CN103087060B - High activity paichongding isomer and preparation method thereof - Google Patents
High activity paichongding isomer and preparation method thereof Download PDFInfo
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- CN103087060B CN103087060B CN201110334941.5A CN201110334941A CN103087060B CN 103087060 B CN103087060 B CN 103087060B CN 201110334941 A CN201110334941 A CN 201110334941A CN 103087060 B CN103087060 B CN 103087060B
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- 0 CCC*[C@](C[C@@]1C)N(CCN2Cc3ccc(C)nc3)C2=C1[N+]([O-])=O Chemical compound CCC*[C@](C[C@@]1C)N(CCN2Cc3ccc(C)nc3)C2=C1[N+]([O-])=O 0.000 description 2
- MOTGVPXRLDDMSK-UHFFFAOYSA-N CCCOC(CC1C)N(CCN2Cc(cn3)ccc3Cl)C2=C1[N+]([O-])=O Chemical compound CCCOC(CC1C)N(CCN2Cc(cn3)ccc3Cl)C2=C1[N+]([O-])=O MOTGVPXRLDDMSK-UHFFFAOYSA-N 0.000 description 2
- SJFPJGQQUXJYPK-UHFFFAOYSA-N CC(C1)C([N+]([O-])=O)=C(N(Cc(cn2)ccc2Cl)CC2)N2C1O Chemical compound CC(C1)C([N+]([O-])=O)=C(N(Cc(cn2)ccc2Cl)CC2)N2C1O SJFPJGQQUXJYPK-UHFFFAOYSA-N 0.000 description 1
- SSKXATQTMOFWGE-PBHICJAKSA-N CCCOC[C@H](C[C@H]1C)N(CCN2Cc3ccc(C)nc3)C2=C1[N+]([O-])=O Chemical compound CCCOC[C@H](C[C@H]1C)N(CCN2Cc3ccc(C)nc3)C2=C1[N+]([O-])=O SSKXATQTMOFWGE-PBHICJAKSA-N 0.000 description 1
- PDEIBUMNVXMIQP-LIRRHRJNSA-N CCCO[C@@](C)(C[C@@H]1C)N(CCN2Cc3ccc(C)nc3)C2=C1[N+]([O-])=O Chemical compound CCCO[C@@](C)(C[C@@H]1C)N(CCN2Cc3ccc(C)nc3)C2=C1[N+]([O-])=O PDEIBUMNVXMIQP-LIRRHRJNSA-N 0.000 description 1
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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
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- 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
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention provides High activity paichongding isomer and preparation method thereof.In particular it relates to High activity paichongding isomer: (11S, the 14R) paichongding shown in (11R, the 14S) paichongding shown in formula A3 and/or formula A4, and preparation method thereof: one is the preparation method of enantiomer A34；Two is the asymmetric Chiral Synthesis of compound shown in single configurational isomer formula A4.Isomer activity provided by the present invention is significantly higher than existing paichongding industrialization product.Method provided by the present invention can remove the isomer of low drug effect easily, thus significantly improves the drug effect of insecticide.
Description
Technical field
The present invention relates to pesticide field, relate more specifically to High activity paichongding isomer and preparation method thereof.
Background technology
Paichongding (i.e. formula A compound) is an environment amenable insecticide of class low toxicity, has the most obtained the interim registration card of pesticide and has produced card, will list at home.This compounds has high activity to imidacloprid resistant rice brown paddy plant hopper strain, and its activity, significantly beyond imidacloprid, is expected to play a significant role in the preventing and treating of imidacloprid resistant strain.
Containing two chiral carbon atoies in paichongding structure, therefore there is formula A1 compound (i.e. (11R, 14R) paichongding), formula A2 compound (i.e. (11S, 14S) paichongding), formula A3 compound (i.e. (11S, 14R) paichongding) and four kinds of stereoisomers of formula A4 compound (i.e. (11R, 14S) paichongding).
(11R, 14R) paichongding (11S, 14S) paichongding
(11R, 14S) paichongding (11S, 14R) paichongding
WO2007101369 have employed by formula B4 compound under concentrated hydrochloric acid is catalyzed, obtain formula A compound, the method response time length (more than 36 hours), and the mixture that end product is four optical isomers.
Pesticide molecule structure the most all has chirality, and in the pesticide species of current commercialization, about 1/4th have chirality.Raceme pesticide contains poor efficiency or invalid enantiomer due to it, not only can reduce drug effect, pollutes environment and reduce agricultural product quality, it is also possible to can cause poisoning or develop immunity to drugs.
Therefore, low activity isomer can be removed in the urgent need to a kind of thus obtain the simple effective method of high activity isomer, or a kind of method of isomer that can directly prepare single configuration, to improve the drug effect of the Field information of insecticide.
Summary of the invention
It is an object of the present invention to provide removal low activity isomer thus obtain the simple effective method of high activity isomer.
A kind of method that it is a further object to provide isomer that can directly prepare single configuration.
First aspect present invention provides the optical isomer of a kind of paichongding, and described isomer is (11S, the 14R) paichongding shown in (11R, the 14S) paichongding shown in formula A3 and/or formula A4:
(11R, 14S) paichongding (11S, 14R) paichongding.
Second aspect present invention provides a kind of agriculturally useful compositions, and it comprises:
(A) acceptable salt or combinations thereof in the Pesticide Science of the optical isomer described in the first aspect present invention of 0.001-99.99 weight %, described optical isomer；And
(B) acceptable carrier and/or excipient in Pesticide Science.
In another preference, component (A) accounts for 0.01-99.9 weight % of described agriculturally useful compositions, preferably 0.05-90 weight %.
In another preferred embodiment, described agriculturally useful compositions is for killing or prevent the insect selected from lower group: coleoptera, Lepidoptera, Semiptera, Orthoptera, Isoptera or dipteral insect.
In another preference, described insect has pierce-suck type or rasping-sucking mouthparts.
In another preference, described insect is aphid, plant hopper, aleyrodid, leafhopper, thrips, bollworm, Pieris rapae, diamondback moth, Prodenia litura or mythimna separata.
In another preference, described agriculturally useful compositions also comprises other active substance, and other active substance described is selected from: insecticide, bait formulation, antibacterial, acaricide, nematicide, antifungal or growth control agent.
Third aspect present invention provides the purposes of agriculturally useful compositions described in a kind of second aspect present invention, for killing or prevent agricultural pests, sanitary insect pest and the insect of harm animal health；Or kill or prevent agricultural pests, sanitary insect pest and the insecticides of harm animal health with acting on.
Fourth aspect present invention provides acceptable salt or the purposes of a combination thereof in optical isomer described in a kind of first aspect present invention, described optical isomer Pesticide Science, is used for preparing insecticides.
Fifth aspect present invention provides the preparation method of optical isomer described in a kind of first aspect present invention, including step: the paichongding raw material containing optical isomer shown in formula A3 and/or formula A4 is split, thus obtain (the 11R shown in formula A3,14S) paichongding and/or (11S, 14R) paichongding shown in formula A4.
In another preference, described paichongding raw material is solid or liquid, and contains formula A3 compound and formula A4 compound or at least contain formula A4 compound.
In another preference, described paichongding raw material is the racemic paichongding simultaneously containing formula A1 compound, formula A2 compound, formula A3 compound and formula A4 compound.
In another preference, described method includes crystallizing Split Method, chemical resolution method, chirality HPLC Split Method, column chromatography or a combination thereof.
In another preference, described method is chirality HPLC Split Method.
Sixth aspect present invention provides (11R, the 14S) paichongding shown in formula A3 described in a kind of first aspect present invention and the preparation method of (11S, the 14R) paichongding shown in formula A4, and described method includes step:
A () is to the paichongding raw material containing optical isomer shown in formula A3 and formula A4, in mixed solvent, optionally in the presence of Bronsted acid or lewis acid catalyst, after carrying out recrystallization, thus form the crystallization of enantiomer A34 of formula A3 compound and formula A4 compound composition；
B () isolates the crystallization of enantiomer A34, and collect mother solution；
C the mother solution of collection optionally, is carried out recrystallization in the presence of Bronsted acid or lewis acid catalyst, thus forms the crystallization of enantiomer A34 by ().
In another preference, repeat step (b)-(c) one or many.
In another preference, repeat step (b)-(c) 1-3 time.
In another preference, recrystallization heating and temperature control is at 40～100 DEG C.
In another preference, described method also includes the preparation process of described paichongding raw material before the step (a):
In atent solvent, in the presence of Bronsted acid or lewis acid catalyst, formula B compound and normal propyl alcohol are reacted, thus forms formula A compound, i.e. paichongding.
In another preference, described atent solvent includes ethyl acetate, dichloromethane, petroleum ether, ether, acetonitrile or a combination thereof.
In another preference, described method includes step:
(I) in atent solvent, in the presence of Bronsted acid or lewis acid catalyst, formula B compound and normal propyl alcohol are reacted, thus forms formula A compound, i.e. paichongding；
(IIa) in mixed solvent, after paichongding is carried out recrystallization, thus the crystallization of enantiomer A34 of formula A3 compound and formula A4 compound composition is formed；
(IIb) isolate the crystallization of enantiomer A34, and collect mother solution；
(IIc) optionally, the mother solution of collection is carried out in the presence of Bronsted acid or lewis acid catalyst recrystallization, thus forms the crystallization of enantiomer A34.
In another preference, repeat step (IIb)-(IIc) one or many.
In another preference, repeat step (IIb)-(IIc) 1-3 time.
In another preference, described Bronsted acid or lewis acid include: hydrochloric acid, sulphuric acid, nitric acid, formic acid, acetic acid, trifluoroacetic acid, aluminum chloride, iron chloride, stannic chloride, boron trifluoride, boron trifluoride diethyl etherate, oxalyl chloride, methylsufonyl chloride, thionyl chloride, paratoluensulfonyl chloride, methacrylic chloride or a combination thereof.
