(2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-phenylpropionic acid; N-((9H-fluoren-9-ylmethoxy)carbonyl)-phenylalanine -Drug Synthesis Database

【结构式】

【分子编号】19030

【品名】(2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-phenylpropionic acid; N-((9H-fluoren-9-ylmethoxy)carbonyl)-phenylalanine

【CA登记号】35661-40-6

【分子式】C₂₄H₂₁NO₄

【分子量】387.43508

【元素组成】C 74.4% H 5.46% N 3.62% O 16.52%

与该中间体有关的原料药合成路线共 11 条

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7 合成路线8 合成路线9 合成路线10 合成路线11

合成路线1

该中间体在本合成路线中的序号：(I)

Fmoc-protected phenylalanine (I) is attached to Rink resin by means of DCC and HOBt coupling, to give the amino acid-resin complex (II). Then, N-Fmoc protecting group is removed with piperidine in DMF to afford (III). This is submitted to further sequential amino acid coupling and deprotection cycles with Fmoc-phenylalanine (I) and alpha-Fmoc-omega-pmc-D-arginine (VI) to yield in turn resins (V) and (VII), respectively.

参考文献中间体

合成目标

【1】 Brown, W.; DiMaio, J.; Schiller, P.; Martel, R. (AstraZeneca plc); Novel opioid peptides for the treatment of pain and use thereof. JP 1997509168; WO 9522557 .

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)	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
(II)	19031	9H-fluoren-9-ylmethyl (1S)-2-amino-1-benzyl-2-oxoethylcarbamate		C₂₄H₂₂N₂O₃	详情	详情
(III)	19032	(2S)-2-amino-3-phenylpropanamide	5241-58-7	C₉H₁₂N₂O	详情	详情
(IV)	19033	9H-fluoren-9-ylmethyl (1S)-2-[[(1S)-2-amino-1-benzyl-2-oxoethyl]amino]-1-benzyl-2-oxoethylcarbamate		C₃₃H₃₁N₃O₄	详情	详情
(V)	19034	(2S)-2-amino-N-[(1S)-2-amino-1-benzyl-2-oxoethyl]-3-phenylpropanamide		C₁₈H₂₁N₃O₂	详情	详情
(VI)	19035	(2R)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-5-[(imino[[(2,2,5,7,8-pentamethyl-3,4-dihydro-2H-chromen-6-yl)sulfonyl]amino]methyl)amino]pentanoic acid	119831-72-0	C₃₅H₄₂N₄O₇S	详情	详情
(VII)	19036	9H-fluoren-9-ylmethyl (1R)-1-[[((1S)-2-[[(1S)-2-amino-1-benzyl-2-oxoethyl]amino]-1-benzyl-2-oxoethyl)amino]carbonyl]-4-[(imino[[(2,2,5,7,8-pentamethyl-3,4,4a,8a-tetrahydro-2H-chromen-6-yl)sulfonyl]amino]methyl)amino]butylcarbamate		C₅₃H₆₃N₇O₈S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

The title compound has been prepared by solid-phase peptide synthesis on a Knorr resin. N-Fmoc-L-Phenylalanine (I) is attached to the resin by means of BOP and HOBt, producing resin (II). Deprotection of the N-Fmoc group of (II) with piperidine in DMF gives the phenylalanine-bound resin (III). Subsequent coupling with N-Fmoc-L-p-fluorophenylalanine (IV) yields the dipeptide resin (V), which is further deprotected to (VI) with piperidine in DMF. Further coupling-deprotection cycles with N-Fmoc-D-alanine (VII) and N-Fmoc-O-tert-butyl-L-tyrosine (IX) provide the peptide resins (VIII) and (X) respectively. Finally, simultaneous cleavage from the resin and side chain deprotection is accomplished by treatment with trifluoroacetic acid.

参考文献中间体

合成目标

【1】 Wang, W. (AstraZeneca plc); Novel opioid peptides. EP 0845003; JP 1999512086; US 6337319; WO 9707130 .

