CN107501131A - One kind guards against platform mycin analog and preparation method thereof - Google Patents
One kind guards against platform mycin analog and preparation method thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C291/00—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00
- C07C291/02—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00 containing nitrogen-oxide bonds
- C07C291/08—Azoxy compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C245/00—Compounds containing chains of at least two nitrogen atoms with at least one nitrogen-to-nitrogen multiple bond
- C07C245/02—Azo compounds, i.e. compounds having the free valencies of —N=N— groups attached to different atoms, e.g. diazohydroxides
- C07C245/04—Azo compounds, i.e. compounds having the free valencies of —N=N— groups attached to different atoms, e.g. diazohydroxides with nitrogen atoms of azo groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C281/00—Derivatives of carbonic acid containing functional groups covered by groups C07C269/00 - C07C279/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
- C07C281/02—Compounds containing any of the groups, e.g. carbazates
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
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Abstract
One kind guards against platform mycin analog and preparation method thereof.The ring platform mycin analog, there is having structure formula II.Preparation method is to substitute aldehyde 1 to be used as initiation material; carry out being condensed to yield imines; obtain substituting hydrazine class compound 2 after reduction; deprotection base and then oxidation obtain azo-compound 3 after being reduced with palladium charcoal; compound 3 obtains azo oxidation category compound 4 by nitrosation reaction, and compound 4 obtains a series of ring platform mycin analogs by elimination reaction.The ring platform mycin analog of the present invention is simpler with the performance suitable with guarding against platform mycin, preparation method.
Description
Technical field
The invention belongs to antibiotic technical field, and in particular to a kind of ring platform mycin analog and preparation method thereof.
Background technology
It is that the nineties is northern by Inst. of Medicinal Biological Technology, Chinese Academy of Medical Sciences and Japan to guard against platform mycin (Jietacins)
In university's joint development one of farm antibiotics, structural formula is as shown in such as following formula I.It is in streptomyces KP-197 bacterial strains
Isolated active material in culture, by antiprotozoan screening model and what is found, it for details, reference can be made in CN 1034580A
The manufacture method of disclosed a kind of antiparasitic new antibiotic and its esters, the loose ends worm activity of killing for guarding against platform mycin is comparison medicament
Ten times of AVM, and its toxicity is relatively low, has extraordinary DEVELOPMENT PROSPECT as new nematicide thing.
N=5 or 6
The preparation method for guarding against platform mycin at present is biological fermentation process, and fermentation time is longer, and fermentation efficiency is very low, far from full
The needs of sufficient actual production.And Starki et al. reports chemically carry out guarding against the fully synthetic of platform mycin, synthetic route is very long,
Severe reaction conditions, total recovery is very low, is not suitable for large-scale production.To guard against platform mycin carry out structure of modification, simplify its structure with
Shortening reaction scheme reduces cost and had important practical significance.Tsuzuki et al. once reported that aliphatic chain was not to influence to guard against platform
The key structural elements of mycin eelworm-killing activity, the ring platform mycin analog after aliphatic chain shortens can keep it to kill nematode work
Property, and be easier to prepare than guarding against platform mycin, there is industrial applications prospect.
Therefore we shorten the long aliphatic chain for guarding against platform mycin in the case where retaining vinyl and azoxy group, if
Count a route and prepare ring platform mycin analog.
The content of the invention
An object of the present invention is that providing one kind guards against platform mycin analog, and the analog shortens the length for guarding against platform mycin
Aliphatic chain, eelworm-killing activity are suitable with guarding against platform mycin.
For the above-mentioned purpose, the present invention adopts the following technical scheme that：
One kind guards against platform mycin analog, has having structure formula II：
Wherein R is unsubstituted alkyl.
Preferably, R is C4-C10 alkyl, preferably C6-C8 alkyl.
Preferably, R is-CH2(CH2)2CH(CH3)2、-CH2(CH2)2CH(CH3)2、-CH2(CH2)3CH(CH3)2、-CH2
(CH2)4CH(CH3)2、-CH2CH2CH(CH3)2CH2CH3Or-CH2(CH2)2CH(CH3)2CH2CH3、-CH3(CH2)5。
An object of the present invention, which also resides in, provides a kind of preparation method of the present invention for guarding against platform mycin analog, bag
Include following steps：
(1) RCHO substitutes aldehyde 1 to be converted into substitution hydrazine class compound 2 by condensation, reducing agent reduction；
(2) compound 2 obtains compound 3 by Deprotection and oxidation；
(3) compound 3 carries out selective nitrosation reaction and obtains compound 4；
(4) compound 4 obtains compound 5 by addition elimination reaction, i.e., a series of ring platform mycin analogs, formula II
Compound.
