CN103087060A - High activity paichongding isomers and preparation method thereof - Google Patents
High activity paichongding isomers and preparation method thereof Download PDFInfo
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- CN103087060A CN103087060A CN2011103349415A CN201110334941A CN103087060A CN 103087060 A CN103087060 A CN 103087060A CN 2011103349415 A CN2011103349415 A CN 2011103349415A CN 201110334941 A CN201110334941 A CN 201110334941A CN 103087060 A CN103087060 A CN 103087060A
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- 0 CC(C1C2)C12C12C(*)C(C3)C3C1C2 Chemical compound CC(C1C2)C12C12C(*)C(C3)C3C1C2 0.000 description 7
- 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
- MOTGVPXRLDDMSK-SWLSCSKDSA-N CCCO[C@H](C[C@@H]1C)N(CCN2Cc(cn3)ccc3Cl)C2=C1[N+]([O-])=O Chemical compound CCCO[C@H](C[C@@H]1C)N(CCN2Cc(cn3)ccc3Cl)C2=C1[N+]([O-])=O MOTGVPXRLDDMSK-SWLSCSKDSA-N 0.000 description 1
- WCXYUOCYBJVZPE-WCQYABFASA-N C[C@@H]1C([N+]([O-])=O)=C(N(Cc2ccc(C)nc2)CC2)N2[C@H](C)C1 Chemical compound C[C@@H]1C([N+]([O-])=O)=C(N(Cc2ccc(C)nc2)CC2)N2[C@H](C)C1 WCXYUOCYBJVZPE-WCQYABFASA-N 0.000 description 1
- BYOSZULJWYKCQL-RXMQYKEDSA-N C[C@H](CC=O)C[N+]([O-])=O Chemical compound C[C@H](CC=O)C[N+]([O-])=O BYOSZULJWYKCQL-RXMQYKEDSA-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
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The present invention provides high activity paichongding isomers and a preparation method thereof. Specifically the present invention relates to high activity paichongding isomers and a preparation method thereof, wherein the isomers comprise a (11R,14S) paichongding isomer represented by a formula A3 and/or (11S,14R) paichongding isomer represented by a formula A4. The preparation method comprises: an enantiomer A34 preparation method, and an asymmetrical chiral synthesis method of the single configuration isomer compound represented by the formula A4. The isomers of the present invention provide higher activity compared to the existing paichongding industrial products. With the method, low efficacy isomers can be easily removed so as to significantly improve efficacy of pesticides. The formula A3 and the formula A4 are as the follows.
Description
Technical field
The present invention relates to pesticide field, relate more specifically to high reactivity piperazine worm pyridine isomer and preparation method thereof.
Background technology
Piperazine worm pyridine (being formula A compound) is an environment amenable sterilant of class low toxicity, has obtained at present the interim registration card of agricultural chemicals and has produced card, is about to listing at home.This compounds has high reactivity to Provado resistant rice brown paddy plant hopper strain, and its active Provado that significantly surpasses is expected to play a significant role in the control of Provado resistant strain.
Contain two chiral carbon atoms in piperazine worm pyridine structure, therefore has formula A1 compound (i.e. (11R, 14R) piperazine worm pyridine), formula A2 compound (i.e. (11S, 14S) piperazine worm pyridine), formula A3 compound (i.e. (11S, 14R) piperazine worm pyridine) and four kinds of steric isomers of formula A4 compound (i.e. (11R, 14S) piperazine worm pyridine).
The pyridine of (11R, 14R) piperazine worm pyridine (11S, 14S) piperazine worm
The pyridine of (11R, 14S) piperazine worm pyridine (11S, 14R) piperazine worm
Adopted in WO2007101369 formula B4 compound under concentrated hydrochloric acid catalysis, obtained formula A compound, this method long reaction time (more than 36 hours), and final product is the mixture of four optical isomers.
The pesticide molecule structure generally all has chirality, in present commercial pesticide species approximately 1st/4th, chirality is arranged.The racemize agricultural chemicals not only can reduce drug effect, contaminate environment and reduction agricultural product quality because it contains poor efficiency or invalid enantiomer, also may cause poisoning or develop immunity to drugs.
Therefore, thereby can remove in the urgent need to a kind of the simple effective method that the low activity isomer obtains the high reactivity isomer, a kind of perhaps method that can directly prepare the isomer of single configuration, the drug effect of using with the field of improving sterilant.
Summary of the invention
Remove thereby an object of the present invention is to provide the simple effective method that the low activity isomer obtains the high reactivity isomer.
Another object of the present invention is to provide a kind of method that can directly prepare the isomer of single configuration.
First aspect present invention provides the optical isomer of a kind of piperazine worm pyridine, and described isomer is (11S, 14R) piperazine worm pyridine shown in (11R, 14S) piperazine worm pyridine shown in formula A3 and/or formula A4:
The pyridine of (11R, 14S) piperazine worm pyridine (11S, 14R) piperazine worm.
Second aspect present invention provides a kind of agricultural composition, and it comprises:
(A) acceptable salt or their combination on the Pesticide Science of the optical isomer described in the first aspect present invention of 0.001-99.99 % by weight, described optical isomer; And
(B) acceptable carrier and/or vehicle on Pesticide Science.
In another preference, component (A) accounts for the 0.01-99.9 % by weight of described agricultural composition, preferred 0.05-90 % by weight.
Another preferred embodiment in, described agricultural composition is used for killing or to prevent to be selected from the insect of lower group: Coleoptera, lepidopteran, Hemiptera, 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, cabbage caterpillar, small cabbage moth, prodenia litura or mythimna separata.
In another preference, described agricultural composition also comprises other active substance, and described other active substance is selected from: sterilant, bait formulation, sterilant, miticide, nematocides, mycocide or growth control agent.
Third aspect present invention provides the purposes of the described agricultural composition of a kind of second aspect present invention, is used for killing or preventing the insect of Agricultural pests, sanitary insect pest and harm animal health; Or with acting on the insecticides of killing or prevent Agricultural pests, sanitary insect pest and harm animal health.
Fourth aspect present invention provides the purposes of acceptable salt on the described optical isomer of a kind of first aspect present invention, described optical isomer Pesticide Science or its combination, for the preparation of insecticides.
Fifth aspect present invention provides the preparation method of the described optical isomer of a kind of first aspect present invention, comprise step: the piperazine worm pyridine raw material that contains optical isomer shown in formula A3 and/or formula A4 is split, thereby obtain (the 11R shown in formula A3,14S) (11S, 14R) piperazine worm pyridine shown in the pyridine of piperazine worm and/or formula A4.
In another preference, described piperazine worm pyridine raw material is solid or liquid, and contains formula A3 compound and formula A4 compound or contain at least formula A4 compound.
In another preference, described piperazine worm pyridine raw material is the racemic piperazine worm pyridine that contains simultaneously formula A1 compound, formula A2 compound, formula A3 compound and formula A4 compound.
In another preference, described method comprises crystallization Split Method, chemical resolution method, chirality HPLC Split Method, column chromatography or its combination.
In another preference, described method is chirality HPLC Split Method.
Sixth aspect present invention provides the preparation method of (11S, 14R) piperazine worm pyridine shown in (11R, 14S) piperazine worm pyridine shown in the described formula A3 of a kind of first aspect present invention and formula A4, and described method comprises step:
(a) to containing the piperazine worm pyridine raw material of optical isomer shown in formula A3 and formula A4, in mixed solvent, randomly under protonic acid or lewis acid catalyst exist, after carrying out recrystallization, thereby form the crystallization of the enantiomer A34 that formula A3 compound and formula A4 compound form;
(b) isolate the crystallization of enantiomer A34, and collect mother liquor;
(c) randomly, the mother liquor of collecting is carried out recrystallization under protonic acid or lewis acid catalyst existence, thereby form the crystallization of enantiomer A34.
In another preference, repeating step (b)-(c) one or many.
In another preference, repeating step (b)-(c) 1-3 time.
In another preference, the recrystallization heating and temperature control is at 40～100 ℃.
In another preference, described method also comprises the preparation process of described piperazine worm pyridine raw material before in step (a):
In inert solvent, under protonic acid or lewis acid catalyst existence, with formula B compound and n-propyl alcohol reaction, thereby form formula A compound, the i.e. pyridine of piperazine worm.
In another preference, described inert solvent comprises ethyl acetate, methylene dichloride, sherwood oil, ether, acetonitrile or its combination.
In another preference, described method comprises step:
(I) in inert solvent, under protonic acid or lewis acid catalyst existence, with formula B compound and n-propyl alcohol reaction, thereby form formula A compound, the i.e. pyridine of piperazine worm;
(IIa) in mixed solvent, after recrystallization is carried out in the pyridine of piperazine worm, thereby form the crystallization of the enantiomer A34 that formula A3 compound and formula A4 compound form;
(IIb) isolate the crystallization of enantiomer A34, and collect mother liquor;
(IIc) randomly, the mother liquor of collecting is carried out recrystallization under protonic acid or lewis acid catalyst existence, thereby form the crystallization of enantiomer A34.