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)	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
(II)	19031	9H-fluoren-9-ylmethyl (1S)-2-amino-1-benzyl-2-oxoethylcarbamate		C₂₄H₂₂N₂O₃	详情	详情
(III)	19032	(2S)-2-amino-3-phenylpropanamide	5241-58-7	C₉H₁₂N₂O	详情	详情
(IV)	61042	(2S)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-3-(4-fluorophenyl)propanoic acid		C₂₄H₂₀FNO₄	详情	详情
(V)	61043	9H-fluoren-9-ylmethyl (1S)-2-{[(1S)-2-amino-1-benzyl-2-oxoethyl]amino}-1-(4-fluorobenzyl)-2-oxoethylcarbamate		C₃₃H₃₀FN₃O₄	详情	详情
(VI)	61044	(2S)-2-amino-N-[(1S)-2-amino-1-benzyl-2-oxoethyl]-3-(4-fluorophenyl)propanamide		C₁₈H₂₀FN₃O₂	详情	详情
(VII)	19926	(2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid		C₁₈H₁₇NO₄	详情	详情
(VIII)	61045	(2S)-N-[(1S)-2-amino-1-benzyl-2-oxoethyl]-2-{[(2R)-2-aminopropanoyl]amino}-3-(4-fluorophenyl)propanamide		C₂₁H₂₅FN₄O₃	详情	详情
(IX)	18858	(2S)-3-[4-(tert-butoxy)phenyl]-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid		C₂₈H₂₉NO₅	详情	详情
(X)	61046	(2S)-2-amino-N-((1R)-2-{[(1S)-2-{[(1S)-2-amino-1-benzyl-2-oxoethyl]amino}-1-(4-fluorobenzyl)-2-oxoethyl]amino}-1-methyl-2-oxoethyl)-3-[4-(tert-butoxy)phenyl]propanamide		C₃₄H₄₂FN₅O₅	详情	详情

合成路线3

该中间体在本合成路线中的序号：(IX)

To the resin (VIII) were in turn incorporated the following aminoacids: N-Fmoc-L-phenylalanine (IX), N-Fmoc-tryptophan (XI), N-Fmoc-L-aspartic acid beta-t-butyl ester (XIII) and the glycosylated asparragine derivative (XV), each followed by an Fmoc deprotection step to furnish the peptide resins (X), (XII), (XIV) and (XVI), respectively.

参考文献中间体

合成目标

【1】 Aimoto, S.; Akaji, K.; Synthesis of MEN11420, a glycosylated bicyclic peptide, by intramolecular double cyclization using a chloroimidazolinium coupling reagent. Tetrahedron 2001, 57, 9, 1749.
【2】 Arcamone, F.; Maggi, C.A.; Quartara, L.; Giannotti, D. (Menarini Industrie Farma Riunite Srl); Bicyclic tachykinins antagonists, preparation thereof and their use in pharmaceutical compsn.. JP 1999501643; WO 9628467 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIII)	56123	(2S)-2-({(2S)-2-amino-3-[(tert-butoxycarbonyl)amino]propanoyl}amino)-4-methylpentanoic acid		C₁₄H₂₇N₃O₅	详情	详情
(IX)	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
(X)	56124	(2S)-2-({(2S)-2-{[(2S)-2-amino-3-phenylpropanoyl]amino}-3-[(tert-butoxycarbonyl)amino]propanoyl}amino)-4-methylpentanoic acid		C₂₃H₃₆N₄O₆	详情	详情
(XI)	56129	(2S)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-3-(1H-indol-3-yl)propanoic acid		C₂₆H₂₂N₂O₄	详情	详情
(XII)	56125	(2S)-2-({(2S)-2-[((2S)-2-{[(2S)-2-amino-3-(1H-indol-3-yl)propanoyl]amino}-3-phenylpropanoyl)amino]-3-[(tert-butoxycarbonyl)amino]propanoyl}amino)-4-methylpentanoic acid		C₃₄H₄₆N₆O₇	详情	详情
(XIII)	22260	(2S)-4-(tert-butoxy)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-oxobutyric acid		C₂₃H₂₅NO₆	详情	详情
(XIV)	56126	(2S,5S,8S,11S,14S)-14-amino-8-benzyl-5-{[(tert-butoxycarbonyl)amino]methyl}-11-(1H-indol-3-ylmethyl)-2-isobutyl-18,18-dimethyl-4,7,10,13,16-pentaoxo-17-oxa-3,6,9,12-tetraazanonadecan-1-oic acid		C₄₂H₅₉N₇O₁₀	详情	详情
(XV)	56127	2,3,4,5,6-pentafluorophenyl (2S)-4-({(2R,3R,4R,5R,6R)-3-(acetylamino)-4,5-bis(acetyloxy)-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-2-yl}amino)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-4-oxobutanoate		C₃₉H₃₆F₅N₃O₁₃	详情	详情
(XVI)	56128	(2S,5S,8S,11S,14S)-14-{[(2S)-4-({(2R,3R,4R,5R,6R)-3-(acetylamino)-4,5-bis(acetyloxy)-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-2-yl}amino)-2-amino-4-oxobutanoyl]amino}-8-benzyl-5-{[(tert-butoxycarbonyl)amino]methyl}-11-(1H-indol-3-ylmethyl)-2-isobutyl-18,18-dimethyl-4,7,10,13,16-pentaoxo-17-oxa-3,6,9,12-tetraazanonadecan-1-oic acid		C₆₀H₈₄N₁₀O₂₀	详情	详情

