CN104650016A - Tripeptide analog compound and preparation method thereof - Google Patents

Tripeptide analog compound and preparation method thereof Download PDF

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CN104650016A
CN104650016A CN201510046379.4A CN201510046379A CN104650016A CN 104650016 A CN104650016 A CN 104650016A CN 201510046379 A CN201510046379 A CN 201510046379A CN 104650016 A CN104650016 A CN 104650016A
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1mmol
peptide bonds
peptide
isonitrile
plan
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王巍
黄靖
何思
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Wuhan University WHU
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Wuhan University WHU
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Abstract

The invention discloses a peptide analog compound containing three peptide bonds and a simple synthesizing method. The synthesized product is a peptide analog product (tripeptide) with a brand new skeleton, wherein the sequences of amido bonds of two peptide bonds are -CONH- and the sequence of the amido bond of the other peptide bond is -NHCO-. At present, the synthetic method of the three peptides comprises the steps of protecting amino acid, forming an amido bond by the coupling reagents such as DCC, EDCI and DCI, and performing deprotection method to step-by-step synthesize. The peptide analog compound containing three peptide bonds can be obtained by means of innovating the synthetic method which is characterized by reacting under a common condition through one step by using the synthetic raw materials mainly including amine, cyclo-anhydride, aldehyde and isonitrile in a one-pot method.

Description

Intend three peptides and preparation method thereof
Technical field
The present invention relates to the easy synthesis that peptide backbone compound library intended by a kind of novel class medicine, such skeleton contains three peptide bonds, is a comparison peptide quasi-molecule.
Background technology
For drug discovery, the acquisition of the symptom of a trend and lead compound is most important for new drug development project initiation.Current symptom of a trend compound mainly comes from for existing compound library screening or bioactive natural product transformation acquisition.Therefore obtain a large amount of novel natural product analog compounds storehouse that has to have great significance for successfully finding novel symptom of a trend compound.
Result of study shows to also exist in vivo the active polypeptide molecular group and active factor that are made up of sequence length and the different active polypeptide of biological activity, wherein some active polypeptide plays very important physiological action in vivo, and these active polypeptide natural products are usually carried out screening active ingredients and transformation is modified to obtaining novel bioactive molecule.The method of general peptide molecule synthesis is taked to use multiple amino acids to go protection to carry out synthesizing (Kawasaki.Chem.Pharm.Bull.43 (12) 2133-2138 (1995)) by protection usually, also has the automatic DNA synthesizer DNA device of solid phase to carry out the synthesis of polypeptide at present.Wherein tripeptides is the special small peptide of a class, there is special medicinal application prospect, such as there is immunocompetent Eisenin (pGlu-Gln-Ala-OH), antidotal GHK-Cu (glycyl-L-histidyl-L-lysine), anti-oxidant gsh (Glutathione), IPP (hypertensin I conversion enzyme inhibitor contained in milk), but melanotropin releases element (Proly-leycyl-glycinamide, the hormone of hypothalamus secretion).Plan peptide in this patent is similar to the peptide of occurring in nature, has potential application prospect (QaisarNadeem.Org.Biomol.Chem., 2014,12,1966) in multiple field such as antibacterial, antitumor.
Compared with traditional Amino acid synthesis polypeptide method, the structure of the product first synthesized is the brand-new skeleton of a class, at present not include by CAS Scifinder (U.S. chemical abstract database).At present in the synthetic method of tripeptides, generally take to use amino acid by protection, use the coupling reagents such as DCC, EDCI, DCI to form amido linkage, then remove the method stepwise synthesis such as protection.And in the present invention, the structure of product of synthesis is plan peptide class product (tripeptides) of the brand-new skeleton of a class, the method of synthesis is innovated, the synthesis material used is based on simple organic molecule amine, acid anhydrides, aldehyde and isonitrile, by the mode for the treatment of different things alike, react under common condition, obtain the plan peptides of a class completely newly containing three peptide bonds, difference compared with general tripeptides structure is, its one of them peptide bond amido linkage sequentially CONH is NHCO.The synthetic method of this kind of brand-new natural product analogue can obtain three adjustable peptide analogs of structure in a large number rapidly, provides the screening study of a class novel plan peptide medicament skeleton for new drug.