In another preference, repeating step (IIb)-(IIc) one or many.
In another preference, repeating step (IIb)-(IIc) 1-3 time.
In another preference, described protonic acid or Lewis acid comprise: hydrochloric acid, sulfuric acid, nitric acid, formic acid, acetic acid, trifluoroacetic acid, aluminum chloride, iron(ic) chloride, tin chloride, boron trifluoride, boron trifluoride diethyl etherate, oxalyl chloride, Methanesulfonyl chloride, sulfur oxychloride, Tosyl chloride, methacrylic chloride or its combination.
In another preference, described protonic acid or Lewis acid are aluminum chloride, oxalyl chloride, sulfur oxychloride, methacrylic chloride or hydrochloric acid.
In another preference, described mixed solvent is the arbitrary combination of A and two groups of solvents of B:
A group solvent comprises: methyl alcohol, ethanol, n-propyl alcohol, Virahol, ethylene glycol, glycerol or its combination;
B group solvent comprises: acetonitrile, tetrahydrofuran (THF), dioxane, water, dimethyl formamide (DMF), dimethyl sulfoxide (DMSO) (DMSO) or its combination;
The volume ratio of A and two groups of solvents of B is 20: 1～1: 20.
In another preference, described mixed solvent is the arbitrary combination of A and two groups of solvents of B:
A group solvent is ethylene glycol, Virahol or n-propyl alcohol;
B group solvent is DMF, water or acetonitrile;
The volume ratio of A and two groups of solvents of B is 5: 1～1: 10.
Seventh aspect present invention provides the preparation method of the pyridine of (11S, 14R) piperazine worm shown in the described formula A4 of a kind of first aspect present invention, and described method comprises step:
(1) in inert solvent, with formula C compound and acid catalyst reaction, thereby form formula B4 compound;
Wherein,
R
1Or R
2Be C independently of one another
1-4Alkyl; Perhaps, R
1And R
2Common formation-(CH
2)
n-, wherein, n is the integer of 2-4;
Described acid catalyst comprises: hydrochloric acid, acetic acid, trifluoroacetic acid, Fe (OTs)
36H
2O, camphorsulfonic acid (CSA), para-methylbenzenepyridinsulfonate sulfonate (PPTS), TsOH or its combination;
In another preference, described acid catalyst is CSA or PPTS.
(2) in inert solvent, under protonic acid or Lewis acid existence, with formula B4 compound and n-propyl alcohol reaction, thereby form formula A4 compound;
Wherein, described protonic acid or Lewis acid comprise: hydrochloric acid, sulfuric acid, nitric acid, formic acid, acetic acid, trifluoroacetic acid, aluminum chloride, iron(ic) chloride, tin chloride, boron trifluoride, boron trifluoride diethyl etherate, sulfur oxychloride, Tosyl chloride, Methanesulfonyl chloride, oxalyl chloride, methacrylic chloride or its combination.
In another preference, described protonic acid or Lewis acid are hydrochloric acid, aluminum chloride, oxalyl chloride, sulfur oxychloride, Tosyl chloride or methacrylic chloride.
In another preference, described step (1) also comprises step before:
(1a) in inert solvent, under alkaline condition, with formula G compound and dithiocarbonic anhydride and R
3I reacts jointly, thereby forms formula F compound;
Wherein, R
1, R
2And R
3Be C independently of one another
1-4Alkyl; Perhaps, R
1And R
2Common formation-(CH
2)
n-, wherein, n is the integer of 2-4;
Described alkali comprises: NaH, sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood or its combination;
In another preference, described alkali is NaH.
(1b) in inert solvent, after formula F compound and reacting ethylenediamine, thereby form formula E compound;
Wherein, R
1, R
2And R
3Described as defined above;
(1c) under alkaline condition, with formula E compound and the reaction of formula D compound, thereby form formula C compound;
Wherein, R
1, R
2Described as defined above;
Described alkali comprises: NaH, sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood or its combination;
In another preference, described alkali is NaH.
In another preference, described step (1a) also comprises step before:
(1a-1) in inert solvent, under catalyzer exists, with Nitromethane 99Min. and crotonic aldehyde reaction, thereby form formula H compound;
Wherein, described catalyzer comprises: the silicon ether derivant of the Prolinol that diaryl replaces, L-PROLINE, (+)-tartrate, (+)-camphor-10-sulfonic acid, the chirality dipeptides that contains glycine or its combination;
(1a-2) in inert solvent, with formula H compound and aldehyde radical protecting group reagent react, thereby form formula G compound;
Wherein, described aldehyde radical protecting group reagent is HO-(CH
2)
n-OH or HO-C (OR
1) (OR
2) (OR
4),
Described R
1, R
2And R
4Be C independently of one another
1-4Alkyl; Perhaps, R
1And R
2Common formation-(CH
2)
n-, wherein, n is the integer of 2-4.
In another preference, described aldehyde radical protecting group reagent comprises: trimethyl orthoformate, ethylene glycol, 1,3-PD or its combination.
In should be understood that within the scope of the present invention, above-mentioned each technical characterictic of the present invention and can making up mutually between specifically described each technical characterictic in below (eg embodiment), thus consist of new or preferred technical scheme.As space is limited, this tired stating no longer one by one.
Description of drawings
Fig. 1 has shown the HPLC of four isomer that obtain by embodiment 1 method fractionation piperazine worm pyridine; From left to right be 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 has shown the HPLC of four isomer that obtain by embodiment 2 methods fractionation piperazine worm pyridines; From left to right be followed successively by piperazine worm pyridine isomer in figure: formula A1 compound, formula A2 compound, formula A3 compound and formula A4 compound, retention time are respectively 3.722,3.976,4.666 and 5.624min.
Fig. 3 has shown the HPLC of piperazine worm pyridine.
Fig. 4 has shown solid that 1 recrystallization obtains and the HPLC contrast figure of piperazine worm pyridine; P3 is the HPLC figure of piperazine worm pyridine; SH01 is the HPLC figure of the solid that obtains of recrystallization.
Fig. 5 has shown the HPLC contrast figure by the solid that obtains after 3 recrystallizations and the pyridine of piperazine worm; P3 is the HPLC figure of piperazine worm pyridine; SH01 is the HPLC figure of the solid that obtains after 3 recrystallizations.
Embodiment
The inventor has been surprised to find that by long-term and deep research, compares with the piperazine worm pyridine of racemization, and the formula A3 compound of enantiomer A34, single configuration or formula A4 compound have more excellent insecticidal activity.
In addition, the contriver also be surprised to find that a kind ofly prepare, the method for separation and purification enantiomer A34, by the acid catalysis raw material reaction, again through alkalization, extraction and mixed solvent recrystallization, can effectively remove the isomer of low insecticidal activity, thereby obtain the enantiomer A34 of the significant piperazine worm of insecticidal activity pyridine.
In addition, the contriver has also found the preparation method of the synthetic single configurational isomer formula A4 compound of a kind of asymmetric chirality.With organic micromolecule catalyst catalysis α, asymmetric Michael addition reaction occurs in β-unsaturated olefine aldehydr and Nitromethane 99Min., introduced chirality methyl, then pass through series reaction, the synthetic formula B4 compound that obtains having high-optical-purity, further etherificate again, thus the optical isomer formula A4 compound of the more significant piperazine worm of insecticidal activity pyridine obtained.
On the basis of the above, the contriver has completed the present invention.
Term
" the piperazine worm pyridine raw material that contains optical isomer shown in formula A3 and/or formula A4 " of the present invention can be to contain formula A3 compound and formula A4 compound or contain at least formula A4 compound.
In another preference, described " piperazine worm pyridine raw material " is the racemic piperazine worm pyridine that contains simultaneously formula A1 compound, formula A2 compound, formula A3 compound and formula A4 compound.
" enantiomer A34 " described in the present invention or " A34 " all refer to the enantiomer by formula A3 compound and the formula A4 compound composition of preparation method's acquisition of the present invention.Both can Alternate.
Described in the present invention, " pyridine of piperazine worm " and " formula A compound ", all refer to compound shown in formula A, the mixture of two pairs of enantiomers that namely are comprised of formula A1 compound, formula A2 compound, formula A3 compound and formula A4 compound.Both can Alternate.
Term " C
1-4Alkyl " refer to contain the straight chain of 1-4 carbon atom, contain the saturated alkyl of side chain or ring-type.
The insecticidal activity of active substance of the present invention
Term " active substance of the present invention " or " active compound of the present invention " refer to acceptable salt on the optical isomer of piperazine worm pyridine or described optical isomer Pesticide Science, and it has excellent insecticidal activity, and insecticidal spectrum is wide, and stability is strong.
