TA-103(ligand), RP-728, -Drug Synthesis Database

【结构式】

【药物名称】TA-103(ligand), RP-728

【化学名称】[N-[2-[4,7,10-Tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-1-yl]acetyl]-L-glutamyl-N1-[2-[4-[N-[4-[1(S)-carboxy-2-[1-[3-(1H-imidazol-2-ylamino)propyl]-1H-indazol-5-ylcarboxamido]ethyl]sulfamoyl]-3,5-dimethylphenoxy]butyramido]ethyl]-L-alpha-glutaminato(3-)]indium-111In

【CA登记号】277329-58-5 (uncomplexed)

【分子式】C₅₇H₇₈InN₁₅O₂₀S

【分子量】1436.40971

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

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

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

3,5-Dimethylphenol (I) was alkylated with ethyl 4-bromobutyrate (II) to provide the (dimethylphenoxy)butyrate ester (III), which was hydrolyzed under basic conditions to yield acid (IV). This was sulfonated with chlorosulfonic acid, and the resultant sulfonyl chloride (V) was condensed with Boc-diaminopropanoic acid (VI) to afford sulfonamide (VII). Coupling of (VII) with mono-benzyloxycarbonyl ethylenediamine (VIII) furnished amide (IX). Then, acid cleavage of the Boc protecting group of (IX) provided amine (X).

参考文献中间体

【1】 Cheesman, E.H.; et al.; Nonpeptide vitronectin antagonists labeles with in-111 for imaging tumors. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 88.
【2】 Rajopadhye, M.; Harris, T.D.; Cheesman, E.H. (DuPont Pharmaceuticals Co.); Vitronectin receptor antagonist pharmaceuticals. WO 0035488 .

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)	46786	3,5-dimethylphenol	108-68-9	C₈H₁₀O	详情	详情
(II)	11263	ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate	2969-81-5	C₆H₁₁BrO₂	详情	详情
(III)	50998	ethyl 4-(3,5-dimethylphenoxy)butanoate		C₁₄H₂₀O₃	详情	详情
(IV)	50999	4-(3,5-dimethylphenoxy)butyric acid		C₁₂H₁₆O₃	详情	详情
(V)	51000	4-[4-(chlorosulfonyl)-3,5-dimethylphenoxy]butyric acid		C₁₂H₁₅ClO₅S	详情	详情
(VI)	25095	methyl (2S)-2-amino-3-[(tert-butoxycarbonyl)amino]propanoate		C₉H₁₈N₂O₄	详情	详情
(VII)	51001	4-(4-[[((1S)-1-[[(tert-butoxycarbonyl)amino]methyl]-2-methoxy-2-oxoethyl)amino]sulfonyl]-3,5-dimethylphenoxy)butyric acid		C₂₁H₃₂N₂O₉S	详情	详情
(VIII)	51002	benzyl 2-aminoethylcarbamate		C₁₀H₁₄N₂O₂	详情	详情
(IX)	51003	methyl (2S)-2-[[(4-[4-[(2-[[(benzyloxy)carbonyl]amino]ethyl)amino]-4-oxobutoxy]-2,6-dimethylphenyl)sulfonyl]amino]-3-[(tert-butoxycarbonyl)amino]propanoate		C₃₁H₄₄N₄O₁₀S	详情	详情
(X)	51004	methyl (2S)-3-amino-2-[[(4-[4-[(2-[[(benzyloxy)carbonyl]amino]ethyl)amino]-4-oxobutoxy]-2,6-dimethylphenyl)sulfonyl]amino]propanoate		C₂₆H₃₆N₄O₈S	详情	详情

合成路线2

Amine (X) was coupled with carboxylic acid (XI) to afford the corresponding amide (XII) (1,2). Basic hydrolysis of the ester group of (XII) gave acid (XIII), and subsequent cleavage of the remaining protecting groups of (XIII) with trifluoroacetic acid in the presence of triethylsilane furnished (XIV).

