CN108380242A - The preparation method of catalyst, the preparation method of catalyst, 28- high brassin lactones - Google Patents
The preparation method of catalyst, the preparation method of catalyst, 28- high brassin lactones Download PDFInfo
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- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
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- C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
- C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
- C07J73/003—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by oxygen as hetero atom
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Abstract
The invention discloses a kind of catalyst, structural formula is as follows：
Description
Technical field
The present invention relates to the preparing technical field of the 28- high of high-purity brassin lactones more particularly to a kind of solid supporteds
The preparation method of asymmetric catalyst, the preparation method of catalyst, 28- high brassin lactones.
Background technology
28- high brassin lactones are a plant growth regulators（Early stage is called plant hormone）, with following two
Feature：（1）They are capable of providing the nutriment of energy；（2）They can promote or inhibit or change plant under very low concentrations
The developmental process of object；Early detection has five major class plant hormones, including auxin, gibberellin, ethylene, abscisic acid and cell point
Element etc. is split, with the continuous development of science, new plant growth regulator is found by science door successively, in brassin
Ester, polyamines, turgescence element, jasmonic, oligosaccharide, salicylic acid, systemin and zearalenone etc., and original weight amount
Also increasing, although people have synthesized many plant growth regulating substances, the environment intermiscibility of synthetic at present
Anyway and it is less than natural products, even natural products, if large dosage uses residual in the natural environment
It pollutes the environment, Just because of this, dosage is very low（10-7—10-9）Brassin lactones it is especially noticeable, in brassin
Therefore ester is also known as the 6th generation plant production and adjusts element.
Brassin lactones also known as brassinolide, brassinosteroid are that the plant newly confirmed in decades recently swashs
Element, can be down to 10-9M concentration plays the role of good（The concentration that general plant hormone works is mostly 10-9M or more）,
It is referred to as the sixth-largest hormone after auxin, the basic element of cell division, gibberellin, abscisic acid and ethylene.
Rape, alias rape, Cruciferae, Btassica, annual herb plant, originating in China and India, north and south is widely
Cultivation, the four seasons have for production；According to culture and utility feature etc., rape is divided into three types, i.e. turnip type rape, juncea oil
Dish and cabbage type rape, and each type includes more dry kinds.
1979, Grove, which steps on the 4mg that researcher is purified to from the rape pollen that 227kg honeybees are collected, had high live
The rape element compound of property, is named as brassinosteroid.By the k x ray diffraction analysis xs and spectrum selective materials to crystal structure,
The chemical constitution of rape rope lactone is determined, the chemical constitution of brassinosteroid is steroidal, skeleton and the progestational hormone phase in animal
Seemingly, but it is hydroxylating steroid hormone.IUPAC titles:(3aS, 5S, 6R, 7aR, 7bS, 9aS, 10R, 12aS, 12bS) -10-
[(2S,3R,4R,5S)-3,4-Dihydroxy-5,6dinethyl-2-heptanyl]-5,6-dihydroxy-7a,9a-
Dimethylhexadecahydro-3H-benzo [C] indeo [5,4-e] oxepin-3-one, alias：2,3,22,23-
Tetrathydroxy-β-homo-7-oxaergostan-6-one.Cas number：72962-43-7.Structural formula See Figure:
Scheme1
In decades, oneself more fully hereinafter studies the mechanism of action and function and effect of brassin lactones warp, and focus is main
Concentrate on promoting the elongation growth aspect of plant, brassin lactones promote the effect highly significant of elongation, the mechanism of action and life
Long element is similar, but activity several order of magnitude lower than auxin, and brassin lactones also have positive coorperativity work with auxin
With, by promote cell membrane system proton pump pumped out to hydrionic, cause free space to be acidified, make Cell wall loosening to promote
Into growth, while brassin lactones can also inhibit the activity of auxin oxidase, improve the content of plant endogenous auxin, so
When brassin lactones and auxin are simultaneously in use, there is apparent addition effect.In addition brassin lactones can also be adjusted and be grown
The distribution of the synthesis of related certain protein and nutriment in metabolism and plant, realizes the control to growth, makes processing
Position part dry weight below obviously increases, and top dry weight is reduced, and the substance total amount of plant remains unchanged.Brassin lactones
It can influence the metabolism of nucleic acid material, moreover it is possible to delay the aging of Vitro Plant cell.