合成路线4

该中间体在本合成路线中的序号：(IX),(XXI)

In an alternative procedure, initial anchoring of N-Fmoc-L-phenylalanine (IX) to the chlorotrityl resin afforded resin (XXI), which was deprotected with piperidine in DMF to provide the phenylalanine-resin (XXII). Sequential coupling and deprotection cycles with N-Fmoc-L-tryptophan (XI), N-Fmoc-L-aspartic acid beta-t-butyl ester (XIII), and N-Fmoc-N’-(tetraacetyl-beta-D-glycosyl)asparragine (XXV) yielded the peptide resins (XXIII), (XXIV) and (XXVI), respectively.

参考文献中间体

合成目标

【1】 Aimoto, S.; Akaji, K.; Synthesis of MEN11420, a glycosylated bicyclic peptide, by intramolecular double cyclization using a chloroimidazolinium coupling reagent. Tetrahedron 2001, 57, 9, 1749.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IX),(XXI)	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
(XI)	56129	(2S)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-3-(1H-indol-3-yl)propanoic acid		C₂₆H₂₂N₂O₄	详情	详情
(XIII)	22260	(2S)-4-(tert-butoxy)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-oxobutyric acid		C₂₃H₂₅NO₆	详情	详情
(XXII)	13952	(S)-(-)-Phenylalanine; L-Phenylalanine	63-91-2	C₉H₁₁NO₂	详情	详情
(XXIII)	56133	(2S)-2-{[(2S)-2-amino-3-(1H-indol-3-yl)propanoyl]amino}-3-phenylpropanoic acid		C₂₀H₂₁N₃O₃	详情	详情
(XXIV)	56134	(2S)-2-{[(2S)-2-{[(2S)-2-amino-4-(tert-butoxy)-4-oxobutanoyl]amino}-3-(1H-indol-3-yl)propanoyl]amino}-3-phenylpropanoic acid		C₂₈H₃₄N₄O₆	详情	详情
(XXV)	56135	(2S)-4-({(2R,3R,4R,5R,6R)-3-(acetylamino)-4,5-bis(acetyloxy)-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-2-yl}amino)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-4-oxobutanoic acid		C₃₃H₃₇N₃O₁₃	详情	详情
(XXVI)	56136	(2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-4-({(2R,3R,4R,5R,6R)-3-(acetylamino)-4,5-bis(acetyloxy)-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-2-yl}amino)-2-amino-4-oxobutanoyl]amino}-4-(tert-butoxy)-4-oxobutanoyl]amino}-3-(1H-indol-3-yl)propanoyl]amino}-3-phenylpropanoic acid		C₄₆H₅₉N₇O₁₆	详情	详情