In another preference, described Bronsted acid or lewis acid are aluminum chloride, oxalyl chloride, thionyl chloride, methacrylic chloride or hydrochloric acid.
In another preference, described mixed solvent is A and the combination in any of two groups of solvents of B:
A group solvent includes: methanol, ethanol, normal propyl alcohol, isopropanol, ethylene glycol, glycerol or a combination thereof；
B group solvent includes: acetonitrile, oxolane, dioxane, water, dimethylformamide (DMF), dimethyl sulfoxide (DMSO) or a combination thereof；
The volume ratio of two groups of solvents of A and B is 20: 1～1: 20.
In another preference, described mixed solvent is A and the combination in any of two groups of solvents of B:
A group solvent is ethylene glycol, isopropanol or normal propyl alcohol；
B group solvent is DMF, water or acetonitrile；
The volume ratio of two groups of solvents of A and B is 5: 1～1: 10.
Seventh aspect present invention provides the preparation method of (11S, 14R) paichongding shown in formula A4 described in a kind of first aspect present invention, and described method includes step:
(1) in atent solvent, formula C compound is reacted with acid catalyst, thus form formula B4 compound；
Wherein,
R1Or R2It is each independently C1-4Alkyl；Or, R1And R2Collectively form-(CH2)n-, wherein, n is the integer of 2-4；
Described acid catalyst includes: hydrochloric acid, acetic acid, trifluoroacetic acid, Fe (OTs)3·6H2O, camphorsulfonic acid (CSA), para-methylbenzenepyridinsulfonate sulfonate (PPTS), TsOH or a combination thereof；
In another preference, described acid catalyst is CSA or PPTS.
(2) in atent solvent, in the presence of Bronsted acid or lewis acid, formula B4 compound is reacted with normal propyl alcohol, thus form formula A4 compound；
Wherein, described Bronsted acid or lewis acid include: hydrochloric acid, sulphuric acid, nitric acid, formic acid, acetic acid, trifluoroacetic acid, aluminum chloride, iron chloride, stannic chloride, boron trifluoride, boron trifluoride diethyl etherate, thionyl chloride, paratoluensulfonyl chloride, methylsufonyl chloride, oxalyl chloride, methacrylic chloride or a combination thereof.
In another preference, described Bronsted acid or lewis acid are hydrochloric acid, aluminum chloride, oxalyl chloride, thionyl chloride, paratoluensulfonyl chloride or methacrylic chloride.
In another preference, further comprise the steps of: before described step (1)
(1a) in atent solvent, in the basic conditions, by formula G compound and Carbon bisulfide and R3I reacts jointly, thus forms formula F compound；
Wherein, R1、R2And R3It is each independently C1-4Alkyl；Or, R1And R2Collectively form-(CH2)n-, wherein, n is the integer of 2-4；
Described alkali includes: NaH, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or a combination thereof；
In another preference, described alkali is NaH.
(1b) in atent solvent, after formula F compound and reacting ethylenediamine, thus formula E compound is formed；
Wherein, R1、R2And R3As defined above；
(1c) in the basic conditions, formula E compound is reacted with formula D compound, thus form formula C compound；
Wherein, R1、R2As defined above；
Described alkali includes: NaH, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or a combination thereof；
In another preference, described alkali is NaH.
In another preference, further comprise the steps of: before described step (1a)
(1a-1) in atent solvent, in the presence of a catalyst, nitromethane is reacted with crotonic aldehyde, thus form formula H compound；
Wherein, described catalyst includes: the silicon ether derivant of the substituted Prolinol of diaryl, L-PROLINE, (+)-tartaric acid, (+)-Camphora-10-sulfonic acid, chirality dipeptides containing glycine or a combination thereof；
(1a-2) in atent solvent, by formula H compound and aldehyde radical protection group reagent reacting, thus formula G compound is formed；
Wherein, described aldehyde radical protection group reagent is HO-(CH2)n-OH or HO-C (OR1)(OR2)(OR4),
Described R1、R2And R4It is each independently C1-4Alkyl；Or, R1And R2Collectively form-(CH2)n-, wherein, n is the integer of 2-4.
In another preference, described aldehyde radical protection group reagent includes: trimethyl orthoformate, ethylene glycol, 1,3-PD or a combination thereof.
In should be understood that within the scope of the present invention, can be combined with each other between above-mentioned each technical characteristic and each technical characteristic specifically described in below (eg embodiment) of the present invention, thus constitute new or preferred technical scheme.As space is limited, the most tired at this state.
Accompanying drawing explanation
Fig. 1 shows the HPLC being split four isomers that paichongding obtains by embodiment 1 method；From left to right being followed successively by formula A1 compound, formula A2 compound, formula A3 compound and formula A4 compound in figure, retention time is respectively 7.500,8.790,10.618 and 13.487min.
Fig. 2 shows the HPLC being split four isomers that paichongding obtains by embodiment 2 method；Figure is from left to right followed successively by paichongding isomer: formula A1 compound, formula A2 compound, formula A3 compound and formula A4 compound, retention time is respectively 3.722,3.976,4.666 and 5.624min.
Fig. 3 shows the HPLC of paichongding.
Fig. 4 shows the HPLC comparison figure of the solid being recrystallized to give and paichongding 1 time；P3 is the HPLC figure of paichongding；SH01 is the HPLC figure of the solid being recrystallized to give.
Fig. 5 shows the HPLC comparison figure of the solid by obtaining after 3 recrystallization and paichongding；P3 is the HPLC figure of paichongding；SH01 is the HPLC figure of the solid obtained after 3 recrystallization.
Detailed description of the invention
The present inventor is by in-depth study for a long time, it has unexpectedly been found that, compare with the paichongding of racemization, enantiomer A34, the formula A3 compound of single configuration or formula A4 compound have more excellent insecticidal activity.
In addition, inventor it has been unexpectedly discovered that a kind of prepare, the method for isolated and purified enantiomer A34, by acid catalysis raw material reaction, again through alkalization, extraction and mixed solvent recrystallization, can effectively remove the isomer of low insecticidal activity, thus obtain enantiomer A34 of the significant paichongding of insecticidal activity.
It addition, inventor is also found that a kind of asymmetric chirality synthesizes the preparation method of single configurational isomer formula A4 compound.It is catalyzed α with organic micromolecule catalyst, β-unsaturation olefine aldehydr and nitromethane generation asymmetric Michael addition reaction, introduce chirality methyl, then series reaction is passed through, synthesis obtains the formula B4 compound with high-optical-purity, further it is etherified, thus obtains the optical isomer formula A4 compound of the more significant paichongding of insecticidal activity.
On the basis of the above, inventor completes the present invention.
Term
" containing the paichongding raw material of optical isomer shown in formula A3 and/or formula A4 " of the present invention can be containing formula A3 compound and formula A4 compound or at least compound Han formula A4.
In another preference, described " paichongding raw material " is the racemic paichongding simultaneously containing formula A1 compound, formula A2 compound, formula A3 compound and formula A4 compound.
Heretofore described " enantiomer A34 " or " A34 ", refer both to formula A3 compound and the enantiomer of formula A4 compound composition obtained by preparation method of the present invention.Both can exchange use.
Heretofore described " paichongding " and " formula A compound ", refers both to compound shown in formula A, the mixture of the two pairs of enantiomers being namely made up of formula A1 compound, formula A2 compound, formula A3 compound and formula A4 compound.Both can exchange use.
Term " C1-4Alkyl " refer to the straight chain containing 1-4 carbon atom, containing side chain or ring-type saturated alkyl.
The insecticidal activity of active substance of the present invention
Term " active substance of the present invention " or " reactive compound of the present invention " refer to acceptable salt in the optical isomer of paichongding or described optical isomer Pesticide Science, and it has the insecticidal activity of excellence, and insecticidal spectrum is wide, and stability is strong.
Term " acceptable salt in Pesticide Science " means that the anion of this salt is that have appreciated that and acceptable when forming insecticide pharmaceutically acceptable salt.This salt is preferably water miscible.Suitably, formula A3 compound and/or formula A4 compound the acid-addition salts formed includes the salt that mineral acid is formed, such as hydrochlorate, phosphate, sulfate, nitrate；And include the salt that organic acid is formed, such as acetate, benzoate.
