CN111909081A - Method for purifying pyriproxyfen technical, product obtained by method and application of pyriproxyfen technical - Google Patents
Method for purifying pyriproxyfen technical, product obtained by method and application of pyriproxyfen technical Download PDFInfo
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- CN111909081A CN111909081A CN201910375684.6A CN201910375684A CN111909081A CN 111909081 A CN111909081 A CN 111909081A CN 201910375684 A CN201910375684 A CN 201910375684A CN 111909081 A CN111909081 A CN 111909081A
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- NHDHVHZZCFYRSB-UHFFFAOYSA-N pyriproxyfen Chemical compound C=1C=CC=NC=1OC(C)COC(C=C1)=CC=C1OC1=CC=CC=C1 NHDHVHZZCFYRSB-UHFFFAOYSA-N 0.000 title claims abstract description 96
- 239000005927 Pyriproxyfen Substances 0.000 title claims abstract description 94
- 238000000034 method Methods 0.000 title claims abstract description 51
- 238000000746 purification Methods 0.000 claims abstract description 36
- 229940079593 drug Drugs 0.000 claims abstract description 32
- 239000003814 drug Substances 0.000 claims abstract description 32
- 239000000203 mixture Substances 0.000 claims description 48
- 238000001816 cooling Methods 0.000 claims description 31
- 239000013078 crystal Substances 0.000 claims description 31
- 239000012535 impurity Substances 0.000 claims description 21
- 238000010438 heat treatment Methods 0.000 claims description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- 238000002425 crystallisation Methods 0.000 claims description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 9
- 230000008025 crystallization Effects 0.000 claims description 9
- 239000005457 ice water Substances 0.000 claims description 9
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 8
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 claims description 8
- -1 alicyclic hydrocarbons Chemical class 0.000 claims description 8
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 8
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims description 8
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 7
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 7
- 150000002148 esters Chemical class 0.000 claims description 7
- 150000002170 ethers Chemical class 0.000 claims description 7
- 150000008282 halocarbons Chemical class 0.000 claims description 7
- 229930195733 hydrocarbon Natural products 0.000 claims description 7
- 150000002825 nitriles Chemical class 0.000 claims description 7
- 238000000926 separation method Methods 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- 150000001298 alcohols Chemical class 0.000 claims description 5
- 150000002576 ketones Chemical class 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 claims description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 4
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 4
- 238000009835 boiling Methods 0.000 claims description 4
- 229940117389 dichlorobenzene Drugs 0.000 claims description 4
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 4
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 4
- 229940090181 propyl acetate Drugs 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000008096 xylene Substances 0.000 claims description 4
- 239000004215 Carbon black (E152) Substances 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims description 2
- 239000002917 insecticide Substances 0.000 claims 1
- 239000002198 insoluble material Substances 0.000 claims 1
- 239000000575 pesticide Substances 0.000 abstract description 5
- 239000000047 product Substances 0.000 description 23
- 239000000243 solution Substances 0.000 description 21
- POAOYUHQDCAZBD-UHFFFAOYSA-N 2-butoxyethanol Chemical compound CCCCOCCO POAOYUHQDCAZBD-UHFFFAOYSA-N 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- ZSBDGXGICLIJGD-UHFFFAOYSA-N 4-phenoxyphenol Chemical compound C1=CC(O)=CC=C1OC1=CC=CC=C1 ZSBDGXGICLIJGD-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000012264 purified product Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- WZWSOGGTVQXXSN-UHFFFAOYSA-N cyclohexanone;toluene Chemical compound CC1=CC=CC=C1.O=C1CCCCC1 WZWSOGGTVQXXSN-UHFFFAOYSA-N 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 238000004445 quantitative analysis Methods 0.000 description 3
- 241000607479 Yersinia pestis Species 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000004557 technical material Substances 0.000 description 2
- RVAHBQKJLFMRFE-UHFFFAOYSA-N 1-(4-phenoxyphenoxy)propan-2-ol Chemical compound C1=CC(OCC(O)C)=CC=C1OC1=CC=CC=C1 RVAHBQKJLFMRFE-UHFFFAOYSA-N 0.000 description 1
- KDTZBYPBMTXCSO-UHFFFAOYSA-N 2-phenoxyphenol Chemical compound OC1=CC=CC=C1OC1=CC=CC=C1 KDTZBYPBMTXCSO-UHFFFAOYSA-N 0.000 description 1
- 229920002101 Chitin Polymers 0.000 description 1
- 241000255925 Diptera Species 0.000 description 1
- 241000258937 Hemiptera Species 0.000 description 1
- 241000256602 Isoptera Species 0.000 description 1
- 241000255777 Lepidoptera Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000257226 Muscidae Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 241001414989 Thysanoptera Species 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 150000001875 compounds Chemical group 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229930014550 juvenile hormone Natural products 0.000 description 1
- 239000002949 juvenile hormone Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a method for purifying pyriproxyfen raw drug, a product obtained by the method and application of the pyriproxyfen raw drug. The purity of the purified pyriproxyfen raw pesticide obtained by the purification method is more than or equal to 98 percent, and the yield of the purification process is more than or equal to 96 percent.
