CN103396372A - 2,5-diketopiperazine derivative, as well as preparation method and application thereof in preparing control agent for resisting marine fouling organisms - Google Patents
2,5-diketopiperazine derivative, as well as preparation method and application thereof in preparing control agent for resisting marine fouling organisms Download PDFInfo
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- URVYKTKGOHQKCC-LRMXHFNYSA-N COc(cc1)cc2c1cc(/C=C(\C(N(CC=C)/C1=C/c(cccc3)c3OC)=O)/NC1=O)cc2 Chemical compound COc(cc1)cc2c1cc(/C=C(\C(N(CC=C)/C1=C/c(cccc3)c3OC)=O)/NC1=O)cc2 URVYKTKGOHQKCC-LRMXHFNYSA-N 0.000 description 1
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Abstract
The invention discloses a 2,5-diketopiperazine derivative, as well as a preparation method and an application thereof in preparing a control agent for resisting marine fouling organisms. The structure of the 2,5-diketopiperazine derivative is as shown in a formula (I), wherein R1 and R2 are aromatic groups, alkane groups or substituted homologues of the alkane groups, and R is a methyl group or a propenyl group. The 2,5-diketopiperazine derivative has an obvious inhibiting effect on adhesion of marine organisms on solids can be used for preparing the control agent for resisting the marine fouling organisms. The 2,5-diketopiperazine derivative has less influence on the water-body environment, can not cause enrichment in an organism by virtue of food-chain transfer and thus is environmentally-friendly and high in safety; meanwhile compounds drive instead of killing marine organisms to realize inhibition to adhesion of the fouling organisms on the surfaces of the solids, and are beneficial to the balance of marine ecology; the 2,5-diketopiperazine derivative is great in promotion and application potentials, and is expected to achieve good application prospect in controlling various fouling organisms of marine artificial facilities.
Description
Technical field:
The invention belongs to the marine antifouling coating field, be specifically related to a class 2,5-Diketopiperazine derivative and preparation method thereof and the application in the anti-preventing and removing marine fouling organisms agent of preparation.
Background technology:
Marine fouling organism refers to set or perches at boats and ships and various Artificial facilities under water on solid surface, and to the marine organisms that economical activities of mankind has a negative impact, its harm is mainly increases the boats and ships running resistance, reduces the speed of a ship or plane, increases fuel consumption; Stop up the water pipeline; Change Process of Metallic Corrosion, cause local corrosion or perforation; Hinder the normal operation of all kinds of maritime facilitieies, initiation drift, unbalance even causing topple; Aspect marine aquaculture, also can fight for adherance and bait with cultivated shellfish, hinder growing of cultivation object, and reduce fishery products quality etc.
In preventing and removing marine fouling organisms technology and method, with being most widely used of antifouling paint.Traditional antifouling paint expects that take poison release type is antifouling as main path, by stain control agents such as the copper in release coatings, mercury, tin, arsenic, form marine plant spore and marine animal larva are had the concentration of poisons layer of toxic action around material, thereby reach antifouling purpose.Yet,, take the compound of arsenic, mercury etc. as the antifouling paint of stain control agent is too large because of toxicity, 50 years last century, be eliminated, from the sixties in 20th century, cupric and stanniferous antifouling paint start to be used in a large number.
With tributyl tin (TBT, Tribu-tytin) be once the marine anti-pollution product that is most widely used in the world for the organo-tin compound coating of representative, its mechanism of action is to destroy the normal function of biological cell membrane, hinder oxidative phosphorylation process, destroy the plastosome of animal, affect the normal vital movement of organism, cause the death of fouling organism body and come off.Since putting goods on the market its sixties in 20th century, because of the extremely favor in market of good anti-fouling effect.Yet the organic tin compound can disturb the calcium metabolism of oyster, brings out marine products snails sex distortion, is accumulated in the organisms such as fish, shellfish, by food chain, human health is produced detrimentally affect, and Marine ecosystems are caused serious destruction.Since last century the mid-80, all in succession found the existence of organo-tin compound in the seawater all over the world, bed mud and biology.Therefore, International Maritime Organizaton (IMO) regulation, completely forbade and use organo-tin compound in antifouling paint from 2008.
A large amount of uses of the antifouling paint of cupric can cause the copper also can be in ocean, particularly a large amount of gathering in harbour, thus the marine eco-environment is produced detrimentally affect, therefore its application certainly will also can be subject to certain limitation.
