SU-058(uncomplexed), RP-698, -Drug Synthesis Database

【结构式】

【药物名称】SU-058(uncomplexed), RP-698

【化学名称】[N-[2-[4,7,10-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-1-yl]acetyl]-L-glutamyl-N1-[3-[7-[N-(1H-benzimidazol-2-ylmethyl)-N-methylcarbamoyl]-2(S)-(carboxymethyl)-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl]propyl]-L-alpha-glutaminato(3-)]lutetium-177Lu

【CA登记号】277327-56-7 (uncomplexed)

【分子式】C₅₀H₆₅LuN₁₂O₁₇

【分子量】1281.11575

【开发单位】Bristol-Myers Squibb (Originator)

【药理作用】Diagnostic Agents, Diagnostic for Cancer, Integrin alphavbeta3 (Vitronectin) Antagonists, Metal Complexes

合成路线1 合成路线2 合成路线3

合成路线1

Condensation of tert-butyl 4-fluoro-3-(bromomethyl)benzoate (I) with N-Boc-1,3-propanediamine (II) afforded the aminomethyl benzoate derivative (III). This was coupled with N-Cbz-L-aspartic acid beta-methyl ester (IV), yielding amide (V). After hydrogenolysis of the carbobenzoxy protecting group of (V), the resultant fluoro amine (VI) was cyclized to the benzodiazepinone (VII) upon treatment with 2,6-di-tert-butylpyridine in hot NMP. Acidic cleavage of both the tert-butyl ester and the N-Boc groups of (VII), followed by reprotection of the amine with Boc2O, furnished the N-Boc acid (VIII). This was then coupled to 2-(methylaminomethyl)benzimidazole (IX) to afford, after acidic Boc group cleavage, the amino amide (X).

参考文献中间体

【1】 Cheesman, E.H.; et al.; Nonpeptide vitronectin antagonists labeled with Tc99m for imaging tumors. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 77.
【2】 Sworin, M.; Cheesman, E.H.; Rajopadhyem, M. (DuPont Pharmaceuticals Co.); Vitronectin receptor antagonist pharmaceuticals. EP 1140864; WO 0035887 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	52473	1,1-dimethylethyl 3-(bromomethyl)-4-fluorobenzoate	C₁₂H₁₄BrFO₂	详情	详情
(II)	52474	1,1-dimethylethyl 3-aminopropylcarbamate	C₈H₁₈N₂O₂	详情	详情
(III)	52475	1,1-dimethylethyl 3-({[3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)propyl]amino}methyl)-4-fluorobenzoate	C₂₀H₃₁FN₂O₄	详情	详情
(IV)	52476	O-methyl-4-oxo-N-{[(phenylmethyl)oxy]carbonyl}homoserine	C₁₃H₁₅NO₆	详情	详情
(V)	52477	1,1-dimethylethyl 3-({[3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)propyl][4-(methyloxy)-4-oxo-2-({[(phenylmethyl)oxy]carbonyl}amino)butanoyl]amino}methyl)-4-fluorobenzoate	C₃₃H₄₄FN₃O₉	详情	详情
(VI)	52478	1,1-dimethylethyl 3-({[2-amino-4-(methyloxy)-4-oxobutanoyl][3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)propyl]amino}methyl)-4-fluorobenzoate	C₂₅H₃₈FN₃O₇	详情	详情
(VII)	52479	1,1-dimethylethyl 4-[3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)propyl]-2-[2-(methyloxy)-2-oxoethyl]-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxylate	C₂₅H₃₇N₃O₇	详情	详情
(VIII)	52480	4-[3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)propyl]-2-[2-(methyloxy)-2-oxoethyl]-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxylic acid	C₂₁H₂₉N₃O₇	详情	详情
(IX)	52481	1H-benzimidazol-2-yl-N-methylmethanamine; N-(1H-benzimidazol-2-ylmethyl)-N-methylamine	C₉H₁₁N₃	详情	详情
(X)	52482	methyl 2-(4-(3-aminopropyl)-7-{[(1H-benzimidazol-2-ylmethyl)(methyl)amino]carbonyl}-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-yl)acetate	C₂₅H₃₀N₆O₄	详情	详情

合成路线2

Coupling between gamma-tert-butoxy glutamic acid (XI) and gamma-tert-butoxy-N-Cbz-glutamic acid succinimidyl ester (XII) produced the protected dipeptide (XIII). This was further coupled to the intermediate amine (X) to furnish the corresponding amide (XIV). After hydrogenolysis of the N-Cbz protecting group of (XIV), the resultant amine (XV) was acylated with tetraazacyclododecanetetraacetic acid tri-tert-butyl ester (XVI), yielding the amide adduct (XVII).

参考文献中间体

【1】 Cheesman, E.H.; et al.; Nonpeptide vitronectin antagonists labeled with Tc99m for imaging tumors. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 77.
【2】 Sworin, M.; Cheesman, E.H.; Rajopadhyem, M. (DuPont Pharmaceuticals Co.); Vitronectin receptor antagonist pharmaceuticals. EP 1140864; WO 0035887 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(X)	52482	methyl 2-(4-(3-aminopropyl)-7-{[(1H-benzimidazol-2-ylmethyl)(methyl)amino]carbonyl}-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-yl)acetate	C₂₅H₃₀N₆O₄	详情	详情
(XI)	51009	(2S)-2-amino-5-(tert-butoxy)-5-oxopentanoic acid	C₉H₁₇NO₄	详情	详情
(XII)	51010	tert-butyl (4S)-4-[[(benzyloxy)carbonyl]amino]-5-[(2,5-dioxo-1-pyrrolidinyl)oxy]-5-oxopentanoate	C₂₁H₂₆N₂O₈	详情	详情
(XIII)	51011	(2S)-2-[[(2S)-2-[[(benzyloxy)carbonyl]amino]-5-(tert-butoxy)-5-oxopentanoyl]amino]-5-(tert-butoxy)-5-oxopentanoic acid	C₂₆H₃₈N₂O₉	详情	详情
(XIV)	52486		C₅₁H₆₆N₈O₁₂	详情	详情
(XV)	51014	2-[4,7,10-tris[2-(tert-butoxy)-2-oxoethyl]-1,4,7,10-tetraazacyclododecan-1-yl]acetic acid	C₂₈H₅₂N₄O₈	详情	详情
(XVI)	52483		C₄₃H₆₀N₈O₁₀	详情	详情
(XVII)	52484		C₇₁H₁₁₀N₁₂O₁₇	详情	详情

合成路线3

Basic hydrolysis of the methyl ester group of (XVII) and subsequent acidic cleavage of the tert-butyl esters gave rise to the hexacarboxylic acid derivative (XVIII). Finally, complexation of (XVIII) with 177LuCl3 furnished the title lutetium complex.

参考文献中间体

【1】 Cheesman, E.H.; et al.; Nonpeptide vitronectin antagonists labeled with Tc99m for imaging tumors. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 77.
【2】 Sworin, M.; Cheesman, E.H.; Rajopadhyem, M. (DuPont Pharmaceuticals Co.); Vitronectin receptor antagonist pharmaceuticals. EP 1140864; WO 0035887 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XVII)	52484			C₇₁H₁₁₀N₁₂O₁₇	详情	详情
(XVIII)	52485			C₅₀H₆₈N₁₂O₁₇	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)