合成路线5

该中间体在本合成路线中的序号：(III)

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

合成目标

【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6

该中间体在本合成路线中的序号：(X)

The title compound was synthesized by stepwise solid-phase peptide synthesis, starting from the protected arginine linked to PAM resin (I). After deprotection of the Boc group of (I) with trifluoroacetic acid, coupling with (Boc)-tryptophan (II) in the presence of TBTU and diisopropylethylamine afforded the dipeptide resin (III). Sequential deprotection and coupling cycles with (Boc)-D-cyclohexylalanine (IV), (Boc)-proline (VI), (Boc)-ornithine (VIII), and (Fmoc)-phenylalanine (X) provided the resins (V), (VII), (IX) and (XI), respectively.

参考文献中间体

合成目标

【1】 Wong, A.K.; Shields, I.A.; Taylor, S.M.; Short, A.; Fairlie, D.P.; Haaima, G.; Finch, A.M.; Effects of a new C5a receptor antagonist on C5a- and endotoxin-induced neutropenia in the rat. Br J Pharmacol 1999, 126, 3, 551.

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)	19064	(2S)-2-[(tert-butoxycarbonyl)amino]-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoic acid		C₁₈H₂₈N₄O₆S	详情	详情
(II)	16114	N-alpha-t-BOC-L-tryptophan; (2S)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propionic acid	13139-14-5	C₁₆H₂₀N₂O₄	详情	详情
(III)	29340	(2S)-2-[[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoic acid		C₂₉H₃₈N₆O₇S	详情	详情
(IV)	29348	(2R)-2-[(tert-butoxycarbonyl)amino]-3-cyclohexylpropionic acid		C₁₄H₂₅NO₄	详情	详情
(V)	29341	(6R,9S,12S)-6-(cyclohexylmethyl)-12-[3-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]propyl]-9-(1H-indol-3-ylmethyl)-2,2-dimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecan-13-oic acid		C₃₈H₅₃N₇O₈S	详情	详情
(VI)	16734	(2S)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-L-proline; (2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid		C₁₀H₁₇NO₄	详情	详情
(VII)	29342	(2S)-2-[[(2S)-2-[[(2R)-2-([[(2S)-1-(tert-butoxycarbonyl)pyrrolidinyl]carbonyl]amino)-3-cyclohexylpropanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoic acid		C₄₃H₆₀N₈O₉S	详情	详情
(VIII)	29343	(2S)-5-amino-2-[(tert-butoxycarbonyl)amino]pentanoic acid	21887-64-9	C₁₀H₂₀N₂O₄	详情	详情
(IX)	29344	(2S)-2-[[(2S)-2-[((2R)-2-[[((2S)-1-[(2S)-5-amino-2-[(tert-butoxycarbonyl)amino]pentanoyl]pyrrolidinyl)carbonyl]amino]-3-cyclohexylpropanoyl)amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoic acid		C₄₈H₇₀N₁₀O₁₀S	详情	详情
(X)	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
(XI)	29345	Fluorenylmethoxycarbonyl-L-phenylalanyl-L-ornithyl-L-prolyl-D-cyclohexylalanyl-L-tryptophyl-L-(Nomega-tosyl)arginine		C₆₇H₈₁N₁₁O₁₁S	详情	详情

合成路线7

该中间体在本合成路线中的序号：(II)

The compound was prepared via solid-phase synthesis using Rink-amide resin (I). After initial Fmoc-deprotection of (I) with piperidine in DMF, Fmoc-L-phenylalanine (II) was coupled to the resin by means of N,N'-diisopropyl carbodiimide (DIC) and hydroxybenzotriazole (HOBt) in DMF, yielding the phenylalanine-linked resin (III). Subsequent Fmoc-deprotection and coupling cycles with protected arginine (IV) and cyclohexylalanine (VI) produced the peptide resins (V) and (VII), respectively. Further deprotection of (VII) with piperidine, followed by coupling with 5-bromonicotinic acid (VIII) gave the corresponding amide (IX). Cleavage of the final peptide amide from the resin (IX) was then accomplished by treatment trifluoroacetic acid and anisole.

