CN111689919A - Synthetic method of isoxazoline anthelmintic - Google Patents

Synthetic method of isoxazoline anthelmintic Download PDF

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CN111689919A
CN111689919A CN202010709950.7A CN202010709950A CN111689919A CN 111689919 A CN111689919 A CN 111689919A CN 202010709950 A CN202010709950 A CN 202010709950A CN 111689919 A CN111689919 A CN 111689919A
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reaction
mixture
tlc
solvent
organic base
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崔志刚
张永赞
程雪娇
余贵菊
姜淋洁
韩怡
杨雪
王猛
甄盼盼
罗潇
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Tianjin Zhongsheng Challenge Biotechnology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/80—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,2

Abstract

The invention belongs to the technical field of chemical drug synthesis, and particularly relates to a synthesis method of an isoxazoline anthelmintic, which is characterized in that the isoxazoline anthelmintic is fraxidin, and an intermediate I is subjected to substitution reaction, addition cyclization reaction and amidation condensation reaction in sequence in the same reaction vessel; and after the reaction is finished, adding water for filtration, and sequentially recrystallizing, filtering and airing the obtained solid to obtain a product. The invention has the beneficial effects that: the method uses a solvent one-pot method to synthesize the fraxidin, reduces the technological operation of the synthesis process, shortens the treatment time and the reaction time, improves the product yield, and is suitable for large-scale production.

Description

Synthetic method of isoxazoline anthelmintic
Technical Field
The invention belongs to the technical field of chemical drug synthesis, and particularly relates to a synthesis method of an isoxazoline anthelmintic.
Background
The fraxidin is an isoxazoline organic compound, can be used as a broad-spectrum pesticide, has good insecticidal activity on pests such as tick, flea, phthiraptera, hemiptera and diptera, and has higher toxicity than or equal to that of the common pesticides. The fraxidin has no obvious cross resistance with the existing pesticide, and even has better insecticidal activity to partially resistant pests. The loratadine serving as a raw material medicine has large demand in the market, but the loratadine is relatively expensive, and the process is to be simplified.
The prior art provides a synthesis process of flurirana (university of industry in north of Hu, Huangdao, research on synthesis process of novel veterinary drug Fluralaner, 2017), which is performed in two steps, namely: adding potassium iodide and potassium hydrogen persulfate composite salt into a flask, adding water to dissolve, adding an intermediate III and an intermediate II, stirring at room temperature to react for 4 hours, extracting by ethyl acetate after TLC detection reaction is finished, washing an organic phase by a saturated sodium chloride solution, drying, spin-drying, and finally performing column chromatography separation to obtain a product 1, wherein the yield is 65.0%, and the purity is 95.6%; the second step is that: adding the intermediate I and sodium hydroxide into a flask, adding water, stirring, reacting at 50 ℃ for 10 minutes, placing the product of the first step and toluene in a constant-pressure titration funnel, dropwise adding the mixture into the solution, keeping the temperature at 50 ℃ for reacting for 2 hours after dropwise adding, extracting the reaction solution with ethyl acetate, washing an organic phase with a saturated sodium chloride solution, drying, evaporating by using a rotary evaporator, and finally performing column chromatography separation to obtain a product 2, wherein the yield is 77.8% and the purity is 98.9%. The technical scheme has more operations, the overall yield is only 50%, and the column chromatography is not suitable for large-scale production. The specific synthetic route is as follows:
Figure BDA0002596167390000011
the synthesis method of the flurarana disclosed in the Chinese patent CN 110028462A is carried out in three steps, wherein the first step is as follows: DMF, intermediate I and NCS were added to the flask, stirred and reacted at 40 ℃ for 2 hours. Cooling to room temperature, adding water to separate out solid, continuously cooling to 5 ℃, filtering and drying to obtain the product 1 with the yield of 92.0%. The second step is that: adding DMF, product 1 and intermediate II into a flask, stirring and dissolving, and adding Et3N was reacted at room temperature for 10 hours. Adding water into the reaction solution, extracting the system for three times by using ethyl acetate, combining organic phases, drying by using anhydrous sodium sulfate, evaporating by using a rotary evaporator to obtain a crude product, and recrystallizing the crude product by using ethyl acetate and petroleum ether to obtain a product 2 with the purity of 99.5 percent and the yield of 85.4 percent. The third step: and carrying out amidation reaction on the product 2 and the intermediate III to obtain a product 3, namely the fraserpine. The specific synthetic route is as follows:
Figure BDA0002596167390000021
according to the technical scheme, the synthesis route has more steps and is complex to operate, some intermediates can be subjected to the next step without separation, and the cost is increased when the production is enlarged.
