CN104327035B - Marine fungi secondary metabolite derivative and application of marine fungi secondary metabolite derivative as marine biological antifoulant - Google Patents
Marine fungi secondary metabolite derivative and application of marine fungi secondary metabolite derivative as marine biological antifoulant Download PDFInfo
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- CN104327035B CN104327035B CN201410696172.7A CN201410696172A CN104327035B CN 104327035 B CN104327035 B CN 104327035B CN 201410696172 A CN201410696172 A CN 201410696172A CN 104327035 B CN104327035 B CN 104327035B
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- 0 CB([C@@](*)(O)O1)c2c(C)cc(CC[C@](C)C(C)C)c(OC)c2C1=O Chemical compound CB([C@@](*)(O)O1)c2c(C)cc(CC[C@](C)C(C)C)c(OC)c2C1=O 0.000 description 2
- PGTHCHRFKWHKLD-STBQITDASA-N CCC/C=C/[C@H]([C@H](c(c1c(c(CC=C(C)C)c2)O)c2OC)OC)OC1=O Chemical compound CCC/C=C/[C@H]([C@H](c(c1c(c(CC=C(C)C)c2)O)c2OC)OC)OC1=O PGTHCHRFKWHKLD-STBQITDASA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/76—Benzo[c]pyrans
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
- A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
- A01N43/14—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom six-membered rings
- A01N43/16—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom six-membered rings with oxygen as the ring hetero atom
Abstract
The invention relates to a marine fungi secondary metabolite derivative and an application of the marine fungi secondary metabolite derivative as a marine biological antifoulant. The derivative has the structure represented by a formula I as shown in the specification, wherein R1 and R2 are independently H, and one of R1 and R2 is H; R3 and R4 are independently H and OCH3 and one of R3 and R4 is H; R5 and R6 are independently H, C1-C4 alkyl, C2-C4 alkylacyl, C1-C4 haloalkyl, C1-C4 alkylsulfonyl, C2-C4 alkenyl, C3-C8 cycloalkyl and C7-C12 arylalkyl, wherein alkyl, alkylacyl, haloalkyl, alkylsulfonyl, alkenyl, cycloalkyl and arylalkyl are optionally substituted with one or more hydroxy, mercapto, amino, halo, C1-C4 alkyl groups; '-----' represents a single bond or absence; and the prerequisite is that at least one of R5 and R6 is not H when '-----' represents a single bond.
Description
Technical field
The invention belongs to marine anti-pollution field, and in particular to a kind of to originate as the marine fungi of marine organisms anti-fouling agent
The derivative of isocoumarin class compound and preparation method thereof.
Background technology
Marine biofouling refers to the larva of marine fouling organism such as barnacle, mussel, bryozoan etc. in hull, fish box, oil
The marine facilities such as well or other marine organisms surface attachments grow and form group, so as to cause huge infringement to being attached to thing,
Such as accelerate metal erosion, reduce marine facility performance, affect culture fishery yield and quality etc..In marine fouling organism,
Barnacle is to be distributed the most wide, class that harm is maximum.The whole world every year due to caused by marine biofouling economic loss it is huge.With
As a example by ship, fouling organism alow adheres to, and makes marine fuel consumption increase by 40%, and navigation cost is up to 77%, is this whole world
Shipping about 3,000,000,000 dollars of loss every year.Mainly on the facility such as hull surface, coating contains desinsection to the anti-fouling material for using at present
Agent or organometallic organic coating.These anti-fouling materials also heavy damage ocean ring while anti-fouling effect is played
Border, such as organotin oxides (TBTO) are destroyed many fish and halobiontic immune system, and insecticide is to target
Fouling organism and nontarget organism all produce murder by poisoning, and directly endanger human health.Therefore, find the efficient, natural sea of low toxicity
Foreign bioantifouling agent has become the key subjects that various countries face.The special bars such as ocean high salt, high pressure, low temperature, oligotrophic, low illumination
Part enables marine microorganism to produce the secondary metabolite that a large amount of structures are novel, activity is unique, and some of which compound has
In Studies On Antifouling Activity, in order to obtain the marine organisms anti-fouling agent of more efficient, low toxicities, carries out structure to marine natural anti-fouling agent and repaiies
Decorations, illustrating its structure-activity relationship becomes the task of top priority.
