CN103396372B - 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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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 marine antifouling coating field, be specifically related to 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 on boats and ships and various Artificial facilities under water solid surface, and to the marine organisms that economical activities of mankind has a negative impact, its harm is mainly and increases boats and ships running resistance, reduces the speed of a ship or plane, increases fuel consumption; Blocking waterpipe; Change Process of Metallic Corrosion, cause local corrosion or perforation; Hinder the normal work of all kinds of maritime facilities, initiation drift, unbalance even causing topple; In 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 techniques and methods, being most widely used with antifouling paint.Traditional antifouling paint is antifouling for main path with poison material release type, by stain control agents such as the copper in release coatings, mercury, tin, arsenic, form the concentration of poisons layer of effect that marine plant spore and marine animal larvae are killed at surrounding materials, thus reach antifouling object.But, the antifouling paint being stain control agent with the compound of arsenic, mercury etc. because of toxicity too large, be eliminated 50 years last century, from the sixties in 20th century, cupric and stanniferous antifouling paint start to be widely used.
With tributyl tin (TBT, Tribu-tytin) for the organo-tin compound coating of representative was once the marine anti-pollution product be most widely used in the world, its mechanism of action is the normal function destroying 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 and come off.Since its sixties in 20th century puts goods on the market, because of the favor in good anti-fouling effect extremely market.But organic tin compound can disturb the calcium metabolism of oyster, bring out Ocean loading sex distortion, be accumulated in the organism such as fish, shellfish, by food chain, detrimentally affect produced to human health, and serious destruction is caused to Marine ecosystems.Since last century the mid-80, in the seawater all over the world, bed mud and biology, all in succession find the existence of organo-tin compound.Therefore, International Maritime Organizaton (IMO) specifies, completely forbids and use organo-tin compound from 2008 in antifouling paint.
A large amount of uses of the antifouling paint of cupric then can cause copper also can in ocean, particularly a large amount of in harbour gatherings, thus produce detrimentally affect to the marine eco-environment, therefore its application also certainly will can be subject to a definite limitation.
Current marine anti-pollution field still lacks safe and effective antifouling paint, and therefore, the green antifouling paint that research and development low toxicity is even nontoxic becomes the important topic being badly in need of in the world solving.Marine natural product is that the class that marine organisms self produce has the secondary metabolite of antifouling activity, and these natural products do not endanger marine organisms life.Find in much research, fouling organism shows some natural product and keeps away the effect of driving, and do not killed by it, marine eco-environment balance can be realized, thus the green antifouling paint preparing a class high effect nontoxic is expected to the exploitation of Marine Natural Product Antifoulants agent.Marine Natural Product Antifoulants research starts from the eighties in last century, but due to extraction and isolation at that time and chemosynthesis level limited, and to antifouling mechanism lack research, antifouling effect is little.In recent years, along with the raising of each side state of the art, the antifouling mechanism of action and the efficient antifouling activity of its uniqueness just come into the picture.But, natural product extraction sepn process is loaded down with trivial details, obtain compound amount also considerably less, and majority of compounds complex structure, larger to its complete synthesis difficulty, cause the research of the antifouling activity of natural product to be mostly only limitted to carry out in laboratory, and later experiments expansion research and commercial production can not be used for.So, utilize organic chemistry and pharmacochemical approach, the structure ━ activity relationship of further investigation antifouling activity material, the simple compound of structure that structural modification or design be easy to synthesize is carried out to active substance, find and develop and there is identical or close, even active better natural product derivative or analogue, the cheapness simultaneously reaching natural product derivative and analogue stain control agent thereof is produced, and may be than being found actual, the more efficient approach of stainblocking material from natural product by extracting method.The natural product derivative or the analogue that pass through structural modification or methodology of organic synthesis synthesis are at present 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, brominated tyrosine bastadin, alkaloid aaptamine and dihydrooroidin, zosterin acid zosteric acid, polybromodiphenyl ether, 2-amyl group-4-hydroxyquinoline, capsaicine, Cannabinoids compound cannabinoids etc., they have the same or analogous anti-fouling effect with natural product.Wherein, what attract people's attention is that 4,5-bis-chloro-Kathon (DCOI) compounds of Rohm & Haas company of U.S. synthesis have good in anti-fouling effect that is wide spectrum, is successfully developed and with SEA-N INE