Therefore, a synthetic route of the flurarana process, which is simple to operate and suitable for mass production, needs to be researched to meet the market demand.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides a method for synthesizing isoxazoline anthelmintics, which uses a solvent one-pot method to synthesize the loratadine, reduces the process operation of the synthesis process, shortens the processing time and the reaction time, improves the product yield, and is suitable for large-scale production.
In order to achieve the purpose, the invention adopts the following technical scheme:
a synthetic method of an isoxazoline anthelmintic is characterized in that the isoxazoline anthelmintic is fraxidin, the structural formula of which is shown as a compound 1, and the method comprises the following operation steps:
Figure BDA0002596167390000031
carrying out substitution reaction, addition cyclization reaction and amidation condensation reaction on the intermediate I in the same reaction vessel in sequence; after the reaction is finished, adding the mixture into water, stirring and filtering the mixture, and sequentially recrystallizing, filtering and airing the obtained solid to obtain a compound 1, wherein the synthetic route is as follows:
Figure BDA0002596167390000032
and (3) substitution reaction: the intermediate I and NCS are reacted in a solvent, and the TLC is used for detecting the reaction progress degree in the reaction process;
addition and cyclization reaction: after the intermediate I completely reacts, adding the intermediate II and organic base into the mixture for reaction, and detecting the degree of reaction progress by TLC in the reaction process;
amidation condensation reaction: and adding the intermediate III and the condensing agent into the obtained mixture after the product 1 completely reacts, reacting under the organic base condition, and detecting the degree of reaction progress by TLC in the reaction process.
The reaction molar ratio of each reactant is as follows: 1.0 equivalent of the intermediate I, 1.1-1.5 mol ratio of each reactant, 1.1-1.5 mol ratio of the intermediate II, 2.0-3.5 mol ratio of the organic base, 1.1-2.5 mol ratio of the condensing agent and 1.1-1.5 mol ratio of the intermediate III.
In the substitution reaction, NCS was slowly added to the solvent of intermediate 1.
In the addition and cyclization reaction, an organic base is dissolved in a solvent and slowly dripped into a mixed solution containing an intermediate II.
The developing solvent and the volume ratio of the developing solvent used for TLC detection are PE: EA-5: 1.
The reaction temperature of each step is 20-30 ℃, and room temperature is preferred.
In the amidation condensation reaction, the condensing agent is one of DCC, BOP-Cl, PYBOP, CDI, DIC, HATU, HBTU, HOBt, EDC hydrochloride and TBTU.
In the amidation condensation reaction, the organic base is Et3N, pyridine, DMAP and DIEA.
The solvent used in the reaction is one of DMF, acetonitrile, dichloromethane, DMSO, NMP and DMA.
The solvent used for recrystallization is at least one of acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, dichloromethane, n-hexane, n-heptane, water, acetone, toluene, petroleum ether and ethyl acetate.
The invention has the beneficial effects that: all steps involved in the reaction process use the same solvent and are carried out in the same reaction bottle, namely the one-pot method is used for synthesizing the frataxin, the intermediate product does not need to be separated in the reaction process, the operation and treatment steps are greatly reduced, meanwhile, the whole reaction process consumes short time, the reaction and the post-treatment process can be completed in 8-9 hours, and compared with the prior art, the reaction efficiency is greatly improved when 10 hours are needed in one step; in addition, the molar yield of the obtained product is as high as 85%, and the detection purity is more than 99%.