The preparation method of the present invention is easy and effective.
Preferably, condensation is to carry out the RCHO hydrazinoethanols for substituting aldehyde 1 and CBZ to protect in step (1).
Preferably, it is condensed and is carried out under the conditions of ice-water bath.
Preferably, the condensation, reduction reaction solvent for use are a kind of in methanol, tetrahydrofuran or 1,2- dichloroethanes
Or it is a variety of, reducing agent system is sodium cyanoborohydride/acetic acid, sodium triacetoxy borohydride/acetic acid or sodium borohydride/boric acid
Middle one or more.
Preferably, compound 1 and the mol ratio of material in reduction system are 1:1~10, preferably 1:2~6, more preferably
1:3。
Preferably, compound 1 and sodium borohydride class material (such as sodium cyanoborohydride, triacetoxy borohydride in reduction system
Sodium hydride or sodium borohydride), the molar ratio of acid (such as acetic acid or boric acid) be 1:1~3:1~3, preferably 1:1.4:
1.6。
Preferably, the process of step (1) is as follows：RCHO is dissolved in organic solvent, is added dropwise to hydrazinoethanol thereto,
Reaction；Reaction adds reducing agent system, reaction after terminating；Reaction terminate after through extracting, washing, drying, chromatographing and obtain compound
2。
Preferably, the organic solvent is one or more in methanol, tetrahydrofuran or 1,2- dichloroethanes, reducing agent
System is one or more in sodium cyanoborohydride/acetic acid, sodium triacetoxy borohydride/acetic acid or sodium borohydride/boric acid.
Condensation or reduction reaction can be carried out under agitation.Reaction process can be monitored with TLC.Reaction is anti-to reactant feed
It should finish.
Ethyl acetate extractive reaction mixture can be used, is preferably then pH 7.2 phosphate-buffered with phosphate buffer
Liquid washs, then is washed with water and saturation strong brine, anhydrous sodium sulfate drying, and revolving removes solvent after filtering.
Column chromatography can use V petroleum ethers：V ethyl acetate=2:1 is carried out.
In a preferred embodiment, the process of step (1) is：RCHO is dissolved in methanol, to it under the conditions of ice-water bath
In be added dropwise to hydrazinoethanol, stirring reaction at room temperature after being added dropwise, TLC is monitored to raw material reaction and finished；At room temperature to reaction
Acetic acid and sodium cyanoborohydride, stirring reaction, TLC monitoring reaction process are added in system；After completion of the reaction, mixture second
Acetoacetic ester is extracted, and is washed afterwards with pH 7.2 phosphate buffer, then is washed with water and saturation strong brine, and anhydrous sodium sulfate is done
Dry, revolving removes solvent after filtering；Column chromatography (can wherein use V petroleum ethers：V ethyl acetate=2:1) pale yellow oil is obtained after
Compound 2.
Preferably, Deprotection available hydrogen palladium charcoal is carried out in step (2).
Preferably, the solvent used in the Deprotection is one or more in methanol, ethanol, tetrahydrofuran.
Preferably, compound 2 and the mol ratio of palladium charcoal are 1:0.2-0.6.
Preferably, oxidation is carried out in atmosphere.
Preferably, the process of step (2) is：Pd/C is added into methanol, the methanol for then adding compound 2 thereto is molten
Liquid, then react under hydrogen, filter, wash after completion of the reaction, aoxidizing, chromatography obtains faint yellow product i.e. compound 3.
Preferably, Pd/C is added into methanol at 0 DEG C, nitrogen protection is lower to be carried out.
Reaction can be carried out at room temperature, more preferably be carried out under agitation.Reaction time can be 1-3h, preferably 2h.
Diatomite can be used to carry out for filtering.Washing can be carried out by methanol-chloroform solution, preferably using 5-20%, such as
The methanol-chloroform solution of 10% (i.e. the wherein volume fraction of methanol) is carried out.Crude product can be exposed in air by oxidation to be carried out.
