622-74-4

【分子式】C₂₂₈H₃₁₃Br₁₂GdN₃₂O₁₁₆

【分子量】6474.27961

【开发单位】Guerbet (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1

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

【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

合成路线2

Coupling between 4-nitrobenzoyl chloride (VI) and 4-aminobenzoic acid (VII) afforded nitrobenzamide (VIII), which was further reduced to amine (IX) by catalytic hydrogenation over Pd/C. Acylation of (IX) with phthalimidoacetyl chloride (X) yielded diamide (XI). The carboxyl group of (XI) was then activated as the corresponding acid chloride (XII) by treatment with SOCl2. Then, condensation of the glycylamide derivative (XIII) with acid chloride (XII) furnished amide (XIV).

参考文献中间体

【1】 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
(VI)	18941	p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride	122-04-3	C₇H₄ClNO₃	详情	详情
(VII)	20004	p-aminobenzoic acid; 4-aminobenzoic acid	150-13-0	C₇H₇NO₂	详情	详情
(VIII)	56045	4-[(4-nitrobenzoyl)amino]benzoic acid		C₁₄H₁₀N₂O₅	详情	详情
(IX)	56046	4-[(4-aminobenzoyl)amino]benzoic acid		C₁₄H₁₂N₂O₃	详情	详情
(X)	10278	2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl chloride	6780-38-7	C₁₀H₆ClNO₃	详情	详情
(XI)	56047	4-[(4-{[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl]amino}benzoyl)amino]benzoic acid		C₂₄H₁₇N₃O₆	详情	详情
(XII)	56048	4-[(4-{[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl]amino}benzoyl)amino]benzoyl chloride		C₂₄H₁₆ClN₃O₅	详情	详情
(XIII)	56049	5-[(2-aminoacetyl)amino]-2,4,6-tribromo-N~1~,N~1~,N~3~,N~3~-tetrakis(2,3,4,5,6-pentahydroxyhexyl)isophthalamide		C₃₄H₅₇Br₃N₄O₂₃	详情	详情
(XIV)	56050	2,4,6-tribromo-5-{[2-({4-[(4-{[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl]amino}benzoyl)amino]benzoyl}amino)acetyl]amino}-N~1~,N~1~,N~3~,N~3~-tetrakis(2,3,4,5,6-pentahydroxyhexyl)isophthalamide		C₅₈H₇₂Br₃N₇O₂₈	详情	详情

合成路线3

Deprotection of the phthaloyl group of (XIV) by hydrazinolysis provided amine (XV). This was then coupled with the octaacid gadolinium chelate (V) in the presence of EDC and HOBt leading to the target amide.

参考文献中间体

【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	分子式	供应商	用于合成
(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
(XIV)	56050	2,4,6-tribromo-5-{[2-({4-[(4-{[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl]amino}benzoyl)amino]benzoyl}amino)acetyl]amino}-N~1~,N~1~,N~3~,N~3~-tetrakis(2,3,4,5,6-pentahydroxyhexyl)isophthalamide	C₅₈H₇₂Br₃N₇O₂₈	详情	详情
(XV)	56051	5-[(2-{[4-({4-[(2-aminoacetyl)amino]benzoyl}amino)benzoyl]amino}acetyl)amino]-2,4,6-tribromo-N~1~,N~1~,N~3~,N~3~-tetrakis(2,3,4,5,6-pentahydroxyhexyl)isophthalamide	C₅₀H₇₀Br₃N₇O₂₆	详情	详情

合成路线4

In a related synthetic route, the glycinamide derivative (XV) was coupled to acid (IV), and the resultant macrocyclic tetramide was subsequently complexed with GdCl3 to form the title gadolinium chelate.

参考文献中间体

【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.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(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
(XV)	56051	5-[(2-{[4-({4-[(2-aminoacetyl)amino]benzoyl}amino)benzoyl]amino}acetyl)amino]-2,4,6-tribromo-N~1~,N~1~,N~3~,N~3~-tetrakis(2,3,4,5,6-pentahydroxyhexyl)isophthalamide		C₅₀H₇₀Br₃N₇O₂₆	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)