The marine anti-pollution field still lacks safe and effective antifouling paint at present, and therefore, the green antifouling paint that the research and development low toxicity is even nontoxic becomes is badly in need of the important topic that solves in the world.Marine natural product is the secondary metabolite that a class of marine organisms self generation has antifouling activity, and these natural products do not endanger marine organisms life.Find in many researchs, fouling organism shows to some natural product the effect of driving that keeps away, and by it, do not killed, can realize marine eco-environment balance, thereby the exploitation of Marine Natural Product Antifoulants agent is expected to prepare the green antifouling paint of a class high effect nontoxic.Marine Natural Product Antifoulants research starts from the eighties in last century, but because at that time extraction separation and chemosynthesis level are limited, and antifouling mechanism is lacked research, antifouling effect is little.In recent years, along with the raising of each side state of the art, the antifouling mechanism of action of its uniqueness and efficient antifouling activity just come into the picture.Yet, the natural product extraction sepn process is loaded down with trivial details, obtain the compound amount also considerably less, and majority of compounds complex structure, larger to its complete synthesis difficulty, cause the antifouling activity research of natural product mostly to only limit to carry out in laboratory, and can not be used for later experiments, enlarge research and commercial production.So, utilize organic chemistry and pharmaceutical chemistry method, the structure ━ activity relationship of further investigation antifouling activity material, active substance is carried out the compound simple in structure that structural modification or design are easy to synthesize, find and develop and have identical or close, even active better natural product derivative or analogue, reaching simultaneously the cheapness production of natural product derivative and analogue stain control agent thereof, may be than find actual, the more efficient approach of anti-soil material from natural product by extracting method.pass through at present the synthetic natural product derivative of structural modification or methodology of organic synthesis or analogue less for the research of biodeterioration control, however, people have still synthesized some natural product compound or derivatives thereof and analogues, such as sesquiterpene hydrogen, naphtoquinone compounds avarone, bromination tyrosine bastadin, alkaloid aaptamine and dihydrooroidin, zosterin acid zosteric acid, polybromodiphenyl ether, 2-amyl group-4-hydroxyquinoline, capsaicine, Cannabinoids compound cannabinoids etc., they have and the same or analogous anti-fouling effect of natural product.That wherein, attract people's attention is U.S. Rohm﹠amp; Haas company synthetic 4,5-two chloro-Kathon (DCOI) compounds have good and anti-fouling effect wide spectrum, by develop and with SEA-N INE
TM211N is that trade mark is put on market, is called as green stain control agent, has won Presidential Green Chemistry Challenge prize in 1996, and its value is gained recognition.In recent years, the isothiazolinone compounds more and more is subject to domestic and international investigators' attention because of its broad spectrum antibacterial and easy degradation characteristic.Wait take methyl acrylate as raw material in the good citizen, obtain 4 by sulfuration, aminolysis, chlorine cyclisation, 5-two chloro-2-methoxycarbonyl propyls-4-isothiazoline-3-ketone (MOP-DCI), the compound that they will synthesize has prepared antifouling paint, the real extra large link plate of the animated period of biological growth four months still without obvious biological attachment.Xu Fengling etc. are by connecting the groups such as hydrazides, hydrazone class on the DCOI compound, attempt to widen by the method that connection has a stronger fungicidal activity group broad spectrum antibiotic activity of DCOI compounds.The author shows the inhibition activity research result of 5 kinds of aquatic bacterium intestinal bacteria (Escherichia coli), streptococcus aureus (Staphyloccus aurueus), vibrio alginolyticus (Vibrio alginolyticus), Aeromonas hydrophila (Aeromonas hydrophila), subtilis (Bacillus subtilis) etc., and this compounds is 1.00 * 10
-6Under mol/L, bacteriostasis rate all reaches more than 90%, and the compound after display structure is modified has broad-spectrum antibacterial activity preferably.The compound 2 that suppresses more by force marine organisms barnacle attachment activity that has to extracting from polyzoan (Zoobotryon pellucidum) such as Li Xia, 5,6-three bromo-1-methyl gramines (TBG) carry out structural modification, have synthesized that 4 novel different halogens replace and N-is replacement and TBG analogue that have better lipophilic performance.The Bioexperiment result shows, these compounds all have growth inhibitory activity preferably to marine alga (Nitzschia closterium), and wherein the restraining effect of part of compounds is more remarkable, its LC
50Can reach respectively 1.33 μ g/mL and 1.06 μ g/mL.The diterpene compound ent-8 (14) that separation obtains to the mangrove Common Ceriops such as Chen Junde-pimarene-15R, 16-diol carries out simple structural modification, and the attachment activity research of its anti-white ridge barnacle (B.albicostatus) larva is studied, compound activity after find modifying and its extraction product active close, but the compound structure after modifying is more stable, and structure activity study shows that the base group modification of compound 15 and 16 positions is that anti-fouling activity is necessary.
Because marine fouling organism is comprised of animal, plant and microorganism three major types, wherein harm large and adhere to after the kind that is difficult to remove be mainly the biologies such as the stockless cirrus class (barnacle) of tool calcium carbonate shell, battalion's set life and bivalve (mussel and oyster).Therefore, anti-fouling compound filler test work multiselect is experimental subjects with stockless cirrus class and mussels.Stockless cirrus class wherein is again take the reticulate pattern barnacle as representative, one way of life at one of the main fouling organism in the torrid zone, sea area, subtropics, extensively distribute at China South Sea, inhabit near subtidal line to the seabed of depth of water 10m left and right, adult is attached on cay, chad and lives with byssus throughout one's life, can be used as the representative of mussels fouling organism.Therefore, in the art, general proof test adopts the reticulate pattern barnacle as experimental subjects, is to have important representative meaning.