Chromatography can be column chromatography, using petroleum ether and the mixture of ethyl acetate, such as V petroleum ethers：V ethyl acetate=4:1 mixture
Carry out.
In a preferred embodiment, the process of step (2) is：0 DEG C, Pd/C is added into methanol under nitrogen protection, after
The methanol solution of compound 2 is added dropwise into system, hydrogen is passed through after being added dropwise, in system and reaction is stirred at room temperature,
Reaction process is monitored, diatomite filters after completion of the reaction, and methanol-chloroformic solution washing, gained crude product is exposed in air
Row oxidation, column chromatography (such as V petroleum ethers：V ethyl acetate=4:1) faint yellow product i.e. compound 3 is obtained after.
Preferably, nitrosation reaction solvent for use described in step (3) is dichloromethane and/or 1,2- dichloroethanes,
Nitrosification agent is double (acetylacetone,2,4-pentanedione) vanadyl/tertbutanol peroxide and/or tetraisopropyl titanate/tert-Butanol peroxide.
Preferably, compound 3 and the mol ratio of nitrosification agent are 1:1~3, optimum ratio 1:2.Compound 3 and Asia
Double (acetylacetone,2,4-pentanedione) vanadyl or the mol ratio of tetraisopropyl titanate and tertbutanol peroxide are 1 in nitrating agent:0.1~0.5:
1.2~2, optimum ratio 1:0.5:1.5.
Preferably, the temperature of reaction is -10~20 DEG C, preferably 0 DEG C.
Preferably, the process of step (3) is：Nitrosification agent is added in the solution of compound 3, is reacted, adds saturation
Extracted after the aqueous solution of sodium thiosulfate with organic solvent, organic layer is dry, filtering, removes solvent, and crude product chromatographs to obtain yellow
Product is compound 4.
Preferably, nitrosification agent is added at -10~20 DEG C, and preferably 0 DEG C, nitrogen protection is lower to be carried out.
Preferably, react at -10~20 DEG C, carried out at preferably 0 DEG C.
Preferably, the time of reaction is more than 20min, preferably 40min.
Preferably, the solvent of the solution of compound 3 is dichloromethane and/or 1,2- dichloroethanes.
Preferably, organic solvent is chloroform.
Chromatography can be column chromatography, using petroleum ether and the mixture of ethyl acetate, such as use V petroleum ethers successively：V ethyl acetate
=10:1 and 7:1 mixture is carried out.
In a preferred embodiment, the process of step (3) is：0 DEG C, under nitrogen protection, to the dichloromethane of compound 3
Tetraisopropyl titanate and 0.11g (1.2mmol) tertbutanol peroxide are added in solution, 40min is stirred at equal temperature
Afterwards, into reaction system add saturated sodium thiosulfate the aqueous solution, after extracted with chloroform, organic layer is dried with sodium sulphate, mistake
Filter, removes solvent, and crude product passes through column chromatography (such as V petroleum ethers：V ethyl acetate=10:1,7:1) yellow product i.e. compound is obtained
4。
Preferably, addition elimination reaction described in step (4) is carried out by being reacted with mesyl chloride.
Preferably, solvent for use is one or more of in dichloromethane, chloroform or tetrahydrofuran.
Preferably, the process in step (4) is：Triethylamine, mesyl chloride, room are added into the organic solvent of compound 4
Temperature reaction, the carbon -7- alkene temperature reactions of 1,8- diazabicylos 11 being added, reaction is washed after terminating, and separates organic phase, is dried,
Solvent is removed after filtering, chromatography obtains colorless oil i.e. compound 5, namely the target product of the present invention, with structural formula I
Compound.
Preferably, organic solvent is one or more of in dichloromethane, chloroform or tetrahydrofuran.
Preferably, compound 4 and the mol ratio of mesyl chloride, triethylamine, the carbon -7- alkene of 1,8- diazabicylos 11 are 1:
2~5:2~3.5:3~5, optimum ratio 1:3:2.5:5.
Preferably, the temperature of temperature reaction is 30-40 DEG C, preferably 35 DEG C.
Preferably, the time of temperature reaction is 1-3h, preferably 2h.