Summary of the invention
Problem to be solved by this invention is to provide a kind of plan peptides containing three peptide bonds, in three peptide bonds, the order of two peptide bond amido linkages is-CONH-, and the order of another peptide bond amido linkage is-NHCO-, and has the structure shown in general formula (I):
Wherein:
R 1and R 3independently selected from alkyl, thiazolinyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, assorted alkyl, Heterocyclylalkyl, and the derivative of above-mentioned group;
R 2be selected from alkylidene group, alkenylene, arylidene, cycloalkylidene;
R 4be selected from alkyl, cycloalkyl, cycloalkylalkyl, arylalkyl, and the derivative of above-mentioned group;
R 5be selected from H, aryl, aryl substituted derivatives, heterocyclic aryl.
Described alkylidene group is C2-C6 alkylidene group.The compound of the structure shown in general formula (I) is preferably compound M1, M2, M3, M4, M5, M6, M7, M8, M9, M10, M11, M12, M13, M14, M15, M16, M17,
Prepare the above-mentioned method containing the plan peptides of three peptide bonds, comprise the following steps: will containing R 1aminated compounds with containing R 2acid anhydrides be together dissolved in methylene dichloride, stirred at ambient temperature is separated out to there being insolubles, then adds methyl alcohol successively, containing R 3aminated compounds, containing R 4isonitrile compounds and containing R 5aldehyde compound, stirred overnight at room temperature, question response completely after, decompression is spin-dried for, and is then separated with silica gel column chromatography, namely obtains the compound with structure shown in general formula (I).
Preferably:
Described contains R 1aminated compounds be (chaff amine), (benzylamine), (TERTIARY BUTYL AMINE), (hexahydropyridine), (morpholine), (phenylalanine methyl ester) or (propargylamine);
Described contains R 2acid anhydrides be (Tetra hydro Phthalic anhydride), (Succinic anhydried), (MALEIC ANHYDRIDE) or (suberic acid acid anhydride);
Described R 3aminated compounds be (chaff amine), (benzylamine), (TERTIARY BUTYL AMINE), (hexahydropyridine), (morpholine), (phenylalanine methyl ester) or (propargylamine);
Described contains R 4isonitrile compounds be (4-isonitrile base butyryl radicals methyl esters), (tert-butyl isonitrile), (adamantyl isonitrile), (diamantane ethyl isonitrile) or (benzyl isonitrile);
Described contains R 5aldehyde compound be HCHO (paraformaldehyde), (phenyl aldehyde), (4-chloro-benzaldehyde), (3-aldehyde radical indoles) or (3-formyl radical 6-chlorine ethyl diacetate).
Preferably: containing R 1aminated compounds, containing R 2acid anhydrides, containing R 3aminated compounds, containing R 4isonitrile compounds and containing R 5the mol ratio of aldehyde compound be 1:1:1:1:1.
Embodiment
Below in conjunction with specific embodiment, the present invention is further described, but the present invention is not limited to following examples.