The active substance of the present invention can serve as controlling and eliminate agriculture and forestry plant insect, the insect of stored grains, the insect of harm animal health and public health insect etc. widely.In this manual, " insecticide " is the general designation of the material with the effect preventing and treating all insects mentioned above.
nullThe example of insect includes but not limited to: coleopteron，Such as sitophilus zea-mais (Sitophiluszeamais)，Red flour beetle (Triboliumcastaneum)，Potato bug (Henosepilachnavigintioctomaculata)，Potato ladybug (Henosepilachnasparsa)，Agriotes fussicollis (Agriotesfuscicollis)，Red foot green gold Testudinis (Anomalacupripes)，Beautiful tortoise with four lines (Popilliaquadriguttata)，Colorado potato beetles (Monoleptahieroglyphica)，Ponderous borer (Monochamusalternatus)，Rice root weevil (Echinocnemussquameus)，Paulownia chrysomelid (Basiprionotabisignata)，Longicorn beetle (Anoplophorachinensis)，Mulberry borer (Apriponagermari)，Umbilicus abdomen bark beetle (Scolytusschevy)，Or Agriotes subrittatus Motschulsky (Agriotesfuscicollis)；nullLepidopteran insects，As waved poison pretty young woman (Lymantriadispar)，Tent caterpillar (Malacosomaneustriatestacea)，Diaphania perspectalis (Diaphaniaperspectalis)，Clania variegata Snellen (Claniavariegata)，Cnidocampa flavescens walker (Cnidocampaflauescens)，Dendrolimus punctatus (Dendrolimuspunctatus)，Orgyia antiqua (Orgyiagonostigma)，Paranthrene tabaniformis (Paranthrenetabaniformis)，Prodenia litura (Spodopteralitura)，Striped rice borer (Chilosuppressalis)，Pyrausta nubilalis (Hubern). (Ostrinianubilalis)，Meal moth (Ephestiacautella)，Lap moth (Adoxophyesorana)，Semen Castaneae steinernema (laspyresiasplendana)，Black cutworm (Agrotisfucosa)，Greater wax moth (Galleriamellonella)，Diamond-back moth (Plutellaxylostella)，Fructus Citri tangerinae lyonetid (Phyllocnistiscitrella)，Or oriental armyworm (Mythimnaseparata)；Homoptera insect, such as rice green leafhopper (Nephotettixcincticeps), brown plant-hopper (Nilaparvatalugens), Kang Shi mealybug (Pseudococcuscomstocki), arrowhead scales (Unaspisyanonensis), black peach aphid (Myzuspersicae), cotten aphid (Aphisgossydii), radish aphid (Lipaphiserysimipseudobrassicae), pears class lace bug (Stephanitisnashi), or aleyrodid (Bemisiatabaci)；Orthopteran, such as Groton bug (Blattellagermanica), the big Lian of the U.S. (Periplanetaamerican), African mole cricket (Gryllotalpaafricana), or Asiatic migratory locust (Locusmigratoria)；Isoptera insect, such as S.invicta Buren (Solenopsisinvicta), or Coptotermes formosanus Shtrari． (Coptotermesformosanus)；Dipteral insect, such as housefly (Muscadomestica), Aedes aegypti (Aedesaegypti), plant fly (Deliaplatura), culex (Culexsp.), or Anopheles sinensis (Anophelessinensis)；nullThe insect of harm animal health，Such as boophilus microplus (Boophilusmicroplus)，Haemaphysalis longicornis (Haemaphysalislongicornis)，Hyalomma anatolicum anatolicum (Hyalommaanatolicum)，Bomb fly (Hypodermaspp.)，Distoma hepaticum (Fasciolahepatica)，Bayesian moniezia (Monieziablanchard)，Ostertagi (Ostertagiaspp.)，Protozoon (Trypanosomaenansi，Babesiabigemina)、Rabbit coccidiosis (Occidiosis)，Cestode (tapeworm)，Coccidiosis (Coccidium) etc..
The compound that the present invention relates to is especially to pierce-suck type, rasping-sucking mouthparts insect such as: the agriculture and forestry injurious insects such as aphid, leafhopper, plant hopper, thrips, aleyrodid have specially good effect.
Insecticides containing active substance of the present invention
The active substance of the present invention can be prepared as insecticides in a conventional way.These reactive compounds can make the preparation of routine, such as solution, Emulsion, suspensoid, powder, foam, paste, granule；Aerosol, with the natural material with synthesis of active substance dipping, microcapsule in polymer, coating compound recipe for seed, and the preparation used with burner-block, such as sootiness cartridge case, sootiness tank and sootiness dish, and the cold mist of ULV (Coldmist) and hot mist (Warmmist) preparation.
These preparations can produce by known method, such as, reactive compound mix with expanding agent, these expansion agent be exactly liquid or liquefied gas or the diluent or carrier of solid, and can arbitrarily select surfactant i.e. emulsifying agent and/or dispersant and/or formation of foam agent.Such as when using water as expanding agent, organic solvent also is used as auxiliary agent.
When making diluent or carrier with liquid flux, the most suitably, such as: arene, such as dimethylbenzene, toluene or alkylnaphthalene；The fragrance of chlorination or the fat hydrocarbon of chlorination, such as chlorobenzene, vinyl chloride or dichloromethane；Fat hydrocarbon, such as hexamethylene or paraffin, such as mineral oil fractions；Alcohols, such as ethanol or ethylene glycol and their ether and lipid；Ketone, such as acetone, butanone, methyl iso-butyl ketone (MIBK) or Ketohexamethylene；Or the polar solvent being of little use, such as dimethylformamide and dimethyl sulfoxide, Yi Jishui.
Diluent or carrier with regard to liquefied gas is said, refers to will become at normal temperatures and pressures the liquid of gas, such as aerosol propellants, such as hydro carbons and the butane of halogenation, propane, nitrogen and carbon dioxide.
Solid carrier can be with mineral natural for (ground) ground, such as Kaolin, clay, Talcum, quartz, active hargil, montmorillonite, or kieselguhr, and the silicic acid of the mineral of the synthesis ground, such as high degree of dispersion, aluminium oxide and silicate.Solid carrier for granule is that pulverize and classification natural announcement stone, such as calcite, marble, Pumex, meerschaum and dolomite, and the granule of inorganic and organic coarse powder synthesis, with organic material such as wood sawdust, Exocarpium cocois (Cocos nucifera L), maize cob and the granule etc. of tobacco stems.
Non-ionic and anion emulsifying row can be used as emulsifying agent and/or formation of foam agent.Such as polyoxyethylene-fatty esters of gallic acid, polyoxyethylene-fatty alcohol ethers, such as alkaryl Polyethylene Glycol ethers, alkyl sulfonates, alkylsurfuric acid esters, aryl sulfonic acid esters and albumin hydrolyzate.Dispersant includes, such as lignin sulfite waste liquor and methylcellulose.
Binding agent can be used in the formulation, such as carboxymethyl cellulose and with powder, granule or natural and the polymer of synthesis, such as arabic gum, polyvinyl alcohol and the polyvinyl acetate of emulsion form.
Can be with coloring agent such as inorganic dyestuff, such as ferrum oxide, oxidation is bored and Prussian blue；Organic dyestuff, such as organic dyestuff, such as azo dyes or Titanium cyanine dyes；With use trace nutritional agent, such as ferrum, suddenly, boron, copper, cobalt, the salt etc. of aluminum and zinc.
These reactive compounds of the present invention can be made a kind of mixture with other reactive compounds and be present in their commercial preparation or from use dosage form prepared by these preparations, these other reactive compound is insecticide, close bait, antibacterial, acaricide, nematicide, antifungal, growth control agent etc..Insecticide includes, such as phosphoric acid ester, carbamates, cinerins, chlorinated hydrocarbons, benzoyl area kind, and neires toxin and the material produced by microorganism, such as avilamycin.
It is present in their commercial preparation to become from use dosage form prepared by these preparations additionally, these reactive compounds of the present invention also can make a kind of mixture with synergist.Synergist is the compound improving reactive compound effect, owing to reactive compound itself is active, it is possible to need not add synergist.
These preparations usually contain and account for described insecticides 0.001-99.99 weight %, preferably 0.01-99.9 weight %, the reactive compound of the present invention of more preferably 0.05-90 weight %.Making from commercial preparation uses the concentration of the reactive compound dosage form can change in wide scope.The concentration using the reactive compound in dosage form can be from 0.0000001-100% (g/v), preferably between 0.0001 and 1% (g/v).
The preparation method of the compounds of this invention
Formula A3 compound and/or formula A4 compound can be prepared by following method, but the condition of the method, such as reactant, solvent, alkali, the amount of compound used therefor, reaction temperature, reaction required time etc. are not limited to explanation below.Various synthetic method that describe in this manual or known in the art optionally can also be combined and prepare easily by the compounds of this invention, and such combination readily can be carried out by those skilled in the art in the invention.
Formula A3 compound and/or the preparation method of formula A4 compound
The formula A3 compound of the present invention and/or the preparation method of formula A4 compound, including step: the paichongding raw material containing optical isomer shown in formula A3 and/or formula A4 is split, thus obtain (the 11R shown in formula A3,14S) paichongding and/or (11S, 14R) paichongding shown in formula A4.
In another preference, described paichongding raw material is solid or liquid, and contains formula A3 compound and formula A4 compound or at least contain formula A4 compound.
In another preference, described paichongding raw material is the racemic paichongding simultaneously containing formula A1 compound, formula A2 compound, formula A3 compound and formula A4 compound.
In another preference, described method includes crystallizing Split Method, chemical resolution method, chirality HPLC Split Method, column chromatography or a combination thereof.
In another preference, described method is chirality HPLC Split Method.
The preparation of isomer A34
The enantiomer A34 preparation method of the present invention, can follow the steps below:
A () is to the paichongding raw material containing optical isomer shown in formula A3 and formula A4, in mixed solvent, optionally in the presence of Bronsted acid or lewis acid catalyst, after carrying out recrystallization, thus form the crystallization of enantiomer A34 of formula A3 compound and formula A4 compound composition；
B () isolates the crystallization of enantiomer A34, and collect mother solution；
C the mother solution of collection optionally, is carried out recrystallization in the presence of Bronsted acid or lewis acid catalyst, thus forms the crystallization of enantiomer A34 by ().
In another preference, repeat step (b)-(c) one or many.It is preferred that repeat step (b)-(c) 1-3 time.
In another preference, recrystallization temperature controls at 40～100 DEG C.
In another preference, described mixed solvent is A and the combination in any of two groups of solvents of B:
A group solvent includes: methanol, ethanol, normal propyl alcohol, isopropanol, ethylene glycol, glycerol or a combination thereof；
B group solvent includes: acetonitrile, oxolane, dioxane, water, dimethylformamide (DMF), dimethyl sulfoxide (DMSO) or a combination thereof；
The volume ratio of two groups of solvents of A and B is 20: 1～1: 20.
It is preferred that A group solvent is ethylene glycol, isopropanol or normal propyl alcohol；B group solvent is DMF, water or acetonitrile；Its volume ratio is A: B to be 5: 1～1: 10.