In recent years studies have shown that brassin lactones are also present in other plants, such as immature Chinese cabbage seed, green tea
Leaf and chestnut insect gall etc., while its analog is also separated in these plants, generally rape steroidal is not in pollen and
Content highest in ripe seed.Oneself has very more analogs to be detached from plant since brassinolide is found
And identification, and also considerable analog is synthesized by organic chemists, they have it is similar (higher or compared with
It is low) physiological activity, this one kind have steroid backbone substance be referred to as rape steroidal (brassinosteroids).
Up to the present, at least oneself is separated to more than 60 kinds brassinolide class compounds to people from plant, right
These structures and its it is active research shows that it is active with four because being known as correlation:（1）2 α, 3 α and 22R, 23R two are to through base;
（2）The 7- lactone structure activity of B rings is higher than 6- ketone structures:(3) No. 24 positions are S configurations;(4) A/B rings are trans- condensed ring, wherein 6-
Ketone structure is rape sterone also known as chestnut sterone, and English name castasterone belongs to rape steroid with brassin lactones
Object is closed, can also be the precursor for synthesizing brassin lactones.Research Literature about rape sterone is relatively more, but up to now also
Not seeing abroad has the rape sterone of commercialization to be registered and sold with the name of plant growth regulator.Simultaneously to artificial synthesized
It has also been found that activity may be enhanced by extending side chain after analog research, 25-methyl brassin lactones (Scheme2) have than rape
Plain lactone is higher active (by taking rice as an example).
At present, it has been found that advantageous easy artificial synthesized have with value and mainly 28- brassin lactones and 24- table rues
Tongue element lactone（Scheme2).When for different crops, different cultivars shows larger otherness, 28- tables Gao Yun
Influence of the tongue element lactone to maize seedling roots endogenous hormones has outstanding role, and is just much worse than 28- on rice and wheat
High brassin lactones.On the whole, for most of crops, 24- table brassin lactones activity is equivalent in brassin
The 20% of ester, the high brassin lactones of 10%, 28- tables that 24-mixed table brassin lactones are equivalent to brassinosteroid are equivalent to brassin
The 30% of lactone, 28- high brassin lactones are equivalent to the 87% of brassin lactones.
But the product of existing market is more chaotic, and dragons and snakes jumbled together under " brassin lactones " label, and isomers is mixed
Close object pretend to be single compound, rape sterone that have to be stained with a cousin and infiltrate lactone compound troop, below we comb with
Brassin lactones (brassinosteroid) related youngster common product on the market.
（1）24- tables brassin lactones, tri- table brassin lactones of 22,23,24- and 24- mix table brassin lactones
From the ergosterol being easy to get, 24- table brassin lactones can be prepared through series reaction, include mainly first
Sulfonylation, oxidation, reduction, open loop, dihydroxylated and Baeyer-Villiber oxidation reactions.Wherein dihydroxylation reaction does not use
Chiral catalyst, so obtained product is the opposite isomer mixture of one group of hydroxyl (cis-) configuration, it is next
Baeye.r-Villiger oxidation reactions and the aerobic isomers being inserted into the positions 5-6 and 6-7, refer to Scheme3.
Scheme3
Compound A is exactly 24- table brassin lactones, and compound B is exactly 22,23,24 one three table brassin lactones (22,23,24-
trisepibrassinolide)；Obtained if directly being post-processed after Baeyer-Villiger oxidation reactions four it is different
The rod of structure body closes object, is exactly that 24- mixes table brassin lactones, wherein A contents highest, (multiple batches of average data, A:B:C:D=
29.68:59.43:9.89:1.00).Further column chromatography can isolate and purify to obtain the sterling of A and B, additionally by addition
Catalyst can adjust the ratio of A and B.
