PTR-3046, -Drug Synthesis Database

【结构式】

【药物名称】PTR-3046

【化学名称】[3S-(3alpha,6alpha,9beta,12alpha,15alpha)]-2(S)-[6-(4-Aminobutyl)-15-benzyl-12-(4-hydroxybenzyl)-9-(1H-indol-3-ylmethyl)-3-isopropyl-2,5,8,11,14,20-hexaoxo-1,4,7,10,13,16,19-heptaazacyclotricosan-1-yl]-3-phenylpropionyl-L-threoninamide

【CA登记号】203200-47-9

【分子式】C₅₉H₇₇N₁₁O₁₀

【分子量】1100.33924

【开发单位】Peptor (Originator), Yissum (Originator)

【药理作用】GASTROINTESTINAL DRUGS, Pancreatic Disorders, Treatment of, Somatostatin Analogs

合成路线1 合成路线2 合成路线3

合成路线1

Compound (XI) was prepared by solid phase peptide synthesis on a Rink amide 4-methylbenzhydrylamine (MBHA) resin. After removal of Fmoc protecting group from the resin with 20% piperidine in N-methyl-2-pyrrolidinone (NMP), a coupling cycle was carried out with Fmoc-Thr(O-t-Bu)OH (I) using bromotripyrrolidino phosphonium hexafluorophosphate (PyBroP) and diisopropylethylamine (DIEA) in NMP, followed by Fmoc removal with 20% piperidine in NMP. To the Thr-bound resin (II) they were stepwise coupled in subsequent coupling and deprotecting cycles the following amino acids: Fmoc- (N-allyloxycarbonylpropyl)PheOH (IV), Fmoc-ValCl (VI), Fmoc-Lys(Boc)OH (VIII), and Fmoc-D-TrpOH (X) to yield the corresponding peptide-bound resins (V), (VII), (IX) and (XI), respectively.

参考文献中间体

【1】 Gilon, C.; et al.; A backbone-cyclic, receptor 5-selective somatostatin analogue: Synthesis, bioactivity, and nuclear magnetic resonance conformational analysis. J Med Chem 1998, 41, 6, 919.
【2】 Hornik, V.; Seri-Levy, A.; Gellerman, G.; Gilon, C. (Yissum Research Development Co.); Conformationally constrained backbone cyclized somatostatin analogs. WO 9804583 .

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)	18847	(2S,3R)-3-(tert-butoxy)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]butyric acid		C₂₃H₂₇NO₅	详情	详情
(II)	18848	9H-fluoren-9-ylmethyl (1S,2R)-1-(aminocarbonyl)-2-(tert-butoxy)propylcarbamate		C₂₃H₂₈N₂O₄	详情	详情
(III)	18849	(2S,3R)-2-amino-3-(tert-butoxy)butanamide		C₈H₁₈N₂O₂	详情	详情
(IV)	18850	(2S)-2-[[4-(allyloxy)-4-oxobutyl][(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-phenylpropionic acid		C₃₁H₃₁NO₆	详情	详情
(V)	18851	allyl 4-[((1S)-2-[[(1S,2R)-1-(aminocarbonyl)-2-(tert-butoxy)propyl]amino]-1-benzyl-2-oxoethyl)amino]butanoate		C₂₄H₃₇N₃O₅	详情	详情
(VI)	18852	9H-fluoren-9-ylmethyl (1S)-1-(chlorocarbonyl)-2-methylpropylcarbamate	103321-53-5	C₂₀H₂₀ClNO₃	详情	详情
(VII)	18853	allyl 4-[((1S)-2-[[(1S,2R)-1-(aminocarbonyl)-2-(tert-butoxy)propyl]amino]-1-benzyl-2-oxoethyl)[(2S)-2-amino-3-methylbutanoyl]amino]butanoate		C₂₉H₄₆N₄O₆	详情	详情
(VIII)	18854	(2S)-6-[(tert-butoxycarbonyl)amino]-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]hexanoic acid		C₂₆H₃₂N₂O₆	详情	详情
(IX)	18855	allyl (10S,13S)-10-amino-15-((1S)-2-[[(1S,2R)-1-(aminocarbonyl)-2-(tert-butoxy)propyl]amino]-1-benzyl-2-oxoethyl)-13-isopropyl-2,2-dimethyl-4,11,14-trioxo-3-oxa-5,12,15-triazanonadecan-19-oate		C₄₀H₆₆N₆O₉	详情	详情
(X)	18856	(2R)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-(1H-indol-3-yl)propionic acid		C₂₆H₂₂N₂O₄	详情	详情
(XI)	18857	allyl (10S,13S)-15-((1S)-2-[[(1S,2R)-1-(aminocarbonyl)-2-(tert-butoxy)propyl]amino]-1-benzyl-2-oxoethyl)-10-[[(2R)-2-amino-3-(1H-indol-3-yl)propanoyl]amino]-13-isopropyl-2,2-dimethyl-4,11,14-trioxo-3-oxa-5,12,15-triazanonadecan-19-oate		C₅₁H₇₆N₈O₁₀	详情	详情