The synthesis method provided by the invention has the advantages that the product yield is improved, the raw material is saved, and the time is saved. The method has the advantages of simple synthetic route, cheap raw materials and low synthetic cost, improves the yield because of reducing the post-treatment operation, is suitable for large-scale production, and can meet a large amount of demands of the market.
Drawings
FIG. 1 is an HPLC chromatogram of the product obtained in example 1 of the present invention;
FIG. 2 shows the product obtained in example 1 of the present invention1H NMR spectrum.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention clearer, the present invention will be described in further detail with reference to the accompanying drawings, and it is apparent that the described embodiments are only a part of the embodiments of the present invention, not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1:
the first step is as follows: substitution reaction
Figure BDA0002596167390000051
160ml of DMF are introduced into a 500ml four-necked flask, stirred and 20g (0.112mol) of intermediate I are added at room temperature. 19.37g (0.145mol) NCS was added slowly in portions, the incubation was completed for 2 hours, TLC was performed using a developing reagent of PE: EA: 5:1, and the next step was performed after the starting intermediate I had reacted.
The second step is that: addition ring-closure reaction
Figure BDA0002596167390000052
32.27g (0.134mol) of intermediate II was added to the reaction mixture of the first step, and 25.97g (0.257mol) Et was slowly added dropwise thereto at room temperature3The reaction was incubated for 3 hours in DMF (60ml) and TLC checked using a developing solvent containing PE: EA: 5:1 (by volume) and the product 1 was reacted to completion and then the next step was carried out.
The third step: amidation condensation reaction
Figure BDA0002596167390000061
To the reaction mixture were added 18.08g (0.134mol) of HOBt, 25.58g (0.134mol) of EDC hydrochloride and 30g (0.156mol) of intermediate III at room temperature, and the mixture was reacted for 2 hours under incubation, followed by TLC detection using a developing solvent of PE: EA 5:1 (volume ratio) until product 2 was reacted.
The reaction mixture was slowly added to 2.2L of purified water with stirring, and after the addition was completed, the mixture was stirred for 1 hour. Filtering, recrystallizing the solid with petroleum ether and ethyl acetate, filtering and airing to obtain 48.96g of a product, wherein the molar yield is 85%.
To illustrate the products obtainedStructure, the obtained product is carried out1H NMR measurement using a Bruker AVANCEIII 400MHz instrument type, CDCl for samples3The nuclear magnetic spectrum obtained by dissolution is shown in figure 1, and the position intensity of each peak in figure 1 is as follows: 7.36-7.54(m,6H), 7.03(t,1H), 6.77(t,1H), 4.20(t,2H), 4.06(t,1H), 3.94(m,2H), 3.72(d,1H), 2.46(s, 1H). Each peak was analyzed, wherein 7.36 to 7.54ppm was all hydrogens on two benzene rings, 7.03ppm was hydrogen on N connected to trifluoroethyl, 6.77ppm was hydrogen on N on benzoyl, 4.20ppm was hydrogen on methylene on trifluoroethyl, 3.94ppm was hydrogen on methylene connected to benzamide, 3.72ppm and 4.06ppm were two hydrogens on methylene on isoxazole, two hydrogen ppm of isoxazole methylene were different due to chirality of carbon adjacent to isoxazole methylene, and 2.46ppm was hydrogen on methyl on benzene rings.
According to the analysis, the nuclear magnetic hydrogen spectrum is consistent with the structure of the frataxin, and the obtained product is determined to be the frataxin.
For the analysis of the purity of the product obtained, the product was subjected to HPLC tests using a chromatograph and chromatographic information as shown in table 1.