Embodiment 1
Take Tetra hydro Phthalic anhydride (148mg respectively, 1mmol), chaff amine (97mg, 1mmol) in the round-bottomed flask of 50mL, add the methylene dichloride of 1.5mL, stirred at ambient temperature is separated out to product, then 1.5mL methanol solvate, benzylamine (107mg is added successively, 1mmol), adamantyl isonitrile (161mg, 1mmol), paraformaldehyde (30mg, 1mmol), stirring at room temperature, reaction is spent the night, and after question response is complete, decompression is spin-dried for, be separated with silicagel column, productive rate is 76.6%.Products therefrom M1 structure is as follows:
1H NMR(400MHz,CDCl 3)δ7.45(d,J＝7.6Hz,1H),7.26(dd,J＝32.7,19.4Hz,7H),7.10(d,J＝9.9Hz,2H),7.01(d,J＝6.8Hz,2H),6.28–6.21(m,1H),6.16(s,1H),4.77(s,1H),4.58(s,1H),4.30(d,J＝36.7Hz,2H),2.07(s,5H),1.97(d,J＝13.4Hz,4H),1.85(s,2H),1.57(d,J＝18.1Hz,6H)。
13C NMR(101MHz,CDCl3)δ167.10,142.17,128.84,127.32,110.56,107.40,52.54,41.36,36.50,29.59.HRMS(ESI)m/z C 32H 35N 3O 4[M+Na] +548.2529,548.2520。
Embodiment 2
Take Tetra hydro Phthalic anhydride (148mg respectively, 1mmol), chaff amine (97mg, 1mmol) in the round-bottomed flask of 50mL, add the methylene dichloride of 1.5mL, stirred at ambient temperature is separated out to product, then the methanol solvate of 1.5mL, benzylamine (107mg is added successively, 1mmol), benzyl isonitrile (117mg, 1mmol), phenyl aldehyde (106mg, 1mmol), stirring at room temperature, reaction is spent the night, and after question response is complete, decompression is spin-dried for, be separated with silicagel column, productive rate is 22.1%.Products therefrom M2 structure is as follows:
1H NMR(400MHz,CDCl 3)δ7.39(d,J＝7.4Hz,5H),7.24(d,J＝13.0Hz,10H),7.14–6.89(m,4H),6.32(d,J＝5.0Hz,1H),6.18(s,1H),5.30(d,J＝9.3Hz,1H),4.68–4.46(m,2H),4.33(s,1H),4.11(s,1H)。
13C NMR(101MHz,CDCl 3)δ＝169.04,167.34,151.07,142.16,130.66,128.45,127.86,127.03,110.54,107.63,62.88,43.79,36.84.MS：C 35H 31N 3O 4[M+H] +558.24。
Embodiment 3
Take Tetra hydro Phthalic anhydride (148mg respectively; 1mmol), chaff amine (97mg; 1mmol) in the round-bottomed flask of 50mL; add the methylene dichloride of 1.5mL; stirred at ambient temperature is separated out to product; then the methanol solvate of 1.5mL, benzylamine (107mg is added successively; 1mmol), 4-isonitrile base butyryl radicals methyl esters (119mg, 1mmol), paraformaldehyde (30mg, 1mmol); stirring at room temperature; reaction is spent the night, and after question response is complete, decompression is spin-dried for; be separated with silicagel column, productive rate is 30.5%.Products therefrom M3 structure is as follows:
1H NMR(400MHz,CDCl 3)δ7.57(t,J＝11.1Hz,1H),7.44–7.09(m,10H),6.30(s,1H),6.26(s,1H),4.86–4.17(m,4H),3.60(s,3H),3.53–3.24(m,2H),2.40(t,J＝7.6Hz,2H),1.95(dd,J＝17.6Hz,2H)。
13C NMR(101MHz,CDCl 3)δ173.81,172.00,168.13,167.54,150.74,142.33,136.38,135.28,131.86,131.36,128.89,127.90,127.11,110.60,107.75,52.99,51.49,39.03,37.15,31.60,24.57.MS：C 27H 29N 3O 6491.92。
Embodiment 4
Take Tetra hydro Phthalic anhydride (148mg respectively, 1mmol), chaff amine (97mg, 1mmol) in the round-bottomed flask of 50mL, add the methylene dichloride of 1.5mL, after stirred at ambient temperature to product is separated out, then the methanol solvate of 1.5mL, benzylamine (107mg is added successively, 1mmol), tert-butyl isonitrile (83mg, 1mmol), 3-aldehyde radical indoles (145mg, 1mmol), stirring at room temperature, reaction is spent the night, and after question response is complete, decompression is spin-dried for, be separated with silicagel column, productive rate is 17.3%.Products therefrom M4 structure is as follows:
1H NMR(400MHz,CDCl 3)δ7.49(d,J＝13.6Hz,1H),7.36(s,4H),6.32(d,J＝1.2Hz,1H),6.26(d,J＝3.0Hz,1H),4.72(s,1H),4.35(s,1H),3.99(s,1H),3.67(d,J＝19.5Hz,1H),1.72(s,1H),1.57(s,6H),1.45(s,2H),1.28(d,J＝18.4Hz,9H)。
13C NMR(101MHz,CDCl 3)δ172.38,169.29,166.97,151.66,141.94,130.77,128.44,127.86,126.02,110.39,107.25,58.69,51.23,36.76,28.84,28.42,28.19.HRMS(ESI)m/z C 23H 31N 3O 4[M+Na] +436.2195,436.2207。
Embodiment 5
Take Tetra hydro Phthalic anhydride (148mg respectively, 1mmol), chaff amine (97mg, 1mmol) in the round-bottomed flask of 50mL, add the methylene dichloride of 1.5mL, stirred at ambient temperature is separated out to product, then the methanol solvate of 1.5mL, TERTIARY BUTYL AMINE (73mg is added successively, 1mmol), adamantyl isonitrile (161mg, 1mmol), paraformaldehyde (30mg, 1mmol), stirring at room temperature, reaction is spent the night, and after question response is complete, decompression is spin-dried for, be separated with silicagel column, productive rate is 71.3%.Products therefrom M5 structure is as follows:
1H NMR(400MHz,CDCl 3)δ7.32(d,J＝7.5Hz,1H),7.18(dd,J＝19.0,11.5Hz,2H),7.03–6.88(m,2H),6.20(d,J＝1.8Hz,1H),6.14(d,J＝2.7Hz,1H),4.79–4.63(m,1H),4.16–3.97(m,1H),3.92–3.79(m,1H),3.51(d,J＝17.1Hz,1H),2.09–1.80(m,10H),1.66–1.39(m,14H)。
13C NMR(101MHz,CDCl 3)δ172.39,169.03,166.94,151.75,141.96,130.76,128.44,127.91,126.01,110.39,107.20,58.73,52.06,41.08,36.35,29.42,28.22.MS：C 29H 37N 3O 4419.90。
Embodiment 6
Take Succinic anhydried (100mg respectively, 1mmol), chaff amine (97mg, 1mmol) in the round-bottomed flask of 50mL, add the methylene dichloride of 1.5mL, stirred at ambient temperature is separated out to product, then the methanol solvate of 1.5mL, TERTIARY BUTYL AMINE (73mg, 1mmol), adamantyl isonitrile (161mg, 1mmol), paraformaldehyde (30mg is added successively, 1mmol), stirring at room temperature, reaction is spent the night, after question response is complete, decompression is spin-dried for, and be separated with silicagel column, productive rate is 59.0%.Products therefrom M6 structure is as follows:
1H NMR(400MHz,CDCl 3)δ7.25(s,1H),6.22(s,1H),6.12(s,1H),4.32(d,J＝5.2Hz,2H),3.79(s,2H),2.47(d,J＝30.9Hz,4H),1.99(s,9H),1.61(s,6H),1.35(s,9H)。
13C NMR(101MHz,CDCl 3)δ173.49,171.81,168.87,151.55,142.02,110.39,107.23,58.04,52.41,49.95,41.17,36.55,36.31,31.27,30.96,29.44,28.42。
MS：C 25H 37N 3O 4443.98。
Embodiment 7
Take Tetra hydro Phthalic anhydride (148mg respectively; 1mmol), TERTIARY BUTYL AMINE (73mg; 1mmol) in the round-bottomed flask of 50mL; add the methylene dichloride of 1.5mL; stirred at ambient temperature is separated out to product; then the methanol solvate of 1.5mL, 2 hydroxy ethylamine (61mg is added successively; 1mmol), 4-isonitrile base butyryl radicals methyl esters (119mg, 1mmol), paraformaldehyde (30mg, 1mmol); stirring at room temperature; reaction is spent the night, and after question response is complete, decompression is spin-dried for; be separated with silicagel column, productive rate is 42.8%.Products therefrom M7 structure is as follows:
1H NMR(400MHz,CDCl 3)δ7.58–7.28(m,4H),3.83(m,2H),3.65(s,3H),3.30(m,J＝117.8,39.4Hz,6H),2.31(dt,J＝59.5,7.5Hz,2H),1.87(dd,J＝48.6,41.4Hz,2H),1.43(s,9H)。
13C NMR(101MHz,CDCl 3)δ173.67,171.96,169.39,168.51,135.87,134.30,130.77,129.16,127.30,127.08,59.66,53.29,52.37,51.59,50.12,38.99,31.47,28.55,24.68。