Description
Technical Field
The invention relates to the technical field of fine chemical engineering, in particular to a method for purifying pyriproxyfen technical, a product obtained by the method and application of the product.
Background
Pyriproxyfen, also known as pyriproxyfen, is a class of alkyl pyridine juvenile hormone chitin synthesis inhibitor developed by Sumitomo Chemical company in 1983, can be used for controlling sanitary pests such as houseflies, mosquitoes, termites and the like, can also be used for controlling agricultural pests such as homoptera, thysanoptera, lepidoptera and the like, and is a class of efficient, environment-friendly and low-toxicity pesticide. Pyriproxyfen has systemic transfer activity and can affect larvae hidden on the back of leaves.
The molecular formula of pyriproxyfen is as follows:
US4751225 protects pyriproxyfen and its synthesis process, which uses p-phenoxy phenol to react with propylene oxide under alkaline condition to obtain 1- (4-phenoxy) -2-propanol, and also discloses a method of silica gel column chromatographic separation to obtain light yellow liquid pyriproxyfen. CN108276255A discloses a method for preparing pyriproxyfen intermediate ether alcohol, which is characterized in that p-phenoxy phenol and propylene oxide are heated and reacted under the catalysis of magnesium oxide to synthesize the product ether alcohol, so that the content of isomer impurities in the pyriproxyfen key intermediate ether alcohol can be obviously reduced.
In the above-mentioned prior art relating to the synthesis of pyriproxyfen, all relate to pyriproxyfen key intermediate ether alcohol [ chemical name: 1- (4-phenoxyphenoxy) -2-propanol ], and the pyriproxyfen is synthesized by taking the same as a raw material. The intermediate is generally prepared by reacting a phenoxy phenol with propylene oxide under basic conditions. Because the epoxypropane has a plurality of reaction sites, the reaction selectivity is difficult to control, and the content of ether alcohol isomers reaches 10-20%. The specific reaction formula is as follows:
the ether alcohol isomer can generate a pyriproxyfen isomer along with the synthesis of the next step, and the specific isomer impurity structural formula is as follows:
from the perspective of similarity of compound structures, the physical properties of the two are very similar, and the separation of original drugs and impurities is difficult through a conventional chemical purification method. Even if the purity of the original drug can be increased to 98% or more by repeating the purification, or a pure product can be obtained by column chromatography, it is not economical from the viewpoint of yield and cost. Moreover, the application of a formulation product with such a high content of impurities to the environment, especially in hygienic applications, poses risks to humans, animals and the environment.
CN1651414A discloses a separation and purification method of pyriproxyfen, which comprises dissolving the crude pyriproxyfen with a certain amount of ethyl acetate or toluene, adding alcohol to make pyriproxyfen and impurities form a partially miscible system in a mixed solvent, separating to remove impurities, and cooling and crystallizing the clear liquid to obtain pyriproxyfen. The method of the scheme is difficult to separate isomer impurities from pyriproxyfen well, and the product obtained by purifying the isomer has high pyriproxyfen isomer content and low overall yield.
Although the above documents disclose some methods for separating and purifying pyriproxyfen crude drug, there still exist the problems of high separation cost, high content of isomer impurities in the separated product and insufficient product purity, so it is still of great significance to develop a method for purifying pyriproxyfen crude drug with simple operation.