The content of the invention
It is an object of the invention to Chinese patent (application number：201310429588.8) in marine fungi source anti-soil
Damage compound to be chemically modified, obtain the excellent derivative of serial anti-fouling activity, while providing the preparation of the analog derivative
Method and its application as marine organisms anti-fouling agent.
The present invention provides a kind of isocoumarin class compound of Formulas I structure, its stereoisomer or which is pharmaceutically acceptable
Salt, it is characterised in that compound of formula I has following structure：
Wherein R1、R2Be each independently H,And R1、R2In
There is one for H；R3、R4It is each independently H, OCH3, and R3、R4In have one for H；R5、R6H, C1-C4 alkane is stood alone as each
Base, C2-C4 alkyl acyls, C1-C4 haloalkyls, C1-C4 alkyl sulphonyls, C2-C4 thiazolinyls, C3-C8 cycloalkyl, C7-C12 are fragrant
Base alkyl, wherein described alkyl, alkyl acyl, haloalkyl, alkyl sulphonyl, thiazolinyl, cycloalkyl, optionally aryl alkyl, quilt
One or more hydroxyls, sulfydryl, amino, halogen, C1-C4 alkyl replace；" --- -- " represents singly-bound or does not exist；Precondition
It is the R when " --- -- " represents singly-bound5、R6Middle at least one is not H.
" alkyl " specifically described herein preferably methyl, ethyl, propyl group, normal-butyl, isobutyl group, tert-butyl group；" alkyl acyl " is excellent
Select acetyl group, propiono, positive bytyry, isobutyryl；" alkyl sulphonyl " preferably methyl sulphonyl, ethylsulfonyl, propyl group
Sulfonyl；" thiazolinyl " preferably pi-allyl；" cycloalkyl " preferably cyclopropane base, cyclobutane base, pentamethylene base, cyclohexyl, cycloheptyl
Alkyl；" aryl alkyl " preferably benzyl, phenylethyl；" halogen " preferably fluorine, chlorine, bromine, iodine.
In the present invention, term " pharmaceutically acceptable salt " refers to the addition of atoxic inorganic or organic acid and/or alkali
Salt.Can be found in " Salt selection for basic drugs ", Int.J.Pharm. (1986), 33,201 217.
Compound of formula I is selected from following compound：
Its stereoisomer or pharmaceutically acceptable salt.
In another preference, R in compound of formula I1、R2、R3、R4、R5、R6Selected from above-mentioned particular compound 2,4-5,7-9,
11-14,16, in 21-27 relevant position concrete group.
It should be understood that above-mentioned preferred group can be mutually combined with formed the present invention various preferred compounds, as space is limited,
This does not tire out one by one states.
The present invention provides a kind of marine organisms anti-fouling agent, it is characterised in that with the isocoumarin class chemical combination of above-mentioned Formulas I structure
Thing, its stereoisomer or its pharmaceutically acceptable salt as active ingredient, for preventing and treating barnacle Balanus
The marine biofouling that the attachment of amphitrite larvas causes.
Other compositions with the antifouling effect of marine organisms be may also include in the marine organisms anti-fouling agent that the present invention is provided.
Carrier, diluent or excipient be may also include in the marine organisms anti-fouling agent that the present invention is provided.
The present invention provides isocoumarin class compound, its stereoisomer or its pharmaceutically acceptable salt of Formulas I structure
Application in terms of marine organisms anti-fouling agent is prepared.