The negatively charged ion that term " acceptable salt on Pesticide Science " means this salt when forming the sterilant pharmacy acceptable salt for understood with acceptable.This salt is water miscible preferably.Suitable, include by the acid salt of formula A3 compound and/or formula A4 compound formation the salt that mineral acid forms, for example hydrochloride, phosphoric acid salt, vitriol, nitrate; And comprise the salt that organic acid forms, and as acetate, benzoate.
Actives mass-energy of the present invention is as controlling and eliminate agriculture and forestry plant insect, the insect of storage cereal, the insect that endangers animal health and public health insect etc. widely.In this manual, " sterilant " is the general designation with material of the effect that prevents and treats above-mentioned all insects of mentioning.
the example of insect includes but not limited to: coleopteron, as sitophilus zea-mais (Sitophilus zeamais), red flour beetle (Tribolium castaneum), potato bug (Henosepilachna vigintioctomaculata), potato ladybug (Henosepilachna sparsa), agriotes fussicollis (Agriotes fuscicollis), red pin green gold tortoise (Anomala cupripes), beautiful tortoise with four lines (Popillia quadriguttata), colorado potato beetles (Monolepta hieroglyphica), ponderous borer (Monochamus alternatus), rice root weevil (Echinocnemus squameus), paulownia chrysomelid (Basiprionota bisignata), longicorn beetle (Anoplophora chinensis), mulberry borer (Apripona germari), navel abdomen bark beetle (Scolytus schevy), or Agriotes subrittatus Motschulsky (Agriotes fuscicollis), lepidopterous insects, as wave malicious pretty young woman (Lymantria dispar), tent caterpillar (Malacosoma neustria testacea), Diaphania perspectalis (Diaphania perspectalis), Clania variegata Snellen (Clania variegata), cnidocampa flavescens walker (Cnidocampa flauescens), dendrolimus punctatus (Dendrolimus punctatus), orgyia antiqua (Orgyia gonostigma), paranthrene tabaniformis (Paranthrene tabaniformis), prodenia litura (Spodoptera litura), striped rice borer (Chilo suppressalis), Pyrausta nubilalis (Hubern). (Ostrinia nubilalis), meal moth (Ephestia cautella), lap moth (Adoxophyes orana), chestnut steinernema (laspyresia splendana), black cutworm (Agrotis fucosa), greater wax moth (Galleria mellonella), diamond-back moth (Plutella xylostella), tangerine lyonetid (Phyllocnistis citrella), or oriental armyworm (Mythimna separata), Homoptera insect, as rice green leafhopper (Nephotettix cincticeps), Nilaparvata lugen (brown planthopper) (Nilaparvata lugens), Kang Shi mealybug (Pseudococcus comstocki), arrowhead scales (Unaspis yanonensis), black peach aphid (Myzus persicae), cotten aphid (Aphis gossydii), radish aphid (Lipaphis erysimi pseudobrassicae), pears class lace bug (Stephanitis nashi), or aleyrodid (Bemisia tabaci), orthopteran, as Groton bug (Blattella germanica), the large Lian of the U.S. (Periplaneta american), African mole cricket (Gryllotalpa africana), or Asiatic migratory locust (Locus migratoria), isoptera insect, as invasion red fire ant (Solenopsis invicta), or Coptotermes formosanus Shtrari． (Coptotermes formosanus), dipteral insect, as housefly (Musca domestica), Aedes aegypti (Aedes aegypti) is planted fly (Delia platura), culex (Culex sp.), or Anopheles sinensis (Anopheles sinensis), the insect of harm animal health, as boophilus microplus (Boophilus microplus), haemaphysalis longicornis (Haemaphysalis longicornis), hyalomma anatolicum anatolicum (Hyalomma anatolicum), bomb fly (Hypoderma spp.), liver fluke (Fasciola hepatica), Bei Shi moniezia (Moniezia blanchard), oersted nematode (Ostertagia spp.), protozoon (Trypanosoma enansi, Babesia bigemina), rabbit coccidia (Occidiosis), tapeworm (tapeworm), coccidia (Coccidium) etc.
The compound that the present invention relates to especially to pierce-suck type, rasping sucking mouthparts insect as: the agriculture and forestry injurious insects such as aphid, leafhopper, plant hopper, thrips, aleyrodid have special efficacy.
The insecticides that contains active substance of the present invention
Active substance of the present invention can be prepared into insecticides with the method for routine.These active compounds can be made conventional preparation, solution for example, emulsion, suspensoid, pulvis, foaming agent, paste, granule; Aerosol, natural and synthetic material with the active substance dipping, microcapsule in polymer, the dressing compound that is used for seed, with the preparation that uses with combustion unit-piece, sootiness cartridge case for example, sootiness tank and sootiness dish, and the cold mist of ULV (Cold mist) and hot mist (Warm mist) preparation.
These preparations can be with known method production, for example, with active compound with expand agent and mix, these expansion agent are exactly the diluent or carrier of liquid or liquefied gas or solid, and can to select arbitrarily tensio-active agent be emulsifying agent and/or dispersion agent and/or formation of foam agent.For example when using water as the expansion agent, organic solvent also can be used as auxiliary agent.
When making diluent or carrier with liquid solvent, be suitable basically, as arene, dimethylbenzene for example, toluene or alkylnaphthalene; The fragrance of chlorination or the fat hydrocarbon of chlorination, chlorobenzene for example, vinylchlorid or methylene dichloride; Fat hydrocarbon, for example hexanaphthene or paraffin, for example mineral oil fractions; Alcohols, for example ethanol or ethylene glycol and their ether and lipid; Ketone, acetone for example, methylethylketone, methyl iso-butyl ketone (MIBK) or pimelinketone; Or the polar solvent that is of little use, for example dimethyl formamide and dimethyl sulfoxide (DMSO), and water.
Diluent or carrier with regard to liquefied gas is said, refers to the liquid that will become at normal temperatures and pressures gas, and aerosol propellants for example is as hydro carbons and butane, propane, nitrogen and the carbonic acid gas of halogenation.
Solid carrier can be with (ground) the natural mineral substance that grinds, kaolin for example, clay, talcum, quartz, atlapulgite, polynite, or diatomite, and the synthetic mineral substance that grinds, for example silicic acid of high dispersing, aluminum oxide and silicate.That pulverize and natural announcement stone classification for the solid carrier of particle, calcite for example, marble, float stone, sepiolite and rhombspar, and the synthetic particle of inorganic and organic meal, with organic materials wood sawdust for example, Exocarpium cocois (Cocos nucifera L), the particle of corn cob and tobacco stems etc.
Emulsification row non-ionic and negatively charged ion can be used as emulsifying agent and/or formation of foam agent.Polyoxyethylene-fatty acid ester for example, polyoxyethylene-Fatty Alcohol(C12-C14 and C12-C18) ethers, for example alkaryl polyoxyethylene glycol ethers, alkyl sulfonates, alkyl sulfuric ester class, aromatic yl sulphonate class and albumin hydrolysate.Dispersion agent comprises, for example xylogen sulfite waste lye and methylcellulose gum.
Can use tackiness agent in preparation, carboxymethyl cellulose and with powder for example, the natural and synthetic polymer of particle or emulsion form, gum arabic for example, the pure and mild polyvinyl acetate of polyvinyl.
Can be with tinting material inorganic dyestuff for example, as ferric oxide, oxidation is bored and is Prussian blue; Organic dye is as organic dye, as azo dyes or metal titanium cyanine dyes; With use the trace nutrition agent, as violent in iron, boron, copper, cobalt, the salt of aluminum and zinc etc.
These active compounds of the present invention can be made in the commodity preparation that a kind of mixture is present in them with other active compounds or from the use formulation of these preparations preparations, these other active compound is sterilant, close bait, sterilant, miticide, nematocides, mycocide, growth control agent etc.Sterilant comprises, phosphoric acid ester for example, amino formate, cinerins, chlorinated hydrocarbons, benzoyl area kind, neires toxin and by the material of microorganisms, as Avrmectin.
In addition, these active compounds of the present invention also can be made to become in the commodity preparation that a kind of mixture is present in them from the use formulation of these preparation preparations with synergistic agent.Synergistic agent is the compound that improves the active compound effect, because active compound itself has activity, also can add synergistic agent.
These preparations usually contain and account for described insecticides 0.001-99.99 % by weight, preferred 0.01-99.9 % by weight, the more preferably active compound of the present invention of 0.05-90 % by weight.Making from the commodity preparation uses the concentration of the active compound formulation to change in wide scope.Use the concentration of the active compound in formulation from 0.0000001-100% (g/v), to be preferably between 0.0001 and 1% (g/v).
The preparation method of the compounds of this invention
Formula A3 compound of the present invention and/or formula A4 compound can make by following method, yet the condition of the method is not limited to following explanation such as the amount of reactant, solvent, alkali, compound used therefor, temperature of reaction, reaction required time etc.The compounds of this invention can also be chosen various synthetic methods that will describe in this manual or known in the art wantonly and combines and make easily, and such combination can be easy to carry out by those skilled in the art in the invention.