Disclosure of Invention
The invention aims to provide a method for purifying pyriproxyfen raw pesticide, a product obtained by the method and application of the pyriproxyfen raw pesticide. The purity of the pyriproxyfen obtained by the purification method of the invention after purification is more than or equal to 98%, such as 98.2%, 98.5%, 98.8%, 99.2%, 99.5% or 99.7%, etc., and the yield of the purification process is more than or equal to 96%, such as 96%, 97% or 99%, etc.
In order to achieve the purpose, the invention adopts the following technical scheme:
in a first aspect, the invention provides a method for purifying pyriproxyfen technical, which comprises the following steps:
(1) dissolving a pyriproxyfen crude drug in a solvent to obtain a solution A;
(2) and (2) carrying out fractional cooling crystallization on the solution A obtained in the step (1) to obtain a purified pyriproxyfen technical product.
According to the method for purifying the pyriproxyfen crude drug, the pyriproxyfen crude drug is dissolved to obtain a solution in which pyriproxyfen is dissolved, and then the purity of the purified pyriproxyfen crude drug obtained through purification is obviously improved through fractional cooling. The purity of the pyriproxyfen obtained by the purification method is more than or equal to 98 percent, and the yield of the purification process is more than or equal to 96 percent.
According to the method, the characteristics of low melting point and high similarity between isomer impurities and a raw material structure of the pyriproxyfen are considered, and the isomer impurities are wrapped in particles by grading and cooling, so that the rapid precipitation of a large amount of main components during rapid cooling is avoided, the content of the isomer impurities in the purified pyriproxyfen raw material is reduced to be below 0.5%, such as 0.1%, 0.2%, 0.3% or 0.4%, and the like, and the purity of the purified pyriproxyfen raw material is guaranteed; meanwhile, the yield of the purification process is further improved.
Preferably, the purity of the crude pyriproxyfen in step (1) is 85-97%, for example, 85%, 88%, 90%, 92%, 95%, or 97%.
Preferably, the ratio of the mass of the crude pyriproxyfen technical product in the step (1) to the volume of the solvent is 0.2-0.8g/mL, such as 0.2g/mL, 0.3g/mL, 0.4g/mL, 0.5g/mL, 0.6g/mL, 0.7g/mL or 0.8g/mL, etc., preferably 0.3-0.6 g/mL.
The method controls the volume ratio of the mass of the crude pyriproxyfen technical product to the solvent to be 0.2-0.8g/mL, thereby being beneficial to the precipitation of pyriproxyfen in the process of fractional cooling and further improving the yield of the purification process.
Preferably, the solvent in step (1) includes any one or a mixture of at least two of aromatic hydrocarbons, aliphatic hydrocarbons, alicyclic hydrocarbons, halogenated hydrocarbons, alcohols, ethers, esters, ketones, or nitriles, and the mixture exemplarily includes a mixture of aromatic hydrocarbons and aliphatic hydrocarbons, a mixture of alicyclic hydrocarbons and halogenated hydrocarbons, a mixture of alcohols and ethers, or a mixture of esters, ketones and nitriles, and the like.
Preferably, the aromatic hydrocarbon includes any one of benzene, toluene, or xylene or a mixture of at least two thereof, which illustratively includes a mixture of benzene and toluene, a mixture of benzene and xylene, or a mixture of toluene and xylene, and the like.
Preferably, the aliphatic hydrocarbon includes any one of pentane, hexane, or octane or a mixture of at least two thereof, which illustratively includes a mixture of pentane and hexane, a mixture of hexane and octane, or a mixture of pentane and octane, and the like.
Preferably, the alicyclic hydrocarbon includes any one of cyclohexane, cyclohexanone or toluene cyclohexanone, or a mixture of at least two thereof, which illustratively includes a mixture of cyclohexane and cyclohexanone, a mixture of cyclohexane and toluene cyclohexanone, or a mixture of cyclohexanone and toluene cyclohexanone, and the like.