The present invention provides the preparation method of compound of formula I, including following scheme：
Scheme one：
Formula II compound obtains -1 compound of Formulas I after hydrogenated reduction, and hydro-reduction condition is this area Conventional catalytic
Hydrogenation conditions：In organic solvent, catalyst, H2The lower reduction reaction of effect, preferably 0～80 DEG C, 0.1～10MPa H2Lower reduction, urges
Agent preferred 10%Pd/C, Pt/C, PtO2Reduction, R in Formula II, Formulas I -11、R2、R3、R4The group of definition is fixed with compound of formula I
The group of justice is identical, and the R in Formulas I -11Or R2In the singly-bound that represents of double bond and " --- -- " can not be while existing.
Scheme two：
- 1 compound of Formula II compound or Formulas I (Formula II, I-1 compounds are defined as above) Jing alkylation reactions or acylation reaction
- 2 compound of Formulas I, alkylation reaction condition are this area normal condition：In organic solvent, react under alkali, the effect of hydrocarbonylation reagent,
The wherein preferred RX of hydrocarbonylation reagent, wherein X are halogen, preferably chlorine, bromine, iodine, and R is C1-C4 alkyl, C1-C4 haloalkyls, C2-C4
Thiazolinyl, C3-C8 cycloalkyl, C7-C12 aryl alkyls, above-mentioned substituent is optionally by one or more hydroxyls, sulfydryl, amino, halogen
Element, C1-C4 alkyl replace；Alkali preferred as alkali hydride (such as NaH, LiH), alkali metal alkyl compound (BuLi, t-BuLi), alkali
Metal hydroxides (such as NaOH, KOH), alkali carbonate are (such as Na2CO3、K2CO3), metal oxide (such as AgO) etc.；It is acylated
Reaction condition is also this area normal condition：In organic solvent, react under alkali, acylating reagent effect, wherein acylating reagent is excellent
Select R ' COX (carboxylic acid halides), R ' COOCOR ' (acid anhydrides) or R '-S (=O)2- X (sulfonic acid halide), wherein X are halogen, preferably chlorine, bromine, iodine,
R ' is C1-C3 alkyl, C1-C3 haloalkyls, C1-C4 alkyl, and above-mentioned substituent is optionally by one or more hydroxyls, sulfydryl, ammonia
Base, halogen, C1-C4 alkyl replace；Alkali preferred alkali metal hydroxide (such as NaOH, KOH), triethylamine, pyridine, sodium acetate, quinoline
Quinoline, imidazoles, dimethylaniline etc.；The wherein preferred benzene of organic solvent, toluene, THF, ether, glycol dimethyl ether, DMF, dioxy six
Ring etc..
Formulas I -1, the synthetic method of Formulas I -2, i.e. formula being included in the range of compound of formula I is given in above-mentioned synthetic method
I is big general formula compound, and Formulas I -1, Formulas I -2 are its subset.
It should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the present invention and concrete in below (eg embodiment)
Each technical characteristic of description can be combined with each other, so as to constitute new or preferred technical scheme.As space is limited, here is not another
One tired states.
Specific embodiment
For the ease of a further understanding of the present invention, examples provided below has done more detailed description to which.But
Be these embodiments only for be better understood from invention and not for limiting the scope of the present invention or implementation principle, the reality of the present invention
The mode of applying is not limited to herein below.
Embodiment 1
Weigh 10mg compounds 1 and be dissolved in 5mL CH3OH/CH2Cl2(volume ratio 1：1) 10%Pd/C of catalytic amount in, is added,
In 1atm H2Under effect, after room temperature reaction 10h, TLC detection reactions are complete, are filtered to remove Pd/C, after concentration, obtain grease
9.9mg, yield 98.4%, HPLC detect purity more than 96%, ESI-MS m/z:373.2[M+Na]+。
Embodiment 2
Weigh 20mg compounds 3 and be dissolved in 5mL CH2Cl2In, add the PtO of catalytic amount2, in 1atm H2Under effect, room temperature
After reaction 4h, TLC detection reaction raw materials are almost wholly absent and generate two polarity point less than normal, are filtered to remove PtO2, after concentration,
(eluant, eluent is EtOAc/ petroleum ether=10 to Jing silica gel column chromatographies：1～8：1), obtain compound 4 (13.5mg), yield 67.2%,
Compound 5 (4.8mg), yield 23.9%, HPLC detect purity more than 98%, ESI-MS m/z:371.2[M+Na]+, Jing1H NMR spectras compare, and determine the structure of compound 4,5, do not exist in compound 4 δ 5.4 or so two H (5', 6' position it is double
Key hydrogen), but there are two unimodal 3 H ((C 1.7 or soH 3 )2C=C-), it is just the opposite in compound 5, there is δ 5.4 left
Right two H (the double bond hydrogen of 5', 6' position), two CH3((CH 3 )2CH-) move to High-Field.