TABLE 1
Figure BDA0002596167390000071
The detection conditions for the HPLC test were: octadecylsilane bonded silica gel as a packing (Asahi Ultimate XBC18 column, 4.6mm × 250mm, 5 μm or equivalent performance column); with 0.2% acetic acid solution: acetonitrile (35:65) as a mobile phase; the flow rate was 1.0ml per minute; the detection wavelength is 254 nm; the amount of sample was 20. mu.l. Sample treatment method: 10mg of solid is weighed, dissolved in 1ml of acetonitrile and injected in 20. mu.l. The liquid chromatogram obtained is shown in FIG. 2, and it can be seen from FIG. 2 that the purity of the product obtained is 99.6%.
Example 2:
160ml of DMSO were added to a 500ml four-necked flask, stirred at room temperature, and then 20g (0.112mol) of intermediate I were added. 19.37g (0.145mol) NCS are added slowly in portions, and after the incubation is finished, the reaction is kept for 2 hoursIn this case, TLC detection was carried out using a developing solvent (PE: EA: 5:1, volume ratio), after completion of the reaction of the starting intermediate I, 32.27g (0.134mol) of the intermediate II was added to the reaction mixture, and 25.97g (0.257mol) of Et was slowly added dropwise thereto at room temperature3The reaction was incubated for 3 hours with N in DMSO (60 ml). After TLC detection, 18.08g (0.134mol) of HOBt, 25.58g (0.134mol) of EDC hydrochloride and 30g (0.156mol) of intermediate III were added to the reaction mixture at room temperature until the reaction was completed (PE: EA: 5:1), and the mixture was incubated for 2 hours and TLC detection was performed until the reaction was completed (PE: EA: 5: 1).
The reaction mixture was slowly added to 2.2L of purified water with stirring, and after the addition was completed, the mixture was stirred for 1 hour. Filtering, recrystallizing the solid with petroleum ether and ethyl acetate, filtering, and air drying to obtain 45g, the molar yield is 80.9%, the purity of the obtained product is 99.1% by HPLC detection, and the HPLC detection conditions and detection method are the same as those in example 1.
Embodiment 3:
to a 500ml four-necked flask was added 200ml of DMF, and the mixture was stirred at room temperature, followed by addition of 20g (0.112mol) of intermediate I. Slowly adding 22.43g (0.168mol) NCS in batches, keeping the temperature for 2 hours, detecting that the intermediate I is completely reacted by TLC (PE: EA is 5:1), adding 40.49g (0.168mol) of the intermediate II into the reaction solution, slowly dropwise adding 39.59g (0.392mol) Et at normal temperature3The reaction was incubated for 3 hours with N in DMF (80 ml). After TLC detection until the reaction was complete (PE: EA: 5:1), 37.8g (0.28mol) of HOBt, 53.48g (0.28mol) of EDC hydrochloride and 32.26g (0.168mol) of intermediate III were added to the reaction mixture at room temperature, the reaction was maintained for 2 hours, and TLC detection was performed until the starting material was complete (PE: EA: 5: 1).
The reaction mixture was slowly added to 2.8L of purified water with stirring, and after the addition was completed, the mixture was stirred for 1 hour. Filtering, recrystallizing the solid with petroleum ether and ethyl acetate, filtering, and air drying to obtain 43.67g, the molar yield is 78.5%, the purity of the obtained product is 98.1% by HPLC detection, and the HPLC detection conditions and detection method are the same as those in example 1.
Embodiment 4:
to a 500ml four-necked flask was added 200ml of DMF, and the mixture was stirred at room temperature, followed by addition of 20g (0.112mol) of intermediate I. Slowly adding 16.45g (0.123mol) NCS in batches, keeping the temperature for 2 hours after the addition, and detecting the original substance by TLCAfter the intermediate I had reacted (PE: EA: 5:1), 29.69g (0.123mol) of intermediate II was added to the reaction mixture, and 22.62g (0.224mol) of Et was slowly added dropwise thereto while the temperature was controlled to room temperature3The reaction was incubated for 3 hours with N in DMF (80 ml). After TLC detection until the reaction was complete (PE: EA: 5:1), 16.63g (0.123mol) of HOBt, 23.53g (0.123mol) of EDC hydrochloride and 23.65g (0.123mol) of intermediate III were added to the reaction mixture at room temperature, the reaction was maintained for 2 hours, and TLC detection was performed until the starting material was reacted completely (PE: EA: 5: 1).