Usually can be divided into two life stages based on fouling organism, one is grown to till exploring off and on body surface and preparing settlement and metamorphosis, for swimming life stage for deviate from egg membrane from larva; Choose and settle down position from larva, after its surface attachment, the abnormal formation young, be set or epiphytism stage.From stained angle, fouling organism produces to the mankind that harm is on its battalion's set or the plant and instrument that adheres to and disadvantageous effect that the latter is produced., if effectively suppress the settlement and metamorphosis of larva or drive it in the adhering to of solid surface, just can reach the purpose that fouling organism is prevented and kill off.Therefore, adopting this larva is the anti-fouling effect that experimental subjects is checked compound, has scientific rationality and representative meaning.
Summary of the invention:
First purpose of the present invention is to provide a class and has 2 of anti-marine biofouling activity, the 5-Diketopiperazine derivative.
A class 2 of the present invention, the 5-Diketopiperazine derivative, under its structure such as formula I:
Wherein, R1, R2 are the replacement homologue of aromatic group, alkyl or alkyl, and R is methyl or propenyl.
Described aromatic group is preferably phenyl, substituted-phenyl, naphthyl or substituted naphthyl, further preferred, described substituted-phenyl is the phenyl that halogen, alkyl or alkoxyl group (as methoxyl group) replace, and described substituted naphthyl is the naphthyl that halogen, alkyl or alkoxyl group (as methoxyl group) replace.
Described alkyl is preferably methyl, ethyl, propyl group, butyl, amyl group, hexyl, heptyl, octyl group, nonyl, decyl, undecyl or dodecyl etc.
R
1, R
2Can be identical, also can be different.As in this structure, R
1, R
2Can be aromatic group simultaneously, or alkyl; Also can be as R
1For aromatic group, R
2For alkyl, vice versa.
Second purpose of the present invention is to provide the preparation method of 2,5-Diketopiperazine derivative, and its building-up process is as follows:
Its synthesis step is as follows:
Glycine anhydride
Reflux in acetic anhydride, after removing unnecessary acetic anhydride, will obtain solid product
It is dissolved in DMF again, with aldehyde R
1At Cs
2CO
3Condition under room temperature reaction, obtain replacing on one side 2, the 5-Diketopiperazine derivative
The one side that then will obtain replace 2, the 5-Diketopiperazine derivative is dissolved in DMF, with halohydrocarbon in anhydrous K
2CO
3Under the condition that exists, room temperature reaction, obtain 2 of N protection, 5-diketopiperazine intermediate
Finally with 2 of N protection, 5-diketopiperazine intermediate
Be dissolved in DMF, with aldehyde R
2At Cs
2CO
3Condition under, room temperature reaction, finally obtain target product 2, the 5-Diketopiperazine derivative
Described aldehyde R
1For aromatic aldehyde or alkanoic; Described halohydrocarbon is methyl iodide, bromopropylene; Described aldehyde R
2For aromatic aldehyde or alkanoic, i.e. R1, R2 is the replacement homologue of aromatic group or alkyl or alkyl, R is methyl or propenyl.
Preferably, in above-mentioned reaction process, the quality of the glycine anhydride that uses and the volume ratio of acetic anhydride are 1:5.0～10.0g/mL; The aldehyde R that uses
1With
The ratio of amount be 1:1.2～2.0, with Cs
2CO
3The ratio of amount be 1.0:1.2～2.0; Use
With the ratio of the amount of halohydrocarbon be 1.0:1.1～1.5, with K
2CO
3The ratio of amount be 1.0:1.5～3.0; Use
With aldehyde R
2The ratio of amount be 1.0:1.2～2.0, with Cs
2CO
3The ratio of amount be 1.0:1.2～2.0.
The present invention finds by the test of anti-ocean Macro-fouling Organisms kentrogon attachment activity, of the present invention as shown in formula I 2, the 5-Diketopiperazine derivative can suppress kentrogon and adhere to, its EC
50Be worth as shown in table 1ly, simultaneously, find in experimentation without any kentrogon death, show as shown in formula I 2, the 5-Diketopiperazine derivative is safety non-toxic.
Therefore, the 3rd purpose of the present invention is to provide 2 shown in formula I, the application of 5-Diketopiperazine derivative in the anti-preventing and removing marine fouling organisms agent of preparation.
The 4th purpose of the present invention is to provide a kind of anti-preventing and removing marine fouling organisms agent, it is characterized in that, contains 2 shown in the formula I of effective dose, the 5-Diketopiperazine derivative.
Compared with prior art, the present invention has following beneficial effect:
1) of the present invention as shown in formula I 2, adhering on solid has significant restraining effect to the 5-Diketopiperazine derivative to marine organisms, can be for the preparation of the agent for preventing and eliminating of anti-marine fouling organism.
2) of the present invention as shown in formula I 2, the 5-Diketopiperazine derivative is the natural product derivative, and is less on the impact of water body environment, can not cause its enrichment in organism by the food chain transmission, thereby environmentally friendly, safe; Simultaneously compound is not killed marine organisms and is realized suppressing fouling organism in the adhering to of solid surface by driveing, and is conducive to the balance of marine ecology chain.