Embodiment 3
Weigh 10mg compounds 6 to be dissolved in 5mL THF, add 5mg Na2CO3, after half an hour being stirred under room temperature, add 5 μ L
EtBr, after reacting 5h at 30 DEG C, TLC detection reaction raw materials are almost wholly absent, and after concentration, (eluant, eluent is Jing silica gel column chromatographies
EtOAc/ petroleum ether=15：1～10：1) compound 7 (9mg), yield 83.3%, is obtained, compound HPLC detections purity is
98.6%, ESI-MS m/z:397.2[M+Na]+。
Embodiment 4
Weigh 20mg compounds 6 to be dissolved in 5mL THF, add 5mg NaH, after half an hour being stirred under room temperature, add 20 μ L
MeI, after reacting 12h at 60 DEG C, TLC detection reaction raw materials are almost wholly absent, and after adding saturated ammonium chloride terminating reaction, use second
Acetoacetic ester is extracted twice, anhydrous sodium sulfate drying organic layer, and after concentration, (eluant, eluent is EtOAc/ petroleum ethers to Jing silica gel column chromatographies
=20：1～10：1) compound 8 (9.5mg), yield 43.9%, ESI-MS m/z, are obtained:397.2[M+Na]+, compound 9
(8.6mg) yield 41.3%, ESI-MS m/z:383.2[M+Na]+, HPLC detection purity is more than 98%.
Embodiment 5
Weigh 10mg compounds 10 to be dissolved in 5mL DMF, add 5mg Na2CO3, after half an hour being stirred under room temperature, add 10
μ L BnBr, after reacting 5h at 40 DEG C, TLC detection reaction raw materials are almost wholly absent, after concentration, Jing silica gel column chromatography (eluant, eluents
For EtOAc/ petroleum ether=15：1～10：1) compound 11 (11.2mg), is obtained, yield 88.9%, compound HPLC detections are pure
Spend for 98.8%, ESI-MS m/z:459.2[M+Na]+。
Embodiment 6
Weigh 10mg compounds 10 and be dissolved in 5mL CH2Cl2In, 10 μ L pyridines of addition, 10 μ L aceticanhydrides, after reacting 2h under room temperature,
TLC detection reaction raw materials are almost wholly absent, and after concentration, (eluant, eluent is EtOAc/ petroleum ether=15 to Jing silica gel column chromatographies：1～
10：1) compound 12 (10.5mg), is obtained, yield 93.7%, compound HPLC detection purity are 98.0%, ESI-MS m/z:
411.2[M+Na]+。
Embodiment 7
Weigh 20mg compounds 10 to be dissolved in 5mL THF, add 20 μ L pyridines, the DMAP of catalytic amount, 30 μ L
ClCH2COCl, after reacting 8h at 60 DEG C, TLC detection reaction raw materials are almost wholly absent, and are extracted with ethyl acetate twice, anhydrous
Sodium sulphate is dried organic layer, and after concentration, (eluant, eluent is EtOAc/ petroleum ether=20 to Jing silica gel column chromatographies：1～10：1), changed
Compound 13 (14.5mg), yield 50.3%, ESI-MS m/z:521.1[M+Na]+, compound 14 (11.5mg) yield 47.1%,
ESI-MS m/z:445.1[M+Na]+, HPLC detection purity is more than 97%.
