PPI-368, -Drug Synthesis Database

【结构式】

【药物名称】PPI-368

【化学名称】(3α,5β,7α,12α)-Trihydroxycholan-24-oyl-L-leucyl-L-valyl-Lphenylalanyl- L-phenylalanyl-L-alanine

【CA登记号】

【分子式】C₅₆H₈₃N₅O₁₀

【分子量】986.31341

【开发单位】Praecis

【药理作用】NEUROLOGIC DRUGS, COGNITION-ENHANCING DRUGS

合成路线1 合成路线2

合成路线1

Title compound was synthesized by solid phase peptide synthesis on a Wang resin using N-9-fluorenylmethoxycarbonyl (Fmoc)-protected amino acids. The (Fmoc)alanine-resin (I) was treated with piperidine in N-methylpyrrolidone to yield deprotected alanine-resin (II). Then, condensation with (Fmoc)-phenylalanine (III) using diisopropyl cabodiimide (DIC) and 1-hydroxybenzotriazole (HOBt) as the coupling reagents provided the (Fmoc)-dipeptide resin (IV), which was deprotected as before with piperidine in NMP. The resulting deprotected dipeptide resin (V) was submitted to further sequential amino acid coupling and deprotection cycles with (Fmoc)-phenylalanine (III), (Fmoc)-valine (VII), and (Fmoc)-leucine (IX), to yield in turn resins (VI), (VIII), and (X), respectively. Resin (X) was then coupled with cholic acid (XI) in the presence of DIC and HOBt to give the corresponding amide (XII).

参考文献中间体

【1】 Reed, M.J.; Hundal, A.; Molineaux, S.; Chin, J.; Kelley, M.; Findeis, M.A.; Kasman, L.; Benjamin, H.; Kubasek, W.; Musso, G.; Signer, E.R.; Wakefield, J.; Lee, J.-J.; Garnick, M.B.; Gefter, M.L. (Praecis Pharmaceuticals Inc.); Modulators of amyloid aggregation. JP 1999514333; WO 9628471 .

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)	19926	(2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid		C₁₈H₁₇NO₄	详情	详情
(II)	10141	D-Alanine; D-2-Aminopropionic Acid	338-69-2	C₃H₇NO₂	详情	详情
(III)	19030	(2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-phenylpropionic acid; N-((9H-fluoren-9-ylmethoxy)carbonyl)-phenylalanine	35661-40-6	C₂₄H₂₁NO₄	详情	详情
(IV)	19929	(2S)-2-[((2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-phenylpropanoyl)amino]propionic acid		C₂₇H₂₆N₂O₅	详情	详情
(V)	19930	(2S)-2-[[(2S)-2-amino-3-phenylpropanoyl]amino]propionic acid	3918-87-4	C₁₂H₁₆N₂O₃	详情	详情
(VI)	19931	(2S)-2-[((2S)-2-[[(2S)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl)amino]propionic acid		C₂₁H₂₅N₃O₄	详情	详情
(VII)	19932	(2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-methylbutyric acid		C₂₀H₂₁NO₄	详情	详情
(VIII)	19933	(2S)-2-([(2S)-2-[((2S)-2-[[(2S)-2-amino-3-methylbutanoyl]amino]-3-phenylpropanoyl)amino]-3-phenylpropanoyl]amino)propionic acid		C₂₆H₃₄N₄O₅	详情	详情
(IX)	19934	(2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-methylpentanoic acid		C₂₁H₂₃NO₄	详情	详情
(X)	19935	(2S,5S,8S,11S,14S)-14-amino-5,8-dibenzyl-11-isopropyl-2,16-dimethyl-4,7,10,13-tetraoxo-3,6,9,12-tetraazaheptadecan-1-oic acid		C₃₂H₄₅N₅O₆	详情	详情
(XI)	19936	(4R)-4-[(3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3,7,12-trihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoic acid		C₂₄H₄₀O₅	详情	详情
(XII)	19937	(2S,5S,8S,11S,14S,19R)-5,8-dibenzyl-14-isobutyl-11-isopropyl-2-methyl-4,7,10,13,16-pentaoxo-19-[(3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3,7,12-trihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl]-3,6,9,12,15-pentaazaicosan-1-oic acid		C₅₆H₈₃N₅O₁₀	详情	详情

合成路线2

Finally, removal of the peptide from the resin was effected by treatment with a mixture of H2O, thioanisole, phenol, and ethanedithiol in trifluoroacetic acid.

参考文献中间体

【1】 Reed, M.J.; Hundal, A.; Molineaux, S.; Chin, J.; Kelley, M.; Findeis, M.A.; Kasman, L.; Benjamin, H.; Kubasek, W.; Musso, G.; Signer, E.R.; Wakefield, J.; Lee, J.-J.; Garnick, M.B.; Gefter, M.L. (Praecis Pharmaceuticals Inc.); Modulators of amyloid aggregation. JP 1999514333; WO 9628471 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XII)	19937	(2S,5S,8S,11S,14S,19R)-5,8-dibenzyl-14-isobutyl-11-isopropyl-2-methyl-4,7,10,13,16-pentaoxo-19-[(3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3,7,12-trihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl]-3,6,9,12,15-pentaazaicosan-1-oic acid		C₅₆H₈₃N₅O₁₀	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)