3) the present invention as shown in formula I 2,5-Diketopiperazine derivative synthesis technique is simple, and is cheap, is suitable for scale operation, thereby steady sources is reliable.And at present in the marine anti-pollution field; there do not is any report openly to cross about this type of ring dipeptides (2; the 5-diketopiperazine) derivative or the analogue applied research in fouling organism is prevented and kill off, therefore seem particularly important to the stain control agent research of this compounds with the protection of intellecture property.It is large that it applies potentiality, is expected to have a good application prospect in the fouling organism of all kinds of artificial ocean facilities is prevented and kill off.
Embodiment
Following examples are to further illustrate of the present invention, rather than limitation of the present invention.
Embodiment one: compound 1 synthetic
The acetic anhydride backflow that the 10g glycine anhydride is placed in 100mL is spent the night, and is cooled to room temperature after completing, and decompression is spin-dried for excessive acetic anhydride, and the solid recrystallization in ethyl acetate that obtains is obtained 16.8g white solid compound 1, productive rate: 97%.
1H?NMR(500MHz,CDCl
3)δ:4.56(s,2H),2.54(s,3H);MS-ESI?m/z:197.1[M-H]
-。
Embodiment two: compound 2a's is synthetic
With 2g(10mmol, 1.5eq) compound 1,0.687ml(6.7mmol, 1.0eq) phenyl aldehyde and 3.26g(10mmol, 1.5eq) Cs
2CO
3Join in the DMF of 20mL drying, stirring at room 5h, TLC slowly are added to the water reaction system after detecting and completing, regulate pH to 5-6 left and right, ethyl acetate extraction, drying with 5% dilute hydrochloric acid, resistates silica gel column chromatography after being spin-dried for, obtain 1.27g white solid compound 2a, productive rate: 78%.
1H?NMR(500MHz,CDCl
3)δ:7.95(s,1H),7.48～7.45(m,2H),7.40～7.38(m,3H),7.18(s,?1H),4.51(s,2H),2.66(s,3H);MS-ESI?m/z:243.1[M-H]
-。
Embodiment three: compound 2b's is synthetic
Synthesis step, with embodiment two, is replaced phenyl aldehyde with o-methoxybenzaldehyde, obtains 1.40g white solid compound 2b, productive rate: 76.3%.
1H?NMR(500MHz,CDCl
3)δ:7.95(s,1H),7.48～7.45(m,2H),7.40～7.38(m,3H),7.18(s,1H),4.51(s,2H),3.85,(s,3H),2.61(s,3H);MS-ESI?m/z:273.4[M-H]
-。
Embodiment four: compound 2c's is synthetic
Synthesis step, with embodiment two, is replaced phenyl aldehyde with the 3-bromobenzaldehyde, obtains 1.7g white solid compound 2c, productive rate: 80.0%.
1H?NMR(500MHz,CDCl
3)δ:8.02(s,1H),7.53～7.52(m,2H),7.34～7.32(m,2H),7.09(s,1H),4.52(s,2H),2.66(s,3H);MS-ESI?m/z:321.2,323.2[M-H]
-。
Embodiment five: compound 2d's is synthetic
Synthesis step, with embodiment two, is replaced phenyl aldehyde with the 3-nitrobenzaldehyde, obtains 1.7g white solid compound 2d, productive rate: 88.1%.
1H?NMR(500MHz,CDCl
3)δ:8.22(d,J=7.5Hz,1H),8.16(s,1H),8.12(s,1H),7.64～7.59(m,2H),7.05(s,1H),4.25(d,J=5.5Hz,2H),2.52(s,3H);MS-ESI?m/z:288.1[M-H]
-。
Embodiment six: compound 2e's is synthetic
Synthesis step, with embodiment two, is replaced phenyl aldehyde with octanal, obtains compound 2e, productive rate: 65%.
1H?NMR(500MHz,CDCl
3)δ:6.32(t,J=7.5Hz,1H),4.42(s,2H),2.60(s,3H),2.21～2.16(m,2H),1.53～1.47(m,2H),1.36～1.27(m,8H),0.88(t,J=7.5Hz,3H);MS-ESI?m/z:267.2[M+H]
+,289.2[M+Na]
+。
Embodiment seven: compound 3a's is synthetic
With 1.0g(4.1mmol, 1eq) compound 2a, 0.425ml(4.9mmol, 1.2eq) bromopropylene and 1.13g(8.2mmol, 2.0eq) anhydrous K
2CO
3Join in the DMF of 10mL drying, stirred overnight at room temperature, TLC slowly is added to the water reaction system after detecting and completing, ethyl acetate extraction, drying, the resistates silica gel column chromatography after being spin-dried for, obtain 0.63g white solid compound 3a, productive rate: 54%.
1H?NMR(500MHz,CDCl
3)δ:7.95(s,1H),7.48～7.45(m,2H),7.40～7.38(m,3H),7.18(s,1H),5.54～5.47(m,1H),5.01(d,J=1.0Hz,1H),4.73(d,J=17Hz,1H),4.51(s,2H),4.02(d,J=6.5Hz,2H),2.66(s,3H);MS-ESI?m/z:283.4[M-H]
-。
Embodiment eight: compound 3b's is synthetic
Replace 2a with compound 2b, synthetic method, with embodiment seven, obtains compound 3b, productive rate: 50%.
