|
【结 构 式】 
|
【分子编号】18858 【品名】(2S)-3-[4-(tert-butoxy)phenyl]-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid 【CA登记号】 |
【 分 子 式 】C28H29NO5 【 分 子 量 】459.542 【元素组成】C 73.18% H 6.36% N 3.05% O 17.41% |
合成路线1
该中间体在本合成路线中的序号：(IX)Compound (VII) is submitted to amino acid coupling and deprotection cycle with O-t-Bu-alpha-Fmoc-tyrosine (IX), to yield resin (XI). Finally, acidic treatment of (XI) with trifluoroacetic acid in anisole and dichloromethane simultaneously effects deprotection of the O-tert-butyl and N-2,2,5,7,8-pentamethylchroman-6-sulfonyl (Pmc) groups, and liberates the peptide amide from the resin.
| 【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 |
|---|---|---|---|---|---|---|
| (VIII) | 19037 | (2R)-2-amino-N-((1S)-2-[[(1S)-2-amino-1-benzyl-2-oxoethyl]amino]-1-benzyl-2-oxoethyl)-5-[(imino[[(2,2,5,7,8-pentamethyl-3,4,4a,8a-tetrahydro-2H-chromen-6-yl)sulfonyl]amino]methyl)amino]pentanamide | C38H53N7O6S | 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) | 19039 | 9H-fluoren-9-ylmethyl (1S)-2-([(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]butyl]amino)-1-[4-(tert-butoxy)benzyl]-2-oxoethylcarbamate | C66H80N8O10S | 详情 | 详情 | |
| (XI) | 19040 | (2R)-N-((1S)-2-[[(1S)-2-amino-1-benzyl-2-oxoethyl]amino]-1-benzyl-2-oxoethyl)-2-([(2S)-2-amino-3-[4-(tert-butoxy)phenyl]propanoyl]amino)-5-[(imino[[(2,2,5,7,8-pentamethyl-3,4,4a,8a-tetrahydro-2H-chromen-6-yl)sulfonyl]amino]methyl)amino]pentanamide | C51H70N8O8S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)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.
| 【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：(XII)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).
| 【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 |
|---|---|---|---|---|---|---|
| (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4
该中间体在本合成路线中的序号：(III)The solid-phase method of peptide synthesis, with an ABIMED AMS 422 synthesizer and a Rink amide resin have been used. N-Fmoc-L-Leucine (I) was attached to Rink amide resin using benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate as the coupling reagent, and the Fmoc protecting group was subsequently removed to afford resin (II). Further coupling and deprotection cycles with N-Fmoc-L-tyrosine(O-t--Bu) (III), N-Fmoc-N-Boc-L-lysine (V) and again N-Fmoc-N-Boc-L-lysine (V) provided peptide resins (IV), (VI) and (VII), respectively.
| 【1】 Davidson, A.; Fridkin, M.; Perl, O.; Rubinraut, S.; Gozes, I.; Ashur-Fabian, O.; Giladi, E.; Mapping the active site in vasoactive intestinal to a core of four amino acids: Neuroprotective drug design. Proc Natl Acad Sci USA 1999, 96, 7, 4143. |
| 【2】 Gozes, I.; Fridkin, M. (Yeda Research & Development Co. Ltd.); Conjugates of lipophilic moieties and fragments of vasoactive intestinal peptide (VIP). WO 9740070 . |
| 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) | 19934 | (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-methylpentanoic acid | C21H23NO4 | 详情 | 详情 | |
| (II) | 27091 | (2S)-2-amino-4-methylpentanamide | C6H14N2O | 详情 | 详情 | |
| (III) | 18858 | (2S)-3-[4-(tert-butoxy)phenyl]-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid | C28H29NO5 | 详情 | 详情 | |
| (IV) | 27096 | (2S)-2-([(2S)-2-amino-3-[4-(tert-butoxy)phenyl]propanoyl]amino)-4-methylpentanamide | C19H31N3O3 | 详情 | 详情 | |
| (V) | 18854 | (2S)-6-[(tert-butoxycarbonyl)amino]-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]hexanoic acid | C26H32N2O6 | 详情 | 详情 | |
| (VI) | 27092 | tert-butyl (5S)-5-amino-6-([(1S)-2-[[(1S)-1-(aminocarbonyl)-3-methylbutyl]amino]-1-[4-(tert-butoxy)benzyl]-2-oxoethyl]amino)-6-oxohexylcarbamate | C30H51N5O6 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VI)The cyclic peptide precursor (XIV) was prepared by solid-phase synthesis on a preformed HMPB-MBHA resin. Attachment of N-Fmoc-glycine (I) to the resin by means of DCC and DMAP afforded resin (II). The Fmoc protecting group was then removed with piperidine in DMF, yielding the glycine-bound resin (III). Further couplings with the following protected amino acids: N-Fmoc-3-(aminomethyl)-5-nitrobenzoic acid (IV), N-Fmoc-L-tyrosine(O-t-butyl) (VI) and N-Fmoc-glycine (I), followed by Fmoc deprotection cycles, produced in turn the peptide resins (V), (VII) and (VIII). To peptide resin (VIII) was then coupled N-Fmoc-L-aspartic acid gamma-t-butyl ester (IX), yielding resin (X). Peptide (XI) was then liberated from the resin by means of 1% trifluoroacetic acid in CH2Cl2. The Fmoc group was subsequently removed by treatment with diethylamine in acetonitrile, giving (XII).