The reaction mixture was slowly added to 2.8L of purified water with stirring, and after the addition was completed, the mixture was stirred for 1 hour. Filtering, recrystallizing the solid with petroleum ether and ethyl acetate, filtering, and air drying to obtain 42.55g, the molar yield is 76.5%, the purity of the obtained product is 99.0% by HPLC detection, and the HPLC detection conditions and detection method are the same as those in example 1.
Embodiment 5:
200ml of DMA were added to a 500ml four-necked flask, stirred at room temperature and 20g (0.112mol) of intermediate I were added. 16.45g (0.123mol) NCS is added in portions slowly, the reaction is kept warm for 2 hours, after TLC detects that the intermediate I is reacted completely (PE: EA is 5:1), 29.69g (0.123mol) of the intermediate II is added into the reaction solution, the temperature is controlled to normal temperature, 17.72g (0.224mol) of DMA (80ml) solution of organic base pyridine is added dropwise slowly, and the reaction is kept warm for 3 hours. After the starting material reaction was completed by TLC (PE: EA ═ 5:1), 19.93g (0.123mol) of the condensing agent CDI and 23.65g (0.123mol) of the intermediate III were added to the reaction mixture at room temperature, and the mixture was reacted for 2 hours while maintaining the temperature, and TLC was performed until the starting material reaction was completed (PE: EA ═ 5: 1).
The reaction mixture was slowly added to 2.8L of purified water with stirring, and after the addition was completed, the mixture was stirred for 1 hour. Filtering, recrystallizing the solid with acetone and water, filtering, and air drying to obtain 40.38g, the molar yield is 72.6%, the purity of the obtained product is 99.2% by HPLC detection, and the HPLC detection conditions and detection method are the same as those in example 1.
Embodiment 6:
200ml of DMSO was added to a 500ml four-necked flask, stirred, the temperature was controlled to normal temperature, and 20g (0.112mol) of intermediate I was added. 16.45g (0.123mol) NCS is added slowly in portions, the reaction is kept warm for 2 hours, after TLC detects that the intermediate I is completely reacted (PE: EA is 5:1), 29.69g (0.123mol) of the intermediate II is added into the reaction solution, the temperature is controlled to normal temperature, 28.95g (0.224mol) of DMSO (80ml) solution of organic base DIPEA is slowly added dropwise, and the reaction is kept warm for 3 hours. After TLC detection, 25.38g (0.123mol) of condensing agent DCC and 23.65g (0.123mol) of intermediate III were added to the reaction mixture at room temperature (PE: EA: 5:1), and the mixture was incubated for 2 hours, and TLC detection was performed until the reaction was complete (PE: EA: 5: 1).
The reaction mixture was slowly added to 2.8L of purified water with stirring, and after the addition was completed, the mixture was stirred for 1 hour. Filtering, recrystallizing the solid with dichloromethane and n-heptane, filtering, and drying to obtain 40.84g, the molar yield is 73.4%, the purity of the obtained product is 99.3% by HPLC, and the HPLC detection conditions and detection method are the same as those of the example 1.
Embodiment 7:
adding 200ml DMF into a 500ml four-mouth bottle, stirring, controlling the temperature to normal temperature, adding 20g (0.112mol) of intermediate I, adding 19.37g (0.145mol) NCS in batches slowly, keeping the temperature for 2 hours after the addition, detecting the reaction completion of the intermediate I by TLC (PE: EA is 5:1), adding 32.27g (0.134mol) of intermediate II into the reaction solution, controlling the temperature to normal temperature, and slowly dropwise adding 25.97g (0.257mol) Et3After completion of the reaction by TLC (PE: EA: 5:1), 50.95g (0.134mol) of HATU and 30g (0.156mol) of intermediate III were added to the reaction mixture, and the reaction was maintained for 2 hours, followed by TLC (PE: EA: 5: 1).