1H?NMR(500MHz,CDCl
3)δ:7.44(s,1H),7.38(t,J=8.5Hz,1H),7.24(d,J=7.5Hz,2H),6.99(t,J=8.5Hz,1H),6.93(d,J=8.5Hz,2H),5.54～5.47(m,1H),5.01(d,J=1.0Hz,1H),4.73(d,J=17Hz,1H),4.51(s,2H),4.02(d,J=6.5Hz,2H),3.85(s,3H),2.63(s,3H);MS-ESI?m/z:?313.4[M-H]
-。
Embodiment nine: compound 3c's is synthetic
Replace 2a with compound 2c, synthetic method, with embodiment seven, obtains compound 3b, productive rate: 58%.
1H?NMR(500MHz,CDCl
3)δ:7.57(s,J=7.5Hz,1H),7.53(s,1H),7.35(t,J=8.0Hz,1H),7.33(s,1H),7.30(s,1H),5.60～5.54(m,1H),5.10(d,J=10.5Hz,1H),4.81(d,J=17.5Hz,1H),4.59(s,2H),4.15(d,J=6.5Hz,2H),2.69(s,3H);MS-ESI?m/z:360.4,362.4[M+H]
+。
Embodiment ten: compound 3d's is synthetic
Replace 2a with compound 2d, synthetic method, with embodiment seven, obtains compound 3d, productive rate: 64%.
1H?NMR(500MHz,CDCl
3)δ:8.22(d,J=7.5Hz,1H),8.16(s,1H),7.64～7.59(m,2H),6.86(s,1H),5.55～5.47(m,1H),5.05(d,J=10.5Hz,1H),4.74(d,J=17.0Hz,1H),4.25(d,J=5.5Hz,2H),4.07(s,2H),2.51(s,3H);MS-ESI?m/z:330.4[M+H]
+。
Embodiment 11: compound 3e's is synthetic
Replace 2a with compound 2e, synthetic method, with embodiment seven, obtains compound 3e, productive rate: 44%.
1H?NMR(500MHz,CDCl
3)δ:6.35(t,J=6.5Hz,1H),5.82～5.74(m,1H),5.21,5.15(dd,J=10.5Hz,J=10.5Hz,2H),4.39(s,2H),4.30(d,J=5.5Hz,2H),2.57(s,3H),2.27～2.22(m,2H),1.52～1.46(m,2H),1.37～1.27(m,8H),0.88(t,J=7.0Hz,3H);MS-ESI?m/z:307.2[M+H]
+,329.2[M+Na]
+。
Embodiment 12: compound 3f's is synthetic
Replace the 3-bromopropylene with methyl iodide, synthetic method, with embodiment seven, obtains compound 3f, productive rate: 54%.
1H?NMR(500MHz,CDCl
3)δ:7.41(t,J=9.0Hz,2H),7.32(d,J=5.0Hz,2H),4.93(s,2H),2.90(s,3H),2.63(s,3H);MS-ESI?m/z:259.2[M+H]
+。
Embodiment 13: compound 4aa's is synthetic
With 50mg(0.21mmol, 1.0eq.) 3a, 29.4 μ L(0.25mmol, 1.2eq.) 3-bromobenzaldehyde and 82mg(0.25mmol, 1.2eq.) Cs
2CO
3The DMF that adds the 1.5mL drying after mixing, stirring at room 5h, after question response is completed, slowly add 10mL water, with 5%HCl adjust pH 5～6, ethyl acetate extraction, anhydrous Na
2SO
4Drying, silica gel column chromatography obtain 38mg faint yellow solid compound 4aa, productive rate: 45%.
1H?NMR(500MHz,MeOD)δ:7.73(s,1H),7.53(t,J=8.0Hz,2H),7.47(d,J=7.0Hz,2H),7.42～7.36(m,4H),7.24(s,1H),6.94(s,1H),5.63～5.55(m,1H),5.03,5.01(dd,J=1.5Hz,J=1.0Hz,1H),4.76,4.72(dd,J=1.5Hz,J=1.5Hz,1H),4.27(d,J=5.5Hz,2H);MS-ESI?m/z:407.4,409.4[M-H]
-。
Embodiment 14: compound 4ab's is synthetic
Synthetic method, with embodiment 13, is replaced the 3-bromobenzaldehyde with o fluorobenzaldehyde, obtains compound 4ab, productive rate: 35%.
1H?NMR(500MHz,CDCl
3)δ:7.98(s,1H),7.43(d,J=8.0Hz,1H),7.40(s,1H),7.39(s,1H),7.37～7.34(m,2H),7.32(s,1H),7.31(s,1H),7.28(s,1H),7.23(t,J=8.5Hz,1H),7.17(t,J=?10.0Hz,1H),7.05(s,1H),5.59～5.51(m,1H),5.02,(d,J=10.0Hz,1H),4.77(d,J=10.0Hz,1H),4.29(d,J=10.0Hz,2H),MS-ESI?m/z:349.2[M+H]
+。
Embodiment 15: compound 4ac's is synthetic
Synthetic method, with embodiment 13, is replaced the 3-bromobenzaldehyde with 2,3,4-TMB, obtains compound 4ac, productive rate: 50%.