The preparation method of formula A3 compound and/or formula A4 compound
The preparation method of formula A3 compound of the present invention and/or formula A4 compound, comprise step: the piperazine worm pyridine raw material that contains optical isomer shown in formula A3 and/or formula A4 is split, thereby obtain (the 11R shown in formula A3,14S) (11S, 14R) piperazine worm pyridine shown in the pyridine of piperazine worm and/or formula A4.
In another preference, described piperazine worm pyridine raw material is solid or liquid, and contains formula A3 compound and formula A4 compound or contain at least formula A4 compound.
In another preference, described piperazine worm pyridine raw material is the racemic piperazine worm pyridine that contains simultaneously formula A1 compound, formula A2 compound, formula A3 compound and formula A4 compound.
In another preference, described method comprises crystallization Split Method, chemical resolution method, chirality HPLC Split Method, column chromatography or its combination.
In another preference, described method is chirality HPLC Split Method.
The preparation of isomer A34
Enantiomer A34 preparation method of the present invention, can carry out according to following steps:
(a) to containing the piperazine worm pyridine raw material of optical isomer shown in formula A3 and formula A4, in mixed solvent, randomly under protonic acid or lewis acid catalyst exist, after carrying out recrystallization, thereby form the crystallization of the enantiomer A34 that formula A3 compound and formula A4 compound form;
(b) isolate the crystallization of enantiomer A34, and collect mother liquor;
(c) randomly, the mother liquor of collecting is carried out recrystallization under protonic acid or lewis acid catalyst existence, thereby form the crystallization of enantiomer A34.
In another preference, repeating step (b)-(c) one or many.Preferably, repeating step (b)-(c) 1-3 time.
In another preference, recrystallization temperature is controlled at 40～100 ℃.
In another preference, described mixed solvent is the arbitrary combination of A and two groups of solvents of B:
A group solvent comprises: methyl alcohol, ethanol, n-propyl alcohol, Virahol, ethylene glycol, glycerol or its combination;
B group solvent comprises: acetonitrile, tetrahydrofuran (THF), dioxane, water, dimethyl formamide (DMF), dimethyl sulfoxide (DMSO) (DMSO) or its combination;
The volume ratio of A and two groups of solvents of B is 20: 1～1: 20.
Preferably, A group solvent is ethylene glycol, Virahol or n-propyl alcohol; B group solvent is DMF, water or acetonitrile; Its volume ratio is that A: B is 5: 1～1: 10.
In another preference, described protonic acid or Lewis acid comprise: hydrochloric acid, sulfuric acid, nitric acid, formic acid, acetic acid, trifluoroacetic acid, aluminum chloride, iron(ic) chloride, tin chloride, boron trifluoride, boron trifluoride diethyl etherate, oxalyl chloride, Methanesulfonyl chloride, sulfur oxychloride, Tosyl chloride, methacrylic chloride or its combination.
Preferably, described protonic acid or Lewis acid are aluminum chloride, oxalyl chloride, sulfur oxychloride, methacrylic chloride or hydrochloric acid.
Can also realize according to following steps:
(I) in inert solvent, under above-mentioned protonic acid or lewis acid catalyst existence, with formula B compound and n-propyl alcohol reaction for some time (as 1-72 hour or 1-60 hour), thereby form formula A compound, the i.e. pyridine of piperazine worm;
In another preference, described inert solvent comprises: ethyl acetate, methylene dichloride, sherwood oil, ether, acetonitrile or its combination.
(IIa) pyridine of piperazine worm is carried out recrystallization with mixed solvent (the same) after, thereby form the crystallization of the enantiomer A34 that formula A3 compound and formula A4 compound form;
(IIb) isolate the crystallization of enantiomer A34, and collect mother liquor;
(IIc) randomly, after the mother liquor process of collecting is extracted and concentrates, carry out recrystallization under protonic acid or lewis acid catalyst existence, thereby form the crystallization of enantiomer A34.
In another preference, repeating step (IIb)-(IIc) one or many.
In another preference, repeating step (IIb)-(IIc) 1-3 time.
Wherein, described extraction solvent used comprises: ether, ethyl acetate, methylene dichloride, ethylene dichloride, sherwood oil or its combination.
The preparation of formula A4 compound
The Chiral Synthesis of formula A4 compound of the present invention, can realize according to flow process 1:
Flow process 1
Concrete steps are as follows:
(1) in inert solvent, under organic micromolecule catalyst exists, with Nitromethane 99Min. and crotonic aldehyde in room temperature reaction for some time (as 3-5 days), thereby form formula H compound, introduced chirality methyl;
Wherein, described catalyzer comprises: the silicon ether derivant of the Prolinol that diaryl replaces, L-PROLINE, (+)-tartrate, (+)-camphor-10-sulfonic acid, the chirality dipeptides that contains glycine or its combination;
(2) in inert solvent, (about 0 ℃) reaction for some time (as 5-30min) in ice bath with formula H compound and aldehyde radical protective material, thus form formula G compound;
Wherein, R
1, R
2And R
4Be C independently of one another
1-4Alkyl; Perhaps, R
1And R
2Common formation-(CH
2)
n-, wherein, n is the integer of 2-4;
Wherein, described aldehyde radical protecting group reagent comprises: trimethyl orthoformate, ethylene glycol, 1,3-PD or its combination;
(3) in inert solvent, with formula G compound and alkali after room temperature reaction for some time (as 0.5-4 hour or 1-3 hour), with dithiocarbonic anhydride and R
3Then the I mixed at room temperature is warming up to certain temperature (as 50-70 ℃) and jointly reacts for some time (as 12-36 hour or 12-24 hour), thereby form formula F compound;
Wherein, R
1, R
2And R
3Be C independently of one another
1-4Alkyl; Perhaps, R
1And R
2Common formation-(CH
2)
n-, wherein, n is the integer of 2-4;
Described alkali comprises: NaH, sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood or its combination;
In another preference, described alkali is NaH.
(4) in inert solvent, with formula F compound and after quadrol back flow reaction for some time (as 3-12 hour or 6-9 hour), form formula E compound; Under alkaline condition, with formula E compound and formula D compound in room temperature reaction for some time (as 1-4 hour or 2-2.5 hour), thereby form formula C compound;
Wherein, R
1, R
2And R
3Be C independently of one another
1-4Alkyl; Perhaps, R
1And R
2Common formation-(CH
2)
n-, wherein, n is the integer of 2-4;
Described alkali comprises: NaH, sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood or its combination;
In another preference, described alkali is NaH.
(5) in inert solvent, with formula C compound and acid catalyst reaction, thereby form formula B4 compound;
Wherein, R
1, R
2Be C independently of one another
1-4Alkyl; Perhaps, R
1And R
2Common formation-(CH
2)
n-, wherein, n is the integer of 2-4;
Described acid catalyst comprises: hydrochloric acid, acetic acid, trifluoroacetic acid, Fe (OTs)
36H
2O, camphorsulfonic acid (CSA), para-methylbenzenepyridinsulfonate sulfonate (PPTS), TsOH or its combination;
In another preference, described acid catalyst is CSA or PPTS.
(6) in inert solvent, formula B4 compound under low temperature (as-20～0 ℃), slowly adds protonic acid or Lewis acid with after n-propyl alcohol mixes, then back flow reaction 1-30 hour, thereby form formula A4 compound;
Wherein, described protonic acid or Lewis acid comprise: hydrochloric acid, sulfuric acid, nitric acid, formic acid, acetic acid, trifluoroacetic acid, aluminum chloride, iron(ic) chloride, tin chloride, boron trifluoride, boron trifluoride diethyl etherate, sulfur oxychloride, Tosyl chloride, oxalyl chloride, methacrylic chloride or its combination.
In another preference, described protonic acid or Lewis acid are hydrochloric acid, aluminum chloride, oxalyl chloride, sulfur oxychloride, Tosyl chloride or methacrylic chloride.
Major advantage of the present invention:
(1) the invention provides the optical isomer that a class has the piperazine worm pyridine of high insecticidal activity, is respectively enantiomer A34, formula A3 compound and formula A4 compound.Described isomer can be used for further studying biological activity, toxicity and the selectivity environmental behaviour of the not piperazine worm pyridine of isomorphism type, and then realizes production and the application of the pyridine of chirality piperazine worm.
(2) the present invention also provides a kind of method for preparing the enantiomer A34 of high insecticidal activity.
(3) the present invention also provides a kind of method for preparing single configuration formula A4 compound.
(4) the present invention also provides a kind of method for preparing four optical isomers of piperazine worm pyridine.
Below in conjunction with concrete enforcement, further set forth the present invention.Should be understood that these embodiment only to be used for explanation the present invention and be not used in and limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, usually according to normal condition, or the condition of advising according to manufacturer.Unless otherwise indicated, otherwise per-cent and umber calculate by weight.