tM211N is marketed under trademark, is called as green stain control agent, has won Presidential Green Chemistry Challenge in 1996 and has encouraged, made it be worth and gain recognition.In recent years, isothiazolinone compounds is more and more subject to the attention of domestic and international investigators because of its broad spectrum antibacterial and easy degradation characteristic.Waiting in good citizen with methyl acrylate is raw material, 4 are obtained by sulfuration, aminolysis, chlorine cyclisation, the chloro-2-methoxycarbonyl propyl of 5-bis--4-isothiazoline-3-ketone (MOP-DCI), the compound of synthesis has been prepared antifouling paint by them, the real extra large link plate of the animated period of biological growth four months still without obvious biological attachment.Xu Fengling etc., by connecting the group such as hydrazides, hydrazone class on DCOI compound, attempt the broad spectrum antibiotic activity widening DCOI compounds by connecting the method with stronger fungicidal activity group.The inhibit activities result of study of author to 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. shows, this compounds is 1.00 × 10
-6under mol/L, bacteriostasis rate all reaches more than 90%, and it is active that the compound after display structure modification has good broad-spectrum antibacterial.Li Xia etc. are to the compound 2 had compared with high inhibition marine organisms barnacle attachment activity extracted from polyzoan (Zoobotryon pellucidum), 5,6-tri-bromo-1-methyl gramine (TBG) carries out structural modification, has synthesized that 4 novel different halogen substiuted and N-replace and has had the TBG analogue of better lipophilic performance.Bioassay results shows, these compounds all have good growth inhibitory activity to marine alga (Nitzschia closterium), and wherein the restraining effect of part of compounds is comparatively remarkable, its LC
501.33 μ g/mL and 1.06 μ g/mL can be reached respectively.Chen Junde etc. are separated diterpene compound ent-8 (the 14)-pimarene-15R obtained to mangrove Common Ceriops, 16-diol carries out simple structural modification, and the attachment activity research of its anti-white ridge barnacle (B.albicostatus) larva is studied, find that the activity of the compound activity after modifying and its extraction product is 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 position is that anti-fouling activity is necessary.
Because marine fouling organism is made up of animal, plant and microorganism three major types, wherein endanger kind that is comparatively large and that be difficult to remove after attachment and mainly have biologies such as calcium carbonate shell, the stockless cirrus class (barnacle) of battalion's set life and bivalve (mussel and oyster).Therefore, anti-fouling compound filler test work multiselect stockless cirrus class and mussels are experimental subjects.Stockless cirrus class wherein again with reticulate pattern barnacle for representative, it is one of one way of life main fouling organism in the torrid zone, sea area, subtropics, extensively distribute at China South Sea, inhabit the seabed to about depth of water 10m near subtidal line, adult is attached on cay, chad with byssus throughout one's life and lives, and can be used as the representative of mussels fouling organism.Therefore, in the art, general proof test adopts reticulate pattern barnacle as experimental subjects, is have important representative meaning.
Usually can be divided into two life stages based on fouling organism, one is developed to explore off and on till body surface prepares settlement and metamorphosis, for swimming life stage for deviating from egg membrane from larva; Choosing colonization sites from larva, after its surface attachment, the abnormal formation young, is set or epiphytism stage.From stained angle, fouling organism to the mankind produce harm be its battalion set or attachment plant and instrument on and to the latter produce disadvantageous effect.If effectively suppress the settlement and metamorphosis of larva or drive its attachment at solid surface, the object that fouling organism is prevented and kill off just can be reached.Therefore, adopt this larva be experimental subjects to check the anti-fouling effect of compound, there is scientific rationality and representative meaning.
Summary of the invention:
First object of the present invention is to provide 2, the 5-Diketopiperazine derivatives that a class has anti-marine biofouling activity.
Class 2, a 5-Diketopiperazine derivative of the present invention, its structure is as under 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 preferably, the phenyl that described substituted-phenyl is halogen, alkyl or alkoxyl group (as methoxyl group) replace, the naphthyl that described substituted naphthyl is 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 the structure shown here, R
1, R
2can be aromatic group simultaneously, or alkyl; Also can as R
1for aromatic group, R
2for alkyl, vice versa.