Preferably, the halogenated hydrocarbon includes any one or a mixture of at least two of chlorobenzene, dichlorobenzene or dichloromethane, and the mixture exemplarily includes a mixture of chlorobenzene and dichlorobenzene, a mixture of chlorobenzene and dichloromethane, or a mixture of dichlorobenzene and dichloromethane, and the like.
Preferably, the alcohol includes any one of methanol, ethanol, or isopropanol, or a mixture of at least two thereof, which illustratively includes a mixture of methanol and ethanol, a mixture of methanol and isopropanol, or a mixture of ethanol and isopropanol, and the like.
Preferably, the ethers include any one of diethyl ether, propylene oxide or tetrahydrofuran or a mixture of at least two thereof, and the mixture exemplarily includes a mixture of diethyl ether and propylene oxide, a mixture of diethyl ether and tetrahydrofuran or a mixture of propylene oxide and tetrahydrofuran, etc.
Preferably, the ester includes any one of methyl acetate, ethyl acetate or propyl acetate or a mixture of at least two of them, and the mixture exemplarily includes a mixture of methyl acetate and ethyl acetate, a mixture of methyl acetate and propyl acetate or a mixture of ethyl acetate and propyl acetate, etc.
Preferably, the nitrile comprises acetonitrile.
Preferably, the dissolving method of step (1) comprises heating for dissolving.
Preferably, the temperature for heating and dissolving is 35 ℃ to the boiling temperature of the solvent, such as 35 ℃, 40 ℃, 45 ℃, 50 ℃, 55 ℃ or 70 ℃ and the like.
Preferably, the method of heating for dissolution comprises heating for reflux.
Preferably, the heating for dissolving further comprises filtering to remove insoluble substances.
Preferably, the fractional temperature-reduction crystallization method comprises the following steps:
(a) cooling the solution A to 20-30 deg.C, such as 20, 25 or 30 deg.C;
(b) and (b) continuously cooling and crystallizing the solution obtained in the step (a) in an ice water bath until crystals are completely separated out.
The method adopts a grading cooling mode, firstly, the solution containing the crude pyriproxyfen is cooled to 20-30 ℃, and at the moment, because the solution is slowly cooled and the melting point of pyriproxyfen is low (about 47 ℃), the solution can be maintained in a supersaturated state and crystals can not be separated out. If the temperature is not controlled to be rapidly reduced, the local temperature of a solution system is low, so that crystallization is performed in advance, and further, a large amount of solid is precipitated in a short time to wrap impurities in particles. On the contrary, the saturated solution obtained by fractional cooling is continuously cooled and crystallized by using an ice water bath, the pyriproxyfen crystals are slowly separated out along with the reduction of the temperature along with the full stirring, and the isomer impurities are always in an unsaturated state and are not separated out, so that the purity of the pyriproxyfen raw drug obtained by purification and the yield of the purification process are obviously improved.
Preferably, the cooling rate of step (a) is 1-8 deg.C/min, such as 1 deg.C/min, 2 deg.C/min, 3 deg.C/min, 4 deg.C/min, 5 deg.C/min, 6 deg.C/min, 7 deg.C/min, or 8 deg.C/min, etc.
Preferably, before carrying out step (b), seed crystals are added to the product obtained via step (a).
Preferably, the seed crystal comprises a pure product of pyriproxyfen.
Preferably, the purity of the pure product of the pyriproxyfen is more than or equal to 98.0%, such as 98%, 98.5%, 99%, 99.5%, 99.7%, 99.9% and the like.
Preferably, the mass ratio of the addition amount of the seed crystal to the crude pyriproxyfen is 1-10%; for example, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, etc., preferably 3 to 6%. The seed crystal is added in one time or in batches under the condition of uniform stirring, and the time is controlled within 3-15 minutes.
The method provided by the invention is beneficial to improving the efficiency of the crystallization process by adding the seed crystal to perform induced crystallization. Meanwhile, the addition amount of the seed crystal can greatly influence the purity of the purified pyriproxyfen raw drug obtained by purification, the ratio of the addition amount of the seed crystal in the purification process to the mass of the crude pyriproxyfen raw drug in the raw material is controlled to be 1-10%, so that the precipitation of isomer impurities is favorably inhibited, and the purity of the product obtained by purification is improved.