Preferably, wash first to be washed with ethyl acetate and saturated ammonium chloride mixed liquor, be washed with water and wash.
Preferably, the number of washing is more than 1 time, preferably 2 times.
Drying can be carried out with anhydrous sodium sulfate.Solvent can be removed by rotating.Chromatography can be column chromatography.
TLC monitoring detection courses of reaction.Reaction is carried out under agitation.
In a preferred embodiment, the process of step (4) is：Three second are added into the dichloromethane solution of compound 4
Amine, mesyl chloride, are stirred at room temperature, and TLC monitorings, treat that raw material 4 reacts complete, add the carbon -7- alkene of 1,8- diazabicylos 11, rise
Temperature adds ethyl acetate, saturated ammonium chloride solution washs 2 times, water washing 2 times, and separation organic phase is with anhydrous to 35 DEG C of reaction 2h
Sodium sulphate is dried, and desolvation is rotated after filtering, and crude product column chromatography obtains colorless oil, namely the target product of the present invention, tool
There is the compound of formula II.
Preferably, preparation method of the present invention comprises the following steps：
(1) aldehyde 1 is substituted with the hydrazinoethanol of CBZ (benzyloxycarbonyl group) protections be condensed as initiation material using RCHO
To imines, obtain substituting hydrazine class compound 2 after reduction reaction；
(2) by compound 2 with CBZ protection groups are removed after the reduction of palladium charcoal, then oxidation obtains azo-compound 3；
(3) compound 3 obtains azo oxidation category compound 4 with isopropyl titanate by nitrosation reaction；
(4) compound 4 is reacted with mesyl chloride obtains compound 5 by elimination reaction, i.e., a series of ring platform mycins are similar
Thing.The reaction equation that the step of above-mentioned preparation method can see below：
Aldehyde is wherein substituted to be made according to existing literature (as disclosed in JP 6084105B2) by alkane substitute and DMF reactions
It is standby to obtain.
The beneficial effects of the invention are as follows：The present invention is using aldehyde compound as raw material, by being condensed, reducing, being deprotected, oxygen
Change, addition elimination reaction obtain guarding against platform mycin analog, and reaction scheme is short, and mild condition, yield is higher, easily prepared.
Embodiment
For ease of understanding the present invention, it is as follows that the present invention enumerates embodiment.Those skilled in the art are it will be clearly understood that the implementation
Example is used only for help and understands the present invention, is not construed as the concrete restriction to the present invention.
Embodiment 1：The preparation of compound 2
0.13g (1mmol) n-Heptaldehyde is dissolved in 20mL methanol, is added dropwise to 0.21g under the conditions of ice-water bath thereto
The hydrazinoethanol of the CBZ protections of (1mmol), stirring reaction, TLC are monitored to raw material reaction and finished at room temperature after being added dropwise.Room
0.12g (2mmol) acetic acid and 0.126g (2mmol) sodium cyanoborohydride are added under temperature into reaction system.Stirring is anti-
Should, TLC monitoring reaction process.After completion of the reaction, mixture is extracted with ethyl acetate, after washed with pH 7.2 phosphate buffer
Wash, then washed with water and saturation strong brine, anhydrous sodium sulfate drying, revolving removes solvent after filtering.Column chromatography (V petroleum ethers：
V ethyl acetate=2:1) pale yellow oil compound 2 is obtained after：0.25g, yield：81.1%.
1H NMR(CDCl3,400Hz)：δ 0.87 (t, J=6.4Hz, 3H), 1.27~1.43 (8H, m), 1.47~1.62
(2H, m), 2.87 (t, J=6.8Hz, 2H), 3.60 (t, J=4.8Hz, 2H), 3.79 (t, J=4.8Hz, 2H), 3.88 (s,
2H), 5.15 (s, 2H), 7.32~7.38 (m, 5H).
Embodiment 2：The preparation of compound 3
0 DEG C, 0.21g (0.2mmol) 10%Pd/C (Pd in Pd/C compounds are added under nitrogen protection into 10ml methanol
Mass fraction for 10%), the methanol solution of 0.31g (1mmol) compound 2 is added dropwise in backward system.After being added dropwise, body
Hydrogen is passed through in system and reaction 2h is stirred at room temperature.Monitor reaction process.Diatomite filters after completion of the reaction, 10% first
Alcohol-chloroformic solution washing, gained crude product, which is exposed in air, to be aoxidized, column chromatography (V petroleum ethers：V ethyl acetate=4:
1) the faint yellow product Compound 3 after：0.12g, yield：69.7%.