Second object 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 solid product be obtained
it is dissolved in DMF again, with aldehyde R
1at Cs
2cO
3condition under room temperature reaction, obtain replace 2,5-Diketopiperazine derivatives
then by obtain while replace 2,5-Diketopiperazine derivatives be dissolved in DMF, with halohydrocarbon in anhydrous K
2cO
3under existent condition, room temperature reaction, obtains 2,5-diketopiperazine intermediates of N protection
finally by 2,5-diketopiperazine intermediates of N protection
be dissolved in DMF, with aldehyde R
2at Cs
2cO
3condition under, room temperature reaction, finally obtains target product 2,5-Diketopiperazine derivative
Described aldehyde R
1for aromatic aldehyde or alkanoic; Described halohydrocarbon is methyl iodide, bromopropylene; Described aldehyde R
2for aromatic aldehyde or alkanoic, namely R1, R2 are the replacement homologue of aromatic group or alkyl or alkyl, and R is methyl or propenyl.
Preferably, in above-mentioned reaction process, the quality of the glycine anhydride used and the volume ratio of acetic anhydride are 1:5.0 ~ 10.0g/mL; Use aldehyde R
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; Used
be 1.0:1.1 ~ 1.5 with the ratio of the amount of halohydrocarbon, with K
2cO
3the ratio of amount be 1.0:1.5 ~ 3.0; Used
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 is found by the test of anti-ocean Macro-fouling Organisms kentrogon attachment activity, and 2,5-Diketopiperazine derivatives as shown in formula I of the present invention can suppress kentrogon to adhere to, its EC
50be worth as shown in table 1, meanwhile, find without any kentrogon dead in experimentation, show that 2,5-Diketopiperazine derivatives as shown in formula I are safety non-toxics.
Therefore, the 3rd object of the present invention is to provide the application of 2,5-Diketopiperazine derivatives shown in formula I in the anti-preventing and removing marine fouling organisms agent of preparation.
4th object of the present invention is to provide a kind of anti-preventing and removing marine fouling organisms agent, it is characterized in that, 2,5-Diketopiperazine derivatives shown in the formula I containing effective dose.
Compared with prior art, the present invention has following beneficial effect:
1) 2,5-Diketopiperazine derivatives as shown in formula I of the present invention have significant restraining effect to the attachment of marine organisms on solid, can for the preparation of the agent for preventing and eliminating of anti-marine fouling organism.
2) 2,5-Diketopiperazine derivatives as shown in formula I of the present invention are natural product derivative, less on the impact of water body environment, and can not cause its enrichment in organism by food chain transmission, thus environmentally friendly, security is high; Compound is not killed marine organisms to realize by driveing and is suppressed fouling organism in the attachment of solid surface simultaneously, is conducive to the balance of marine ecology chain.
3) the present invention as shown in formula I 2,5-Diketopiperazine derivative synthesis techniques simple, cheap, be suitable for scale operation, thus steady sources is reliable.And at present in marine anti-pollution field; any report is not had to be disclosed about this similar cyclic dipeptide (2; 5-diketopiperazine) derivative or the applied research of analogue in fouling organism is prevented and kill off, therefore the stain control agent research of this compounds and the protection of intellecture property are seemed particularly important.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 facility is prevented and kill off.
Embodiment
Following examples further illustrate of the present invention, instead of limitation of the present invention.