Preferably, the step (2) of fractional cooling crystallization further comprises the steps of performing solid-liquid separation and drying on the product.
Preferably, the method of solid-liquid separation comprises filtration.
Preferably, the drying method comprises reduced pressure drying.
As a preferred technical scheme of the invention, the method comprises the following steps:
(1) heating and dissolving a pyriproxyfen crude drug with the purity of 85-97% in a solvent to obtain a solution A, wherein the heating and dissolving temperature is 35-solvent boiling point temperature; the solvent comprises any one or a mixture of at least two of aromatic hydrocarbons, aliphatic hydrocarbons, alicyclic hydrocarbons, halogenated hydrocarbons, alcohols, ethers, esters, ketones or nitriles;
(2) and (3) cooling the solution A to 20-30 ℃ at the cooling rate of 1-8 ℃/min, adding seed crystals, then placing the solution A in an ice water bath, continuously cooling and crystallizing until crystals are completely separated out, filtering, and drying under reduced pressure to obtain the purified pyriproxyfen original drug.
In a second aspect, the invention provides a pyriproxyfen crude drug purified according to the method of the first aspect, wherein the content of isomer impurities in the pyriproxyfen crude drug purified is less than or equal to 0.5%, for example, 0.1%, 0.2%, 0.3%, 0.4% or 0.5%.
In a third aspect, the invention provides the use of the pyriproxyfen technical material obtained by purification in the second aspect, and the pyriproxyfen technical material obtained by purification is used for preparing pesticides.
Compared with the prior art, the invention has the following beneficial effects:
(1) according to the method for purifying the pyriproxyfen crude drug, the pyriproxyfen crude drug is heated and dissolved to obtain a solution in which pyriproxyfen is dissolved, and then the purity of the purified pyriproxyfen crude drug is obviously improved by grading and cooling. The purity of the pyriproxyfen obtained by the purification method is more than or equal to 98 percent, and the yield of the purification process is more than or equal to 96 percent;
(2) according to the method, the characteristics of low melting point and high similarity between isomer impurities and the original drug structure of the pyriproxyfen are considered, and the isomer impurities are prevented from being separated out through graded cooling, so that the pyriproxyfen original drug is favorably separated out, the content of the isomer impurities in the purified pyriproxyfen original drug is reduced to be below 0.5%, and the purity of the purified pyriproxyfen original drug is guaranteed;
(3) the method of the invention has simple operation and low cost.
Detailed Description
The technical solution of the present invention is further explained by the following embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.
Example 1
The method for purifying the pyriproxyfen crude drug comprises the following steps:
(1) adding 100g of crude pyriproxyfen with the purity of 87.5% into a flask filled with 90mL of dimethylbenzene, adding 100mL of tetrahydrofuran, heating and refluxing at 45 ℃, and filtering to remove insoluble impurities to obtain a solution A;
(2) and (2) cooling the solution A obtained in the step (1) to 25 ℃ at a cooling rate of 2 ℃/min, then placing the solution A in an ice water bath, continuously cooling and crystallizing until crystals are completely separated out, filtering, and drying under reduced pressure to obtain the purified pyriproxyfen original drug.
In this example, 86g of white crystals are obtained by purification, and the purity of the obtained pyriproxyfen after purification is 98.7% and the yield in the purification process is 97% by quantitative analysis of high performance liquid chromatography.
Example 2
The method for purifying the pyriproxyfen crude drug comprises the following steps:
(1) adding 100g of pyriproxyfen crude drug with the purity of 93% into a flask filled with 90mL of n-hexane, adding 100mL of methanol, heating and refluxing at 45 ℃, and filtering to remove insoluble impurities to obtain a solution A;
(2) and (2) cooling the solution A obtained in the step (1) to 25 ℃ at a cooling rate of 3 ℃/min, adding 3g of pyriproxyfen pure product, then placing the solution A in an ice water bath, continuously cooling and crystallizing until crystals are completely separated out, filtering, and drying under reduced pressure to obtain the purified pyriproxyfen original drug.
92.4g of white crystals are obtained by the purification of the embodiment, and the purity of the obtained pyriproxyfen after purification is 99.2% and the yield in the purification process is 98.5% by the quantitative analysis of high performance liquid chromatography.