(2) 28- high brassin lactones and the high brassin lactones of 28- tables
28- high brassin lactones and the high brassin lactones of 28- tables can be prepared from stigmasterol by similar reaction.By
The variation of steric hindrance after the ethyl that pendant methyl is changed to opposite configuration, direct dihydroxylation reaction reoxidize to obtain with 28- tables
The content of product based on high brassin lactones, 28- high brassin lactones can be controlled less than 5%, and product is easy to recrystallize
Obtain the high brassin lactones sterling of 28- tables (activity is more much lower than 28- high brassin lactones)；It can using chiral catalysts such as quinines
To greatly improve the ratio of 28- high brassin lactones, sterling is obtained through column chromatography for separation, so while in 28- high brassins
Although ester activity brassin lactones higher than 28 1 tables are much higher, production cost also wants much higher, and natural price is also highest
's.
The enterprise of country's brassin lactones active compound registration at present is many, mainly has:Zhejiang Sega Science and Technology Co., Ltd.'s (90% rue
Tongue element lactone), the fluffy biological medicine company limited liability company (90% brassin lactones) in Shandong capital, Chengdu new photograph sun crop science is limited
Company（90% brassin lactones）, the big scientific and technological agrochemical of the Jiangxi bio tech ltd Wei Di (95% brassin lactones), Yunnan cloud
Co., Ltd's (90% brassin lactones), Shandong Weifang Shuangxing Pesticide Co., Ltd.'s (90% brassin lactones), Japan defend material food
Chemical Co., Ltd. (95% propionylbrassinolide), Sichuan Lanyue Science ＆ Technology Co., Ltd.'s (95% brassin lactones) and Jiangmen city
Big light agrochemical Xin Hui Co., Ltds (90% brassin lactones).
It is above-mentioned to be registered with accurate name " propionylbrassinolide " except Wei Cai Food Chemistries Co., Ltd. of Japan
In addition, other producers are registered with " brassin lactones ", and small part producer indicated active ingredient (example in product packaging
Such as, the high brassin lactones of 28 1 tables of the 28- high brassin lactones and the big science and technology of cloud of prestige enemy), most of producer is all without specific
Active constituent marks, this does not conform to specification in fact inside agriculture chemical registration.
One high brassin lactones production Technology introduction
At present the synthetic technology of mainstream be with Sumitomo Chemical synthesize 28- high brassin lactones technique, reaction approximately as
(Scheme4):
Scheme4
（1）Stigmasterol methane sulfonyl chloride either paratoluensulfonyl chloride organic base such as triethylamine or pyridine effect under ester
Change, then is handled with saleratus to obtain different stigmasterol (II);
(2) it is ketone (III) with Jones reagent oxidation hydroxyls, then ketenes (IV) is obtained with smelling lithium or p-methyl benzenesulfonic acid open loop;
（3）With catalytic osmium tetroxide, N- methylmorphine oxide moieties carry out the dihydroxylation reaction of two double bonds, finally use hydrogen peroxide
Mono- Villiger oxidation reactions of Baeyer are carried out with three atmosphere acetic anhydrides to obtain in 28- high brassin lactones and the high brassin of 28- tables
The mixture of ester, general proportion is 5:95-20:Between 80, mainly based on the high brassin lactones of 28 1 tables, mixture can be used
Column chromatography for separation obtains the 28 1 high brassin lactones and the high brassin lactones of 28 1 tables of sterling.
In addition to this, SuguruTakatsuto etc. is ester the mixture aceticanhydride processing of (V), and column chromatography purifies soap again
Change obtains sterling, because the ratios of the isomers hydroxyl parent of ester is easier to detach；And BrajaG.Hazra etc. uses ketenes (IV)
C4H29NMe3MnO42 and No. 3 positions are first introduced cis hydroxyl groups as dihydroxylated reagent.
For Baeyer-Villiger oxidation reactions again it is aerobic at 5-6 and 6-7 insertion isomers, (Scheme3),
A kind of all fine kind equal methods one that develops can obtain single-minded 6-7 position isomers.