Embodiment 1: chirality HPLC separation obtains four isomer of piperazine worm pyridine
Instrument and condition
Colleges and universities' liquid chromatograph: Shimadzu, LC-20ATvp, SPD-M20Avp;
Chromatographic column: CHIRALPAK IC (Daicel, 30 * 250mm, 5 μ m);
Moving phase: ethanol=100
Flow velocity: 1-20mL/min;
Sampling volume: 2 μ L-2mL;
Detect wavelength: 325nm;
Column temperature: 20-35 ℃.
Experimental procedure
Get piperazine worm pyridine configuration sample ethanolic soln, extracting sample solution carries out colleges and universities' liquid chromatography preparation by above-mentioned condition, collects target components, and sampling analysis also records color atlas.Result from left to right is followed successively by piperazine worm pyridine isomer A1 as shown in Figure 1 in figure, A2, and A3 and A4, retention time is respectively 7.500,8.790, and 10.618 and 13.487min, realized the baseline separation to four isomer.
The above-mentioned condition of final employing is separated in a large number to four steric isomers of piperazine worm pyridine.
Formula A1 compound:
1H NMR (400MHz, CDCl
3): 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, J
1=12.6Hz, J
2=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;
13C NMR (100MHz, CDCl
3): 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:
1H NMR (400MHz, CDCl
3): 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, J
1=15.6Hz, J
2=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, J
1=8.0Hz, J
2=3.0Hz, 3H) ppm;
13C NMR (100MHz, CDCl
3): 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:
1H NMR (400MHz, CDCl
3): δ 8.28 (s, 1H), 7.75 (s, 1H), 7.26 (dd, J
1=12.0Hz, J
2=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;
13C NMR (100MHz, CDCl
3): 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:
1H NMR (400MHz, CDCl
3): 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, J
1=4.0Hz, J
2=2.8Hz, 3H) ppm;
13CNMR (100MHz, CDCl
3): 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 separation obtains piperazine worm pyridine isomer A34
Instrument and condition
High performance liquid chromatograph: Shimadzu, LC-20ATvp, SPD-M20Avp;
Chromatographic column: CHIRALPAK IC (Daicel, 30 * 250mm, 5 μ m);
Moving phase: methylene dichloride: methyl alcohol: diethylamine=50: 50: 0.1
Flow velocity: 1-20mL/min;
Sampling volume: 2 μ L-2mL;
Detect wavelength: 325nm;
Column temperature: 20-35 ℃.
Experimental procedure
Get piperazine worm pyridine configuration sample ethanolic soln, carry out colleges and universities' liquid chromatography preparation by above-mentioned condition, collect target components, sampling analysis also records color atlas, result as shown in Figure 2, from left to right be followed successively by piperazine worm pyridine isomer A1 in figure, A2, A3 and A4, retention time is respectively 3.722,3.976,4.666 and 5.624min, separate obtaining piperazine worm pyridine isomer A34.
Embodiment 3: the pyridine of raceme piperazine worm with and the test of the insecticidal activity of four single configurational isomers
We carry out the insecticidal activity test to four isomer of single configuration.According to piperazine worm pyridine isomer etc., indoor aphis craccivora (Aphis craccivora Koch) population biological activity determination report (table 1) is shown, 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 piperazine worm pyridine isomer etc. are to aphis craccivora active testing result
| Compound | LC50(mg/L) | 95% fiducial limit | Slope |
| 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 |
| The pyridine of raceme piperazine worm | 31.481 | 20.510-48.373 | 4.542±0.376 |
*The preparation method of A34 sees embodiment 2.
Embodiment 4: the preparation of enantiomer A34
4.1 compd A is synthetic
10g (31mmol) compd B is dissolved in 100mL reaction solvent (n-propyl alcohol), then adds the n-propyl alcohol of 4 times of amounts.Under low temperature, (20～0 ℃) slowly drip the oxalyl chloride of 3 times of amounts, and solid dissolves gradually, become the red-brown settled solution, become again afterwards turbid solution.Reflux is 3～48h approximately, and TLC follows the tracks of, and raw material disappears, stopped reaction.Ice-water bath is cooled to low temperature with solution, then under cold condition, reaction solution is slowly poured in the alkaline aqueous solution (aqueous sodium carbonate) of 50mL, add 20mL saturated aqueous common salt separatory, water layer is used 50mL extraction solvent (ether) extracting twice more again.Merge organic layer, the evaporated under reduced pressure solvent obtains 9.23g faint yellow solid piperazine worm pyridine (formula A compound).
The HPLC detected result as shown in Figure 3, HPLC condition: RX-C18,4.6 * 250mm, 62:38, Acetone:buffer; 325nm 6.923min 74.363%12.34min 23.776%.Mp＝130.2-131.9℃；
1H NMR(400MHz，CDCl
3)：δ8.31-8.33(m，1H)，7.86(dd，J
1＝2.4Hz，J
2＝8.4Hz，0.5H)，7.82(dd，J
1＝2.4Hz，J
2＝8.2Hz，0.5H)，7.33(dd，J
1＝0.8Hz，J
2＝1.2Hz，0.5H)，7.31(dd，J
1＝0.8Hz，J
2＝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，J
1＝3.6Hz，J
2＝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+)calcd for C
17H
23N
4O
3 35Cl(M
+)，366.1459；found，366.1487。
4.2 the purifying of enantiomer A34
4.2.1 recrystallization
(a) recrystallization
40mL A and B mixed solvent (methyl alcohol/acetonitrile (V: V is 3: 1)) are joined in formula A compound, be heated to whole dissolvings, then be cooled to low temperature, suction filtration, filter cake is used the above-mentioned mixed solvent drip washing of 30mL again, obtains faint yellow solid A345.09g (yield 45.1%), and the HPLC detected result as shown in Figure 4, SH01 is the HPLC figure of enantiomer A34, and P3 is the HPLC figure of piperazine worm pyridine raceme.
Mother liquor adds 50mL extraction solvent (the same) and the extraction of 20mL saturated aqueous common salt, and water layer with the extraction of 50mL extraction solvent once, merges organic layer again, adds the 7g anhydrous sodium sulfate drying.
(b) mother liquid disposal
The mother liquor that merges is concentrated into half, slowly drips 1.7mL (20mmol) oxalyl chloride at low temperatures in solution, reflux is 3～48h approximately.Ice-water bath is cooled to low temperature with solution, then at low temperatures reaction solution is slowly poured in 15mL alkaline aqueous solution (the same), then adds the extraction of 10mL saturated aqueous common salt, water layer again with the extraction of 30mL extraction solvent once, merge organic layer, the evaporated under reduced pressure solvent obtains the brown color solid.
4.2.2 secondary recrystallization
(a) recrystallization
A and the B mixed solvent (the same) of 24mL are joined in solid, be heated to whole dissolvings, then be cooled to low temperature, suction filtration, filter cake are used the above-mentioned mixed solvent drip washing of 15mL again, obtain faint yellow solid A342.26g (yield 20%);
Mother liquor adds 30mL extraction solvent (the same) extraction once to extract with the 10mL saturated aqueous common salt, and water layer is used 30mL extraction solvent (the same) extraction once again, merges organic layer.Add the 5g anhydrous sodium sulfate drying.
(b) mother liquid disposal
The mother liquor that merges is concentrated into 30mL, slowly drips 0.3mL (3.80mmol) oxalyl chloride at low temperatures in solution, reflux is 3～48h approximately.Ice-water bath is cooled to low temperature with solution, then reaction solution is slowly poured in 6mL basic solution (the same) at low temperatures, add again the extraction of 2.5mL saturated aqueous common salt, water layer is used 30mL extraction solvent (the same) extraction once again, merge organic layer, the evaporated under reduced pressure solvent, faint yellow solid.
4.2.3 three recrystallizations
18mL mixed solvent (the same) is joined in solid, be heated to whole dissolvings, then be cooled to low temperature, suction filtration, filter cake are used the above-mentioned mixed solvent drip washing of 15mL again, obtain faint yellow solid A341.39g (yield 12.3%).
The A34 solid that merges above-mentioned gained, gross weight 8.74g (total recovery 77.4%).The HPLC detected result as shown in Figure 5, SH01 is the HPLC figure of enantiomer A34, P3 is the HPLC figure of piperazine worm pyridine raceme.As seen, the solid that obtains by 3 recrystallizations is enantiomer A34.
The related reagent of table 2 embodiment 4-11
Embodiment 5: the preparation of enantiomer A34
5.1 compd A is synthetic
10g (31mmol) compd B is dissolved in 100mL reaction solvent (methylene dichloride), then adds the n-propyl alcohol of 8 times of amounts.Under low temperature, (0 ℃) slowly drips as after the oxalyl chloride of 3 times of amounts, and reflux is 3～48h approximately, and TLC follows the tracks of, after reaction finishes, and processing reaction, operation is with embodiment 4.1, and the reagent that specifically uses sees Table 2, obtains the pyridine of 9.08g faint yellow solid piperazine worm.