参考文献中间体

合成目标

【1】 Addo, M.F.; Hawkins, M.J.; Maryanoff, B.E.; Oksenberg, D.; McComsey, D.F.; Andrade-Gordon, P.; Heterocycle-peptide hybrid compounds. Aminotriazole-containing agonists of the thrombin receptor (PAR-1). Bioorg Med Chem Lett 1999, 9, 10, 1423.
【2】 Hawkins, M.J.; Maryanoff, B.E.; McComsey, D.F. (Ortho-McNeil Pharmaceutical, Inc.); Substd. heterocyclic acyl-tripeptides useful as thrombin receptor modulators. WO 0035942 .

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)	28722	9H-fluoren-9-ylmethyl carbamate	84418-43-9	C₁₅H₁₃NO₂	详情	详情
(II)	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
(III)	19031	9H-fluoren-9-ylmethyl (1S)-2-amino-1-benzyl-2-oxoethylcarbamate		C₂₄H₂₂N₂O₃	详情	详情
(IV)	30825	(2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-5-[(imino[[(2,2,5,7,8-pentamethyl-3,4,4a,8a-tetrahydro-2H-chromen-6-yl)sulfonyl]amino]methyl)amino]pentanoic acid		C₃₅H₄₄N₄O₇S	详情	详情
(V)	30826	9H-fluoren-9-ylmethyl (1S)-1-([[(1S)-2-amino-1-benzyl-2-oxoethyl]amino]carbonyl)-4-[(imino[[(2,2,5,7,8-pentamethyl-3,4,4a,8a-tetrahydro-2H-chromen-6-yl)sulfonyl]amino]methyl)amino]butylcarbamate		C₄₄H₅₄N₆O₇S	详情	详情
(VI)	30827	(2S)-3-cyclohexyl-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid		C₂₄H₂₇NO₄	详情	详情
(VII)	30828	9H-fluoren-9-ylmethyl (1S)-2-([(1S)-1-([[(1S)-2-amino-1-benzyl-2-oxoethyl]amino]carbonyl)-4-[(imino[[(2,2,5,7,8-pentamethyl-3,4,4a,8a-tetrahydro-2H-chromen-6-yl)sulfonyl]amino]methyl)amino]butyl]amino)-1-(cyclohexylmethyl)-2-oxoethylcarbamate		C₅₃H₆₉N₇O₈S	详情	详情
(VIII)	17913	5-Bromonicotinic acid	20826-04-4	C₆H₄BrNO₂	详情	详情
(IX)	30829	N-[(1S)-2-([(1S)-1-([[(1S)-2-amino-1-benzyl-2-oxoethyl]amino]carbonyl)-4-[(imino[[(2,2,5,7,8-pentamethyl-3,4,4a,8a-tetrahydro-2H-chromen-6-yl)sulfonyl]amino]methyl)amino]butyl]amino)-1-(cyclohexylmethyl)-2-oxoethyl]-5-bromonicotinamide		C₄₄H₆₁BrN₈O₇S	详情	详情

合成路线8

该中间体在本合成路线中的序号：(XII)

Preparation of the title compound was carried out by solid-phase peptide synthesis, starting from Wang resin bounded to N-Fmoc-phenylalanine (XII). Removal of the Fmoc group of (XII) with piperidine in DMF provided phenylalanine-resin (XIII), which was subsequently coupled with N-Fmoc-glutamic acid gamma-tert-butyl ester (XIV) in the presence of O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) and 1-hydroxybenzotriazole (HOBt). Cleavage of the Fmoc group from the resulting protected dipeptide-resin furnished (XV). Sequential coupling-deprotection cycles with N-Fmoc-alanine (XVI), intermediate (XI) and Nalpha-Fmoc-Nbeta-trityl-asparagine (XIX) furnished the peptide resins (XVII), (XVIII) and (XX), respectively. (Scheme 28685901b).