Above method all obtains the product mix based on the high brassin lactones of 28 1 tables, by column chromatography isomers
It separates, and 28- high brassin lactones content is not high, so existing method is in the production high brassin of 28 1 tables
Ester is very suitable, but is had little significance to 28- high brassin lactones, and the control of the effective isomers of dihydroxylation reaction is needed
Using asymmetric catalysis agent, Zhou Weishan etc. has more in-depth study for this step reaction.With chinidine parachlorobenzoic-acid
The asymmetric dihydroxylation technology of ester (DHQD) catalysis can just be obtained with efficient 22R, the product based on 23R bodies, (XIV):(XV)=
1.3:1, but catalyst is expensive, needs good recovery technology that could reduce production cost；The discoveries such as yellow good richness later
Methanesulfomide, which is added, can accelerate to react, and improve isomer proportion to 5:1.Huang Liangfu etc. also found if using phenanthryl
(phenanthryl) ratio can be increased to 8 by the DHQD modified:1.
Once report is carried on asymmetric pair of 7nm mesoporous silica gels catalysis to Lee etc. with one benzo pyridazine system of quinine/quinindium
The effect of hydroxylation reaction, catalyst is followed successively by (XV)<（XVI)<（XVII) best catalytic effect can reach 99.5%e.e.,
(XV) 97%e.e. can be reached to individual olefin substrates.
If according to industrialized requirement, it should which the achievement in research more than saying also is not enough to mass produce.One meets
The chemical process of the market demand will at least meet following youngster and require:（i）Optimum cost principle；(ii) production safety is reliable;
(iii) reach environmental protection, the three wastes are few and within the scope of manageable;（iv）With stronger production operability.Its
In used abnormally dangerous as chromium trioxide and osmium tetroxide and to the great reagent of environmental hazard, just safety and environmental protection
The requirement that modern chemical industry is not just met from the point of view of 2 points needs to purify that just with column chromatography let alone big production as finished product
, so meeting the technique produced greatly with regard to more meaningful according to the exploitation of existing achievement in research.
Invention content
It is an object of the invention to overcome the deficiencies in the prior art, adapt to reality and need, provide one kind, to solve currently
Technical problem.
In order to achieve the object of the present invention, the technical solution adopted in the present invention is：
The present invention discloses a kind of catalyst, and structural formula is as follows：
Wherein：In structure above, n=3,4,5,6,7,8,9 or 10.
Preferably, n=4 in structure above or 6.
The invention also discloses a kind of preparation method of catalyst, this method is used to prepare catalyst as described above；It
Include the following steps：
（1）The dichloro benzo pyridazine and dihydrochinidin of equivalent are condensed, the compound formed after condensation again with equivalent
Hexylene glycol or ethohexadiol condensation；
（2）After 300-400 mesh silica gel is handled with thionyl chloride with step（1）In final condensation product be condensed with alkali.
The invention also discloses a kind of preparation methods of 28- high brassin lactones, use catalyst as described above；It is wrapped
Include following steps：
（1）Stigmasterol is added in isopropyl acetate, triethylamine is added later, methane sulfonyl chloride stirring is added dropwise under low temperature；
（2）It is filtered after continuing stirring at room temperature 1.5-2.5 hours, extract filtrate and saleratus is added in filtrate；
（3）2.5-3.5 hours postcoolings that flow back are to room temperature, and concentration and recovery solvent obtains intermediate (II) after filtering；
（4）Intermediate (II), two chlordantoins and above-mentioned catalyst are added in tetrachloro-ethylene, triethylamine is added dropwise after heating；
（5）After temperature rising reflux 4.5-5.5 hours, heat filtering after cooling is concentrated to give intermediate (III)；
（6）Intermediate (III) is dissolved in after DMF, lithium bromide is added, reacted after being then warming up to 135-145 DEG C under nitrogen protection
7-9 hours, then it is cooled to 75-85 DEG C；
（7）Vacuum distillation recycling DMF, is added isopropyl acetate, rear concentration and recovery solvent is washed with water, obtains intermediate later
(IV)；Then sterling intermediate (IV) is obtained with recrystallizing methanol；
(8) double bond and pendant double bonds activity difference on ring are utilized, BrajaG.Hazra methods are can refer to, by step（7）In in
Double bond on mesosome (IV) ring carries out dihydroxylated；In this step, intermediate is then added as mixed solvent using acetonitrile and water
(IV)；
（9）Permanganic acid benzyl triethyl ammonium ammonium salt acetonitrile solution is added dropwise, reaction is filtered after 0.5-1.5 hours, concentrates successively,
It is then dissolved with isopropyl acetate, is concentrated to give intermediate after being washed with water later again（Ⅷ）；
（10）With the asymmetric catalyst DHQ of silica gel load2PHAL is as ligand, using the potassium ferricyanide as oxidant, carbonic acid
Potassium is methine, and Methanesulfonamide is catalyst, and the tert-butyl alcohol and water are that mixed solvent is reacted；Then obtained with ethyl alcohol recrystallization
Intermediate（XⅣ）；
（11）Intermediate (X IV) Baeyer-Villiger is carried out with peroxy trifluoroacetic acid to aoxidize to obtain the mixture of isomers,
Then at least recrystallization is primary.