5.2 the purifying of enantiomer A34
Formula A compound is carried out recrystallization, and totally 3 times, operation is with embodiment 4.2, and the concrete reagent that uses sees Table 2.
The A34 solid that merges at last three recrystallization gained, gross weight 8.53g (total recovery 75.0%).
Embodiment 6: the preparation of enantiomer A34
6.1 compd A is synthetic
10g (31mmol) compd B is dissolved in 100mL reaction solvent (ethyl acetate), then adds the n-propyl alcohol of 8 times of amounts.After under low temperature, (0 ℃) slowly was added dropwise to the oxalyl chloride of 3 times of amounts, reflux is 3～48h approximately, and TLC follows the tracks of, after reaction finishes, and processing reaction, operation is with embodiment 4.1, and the concrete reagent that uses sees Table 2, obtains the pyridine of 8.93g faint yellow solid piperazine worm.
6.2 the purifying of enantiomer A34
Formula A compound is carried out recrystallization, and totally 3 times, operation is with embodiment 4.2, and the concrete reagent that uses sees Table 2.
The A34 solid that merges at last three recrystallization gained, gross weight 8.24g (total recovery 72.5%).
Embodiment 7: the preparation of enantiomer A34
7.1 compd A is synthetic
10g (31mmol) compd B is dissolved in 100mL reaction solvent (acetonitrile), then adds the n-propyl alcohol of 8 times of amounts.After under low temperature, (0 ℃) added the aluminum chloride of 5 times of amounts in batches, reflux is 3～48h approximately, and TLC follows the tracks of, after reaction finishes, and processing reaction, operation is with embodiment 4.1, and the concrete reagent that uses sees Table 2, obtains the pyridine of 8.76g faint yellow solid piperazine worm.
7.2 the purifying of enantiomer A34
Formula A compound is carried out recrystallization, and totally 3 times, operation is with embodiment 4.2, and the concrete reagent that uses sees Table 2.
The A34 solid that merges at last three recrystallization gained, gross weight 8.15g (total recovery 71.7%).
Embodiment 8: the preparation of enantiomer A34
8.1 compd A is synthetic
10g (31mmol) compd B is dissolved in 100mL reaction solvent (methylene dichloride), then adds the n-propyl alcohol of 8 times of amounts.After under low temperature, (20～0 ℃) added the aluminum chloride of 5 times of amounts in batches, reflux is 5～20h approximately, becomes red tan solution, after TLC follows the tracks of the reaction end.Processing reaction, operation are with embodiment 3.1, and the concrete reagent that uses sees Table 2, obtains the pyridine of 8.58g faint yellow solid piperazine worm.
8.2 the purifying of enantiomer A34
Formula A compound is carried out recrystallization, and totally 3 times, operation is with embodiment 4.2, and the concrete reagent that uses sees Table 2.
The isomer A34 gross weight 8.09g (total recovery 71.2%) that merges at last three recrystallization merging gained.
Embodiment 9: the preparation of enantiomer A34
9.1 compd A is synthetic
10g (31mmol) compd B is dissolved in 100mL reaction solvent (n-propyl alcohol), then adds the n-propyl alcohol of 8 times of amounts.After under low temperature, (0 ℃) slowly was added dropwise to sulfur oxychloride, reflux is 3～48h approximately, and TLC follows the tracks of, after reaction finishes, and processing reaction, operation is with embodiment 4.1, and the concrete reagent that uses sees Table 2, obtains the pyridine of 8.44g faint yellow solid piperazine worm.
9.2 the purifying of enantiomer A34
Formula A compound is carried out recrystallization, and totally 3 times, operation is with embodiment 4.2, and the concrete reagent that uses sees Table 2.
The A34 solid that merges at last three recrystallization gained, gross weight 8.04g (total recovery 70.7%).
Embodiment 10: the preparation of enantiomer A34
10.1 compd A is synthetic
10g (31mmol) compd B is dissolved in 100mL reaction solvent (ethyl acetate), then adds the n-propyl alcohol of 8 times of amounts.After under low temperature, (0 ℃) slowly was added dropwise to sulfur oxychloride, reflux is 3～48h approximately, and TLC follows the tracks of, after reaction finishes, and processing reaction, operation is with embodiment 4.1, and the concrete reagent that uses sees Table 2, obtains the pyridine of 8.29g faint yellow solid piperazine worm.
10.2 the purifying of enantiomer A34
Formula A compound is carried out recrystallization, and totally 3 times, operation is with embodiment 4.2, and the concrete reagent that uses sees Table 2.
The A34 solid that merges at last three recrystallization gained, gross weight 7.95g (total recovery 69.9%).
Embodiment 11: the preparation of enantiomer A34
11.1 compd A is synthetic
10g (31mmol) compd B is dissolved in 100mL reaction solvent (ethyl acetate), then adds the n-propyl alcohol of 8 times of amounts.After under low temperature, (0 ℃) slowly was added dropwise to sulfur oxychloride, reflux is 3～48h approximately, and TLC follows the tracks of, after reaction finishes, and processing reaction, operation is with embodiment 4.1, and the concrete reagent that uses sees Table 2, obtains the pyridine of 8.15g faint yellow solid piperazine worm.
11.2 the purifying of enantiomer A34
Formula A compound is carried out recrystallization, and totally 3 times, operation is with embodiment 4.2, and the concrete reagent that uses sees Table 2.
The A34 solid that merges at last three recrystallization gained, gross weight 7.79g (total recovery 69.0%).
Embodiment 12: the preparation of formula A4 compound
12.1 formula H compound is synthetic
L-diphenylprolinol silicon ether (501mg, 1.5mmol) is dissolved in 100mL solvent (CH
3OH: CH
2Cl
2=9: 1), under agitation drip respectively crotonic aldehyde (6.0mL, 0.7mol) and Nitromethane 99Min. (12.0mL, 0.2mol), add at last Lithium Acetate (0.7g, 6.9mmol).Reaction solution stirred under room temperature 4 days, and the TLC detection reaction is complete.Stopped reaction, concentrated, the gained crude product adds as appropriate dichloromethane extraction three times, merges organic phase.Organic phase is used respectively saturated common salt water washing, anhydrous sodium sulfate drying again.The filtering siccative, filtrate decompression desolventizes, and residuum gets 5.0g yellow oily liquid-type H compound through the rapid column chromatography purifying, and productive rate is 53%.[α]
D 23 0.9(c 1.20，CH
2Cl
2)；
1H NMR(400MHz，CDCl
3)：δ9.77(s，1H)，4.34-4.45(m，2H)，2.84-2.93(m，1H)，2.66(dd，J
1＝18.2Hz，J
2＝6.1Hz，1H)，2.53(dd，J
1＝18.2Hz，J
2＝7.0Hz，1H)，1.11(d，J＝6.8Hz，3H)；
13C NMR(100MHz，CDCl
3)：δ199.6，80.1，47.0，27.2，17.4。
12.2 formula G1 compound is synthetic
Formula H compound (7.0g, 53.8mmol) is dissolved in the 30mL methylene dichloride, drips wherein trimethyl orthoformate (14.7mL, 0.1mol), reaction flask is placed in ice bath is cooled to 0 ℃.Take again tosic acid monohydrate (3.1g, 16.4mmol), add in reaction solution in batches, after all adding, continue to stir 15 minutes under ice bath.Then reaction solution is moved to room temperature, at room temperature reaction, TLC follows the tracks of reaction, after the compound complete reaction, stopped reaction.Add the aqueous solution cancellation of saturated sodium bicarbonate to react in reaction solution, dichloromethane extraction is collected organic phase.Organic phase is used respectively saturated common salt water washing, anhydrous sodium sulfate drying.The filtering siccative, filtrate decompression desolventizes, and residuum gets 7.8g pale yellow oily liquid body formula G1 compound through the rapid column chromatography separation and purification, and productive rate is 83%.[α]
D 23 5.3(c 1.08，CH
2Cl
2)；
1H NMR(400MHz，CDCl
3)：δ4.47-4.40(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)；
13C NMR(100MHz，CDCl
3)：δ102.5，81.2，52.9，52.9，36.4，29.0，17.6。
12.3 formula F1 compound is synthetic
With NaH (content is 60%, 1.7g, 43.7mmol), N
2Add the tetrahydrofuran solution of 5mL drying under protection, then take in the THF solvent that formula G1 compound (1.5g, 8.8mmol) is dissolved in the 3mL drying, and under agitation be added drop-wise in above-mentioned reaction solution, stirred 2 hours under room temperature; Then draw methyl iodide (5.0mL, 80.3mmol) and dithiocarbonic anhydride (5.0mL, 83.1mmol), mix, at room temperature be added dropwise in reaction solution, then reaction is warming up to 60 ℃ of reactions.The TLC following response, after 24 hours, reaction finishes.Stopped reaction is cooled to room temperature with reaction solution, slowly adds frozen water cancellation reaction in reaction solution, uses dichloromethane extraction three times, merges organic layer.Organic phase is used respectively saturated common salt water washing, anhydrous sodium sulfate drying.The filtering siccative, filtrate decompression desolventizes, and residuum obtains the formula F1 compound of 600mg yellow oily liquid through the rapid column chromatography separation and purification, and productive rate is 25%.[α]
D 23 66.4(c 1.19，CH
2Cl
2)；
1H NMR(400MHz，CDCl
3)：δ4.40(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)；
13C NMR(100MHz，CDCl
3)：δ157.83，134.6，102.6，53.2，52.8，37.1，32.8，18.7，17.4，16.7。
12.4 formula E1 compound is synthetic
Formula F1 compound (1.1g, 4.1mmol) is dissolved in 30mL ethanol, then drips wherein quadrol (0.9mL, 13.5mmol), reflux.After 8 hours, the reaction of TLC detection display finishes.Stopped reaction is cooled to room temperature with reaction solution, the concentrating under reduced pressure desolventizing, and the gained crude product gets 379mg faint yellow solid formula E1 compound through the rapid column chromatography separation and purification, and productive rate is 38%.[α]
D 23 141.9(c 0.652，CH
2Cl
2)；
1H NMR(400MHz，CDCl
3)：δ4.27-4.24(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)；
13C NMR(100MHz，CDCl
3)：δ162.3，109.7，103.7，54.1，51.4，44.0，34.4，28.9，17.1。
12.5 formula D compound is synthetic
Under nitrogen protection, 2-chloro-5-4-hydroxymethylpiperidine (3.8g, 26.7mmol) is dissolved in methylene dichloride 40mL, drip wherein triethylamine (5.8mL, 40.1mmol), stirred 15 minutes under-40 ℃.Drip wherein MsCl (2.5mL, 32.3mmol) again, and continue reaction under-40 ℃, after 1 hour, the reaction of TLC detection display finishes.After reaction solution is cooled to room temperature, add 20mL water and 20mL methylene dichloride cancellation reaction in reaction solution, organic phase is collected in layering, water dichloromethane extraction three times.Merge organic phase, use respectively the saturated common salt water washing, anhydrous sodium sulfate drying.The filtering siccative, filtrate decompression desolventizes, and gets white solid, through recrystallization, obtains 6.0g white crystal formula D compound, and productive rate is 99%.