参考文献中间体

合成目标

【1】 Lin, X.; Shin, D.; Downs, D.; Tang, J.; Koelsch, G.; Ghosh, A.K.; Ermolieff, J.; Design of potent inhibitors for human brain memapsin 2 (beta-secretase). J Am Chem Soc 2000, 122, 14, 3522.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XI)	40633	(2R,4S,5S)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-2,7-dimethyloctanoic acid		C₃₁H₄₅NO₅Si	详情	详情
(XII)	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
(XIII)	13952	(S)-(-)-Phenylalanine; L-Phenylalanine	63-91-2	C₉H₁₁NO₂	详情	详情
(XIV)	22258	(2S)-5-(tert-butoxy)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-5-oxopentanoic acid	104091-08-9	C₂₄H₂₇NO₆	详情	详情
(XV)	40634	(2S)-2-[[(2S)-2-amino-5-(tert-butoxy)-5-oxopentanoyl]amino]-3-phenylpropionic acid		C₁₈H₂₆N₂O₅	详情	详情
(XVI)	19926	(2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid		C₁₈H₁₇NO₄	详情	详情
(XVII)	40635	(2S)-2-[[(2S)-2-[[(2S)-2-aminopropanoyl]amino]-5-(tert-butoxy)-5-oxopentanoyl]amino]-3-phenylpropionic acid		C₂₁H₃₁N₃O₆	详情	详情
(XVIII)	40636	(5S,7R,10S,13S,16S)-5-[(1S)-1-amino-3-methylbutyl]-16-benzyl-13-[3-(tert-butoxy)-3-oxopropyl]-2,2,3,3,7,10-hexamethyl-8,11,14-trioxo-4-oxa-9,12,15-triaza-3-silaheptadecan-17-oic acid		C₃₇H₆₄N₄O₈Si	详情	详情
(XIX)	40637	(2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-oxo-4-(tritylamino)butyric acid		C₃₈H₃₂N₂O₅	详情	详情
(XX)	40638	(5S,8S,9S,11R,14S,17S,20S)-5-amino-20-benzyl-17-[3-(tert-butoxy)-3-oxopropyl]-9-[[tert-butyl(dimethyl)silyl]oxy]-8-isobutyl-11,14-dimethyl-3,6,12,15,18-pentaoxo-1,1,1-triphenyl-2,7,13,16,19-pentaazahenicosan-21-oic acid		C₆₀H₈₄N₆O₁₀Si	详情	详情

合成路线9

该中间体在本合成路线中的序号：(XII)

参考文献中间体

合成目标

【1】 Lin, X.; Shin, D.; Downs, D.; Tang, J.; Koelsch, G.; Ghosh, A.K.; Ermolieff, J.; Design of potent inhibitors for human brain memapsin 2 (beta-secretase). J Am Chem Soc 2000, 122, 14, 3522.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XI)	40633	(2R,4S,5S)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-2,7-dimethyloctanoic acid		C₃₁H₄₅NO₅Si	详情	详情
(XII)	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
(XIII)	13952	(S)-(-)-Phenylalanine; L-Phenylalanine	63-91-2	C₉H₁₁NO₂	详情	详情
(XIV)	22258	(2S)-5-(tert-butoxy)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-5-oxopentanoic acid	104091-08-9	C₂₄H₂₇NO₆	详情	详情
(XV)	40634	(2S)-2-[[(2S)-2-amino-5-(tert-butoxy)-5-oxopentanoyl]amino]-3-phenylpropionic acid		C₁₈H₂₆N₂O₅	详情	详情
(XVI)	19926	(2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid		C₁₈H₁₇NO₄	详情	详情
(XVII)	40635	(2S)-2-[[(2S)-2-[[(2S)-2-aminopropanoyl]amino]-5-(tert-butoxy)-5-oxopentanoyl]amino]-3-phenylpropionic acid		C₂₁H₃₁N₃O₆	详情	详情
(XVIII)	40636	(5S,7R,10S,13S,16S)-5-[(1S)-1-amino-3-methylbutyl]-16-benzyl-13-[3-(tert-butoxy)-3-oxopropyl]-2,2,3,3,7,10-hexamethyl-8,11,14-trioxo-4-oxa-9,12,15-triaza-3-silaheptadecan-17-oic acid		C₃₇H₆₄N₄O₈Si	详情	详情
(XIX)	40637	(2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-oxo-4-(tritylamino)butyric acid		C₃₈H₃₂N₂O₅	详情	详情
(XX)	40638	(5S,8S,9S,11R,14S,17S,20S)-5-amino-20-benzyl-17-[3-(tert-butoxy)-3-oxopropyl]-9-[[tert-butyl(dimethyl)silyl]oxy]-8-isobutyl-11,14-dimethyl-3,6,12,15,18-pentaoxo-1,1,1-triphenyl-2,7,13,16,19-pentaazahenicosan-21-oic acid		C₆₀H₈₄N₆O₁₀Si	详情	详情