In another preference, described Bronsted acid or lewis acid include: hydrochloric acid, sulphuric acid, nitric acid, formic acid, acetic acid, trifluoroacetic acid, aluminum chloride, iron chloride, stannic chloride, boron trifluoride, boron trifluoride diethyl etherate, oxalyl chloride, methylsufonyl chloride, thionyl chloride, paratoluensulfonyl chloride, methacrylic chloride or a combination thereof.
It is preferred that described Bronsted acid or lewis acid are aluminum chloride, oxalyl chloride, thionyl chloride, methacrylic chloride or hydrochloric acid.
Can also realize according to following steps:
(I) in atent solvent, in the presence of above-mentioned Bronsted acid or lewis acid catalyst, formula B compound and normal propyl alcohol are reacted a period of time (such as 1-72 hour or 1-60 hour), thus forms formula A compound, i.e. paichongding；
In another preference, described atent solvent includes: ethyl acetate, dichloromethane, petroleum ether, ether, acetonitrile or a combination thereof.
(IIa) after paichongding mixed solvent (ibid) being carried out recrystallization, thus the crystallization of enantiomer A34 of formula A3 compound and formula A4 compound composition is formed；
(IIb) isolate the crystallization of enantiomer A34, and collect mother solution；
(IIc) optionally, by the mother solution collected after extraction and concentrating, in the presence of Bronsted acid or lewis acid catalyst, carry out recrystallization, thus form the crystallization of enantiomer A34.
In another preference, repeat step (IIb)-(IIc) one or many.
In another preference, repeat step (IIb)-(IIc) 1-3 time.
Wherein, the solvent used by described extraction includes: ether, ethyl acetate, dichloromethane, dichloroethanes, petroleum ether or a combination thereof.
The preparation of formula A4 compound
The Chiral Synthesis of formula A4 compound, can realize according to flow process 1:
Flow process 1
Specifically comprise the following steps that
(1) in atent solvent, in the presence of organic micromolecule catalyst, by nitromethane with crotonic aldehyde in room temperature reaction a period of time (such as 3-5 days), thus form formula H compound, introduce chirality methyl；
Wherein, described catalyst includes: the silicon ether derivant of the substituted Prolinol of diaryl, L-PROLINE, (+)-tartaric acid, (+)-Camphora-10-sulfonic acid, chirality dipeptides containing glycine or a combination thereof；
(2) in atent solvent, (about 0 DEG C) reaction a period of time (such as 5-30min) in ice bath by formula H compound and aldehyde radical protective agent, thus form formula G compound；
Wherein, R1、R2And R4It is each independently C1-4Alkyl；Or, R1And R2Collectively form-(CH2)n-, wherein, n is the integer of 2-4；
Wherein, described aldehyde radical protection group reagent includes: trimethyl orthoformate, ethylene glycol, 1,3-PD or a combination thereof；
(3) in atent solvent, by formula G compound and alkali after room temperature reaction a period of time (such as 0.5-4 hour or 1-3 hour), with Carbon bisulfide and R3I mixed at room temperature, then heats to uniform temperature (such as 50-70 DEG C) and jointly reacts a period of time (such as 12-36 hour or 12-24 hour), thus form formula F compound；
Wherein, R1、R2And R3It is each independently C1-4Alkyl；Or, R1And R2Collectively form-(CH2)n-, wherein, n is the integer of 2-4；
Described alkali includes: NaH, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or a combination thereof；
In another preference, described alkali is NaH.
(4) in atent solvent, after formula F compound and ethylenediamine back flow reaction a period of time (such as 3-12 hour or 6-9 hour), formula E compound is formed；In the basic conditions, by formula E compound with formula D compound in room temperature reaction a period of time (such as 1-4 hour or 2-2.5 hour), thus formula C compound is formed；
Wherein, R1、R2And R3It is each independently C1-4Alkyl；Or, R1And R2Collectively form-(CH2)n-, wherein, n is the integer of 2-4；
Described alkali includes: NaH, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or a combination thereof；
In another preference, described alkali is NaH.
(5) in atent solvent, formula C compound is reacted with acid catalyst, thus form formula B4 compound；
Wherein, R1、R2It is each independently C1-4Alkyl；Or, R1And R2Collectively form-(CH2)n-, wherein, n is the integer of 2-4；
Described acid catalyst includes: hydrochloric acid, acetic acid, trifluoroacetic acid, Fe (OTs)3·6H2O, camphorsulfonic acid (CSA), para-methylbenzenepyridinsulfonate sulfonate (PPTS), TsOH or a combination thereof；
In another preference, described acid catalyst is CSA or PPTS.
(6), in atent solvent, after formula B4 compound mixes with normal propyl alcohol, under low temperature (such as-20～0 DEG C), it is slowly added into Bronsted acid or lewis acid, then back flow reaction 1-30 hour, thus forms formula A4 compound；
Wherein, described Bronsted acid or lewis acid include: hydrochloric acid, sulphuric acid, nitric acid, formic acid, acetic acid, trifluoroacetic acid, aluminum chloride, iron chloride, stannic chloride, boron trifluoride, boron trifluoride diethyl etherate, thionyl chloride, paratoluensulfonyl chloride, oxalyl chloride, methacrylic chloride or a combination thereof.
In another preference, described Bronsted acid or lewis acid are hydrochloric acid, aluminum chloride, oxalyl chloride, thionyl chloride, paratoluensulfonyl chloride or methacrylic chloride.
Main advantages of the present invention:
(1) the invention provides the optical isomer that a class has the paichongding of high insecticidal activity, be enantiomer A34, formula A3 compound and formula A4 compound respectively.Described isomer can be used for studying the biological activity of the paichongding of various configuration, toxicity and selectivity environmental behaviour further, and then realizes production and the application of chirality paichongding.
(2) a kind of method that present invention also offers enantiomer A34 preparing high insecticidal activity.
(3) present invention also offers a kind of method preparing single configuration formula A4 compound.
(4) a kind of method that present invention also offers four optical isomers preparing paichongding.
Below in conjunction with being embodied as, the present invention is expanded on further.Should be understood that these embodiments are merely to illustrate the present invention rather than limit the scope of the present invention.The experimental technique of unreceipted actual conditions in the following example, generally according to normal condition, or according to the condition proposed by manufacturer.Unless otherwise indicated, otherwise percentage ratio and number are calculated by weight.
Embodiment 1: four isomers of chirality HPLC isolated paichongding
Instrument and condition
High performance liquid chromatography instrument: Shimadzu, LC-20ATvp, SPD-M20Avp；
Chromatographic column: CHIRALPAKIC (Daicel, 30 × 250mm, 5 μm)；
Flowing phase: ethanol=100
Flow velocity: 1-20mL/min；
Sampling volume: 2 μ L-2mL；
Detection wavelength: 325nm；
Column temperature: 20-35 DEG C.
Experimental procedure
Taking paichongding configuration sample ethanol solution, take sample solution and carry out high performance liquid chromatography by above-mentioned condition and prepare, collect target components, sample analysis also records chromatogram.Result is as it is shown in figure 1, be from left to right followed successively by paichongding isomer A1, A2, A3 and A4 in figure, retention time is respectively 7.500, and 8.790,10.618 and 13.487min, it is achieved that the baseline separation to four isomers.
Four stereoisomers of paichongding are separated by final employing above-mentioned condition in a large number.
Formula A1 compound:1HNMR (400MHz, CDCl3): δ 8.24 (s, 1H), 7.75 (s, 1H), 7.19 (s, 1H), 4.91-4.73 (m, 1H), 4.47 (s, 2H), 3.73 (d, J=7.2Hz, 1H), 3.68-3.53 (m, 2H), 3.47 (dd, J1=12.6Hz, J2=8.8Hz, 1H), 3.33 (d, J=1.7Hz, 2H), 3.19 (s, 1H), 2.06 (s, 1H), 1.73-1.55 (m, 1H), 1.44 (s, 2H), 1.10 (d, J=6.4Hz, 3H), 0.78 (t, J=7.4Hz, 3H) ppm；13CNMR (100MHz, CDCl3): δ 158.7,150.8,149.2,139.2,130.9,124.2,109.9,83.2,70.2,52.5,49.4,45.9,36.1,27.8,22.9,19.7,10.4ppm.
Formula A2 compound:1HNMR (400MHz, CDCl3): δ 8.26 (s, 1H), 7.76 (s, 1H), 7.22 (s, 1H), 4.85 (d, J=15.1Hz, 1H), 4.50 (s, 2H), 3.76 (d, J=8.9Hz, 1H), 3.62 (dt, J1=15.6Hz, J2=7.6Hz, 2H), 3.55-3.44 (m, 1H), 3.36 (s, 2H), 3.25 (s, 1H), 2.09 (d, J=5.2Hz, 1H), 1.69 (d, J=3.7Hz, 1H), 1.49 (d, J=6.5Hz, 2H), 1.14 (d, J=5.2Hz, 3H), 0.82 (dd, J1=8.0Hz, J2=3.0Hz, 3H) ppm；13CNMR (100MHz, CDCl3): δ 158.7,150.8,149.2,139.3130.9,124.3,110.0,83.2,70.2,52.5,49.4,45.8,36.1,27.8,22.9,19.7,10.5ppm.
Formula A3 compound:1HNMR (400MHz, CDCl3): δ 8.28 (s, 1H), 7.75 (s, 1H), 7.26 (dd, J1=12.0Hz, J2=3.9Hz, 1H), 4.77 (d, J=15.0Hz, 1H), 4.64-4.52 (m, 1H), 4.47 (s, 1H), 3.93 (s, 1H), 3.72-3.59 (m, 1H), 3.54-3.30 (m, 5H), 1.93 (s, 2H), 1.55 (d, J=3.5Hz, 2H), 1.18 (d, J=3.2Hz, 3H), 0.93-0.80 (m, 3H) ppm；13CNMR (100MHz, CDCl3): δ 157.1,150.7,149.1,139.1,131.0,124.3,110.0,84.9,70.3,52.3,49.1,45.7,33.1,28.3,23.0,19.2,10.6ppm.