参考文献中间体

【1】 Rajopadhye, M.; Harris, T.D.; Cheesman, E.H. (DuPont Pharmaceuticals Co.); Vitronectin receptor antagonist pharmaceuticals. WO 0035488 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(X)	51004	methyl (2S)-3-amino-2-[[(4-[4-[(2-[[(benzyloxy)carbonyl]amino]ethyl)amino]-4-oxobutoxy]-2,6-dimethylphenyl)sulfonyl]amino]propanoate	C₂₆H₃₆N₄O₈S	详情	详情
(XI)	51005	1-[3-[(1-trityl-1H-imidazol-2-yl)amino]propyl]-1H-indazole-5-carboxylic acid	C₃₃H₂₉N₅O₂	详情	详情
(XII)	51006	methyl (2S)-2-[[(4-[4-[(2-[[(benzyloxy)carbonyl]amino]ethyl)amino]-4-oxobutoxy]-2,6-dimethylphenyl)sulfonyl]amino]-3-[[(1-[3-[(1-trityl-1H-imidazol-2-yl)amino]propyl]-1H-indazol-5-yl)carbonyl]amino]propanoate	C₅₉H₆₃N₉O₉S	详情	详情
(XIII)	51007	(2S)-2-[[(4-[4-[(2-[[(benzyloxy)carbonyl]amino]ethyl)amino]-4-oxobutoxy]-2,6-dimethylphenyl)sulfonyl]amino]-3-[[(1-[3-[(1-trityl-1H-imidazol-2-yl)amino]propyl]-1H-indazol-5-yl)carbonyl]amino]propionic acid	C₅₈H₆₁N₉O₉S	详情	详情
(XIV)	51008	(2S)-2-[[(4-[4-[(2-aminoethyl)amino]-4-oxobutoxy]-2,6-dimethylphenyl)sulfonyl]amino]-3-[([1-[3-(1H-imidazol-2-ylamino)propyl]-1H-indazol-5-yl]carbonyl)amino]propionic acid	C₃₁H₄₁N₉O₇S	详情	详情

合成路线3

Coupling of the succinimidyl ester of protected glutamic acid (XVI) with glutamic acid gamma-tert-butyl ester (XV) provided the protected dipeptide (XVII), which was then activated with tetrafluorophenol (XVIII) by means of EDC in DMF to yield the tetrafluorophenyl ester (XIX). Condensation of (XIX) with amine (XIV) produced amide (XX), whose N-benzyloxycarbonyl group was then removed by hydrogenolysis over Pd/C to yield amine (XXI).

参考文献中间体

【1】 Rajopadhye, M.; Harris, T.D.; Cheesman, E.H. (DuPont Pharmaceuticals Co.); Vitronectin receptor antagonist pharmaceuticals. WO 0035488 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIV)	51008	(2S)-2-[[(4-[4-[(2-aminoethyl)amino]-4-oxobutoxy]-2,6-dimethylphenyl)sulfonyl]amino]-3-[([1-[3-(1H-imidazol-2-ylamino)propyl]-1H-indazol-5-yl]carbonyl)amino]propionic acid		C₃₁H₄₁N₉O₇S	详情	详情
(XV)	51009	(2S)-2-amino-5-(tert-butoxy)-5-oxopentanoic acid		C₉H₁₇NO₄	详情	详情
(XVI)	51010	tert-butyl (4S)-4-[[(benzyloxy)carbonyl]amino]-5-[(2,5-dioxo-1-pyrrolidinyl)oxy]-5-oxopentanoate		C₂₁H₂₆N₂O₈	详情	详情
(XVII)	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
(XVIII)	49986	2,3,5,6-Tetrafluorophenol	769-39-1	C₆H₂F₄O	详情	详情
(XIX)	51012	5-(tert-butyl) 1-(2,3,5,6-tetrafluorophenyl) (2S)-2-[[(2S)-2-[[(benzyloxy)carbonyl]amino]-5-(tert-butoxy)-5-oxopentanoyl]amino]pentanedioate		C₃₂H₃₈F₄N₂O₉	详情	详情
(XX)	51013	(2S)-2-([[4-([(10S,13S)-10,13-bis[3-(tert-butoxy)-3-oxopropyl]-4,9,12,15-tetraoxo-17-phenyl-16-oxa-5,8,11,14-tetraazaheptadec-1-yl]oxy)-2,6-dimethylphenyl]sulfonyl]amino)-3-[([1-[3-(1H-imidazol-2-ylamino)propyl]-1H-indazol-5-yl]carbonyl)amino]propionic acid		C₅₇H₇₇N₁₁O₁₅S	详情	详情
(XXI)	51021	(2S)-2-([[4-([(10S,13S)-13-amino-10-[3-(tert-butoxy)-3-oxopropyl]-18,18-dimethyl-4,9,12,16-tetraoxo-17-oxa-5,8,11-triazanonadec-1-yl]oxy)-2,6-dimethylphenyl]sulfonyl]amino)-3-[([1-[3-(1H-imidazol-2-ylamino)propyl]-1H-indazol-5-yl]carbonyl)amino]propionic acid		C₄₉H₇₁N₁₁O₁₃S	详情	详情