1H?NMR(500MHz,CDCl
3)δ:7.99(s,1H),7.41(t,J=7.5Hz,2H),7.37(d,J=6.5Hz,1H),7.33(d,J=7.0Hz,2H),7.29(s,1H),7.01(s,1H),6.20(s,1H),5.59～5.51(m,1H),5.02(d,J=10.5Hz,1H),4.77(d,J=17.0Hz,1H),4.29(d,J=5.5Hz,2H),3.89(s,9H);MS-ESI?m/z:419.5[M-H]
-。
Embodiment 16: compound 4ad's is synthetic
Synthetic method, with embodiment 13, is replaced the 3-bromobenzaldehyde with lauric aldehyde, obtains compound 4ad, productive rate: 25%.
1H?NMR(500MHz,CDCl
3)δ:8.14(s,1H),7.37(d,J=7.5Hz,2H),7.34(d,J=7.5Hz,1H),7.28(d,J=7.0Hz,2H),7.25(t,J=8.0Hz,1H),5.57～5.47(m,1H),4.90(d,J=10.5Hz,1H),?4.73(d,J=17.0Hz,1H),4.22(d,J=6.0Hz,2H),2.18(q,J=7.0Hz,2H),1.25(s,18H),0.88(t,J=7.0Hz,3H);MS-ESI?m/z:407.5[M-H]
-。
Embodiment 17: compound 4ba's is synthetic
Synthetic method is with embodiment 13, and compound 3b replaces compound 3a, with 6-methoxyl group-2-naphthaldehyde, replaces the 3-bromobenzaldehyde, obtains compound 4ba, productive rate: 53%.
1H?NMR(500MHz,CDCl
3)δ:8.13(s,1H),7.85(s,1H),7.79,7.75(dd,J=8.5Hz,J=9.0Hz,2H),7.48(d,J=7.5Hz,1H),7.36(d,J=7.5Hz,1H),7.34(s,1H),7.24(d,J=7.0Hz,1H),7.20(d,J=10.5Hz,1H),7.18(s,1H),7.14(s,1H),6.99(t,J=7.5Hz,1H),6.93(d,J=8.5Hz,1H),5.60～5.54(m,1H),4.78(d,J=17.0Hz,1H),4.26(d,J=6.0Hz,2H),3.94(s,3H),3.86(s,3H);MS-ESI?m/z:439.4[M-H]
-。
Embodiment 18: compound 4ca's is synthetic
Synthetic method, with embodiment 13, is replaced compound 3a with compound 3c, obtains compound 4ca, productive rate: 51%.
1H?NMR(500MHz,CDCl
3)δ:8.50(s,1H),7.59(s,1H),7.50～7.45(m,3H),7.36(d,J=3.5?Hz,1H),7.32(s,J=4.5Hz,1H),7.29(m,1H),7.24(d,J=7.5Hz,1H),7.15(s,1H),7.02(s,1H),5.58～5.50(m,1H),5.05(d,J=10.0Hz,1H),4.79(d,J=17.0Hz,2H),4.26(d,J=6.0Hz,2H);MS-ESI?m/z:486.1,488.2[M-H]
-。
Embodiment 19: compound 4cb's is synthetic
Synthetic method, with embodiment 18, is replaced the 3-bromobenzaldehyde with 2,3,4-TMB, obtains compound 4cb, productive rate: 58%.
1H?NMR(500MHz,CDCl
3)δ:8.25(s,1H),7.59(s,1H),7.56(d,J=7.5Hz,1H),7.54(s,1H),7.34～7.32(m,3H),7.10(s,1H),6.69(s,1H),5.66～5.60(m,1H),5.13(d,J=10.0Hz,1H),4.88(d,J=17.0Hz,2H),4.35(d,J=5.5Hz,2H),3.96(s,9H);MS-ESI?m/z:497.4,499.4[M-H]
-。
Embodiment 20: compound 4cc's is synthetic
Synthetic method, with embodiment 18, is replaced the 3-bromobenzaldehyde with Benzaldehyde,2-methoxy, obtains compound 4cc, productive rate: 65%.
1H?NMR(500MHz,CDCl
3)δ:8.62(s,1H),7.47(d,J=6.5Hz,1H),7.44(s,1H),7.37(t,J=7.5Hz,1H),7.33(d,J=7.5Hz,1H),7.28～7.22(m,2H),7.17(s,1H),7.08(s,1H),7.02(t,J=7.0Hz,1H),7.00(d,J=8.5Hz,1H),5.60～5.52(m,1H),5.04(d,J=10.Hz,1H),4.89(d,J=17.5Hz,1H),4.27(d,J=6.0Hz,2H),3.96(s,3H);MS-ESI?m/z:439.1,441.1[M+H]
+。
Embodiment 21: compound 4cd's is synthetic
Synthetic method, with embodiment 18, is replaced the 3-bromobenzaldehyde with octanal, obtains compound 4cd, productive rate: 23%.