Step（1）It is middle to be cooled down using ice water, and control temperature and be not higher than 20 DEG C.
Step（4）In be heated to 75-85 DEG C.
Step（5）In be cooled to 45-55 DEG C after carry out heat filtering.
The beneficial effects of the present invention are：
For this method, the core technology of this method is to use solid supported asymmetric catalyst, especially for Lee etc.
Work the present inventor conduct in-depth analysis discovery, it is better that ligand leaves the remoter catalytic effect of carrier, illustrates that steric hindrance is imitated
Substrate and ligand should be made to be difficult to close and play catalytic action；Given this present inventor devises from synthesis convenience
Catalyst suitable for this method；The catalyst of the present invention may be reused ten times or so, although its catalytic effect after use
It is decreased obviously；But be free ligand by alkali process is used after catalyst acid processing again, then handled again with thionyl chloride
The silica gel load crossed can restore to use, referring now to using its reuse rate higher of existing catalyst, and it is pollution-free, it is right
The production cost of enterprise can be reduced for enterprise.
The 28- high brassin lactones that method through the invention is prepared have the advantage that：
（1）Whole process route of this method is more smooth, and solvent can be uniformly processed in implementation as far as possible, improves fully synthetic total
Yield, the total recovery of the overall reaction calculated with stigmasterol is 42%;
（2）Entire production process does not generate exhaust gas and (there was only the uncontrollable discharge that a small amount of solvent volatilization generates, and in entire method
Three classes solvent is selected as possible), heavily contaminated oxidant as chromium trioxide is not used, replaces having using stable compound potassium osmate
Malicious and volatile osmium tetroxide, the oxidant potassium ferricyanide become potassium ferrocyanide after use, become iron cyanogen with chlorine oxidation
It can be recycled after changing potassium, by-product triethylammonium salts hydrochlorate can use sodium hydroxide simple process recovery, can reduce cost,
And by-product glycolylurea and manganese dioxide can be exchanged with corresponding raw material manufacturer, can finally reduce the production cost of enterprise；
(3) referring now to the prior art, this method aoxidized using two chlordantoins different stigmasterol avoid oxidant chromium trioxide and
The concentrated sulfuric acid pollutes.
Specific implementation mode
With reference to embodiment, the present invention is further described：
Embodiment 1：A kind of catalyst, structural formula are as follows：
Wherein：In structure above, n=3,4,5,6,7,8,9 or 10；Preferably, n=4 in structure above or 6.
Embodiment 2：A kind of preparation method of catalyst, this method are used to prepare catalyst described in embodiment 1；It includes
Following steps：
（1）The dichloro benzo pyridazine and dihydrochinidin of equivalent are condensed, the compound formed after condensation again with equivalent
Hexylene glycol or ethohexadiol condensation；
（2）After 300-400 mesh silica gel is handled with thionyl chloride with step（1）In final condensation product alkali condensation can be obtained
The catalyst of silica gel load.
It may be reused ten times or so through catalyst made from this method, under its catalytic effect is apparent after use for several times
Drop；But be free ligand by alkali process is used after the acid processing of this catalyst again, it is then again processed with thionyl chloride
Silica gel load can restore to use, referring now to using its reuse rate higher of existing catalyst, and it is pollution-free, to enterprise
For can reduce the production cost of enterprise.