Formula A4 compound:1HNMR (400MHz, CDCl3): δ 8.27 (s, 1H), 7.72 (s, 1H), 7.24 (d, J=7.8Hz, 1H), 4.75 (d, J=14.3Hz, 1H), 4.63-4.53 (m, 1H), 4.47 (d, J=2.2Hz, 1H), 3.93 (d, J=7.7Hz, 1H), 3.71-3.56 (m, 1H), 3.56-3.27 (m, 5H), 1.92 (s, 2H), 1.53 (d, J=3.7Hz, 2H), 1.17 (d, J=3.7Hz, 3H), 0.87 (dd, J1=4.0Hz, J2=2.8Hz, 3H) ppm；13CNMR (100MHz, CDCl3): δ 157.1,150.8,149.1,139.1,131.0,124.3,110.0,84.9,70.3,52.3,49.1,45.7,33.1,28.3,23.0,19.1,10.6ppm.
Embodiment 2: chirality HPLC isolated paichongding isomer A34
Instrument and condition
High performance liquid chromatograph: Shimadzu, LC-20ATvp, SPD-M20Avp；
Chromatographic column: CHIRALPAKIC (Daicel, 30 × 250mm, 5 μm)；
Flowing phase: dichloromethane: methanol: diethylamine=50: 50: 0.1
Flow velocity: 1-20mL/min；
Sampling volume: 2 μ L-2mL；
Detection wavelength: 325nm；
Column temperature: 20-35 DEG C.
Experimental procedure
Take paichongding configuration sample ethanol solution, carrying out high performance liquid chromatography by above-mentioned condition to prepare, collect target components, sample analysis also records chromatogram, result is as shown in Figure 2, figure is from left to right followed successively by paichongding isomer A1, A2, A3 and A4, retention time is respectively 3.722,3.976,4.666 and 5.624min, isolated paichongding isomer A34.
Embodiment 3: the insecticidal activity test of raceme paichongding and its four single configurational isomers
We carry out insecticidal activity test to four isomers of single configuration.Showing indoor aphis craccivora (AphiscraccivoraKoch) population biological activity determination report (table 1) according to paichongding isomer etc., the isomer formula A4 compound of enantiomer A34 and single configuration or the insecticidal activity of formula A3 compound are significantly higher than isomer A1 and A2.
Table 1 paichongding isomers etc. are to aphis craccivora active testing result
| Compound | LC50(mg/L) | 95% confidence limit | Slope 14 --> |
| A1 | 288.139 | 246.395-340.344 | 2.942±0.243 |
| A2 | 50.090 | 42.460-59.330 | 4.368±0.343 |
| A3 | 19.401 | 14.130-26.744 | 4.502±0.338 |
| A4 | 14.364 | 9.679-21.455 | 4.033±0.303 |
| A34* | 21.518 | 15.843-28.277 | 4.375±-0.350 |
| Raceme paichongding | 31.481 | 20.510-48.373 | 4.542±0.376 |
*The preparation method of A34 is shown in embodiment 2.
Embodiment 4: the preparation of enantiomer A34
The synthesis of 4.1 compound A
10g (31mmol) compound B is dissolved in 100mL reaction dissolvent (normal propyl alcohol), is subsequently adding the normal propyl alcohol of 4 times amount.Under low temperature, (-20～0 DEG C) slowly drip the oxalyl chloride of 3 times amount, and solid gradually dissolves, and become brownish red settled solution, become the most again turbid solution.Be heated to reflux about 3～48h, TLC follow the tracks of, raw material disappear, stopped reaction.Solution is cooled to low temperature by ice-water bath, the most under cryogenic reactant liquor is slowly poured in the alkaline aqueous solution (aqueous sodium carbonate) of 50mL, adding 20mL saturated aqueous common salt separatory, water layer is extracted twice with 50mL extractant (ether) again.Merge organic layer, evaporated under reduced pressure solvent, obtain 9.23g faint yellow solid paichongding (formula A compound).
HPLC testing result is as it is shown on figure 3, HPLC condition: RX-C18,4.6 × 250mm, 62:38, Acetone:buffer；325nm6.923min74.363%12.34min23.776%.Mp=130.2-131.9 DEG C；
1HNMR (400MHz, CDCl3): δ 8.31-8.33 (m, 1H), 7.86 (dd, J1=2.4Hz, J2=8.4Hz, 0.5H), 7.82 (dd, J1=2.4Hz, J2=8.2Hz, 0.5H), 7.33 (dd, J1=0.8Hz, J2=1.2Hz, 0.5H), 7.31 (dd, J1=0.8Hz, J2=1.2Hz, 0.5H), 4.88 (d, J=15.2Hz, 0.5H), 4.82 (d, J=15.2Hz, 0.5H), 4.61-4.67 (m, 1H), 4.55 (dd, J1=3.6Hz, J2null=6.0Hz，0.5H)，4.50(t，J=3.6Hz，0.5H)，3.95-4.02(m，0.5H)，3.81-3.86(m，0.5H)，3.64-3.72(m，1H)，3.35-3.59(m，5H)，2.14-2.21(m，0.5H)，1.99-2.01(m，1H)，1.75-1.82(m，0.5H)，1.54-1.65(m，2H)，1.22-1.27(d，J=6.8Hz，0.5H)，1.23(d，J=6.8Hz，0.5H)，0.95(t，J=6.2Hz，0.5H)，0.92(t，J=6.2Hz，0.5H)ppm；HRMS(EI+)calcdforC17H23N4O3 35Cl(M+), 366.1459；Found, 366.1487.
The purification of 4.2 enantiomers A34
4.2.1 a recrystallization
(a) recrystallization
40mLA and B mixed solvent (methanol/acetonitrile (V: V is 3: 1)) is joined in formula A compound, it is heated to all dissolving, it is subsequently cooled to low temperature, sucking filtration, filter cake with 30mL above-mentioned mixed solvent drip washing, obtains faint yellow solid A345.09g (yield 45.1%) again, and HPLC testing result is as shown in Figure 4, SH01 is the HPLC figure of enantiomer A34, and P3 is the HPLC figure of paichongding raceme.
Mother solution adds 50mL extractant (ibid) and the extraction of 20mL saturated aqueous common salt, and water layer extracts once with 50mL extractant again, merges organic layer, adds 7g anhydrous sodium sulfate and is dried.
(b) mother liquid disposal
By the mother liquor concentrations of merging to half, in solution, slowly drip 1.7mL (20mmol) oxalyl chloride at low temperatures, be heated to reflux about 3～48h.Solution is cooled to low temperature by ice-water bath, is slowly poured into by reactant liquor in 15mL alkaline aqueous solution (ibid) the most at low temperatures, adds the extraction of 10mL saturated aqueous common salt, water layer extracts once with 30mL extractant again, merge organic layer, evaporated under reduced pressure solvent, obtain yellow-brown solid.
4.2.2 secondary recrystallization
(a) recrystallization
Joining in solid by A and the B mixed solvent (ibid) of 24mL, be heated to all dissolving, be subsequently cooled to low temperature, sucking filtration, filter cake with 15mL above-mentioned mixed solvent drip washing, obtains faint yellow solid A342.26g (yield 20%) again；
Mother solution adds 30mL extractant (ibid) extraction and once extracts with 10mL saturated aqueous common salt, and water layer extracts once with 30mL extractant (ibid) again, merges organic layer.Add 5g anhydrous sodium sulfate to be dried.
(b) mother liquid disposal
By the mother liquor concentrations of merging to 30mL, in solution, slowly drip 0.3mL (3.80mmol) oxalyl chloride at low temperatures, be heated to reflux about 3～48h.Solution is cooled to low temperature by ice-water bath, the most at low temperatures reactant liquor is slowly poured in 6mL alkaline solution (ibid), add the extraction of 2.5mL saturated aqueous common salt, water layer extracts once with 30mL extractant (ibid) again, merge organic layer, evaporated under reduced pressure solvent, faint yellow solid.
4.2.3 three recrystallization
Joining in solid by 18mL mixed solvent (ibid), be heated to all dissolving, be subsequently cooled to low temperature, sucking filtration, filter cake with 15mL above-mentioned mixed solvent drip washing, obtains faint yellow solid A341.39g (yield 12.3%) again.
Merge the A34 solid of above-mentioned gained, gross weight 8.74g (total recovery 77.4%).HPLC testing result is as it is shown in figure 5, SH01 is the HPLC figure of enantiomer A34, and P3 is the HPLC figure of paichongding raceme.Visible, it is enantiomer A34 by the solid being recrystallized to give for 3 times.
The related reagent of table 2 embodiment 4-11
Embodiment 5: the preparation of enantiomer A34
The synthesis of 5.1 compound A
10g (31mmol) compound B is dissolved in 100mL reaction dissolvent (dichloromethane), is subsequently adding the normal propyl alcohol of 8 times amount.Under low temperature, (0 DEG C) is slowly added dropwise as after the oxalyl chloride of 3 times amount, be heated to reflux about 3～48h, TLC follow the tracks of, after reaction terminates, process reaction, operation is with embodiment 4.1, and specifically used reagent is shown in Table 2, obtains 9.08g faint yellow solid paichongding.
The purification of 5.2 enantiomers A34
Formula A compound carries out recrystallization, and totally 3 times, operation is with embodiment 4.2, and specifically used reagent is shown in Table 2.
Finally merge the A34 solid of three recrystallization gained, gross weight 8.53g (total recovery 75.0%).