1H NMR(CDCl3,400Hz)：δ 0.88 (t, J=6.5Hz, 3H), 1.29~1.67 (m, 10H), 2.19 (s, 1H),
3.79 (t, J=7.6Hz, 2H), 3.96 (t, J=4.8Hz, 2H), 4.01 (t, J=4.8Hz, 2H).
Embodiment 3：The preparation of compound 4
0 DEG C, under nitrogen protection, 0.0284g is added into the dichloromethane solution of 0.172g (1mmol) compound 3
The tertbutanol peroxide of (0.1mmol) tetraisopropyl titanate and 0.11g (1.2mmol).40min is stirred at equal temperature
Afterwards, into reaction system add 25ml saturated sodium thiosulfates the aqueous solution, after extracted with chloroform, organic layer is done with sodium sulphate
It is dry, filtering, remove solvent.Crude product passes through column chromatography (V petroleum ethers：V ethyl acetate=10:1,7:1) yellow product compound
4：0.15g, yield：79.8%.
1H NMR(CDCl3,400Hz)：1H NMR(CDCl3,400Hz)：δ 0.87 (t, J=6.5Hz, 3H), 1.32~
1.70(m,10H),2.21(s,1H),3.82(m,2H),4.02(m,2H),4.28(m,2H)。
Embodiment 4：The preparation of compound 5
Triethylamine 0.2g (2mmol), mesyl chloride are added into the dichloromethane solution of 0.188g (1mmol) compound 4
0.23g (2mmol), is stirred at room temperature, TLC monitorings.Treat that raw material 4 reacts complete, add the carbon -7- alkene of 1,8- diazabicylos 11
0.456g (3mmol), it is warming up to 35 DEG C of reaction 2h.Ethyl acetate 25mL is added, saturated ammonium chloride solution washs 2 times, water washing 2
It is secondary, organic phase anhydrous sodium sulfate drying is separated, desolvation is rotated after filtering, crude product column chromatography obtains colorless oil compounds
5(C9H18N2O)：1.5g, yield 88%, structural formula sees below formula.
1H NMR(CDCl3,400Hz)：1H NMR(CDCl3,400Hz)：δ 0.87 (t, J=6.5Hz, 3H), 1.32~
1.70 (m, 10H), 3.54 (t, J=6.9Hz, 2H), 5.46 (t, J=7.6Hz, 1H), 6.41 (d, J=15Hz, 1H), 7.12
(dd, J=15.0,7.6Hz, 1H).
The activity test of anti parasitic and toxicity test
Experimental method with reference to the introduction such as Kimura method (ARGICULTURE BIOLOGICAL CHEMISRY45,249,
1981) locomotor activity of the compound 5 to loose ends worm, is determined, the result is that：
0.5ug/ml fatal rates：100%
0.25ug/ml fatal rates：98%
0.125ug/ml fatal rates：89%
0.063ug/ml fatal rates：70%.
Acute toxicity test is that Transperitoneal injects the compound obtained by above-described embodiment by the use of mouse as experimental animal
5：10mg/kg is not lethal.
The above is active and toxicity test shows, the ring platform mycin analog obtained by the present invention, as people, animal and plant
Antiparasitic agent be useful.
Obviously, above-described embodiment is only intended to clearly illustrate example, and is not the restriction to embodiment.It is right
For those of ordinary skill in the art, can also make on the basis of the above description it is other it is various forms of change or
Change.There is no necessity and possibility to exhaust all the enbodiments.And the obvious change thus extended out or
Among changing still in the protection domain of the invention.
Claims (10)
1. one kind guards against platform mycin analog, there is having structure formula II：
Wherein R is unsubstituted alkyl.