Embodiment 3：A kind of preparation method of 28- high brassin lactones, uses catalyst as described in Example 1；First
The preparation method for introducing the 28- high brassin lactones of the present invention designs original intention：
The present inventor has found the in-depth analysis of the prior art, in existing method：(1) first step sulfonylation and the second one-step hydrolysis
Simplification can be merged by preparing different ergosterol, and the solvent for selecting two steps that can be used in conjunction with is direct after reaction in the first step
In the reaction system plus enough saleratus, post-reaction treatment can obtain different stigmasterol.（2）For the oxidation side of alcohol
Method, Research Literature is found, is met production requirement and is not destroyed the less of three-membered ring, and american documentation literature US4891168 is provided
A kind of method, the Oppenauer oxidation reactions being catalyzed with aluminium isopropoxide, oxidant use cyclohexanone, this is one to be worth
The approach that must be studied, the patent additionally provide a kind of oxygen with NIS (two phthalimide of N- iodos fourth) and tetrabutylammonium iodide combination
Agent can obtain 96% yield, but reagent is too expensive, does not have application value, and it is imperative to develop new method for oxidation.
For this purpose, present inventors studied this method, the core technology of this method essentially consists in asymmetric dihydroxylation reaction system
The 28- high brassin lactones of high-content are obtained, the selectivity of 20- high brassin lactones is improved, product mix is conducive to by tying again
Crystalline substance purifying, secondly used catalyst price costly, can returning catalyst using advanced immobilized catalysis technique
Yield improves, and easy to operate, and cost recovery is relatively low, and also strong volatility and toxicity osmium tetroxide can be replaced with hungry sour potassium
Generation.
Specifically, the present invention 28- high brassin lactones preparation method it include the following steps：
（1）Stigmasterol is added in isopropyl acetate, triethylamine, ice water cooling are added later, and control temperature and be not higher than 20 DEG C,
Methane sulfonyl chloride stirring is added dropwise at low temperature；
（2）It is filtered after continuing stirring at room temperature 1.5-2.5 hours, extract filtrate and saleratus is added in filtrate；
（3）2.5-3.5 hours postcoolings that flow back are to room temperature, and concentration and recovery solvent obtains intermediate (II) after filtering；This step
Yield can reach 98%.
（4）Intermediate (II), two chlordantoins and catalyst described in embodiment 1 are added in tetrachloro-ethylene, are heated to
Triethylamine is added dropwise after 75-85 DEG C；
（5）After flowing back 4.5-5.5 hours after heating, heat filtering after being then cooled to 45-55 DEG C is concentrated to give intermediate
(Ⅲ)；Yield 95% is directly entered in next step without purifying；
（6）Intermediate (III) is dissolved in after DMF, lithium bromide is added, reacted after being then warming up to 135-145 DEG C under nitrogen protection
7-9 hours, then it is cooled to 75-85 DEG C；
（7）Vacuum distillation recycling DMF, is added isopropyl acetate, rear concentration and recovery solvent is washed with water, obtains intermediate later
(IV)；Then sterling intermediate (IV), yield 82% are obtained with recrystallizing methanol；
(8) double bond and pendant double bonds activity difference on ring are utilized, BrajaG.Hazra methods are can refer to, by step（7）In in
Double bond on mesosome (IV) ring carries out dihydroxylated；In this step, intermediate is then added as mixed solvent using acetonitrile and water
(IV)；
（9）Permanganic acid benzyl triethyl ammonium ammonium salt acetonitrile solution is added dropwise, reaction is filtered after 0.5-1.5 hours, concentrates successively,
It is then dissolved with isopropyl acetate, is concentrated to give intermediate after being washed with water later again（Ⅷ）, yield 85%；
（10）With the asymmetric catalyst DHQ of silica gel load2PHAL is as ligand, using the potassium ferricyanide as oxidant, carbonic acid
Potassium is methine, and Methanesulfonamide is catalyst, and the tert-butyl alcohol and water are that mixed solvent is reacted；The mixture isomery dealt
Body ratio is up to 20:1, then the intermediate that content is more than 98% can be obtained with ethyl alcohol recrystallization（XⅣ））, yield 80%；
（11）Intermediate (X IV) Baeyer-Villiger is carried out with peroxy trifluoroacetic acid to aoxidize to obtain isomers (7- oxa-s:
6- oxa-s) 94:6 mixture, then at least recrystallization is primary；The 28- high of 95% or more purity once just can be obtained in crystallization
Brassin lactones [the high brassinolides of (22R, 23R) -28-, yield 81%.