Embodiment 6: the preparation of enantiomer A34
The synthesis of 6.1 compound A
10g (31mmol) compound B is dissolved in 100mL reaction dissolvent (ethyl acetate), is subsequently adding the normal propyl alcohol of 8 times amount.After under low temperature, (0 DEG C) is slowly added dropwise the oxalyl chloride of 3 times amount, be heated to reflux about 3～48h, TLC follow the tracks of, reaction terminate after, process reaction, operation with embodiment 4.1, specifically used reagent is shown in Table 2, obtains 8.93g faint yellow solid paichongding.
The purification of 6.2 enantiomers A34
Formula A compound carries out recrystallization, and totally 3 times, operation is with embodiment 4.2, and specifically used reagent is shown in Table 2.
Finally merge the A34 solid of three recrystallization gained, gross weight 8.24g (total recovery 72.5%).
Embodiment 7: the preparation of enantiomer A34
7.1 the synthesis of compound A
10g (31mmol) compound B is dissolved in 100mL reaction dissolvent (acetonitrile), is subsequently adding the normal propyl alcohol of 8 times amount.After under low temperature, (0 DEG C) is dividedly in some parts the aluminum chloride of 5 times amount, be heated to reflux about 3～48h, TLC follow the tracks of, reaction terminate after, process reaction, operation with embodiment 4.1, specifically used reagent is shown in Table 2, obtains 8.76g faint yellow solid paichongding.
The purification of 7.2 enantiomers A34
Formula A compound carries out recrystallization, and totally 3 times, operation is with embodiment 4.2, and specifically used reagent is shown in Table 2.
Finally merge the A34 solid of three recrystallization gained, gross weight 8.15g (total recovery 71.7%).
Embodiment 8: the preparation of enantiomer A34
The synthesis of 8.1 compound A
10g (31mmol) compound B is dissolved in 100mL reaction dissolvent (dichloromethane), is subsequently adding the normal propyl alcohol of 8 times amount.After (-20～0 DEG C) are dividedly in some parts the aluminum chloride of 5 times amount under low temperature, it is heated to reflux about 5～20h, becomes red tan solution, after TLC tracking reaction terminates.Processing reaction, operation is with embodiment 3.1, and specifically used reagent is shown in Table 2, obtains 8.58g faint yellow solid paichongding.
The purification of 8.2 enantiomers A34
Formula A compound carries out recrystallization, and totally 3 times, operation is with embodiment 4.2, and specifically used reagent is shown in Table 2.
Finally merge isomer A34 gross weight 8.09g (total recovery 71.2%) of three recrystallization merging gained.
Embodiment 9: the preparation of enantiomer A34
The synthesis of 9.1 compound A
10g (31mmol) compound B is dissolved in 100mL reaction dissolvent (normal propyl alcohol), is subsequently adding the normal propyl alcohol of 8 times amount.After under low temperature, (0 DEG C) is slowly added dropwise thionyl chloride, be heated to reflux about 3～48h, TLC follow the tracks of, reaction terminate after, process reaction, operation with embodiment 4.1, specifically used reagent is shown in Table 2, obtains 8.44g faint yellow solid paichongding.
The purification of 9.2 enantiomers A34
Formula A compound carries out recrystallization, and totally 3 times, operation is with embodiment 4.2, and specifically used reagent is shown in Table 2.
Finally merge the A34 solid of three recrystallization gained, gross weight 8.04g (total recovery 70.7%).
Embodiment 10: the preparation of enantiomer A34
The synthesis of 10.1 compound A
10g (31mmol) compound B is dissolved in 100mL reaction dissolvent (ethyl acetate), is subsequently adding the normal propyl alcohol of 8 times amount.After under low temperature, (0 DEG C) is slowly added dropwise thionyl chloride, be heated to reflux about 3～48h, TLC follow the tracks of, reaction terminate after, process reaction, operation with embodiment 4.1, specifically used reagent is shown in Table 2, obtains 8.29g faint yellow solid paichongding.
The purification of 10.2 enantiomers A34
Formula A compound carries out recrystallization, and totally 3 times, operation is with embodiment 4.2, and specifically used reagent is shown in Table 2.
Finally merge the A34 solid of three recrystallization gained, gross weight 7.95g (total recovery 69.9%).
Embodiment 11: the preparation of enantiomer A34
The synthesis of 11.1 compound A
10g (31mmol) compound B is dissolved in 100mL reaction dissolvent (ethyl acetate), is subsequently adding the normal propyl alcohol of 8 times amount.After under low temperature, (0 DEG C) is slowly added dropwise thionyl chloride, be heated to reflux about 3～48h, TLC follow the tracks of, reaction terminate after, process reaction, operation with embodiment 4.1, specifically used reagent is shown in Table 2, obtains 8.15g faint yellow solid paichongding.
The purification of 11.2 enantiomers A34
Formula A compound carries out recrystallization, and totally 3 times, operation is with embodiment 4.2, and specifically used reagent is shown in Table 2.
Finally merge the A34 solid of three recrystallization gained, gross weight 7.79g (total recovery 69.0%).
Embodiment 12: the preparation of formula A4 compound
The synthesis of 12.1 formula H compounds
L-diphenylprolinol silicon ether (501mg, 1.5mmol) is dissolved in 100mL solvent (CH3OH∶CH2Cl2=9: 1), in, drip crotonic aldehyde (6.0mL, 0.7mol) and nitromethane (12.0mL, 0.2mol) the most respectively, be eventually adding lithium acetate (0.7g, 6.9mmol).Reactant liquor stirs 4 days at room temperature, and TLC detection reaction is completely.Stopped reaction, concentrates, and gained crude product adds appropriate dichloromethane such as and extracts three times, merges organic facies.Organic facies is washed with saturated aqueous common salt the most respectively, and anhydrous sodium sulfate is dried.Filtering desiccant, filtrate decompression removes solvent, and residue obtains 5.0g yellow oily liquid-type H compound through flash column chromatography, and productivity is 53%.[α]D 230.9 (c1.20, CH2Cl2)；1HNMR (400MHz, CDCl3): δ 9.77 (s, 1H), 4.34-4.45 (m, 2H), 2.84-2.93 (m, 1H), 2.66 (dd, J1=18.2Hz, J2=6.1Hz, 1H), 2.53 (dd, J1=18.2Hz, J2=7.0Hz, 1H), 1.11 (d, J=6.8Hz, 3H)；13CNMR (100MHz, CDCl3): δ 199.6,80.1,47.0,27.2,17.4.
The synthesis of 12.2 formula G1 compounds
Formula H compound (7.0g, 53.8mmol) is dissolved in 30mL dichloromethane, drips trimethyl orthoformate (14.7mL, 0.1mol) wherein, reaction bulb is placed in ice bath and is cooled to 0 DEG C.Weigh p-methyl benzenesulfonic acid monohydrate (3.1g, 16.4mmol) again, be dividedly in some parts in reactant liquor, after all adding, continue to stir 15 minutes under ice bath.Then reactant liquor being moved to room temperature, at room temperature react, TLC follows the tracks of reaction, after compound reacts completely, stopped reaction.Adding the aqueous solution cancellation reaction of saturated sodium bicarbonate in reactant liquor, dichloromethane extracts, and collects organic facies.Organic facies is washed with saturated aqueous common salt respectively, and anhydrous sodium sulfate is dried.Filtering desiccant, filtrate decompression removes solvent, and residue is isolated and purified through rapid column chromatography, obtains 7.8g pale yellow oily liquid body formula G1 compound, and productivity is 83%.[α]D 235.3 (c1.08, CH2Cl2)；1HNMR (400MHz, CDCl3): δ 4.47-4.40 (m, 2H), 4.23-4.18 (m, 1H), 3.31 (s, 6H), 2.52-2.45 (m, 1H), 1.73-1.66 (m, 1H), 1.60-1.54 (m, 1.54), 1.05 (d, J=6.0Hz, 3H)；13CNMR (100MHz, CDCl3): δ 102.5,81.2,52.9,52.9,36.4,29.0,17.6.
The synthesis of 12.3 formula F1 compounds
By NaH (content is 60%, 1.7g, 43.7mmol), N2Protection is lower adds the tetrahydrofuran solution that 5mL is dried, then weighs formula G1 compound (1.5g, 8.8mmol) and be dissolved in the THF solvent that 3mL is dried, and is under agitation added drop-wise in above-mentioned reactant liquor, stirs 2 hours under room temperature；Then draw iodomethane (5.0mL, 80.3mmol) and Carbon bisulfide (5.0mL, 83.1mmol), mix homogeneously, be at room temperature added dropwise in reactant liquor, then reaction is warming up to 60 DEG C of reactions.TLC following response, after 24 hours, reaction terminates.Stopped reaction, is cooled to room temperature by reactant liquor, is slowly added to frozen water cancellation reaction, extracts three times with dichloromethane, merge organic layer in reactant liquor.Organic facies is washed with saturated aqueous common salt respectively, and anhydrous sodium sulfate is dried.Filtering desiccant, filtrate decompression removes solvent, and residue is isolated and purified through rapid column chromatography, obtains the formula F1 compound of 600mg yellow oily liquid, and productivity is 25%.[α]D 2366.4 (c1.19, CH2Cl2)；1HNMR (400MHz, CDCl3): δ 4.40 (t, J=10.4Hz, 1H), 3.68-3.63 (m, 1H), 3.33-3.32 (overlapping, 6H), 2.36 (s, 3H), 2.33 (s, 3H), 1.87-1.72 (m, 2H), (1.18 d, J=6.9Hz, 3H)；13CNMR (100MHz, CDCl3): δ 157.83,134.6,102.6,53.2,52.8,37.1,32.8,18.7,17.4,16.7.