Example 3
In the present example, the temperature decrease rate in step (2) in example 1 was replaced with 3.5 ℃/min, and the other conditions were completely the same as in example 1.
Example 4
In the present example, the temperature decrease rate in step (2) in example 1 was replaced with 4.5 ℃/min, and the other conditions were completely the same as in example 1.
Example 5
In the present example, the temperature decrease rate in step (2) in example 1 was replaced with 5.5 ℃/min, and the other conditions were completely the same as in example 1.
Example 6
In the present example, the temperature decrease rate in step (2) in example 1 was replaced with 8 ℃/min, and the other conditions were completely the same as in example 1.
Example 7
The difference between this example and example 1 is that in step (2), after the temperature is reduced to 25 ℃, 1g of seed crystal is added, and then the mixture is placed in an ice water bath to continue temperature reduction and crystallization, and other conditions are completely the same as those in example 1.
Example 8
In this example, the amount of the seed crystal added in example 7 was changed to 3g, and the other conditions were completely the same as those in example 7.
Example 9
This example replaces the amount of seed crystal added in example 7 with 6g, and the other conditions were exactly the same as in example 7.
Example 10
In this example, the amount of seed crystal added in example 7 was replaced with 8g, and the other conditions were completely the same as in example 7.
Example 11
In this example, the amount of the seed crystal added in example 7 was replaced with 10g, and the other conditions were completely the same as those in example 7.
Comparative example 1
Compared with the example 1, the comparative example does not carry out fractional temperature reduction, the solution A is directly placed in an ice water bath for temperature reduction and crystallization in the step (2), and other conditions are completely the same as those of the example 1.
The method for analyzing the purity of the purified pyriproxyfen technical products obtained by purification in examples 1 to 11 and comparative example 1 is quantitative analysis by high performance liquid chromatography, and the purity and the purification process yield of the purified pyriproxyfen technical products obtained by testing in examples 1 to 11 and comparative example 1 are shown in table 1:
TABLE 1
As can be seen from the above table, comparing examples 1-2 and examples 3-6, when the cooling rate is controlled at 1-8 ℃, the purity of the purified product is equal to or greater than 98.1%, and with the increase of the cooling rate, the purity of the product is reduced to some extent, and the yield is slightly increased and is equal to or greater than 96.2%; in contrast to comparative example 1, the product obtained by purification and the yield in the purification process were both significantly reduced without carrying out a step-wise temperature reduction.
Comparing example 1 with examples 7-11, it can be seen that the addition amount of the seed crystal has an influence on the purity of the purified product and the yield of the purification process, and the optimal ratio of the addition amount of the seed crystal to the mass of the crude pyriproxyfen is 3-6%, within the above addition amount range, the purity and the purification yield of the purified product are both obviously improved compared with the purification process without the seed crystal. When the addition amount of the seed crystal is more than 6 percent of the quality of the crude pyriproxyfen, the purity of the purified product is reduced, but the yield is increased.
The applicant declares that the above description is only a specific embodiment of the present invention, but the scope of the present invention is not limited thereto, and it should be understood by those skilled in the art that any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope of the present invention are within the scope and disclosure of the present invention.
Claims (10)
1. A method for purifying pyriproxyfen technical is characterized by comprising the following steps:
(1) dissolving a pyriproxyfen crude drug in a solvent to obtain a solution A;
(2) and (2) carrying out fractional cooling crystallization on the solution A obtained in the step (1) to obtain a purified pyriproxyfen technical product.
2. The method of claim 1, wherein the crude pyriproxyfen in step (1) has a purity of 85-97%;
preferably, the ratio of the mass of the crude pyriproxyfen in the step (1) to the volume of the solvent is 0.2-0.8g/mL, preferably 0.3-0.6 g/mL.