Above-mentioned entire technological process is referring to Scheme9：
Scheme9
The 28- high brassin lactones that method through the invention is prepared have the advantage that：
（1）Whole process route of this method is more smooth, and solvent can be uniformly processed in implementation as far as possible, improves fully synthetic total
Yield, the total recovery of the overall reaction calculated with stigmasterol is 42%；
（2）Entire production process does not generate exhaust gas and (there was only the uncontrollable discharge that a small amount of solvent volatilization generates, and in entire method
Three classes solvent is selected as possible), heavily contaminated oxidant as chromium trioxide is not used, replaces having using stable compound potassium osmate
Malicious and volatile osmium tetroxide, the oxidant potassium ferricyanide become potassium ferrocyanide after use, become iron cyanogen with chlorine oxidation
It can be recycled after changing potassium, by-product triethylammonium salts hydrochlorate can use sodium hydroxide simple process recovery, can reduce cost,
And by-product glycolylurea and manganese dioxide can be exchanged with corresponding raw material manufacturer, can finally reduce the production cost of enterprise；
(3) referring now to the prior art, this method aoxidized using two chlordantoins different stigmasterol avoid oxidant chromium trioxide and
The concentrated sulfuric acid pollutes.
Implement 4, place same as Example 3 repeats no more, the difference is that：
In embodiment 3：
Step（2）Middle mixing time is 1.5 hours；
Step（3）Middle return time is 2.5 hours；
Step（4）In be heated to 75 DEG C；
Step（5）In be cooled to 45 DEG C；
Step（6）In be warming up to 135 DEG C after react 7 hours, be then cooled to 75 DEG C；
Step（10）The middle reaction time is 0.5 hour.
Implement 5, place same as Example 3 repeats no more, the difference is that：
In embodiment 3：
Step（2）Middle mixing time is 2.0 hours；
Step（3）Middle return time is 3.0 hours；
Step（4）In be heated to 80 DEG C；
Step（5）In be cooled to 50 DEG C；
Step（6）In be warming up to 135 DEG C after react 8 hours, be then cooled to 80 DEG C；
Step（10）The middle reaction time is 1.0 hours.
Implement 6, place same as Example 3 repeats no more, the difference is that：
In embodiment 3：
Step（2）Middle mixing time is 2.5 hours；
Step（3）Middle return time is 3.5 hours；
Step（4）In be heated to 85 DEG C；
Step（5）In be cooled to 55 DEG C；
Step（6）In be warming up to 140 DEG C after react 9 hours, be then cooled to 85 DEG C；
Step（10）The middle reaction time is 1.5 hours.
Implement 7, place same as Example 3 repeats no more, the difference is that：
In embodiment 3：
Step（2）Middle mixing time is 2.3 hours；
Step（3）Middle return time is 3.3 hours；
Step（4）In be heated to 82 DEG C；
Step（5）In be cooled to 54 DEG C；
Step（6）In be warming up to 145 DEG C after react 8.5 hours, be then cooled to 83 DEG C；
Step（10）The middle reaction time is 1.2 hours.
What the embodiment of the present invention was announced is preferred embodiment, and however, it is not limited to this, the ordinary skill people of this field
Member understands the spirit of the present invention easily according to above-described embodiment, and makes different amplification and variation, but as long as not departing from this
The spirit of invention, all within the scope of the present invention.
Claims (7)
1. a kind of catalyst, it is characterised in that：Its structural formula is as follows：
Wherein, in structure above, n=3,4,5,6,7,8,9 or 10.
2. catalyst as described in claim 1, it is characterised in that：The n=4 or 6.
3. a kind of preparation method of catalyst, this method are used to prepare catalyst as described in claim 1；It is characterized in that：
It includes the following steps：
(1) by the dichloro benzo pyridazine and dihydrochinidin of equivalent be condensed, the compound formed after condensation again with equivalent
Hexylene glycol or ethohexadiol condensation；
(2) it is condensed with alkali with the final condensation product in step (1) after handling 300-400 mesh silica gel with thionyl chloride.