Embodiment 8
Take Succinic anhydried (148mg respectively, 1mmol), hexahydropyridine (85mg, 1mmol) in the round-bottomed flask of 50mL, add the methylene dichloride of 1.5mL, stirred at ambient temperature is separated out to product, then the methanol solvate of 1.5mL, benzylamine (107mg is added successively, 1mmol), TERTIARY BUTYL AMINE isonitrile (83mg, 1mmol), 4-chloro-benzaldehyde (140mg, 1mmol), stirring at room temperature, reaction is spent the night, and after question response is complete, decompression is spin-dried for, be separated with silicagel column, productive rate is 24.1%.Products therefrom M8 structure:
1H NMR(400MHz,CDCl 3)δ7.34–7.11(m,9H),6.04(s,1H),5.04–4.36(m,2H),3.46(dt,J＝54.3,5.1Hz,4H),2.80(dd,J＝17.8,10.3Hz,1H),2.62(dd,J＝11.4,6.2Hz,3H),2.29(d,J＝17.1Hz,1H),1.70–1.48(m,6H),1.37(s,9H)。
13C NMR(101MHz,CDCl 3)δ174.73,170.06,168.39,137.44,134.30,133.85,131.44,128.49,128.43,127.01,126.14,62.51,51.73,50.24,46.35,42.93,29.28,28.91,28.68,26.25,25.53,24.47.MS：C 28H 36ClN 3O 3，498.05。
Embodiment 9
Take Tetra hydro Phthalic anhydride (148mg respectively, 1mmol), chaff amine (97mg, 1mmol) in the round-bottomed flask of 50mL, add the methylene dichloride of 1.5mL, stirred at ambient temperature is separated out to product, then the methanol solvate of 1.5mL, benzylamine (107mg is added successively, 1mmol), rimantadine isonitrile (83mg, 1mmol), paraformaldehyde (30mg, 1mmol), stirring at room temperature, reaction is spent the night, and after question response is complete, decompression is spin-dried for, be separated with silicagel column, productive rate is 61.8%.Products therefrom M9 structure is as follows:
1H NMR(400MHz,DMSO)δ7.87(d,J＝7.0Hz,1H),7.66(d,J＝8.8Hz,1H),7.61(s,1H),7.52(dd,J＝13.7,6.1Hz,1H),7.44(s,2H),7.30(d,J＝43.8Hz,4H),6.43(d,J＝8.1Hz,1H),6.34(d,J＝11.8Hz,1H),4.42(dd,J＝70.9,22.3Hz,4H),3.72(d,J＝29.5Hz,1H),3.49(dd,J＝15.8,7.0Hz,1H),3.42(s,2H),1.89(s,3H),1.55(dd,J＝30.9,14.7Hz,10H),1.34(d,J＝15.7Hz,3H),1.04(s,2H),0.83(s,1H).HRMS(ESI)m/z calcd.for C 32H 35N 3O 4[M+Na]+576.2814,found576.2833。
Embodiment 10
Take Succinic anhydried (100mg respectively, 1mmol), chaff amine (97mg, 1mmol) in the round-bottomed flask of 50mL, add the methylene dichloride of 1.5mL, stirred at ambient temperature is separated out to product, then the methanol solvate of 1.5mL, n-Butyl Amine 99 (73mg is added successively, 1mmol), adamantyl isonitrile (161mg, 1mmol), paraformaldehyde (30mg, 1mmol), stirring at room temperature, reaction is spent the night, and after question response is complete, decompression is spin-dried for, be separated with silicagel column, productive rate is 33.9%.Products therefrom M10 structure is as follows:
1H NMR(400MHz,CDCl 3)δ7.34(s,1H),6.31(d,J＝4.8Hz,1H),6.20(d,J＝3.0Hz,1H),4.40(d,J＝8.9Hz,2H),3.89(s,2H),3.47–3.26(m,2H),2.78–2.46(m,4H),2.14–1.91(m,8H),1.76–1.54(m,7H),1.33(dd,J＝15.1,7.5Hz,2H),1.26(s,1H),1.02–0.74(m,3H).MS：C 25H 37N 3O 4444.07。
Embodiment 11
Take suberic acid acid anhydride (156mg respectively, 1mmol), benzylamine (107mg, 1mmol) in the round-bottomed flask of 50mL, add the methylene dichloride of 1.5mL, stirred at ambient temperature is separated out to product, then the methanol solvate of 1.5mL, TERTIARY BUTYL AMINE (73mg is added successively, 1mmol), adamantyl isonitrile (161mg, 1mmol), paraformaldehyde (30mg, 1mmol), stirring at room temperature, reaction is spent the night, and after question response is complete, decompression is spin-dried for, be separated with silicagel column, productive rate is 31.4%.Products therefrom M11 structure is as follows:
1H NMR(400MHz,CDCl 3)δ7.32–7.21(m,5H),6.16(d,J＝12.9Hz,1H),5.95(d,J＝12.9Hz,1H),5.65(d,J＝12.0Hz,1H),1.96(t,J＝10.2Hz,10H),1.58(s,5H),1.43(s,9H),1.30(s,9H).MS：C 31H 47N 3O 3510.08。
Embodiment 12
Take MALEIC ANHYDRIDE (98mg respectively, 1mmol), TERTIARY BUTYL AMINE (107mg, 1mmol) in the round-bottomed flask of 50mL, add the methylene dichloride of 1.5mL, stirred at ambient temperature is separated out to product, then the methanol solvate of 1.5mL, TERTIARY BUTYL AMINE (73mg is added successively, 1mmol), adamantyl isonitrile (161mg, 1mmol), paraformaldehyde (30mg, 1mmol), stirring at room temperature, reaction is spent the night, and after question response is complete, decompression is spin-dried for, be separated with silicagel column, productive rate is 31.4%.Products therefrom M12 structure is as follows:
1H NMR(400MHz,CDCl 3)δ7.32–7.21(m,5H),6.16(d,J＝12.9Hz,1H),5.95(d,J＝12.9Hz,1H),5.65(d,J＝12.0Hz,1H),1.96(t,J＝10.2Hz,10H),1.58(s,5H),1.43(s,9H),1.30(s,9H)。
Embodiment 13
Take Tetra hydro Phthalic anhydride (148mg respectively, 1mmol), phenylalanine methyl ester (179mg, 1mmol) in the round-bottomed flask of 50mL, add the methylene dichloride of 1.5mL, after stirred at ambient temperature to product is separated out, then the methanol solvate of 1.5mL, benzylamine (107mg is added successively, 1mmol), TERTIARY BUTYL AMINE isonitrile (83mg, 1mmol), phenyl aldehyde (106mg, 1mmol), stirring at room temperature, reaction is spent the night, and after question response is complete, decompression is spin-dried for, be separated with silicagel column, productive rate is 17.7%.Products therefrom M13 structure is as follows:
1H NMR(400MHz,CDCl 3)δ7.45-7.07(m,19H),5.41–5.25(m,1H),5.00(d,J＝16.8Hz,1H),4.49(dd,J＝36.4,23.0Hz,2H),3.81–3.68(m,3H),3.24(dt,J＝30.1,16.6Hz,2H),1.27(d,J＝12.3Hz,9H).MS：C 37H 39N 3O 5605.86。
Embodiment 14
Take Succinic anhydried (100mg respectively, 1mmol), hexahydropyridine (85mg, 1mmol) in the round-bottomed flask of 50mL, add the methylene dichloride of 1.5mL, stirred at ambient temperature is separated out to product, then the methanol solvate of 1.5mL, benzylamine (107mg is added successively, 1mmol), TERTIARY BUTYL AMINE isonitrile (83mg, 1mmol), 4-chloro-benzaldehyde (140mg, 1mmol), stirring at room temperature, reaction is spent the night, and after question response is complete, decompression is spin-dried for, be separated with silicagel column, productive rate is 24.1%.Products therefrom M8 structure is as follows:
1H NMR(400MHz,CDCl 3)δ7.34–7.11(m,9H),6.04(s,1H),5.04–4.36(m,2H),3.46(dt,J＝54.3,5.1Hz,4H),2.80(dd,J＝17.8,10.3Hz,1H),2.62(dd,J＝11.4,6.2Hz,3H),2.29(d,J＝17.1Hz,1H),1.70–1.48(m,6H),1.37(s,9H).MS：C 28H 36ClN 3O 3498.05。
Embodiment 15
Take Tetra hydro Phthalic anhydride (148mg respectively; 1mmol), morpholine (87mg; 1mmol) in the round-bottomed flask of 50mL; add the methylene dichloride of 1.5mL; stirred at ambient temperature is separated out to product; then the methanol solvate of 1.5mL, benzylamine (107mg is added successively; 1mmol), TERTIARY BUTYL AMINE isonitrile (83mg, 1mmol), 3-formyl radical 6-chlorine ethyl diacetate (251mg, 1mmol); stirring at room temperature; reaction is spent the night, and after question response is complete, decompression is spin-dried for; be separated with silicagel column, productive rate is 25.4%.Products therefrom M14 structure is as follows:
1H NMR(400MHz,CDCl 3)7.72-7.57(m,1H),7.24(dd,J＝14.2,7.1,3H),7.14(d,J＝7.0,2H),6.95(d,J＝7.2,2H),6.91–6.80(m,2H),6.70(d,J＝19.1,2H),4.59–4.16(m,3H),3.70(dd,J＝63.2,24.0,6H),3.34(s,2H),1.34(s,9H),1.15–1.00(m,3H)。
Embodiment 16
Take Tetra hydro Phthalic anhydride (148mg respectively, 1mmol), benzylamine (107mg, 1mmol) in the round-bottomed flask of 50mL, add the methylene dichloride of 1.5mL, stirred at ambient temperature is separated out to product, then the methanol solvate of 1.5mL, chaff amine (97mg is added successively, 1mmol), diamantane ethyl isonitrile (189mg, 1mmol), paraformaldehyde (30mg, 1mmol), stirring at room temperature, reaction is spent the night, and after question response is complete, decompression is spin-dried for, be separated with silicagel column, productive rate is 36.2%.Products therefrom structure M15 is as follows:
1H NMR(400MHz,CDCl 3)δ7.42–7.28(m,10H),6.31(s,1H),6.13(s,1H),4.97–4.65(m,2H),4.43–4.17(m,2H),3.75(dd,J＝46.6,26.3Hz,2H),3.60(d,J＝33.5Hz,1H),1.91(s,5H),1.58(s,15H),1.26(t,J＝7.1Hz,3H)。
Embodiment 17
Take fourth dicarboxylic acid anhydride (100mg respectively, 1mmol), chaff amine (97mg, 1mmol) in the round-bottomed flask of 50mL, add the methylene dichloride of 1.5mL, stirred at ambient temperature is separated out to product, then the methanol solvate of 1.5mL, propargylamine (55mg is added successively, 1mmol), tert-butyl isonitrile (83mg, 1mmol), 4-chloro-benzaldehyde (140mg, 1mmol), stirring at room temperature, reaction is spent the night, and after question response is complete, decompression is spin-dried for, be separated with silicagel column, productive rate is 22.5%.Products therefrom M16 structure is as follows:
1H NMR(400MHz,CDCl 3)δ7.31(dd,J＝14.6,7.5Hz,5H),6.32(d,J＝10.3Hz,2H),6.21(s,1H),6.05(s,1H),5.93(s,1H),4.42(s,2H),2.89(t,J＝6.2Hz,2H),2.63(d,J＝5.7Hz,2H),2.09(s,1H),1.36(s,9H).MS：C 24H 28ClN 3O 4457.70。
Embodiment 18
Take fourth dicarboxylic acid anhydride (100mg respectively, 1mmol), propargylamine (55mg, 1mmol) in the round-bottomed flask of 50mL, add the methylene dichloride of 1.5mL, stirred at ambient temperature is separated out to product, then the methanol solvate of 1.5mL, propargylamine (55mg is added successively, 1mmol), tert-butyl isonitrile (83mg, 1mmol), 4-chloro-benzaldehyde (140mg, 1mmol), stirring at room temperature, reaction is spent the night, and after question response is complete, decompression is spin-dried for, be separated with silicagel column, productive rate is 22.5%.Products therefrom M17 structure is as follows:
1H NMR(400 MHz,CDCl 3)δ7.41–7.29(m,4H),6.55(s,1H),6.06(d,J＝16.5 Hz,2H),4.07–3.96(m,2H),2.82(ddd,J＝17.2,12.6,6.4 Hz,2H),2.70–2.21(m,4H),1.43–1.30(m,9H).MS：C 22H 26ClN 3O 3[M+Na] +438.19。

Claims (10)

1. the plan peptides containing three peptide bonds, it is characterized in that: in three peptide bonds, the order of two peptide bond amido linkages is-CONH-, and the order of another peptide bond amido linkage is-NHCO-, and has the structure shown in general formula (I):
Wherein:
R 1and R 3independently selected from alkyl, thiazolinyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, assorted alkyl, Heterocyclylalkyl, and the derivative of above-mentioned group;
R 2be selected from alkylidene group, alkenylene, arylidene, cycloalkylidene;
R 4be selected from alkyl, cycloalkyl, cycloalkylalkyl, arylalkyl, and the derivative of above-mentioned group;
R 5be selected from H, aryl, aryl substituted derivatives, heterocyclic aryl.