The synthesis of 12.4 formula E1 compounds
Formula F1 compound (1.1g, 4.1mmol) is dissolved in 30mL ethanol, then drips ethylenediamine (0.9mL, 13.5mmol) wherein, be heated to reflux.After 8 hours, TLC detection display reaction terminates.Stopped reaction, is cooled to room temperature by reactant liquor, and concentrating under reduced pressure removes solvent, and gained crude product is isolated and purified through rapid column chromatography, obtains 379mg faint yellow solid formula E1 compound, and productivity is 38%.[α]D 23141.9 (c0.652, CH2Cl2)；1HNMR (400MHz, CDCl3): δ 4.27-4.24 (q, J=7.8Hz, 1H), 3.83-3.77 (m, 4H), 3.29 (s, 3H), 3.26 (s, 3H), 3.61-3.55 (m, 1H), 2.41-2.34 (m, 1H), 1.76-1.69 (m, 1H), 1.31 (d, 3H)；13CNMR (100MHz, CDCl3): δ 162.3,109.7,103.7,54.1,51.4,44.0,34.4,28.9,17.1.
The synthesis of 12.5 formula D compounds
Under nitrogen protection, chloro-for 2-5-hydroxymethylpyridine (3.8g, 26.7mmol) is dissolved in dichloromethane 40mL, drips triethylamine (5.8mL, 40.1mmol) wherein, stir 15 minutes at-40 DEG C.Dripping MsCl (2.5mL, 32.3mmol) the most wherein, and continue reaction at-40 DEG C, after 1 hour, TLC detection display reaction terminates.After reactant liquor is cooled to room temperature, adding 20mL water and 20mL dichloromethane cancellation reaction in reactant liquor, organic facies is collected in layering, and aqueous phase dichloromethane extracts three times.Merging organic facies, wash with saturated aqueous common salt respectively, anhydrous sodium sulfate is dried.Filtering desiccant, filtrate decompression removes solvent, obtains white solid, through recrystallization, obtains 6.0g white crystal formula D compound, and productivity is 99%.1HNMR (400MHz, CDCl3): δ 8.46 (d, J=2.2Hz, 1H), 7.77 (dd, J1=2.4Hz, J2=8.2Hz, 1H), 7.42 (d, 1H), 5.26 (s, 2H), 3.06 (s, 3H).
The synthesis of 12.6 formula C1 compounds
By formula E1 compound (662mg; 2.7mmol) it is dissolved in the DMSO that 20mL is dried; (content is 60% to add NaH under nitrogen protection; 240mg; 6.0mmol); stirring 2 hours at room temperature, then weigh formula D compound (304mg, 1.4mmol) and be dividedly in some parts under nitrogen protection in reactant liquor; after addition; reactant liquor is stirred at room temperature overnight, stopped reaction, places reaction liquid in ice bath and cools down; in reactant liquor, add appropriate shrend go out reaction; ethyl acetate extracts, separatory, retains organic facies.Organic facies is washed with saturated aqueous common salt respectively, and anhydrous sodium sulfate is dried.Filtering desiccant, filtrate decompression removes solvent, and residue obtains 180mg weak yellow liquid formula C1 compound through column chromatography, and productivity is 18%.[α]D 23141.9 (c0.652, CH2Cl2)；1HNMR (400MHz, CDCl3): δ 8.39 (d, J=2.0Hz, 1H), 7.71-7.69 (m, 1H), 7.35 (d, J=8.4Hz, 1H), 5.17 (s, 2H), 4.29 (t, J=5.6Hz, 1H), 3.76-3.73 (m, 4H), 3.49-3.45 (m, 1H), 3.26 (d, J=8.8Hz, 6H), 2.30-2.23 (m, 1H), 1.86-1.80 (m, 1H), 1.27-1.26 (m, 3H) .HRMS (ESI): m/z [M-OMe]-calcdforC15H20ClN4O3: 339.1224；Found:339.2018.
12.7 the synthesis of formula A4 compound
10g (31mmol) formula C1 compound is dissolved in 100mL reaction dissolvent (dichloromethane), adds acid (hydrochloric acid) deprotection, be subsequently adding the normal propyl alcohol of 8 times amount.Under low temperature, the catalyst (acetic acid) of 2 times amount is slowly dripped by (-20～0 DEG C), is heated to reflux about 5～20h, becomes red tan solution, and TLC follows the tracks of, and compound disappears, stopped reaction.Solution is cooled to low temperature by ice-water bath, is slowly poured into by reactant liquor the most under cryogenic in the alkaline aqueous solution of 50mL, adds 20mL saturated aqueous common salt separatory, and water layer is extracted twice with 50mL extractant again.Merge organic layer, evaporated under reduced pressure solvent, obtain 5.22g faint yellow solid A4, yield 46%.[α]D 2376.5 (c0.005, CHCl3)；1HNMR (400MHz, CDCl3): δ 8.27 (s, 1H), 7.72 (s, 1H), 7.24 (d, J=7.8Hz, 1H), 4.75 (d, J=14.3Hz, 1H), 4.63-4.53 (m, 1H), 4.47 (d, J=2.2Hz, 1H), 3.93 (d, J=7.7Hz, 1H), 3.71-3.56 (m, 1H), 3.56-3.27 (m, 5H), 1.92 (s, 2H), 1.53 (d, J=3.7Hz, 2H), 1.17 (d, J=3.7Hz, 3H), 0.87 (dd, J1=6.5Hz, J2=3.3Hz, 3H) ppm；13CNMR (100MHz, CDCl3): δ 157.1,150.8,149.1,139.1,131.0,124.3,110.0,84.9,70.3,52.3,49.1,45.7,33.1,28.3,23.0,19.1,10.6ppm.
Embodiment 13: the preparation of formula A4 compound
The synthesis of 13.1 formula G2 compounds
Formula H compound (1.1g, 8.3mmol) is dissolved in 40mL anhydrous methylene chloride, under nitrogen protection, in reactant liquor, drips 1，2-ethandiol (1.0mL, 17.8mmol) and BF respectively3·Et2O (0.5mL, 3.9mmol).After completion of dropwise addition, put and react at room temperature, TLC following response.After reaction terminates, add saturated sodium bicarbonate aqueous solution cancellation reaction.Dichloromethane extracts, and organic facies is washed with saturated aqueous common salt the most respectively, and anhydrous sodium sulfate is dried.Filtering desiccant, filtrate decompression is evaporated off solvent, and residue obtains 690mg pale yellow oily liquid body formula G2 compound through rapid column chromatography, and productivity is 47%.1HNMR (400MHz, CDCl3): δ 4.93 (t, J=4.6Hz, 1H), 4.53 (dd, J1=5.5Hz, J2=12.0Hz, 1H), 4.24-4.19 (m, 1H), 3.98-3.82 (m, 4H), 2.63-2.55 (m, 1H), 1.71 (t, J=6.2Hz, 2H), 1.08 (d, J=6.8Hz, 3H).
The synthesis of 13.2 formula F2 compounds
Operation, with embodiment 12.3, obtains 600mg formula F2 compound, productivity 54.5%.1HNMR (400MHz, CDCl3): δ 4.91 (t, J=4.6Hz, 1H), 3.98-3.95 (m, 2H), 3.86-3.83 (m, 2H), 3.77 (q, J=7.1Hz, 1H), 2.38 (s, 3H), 2.33 (s, 3H), 2.01-1.94 (m, 1H), 1.82-1.75 (m, 1H), 1.23 (d, J=6.9Hz, 3H).
The synthesis of 13.3 formula E2 compounds
Operation, with embodiment 12.4, obtains 379mg formula E2 compound, productivity 72.5%.1HNMR (400MHz, CDCl3): δ 5.29 (s, 1H), 4.75 (dd, J1=3.4Hz, J2=7.3Hz, 1H), 3.94-3.97 (m, 1H), 3.94-3.88 (m, 1H), 3.82-3.76 (m, 6H), 2.70-2.64 (m, 1H), 2.53-2.46 (m, 1H), 1.70-1.63 (m, 1H), 1.33 (d, J=6.8Hz, 3H).
The synthesis of 13.4 formula C2 compounds
Operation, with embodiment 12.6, obtains 404mg formula C2 compound, yield 70.4%.[α]D 2344.6 (c0.763, CH2Cl2)；1HNMR (400MHz, CDCl3): δ 8.37 (d, J=2.0Hz, 1H), 7.72-7.70 (m, 1H), 7.34 (d, J=8.4Hz, 1H), 5.15 (s, 2H), 4.32 (t, J=5.6Hz, 1H), 3.78-3.73 (m, 4H), 3.51-3.46 (m, 1H), 4.05-3.95 (d, J=4.8Hz, 4H), 2.33-2.26 (m, 1H), 1.89-1.85 (m, 1H), 1.30-1.28 (m, 3H) .HRMS (ESI): m/z [M]+calcdforC16H21ClN4O4: 368.1251；Found:368.1248.
The synthesis of 13.5 formula A4 compounds
Operation, with embodiment 12.7, obtains 315mg formula A4 compound, yield 78.0%.[α]D 2376.5 (c0.005, CHCl3)；1HNMR (400MHz, CDCl3): δ 8.27 (s, 1H), 7.72 (s, 1H), 7.24 (d, J=7.8Hz, 1H), 4.75 (d, J=14.3Hz, 1H), 4.63-4.53 (m, 1H), 4.47 (d, J=2.2Hz, 1H), 3.93 (d, J=7.7Hz, 1H), 3.71-3.56 (m, 1H), 3.56-3.27 (m, 5H), 1.92 (s, 2H), 1.53 (d, J=3.7Hz, 2H), 1.17 (d, J=3.7Hz, 3H), 0.87 (dd, J1=6.5Hz, J2=3.3Hz, 3H) ppm；13CNMR (100MHz, CDCl3): δ 157.1,150.8,149.1,139.1,131.0,124.3,110.0,84.9,70.3,52.3,49.1,45.7,33.1,28.3,23.0,19.1,10.6ppm.