1H NMR(400MHz，CDCl
3)：δ8.46(d，J＝2.2Hz，1H)，7.77(dd，J
1＝2.4Hz，J
2＝8.2Hz，1H)，7.42(d，1H)，5.26(s，2H)，3.06(s，3H)。
12.6 formula C1 compound is synthetic
With formula E1 compound (662mg; 2.7mmol) be dissolved in the DMSO of 20mL drying; (content is 60% to add NaH under nitrogen protection; 240mg; 6.0mmol); stirred under room temperature 2 hours, then take formula D compound (304mg, 1.4mmol) adds reaction solution under nitrogen protection in batches; add complete after; reaction solution at room temperature stirs and spends the night, and stopped reaction is placed in ice bath with reaction solution cooling; add the appropriate shrend reaction of going out in the reaction solution; ethyl acetate extraction, separatory keeps organic phase.Organic phase is used respectively saturated common salt water washing, anhydrous sodium sulfate drying.The filtering siccative, filtrate decompression desolventizes, and residuum gets 180mg weak yellow liquid formula C1 compound through column chromatography, and productive rate is 18%.[α]
D 23 141.9(c 0.652，CH
2Cl
2)；
1H NMR(400MHz，CDCl
3)：δ8.39(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]
-calcd for C
15H
20ClN
4O
3：339.1224；found：339.2018。
12.7 formula A4 compound is synthetic
10g (31mmol) formula C1 compound is dissolved in 100mL reaction solvent (methylene dichloride), adds acid (hydrochloric acid) deprotection, then add the n-propyl alcohol of 8 times of amounts.Under low temperature, (20～0 ℃) slowly drip the catalyzer (acetic acid) of 2 times of amounts, and reflux is 5～20h approximately, becomes red tan solution, and TLC follows the tracks of, and compound disappears, stopped reaction.Ice-water bath is cooled to low temperature with solution, then under cold condition, reaction solution is slowly poured in the alkaline aqueous solution of 50mL, then adds 20mL saturated aqueous common salt separatory, and water layer is used 50mL extraction solvent extracting twice again.Merge organic layer, the evaporated under reduced pressure solvent obtains 5.22g faint yellow solid A4, yield 46%.[α]
D 23 76.5(c0.005，CHCl
3)；
1H NMR(400MHz，CDCl
3)：δ8.27(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，J
1＝6.5Hz，J
2＝3.3Hz，3H)ppm；
13CNMR(100MHz，CDCl
3)：δ157.1，150.8，149.1，139.1，131.0，124.3，110.0，84.9，70.3，52.3，49.1，45.7，33.1，28.3，23.0，19.1，10.6ppm。
Embodiment 13: the preparation of formula A4 compound
13.1 formula G2 compound is synthetic
Formula H compound (1.1g, 8.3mmol) is dissolved in the 40mL anhydrous methylene chloride, under nitrogen protection, drips respectively 1，2-ethandiol (1.0mL, 17.8mmol) and BF in reaction solution
3Et
2O (0.5mL, 3.9mmol).After dripping end, be placed under room temperature and react, the TLC following response.After reaction finishes, add saturated sodium bicarbonate aqueous solution cancellation reaction.Dichloromethane extraction, organic phase are used respectively saturated common salt water washing, anhydrous sodium sulfate drying again.Filtering siccative, filtrate decompression steam and desolventize, and residuum obtains 690mg pale yellow oily liquid body formula G2 compound through rapid column chromatography, and productive rate is 47%.
1H NMR(400MHz，CDCl
3)：δ4.93(t，J＝4.6Hz，1H)，4.53(dd，J
1＝5.5Hz，J
2＝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)。
13.2 formula F2 compound is synthetic
Operation gets 600mg formula F2 compound, productive rate 54.5% with embodiment 12.3.
1H NMR(400MHz，CDCl
3)：δ4.91(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)。
13.3 formula E2 compound is synthetic
Operation gets 379mg formula E2 compound, productive rate 72.5% with embodiment 12.4.
1H NMR(400MHz，CDCl
3)：δ5.29(s，1H)，4.75(dd，J
1＝3.4Hz，J
2＝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)。
13.4 formula C2 compound is synthetic
Operation gets 404mg formula C2 compound, yield 70.4% with embodiment 12.6.[α]
D 23 44.6(c 0.763，CH
2Cl
2)；
1H NMR(400MHz，CDCl
3)：δ8.37(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]
+calcd for C
16H
21ClN
4O
4：368.1251；found：368.1248。
13.5 formula A4 compound is synthetic
Operation obtains 315mg formula A4 compound, yield 78.0% with embodiment 12.7.[α]
D 23 76.5(c 0.005，CHCl
3)；
1H NMR(400MHz，CDCl
3)：δ8.27(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，J
1＝6.5Hz，J
2＝3.3Hz，3H)ppm；
13C NMR(100MHz，CDCl
3)：δ157.1，150.8，149.1，139.1，131.0，124.3，110.0，84.9，70.3，52.3，49.1，45.7，33.1，28.3，23.0，19.1，10.6ppm。
Embodiment 14: the insecticidal activity of the compounds of this invention to the aphis craccivora kind
The compound that embodiment 1-2 and embodiment 4-13 are prepared carries out the insecticidal activity test.Wherein, 4 pairs of indoor aphis craccivoras of the compound A-13 that the compd A 4 that embodiment 1 and embodiment 13 prepare and embodiment 1, embodiment 5 and embodiment 6 prepare (Aphis craccivora Koch) population biological activity determination report (table 3) demonstration, the insecticidal activity of the isomer formula A4 compound of the enantiomer A34 that obtains prepared according to the methods of the invention and single configuration is fabulous.
Table 3 pair aphis craccivora active testing result contrast
| Compound | LC50(mg/L) | 95% fiducial 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: contain the preparation of the insecticides of the compounds of this invention
(a) oily suspension
Prepare in proportion following component: any compound in 25% (weight percent, lower same) formula A3 compound, formula A4 compound or enantiomer A34; 5% polyoxyethylene sorbitol six oleic acid esters; 70% senior aliphatics hydrocarbon ils.Each component is ground in the sand mill together, until solid particulate is down to approximately below 5 microns.The thickness suspension of gained can directly use, but also can use after emulsification in water.
(b) aqeous suspension
Prepare in proportion following component: any compound in 25% formula A3 compound, formula A4 compound or enantiomer A34; 3% hydration attapulgite (hydrate attapulgit); 10% calcium lignin sulphonate; 0.5% SODIUM PHOSPHATE, MONOBASIC; 61.5% water.Each component is ground in ball mill together, until solid particulate is down to approximately below 10 microns.This aqeous suspension can directly use.