The reaction mixture was slowly added to 2.8L of purified water with stirring, and after the addition was completed, the mixture was stirred for 1 hour. Filtering, recrystallizing the solid with isopropanol and water, filtering and airing to obtain 43.62g of a product with the molar yield of 75.73%. The purity of the product was 99.2% by HPLC, which was performed under the same conditions as in example 1.
The present invention has been described in detail with reference to the examples, but the description is only for the preferred embodiments of the present invention and should not be construed as limiting the scope of the present invention. All equivalent changes and modifications made within the scope of the present invention shall fall within the scope of the present invention.

Claims (9)

1. A synthetic method of an isoxazoline anthelmintic is characterized in that the isoxazoline anthelmintic is fraxidin, the structural formula of which is shown as a compound 1, and the method comprises the following operation steps:
Figure FDA0002596167380000011
carrying out substitution reaction, addition cyclization reaction and amidation condensation reaction on the intermediate I in the same reaction vessel in sequence; pouring the mixture into water after the reaction is finished, stirring and filtering the mixture, and sequentially recrystallizing, filtering and airing the obtained solid to obtain a compound 1, wherein the synthetic route is as follows:
Figure FDA0002596167380000012
and (3) substitution reaction: the intermediate I and NCS are reacted in a solvent, and the degree of reaction progress is detected by TLC in the reaction process;
addition and cyclization reaction: after the intermediate I finishes the reaction, adding the intermediate II and organic base into the mixture for reaction, and detecting the degree of the reaction by TLC in the reaction process;
amidation condensation reaction: after the reaction of the product 1 is completed, adding the intermediate III and the condensing agent into the obtained mixture, reacting under the organic base condition, and detecting the degree of the reaction progress by TLC in the reaction process.
2. The method according to claim 1, wherein the molar ratio of the intermediate I is 1.0 equivalent, and the reactants are NCS 1.1-1.5, intermediate II 1.1-1.5, organic base 2.0-3.5, condensing agent 1.1-2.5, and intermediate III 1.1-1.5.
3. The synthesis according to claim 1, characterized in that in the substitution reaction, NCS is slowly added to the solvent of intermediate 1.
4. The method according to claim 1, wherein in the addition-ring-polymerization reaction, an organic base is dissolved in a solvent and slowly added dropwise to a mixed solution containing the intermediate II.
5. The method of claim 1, wherein the TLC assay uses a developing solvent and a volume ratio of PE: EA: 5: 1.
6. The synthesis method according to claim 1, wherein the reaction in each step is carried out at normal temperature.
7. The synthesis method according to claim 1, wherein in the amidation condensation reaction, the condensing agent is one of DCC, BOP-Cl, PYBOP, CDI, DIC, HATU, HBTU, HOBt and EDC hydrochloride, TBTU; in the amidation condensation reaction, the organic base is Et3N, pyridine, DMAP and DIPEA.
8. The synthesis method according to claim 1, wherein the solvent used in the reaction is one of DMF, acetonitrile, dichloromethane, DMSO, NMP and DMA.
9. The synthesis method according to claim 1, wherein the solvent used for recrystallization is at least one of acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, dichloromethane, n-hexane, n-heptane, water, acetone, toluene, petroleum ether, and ethyl acetate.
CN202010709950.7A 2020-07-22 2020-07-22 Synthetic method of isoxazoline anthelmintic Pending CN111689919A (en)

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CN113735681A (en) * 2021-10-11 2021-12-03 丽珠集团新北江制药股份有限公司 Flurarana intermediate and method for preparing flurarana by using same
CN113735681B (en) * 2021-10-11 2023-12-12 丽珠集团新北江制药股份有限公司 Florarana intermediate and method for preparing same
CN113896690A (en) * 2021-11-22 2022-01-07 常州齐晖药业有限公司 Preparation method of isoxazoline anthelmintic agent fluranide

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Application publication date: 20200922