合成路线10

该中间体在本合成路线中的序号：(XXII)

The deprotection of Wang-RESIN-coupled N-Fmoc-D-aspartic acid alpha-methyl ester (XII) with piperidine in DMF gives the free RESIN-coupled aspartic acid monoester (XIII), which is condensed with N-Fmoc-sarcosine (XIV) by means of PyBOP in DMF to yield the dipeptide (XV). Deprotection with piperidine affords (XVI), and coupling with PyBOP was repeated with the L-glutamate (XVII) to afford tripeptide (XVIII); with deprotected (XIX) and the intermediate amino acid (XI) to provide tetrapeptide (XX); and with deprotected (XXI) and -Fmoc-L-phenylalanine (XXII) to furnish finally the protected RESIN-bounded pentapeptide (XXIII).

参考文献中间体

合成目标

【1】 O'Donnell, M.E.; et al.; Serine-threonine protein phosphatase inhibitors derived from nodularin: Role of the 2-methyl and 3-diene groups in the Adda residue and the effect of macrocyclic conformational restraint. J Chem Soc - Perkins Trans I 2001, 14, 1696.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XI)	52438	3-({[(9H-fluoren-9-ylmethyl)oxy]carbonyl}amino)-2-methyl-5-phenyl-4-pentenoic acid		C₂₇H₂₅NO₄	详情	详情
(XII)	52439	3-({[(9H-fluoren-9-ylmethyl)oxy]carbonyl}amino)-4-(methyloxy)-4-oxobutanoic acid		C₂₀H₁₉NO₆	详情	详情
(XIII)	52440	3-amino-4-(methyloxy)-4-oxobutanoic acid		C₅H₉NO₄	详情	详情
(XIV)	52441	2-[{[(9H-fluoren-9-ylmethyl)oxy]carbonyl}(methyl)amino]acetic acid		C₁₈H₁₇NO₄	详情	详情
(XV)	52442	3-({2-[{[(9H-fluoren-9-ylmethyl)oxy]carbonyl}(methyl)amino]acetyl}amino)-4-(methyloxy)-4-oxobutanoic acid		C₂₃H₂₄N₂O₇	详情	详情
(XVI)	52443	3-{[2-(methylamino)acetyl]amino}-4-(methyloxy)-4-oxobutanoic acid		C₈H₁₄N₂O₅	详情	详情
(XVII)	52444	4-({[(9H-fluoren-9-ylmethyl)oxy]carbonyl}amino)-5-(methyloxy)-5-oxopentanoic acid		C₂₁H₂₁NO₆	详情	详情
(XVIII)	52445	1-(9H-fluoren-9-yl)-9-methyl-5,13-bis[(methyloxy)carbonyl]-3,8,11-trioxo-2-oxa-4,9,12-triazapentadecan-15-oic acid		C₂₉H₃₃N₃O₁₀	详情	详情
(XIX)	52446	3-({2-[[4-amino-5-(methyloxy)-5-oxopentanoyl](methyl)amino]acetyl}amino)-4-(methyloxy)-4-oxobutanoic acid		C₁₄H₂₃N₃O₈	详情	详情
(XX)	52447	1-(9H-fluoren-9-yl)-6,13-dimethyl-9,17-bis[(methyloxy)carbonyl]-3,7,12,15-tetraoxo-5-(2-phenylethenyl)-2-oxa-4,8,13,16-tetraazanonadecan-19-oic acid		C₄₁H₄₆N₄O₁₁	详情	详情
(XXI)	52448	3-({2-[[4-[(3-amino-2-methyl-5-phenyl-4-pentenoyl)amino]-5-(methyloxy)-5-oxopentanoyl](methyl)amino]acetyl}amino)-4-(methyloxy)-4-oxobutanoic acid		C₂₆H₃₆N₄O₉	详情	详情
(XXII)	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
(XXIII)	52449	1-(9H-fluoren-9-yl)-9,16-dimethyl-12,20-bis[(methyloxy)carbonyl]-3,6,10,15,18-pentaoxo-8-(2-phenylethenyl)-5-(phenylmethyl)-2-oxa-4,7,11,16,19-pentaazadocosan-22-oic acid		C₅₀H₅₅N₅O₁₂	详情	详情