| 【1】 Park, H.S.; et al.; Protein surface recognition by synthetic receptors: A route to novel submicromolar inhibitors for alpha-chymotrypsin. J Am Chem Soc 1999, 121, 1, 8. |
| 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),(II) | 42131 | 2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]acetic acid | 29022-11-5 | C17H15NO4 | 详情 | 详情 |
| (X),(XI) | 47339 | 2-([3-[(4S,10S)-4-[4-(tert-butoxy)benzyl]-10-[2-(tert-butoxy)-2-oxoethyl]-14-(9H-fluoren-9-yl)-3,6,9,12-tetraoxo-13-oxa-2,5,8,11-tetraazatetradec-1-yl]-5-nitrobenzoyl]amino)acetic acid | C48H54N6O13 | 详情 | 详情 | |
| (III) | 20436 | glycine | 56-40-6 | C2H5NO2 | 详情 | 详情 |
| (IV) | 47335 | 3-([[(9H-fluoren-9-ylmethoxy)carbonyl]amino]methyl)-5-nitrobenzoic acid | C23H18N2O6 | 详情 | 详情 | |
| (V) | 47336 | 2-[[3-(aminomethyl)-5-nitrobenzoyl]amino]acetic acid | C10H11N3O5 | 详情 | 详情 | |
| (VI) | 18858 | (2S)-3-[4-(tert-butoxy)phenyl]-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid | C28H29NO5 | 详情 | 详情 | |
| (VII) | 47337 | 2-([3-[([(2S)-2-amino-3-[4-(tert-butoxy)phenyl]propanoyl]amino)methyl]-5-nitrobenzoyl]amino)acetic acid | C23H28N4O7 | 详情 | 详情 | |
| (VIII) | 47338 | 2-([3-[([(2S)-2-[(2-aminoacetyl)amino]-3-[4-(tert-butoxy)phenyl]propanoyl]amino)methyl]-5-nitrobenzoyl]amino)acetic acid | C25H31N5O8 | 详情 | 详情 | |
| (IX) | 22260 | (2S)-4-(tert-butoxy)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-oxobutyric acid | C23H25NO6 | 详情 | 详情 | |
| (XII) | 47340 | 2-[(3-[(4S,10S)-10-amino-4-[4-(tert-butoxy)benzyl]-14,14-dimethyl-3,6,9,12-tetraoxo-13-oxa-2,5,8-triazapentadec-1-yl]-5-nitrobenzoyl)amino]acetic acid | C33H44N6O11 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(VI)In an alternative method for the solution-phase synthesis of this intermediate, methyl 3-carbamoyl-5-nitrobenzoate (XV) was reduced with borane to amino ester (XVI), which was subsequently hydrolyzed to the corresponding amino acid (XVII). Coupling of amino acid (XVII) with N-Fmoc-L-tyrosine(O-t-butyl) (VI) using DCC and N-hydroxysuccinimide produced dipeptide (XVIII). This was then coupled with the tripeptide H-Gly-Asp(t-Bu)-Gly-OH (XIX) to yield the linear peptide (XX). After Fmoc deprotection, cyclization in the presence of TBTU and DMAP furnished the cyclic peptide (XIII), which was further reduced to the amino derivative (XIV) as above.
| 【1】 Lin, Q.; et al.; Protein surface recognition by synthetic receptors. NATO ASI Series. Series C: Mathematical and Physical Sciences 1999, 527, 197. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 18858 | (2S)-3-[4-(tert-butoxy)phenyl]-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid | C28H29NO5 | 详情 | 详情 | |
| (XIII) | 47341 | tert-butyl 2-[(7S,13S)-13-[4-(tert-butoxy)benzyl]-19-nitro-2,5,8,11,14-pentaoxo-3,6,9,12,15-pentaazabicyclo[15.3.1]henicosa-1(21),17,19-trien-7-yl]acetate | C33H42N6O10 | 详情 | 详情 | |
| (XV) | 47343 | methyl 3-(aminocarbonyl)-5-nitrobenzoate | C9H8N2O5 | 详情 | 详情 | |
| (XVI) | 47344 | methyl 3-(aminomethyl)-5-nitrobenzoate | C9H10N2O4 | 详情 | 详情 | |
| (XVII) | 47345 | 3-(aminomethyl)-5-nitrobenzoic acid | C8H8N2O4 | 详情 | 详情 | |
| (XVIII) | 47346 | 3-[[((2S)-3-[4-(tert-butoxy)phenyl]-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propanoyl)amino]methyl]-5-nitrobenzoic acid | C36H35N3O8 | 详情 | 详情 | |
| (XIX) | 47347 | 2-[[(2S)-2-[(2-aminoacetyl)amino]-4-(tert-butoxy)-4-oxobutanoyl]amino]acetic acid | C12H21N3O6 | 详情 | 详情 | |
| (XX) | 47348 | 2-[[(2S)-4-(tert-butoxy)-2-([2-[(3-[[((2S)-3-[4-(tert-butoxy)phenyl]-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propanoyl)amino]methyl]-5-nitrobenzoyl)amino]acetyl]amino)-4-oxobutanoyl]amino]acetic acid | C48H54N6O13 | 详情 | 详情 |