Embodiment 8
Weigh 10mg compound 15-1 and be dissolved in 5mL CH2Cl2In, add 10 μ L pyridines, 10 μ L MsCl to react 2h under room temperature
Afterwards, TLC detections reaction raw materials are almost wholly absent, and after concentration, (eluant, eluent is EtOAc/ petroleum ether=15 to Jing silica gel column chromatographies：1
～10：1) compound 16 (10.0mg), is obtained, yield 81.6%, compound HPLC detection purity are 95.3%, ESI-MS m/
z:447.1[M+Na]+。
Embodiment 9
Weigh 10mg compounds 10 to be dissolved in 5mL THF, 30 μ L pyridines of addition, 15 μ L chloroacetic chlorides, after reacting 2h at 60 DEG C,
TLC detection reaction raw materials are almost wholly absent, and after concentration, (eluant, eluent is EtOAc/ petroleum ether=15 to Jing silica gel column chromatographies：1～
12：1) compound 21 (7.7mg), is obtained, yield 62%, HPLC detection purity are 98.6%, ESI-MS m/z:453.2[M+
Na]+；And minority specioz 12, yield is 31%.
Embodiment 10
Weigh 10mg compounds 6 to be dissolved in 5mL THF, add 10mg Na2CO3, after half an hour being stirred at 30 DEG C, add 15
μ L EtBr, after reacting 4h at 60 DEG C, TLC detection reaction raw materials are almost wholly absent, after concentration, Jing silica gel column chromatography (eluant, eluents
For EtOAc/ petroleum ether=20：1～15：1) compound 22 (6.1mg), yield 52.3%, is obtained, HPLC detections purity is
98.5%, ESI-MS m/z:425.2[M+Na]+；And compound 7, yield is 42.5%.
Embodiment 11
Weigh 5mg compounds 22 and be dissolved in 2mL CH3OH/CH2Cl2(volume ratio 1：1) 10%Pd/C of catalytic amount in, is added,
In 1atm H2Under effect, room temperature reaction overnight after, TLC detection reactions are complete, are filtered to remove Pd/C, after concentration, obtain compound
23 (5.0mg), yield 99%, HPLC detect purity in 97.8%, ESI-MS m/z:429.3[M+Na]+。
In a similar way, compound 12 is in appropriate CH3OH/CH2Cl2(volume ratio 1：1) in, the 10% of catalytic amount
Pd/C, in 1atm H2Compound 24 is obtained with 98.5% yield under effect, HPLC detects purity in 98.3%, ESI-MS m/
z:415.2[M+Na]+。
Embodiment 12
Weigh 10mg compounds 19 and be dissolved in 5mL CH2Cl2In, add 20 μ L pyridines, 10mg TsCl to react 2h under room temperature
Afterwards, TLC detections reaction raw materials are almost wholly absent, and after concentration, (eluant, eluent is EtOAc/ petroleum ether=15 to Jing silica gel column chromatographies：1
～10：1) compound 25 (12.3mg), is obtained, yield 85%, HPLC detection purity are 96.5%, ESI-MS m/z:523.2[M
+Na]+。
Embodiment 13
Weigh 10mg compounds 17 to be dissolved in 5mL dichloromethane, 50 μ L pyridines of addition, 25 μ L propionyl chlorides, at room temperature instead
After answering 2.5h, TLC detection reaction raw materials are almost wholly absent, and after concentration, (eluant, eluent is EtOAc/ oil to Jing silica gel column chromatographies
Ether=15：1～10：1) compound 26 (9.7mg), is obtained, yield 83.6%, HPLC detection purity are 98.8%, ESI-MS m/
z:427.2[M+Na]+。
Embodiment 14
Weigh 10mg compounds 18 to be dissolved in 5mL dichloromethane, add 50 μ L pyridines, 25 μ L the third formyl chlorides of ring, in room temperature
After lower reaction 5h, TLC detection reaction raw materials are almost wholly absent, and after concentration, (eluant, eluent is EtOAc/ oil to Jing silica gel column chromatographies
Ether=15：1～10：1) compound 27 (9.5mg), is obtained, yield 79.4%, HPLC detection purity are 97.8%, ESI-MS m/
z:437.2[M+Na]+。
In embodiment 1-14, raw materials used compound 1,3,6,10,15,15-1,17,18,19 are according to Chinese patent
201310429588.8,201310429589.2 (or doctors Chen Min《Chinese Marine University Ph.D. Dissertation》2013 is annual)
Described in method prepare.