合成路线4

Acylation of amine (XXI) with tetraazacyclododecanetetraacetic acid tri-tert-butyl ester (XXII) produced amide (XXIII) (1). After acidic cleavage of the tert-butyl ester groups of (XXIII), the resultant macrocyclic tetraamine (XXIV) was complexed with 111InCl3 in the presence of NH4OAc buffer to furnish the title indium-111 complex.

参考文献中间体

【1】 Cheesman, E.H.; et al.; Nonpeptide vitronectin antagonists labeles with in-111 for imaging tumors. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 88.
【2】 Rajopadhye, M.; Harris, T.D.; Cheesman, E.H. (DuPont Pharmaceuticals Co.); Vitronectin receptor antagonist pharmaceuticals. WO 0035488 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XXI)	51021	(2S)-2-([[4-([(10S,13S)-13-amino-10-[3-(tert-butoxy)-3-oxopropyl]-18,18-dimethyl-4,9,12,16-tetraoxo-17-oxa-5,8,11-triazanonadec-1-yl]oxy)-2,6-dimethylphenyl]sulfonyl]amino)-3-[([1-[3-(1H-imidazol-2-ylamino)propyl]-1H-indazol-5-yl]carbonyl)amino]propionic acid	C₄₉H₇₁N₁₁O₁₃S	详情	详情
(XXII)	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
(XXIII)	51015	(2S)-2-([[4-([(10S,13S)-10-[3-(tert-butoxy)-3-oxopropyl]-18,18-dimethyl-4,9,12,16-tetraoxo-13-[(2-[4,7,10-tris[2-(tert-butoxy)-2-oxoethyl]-1,4,7,10-tetraazacyclododecan-1-yl]acetyl)oxy]-17-oxa-5,8,11-triazanonadec-1-yl]oxy)-2,6-dimethylphenyl]sulfonyl]amino)-3-[([1-[3-(1H-imidazol-2-ylamino)propyl]-1H-indazol-5-yl]carbonyl)amino]propionic acid	C₇₇H₁₂₀N₁₄O₂₁S	详情	详情
(XXIV)	51016	(4S)-5-([(1S)-3-carboxy-1-[([2-[(4-[4-[([(1S)-1-carboxy-2-[([1-[3-(1H-imidazol-2-ylamino)propyl]-1H-indazol-5-yl]carbonyl)amino]ethyl]amino)sulfonyl]-3,5-dimethylphenoxy]butanoyl)amino]ethyl]amino)carbonyl]propyl]amino)-5-oxo-4-([2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]acetyl]oxy)pentanoic acid	C₅₇H₈₀N₁₄O₂₁S	详情	详情

合成路线5

In a related procedure, intermediate (XII) was first deprotected by hydrogenolysis of the N-benzyloxycarbonyl group, yielding amine (XXV). Coupling of this amine with the dipeptide (XVII) furnished adduct (XXVI), which was again deprotected by hydrogenolysis, yielding (XXVII).