合成路线11

该中间体在本合成路线中的序号：(I)

The title compound is prepared by solid-phase peptide synthesis starting from N-Fmoc-L-phenylalanine attached to Wang resin (I). Deprotection of (I) with piperidine in NMP removes the N-Fmoc group, yielding the phenylalanine resin (II). Coupling of (II) with N-trityl glycine (III) in the presence of PyBOP and HOBt, followed by acidic cleavage of the N-trityl group furnishes the dipeptide derivative (IV). To this is assembled N-Fmoc-S-trityl-D-penicillamine (V), followed by deprotection with piperidine in NMP, to produce resin (VI). Subsequent coupling of (VI) with N-Cbz-O-benzyl-L-tyrosine (VII) leads to the protected tetrapeptide (VIII). Removal of the S-trityl protecting group of (VIII) employing trifluoroacetic acid provides thiol (IX).

参考文献中间体

合成目标

【1】 Rew, Y.; Malkmus, S.; Svensson, C.; Yaksh, T.L.; Chung, N.N.; Schiller, P.W.; Cassel, J.A.; DeHaven, R.; Goodman, M.; Synthesis and biological activities of cyclic lanthionine enkephalin analogues: delta-Opioid receptor selective ligands. J Med Chem 2002, 45, 17, 3746.

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)	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
(II)	13952	(S)-(-)-Phenylalanine; L-Phenylalanine	63-91-2	C₉H₁₁NO₂	详情	详情
(III)	63269	2-(tritylamino)acetic acid		C₂₁H₁₉NO₂	详情	详情
(IV)	63270	(2S)-2-[(2-aminoacetyl)amino]-3-phenylpropanoic acid		C₁₁H₁₄N₂O₃	详情	详情
(V)	63271	(2S)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-3-methyl-3-(tritylsulfanyl)butanoic acid		C₃₉H₃₅NO₄S	详情	详情
(VI)	63272	(2S)-2-[(2-{[(2S)-2-amino-3-methyl-3-(tritylsulfanyl)butanoyl]amino}acetyl)amino]-3-phenylpropanoic acid		C₃₅H₃₇N₃O₄S	详情	详情
(VII)	27842	(2S)-2-[[(benzyloxy)carbonyl]amino]-3-[4-(benzyloxy)phenyl]propionic acid		C₂₄H₂₃NO₅	详情	详情
(VIII)	63273	(5S,8S,14S)-14-benzyl-5-[4-(benzyloxy)benzyl]-8-[1-methyl-1-(tritylsulfanyl)ethyl]-3,6,9,12-tetraoxo-1-phenyl-2-oxa-4,7,10,13-tetraazapentadecan-15-oic acid		C₅₉H₅₈N₄O₈S	详情	详情
(IX)	63274	(5S,8S,14S)-14-benzyl-5-[4-(benzyloxy)benzyl]-8-(1-methyl-1-sulfanylethyl)-3,6,9,12-tetraoxo-1-phenyl-2-oxa-4,7,10,13-tetraazapentadecan-15-oic acid		C₄₀H₄₄N₄O₈S	详情	详情

Extended Information