Embodiment 15
The anti-kentrogon attachment activity (table 1) of embodiment of the present invention compound.
Embodiment of the present invention compound is tested according to such as to barnacle Balanus amphitrite larvas attachment inhibitory activity
Publication about Document method is tested：Thiyagarajan V.；Harder T.；Qiu J.W.；Qian P.Y.Mar Biol(Berl)
2003,143,543–554.By suppressing the test of barnacle B.amphitrite larvas attachment activity, the embodiment of the present invention is found
Medium effective concentration (the EC of compound50) it is respectively less than 12.5 μ g/mL, its LC50 (LC50) it is all higher than 50 μ g/mL.This table
Bright the compounds of this invention in terms of barnacle B.amphitrite larva attachments are suppressed, the characteristics of show high-efficiency low-toxicity.
1 embodiment of the present invention compound of table adheres to inhibitory activity and toxicity to kentrogon B.amphitrite
Kentrogon B.amphitrite attachment inhibiting rates are existed when in table 1, " A " represents that compound concentration is 6.25 μ g/mL
More than 50%, when " B " expression compound concentration is 12.5 μ g/mL, kentrogon B.amphitrite attachment inhibiting rates are existed
More than 50%, when " C " expression compound concentration is 25.0 μ g/mL, kentrogon B.amphitrite attachment inhibiting rates are existed
More than 50%, " D " represents compound concentration when being 50 μ g/mL, to the fatal rate of kentrogon B.amphitrite 50% with
Under, " E " represents compound concentration when being 100 μ g/mL, to the fatal rate of kentrogon B.amphitrite below 50%, its
Medium effective concentration (the EC of middle compound 21-2750) it is B, LC50 (LC50) it is D.
The change in other Formulas I range of structures in addition to embodiment of the present invention compound 2,4-5,7-9,11-14,16,21-27
Compound also can be by the raw material described in Chinese patent 201310429588.8,201310429589.2 according to scheme one, two or real
Apply a similar approach for 1-14 records to be synthesized, in the test of barnacle B.amphitrite larvas attachment activity is suppressed, this
Medium effective concentration (the EC of Ming Dynasty style I50) it is respectively less than 12.5 μ g/mL, its LC50 (LC50) it is all higher than 50 μ g/
ML, as space is limited, here is not tired one by one to be stated.
The all documents referred in the present invention are all incorporated as bibliography in this application, just as each document quilt
It is individually recited such as reference.In addition, it is to be understood that after the above for having read the present invention, those skilled in the art
The present invention can be made various changes or modifications, these equivalent form of values equally fall within what the application appended claims were limited
Scope.
Claims (14)
1. a kind of isocoumarin class compound, it is characterised in that with Formulas I structure：
Wherein R1、R2Be each independently H,And R1、R2In have one
It is individual for H；R3、R4It is each independently H, OCH3, and R3、R4In have one for H；R5、R6H, C1-C4 alkyl, C2- are stood alone as each
C4 alkyl acyls, C1-C4 haloalkyls, C1-C4 alkyl sulphonyls, C2-C4 thiazolinyls, C3-C8 cycloalkyl, C7-C12 aryl alkane
Base, wherein described alkyl, alkyl acyl, haloalkyl, alkyl sulphonyl, thiazolinyl, cycloalkyl, aryl alkyl, optionally by one
Or multiple hydroxyls, sulfydryl, amino, halogen, C1-C4 alkyl replace；" --- -- " represents singly-bound or does not exist；Precondition is to work as
When " --- -- " represents singly-bound, R5、R6Middle at least one is not H.
2. the stereoisomer or pharmaceutically acceptable salt of compound described in claim 1.