3. The method according to claim 1 or 2, wherein the solvent in step (1) comprises any one or a mixture of at least two of aromatic hydrocarbons, aliphatic hydrocarbons, alicyclic hydrocarbons, halogenated hydrocarbons, alcohols, ethers, esters, ketones or nitriles;
preferably, the aromatic hydrocarbon comprises any one of benzene, toluene or xylene or a combination of at least two of the same;
preferably, the aliphatic hydrocarbon comprises any one or a mixture of at least two of pentane, hexane or octane;
preferably, the alicyclic hydrocarbon comprises any one or a mixture of at least two of cyclohexane, cyclohexanone or tolucyclohexanone;
preferably, the halogenated hydrocarbon comprises any one or a mixture of at least two of chlorobenzene, dichlorobenzene or dichloromethane;
preferably, the alcohol comprises any one of methanol, ethanol or isopropanol or a mixture of at least two thereof;
preferably, the ethers include any one or a mixture of at least two of diethyl ether, propylene oxide or tetrahydrofuran;
preferably, the esters include any one or a mixture of at least two of methyl acetate, ethyl acetate or propyl acetate;
preferably, the nitrile comprises acetonitrile.
4. The method of any one of claims 1-3, wherein the dissolving of step (1) comprises dissolving by heating;
preferably, the temperature for heating and dissolving is 35 ℃ to the boiling temperature of the solvent;
preferably, the method of heating for dissolution comprises heating for reflux.
5. The method of claim 4, wherein said heating to dissolve further comprises filtering to remove insoluble material.
6. The method according to any one of claims 1 to 5, wherein the fractional temperature-reduction crystallization method comprises the steps of:
(a) cooling the solution A to 20-30 ℃;
(b) continuously cooling and crystallizing the solution obtained in the step (a) in an ice water bath until crystals are completely separated out;
preferably, the rate of said temperature reduction of step (a) is 1-8 ℃/min;
preferably, before carrying out step (b), seed crystals are added to the product obtained via step (a);
preferably, the seed crystal comprises a pure product of pyriproxyfen;
preferably, the mass ratio of the addition amount of the seed crystal to the crude pyriproxyfen is 1-10%; preferably 3 to 6%.
7. The method according to any one of claims 1 to 6, wherein the step (2) of fractional temperature reduction crystallization further comprises the steps of solid-liquid separation and drying of the product;
preferably, the method of solid-liquid separation comprises filtration;
preferably, the drying method comprises reduced pressure drying.
8. The method according to any one of claims 1 to 7, characterized in that it comprises the steps of:
(1) heating and dissolving a pyriproxyfen crude drug with the purity of 85-97% in a solvent to obtain a solution A, wherein the heating and dissolving temperature is 35-solvent boiling point temperature; the solvent comprises any one or a mixture of at least two of aromatic hydrocarbons, aliphatic hydrocarbons, alicyclic hydrocarbons, halogenated hydrocarbons, alcohols, ethers, esters, ketones or nitriles;
(2) and (3) cooling the solution A to 20-30 ℃ at the cooling rate of 1-8 ℃/min, adding seed crystals, then placing the solution A in an ice water bath, continuously cooling and crystallizing until crystals are completely separated out, filtering, and drying under reduced pressure to obtain the purified pyriproxyfen original drug.
9. A pyriproxyfen technical product purified according to any one of claims 1 to 8, characterized in that the content of isomer impurities in the pyriproxyfen technical product obtained by purification is less than or equal to 0.5%.
10. The use of a technical purified pyriproxyfen according to claim 9, characterized in that the technical purified pyriproxyfen is used in insecticides.
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| CN1286814C (en) * | 2005-01-18 | 2006-11-29 | 上海应用技术学院 | Separation and purification method of pyriproxyfen |
| CN107474012A (en) * | 2017-09-05 | 2017-12-15 | 南通派斯第农药化工股份有限公司 | A kind of preparation method of Nylar |
| CN109503471A (en) * | 2018-11-23 | 2019-03-22 | 江苏龙灯化学有限公司 | A kind of crystal form of Nylar and its preparation method and application |
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| CN1286814C (en) * | 2005-01-18 | 2006-11-29 | 上海应用技术学院 | Separation and purification method of pyriproxyfen |
| CN107474012A (en) * | 2017-09-05 | 2017-12-15 | 南通派斯第农药化工股份有限公司 | A kind of preparation method of Nylar |
| CN109503471A (en) * | 2018-11-23 | 2019-03-22 | 江苏龙灯化学有限公司 | A kind of crystal form of Nylar and its preparation method and application |
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