(c) bait formulation
Prepare in proportion following component: any compound in 0.1-10% formula A3 compound, formula A4 compound or enantiomer A34; 80% whole meal flour; The 19.9-10% molasses.These components are mixed fully, form on demand the bait shape.The edible bait can be distributed to the place that sanitary insect pest infects, and for example household or industrial site, regional such as kitchen, hospital or shop or open air, to come pest control by oral absorption.
All quote in this application as a reference at all documents that the present invention mentions, just as each piece document is quoted separately as a reference.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims limited range equally.
Claims (14)
1. the optical isomer of piperazine worm pyridine, is characterized in that, described isomer is (11S, 14R) piperazine worm pyridine shown in (11R, 14S) piperazine worm pyridine shown in formula A3 and/or formula A4:
The pyridine of (11R, 14S) piperazine worm pyridine (11S, 14R) piperazine worm.
2. agricultural composition, it comprises:
(A) acceptable salt or their combination on the Pesticide Science of the optical isomer described in the claim 1 of 0.001-99.99 % by weight, described optical isomer; And
(B) acceptable carrier and/or vehicle on Pesticide Science.
3. the purposes of agricultural composition as claimed in claim 2, is characterized in that, is used for killing or preventing the insect of Agricultural pests, sanitary insect pest and harm animal health; Or with acting on the insecticides of killing or prevent Agricultural pests, sanitary insect pest and harm animal health.
4. the purposes of acceptable salt or its combination on optical isomer, described optical isomer Pesticide Science as claimed in claim 1, is characterized in that, for the preparation of insecticides.
5. preparation method of optical isomer as claimed in claim 1, it is characterized in that, comprise step: the piperazine worm pyridine raw material that contains optical isomer shown in formula A3 and/or formula A4 is split, thereby obtain (the 11R shown in formula A3,14S) (11S, 14R) piperazine worm pyridine shown in the pyridine of piperazine worm and/or formula A4.
6. preparation method as claimed in claim 5, is characterized in that, described method is chirality HPLC Split Method.
7. the preparation method of (11S, 14R) piperazine worm pyridine shown in (11R, 14S) piperazine worm pyridine shown in formula A3 and formula A4 as claimed in claim 1, is characterized in that, described method comprises step:
(a) to containing the piperazine worm pyridine raw material of optical isomer shown in formula A3 and formula A4, in mixed solvent, randomly under protonic acid or lewis acid catalyst exist, after carrying out recrystallization, thereby form the crystallization of the enantiomer A34 that formula A3 compound and formula A4 compound form;
(b) isolate the crystallization of enantiomer A34, and collect mother liquor;
(c) randomly, the mother liquor of collecting is carried out recrystallization under protonic acid or lewis acid catalyst existence, thereby form the crystallization of enantiomer A34.
8. preparation method as claimed in claim 7, is characterized in that, described method also comprises the preparation process of described piperazine worm pyridine raw material before in step (a):
In inert solvent, under protonic acid or lewis acid catalyst existence, with formula B compound and n-propyl alcohol reaction, thereby form formula A compound, the i.e. pyridine of piperazine worm.
9. as preparation method as described in claim 7 or 8, it is characterized in that, described method comprises step:
(I) in inert solvent, under protonic acid or lewis acid catalyst existence, with formula B compound and n-propyl alcohol reaction, thereby form formula A compound, the i.e. pyridine of piperazine worm;
(IIa) in mixed solvent, after recrystallization is carried out in the pyridine of piperazine worm, thereby form the crystallization of the enantiomer A34 that formula A3 compound and formula A4 compound form;
(IIb) isolate the crystallization of enantiomer A34, and collect mother liquor;
(IIc) randomly, the mother liquor of collecting is carried out recrystallization under protonic acid or lewis acid catalyst existence, thereby form the crystallization of enantiomer A34.
10. as preparation method as described in claim 7-9 any one, it is characterized in that, described protonic acid or Lewis acid comprise: hydrochloric acid, sulfuric acid, nitric acid, formic acid, acetic acid, trifluoroacetic acid, aluminum chloride, iron(ic) chloride, tin chloride, boron trifluoride, boron trifluoride diethyl etherate, oxalyl chloride, Methanesulfonyl chloride, sulfur oxychloride, Tosyl chloride, methacrylic chloride or its combination.
11. as preparation method as described in claim 7-9 any one, it is characterized in that, described mixed solvent is the arbitrary combination of A and two groups of solvents of B:
A group solvent comprises: methyl alcohol, ethanol, n-propyl alcohol, Virahol, ethylene glycol, glycerol or its combination;
B group solvent comprises: acetonitrile, tetrahydrofuran (THF), dioxane, water, dimethyl formamide (DMF), dimethyl sulfoxide (DMSO) (DMSO) or its combination;
The volume ratio of A and two groups of solvents of B is 20: 1～1: 20.
12. the preparation method of the worm of (11S, 14R) piperazine shown in formula A4 pyridine as claimed in claim 1 is characterized in that, described method comprises step:
(1) in inert solvent, with formula C compound and acid catalyst reaction, thereby form formula B4 compound;
Wherein,
R
1Or R
2Be C independently of one another
1-4Alkyl; Perhaps, R
1And R
2Common formation-(CH
2)
n-, wherein, n is the integer of 2-4;
Described acid catalyst comprises: hydrochloric acid, acetic acid, trifluoroacetic acid, Fe (OTs)
36H
2O, camphorsulfonic acid (CSA), para-methylbenzenepyridinsulfonate sulfonate (PPTS), TsOH or its combination;
(2) in inert solvent, under protonic acid or Lewis acid existence, with formula B4 compound and n-propyl alcohol reaction, thereby form formula A4 compound;
Wherein, described protonic acid or Lewis acid comprise: hydrochloric acid, sulfuric acid, nitric acid, formic acid, acetic acid, trifluoroacetic acid, aluminum chloride, iron(ic) chloride, tin chloride, boron trifluoride, boron trifluoride diethyl etherate, sulfur oxychloride, Tosyl chloride, Methanesulfonyl chloride, oxalyl chloride, methacrylic chloride or its combination.
13. the preparation method, is characterized in that as claimed in claim 12, described step (1) also comprises step before:
(1a) in inert solvent, under alkaline condition, with formula G compound and dithiocarbonic anhydride and R
3I reacts jointly, thereby forms formula F compound;
Wherein, R
1, R
2And R
3Be C independently of one another
1-4Alkyl; Perhaps, R
1And R
2Common formation-(CH
2)
n-, wherein, n is the integer of 2-4;
Described alkali comprises: NaH, sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood or its combination;
(1b) in inert solvent, after formula F compound and reacting ethylenediamine, thereby form formula E compound;
Wherein, R
1, R
2And R
3Described as defined above;
(1c) under alkaline condition, with formula E compound and the reaction of formula D compound, thereby form formula C compound;
Wherein, R
1, R
2Described as defined above;
Described alkali comprises: NaH, sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood or its combination.
14. the preparation method, is characterized in that as claimed in claim 13, described step (1a) also comprises step before:
(1a-1) in inert solvent, under catalyzer exists, with Nitromethane 99Min. and crotonic aldehyde reaction, thereby form formula H compound;
Wherein, described catalyzer comprises: the silicon ether derivant of the Prolinol that diaryl replaces, L-PROLINE, (+)-tartrate, (+)-camphor-10-sulfonic acid, the chirality dipeptides that contains glycine or its combination;
(1a-2) in inert solvent, with formula H compound and aldehyde radical protecting group reagent react, thereby form formula G compound;
Wherein, described aldehyde radical protecting group reagent is HO-(CH
2)
n-OH or HO-C (OR
1) (OR
2) (OR
4),
Described R
1, R
2And R
4Be C independently of one another
1-4Alkyl; Perhaps, R
1And R
2Common formation-(CH
2)
n-, wherein, n is the integer of 2-4.
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| CN103503907A (en) * | 2013-10-24 | 2014-01-15 | 江苏龙灯化学有限公司 | Insecticidal composition containing 1-((6-chloropyridine-3-yl) methyl)-5-propoxy-7-methyl-8-nitryl-1,2,3,5,6,7-hexahydroimidazo[1,2-alpha] pyridine) and deltamethrin |
| CN103503907B (en) * | 2013-10-24 | 2015-04-22 | 江苏龙灯化学有限公司 | Insecticidal composition containing 1-((6-chloropyridine-3-yl) methyl)-5-propoxy-7-methyl-8-nitryl-1,2,3,5,6,7-hexahydroimidazo[1,2-alpha] pyridine) and deltamethrin |
| CN109311833A (en) * | 2016-06-16 | 2019-02-05 | 广东东阳光药业有限公司 | Diaryl sulfide piperazine compounds and its preparation method and application |
| CN109666020A (en) * | 2018-12-20 | 2019-04-23 | 苏州麦迪耐斯医药科技有限公司 | A kind of new compound and its preparation method and application |
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