Embodiment one: the synthesis of compound 1
Acetic anhydride backflow 10g glycine anhydride being placed in 100mL is spent the night, and be cooled to room temperature after to be done, decompression is spin-dried for excessive acetic anhydride, the solid obtained recrystallization in ethyl acetate is obtained 16.8g compound as white solid 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: the synthesis of compound 2a
By 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, after stirring at room temperature 5h, TLC have detected, reaction system is slowly added to the water, about pH to 5-6 is regulated, extraction into ethyl acetate with 5% dilute hydrochloric acid, dry, resistates silica gel column chromatography after being spin-dried for, obtains 1.27g compound as white solid 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: the synthesis of compound 2b
Synthesis step, with embodiment two, replaces phenyl aldehyde with o-methoxybenzaldehyde, obtains 1.40g compound as white solid 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: the synthesis of compound 2c
Synthesis step, with embodiment two, is replaced phenyl aldehyde with 3-bromobenzaldehyde, is obtained 1.7g compound as white solid 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: the synthesis of compound 2d
Synthesis step, with embodiment two, is replaced phenyl aldehyde with 3-nitrobenzaldehyde, is obtained 1.7g compound as white solid 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: the synthesis of compound 2e
Synthesis step, with embodiment two, replaces 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: the synthesis of compound 3a
By 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, after TLC has detected, reaction system be slowly added to the water, extraction into ethyl acetate, dry, the resistates silica gel column chromatography after being spin-dried for, obtains 0.63g compound as white solid 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: the synthesis of compound 3b
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: the synthesis of compound 3c
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: the synthesis of compound 3d
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: the synthesis of compound 3e
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: the synthesis of compound 3f
Replace 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: the synthesis of compound 4aa
By 50mg(0.21mmol, 1.0eq.) 3a, 29.4 μ L(0.25mmol, 1.2eq.) 3-bromobenzaldehyde and 82mg(0.25mmol, 1.2eq.) Cs
2cO
3add the DMF of 1.5mL drying after mixing, stirring at room temperature 5h, after question response completes, slowly add 10mL water, with 5%HCl adjust pH 5 ~ 6, extraction into ethyl acetate, anhydrous Na
2sO
4drying, silica gel column chromatography obtains 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: the synthesis of compound 4ab
Synthetic method, with embodiment 13, is replaced 3-bromobenzaldehyde with o fluorobenzaldehyde, is obtained 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: the synthesis of compound 4ac
Synthetic method, with embodiment 13, is replaced 3-bromobenzaldehyde by 2,3,4-TMB, is obtained 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: the synthesis of compound 4ad
Synthetic method, with embodiment 13, is replaced 3-bromobenzaldehyde by lauric aldehyde, is obtained 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: the synthesis of compound 4ba
Synthetic method is with embodiment 13, and compound 3b replaces compound 3a, replaces 3-bromobenzaldehyde, obtain compound 4ba, productive rate: 53% with 6-methoxyl group-2-naphthaldehyde.
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: the synthesis of compound 4ca
Synthetic method, with embodiment 13, is replaced compound 3a with compound 3c, is obtained 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: the synthesis of compound 4cb
Synthetic method, with embodiment 18, is replaced 3-bromobenzaldehyde by 2,3,4-TMB, is obtained 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: the synthesis of compound 4cc
Synthetic method, with embodiment 18, is replaced 3-bromobenzaldehyde with Benzaldehyde,2-methoxy, is obtained 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: the synthesis of compound 4cd
Synthetic method, with embodiment 18, is replaced 3-bromobenzaldehyde with octanal, is obtained 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: the synthesis of compound 4ce
Synthetic method, with embodiment 18, is replaced 3-bromobenzaldehyde by lauric aldehyde, is obtained 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: the synthesis of compound 4da
Synthetic method, with embodiment 18, replaces compound 3a with compound 3d, replaces 3-bromobenzaldehyde, obtain compound 4da, productive rate: 38% with 3-chlorobenzaldehyde.
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: the synthesis of compound 4ea and 4eb
Synthetic method, with embodiment 18, replaces compound 3a with compound 3e, replaces 3-bromobenzaldehyde with phenyl aldehyde, is separated simultaneously and obtains compound 4ea and compound 4eb.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: the synthesis of compound 4fa
Synthetic method, with embodiment 18, replaces compound 3a with compound 3f, replaces 3-bromobenzaldehyde, obtain compound 4fa with 3,4,5-Trimethoxybenzaldehyde.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: anti-attachment is tested
Use settled organism: reticulate pattern barnacle cyprids;
Use the compound of anti-attachment: 2,5-Diketopiperazine derivative;
The acquisition methods of cyprids is as follows: first from tideland, Hong Kong, gather reticulate pattern barnacle of growing up, it to be exposed under room temperature in air 12 as a child after, be placed in the seawater filtered with 0.22 μm of filtering membrane again, it is allowed slowly to hatch naupiar larva, then be bait with Chaetoceros gracilis, be placed in by naupiar larva in constant incubator under the condition of 26-28 DEG C, be cultured to cyprids, the new cyprids cultivated is tested for anti-attachment immediately.