1H?NMR(500MHz,CDCl
3)δ:9.08(s,1H),7.49(d,J=8.0Hz,1H),7.44(s,1H),7.27(d,J=8.0Hz,1H),7.24(d,1H),7.17(s,1H),6.26(t,J=7.5Hz,1H),5.58～5.50(m,1H),5.04(d,J=10.5Hz,1H),4.78(d,J=17.5Hz,1H),4.25(d,J=5.5Hz,2H),2.28～2.25(m,2H),1.57～1.51(m,2H),1.39～1.29(m,8H);0.89(t,J=6.5Hz,3H);MS-ESI?m/z:429.4,431.4[M-H]
-。
Embodiment 22: compound 4ce's is synthetic
Synthetic method, with embodiment 18, is replaced the 3-bromobenzaldehyde with lauric aldehyde, obtains compound 4ce, productive rate: 34%.
1H?NMR(500MHz,CDCl
3)δ:8.43(s,1H),7.46(d,J=6.5Hz,1H),7.41(s,1H),7.24(d,J=8.0Hz,1H),7.20(d,J=8.0Hz,1H),7.15(s,1H),6.21(t,J=7.5Hz,1H),5.56～5.47(m,1H),5.02(d,J=10.5Hz,1H),4.75(d,J=17.5Hz,1H),4.21(d,J=5.5Hz,2H),2.21～2.18(m,2H),1.54～1.48(m,2H),1.36～1.24(m,16H);0.88(t,J=6.5Hz,3H);MS-ESI?m/z:485.4,487.4[M-H]
-。
Embodiment 23: compound 4da's is synthetic
Synthetic method, with embodiment 18, is replaced compound 3a with compound 3d, with the 3-chlorobenzaldehyde, replaces the 3-bromobenzaldehyde, obtains compound 4da, productive rate: 38%.
1H?NMR(500MHz,CDCl
3)δ:8.22(d,J=7.5Hz,1H),8.16(s,1H),8.12(s,1H),7.64～7.59(m,2H),7.41～7.39(m,2H),7.36(t,J=13.5Hz,1H),7.31(d,J=8.0Hz,1H),7.27(s,1H),7.05(s,1H),5.55～5.47(m,1H),5.05(d,J=10.5Hz,1H),4.74(d,J=17.0Hz,1H),4.25(d,J=5.5Hz,2H);MS-ESI?m/z:408.4[M-H]
-。
Embodiment 24: compound 4ea and 4eb's is synthetic
Synthetic method, with embodiment 18, is replaced compound 3a with compound 3e, with phenyl aldehyde, replaces the 3-bromobenzaldehyde, separates and obtains compound 4ea and compound 4eb simultaneously.Productive rate: 24%(4ea), 36%(4eb).
4ea:
1H?NMR(500MHz,CDCl
3)δ:7.97(s,1H),7.43(t,J=7.5Hz,3H),7.38(d,J=7.5Hz,2H),7.34(d,J=7.5Hz,1H),6.98(s,1H),5.90～5.82(m,1H),5.76(t,J=7.5Hz,1H),5.27(d,J=10.5Hz,1H),5.21(d,J=17.0Hz,1H),4.49(d,J=4.5Hz,2H),2.76～2.71(m,2H),1.48～1.43(m,2H),1.30～1.25(m,8H);0.88(t,J=7.0Hz,3H);MS-ESI?m/z:351.4[M-H]
-。
4eb:
1H?NMR(500MHz,CDCl
3)δ:8.18(s,1H),7.45(t,J=10.5Hz,1H),7.42(d,J=7.5Hz,1H),7.38(d,J=7.5Hz,2H),7.33(d,J=7.5Hz,1H),7.01(s,1H),6.28(t,J=7.5Hz,1H),5.95～5.89(m,1H),5.25(d,J=10.5Hz,1H),5.19(d,J=17.5Hz,1H),5.51(d,J=9.9Hz,2H),2.40～2.35(m,2H),1.53～1.46(m,2H),1.33～1.25(m,8H);0.88(t,J=6.5Hz,3H);MS-ESI?m/z:351.4[M-H]
-。
Embodiment 25: compound 4fa's is synthetic
Synthetic method, with embodiment 18, is replaced compound 3a with compound 3f, with 3,4,5-Trimethoxybenzaldehyde, replaces the 3-bromobenzaldehyde, obtains compound 4fa.Productive rate: 63%.
4fa:
1H?NMR(500MHz,CDCl
3)δ:8.02(s,1H),7.40(t,J=7.0Hz,2H),7.35(d,J=7.0Hz,1H),7.31(d,J=2.5Hz,2H),7.29(s,1H),7.00(s,1H),6.62(s,2H),3.89(s,9H),3.01(s,3H);;MS-ESI?m/z:393.4[M-H]
-。
Embodiment 26: resist and adhere to experiment
Use settled organism: reticulate pattern barnacle cyprids;
Use the anti-compound that adheres to: 2,5-Diketopiperazine derivative;
The acquisition methods of cyprids is as follows: at first gather the reticulate pattern barnacle of growing up from tideland, Hong Kong, it is exposed in air under room temperature 12 as a child after, be placed in again the seawater that has filtered with 0.22 μ m filtering membrane, allow it slowly hatch naupiar larva, then be bait with Chaetoceros gracilis, naupiar larva is placed in constant incubator under the condition of 26-28 ℃, it is cultured to cyprids, the new cyprids of cultivating is used for the anti-experiment of adhering to immediately.