4. a kind of preparation method of 28- high brassin lactones, uses catalyst as described in claim 1；It is characterized in that：It
Include the following steps：
(1) stigmasterol is added in isopropyl acetate, triethylamine is added later, methane sulfonyl chloride stirring is added dropwise under low temperature；
(2) it is filtered after continuing stirring at room temperature 1.5-2.5 hours, extract filtrate and saleratus is added in filtrate；
(3) 2.5-3.5 hours postcoolings that flow back are to room temperature, and concentration and recovery solvent obtains intermediate (II) after filtering；
(4) intermediate (II), two chlordantoins and catalyst described in claim 1 are added in tetrachloro-ethylene, are dripped after heating
Add triethylamine；
(5) for temperature rising reflux after 4.5-5.5 hours, heat filtering after cooling is concentrated to give intermediate (III)；
(6) intermediate (III) is dissolved in after DMF and lithium bromide is added, it is anti-after being then warming up to 135-145 DEG C under nitrogen protection
It answers 7-9 hours, is then cooled to 75-85 DEG C；
(7) vacuum distillation recycling DMF, is added isopropyl acetate, rear concentration and recovery solvent is washed with water, obtains intermediate later
(IV)；Then sterling intermediate (IV) is obtained with recrystallizing methanol；
(8) double bond on intermediate (IV) ring in step (7) is subjected to dihydroxylated；
(9) permanganic acid benzyl triethyl ammonium ammonium salt acetonitrile solution is added dropwise, reaction is filtered after 0.5-1.5 hours, concentrates successively,
It is then dissolved with isopropyl acetate, is concentrated to give intermediate (VIII) after being washed with water later again；
(10) the asymmetric catalyst DHQ of silica gel load is used2PHAL is as ligand, using the potassium ferricyanide as oxidant, potassium carbonate
First is alkali, and Methanesulfonamide is catalyst, and the tert-butyl alcohol and water are that mixed solvent is reacted；In then being obtained with ethyl alcohol recrystallization
Mesosome (X IV)；
(11) intermediate (X IV) Baeyer-Villiger is carried out with peroxy trifluoroacetic acid to aoxidize to obtain the mixture of isomers,
Then at least recrystallization is primary.
5. the preparation method of 28- high brassin lactones as claimed in claim 4, it is characterised in that：Ice water is used in step (1)
It is cooling, and control temperature and be not higher than 20 DEG C.
6. the preparation method of 28- high brassin lactones as claimed in claim 4, it is characterised in that：Step is heated in (4)
75—85℃。
7. the preparation method of 28- high brassin lactones as claimed in claim 4, it is characterised in that：Step is cooled in (5)
Heat filtering is carried out after 45-55 DEG C.
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| CN110452284A (en) * | 2019-08-30 | 2019-11-15 | 郑州万牛生物技术有限公司 | A kind of preparation method of 28- high brassin lactones |
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| CN101245063A (en) * | 2008-03-12 | 2008-08-20 | 中国人民解放军第四军医大学 | Method for synthesizing cinchona alkaloids microwave radiation non-solvent |
| WO2009131692A1 (en) * | 2008-04-23 | 2009-10-29 | The Board Of Trustees Of The University Of Alabama | Substrates for delivery of physiologically active agents |
| CN101812114A (en) * | 2010-05-14 | 2010-08-25 | 上海威敌生化(南昌)有限公司 | Preparation method of 24-epibrassinolide |
| CN101941872A (en) * | 2010-08-19 | 2011-01-12 | 北京农学院 | Pesticidal foliage fertilizer mixed with plant growth factors and preparation method thereof |
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| CN101245063A (en) * | 2008-03-12 | 2008-08-20 | 中国人民解放军第四军医大学 | Method for synthesizing cinchona alkaloids microwave radiation non-solvent |
| WO2009131692A1 (en) * | 2008-04-23 | 2009-10-29 | The Board Of Trustees Of The University Of Alabama | Substrates for delivery of physiologically active agents |
| CN101812114A (en) * | 2010-05-14 | 2010-08-25 | 上海威敌生化(南昌)有限公司 | Preparation method of 24-epibrassinolide |
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| CN110452284A (en) * | 2019-08-30 | 2019-11-15 | 郑州万牛生物技术有限公司 | A kind of preparation method of 28- high brassin lactones |
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