3. the compound described in any one of claim 1-2, selected from following compound：
4. a kind of isocoumarin class compound, its stereoisomer or pharmaceutically acceptable salt, it is characterised in that an unusually sweet smell
Beans chlorins compound has following structure：
5. the preparation method of compound described in any one of claim 1-3, comprises the steps：
Formula II compound in organic solvent, in catalyst, 0.1～10MPa H2The lower reduction of effect obtains -1 compound of Formulas I, formula
R in II, Formulas I -11、R2、R3、R4The group of definition is identical with the group defined in the compound of formula I of claim 1 or 3, wherein
R in Formulas I -11Or R2In the singly-bound that represents of double bond and " --- -- " can not be while existing.
6. the preparation method described in claim 5, it is characterised in that preferably 0～80 DEG C of reaction temperature, the preferred 10%Pd/ of catalyst
C、Pt/C、PtO2。
7. the preparation method of compound described in any one of claim 1-3, comprises the steps：
Formula II compound or -1 compound of Formulas I in organic solvent, are alkylated in hydrocarbonylation reagent and alkali metal hydride, alkali metal
The lower reaction of thing, alkali metal hydroxide, alkali carbonate or metal oxide effect obtains -2 compound of Formulas I,
Or Formula II compound or -1 compound of Formulas I are in organic solvent, in acylating reagent and alkali metal hydroxide, three second
The lower reaction of amine, pyridine, sodium acetate, quinoline, imidazoles or dimethylaniline effect obtains -2 compound of Formulas I；
Formulas I -1, the definition of Formula II compound are identical with the definition in claim 5, R in Formulas I -21、R2、R3、R4、R5、R6Determine
Justice is identical with the definition in claim 1 or 3.
8. the preparation method described in claim 7, it is characterised in that hydrocarbonylation reagent is selected from RX, wherein X is halogen, and R is C1-C4 alkane
Base, C1-C4 haloalkyls, C2-C4 thiazolinyls, C3-C8 cycloalkyl, C7-C12 aryl alkyls, above-mentioned substituent optionally by one or
Multiple hydroxyls, sulfydryl, amino, halogen, C1-C4 alkyl replace；Acylating reagent is selected from R ' COX (carboxylic acid halides), R ' COOCOR ' (acid anhydrides)
Or R '-S (=O)2- X (sulfonic acid halide), wherein X be halogen, R ' be C1-C3 alkyl, C1-C3 haloalkyls, C1-C4 alkyl, it is above-mentioned
Substituent is optionally replaced by one or more hydroxyls, sulfydryl, amino, halogen, C1-C4 alkyl.
9. the preparation method described in claim 8, it is characterised in that the halogen is selected from chlorine, bromine, iodine.
10. the preparation method described in any one of claim 7-9, it is characterised in that the alkali metal hydride is selected from NaH, LiH,
The alkali metal alkyl compound is selected from BuLi, t-BuLi, and the metal hydroxides is selected from NaOH, KOH, the alkali metal carbonic acid
Salt is selected from Na2CO3、K2CO3, the metal oxide is selected from AgO.
Preparation method described in 11. any one of claim 7-9, it is characterised in that organic solvent is selected from benzene, toluene, THF, second
Ether, glycol dimethyl ether, DMF or dioxane.
Preparation method described in 12. claims 10, it is characterised in that organic solvent is selected from benzene, toluene, THF, ether, ethylene glycol
Dimethyl ether, DMF or dioxane.
13. a kind of marine organisms anti-fouling agents, it is characterised in that with the compound described in any one of claim 1-4, alloisomerism
Body or its pharmaceutically acceptable salt are used as active ingredient.
Compound, stereoisomer or its pharmaceutically acceptable salt described in 14. any one of claim 1-4 is in preventing and treating barnacle
Application in the marine biofouling for causing.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410696172.7A CN104327035B (en) | 2013-12-14 | 2014-11-27 | Marine fungi secondary metabolite derivative and application of marine fungi secondary metabolite derivative as marine biological antifoulant |
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