参考文献中间体

【1】 Cheesman, E.H.; et al.; Nonpeptide vitronectin antagonists labeles with in-111 for imaging tumors. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 88.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XII)	51006	methyl (2S)-2-[[(4-[4-[(2-[[(benzyloxy)carbonyl]amino]ethyl)amino]-4-oxobutoxy]-2,6-dimethylphenyl)sulfonyl]amino]-3-[[(1-[3-[(1-trityl-1H-imidazol-2-yl)amino]propyl]-1H-indazol-5-yl)carbonyl]amino]propanoate	C₅₉H₆₃N₉O₉S	详情	详情
(XVII)	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
(XXV)	51017	methyl (2S)-2-[[(4-[4-[(2-aminoethyl)amino]-4-oxobutoxy]-2,6-dimethylphenyl)sulfonyl]amino]-3-[[(1-[3-[(1-trityl-1H-imidazol-2-yl)amino]propyl]-1H-indazol-5-yl)carbonyl]amino]propanoate	C₅₁H₅₇N₉O₇S	详情	详情
(XXVI)	51018	tert-butyl (4S)-4-[[(benzyloxy)carbonyl]amino]-5-[[(1S)-4-(tert-butoxy)-1-([[2-([4-[4-([[(1S)-2-methoxy-2-oxo-1-([[(1-[3-[(1-trityl-1H-imidazol-2-yl)amino]propyl]-1H-indazol-5-yl)carbonyl]amino]methyl)ethyl]amino]sulfonyl)-3,5-dimethylphenoxy]butanoyl]amino)ethyl]amino]carbonyl)-4-oxobutyl]amino]-5-oxopentanoate	C₇₇H₉₃N₁₁O₁₅S	详情	详情
(XXVII)	51019	tert-butyl (4S)-4-amino-5-[[(1S)-4-(tert-butoxy)-1-([[2-([4-[4-([[(1S)-2-methoxy-2-oxo-1-([[(1-[3-[(1-trityl-1H-imidazol-2-yl)amino]propyl]-1H-indazol-5-yl)carbonyl]amino]methyl)ethyl]amino]sulfonyl)-3,5-dimethylphenoxy]butanoyl]amino)ethyl]amino]carbonyl)-4-oxobutyl]amino]-5-oxopentanoate	C₆₉H₈₇N₁₁O₁₃S	详情	详情

合成路线6

Coupling of (XXVII) with the macrocyclic tetraacetic acid tri-tert-butyl ester (XXII) produced amide (XXVIII). Basic hydrolysis of the methyl ester group of (XXVIII), followed by acidic cleavage of the remaining protecting groups, furnished intermediate (XXIV), which was finally complexed as above.

参考文献中间体

【1】 Cheesman, E.H.; et al.; Nonpeptide vitronectin antagonists labeles with in-111 for imaging tumors. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 88.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XXII)	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
(XXIV)	51016	(4S)-5-([(1S)-3-carboxy-1-[([2-[(4-[4-[([(1S)-1-carboxy-2-[([1-[3-(1H-imidazol-2-ylamino)propyl]-1H-indazol-5-yl]carbonyl)amino]ethyl]amino)sulfonyl]-3,5-dimethylphenoxy]butanoyl)amino]ethyl]amino)carbonyl]propyl]amino)-5-oxo-4-([2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]acetyl]oxy)pentanoic acid	C₅₇H₈₀N₁₄O₂₁S	详情	详情
(XXVII)	51019	tert-butyl (4S)-4-amino-5-[[(1S)-4-(tert-butoxy)-1-([[2-([4-[4-([[(1S)-2-methoxy-2-oxo-1-([[(1-[3-[(1-trityl-1H-imidazol-2-yl)amino]propyl]-1H-indazol-5-yl)carbonyl]amino]methyl)ethyl]amino]sulfonyl)-3,5-dimethylphenoxy]butanoyl]amino)ethyl]amino]carbonyl)-4-oxobutyl]amino]-5-oxopentanoate	C₆₉H₈₇N₁₁O₁₃S	详情	详情
(XXVIII)	51020	tert-butyl (4S)-5-[[(1S)-4-(tert-butoxy)-1-([[2-([4-[4-([[(1S)-2-methoxy-2-oxo-1-([[(1-[3-[(1-trityl-1H-imidazol-2-yl)amino]propyl]-1H-indazol-5-yl)carbonyl]amino]methyl)ethyl]amino]sulfonyl)-3,5-dimethylphenoxy]butanoyl]amino)ethyl]amino]carbonyl)-4-oxobutyl]amino]-5-oxo-4-[(2-[4,7,10-tris[2-(tert-butoxy)-2-oxoethyl]-1,4,7,10-tetraazacyclododecan-1-yl]acetyl)amino]pentanoate	C₉₇H₁₃₇N₁₅O₂₀S	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)