合成路线2

Compound (XVI) was prepared by solid phase peptide synthesis on a Rink amide 4-methylbenzhydrylamine (MBHA) resin. To the Thr-bound resin (XI) they were stepwise coupled in subsequent coupling and deprotecting cycles the following amino acids: Fmoc-Tyr(t-Bu)OH (XII), and Fmoc- (N-allyloxycarbonylaminoethyl)PheOH (XIV) to yield the corresponding peptide-bound resins (XIII) and (XV), respectively. Then, allyl and allyoxycarbonyl protecting groups were both removed from the linear peptide-bound resin (XV) by treatment with tetrakis(triphenylphosphine)palladium, acetic acid, and N-methylmorpholine (NMM) in chloroform to yield compound (XVI).

参考文献中间体

【1】 Gilon, C.; et al.; A backbone-cyclic, receptor 5-selective somatostatin analogue: Synthesis, bioactivity, and nuclear magnetic resonance conformational analysis. J Med Chem 1998, 41, 6, 919.
【2】 Hornik, V.; Seri-Levy, A.; Gellerman, G.; Gilon, C. (Yissum Research Development Co.); Conformationally constrained backbone cyclized somatostatin analogs. WO 9804583 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XI)	18857	allyl (10S,13S)-15-((1S)-2-[[(1S,2R)-1-(aminocarbonyl)-2-(tert-butoxy)propyl]amino]-1-benzyl-2-oxoethyl)-10-[[(2R)-2-amino-3-(1H-indol-3-yl)propanoyl]amino]-13-isopropyl-2,2-dimethyl-4,11,14-trioxo-3-oxa-5,12,15-triazanonadecan-19-oate	C₅₁H₇₆N₈O₁₀	详情	详情
(XII)	18858	(2S)-3-[4-(tert-butoxy)phenyl]-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid	C₂₈H₂₉NO₅	详情	详情
(XIII)	18859	allyl (10S,13S)-10-[[(2R)-2-([(2S)-2-amino-3-[4-(tert-butoxy)phenyl]propanoyl]amino)-3-(1H-indol-3-yl)propanoyl]amino]-15-((1S)-2-[[(1S,2R)-1-(aminocarbonyl)-2-(tert-butoxy)propyl]amino]-1-benzyl-2-oxoethyl)-13-isopropyl-2,2-dimethyl-4,11,14-trioxo-3-oxa-5,12,15-triazanonadecan-19-oate	C₆₄H₉₃N₉O₁₂	详情	详情
(XIV)	18860	(2S)-2-[(2-[[(allyloxy)carbonyl]amino]ethyl)[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-phenylpropionic acid	C₃₀H₃₀N₂O₆	详情	详情
(XV)	18861	allyl (10S,13S,16R,19S,22S)-24-((1S)-2-[[(1S,2R)-1-(aminocarbonyl)-2-(tert-butoxy)propyl]amino]-1-benzyl-2-oxoethyl)-10-benzyl-13-[4-(tert-butoxy)benzyl]-19-[4-[(tert-butoxycarbonyl)amino]butyl]-9-[(9H-fluoren-9-ylmethoxy)carbonyl]-16-(1H-indol-3-ylmethyl)-22-isopropyl-5,11,14,17,20,23-hexaoxo-4-oxa-6,9,12,15,18,21,24-heptaaza-1-octacosen-28-oate	C₉₄H₁₂₁N₁₁O₁₇	详情	详情
(XVI)	18862	(5S,8S,11R,14S,17S)-19-((1S)-2-[[(1S,2R)-1-(aminocarbonyl)-2-(tert-butoxy)propyl]amino]-1-benzyl-2-oxoethyl)-4-(2-aminoethyl)-5-benzyl-8-[4-(tert-butoxy)benzyl]-14-[4-[(tert-butoxycarbonyl)amino]butyl]-1-(9H-fluoren-9-yl)-11-(1H-indol-3-ylmethyl)-17-isopropyl-3,6,9,12,15,18-hexaoxo-2-oxa-4,7,10,13,16,19-hexaazatricosan-23-oic acid	C₈₇H₁₁₃N₁₁O₁₅	详情	详情