2. the plan peptides containing three peptide bonds according to claim 1, is characterized in that: described alkylidene group is C2-C6 alkylidene group.
3. the plan peptides containing three peptide bonds according to claim 1, is characterized in that for compound M1, M2, M3, M4, M5, M6, M7, M8, M9, M10, M11, M12, M13, M14, M15, M16, M17,
4. prepare a method for the plan peptides containing three peptide bonds described in any one of claim 1-3, it is characterized in that, comprise the following steps: will containing R 1aminated compounds with containing R 2acid anhydrides be together dissolved in methylene dichloride, stirred at ambient temperature is separated out to there being insolubles, then adds methyl alcohol successively, containing R 3aminated compounds, containing R 4isonitrile compounds and containing R 5aldehyde compound, stirred overnight at room temperature, question response completely after, decompression is spin-dried for, and is then separated with silica gel column chromatography, namely obtains the compound with structure shown in general formula (I).
5. the method containing the plan peptides of three peptide bonds according to claim 4, is characterized in that: described contains R 1aminated compounds be
6. the method containing the plan peptides of three peptide bonds according to claim 4, is characterized in that: described contains R 2acid anhydrides be
7. the method containing the plan peptides of three peptide bonds according to claim 4, is characterized in that: described contains R 3aminated compounds be
8. the method containing the plan peptides of three peptide bonds according to claim 4, is characterized in that: described contains R 4isonitrile compounds be
9. the method containing the plan peptides of three peptide bonds according to claim 4, is characterized in that: described contains R 5aldehyde compound be paraformaldehyde,
10. the preparation method containing the plan peptides of three peptide bonds according to claim 4, is characterized in that: described contains R 1aminated compounds, containing R 2acid anhydrides, containing R 3aminated compounds, containing R 4isonitrile compounds and containing R 5the mol ratio of aldehyde compound be 1:1:1:1:1.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1063108A (en) * 1990-12-31 1992-07-29 藤泽药品工业株式会社 Trifluoromethyl ketone derivatives and its production and use
CN1127511C (en) * 1995-12-20 2003-11-12 沃泰克斯药物股份有限公司 Inhibitors of interleukin-1 'beta' converting enzyme
CN101875617A (en) * 2009-03-23 2010-11-03 中国医学科学院药物研究所 Carbamyl aromatic acid compound with alkoxy replacing aromatic ring, preparation method and application thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1063108A (en) * 1990-12-31 1992-07-29 藤泽药品工业株式会社 Trifluoromethyl ketone derivatives and its production and use
CN1127511C (en) * 1995-12-20 2003-11-12 沃泰克斯药物股份有限公司 Inhibitors of interleukin-1 'beta' converting enzyme
CN101875617A (en) * 2009-03-23 2010-11-03 中国医学科学院药物研究所 Carbamyl aromatic acid compound with alkoxy replacing aromatic ring, preparation method and application thereof

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
MARCO AURELIO MOSTARDEIRO ET AL.: "Synthesis of Tripeptide Fragments of 14-Membered Cyclopeptide Alkaloids", 《J. PRAKT. CHEM.》 *
OAISAR NADEEM ET AL.: "Synthesis of tripeptide derivatized cyclopentadienyl complexes of technetium and rhenium as radiopharmaceutical probes", 《ORG. BIOMOL.CHEM.》 *
徐萍等: "HCMV蛋白酶抑制剂的研究（I）拟肽类抑制剂的设计及其液相组合构建块前体的合成", 《中国药物化学杂志》 *

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