Embodiment 14: the compounds of this invention insecticidal activity to aphis craccivora kind
The compound preparing embodiment 1-2 and embodiment 4-13 carries out insecticidal activity test.Wherein, compound A4 that embodiment 1 and embodiment 13 prepare and the compound A-13 4 that embodiment 1, embodiment 5 and embodiment 6 prepare are to indoor aphis craccivora (AphiscraccivoraKoch) population biological activity determination report (table 3) display, and the insecticidal activity of the isomer formula A4 compound of enantiomer A34 obtained prepared according to the methods of the invention and single configuration is fabulous.
Table 3 is to aphis craccivora active testing Comparative result
| Compound | LC50(mg/L) | 95% confidence limit | Slope |
| A4 (embodiment 1) | 14.364 | 9.679-21.455 | 4.033±0.303 |
| A4 (embodiment 13) | 17.238 | 11.976-24.677 | 2.844±0.204 |
| A34 (embodiment 2) | 21.518 | 15.843-28.277 | 4.375±0.350 |
| A34 (embodiment 5) | 28.420 | 24.686-32.546 | 3.645±0.284 |
| A34 (embodiment 6) | 23.894 | 19.429-28.982 | 4.125±0.325 |
Embodiment 15: the preparation of the insecticides containing the compounds of this invention
(a) oleaginous suspension
Prepare following components in proportion: any one compound in 25% (percentage by weight, lower with) formula A3 compound, formula A4 compound or enantiomer A34；5% polyoxyethylene sorbitol six oleate；70% higher aliphatic hydrocarbon ils.Each component is ground in sand grinds together, until solid particle is down to less than about 5 microns.The thick suspension of gained can be used directly, but also can use after emulsifying in water.
(b) water slurry
Prepare following components in proportion: any one compound in 25% formula A3 compound, formula A4 compound or enantiomer A34；3% hydration Attagel (hydrateattapulgit)；10% calcium lignosulfonate；0.5% sodium dihydrogen phosphate；61.5% water.Each component is ground in ball mill together, until solid particle is down to less than about 10 microns.This water slurry can be used directly.
(c) bait formulation
Prepare following components in proportion: any one compound in 0.1-10% formula A3 compound, formula A4 compound or enantiomer A34；80% Semen Tritici aestivi flour；19.9-10% molasses.These components are thoroughly mixed, form bait shape on demand.Edible bait can be distributed to the place that sanitary insect pest is infected, such as household or industrial site, and such as kitchen, hospital or shop or outdoor zone, with by being orally ingested pest control.
The all documents mentioned in the present invention are incorporated as reference the most in this application, are individually recited as with reference to like that just as each document.In addition, it is to be understood that after the above-mentioned teachings having read the present invention, the present invention can be made various changes or modifications by those skilled in the art, these equivalent form of values fall within the application appended claims limited range equally.
Claims (10)
1. (11R, the 14S) paichongding shown in formula A3 and the preparation method of (11S, the 14R) paichongding shown in formula A4,
It is characterized in that, described method includes step:
A () is to the paichongding raw material containing optical isomer shown in formula A3 and formula A4, in mixed solvent, optionally at Bronsted acid, lewis acid or in the presence of the agent catalyst of lower group, after carrying out recrystallization, thus form the crystallization of enantiomer A34 of formula A3 compound and formula A4 compound composition: oxalyl chloride, methylsufonyl chloride, thionyl chloride, paratoluensulfonyl chloride, methacrylic chloride；
B () isolates the crystallization of enantiomer A34, and collect mother solution；
C () optionally, by the mother solution of collection at Bronsted acid or lewis acid, or carry out recrystallization in the presence of the agent catalyst of lower group, thus form the crystallization of enantiomer A34: oxalyl chloride, methylsufonyl chloride, thionyl chloride, paratoluensulfonyl chloride, methacrylic chloride；
Wherein, described mixed solvent is A and the combination in any of two groups of solvents of B:
A group solvent includes: methanol, normal propyl alcohol, isopropanol or a combination thereof；
B group solvent includes: acetonitrile, water or a combination thereof；
The volume ratio of two groups of solvents of A and B is 20:1～1:20.
2. as claimed in claim 1 preparation method, it is characterised in that described method also included the preparation process of described paichongding raw material before step (a):
In atent solvent, at Bronsted acid or lewis acid, or in the presence of the agent catalyst of lower group, formula B compound and normal propyl alcohol are reacted, thus form formula A compound, i.e. paichongding: oxalyl chloride, methylsufonyl chloride, thionyl chloride, paratoluensulfonyl chloride, methacrylic chloride.
3. (11R, the 14S) paichongding shown in formula A3 and the preparation method of (11S, the 14R) paichongding shown in formula A4,
It is characterized in that, described method includes step:
(I) in atent solvent, at Bronsted acid, lewis acid or in the presence of the agent catalyst of lower group, formula B compound and normal propyl alcohol are reacted, thus forms formula A compound, i.e. paichongding: oxalyl chloride, methylsufonyl chloride, thionyl chloride, paratoluensulfonyl chloride, methacrylic chloride；
(IIa) in mixed solvent, after paichongding is carried out recrystallization, thus the crystallization of enantiomer A34 of formula A3 compound and formula A4 compound composition is formed；
(IIb) isolate the crystallization of enantiomer A34, and collect mother solution；
(IIc) optionally, the mother solution of collection at Bronsted acid, lewis acid or is carried out recrystallization in the presence of the catalyst of lower group, thus forms the crystallization of enantiomer A34: oxalyl chloride, methylsufonyl chloride, thionyl chloride, paratoluensulfonyl chloride, methacrylic chloride.
4. preparation method as described in any one of claim 1-3, it is characterized in that, described Bronsted acid or lewis acid include: hydrochloric acid, sulphuric acid, nitric acid, formic acid, acetic acid, trifluoroacetic acid, aluminum chloride, iron chloride, stannic chloride, boron trifluoride, boron trifluoride diethyl etherate or a combination thereof.
5. preparation method as described in any one of claim 1-3, it is characterised in that described mixed solvent is A and the combination in any of two groups of solvents of B:
A group solvent includes: methanol, normal propyl alcohol, isopropanol or a combination thereof；
B group solvent includes: acetonitrile, water or a combination thereof；
The volume ratio of two groups of solvents of A and B is 5:1～1:10.
6. the preparation method as described in any one of claim 1-3, it is characterised in that in the process, recrystallization heating and temperature control is at 40～100 DEG C.
7. the preparation method of (11S, 14R) paichongding shown in formula A4,
It is characterized in that, described method includes step:
(1) in atent solvent, formula C compound is reacted with acid catalyst, thus form formula B4 compound；
Wherein,
R1Or R2It is each independently C1-4Alkyl；Or, R1And R2Collectively form-(CH2)n-, wherein, n is the integer of 2-4；
Described acid catalyst includes: hydrochloric acid, acetic acid, trifluoroacetic acid, Fe (OTs)3·6H2O, camphorsulfonic acid (CSA), para-methylbenzenepyridinsulfonate sulfonate (PPTS), TsOH or a combination thereof；
(2) in atent solvent, at Bronsted acid, lewis acid or in the presence of the reagent of lower group, formula B4 compound is reacted with normal propyl alcohol, thus forms formula A4 compound: oxalyl chloride, methylsufonyl chloride, thionyl chloride, paratoluensulfonyl chloride, methacrylic chloride；
Wherein, described Bronsted acid or lewis acid include: hydrochloric acid, sulphuric acid, nitric acid, formic acid, acetic acid, trifluoroacetic acid, aluminum chloride, iron chloride, stannic chloride, boron trifluoride, boron trifluoride diethyl etherate or a combination thereof.
8. preparation method as claimed in claim 7, it is characterised in that further comprise the steps of: before described step (1)
(1a) in atent solvent, in the basic conditions, by formula G compound and Carbon bisulfide and R3I reacts jointly, thus forms formula F compound；
Wherein, R1、R2And R3It is each independently C1-4Alkyl；Or, R1And R2Collectively form-(CH2)n-, wherein, n is the integer of 2-4；
Described alkali includes: NaH, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or a combination thereof；
(1b) in atent solvent, after formula F compound and reacting ethylenediamine, thus formula E compound is formed；
Wherein, R1、R2And R3As defined above；
(1c) in the basic conditions, formula E compound is reacted with formula D compound, thus form formula C compound；
Wherein, R1、R2As defined above；
Described alkali includes: NaH, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or a combination thereof.
9. preparation method as claimed in claim 8, it is characterised in that further comprise the steps of: before described step (1a)
(1a-1) in atent solvent, in the presence of a catalyst, nitromethane is reacted with crotonic aldehyde, thus form formula H compound；
Wherein, described catalyst includes: the silicon ether derivant of the substituted Prolinol of diaryl, L-PROLINE, (+)-tartaric acid, (+)-Camphora-10-sulfonic acid, chirality dipeptides containing glycine or a combination thereof；
(1a-2) in atent solvent, by formula H compound and aldehyde radical protection group reagent reacting, thus formula G compound is formed；
Wherein, described aldehyde radical protection group reagent is HO-(CH2)n-OH or HO-C (OR1)(OR2)(OR4),
Described R1、R2And R4It is each independently C1-4Alkyl；Or, R1And R2Collectively form-(CH2)n-, wherein, n is the integer of 2-4.
10. preparation method as claimed in claim 9, it is characterised in that described aldehyde radical protection group reagent includes: trimethyl orthoformate, ethylene glycol, 1,3-PD or a combination thereof.
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