Anti-attachment experiment carries out in a kind of 24 hole polystyrene plates, and first compound is dissolved in DMSO, is then diluted to required concentration with the seawater filtered: 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 by filtering sea and DMSO alternative compounds.Then, all sample solutions are placed in inherent 25 DEG C of constant incubator and cultivate 24-48 hour.Test result anatomical lens detects barnacle in the quantity of solid surface-attached, the quantity of not adhering to and the death of barnacle or the quantity etc. of pathology.The inhibiting rate of compound is by calculating in single hole respectively, and the larva quantity of attachment or the larva quantity of generation pathology obtain with the ratio adding kentrogon sum, EC
50value is used for representing that compound suppresses the quantity of larva attachment to be the concentration adding larva sum one half compound.Finally process 3 revision tests with Probit software, result mean value represents.
Experimental result shows, do not find in all samples that dead situation appears in any larva, compound safety non-toxic is described, half inhibiting rate concentration of compound is as shown in table 1.
Table 1: compound suppresses kentrogon experimental result
。
Claims (5)
1. class 2, a 5-Diketopiperazine derivative, its structure is as under formula I:
Wherein, R1, R2 are aromatic group or alkyl, and R is methyl or propenyl;
Described aromatic group is the phenyl of phenyl, halogen, alkyl or methoxy substitution, naphthyl, or the naphthyl of halogen, alkyl or methoxy substitution;
Described alkyl is methyl, ethyl, propyl group, butyl, amyl group, hexyl, heptyl, octyl group, nonyl, decyl, undecyl or dodecyl.
2. the preparation method of 2,5-Diketopiperazine derivatives according to claim 1, 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 solid product be obtained
it is dissolved in DMF again, with R
1cHO is at Cs
2cO
3condition under room temperature reaction, obtain replace 2,5-Diketopiperazine derivatives
then by obtain while replace 2,5-Diketopiperazine derivatives be dissolved in DMF, with halohydrocarbon in anhydrous K
2cO
3under existent condition, room temperature reaction, obtains 2,5-diketopiperazine intermediates of N protection
finally by 2,5-diketopiperazine intermediates of N protection
be dissolved in DMF, with R
2cHO is at Cs
2cO
3condition under, room temperature reaction, finally obtains target product 2,5-Diketopiperazine derivative
Described R
1cHO is aromatic aldehyde or alkanoic; Described halohydrocarbon is methyl iodide, bromopropylene; Described R
2cHO is aromatic aldehyde or alkanoic, and namely R1, R2 are aromatic group or alkyl, and R is methyl or propenyl;
Described aromatic group is the phenyl of phenyl, halogen, alkyl or methoxy substitution, naphthyl, or, the naphthyl of halogen, alkyl or methoxy substitution;
Described alkyl is methyl, ethyl, propyl group, butyl, amyl group, hexyl, heptyl, octyl group, nonyl, decyl, undecyl or dodecyl.
3. preparation method according to claim 2, is characterized in that, in reaction process, the quality of the glycine anhydride used and the volume ratio of acetic anhydride are 1:5.0 ~ 10.0g/mL; Use R
1cHO with
the ratio of amount be 1:1.2 ~ 2.0, with Cs
2cO
3the ratio of amount be 1.0:1.2 ~ 2.0; Used
be 1.0:1.1 ~ 1.5 with the ratio of the amount of halohydrocarbon, with K
2cO
3the ratio of amount be 1.0:1.5 ~ 3.0; Used
with R
2the ratio of the amount of CHO is 1.0:1.2 ~ 2.0, with Cs
2cO
3the ratio of amount be 1.0:1.2 ~ 2.0.
4. the application of 2,5-Diketopiperazine derivatives as shown in formula I according to claim 1 in the anti-preventing and removing marine fouling organisms agent of preparation.
5. an anti-preventing and removing marine fouling organisms agent, is characterized in that, 2, the 5-Diketopiperazine derivatives as shown in formula I according to claim 1 containing effective dose.
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