2. it is according to claim 1 ring platform mycin analog, it is characterised in that R be C4-C10 alkyl, preferably C6-
C8 alkyl；
Preferably, R is-CH2(CH2)2CH(CH3)2、-CH2(CH2)2CH(CH3)2、-CH2(CH2)3CH(CH3)2、-CH2(CH2)4CH
(CH3)2、-CH2CH2CH(CH3)2CH2CH3Or-CH2(CH2)2CH(CH3)2CH2CH3、-CH3(CH2)5。
3. a kind of preparation method of the ring platform mycin analog described in claim 1 or 2, comprises the following steps：
(1) RCHO substitutes aldehyde 1 to be converted into substitution hydrazine class compound 2 by condensation, reducing agent reduction；
(2) compound 2 obtains compound 3 by Deprotection and oxidation；
(3) compound 3 carries out selective nitrosation reaction and obtains compound 4；
(4) compound 4 obtains the compound of compound 5, i.e. formula II by addition elimination reaction.
4. preparation method according to claim 3, it is characterised in that in step (1) condensation be by RCHO substitute aldehyde 1 and
The hydrazinoethanol of CBZ protections is carried out；
Preferably, it is condensed and is carried out under the conditions of ice-water bath.
5. the preparation method according to claim 3 or 4, it is characterised in that condensation, reduction reaction institute described in step (1)
It is one or more in methanol, tetrahydrofuran or 1,2- dichloroethanes with solvent, reducing agent system is sodium cyanoborohydride/vinegar
It is one or more in acid, sodium triacetoxy borohydride/acetic acid or sodium borohydride/boric acid；
Preferably, compound 1 and the mol ratio of material in reduction system are 1:1~10, preferably 1:2-6, more preferably 1:3.
6. according to the preparation method described in claim any one of 3-5, it is characterised in that Deprotection hydrogen in step (2)
Palladium charcoal is carried out；
Preferably, the solvent used in the Deprotection is one or more in methanol, ethanol, tetrahydrofuran；
Preferably, compound 2 and the mol ratio of palladium charcoal are 1:0.2-0.6；
Preferably, oxidation is carried out in atmosphere.
7. according to the preparation method described in claim any one of 3-6, it is characterised in that nitrosation reaction described in step (3)
Solvent for use is dichloromethane and/or 1,2- dichloroethanes, and nitrosification agent is double (acetylacetone,2,4-pentanedione) vanadyl/tertbutanol peroxides
And/or tetraisopropyl titanate/tert-Butanol peroxide；
Preferably, compound 3 and the mol ratio of nitrosification agent are 1:1~3, preferably 1:2；
Preferably, the temperature of reaction is -10~20 DEG C, preferably 0 DEG C.
8. according to the preparation method described in claim any one of 3-7, it is characterised in that addition described in step (4) eliminates anti-
It should be carried out by being reacted with mesyl chloride；
Preferably, solvent for use is one or more of in dichloromethane, chloroform or tetrahydrofuran.
9. according to the preparation method described in claim any one of 3-8, it is characterised in that the process in step (4) is：To chemical combination
Triethylamine, mesyl chloride are added in the organic solvent of thing 4, room temperature reaction, adds the carbon -7- alkene heating of 1,8- diazabicylos 11
Reaction, reaction are washed after terminating, and separate organic phase, are dried, and solvent is removed after filtering, and chromatography obtains colorless oil i.e. compound
5, namely the compound with formula II.
10. preparation method according to claim 9, it is characterised in that the organic solvent is dichloromethane, chloroform or four
It is one or more of in hydrogen furans；
Preferably, compound 4 and the mol ratio of mesyl chloride, triethylamine, the carbon -7- alkene of 1,8- diazabicylos 11 are 1:2~
5:2~3.5:3~5, preferably 1:3:2.5:5；
Preferably, the temperature of temperature reaction is 30-40 DEG C, preferably 35 DEG C；
Preferably, the time of temperature reaction is 1-3h, preferably 2h；
Preferably, wash first to be washed with ethyl acetate and saturated ammonium chloride mixed liquor, be washed with water and wash；
Preferably, the number of washing is more than 1 time, preferably 2 times.
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| CN1034580A (en) * | 1988-01-27 | 1989-08-09 | 中国医学科学院医药生物技术研究所 | The manufacture method of a kind of antiparasitic new antibiotic and its esters |
| JPH01211557A (en) * | 1988-02-19 | 1989-08-24 | Kitasato Inst:The | Diethasine a derivative, its preparation, and production of diethasine a |
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| WO2019059132A1 (en) * | 2017-09-21 | 2019-03-28 | 学校法人北里研究所 | NOVEL NF-κB INHIBITOR |
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