Resisting and adhering to experiment is to carry out in a kind of 24 hole polystyrene plates, and at first compound is dissolved in DMSO, then with the seawater that filters, is diluted to needed concentration: 25,10,5,2.5,1.25,0.625,0.31,0.15 μ g/mL.
Put into the compound solution of 15-20 cyprids and 1mL in each hole, each sample 3 repeated experiments, join in sample solution as positive control with filtering sea and DMSO alternative compounds.Then, all sample solutions are placed in inherent 25 ℃ of constant incubator and cultivate 24-48 hour.Test result detects barnacle in the death of the quantity of solid surface-attached, the quantity of not adhering to and barnacle or the quantity of pathology etc. with anatomical lens.The inhibiting rate of compound is by calculating respectively in single hole, the larva quantity of adhering to or larva quantity that pathology occurs with add the ratio of kentrogon sum to obtain, EC
50Value is used for representing that the quantity that compound inhibition larva adheres to is the concentration that adds larva sum one half compound.With Probit software, 3 revision tests are processed finally, result represents with mean value.
Experimental result shows, does not find in all samples that dead situation appears in any larva, and the compound safety non-toxic is described, half inhibiting rate concentration of compound is as shown in table 1.
Table 1: compound suppresses the kentrogon experimental result
Claims (9)
1. a class 2, the 5-Diketopiperazine derivative, under its structure such as formula I:
Wherein, R1, R2 are the replacement homologue of aromatic group, alkyl or alkyl, and R is methyl or propenyl.
2. according to claim 12, the 5-Diketopiperazine derivative, is characterized in that, described aromatic group is phenyl, substituted-phenyl, naphthyl or substituted naphthyl.
3. according to claim 22, the 5-Diketopiperazine derivative, is characterized in that, described substituted-phenyl is the phenyl that halogen, alkyl or alkoxyl group replace, and described substituted naphthyl is the naphthyl that halogen, alkyl or alkoxyl group replace.
4. according to claim 32, the 5-Diketopiperazine derivative, is characterized in that, described alkoxyl group is the oxygen methyl.
5. according to claim 22, the 5-Diketopiperazine derivative, is characterized in that, described alkyl is methyl, ethyl, propyl group, butyl, amyl group, hexyl, heptyl, octyl group, nonyl, decyl, undecyl or dodecyl.
One kind claimed in claim 12, the preparation method of 5-Diketopiperazine derivative, is characterized in that, its building-up process is as follows:
Its synthesis step is as follows:
Glycine anhydride
Reflux in acetic anhydride, after removing unnecessary acetic anhydride, will obtain solid product
It is dissolved in DMF again, with aldehyde R
1At Cs
2CO
3Condition under room temperature reaction, obtain replacing on one side 2, the 5-Diketopiperazine derivative
The one side that then will obtain replace 2, the 5-Diketopiperazine derivative is dissolved in DMF, with halohydrocarbon in anhydrous K
2CO
3Under the condition that exists, room temperature reaction, obtain 2 of N protection, 5-diketopiperazine intermediate
Finally with 2 of N protection, 5-diketopiperazine intermediate
Be dissolved in DMF, with aldehyde R
2At Cs
2CO
3Condition under, room temperature reaction, finally obtain target product 2, the 5-Diketopiperazine derivative
Described aldehyde R
1For aromatic aldehyde or alkanoic; Described halohydrocarbon is methyl iodide, bromopropylene; Described aldehyde R
2For aromatic aldehyde or alkanoic, i.e. R1, R2 is the replacement homologue of aromatic group or alkyl or alkyl, R is methyl or propenyl.
7. preparation method according to claim 6, is characterized in that, in reaction process, the quality of the glycine anhydride that uses and the volume ratio of acetic anhydride are 1:5.0～10.0g/mL; The aldehyde R that uses
1With
The ratio of amount be 1:1.2～2.0, with Cs
2CO
3The ratio of amount be 1.0:1.2～2.0; Use
With the ratio of the amount of halohydrocarbon be 1.0:1.1～1.5, with K
2CO
3The ratio of amount be 1.0:1.5～3.0; Use
With aldehyde R
2The ratio of amount be 1.0:1.2～2.0, with Cs
2CO
3The ratio of amount be 1.0:1.2～2.0.
Claimed in claim 1 as shown in formula I 2, the 5-Diketopiperazine derivative is in the application of preparation in anti-preventing and removing marine fouling organisms agent.
9. an anti-preventing and removing marine fouling organisms agent, is characterized in that, contain effective dose claimed in claim 1 as shown in formula I 2, the 5-Diketopiperazine derivative.
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