合成路线3

The cyclization between free amino and acid groups of compound (XVI) was effected by reaction with benzotriazol-1-yloxy-tripyrrolidinophosphonium hexafluorophosphate (PyBOP) to give the cyclic peptide (XVII). Finally, treatment with moist trifluoroacetic acid (TFA) containing a trace of ethanedithiol (EDT) and triisopropylsilane (TIS) at 0 C removed all protecting groups and liberated from the resin the peptide amide, which was finally purified by reversed-phase preparative HPLC.

参考文献中间体

【1】 Gilon, C.; et al.; A backbone-cyclic, receptor 5-selective somatostatin analogue: Synthesis, bioactivity, and nuclear magnetic resonance conformational analysis. J Med Chem 1998, 41, 6, 919.
【2】 Hornik, V.; Seri-Levy, A.; Gellerman, G.; Gilon, C. (Yissum Research Development Co.); Conformationally constrained backbone cyclized somatostatin analogs. WO 9804583 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XVI)	18862	(5S,8S,11R,14S,17S)-19-((1S)-2-[[(1S,2R)-1-(aminocarbonyl)-2-(tert-butoxy)propyl]amino]-1-benzyl-2-oxoethyl)-4-(2-aminoethyl)-5-benzyl-8-[4-(tert-butoxy)benzyl]-14-[4-[(tert-butoxycarbonyl)amino]butyl]-1-(9H-fluoren-9-yl)-11-(1H-indol-3-ylmethyl)-17-isopropyl-3,6,9,12,15,18-hexaoxo-2-oxa-4,7,10,13,16,19-hexaazatricosan-23-oic acid		C₈₇H₁₁₃N₁₁O₁₅	详情	详情
(XVII)	18863	9H-fluoren-9-ylmethyl (5S,8S,11R,14S,17S)-19-((1S)-2-[[(1S,2R)-1-(aminocarbonyl)-2-(tert-butoxy)propyl]amino]-1-benzyl-2-oxoethyl)-5-benzyl-8-[4-(tert-butoxy)benzyl]-14-[4-[(tert-butoxycarbonyl)amino]butyl]-11-(1H-indol-3-ylmethyl)-17-isopropyl-6,9,12,15,18,23-hexaoxo-1,4,7,10,13,16,19-heptaazacyclotricosane-4-carboxylate		C₈₇H₁₁₁N₁₁O₁₄	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)